WO2013020993A1 - Compounds for the treatment and prophylaxis of respiratory syncytial virus disease - Google Patents

Compounds for the treatment and prophylaxis of respiratory syncytial virus disease Download PDF

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Publication number
WO2013020993A1
WO2013020993A1 PCT/EP2012/065499 EP2012065499W WO2013020993A1 WO 2013020993 A1 WO2013020993 A1 WO 2013020993A1 EP 2012065499 W EP2012065499 W EP 2012065499W WO 2013020993 A1 WO2013020993 A1 WO 2013020993A1
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WIPO (PCT)
Prior art keywords
dihydro
benzothiazepin
dioxido
amino
methyl
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PCT/EP2012/065499
Other languages
French (fr)
Inventor
Li Chen
Lichun Feng
Song Feng
Lu Gao
Tao Guo
Mengwei Huang
Chungen Liang
Yongfu Liu
Lisha Wang
Jason Christopher Wong
Jim Zhen Wu
Xihan Wu
Hongying Yun
Xiufang ZHENG
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F. Hoffmann-La Roche Ag
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Publication date
Priority to EP12746320.6A priority Critical patent/EP2742039B1/en
Priority to NZ620079A priority patent/NZ620079B2/en
Priority to ES12746320.6T priority patent/ES2552016T3/en
Priority to KR1020147006355A priority patent/KR101570627B1/en
Priority to AU2012293644A priority patent/AU2012293644B2/en
Priority to MX2014001481A priority patent/MX349881B/en
Priority to JP2014524370A priority patent/JP5746793B2/en
Application filed by F. Hoffmann-La Roche Ag filed Critical F. Hoffmann-La Roche Ag
Priority to CA2842123A priority patent/CA2842123C/en
Priority to BR112014003198-3A priority patent/BR112014003198B1/en
Priority to MYPI2014700267A priority patent/MY184306A/en
Priority to UAA201402305A priority patent/UA110849C2/en
Priority to CN201280039193.0A priority patent/CN103717589B/en
Priority to EA201490419A priority patent/EA023262B1/en
Publication of WO2013020993A1 publication Critical patent/WO2013020993A1/en
Priority to IL230458A priority patent/IL230458A/en
Priority to ZA2014/00442A priority patent/ZA201400442B/en
Priority to MA36815A priority patent/MA35432B1/en
Priority to MA36918A priority patent/MA35534B1/en
Priority to HK14109553.4A priority patent/HK1196131A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D493/00—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system
    • C07D493/02—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system in which the condensed system contains two hetero rings
    • C07D493/10—Spiro-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—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
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D407/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00
    • C07D407/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing three or more hetero rings
    • 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
    • C07D413/04—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 directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
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    • 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
    • C07D417/04—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 directly linked by a ring-member-to-ring-member bond
    • 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
    • C07D417/14—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 three or more hetero rings
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    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
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    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
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    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/10—Spiro-condensed systems
    • C07D491/107—Spiro-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D498/04—Ortho-condensed systems

Definitions

  • the invention relates to compounds which are respiratory syncytial virus (RSV) inhibitors and which are useful in the treatment or prophylaxis of RSV disease.
  • RSV respiratory syncytial virus
  • the invention relates in particular to (i) a compound of formula (I)
  • R 1 is hydrogen, halogen, or Ci_ 6 alkyl
  • R 2 is hydrogen, halogen, or Ci_ 6 alkyl
  • R 3 is hydrogen, halogen, or Ci_ 6 alkyl
  • R 4 is hydrogen, or Ci_ 6 alkyl
  • R 5 is hydrogen, or halogen
  • R 6 is hydrogen, halogen, hydroxy, Ci_ 6 alkoxy, carboxy, morpholinyl, or 4-C 0- 6 alkylpiperazin- 1 -yl;
  • R 7 is hydrogen, halogen, Ci_ 6 alkyl, Ci_ 6 alkoxy, Ci_ 6 alkylaminocarbonyl, diCi_ 6 alkylaminocarbonyl, Ci_ 6 alkylsulfonyl, phenoxy, or hydroxy(CH 2 ) 2 -6-0-;
  • R 8 is hydrogen, halogen, or Ci_ 6 alkoxy;
  • A is nitrogen, or -C-R 1 1 , wherein R 1 1 is hydrogen, halogen, Ci_6alkyl, cycloalkyl, Ci_ 6 alkoxy, trifluoromethyl, trifluoromethoxy, pyridinyloxy, Ci_6alkoxy(CH 2 )i_6-0-,
  • Y is -CH-, or nitrogen
  • Q is hydrogen; halogen; Ci_6alkyl, unsubstituted or once or twice substituted by amino or hydroxy, provided that di-substitution is not on the same carbon; amino(CH 2 ) 2 _
  • hydro xy(CH 2 ) i _ 6 carbonyl; hydro xy(CH 2 ) 0 _6Oxetanyl(CH 2 ) i _ 6 ; hydro xy(CH 2 ) i _
  • phenylaminocarbonyl phenyl(CH 2 )o-6aminooxetanyl(CH 2 ) i _ 6 ; phenylcarbonyl;
  • R 15 is hydroxy, Ci_ 6 alkyl, hydroxy(CH 2 )i_6 or amino; and R 16 is Ci_ 6 alkyl, trifluoromethyl, hydroxy(CH 2 )i_6, amino (CH 2 )i_6, aminocarboxy or carboxy(CH 2 )i_6;
  • R 17 R wherein R 17 is hydrogen, Ci_6alkyl or hydroxy(CH 2 )i_6; R 18 is hydroxy(CH 2 )i_6 or
  • Ci is hydroxy(CH 2 )i_6, amino (CH 2 )i_6, carboxy or aminocarboxy(CH 2 )o-6; or , wherein R 20 is hydrogen or Ci_ 6 alkyl; R .21 is Ci_ 6 alkyl; R , 22 is Ci_ 6 alkoxy or amino;
  • R 12 and R 13 with the nitrogen atom to which they are attached, may form a pyrrolidinyl, piperazinyl, piperidinyl, morpholinyl, azetidinyl, diazepanyl or oxopyrrolidinyl ring; which may be unsubstituted, once or twice substituted by a group selected from halogen, Ci_ 6alkyl, Ci_6alkoxy, gemdimethyl, amino, aminocarbonyl, hydroxy, oxetanylamino, Ci_ 6alkylpiperazinyl, and amino (CH 2 )i_6;
  • R 12 and R 13 with the nitrogen atom to which they are attached may form a bridge ring or a spiral ring selected from 2-oxa-6-aza-spiro[3.4]octan-6-yl, 2-oxa-5,7-diazaspiro[3.4]octan- 6-one-5-yl, (4aS,7aR)-hexahydropyrrolo[3,4-b][l,4]oxazin-6(2H)-yl, 4,5,6,6a-tetrahydro- 3aH-pyrrolo[3,4-d][l,3]oxazol-5-yl, 2-aza-bicyclo[2.1.1]hexan-2-yl, and 3-aza- bicyclo[3.1.0]hexan-3-yl; which may be unsubstituted or further substituted by amino; and pharmaceutically acceptable salt and stereoisomers thereof.
  • Respiratory Syncytial Virus belongs to the family of Paramyxoviridae, subfamily of Pneumovirinae.
  • the human RSV is a major cause of acute upper and lower respiratory tract infection in infants and children. Almost all children are infected by RSV at least once by age of three.
  • Natural human immunity against RSV is incomplete. In normal adults and older children, RSV infection is mainly associated with upper respiratory track symptoms. Severe case of RSV infection often leads to bronchiolitis and pneumonia, which requires hospitalization.
  • High-risk factors for lower respiratory track infections include premature birth, congenital heart disease, chronic pulmonary disease, and immuno-compromised conditions. A severe infection at young age may lead to recurrent wheezing and asthma. For the elderly, RSV-related mortality rate becomes higher with advancing age.
  • Virazole® the aerosol form of ribavirin
  • CA Medlmmune
  • RSV-IGIV brand name RespiGam
  • RSV-IGIV brand name RespiGam
  • RSV-IGIV a humanized monoclonal antibody against RSV fusion (F) protein approved for prophylaxis in high-risk infants in 1998.
  • palivizumab demonstrated 45 - 55% reduction of hospitalization rate caused by RSV infection in selected infants (Pediatrics. 1998 Sep;102(3):531-7; Feltes TF et al, J Pediatr. 2003 Oct;143(4):532-40).
  • palivizumab is not effective in the treatment of established RSV infection.
  • motavizumab was designed as potential replacement of palivizumab but failed to show additional benefit over palivizumab in recent Phase III clinical trials (Feltes TF et al, Pediatr Res. 2011 Apr 25, Epub ahead of print).
  • RNAi therapeutics against RSV have also been thoroughly studied.
  • ALN-RSVOl Alnylam Pharmaceuticals, MA, USA
  • a nasal spay administered for two days before and for three days after RSV inoculation decreased infection rate among adult volunteers (DeVincenzo J. et al, Proc Natl Acad Sci U S A. 2010 May 11;107(19):8800-5).
  • results were not sufficient for conclusion of antiviral efficacy, though certain health benefits have been observed Zamora MR et al, Am J Respir Crit Care Med. 2011 Feb 15;183(4):531-8).
  • Additional Phase lib clinical trials in similar patient population for ALN-RSV01 are on-going
  • the compounds of the present invention belong to a new chemical class of RSV inhibitors for the treatment or prophylaxis of RSV infection.
  • the compounds of the invention are therefore useful in the treatment or prophylaxis of RSV disease.
  • Co- 6 alkyl alone or in combination signifies a chemical bond, or hydrogen, or saturated, linear- or branched chain alkyl group containing 1 to 6, preferably 1 to 4 carbon atoms, for example methyl, ethyl, propyl, isopropyl, 1 -butyl, 2-butyl, tert-butyl and the like.
  • Preferred “Co- 6 alkyl” groups are chemical bond, hydrogen, methyl, ethyl, isopropyl, tert- butyl
  • Ci_ 6 alkyl alone or in combination signifies a saturated, linear- or branched chain alkyl group containing 1 to 6, preferably 1 to 4 carbon atoms, for example methyl, ethyl, propyl, isopropyl, 1 -butyl, 2-butyl, tert-butyl and the like.
  • Preferred “Ci_ 6 alkyl” groups are methyl, ethyl, isopropyl, tert-butyl.
  • C2- 6 alkyl alone or in combination signifies a saturated, linear- or branched chain alkyl group containing 2 to 6, preferably 2 to 4 carbon atoms, for example ethyl, propyl, isopropyl, 1 -butyl, 2-butyl, tert-butyl and the like.
  • Preferred "C 2 - 6 alkyl” groups are ethyl, isopropyl, tert-butyl.
  • -(CH 2 )o-6- signifies a chemical link, hydrogen, or a saturated, linear alkyl chain containing from 1 to 6 carbon atoms, preferably, the term signifies hydrogen or
  • the term "-(CH 2 )i_6-" signifies a saturated, linear alkyl chain containing from 1 to 6 carbon atoms, preferably from 1 to 4 carbon atoms.
  • the term “-(CH 2 ) 2 -6-” signifies a saturated, linear alkyl chain containing from 2 to 6 carbon atoms, preferably from 2 to 4 carbon atoms.
  • -(CH 2 ) 2-10 - signifies a saturated, linear alkyl chain containing from 2 to 10 carbon atoms, preferably from 2 to 4 carbon atoms.
  • cycloalkyl refers to a saturated carbon ring containing from 3 to 7 carbon atoms, preferably from 3 to 6 carbon atoms, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and the like.
  • Preferred cycloalkyl groups are cyclopropyl, cyclopentyl and cyclohexyl.
  • Ci_ 6 alkoxy alone or in combination signifies a group Ci_ 6 alkyl-0-, wherein the "Ci_ 6 alkyl” is as defined above; for example methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, i- butoxy, 2-butoxy, t-butoxy and the like.
  • Preferred Ci_ 6 alkoxy groups are methoxy and ethoxy and more preferably methoxy.
  • C 2 - 6 alkoxy alone or in combination signifies a group C 2 - 6 alkyl-0-, wherein the "C 2 - 6 alkyl” is as defined above; for example ethoxy, propoxy, isopropoxy, n-butoxy, z ' -butoxy, 2- butoxy, t-butoxy and the like.
  • Preferred Ci_ 6 alkoxy groups is ethoxy.
  • halogen means fluorine, chlorine, bromine or iodine. Halogen is preferably fluorine or chlorine.
  • hydroxy alone or in combination refers to the group OH.
  • carbonyl alone or in combination refers to the group -C(O)-.
  • amino alone or in combination, refers to primary (-NH 2 ), secondary (-NH-
  • Ci_ 6 alkylsulfanyl alone or in combination refers to the group -S-Ci_ 6 alkyl.
  • Ci_ 6 alkylsulfmyl alone or in combination refers to the group -S(O) -Ci_ 6 alkyl.
  • the compounds according to formula I does not include those in which the sp 3 hybrid carbon atom is disubstituted by two nitrogen atoms, or one nitrogen atom and one oxygen atom simultaneously.
  • the compounds according to the present invention may exist in the form of their pharmaceutically acceptable salts.
  • pharmaceutically acceptable salt refers to conventional acid-addition salts or base-addition salts that retain the biological effectiveness and properties of the compounds of formula (I) and are formed from suitable non-toxic organic or inorganic acids or organic or inorganic bases. Acid-addition salts include for example those j .... ⁇ __ . j c .
  • Base-addition salts include those derived from ammonium, potassium, sodium and, quaternary ammonium hydroxides, such as for example, tetramethyl ammonium hydroxide.
  • the chemical modification of a pharmaceutical compound into a salt is a technique well known to pharmaceutical chemists in order to obtain improved physical and chemical stability, hygroscopicity, flowability and solubility of compounds. It is for example described in Bastin R.J., et. al, Organic Process Research & Development 2000, 4, 427-435; or in Ansel, H., et. al, In: Pharmaceutical Dosage Forms and Drug Delivery Systems, 6th ed. (1995), pp. 196 and 1456-1457. Preferred are the sodium salts of the compounds of formula (I).
  • “Pharmaceutically acceptable esters” means that compounds of general formula (I) may be derivatised at functional groups to provide derivatives which are capable of conversion back to the parent compounds in vivo. Examples of such compounds include physiologically acceptable and metabolically labile ester derivatives, such as acetate, propionate and isobutyrate.
  • any physiologically acceptable equivalents of the compounds of general formula (I), similar to the metabolically labile esters, which are capable of producing the parent compounds of general formula (I) in vivo are within the scope of this invention.
  • Compounds of the general formula (I) which contain one or several chiral centers can either be present as racemates, diastereomeric mixtures, or optically active single isomers.
  • the racemates can be separated according to known methods into the enantiomers.
  • diastereomeric salts which can be separated by crystallization are formed from the racemic mixtures by reaction with an optically active acid such as e.g. D- or L-tartaric acid, mandelic acid, malic acid, lactic acid or camphorsulfonic acid.
  • Another embodiment of present invention is (ii) a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein
  • R is hydrogen, halogen or Ci_ 6 alkyl
  • R 2 is hydrogen, halogen or Ci_ 6 alkyl
  • R 3 is hydrogen, halogen or Ci_ 6 alkyl
  • R 4 is hydrogen or Ci_ 6 alkyl
  • R 5 is hydrogen;
  • R 6 is hydrogen, halogen, hydroxy, Ci_ 6 alkoxy, morpholinyl or 4-Co-6alkylpiperazin-l-yl;
  • R 7 is hydrogen, halogen, Ci_6alkyl, Ci_6alkoxy, phenoxy or hydroxy(CH 2 )2-6-0-; hydrogen, halogen or Ci_6alkoxy; hydrogen or Ci_6alkyl;
  • R is hydrogen
  • A is nitrogen or -C-R 11 , wherein R 11 is hydrogen, halogen, Ci_ 6 alkyl, cycloalkyl, Ci_ 6 alkoxy, trifluoromethyl, trifluoromethoxy, pyridinyloxy, Ci_6alkoxy(CH 2 )i_6-0-,
  • Y is -CH- or nitrogen
  • Q is Ci_6alkyl, unsubstituted or once substituted by amino; amino(CH 2 ) 2 _ 6 aminosulfonyl; 2-amino-4,5-dihydro-l,3-oxazol-4-ylethyl; carboxy(CH 2 )i_ 6 ; phenylsulfonyl; piperidin-4-yl- carbonyl; lH-pyrazol-3-yl; pyrrolidin-3-yloxy; piperidin-4-yloxy; amino(CH 2 ) 2 _ 6 -0-; or
  • R and R are hydrogen, Ci_6alkyl or hydro xy(CH 2 ) 2 _ 6 ; and the other one is
  • pyrrolidin-4-yl unsubstituted or 3-substituted by hydroxy or Ci_6alkoxy; pyrrolidin-2- yl(CH 2 )i_ 6 ; pyrrolidinylcarbonyl; tetrahydrofuran-3-yl; tetrahydropyran-4-yl;
  • R 16 is Ci_6alkyl, trifluoromethyl, hydroxy(CH 2 )i_ 6 , amino (CH 2 )i_ 6 , aminocarbonyl or
  • R 17 carboxy(CH 2 )i_ 6 ; R , wherein R 17 is hydrogen, Ci_6alkyl or hydroxy(CH 2 )i_ 6 ; R 18 is amino (CH 2 )i_ 6 , carboxy or hydrogen or Ci_6alkyl; R 21 is Ci_ 6alkyl; R 22 is Ci_6alkoxy or amino;
  • R 12 and R 13 with the nitrogen atom to which they are attached, may form a pyrrolidinyl, piperazinyl, piperidinyl, morpholinyl, azetidinyl, diazepanyl or oxopyrrolidinyl ring; which may be unsubstituted, once or twice substituted by a group selected from halogen, Ci_ 6alkyl, Ci_6alkoxy, gemdimethyl, amino, aminocarbonyl, hydroxy, oxetanylamino, Ci_ 6 alkylpiperazinyl, and amino (CH 2 )i_ 6 ;
  • R 12 and R 13 with the nitrogen atom to which they are may form a bridge ring or a spiral ring selected from 2-oxa-6-aza-spiro[3.4]octan-6-yl, 2-oxa-5,7-diazaspiro[3.4]octan-6-one- 5-yl, (4a5',7ai?)-hexahydropyrrolo[3,4-b] [ l,4]oxazin-6(2H)-yl, 4,5,6,6a-tetrahydro-3aH- pyrrolo[3,4-d][l,3]oxazol-5-yl, 2-aza-bicyclo[2.1.1]hexan-2-yl and 3-aza- bicyclo[3.1.0]hexan-3-yl; which may be unsubstituted or further substituted by amino.
  • R 1 , R 2 or R 3 are hydrogen, fluoro, chloro or methyl
  • R 4 is hydrogen or methyl
  • R 5 is hydrogen
  • R 6 is hydrogen, fluoro, hydroxy, methoxy, morpholinyl or 4-(propan-2-yl)piperazin-l-yl;
  • R 7 is hydrogen, fluoro, chloro, methyl, methoxy, ethoxy, hydroxyethoxy or phenoxy;
  • R 8 is hydrogen, fluoro or methoxy;
  • R 9 is hydrogen or methyl;
  • R 10 is hydrogen;
  • A is nitrogen or -C-R 11 , wherein R 11 is hydrogen, fluoro, chloro, bromo, methyl, ethyl, cyclopropyl, methoxy, trifluoromethyl, trifiuoromethoxy, pyridinyloxy, methoxyethoxy, difiuoromethoxy, cyano, nitro, amino, vinyl, acetylenyl, amino carbonyl, hydroxyethoxy, methylsulfanyl, methylsulfinyl, hydroxymethyl, deuteratedmethyl, carboxyl, methoxycarbonyl, hydroxy, difluoromethyl, methylCH(hydroxy)- or methylsulfonyl;
  • Y is -CH- or nitrogen
  • Q is 2-amino-4,5-dihydro-l,3-oxazol-4-ylethyl; aminoethoxy; aminoethylaminosulfonyl; aminopropyl; carboxyethyl; methyl; phenylsulfonyl; piperidin-4-yl-carbonyl; piperidin-4- yloxy; lH-pyrazol-3-yl; pyrrolidin-3-yloxy; or
  • R 12 and R 13 is hydrogen, methyl or hydro xyethyl; and the other one is amino butyl; amino carbonylethyl; aminocarbonylmethyl; 1-aminocyclobutylmethyl; 2- aminocyclohexyl; 3-aminocyclohexyl; 4-aminocyclohexyl; 1-aminocyclohexylmethyl; 2- aminocyclopentyl; 1-aminocyclopropylethyl; 1-aminocyclopropylmethyl; aminodecyl; (2- amino-4,5-dihydro-oxazol-5-yl)methyl; (2-amino-4,5-dihydro-oxazol-4-yl)methyl;
  • aminomethyldifluoromethyldifluoromethylmethyl ammomethyldifluoromethylmethyl; (2- amino-5-methyl-4,5-dihydro- 1 ,3-oxazol-5-yl)methyl; 3 -amino methyl- 1 , 1 -dioxidothietan-3- ylmethyl; aminomethylfluoromethylethyl; aminomethylfluoromethylmethyl;
  • aminomethyloxetanyl aminomethyloxetanylmethyl; 3-(aminomethyl)thietan-3-ylmethyl; aminononyl; aminooctyl; aminooxetanylethyl; aminooxetanylmethyl; aminopentyl;
  • ethylammooxetanylmethyl ethyl (oxetanyl)amino ethyl; hydrogen; 4-hydroxycyclohexyl; hydroxyethyl; hydroxyethylaminoethyl; hydroxyethyloxetanyl; hydroxymethylcarbonyl; hydroxymethyloxetanylmethyl; hydroxynonyl; hydroxypropyl; isoxazol-3-yl;
  • K wherein R is hydrogen or methyl; R 15 is hydroxy, methyl or amino; and R 16 is methyl, trifluoromethyl,
  • R 17 ⁇ C- R 18 hydroxymethyl, hydroxyethyl, aminomethyl, aminocarbonyl or carboxymethyl; K , wherein R 17 is hydrogen, methyl or hydroxymethyl; R 18 is hydroxymethyl or methyl; R 19 is hydroxymethyl, aminomethyl, carboxy, aminocarbonyl or amino carbonylmethyl; methyl or ethyl; R 22 is methoxy or amino;
  • R 12 and R 13 with the nitrogen atom to which they are attached, may form a pyrrolidinyl, piperazinyl, piperidinyl, morpholinyl, azetidinyl, diazepanyl or oxopyrrolidinyl ring; which may be unsubstituted, once or twice substituted by a group selected from fluoro, methyl, methoxy, gemdimethyl, amino, aminocarbonyl, hydroxy, oxetanylamino,
  • R 12 and R 13 with the nitrogen atom to which they are attached may form a bridge ring or a spiral ring selected from 2-oxa-6-aza-spiro[3.4]octan-6-yl, 2-oxa-5,7-diazaspiro[3.4]octan- 6-one-5-yl, (4a5',7ai?)-hexahydropyrrolo[3,4-b][l,4]oxazin-6(2H)-yl, 4,5,6,6a-tetrahydro- 3aH-pyrrolo[3,4-d][l,3]oxazol-5-yl, 2-aza-bicyclo[2.1.1]hexan-2-yl or 3-aza- bicyclo[3.1.0]hexan-3-yl; which may be unsubstituted or further substituted by amino; and all the remaining substituents are as defined above in embodiment (i) or (ii).
  • Another embodiment of present invention is (iv) a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 and R 10 are hydrogen;
  • A is -C-R 11 , wherein R 11 is hydrogen, halogen or Ci_ 6 alkyl;
  • X is S
  • Y is -CH- or nitrogen
  • Q is NR R , wherein one of R and R is hydrogen; and the other one is
  • R 12 and R 13 with the nitrogen atom to which they are attached, may form a pyrrolidinyl ring, which may be once substituted by amino; and all the remaining substituents are as defined above in embodiment (i) to (iii).
  • R 8 , R 9 and R 10 are hydrogen;
  • A is -C-R 11 , wherein R 11 is hydrogen, chloro or methyl;
  • u is NR 1Z R , wherein one of R and R is hydrogen; and the other one is amino ethyl, ammomethyldifluoromethylmethyl, ammomethyloxetanylmethyl, aminooxetanylmethyl or hydrogen;
  • R 12 and R 13 with the nitrogen atom to which they are attached, may form a pyrrolidinyl ring, which may be once substituted by amino; and all the remaining substituents are as defined above in embodiment (iv).
  • Another further embodiment of present invention is (vi) a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein
  • R 1 R 2 R 3 R 4 R 5 R 6 R 7 R 8 , R 9 and R 10 are hydrogen;
  • A is -C-R 11 , wherein R 11 is hydrogen, halogen, Ci_6alkyl, hydro xy(CH 2 )i_6,
  • Y is -CH- or nitrogen
  • Q is NR R , wherein one of R and R is hydrogen; and the other one is amino (CH 2 ) 2 _ 6 ; amino (CH 2 ) i _ 6 difluoromethy 1(CH 2 ) i _ 6 ; amino (CH 2 ) i _ 6 fluoromethy 1(CH 2 ) i _ 6 ; amino(CH 2 )i_ 6 oxetanyl; amino(CH 2 )i_ 6 oxetanyl(CH 2 )i_ 6 ; aminooxetanyl(CH 2 )i_ 6 ; hydroxy(CH 2 ) 2 _ io; phenyl(CH 2 )i_ 6 aminooxetanyl(CH 2 )i_ 6 ; pyrrolidin-3-yl, 4-substituted by halogen;
  • R 14 is hydrogen, R 15 is hydroxy, and R 16 is hydroxy(CH 2 )i_ 6 ;
  • R 12 and R 13 with the nitrogen atom to which they are attached, may form a pyrrolidinyl ring, which may be once or twice substituted by a group selected from halogen, amino and hydroxyl; and all the remaining substituents are as defined above in embodiment (i) to (v).
  • More further embodiment of present invention is (vii) a compound of formula (I) or a pharmaceutically acceptable salt thereof , wherein
  • R 1 R 2 R 3 R 4 R 5 R 6 R 7 R 8 , R 9 and R 10 are hydrogen;
  • A is -C-R 11 , wherein R 11 is hydrogen, chloro, methyl, hydro xymethyl, deuteratedmethyl or carboxyl; 12 13 12 13
  • u is NR 1Z R , wherein one of R and R is hydrogen; and the other one is amino ethyl; ammomethyldifluoromethylmethyl; ammomethylfluoromethylmethyl; aminomethyloxetanyl; ammomethyloxetanylmethyl; aminooxetanylmethyl; phenylmethylaminooxetanylmethyl; pyrrolidin-3-yl, wherein R 14 is hydrogen, R 15 is hydroxy, and R 16 is hydroxymethyl;
  • R 12 and R 13 with the nitrogen atom to which they are attached, may form a pyrrolidinyl ring, which may be once or twice substituted by a group selected from fluoro, amino and hydroxyl; and all the remaining substituents are as defined above in embodiment (vi).
  • Still further embodiment of present invention is (viii) a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein
  • R 1 , R 2 , and R 3 are hydrogen, halogen or Ci_ 6 alkyl
  • R 4 is hydrogen or Ci_ 6 alkyl
  • R 5 is hydrogen
  • R 6 is hydrogen, halogen, hydroxy, Ci_ 6 alkoxy, morpholinyl or 4-(propan-2-yl)piperazin- 1-yl;
  • R 7 is hydrogen, halogen, Ci_ 6 alkyl, Ci_ 6 alkoxy, hydroxy(CH 2 )2-6-0-, or phenoxy;
  • R 8 is hydrogen, halogen or Ci_ 6 alkoxy;
  • R 9 is hydrogen or Ci_ 6 alkyl;
  • R 10 is hydrogen;
  • A is nitrogen or -C-R 1 1 , wherein R 1 1 is hydrogen, halogen, C h alky!, Ci_ 6 alkoxy, trifluoromethyl, trifluoromethoxy, pyridinyloxy, Ci_ 6 alkoxy(CH 2 )i_6-0-, difluoromethoxy, nitro, cycloalkyl, cyano, amino, vinyl, acetylenyl, amino carbonyl, hydroxy(CH 2 ) 2 -6-0-, Ci_
  • Y is -CH- or nitrogen
  • Q is 2-amino-4,5-dihydro-l ,3-oxazol-4-ylethyl; amino(CH 2 ) 2 _ 6 -0-; amino(CH 2 ) 2 _
  • R and R is hydrogen, Ci_6alkyl or hydro xy(CH 2 )2-6; and the other one is ⁇ l-[amino(CH 2 )o-6]-3,3-difluorocyclobutyl ⁇ (CH2)i-6; (5 , -Ci_6alkylsulfonimidoyl)(CH2) 2 -6; 3-aminotetrahydrofuran-3-yl(CH 2 )i-6; (2-amino-5-methyl-4,5-dihydro- 1 ,3-oxazol-5-yl)methyl; 3- amino methyl- 1 , 1 -dioxidothietan-3 -ylmethyl; 3 -(amino methyl)thietan-3 -ylmethyl; (1,1- dioxidothiomorpholin-4-yl)ethyl; Co-6alkyl(oxetanyl)N(CH 2 ) 2 -6; 4,5-di
  • Ci_6alkyl 6 amino(CH 2 )2-6; Ci_6alkyl; Ci_6alkylamino(CH 2 ) 2 -6; Ci_6alkylaminooxetanyl(CH 2 )i-6; Ci_
  • Ci_6alkylcarbonyl Ci_6alkylcarbonylamino(CH 2 )2-6; Ci_6alkylcarbonylamino(CH 2 )i-60xetanyl(CH 2 )o- 6 ; Ci_6alkylsulfinyl(CH 2 ) 2 -6; Ci_6alkylsulfonyl; carboxy(CH 2 )i_6; cyano(CH 2 )i_6; Ci_
  • R wherein R is hydrogen or Ci_ 6 alkyl; R is hydroxy, Ci_ 6 alkyl or amino;
  • R 12 and R 13 with the nitrogen atom to which they are attached, may form a pyrrolidinyl, piperazinyl, piperidinyl, morpholinyl, azetidinyl, diazepanyl or oxopyrrolidinyl ring; which may be unsubstituted, once or twice substituted by a group selected from halogen, Ci_ 6 alkyl, Ci_
  • R 12 and R 13 with the nitrogen atom to which they are attached may form a bridge ring or a spiral ring selected from 2-oxa-6-aza-spiro[3.4]octan-6-yl, 2-oxa-5,7-diazaspiro[3.4]octan-6-one- 5-yl, (4a5', 7ai?)-hexahydropyrrolo[3,4-b][l ,4]oxazin-6(2H)-yl, 4,5,6,6a-tetrahydro-3aH- pyrrolo[3,4-d][l ,3]oxazol-5-yl, 2-aza-bicyclo[2.1.1]hexan-2-yl or 3-aza-bicyclo[3.1.0]hexan-3- yl; which may be unsubstituted or further substituted by amino; and all the remaining
  • Particular embodiment of present invention is (ix) a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein R 1 , R 2 , and R 3 are hydrogen, fluoro, chloro or methyl;
  • R 4 is hydrogen or methyl
  • R 5 is hydrogen
  • R 6 is hydrogen, fluoro, hydroxy, methoxy, morpholinyl or 4-(propan-2-yl)piperazin-l-yl;
  • R 7 is hydrogen, fluoro, chloro, methyl, methoxy, hydroxyethoxy, or phenoxy;
  • R 8 is hydrogen, fluoro or methoxy
  • R 9 is hydrogen or methyl
  • R 10 is hydrogen
  • A is nitrogen or -C-R 1 1 , wherein R 1 1 is hydrogen, fluoro, chloro, bromo, methyl, ethyl, methoxy, trifluoromethyl, trif uoromethoxy, pyridinyloxy, methoxyethoxy, difluoromethoxy, nitro, cyclopropyl, cyano, amino, vinyl, acetylenyl, amino carbonyl, hydroxyethoxy,
  • Y is -CH- or nitrogen
  • Q is 2-amino-4,5-dihydro-l,3-oxazol-4-ylethyl; aminoethoxy; aminoethylaminosulfonyl; aminopropyl; carboxyethyl; methyl; phenylsulfonyl; piperidin-4-yl-carbonyl; piperidin-4-yloxy;
  • R and R is hydrogen, methyl or hydroxyethyl, and the other one is aminobutyl; amino carbonylethyl;
  • aminoheptyl aminohexyl; aminomethylcarbonyl; (l-aminomethyl-3,3- difluorocyclobutyl)methyl; aminomethyldifluoromethyldifluoromethylmethyl;
  • aminomethylfluoromethylmethyl aminomethyloxetanyl; aminomethyloxetanylmethyl; 3- (aminomethyl)thietan-3-ylmethyl; aminononyl; aminooctyl; aminooxetanylethyl;
  • ethylamino ethyl ethylaminooxetanylmethyl; ethyl (oxetanyl)aminoethyl; hydrogen; 4- hydroxycyclohexyl; hydroxyethyl; hydroxyethylaminoethyl; hydroxyethyloxetanyl;
  • oxetanylmethyl N-oxetanylpyrrolidin-3-yl; oxo-pyrrolidin-4-ylcarbonyl; phenylaminocarbonyl; phenylcarbonyl; phenylmethylaminooxetanylmethyl; piperazin-l-ylethyl; piperidin-2- ylcarbonyl; piperidin-3 -ylcarbonyl; piperidin-4-ylcarbonyl; piperidine-3-yl; piperidine-4-yl; piperidin-l-ylethyl; piperidin-2-ylmethyl; pyrazin-2-ylcarbonyl; pyrazol-3-yl; pyridazin-3- ylcarbonyl; pyridine-2-ylmethylcarbonyl; pyridine-2-ylaminoethyl; pyridine-2-ylcarbonyl;
  • R is hydrogen or methyl
  • R 15 is hydroxy, methyl or amino; and R 16 is methyl, trifiuoromethyl, hydro xymethyl,
  • R 18 is hydroxymethyl or methyl
  • R 19 is hydroxymethyl
  • R 20 is hydrogen or methyl
  • R 21 is methyl or ethyl
  • R 22 is methoxy or amino
  • R 12 and R 13 with the nitrogen atom to which they are attached, may form a pyrrolidinyl, piperazinyl, piperidinyl, morpholinyl, azetidinyl, diazepanyl or oxopyrrolidinyl ring; which may be unsubstituted, once or twice substituted by a group selected from fluoro, methyl, methoxy, gemdimethyl, amino, aminocarbonyl, hydroxy, oxetanylamino, methylpiperazinyl and aminomethyl;
  • R 12 and R 13 with the nitrogen atom to which they are attached may form a bridge ring or a spiral ring selected from 2-oxa-6-aza-spiro[3.4]octan-6-yl, 2-oxa-5,7-diazaspiro[3.4]octan-6-one- 5-yl, (4a5',7ai?)-hexahydropyrrolo[3,4-b][l,4]oxazin-6(2H)-yl, 4,5,6,6a-tetrahydro-3aH- pyrrolo[3,4-d][l,3]oxazol-5-yl, 2-aza-bicyclo[2.1.1]hexan-2-yl or 3-aza-bicyclo[3.1.0]hexan-3- yl; which may be unsubstituted or further substituted by amino; and all the remaining
  • Another particular embodiment of present invention is (x) a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , and R 10 are hydrogen;
  • R 11 is Ci_ 6 alkyl
  • X is S(0)NH
  • Y is -CH-
  • Q is NR R , wherein one of R and R is hydrogen; and the other one is
  • R 12 and R 13 with the nitrogen atom to which they are attached, may form a pyrrolidinyl ring, which may be twice substituted by a group selected from amino and hydro xyl; and all the remaining substituents are as defined above in embodiment (i) to (ix).
  • Still another particular embodiment of invention is (xi) a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , and R 10 are hydrogen;
  • A is -C-R 11 , wherein R 11 is methyl
  • u is NR 1Z R , wherein one of R and R is hydrogen; and the other one is amino ethyl;
  • R 12 and R 13 with the nitrogen atom to which they are attached, may form a pyrrolidinyl ring, which may be twice substituted by a group selected from amino and hydro xyl; and all the remaining substituents are as defined above in embodiment (x).
  • Particular embodiment of present invention is a compound of formula (I) or a
  • Another embodiment of invention is (xii) a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein
  • R 1 is hydrogen or halogen
  • R 2 and R 4 are hydrogen;
  • R 3 is hydrogen or halogen;
  • R 5 is hydrogen or halogen
  • R 6 is hydrogen, halogen, hydroxy, Ci_6alkoxy or carboxy
  • R 7 is hydrogen, halogen, Ci_6alkoxy, Ci_6alkylaminocarbonyl, diCi_ 6
  • R 8 is hydrogen or halogen
  • A is -C-R 11 , wherein R 11 is hydrogen, halogen, C h alky!, Ci_ 6 alkoxy, trifluoromethyl, trifluoromethoxy, pyridinyloxy, difluoromethoxy or Ci_6alkylsulfonyl;
  • Y is -CH- or nitrogen
  • Q is hydrogen; halogen; Ci_6alkyl, once or twice substituted by hydroxy provided that disubstitution of hydroxy is not on the same carbon; amino(CH 2 ) 2 _ 6 aminosulfonyl; 2-amino-4,5- A ⁇ r A ⁇ 1 hail exertingTMi . ⁇ thyl; or NR 12 R 13 , wherein one of R 12 and R 13 is hydrogen, Ci_ 6 alkyl or hydroxy(CH 2 )2-6, and the other one is guanidino(CH 2 ) 2 -6; 3 -amino methyl- 1,1 -dioxidothietan-3 - ylmethyl; 3-amino- 1 , 1 -dioxidothietan-3 -ylmethyl; 3 -(amino methyl)thietan-3 -ylmethyl;
  • R 14 is hydrogen, Ci_6alkyl or hydroxy(CH 2 )i_6; R 15 is hydroxy, hydroxy(CH 2 )i_6 or amino; and R 16 is Ci_6alkyl, hydroxy(CH 2 )i_6 or amino (CH 2 )i_6; R 12 and R 13 , with the nitrogen atom to which they are attached, may form a pyrrolidinyl, piperazinyl or diazepanyl ring; which may be unsubstituted, once or twice substituted by a group selected from Ci_ 6 alkyl, amino or hydroxy.
  • Another particular embodiment of invention is (xiii) a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein R 1 is hydrogen or chloro;
  • R 2 and R 4 are hydrogen
  • R 3 is hydrogen or chloro
  • R 5 is hydrogen or fluoro
  • R 6 is hydrogen, fluoro, hydroxy, methoxy, ethoxy or carboxy
  • R 7 is hydrogen, fluoro, bromo, methoxy, dimethylaminocarbonyl, methylsulfonyl or ethylsulfonyl
  • R 8 is hydrogen or chloro.
  • A is CR 1 1 , wherein R 1 1 is hydrogen, fluoro, chloro, bromo, methyl, methoxy,
  • aminoethylaminosulfonyl 2-amino-4,5-dihydro-l,3-oxazol-4-ylethyl; or NR 12 R 13 , wherein one of R 12 and R 13 is hydrogen, methyl or hydroxyethyl, and the other one is aminobutyl; 3- aminocyclohexyl; 4-aminocyclohexyl; 2-amino-4,5-dihydro-oxazol-5-ylmethyl; 3-amino- 1,1 - dioxidothietan-3 -ylmethyl; aminoethoxyethyl; aminoethyl; ammoethylsulfonylethyl; aminomethylcarbonyl; amino methyldifluoromethylmethyl; 3 -amino methyl- 1 , 1 -dioxidothietan-3 - ylmethyl; 3 -(amino methyl)thietan-3 -ylmethyl; amino methyloxetany
  • aminooxetanylmethyl aminopropyl; dimethylamino ethyl; ethylaminocarbonyl; guanidino ethyl;
  • R 15 is hydroxy
  • R 16 is methyl, hydroxymethyl or amino methyl
  • R 12 and R 13 with the nitrogen atom to which they are attached, may form a pyrrolidinyl, piperazinyl or diazepanyl ring; which may be unsubstituted, once or twice substituted by a group selected from methyl, amino or hydroxy; and all the remaining substituents are as defined above 10 in embodiment (xii).
  • a particular embodiment of present invention is a compound of formula (I) or a pharmaceutically acceptable salt thereof, selected from:
  • FBS fetal bovine serum
  • EC50 the concentration of a compound where 50% of its maximal protection effect against viral induced CPE is observed
  • CD3OD deuterated methanol
  • Methyl 2-sulfanylbenzoates IXa can be prepared by esterification of 2-sulfanylbenzoic acids X. The conversion can be achieved by heating under reflux in the presence of sulfuric acid in methanol overnight or stirring with thionyl chloride in methanol at room temperature for several hours. 3,4-Dihydro-l,4-benzothiazepin-5(2H)-ones Villa can be prepared from methyl 2- sulfanylbenzoates IXa by annulation with 2-bromo-ethylamine hydrochloride.
  • the reaction can be carried out with a standard basic agent such as sodium hydride, potassium tert-butoxide in a suitable organic solvent such as tetrahydrofuran, 1,4-dioxane, N,N-dimethylformamide or mixtures thereof, typically at 0 °C, followed by stirring at room temperature overnight.
  • a standard basic agent such as sodium hydride, potassium tert-butoxide
  • a suitable organic solvent such as tetrahydrofuran, 1,4-dioxane, N,N-dimethylformamide or mixtures thereof, typically at 0 °C, followed by stirring at room temperature overnight.
  • 2,3,4,5-Tetrahydro-l,4-benzothiazepines IVa can be prepared by reduction of 3,4- dihydro-l,4-benzothiazepin-5(2H)-ones Villa.
  • the reaction can be carried out with a standard reducing agent such as lithium aluminium hydride, boron hydride or combination of sodium borohydride and boron trifluoride in a suitable inert organic solvent such as tetrahydrofuran, diethyl ether or mixtures thereof, typically at 0 °C, followed by stirring at a temperature between 25 °C and 70 °C for several hours.
  • a standard reducing agent such as lithium aluminium hydride, boron hydride or combination of sodium borohydride and boron trifluoride in a suitable inert organic solvent such as tetrahydrofuran, diethyl ether or mixtures thereof, typically at 0 °C, followed by stirring at a temperature between 25 °C and 70
  • Amides IVb can be prepared by acylation of IVa with acetyl chloride or acetic anhydride.
  • the reaction can be carried out with a suitable base such as triethylamine or pyridine in a suitable inert organic solvent such as dichloromethane, tetrahydrofuran or pyridine at 0 °C, followed by stirring at room temperature for 30 minutes.
  • Compounds IVc can be prepared by oxidation of IVb followed by deacylation.
  • Oxidation can be carried out with 1-2 equivalents of 3-chloroperoxybenzoic acid, in a suitable solvent such as dichloromethane, chloroform, 1,2-dichloroethane, or the mixture thereof, typically at 0 °C, followed by stirring at room temperature for 10 to 20 minutes.
  • Deacylation can be achieved by stirring amides with a suitable base such as sodium hydroxide or potassium hydroxide in a mixture of alcohol such as methanol or ethanol and water under reflux overnight.
  • Compounds IVd can be prepared by oxidation of IVb followed by deacylation.
  • Oxidation can be carried out with 4 equivalents of 3-chloroperoxybenzoic acid, in a suitable solvent such as dichloromethane, chloroform, 1,2-dichloroethane, or the mixture thereof, typically at 0 °C, followed by stirring at room temperature for 1 to 2 hours.
  • Deacylation can be achieved by stirring amides with a suitable base such as sodium hydroxide or potassium hydroxide in a mixture of alcohol such as methanol or ethanol and water under reflux overnight.
  • Vlllb can be prepared from l-(2- sulfanylphenyl)ethanones IXb by annulation with 2-bromo-ethylamine.
  • the reaction can be carried out with a standard basic agent such as sodium hydride, potassium tert-butoxide in a suitable organic solvent such as tetrahydrofuran, 1,4-dioxane, N,N-dimethylformamide or mixtures thereof, typically at 0 °C, followed by stirring at room temperature overnight.
  • 5-Methyl-2,3,4,5-tetrahydro-l,4-benzothiazepines IVe can be prepared from reduction of 5-methyl-2,3-dihydro-l,4-benzothiazepines Vlllb.
  • the reaction can be carried out with a reducing reagent such as sodium borohydride in a suitable organic solvent such as methanol, water or mixtures thereof at room temperature for several hours or overnight, followed by treatment with concentrated hydrochloric acid at room temperature for 30 minutes. After neutralization with sodium carbonate or sodium hydroxide, free form of IVe is obtained.
  • E is CI or Br
  • W 1 is (oxetan-S-ylJC ⁇ alkyl, (tetrahydrofuran-S-ylJC ⁇ alkyl, (tetrahydro ⁇ H-pyran- ⁇ ylJC ⁇ alkyl,
  • L 1 is H or benzyl
  • Quino lines Ilac can be prepared by coupling of 2,4-dihalogen quino lines Ilia with benzothiazepines IVf.
  • the reaction can be carried out with or without a solvent such as isopropanol, n-butanol, tert-butanol or the mixture thereof at a temperature between 120 °C and 180 °C, typically at 160 °C under microwave irradiation for several hours.
  • Sulfones Ilab can be prepared by oxidation of sulfides Ilac.
  • the reaction can be carried out with a suitable oxidant such as 3-chloroperoxybenzoic acid in a suitable inert organic solvent such as dichloromethane typically at 0 °C, followed by stirring at room temperature for several hours.
  • reaction can be carried out with a suitable oxidant such as hydrogen peroxide, sodium periodate or potassium permanganate, in a suitable solvent such as methanol, tetrahydroiuran, water or the mixture thereof, typically at 0 °C, followed by stirring at a temperature between room temperature and 70 °C for several hours.
  • a suitable oxidant such as hydrogen peroxide, sodium periodate or potassium permanganate
  • a suitable solvent such as methanol, tetrahydroiuran, water or the mixture thereof
  • 4-Benzyl diamino quino lines Ilaa can be prepared by coupling of quino lines Ilab with various benzyl diamines Va.
  • the reaction can be carried out in the presence of a palladium catalyst such as l, -bis(diphenylphosphino)ferrocene-palladium (II), palladium (II) acetate, tri(dibenzylideneacetone)dipalladium(0), or palladium (II) chloride in the presence of a phosphine ligand such as triphenyl phosphane, l,l'-bis(diphenylphosphino)ferrocene, 9,9- dimethyl-4,5-bis(diphenylphosphino)xanthene, or tricyclohexylphosphine, with a suitable base such as sodium carbonate, potassium carbonate, cesium carbonate, sodium tert-butoxide or potassium tert-butoxide, in a suitable inert
  • Compounds of interest Iaa can be prepared by standard debenzylation of Ilaa.
  • the reaction can be carried out in the presence of palladium on carbon, palladium hydroxide on carbon or platinum oxide, typically with an acid such as hydrochloric acid, acetic acid or trifluoro acetic acid in a suitable solvent such as methanol, ethanol, tetrahydroiuran, ethyl acetate or the mixture thereof, at room temperature for several hours under hydrogen atmosphere.
  • E is CI or Br
  • 4-Amino quino lines lab can be prepared by coupling of 4-halogen quino lines Ilac with various amines XI in the presence or absence of a palladium catalyst.
  • Palladium-catalyzed coupling reaction can be carried out in the presence of a palladium catalyst such as ⁇ , ⁇ - bis(diphenylphosphino)ferrocene-palladium(II)dichloride, palladium acetate or
  • phosphine ligand such as 1,1 '- bis(diphenylphosphino)ferrocene, 2,2'-bis(diphenylphosphino)-l,l '-binaphthalene, 4,5- bis(diphenylphosphino)-9,9-dimethylxanthene or 2-dicyclohexylphosphino-2'-(N,N- dimethylamino)biphenyl, and a base such as sodium tert-butoxide, cesium carbonate or potassium phosphate in a suitable solvent such as 1,4-dioxane or toluene, at a temperature between 100 °C and 140 °C for 1 to 2 hours under microwave irradiation.
  • a phosphine ligand such as 1,1 '- bis(diphenylphosphino)ferrocene, 2,2'-bis(diphenylphosphino)-l,l '-binaphthalene,
  • palladium-catalyzed coupling reaction can be carried out at an elevated temperature such as 110 °C or 120 °C without microwave irradiation for a longer reaction time.
  • Coupling of 4-halogen quino lines Ilac with various amines XI in the absence of a palladium catalyst can be carried out with a suitable base such as N,N-diisopropylethylamine or without any base in a suitable solvent such as n-butanol, l-methyl-2-pyrrolidinone or phenol, at a temperature between 130 °C and 160 °C for 1.5 to 2 hours under microwave irradiation.
  • the reaction can be carried out at an elevated temperature between 150 °C and 180 °C without microwave irradiation for a longer reaction time.
  • the reaction can also be carried out without any base and without any solvent at 160 °C for one to several hours under microwave irradiation.
  • 4-Amino quino lines lac can be prepared by coupling of 4-halogen quino lines Ilab with various amines XI in the presence of a metal catalyst such as a palladium catalyst or copper (I) iodide, or absence of a metal catalyst. Coupling of 4-halogen quino lines Ilab with various amines XI in the presence of a palladium catalyst or in the absence of any metal catalyst can be carried out in analogy to coupling of 4-halogen quino lines Ilac with various amines XI.
  • a metal catalyst such as a palladium catalyst or copper (I) iodide
  • Copper(I) iodide catalyzed coupling of 4-halogen quino lines Ilab with various amines XI can be carried out in the presence of copper(I) iodide with a ligand such as N,N'-dimethylcyclohexane- 1,2-diamine or cyclohexane-l,3-diamine, and a base such as potassium carbonate or potassium phosphate in a suitable solvent such as 1,4-dioxane or diethylene glycol dimethyl ether, at a temperature between 140 °C and 150 °C for 2 to 3 hours under microwave irradiation.
  • a ligand such as N,N'-dimethylcyclohexane- 1,2-diamine or cyclohexane-l,3-diamine
  • a base such as potassium carbonate or potassium phosphate
  • a suitable solvent such as 1,4-dioxane or diethylene glycol dimethyl ether
  • reaction can be carried out at an elevated temperature without microwave irradiation for a longer reaction time.
  • 4-Amino quino lines lac can be prepared from oxidation of sulfides lab. The reaction can be carried out in analogy to oxidation of quino lines Ilac in Scheme 4.
  • 2-Benzothiazepin-4-halogen quino lines Had can be prepared from coupling of 2,4- halogen quino lines Ilia with benzothiazepines IVg.
  • the reaction can be carried out in the absence of solvent or in a suitable solvent such as isopropanol, n-butanol, tert-butanol or the mixtures thereof at a temperature between 120 °C and 180 °C, typically at 160 °C under microwave irradiation for several hours.
  • Compounds of interest Iae, Iaf and lag can be prepared from deprotection of tert- butyloxycarbonyl of Ilaf, Hag and Hah.
  • the reaction can be carried out with a suitable acid such as trifluoro acetic acid or hydrochloric acid in a suitable solvent such as dichloromethane, ethyl acetate or 1,4-dioxane, at 0 °C to room temperature for 4 to 16 hours.
  • a suitable acid such as trifluoro acetic acid or hydrochloric acid
  • a suitable solvent such as dichloromethane, ethyl acetate or 1,4-dioxane
  • Compounds Hai can be prepared from coupling of 4-halogen quino lines Hae with various amines XIV.
  • the reaction can be carried out in the presence of a metal catalyst or in absence of a metal catalyst in analogy to coupling of 4-halogen quino lines Hab with various amines XI in Scheme 5.
  • the reaction can be carried out in the presence of
  • Compounds of interest Iah can be prepared from deprotection of benzyloxycarbonyl of Ilai.
  • the conversion can be achieved under strong acidic conditions, under basic conditions or by hydro genation.
  • Treating Ilai with a mixture of aqueous solution of potassium hydroxide and methanol under reflux for 30 minutes to several hours can generate Iah.
  • Treating Ilai under strong acidic conditions such as reflux in 6 N hydrochloride in methanol for several hours can also generate Iah.
  • Hydrogenation of Ilai can be carried out in the presence of palladium on carbon or palladium black, under hydrogen atmosphere or with a hydrogen donor such as formic acid or ammonium formate, in a suitable solvent such as methanol or ethanol, at a temperature between room temperature and 80 °C for 15 minutes to several hours.
  • a hydrogen donor such as formic acid or ammonium formate
  • a suitable solvent such as methanol or ethanol
  • E is CI or Br
  • L 7 is ydroxyet yl, met oxyet yl or pyridin-2-yl
  • 6-Hydroxy quino lines Hak can be prepared by demethylation of 6-methoxy quino lines Haj.
  • the reaction can be carried out in an aqueous solution of hydrobromic acid by heating under reflux for 2 days.
  • Ham can be prepared by reaction of Hak with bromides XV.
  • L 7 is pyridin-2-yl
  • the reaction can be carried out in the presence of a metal catalyst such as Copper(I) iodide with a ligand such as N,N'-dimethylcyclohexane-l,2-diamine and with a suitable base such as potassium carbonate in a suitable solvent such as 1 ,2-dimethoxyethane at 120 °C for 1 hours under microwave irradiation.
  • a metal catalyst such as Copper(I) iodide
  • a ligand such as N,N'-dimethylcyclohexane-l,2-diamine
  • a suitable base such as potassium carbonate
  • a suitable solvent such as 1 ,2-dimethoxyethane at 120 °C for 1 hours under microwave irradiation.
  • L 7 is substituted alkyl such as hydro xyethyl or
  • the reaction can be carried out in the presence of a suitable base such as potassium carbonate in a suitable solvent such as acetone at room temperature overnight.
  • a suitable base such as potassium carbonate
  • a suitable solvent such as acetone
  • Compounds of interest lai and Iaj can be prepared by coupling of Hak and Ham with propane- 1,3-diamine separately. The reaction can be carried out at 150 °C for 1.5 hours under microwave irradiation.
  • E is CI or Br
  • Han can be obtained by coupling of 4-halogen quino lines Ilae with C-(2,2-dimethyl- [l,3]dioxolan-4-yl)-methylamine.
  • the reaction can be carried out in analogy to coupling of 4- halogen quino lines Ilab with various amines XI in Scheme 5.
  • the reaction can be carried out by heating a mixture of 4-halogen quinolines Ilae and C-(2,2-dimethyl- [l,3]dioxolan-4-yl)-methylamine at 160 °C for 16 hours.
  • Iak 4-(2,3-Diol-propylamino)-quino lines Iak can be prepared by deprotection of Han.
  • the reaction can be carried out in the presence of an acid such as hydrochloric acid in a suitable solvent such as methanol, ethanol, water or mixtures thereof at room temperature for several hours.
  • Quino lines Hap can be prepared from coupling of fluorides Ilao (which can be prepared in analogy to 4-benzyl diamino quino lines Ilaa in Scheme 4) with amines XVI.
  • the reaction can be carried out by heating a mixture of fluorides Ilao and amines XVI with a suitable solvent such as N,N-dimethyl formamide, N,N-dimethyl acetamide, N-methyl-2-pyrrolidinone, dimethyl sulfoxide or the mixtures thereof, or without any solvent at a temperature between 100 °C and 150 °C, typically at 120 °C under microwave irradiation for several hours.
  • a suitable solvent such as N,N-dimethyl formamide, N,N-dimethyl acetamide, N-methyl-2-pyrrolidinone, dimethyl sulfoxide or the mixtures thereof, or without any solvent at a temperature between 100 °C and 150 °C, typically at 120 °C under microwave irradi
  • E is CI or Br
  • liar can be prepared by demethylation of Ilaq.
  • the reaction can be carried out by treating Ilaq with a suitable Lewis acid such as tribromoborane, aluminum chloride, aluminum bromide, and stannous chloride in a dry organic inert solvent such as dichloromethane, chloroform, acetonitrile and N,N-dimethylformamide at a temperature between 0 and 80 °C, typically at 0 °C, for a period of 5 minutes to 3 hours, typically for 1 hour.
  • Has can be obtained by coupling of liar with iodobenzene.
  • the reaction can be carried out by heating in the presence of copper(I) iodide or copper(I) bromide, with a ligand such as N,N-dimethylglycine hydrochloride, (2-pyridyl)acetone or l,l,l-tris(hydroxymethyl)ethane, and a base such as cesium carbonate, potassium carbonate, or potassium phosphate, in an organic solvent such as dimethyl sulfoxide, N,N-dimethylformamide, acetonitrile or 1,4-dioxane at a temperature between 80 °C and 120 °C for 4 to 24 hours.
  • the reaction can be carried out by heating in the presence of copper(I) iodide, N,N-dimethylglycine hydrochloride and potassium carbonate in dimethyl sulfoxide at 120 °C for 6 hours.
  • Iam can be obtained by coupling of Has with (3-aminomethyl-oxetan-3-yl)-dibenzylamine followed by debenzylation.
  • the reactions can be conducted in analogy to preparation of laa from Hab in Scheme 4.
  • coupling of Has with (3-aminomethyl-oxetan-3-yl)-dibenzylamine can be carried out in the presence of bis(diphenylphosphino)-ferrocenedichloropalladium(II), l,l'-bis(diphenylphosphino)-ferrocene and sodium-tert-butoxide in 1,4-dioxane at 120 °C for 2 hours under microwave irradiation.
  • Debenzylation of Hat can be achieved by stirring a solution of Hat in methanol in the presence of palladium hydroxide on carbon and trifluoro acetic acid at room temperature under 2 bar of hydrogen atmosphere for 14 hours.
  • Ilau can be prepared by coupling of liar with 3-bromo-propan-l-ol.
  • the reaction can be carried out with a suitable base such as potassium carbonate, cesium carbonate, sodium tert- butoxide, potassium tert-butoxide, sodium hydride or l,8-diazabicyclo[5.4.0]undec-7-ene in an inert organic solvent such as dichloromethane, N,N-dimethylformamide, dimethyl sulfoxide or 1- methyl-pyrrolidin-2-one at a temperature between room temperature and 100 °C, typically at 70 °C for several hours.
  • a suitable base such as potassium carbonate, cesium carbonate, sodium tert- butoxide, potassium tert-butoxide, sodium hydride or l,8-diazabicyclo[5.4.0]undec-7-ene
  • an inert organic solvent such as dichloromethane, N,N-dimethylformamide, dimethyl
  • Ilav can be prepared by coupling of 4-halogen quino lines Ilau with carbamic acid tert- butyl ester.
  • the reaction can be carried out in the presence of a palladium catalyst in analogy to coupling of 4-halogen quino lines Ilab with various amines XI in Scheme 5.
  • the reaction can be carried out by heating a mixture of 4-halogen quino lines Ilau and carbamic acid tert- vXy ⁇ ester in the presence of bis(diphenylphosphino)ferrocenedichloropalladium(II), with l,l'-bis(diphenylphosphino)ferrocene and sodium- tert-butoxide in 1,4-dioxane at 120 °C for 2 hours.
  • 4-Amine quino lines Ian can be obtained by standard deprotection of tert- butyloxycarbonyl of Ilav.
  • the reaction can be carried out by treating Ilav with a suitable acid such as hydrochloric acid, trifluoro acetic acid, or sulfuric acid in a suitable solvent such as methanol, ethyl acetate, dichloromethane, 1,4-dioxane, water or the mixtures thereof at a temperature between 0 °C and room temperature for 30 minutes to several hours.
  • a suitable acid such as hydrochloric acid, trifluoro acetic acid, or sulfuric acid
  • a suitable solvent such as methanol, ethyl acetate, dichloromethane, 1,4-dioxane, water or the mixtures thereof
  • a suitable solvent such as methanol, ethyl acetate, dichloromethane, 1,4-dioxane, water or the mixtures thereof
  • the reaction can be carried
  • E is CI or Br
  • W is CH 2 , CH(CH 3 ), CH 2 CH(CH 3 ), or CH(CH 3 )CH 2 ;
  • L 8 is H or CH 3
  • Compounds of interest Iao can be prepared according to Scheme 13. Coupling of 4- halogen quino lines Ilab with various amino acids XVII gives acids Haw. Esterification of acids Haw followed by amino lysis affords amides Iao.
  • Acids Haw can be prepared by coupling of 4-halogen-quino lines Ilab with amino acids XVII. The reaction can be carried out in phenol, preferably at 150 °C in a sealed tube overnight.
  • Esters Hax can be prepared by esterification of carboxylic acids Haw.
  • the reaction can be carried out by heating Haw and methanol in the presence of a suitable catalyst such as concentrated sulfuric acid, dry hydrochloride gas, or thionyl chloride for several hours.
  • a suitable catalyst such as concentrated sulfuric acid, dry hydrochloride gas, or thionyl chloride for several hours.
  • the reaction can be carried out by heating Haw and methanol in the presence of thionyl chloride under reflux for 2 hours.
  • Amides Iao can be prepared by aminolysis of methyl esters Hax.
  • the reaction can be carried out by heating methyl esters Hax with various concentrated amines in alcohol, such as 7N ammonia in methanol or 33% (wt%) methyl amine in absolute ethanol.
  • the reaction can be preferably carried out at 85 °C in a sealed tube overnight.
  • Oxazolidines can be prepared by coupling of 4-halogen quinolines Hab with 4- aminomethyl-2,2-dimethyl-oxazolidine-3-carboxylic acid tert-butyl ester. The reaction can be carried out in the presence of a palladium catalyst in analogy to coupling of 4-halogen quinolines Hab with various amines XI in Scheme 5.
  • reaction can be carried out by heating a mixture of 4-halogen quinolines Hab and 4-aminomethyl-2,2-dimethyl-oxazolidine-3-carboxylic acid tert-bvXy ⁇ ester in the presence of bis(diphenylphosphino)ferrocenedichloropalladium(II), with l,l'-bis(diphenylphosphino)ferrocene and sodium-tert-butoxide in 1,4-dioxane at 120 °C for 1.5 hours.
  • Amino alcohols lap can be prepared by acid catalyzed cleavage of tert-butyloxycarbonyl and acetal of acetonides Hay. The reaction is typically carried out in a solution of hydrochloride in ethyl acetate for several hours at room temperature.
  • L 9 is H or CH 3 .
  • W 5 is CH 2 .
  • L 10 is CH 2 and W 5 is CH, they attach and form a pyrrolidine ring.
  • Compounds of interest Iat can be prepared according to Scheme 16. Starting with amino alcohols las (prepared in analogue to lap in Scheme 14 and laf in Scheme 7), cyclization with cyanogen bromide affords oxazoles Iat. Compounds of interest Iat can be prepared by cyclization of amino alcohols las with a slight excess of cyanogen bromide. The reaction can be carried out in the presence of a suitable base such as sodium acetate, sodium carbonate, potassium acetate or potassium carbonate, in a suitable solvent such as methanol, water, or the mixtures thereof, typically at 0 °C, followed by stirring at room temperature for several hours.
  • a suitable base such as sodium acetate, sodium carbonate, potassium acetate or potassium carbonate
  • a suitable solvent such as methanol, water, or the mixtures thereof
  • Sulfones IVh can be prepared by oxidation of IVb.
  • the reaction can be carried out with a suitable oxidant such as 3-chloroperoxybenzoic acid, hydrogen peroxide, sodium periodate or potassium permanganate, in a suitable solvent such as dichloromethane, acetic acid, water or the mixtures thereof, typically at 0 °C, followed by stirring at room temperature for several hours.
  • a suitable oxidant such as 3-chloroperoxybenzoic acid, hydrogen peroxide, sodium periodate or potassium permanganate
  • a suitable solvent such as dichloromethane, acetic acid, water or the mixtures thereof, typically at 0 °C, followed by stirring at room temperature for several hours.
  • Imines liaz can be prepared by heating a mixture of IVh, 2-aminobenzonitriles XVIII and phosphorous oxychloride. The reaction can be carried out in a suitable inert organic solvent such as dichloromethane, chloroform or the mixtures thereof, typically at 0-10 °C, followed by stirring at reflux for 24 hours. Compounds of interest lau can be prepared by ring closure of imines Ilaz. The reaction can be achieved by treatment of Ilaz with Lewis acid such as zinc chloride in N,N- dimethylacetamide at 120-180 °C for several hours in an inert atmosphere.
  • Lewis acid such as zinc chloride in N,N- dimethylacetamide at 120-180 °C for several hours in an inert atmosphere.
  • Amides Ilba can be prepared from 4-amino quino lines lae by acylation with acy chlorides XIX.
  • the reaction can be carried out with a suitable base such as potassium carbonate, cesium carbonate, sodium hydride or l,8-diazabicyclo[5.4.0]undec-7-ene in an inert organic solvent such as dichloromethane, tetrahydrofuran or N,N-dimethylformamide, typically at room temperature, followed by stirring at 50-100 °C for several hours.
  • Methyl ethers lav can be prepared by reaction of Ilba with methanol. The reaction can be realized by refluxing Ilba in methanol in the presence of ethylamine overnight.
  • Azides Ilbb can be prepared by reaction of amides Ilba with sodium azide.
  • the reaction can be carried out in a suitable solvent such as acetonitrile, N,N-dimethylformamide, dimethyl sulfoxide, water or mixtures thereof, typically at 25-70 °C for several hours.
  • Amines law can be prepared by hydrogenation of azides Ilbb.
  • the reaction can be carried out in the presence of 10% palladium on carbon under hydrogen atmosphere in an organic solvent such as ethyl acetate, methanol, or ethanol, typically at room temperature for several hours.
  • organic solvent such as ethyl acetate, methanol, or ethanol
  • L 13 is H or CF 3
  • Ilbc can be prepared by acylation of 4-aminoquino lines lae.
  • the reaction can be carried out by stirring a mixture of lae and acyl chlorides XX with a suitable base such as N,N- diisopropylethylamine or cesium carbonate, in a suitable organic solvent such as dichloromethane, N,N-dimethylformamide or the mixtures thereof, at room temperature for several hours.
  • a suitable base such as N,N- diisopropylethylamine or cesium carbonate
  • a suitable organic solvent such as dichloromethane, N,N-dimethylformamide or the mixtures thereof
  • Amides lax can be prepared by cleavage of phthalic protecting group from Ilbc.
  • the reaction can be carried out with a suitable base such as hydrazine, hydrazine acetate or low alkyl amine such as methylamine or n-butylamine in an alcohol solvent such as methanol or ethanol at a temperature between room temperature and 90 °C for several hours.
  • a suitable base such as hydrazine, hydrazine acetate or low alkyl amine such as methylamine or n-butylamine
  • an alcohol solvent such as methanol or ethanol
  • the reaction can be carried out by heating Ilbc with methylamine in ethanol, at 90 °C for 2 hours.
  • lay can be obtained by reduction of amides of lax.
  • the reaction can be carried out by heating lax in a solution of borane-methyl sulfide complex in diethyl ether at 80 °C for several hours.
  • L 5 is H or ethyl
  • L 6 is CH 2 CH 3 ,oxetan-3-yl, or pyridin-2-yl,
  • W 6 is (CH 2 ) 2 , (CH 2 ) 3 , or methyl-oxetan-3-yl
  • Compounds of interest Iba can be prepared according to Scheme 20. Starting with amines laz (prepared in analogue to lac in Scheme 5 and Iaf, lag in Scheme 7), reductive amination with various aldehydes or ketones provides substituted amines Iba when L 16 is ethyl or oxetan-3-yl; coupling of amines laz with 2-bromo-pyridine generates Iba when L 16 is pyridine-2-yl. Compounds of interest Iba can be prepared by reductive amination of laz with various aldehydes or ketones.
  • This reaction can be carried out with a suitable reducing agent such as sodium triacetoxyborohydride or sodium cyanoborohydride in a suitable organic solvent such as dichloromethane, 1,2-dichloroethane, tetrahydrofuran, methanol or the mixtures thereof, typically with the addition of molecular sieves or acetic acid, at a temperature between room temperature and 70 °C for 2 to 12 hours.
  • a suitable reducing agent such as sodium triacetoxyborohydride or sodium cyanoborohydride
  • a suitable organic solvent such as dichloromethane, 1,2-dichloroethane, tetrahydrofuran, methanol or the mixtures thereof, typically with the addition of molecular sieves or acetic acid
  • Compounds of interest Iba can also be prepared by coupling of amines Iaz with 2- bromo-pyridine. The reaction is typically performed in N-methylpyrolidinone with
  • L 17 is phenyl or ethyl
  • Ureas Ibb can be prepared by reaction of 4-amino-quino lines lae with isocyanides XXI. The reaction can be carried out by stirring 4-amino-quino lines lae with various isocyanide XXI in the presence of a suitable base such as triethylamine in an organic solvent such as tetrahydrofuran at a temperature between 0 °C to 50 °C for several hours.
  • a suitable base such as triethylamine
  • organic solvent such as tetrahydrofuran
  • Compounds Ilbe can be prepared from reaction of bromides Ilbd with various organoboronic acids or various metal reagents such as zinc cyanide or organo stannic reagents. Reaction of bromides Ilbd with various organoboronic acids can be carried out in the presence of a palladium catalyst such as tetra(triphenylphosphino)palladium or palladium acetate with a phosphine ligand such as 2,2'-bis(diphenylphosphino)-l,l '-binaphthalene and a base such as potassium carbonate in a suitable solvent such as toluene at 90 °C for 16 hours under argon atmosphere.
  • a palladium catalyst such as tetra(triphenylphosphino)palladium or palladium acetate
  • a phosphine ligand such as 2,2'-bis(diphenylphosphino)-l,l '-binaphthalene
  • Reaction of bromides Ilbd with various organometallic reagents can be carried out in the presence of a palladium catalyst such as tetra(tri-phenylphosphino)palladium in a suitable solvent such as N,N-dimethylformamide under reflux for 1 to 2 hours under argon atmosphere.
  • a palladium catalyst such as tetra(tri-phenylphosphino)palladium in a suitable solvent such as N,N-dimethylformamide under reflux for 1 to 2 hours under argon atmosphere.
  • Coupling of halogens Ilbe with propane- 1,3-diamine can be carried out in analogy to coupling of 4-halogen quino lines Ilab with various amines XI in Scheme 5.
  • the reaction can be carried out with a palladium catalyst such as
  • 2-Chloro-4-hydroxy-quinozalines IIIc can be prepared by hydrolysis of 2,4-dichloro- quinozalines Mb. The reaction can be carried out in the presence of a suitable base such as sodium hydroxide in a suitable solvent such as tetrahydrofuran, water or mixtures thereof at room temperature for several hours.
  • a suitable base such as sodium hydroxide
  • a suitable solvent such as tetrahydrofuran, water or mixtures thereof at room temperature for several hours.
  • 4-Hydroxy quinozalines Ilbg can be prepared by coupling of IIIc with benzoazapines
  • the reaction can be carried out in the presence of a suitable base such as triethylamine in a suitable solvent such as toluene or N,N-dimethylformamide at a temperature between 110 °C and 160 °C under microwave irradiation for 30 minutes to 2 hours.
  • a suitable base such as triethylamine
  • a suitable solvent such as toluene or N,N-dimethylformamide
  • the reaction can be carried out at an elevated temperature such as under reflux overnight without microwave irradiation.
  • 2-Chloro-4-amino quinozalines Ilbf can be prepared by coupling of Illb with various amines XI. The reaction can be carried out in the presence of a suitable base such as
  • the reaction can be carried out in the presence of a suitable base such as 1,8- diazabicyclo[5.4.0]undec-7-ene with a suitable coupling reagents such as benzotriazol-1- yloxytris(dimethylamino)-phosphonium hexafluorophosphate, in a suitable solvent such as N,N- dimethylformamide at room temperature for several hours.
  • a suitable base such as 1,8- diazabicyclo[5.4.0]undec-7-ene
  • a suitable coupling reagents such as benzotriazol-1- yloxytris(dimethylamino)-phosphonium hexafluorophosphate
  • a suitable solvent such as N,N- dimethylformamide
  • the reaction can be carried out with or without a base such as triethylamine, in a suitable solvent such as n-butanol or N,N-dimethylformamide at a temperature between 130 °C and 160 °C for 30 minutes to several hours under microwave irradiation.
  • a base such as triethylamine
  • a suitable solvent such as n-butanol or N,N-dimethylformamide
  • this reaction can be carried out with triethylamine in n-butanol in a sealed tube at a lower temperature for several hours, typically at 100 °C for 4 hours.
  • Compounds of interest Ibe can be prepared by coupling of Ilbf with benzothioazapines IVf.
  • the reaction can be carried out without any base or with a suitable base such as
  • Ibi can be prepared by oxidation of Ibh.
  • the reaction can be carried out with a suitable oxidant such as 3-chloroperoxybenzoic acid, hydrogen peroxide, sodium periodate or potassium permanganate, in a suitable solvent such as dichloromethane, acetic acid, water or the mixture thereof, typically at 0 °C, followed by stirring at room temperature for several hours.
  • a suitable oxidant such as 3-chloroperoxybenzoic acid, hydrogen peroxide, sodium periodate or potassium permanganate
  • a suitable solvent such as dichloromethane, acetic acid, water or the mixture thereof, typically at 0 °C, followed by stirring at room temperature for several hours.
  • Compounds Ibj can be prepared by standard debenzylation of Ibi.
  • the reaction can be carried out with palladium on carbon, palladium hydroxide on carbon or platinum oxide, typically with an acid such as acetic acid or trifluoro acetic acid in a suitable solvent such as methanol, ethanol, tetrahydroiuran, ethyl acetate or the mixtures thereof, at room temperature — iTM.appel consider technically faced ⁇ re f or se veral hours.
  • a suitable solvent such as methanol, ethanol, tetrahydroiuran, ethyl acetate or the mixtures thereof.
  • W 8 is (CH 2 ) 2 , (CH 2 ) 3 or oxetan-3-ylmethyl
  • Compounds Ilbh can be prepared by coupling of 4-halogen-quino lines Ilab with N-(3- methyl-pyrrolidin-3-yl)-acetamide.
  • the reaction can be carried out in the presence of a metal catalyst or in the absence of a metal catalyst in analogy to coupling of 4-halogen quino lines Ilab with various amines XI in Scheme 5.
  • the reaction can be carried out with ⁇ , ⁇ - bis(diphenylphosphino)ferrocene, 1 , 1 '-bis(diphenylphosphino)ferrocenedichloropalladium(II), and sodium-tert-butoxide in 1,4-dioxane at 120 °C for 1.5 hours under microwave irradiation.
  • Compounds of interest Ibm can be prepared by deactylation of Ilbh.
  • the reaction can be carried out in 2 N hydrochloric acid at 100 °C for 16 hours.
  • 1,3-Diols Ibr can be prepared by reduction of acids Ilbj.
  • the reaction can be carried out by treating acids with sodium borohydride in the presence of iodine in tetrahydrofuran, typically at 0 °C, followed by stirring at room temperature for 16 hours.
  • 1,2-Diols lbs can be prepared by dihydroxylation of alkenes Ilbk.
  • the reaction can be accomplished by treating alkenes with 4-methylmorpholine N-oxide monohydrate and osmium tetroxide in acetone at room temperature for 1 hour.
  • Compounds Ilbi can be prepared by alkylation of Ilbi with methyl iodide.
  • compounds can be obtained by deprotonation of a-H of sulfone followed by reaction with methyl iodide.
  • Deprotonation of a-H of sulfone can be carried out by treating sulfone Ilbi with n-butyl lithium in tetrahydrofuran at -78 °C under argon atmosphere for 1 hour.
  • Reaction with methyl iodide can be accomplished by addition of methyl iodide to the above reaction mixture at -78 °C, followed by stirring at room temperature overnight.
  • Compounds of interest Ibt can be prepared by coupling of Ilbl with various amines.
  • the reaction can be carried out in analogy to coupling of 4-halogen quino lines Ilab with various amines XI in Scheme 5.
  • the reaction preferably can be achieved by heating a mixture of Ilbl and various amines with or without organic solvent such as N,N-dimethylformamide, 1- methylpyrrolidin-2-one or /? -butyl alcohol, under microwave irradiation at 140-160 °C for 1-3 hours.
  • organic solvent such as N,N-dimethylformamide, 1- methylpyrrolidin-2-one or /? -butyl alcohol
  • Compounds Ibu can be prepared by coupling of 4-chloroquinolines libi with N-(3-amino- oxetan-3-ylmethyl)-trifluoro-acetamide.
  • the reaction can be carried out in the presence of a palladium catalvst such as [l,l'-bis(diphenylphosphino)ferrocene] dichloropalladium(II), (triphenylphosphine)dichloropalladium(II), palladium(II) acetate, or
  • tri(dibenzylideneacetone)dipalladium(0) in combination of a phosphine ligand such as bis(diphenylphosphino)ferrocene, tricyclohexylphosphine, or 9,9-dimethyl-4,5- bis(diphenylphosphino)xanthene, with a suitable base such as sodium tert-butoxide, in a suitable inert organic solvent such as 1,4-dioxane, or N,N-dimethylformamide, at 100-150 °C for 1-3 hours under microwave irradiation.
  • the reactions can be carried out at an elevated temperature such as 100-140 °C for a longer reaction time without microwave irradiation.
  • Compounds Ibv can be prepared by standard trifluoro acetyl deprotection of Ibu.
  • the reaction can be carried out with potassium carbonate, in a suitable solvent such as the mixture of methanol and water, at room temperature for several hours.
  • Compounds Ibw can be prepared by trifluoro acetyl deprotection and hydrolysis of Ibu. The reaction is typically carried out with ammonia solution in methanol for several hours at room temperature.
  • Amides Ilbm can be prepared by copper-mediated coupling reaction of Ilab with 5-oxo- pyrrolidine-3-carboxylic acid amide.
  • the reaction can be carried out in the presence of a copper source such as copper(I) iodide and a ligand such as 2,2'-bipyridine, Z-proline, N,N-dimethyl n j rin p rt v] p n p ⁇ ⁇ ] r trans-N,N'-dimethylcyclohexane- 1 ,2-diamine, with a suitable base such as triethylamine, sodium carbonate, potassium carbonate, cesium carbonate, sodium tert- butoxide, potassium tert-butoxide, sodium hydride or l,8-diazabicyclo[5.4.0]undec-7-ene.
  • a copper source such as copper(I) iodide and a ligand such as 2,2'-bipyridine
  • the reaction can be carried out in a suitable organic solvent such as diethylene glycol dimethyl ether, toluene, 1,4-dioxane, N,N-dimethylformamide, dimethyl sulfoxide or l-methyl-pyrrolidin-2-one at a temperature between 100 °C and 180 °C for several hours under microwave irradiation.
  • a suitable organic solvent such as diethylene glycol dimethyl ether, toluene, 1,4-dioxane, N,N-dimethylformamide, dimethyl sulfoxide or l-methyl-pyrrolidin-2-one
  • the reactions can be carried out at a temperature such as 130 °C for a longer reaction time without microwave irradiation.
  • Aminopyrrolidines Ibx can be prepared by rearrangement of amides Ilbm.
  • the reaction can be typically carried out in the presence of (diacetoxyiodo)benzene in a mixture of acetonitrile and water for several hours at room temperature.
  • Acids Ilbn can be prepared by coupling of halogens Ilab with pyrrolidine-3-carboxylic acid methyl ester.
  • the reaction can be carried out with a suitable base such as
  • Ilbo can be prepared by chlorination of Ilbn.
  • the reaction can be carried out with such as oxalyl dichloride in the presence of N,N-dimethylformamide, in a suitable solvent such as dichloromethane at 0 °C to room temperature for 16 hours.
  • Sulfides Ilbp can be prepared from coupling of 2-benzoazapin-4-chloroquino lines Ilbi with 2-methylsulfanyl-ethylamine.
  • the reaction can be carried out in the presence of a palladium catalyst in analogy to coupling of 4-halogen quino lines Ilab with various amines XI in Scheme 5.
  • the reaction can be carried out in the presence of
  • Sulfoxides Ibz can be prepared by oxidation of sulfides Ilbp.
  • the reaction preferably can be carried out with a standard oxidant agent such as hydrogen peroxide in a suitable organic solvent such as acetic acid at room temperature for several hours.
  • Compounds of interest lea can be prepared by metal-catalyzed imination of sulfoxides followed by hydrolysis.
  • Imination of sulfoxides can be carried out by treating sulfoxides with rhodium (II) acetate and trifluoroacetamide or sulfonylamides in combination with iodobenzene diacetate and magnesium oxide in dichloromethane at room temperature overnight, preferably trifiuoroacetamide was used.
  • Hydrolysis can be carried out in the presence of a suitable base, such as potassium carbonate, sodium hydroxide or potassium hydroxide in methanol under reflux for 30 minutes to several hours.
  • Compounds of interest Ice can be prepared by oxidation of sulfides Icb.
  • the reaction can be carried out in analogy to oxidation of quino lines Ilac in Scheme 4.
  • the reaction can be carried out by treating sufides with potassium permanganate in acetic acid at room
  • Sulfoximines can be prepared from imination of sulfoxides Ilbq followed by hydrolysis.
  • Imination of sulfoxides can be carried out by treating sulfoxides with rhodium (II) acetate and trifluoroacetamide or sulfonylamides in combination with iodobenzene diacetate and magnesium oxide in dichloromethane at room temperature overnight, preferably trifluoroacetamide was used.
  • Hydrolysis can be carried out in the presence of a suitable base, such as potassium carbonate, sodium hydroxide, potassium hydroxide or sodium methoxide in methanol under reflux for 30 minutes to several hours.
  • Compounds of interest led can be prepared by coupling of Ilbr with 1,2- ethylenediamine.
  • the reaction can be carried out in analogy to coupling of 4-halogen quino lines Ilac with various amines XI in Scheme 5.
  • the reaction can be carried out with or without an organic solvent such as N,N-dimethylformamide, l-methylpyrrolidin-2-one or n-butyl alcohol at a temperature between 140 °C and 160 °C under microwave irradiation for 1 to 3 hours.
  • Compounds of interest Ice can be prepared according to Scheme 36. Oxidation of sulfides libs followed by coupling of Ilbt with propane- 1,3-diamine affords compounds of interest Ice. Sulfoxides Ilbt can be prepared by oxidation of sulfides libs. The reaction can be carried out with a suitable oxidation reagent such as m-chloroperbenzoic acid in a suitable solvent such as dichloromethane at 0 °C for 20 minutes.
  • a suitable oxidation reagent such as m-chloroperbenzoic acid in a suitable solvent such as dichloromethane at 0 °C for 20 minutes.
  • Compounds of interest Ice can be prepared by coupling of Ilbt with propane-1,3- diamine.
  • the reaction can be carried out in analogy to coupling of 4-halogen quino lines Ilac with various amines XI in Scheme 5.
  • the reaction can be carried out by treating a mixture of Ilbt and propane- 1,3-diamine without any base and without any solvent at 150 °C for 1 hour under microwave irradiation.
  • the reaction can be carried out in a solution of ammonia in a suitable solvent such as methanol, tetrahydroiuran or mixture thereof in a sealed tube at a temperature between 100 °C and 150 °C for several hours, typically at 120 °C for 16 hours.
  • Sulfones Ilbz can be prepared by oxidation of sulfides Ilby.
  • the reaction can be carried out in analogy to oxidation of quino lines Ilac in Scheme 4.
  • the reaction can be carried out with m-chloroperbenzoic acid in dichloromethane at 0 °C for 2 hours.
  • Compounds of interest leg can be prepared by coupling of Ilbz with propane-1,3- diamine.
  • the reaction can be carried out in analogy to coupling of 4-halogen- quino lines Ilac with various amines XI in Scheme 5.
  • the reaction can be carried out by treating a mixture of Ilbz and propane- 1,3-diamine without any base and without any solvent at 120 °C for 1 hour under microwave irradiation.
  • Sulfones Ilbv can be prepared by oxidation of sulfides Ilbu.
  • the reaction can be carried out in analogy to oxidation of quino lines Ilac in Scheme 4.
  • the reaction can be carried out with m-chloroperbenzoic acid in dichloromethane at 0 °C for 1 hour.
  • Aldehydes Ilbw can be prepared by reduction of carboxylic acid esters Ilbv followed by Swern oxidation. Reduction can be carried out with a standard reducing agent such as sodium boronhydride in a suitable solvent such as tetrahydroiuran, under reflux for several hours to several days, typically 60 hours. Swern oxidation can be carried out with oxalyl dichloride and dimethyl sulfoxide in the presence of triethylamine in a suitable solvent such as dichloromethane at -78 °C, then at room temperature for 1 to several hours.
  • a standard reducing agent such as sodium boronhydride in a suitable solvent such as tetrahydroiuran
  • Swern oxidation can be carried out with oxalyl dichloride and dimethyl sulfoxide in the presence of triethylamine in a suitable solvent such as dichloromethane at -78 °C, then at room temperature for 1 to several hours.
  • 6-(l -Hydro xyethyl)quino lines Ilbx can be prepared by methylation of Ilbw.
  • the reaction can be carried out with a methylation reagent such as methyl magnesium bromide in
  • Compounds of interest leg can be prepared by coupling of Ilbw with propane-1,3- diamine.
  • the reaction can be carried out in analogy to coupling of 4-halogen quino lines Ilac with various amines XI in Scheme 5.
  • the reaction can be carried out without any metal catalyst and without any solvent at 150 °C for 1.5 hours under microwave irradiation.
  • Ici Compounds of interest Ici can be prepared according to Scheme 38. Standard coupling of Ilbi with 3-amino-propionitrile generates Ich, cyclization of nitriles with sodium azide affords tetrazoles Ici.
  • Nitriles Ich can be prepared by coupling reaction of chlorides Ilbi with 3-amino- propionitrile. The reaction can be carried out in analogy to coupling of 4-halogen quino lines Ilac with various amines XI in Scheme 5.
  • the reaction can be carried out by heating with tri(dibenzylideneacetone)dipalladium(0), 2,2'-bis(diphenylphosphino)- 1 , 1 '-binaphthyl, and sodium tert-butoxide in toluene at 110 °C overnight.
  • Tetrazoles Ici can be prepared by cyclization of nitriles Ich with sodium azide.
  • the reaction can be typically carried out in the presence of sodium azide and ammonium chloride in N,N-dimethylformamide at a temperature between 60 °C and 100 °C, typically at 80 °C for several hours.
  • phosphine ligand such as 2,2'- bis(diphenylphosphino)- 1 , 1 '-binaphthyl, bis(diphenylphosphino)ferrocene,
  • Ilea can be obtained by coupling of 2,4-dichloroquinazo lines Mb with C-(2,2-dimethyl- [l,3]dioxolan-4-yl)-methylamine.
  • the reaction can be carried out with a base such as
  • Ilcb can be prepared by coupling of 2-chloro-4-amino quinazo lines Ilea with 6,7,8,9-tetrahydro-5-thia-8-aza-benzocycloheptene 5,5-dioxides IVd.
  • the reaction can be carried out in the presence of a base such as triethylamine in N,N-dimethylformamide at a temperature between 120 °C and 180 °C, typically at 160 °C for several hours.
  • 4-(2,3-Diol-propylamino)-quinazolines Icm can be prepared by deprotection of Ilcb.
  • the reaction can be carried out in the presence of an acid such as hydrochloric acid in a suitable solvent such as methanol, ethanol, water or mixtures thereof at room temperature for several hours.
  • n 1 or 2
  • Ilcd can be prepared by oxidation of thio group of compounds IIcc.
  • the reaction can be carried out with a suitable oxidant such as oxone, meto-chloroperoxybenzoic acid, hydrogen peroxide, sodium periodate or potassium permanganate, in a suitable solvent such as methanol, dichloromethane, acetic acid, water or the mixtures thereof, typically at 0 °C, followed by stirring at room temperature for several hours.
  • Amines Icn and Ico can be prepared by cleavage of tert-butoxycarbonyl of IIcc and lied respectively.
  • the reaction can be typically carried out with trifluoro acetic acid in
  • Ilcf and Ilcg can be prepared from coupling reaction of Ilbg with 3-( tert-butoxycarbonyl- amino)pyrrolidine and tra/75-3-amino-4-fluoro-pyrrolidine-l-carboxylic acid benzyl ester separately.
  • the reaction can be carried out in the presence of benzotriazol-l-yloxytris
  • the reaction can be carried out by treating tert-butyl carbamates Ilcf with a suitable acid such as hydrochloric acid, trifluoro acetic acid, or sulfuric acid in a suitable solvent such as methanol, ethyl acetate, dichloromethane, 1,4-dioxane, water or the mixtures thereof at a temperature between 0 °C and room temperature for 30 minutes to several hours.
  • a suitable acid such as hydrochloric acid, trifluoro acetic acid, or sulfuric acid
  • a suitable solvent such as methanol, ethyl acetate, dichloromethane, 1,4-dioxane, water or the mixtures thereof
  • a suitable solvent such as methanol, ethyl acetate, dichloromethane, 1,4-dioxane, water or the mixtures thereof
  • a suitable solvent such as methanol, ethyl acetate, dichloromethane, 1,4-di
  • Compounds of interest Icr can be prepared by cleavage of benzyl carbomates Ilcg.
  • the conversion can be achieved by hydro geno lysis or under strong acidic conditions.
  • Hydro geno lysis of Ilcg can be carried out in the presence of palladium on carbon or palladium black, under hydrogen atmosphere or with a hydrogen donor such as formic acid or ammonium formate, in a suitable solvent such as methanol or ethanol, at a temperature between room temperature and 80 °C for 15 minutes to several hours.
  • the conversion can also be achieved by treating Ilcg under strong acidic conditions such as reflux in 6 N hydrochloride in methanol for several hours.
  • Vinyl quino lines Ilch can be prepared by coupling of 4-chloro-quinolines Ilbi with (R)- 2,2-dimethyl-4-vinyl-oxazolidine-3-carboxylic acid tert-butyl ester.
  • the reaction can be typically conducted in deoxygenated N,N-dimethylformamide with triethylamine, bis(tri-tert- butylphosphine)palladium(0), at a temperature between 100 °C and 160 °C for several hours under microwave irradiation.
  • the reactions can be carried out at an elevated temperature such as between 100 and 140 °C for a longer reaction time without microwave irradiation.
  • Amino alcohols Ilci can be prepared from vinyl quino lines Ilch by hydrogenolysis and deprotection of tert-butyloxycarbonyl and acetal.
  • the hydrogenolysis can be carried out in the presence of 10% palladium on carbon under an atmospheric pressure of hydrogen, in an organic solvent such as ethyl acetate, methanol, or ethanol, typically at room temperature for several hours.
  • Deprotection of acetonides is typically carried out in a solution of hydrochloric acid in ethyl acetate for several hours at room temperature.
  • Compounds Ics can be prepared from amino alcohols Ilci by ring closure with cyanogen bromide.
  • the reaction can be carried out with a suitable base such as sodium acetate, sodium carbonate, potassium acetate or potassium carbonate, in a suitable solvent such as methanol, water, or the mixtures thereof, typically at 0 °C, followed by stirring at room temperature for several hours.
  • n 0 or 1
  • Alkenes Ilcj and lick can be prepared by Heck coupling of 4-chloro-quino lines Ilbi with ethyl acrylate and acrylonitrile separately.
  • the reaction can be typically conducted in the presence of bis(tri-tert-butylphosphine)palladium(0) with triethylamine in deoxygenated N,N- dimethylformamide, at a temperature between 100 °C and 160 °C for 30 minutes to several hours under microwave irradiation.
  • the reactions can be carried out at an elevated temperature such as between 100 °C and 140 °C for a longer reaction time without microwave irradiation.
  • Amides Icu can be prepared by hydrogenation of alkenes lick followed by hydrolysis of nitriles. Hydrogenation reaction can be carried out in the presence of palladium on carbon under hydrogen atmosphere in methanol at room temperature for several hours. Hydrolysis can be achieved by treating nitriles with a base such as potassium hydroxide in tert-butanol under reflux for several hours.
  • a base such as potassium hydroxide in tert-butanol under reflux for several hours.
  • amides Icu can be prepared by amino lysis of esters Ilcj.
  • the reaction can be typically conducted in an ammonia solution in tetrahydrofuran at a temperature between 25 °C to 70 °C for several hours.
  • Amines lev can be prepared by reduction of amides Icu.
  • the reaction can be achieved by treating amides Icu with borane in tetrahydrofuran at an elevated temperature such as 65 °C for several hours.
  • General synthetic route for formula lew and lex (Scheme 47)
  • E is Br or cl
  • n 1 or 2
  • Ethers IIcl and Ilcm can be prepared by coupling of 4-halogen quino lines Ilab with N- (2-hydroxyethyl)acetamide and XXII separately.
  • the reaction can be carried out with a palladium catalyst such as l, -bis(diphenylphosphino)ferrocene-palladium(II)dichloride in combination with l,l'-bis(diphenylphosphino)ferrocene and sodium tert-butoxide in a suitable organic solvent such as 1,4-dioxane in a sealed microwave process vial at an elevated temperature such as 130 °C under microwave irradiation for 1 to several hours.
  • 2-Aminoethyl ethers lew can be prepared by deacylation of IIcl.
  • the reaction can be carried out in an aqueous solution of hydrochloric acid at an elevated temperature such as 80 °C for several hours.
  • Compounds of interest lex can be prepared by cleavage of tert- butyloxycarbonyl.
  • the reaction can be carried out with trifluoro acetic acid in dichloromethane or hydrochloride in ethyl acetate at room temperature for several hours.
  • Ilcn can be prepared from regioselective nucleophiUic replacement with diethyl malonate.
  • the reaction can be carried out in the presence of a suitable base such as sodium hydride or potassium carbonate, in an organic solvent such as N,N-dimethylformamide, at an elevated temperature, typically at 70 °C for several hours to overnight.
  • a suitable base such as sodium hydride or potassium carbonate
  • organic solvent such as N,N-dimethylformamide
  • Carboxylic acids IIco can be prepared from hydrolysis of lien.
  • the reaction can be carried out with a suitable base such as lithium hydroxide or sodium hydroxide in a suitable mixed solvent such as tetrahydrofuran and water or methanol and water, at room temperature for several hours.
  • a suitable base such as lithium hydroxide or sodium hydroxide
  • a suitable mixed solvent such as tetrahydrofuran and water or methanol and water
  • IIcp can be obtained by coupling of 2-chloroquino lines IIco with benzodiazepines and decarboxylation in a tandem reaction.
  • the reaction preferably can be carried out with or without an organic solvent such as n-butanol under microwave irradiation at a temperature between 150 °C and 170 °C for several hours.
  • Ilcr can be obtained by reaction of 4-bromoquinolines Ilcq with a lithium alkylide followed by reaction with l-tert-butoxycarbonyl-4-piperidinecarboxaldehyde.
  • the conversion can be achieved by treating 4-bromo-quino lines Ilcq with n-butyllithium and l-tert- butoxycarbonyl-4-piperidinecarboxaldcehyde in an inert organic solvent such as tetrahydrofuran at -78 °C, then at room temperature overnight.
  • Compounds of interest Icz can be obtained by Dess-Martin oxidation of Ilcr followed by cleavage of tert-butyl carbamates. Oxidation of Ilcr can be carried out with a suitable oxidant such as Dess-martin reagent in dichloromethane at room temperature overnight, or with manganese dioxide in toluene under reflux for several hours.
  • a suitable oxidant such as Dess-martin reagent in dichloromethane at room temperature overnight, or with manganese dioxide in toluene under reflux for several hours.
  • Cleavage of tert-butyl carbamates can be achieved by treating tert-butyl carbamates lies with a suitable acid such as hydrochloric acid, trifluoro acetic acid, or sulfuric acid in a suitable solvent such as methanol, ethyl acetate, dichloromethane, 1,4-dioxane, water or the mixture thereof at a temperature between 0 °C and room temperature for 30 minutes to several hours.
  • a suitable acid such as hydrochloric acid, trifluoro acetic acid, or sulfuric acid in a suitable solvent such as methanol, ethyl acetate, dichloromethane, 1,4-dioxane, water or the mixture thereof at a temperature between 0 °C and room temperature for 30 minutes to several hours.
  • a suitable acid such as hydrochloric acid, trifluoro acetic acid, or sulfuric acid
  • a suitable solvent such as methanol, ethyl acetate,
  • Compounds of interest of formula IIcu can be prepared by coupling of chlorides Ilbi with benzenethiol.
  • the reaction can be carried out with a suitable base such as N,N- dimethylpyridin-4-amine in a suitable solvent such as ethanol at room temperature for several days.
  • Sulfones Idb can be prepared by oxidation of IIcu.
  • the reaction can be carried out with a suitable oxidation reagent such as m-chloroperbenzoic acid in a suitable solvent such as dichloromethane at a temperature between 0 °C and room temperature for 1 to several hours.
  • Thiols IIcv can be prepared by coupling of chlorides Ilbi with sodium methanethiolate.
  • the reaction can be carried out in a suitable solvent such as N,N-dimethylformamide under reflux overnight.
  • Sulfonyl chlorides II cw can be prepared by oxidation-chlorination of IIcv.
  • the reaction can be carried out in a suitable solvent such as hydrochloric acid by bubbling of chlorine at a temperature between 0 °C and 10 °C for 30 minutes.
  • Compounds of interest Idc can be prepared by coupling of chlorides IIcw with ethyl- 1,2- diamine.
  • the reaction can be carried out with a suitable base such as triethylamine or ethyl- diisopropyl- amine in a suitable solvent such as dichloromethane at a temperature between 0 °C and room temperature overnight.
  • the reaction can be carried out with tris(dibenzylideneacetone)dipalladium(0), 2,2'-bis(diphenylphosphino)-l, -binaphthyl and sodium tert-butoxide in toluene at 110 °C overnight under nitrogen atmosphere.
  • Acids Ide can be prepared from hydrolysis of methyl esters Idd.
  • the reaction can be carried out with a suitable base such as sodium hydroxide or lithium hydroxide in a mixture solvent of tetrahydrofuran and water at a temperature between room temperature and 60 °C, typically at room temperature for several hours or overnight.
  • Hydroxides Ilex can be prepared by reduction of esters Ilbv.
  • the reaction can be carried out with a standard reduction agent such as lithium aluminium hydride in a suitable solvent such as tetrahydrofuran, at a temperature between 0 °C and room temperature for several hours, typically at room temperature for 2 hours.
  • a standard reduction agent such as lithium aluminium hydride in a suitable solvent such as tetrahydrofuran
  • Compounds Idf can be prepared by coupling of Ilex with C-(3 -amino methyl-oxetan-3- yl)-methylamine.
  • the reaction can be carried out in analogy to coupling of Ilbv with C-(3- aminomethyl-oxetan-3-yl)-methylamine in this scheme.
  • benzothiazepines IVf affords benzyloxy compounds IIcz. Substitution of bromo with methyl- ⁇ i 3 followed by oxidation affords 6-methyl- ⁇ i 3 -quinazolines Ildb. Coupling of Ildb with C-(3- aminomethyl-oxetan-3-yl)-methylamine affords compounds of interest Idg.
  • 2-Chloro-4-benzoxy quinazo lines Ilcy can be prepared by reaction of 2,4-dichloro- quinazo lines Hid with benzyl alcohol. The reaction can be carried out in the presence of a suitable base such as sodium hydride in an organic solvent such as tetrahydrofuran, acetonitrile or N,N-dimethylformamide at 0 °C followed by at room temperature for several hours.
  • a suitable base such as sodium hydride
  • organic solvent such as tetrahydrofuran, acetonitrile or N,N-dimethylformamide
  • IIcz can be prepared by coupling of Ilcy with benzothiazepines IVf.
  • the reaction can be carried out without any base and without any solvent at a temperature between 80 °C and 160 °C, typically at 80 °C for 10 minutes to 2 hours.
  • 6-Methyl- ⁇ i 3 -quinazo lines Ilda can be prepared by substitution of bromo with methyl- ⁇ i 3 .
  • the reaction can be carried out by treating Ilcy with n-butyllithium in anhydrous tetrahydrofuran at -78 °C for several minutes under nitrogen followed by stirring with methyl- ⁇ i 3 trifluoromethanesulfonate at -78 °C and then at room temperature for 1 to several hours.
  • Sulfoxides Ildb can be prepared by oxidation of Ilda.
  • the reaction can be carried out by treating Ilda with 1-2 equivalents of 3-chloroperoxybenzoic acid in a suitable organic solvent such as dichloromethane, chloroform, 1,2-dichloroethane or the mixtures thereof, typically at 0 °C, followed by stirring at room temperature for 10 to 20 minutes.
  • a suitable organic solvent such as dichloromethane, chloroform, 1,2-dichloroethane or the mixtures thereof, typically at 0 °C
  • Compounds Ildd can be prepared by oxidation of Ildc. Oxidation can be carried out by treating Ildc with 1-2 equivalent(s) of 3-chloroperoxybenzoic acid in a suitable organic solvent such as dichloromethane, chloroform, 1,2-dichloroethane or mixtures thereof, typically at 0 °C, followed by stirring at room temperature for 10 minutes to several hours. Acids Ilde can be prepared by hydrolysis of methyl esters Ildd. The reaction can be carried out with a suitable base such as sodium hydroxide or lithium hydroxide in a mixture of tetrahydrofuran and water at a temperature between room temperature and 60 °C, typically at room temperature for several hours or overnight.
  • a suitable base such as sodium hydroxide or lithium hydroxide in a mixture of tetrahydrofuran and water at a temperature between room temperature and 60 °C, typically at room temperature for several hours or overnight.
  • Compounds of interest Idh can be prepared by couplin, g of Ilde with C-(3- aminomethyl-oxetan-3-yl)-methylamine. The reaction can be carried out without any solvent and without any base at 170 °C for 30 minutes.
  • Aldehydes Ildf can be prepared by Bouveault formylation. The reaction can be carried out by treating bromide with n-butyllithium in anhydrous tetrahydrofuran at -78 °C followed by stirring with anhydrous N,N-dimethylformamide at -78 °C for 30 minutes to several hours .
  • 6-Hydroxymethyl-quinazo lines Ildg can be prepared by reduction of aldehydes.
  • the reaction can be carried out with sodium boro hydride in a suitable organic solvent such as methanol, tetrahydrofuran or the mixture thereof at 0 °C for 15 minutes to several hours.
  • Ildh can be prepared by oxidation of sulfides. Oxidation can be carried out with 1-2 equivalents of 3-chloroperoxybenzoic acid in a suitable organic solvent such as dichloromethane, chloroform, 1,2-dichloroethane or mixtures thereof, typically at 0 °C, followed by stirring at
  • Compounds of interest Idi can be prepared by coupling Ildh with C-(3 -amino methyl- oxetan-3-yl)-methylamine. The reaction can be carried out without any solvent and without any base at 160 °C for 30 minutes.
  • Compounds of interest Idj can be prepared by coupling of Ildi with various amines.
  • the reaction can be carried out in analogy to coupling of 4-halogen-quino lines Ilab with various amines XI in Scheme 5.
  • the reaction can be carried out in the presence of ⁇ , ⁇ - bis(diphenylphosphino)ferrocene, 1 , 1 '-bis(diphenylphosphino)ferrocene-palladium(II)dichloride and sodium tert-butoxide in 1,4-dioxane at 120 °C for 1.5 hours under microwave irradiation.
  • 2-Benzoazepin-quino lines Ildj can be prepared by coupling of IIIc with 1,2,3,4- tetrahydro-benzo[c]azepin-5-one. The reaction can be carried out in the presence of an organic base such as triethylamine in toluene under reflux overnight.
  • 5 -Methyl-5 -hydroxy benzothiazepines Ildk can be prepared by reaction of ketones Ildj with methyl magnesium bromide. The conversion can be achieved by stirring of Ildj with methyl magnesium bromide in tetrahydrofuran at 50 °C for several hours.
  • Compounds of interest Idk can be prepared by coupling of Ildj with 3-aminomethyl- oxetan-3-ylamine.
  • the reaction can be carried out in the presence of a suitable base such as 1,8- diazabicyclo[5.4.0]undec-7-ene with a suitable phosphine ligand such as benzotriazol-1- yloxytris(dimethylamino)-phosphonium hexafluorophosphate, in a suitable solvent such as N,N- dimethylformamide at room temperature for several hours.
  • a suitable base such as 1,8- diazabicyclo[5.4.0]undec-7-ene
  • a suitable phosphine ligand such as benzotriazol-1- yloxytris(dimethylamino)-phosphonium hexafluorophosphate
  • 2-Chloro-quinazo lines Ildl can be prepared by coupling of Illb with various amines XXIII.
  • the reaction can be carried out in the presence of a suitable base such as triethylamine in a suitable solvent such as methanol, tetrahydroiuran, dichloromethane or mixtures thereof at a temperature between 0 °C and room temperature for several hours or overnight.
  • a suitable base such as triethylamine
  • a suitable solvent such as methanol, tetrahydroiuran, dichloromethane or mixtures thereof
  • Compounds Idl can be prepared by standard benzyl deprotection of Ildm.
  • the reaction can be carried out with palladium on carbon, palladium hydroxide on carbon or platinum oxide, typically with addition of acetic acid or trifluoro acetic acid in a suitable solvent such as methanol, ethanol, tetrahydroiuran, ethyl acetate or the mixture thereof, at room temperature for several hours under hydrogen atmosphere.
  • E is chloro or bromo
  • Benzoazepin-3-ones IVj can be prepared from ring expansion of naphthalen-2-ones XXIV by using sodium azide.
  • the reaction can be carried out in toluene with a suitable acid such as trifluoromethanesulfonic acid, trifluoro acetic acid or hydrochloric acid, typically at 0 °C, followed by stirring at room temperature for several hours.
  • Benzoazepines IVk can be prepared from benzoazepin-3-ones IVj by reduction of lactams.
  • the reaction can be carried out with standard reducing agent such as lithium aluminium hydride, boron hydride or combination of sodium borohydride and boron trifluoride in a suitable inert organic solvent such as tetrahydrofuran, diethyl ether or mixtures thereof, typically at 0 °C, followed by stirring at a temperature between 25 °C and 70 °C for several hours.
  • 4-Halogen quinolines Ildn can be prepared from coupling of benzoazepines IVk and 2,4- dihalogen quinolines Ilia.
  • the reaction can be carried out with a suitable acid such as
  • luenesulfonic acid in a suitable organic solvent such as toluene, dioxane, /? -butyl alcohol or 2-methyl-2-pentanol at a temperature between 100 °C and 120 °C for several hours.
  • a suitable organic solvent such as toluene, dioxane, /? -butyl alcohol or 2-methyl-2-pentanol
  • the reaction can be carried out without acid at a temperature between 100 °C and 160 °C for 1 to 3 hours under microwave irradiation.
  • Compounds of interest Idm can be prepared by coupling of 4-halogen quino lines Ildn with various amines XI.
  • the reaction can be achieved by microwave irradiation at a temperature between 140 °C and 160 °C for 1 to 3 hours with or without organic solvent such as N,N- dimethylformamide, l-methylpyrrolidin-2-one or /? -butyl alcohol.
  • Acetyl benzoazepines IVm can be prepared by acylation of benzoazepines IVk with acetyl chloride or acetic anhydride.
  • the reaction can be carried out with a suitable base such as triethylamine or pyridine in a suitable inert organic solvent such as dichloromethane,
  • Imines lido can be prepared by heating a mixture of IVm, 2-aminobenzonitriles XVIII and phosphorous oxychloride.
  • the reaction can be carried out in a suitable inert organic solvent such as dichloromethane, chloroform or the mixtures thereof, typically at a temperature between 0 °C and 10 °C, followed by stirring under reflux for 24 hours.
  • Ring closure of imines lido to give 4-aminoquino lines Ildp can be achieved by treatment of lido with Lewis acid such as zinc chloride in N,N-dimethyl-acetamide at a temperature between 120 °C and 180 °C for several hours in an inert atmosphere.
  • Lewis acid such as zinc chloride in N,N-dimethyl-acetamide at a temperature between 120 °C and 180 °C for several hours in an inert atmosphere.
  • Intermediates Ildq can be prepared from 4-aminoquino lines Ildp by using Sandmeyer reaction.
  • the conversion is typically conducted in standard Sandmeyer reaction conditions such as sodium nitrite, hydrochloric acid and sodium chloride or copper(I) chloride in a suitable solvent such as water, typically at -10 °C, followed by stirring at room temperature for several hours.
  • Compounds of interest Idm can be prepared by coupling of Ildq with various amines XI.
  • the reaction can be achieved by microwave irradiation at a temperature between 140 °C and 160 °C for 1-3 hours with or without organic solvent such as N,N-dimethylformamide, 1-methyl- pyrrolidin-2-one or n-butyl alcohol.
  • L 20 is C, .6 alkyl
  • E is chloro or bromo.
  • the copper-mediated coupling reaction of 7-bromo-2,3,4,5-tetrahydro-lH-benzo[c]azepine IVn with sodium sulfmates XXV illustrated above can be carried out in the presence of a copper source such as copper(I) iodide (Cul), and a ligand such as 2,2'-bipyridine, Z-proline, N,N- dimethyl glycine or ethylene glycol, with a suitable base such as triethylamine, sodium carbonate, potassium carbonate, cesium carbonate, sodium tert-butoxide, potassium tert- butoxide, sodium hydride or l,8-diazabicyclo[5.4.0]undec-7-ene.
  • a copper source such as copper(I) iodide (Cul)
  • a ligand such as 2,2'-bipyridine, Z-proline, N,N- dimethyl glycine or ethylene glycol
  • a suitable base
  • the reaction can be carried out in a suitable organic solvent such as acetonitrile, toluene, 1,4-dioxane, N,N-dimethylformamide, dimethyl sulfoxide or l-methyl-pyrrolidin-2-one at a temperature between 100 °C and 180 °C for 15 to 60 minutes under microwave irradiation.
  • a suitable organic solvent such as acetonitrile, toluene, 1,4-dioxane, N,N-dimethylformamide, dimethyl sulfoxide or l-methyl-pyrrolidin-2-one
  • the reactions can be carried out at a temperature such as 130 °C for a longer reaction time without the use of microwave irradiation.
  • Compounds Ildr can be prepared from coupling of benzoazepine IVo and 2,4-dihalogen quinolines Ilia.
  • the reaction can be carried out with a suitable acid such as hydrochloric acid or /?-toluenesulfonic acid in a suitable organic solvent such as toluene, dioxane, n-butyl alcohol or TMschreib * .. i *— 1 hail temperature between 100 °C and 120 °C for several hours.
  • the reaction can be carried out without acid at a temperature between 100 °C and 160 °C for 1-3 hours under microwave irradiation.
  • Compounds of interest Idn can be prepared by coupling of Ildr with various amines XI.
  • the reaction can be achieved by microwave irradiation at 140-160 °C for 1-3 hours with or without organic solvent such as N,N-dimethylformamide, l-methyl-pyrrolidin-2-one or n-butyl alcohol.
  • Compounds Ildt can be prepared by alkylation of phenols lids with XXVI.
  • the reaction can be carried out with a suitable base such as cesium carbonate, sodium tert-butoxide, potassium tert-butoxide, sodium hydride or l,8-diazabicyclo[5.4.0]undec-7-ene in an inert organic solvent such as dichloromethane, N,N-dimethylformamide, dimethyl sulfoxide or 1- methyl-pyrrolidin-2-one, typically at room temperature for several hours.
  • a suitable base such as cesium carbonate, sodium tert-butoxide, potassium tert-butoxide, sodium hydride or l,8-diazabicyclo[5.4.0]undec-7-ene
  • an inert organic solvent such as dichloromethane, N,N-dimethylformamide, dimethyl sulfoxide or 1- methyl-pyrrolidin-2-one
  • Compounds of interest Ido can be prepared by coupling of Ildt with various amines XI.
  • the reaction can be achieved by microwave irradiation at a temperature between 140 °C and 160 °C for 1 to 3 hours with or without organic solvent such as N,N-dimethylformamide, 1-methyl- pyrrolidin-2-one or n-butyl alcohol.
  • tetrakis(triphenylphosphine)palladium(0), or tri(dibenzylideneacetone)dipalladium(0) in the presence or absence of a phosphine ligand such as tricyclohexylphosphine or triphenylphosphine, and a suitable base such as triethylamine, sodium carbonate or potassium carbonate at a temperature between 60 °C and 120 °C for several hours.
  • a phosphine ligand such as tricyclohexylphosphine or triphenylphosphine
  • a suitable base such as triethylamine, sodium carbonate or potassium carbonate at a temperature between 60 °C and 120 °C for several hours.
  • Hydrolysis of the methyl esters Ildv to acids Ildw can be carried out in the presence of an aqueous inorganic base such as lithium hydroxide, sodium hydroxide, or potassium hydroxide in a solvent such as methanol, 1,4-dioxane or tetrahydrofuran at room temperature for several hours.
  • an aqueous inorganic base such as lithium hydroxide, sodium hydroxide, or potassium hydroxide
  • a solvent such as methanol, 1,4-dioxane or tetrahydrofuran
  • Amides Ildx can be prepared by coupling various amines XXVII with carboxylic acids Ildw.
  • the reaction is typically conducted with standard peptide coupling reagents such as 1- ethyl-3-(3-dimethylaminopropyl)carbodiimide and 1 -hydro xybenzotriazole, bromo-tm- pyrrolidino-phosphoniumhexafluorophosphate and diisopropylethylamine, or 0-(7- azabenzotriazol-l-y ⁇ -A .A .N'.N'-tetramethyluronium hexafluorophosphate and a base such as triethylamine, or diisopropylethylamine in a suitable inert solvent such as dichloromethane or N,N-dimethylformamide or mixtures thereof at room temperature for several hours.
  • suitable inert solvent such as dichloromethane or N,N-d
  • Compounds of interest Idp can be prepared by coupling of amides Ildx with various amines XI.
  • the reaction can be conducted by microwave irradiation at a temperature between 140 °C and 160 °C for 1 to 3 hours with or without organic solvent such as N,N- dimethylformamide, l-methyl-pyrrolidin-2-one or n-butyl alcohol.
  • the reaction can be carried out typically in the presence of a palladium catalyst such as bis(triphenylphosphine)dichloropalladium(II), palladium(II) acetate, tetrakis(triphenylphosphine)palladium(0), or tri(dibenzylideneacetone)dipalladium(0), in the presence of a phosphine ligand such as tricyclohexylphosphine, or 9,9-dimethyl-4,5- bis(diphenylphosphino)xanthene, with a suitable base such as potassium phosphate tribasic, sodium carbonate or potassium carbonate, in a suitable inert organic solvent such as dioxane, or N,N-dimethylformamide, at a temperature between 100 °C and 150 °C for several hours.
  • a palladium catalyst such as bis(triphenylphosphine)dichloropalladium(II), palladium(II)
  • Compounds of interest Idq can be prepared by coupling of Ildy with various amines XI.
  • the reaction can be achieved by microwave irradiation at a temperature between 140 °C and 160 °C for 1 to 3 hours with or without organic solvent such as N,N-dimethylformamide, 1-methyl- pyrrolidin-2-one or n-butyl alcohol.
  • Esters lldz can be prepared from benzoazepines IVk by coupling with 2-chloro-quinoline- 1 ester XXVIII.
  • the reaction can be carried out with a suitable acid such as hydrochloric acid or /?-toluenesulfonic acid in a suitable organic solvent such as toluene, dioxane, /? -butyl alcohol or 2-methyl-2-pentanol at a temperature between 100 °C and 120 °C for several hours.
  • the reaction can be carried out without acid at a temperature between 100 °C and 160 °C for 1 to 3 hours under microwave irradiation.
  • Alcohols Idt can be prepared from methyl esters Ildz by reduction.
  • the reaction is typically conducted in a tetrahydrofuran solution of borane at 0 °C, followed by stirring at reflux temperature for several hours.
  • the reactions can be carried out at a heated temperature such as a temperature between 100 °C and 140 °C for a longer reaction time without the use of microwave irradiation.
  • Compounds of interest Idu can be prepared from 4-allyl-quino lines Ilea by Upjohn dihydroxylation.
  • the reaction can be typically carried out in water with osmium tetroxide and N- methyl morpholine-N-oxide at room temperature for several hours.
  • Compounds of interest Idw can be prepared according to Scheme 68. Starting with diazepines IVq, coupling of 2,4-dihalogen quino lines Ilia with IVq furnishes Ileb. Subsequent coupling of Ileb with various amines XI generates compounds of interest Idw. Compounds Ileb can be prepared from coupling of 2,4-dihalogen quino lines Ilia with diazepines IVq.
  • the reaction can be carried out with a suitable acid such as hydrochloric acid or /?-toluenesulfonic acid in a suitable organic solvent such as toluene, dioxane, n-butyl alcohol or 2-methyl-2-pentanol at a temperature between 100 °C and 120 °C for several hours.
  • a suitable acid such as hydrochloric acid or /?-toluenesulfonic acid
  • a suitable organic solvent such as toluene, dioxane, n-butyl alcohol or 2-methyl-2-pentanol
  • reaction can be carried out without acid at a temperature between 100 °C and 160 °C for 1 to 3 hours under microwave irradiation.
  • Compounds of interest Idw can be prepared by coupling of compounds Ileb with various amines XI.
  • the reaction can be carried out typically in the presence of a palladium catalyst such as [ 1 , 1 '-bis(diphenylphosphino)ferrocene]dichloropalladium(II),
  • Intramolecular cyclization of compounds XXX gives benzooxazepin-3-ones IVr, which are in turn converted to benzooxazepines IVs by reduction. Coupling of IVs with 2,4-dihalogen quino lines Ilia furnishes Ilec. Subsequent coupling of Ilec with various amines XI affords compounds of interest Idx.
  • Esters XXX can be prepared from alkylation of hydroxybenzonitriles XXIX with methyl bromoacetate. The reaction is typically carried out in acetone with potassium carbonate at room temperature for several hours.
  • Benzooxazepin-3-ones IVr can be prepared from esters XXX by intramolecular cyclization. The reaction can be carried out in methanol with Raney nickel at room temperature for several hours under an atmospheric pressure of hydrogen.
  • Benzooxazepines IVs can be prepared from benzooxazepin-3-ones IVr by reduction of lactam. The reaction is typically conducted in an inert solvent such as tetrahydrofuran, diethyl ether or mixtures thereof with lithium aluminium hydride, typically at 0 °C, followed by stirring
  • quino lines Ilec can be prepared from coupling of benzooxazepines IVs with 2,4-dihalogen quino lines Ilia.
  • the reaction can be carried out with a suitable base such as potassium carbonate, cesium carbonate, diisopropylethylamine, triethylamine, or 1,8- diazabicyclo[5.4.0]undec-7-ene in an inert organic solvent such as toluene, tetrahydrofuran, 1- methyl-pyrrolidin-2-one or N,N-dimethylformamide, typically at a temperature between 100 °C and 180 °C for 1 to 3 hours under microwave irradiation.
  • a suitable base such as potassium carbonate, cesium carbonate, diisopropylethylamine, triethylamine, or 1,8- diazabicyclo[5.4.0]undec-7-ene
  • an inert organic solvent such as toluene, tetrahydrofuran,
  • Compounds of interest Idx can be prepared by coupling of substituted quino lines Ilec with various amines XI.
  • the reaction can be achieved by microwave irradiation at a temperature between 140 °C and 180 °C for 1 to 3 hours with or without organic solvent such as N,N- dimethylformamide, l-methyl-pyrrolidin-2-one or n-butyl alcohol.
  • the reaction can be carried out in the presence of a suitable base such as triethylamine in a suitable solvent such as methanol, tetrahydrofuran, dichloromethane or mixture thereof at a temperature between 0 °C to room temperature for several hours.
  • a suitable base such as triethylamine
  • a suitable solvent such as methanol, tetrahydrofuran, dichloromethane or mixture thereof
  • Compounds of interest of formula Idy can be prepared from deprotection of tert- butyloxycarbonyl of 4 - disubstituted quinozalines lief.
  • the reaction can be carried out with a suitable acid such as trifluoro acetic acid or hydrochloric acid in a suitable solvent such as dichloromethane, ethyl acetate or 1,4-dioxane, at 0 °C to room temperature for 30 minutes to 16 hours.
  • the invention also relates to a compound of formula (I) for use as therapeutically active substance.
  • the invention relates to a compound of formula (I) for use as a medicament.
  • the invention also relates to a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of formula (I) and a therapeutically inert carrier.
  • the invention relates in particular to the use of a compound of formula (I) for the preparation of a medicament for the treatment or prophylaxis of respiratory syncytial virus infection.
  • Said medicaments e.g. in the form of pharmaceutical preparations, can be administered orally, e.g. in the form of tablets, coated tablets, dragees, hard and soft gelatine capsules, solutions, emulsions or suspensions.
  • the administration can, however, also be effected rectally, e.g. in the form of suppositories, or parenterally, e.g. in the form of injection solutions with an effective amount of a compound as defined above.
  • the above-mentioned pharmaceutical composition can be obtained by processing the compounds according to this invention with pharmaceutically inert inorganic or organic carriers.
  • pharmaceutically inert inorganic or organic carriers for example, lactose, corn starch or derivatives thereof, talc, stearic acids or its salts and the like can be used, as such carriers for tablets, coated tablets, dragees and hard gelatine capsules.
  • Suitable carriers for soft gelatine capsules are, for example, vegetable oils, waxes, fats, semisolid and liquid polyols and the like. Depending on the nature of the active substance no carriers are, however, usually required in the case of soft gelatine capsules.
  • Suitable carriers for the production of solutions and syrups are, for example, water, polyols, glycerol, vegetable oil and the like.
  • Suitable carriers for suppositories are, for example, natural or hardened oils, waxes, fats, semi- liquid or liquid polyols and the like.
  • the pharmaceutical composition can, moreover, contain preservatives, solubilizers, stabilizers, wetting agents, emulsifiers, sweeteners, colorants, flavorants, salts for varying the osmotic pressure, buffers, masking agents or antioxidants. They can also contain still other therapeutically valuable substances.
  • the dosage depends on various factors such as manner of administration, species, age and/or individual state of health.
  • the doses to be administered daily are about 5-400 mg/kg, preferably about 10-100 mg/kg, and can be taken singly or distributed over several
  • a compound of formula (I) when manufactured according to the above process is also an object of the invention.
  • This invention relates to the use of a compound of formula (I) for the manufacture of a medicament for treatment or prophylaxis of RSV infection.
  • the invention further relates to a method for the treatment or prophylaxis of respiratory syncytial virus infection, which method comprises administering an effective amount of a compound of formula (I).
  • Acidic condition A: 0.1% formic acid in H 2 0; B: 0.1% formic acid in acetonitrile;
  • Mass spectra generally only ions which indicate the parent mass are reported, and unless otherwise stated the mass ion quoted is the positive mass ion (M+H) + .
  • the microwave assisted reactions were carried out in a Biotage Initiator Sixty.
  • Intermediate 1-2 can be prepared in analogy to Intermediate 1-1 by using 4- (methylsulfanyl)aniline. MS obsd. (ESI + ) [(M+H) + ] 244.
  • Intermediate 1-12 can be prepared in analogy to Intermediate 1-1 by using 4- (difluoromethoxy)aniline. MS obsd. (ESI + ) [(M+H) + ] 264.
  • Intermediate 1-15 can be prepared in analogy to Intermediate 1-1 by using 4-methylaniline, propanedioic acid and phosphoryl bromide.
  • Methyl 4-aminopyridine-3-carboxylate A mixture of compound 4-aminopyridine-3-carboxylic acid (100 g, 0.7 mol) and concentrated sulfuric acid (400 g, 4.0 mol) in absolute methanol (1.5 L) was stirred under reflux for 24 hours. The reaction mixture was concentrated in vacuo. The residue was diluted with ice-water (800 mL), basified with 2 N of aqueous solution of sodium hydroxide to about pH 10 and then extracted with ethyl acetate (300 mL x 3). The combined organic layers were washed with water (500 mL), dried over sodium sulfate and concentrated in vacuo to afford the crude product, which was used for next step without further purification.
  • Methyl 4-fluoro-2-sulfanylbenzoate A mixture of 4-fluoro-2-sulfanylbenzoic acid (6.0 g, 34.9 mmol), concentrated sulfuric acid (6 mL) in methanol (200 mL) was refluxed for 18 hours under argon atmosphere. The resulting mixture was concentrated in vacuo. The residue was diluted with ethyl acetate, washed with water, basified with a saturated aqueous solution of sodium bicarbonate to about pH 8.
  • Intermediate 2-2 can be prepared in analogy to intermediate 2-1 by using 8-methoxy-3,4- dihydro-l ,4-benzothiazepin-5(2H)-one (yield was 90%). MS obsd. (ESI + ) [(M+H) + ] 196.
  • Intermediate 2-4 can be prepared in analogy to intermediate 2-1 by using 5-fluoro-2- sulfanylbenzoic acid. MS obsd. (ESI + ) [(M+H) + ] 184.
  • Intermediate 2-5 can be prepared in analogy to intermediate 2-1 by using 3-fluoro-2- sulfanylbenzoic acid. MS obsd. (ESI + ) [(M+H) + ] 184.
  • Methyl 2-[(dimethylcarbamothioyl)oxy]-4-methylbenzoate (52.0 g, 205.5 mmol) in a round bottle flask which was vacuumed and backfilled with nitrogen, was heated at 210 °C for 4 hours. The mixture was then cooled to room temperature and used for next step without further purification.
  • the cold diazonium salt solution was added slowly to the above hot solution while evolution of gas was observed. After the addition the mixture was cooled to room temperature and acidified to about pH 3 with an aqueous solution of hydrochloric acid (4 N). The aqueous phase was decanted from the resulting semisolid and the sludge was dissolved in 10% aqueous sodium hydroxide (20 mL). The solution was heated for 2 hours at 100 °C followed by addition of sodium hydrosulfite (2 g). The resulting mixture was heated with stirring at 100 °C for an additional 10 minutes, then cooled to room temperature and filtered through a pad of celite. The filtrate was acidified to about pH 4 with concentrated hydrochloric acid.
  • the separated organic layer was washed with water and extracted with 5% aqueous solution of sodium hydroxide (300 mL).
  • the aqueous layer was acidified to about pH 3 with concentrated hydrochloric acid (12 N) and extracted with dichloromethane (300 mL x 3).
  • the combined organic layers were washed with brine, dried over anhydrous sodium sulfate, concentrated in vacuo to afford 6.47 g of the crude product l-(2-sulfanylphenyl)ethanone.
  • the acidic aqueous layer was washed with ethyl acetate (1500 mL x 2), then basified with a saturated aqueous solution of sodium bicarbonate to pH > 7, and extracted with ethyl acetate (1500 mL x 4).
  • the combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo to afford 151 g of 2,3,4, 5-tetrahydro-l ,4-benzothiazepine 1 , 1- dioxide (yield was 76%), MS obsd.
  • Intermediate 9-2 can be prepared in analogy to intermediate 9-1 by using oxetan-3-one. MS obsd. (ESI + ) [(M+H) + ] 283.

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Abstract

A compound of formula (I), as well as pharmaceutically acceptable salt thereof, wherein R1 to R10, A, Q, X and Y are as defined in description and in claims, can be used as a medicament for the treatment of respiratory syncytial virus.

Description

COMPOUNDS FOR THE TREATMENT AND PROPHYLAXIS OF
RESPIRATORY SYNCYTIAL VIRUS DISEASE
The invention relates to compounds which are respiratory syncytial virus (RSV) inhibitors and which are useful in the treatment or prophylaxis of RSV disease.
The invention relates in particular to (i) a compound of formula (I)
Figure imgf000003_0001
Wherein
R1 is hydrogen, halogen, or Ci_6alkyl;
R2 is hydrogen, halogen, or Ci_6alkyl;
R3 is hydrogen, halogen, or Ci_6alkyl;
R4 is hydrogen, or Ci_6alkyl; R5 is hydrogen, or halogen;
R6 is hydrogen, halogen, hydroxy, Ci_6alkoxy, carboxy, morpholinyl, or 4-C0- 6alkylpiperazin- 1 -yl;
R7 is hydrogen, halogen, Ci_6alkyl, Ci_6alkoxy, Ci_6alkylaminocarbonyl, diCi_6 alkylaminocarbonyl, Ci_6alkylsulfonyl, phenoxy, or hydroxy(CH2)2-6-0-; R8 is hydrogen, halogen, or Ci_6alkoxy;
R9 is hydrogen, Ci_6alkyl, or =0;
R10 is hydrogen, or =0, provided that R9 and R10 are not =0 simultaneously; A is nitrogen, or -C-R1 1, wherein R1 1 is hydrogen, halogen, Ci_6alkyl, cycloalkyl, Ci_ 6alkoxy, trifluoromethyl, trifluoromethoxy, pyridinyloxy, Ci_6alkoxy(CH2)i_6-0-,
difluoromethoxy, cyano, nitro, amino, vinyl, acetylenyl, amino carbonyl, hydroxy(CH2)2-6-0-, Ci_ 6alkylsulfinyl, Ci_6alkylsulfonyl, hydroxy(CH2)i_6, deuteratedCi_6alkyl, carboxyl, Ci_
6alkoxycarbonyl, hydroxy, difluoromethyl, -CH(hydroxy) Ci_6alkyl, or Ci_6alkylsulfanyl;
X is -CH2-, -0-, -NH-, -CF2-, -C(Ci_6alkyl)(OH)-, -S-, -C(=0)-, -C(=NOC0-6alkyl)-, - S(=0)-, -S(02)- or -S(=0)(NH)-;
Y is -CH-, or nitrogen;
Q is hydrogen; halogen; Ci_6alkyl, unsubstituted or once or twice substituted by amino or hydroxy, provided that di-substitution is not on the same carbon; amino(CH2)2_
6aminosulfonyl; 2-amino-4,5-dihydro- 1 ,3-oxazol-4-yl(CH2)i_6; carboxy(CH2)i_6;
phenylsulfonyl; piperidin-4-yl-carbonyl; lH-pyrazol-3-yl; pyrrolidin-3-yloxy; piperidin-4-
12 13 12 13
yloxy; amino(CH2)2_6-0-; orNR R , wherein one of R and R is hydrogen, Chalky!, or hydroxy(CH2)2_6; and the other one is
{ 1 - [amino(CH2)o_6] -3 ,3 -difluorocyclo butyl} (CH2) i _6 ; guanidino(CH2)2_6 ; (S-C i _
6alkylsulfonimidoyl)(CH2)2_6 ; 2-oxa-6-aza-spiro[3.4]oct-8-yl; {3-[amino(CH2)0_
6]tetrahydrofuran-3-yl} (CH2)i_6; 3 -amino methyl- 1 , 1 -dioxidothietan-3 -ylmethyl; 3-amino- 1 , 1 -dioxidothietan-3 -ylmethyl; 3 -(amino methyl)thietan-3 -ylmethyl; (1 , 1- dioxidothiomorpholin-4-yl)ethyl; Co-6alkyl(oxetanyl)N(CH2)2_6; 4,5-dihydro- lH-imidazol- 2-yl; amino(CH2)2_6-0-(CH2)2_6; amino(CH2)2_i0; amino(CH2)i_6difluoromethyl(CH2)i_6; amino (CH2) i _6difluoromethy ldifluoromethy 1(CH2) i _6 ; amino (CH2) i _6 fluoromethy 1(CH2) i _6 ; amino (CH2) i _6oxetany 1(CH2)0_6 ; amino (CH2)0_6Oxetanyl(CH2) i _6 ; amino (CH2)2_
6Sulfanyl(CH2)2_6; amino(CH2)2_6sulfonyl(CH2)2_6; amino(CH2)o-6carbonyl(CH2)0- 6; aminocycloalkyl(CH2)o-6 ; 2-aminodihydrooxazol-4-yl(CH2)i_6 ; 2-aminodihydrooxazol-5- yl(CH2)i_6; (2-amino-5-methyl-4,5-dihydro-l ,3-oxazol-5-yl)methyl; aminophenyl; 4- aminotetrahydropyran-4-yl(CH2) i _6; azetidin-2-yl(CH2) i _6; azetidin-3 -yl(CH2)0_6 ;
azetidinylcarbonyl; Ci_6alkoxy(CH2)2_6; Ci_6alkoxy(CH2)2_6amino(CH2)2_6; Ci_6alkyl; Ci_ 6alkylamino(CH2)2_6; Ci_6alkylamino carbonyl(CH2)0-6; Ci_6alkylaminooxetanyl(CH2)i_6; Ci_ 6alkylcarbonyl; Ci_6alkylcarbonylamino(CH2)2_6; Ci_6alkylcarbonylamino(CH2)i_
6oxetanyl(CH2)o_6 ; Ci_6alkylsulfinyl(CH2)2_6; Ci_6alkylsulfonyl; carboxy(CH2)i_6;
cyano (CH2)i_6; diCi_6alkylamino(CH2)2_6; diCi_6alkylaminocarbonyl; difluoromethyl(CH2)i_ 6amino(CH2)2_6; hydrogen; hydroxy(CH2)2_i0; hydroxy(CH2)2_6amino(CH2)2_6;
hydro xy(CH2) i _6carbonyl; hydro xy(CH2)0_6Oxetanyl(CH2) i _6 ; hydro xy(CH2) i _
^^^ τ Γ^υΛ- hydroxycycloalkyl; isoxazolyl; morpholin-2-yl(CH2)i_6; morpholin-4- yl(CH2)2-6; oxetanyl(CH2)o-6; N-oxetanylpyrrolidin-3-yl; oxo-pyrrolidinylcarbonyl;
phenylaminocarbonyl; phenyl(CH2)o-6aminooxetanyl(CH2) i _6 ; phenylcarbonyl;
piperazinyl(CH2)2-6; piperidin-l-yl(CH2)2-6; piperidin-2-yl(CH2)i-6; piperidin-3-yl(CH2)o-6; piperidin-4-yl(CH2)o-6; piperidinylcarbonyl; pyrazinylcarbonyl; pyrazol-3-yl;
pyridazinylcarbonyl; pyridinyl(CH2)o-6carbonyl; pyridinylamino(CH2)2-6; pyrrolidin-3-yl, unsubstituted or 4-substituted by halogen; pyrrolidin-4-yl, unsubstituted or 3-substituted by hydroxy or Ci_6alkoxy; pyrrolidin-2-yl(CH2)i-6; pyrrolidinylcarbonyl; tetrahydrofuran-3-yl; tetrahydropyran-4-yl; tetrazolyl(CH2)2-6; trifluoromethylcarbonylamino(CH2)1_60xetanyl;
R14
-(CH2)1_6 C R
trifluoromethylsulfonyl; , wherein R is hydrogen, Ci_6alkyl or
hydroxy(CH2)i_6; R15 is hydroxy, Ci_6alkyl, hydroxy(CH2)i_6 or amino; and R16 is Ci_6alkyl, trifluoromethyl, hydroxy(CH2)i_6, amino (CH2)i_6, aminocarboxy or carboxy(CH2)i_6;
R17 R , wherein R17 is hydrogen, Ci_6alkyl or hydroxy(CH2)i_6; R18 is hydroxy(CH2)i_6 or
Ci is hydroxy(CH2)i_6, amino (CH2)i_6, carboxy or aminocarboxy(CH2)o-6; or
Figure imgf000005_0001
, wherein R 20 is hydrogen or Ci_6alkyl; R .21 is Ci_6alkyl; R , 22 is Ci_6alkoxy or amino;
R12 and R13, with the nitrogen atom to which they are attached, may form a pyrrolidinyl, piperazinyl, piperidinyl, morpholinyl, azetidinyl, diazepanyl or oxopyrrolidinyl ring; which may be unsubstituted, once or twice substituted by a group selected from halogen, Ci_ 6alkyl, Ci_6alkoxy, gemdimethyl, amino, aminocarbonyl, hydroxy, oxetanylamino, Ci_ 6alkylpiperazinyl, and amino (CH2)i_6;
R12 and R13, with the nitrogen atom to which they are attached may form a bridge ring or a spiral ring selected from 2-oxa-6-aza-spiro[3.4]octan-6-yl, 2-oxa-5,7-diazaspiro[3.4]octan- 6-one-5-yl, (4aS,7aR)-hexahydropyrrolo[3,4-b][l,4]oxazin-6(2H)-yl, 4,5,6,6a-tetrahydro- 3aH-pyrrolo[3,4-d][l,3]oxazol-5-yl, 2-aza-bicyclo[2.1.1]hexan-2-yl, and 3-aza- bicyclo[3.1.0]hexan-3-yl; which may be unsubstituted or further substituted by amino; and pharmaceutically acceptable salt and stereoisomers thereof.
Respiratory Syncytial Virus (RSV) belongs to the family of Paramyxoviridae, subfamily of Pneumovirinae. The human RSV is a major cause of acute upper and lower respiratory tract infection in infants and children. Almost all children are infected by RSV at least once by age of three. Natural human immunity against RSV is incomplete. In normal adults and older children, RSV infection is mainly associated with upper respiratory track symptoms. Severe case of RSV infection often leads to bronchiolitis and pneumonia, which requires hospitalization. High-risk factors for lower respiratory track infections include premature birth, congenital heart disease, chronic pulmonary disease, and immuno-compromised conditions. A severe infection at young age may lead to recurrent wheezing and asthma. For the elderly, RSV-related mortality rate becomes higher with advancing age.
There is no RSV vaccine available for human use, despite of many attempts in subunit vaccine and live-attenuated vaccine approaches. Virazole®, the aerosol form of ribavirin, is the only approved antiviral drug for treatment of RSV infection. However, it is rarely used clinically, due to limited efficacy and potential side effects. Two marketed prophalyxis antibodies were developed by Medlmmune (CA, USA).
RSV-IGIV (brand name RespiGam) is polyclonal-concentrated RSV neutralizing antibody administered through monthly infusion of 750 mg/kg in hospital (Wandstrat TL, Ann
Pharmacother. 1997 Jan;31(l):83-8). Subsequently, the usage of RSV-IGIV was largely replaced by palivizumab (brand name Synagis®), a humanized monoclonal antibody against RSV fusion (F) protein approved for prophylaxis in high-risk infants in 1998. When administered
intramuscularly at 15 mg/kg once a month for the duration of RSV season, palivizumab demonstrated 45 - 55% reduction of hospitalization rate caused by RSV infection in selected infants (Pediatrics. 1998 Sep;102(3):531-7; Feltes TF et al, J Pediatr. 2003 Oct;143(4):532-40). Unfortunately, palivizumab is not effective in the treatment of established RSV infection. A newer version monoclonal antibody, motavizumab, was designed as potential replacement of palivizumab but failed to show additional benefit over palivizumab in recent Phase III clinical trials (Feltes TF et al, Pediatr Res. 2011 Apr 25, Epub ahead of print).
A number of small molecule RSV inhibitors have been discovered. Among them, only a few reached Phase I or II clinical trials. Arrow Therapeutics (now a group in AstraZeneca, UK) completed a five-year Phase II trial of nucleocapsid (N) protein inhibitor RSV-604 in stem cell transplantation patients by February 2010 (www.clinicaltrials.gov). but has not released the final results. Most of other small molecules were put on hold for various reasons.
RNAi therapeutics against RSV have also been thoroughly studied. ALN-RSVOl (Alnylam Pharmaceuticals, MA, USA) is a siRNA targeting on RSV gene. A nasal spay administered for two days before and for three days after RSV inoculation decreased infection rate among adult volunteers (DeVincenzo J. et al, Proc Natl Acad Sci U S A. 2010 May 11;107(19):8800-5). In another Phase II trial using naturally infected lung transplantation patients, results were not sufficient for conclusion of antiviral efficacy, though certain health benefits have been observed (Zamora MR et al, Am J Respir Crit Care Med. 2011 Feb 15;183(4):531-8). Additional Phase lib clinical trials in similar patient population for ALN-RSV01 are on-going
(www, clinicaltrials. go v) .
Nevertheless, safe and effective treatment for RSV disease is needed urgently.
It has been found that the compounds of the present invention belong to a new chemical class of RSV inhibitors for the treatment or prophylaxis of RSV infection. The compounds of the invention are therefore useful in the treatment or prophylaxis of RSV disease.
As used herein, the term "Co-6alkyl" alone or in combination signifies a chemical bond, or hydrogen, or saturated, linear- or branched chain alkyl group containing 1 to 6, preferably 1 to 4 carbon atoms, for example methyl, ethyl, propyl, isopropyl, 1 -butyl, 2-butyl, tert-butyl and the like. Preferred "Co-6alkyl" groups are chemical bond, hydrogen, methyl, ethyl, isopropyl, tert- butyl
As used herein, the term "Ci_6alkyl" alone or in combination signifies a saturated, linear- or branched chain alkyl group containing 1 to 6, preferably 1 to 4 carbon atoms, for example methyl, ethyl, propyl, isopropyl, 1 -butyl, 2-butyl, tert-butyl and the like. Preferred "Ci_6alkyl" groups are methyl, ethyl, isopropyl, tert-butyl.
As used herein, the term "C2-6alkyl" alone or in combination signifies a saturated, linear- or branched chain alkyl group containing 2 to 6, preferably 2 to 4 carbon atoms, for example ethyl, propyl, isopropyl, 1 -butyl, 2-butyl, tert-butyl and the like. Preferred "C2-6alkyl" groups are ethyl, isopropyl, tert-butyl. As used herein, the term "-(CH2)o-6-" signifies a chemical link, hydrogen, or a saturated, linear alkyl chain containing from 1 to 6 carbon atoms, preferably, the term signifies hydrogen or
As used herein, the term "-(CH2)i_6-" signifies a saturated, linear alkyl chain containing from 1 to 6 carbon atoms, preferably from 1 to 4 carbon atoms. As used herein, the term "-(CH2)2-6-" signifies a saturated, linear alkyl chain containing from 2 to 6 carbon atoms, preferably from 2 to 4 carbon atoms.
As used herein, the term "-(CH2)2-10-" signifies a saturated, linear alkyl chain containing from 2 to 10 carbon atoms, preferably from 2 to 4 carbon atoms.
The term "cycloalkyl", alone or in combination, refers to a saturated carbon ring containing from 3 to 7 carbon atoms, preferably from 3 to 6 carbon atoms, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and the like. Preferred cycloalkyl groups are cyclopropyl, cyclopentyl and cyclohexyl.
The term "Ci_6alkoxy" alone or in combination signifies a group Ci_6alkyl-0-, wherein the "Ci_6alkyl" is as defined above; for example methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, i- butoxy, 2-butoxy, t-butoxy and the like. Preferred Ci_6alkoxy groups are methoxy and ethoxy and more preferably methoxy.
The term "C2-6alkoxy" alone or in combination signifies a group C2-6alkyl-0-, wherein the "C2-6alkyl" is as defined above; for example ethoxy, propoxy, isopropoxy, n-butoxy, z'-butoxy, 2- butoxy, t-butoxy and the like. Preferred Ci_6alkoxy groups is ethoxy.
The term "halogen" means fluorine, chlorine, bromine or iodine. Halogen is preferably fluorine or chlorine.
The term "hydroxy" alone or in combination refers to the group OH.
The term "carbonyl" alone or in combination refers to the group -C(O)-.
The term "carboxy" alone or in combination refers to the group COOH.
The term "amino", alone or in combination, refers to primary (-NH2), secondary (-NH-
/
) or tertiary amino ( ).
The term "sulfonyl" alone or in combination refers to the group -S(0)2-.
The term "Ci_6alkylsulfanyl" alone or in combination refers to the group -S-Ci_6alkyl.
The term "Ci_6alkylsulfmyl" alone or in combination refers to the group -S(O) -Ci_6alkyl.
Figure imgf000008_0001
The term "oxetanyl" alone or in combination refers to the group
The compounds according to formula I does not include those in which the sp3 hybrid carbon atom is disubstituted by two nitrogen atoms, or one nitrogen atom and one oxygen atom simultaneously.The compounds according to the present invention may exist in the form of their pharmaceutically acceptable salts. The term "pharmaceutically acceptable salt" refers to conventional acid-addition salts or base-addition salts that retain the biological effectiveness and properties of the compounds of formula (I) and are formed from suitable non-toxic organic or inorganic acids or organic or inorganic bases. Acid-addition salts include for example those j ....·__. j c .· - -.jds such as hydrochloric acid, hydrobromic acid, hydro iodic acid, sulfuric acid, sulfamic acid, phosphoric acid and nitric acid, and those derived from organic acids such as p-toluenesulfonic acid, salicylic acid, methanesulfonic acid, oxalic acid, succinic acid, citric acid, malic acid, lactic acid, fumaric acid, and the like. Base-addition salts include those derived from ammonium, potassium, sodium and, quaternary ammonium hydroxides, such as for example, tetramethyl ammonium hydroxide. The chemical modification of a pharmaceutical compound into a salt is a technique well known to pharmaceutical chemists in order to obtain improved physical and chemical stability, hygroscopicity, flowability and solubility of compounds. It is for example described in Bastin R.J., et. al, Organic Process Research & Development 2000, 4, 427-435; or in Ansel, H., et. al, In: Pharmaceutical Dosage Forms and Drug Delivery Systems, 6th ed. (1995), pp. 196 and 1456-1457. Preferred are the sodium salts of the compounds of formula (I).
"Pharmaceutically acceptable esters" means that compounds of general formula (I) may be derivatised at functional groups to provide derivatives which are capable of conversion back to the parent compounds in vivo. Examples of such compounds include physiologically acceptable and metabolically labile ester derivatives, such as acetate, propionate and isobutyrate.
Additionally, any physiologically acceptable equivalents of the compounds of general formula (I), similar to the metabolically labile esters, which are capable of producing the parent compounds of general formula (I) in vivo, are within the scope of this invention. Preferred are the methyl and ethyl esters of the compounds of formula (I). Compounds of the general formula (I) which contain one or several chiral centers can either be present as racemates, diastereomeric mixtures, or optically active single isomers. The racemates can be separated according to known methods into the enantiomers. Preferably, diastereomeric salts which can be separated by crystallization are formed from the racemic mixtures by reaction with an optically active acid such as e.g. D- or L-tartaric acid, mandelic acid, malic acid, lactic acid or camphorsulfonic acid.
Another embodiment of present invention is (ii) a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein
R is hydrogen, halogen or Ci_6alkyl;
R2 is hydrogen, halogen or Ci_6alkyl;
R3 is hydrogen, halogen or Ci_6alkyl;
R4 is hydrogen or Ci_6alkyl;
R5 is hydrogen; R6 is hydrogen, halogen, hydroxy, Ci_6 alkoxy, morpholinyl or 4-Co-6alkylpiperazin-l-yl;
R7 is hydrogen, halogen, Ci_6alkyl, Ci_6alkoxy, phenoxy or hydroxy(CH2)2-6-0-; hydrogen, halogen or Ci_6alkoxy; hydrogen or Ci_6alkyl;
R is hydrogen;
A is nitrogen or -C-R11, wherein R11 is hydrogen, halogen, Ci_6 alkyl, cycloalkyl, Ci_ 6alkoxy, trifluoromethyl, trifluoromethoxy, pyridinyloxy, Ci_6alkoxy(CH2)i_6-0-,
difluoromethoxy, cyano, nitro, amino, vinyl, acetylenyl, amino carbonyl, hydroxy(CH2)2-6-0-, Ci_ 6alkylsulfinyl, hydroxy(CH2)i_6, deuteratedCi_6alkyl, carboxyl, alkoxycarbonyl, hydroxy, difluoromethyl, -CH(hydroxy)C i _6alkyl or C i _6alkylsulfanyl;
X is S, S=0, S02 or S(0)NH;
Y is -CH- or nitrogen;
Q is Ci_6alkyl, unsubstituted or once substituted by amino; amino(CH2)2_6aminosulfonyl; 2-amino-4,5-dihydro-l,3-oxazol-4-ylethyl; carboxy(CH2)i_6; phenylsulfonyl; piperidin-4-yl- carbonyl; lH-pyrazol-3-yl; pyrrolidin-3-yloxy; piperidin-4-yloxy; amino(CH2)2_6-0-; or
12 13 12 13
NR R , wherein one of R and R is hydrogen, Ci_6alkyl or hydro xy(CH2)2_6; and the other one is
{l-[amino(CH2)o-6]-3,3-difluorocyclobutyl}(CH2)i_6; (5,-Ci_6alkylsulfonimidoyl)(CH2)2_6; {3-[amino(CH2)o-6]tetrahydrofuran-3-yl} (CH2)i_6; (2-amino-5-methyl-4,5-dihydro- 1 ,3- oxazol-5-yl)methyl; 3 -amino methyl- 1 , 1 -dioxidothietan-3-ylmethyl; 3- (aminomethyl)thietan-3-ylmethyl; (1,1 -dioxidothiomorpholin-4-yl)ethyl; Co_
6alkyl(oxetanyl)N(CH2)2_6; 4,5-dihydro- lH-imidazol-2-yl; amino(CH2)2_6-0-(CH2)2_6;
amino(CH2)2_i0; amino(CH2)o-6carbonyl(CH2)0-6; amino(CH2)i_6difluoromethyl(CH2)i_6; amino (CH2) i _6difluoromethy ldifluoromethy 1(CH2) i _6 ; amino (CH2) i _6 fluoromethy 1(CH2) i _6 ; amino (CH2) i _6oxetany 1(CH2)0_6 ; amino (CH2)0_6Oxetanyl(CH2) i _6 ; amino (CH2)2_
6Sulfanyl(CH2)2_6; amino(CH2)2_6sulfonyl(CH2)2_6; 1-aminocyclobutylmethyl; 2- aminocyclohexyl; 3-aminocyclohexyl; 4-aminocyclohexyl; 1-aminocyclohexylmethyl; 2- aminocyclopentyl; 1-aminocyclopropylethyl; 1-aminocyclopropylmethyl; (2-amino-4,5- dihydro-oxazol-5-yl)(CH2)i_6; (2-amino-4,5-dihydro-oxazol-4-yl)(CH2)i_6; aminophenyl; 4- aminotetrahydropyran-4-yl(CH2)i-6; azetidin-2-yl(CH2)i_6; azetidin-3-yl(CH2)0_6; azetidin- 3-ylcarbonyl; Ci_6alkoxy(CH2)2_6; Ci_6alkoxy(CH2)2_6amino(CH2)2_6; Ci_6alkyl; Ci_ 6alkylamino(CH2)2_6; Ci_6alkylaminooxetanyl(CH2)i_6; Ci_6alkylcarbonyl; Ci_
6alkylaminocarbonyl(CH2)o-6; Ci_6alkylcarbonylamino(CH2)2_6; Ci_
6alkylcarbonylamino(CH2)i_60xetanyl(CH2)o-6; Ci_6alkylsulfinyl(CH2)2_6; Ci_6alkylsulfonyl; carboxy(CH2)i_6; cyano(CH2)i_6; diCi_6alkylamino(CH2)2_6; diCi_6alkylaminocarbonyl; difluoromethyl(CH2)i_6amino(CH2)2_6; hydrogen; hydroxy(CH2)2_i0; hydroxy(CH2)2_ 6amino(CH2)2_6; hydro xy(CH2) i _6carbonyl; hydro xy(CH2) i _6oxetanyl(CH2)0_6 ;
hydroxy(CH2)o_60xetanyl(CH2)i_6; 4-hydroxycyclohexyl; isoxazol-3-yl; morpholin-2- yl(CH2)i_6; morpholin-4-yl(CH2)2_6; 2-oxa-6-aza-spiro[3.4]oct-8-yl; oxetanyl(CH2)0_6; N- oxetanylpyrrolidin-3-yl; oxo-pyrrolidinylcarbonyl; phenylaminocarbonyl; phenyl(CH2)o_ 6aminooxetanyl(CH2)i_6; phenylcarbonyl; piperazinyl(CH2)2_6; piperidin- l -yl(CH2)2_6; piperidin-2-yl(CH2)i_6; piperidin-3-yl(CH2)0_6; piperidin-4-yl(CH2)0_6; piperidinylcarbonyl; pyrazinylcarbonyl; pyrazol-3-yl; pyridazinylcarbonyl; pyridinyl(CH2)0-6carbonyl;
pyridinylamino(CH2)2_6; pyrrolidin-3-yl, unsubstituted or 4-substituted by halogen;
pyrrolidin-4-yl, unsubstituted or 3-substituted by hydroxy or Ci_6alkoxy; pyrrolidin-2- yl(CH2)i_6; pyrrolidinylcarbonyl; tetrahydrofuran-3-yl; tetrahydropyran-4-yl;
Figure imgf000011_0001
R16 is Ci_6alkyl, trifluoromethyl, hydroxy(CH2)i_6, amino (CH2)i_6, aminocarbonyl or
R17 carboxy(CH2)i_6; R , wherein R17 is hydrogen, Ci_6alkyl or hydroxy(CH2)i_6; R18 is amino (CH2)i_6, carboxy or
Figure imgf000011_0002
hydrogen or Ci_6alkyl; R21 is Ci_ 6alkyl; R22 is Ci_6alkoxy or amino;
R12 and R13, with the nitrogen atom to which they are attached, may form a pyrrolidinyl, piperazinyl, piperidinyl, morpholinyl, azetidinyl, diazepanyl or oxopyrrolidinyl ring; which may be unsubstituted, once or twice substituted by a group selected from halogen, Ci_ 6alkyl, Ci_6alkoxy, gemdimethyl, amino, aminocarbonyl, hydroxy, oxetanylamino, Ci_ 6alkylpiperazinyl, and amino (CH2)i_6;
R12 and R13, with the nitrogen atom to which they are may form a bridge ring or a spiral ring selected from 2-oxa-6-aza-spiro[3.4]octan-6-yl, 2-oxa-5,7-diazaspiro[3.4]octan-6-one- 5-yl, (4a5',7ai?)-hexahydropyrrolo[3,4-b] [ l,4]oxazin-6(2H)-yl, 4,5,6,6a-tetrahydro-3aH- pyrrolo[3,4-d][l,3]oxazol-5-yl, 2-aza-bicyclo[2.1.1]hexan-2-yl and 3-aza- bicyclo[3.1.0]hexan-3-yl; which may be unsubstituted or further substituted by amino.
Further embodiment of present invention is (iii) a compound of formula (I) or a
pharmaceutically acceptable salt thereof, wherein
R1, R2 or R3 are hydrogen, fluoro, chloro or methyl;
R4 is hydrogen or methyl;
R5 is hydrogen;
R6 is hydrogen, fluoro, hydroxy, methoxy, morpholinyl or 4-(propan-2-yl)piperazin-l-yl; R7 is hydrogen, fluoro, chloro, methyl, methoxy, ethoxy, hydroxyethoxy or phenoxy; R8 is hydrogen, fluoro or methoxy; R9 is hydrogen or methyl; R10 is hydrogen;
A is nitrogen or -C-R11, wherein R11 is hydrogen, fluoro, chloro, bromo, methyl, ethyl, cyclopropyl, methoxy, trifluoromethyl, trifiuoromethoxy, pyridinyloxy, methoxyethoxy, difiuoromethoxy, cyano, nitro, amino, vinyl, acetylenyl, amino carbonyl, hydroxyethoxy, methylsulfanyl, methylsulfinyl, hydroxymethyl, deuteratedmethyl, carboxyl, methoxycarbonyl, hydroxy, difluoromethyl, methylCH(hydroxy)- or methylsulfonyl;
X is S, S=0, S02 or S(0)NH;
Y is -CH- or nitrogen;
Q is 2-amino-4,5-dihydro-l,3-oxazol-4-ylethyl; aminoethoxy; aminoethylaminosulfonyl; aminopropyl; carboxyethyl; methyl; phenylsulfonyl; piperidin-4-yl-carbonyl; piperidin-4- yloxy; lH-pyrazol-3-yl; pyrrolidin-3-yloxy; or
NR 112ZR13 , wherein one of R 12 and R 13 is hydrogen, methyl or hydro xyethyl; and the other one is amino butyl; amino carbonylethyl; aminocarbonylmethyl; 1-aminocyclobutylmethyl; 2- aminocyclohexyl; 3-aminocyclohexyl; 4-aminocyclohexyl; 1-aminocyclohexylmethyl; 2- aminocyclopentyl; 1-aminocyclopropylethyl; 1-aminocyclopropylmethyl; aminodecyl; (2- amino-4,5-dihydro-oxazol-5-yl)methyl; (2-amino-4,5-dihydro-oxazol-4-yl)methyl;
aminoethoxyethyl; aminoethyl; amino ethylcarbonyl; amino ethylfluoromethylmethyl;
amino ethylsulfanylethyl; aminoethylsulfonylethyl; aminoheptyl; aminohexyl;
aminomethylcarbonyl; (l-aminomethyl-3,3-difluorocyclobutyl)methyl;
aminomethyldifluoromethyldifluoromethylmethyl; ammomethyldifluoromethylmethyl; (2- amino-5-methyl-4,5-dihydro- 1 ,3-oxazol-5-yl)methyl; 3 -amino methyl- 1 , 1 -dioxidothietan-3- ylmethyl; aminomethylfluoromethylethyl; aminomethylfluoromethylmethyl;
aminomethyloxetanyl; aminomethyloxetanylmethyl; 3-(aminomethyl)thietan-3-ylmethyl; aminononyl; aminooctyl; aminooxetanylethyl; aminooxetanylmethyl; aminopentyl;
aminophenyl; aminopropyl; 4-aminotetrahydropyran-4-ylmethyl; 3-aminotetrahydrofuran-
3-ylmethyl; azetidin-3-yl; azetidin-3-ylcarbonyl; azetidin-2-ylmethyl; azetidin-3-ylmethyl; carboxyethyl; carboxymethyl; cyanoethyl; difluoromethylmethylamino ethyl; 4,5-dihydro- lH-imidazol-2-yl; dimethylaminocarbonyl; dimethylamino ethyl; (1,1- dioxidothiomorpholin-4-yl)ethyl; ethyl; ethylaminocarbonyl; ethylamino ethyl;
ethylammooxetanylmethyl; ethyl (oxetanyl)amino ethyl; hydrogen; 4-hydroxycyclohexyl; hydroxyethyl; hydroxyethylaminoethyl; hydroxyethyloxetanyl; hydroxymethylcarbonyl; hydroxymethyloxetanylmethyl; hydroxynonyl; hydroxypropyl; isoxazol-3-yl;
methoxyethyl; methoxyethylaminoethyl; methyl; methylaminocarbonylmethyl;
methylamino ethyl; methylcarbonyl; methylcarbonylaminoethyl;
methylcarbonylaminomethyloxetanylmethyl; methylcarbonylaminopropyl;
methylsulfinylethyl; 2-(S'-methylsulfonimidoyl)ethyl; methylsulfonyl; morpholin-4-ylethyl; morpholin-2-ylmethyl; 2-oxa-6-aza-spiro[3.4]oct-8-yl; oxetanyl; oxetanylaminoethyl; oxetanylaminopropyl; oxetanylmethyl; N-oxetanylpyrrolidin-3-yl; oxo-pyrrolidin-4- ylcarbonyl; phenylaminocarbonyl; phenylcarbonyl; phenylmethylaminooxetanylmethyl; piperazin-l-ylethyl; piperidin-2-ylcarbonyl; piperidin-3-ylcarbonyl; piperidin-4-ylcarbonyl; piperidin-3-yl; piperidin-4-yl; piperidin-l-ylethyl; piperidin-2-ylmethyl; pyrazin-2- ylcarbonyl; pyrazol-3-yl; pyridazin-3-ylcarbonyl; pyridine-2-ylmethylcarbonyl; pyridine-2- ylaminoethyl; pyridine-2-ylcarbonyl; pyridine-3-ylcarbonyl; pyrrolidin-3-yl, unsubstituted or 4-substituted by fluoro; pyrrolidin-4-yl, unsubstituted or 3-substituted by hydroxy or methoxy; pyrrolidin-2-ylmethyl; pyrrolidin-2-ylcarbonyl; tetrahydrofuran-3-yl;
tetrahydropyran-4-yl; tetrazolylethyl; trifluoromethylsulfonyl;
R14
"(CH2)i_g _C— R
trifiuoromethylcarbonylaminomethyloxetanyl; K , wherein R is hydrogen or methyl; R15 is hydroxy, methyl or amino; and R16 is methyl, trifluoromethyl,
R17 ^C- R18 hydroxymethyl, hydroxyethyl, aminomethyl, aminocarbonyl or carboxymethyl; K , wherein R17 is hydrogen, methyl or hydroxymethyl; R18 is hydroxymethyl or methyl; R19 is hydroxymethyl, aminomethyl, carboxy, aminocarbonyl or amino carbonylmethyl;
Figure imgf000014_0001
methyl or ethyl; R 22 is methoxy or amino;
R12 and R13, with the nitrogen atom to which they are attached, may form a pyrrolidinyl, piperazinyl, piperidinyl, morpholinyl, azetidinyl, diazepanyl or oxopyrrolidinyl ring; which may be unsubstituted, once or twice substituted by a group selected from fluoro, methyl, methoxy, gemdimethyl, amino, aminocarbonyl, hydroxy, oxetanylamino,
methylpiperazinyl and aminomethyl;
R12 and R13, with the nitrogen atom to which they are attached may form a bridge ring or a spiral ring selected from 2-oxa-6-aza-spiro[3.4]octan-6-yl, 2-oxa-5,7-diazaspiro[3.4]octan- 6-one-5-yl, (4a5',7ai?)-hexahydropyrrolo[3,4-b][l,4]oxazin-6(2H)-yl, 4,5,6,6a-tetrahydro- 3aH-pyrrolo[3,4-d][l,3]oxazol-5-yl, 2-aza-bicyclo[2.1.1]hexan-2-yl or 3-aza- bicyclo[3.1.0]hexan-3-yl; which may be unsubstituted or further substituted by amino; and all the remaining substituents are as defined above in embodiment (i) or (ii).
Another embodiment of present invention is (iv) a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein
R1, R2, R3, R4, R5, R6, R7, R8, R9 and R10 are hydrogen;
A is -C-R11 , wherein R11 is hydrogen, halogen or Ci_6alkyl;
X is S;
Y is -CH- or nitrogen;
12 13 12 13
Q is NR R , wherein one of R and R is hydrogen; and the other one is
amino (CH2)2-6, amino(CH2)i-6difluoromethyl(CH2)i-6, amino(CH2)o-60xetanyl(CH2)i-6 or hydrogen;
R12 and R13, with the nitrogen atom to which they are attached, may form a pyrrolidinyl ring, which may be once substituted by amino; and all the remaining substituents are as defined above in embodiment (i) to (iii).
Further embodiment of present invention is (v) a compound of formula (I) or a
pharmaceutically acceptable salt thereof, wherein
R8, R9 and R10 are hydrogen; A is -C-R11 , wherein R11 is hydrogen, chloro or methyl;
12 13 12 13
u is NR1ZR , wherein one of R and R is hydrogen; and the other one is amino ethyl, ammomethyldifluoromethylmethyl, ammomethyloxetanylmethyl, aminooxetanylmethyl or hydrogen;
R12 and R13, with the nitrogen atom to which they are attached, may form a pyrrolidinyl ring, which may be once substituted by amino; and all the remaining substituents are as defined above in embodiment (iv).
Another further embodiment of present invention is (vi) a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein
R1 R2 R3 R4 R5 R6 R7 R8, R9 and R10 are hydrogen;
A is -C-R11, wherein R11 is hydrogen, halogen, Ci_6alkyl, hydro xy(CH2)i_6,
deuteratedmethyl or carboxyl;
X is S=0;
Y is -CH- or nitrogen;
12 13 12 13
Q is NR R , wherein one of R and R is hydrogen; and the other one is amino (CH2)2_6 ; amino (CH2) i _6difluoromethy 1(CH2) i _6 ; amino (CH2) i _6 fluoromethy 1(CH2) i _6 ; amino(CH2)i_6oxetanyl; amino(CH2)i_6oxetanyl(CH2)i_6; aminooxetanyl(CH2)i_6; hydroxy(CH2)2_ io; phenyl(CH2)i_6aminooxetanyl(CH2)i_6; pyrrolidin-3-yl, 4-substituted by halogen;
R14
"(CH2)i_g _C-- R
or R , wherein R14 is hydrogen, R15 is hydroxy, and R16 is hydroxy(CH2)i_6;
R12 and R13, with the nitrogen atom to which they are attached, may form a pyrrolidinyl ring, which may be once or twice substituted by a group selected from halogen, amino and hydroxyl; and all the remaining substituents are as defined above in embodiment (i) to (v).
More further embodiment of present invention is (vii) a compound of formula (I) or a pharmaceutically acceptable salt thereof , wherein
R1 R2 R3 R4 R5 R6 R7 R8, R9 and R10 are hydrogen;
A is -C-R11, wherein R11 is hydrogen, chloro, methyl, hydro xymethyl, deuteratedmethyl or carboxyl; 12 13 12 13
u is NR1ZR , wherein one of R and R is hydrogen; and the other one is amino ethyl; ammomethyldifluoromethylmethyl; ammomethylfluoromethylmethyl; aminomethyloxetanyl; ammomethyloxetanylmethyl; aminooxetanylmethyl; phenylmethylaminooxetanylmethyl; pyrrolidin-3-yl,
Figure imgf000016_0001
, wherein R14 is hydrogen, R15 is hydroxy, and R16 is hydroxymethyl;
R12 and R13, with the nitrogen atom to which they are attached, may form a pyrrolidinyl ring, which may be once or twice substituted by a group selected from fluoro, amino and hydroxyl; and all the remaining substituents are as defined above in embodiment (vi).
Still further embodiment of present invention is (viii) a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein
R1, R2, and R3 are hydrogen, halogen or Ci_6alkyl;
R4 is hydrogen or Ci_6alkyl;
R5 is hydrogen;
R6 is hydrogen, halogen, hydroxy, Ci_6alkoxy, morpholinyl or 4-(propan-2-yl)piperazin- 1-yl;
R7 is hydrogen, halogen, Ci_6alkyl, Ci_6alkoxy, hydroxy(CH2)2-6-0-, or phenoxy; R8 is hydrogen, halogen or Ci_6alkoxy; R9 is hydrogen or Ci_6alkyl; R10 is hydrogen; A is nitrogen or -C-R1 1, wherein R1 1 is hydrogen, halogen, Chalky!, Ci_6alkoxy, trifluoromethyl, trifluoromethoxy, pyridinyloxy, Ci_6alkoxy(CH2)i_6-0-, difluoromethoxy, nitro, cycloalkyl, cyano, amino, vinyl, acetylenyl, amino carbonyl, hydroxy(CH2)2-6-0-, Ci_
6alkylsulfanyl, Ci_6alkylsulfinyl, hydroxy(CH2)i_6, deuteratedmethyl, carboxyl, Ci_
6alkoxycarbonyl, hydroxy, difluoromethyl or methylCH(hydroxy)-; X is S02;
Y is -CH- or nitrogen;
Q is 2-amino-4,5-dihydro-l ,3-oxazol-4-ylethyl; amino(CH2)2_6-0-; amino(CH2)2_
", unsubstituted or once substituted by amino; carboxy(CH2)i_6; phenylsulfonyl; piperidin-4-yl-carbonyl; piperidin-4-yloxy; lH-pyrazol-3-yl; pyrrolidin-3-yloxy;
12 13 12 13
or NR R , wherein one of R and R is hydrogen, Ci_6alkyl or hydro xy(CH2)2-6; and the other one is { l-[amino(CH2)o-6]-3,3-difluorocyclobutyl} (CH2)i-6; (5,-Ci_6alkylsulfonimidoyl)(CH2)2-6; 3-aminotetrahydrofuran-3-yl(CH2)i-6; (2-amino-5-methyl-4,5-dihydro- 1 ,3-oxazol-5-yl)methyl; 3- amino methyl- 1 , 1 -dioxidothietan-3 -ylmethyl; 3 -(amino methyl)thietan-3 -ylmethyl; (1,1- dioxidothiomorpholin-4-yl)ethyl; Co-6alkyl(oxetanyl)N(CH2)2-6; 4,5-dihydro- lH-imidazol-2-yl; amino(CH2)2-6-0-(CH2)2-6; amino(CH2)2-io; amino(CH2)i_6carbonyl; amino carbonyl(CH2)i_6; amino (CH2) i _6difluoromethy 1(CH2) i _6 ; amino (CH2) i _6difluoromethyldifluoromethy 1(CH2) i _6 ; amino (CH2) i _6 fluoromethy 1(CH2) i _6 ; amino (CH2) i _60xetanyl(CH2)o-6 ; amino (CH2)o- 60xetanyl(CH2)i_6; amino(CH2)2-6Sulfanyl(CH2)2-6; amino(CH2)2-6Sulfonyl(CH2)2-6; 1- aminocyclobutylmethyl; 2-aminocyclohexyl; 3-aminocyclohexyl; 4-aminocyclohexyl; 1- aminocyclohexylmethyl; 2-aminocyclopentyl; 1-aminocyclopropylethyl; 1- aminocyclopropylmethyl; (2-amino-4,5-dihydro-oxazol-5-yl)(CH2)i_6; (2-amino-4,5-dihydro- oxazol-4-yl) (CH2)i_6; aminophenyl; 4-aminotetrahydropyran-4-yl(CH2)i-6; azetidin-2-yl(CH2)i_6; azetidin-3-yl(CH2)o-6; azetidin-3-ylcarbonyl; Ci_6alkoxy(CH2)2-6; Ci_6alkoxy(CH2)2-
6amino(CH2)2-6; Ci_6alkyl; Ci_6alkylamino(CH2)2-6; Ci_6alkylaminooxetanyl(CH2)i-6; Ci_
6alkylcarbonyl; Ci_6alkylcarbonylamino(CH2)2-6; Ci_6alkylcarbonylamino(CH2)i-60xetanyl(CH2)o- 6; Ci_6alkylsulfinyl(CH2)2-6; Ci_6alkylsulfonyl; carboxy(CH2)i_6; cyano(CH2)i_6; Ci_
6alkylaminocarbonyl(CH2)o-6; diCi_6alkylamino(CH2)2-6; diCi_6alkylaminocarbonyl;
difluoromethyl(CH2)i-6amino(CH2)2-6; hydrogen; hydroxy(CH2)2-io; hydroxy(CH2)2- 6amino(CH2)2-6; hydroxy(CH2)i_6carbonyl; hydroxy(CH2)i_60xetanyl(CH2)o-6; 4- hydroxycyclohexyl; isoxazol-3-yl; morpholin-2-yl(CH2)i_6; morpholin-4-yl(CH2)2-6; 2-oxa-6- aza-spiro[3.4]oct-8-yl; oxetanyl(CH2)o-6; N-oxetanylpyrrolidin-3-yl; oxo-pyrrolidin-4- ylcarbonyl; phenylaminocarbonyl; phenyl(CH2)i-6aminooxetanyl(CH2)i-6; phenylcarbonyl;
piperazinyl(CH2)2-6; piperidin- 1 -yl(CH2)2-6; piperidin-2-yl(CH2)i-6; piperidin-3-yl(CH2)o-6;
piperidin-4-yl(CH2)o-6; piperidin-2-ylcarbonyl; piperidin-3-ylcarbonyl; piperidin-4-ylcarbonyl; pyrazin-2-ylcarbonyl; pyrazol-3-yl; pyridazin-3-ylcarbonyl; pyridine-2-yl(CH2)o-6carbonyl;
pyridine-3-yl(CH2)o-6carbonyl; pyridine-2-ylamino(CH2)2-6; pyrrolidin-3-yl, unsubstituted or 4- substituted by halogen; pyrrolidin-4-yl, unsubstituted or 3-substituted by hydroxy or Ci_6alkoxy; pyrrolidin-2-yl(CH2)i-6; pyrrolidin-2-ylcarbonyl; tetrahydrofuran-3-yl; tetrahydropyran-4-yl;
Figure imgf000017_0001
R , wherein R is hydrogen or Ci_6alkyl; R is hydroxy, Ci_6alkyl or amino;
is CH2)i_
6,
Figure imgf000017_0002
i_6 or nyl(CH2)0_6;
Figure imgf000018_0001
is Ci_6alkoxy or amino;
R12 and R13, with the nitrogen atom to which they are attached, may form a pyrrolidinyl, piperazinyl, piperidinyl, morpholinyl, azetidinyl, diazepanyl or oxopyrrolidinyl ring; which may be unsubstituted, once or twice substituted by a group selected from halogen, Ci_6alkyl, Ci_
6alkoxy, gemdimethyl, amino, amino carbonyl, hydroxy, oxetanylamino, Ci_6alkylpiperazinyl and amino(CH2)i_6;
R12 and R13, with the nitrogen atom to which they are attached may form a bridge ring or a spiral ring selected from 2-oxa-6-aza-spiro[3.4]octan-6-yl, 2-oxa-5,7-diazaspiro[3.4]octan-6-one- 5-yl, (4a5', 7ai?)-hexahydropyrrolo[3,4-b][l ,4]oxazin-6(2H)-yl, 4,5,6,6a-tetrahydro-3aH- pyrrolo[3,4-d][l ,3]oxazol-5-yl, 2-aza-bicyclo[2.1.1]hexan-2-yl or 3-aza-bicyclo[3.1.0]hexan-3- yl; which may be unsubstituted or further substituted by amino; and all the remaining
substituents are as defined above in embodiment (i) to (vii).
Particular embodiment of present invention is (ix) a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein R1, R2, and R3 are hydrogen, fluoro, chloro or methyl;
R4 is hydrogen or methyl;
R5 is hydrogen;
R6 is hydrogen, fluoro, hydroxy, methoxy, morpholinyl or 4-(propan-2-yl)piperazin-l-yl;
R7 is hydrogen, fluoro, chloro, methyl, methoxy, hydroxyethoxy, or phenoxy;
R8 is hydrogen, fluoro or methoxy;
R9 is hydrogen or methyl;
R10 is hydrogen;
A is nitrogen or -C-R1 1, wherein R1 1 is hydrogen, fluoro, chloro, bromo, methyl, ethyl, methoxy, trifluoromethyl, trif uoromethoxy, pyridinyloxy, methoxyethoxy, difluoromethoxy, nitro, cyclopropyl, cyano, amino, vinyl, acetylenyl, amino carbonyl, hydroxyethoxy,
methylsulfanyl, methylsulfinyl, hydroxymethyl, deuteratedmethyl, carboxyl, methoxycarbonyl, hydroxy, difluoromethyl or methylCH(hydroxy)-; Y is -CH- or nitrogen;
Q is 2-amino-4,5-dihydro-l,3-oxazol-4-ylethyl; aminoethoxy; aminoethylaminosulfonyl; aminopropyl; carboxyethyl; methyl; phenylsulfonyl; piperidin-4-yl-carbonyl; piperidin-4-yloxy;
12 13 12 13
lH-pyrazol-3-yl; pyrrolidin-3-yloxy; or NR R , wherein one of R and R is hydrogen, methyl or hydroxyethyl, and the other one is aminobutyl; amino carbonylethyl;
amino carbonylmethyl; 1-aminocyclobutylmethyl; 2-aminocyclohexyl; 3-aminocyclohexyl; 4- aminocyclohexyl; 1-aminocyclohexylmethyl; 2-aminocyclopentyl; 1-aminocyclopropylethyl; 1- aminocyclopropylmethyl; aminodecyl; (2-amino-4,5-dihydro-oxazol-5-yl)methyl; (2-amino-4,5- dihydro-oxazol-4-yl)methyl; aminoethoxyethyl; aminoethyl; amino ethylcarbonyl;
amino ethylfluoromethylmethyl; amino ethylsulfanylethyl; aminoethylsulfonylethyl;
aminoheptyl; aminohexyl; aminomethylcarbonyl; (l-aminomethyl-3,3- difluorocyclobutyl)methyl; aminomethyldifluoromethyldifluoromethylmethyl;
aminomethyldifluoromethylmethyl; (2-amino-5-methyl-4,5-dihydro- 1 ,3-oxazol-5-yl)methyl; 3- amino methyl- 1 , 1 -dioxidothietan-3 -ylmethyl; aminomethylfluoromethylethyl;
aminomethylfluoromethylmethyl; aminomethyloxetanyl; aminomethyloxetanylmethyl; 3- (aminomethyl)thietan-3-ylmethyl; aminononyl; aminooctyl; aminooxetanylethyl;
aminooxetanylmethyl; aminopentyl; aminophenyl; aminopropyl; 4-aminotetrahydropyran-4- ylmethyl; 3-aminotetrahydrofuran-3-ylmethyl; azetidin-3-yl; azetidin-3 -ylcarbonyl; azetidin-2- ylmethyl; azetidin-3 -ylmethyl; carboxyethyl; carboxymethyl; cyanoethyl;
difluoromethylmethylamino ethyl; 4,5-dihydro-lH-imidazol-2-yl; dimethylaminocarbonyl;
dimethylamino ethyl; (l,l-dioxidothiomorpholin-4-yl)ethyl; ethyl; ethylaminocarbonyl;
ethylamino ethyl; ethylaminooxetanylmethyl; ethyl (oxetanyl)aminoethyl; hydrogen; 4- hydroxycyclohexyl; hydroxyethyl; hydroxyethylaminoethyl; hydroxyethyloxetanyl;
hydroxymethylcarbonyl; hydroxymethyloxetanylmethyl; hydroxynonyl; hydroxypropyl;
isoxazol-3-yl; methoxyethyl; methoxyethylamino ethyl; methyl; methylammocarbonylmethyl; methylamino ethyl; methylcarbonyl; methylcarbonylaminoethyl;
methylcarbonylaminomethyloxetanylmethyl; methylcarbonylammopropyl; methylsulfinylethyl; 2-(S'-methylsulfonimidoyl)ethyl; methylsulfonyl; morpholin-4-ylethyl; morpholin-2-ylmethyl; 2- oxa-6-aza-spiro[3.4]oct-8-yl; oxetanyl; oxetanylaminoethyl; oxetanylaminopropyl;
oxetanylmethyl; N-oxetanylpyrrolidin-3-yl; oxo-pyrrolidin-4-ylcarbonyl; phenylaminocarbonyl; phenylcarbonyl; phenylmethylaminooxetanylmethyl; piperazin-l-ylethyl; piperidin-2- ylcarbonyl; piperidin-3 -ylcarbonyl; piperidin-4-ylcarbonyl; piperidine-3-yl; piperidine-4-yl; piperidin-l-ylethyl; piperidin-2-ylmethyl; pyrazin-2-ylcarbonyl; pyrazol-3-yl; pyridazin-3- ylcarbonyl; pyridine-2-ylmethylcarbonyl; pyridine-2-ylaminoethyl; pyridine-2-ylcarbonyl;
pyridine-3 -ylcarbonyl; pyrrolidin-3-yl, unsubstituted or 4-substituted by fluoro; pyrrolidin-4-yl, unsubstituted or 3 -substituted by hydroxy or methoxy; pyrrolidin-2-ylmethyl; pyrrolidin-2- ylcarbonyl; tetrahydrofuran-3-yl; tetrahydropyran-4-yl; tetrazolylethyl; trifluoromethylsulfonyl; -(CH^-C-R15
trifluoromethylcarbonylaminomethyloxetanyl; R , wherein R14 is hydrogen or methyl;
R15 is hydroxy, methyl or amino; and R16 is methyl, trifiuoromethyl, hydro xymethyl,
Figure imgf000020_0001
hydrogen, methyl or hydroxymethyl; R18 is hydroxymethyl or methyl; R19 is hydroxymethyl,
o
\ 22
aminomethyl, carboxy, aminocarbonyl or aminocarbonylmethyl; or R , wherein R20 is hydrogen or methyl; R21 is methyl or ethyl; R22 is methoxy or amino;
R12 and R13, with the nitrogen atom to which they are attached, may form a pyrrolidinyl, piperazinyl, piperidinyl, morpholinyl, azetidinyl, diazepanyl or oxopyrrolidinyl ring; which may be unsubstituted, once or twice substituted by a group selected from fluoro, methyl, methoxy, gemdimethyl, amino, aminocarbonyl, hydroxy, oxetanylamino, methylpiperazinyl and aminomethyl;
R12 and R13, with the nitrogen atom to which they are attached may form a bridge ring or a spiral ring selected from 2-oxa-6-aza-spiro[3.4]octan-6-yl, 2-oxa-5,7-diazaspiro[3.4]octan-6-one- 5-yl, (4a5',7ai?)-hexahydropyrrolo[3,4-b][l,4]oxazin-6(2H)-yl, 4,5,6,6a-tetrahydro-3aH- pyrrolo[3,4-d][l,3]oxazol-5-yl, 2-aza-bicyclo[2.1.1]hexan-2-yl or 3-aza-bicyclo[3.1.0]hexan-3- yl; which may be unsubstituted or further substituted by amino; and all the remaining
substituents are as defined above in embodiment (viii).
Another particular embodiment of present invention is (x) a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein R1, R2, R3, R4, R5, R6, R7, R8, R9, and R10 are hydrogen;
Ais -C-R11, wherein R11 is Ci_6alkyl;
X is S(0)NH;
Y is -CH-;
12 13 12 13
Q is NR R , wherein one of R and R is hydrogen; and the other one is
amino (CH2)2-6;
R12 and R13, with the nitrogen atom to which they are attached, may form a pyrrolidinyl ring, which may be twice substituted by a group selected from amino and hydro xyl; and all the remaining substituents are as defined above in embodiment (i) to (ix). Still another particular embodiment of invention is (xi) a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein
R1, R2, R3, R4, R5, R6, R7, R8, R9, and R10 are hydrogen;
A is -C-R11 , wherein R11 is methyl;
12 13 12 13
u is NR1ZR , wherein one of R and R is hydrogen; and the other one is amino ethyl;
R12 and R13, with the nitrogen atom to which they are attached, may form a pyrrolidinyl ring, which may be twice substituted by a group selected from amino and hydro xyl; and all the remaining substituents are as defined above in embodiment (x).
Particular embodiment of present invention is a compound of formula (I) or a
pharmaceutically acceptable salt thereof, selected from:
N-[(3-aminooxetan-3-yl)methyl]-2-(8-methoxy- 1 , 1 -dioxido-2,3-dihydro- 1 ,4-benzothiazepin- 4(5H)-yl)-6-methylquinolin-4-amine; N-[(3-aminooxetan-3-yl)methyl]-2-(8-fluoro- 1 , 1 -dioxido- 2,3-dihydro- 1 ,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-amine; N-[(3-aminooxetan-3- yl)methyl]-2-(7-fluoro- 1 , 1 -dioxido-2,3-dihydro- 1 ,4-benzothiazepin-4(5H)-yl)-6-methylquinolin- 4-amine; N-[(3-aminooxetan-3-yl)methyl]-2-(9-fluoro- 1 , l-dioxido-2,3-dihydro- 1 ,4- benzothiazepin-4(5H)-yl)-6-methylquinolin-4-amine; N-[(3-aminooxetan-3-yl)methyl]-2-(7- methoxy- 1 , 1 -dioxido-2,3-dihydro- 1 ,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-amine; N- [(3-aminooxetan-3-yl)methyl]-2-(8-chloro- 1 , 1 -dioxido-2,3-dihydro- 1 ,4-benzothiazepin-4(5H)- yl)-6-methylquinolin-4-amine; N-[(3-aminooxetan-3-yl)methyl]-2-(7-methoxy- 1 , 1 -dioxido-2,3- dihydro- 1 ,4-benzothiazepin-4(5H)-yl)quinolin-4-amine; N-[(3-aminotetrahydrofuran-3- yl)methyl]-2-(l , 1 -dioxido-2,3-dihydro- 1 ,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-amine; N-[(3-aminooxetan-3-yl)methyl]-2-(l , 1 -dioxido-2,3-dihydro- 1 ,4-benzothiazepin-4(5H)-yl)-6- methylquinolin-4-amine; N-[(4-aminotetrahydro-2H-pyran-4-yl)methyl]-2-(l,l-dioxido-2,3- dihydro- 1 ,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-amine; N-[(3-aminooxetan-3- yl)methyl]-2-(8-methyl- 1 , 1 -dioxido-2,3-dihydro- 1 ,4-benzothiazepin-4(5H)-yl)quinolin-4-amine; N-[(3-aminooxetan-3-yl)methyl]-6-methyl-2-(8-methyl- 1 , 1 -dioxido-2,3-dihydro- 1 ,4- benzothiazepin-4(5H)-yl)quinolin-4-amine; 2-(l , 1 -dioxido-2,3-dihydro- 1 ,4-benzothiazepin- 4(5H)-yl)-6-methyl-N-(2-oxa-6-azaspiro[3.4]oct-8-yl)quinolin-4-amine; N-[2-(3-aminooxetan-3- yl)ethyl]-2-(l , 1 -dioxido-2,3-dihydro- 1 ,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-amine; N- [(3 -aminooxetan-3-yl)methyl]-6-methyl-2-(5 -methyl- 1 , 1 -dioxido-2,3-dihydro- 1 ,4- benzothiazepin-4(5H)-yl)quinolin-4-amine; N-[(3-aminooxetan-3-yl)methyl]-2-(8-methoxy- 1,1- dioxido-2,3-dihydro- 1 ,4-benzothiazepin-4(5H)-yl)quinolin-4-amine; N-[(3-aminooxetan-3- yl)methyl]-2-(l , 1 -dioxido-2,3-dihydro- 1 ,4-benzothiazepin-4(5H)-yl)- 1 ,6-naphthyridin-4-amine; N-[(l-aminocyclohexyl)methyl]-2-(l,l-dioxido-2,3-dihydro-l,4-benzothiazepin-4(5H)-yl)-6- methylquinolin-4-amine; N-{[3-(aminomethyl)oxetan-3-yl]methyl}-2-(8-fluoro-l,l-dioxido-2,3- dihydro-l,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-amine; N-{[3-(benzylamino)oxetan-3- yljmethyl} -6-chloro-2-(7-fluoro- 1 , 1 -dioxido-2,3-dihydro- 1 ,4-benzothiazepin-4(5H)-yl)quinolin- 4-amine; N-[(3-aminooxetan-3-yl)methyl]-6-chloro-2-(7-fluoro- 1 , 1 -dioxido-2,3-dihydro- 1 ,4- benzothiazepin-4(5H)-yl)quinolin-4-amine; N-{[3-(aminomethyl)oxetan-3-yl]methyl}-2-(7- methoxy- 1 , 1 -dioxido-2,3-dihydro- 1 ,4-benzothiazepin-4(5H)-yl)quinolin-4-amine; N- {[3- (aminomethyl)oxetan-3-yl]methyl} -2-(7-methoxy- 1 , 1 -dioxido-2,3-dihydro- 1 ,4-benzothiazepin- 4(5H)-yl)-6-methylquinolin-4-amine; N- {[3-( {[2-(7-methoxy- 1 , 1 -dioxido-2,3-dihydro- 1 ,4- benzothiazepin-4(5H)-yl)-6-methylquino lin-4-yl] amino } methyl)oxetan-3 -yl]methyl}acetamide; N- {[3-(aminomethyl)oxetan-3-yl]methyl} -2-(8-methyl- 1 , 1 -dioxido-2,3-dihydro- 1 ,4- benzothiazepin-4(5H)-yl)quinolin-4-amine; N-{[3-(aminomethyl)oxetan-3-yl]methyl}-6-methyl- 2-(8-methyl- 1 , 1 -dioxido-2,3-dihydro- 1 ,4-benzothiazepin-4(5H)-yl)quinolin-4-amine; [3-( {[2- (1,1 -dioxido-2,3-dihydro- 1 ,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4- yl]amino}methyl)oxetan-3-yl]methanol; (2S)-3- {[2-(l , l-dioxido-2,3-dihydro-l ,4- benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl] amino} propane- 1,2-diol; (2i?)-3- {[2-(l, 1- dioxido-2,3-dihydro-l,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]amino}propane- diol; N- { [ 1 -(aminomethyl)-3 ,3-difluorocyclobutyl]methyl} -2-( 1 , 1 -dioxido-2,3-dihydro- 1 ,4- benzothiazepin-4(5H)-yl)-6-methylquino lin-4-amine; N- [(3 -aminooxetan-3 -yl)methyl] -6-chloro- 2-(8-methoxy- 1 , 1 -dioxido-2,3-dihydro- 1 ,4-benzothiazepin-4(5H)-yl)quinolin-4-amine; N- {[3- (aminomethyl)oxetan-3-yl]methyl} -6-chloro-2-(8-methoxy- 1 , 1 -dioxido-2,3-dihydro- 1 ,4- benzothiazepin-4(5H)-yl)quinolin-4-amine; trans-N-[2-{\ , 1 -dioxido-2,3-dihydro- 1 ,4- benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]cyclohexane-l,2-diamine; N-[2-(l,l-dioxido- 2,3-dihydro-l,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]cyclohexane-l,3-diamine; (Ji?)-l-[2-(l,l-dioxido-2,3-dihydro-l,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]-4,4 dimethylpyrrolidin-3-ol; cz5-N-[2-(l,l-dioxido-2,3-dihydro-l,4-benzothiazepin-4(5H)-yl)-6- methylquinolin-4-yl]cyclohexane-l ,4-diamine; N-[2-(l , l-dioxido-2,3-dihydro-l ,4- benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]-2,2-difluoropropane- 1 ,3-diamine; N-[6-chloro- 2-(l,l-dioxido-2,3-dihydro-l,4-benzothiazepin-4(5H)-yl)quinolin-4-yl]-2,2-difluoropropan^ diamine; N-[2-(l,l-dioxido-2,3-dihydro-l,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]-2- fluoropropane- 1 ,3-diamine; N-[(3-aminooxetan-3-yl)methyl]-6-chloro-2-(l , 1 -dioxido-2,3- dihydro-l,4-benzothiazepin-4(5H)-yl)quinolin-4-amine; [4- {[(3 -aminooxetan-3 - yl)methyl] amino } -2-(l , 1 -dioxido-2,3-dihydro- 1 ,4-benzothiazepin-4(5H)-yl)quinolin-6- yljmethanol; N- [(3 -aminooxetan-3 -yl)methyl] -2-( 1 , 1 -dioxido-2,3-dihydro- 1 ,4-benzothiazepin- 4(5H)-yl)-7-fluoro-6-methylquinolin-4-amine; N-[(3-aminooxetan-3-yl)methyl]-2-(l,l-dioxido- 2,3-dihydro-l,4-benzothiazepin-4(5H)-yl)-5-fluoro-6-methylquinolin-4-amine; N~l— [6-chloro- 2-(l,l-dioxido-2,3-dihydro-l,4-benzothiazepin-4(5H)-yl)quinolin-4-yl]-2-methylpropane-l,2- diamine; 2-( 1 , 1 -dioxido-2,3-dihydro- 1 ,4-benzothiazepin-4(5H)-yl)-6-methyl-N-(tetrahydro-2H- pyran-4-yl)quinolin-4-amine; 2-(l , 1 -dioxido-2,3-dihydro- 1 ,4-benzothiazepin-4(5H)-yl)-6- methyl-N-[2-(piperazin- 1 -yl)ethyl]quinolin-4-amine; 2-(l , 1 -dioxido-2,3-dihydro- 1 ,4- benzothiazepin-4(5H)-yl)-6-methyl-N-(piperidr^^ N-[2-(l,l- dioxido-2,3-dihydro- 1 ,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]heptane- 1 ,7-diamine; N-[2-(l , 1 -dioxido-2,3-dihydro- 1 ,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]-N'- methylethane- 1 ,2-diamine; N-[2-(l , 1 -dioxido-2,3-dihydro- 1 ,4-benzothiazepin-4(5H)-yl)-6- methylquinolin-4-yl]-N,N-dimethylethane- 1 ,2-diamine; 2-(l , 1 -dioxido-2,3-dihydro- 1 ,4- benzothiazepin-4(5H)-yl)-N,6-dimethylquinolin-4-amine trifluoroacetate; (3S,4S)-\-\2-(\,\- dioxido-2,3-dihydro-l,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]pyr^
2-(l,l-dioxido-2,3-dihydro-l,4-benzothiazepin-4(5H)-yl)-6-methyl-N-(pyrrolidm^
ylmethyl)quinolin-4-amine; 4-[4-(l,4-diazepan-l-yl)-6-methylquinolin-2-yl]-2,3,4,5-tetrahydro- 1 ,4-benzothiazepine 1 , 1 -dioxide; N-[2-(l , 1 -dioxido-2,3-dihydro- 1 ,4-benzothiazepin-4(5H)-yl)-6- methylquinolin-4-yl]-N'-ethylethane- 1 ,2-diamine; 2- {[2-(l , 1 -dioxido-2,3-dihydro- 1 ,4- benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl] amino }ethanol; 2-(l,l-dioxido-2,3-dihydro-l,4- benzothiazepin-4(5H)-yl)-6-methyl-N-(piperidin-4-yl)quinolin-4-amine; 2-(l,l-dioxido-2,3- dihydro- 1 ,4-benzothiazepin-4(5H)-yl)-6-methyl-N-(piperidin-3-yl)quinolin-4-amine; 2-(l , 1 - dioxido-2,3-dihydro-l,4-benzothiazepin-4(5H)-yl)-6-methyl-N-(piperidin-2-ylmethyl)quinolin 4-amine; 2-[(2- {[2-(l , 1 -dioxido-2,3-dihydro- 1 ,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4- yljamino} ethyl)amino]ethanol; N-[2-(l , l-dioxido-2,3-dihydro-l ,4-benzothiazepin-4(5H)-yl)-6- methylquinolin-4-yl]-2,2,3,3-tetrafluorobutane- 1 ,4-diamine; N-[2-(l , 1 -dioxido-2,3-dihydro- 1 ,4- benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]-N'-(2-methoxyethyl)ethane- 1 ,2-diamine; 1 -[2- (1,1 -dioxido-2,3-dihydro- 1 ,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]-3- methylpyrrolidin-3-ol; N-[6-chloro-2-(l,l-dioxido-2,3-dihydro-l,4-benzothiazepin-4(5H)- yl)quinolin-4-yl] ethane- 1 ,2-diamine; 2-(l , 1 -dioxido-2,3-dihydro- 1 ,4-benzothiazepin-4(5H)-yl)- 6-methyl-N-(oxetan-3 -yl)quino lin-4-amine; N- [(3 -aminooxetan-3 -yl)methyl] -2-( 1 , 1 -dioxido-2,3 - dihydro- 1 ,4-benzothiazepin-4(5H)-yl)quinolin-4-amine; 2-( 1 , 1 -dioxido-2,3-dihydro- 1 ,4- benzothiazepin-4(5H)-yl)-6-methyl-N- [( Ji?)-tetrahydrofuran-3 -yl] quino lin-4-amine; N- { [3 - (aminomethyl)oxetan-3-yl]methyl} -2-(l , 1 -dioxido-2,3-dihydro- 1 ,4-benzothiazepin-4(5H)-yl)-6- methylquinolin-4-amine; N-{[3-(aminomethyl)oxetan-3-yl]methyl}-6-chloro-2-(l,l-dioxido-2,3- dihydro-l,4-benzothiazepin-4(5H)-yl)quinolin-4-amine; N-{[3-(aminomethyl)oxetan-3- yljmethyl} -2-(l , 1 -dioxido-2,3-dihydro- 1 ,4-benzothiazepin-4(5H)-yl)quinolin-4-amine; 2-(l , 1 - dioxido-2,3-dihydro-l,4-benzothiazepin-4(5H)-yl)-6-methyl-N-(oxetan-3-ylmethyl)quinolin-4- amine; N-[(l-aminocyclobutyl)methyl]-2-(l,l-dioxido-2,3-dihydro-l,4-benzothiazepin-4(5H)- yl)-6-methylquinolin-4-amine; N-[2-(l,l-dioxido-2,3-dihydro-l,4-benzothiazepin-4(5H)-yl)-6- methylquinolin-4-yl]pentane- 1 ,5-diamine; N-[2-(l , 1 -dioxido-2,3-dihydro- 1 ,4-benzothiazepin- 4(5H)-yl)-6-methylquinolin-4-yl]hexane- 1 ,6-diamine; N-[2-(l , 1 -dioxido-2,3-dihydro- 1 ,4- benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]- 1 ,1,1 -trifluoromethanesulfonamide
hydrochloride; N-[2-(l , 1 -dioxido-2,3-dihydro- 1 ,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4- yl]pyridazine-3-carboxamide; N-[2-(l,l-dioxido-2,3-dihydro-l,4-benzothiazepin-4(5H)-yl)-6- methylquinolin-4-yl]benzamide; N-[2-(l,l-dioxido-2,3-dihydro-l,4-benzothiazepin-4(5H)-yl)-6- methylquinolin-4-yl]acetamide; N-[2-(l,l-dioxido-2,3-dihydro-l,4-benzothiazepin-4(5H)-yl)-6- methylquinolin-4-yl]piperidine-3-carboxamide; N-[2-(l,l-dioxido-2,3-dihydro-l,4- benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]piperidine-4-carboxamide; 3-[2-(l , 1-dioxido- 2,3-dihydro- 1 ,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]- 1 , 1 -dimethylurea; 2-(l,l- dioxido-2,3-dihydro- 1
Figure imgf000024_0001
amine; N- {[3-(aminomethyl)oxetan-3-yl]methyl}-2-(l , l-dioxido-2,3-dihydro-l ,4- benzothiazepin-4(5H)-yl)-6-(~2~H_3_)methylquinolin-4-amine; N-[(3-aminooxetan-3- yl)methyl]-6-chloro-2-(2,3-dihydro- 1 ,4-benzothiazepin-4(5H)-yl)quinolin-4-amine; N-[6-chloro- 2-(2,3-dihydro- 1 ,4-benzothiazepin-4(5H)-yl)quinolin-4-yl]ethane- 1 ,2-diamine; N-[(3- aminooxetan-3-yl)methyl]-2-(2,3-dihydro-l,4-benzothiazepin-4(5H)-yl)-6-methylquinolm amine; 1 -[2-(2,3-dihydro- 1 ,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]pyrrolidin-3- amine; N-[2-(2,3-dihydro- 1 ,4-benzothiazepin-4(5H)-yl)-6-methylquinazolin-4-yl]-2,2- difluoropropane- 1 ,3-diamine; 2-(l , 1 -dioxido-2,3-dihydro- 1 ,4-benzothiazepin-4(5H)-yl)-N-[2- (l,l-dioxidothiomorpholin-4-yl)ethyl]-6-methylquinolin-4-amine; N-[2-(2-aminoethoxy)ethyl]- 2-(l,l-dioxido-2,3-dihydro-l,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-amine; N~l— [2- (1,1 -dioxido-2,3-dihydro- 1 ,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]-2- methylpropane- 1 ,2-diamine; N~ 1 ~-[2-( 1 , 1 -dioxido-2,3-dihydro- 1 ,4-benzothiazepin-4(5H)- yl)quinolin-4-yl]-2-methylpropane-l,2-diamine; N~l~- [2-(l,l-dioxido-2,3-dihydro-l,4- benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]propane- 1 ,2-diamine; 4-[6-methyl-4-(4- methylpiperazin- 1 -yl)quinolin-2-yl]-2,3,4,5-tetrahydro- 1 ,4-benzothiazepine 1 , 1 -dioxide; 1 - {[2- (l,l-dioxido-2,3-dihydro-l,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]amino}propan^ ol; (25)-N~l~-[2-(l,l-dioxido-2,3-dihydro-l,4-benzothiazepin-4(5H)-yl)-6-methylquinolm^ yl]propane- 1 ,2-diamine; (2R)-N~ 1 ~-[2-( 1 , 1 -dioxido-2,3-dihydro- 1 ,4-benzothiazepin-4(5H)-yl)- 6-methylquinolin-4-yl]propane- 1 ,2-diamine; N-[(3-aminooxetan-3-yl)methyl]-2-(l , 1 -dioxido- 2,3-dihydro- 1 ,4-benzothiazepin-4(5H)-yl)-7,8-difluoro-6-methylquinolin-4-amine; N-(2,2- difluoroethyl)-A '-[2-(l,l-dioxido-2,3-dihydro-l,4-benzothiazepin-4(5H)-yl)-6-meth^
yljethane- 1 ,2-diamine; 3- { [2-( 1 , 1 -dioxido-2,3-dihydro- 1 ,4-benzothiazepin-4(5H)-yl)-6- methylquino lin-4-yl] amino } oxetan-3 -ethano 1; N- { [3 -(amino methyl)thietan-3 -yljmethyl} -2-( 1 , 1 - dioxido-2,3-dihydro-l,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-amine; N-{[3-
(aminomethyl)- 1 , 1 -dioxidothietan-3-yl]methyl} -2-( 1 , 1 -dioxido-2,3-dihydro- 1 ,4-benzothiazepin- 4(5H)-yl)-6-methylquinolin-4-amine; N-(4,5-dihydro-lH-imidazol-2-yl)-2-(l,l-dioxido-2,3- dihydro- 1 ,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-amine; trans-4- { [2-( 1 , 1 -dioxido-2,3- dihydro-l,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]amino}cyclohexanol; (2S)-2-{[2- (l,l-dioxido-2,3-dihydro-l,4-berizothiazepin-4(5
ol; tran5-l-[2-(l,l-dioxido-2,3-dihydro-l,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]-4- methoxypyrrolidin-3-amine; 2-(l , 1 -dioxido-2,3-dihydro- 1 ,4-benzothiazepin+D 154-4(5H)-yl)-N- [tra/75-4-methoxypyrrolidin-3-yl]-6-methylquinolin-4-amine; 4- {4-[(4aS, 7aR)- hexahydropyrrolo [3 ,4-b] [ 1 ,4]oxazin-6(2H)-yl]-6-methylquinolin-2-yl} -2,3 ,4,5-tetrahydro- 1 ,4- benzothiazepine 1 , 1 -dioxide; (3R,4R)- 1 -[2-(l , 1 -dioxido-2,3-dihydro- 1 ,4-benzothiazepin-4(5H)- yl)-6-methylquinolin-4-yl]-4-(4-methylpiperazin- 1 -yl)pyrrolidin-3-ol; N- {2-[(2- aminoethyl)sulfanyl]ethyl} -2-(l , 1 -dioxido-2,3-dihydro- 1 ,4-benzothiazepin-4(5H)-yl)-6- methylquinolin-4-amine; 1 - { 1 -[2-(l , 1 -dioxido-2,3-dihydro- 1 ,4-benzothiazepin-4(5H)-yl)-6- methylquinolin-4-yl]piperidin-4-yl}methanamine; 2-{[2-(8-methoxy-l,l-dioxido-2,3-dihydro- 1 ,4-benzothiazepin-4(5H)-yl)quino lin-4-yl] amino } ethanol; N-[2-(l , l-dioxido-2,3-dihydro-l ,4- benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]propane- 1 ,3-diamine; 4-[6-methyl-4- (morpholin-4-yl)quinolin-2-yl]-2,3,4,5-tetrahydro-l ,4-benzothiazepine 1 , 1-dioxide; 3- {[2-(l , 1- dioxido-2,3-dihydro- 1 ,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]amino}propan- 1 -ol; 2- (1,1 -dioxido-2,3-dihydro- 1 ,4-benzothiazepin-4(5H)-yl)-6-methyl-N-[2-(piperidin- 1 - yl)ethyl]quinolin-4-amine; 1 -amino-3- {[2-(l , 1 -dioxido-2,3-dihydro- 1 ,4-benzothiazepin-4(5H)- yl)-6-methylquinolin-4-yl]amino}propan-2-ol; N-[2-(l,l-dioxido-2,3-dihydro-l,4- benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]glycine; N-[2-(l , 1 -dioxido-2,3-dihydro- 1 ,4- benzothiazepin-4(5H)-yl)-6-fluoroquinolin-4-yl]ethane- 1 ,2-diamine; N-[2-(l , 1 -dioxido-2,3- dihydro- 1 ,4-benzothiazepin-4(5H)-yl)-6-ethylquinolin-4-yl]ethane- 1 ,2-diamine; N-[7-chloro-2- (1,1 -dioxido-2,3-dihydro- 1 ,4-benzothiazepin-4(5H)-yl)quinolin-4-yl]propane- 1 ,3-diamine; N-[8- chloro-2-(l , 1 -dioxido-2,3-dihydro- 1 ,4-benzothiazepin-4(5H)-yl)quinolin-4-yl]propane- 1 ,3- diamine; N-[5-chloro-2-(l,l-dioxido-2,3-dihydro-l,4-benzothiazepin-4(5H)-yl)quinolin-4- yl]propane- 1 ,3-diamine; N-[2-(l , 1 -dioxido-2,3-dihydro- 1 ,4-benzothiazepin-4(5H)-yl)-6- methylquinolin-4-yl]-2,2-dimethylpropane-l,3-diamine; N-[2-(l,l-dioxido-2,3-dihydro-l,4- benzothiazepin-4(5H)-yl)quinolin-4-yl]ethane-l,2-diamine; N-[2-(l,l-dioxido-2,3-dihydro-l,4- benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]ethane-l,2-diamine; N~2— [2-(l,l-dioxido-2,3- dihydro- 1 ,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]-2-methylpropane- 1 ,2-diamine; N~2~-[2-(l,l-dioxido-2,3-dihydro-l,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4- yl]propane- 1 ,2-diamine; N-[2-( 1 , 1 -dioxido-2,3-dihydro- 1 ,4-benzothiazepin-4(5H)-yl)-6- methylquinolin-4-yl]butane-l,4-diamine; N-[2-(l,l-dioxido-2,3-dihydro-l,4-benzothiazepin- 4(5H)-yl)-6-nitroquinolin-4-yl]ethane-l,2-diamine; N-[2-(l,l-dioxido-2,3-dihydro-l,4- benzothiazepin-4(5H)-yl)-5-fluoro-6-methylquinolin-4-yl]ethane-l,2-diamine; 2-{[2-(l,l- dioxido-2,3-dihydro- 1 ,4-benzothiazepin-4(5H)-yl)-5-fluoro-6-methylquinolin-4- yljamino } ethanol; 2- { [2-( 1 , 1 -dioxido-2,3-dihydro- 1 ,4-benzothiazepin-4(5H)-yl)-7-fluoro-6- methylquinolin-4-yl] amino} ethanol; N-[2-(l,l-dioxido-2,3-dihydro-l,4-benzothiazepin-4(5H)- yl)-7-fluoro-6-methylquinolin-4-yl]ethane-l,2-diamine; N-[2-(l,l-dioxido-2,3-dihydro-l,4- benzothiazepin-4(5H)-yl)-7,8-difluoro-6-methylquinolin-4-yl]ethane-l,2-diamine; 2-(l,l- dioxido-2,3-dihydro- 1 ,4-benzothiazepin-4(5H)-yl)-N-(2-methoxyethyl)-6-methylquinolin-4- amine; l-[2-(l,l-dioxido-2,3-dihydro-l,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4- yl]piperidin-4-amine; 1 -[2-(l , 1 -dioxido-2,3-dihydro- 1 ,4-benzothiazepin-4(5H)-yl)- 1 ,6- naphthyridin-4-yl]pyrrolidin-3-amine; N-[6-(difluoromethyl)-2-(l , 1 -dioxido-2,3-dihydro- 1 ,4- benzothiazepin-4(5H)-yl)quinolin-4-yl]propane- 1 ,3-diamine; 6-chloro-2-(l , 1 -dioxido-2,3- dihydro- 1 ,4-benzothiazepin-4(5H)-yl)-N-ethylquinolin-4-amine; 2- { [6-chloro-2-( 1 , 1 -dioxido-
2.3- dihydro-l,4-benzothiazepin-4(5H)-yl)quinolin-4-yl]amino}ethanol; N-[6-chloro-2-(l,l- dioxido-2,3-dihydro- 1 ,4-benzothiazepin-4(5H)-yl)quinolin-4-yl]-N'-methylethane- 1 ,2-diamine; N-[2-(l , 1 -dioxido-2,3-dihydro- 1 ,4-benzothiazepin-4(5H)-yl)-6-(methylsulfanyl)quinolin-4- yl]propane- 1 ,3-diamine; N-[6-bromo-2-(l , 1 -dioxido-2,3-dihydro- 1 ,4-benzothiazepin-4(5H)- yl)quinolin-4-yl]propane-l,3-diamine; {4-[(2-aminoethyl)amino]-2-(l,l-dioxido-2,3-dihydro-
1.4- benzothiazepin-4(5H)-yl)quinolin-6-yl} methanol; 2-{[2-(l,l-dioxido-2,3-dihydro-l,4- benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]amino}propane-l,3-diol; 2,2'-{[2-(l,l-dioxido- 2, 3 -dihydro- 1 ,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]imino} diethanol; 4- {[2-(l , 1 - dioxido-2,3-dihydro-l,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]amino}-3- hydro xybutanoic acid; 1 -amino-3- { [2-( 1 , 1 -dioxido-2,3-dihydro- 1 ,4-benzothiazepin-4(5H)-yl)-6- methylquinolin-4-yl] amino } -2-methylpropan-2-ol; 2-( 1 , 1 -dioxido-2,3-dihydro- 1 ,4- benzothiazepin-4(5H)-yl)-6-methyl-N-[2-(morpholin-4-yl)ethyl]quinolin-4-amine; 2-{[2-(l,l- dioxido-2,3-dihydro- 1 ,4-benzothiazepin-4(5H)-yl)- 1 ,6-naphthyridin-4-yl]amino} ethanol; N-[2- (1,1 -dioxido-2,3-dihydro- 1 ,4-benzothiazepin-4(5H)-yl)-8-methylquinolin-4-yl]nonane- 1 ,9- diamine; N-[2-(l,l-dioxido-2,3-dihydro-l,4-benzothiazepin-4(5H)-yl)-8-methylquinolin-4- yl]decane- 1 , 10-diamine; N-[2-(l , 1 -dioxido-2,3-dihydro- 1 ,4-benzothiazepin-4(5H)-yl)-6- methylquinolin-4-yl]octane- 1 ,8-diamine; 9- {[2-(l , 1 -dioxido-2,3-dihydro- 1 ,4-benzothiazepin- 4(5H)-yl)-6-methylquinolin-4-yl]amino}nonan-l-ol; N-[2-(l,l-dioxido-2,3-dihydro-l,4- benzothiazepin-4(5H)-yl)-8-methylquinolin-4-yl]octane- 1 ,8-diamine; czs-4-amino- 1 -[2-(l , 1 - dioxido-2,3-dihydro- 1 ,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]pyrrolidin-3-ol; N-[2- (1,1 -dioxido-2,3-dihydro- 1 ,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]-L-alanine; N-[2- (1,1 -dioxido-2,3-dihydro- 1 ,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]-beta-alanine; N- [2-(l , 1 -dioxido-2,3-dihydro- 1 ,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]benzene- 1 ,3- diamine; N-[2-(l,l-dioxido-2,3-dihydro-l,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4- yljbenzene- 1 ,4-diamine; (3S)- 1 -[2-(l , 1 -dioxido-2,3-dihydro- 1 ,4-benzothiazepin-4(5H)-yl)-6- methylquinolin-4-yl]pyrrolidin-3-ol; (3R)- 1 -[2-(l , 1 -dioxido-2,3-dihydro- 1 ,4-benzothiazepin- 4(5H)-yl)-6-methylquinolin-4-yl]pyrrolidin-3-ol; trans-N-[2-{\ , 1 -dioxido-2,3-dihydro- 1 ,4- benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]cyclopentane-l,2-diamine; l-[2-(l,l-dioxido- 2,3-dihydro- 1 ,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]piperidin-3-amine; 2-(l , 1 - dioxido-2,3-dihydro- 1 ,4-benzothiazepin-4(5H)-yl)-N,N,6-trimethylquinolin-4-amine; N-[2-(l , 1 - dioxido-2,3-dihydro-l,4-benzothiazepin-4(5H)-yl)-6-(trifluoromethoxy)quinolin-4-yl]prop 1 ,3-diamine; N-[2-(l , 1 -dioxido-2,3-dihydro- 1 ,4-benzothiazepin-4(5H)-yl)-6- (trifluoromethyl)quinolin-4-yl]propane- 1 ,3-diamine; N-[6-(difluoromethoxy)-2-(l , 1 -dioxido-2,3- dihydro- 1 ,4-benzothiazepin-4(5H)-yl)quinolin-4-yl]propane- 1 ,3-diamine; N-[2-(l , 1 -dioxido-2,3- dihydro- 1 ,4-benzothiazepin-4(5H)-yl)-6-methoxyquinolin-4-yl]propane- 1 ,3-diamine; N-[2-(l , 1 - dioxido-2,3-dihydro- 1 ,4-benzothiazepin-4(5H)-yl)-8-methylquinolin-4-yl]propane- 1 ,3-diamine; N-[2-(l , 1 -dioxido-2,3-dihydro- 1 ,4-benzothiazepin-4(5H)-yl)-5-methylquinolin-4-yl]propane-
1.3- diamine; N-[2-(l , 1 -dioxido-2,3-dihydro- 1 ,4-benzothiazepin-4(5H)-yl)-7-methylquinolin-4- yl]propane- 1 ,3-diamine; N- {[3-(aminomethyl)oxetan-3-yl]methyl} -2-(l , 1 -dioxido-2,3-dihydro-
1.4- benzothiazepin-4(5H)-yl)-6-fluoroquinolin-4-amine; N-[(3-aminooxetan-3-yl)methyl]-6- methyl-2-(l-oxido-2,3-dihydro-l,4-benzothiazepin-4(5H)-yl)quinolin-4-amine; (+)-N-[(3- aminooxetan-3-yl)methyl]-6-methyl-2-[ 1 -oxido-2,3-dihydro- 1 ,4-benzothiazepin-4(5H)- yl]quinolin-4-amine; (-)-N-[(3-aminooxetan-3-yl)methyl]-6-methyl-2-[ 1 -oxido-2,3-dihydro- 1 ,4- benzothiazepin-4(5H)-yl] quino lin-4-amine; N- [(3 -aminooxetan-3 -yl)methyl] -6-chloro-2-( 1 - oxido-2,3-dihydro- 1 ,4-benzothiazepin-4(5H)-yl)quinolin-4-amine; 2,2-difluoro-N-[6-methyl-2- (1 -oxido-2,3-dihydro- 1 ,4-benzothiazepin-4(5H)-yl)quinolin-4-yl]propane- 1 ,3-diamine; N-[6- chloro-2-(l-oxido-2,3-dihydro-l,4-benzothiazepm
1,3-diamine; N-[6-chloro-2-(l-oxido-2,3-dihydro-l,4-benzothiazepin-4(5H)-yl)quinolin-4- yl]ethane-l,2-diamine; N-{[3-(aminomethyl)oxetan-3-yl]methyl}-6-methyl-2-(l-oxido-2,3- dihydro-l,4-benzothiazepin-4(5H)-yl)quinolin-4-amine; N-{[3-(aminomethyl)oxetan-3- yljmethyl} -6-chloro-2-(l -oxido-2,3-dihydro- 1 ,4-benzothiazepin-4(5H)-yl)quinolin-4-amine; N- [6-methyl-2-(l -oxido-2,3-dihydro- 1 ,4-benzothiazepin-4(5H)-yl)quinolin-4-yl] ethane- 1 ,2- diamine; 2- { [6-methyl-2-( 1 -oxido-2,3-dihydro- 1 ,4-benzothiazepin-4(5H)-yl)quinolin-4- yl] amino }ethanol; tra/75-4-amino-l-[6-methyl-2-(l-oxido-2,3-dihydro-l,4-benzothiazepin- 4(5H)-yl)quinolin-4-yl]pyrrolidin-3-ol; (7R,JS, S)-3-[2-(1 -dioxido-2,3-dihydro-l,4- benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]-3-azabicyclo[3.1.0]hexan-6-amine; trans-4- amino-l-[2-(l,l-dioxido-2,3-dihydro-l,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4- yl]pyrrolidin-3-ol; l-[6-methyl-2-(l-oxido-2,3-dihydro-l,4-benzothiazepin-4(5H)-yl)quinolin-4- yl]pyrrolidin-3-amine; tran5-l-[6-chloro-2-(l,l-dioxido-2,3-dihydro-l,4-benzothiazepin-4(5H)- yl)quinolin-4-yl]-4-fluoropyrrolidin-3-amine; trans-4-ammo- 1 -[6-chloro-2-(l , 1 -dioxido-2,3- dihydro- 1 ,4-benzothiazepin-4(5H)-yl)quinolin-4-yl]pyrrolidin-3-ol; trans- 1 -[6-chloro-2-(l - oxido-2,3-dihydro- 1 ,4-benzothiazepin-4(5H)-yl)quinolin-4-yl]-4-fluoropyrrolidin-3-amine; 2-[2- (1,1 -dioxido-2,3-dihydro- 1 ,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]-2- azabicyclo[2.1.1 ]hexan-5-amine; 2-(8-methoxy- 1 , 1 -dioxido-2,3-dihydro- 1 ,4-benzothiazepin- 4(5H)-yl)-6-methylquinolin-4-amine; 2-(7-methoxy- 1 , 1 -dioxido-2,3-dihydro- 1 ,4- benzothiazepin-4(5H)-yl)-6-methylquinolin-4-amine; N-[2-(l-aminocyclopropyl)ethyl]-2-(l,l- dioxido-2,3-dihydro- 1 ,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-amine; 2-(l , 1 -dioxido- 2,3-dihydro-l,4-benzothiazepin-4(5H)-yl)-6-methyl-N-(morpholin-2-ylmethyl)quinolin-4-am N-[2-(l , 1 -dioxido-2,3-dihydro- 1 ,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]-N- methylethane- 1 ,2-diamine; N-(azetidin-2-ylmethyl)-2-( 1 , 1 -dioxido-2,3-dihydro- 1 ,4- benzothiazepin-4(5H)-yl)-6-methylquinolin-4-amine; 2-(l , 1 -dioxido-2,3-dihydro- 1 ,4- benzothiazepin-4(5H)-yl)-6-methyl-N-(pyrrolidin-3-yl)quinolin-4-amine; N-[(l- aminocyclopropyl)methyl]-2-(l , 1 -dioxido-2,3-dihydro- 1 ,4-benzothiazepin-4(5H)-yl)-6- methylquinolin-4-amine; N-(azetidin-3-yl)-6-chloro-2-(l , 1 -dioxido-2,3-dihydro- 1 ,4- benzothiazepin-4(5H)-yl)quinolin-4-amine; 6-[2-(l , 1 -dioxido-2,3-dihydro- 1 ,4-benzothiazepin- 4(5H)-yl)-6-methylquinolin-4-yl]-2-oxa-6-azaspiro[3.4]octan-8-amine; trans-4-amino-l-[2-(l,l- dioxido-2,3-dihydro- 1 ,4-benzothiazepin-4(5H)-yl)- 1 ,6-naphthyridin-4-yl]pyrrolidin-3-ol; 1 -[2- (1,1 -dioxido-2,3-dihydro- 1 ,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]pyrrolidin-3- amine; N-(azetidin-3-yl)-2-(l , 1 -dioxido-2,3-dihydro- 1 ,4-benzothiazepin-4(5H)-yl)-6- methylquinolin-4-amine; 1 -[2-(l , 1 -dioxido-2,3-dihydro- 1 ,4-benzothiazepin-4(5H)-yl)-6- methylquinolin-4-yl]azetidin-3-amine; N-[2-(l,l-dioxido-2,3-dihydro-l,4-benzothiazepin-4(5H)- yl)-6-methylquinolin-4-yl]prolinamide; 2-(l , 1 -dioxido-2,3-dihydro- 1 ,4-benzothiazepin-4(5H)- yl)-N-(tran5-4-fluoropyrrolidin-3-yl)-6-methylquinolin-4-amine; trans-4- { [2-( 1 , 1 -dioxido-2,3- dihydro- 1 ,4-benzothiazepin-4(5H)-yl)quino lin-4-yl] amino } pyrro lidin-3 -o 1; trans-4- { [2-( 1 , 1 - dioxido-2,3-dihydro- 1 ,4-benzothiazepin-4(5H^
cis-4- { [2-( 1 , 1 -dioxido-2,3-dihydro- 1 ,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4- yl] amino} pyrro lidin-3 -ol; N-[tra/75-4-fluoropyrrolidin-3-yl]-6-methyl-2-(l-oxido-2,3-dihydro- l,4-benzothiazepin-4(5H)-yl)quinolin-4-amine; 4-[(3-aminopropyl)amino]-2-(l,l-dioxido-2,3- dihydro- 1 ,4-benzothiazepin-4(5H)-yl)quinolin-6-ol; 2-( {4-[(3-aminopropyl)amino]-2-(l , 1 - dioxido-2,3-dihydro-l,4-benzothiazepin-4(5H)-yl)quinolin-6-yl}oxy)ethanol; N-[2-(l,l-dioxido- 2,3-dihydro- 1 ,4-benzothiazepin-4(5H)-yl)-6-(2-methoxyethoxy)quinolin-4-yl]propane- 1,3- diamine; N-[2-(l,l-dioxido-2,3-dihydro-l,4-benzothiazepin-4(5H)-yl)-6-(pyridin-2- yloxy)quinolin-4-yl]propane- 1 ,3-diamine; 3- {[2-(l , 1 -dioxido-2,3-dihydro- 1 ,4-benzothiazepin- 4(5H)-yl)-6-methylquinolin-4-yl] amino} propane- 1 ,2-diol; 3-{[6-chloro-2-(l,l-dioxido-2,3- dihydro- 1 ,4-benzothiazepin-4(5H)-yl)quino lin-4-yl] amino } propane- 1 ,2-dio 1; 3 - { [2-(8-chloro- 1 , 1 -dioxido-2,3-dihydro- 1 ,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]amino}propane- 1 ,2-dio 1; 3-{[6-methyl-2-(l-oxido-2,3-dihydro-l,4-benzothiazepin-4(5H)-yl)quinolin-4- yl] amino} propane- 1 ,2-dio 1; 3- {[6-methyl-2-(5 -methyl- 1 , 1 -dioxido-2,3-dihydro- 1 ,4- benzothiazepin-4(5H)-yl)quino lin-4-yl] amino } propane- 1 ,2-dio 1; N- [(3 -aminooxetan-3 - yl)methyl]-6-methyl-2-[7-(morpholin-4-yl)- 1 , 1 -dioxido-2,3-dihydro- 1 ,4-benzothiazepin-4(5H)- yl]quinolin-4-amine; N- [(3 -aminooxetan-3 -yl)methyl] -2- {1,1 -dioxido-7-[4-(propan-2- yl)piperazin- 1 -yl]-2,3-dihydro- 1 ,4-benzothiazepin-4(5H)-yl} -6-methylquinolin-4-amine; 3- {[4- (4-aminoquinolin-2-yl)- 1 , 1 -dioxido-2,3,4,5-tetrahydro- 1 ,4-benzothiazepin-8-yl]oxy}propan- 1 - ol; N- [(3 -aminooxetan-3 -yl)methyl] -2-( 1 , 1 -dioxido-8-phenoxy-2,3-dihydro- 1 ,4-benzothiazepin- 4(5H)-yl)-6-methylquinolin-4-amine; N~3— [2-(l , 1 -dioxido-2,3-dihydro- 1 ,4-benzothiazepin- 4(5H)-yl)-6-methylquinolin-4-yl]-beta-alaninamide; 3-{[2-(l,l-dioxido-2,3-dihydro-l,4- benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl] amino } butanamide; 3- { [2-( 1 , 1 -dioxido-2,3- dihydro-l,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]amino}-2-methylpropanamide; N~2~-[2-(l,l-dioxido-2,3-dihydro-l,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]-L- alaninamide; N~2— [2-(l , 1 -dioxido-2,3-dihydro- 1 ,4-benzothiazepin-4(5H)-yl)-6-methylquinolin- 4-yl]glycinamide; N~2~- [2-(l , 1 -dioxido-2,3-dihydro- 1 ,4-benzothiazepin-4(5H)-yl)-6- methylquinolin-4-yl]-N-methylglycinamide; (25)-2-amino-3-{[2-(l,l-dioxido-2,3-dihydro-l,4- benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]amino}propan-l-ol; (2i?)-2-amino-3-{[2-(l,l- dioxido-2,3-di ydro-l,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]am
N-[(2-amino-4,5-dihydro- 1 ,3-oxazol-5-yl)methyl]-2-(l , l-dioxido-2,3-dihydro- 1 ,4- benzothiazepin-4(5H)-yl)-6-methylquinolin-4-amine; N-[(2-amino-5-methyl-4,5-dihydro- 1,3- oxazol-5-yl)methyl]-2-(l , 1 -dioxido-2,3-dihydro- 1 ,4-benzothiazepin-4(5H)-yl)-6-methylquinolin- 4-amine; N- {[(4i?)-2-amino-4,5-dihydro- 1 ,3-oxazol-4-yl]methyl} -2-(l , 1 -dioxido-2,3-dihydro- l,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-amine; N-{[(4S)-2-amino-4,5-dihydro-l,3- oxazol-4-yl]methyl} -2-( 1 , 1 -dioxido-2,3-dihydro- 1 ,4-benzothiazepin-4(5H)-yl)-6- methylquinolin-4-amine; cz5-5-[2-(l,l-dioxido-2,3-dihydro-l,4-benzothiazepin-4(5H)-yl)-6- methylquinolin-4-yl]-4,5,6,6a-tetrahydro-3aH-pyrrolo[3,4-d][l,3]oxazol-2-amine; 2-(l,l- dioxido-2,3-dihydro- 1 ,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-amine; N-[2-(l , 1 - dioxido-2,3-dihydro- 1 ,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]glycinamide; N-[2- (1,1 -dioxido-2,3-dihydro- 1 ,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]-2- methylalaninamide; N-[2-(l , 1 -dioxido-2,3-dihydro- 1 ,4-benzothiazepin-4(5H)-yl)-6- methylquinolin-4-yl]alaninamide; 2-amino-N-[2-(l , 1 -dioxido-2,3-dihydro- 1 ,4-benzothiazepin- 4(5H)-yl)-6-methylquinolin-4-yl]butanamide; N-[2-(l,l-dioxido-2,3-dihydro-l,4- benzothiazepin-4(5H)-yl)-6-methylquino lin-4-yl] -2-methoxy-2-methylpropanamide; N~ 1— [2- (1,1 -dioxido-2,3-dihydro- 1 ,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]-4,4,4- trifluorobutane- 1 ,3-diamine; N-[2-(l , 1 -dioxido-2,3-dihydro- 1 ,4-benzothiazepin-4(5H)-yl)-6- methylquinolin-4-yl]-beta-alaninamide; 2-(l , 1 -dioxido-2,3-dihydro- 1 ,4-benzothiazepin-4(5H)- yl)-N-{[3-(ethylamino)oxetan-3-yl]methyl}-6-methylquinolin-4-amine; 2-(l,l-dioxido-2,3- dihydro- 1 ,4-benzothiazepin-4(5H)-yl)-6-methyl-N-[ 1 -(oxetan-3-yl)pyrrolidin-3-yl]quinolin-4- amine; N"-[2-(l , 1 -dioxido-2,3-dihydro- 1 ,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]-N- ethyl-N-(oxetan-3-yl)ethane- 1 ,2-diamine; N-[2-(l , 1 -dioxido-2,3-dihydro- 1 ,4-benzothiazepin- 4(5H)-yl)-6-methylquinolin-4-yl]-N'-(oxetan-3-yl)propane- 1 ,3-diamine; 1 -[2-(l , 1 -dioxido-2,3- dihydro-l,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]-N-(oxetan-3-yl)pyrrolidin-3- amine; N-[2-(l , 1 -dioxido-2,3-dihydro- 1 ,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]-N'- (oxetan-3-yl)ethane-l,2-diamine; N-[2-(l,l-dioxido-2,3-dihydro-l,4-benzothiazepin-4(5H)-yl)- 6-methylquinolin-4-yl]-N'-(pyridin-2-yl)ethane-l,2-diamine; (4i?)-l-[2-(l,l-dioxido-2,3-dihydro- 1 ,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]-4-hydroxypyrrolidin-2-one; N-[2-(l , 1- dioxido-2,3-dihydro-l,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]-5-oxopyrroi^^^ carboxamide; 2-( 1 , 1 -dioxido-2,3-dihydro- 1 ,4-benzothiazepin-4(5H)-yl)-6-methyl-N-( 1H- pyrazol-3-yl)quinolin-4-amine; N-[2-(l,l-dioxido-2,3-dihydro-l,4-benzothiazepin-4(5H)-yl)-6- methylquinolin-4-yl]pyridine-3-carboxamide; N-[2-(l,l-dioxido-2,3-dihydro-l,4- benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]piperidine-2-carboxamide; N-[2-(l,l-dioxido- 2,3-dihydro- 1 ,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]-2-(pyridin-2-yl)acetamide; N- [2-(l , 1 -dioxido-2,3-dihydro- 1 ,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4- yljmethanesulfonamide trifluoroacetate; N-[2-(l , l-dioxido-2,3-dihydro-l ,4-benzothiazepin- 4(5H)-yl)-6-methylquinolin-4-yl]pyrazine-2-carboxamide; N-[2-(l , 1 -dioxido-2,3-dihydro- 1 ,4- benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]-2-hydroxyacetamide; N-[2-(l , l-dioxido-2,3- dihydro- 1 ,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]pyridine-2-carboxamide; N-[2- (1,1 -dioxido-2,3-dihydro- 1 ,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl] azetidine-2- carboxamide; l-[2-(l,l-dioxido-2,3-dihydro-l,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4- yl]-3-phenylurea; 1 -[2-(l , 1 -dioxido-2,3-dihydro- 1 ,4-benzothiazepin-4(5H)-yl)-6- methylquinolin-4-yl]-3-ethylurea; N-[6-cyclopropyl-2-(l , 1 -dioxido-2,3-dihydro- 1 ,4- benzothiazepin-4(5H)-yl)quino lin-4-yl]propane- 1 ,3 -diamine; 4- [(3 -aminopropyl)amino] -2-( 1,1- dioxido-2,3-dihydro- 1 ,4-benzothiazepin-4(5H)-yl)quinoline-6-carbonitrile; N-[2-(l , 1 -dioxido- 2,3-dihydro- 1 ,4-benzothiazepin-4(5H)-yl)-6-ethenylquinolin-4-yl]propane- 1 ,3-diamine; N-[2- (1,1 -dioxido-2,3-dihydro- 1 ,4-benzothiazepin-4(5H)-yl)-6-ethynylquinolin-4-yl]propane- 1 ,3- diamine; N-[(3-aminooxetan-3-yl)methyl]-6-methyl-2-(l-oxido-2,3-dihydro-l,4-benzothiazepin- 4(5H)-yl)quinazolin-4-amine; N-{[3-(benzylamino)oxetan-3-yl]methyl}-6-methyl-2-(l-oxido-
2.3- dihydro-l,4-benzothiazepin-4(5H)-yl)quinazolin-4-amine; 2-fluoro-N-[6-methyl-2-(l-oxido- 2,3-dihydro- 1 ,4-benzothiazepin-4(5H)-yl)quinazolin-4-yl]propane- 1 ,3-diamine; N- {[3-
(aminomethyl)oxetan-3-yl]methyl} -2-(l , 1 -dioxido-2,3-dihydro- 1 ,4-benzothiazepin-4(5H)-yl)-6- methylquinazolin-4-amine; 2,2-difluoro-N-[6-methyl-2-(l-oxido-2,3-dihydro-l,4- benzothiazepin-4(5H)-yl)quinazolin-4-yl]propane-l,3-diamine; N-{[3-(aminomethyl)oxetan-3- yl]methyl}-6-chloro-2-(l,l-dioxido-2,3-dihydro-l,4-benzothiazepin-4(5H)-yl)quinazolin-4- amine; N-[2-(l , 1 -dioxido-2,3-dihydro- 1 ,4-benzothiazepin-4(5H)-yl)-6-methylquinazolin-4-yl]- 2,2-difluoropropane-l,3-diamine; N-[2-(l,l-dioxido-2,3-dihydro-l,4-benzothiazepin-4(5H)-yl)- 6-methylquinazolin-4-yl]-2-fluoropropane-l,3-diamine; N-[6-methyl-2-(l-oxido-2,3-dihydro-
1.4- benzothiazepin-4(5H)-yl)quinazolin-4-yl]propane- 1 ,3-diamine; N-[(3-aminooxetan-3- yl)methyl]-2-(2,3-dihydro- 1 ,4-benzothiazepin-4(5H)-yl)quinazolin-4-amine; N-[(3-aminooxetan- 3-yl)methyl]-2-(l-oxido-2,3-dihydro-l,4-benzothiazepin-4(5H)-yl)quinazolin-4-amine; N-[(3- aminooxetan-3-yl)methyl]-2-(l , 1 -dioxido-2,3-dihydro- 1 ,4-benzothiazepin-4(5H)-yl)quinazolin- 4-amine; N-[(3-aminooxetan-3-yl)methyl]-6-chloro-2-(2,3-dihydro- 1 ,4-benzothiazepin-4(5H)- yl)quinazolin-4-amine; N-[(3-aminooxetan-3-yl)methyl]-6-chloro-2-(l-oxido-2,3-dihydro-l,4- benzothiazepin-4(5H)-yl)quinazolin-4-amine; N-[(3-aminooxetan-3-yl)methyl]-6-chloro-2-(l , 1- dioxido-2,3-dihydro-l,4-benzothiazepin-4(5H)-yl)quinazolin-4-amine; 2-{[2-(l,l-dioxido-2,3- dihydro-l,4-benzothiazepin-4(5H)-yl)-6-methylquinazolin-4-yl]amino}ethanol; 2-(2,3-dihydro- 1 ,4-benzothiazepin-4(5H)-yl)-6-methylquinazolin-4-amine; 2-(l , 1 -dioxido-2,3-dihydro- 1 ,4- benzothiazepin-4(5H)-yl)-6-methylquinazolin-4-amine; N~l— [2-(l,l-dioxido-2,3-dihydro-l,4- benzothiazepin-4(5H)-yl)-6-methylquinazolin-4-yl]-2-methylpropane- 1 ,2-diamine; N-[(3- aminooxetan-3-yl)methyl]-2-(l , 1 -dioxido-2,3-dihydro- 1 ,4-benzothiazepin-4(5H)-yl)-6- methylquinazolin-4-amine; N-[(l-aminocyclobutyl)methyl]-2-(l,l-dioxido-2,3-dihydro-l,4- benzothiazepin-4(5H)-yl)-6-methylquinazolin-4-amine; N-{[3-(aminomethyl)oxetan-3- yljmethyl} -6-methyl-2-(l -oxido-2,3-dihydro- 1 ,4-benzothiazepin-4(5H)-yl)quinazolin-4-amine; (-)-N- {[3-(aminomethyl)oxetan-3-yl]methyl} -6-methyl-2-[ 1 -oxido-2,3-dihydro- 1 ,4- benzothiazepin-4(5H)-yl]quinazolin-4-amine; (+)-N-{[3-(aminomethyl)oxetan-3-yl]methyl}-6- methyl-2-[l-oxido-2,3-dihydro-l,4-benzothiazepin-4(5H)-yl]quinazolin-4-amine; N~4— [2-(l,l- dioxido-2,3-dihydro- 1 ,4-benzothiazepin-4(5H)-yl)-6-methylquinazolin-4-yl]-2-fluorobutane- 1 ,4- diamine; N~l— [2-(l,l-dioxido-2,3-dihydro-l,4-benzothiazepin-4(5H)-yl)-6-methylquinazolin-4- yl]-2-fluorobutane- 1 ,4-diamine; N- {[3-(aminomethyl)oxetan-3-yl]methyl} -2-(2,3-dihydro- 1 ,4- benzothiazepin-4(5H)-yl)-6-methylquinazolin-4-amine; trans-4-fluoro-l-[6-methyl-2-(l-oxido- 2,3-dihydro- 1 ,4-benzothiazepin-4(5H)-yl)quinazolin-4-yl]pyrrolidin-3-amine; N-(Azetidin-3-yl)- 6-methyl-2-(l , 1 -dioxido-2,3-dihydro- 1 ,4-benzothiazepin-4(5H)-yl) quinazolin-4-amine; N-(2- { [2-( 1 , 1 -dioxido-2,3-dihydro- 1 ,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4- yljamino } ethyl)acetamide; N- { [3-( { [2-( 1 , 1 -dioxido-2,3-dihydro- 1 ,4-benzothiazepin-4(5H)-yl)-6- methylquino lin-4-yl] amino } methyl)oxetan-3 -yljmethyl} acetamide; N-(3 - { [2-( 1 , 1 -dioxido-2,3 - dihydro-l,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]amino}propyl)acetamide; N-[2- (1,1 -dioxido-2,3-dihydro- 1 ,4-benzothiazepin-4(5H)-yl)-6-methylquinazolin-4-yl]acetamide; 1 - [2-(l , 1 -dioxido-2,3-dihydro- 1 ,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]-3- methylpyrrolidin-3-amine; N-[(3-aminooxetan-3-yl)methyl]-2-(9-methoxy- 1 , 1 -dioxido-2,3- dihydro-l,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-amine; 4-(4-{[(3-aminooxetan-3- yl)methyl]amino}-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-l,4-benzothiazepin-7-ol 1,1- dioxide; 3-{[2-(l,l-dioxido-2,3-dihydro-l,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4- yljamino } -2-methylpropane- 1 ,2-diol; 4- { [2-( 1 , 1 -dioxido-2,3-dihydro- 1 ,4-benzothiazepin-4(5H)- yl)-6-methylquino lin-4-yl] amino } butane- 1 ,3 -dio 1; N- [6-methyl-2-(2-methyl- 1 , 1 -dioxido-2,3 - dihydro- 1 ,4-benzothiazepin-4(5H)-yl)quinolin-4-yl] ethane- 1 ,2-diamine; N-[(3-aminooxetan-3- yl)methyl]-6-methyl-2-(2-methyl- 1 , 1 -dioxido-2,3-dihydro- 1 ,4-benzothiazepin-4(5H)- yl)quinolin-4-amine; N-[(3-{[2-(l,l-dioxido-2,3-dihydro-l,4-benzothiazepin-4(5H)-yl)-6- methylquinolin-4-yl]amino}oxetan-3-yl)methyl]-2,2,2-trifluoroacetamide; N-[3-
(aminomethyl)oxetan-3-yl]-2-(l , 1 -dioxido-2,3-dihydro- 1 ,4-benzothiazepin-4(5H)-yl)-6- methylquinolin-4-amine; 2-(aminomethyl)-2- {[2-(l , 1 -dioxido-2,3-dihydro- 1 ,4-benzothiazepin- 4(5H)-yl)-6-methylquinolin-4-yl]amino}propane-l ,3-diol; 4-amino-l-[2-(l,l-dioxido-2,3- dihydro- 1 ,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]pyrrolidin-2-one; 2-(l , 1 -dioxido- 2,3-dihydro- 1 ,4-benzothiazepin-4(5H)-yl)-6-methyl-N-[2-(methylsulfinyl)ethyl]quinolin-4- amine; N- {2-[(2-aminoethyl)sulfonyl]ethyl} -2-(l , 1 -dioxido-2,3-dihydro- 1 ,4-benzothiazepin- 4(5H)-yl)-6-methylquinolin-4-amine; N-[2-(l-imino-l-oxido- 1,2,3, 5-tetrahydro-4H- 1 /am¾(ia~4~,4-benzothiazepin-4-yl)-6-methylquinolin-4-yl]ethane- 1 ,2-diamine; 2-( 1 , 1 -dioxido- 2,3-dihydro- 1 ,4-benzothiazepin-4(5H)-yl)-6-methyl-N-[2-(5*- methylsulfonimidoyl)ethyl]quinolin-4-amine; trans-4-ammo- 1 -[2-(l -imino- 1 -oxido- 1 ,2,3,5- tetrahydro-4H- 1 /am¾<ia~4~,4-benzothiazepin-4-yl)-6-methylquinolin-4-yl]pyrrolidin-3-ol; trans- 1 -[2-(l , 1 -dioxido-2,3-dihydro- 1 ,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]-4- fluoropyrrolidin-3-amine; 1 -[2-(l , 1 -dioxido-2,3-dihydro- 1 ,4-benzothiazepin-4(5H)-yl)-6- methylquinolin-4-yl]pyrrolidine-3-carboxamide; N-[2-(l , 1 -dioxido-2,3-dihydro- 1 ,4- benzothiazepin-4(5H)-yl)-6-(methylsulfinyl)quinolin-4-yl]propane- 1 ,3-diamine; 4-[(3- aminopropyl)amino]-2-(l , 1 -dioxido-2,3-dihydro- 1 ,4-benzothiazepin-4(5H)-yl)quinoline-6- carboxamide; l-{4-[(3-aminopropyl)amino]-2-(l,l-dioxido-2,3-dihydro-l,4-benzothiazepin- 4(5H)-yl)quinolin-6-yl} ethanol; 3- {[2-(l , 1 -dioxido-2,3-dihydro- 1 ,4-benzothiazepin-4(5H)-yl)-6- methylquinolin-4-yl]amino}propanenitrile; 2-(l,l-dioxido-2,3-dihydro-l,4-benzothiazepin- 4(5H)-yl)-6-methyl-N-[2-(lH-tetrazol-5-yl)ethyl]quinolin-4-amine; N~4~-(2-amm^
dioxido-2,3-dihydro- 1 ,4-benzothiazepin-4(5H)-yl)quinoline-4,6-diamine; 5-[2-(l , 1 -dioxido-2,3- dihydro-l,4-benzothiazepin-4(5H)-yl)-6-methyl^^
one; 3-{[2-(l,l-dioxido-2,3-dihydro-l,4-benzothiazepin-4(5H)-yl)-6-methylquinazolin-4- yl] amino} propane- 1,2-diol; 3-{[6-chloro-2-(l,l-dioxido-2,3-dihydro-l,4-benzothiazepin-4(5H)- yl)quinazolin-4-yl] amino} propane- 1,2-diol; N-[2-(2,3-dihydro-l,4-benzothiazepin-4(5H)-yl)-6- methylquinazolin-4-yl] ethane- 1 ,2-diamine; N-[6-methyl-2-(l -oxido-2,3-dihydro- 1 ,4- benzothiazepin-4(5H)-yl)quinazolin-4-yl] ethane- 1 ,2-diamine; N-[2-(l , 1 -dioxido-2,3-dihydro- 1 ,4-benzothiazepin-4(5H)-yl)-6-methylquinazolin-4-yl] ethane- 1 ,2-diamine; N-[3-
(aminomethyl)oxetan-3-yl]-6-methyl-2-(l-oxido-2,3-dihydro-l,4-benzothiazepin-4(5H)- yl)quinazolin-4-amine; N-(tra/?5-4-fluoropyrrolidin-3-yl)-6-methyl-2-(l-oxido-2,3-dihydro-l,4- benzothiazepin-4(5H)-yl)quinazolin-4-amine; N-(tra/?5-4-fluoropyrrolidin-3-yl)-6-methyl-2-(l,l- dioxido-2,3-dihydro-l,4-benzothiazepin-4(5H)-yl)quinazolin-4-amine; l-[6-methyl-2-(l-oxido- 2,3-dihydro- 1 ,4-benzothiazepin-4(5H)-yl)quinazolin-4-yl]pyrrolidin-3-amine; N-(azetidin-3-yl)- 6-methyl-2-(l , 1 -dioxido-2,3-dihydro- 1 ,4-benzothiazepin-4(5H)-yl)quinazolin-4-amine; (4R)-4- {2-[2-(l , 1 -dioxido-2,3-dihydro- 1 ,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl] ethyl} -4,5- dihydro- 1 ,3-oxazol-2-amine; 3-[2-(l , 1 -dioxido-2,3-dihydro- 1 ,4-benzothiazepin-4(5H)-yl)-6- ethylquinolin-4-yl]propanoic acid; 3-[2-(l,l-dioxido-2,3-dihydro-l,4-benzothiazepin-4(5H)-yl)- 6-methylquinolin-4-yl]propan- 1 -amine; 2- { [2-( 1 , 1 -dioxido-2,3-dihydro- 1 ,4-benzothiazepin- 4(5H)-yl)-6-methylquinolin-4-yl]oxy}ethanamine; 4-[6-methyl-4-(pyrrolidin-3-yloxy)quinolin- 2-yl]-2,3,4,5-tetrahydro- 1 ,4-benzothiazepine 1 , 1 -dioxide; 4-[6-methyl-4-(piperidin-4- yloxy)quinolin-2-yl]-2,3,4,5-tetrahydro- 1 ,4-benzothiazepine 1 , 1 -dioxide; 4-(4,6- dimethylquinolin-2-yl)-2,3,4,5-tetrahydro- 1 ,4-benzothiazepine 1 , 1 -dioxide; [2-(l , 1 -dioxido-2,3- dihydro- 1 ,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl](piperidin-4-yl)methanone; 4-[6- methyl-4-(lH-pyrazol-3-yl)quinolin-2-yl]-2,3,4,5-tetrahydro-l,4-benzothiazepine 1,1 -dioxide; 4- [6-methyl-4-(phenylsulfonyl)quinolin-2-yl]-2,3,4,5-tetrahydro- 1 ,4-benzothiazepine 1 , 1 -dioxide; N-(2-aminoethyl)-2-( 1 , 1 -dioxido-2,3-dihydro- 1 ,4-benzothiazepin-4(5H)-yl)-6-methylquinoline- 4-sulfonamide; methyl 4-({[3-(aminomethyl)oxetan-3-yl]methyl}amino)-2-(l,l-dioxido-2,3- dihydro- 1 ,4-benzothiazepin-4(5H)-yl)quino line-6-carboxylate; 4-( { [3 -(amino methyl)oxetan-3 - yljmethyl} amino)-2-(l , 1 -dioxido-2,3-dihydro- 1 ,4-benzothiazepin-4(5H)-yl)quinoline-6- carboxylic acid; [4-({[3-(aminomethyl)oxetan-3-yl]methyl}amino)-2-(l,l-dioxido-2,3-dihydro- l,4-benzothiazepin-4(5H)-yl)quinolin-6-yl]methanol; N-{[3-(aminomethyl)oxetan-3-yl]methyl}- 6-(~2~H_3_)methyl-2-(l-oxido-2,3-dihydro-l,4-ber^^
4-({[3-(aminomethyl)oxetan-3-yl]methyl}amino)-2-(l,l-dioxido-2,3-dihydro-l,4- benzothiazepin-4(5H)-yl)quinazoline-6-carboxylic acid; 4-({[3-(aminomethyl)oxetan-3- yl]methyl}amino)-2-(l-oxido-2,3-dihydro-l,4-benzothiazepin-4(5H)-yl)quinazoline-6- carboxylic acid; [4-({[3-(aminomethyl)oxetan-3-yl]methyl}amino)-2-(l-oxido-2,3-dihydro-l,4- benzothiazepin-4(5H)-yl)quinazo lin-6-yl]methano 1; [4-( { [3 -(amino methyl)oxetan-3 - yljmethyl} amino)-2-(l , 1 -dioxido-2,3-dihydro- 1 ,4-benzothiazepin-4(5H)-yl)quinazolin-6- yljmethanol; N-[(l-aminocyclopropyl)methyl]-2-(l,l-dioxido-2,3-dihydro-l,4-benzothiazepin- 4(5H)-yl)-6-methylquinazolin-4-amine; and 2-(l,l-dioxido-2,3-dihydro-l,4-benzothiazepin- 4(5H)-yl)-6-methyl-N-(pyrrolidin-3-yl)quinazolin-4-amine.
Another embodiment of invention is (xii) a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein
R1 is hydrogen or halogen;
R2 and R4 are hydrogen; R3 is hydrogen or halogen;
R5 is hydrogen or halogen;
R6 is hydrogen, halogen, hydroxy, Ci_6alkoxy or carboxy;
R7 is hydrogen, halogen, Ci_6alkoxy, Ci_6alkylaminocarbonyl, diCi_6
alkylaminocarbonyl or Ci_6alkylsulfonyl; R8 is hydrogen or halogen;
R9 is hydrogen or =0;
R10 is hydrogen or =0, provided that R9 and R10 are not =0 simultaneously;
A is -C-R11, wherein R11 is hydrogen, halogen, Chalky!, Ci_6alkoxy, trifluoromethyl, trifluoromethoxy, pyridinyloxy, difluoromethoxy or Ci_6alkylsulfonyl; X is -CH2-, -0-, -NH-, -CF2, -C(CH3)(OH)-, C=0, or -C(=N-Ci_6alkoxy)-;
Y is -CH- or nitrogen;
Q is hydrogen; halogen; Ci_6alkyl, once or twice substituted by hydroxy provided that disubstitution of hydroxy is not on the same carbon; amino(CH2)2_6aminosulfonyl; 2-amino-4,5- A ^ rA^ 1 „„„™i .^thyl; or NR12R13, wherein one of R12 and R13 is hydrogen, Ci_6alkyl or hydroxy(CH2)2-6, and the other one is guanidino(CH2)2-6; 3 -amino methyl- 1,1 -dioxidothietan-3 - ylmethyl; 3-amino- 1 , 1 -dioxidothietan-3 -ylmethyl; 3 -(amino methyl)thietan-3 -ylmethyl;
amino(CH2)2-6-0-(CH2)2-6; amino(CH2)2-io; amino(CH2)i_6carbonyl; amino(CH2)i_
6difluoromethyl(CH2)i_6; amino(CH2)i-60xetanyl(CH2)i-6; amino(CH2)2-6Sulfonyl(CH2)2-6; 3- aminocyclohexyl; 4-aminocyclohexyl; 2-amino-4,5-dihydro-oxazol-5-yl(CH2)i_6;
aminooxetanyl(CH2)i_6; Ci_6alkylamino(CH2)2-6; Ci_6alkylaminocarbonyl; diCi_
Figure imgf000034_0001
6alkylamino(CH2)2-6; hydroxy(CH2)2-6; piperazinyl(CH2)2-6; pyrrolidin-3-yl; or , wherein R14 is hydrogen, Ci_6alkyl or hydroxy(CH2)i_6; R15 is hydroxy, hydroxy(CH2)i_6 or amino; and R16 is Ci_6alkyl, hydroxy(CH2)i_6 or amino (CH2)i_6; R12 and R13, with the nitrogen atom to which they are attached, may form a pyrrolidinyl, piperazinyl or diazepanyl ring; which may be unsubstituted, once or twice substituted by a group selected from Ci_6alkyl, amino or hydroxy.
Another particular embodiment of invention is (xiii) a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein R1 is hydrogen or chloro;
R2 and R4 are hydrogen;
R3 is hydrogen or chloro;
R5 is hydrogen or fluoro;
R6 is hydrogen, fluoro, hydroxy, methoxy, ethoxy or carboxy; R7 is hydrogen, fluoro, bromo, methoxy, dimethylaminocarbonyl, methylsulfonyl or ethylsulfonyl;
R8 is hydrogen or chloro.
A is CR1 1, wherein R1 1 is hydrogen, fluoro, chloro, bromo, methyl, methoxy,
trif uoromethyl, trif uoromethoxy, pyridinyloxy, difluoromethoxy or methylsulfonyl; Q is hydrogen; chloro; hydroxymethyl; hydroxymethyl(hydroxy)ethyl;
aminoethylaminosulfonyl; 2-amino-4,5-dihydro-l,3-oxazol-4-ylethyl; or NR12R13, wherein one of R12 and R13 is hydrogen, methyl or hydroxyethyl, and the other one is aminobutyl; 3- aminocyclohexyl; 4-aminocyclohexyl; 2-amino-4,5-dihydro-oxazol-5-ylmethyl; 3-amino- 1,1 - dioxidothietan-3 -ylmethyl; aminoethoxyethyl; aminoethyl; ammoethylsulfonylethyl; aminomethylcarbonyl; amino methyldifluoromethylmethyl; 3 -amino methyl- 1 , 1 -dioxidothietan-3 - ylmethyl; 3 -(amino methyl)thietan-3 -ylmethyl; amino methyloxetanylmethyl;
aminooxetanylmethyl; aminopropyl; dimethylamino ethyl; ethylaminocarbonyl; guanidino ethyl;
piperazin-l-ylethyl; pyrrolidin-3-yl; or
5
Figure imgf000035_0001
or hydroxymethyl; R15 is hydroxy,
hydro xymethyl or amino; and R16 is methyl, hydroxymethyl or amino methyl;
R12 and R13, with the nitrogen atom to which they are attached, may form a pyrrolidinyl, piperazinyl or diazepanyl ring; which may be unsubstituted, once or twice substituted by a group selected from methyl, amino or hydroxy; and all the remaining substituents are as defined above 10 in embodiment (xii).
A particular embodiment of present invention is a compound of formula (I) or a pharmaceutically acceptable salt thereof, selected from:
N- [(3 -aminooxetan-3 -yl)methyl] -2-(5 ,5 -difluoro- 1 ,3 ,4,5 -tetrahydro-2H-2-benzazepin-2-yl)-6- methylquinolin-4-amine; N-[2-(2-aminoethoxy)ethyl]-2-(5,5-difluoro- 1,3,4, 5-tetrahydro-2H-2-
15 benzazepin-2-yl)-6-methylquinolin-4-amine; N-[2-(5,5-difluoro- 1,3,4, 5-tetrahydro-2H-2- benzazepin-2-yl)-6-methylquinolin-4-yl]-N'-methylethane-l,2-diamine; l-amino-3-{[2-(5,5- difluoro-l,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)-6-methylquinolin-4-yl]amino}propan-2-ol; 3- {[2-(5,5-difluoro-l,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)-6-methylquinolin-4- yl] amino} propane- 1,2-diol; 3-{[2-(5,5-difluoro-l,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)-6-
20 methylquinolin-4-yl]amino}propan-l-ol; 2-(5,5-difluoro-l,3,4,5-tetrahydro-2H-2-benzazepin-2- yl)-6-methyl-N-[2-(piperazin-l-yl)ethyl]quinolin-4-amine; N~l~- [2-(5,5-difluoro-l,3,4,5- tetrahydro-2H-2-benzazepin-2-yl)-6-methylquinolin-4-yl]propane-l,2-diamine; c«-N-[2-(5,5- difluoro-l,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)-6-methylquinolin-4-yl]cyclohexane-l,4- diamine; 2-(9,9-difluoro-6,7,8,9-tetrahydro-5H-benzo[7]annulen-6-yl)-6-methyl-N-(pyrrolidin-3-
25 yl)quinolin-4-amine; 2,2'-{[2-(5,5-difluoro-l,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)-6- methylquinolin-4-yl]imino}diethanol; N~l— [2-(5, 5 -difluoro- 1,3,4, 5-tetrahydro-2H-2- benzazepin-2-yl)-6-methylquinolin-4-yl]-2-methylpropane-l,2-diamine; 5,5-difluoro-2-[6- methyl-4-(4-methylpiperazin- 1 -yl)quinolin-2-yl]-2,3,4,5-tetrahydro- lH-2-benzazepine; 1 -[2- (9,9-difiuoro-6,7,8,9-tetrahydro-5H-benzo[7]annulen-6-yl)-6-methylquinolin-4-yl]-3-ethylurea;
30 N-{[3-(aminomethyl)oxetan-3-yl]methyl}-2-(5,5-difluoro-l,3,4,5-tetrahydro-2H-2-benzazepin- 2-yl)-6-methylquinolin-4-amine; 5,5-difluoro-2-[6-methyl-4-(piperazin-l-yl)quinolin-2-yl]- 2,3,4,5-tetrahydro-lH-2-benzazepine; 2-[4-(l,4-diazepan-l-yl)-6-methylquinolin-2-yl]-5,5- difluoro-2,3,4,5-tetrahydro-lH-2-benzazepine; N-[2-(5,5-difluoro-l,3,4,5-tetrahydro-2H-2- benzazepin-2-yl)-6-methylquinolin-4-yl]-N-methylethane-l,2-diamine; l-[2-(5,5-difluoro-
¾ ς w ^-benzazepin-2-yl)-6-methylquinolin-4-yl]pyrrolidin-3-amine; 2-{[2-(5,5- difluoro-l,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)-6-methylqu^ N-[2- (5,5-difluoro-l,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)-6-methylquinolin-4-yl]ethane-l,2- diamine; N-[2-(5,5-difluoro- 1,3,4, 5-tetrahydro-2H-2-benzazepin-2-yl)-6-methylquinolin-4- yl]cyclohexane-l,3-diamine; N,-[2-(5,5-difluoro-l,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)-6- methylquinolin-4-yl]-N,N-dimethylethane-l,2-diamine; N-[2-(5,5-difluoro-l,3,4,5-tetrahydro- 2H-2-benzazepin-2-yl)-6-methylquinolin-4-yl]propane-l,3-diamine; N-[2-(5,5-difluoro-l, 3,4,5- tetrahydro-2H-2-benzazepin-2-yl)-6-methylquinolin-4-yl]butane- 1 ,4-diamine; trans-4-ammo- 1 - [2-(5,5-difluoro-l,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)-6-methylquinolin-4-yl]pyrrolid N- {[3 -(amino methyl)- 1 , 1 -dioxidothietan-3-yl]methyl} -2-(5,5-difluoro- 1 ,3,4,5-tetrahydro-2H-2- benzazepin-2-yl)-6-methylquinolin-4-amine; N-{2-[(2-aminoethyl)sulfonyl]ethyl}-2-(5,5- difluoro-l,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)-6-methylquinolin-4-amine; N-{[3- (aminomethyl)thietan-3-yl]methyl}-2-(5,5-difluoro-l,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)-6- methylquinazolin-4-amine; N-{[3-(aminomethyl)oxetan-3-yl]methyl}-2-(5,5-difluoro- 1,3,4,5- tetrahydro-2H-2-benzazepin-2-yl)-6-methylquinazolin-4-amine; 2-(aminomethyl)-2-( { [2-(5 ,5- difluoro-l,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)-6-methylquinazolin-4- yl] amino } methyl)propane- 1 ,3 -dio 1; 2-(4- { [(3 -aminooxetan-3 -yl)methyl] amino } -6- methylquinazolin-2-yl)-5-methyl-2,3,4,5-tetrahydro-lH-2-benzazepin-5-ol; N-[(3-aminooxetan- 3-yl)methyl]-2-(5,5-difluoro- 1,3,4, 5-tetrahydro-2H-2-benzazepin-2-yl)-6-methylquinazolin-4- amine; N-[(3-amino- 1 , 1 -dioxidothietan-3-yl)methyl]-2-(5,5-difluoro- 1 ,3,4,5-tetrahydro-2H-2- benzazepin-2-yl)-6-methylquinazolin-4-amine; N-[2-(5,5-difluoro- 1,3,4, 5-tetrahydro-2H-2- benzazepin-2-yl)-6-methylquinazolin-4-yl]-2,2-difluoropropane- 1 ,3-diamine; N-[2-(7-bromo- l,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)-6-chloroquinolin-4-yl]ethane-l,2-diamine; 2-{4-[(2- aminoethyl)amino]quinolin-2-yl}-2,3,4,5-tetrahydro-lH-2-benzazepin-8-ol; N-[6-methyl-2- (l,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)quinolin-4-yl]ethane-l,2-diamine; N-[2-(8-fluoro- l,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)-6-methylquinolin-4-yl]ethane-l,2-diamine; N-[6- chloro-2-(l,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)quinolin-4-yl]ethane-l,2-diamine; N-[6- chloro-2-(9-fluoro-l,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)quinolin-4-yl]ethane-l,2-diamine; N-[2-(8-fluoro- 1 ,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)quinolin-4-yl]ethane- 1 ,2-diamine; 1 - amino-3-{[2-(l,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)quinolin-4-yl]amino}propan-2-ol trifluoroacetate; N-[2-(l,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)quinolin-4-yl]ethane-l,2- diamine; N-[6-bromo-2-(l,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)quinolin-4-yl]ethane-l,2- diamine; N-[6-methoxy-2-(l,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)quinolin-4-yl]ethane-l,2- diamine; N-[2-(6-chloro- 1 ,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)quinolin-4-yl]ethane- 1 ,2- diamine; N-[2-(7-fluoro-l,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)-6-methylquinolin-4- yl]ethane-l,2-diamine; N-methyl-N'-[2-(l,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)quinolin-4- yl]ethane-l,2-diamine; N-[2-(7-methoxy- 1,3,4, 5-tetrahydro-2H-2-benzazepin-2-yl)quinolin-4- yl]ethane-l,2-diamine; N-[2-(7-fluoro-l,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)quinolin-4- yl]ethane-l,2-diamine; N-[2-(8-methoxy-l,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)quinolin-4- yl]ethane-l,2-diamine; N-[6-(difluoromethoxy)-2-(l,3,4,5-tetrahydro-2H-2-benzazepin-2- yl)quinolin-4-yl]ethane-l,2-diamine; N-[2-(l,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)-6- (trifluoromethyl)quinolin-4-yl]ethane-l,2-diamine; N-[8-chloro-2-(l,3,4,5-tetrahydro-2H-2- benzazepin-2-yl)quinolin-4-yl]ethane-l,2-diamine; N-[6-fluoro-2-(l,3,4,5-tetrahydro-2H-2- benzazepin-2-yl)quinolin-4-yl]ethane-l,2-diamine; N,N-dimethyl-N'-[2-(l,3,4,5-tetrahydro-2H- 2-benzazepin-2-yl)quinolin-4-yl]ethane-l,2-diamine; N-[2-(l,3,4,5-tetrahydro-2H-2-benzazepin- 2-yl)-6-(trifluoromethoxy)quinolin-4-yl]ethane-l,2-diamine; N-[6-(methylsulfonyl)-2-(l, 3,4,5- tetrahydro-2H-2-benzazepin-2-yl)quinolin-4-yl]ethane- 1 ,2-diamine; 2- {4-[(2- aminoethyl)amino]quinolin-2-yl}-2,3,4,5-tetrahydro-lH-2-benzazepine-8-carboxylic acid; 2-(4- chloroquinolin-2-yl)-2,3,4,5-tetrahydro-lH-2-benzazepine; N-[5-chloro-2-(l,3,4,5-tetrahydro- 2H-2-benzazepin-2-yl)quinolin-4-yl] ethane- 1 ,2-diamine; N- (2-[7-(methylsulfonyl)- 1 ,3,4,5- tetrahydro-2H-2-benzazepin-2-yl]quinolin-4-yl} ethane- 1 ,2-diamine; N- (2-[7-(ethylsulfonyl)- l,3,4,5-tetrahydro-2H-2-benzazepin-2-yl]quinolin-4-yl} ethane- 1,2-diamine; N-[2-(8-ethoxy- l,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)quinolin-4-yl]ethane-l,2-diamine; N-[6-(pyridin-2- yloxy)-2-(l ,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)quinolin-4-yl]ethane- 1 ,2-diamine; 2- {4-[(2- aminoethyl)amino]-6-chloroquinolin-2-yl}-N,N-dimethyl-2,3,4,5-tetrahydro-lH-2-benzazepine- 7-carboxamide; 2- {4-[(2-aminoethyl)amino]quinolin-2-yl} -7-bromo- 1 ,2,4,5-tetrahydro-3H-2- benzazepin-3-one; l-(2-{[2-(l,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)quinolin-4- yl] amino }ethyl)guanidine trifluoroacetate; N-[(2-amino-4,5-dihydro-l,3-oxazol-5-yl)methyl]-2- (l,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)quinolin-4-amine trifluoroacetate; N-[(2-amino-4,5- dihydro- l,3-o xazol-5-yl)methyl]-6-chloro-2-(l,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)quinolin- 4-amine; N-[2-(l ,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)quinolin-4-yl]glycinamide; 3-[2- (l,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)quinolin-4-yl]propan-l-amine; [2-(l,3,4,5-tetrahydro- 2H-2-benzazepin-2-yl)quinolin-4-yl]methanol; 2-(6-chloroquinolin-2-yl)-2,3,4,5-tetrahydro-lH- 2-benzazepine; 3-[6-chloro-2-(l,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)quinolin-4-yl]propane- 1,2-diol; (45)-4-{2-[2-(l,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)quinolin-4-yl]ethyl}-4,5- dihydro-l,3-oxazol-2-amine; N-(2-aminoethyl)-2-(l,3,4,5-tetrahydro-2H-2-benzazepin-2- yl)quinoline-4-sulfonamide trifluoroacetate; 4- {4-[(2-aminoethyl)amino]-6-methylquinolin-2- yl} - 1 ,3 ,4,5-tetrahydro-2H- 1 ,4-benzodiazepin-2-one; N-[6-methyl-2-( 1 ,2,3 ,5-tetrahydro-4H- 1 ,4- benzodiazepin-4-yl)quinolin-4-yl]ethane- 1 ,2-diamine; N-[2-(2,3-dihydro- 1 ,4-benzoxazepin- 4(5H)-yl)quinolin-4-yl] ethane- 1 ,2-diamine; N-[(3-aminooxetan-3-yl)methyl]-2-[(5E)-5- (methoxyimino)-l,3,4,5-tetrahydro-2H-2-benzazepin-2-yl]-6-methylquinolin-4-amine and 2-(4- {[(3-aminooxetan-3-yl)methyl]amino}-6-methylquinazolin-2-yl)-l,2,3,4-tetrahydro-5H-2- benzazepin-5-one. The compounds of the present invention can be prepared by any conventional means.
Suitable processes for synthesizing these compounds as well as their starting materials are provided in the schemes below and in the examples. All substituents, in particular, R1 to R10, A, Q, X and Y are as defined above unless otherwise indicated. Furthermore, and unless explicitly otherwise stated, all reactions, reaction conditions, abbreviations and symbols have the meanings well known to a person of ordinary skill in organic chemistry.
Abbreviations OMSO-d6: deuterated dimethylsulfoxide
FBS: fetal bovine serum
g: gram
μg: microgram
EC50: the concentration of a compound where 50% of its maximal protection effect against viral induced CPE is observed
HPLC: high performance liquid chromatography
Hz: Hertz
CDCI3 deuterated chloroform
CD3OD: deuterated methanol
mg: milligram
MHz: megahertz
mL: milliliter
mmol: millimole
obsd. Observed
μί: microliter
μιη: micrometer
μΜ: micromoles per liter
mm: millimeter
MS (ESI): mass spectroscopy (electron spray ionization)
NMR: nuclear magnetic resonance
TLC: thin layer chromatography
General synthetic route for 2,4-dihalogen quino lines Ilia (Scheme 1)
Scheme 1
Figure imgf000038_0001
VII Ilia
E is CI or Br Compounds of interest of formula Ilia can be prepared according to Scheme 1. Starting with various VII, cyclization reaction with propanedioic acid in the presence of VI affords 2,4- dihalogen-quino lines Ilia. The reaction can be carried out at a temperature between 100 °C and 150 °C for 6 to 12 hours. VI can be phosphoryl trichloride or phosphoryl tribromide. General synthetic route for 2,3,4,5-tetrahydro-l,4-benzothiazepines (Scheme 2)
Scheme 2
Figure imgf000039_0001
Compounds of interest IVa, IVb, IVc and IVd can be prepared according to Scheme 2. Starting with 2-sulfanylbenzoic acids X, esterification with methanol gives methyl 2- sulfanylbenzoates IXa. Annulation of esters IXa with 2-bromo ethylamine affords 3,4-dihydro- l ,4-benzothiazepin-5(2H)-ones Villa. Reduction of Villa affords 2,3,4,5-tetrahydro-l ,4- benzothiazepines IVa. Acylation of IVa generates amides IVb. Oxidation of IVb followed by deacylation affords compounds of interest IVc and IVd.
Methyl 2-sulfanylbenzoates IXa can be prepared by esterification of 2-sulfanylbenzoic acids X. The conversion can be achieved by heating under reflux in the presence of sulfuric acid in methanol overnight or stirring with thionyl chloride in methanol at room temperature for several hours. 3,4-Dihydro-l,4-benzothiazepin-5(2H)-ones Villa can be prepared from methyl 2- sulfanylbenzoates IXa by annulation with 2-bromo-ethylamine hydrochloride. The reaction can be carried out with a standard basic agent such as sodium hydride, potassium tert-butoxide in a suitable organic solvent such as tetrahydrofuran, 1,4-dioxane, N,N-dimethylformamide or mixtures thereof, typically at 0 °C, followed by stirring at room temperature overnight.
2,3,4,5-Tetrahydro-l,4-benzothiazepines IVa can be prepared by reduction of 3,4- dihydro-l,4-benzothiazepin-5(2H)-ones Villa. The reaction can be carried out with a standard reducing agent such as lithium aluminium hydride, boron hydride or combination of sodium borohydride and boron trifluoride in a suitable inert organic solvent such as tetrahydrofuran, diethyl ether or mixtures thereof, typically at 0 °C, followed by stirring at a temperature between 25 °C and 70 °C for several hours.
Amides IVb can be prepared by acylation of IVa with acetyl chloride or acetic anhydride. The reaction can be carried out with a suitable base such as triethylamine or pyridine in a suitable inert organic solvent such as dichloromethane, tetrahydrofuran or pyridine at 0 °C, followed by stirring at room temperature for 30 minutes.
Compounds IVc can be prepared by oxidation of IVb followed by deacylation. Oxidation can be carried out with 1-2 equivalents of 3-chloroperoxybenzoic acid, in a suitable solvent such as dichloromethane, chloroform, 1,2-dichloroethane, or the mixture thereof, typically at 0 °C, followed by stirring at room temperature for 10 to 20 minutes. Deacylation can be achieved by stirring amides with a suitable base such as sodium hydroxide or potassium hydroxide in a mixture of alcohol such as methanol or ethanol and water under reflux overnight.
Compounds IVd can be prepared by oxidation of IVb followed by deacylation. Oxidation can be carried out with 4 equivalents of 3-chloroperoxybenzoic acid, in a suitable solvent such as dichloromethane, chloroform, 1,2-dichloroethane, or the mixture thereof, typically at 0 °C, followed by stirring at room temperature for 1 to 2 hours. Deacylation can be achieved by stirring amides with a suitable base such as sodium hydroxide or potassium hydroxide in a mixture of alcohol such as methanol or ethanol and water under reflux overnight.
General synthetic route for 5-methyl-2,3,4,5-tetrahydro-l,4-benzothiazepines (Scheme 3)
Scheme 3
Figure imgf000041_0001
IXb Vlllb IVe
Compounds of interest IVe can be prepared according to Scheme 3. Starting from l-(2- sulfanylphenyl)ethanones IXb, annulation of esters IXb with 2-bromo ethylamine hydrochloride affords 5-methyl-2,3-dihydro-l,4-benzothiazepines Vlllb. Reduction of Vlllb affords 5-methyl- 2,3,4,5-tetrahydro-l,4-benzothiazepines IVe.
5-Methyl-2,3-dihydro-l,4-benzothiazepine Vlllb can be prepared from l-(2- sulfanylphenyl)ethanones IXb by annulation with 2-bromo-ethylamine. The reaction can be carried out with a standard basic agent such as sodium hydride, potassium tert-butoxide in a suitable organic solvent such as tetrahydrofuran, 1,4-dioxane, N,N-dimethylformamide or mixtures thereof, typically at 0 °C, followed by stirring at room temperature overnight.
5-Methyl-2,3,4,5-tetrahydro-l,4-benzothiazepines IVe can be prepared from reduction of 5-methyl-2,3-dihydro-l,4-benzothiazepines Vlllb. The reaction can be carried out with a reducing reagent such as sodium borohydride in a suitable organic solvent such as methanol, water or mixtures thereof at room temperature for several hours or overnight, followed by treatment with concentrated hydrochloric acid at room temperature for 30 minutes. After neutralization with sodium carbonate or sodium hydroxide, free form of IVe is obtained.
General synthetic route for formulas Iaa (Scheme 4)
Scheme 4
Figure imgf000042_0001
E is CI or Br,
W1 is (oxetan-S-ylJC^ alkyl, (tetrahydrofuran-S-ylJC^alkyl, (tetrahydro^H-pyran-^ylJC^alkyl,
(C3.6cycloalkyl)C14alkyl
L1 is H or benzyl,
or L1 and W1 with the nitrogen atom to which they are attached form 2-Oxa-6-aza-spiro[3.4]oct-
Compounds of interest Iaa can be prepared according to Scheme 4. Coupling of 2,4- dihalogen quino lines Ilia with benzodiazepines IVf followed by oxidation gives 4-halogen quino lines Ilab. Coupling of 4-halogen quino lines Ilab with various benzyl diamines Va followed by debenzylation generates Iaa.
Quino lines Ilac can be prepared by coupling of 2,4-dihalogen quino lines Ilia with benzothiazepines IVf. The reaction can be carried out with or without a solvent such as isopropanol, n-butanol, tert-butanol or the mixture thereof at a temperature between 120 °C and 180 °C, typically at 160 °C under microwave irradiation for several hours. Sulfones Ilab can be prepared by oxidation of sulfides Ilac. The reaction can be carried out with a suitable oxidant such as 3-chloroperoxybenzoic acid in a suitable inert organic solvent such as dichloromethane typically at 0 °C, followed by stirring at room temperature for several hours. Alternatively, the reaction can be carried out with a suitable oxidant such as hydrogen peroxide, sodium periodate or potassium permanganate, in a suitable solvent such as methanol, tetrahydroiuran, water or the mixture thereof, typically at 0 °C, followed by stirring at a temperature between room temperature and 70 °C for several hours.
4-Benzyl diamino quino lines Ilaa can be prepared by coupling of quino lines Ilab with various benzyl diamines Va. The reaction can be carried out in the presence of a palladium catalyst such as l, -bis(diphenylphosphino)ferrocene-palladium (II), palladium (II) acetate, tri(dibenzylideneacetone)dipalladium(0), or palladium (II) chloride in the presence of a phosphine ligand such as triphenyl phosphane, l,l'-bis(diphenylphosphino)ferrocene, 9,9- dimethyl-4,5-bis(diphenylphosphino)xanthene, or tricyclohexylphosphine, with a suitable base such as sodium carbonate, potassium carbonate, cesium carbonate, sodium tert-butoxide or potassium tert-butoxide, in a suitable inert organic solvent such as toluene, 1,4-dioxane, tetrahydroiuran or N,N-dimethylformamide at a temperature between 100 °C and 160 °C for 1 to 3 hours under microwave irradiation. Alternatively, the reactions can be carried out at a heated temperature such as between 100 °C and 140 °C for a longer reaction time without microwave irradiation.
Compounds of interest Iaa can be prepared by standard debenzylation of Ilaa. The reaction can be carried out in the presence of palladium on carbon, palladium hydroxide on carbon or platinum oxide, typically with an acid such as hydrochloric acid, acetic acid or trifluoro acetic acid in a suitable solvent such as methanol, ethanol, tetrahydroiuran, ethyl acetate or the mixture thereof, at room temperature for several hours under hydrogen atmosphere.
General synthetic route for formula lab and lac (Scheme 5)
Scheme 5
Figure imgf000044_0001
Figure imgf000044_0002
E is CI or Br
Compounds of interest lab and lac can be prepared according to Scheme 5. Coupling of 4-halogen quino lines Ilac with various amines XI affords lab. Coupling of 4-halogen quino lines Ilab and various amines XI affords 4-amino quino lines lac. Alternatively, lac can be obtained by oxidation of the sulfides lab.
4-Amino quino lines lab can be prepared by coupling of 4-halogen quino lines Ilac with various amines XI in the presence or absence of a palladium catalyst. Palladium-catalyzed coupling reaction can be carried out in the presence of a palladium catalyst such as Ι,Γ- bis(diphenylphosphino)ferrocene-palladium(II)dichloride, palladium acetate or
tris(dibenzylideneacetone) dipalladium(0), in combination with a phosphine ligand such as 1,1 '- bis(diphenylphosphino)ferrocene, 2,2'-bis(diphenylphosphino)-l,l '-binaphthalene, 4,5- bis(diphenylphosphino)-9,9-dimethylxanthene or 2-dicyclohexylphosphino-2'-(N,N- dimethylamino)biphenyl, and a base such as sodium tert-butoxide, cesium carbonate or potassium phosphate in a suitable solvent such as 1,4-dioxane or toluene, at a temperature between 100 °C and 140 °C for 1 to 2 hours under microwave irradiation. Alternatively, palladium-catalyzed coupling reaction can be carried out at an elevated temperature such as 110 °C or 120 °C without microwave irradiation for a longer reaction time. Coupling of 4-halogen quino lines Ilac with various amines XI in the absence of a palladium catalyst can be carried out with a suitable base such as N,N-diisopropylethylamine or without any base in a suitable solvent such as n-butanol, l-methyl-2-pyrrolidinone or phenol, at a temperature between 130 °C and 160 °C for 1.5 to 2 hours under microwave irradiation. Alternatively, the reaction can be carried out at an elevated temperature between 150 °C and 180 °C without microwave irradiation for a longer reaction time. Alternatively, the reaction can also be carried out without any base and without any solvent at 160 °C for one to several hours under microwave irradiation.
4-Amino quino lines lac can be prepared by coupling of 4-halogen quino lines Ilab with various amines XI in the presence of a metal catalyst such as a palladium catalyst or copper (I) iodide, or absence of a metal catalyst. Coupling of 4-halogen quino lines Ilab with various amines XI in the presence of a palladium catalyst or in the absence of any metal catalyst can be carried out in analogy to coupling of 4-halogen quino lines Ilac with various amines XI.
Copper(I) iodide catalyzed coupling of 4-halogen quino lines Ilab with various amines XI can be carried out in the presence of copper(I) iodide with a ligand such as N,N'-dimethylcyclohexane- 1,2-diamine or cyclohexane-l,3-diamine, and a base such as potassium carbonate or potassium phosphate in a suitable solvent such as 1,4-dioxane or diethylene glycol dimethyl ether, at a temperature between 140 °C and 150 °C for 2 to 3 hours under microwave irradiation.
Alternatively, the reaction can be carried out at an elevated temperature without microwave irradiation for a longer reaction time.
Alternatively, 4-Amino quino lines lac can be prepared from oxidation of sulfides lab. The reaction can be carried out in analogy to oxidation of quino lines Ilac in Scheme 4.
General synthetic route for formula lad (Scheme 6)
Scheme 6
Figure imgf000046_0001
Compounds of interest lad can be prepared according to Scheme 6. Coupling of 2,4- halogen quino lines Ilia with benzodiazepines IVg affords 2-benzothiazepin-4-halogen quino lines Had. Coupling of Had with various amines XI affords compounds of interest lad.
2-Benzothiazepin-4-halogen quino lines Had can be prepared from coupling of 2,4- halogen quino lines Ilia with benzothiazepines IVg. The reaction can be carried out in the absence of solvent or in a suitable solvent such as isopropanol, n-butanol, tert-butanol or the mixtures thereof at a temperature between 120 °C and 180 °C, typically at 160 °C under microwave irradiation for several hours.
Compounds of interest of formula lad can be prepared from coupling of 2- benzothiazepin-4-halogen quino lines Had with various amines XI. The reaction can be carried out in the presence of a metal catalyst or in the absence of a metal catalyst in analogy to coupling of 4-halogen quino lines Hab with various amines XI in Scheme 5.
General synthetic route for formula Iae, Iaf and lag (Scheme 7)
Scheme 7
Figure imgf000047_0001
azetidin-2-yl-carbonyl or pyrrolindin-2-yl-carbonyl.
Compounds of interest lae, laf and lag can be prepared according to Scheme 7. Coupling of 4-halogen quino lines Ilae with various protected amines affords intermediates Ilaf, Hag and
Hah. Deprotection of Ilaf, Hag and Hah affords compounds of interest lae, laf and lag. Compounds of interest Ilaf, Hag and Hah can be prepared from coupling of 4-halogen quino lines Hae with various protected amines. Coupling of 4-halogen quino lines Hae with various amines such as tert-butyl carbamate, XII or XIII can be carried out in the presence of a metal catalyst or in the absence of a metal catalyst in analogy to coupling of 4-halogen quino lines Hab with various amines XI in Scheme 5.
Compounds of interest Iae, Iaf and lag can be prepared from deprotection of tert- butyloxycarbonyl of Ilaf, Hag and Hah. The reaction can be carried out with a suitable acid such as trifluoro acetic acid or hydrochloric acid in a suitable solvent such as dichloromethane, ethyl acetate or 1,4-dioxane, at 0 °C to room temperature for 4 to 16 hours. General synthetic route for formula Iah (Scheme 8)
Scheme 8
Figure imgf000048_0001
Compounds of interest Iah can be prepared according to Scheme 8. Coupling of 4- halogen quino lines Hae with various protected amines XIV affords intermediates Hai.
Deprotection of benzyloxycarbonyl of Hai affords compounds of interest Iah.
Compounds Hai can be prepared from coupling of 4-halogen quino lines Hae with various amines XIV. The reaction can be carried out in the presence of a metal catalyst or in absence of a metal catalyst in analogy to coupling of 4-halogen quino lines Hab with various amines XI in Scheme 5. Typically, the reaction can be carried out in the presence of
tnV HiVii-ri7Ail irl i-ni-ani-tr>nf;)dipalladium(0) with 2-dicyclohexylphosphino-2'-(N,N- dimethylamino)biphenyl, and sodium tert-butoxide in a suitable solvent such as 1,4-dioxane, at 120 °C for 2 hours under microwave irradiation.
Compounds of interest Iah can be prepared from deprotection of benzyloxycarbonyl of Ilai. The conversion can be achieved under strong acidic conditions, under basic conditions or by hydro genation. Treating Ilai with a mixture of aqueous solution of potassium hydroxide and methanol under reflux for 30 minutes to several hours can generate Iah. Treating Ilai under strong acidic conditions such as reflux in 6 N hydrochloride in methanol for several hours can also generate Iah. Hydrogenation of Ilai can be carried out in the presence of palladium on carbon or palladium black, under hydrogen atmosphere or with a hydrogen donor such as formic acid or ammonium formate, in a suitable solvent such as methanol or ethanol, at a temperature between room temperature and 80 °C for 15 minutes to several hours.
General synthetic route for formula Iai and Iaj (Scheme 9)
Scheme 9
Figure imgf000049_0001
Figure imgf000049_0002
E is CI or Br,
L7 is ydroxyet yl, met oxyet yl or pyridin-2-yl
Compounds of interest Iai and Iaj can be prepared according to Scheme 8. Demethylation of 6-methoxy quino lines Ilaj affords 6-hydroxy quino lines Ilak. Reaction of Ilak with bromides
"ng of 6-hydroxy quino lines Ilak with propane- 1,3-diamine affords compounds of interest lai. Coupling of Ham with propane- 1,3-diamine affords compounds of interest Iaj .
6-Hydroxy quino lines Hak can be prepared by demethylation of 6-methoxy quino lines Haj. The reaction can be carried out in an aqueous solution of hydrobromic acid by heating under reflux for 2 days.
Ham can be prepared by reaction of Hak with bromides XV. When L7 is pyridin-2-yl, the reaction can be carried out in the presence of a metal catalyst such as Copper(I) iodide with a ligand such as N,N'-dimethylcyclohexane-l,2-diamine and with a suitable base such as potassium carbonate in a suitable solvent such as 1 ,2-dimethoxyethane at 120 °C for 1 hours under microwave irradiation. When L7 is substituted alkyl such as hydro xyethyl or
methoxyethyl, the reaction can be carried out in the presence of a suitable base such as potassium carbonate in a suitable solvent such as acetone at room temperature overnight.
Compounds of interest lai and Iaj can be prepared by coupling of Hak and Ham with propane- 1,3-diamine separately. The reaction can be carried out at 150 °C for 1.5 hours under microwave irradiation.
General synthetic route for formula Iak (Scheme 10)
Scheme 10
Figure imgf000050_0001
E is CI or Br,
Figure imgf000050_0002
Compounds of interest Iak can be prepared according to Scheme 10. Coupling of 4- halogen quino lines Ilae with C-(2,2-dimethyl-[l,3]dioxolan-4-yl)-methylamine followed by deprotection affords 4-(2,3-diol-propylamino)-quino lines Iak.
Han can be obtained by coupling of 4-halogen quino lines Ilae with C-(2,2-dimethyl- [l,3]dioxolan-4-yl)-methylamine. The reaction can be carried out in analogy to coupling of 4- halogen quino lines Ilab with various amines XI in Scheme 5. Typically the reaction can be carried out by heating a mixture of 4-halogen quinolines Ilae and C-(2,2-dimethyl- [l,3]dioxolan-4-yl)-methylamine at 160 °C for 16 hours.
4-(2,3-Diol-propylamino)-quino lines Iak can be prepared by deprotection of Han. The reaction can be carried out in the presence of an acid such as hydrochloric acid in a suitable solvent such as methanol, ethanol, water or mixtures thereof at room temperature for several hours.
General synthetic route for formula Ial (Scheme 1 1)
Scheme 11
Figure imgf000051_0001
Figure imgf000051_0002
Compounds of interest lal can be prepared according to Scheme 11. Coupling of fluorides Ilao with amines XVI followed by debenzylation affords compounds of interest lal.
Quino lines Hap can be prepared from coupling of fluorides Ilao (which can be prepared in analogy to 4-benzyl diamino quino lines Ilaa in Scheme 4) with amines XVI. The reaction can be carried out by heating a mixture of fluorides Ilao and amines XVI with a suitable solvent such as N,N-dimethyl formamide, N,N-dimethyl acetamide, N-methyl-2-pyrrolidinone, dimethyl sulfoxide or the mixtures thereof, or without any solvent at a temperature between 100 °C and 150 °C, typically at 120 °C under microwave irradiation for several hours.
Compounds of interest lal can be prepared by standard benzyl deprotection of Hap. The reaction can be carried out in analogy to debenzylation of Ilaa in Scheme 4.
General synthetic route for formula lam and Ian (Scheme 12)
Scheme 12
Figure imgf000053_0001
E is CI or Br,
Compounds of interest lam and Ian can be prepared according to Scheme 12.
Demethylation of Ilaq affords liar. Coupling of liar with iodobenzene affords 4-phenoxy benzothiazepines Has. Coupling of Has with (3-aminomethyl-oxetan-3-yl)-dibenzylamine followed by debenzylation provides 4-[(3-amino-oxetan-3-ylmethyl)-amino]quino lines lam. Coupling of liar with 3-bromo-propan-l-ol affords Ilau. Coupling of 4-halogen quino lines Ilau with carbamic acid tert-butyl ester followed by deprotection of tert-butyloxycarbonyl affords 4- amino quino lines Ian. liar can be prepared by demethylation of Ilaq. The reaction can be carried out by treating Ilaq with a suitable Lewis acid such as tribromoborane, aluminum chloride, aluminum bromide, and stannous chloride in a dry organic inert solvent such as dichloromethane, chloroform, acetonitrile and N,N-dimethylformamide at a temperature between 0 and 80 °C, typically at 0 °C, for a period of 5 minutes to 3 hours, typically for 1 hour. Has can be obtained by coupling of liar with iodobenzene. The reaction can be carried out by heating in the presence of copper(I) iodide or copper(I) bromide, with a ligand such as N,N-dimethylglycine hydrochloride, (2-pyridyl)acetone or l,l,l-tris(hydroxymethyl)ethane, and a base such as cesium carbonate, potassium carbonate, or potassium phosphate, in an organic solvent such as dimethyl sulfoxide, N,N-dimethylformamide, acetonitrile or 1,4-dioxane at a temperature between 80 °C and 120 °C for 4 to 24 hours. Typically, the reaction can be carried out by heating in the presence of copper(I) iodide, N,N-dimethylglycine hydrochloride and potassium carbonate in dimethyl sulfoxide at 120 °C for 6 hours.
Iam can be obtained by coupling of Has with (3-aminomethyl-oxetan-3-yl)-dibenzylamine followed by debenzylation. The reactions can be conducted in analogy to preparation of laa from Hab in Scheme 4. Typically, coupling of Has with (3-aminomethyl-oxetan-3-yl)-dibenzylamine can be carried out in the presence of bis(diphenylphosphino)-ferrocenedichloropalladium(II), l,l'-bis(diphenylphosphino)-ferrocene and sodium-tert-butoxide in 1,4-dioxane at 120 °C for 2 hours under microwave irradiation. Debenzylation of Hat can be achieved by stirring a solution of Hat in methanol in the presence of palladium hydroxide on carbon and trifluoro acetic acid at room temperature under 2 bar of hydrogen atmosphere for 14 hours.
Ilau can be prepared by coupling of liar with 3-bromo-propan-l-ol. The reaction can be carried out with a suitable base such as potassium carbonate, cesium carbonate, sodium tert- butoxide, potassium tert-butoxide, sodium hydride or l,8-diazabicyclo[5.4.0]undec-7-ene in an inert organic solvent such as dichloromethane, N,N-dimethylformamide, dimethyl sulfoxide or 1- methyl-pyrrolidin-2-one at a temperature between room temperature and 100 °C, typically at 70 °C for several hours. Ilav can be prepared by coupling of 4-halogen quino lines Ilau with carbamic acid tert- butyl ester. The reaction can be carried out in the presence of a palladium catalyst in analogy to coupling of 4-halogen quino lines Ilab with various amines XI in Scheme 5. Typically the reaction can be carried out by heating a mixture of 4-halogen quino lines Ilau and carbamic acid tert- vXy\ ester in the presence of bis(diphenylphosphino)ferrocenedichloropalladium(II), with l,l'-bis(diphenylphosphino)ferrocene and sodium- tert-butoxide in 1,4-dioxane at 120 °C for 2 hours.
4-Amine quino lines Ian can be obtained by standard deprotection of tert- butyloxycarbonyl of Ilav. The reaction can be carried out by treating Ilav with a suitable acid such as hydrochloric acid, trifluoro acetic acid, or sulfuric acid in a suitable solvent such as methanol, ethyl acetate, dichloromethane, 1,4-dioxane, water or the mixtures thereof at a temperature between 0 °C and room temperature for 30 minutes to several hours. Typically the reaction can be carried out by treating Ilav with trifluoro acetic acid in dichloromethane at room temperature for 6 hours. General synthetic route for formula Iao (Scheme 12)
Scheme 12
Figure imgf000055_0001
E is CI or Br;
W is CH2, CH(CH3), CH2CH(CH3), or CH(CH3)CH2;
L8 is H or CH3 Compounds of interest Iao can be prepared according to Scheme 13. Coupling of 4- halogen quino lines Ilab with various amino acids XVII gives acids Haw. Esterification of acids Haw followed by amino lysis affords amides Iao.
Acids Haw can be prepared by coupling of 4-halogen-quino lines Ilab with amino acids XVII. The reaction can be carried out in phenol, preferably at 150 °C in a sealed tube overnight.
Esters Hax can be prepared by esterification of carboxylic acids Haw. The reaction can be carried out by heating Haw and methanol in the presence of a suitable catalyst such as concentrated sulfuric acid, dry hydrochloride gas, or thionyl chloride for several hours. Typically the reaction can be carried out by heating Haw and methanol in the presence of thionyl chloride under reflux for 2 hours.
Amides Iao can be prepared by aminolysis of methyl esters Hax. The reaction can be carried out by heating methyl esters Hax with various concentrated amines in alcohol, such as 7N ammonia in methanol or 33% (wt%) methyl amine in absolute ethanol. The reaction can be preferably carried out at 85 °C in a sealed tube overnight.
General synthetic route for formula lap (Scheme 14)
Scheme 14
Figure imgf000057_0001
Figure imgf000057_0002
Compounds of interest lap can be prepared according to Scheme 14. Coupling of 4- halogen quino lines Hab with 4-aminomethyl-2,2-dimethyl-oxazolidine-3-carboxylic acid tert- butyl ester affords Hay. Cleavage of tert-butyloxycarbonyl and acetal generates amino alcohols lap.
Oxazolidines can be prepared by coupling of 4-halogen quinolines Hab with 4- aminomethyl-2,2-dimethyl-oxazolidine-3-carboxylic acid tert-butyl ester. The reaction can be carried out in the presence of a palladium catalyst in analogy to coupling of 4-halogen quinolines Hab with various amines XI in Scheme 5. Typically the reaction can be carried out by heating a mixture of 4-halogen quinolines Hab and 4-aminomethyl-2,2-dimethyl-oxazolidine-3-carboxylic acid tert-bvXy\ ester in the presence of bis(diphenylphosphino)ferrocenedichloropalladium(II), with l,l'-bis(diphenylphosphino)ferrocene and sodium-tert-butoxide in 1,4-dioxane at 120 °C for 1.5 hours.
Amino alcohols lap can be prepared by acid catalyzed cleavage of tert-butyloxycarbonyl and acetal of acetonides Hay. The reaction is typically carried out in a solution of hydrochloride in ethyl acetate for several hours at room temperature.
General synthetic route for formula Iar (Scheme 15)
Scheme 15
Figure imgf000058_0001
L9 is H or CH3,
Compounds of interest lar can be prepared according to Scheme 15. Starting with amino alcohols Iaq (prepared in analogue to Idj in Scheme 56), ring closure with cyanogen bromide gives oxazoles lar. The reaction can be carried out with a suitable base such as sodium acetate, sodium carbonate, potassium acetate or potassium carbonate, in a suitable solvent such as methanol, water, or the mixtures thereof, typically at 0 °C, followed by stirring at room temperature for several hours.
General synthetic route for formula Iat (Scheme 16)
Scheme 16
Figure imgf000058_0002
L10 is H,
W5 is CH2,
or L10 is CH2 and W5 is CH, they attach and form a pyrrolidine ring.
Compounds of interest Iat can be prepared according to Scheme 16. Starting with amino alcohols las (prepared in analogue to lap in Scheme 14 and laf in Scheme 7), cyclization with cyanogen bromide affords oxazoles Iat. Compounds of interest Iat can be prepared by cyclization of amino alcohols las with a slight excess of cyanogen bromide. The reaction can be carried out in the presence of a suitable base such as sodium acetate, sodium carbonate, potassium acetate or potassium carbonate, in a suitable solvent such as methanol, water, or the mixtures thereof, typically at 0 °C, followed by stirring at room temperature for several hours. General synthetic route for formula lau (Scheme 17)
Scheme 17
Figure imgf000059_0001
Compounds of interest lau can be prepared according to Scheme 17. Starting with IVb, oxidation of IVb gives sulfones IVh, which was coupled with 2-aminobenzonitriles XVIII to afford imines Ilaz. Ring closure of imines liaz gives 4-amino quino lines lau.
Sulfones IVh can be prepared by oxidation of IVb. The reaction can be carried out with a suitable oxidant such as 3-chloroperoxybenzoic acid, hydrogen peroxide, sodium periodate or potassium permanganate, in a suitable solvent such as dichloromethane, acetic acid, water or the mixtures thereof, typically at 0 °C, followed by stirring at room temperature for several hours.
Imines liaz can be prepared by heating a mixture of IVh, 2-aminobenzonitriles XVIII and phosphorous oxychloride. The reaction can be carried out in a suitable inert organic solvent such as dichloromethane, chloroform or the mixtures thereof, typically at 0-10 °C, followed by stirring at reflux for 24 hours. Compounds of interest lau can be prepared by ring closure of imines Ilaz. The reaction can be achieved by treatment of Ilaz with Lewis acid such as zinc chloride in N,N- dimethylacetamide at 120-180 °C for several hours in an inert atmosphere.
General synthetic route for formula lav and law (Scheme 18)
Scheme 18
Figure imgf000060_0001
Compounds of interest law and lav can be prepared according to Scheme 18. Staring from 4-amino quino lines lae, acylation of lae with acyl chlorides XIX gives amides Ilba. Reaction of Ilba with methanol affords methyl ethers lav. Reaction of Ilba with sodium azide followed by hydrogenation of azides generates compounds of formula law.
Amides Ilba can be prepared from 4-amino quino lines lae by acylation with acy chlorides XIX. The reaction can be carried out with a suitable base such as potassium carbonate, cesium carbonate, sodium hydride or l,8-diazabicyclo[5.4.0]undec-7-ene in an inert organic solvent such as dichloromethane, tetrahydrofuran or N,N-dimethylformamide, typically at room temperature, followed by stirring at 50-100 °C for several hours. Methyl ethers lav can be prepared by reaction of Ilba with methanol. The reaction can be realized by refluxing Ilba in methanol in the presence of ethylamine overnight.
Azides Ilbb can be prepared by reaction of amides Ilba with sodium azide. The reaction can be carried out in a suitable solvent such as acetonitrile, N,N-dimethylformamide, dimethyl sulfoxide, water or mixtures thereof, typically at 25-70 °C for several hours.
Amines law can be prepared by hydrogenation of azides Ilbb. The reaction can be carried out in the presence of 10% palladium on carbon under hydrogen atmosphere in an organic solvent such as ethyl acetate, methanol, or ethanol, typically at room temperature for several hours. General synthetic route for formula lax and lay (Scheme 19)
Scheme 19
Figure imgf000061_0001
L13 is H or CF3
Compounds of interest lax and lay can be prepared according to Scheme 19. Starting from 4-aminoquino lines lae, acylation of lae with acyl chlorides XX gives Ilbc. Cleavage of phthalic protecting group from Ilbc generates amides lax. Reduction of amides of lax generates lay.
Ilbc can be prepared by acylation of 4-aminoquino lines lae. The reaction can be carried out by stirring a mixture of lae and acyl chlorides XX with a suitable base such as N,N- diisopropylethylamine or cesium carbonate, in a suitable organic solvent such as dichloromethane, N,N-dimethylformamide or the mixtures thereof, at room temperature for several hours.
Amides lax can be prepared by cleavage of phthalic protecting group from Ilbc. The reaction can be carried out with a suitable base such as hydrazine, hydrazine acetate or low alkyl amine such as methylamine or n-butylamine in an alcohol solvent such as methanol or ethanol at a temperature between room temperature and 90 °C for several hours. Typically, the reaction can be carried out by heating Ilbc with methylamine in ethanol, at 90 °C for 2 hours. lay can be obtained by reduction of amides of lax. The reaction can be carried out by heating lax in a solution of borane-methyl sulfide complex in diethyl ether at 80 °C for several hours.
General synthetic route for formula Iba (Scheme 20)
Scheme 20
Figure imgf000062_0001
L 4 is H,
L 5 is H or ethyl,
L 6 is CH2CH3,oxetan-3-yl, or pyridin-2-yl,
W6 is (CH2)2, (CH2)3, or methyl-oxetan-3-yl,
L 4 and W6 with nitrogen they are attached to form pyrrolidin-3-yl,
L 5 and W6 with nitrogen they are attached to form pyrrolidin-3-y,
Compounds of interest Iba can be prepared according to Scheme 20. Starting with amines laz (prepared in analogue to lac in Scheme 5 and Iaf, lag in Scheme 7), reductive amination with various aldehydes or ketones provides substituted amines Iba when L16 is ethyl or oxetan-3-yl; coupling of amines laz with 2-bromo-pyridine generates Iba when L16 is pyridine-2-yl. Compounds of interest Iba can be prepared by reductive amination of laz with various aldehydes or ketones. This reaction can be carried out with a suitable reducing agent such as sodium triacetoxyborohydride or sodium cyanoborohydride in a suitable organic solvent such as dichloromethane, 1,2-dichloroethane, tetrahydrofuran, methanol or the mixtures thereof, typically with the addition of molecular sieves or acetic acid, at a temperature between room temperature and 70 °C for 2 to 12 hours.
Compounds of interest Iba can also be prepared by coupling of amines Iaz with 2- bromo-pyridine. The reaction is typically performed in N-methylpyrolidinone with
tri(dibenzylideneacetone)dipalladium(0), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthe, cesium carbonate at a temperature between 100 °C and 150 °C for several hours under inert atmosphere.
General synthetic route for formula Ibb (Scheme 21)
Scheme 21
Figure imgf000063_0001
L17 is phenyl or ethyl
Compounds of formula Ibb can be prepared as shown in Scheme 21. Ureas Ibb can be prepared by reaction of 4-amino-quino lines lae with isocyanides XXI. The reaction can be carried out by stirring 4-amino-quino lines lae with various isocyanide XXI in the presence of a suitable base such as triethylamine in an organic solvent such as tetrahydrofuran at a temperature between 0 °C to 50 °C for several hours.
General synthetic route for formula Ibc (Scheme 22)
Scheme 22
Figure imgf000064_0001
Figure imgf000064_0002
Compounds of interest of formula Ibc can be prepared according to Scheme 22. Reaction of bromides Ilbd with various organoboronic acids or various organometallic reagents affords compounds Ilbe. Coupling of Ilbe with propane- 1,3-diamine affords compounds of interest of formula Ibc.
Compounds Ilbe can be prepared from reaction of bromides Ilbd with various organoboronic acids or various metal reagents such as zinc cyanide or organo stannic reagents. Reaction of bromides Ilbd with various organoboronic acids can be carried out in the presence of a palladium catalyst such as tetra(triphenylphosphino)palladium or palladium acetate with a phosphine ligand such as 2,2'-bis(diphenylphosphino)-l,l '-binaphthalene and a base such as potassium carbonate in a suitable solvent such as toluene at 90 °C for 16 hours under argon atmosphere. Reaction of bromides Ilbd with various organometallic reagents can be carried out in the presence of a palladium catalyst such as tetra(tri-phenylphosphino)palladium in a suitable solvent such as N,N-dimethylformamide under reflux for 1 to 2 hours under argon atmosphere. Coupling of halogens Ilbe with propane- 1,3-diamine can be carried out in analogy to coupling of 4-halogen quino lines Ilab with various amines XI in Scheme 5. Typically, the reaction can be carried out with a palladium catalyst such as
bis(diphenylphosphino)ferrocenedichloropalladium(II), with a phosphine ligand such as Ι,Γ- bis(diphenylphosphino)ferrocene, and a suitable base such as sodium-tert-butoxide in a suitable solvent such as 1,4-dioxane, heated at 120 °C for 2 hours under microwave irradiation.
Hpnpral «vn†Vip†ir route for formula Ibd, Ibe and Ibf (Scheme 23) Scheme 23
Figure imgf000065_0001
Compounds of interest Ibd, Ibe and Ibf can be prepared according to Scheme 23.
Hydrolysis of 2,4-dichloro-quinozalines Mb affords 2-chloro-4-hydroxy-quinozalines IIIc. Coupling of 2,4-dichloro-quinozalines Mb with various amines XI affords Ilbf. Coupling of IIIc with benzoazapines IVi followed by coupling with various amines XI affords compounds of interest Ibd. Coupling of Ilbf with benzoazapines IVi affords compounds of interest Ibd.
Coupling of Ilbf with benzothioazapines IVf affords compounds of interest Ibe. Oxidation of
'''' ' mpounds of interest Ibf. 2-Chloro-4-hydroxy-quinozalines IIIc can be prepared by hydrolysis of 2,4-dichloro- quinozalines Mb. The reaction can be carried out in the presence of a suitable base such as sodium hydroxide in a suitable solvent such as tetrahydrofuran, water or mixtures thereof at room temperature for several hours. 4-Hydroxy quinozalines Ilbg can be prepared by coupling of IIIc with benzoazapines
IVi. The reaction can be carried out in the presence of a suitable base such as triethylamine in a suitable solvent such as toluene or N,N-dimethylformamide at a temperature between 110 °C and 160 °C under microwave irradiation for 30 minutes to 2 hours. Alternatively, the reaction can be carried out at an elevated temperature such as under reflux overnight without microwave irradiation.
2-Chloro-4-amino quinozalines Ilbf can be prepared by coupling of Illb with various amines XI. The reaction can be carried out in the presence of a suitable base such as
triethylamine in a suitable solvent such as methanol, tetrahydrofuran, dichloromethane or mixtures thereof at a temperature between 0 °C to room temperature for several hours. Compounds of interest Ibd can be prepared by coupling of Ilbg with various amines XI.
The reaction can be carried out in the presence of a suitable base such as 1,8- diazabicyclo[5.4.0]undec-7-ene with a suitable coupling reagents such as benzotriazol-1- yloxytris(dimethylamino)-phosphonium hexafluorophosphate, in a suitable solvent such as N,N- dimethylformamide at room temperature for several hours. Alternatively, compounds of interest Ibd can be obtained by the coupling of Ilbf with benzoazapines IVi. The reaction can be carried out with or without a base such as triethylamine, in a suitable solvent such as n-butanol or N,N-dimethylformamide at a temperature between 130 °C and 160 °C for 30 minutes to several hours under microwave irradiation. Alternatively, this reaction can be carried out with triethylamine in n-butanol in a sealed tube at a lower temperature for several hours, typically at 100 °C for 4 hours.
Compounds of interest Ibe can be prepared by coupling of Ilbf with benzothioazapines IVf. The reaction can be carried out without any base or with a suitable base such as
triethylamine in a suitable solvent such as n-butanol or N,N-dimethylformamide at a temperature between 130 °C and 160 °C for several hours under microwave irradiation. Compounds of interest Ibf can be prepared by oxidation of Ibe. The reaction can be carried out with 3-chloroperoxybenzoic acid in dichloromethane or oxone in a mixture solvent such as methanol and tetrahydroiuran at a temperature between 0 °C and room temperature for several hours.
General synthetic route for formula Ibj (Scheme 24)
Scheme 24
Figure imgf000067_0001
Figure imgf000067_0002
Compounds of interest Ibj can be prepared according to Scheme 24. Starting with Ibh (prepared in analogue to Ibe in Scheme 23), oxidation with a suitable oxidant provides Ibi. Subsequent debenzylation generates amines Ibj .
Ibi can be prepared by oxidation of Ibh. The reaction can be carried out with a suitable oxidant such as 3-chloroperoxybenzoic acid, hydrogen peroxide, sodium periodate or potassium permanganate, in a suitable solvent such as dichloromethane, acetic acid, water or the mixture thereof, typically at 0 °C, followed by stirring at room temperature for several hours.
Compounds Ibj can be prepared by standard debenzylation of Ibi. The reaction can be carried out with palladium on carbon, palladium hydroxide on carbon or platinum oxide, typically with an acid such as acetic acid or trifluoro acetic acid in a suitable solvent such as methanol, ethanol, tetrahydroiuran, ethyl acetate or the mixtures thereof, at room temperature — i™. „A„ „ ^re for several hours. General synthetic route for formula Ibl (Scheme 25)
Scheme 25
Figure imgf000068_0001
W8 is (CH2)2, (CH2)3 or oxetan-3-ylmethyl,
Compounds of interest Ibl can be prepared according to Scheme 25. Starting with amines Ibk (prepared in analogue to lac in Scheme 5 and Ibf in Scheme 23), acylation with acetic anhydride or acetyl chloride gives acetamides Ibl. The reaction can be carried out with a suitable base such as triethylamine or pyridine in a suitable inert organic solvent such as dichloromethane, tetrahydroiuran or pyridine at 0 °C, followed by stirring at room temperature for several hours.
General synthetic route for formula Ibm (Scheme 26)
Scheme 26
Figure imgf000068_0002
Compounds of interest Ibm can be prepared according to Scheme 26. Coupling of 4- halogen-quino lines Ilab with N-(3-methyl-pyrrolidin-3-yl)-acetamide affords compounds Ilbh. Deactylation of Ilbh affords compounds of interest Ibm.
Compounds Ilbh can be prepared by coupling of 4-halogen-quino lines Ilab with N-(3- methyl-pyrrolidin-3-yl)-acetamide. The reaction can be carried out in the presence of a metal catalyst or in the absence of a metal catalyst in analogy to coupling of 4-halogen quino lines Ilab with various amines XI in Scheme 5. Typically, the reaction can be carried out with Ι,Γ- bis(diphenylphosphino)ferrocene, 1 , 1 '-bis(diphenylphosphino)ferrocenedichloropalladium(II), and sodium-tert-butoxide in 1,4-dioxane at 120 °C for 1.5 hours under microwave irradiation.
Compounds of interest Ibm can be prepared by deactylation of Ilbh. The reaction can be carried out in 2 N hydrochloric acid at 100 °C for 16 hours.
General synthetic route for formula Ibo (Scheme 27)
Scheme 27
Figure imgf000069_0001
Compounds of interest Ibo can be prepared according to Scheme 27. Starting with fluorides Ibn, substitution of fluoro with methoxy group affords Ibo. The reaction can be carried out by heating of fluorides with sodium methoxide in methanol, typically at 100 °C for 20 minutes under microwave irradiation.
General synthetic route for formula Ibq (Scheme 28)
Scheme 28
Figure imgf000069_0002
Compounds of interest Ibq can be prepared according to Scheme 28. Demethylation of methoxybenzenes Ibp affords phenols Ibq. The reaction can be carried out by heating of Ibp with potassium hydroxide in dimethylsulfoxide, typically at 100 °C for 20 minutes under microwave irradiation. General synthetic route for formula Ibr and lbs (Scheme 29)
Scheme 29
Figure imgf000070_0001
Compounds of interest Ibr and lbs can be prepared according to Scheme 29. Coupling of 4-chloroquino lines Ilbi with 4-amino-3-hydroxy-butyric acid followed by reduction of acids Ilbj affords 1,3-diols Ibr. Coupling of 4-chloroquino lines Ilbi with 2-methyl-allyll amine followed by dihydroxylation of alkenes Ilbk affords 1,2-diols lbs. Acids Ilbj can be obtained by coupling of 4-chloroquino lines Ilbi with 4-amino-3- hydroxy-butyric acid. Alkenes Ilbk can be obtained by coupling of 4-chloro quino lines Ilbi with 2-methyl-allylamine. Coupling reaction can be carried out by heating 4-chloroquino lines Ilbi with amines in a suitable organic solvent such as l-methyl-2-pyrrolidinone at an elevated temperature, typically at 160 °C for 16 hours.
1,3-Diols Ibr can be prepared by reduction of acids Ilbj. The reaction can be carried out by treating acids with sodium borohydride in the presence of iodine in tetrahydrofuran, typically at 0 °C, followed by stirring at room temperature for 16 hours.
1,2-Diols lbs can be prepared by dihydroxylation of alkenes Ilbk. The reaction can be accomplished by treating alkenes with 4-methylmorpholine N-oxide monohydrate and osmium tetroxide in acetone at room temperature for 1 hour.
General synthetic route for formula Ibt (Scheme 30)
Scheme 30
Figure imgf000071_0001
Figure imgf000071_0002
Compounds of interest Ibt can be prepared according to Scheme 30. Starting with Ilbi, alkylation with methyl iodide followed by coupling with various amines affords compounds of interest Ibt.
Compounds Ilbi can be prepared by alkylation of Ilbi with methyl iodide. Preferably, compounds can be obtained by deprotonation of a-H of sulfone followed by reaction with methyl iodide. Deprotonation of a-H of sulfone can be carried out by treating sulfone Ilbi with n-butyl lithium in tetrahydrofuran at -78 °C under argon atmosphere for 1 hour. Reaction with methyl iodide can be accomplished by addition of methyl iodide to the above reaction mixture at -78 °C, followed by stirring at room temperature overnight.
Compounds of interest Ibt can be prepared by coupling of Ilbl with various amines. The reaction can be carried out in analogy to coupling of 4-halogen quino lines Ilab with various amines XI in Scheme 5. The reaction preferably can be achieved by heating a mixture of Ilbl and various amines with or without organic solvent such as N,N-dimethylformamide, 1- methylpyrrolidin-2-one or /? -butyl alcohol, under microwave irradiation at 140-160 °C for 1-3 hours. General synthetic route for formula Ibu, Ibv and Ibw (Scheme 31)
Scheme 31
Figure imgf000072_0001
Compounds of interest Ibu, Ibv and Ibw can be prepared according to Scheme 31.
Coupling of 4-chloroquino lines libi with N-(3-amino-oxetan-3-ylmethyl)-2,2,2-trifluoro- acetamide affords Ibu. Standard trifluoro acetyl deprotection of Ibu generates compounds Ibv. Trifluoro acetyl deprotection and hydrolysis of Ibu affords Ibw.
Compounds Ibu can be prepared by coupling of 4-chloroquinolines libi with N-(3-amino- oxetan-3-ylmethyl)-trifluoro-acetamide. The reaction can be carried out in the presence of a palladium catalvst such as [l,l'-bis(diphenylphosphino)ferrocene] dichloropalladium(II), (triphenylphosphine)dichloropalladium(II), palladium(II) acetate, or
tri(dibenzylideneacetone)dipalladium(0), in combination of a phosphine ligand such as bis(diphenylphosphino)ferrocene, tricyclohexylphosphine, or 9,9-dimethyl-4,5- bis(diphenylphosphino)xanthene, with a suitable base such as sodium tert-butoxide, in a suitable inert organic solvent such as 1,4-dioxane, or N,N-dimethylformamide, at 100-150 °C for 1-3 hours under microwave irradiation. Alternatively, the reactions can be carried out at an elevated temperature such as 100-140 °C for a longer reaction time without microwave irradiation.
Compounds Ibv can be prepared by standard trifluoro acetyl deprotection of Ibu. The reaction can be carried out with potassium carbonate, in a suitable solvent such as the mixture of methanol and water, at room temperature for several hours.
Compounds Ibw can be prepared by trifluoro acetyl deprotection and hydrolysis of Ibu. The reaction is typically carried out with ammonia solution in methanol for several hours at room temperature.
General synthetic route for formula Ibx and Iby (Scheme 32) Scheme 32
Figure imgf000074_0001
Figure imgf000074_0002
Compounds of interest Ibx and Iby can be prepared according to Scheme 32. Standard coupling of Ilab with 5-oxo-pyrrolidine-3-carboxylic acid amide generates Ilbm, followed by rearrangement of amides Ilbm gives aminopyrrolidines Ibx. Coupling of halogens Ilab with pyrrolidine-3-carboxylic acid methyl ester affords compounds Ilbn. Conversion of Ilbn to acylchlorides Ilbo followed by treatment with ammonia affords compounds of interest Iby.
Amides Ilbm can be prepared by copper-mediated coupling reaction of Ilab with 5-oxo- pyrrolidine-3-carboxylic acid amide. The reaction can be carried out in the presence of a copper source such as copper(I) iodide and a ligand such as 2,2'-bipyridine, Z-proline, N,N-dimethyl n jrinp rt v]pnp αΚτηη] r trans-N,N'-dimethylcyclohexane- 1 ,2-diamine, with a suitable base such as triethylamine, sodium carbonate, potassium carbonate, cesium carbonate, sodium tert- butoxide, potassium tert-butoxide, sodium hydride or l,8-diazabicyclo[5.4.0]undec-7-ene. The reaction can be carried out in a suitable organic solvent such as diethylene glycol dimethyl ether, toluene, 1,4-dioxane, N,N-dimethylformamide, dimethyl sulfoxide or l-methyl-pyrrolidin-2-one at a temperature between 100 °C and 180 °C for several hours under microwave irradiation. Alternatively, the reactions can be carried out at a temperature such as 130 °C for a longer reaction time without microwave irradiation.
Aminopyrrolidines Ibx can be prepared by rearrangement of amides Ilbm. The reaction can be typically carried out in the presence of (diacetoxyiodo)benzene in a mixture of acetonitrile and water for several hours at room temperature.
Acids Ilbn can be prepared by coupling of halogens Ilab with pyrrolidine-3-carboxylic acid methyl ester. The reaction can be carried out with a suitable base such as
diisopropylethylamine without any solvent at 140 °C for 1.5 hours under microwave irradiation.
Acyl chlorides Ilbo can be prepared by chlorination of Ilbn. The reaction can be carried out with such as oxalyl dichloride in the presence of N,N-dimethylformamide, in a suitable solvent such as dichloromethane at 0 °C to room temperature for 16 hours.
Compounds of interest Iby can be prepared by reaction of Ilbo with ammonia. The reaction can be carried out in suitable solvent such as dichloromethane at 0 °C to room temperature for 16 hours. General synthetic route for formula Ibz and lea (Scheme 33)
Scheme 33
Figure imgf000076_0001
Figure imgf000076_0002
Compounds of interest Ibz and lea can be prepared according to Scheme 33. Starting with Ilbi, coupling with 2-methylsulfanyl-ethylamine gives sulfides Ilbp. Selective oxidation of sulfides Ilbi gives sulfoxides Ibz. Imination of sulfoxides, followed by hydrolyzation affords compounds of interest lea.
Sulfides Ilbp can be prepared from coupling of 2-benzoazapin-4-chloroquino lines Ilbi with 2-methylsulfanyl-ethylamine. The reaction can be carried out in the presence of a palladium catalyst in analogy to coupling of 4-halogen quino lines Ilab with various amines XI in Scheme 5. Typically the reaction can be carried out in the presence of
tri(dibenzylideneacetone)dipalladium(0), 2-(dicyclohexylphosphino)-2'-(N,N- dimethylamino)biphenyl, and sodium-tert-butoxide in 1 ,4-dioxane under microwave irradiation at 100 °C for 1.5 hours.
Sulfoxides Ibz can be prepared by oxidation of sulfides Ilbp. The reaction preferably can be carried out with a standard oxidant agent such as hydrogen peroxide in a suitable organic solvent such as acetic acid at room temperature for several hours.
Compounds of interest lea can be prepared by metal-catalyzed imination of sulfoxides followed by hydrolysis. Imination of sulfoxides can be carried out by treating sulfoxides with rhodium (II) acetate and trifluoroacetamide or sulfonylamides in combination with iodobenzene diacetate and magnesium oxide in dichloromethane at room temperature overnight, preferably trifiuoroacetamide was used. Hydrolysis can be carried out in the presence of a suitable base, such as potassium carbonate, sodium hydroxide or potassium hydroxide in methanol under reflux for 30 minutes to several hours.
General synthetic route for formula Ice (Scheme 34)
Scheme 34
Figure imgf000077_0001
Compounds of interest Ice can be prepared according to Scheme 34. Starting with sulfides Icb (prepared in analogue to lac in Scheme 5), oxidation of sulfides affords compounds of interest Ice.
Compounds of interest Ice can be prepared by oxidation of sulfides Icb. The reaction can be carried out in analogy to oxidation of quino lines Ilac in Scheme 4. Typically the reaction can be carried out by treating sufides with potassium permanganate in acetic acid at room
temperature for 30 minutes to several hours.
General synthetic route for formula led (Scheme 35)
Scheme 35
Figure imgf000077_0002
Figure imgf000077_0003
Compounds of interest led can be prepared according to Scheme 35. Starting with sulfoxides Ilbq, metal-catalyzed imination of sulfoxides followed by hydrolysis gives sulfoximines Ilbr. Coupling of Ilbr with various amines affords compounds of interest led.
Sulfoximines can be prepared from imination of sulfoxides Ilbq followed by hydrolysis. Imination of sulfoxides can be carried out by treating sulfoxides with rhodium (II) acetate and trifluoroacetamide or sulfonylamides in combination with iodobenzene diacetate and magnesium oxide in dichloromethane at room temperature overnight, preferably trifluoroacetamide was used. Hydrolysis can be carried out in the presence of a suitable base, such as potassium carbonate, sodium hydroxide, potassium hydroxide or sodium methoxide in methanol under reflux for 30 minutes to several hours.
Compounds of interest led can be prepared by coupling of Ilbr with 1,2- ethylenediamine. The reaction can be carried out in analogy to coupling of 4-halogen quino lines Ilac with various amines XI in Scheme 5. Typically the reaction can be carried out with or without an organic solvent such as N,N-dimethylformamide, l-methylpyrrolidin-2-one or n-butyl alcohol at a temperature between 140 °C and 160 °C under microwave irradiation for 1 to 3 hours.
General synthetic route for formula Ice (Scheme 36)
Scheme 36
Figure imgf000078_0001
Compounds of interest Ice can be prepared according to Scheme 36. Oxidation of sulfides libs followed by coupling of Ilbt with propane- 1,3-diamine affords compounds of interest Ice. Sulfoxides Ilbt can be prepared by oxidation of sulfides libs. The reaction can be carried out with a suitable oxidation reagent such as m-chloroperbenzoic acid in a suitable solvent such as dichloromethane at 0 °C for 20 minutes.
Compounds of interest Ice can be prepared by coupling of Ilbt with propane-1,3- diamine. The reaction can be carried out in analogy to coupling of 4-halogen quino lines Ilac with various amines XI in Scheme 5. Typically, the reaction can be carried out by treating a mixture of Ilbt and propane- 1,3-diamine without any base and without any solvent at 150 °C for 1 hour under microwave irradiation.
General synthetic route for formula Icf and leg (Scheme 37)
Scheme 37
Figure imgf000080_0001
Figure imgf000080_0002
Figure imgf000080_0003
Compounds of interest leg and Icf can be prepared according to Scheme 37. Amination of Ilbu affords amides Ilby. Oxidation of sulfides Ilby affords sulfones Ilbz. Coupling of Ilbz with propane- 1,3-diamine affords compounds of interest leg. Oxidation of sulfides Ilbu affords sulfones Ilbv. Reduction of carboxylic acid esters Ilbv followed by Swern-oxidation affords aldehydes Ilbw. Methylation of Ilbw followed by coupling with propane- 1,3-diamine affords compounds of interest Icf. Amides Ilby can be prepared by animation of Ilbu. The reaction can be carried out in a solution of ammonia in a suitable solvent such as methanol, tetrahydroiuran or mixture thereof in a sealed tube at a temperature between 100 °C and 150 °C for several hours, typically at 120 °C for 16 hours. Sulfones Ilbz can be prepared by oxidation of sulfides Ilby. The reaction can be carried out in analogy to oxidation of quino lines Ilac in Scheme 4. Typically, the reaction can be carried out with m-chloroperbenzoic acid in dichloromethane at 0 °C for 2 hours.
Compounds of interest leg can be prepared by coupling of Ilbz with propane-1,3- diamine. The reaction can be carried out in analogy to coupling of 4-halogen- quino lines Ilac with various amines XI in Scheme 5. Typically, the reaction can be carried out by treating a mixture of Ilbz and propane- 1,3-diamine without any base and without any solvent at 120 °C for 1 hour under microwave irradiation.
Sulfones Ilbv can be prepared by oxidation of sulfides Ilbu. The reaction can be carried out in analogy to oxidation of quino lines Ilac in Scheme 4. Typically, the reaction can be carried out with m-chloroperbenzoic acid in dichloromethane at 0 °C for 1 hour.
Aldehydes Ilbw can be prepared by reduction of carboxylic acid esters Ilbv followed by Swern oxidation. Reduction can be carried out with a standard reducing agent such as sodium boronhydride in a suitable solvent such as tetrahydroiuran, under reflux for several hours to several days, typically 60 hours. Swern oxidation can be carried out with oxalyl dichloride and dimethyl sulfoxide in the presence of triethylamine in a suitable solvent such as dichloromethane at -78 °C, then at room temperature for 1 to several hours.
6-(l -Hydro xyethyl)quino lines Ilbx can be prepared by methylation of Ilbw. The reaction can be carried out with a methylation reagent such as methyl magnesium bromide in
tetrahydrofuran at a temperature below 12 °C for 10 minutes to several hours. Compounds of interest leg can be prepared by coupling of Ilbw with propane-1,3- diamine. The reaction can be carried out in analogy to coupling of 4-halogen quino lines Ilac with various amines XI in Scheme 5. Typically, the reaction can be carried out without any metal catalyst and without any solvent at 150 °C for 1.5 hours under microwave irradiation.
General synthetic route for formula Ich and Ici (Scheme 38)
Scheme 38
Figure imgf000082_0001
Compounds of interest Ici can be prepared according to Scheme 38. Standard coupling of Ilbi with 3-amino-propionitrile generates Ich, cyclization of nitriles with sodium azide affords tetrazoles Ici. Nitriles Ich can be prepared by coupling reaction of chlorides Ilbi with 3-amino- propionitrile. The reaction can be carried out in analogy to coupling of 4-halogen quino lines Ilac with various amines XI in Scheme 5. Typically, the reaction can be carried out by heating with tri(dibenzylideneacetone)dipalladium(0), 2,2'-bis(diphenylphosphino)- 1 , 1 '-binaphthyl, and sodium tert-butoxide in toluene at 110 °C overnight. Tetrazoles Ici can be prepared by cyclization of nitriles Ich with sodium azide. The reaction can be typically carried out in the presence of sodium azide and ammonium chloride in N,N-dimethylformamide at a temperature between 60 °C and 100 °C, typically at 80 °C for several hours.
General synthetic route for formula Ick (Scheme 39)
Scheme 39
Figure imgf000083_0001
Compounds of formula Ick can be prepared according to Scheme 39. Reduction of 6-nitro quino lines Icj generates 6-amino-quino lines Ick. The reaction can be carried out with stannous chloride in methanol under reflux overnight. General synthetic route for formula Icl (Scheme 40)
Scheme 40
Figure imgf000083_0002
Compounds of interest Icl can be prepared according to Scheme 40. Starting with Ilbi, coupling with (3-amino-oxetan-3-ylmethyl)-carbamic acid tert-butyl ester gives spiral compounds Icl. This reaction can be carried out in the presence of a palladium catalyst such as (triphenylphosphine)dichloropalladium(II), [ 1 , Γ- bis(diphenylphosphino)ferrocene]dichloropalladium(II), palladium(II) acetate, or
tri(dibenzylideneacetone)dipalladium(0), with a phosphine ligand such as 2,2'- bis(diphenylphosphino)- 1 , 1 '-binaphthyl, bis(diphenylphosphino)ferrocene,
tricyclohexylphosphine, or 9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene, with a suitable base such as sodium tert-butoxide, in a suitable inert organic solvent such as toluene, dioxane, or N,N-dimethylformamide, at a temperature between 100 °C and 150 °C for 1 to 3 hours under microwave irradiation. Alternatively, the reactions can be carried out at a temperature such as 100 °C to 140 °C for a longer reaction time without microwave irradiation. General synthetic route for formula Icm (Scheme 41)
Scheme 41
Figure imgf000084_0001
Compounds of interest Icm can be prepared according to Scheme 41. Coupling of 2,4- dichloroquinazo lines Mb with C-(2,2-dimethyl-[l ,3]dioxolan-4-yl)-methylamine affords Ilea. Reaction of 2-chloro-4-aminoquinazo lines Ilea with 6,7,8,9-tetrahydro-5-thia-8-aza- benzocycloheptene 5,5-dioxides IVd followed by deprotection affords 4-(2,3-diol-propylamino)- quino lines Iak.
Ilea can be obtained by coupling of 2,4-dichloroquinazo lines Mb with C-(2,2-dimethyl- [l,3]dioxolan-4-yl)-methylamine. The reaction can be carried out with a base such as
triethylamine in a suitable solvent such as methanol or dichloromethane at room temperature for several hours.
Intermediates Ilcb can be prepared by coupling of 2-chloro-4-amino quinazo lines Ilea with 6,7,8,9-tetrahydro-5-thia-8-aza-benzocycloheptene 5,5-dioxides IVd. The reaction can be carried out in the presence of a base such as triethylamine in N,N-dimethylformamide at a temperature between 120 °C and 180 °C, typically at 160 °C for several hours. 4-(2,3-Diol-propylamino)-quinazolines Icm can be prepared by deprotection of Ilcb. The reaction can be carried out in the presence of an acid such as hydrochloric acid in a suitable solvent such as methanol, ethanol, water or mixtures thereof at room temperature for several hours.
General synthetic route for formula Icn (Scheme 42)
Scheme 42
Figure imgf000085_0001
m is 1 or 2
Compounds of interest Icn and Ico can be prepared according to Scheme 42. Starting with IIcc, cleavage of tert-butoxycarbonyl gives compounds of interest Icn. Oxidation of sulfides IIcc generates oxides Ilcd, followed by cleavage of tert-butoxycarbonyl generates compounds of interest Ico.
Ilcd can be prepared by oxidation of thio group of compounds IIcc. The reaction can be carried out with a suitable oxidant such as oxone, meto-chloroperoxybenzoic acid, hydrogen peroxide, sodium periodate or potassium permanganate, in a suitable solvent such as methanol, dichloromethane, acetic acid, water or the mixtures thereof, typically at 0 °C, followed by stirring at room temperature for several hours. Amines Icn and Ico can be prepared by cleavage of tert-butoxycarbonyl of IIcc and lied respectively. The reaction can be typically carried out with trifluoro acetic acid in
dichloromethane, or hydrogen chloride in methanol for several hours at room temperature.
General synthetic route for formula Icp (Scheme 43) Scheme 43
Figure imgf000086_0001
Compounds of interest Icp can be prepared according to Scheme 43. Starting with lice, removal of trifluoro acetyl generates amines Icp. The reaction can be carried out with potassium carbonate or sodium hydroxide, in a suitable solvent such as the mixture of ethanol and water, at room temperature for several hours.
General synthetic route for formula Icq and Icr (Scheme 44)
Scheme 44
Figure imgf000087_0001
Figure imgf000087_0002
Compounds of interest Icq and Icr can be prepared according to Scheme 44. Starting with quinazolinones Ilbg, coupling reaction with amine gives Ilcf, followed by cleavage of tert- butoxycarbonyl of Ilcf affords compounds of interest Icq. Starting with quinazolinones Ilbg, coupling reaction with amine gives Ilcg, followed by cleavage of benzoxycarbonyl of Ilcg affords compounds of interest Icr.
Ilcf and Ilcg can be prepared from coupling reaction of Ilbg with 3-( tert-butoxycarbonyl- amino)pyrrolidine and tra/75-3-amino-4-fluoro-pyrrolidine-l-carboxylic acid benzyl ester separately. The reaction can be carried out in the presence of benzotriazol-l-yloxytris
(dimethylamino)phosphonium hexafluorophosphate, with a suitable base such as 1,8- diazabicyclo[5.4.0]undec-7-ene, or triethyl amine, in a solvent such as N,N-dimethylformamide or acetonitrile at room temperature overnight. Compounds of interest Icq can be prepared by standard cleavage of tert-butoxycarbonyl of Ilcf. The reaction can be carried out by treating tert-butyl carbamates Ilcf with a suitable acid such as hydrochloric acid, trifluoro acetic acid, or sulfuric acid in a suitable solvent such as methanol, ethyl acetate, dichloromethane, 1,4-dioxane, water or the mixtures thereof at a temperature between 0 °C and room temperature for 30 minutes to several hours. Typically the reaction can be carried out by treating tert-butyl carbamates Ilaf with trifluoro acetic acid in dichloromethane at room temperature for 6 hours.
Compounds of interest Icr can be prepared by cleavage of benzyl carbomates Ilcg. The conversion can be achieved by hydro geno lysis or under strong acidic conditions. Hydro geno lysis of Ilcg can be carried out in the presence of palladium on carbon or palladium black, under hydrogen atmosphere or with a hydrogen donor such as formic acid or ammonium formate, in a suitable solvent such as methanol or ethanol, at a temperature between room temperature and 80 °C for 15 minutes to several hours. Alternatively the conversion can also be achieved by treating Ilcg under strong acidic conditions such as reflux in 6 N hydrochloride in methanol for several hours.
General synthetic route for formula Ics (Scheme 45)
Scheme 45
Figure imgf000088_0001
Figure imgf000088_0002
Compounds of interest Ics can be prepared according to Scheme 45. Starting with 4- chloro-quino lines Ilbi, coupling with (i?)-2,2-dimethyl-4-vinyl-oxazolidine-3-carboxylic acid tert-butyl ester gives vinyl quino lines Ilch. Subsequent reduction and deprotection of tert- butyloxycarbonyl and acetal of Ilch generates amino alcohols Ilci, which are then cyclized to compounds of interest Ics.
Vinyl quino lines Ilch can be prepared by coupling of 4-chloro-quinolines Ilbi with (R)- 2,2-dimethyl-4-vinyl-oxazolidine-3-carboxylic acid tert-butyl ester. The reaction can be typically conducted in deoxygenated N,N-dimethylformamide with triethylamine, bis(tri-tert- butylphosphine)palladium(0), at a temperature between 100 °C and 160 °C for several hours under microwave irradiation. Alternatively, the reactions can be carried out at an elevated temperature such as between 100 and 140 °C for a longer reaction time without microwave irradiation.
Amino alcohols Ilci can be prepared from vinyl quino lines Ilch by hydrogenolysis and deprotection of tert-butyloxycarbonyl and acetal. The hydrogenolysis can be carried out in the presence of 10% palladium on carbon under an atmospheric pressure of hydrogen, in an organic solvent such as ethyl acetate, methanol, or ethanol, typically at room temperature for several hours. Deprotection of acetonides is typically carried out in a solution of hydrochloric acid in ethyl acetate for several hours at room temperature.
Compounds Ics can be prepared from amino alcohols Ilci by ring closure with cyanogen bromide. The reaction can be carried out with a suitable base such as sodium acetate, sodium carbonate, potassium acetate or potassium carbonate, in a suitable solvent such as methanol, water, or the mixtures thereof, typically at 0 °C, followed by stirring at room temperature for several hours.
General synthetic route for formula let, Icu and lev (Scheme 46) Scheme 46
Figure imgf000090_0001
Figure imgf000090_0002
n is 0 or 1
Compounds of interest let, Icu and lev can be prepared according to Scheme 46. Starting with 4-chloro quino lines Ilbi, coupling with ethyl acrylate gives alkenes Ilcj. Reduction of alkenes Ilcj followed by hydrolysis of esters affords compounds of interest let. Heck reaction coupling with acrylonitrile gives alkenes lick. Hydrogenation of alkenes followed by hydrolysis of nitriles affords amides Icu. Alternatively, amides Icu can be formed by aminolysis of esters Ilcj. Reduction of amides Icu affords compounds of interest lev.
Alkenes Ilcj and lick can be prepared by Heck coupling of 4-chloro-quino lines Ilbi with ethyl acrylate and acrylonitrile separately. The reaction can be typically conducted in the presence of bis(tri-tert-butylphosphine)palladium(0) with triethylamine in deoxygenated N,N- dimethylformamide, at a temperature between 100 °C and 160 °C for 30 minutes to several hours under microwave irradiation. Alternatively, the reactions can be carried out at an elevated temperature such as between 100 °C and 140 °C for a longer reaction time without microwave irradiation.
Compounds of interest let can be prepared by reduction of alkenes Ilcj followed by hydrolysis. Reduction can be achieved by treating alkenes Ilcj with 2- nitrobenzenesulfonylhydrazide in the presence of triethylamine in dichloromethane at room temperature for several hours. Hydrolysis can be carried out with a suitable base, such as lithium hydroxide, or sodium hydroxide in a mixture of water and organic solvent, such as
tetrahydrofuran or methanol at room temperature for several hours.
Amides Icu can be prepared by hydrogenation of alkenes lick followed by hydrolysis of nitriles. Hydrogenation reaction can be carried out in the presence of palladium on carbon under hydrogen atmosphere in methanol at room temperature for several hours. Hydrolysis can be achieved by treating nitriles with a base such as potassium hydroxide in tert-butanol under reflux for several hours.
Alternatively, amides Icu can be prepared by amino lysis of esters Ilcj. The reaction can be typically conducted in an ammonia solution in tetrahydrofuran at a temperature between 25 °C to 70 °C for several hours.
Amines lev can be prepared by reduction of amides Icu. The reaction can be achieved by treating amides Icu with borane in tetrahydrofuran at an elevated temperature such as 65 °C for several hours. General synthetic route for formula lew and lex (Scheme 47)
Scheme 47
Figure imgf000092_0001
E is Br or cl,
m is 1 or 2
Compounds of interest lew and lex can be prepared according to Scheme 47. Coupling of 4- halogen quino lines Ilab with N-(2-hydroxyethyl)acetamide followed by deacylation of IIcl affords compounds of interest lew. Coupling of Ilab with protected alcohol XXII followed by cleavage of tert-butyloxycarbonyl affords compounds of interest lex.
Ethers IIcl and Ilcm can be prepared by coupling of 4-halogen quino lines Ilab with N- (2-hydroxyethyl)acetamide and XXII separately. The reaction can be carried out with a palladium catalyst such as l, -bis(diphenylphosphino)ferrocene-palladium(II)dichloride in combination with l,l'-bis(diphenylphosphino)ferrocene and sodium tert-butoxide in a suitable organic solvent such as 1,4-dioxane in a sealed microwave process vial at an elevated temperature such as 130 °C under microwave irradiation for 1 to several hours. 2-Aminoethyl ethers lew can be prepared by deacylation of IIcl. The reaction can be carried out in an aqueous solution of hydrochloric acid at an elevated temperature such as 80 °C for several hours.
Compounds of interest lex can be prepared by cleavage of tert- butyloxycarbonyl. The reaction can be carried out with trifluoro acetic acid in dichloromethane or hydrochloride in ethyl acetate at room temperature for several hours.
General synthetic route for formula Icy (Scheme 48)
Scheme 48
Figure imgf000093_0001
Compounds of interest Icy can be prepared according to Scheme 48. Starting with 2,4- dichloro-quino lines Hid, regioselective nucleophiUic replacement with diethyl malonate followed by hydrolysis affords carboxylic acids IIco. Coupling of IIco with benzothiazepines and decarboxylation in a tandem reaction affords 4-methyl-quino lines IIcp. Oxidation of sulfides IIcp affords sulfones Icy.
Ilcn can be prepared from regioselective nucleophiUic replacement with diethyl malonate. The reaction can be carried out in the presence of a suitable base such as sodium hydride or potassium carbonate, in an organic solvent such as N,N-dimethylformamide, at an elevated temperature, typically at 70 °C for several hours to overnight.
Carboxylic acids IIco can be prepared from hydrolysis of lien. The reaction can be carried out with a suitable base such as lithium hydroxide or sodium hydroxide in a suitable mixed solvent such as tetrahydrofuran and water or methanol and water, at room temperature for several hours.
IIcp can be obtained by coupling of 2-chloroquino lines IIco with benzodiazepines and decarboxylation in a tandem reaction. The reaction preferably can be carried out with or without an organic solvent such as n-butanol under microwave irradiation at a temperature between 150 °C and 170 °C for several hours.
Compounds of interest Icy can be prepared by oxidation of IIcp. The reaction can be carried out in analogy to oxidation of quino lines Ilac in Scheme 4.
General synthetic route for formula Icz (Scheme 49)
Scheme 49
Figure imgf000094_0001
Compounds of interest Icz can be prepared according to Scheme 49. Starting with 4- bromoquino lines Ilcq, reaction with a lithium alkylide followed by reaction with \-tert- butoxycarbonyl-4-piperidinecarboxaldehyde provides the secondary alcohols Ilcr. Dess-Martin oxidation of Ilcr followed by cleavage of tert-butyl carbamates affords compounds of interest Icz.
Ilcr can be obtained by reaction of 4-bromoquinolines Ilcq with a lithium alkylide followed by reaction with l-tert-butoxycarbonyl-4-piperidinecarboxaldehyde. The conversion can be achieved by treating 4-bromo-quino lines Ilcq with n-butyllithium and l-tert- butoxycarbonyl-4-piperidinecarboxaldcehyde in an inert organic solvent such as tetrahydrofuran at -78 °C, then at room temperature overnight.
Compounds of interest Icz can be obtained by Dess-Martin oxidation of Ilcr followed by cleavage of tert-butyl carbamates. Oxidation of Ilcr can be carried out with a suitable oxidant such as Dess-martin reagent in dichloromethane at room temperature overnight, or with manganese dioxide in toluene under reflux for several hours. Cleavage of tert-butyl carbamates can be achieved by treating tert-butyl carbamates lies with a suitable acid such as hydrochloric acid, trifluoro acetic acid, or sulfuric acid in a suitable solvent such as methanol, ethyl acetate, dichloromethane, 1,4-dioxane, water or the mixture thereof at a temperature between 0 °C and room temperature for 30 minutes to several hours. Typically the reaction can be carried out by treating tert-butyl carbamates lies with trifluoro acetic acid in dichloromethane at room temperature for 6 hours.
General synthetic route for formula Ida (Scheme 50)
Scheme 50
Figure imgf000095_0001
Compounds of interest Ida can be prepared according to Scheme 50. Coupling of bromides Ilct with lH-pyrazole-3-boronic acid affords Ida. The reaction can be carried out in the presence of a palladium catalyst such as (triphenylphosphine)palladium with sodium carbonate in a suitable organic solvent such as benzene or dimethoxyethane, at a temperature between 80 °C and 120 °C, typically at 80 °C for 1 hour under microwave irradiation
General synthetic route for formula Ida (Scheme 51) Scheme 51
Figure imgf000096_0001
Compounds of interest Idb and Idc can be prepared according to Scheme 51. Coupling of chlorides Ilbi with benzenethiol affords IIcu. Oxidation of IIcu affords compounds of interest Idb. Coupling of chlorides Ilbi with sodium methanethiolate affords IIcv. Oxidation and chlorination of IIcv affords sulfonyl chlorides IIcw. Coupling of sulfonyl chlorides IIcw with ethyl- 1,2-diamine affords compounds of interest Idc.
Compounds of interest of formula IIcu can be prepared by coupling of chlorides Ilbi with benzenethiol. The reaction can be carried out with a suitable base such as N,N- dimethylpyridin-4-amine in a suitable solvent such as ethanol at room temperature for several days.
Sulfones Idb can be prepared by oxidation of IIcu. The reaction can be carried out with a suitable oxidation reagent such as m-chloroperbenzoic acid in a suitable solvent such as dichloromethane at a temperature between 0 °C and room temperature for 1 to several hours. Thiols IIcv can be prepared by coupling of chlorides Ilbi with sodium methanethiolate. The reaction can be carried out in a suitable solvent such as N,N-dimethylformamide under reflux overnight.
Sulfonyl chlorides II cw can be prepared by oxidation-chlorination of IIcv. The reaction can be carried out in a suitable solvent such as hydrochloric acid by bubbling of chlorine at a temperature between 0 °C and 10 °C for 30 minutes.
Compounds of interest Idc can be prepared by coupling of chlorides IIcw with ethyl- 1,2- diamine. The reaction can be carried out with a suitable base such as triethylamine or ethyl- diisopropyl- amine in a suitable solvent such as dichloromethane at a temperature between 0 °C and room temperature overnight.
General synthetic route for formula Idd, Ide and Idf (Scheme 52)
Scheme 52
Figure imgf000097_0001
Compounds of interest Idd, Ide and Idf can be prepared according to Scheme 52.
Coupling of chlorides Ilbv with C-(3 -amino methyl-oxetan-3-yl)-methylamine generates Idd. Hydrolysis of esters affords carboxylic acids Ide. Reduction of esters Ilbv followed by coupling with C-(3 -amino methyl-oxetan-3-yl)-methylamine generates compounds Idf. Compounds Idd can be prepared by coupling of chlorides Ilbv with C-(3 -amino methyl- oxetan-3-yl)-methylamine. The reaction can be carried in analogy to coupling of 4-halogen quino lines Ilab with various amines XI in Scheme 5. Typically the reaction can be carried out with tris(dibenzylideneacetone)dipalladium(0), 2,2'-bis(diphenylphosphino)-l, -binaphthyl and sodium tert-butoxide in toluene at 110 °C overnight under nitrogen atmosphere. Acids Ide can be prepared from hydrolysis of methyl esters Idd. The reaction can be carried out with a suitable base such as sodium hydroxide or lithium hydroxide in a mixture solvent of tetrahydrofuran and water at a temperature between room temperature and 60 °C, typically at room temperature for several hours or overnight.
Hydroxides Ilex can be prepared by reduction of esters Ilbv. The reaction can be carried out with a standard reduction agent such as lithium aluminium hydride in a suitable solvent such as tetrahydrofuran, at a temperature between 0 °C and room temperature for several hours, typically at room temperature for 2 hours.
Compounds Idf can be prepared by coupling of Ilex with C-(3 -amino methyl-oxetan-3- yl)-methylamine. The reaction can be carried out in analogy to coupling of Ilbv with C-(3- aminomethyl-oxetan-3-yl)-methylamine in this scheme.
General synthetic route for formula Idg (Scheme 53)
Scheme 53
Figure imgf000099_0001
Compounds of interest Idg can be prepared according to Scheme 53. Starting with 2,4- dichloro-quinazo lines Hid, reaction with benzyl alcohol followed by coupling with
benzothiazepines IVf affords benzyloxy compounds IIcz. Substitution of bromo with methyl-<i3 followed by oxidation affords 6-methyl-<i3-quinazolines Ildb. Coupling of Ildb with C-(3- aminomethyl-oxetan-3-yl)-methylamine affords compounds of interest Idg.
2-Chloro-4-benzoxy quinazo lines Ilcy can be prepared by reaction of 2,4-dichloro- quinazo lines Hid with benzyl alcohol. The reaction can be carried out in the presence of a suitable base such as sodium hydride in an organic solvent such as tetrahydrofuran, acetonitrile or N,N-dimethylformamide at 0 °C followed by at room temperature for several hours.
IIcz can be prepared by coupling of Ilcy with benzothiazepines IVf. The reaction can be carried out without any base and without any solvent at a temperature between 80 °C and 160 °C, typically at 80 °C for 10 minutes to 2 hours.
6-Methyl-<i3-quinazo lines Ilda can be prepared by substitution of bromo with methyl-<i3. The reaction can be carried out by treating Ilcy with n-butyllithium in anhydrous tetrahydrofuran at -78 °C for several minutes under nitrogen followed by stirring with methyl-<i3 trifluoromethanesulfonate at -78 °C and then at room temperature for 1 to several hours.
Sulfoxides Ildb can be prepared by oxidation of Ilda. The reaction can be carried out by treating Ilda with 1-2 equivalents of 3-chloroperoxybenzoic acid in a suitable organic solvent such as dichloromethane, chloroform, 1,2-dichloroethane or the mixtures thereof, typically at 0 °C, followed by stirring at room temperature for 10 to 20 minutes.
Compounds of interest Idg can be prepared by coupling of Ildb with C-(3 -amino methyl- oxetan-3-yl)-methylamine. The reaction can be carried out without any solvent and without any base at an elevated temperature such as 170 °C for 20 minutes. General synthetic route for formula Idh (Scheme 54)
Scheme 54
Figure imgf000100_0001
Figure imgf000100_0002
Compounds of interest Idh can be prepared according to Scheme 54. Starting with 6- bromo-quinazo lines Ilda, carbonylation followed by esterification, oxidation and hydrolysis affords acids Ilde. Coupling of Ilde with C-(3 -amino methyl-oxetan-3-yl)-methylamine generates compounds of interest Idh. 6-Methoxycarbonyl quinazolines Ildc can be prepared by carbonylation of 6-bromo- quinazo lines Ilda followed by esterification. Carbonylation can be carried out with dry ice in the presence of n-butyllithium in tetrahydrofuran at -78 °C under nitrogen atmosphere, followed by stirring at room temperature for 1 to several hours. Methyl esterification can be carried out in methanol in the presence of sulfinyl chloride or concentrated sulfuric acid at a temperature between room temperature and 70 °C for 1 to several hours
Compounds Ildd can be prepared by oxidation of Ildc. Oxidation can be carried out by treating Ildc with 1-2 equivalent(s) of 3-chloroperoxybenzoic acid in a suitable organic solvent such as dichloromethane, chloroform, 1,2-dichloroethane or mixtures thereof, typically at 0 °C, followed by stirring at room temperature for 10 minutes to several hours. Acids Ilde can be prepared by hydrolysis of methyl esters Ildd. The reaction can be carried out with a suitable base such as sodium hydroxide or lithium hydroxide in a mixture of tetrahydrofuran and water at a temperature between room temperature and 60 °C, typically at room temperature for several hours or overnight.
Compounds of interest Idh can be prepared by couplin, g of Ilde with C-(3- aminomethyl-oxetan-3-yl)-methylamine. The reaction can be carried out without any solvent and without any base at 170 °C for 30 minutes.
General synthetic route for formula Idi (Scheme 55)
Scheme 55
Figure imgf000102_0001
Figure imgf000102_0002
Compounds of Idi can be prepared according to Scheme 55. Starting with 6-bromo quinazo lines Ilda, Bouveault formylation followed by reduction of aldehyde and oxidation of sulfide affords 4-benzyloxy-6-hydroxymethyl-quinazolines Ildh. Coupling of lidh with C-(3- aminomethyl-oxetan-3-yl)-methylamine generates compounds of interest Idi.
Aldehydes Ildf can be prepared by Bouveault formylation. The reaction can be carried out by treating bromide with n-butyllithium in anhydrous tetrahydrofuran at -78 °C followed by stirring with anhydrous N,N-dimethylformamide at -78 °C for 30 minutes to several hours .
6-Hydroxymethyl-quinazo lines Ildg can be prepared by reduction of aldehydes. The reaction can be carried out with sodium boro hydride in a suitable organic solvent such as methanol, tetrahydrofuran or the mixture thereof at 0 °C for 15 minutes to several hours.
Ildh can be prepared by oxidation of sulfides. Oxidation can be carried out with 1-2 equivalents of 3-chloroperoxybenzoic acid in a suitable organic solvent such as dichloromethane, chloroform, 1,2-dichloroethane or mixtures thereof, typically at 0 °C, followed by stirring at
~ minutes to several hours. Compounds of interest Idi can be prepared by coupling Ildh with C-(3 -amino methyl- oxetan-3-yl)-methylamine. The reaction can be carried out without any solvent and without any base at 160 °C for 30 minutes.
General synthetic route for formula Idj (Scheme 56) Scheme 56
Figure imgf000103_0001
Compounds of interest Idj can be prepared according to Scheme 56. Starting with 2,4- dihalogen-quino lines Ilia, coupling with benzoazepines IVi affords 2-benzoazepin-4-halogen- quno lines Ildi. Coupling of Ildi with various amines generates compounds of interest Idj. 2-Benzoazepin-4-halogen-quno lines Ildi can be prepared by coupling of 2,4-dihalogen- quino lines Ilia with benzoazepines IVi. The reaction can be carried out with or without a solvent such as n-butanol at 160 °C for several hours under microwave irradiation.
Compounds of interest Idj can be prepared by coupling of Ildi with various amines. The reaction can be carried out in analogy to coupling of 4-halogen-quino lines Ilab with various amines XI in Scheme 5. Typically the reaction can be carried out in the presence of Ι,Γ- bis(diphenylphosphino)ferrocene, 1 , 1 '-bis(diphenylphosphino)ferrocene-palladium(II)dichloride and sodium tert-butoxide in 1,4-dioxane at 120 °C for 1.5 hours under microwave irradiation.
General synthetic route for formula Idk (Scheme 57)
Figure imgf000104_0001
Figure imgf000104_0002
Compounds of interest Idk can be prepared according to Scheme 57. Starting with IIIc, coupling with l,2,3,4-tetrahydro-benzo[c]azepin-5-one followed by reaction with methyl magnesium bromide affords 5 -methyl-5 -hydroxy benzothiazepines Ildk. Coupling of Ildk with 3-aminomethyl-oxetan-3-ylamine generates compounds of interest Idk.
2-Benzoazepin-quino lines Ildj can be prepared by coupling of IIIc with 1,2,3,4- tetrahydro-benzo[c]azepin-5-one. The reaction can be carried out in the presence of an organic base such as triethylamine in toluene under reflux overnight. 5 -Methyl-5 -hydroxy benzothiazepines Ildk can be prepared by reaction of ketones Ildj with methyl magnesium bromide. The conversion can be achieved by stirring of Ildj with methyl magnesium bromide in tetrahydrofuran at 50 °C for several hours.
Compounds of interest Idk can be prepared by coupling of Ildj with 3-aminomethyl- oxetan-3-ylamine. The reaction can be carried out in the presence of a suitable base such as 1,8- diazabicyclo[5.4.0]undec-7-ene with a suitable phosphine ligand such as benzotriazol-1- yloxytris(dimethylamino)-phosphonium hexafluorophosphate, in a suitable solvent such as N,N- dimethylformamide at room temperature for several hours.
General synthetic route for formula Idl (Scheme 58)
Scheme 58
Figure imgf000105_0001
Compounds of interest Idl can be prepared according to Scheme 58. Starting with Mb, reaction with various benzylamino ethylamines XXIII affords Ildl. Substitution of 2-chloro with 5,5-difluoro-2,3,4,5-tetrahydro-lH-benzo[c]azepine followed by deprotection of benzyl generates compounds of interest Idl.
2-Chloro-quinazo lines Ildl can be prepared by coupling of Illb with various amines XXIII. The reaction can be carried out in the presence of a suitable base such as triethylamine in a suitable solvent such as methanol, tetrahydroiuran, dichloromethane or mixtures thereof at a temperature between 0 °C and room temperature for several hours or overnight.
Compounds Idl can be prepared by standard benzyl deprotection of Ildm. The reaction can be carried out with palladium on carbon, palladium hydroxide on carbon or platinum oxide, typically with addition of acetic acid or trifluoro acetic acid in a suitable solvent such as methanol, ethanol, tetrahydroiuran, ethyl acetate or the mixture thereof, at room temperature for several hours under hydrogen atmosphere.
A. General synthetic route for formula Idm (Scheme 59)
Scheme 59
Figure imgf000106_0001
Figure imgf000106_0002
E is chloro or bromo
Compounds of interest Idm can be prepared according to Scheme 59. Starting with naphthalen-2-ones XXIV, ring expansion with hydrazoic acid gives benzoazepin-3-ones IVj. Reduction of lactams IVj to benzoazepines IVk followed by coupling of IVk with 2,4-dihalogen quinolines Ilia gives 4-halogen quinolines Ildn. Coupling of Ildn with various amines XI affords compounds of interest Idm.
Benzoazepin-3-ones IVj can be prepared from ring expansion of naphthalen-2-ones XXIV by using sodium azide. The reaction can be carried out in toluene with a suitable acid such as trifluoromethanesulfonic acid, trifluoro acetic acid or hydrochloric acid, typically at 0 °C, followed by stirring at room temperature for several hours.
Benzoazepines IVk can be prepared from benzoazepin-3-ones IVj by reduction of lactams. The reaction can be carried out with standard reducing agent such as lithium aluminium hydride, boron hydride or combination of sodium borohydride and boron trifluoride in a suitable inert organic solvent such as tetrahydrofuran, diethyl ether or mixtures thereof, typically at 0 °C, followed by stirring at a temperature between 25 °C and 70 °C for several hours.
4-Halogen quinolines Ildn can be prepared from coupling of benzoazepines IVk and 2,4- dihalogen quinolines Ilia. The reaction can be carried out with a suitable acid such as
luenesulfonic acid in a suitable organic solvent such as toluene, dioxane, /? -butyl alcohol or 2-methyl-2-pentanol at a temperature between 100 °C and 120 °C for several hours. Alternatively, the reaction can be carried out without acid at a temperature between 100 °C and 160 °C for 1 to 3 hours under microwave irradiation.
Compounds of interest Idm can be prepared by coupling of 4-halogen quino lines Ildn with various amines XI. The reaction can be achieved by microwave irradiation at a temperature between 140 °C and 160 °C for 1 to 3 hours with or without organic solvent such as N,N- dimethylformamide, l-methylpyrrolidin-2-one or /? -butyl alcohol.
B. General synthetic route for formula Idm (Scheme 60)
Scheme 60
Figure imgf000107_0001
Figure imgf000107_0002
Compounds of interest Idm can be prepared according to Scheme 60. Acylation of benzoazepines IVk, followed by coupling with 2-aminobenzonitriles XVIII provides imines Ildo. Ring closure of imines Ildo gives 4-aminoquino lines Ildp. Sandmeyer reaction of 4- aminoquino lines Ildp provides 4-halogen quino lines Ildq. Coupling of Ildq with various amines XI generates compounds of interest Idm.
Acetyl benzoazepines IVm can be prepared by acylation of benzoazepines IVk with acetyl chloride or acetic anhydride. The reaction can be carried out with a suitable base such as triethylamine or pyridine in a suitable inert organic solvent such as dichloromethane,
tetrahydrofuran or pyridine at 0 °C, followed by stirring at room temperature for 30 minutes.
Imines lido can be prepared by heating a mixture of IVm, 2-aminobenzonitriles XVIII and phosphorous oxychloride. The reaction can be carried out in a suitable inert organic solvent such as dichloromethane, chloroform or the mixtures thereof, typically at a temperature between 0 °C and 10 °C, followed by stirring under reflux for 24 hours.
Ring closure of imines lido to give 4-aminoquino lines Ildp can be achieved by treatment of lido with Lewis acid such as zinc chloride in N,N-dimethyl-acetamide at a temperature between 120 °C and 180 °C for several hours in an inert atmosphere.
Intermediates Ildq can be prepared from 4-aminoquino lines Ildp by using Sandmeyer reaction. The conversion is typically conducted in standard Sandmeyer reaction conditions such as sodium nitrite, hydrochloric acid and sodium chloride or copper(I) chloride in a suitable solvent such as water, typically at -10 °C, followed by stirring at room temperature for several hours.
Compounds of interest Idm can be prepared by coupling of Ildq with various amines XI. The reaction can be achieved by microwave irradiation at a temperature between 140 °C and 160 °C for 1-3 hours with or without organic solvent such as N,N-dimethylformamide, 1-methyl- pyrrolidin-2-one or n-butyl alcohol.
General synthetic route for formula Idn (Scheme 61)
Scheme 61
Figure imgf000109_0001
L20 is C,.6 alkyl;
E is chloro or bromo.
Compounds of interest Idn can be prepared according to Scheme 61. Starting with 7- bromo-2,3,4,5-tetrahydro-lH-benzo[c]azepine IVn, copper-catalyzed coupling with sodium sulfmates XXV gives sulfonyls IVo. Coupling of IVo with 2,4-dihalogen quino lines Ilia gives 4-halogen quinolines Ildr. Coupling of Ildr with various amines XI affords compounds of interest Idn.
The copper-mediated coupling reaction of 7-bromo-2,3,4,5-tetrahydro-lH-benzo[c]azepine IVn with sodium sulfmates XXV illustrated above can be carried out in the presence of a copper source such as copper(I) iodide (Cul), and a ligand such as 2,2'-bipyridine, Z-proline, N,N- dimethyl glycine or ethylene glycol, with a suitable base such as triethylamine, sodium carbonate, potassium carbonate, cesium carbonate, sodium tert-butoxide, potassium tert- butoxide, sodium hydride or l,8-diazabicyclo[5.4.0]undec-7-ene. The reaction can be carried out in a suitable organic solvent such as acetonitrile, toluene, 1,4-dioxane, N,N-dimethylformamide, dimethyl sulfoxide or l-methyl-pyrrolidin-2-one at a temperature between 100 °C and 180 °C for 15 to 60 minutes under microwave irradiation. Alternatively, the reactions can be carried out at a temperature such as 130 °C for a longer reaction time without the use of microwave irradiation.
Compounds Ildr can be prepared from coupling of benzoazepine IVo and 2,4-dihalogen quinolines Ilia. The reaction can be carried out with a suitable acid such as hydrochloric acid or /?-toluenesulfonic acid in a suitable organic solvent such as toluene, dioxane, n-butyl alcohol or ™„* ..i *— 1 „ temperature between 100 °C and 120 °C for several hours. Alternatively, the reaction can be carried out without acid at a temperature between 100 °C and 160 °C for 1-3 hours under microwave irradiation.
Compounds of interest Idn can be prepared by coupling of Ildr with various amines XI. The reaction can be achieved by microwave irradiation at 140-160 °C for 1-3 hours with or without organic solvent such as N,N-dimethylformamide, l-methyl-pyrrolidin-2-one or n-butyl alcohol.
D. General synthetic route for formula Ido (Scheme 62)
Scheme 62
Figure imgf000110_0001
Compounds of interest Ido can be prepared according to Scheme 62. Starting with phenols lids, alkylation with various XXVI provides Ildt. Coupling of Ildt with various amines XI affords compounds of interest Ido.
Compounds Ildt can be prepared by alkylation of phenols lids with XXVI. The reaction can be carried out with a suitable base such as cesium carbonate, sodium tert-butoxide, potassium tert-butoxide, sodium hydride or l,8-diazabicyclo[5.4.0]undec-7-ene in an inert organic solvent such as dichloromethane, N,N-dimethylformamide, dimethyl sulfoxide or 1- methyl-pyrrolidin-2-one, typically at room temperature for several hours.
Compounds of interest Ido can be prepared by coupling of Ildt with various amines XI. The reaction can be achieved by microwave irradiation at a temperature between 140 °C and 160 °C for 1 to 3 hours with or without organic solvent such as N,N-dimethylformamide, 1-methyl- pyrrolidin-2-one or n-butyl alcohol.
F. General synthetic route for formula Idp (Scheme 63)
Scheme 63
Figure imgf000111_0001
Compounds of interest Idp can be prepared according to Scheme 63. Starting with Ildu, palladium-catalyzed carbonylation gives carboxylic acid methyl esters Ildv. Basic hydrolysis of esters Ildv to acids Ildw followed by coupling with various amines XXVII to furnishes amides Ildx. Coupling of Ildx with various amines XI affords compounds of interest Idp. Palladium-catalyzed carbonylation of Ildu to the corresponding methyl esters Ildv can be accomplished under an atmosphere of carbon monoxide (1 atmospheric pressure) in methanol. The reaction can be carried out in the presence of a palladium catalyst such as
bis(triphenylphosphine)dichloropalladium(II), palladium(II) acetate,
tetrakis(triphenylphosphine)palladium(0), or tri(dibenzylideneacetone)dipalladium(0), in the presence or absence of a phosphine ligand such as tricyclohexylphosphine or triphenylphosphine, and a suitable base such as triethylamine, sodium carbonate or potassium carbonate at a temperature between 60 °C and 120 °C for several hours.
Hydrolysis of the methyl esters Ildv to acids Ildw can be carried out in the presence of an aqueous inorganic base such as lithium hydroxide, sodium hydroxide, or potassium hydroxide in a solvent such as methanol, 1,4-dioxane or tetrahydrofuran at room temperature for several hours.
Amides Ildx can be prepared by coupling various amines XXVII with carboxylic acids Ildw. The reaction is typically conducted with standard peptide coupling reagents such as 1- ethyl-3-(3-dimethylaminopropyl)carbodiimide and 1 -hydro xybenzotriazole, bromo-tm- pyrrolidino-phosphoniumhexafluorophosphate and diisopropylethylamine, or 0-(7- azabenzotriazol-l-y^-A .A .N'.N'-tetramethyluronium hexafluorophosphate and a base such as triethylamine, or diisopropylethylamine in a suitable inert solvent such as dichloromethane or N,N-dimethylformamide or mixtures thereof at room temperature for several hours.
Compounds of interest Idp can be prepared by coupling of amides Ildx with various amines XI. The reaction can be conducted by microwave irradiation at a temperature between 140 °C and 160 °C for 1 to 3 hours with or without organic solvent such as N,N- dimethylformamide, l-methyl-pyrrolidin-2-one or n-butyl alcohol.
G. General synthetic route for formula Idq (Scheme 64)
Scheme 64
Figure imgf000113_0001
Figure imgf000113_0002
Compounds of interest Idq can be prepared according to Scheme 64. Palladium-catalyzed coupling of lactams IVp with 2,4-dihalogenquino lines Ilia gives intermediates Ildy. Coupling of Ildy with various amines XI generates compounds of interest Idq. Intermediates Ildy can be prepared from lactams IVp by coupling with 2,4- dihhalogenquino lines Ilia. The reaction can be carried out typically in the presence of a palladium catalyst such as bis(triphenylphosphine)dichloropalladium(II), palladium(II) acetate, tetrakis(triphenylphosphine)palladium(0), or tri(dibenzylideneacetone)dipalladium(0), in the presence of a phosphine ligand such as tricyclohexylphosphine, or 9,9-dimethyl-4,5- bis(diphenylphosphino)xanthene, with a suitable base such as potassium phosphate tribasic, sodium carbonate or potassium carbonate, in a suitable inert organic solvent such as dioxane, or N,N-dimethylformamide, at a temperature between 100 °C and 150 °C for several hours.
Compounds of interest Idq can be prepared by coupling of Ildy with various amines XI. The reaction can be achieved by microwave irradiation at a temperature between 140 °C and 160 °C for 1 to 3 hours with or without organic solvent such as N,N-dimethylformamide, 1-methyl- pyrrolidin-2-one or n-butyl alcohol.
H. General synthetic route for formula Ids(Scheme 65)
Scheme 65
Figure imgf000114_0001
Compounds of interest Ids can be prepared according to Scheme 65. Starting with diamines Idr (prepared in analogue to Idm in Scheme 59 or Scheme 60), guanidation with 3,5- dimethyl-lH-pyrazole-l-carboximidamide nitrate gives guanidines Ids. The reaction can be carried out in a suitable solvent such as ethanol, typically at a temperature between 70 °C and 90 °C for several hours.
L. General synthetic route for formula Idt (Scheme 66)
Scheme 66
Figure imgf000114_0002
Compounds of interest Idt can be prepared according to Scheme 66. Starting with benzoazepines IVk, coupling with 2-chloro-quinoline-4-carboxylic acid methyl ester XXVIII gives compounds lldz, which are in turn reduced to compounds of interest Idt.
Esters lldz can be prepared from benzoazepines IVk by coupling with 2-chloro-quinoline- 1 ester XXVIII. The reaction can be carried out with a suitable acid such as hydrochloric acid or /?-toluenesulfonic acid in a suitable organic solvent such as toluene, dioxane, /? -butyl alcohol or 2-methyl-2-pentanol at a temperature between 100 °C and 120 °C for several hours. Alternatively, the reaction can be carried out without acid at a temperature between 100 °C and 160 °C for 1 to 3 hours under microwave irradiation.
Alcohols Idt can be prepared from methyl esters Ildz by reduction. The reaction is typically conducted in a tetrahydrofuran solution of borane at 0 °C, followed by stirring at reflux temperature for several hours.
M. General synthetic route for formulas Idu and Idv (Scheme 67)
Scheme 67
Figure imgf000115_0001
Figure imgf000115_0002
Compounds of interest Idu and Idv can be prepared according to Scheme 67. Starting with 4-halogen quino lines Ildn, Suzuki reaction coupling with 2-allyl-4,4,5,5-tetramethyl- [l,3,2]dioxaborolane gives 4-allyl-quino lines Ilea and compounds Idv as a byproduct. 4-Allyl- quino lines Ilea are then converted to compounds of interest Idu by Upjohn dihydroxylation. 4-Allyl-quinolines Ilea and compounds Idv can be prepared from 4-halogen quino lines Ildn by Suzuki coupling with 2-allyl-4,4,5,5-tetramethyl-[l,3,2]dioxaborolane. The reaction is typically conducted in 1 ,2-dimethoxyethane and water with potassium carbonate,
tetrakis(triphenylphosphine)palladium(0), at a temperature between 80 °C and 140 °C for several hours under microwave irradiation. Alternatively, the reactions can be carried out at a heated temperature such as a temperature between 100 °C and 140 °C for a longer reaction time without the use of microwave irradiation.
Compounds of interest Idu can be prepared from 4-allyl-quino lines Ilea by Upjohn dihydroxylation. The reaction can be typically carried out in water with osmium tetroxide and N- methyl morpholine-N-oxide at room temperature for several hours.
P. General synthetic route for formula Idw (Scheme 68)
Scheme 68
Figure imgf000116_0001
Compounds of interest Idw can be prepared according to Scheme 68. Starting with diazepines IVq, coupling of 2,4-dihalogen quino lines Ilia with IVq furnishes Ileb. Subsequent coupling of Ileb with various amines XI generates compounds of interest Idw. Compounds Ileb can be prepared from coupling of 2,4-dihalogen quino lines Ilia with diazepines IVq. The reaction can be carried out with a suitable acid such as hydrochloric acid or /?-toluenesulfonic acid in a suitable organic solvent such as toluene, dioxane, n-butyl alcohol or 2-methyl-2-pentanol at a temperature between 100 °C and 120 °C for several hours.
Alternatively, the reaction can be carried out without acid at a temperature between 100 °C and 160 °C for 1 to 3 hours under microwave irradiation.
Compounds of interest Idw can be prepared by coupling of compounds Ileb with various amines XI. The reaction can be carried out typically in the presence of a palladium catalyst such as [ 1 , 1 '-bis(diphenylphosphino)ferrocene]dichloropalladium(II),
(triphenylphosphine)dichloropalladium(II), palladium(II) acetate, or
tri(dibenzylideneacetone)dipalladium(0), in the presence of a phosphine ligand such
bis(diphenylphosphino)ferrocene, tricyclohexylphosphine, or 9,9-dimethyl-4,5- bis(diphenylphosphino)xanthene, with a suitable base such as sodium tert-butoxide, in a suitable inert organic solvent such as dioxane, or N,N-dimethylformamide, at a temperature between 100 °C and 150 °C for 1 to 3 hours under microwave irradiation. Alternatively, the reactions can be carried out at a heated temperature such as a temperature between 100 °C and 140 °C for a longer reaction time without the use of microwave irradiation.
R. General synthetic route for formula Idx (Scheme 69)
Scheme 69
Figure imgf000118_0001
Figure imgf000118_0002
Compounds of interest Idx can be prepared according to Scheme 69. Starting with hydroxybenzonitriles XXIX, alkylation with methyl bromoacetate gives esters XXX.
Intramolecular cyclization of compounds XXX gives benzooxazepin-3-ones IVr, which are in turn converted to benzooxazepines IVs by reduction. Coupling of IVs with 2,4-dihalogen quino lines Ilia furnishes Ilec. Subsequent coupling of Ilec with various amines XI affords compounds of interest Idx.
Esters XXX can be prepared from alkylation of hydroxybenzonitriles XXIX with methyl bromoacetate. The reaction is typically carried out in acetone with potassium carbonate at room temperature for several hours.
Benzooxazepin-3-ones IVr can be prepared from esters XXX by intramolecular cyclization. The reaction can be carried out in methanol with Raney nickel at room temperature for several hours under an atmospheric pressure of hydrogen.
Benzooxazepines IVs can be prepared from benzooxazepin-3-ones IVr by reduction of lactam. The reaction is typically conducted in an inert solvent such as tetrahydrofuran, diethyl ether or mixtures thereof with lithium aluminium hydride, typically at 0 °C, followed by stirring
Several llOUTS Substituted quino lines Ilec can be prepared from coupling of benzooxazepines IVs with 2,4-dihalogen quino lines Ilia. The reaction can be carried out with a suitable base such as potassium carbonate, cesium carbonate, diisopropylethylamine, triethylamine, or 1,8- diazabicyclo[5.4.0]undec-7-ene in an inert organic solvent such as toluene, tetrahydrofuran, 1- methyl-pyrrolidin-2-one or N,N-dimethylformamide, typically at a temperature between 100 °C and 180 °C for 1 to 3 hours under microwave irradiation.
Compounds of interest Idx can be prepared by coupling of substituted quino lines Ilec with various amines XI. The reaction can be achieved by microwave irradiation at a temperature between 140 °C and 180 °C for 1 to 3 hours with or without organic solvent such as N,N- dimethylformamide, l-methyl-pyrrolidin-2-one or n-butyl alcohol.
General synthetic route for formula Idy (Scheme 70)
Scheme 70
Figure imgf000119_0001
.W10 is met ylcyclopropyl and L25 is hydrogen,
or W10 and L25 with nitrogen they are attached with form pyrrolindin-3-yl.
Compounds of interest of formula Idy can be prepared according to Scheme 70.
Coupling of 2,4-dichloro-quinozalines Illb with various amines XXXI followed by reaction with 6,7,8,9-tetrahydro-5-thia-8-aza-benzocycloheptene 5,5-dioxides IVd affords 2,4 - disubstituted quinozalines Ilef. Deprotection of tert-butyloxycarbonyl of Ilef generates the target compounds Idy. 2-Chloro-4-amino quinozalines lied can be prepared by coupling of Illb with various amines XXXI. The reaction can be carried out in the presence of a suitable base such as triethylamine in a suitable solvent such as methanol, tetrahydrofuran, dichloromethane or mixture thereof at a temperature between 0 °C to room temperature for several hours.
4 - Disubstituted quinozalines lief can be obtained by the coupling of lied with 6,7,8,9- tetrahydro-5-thia-8-aza-benzocycloheptene 5,5-dioxides IVd. The reaction can be carried out with or without an acid such as 4--nK;i b ibo:i/es -e:-> Horne i-dd and ammonium chloride, in a suitable solvent such as ethanol or N,N-dimethylformamide at an elevated temperature between 50°C and 120 °C for several hours, typically at 70 °C overnight.
Compounds of interest of formula Idy can be prepared from deprotection of tert- butyloxycarbonyl of 4 - disubstituted quinozalines lief. The reaction can be carried out with a suitable acid such as trifluoro acetic acid or hydrochloric acid in a suitable solvent such as dichloromethane, ethyl acetate or 1,4-dioxane, at 0 °C to room temperature for 30 minutes to 16 hours.
The invention also relates to a compound of formula (I) for use as therapeutically active substance.
The invention relates to a compound of formula (I) for use as a medicament.
The invention also relates to a pharmaceutical composition comprising a compound of formula (I) and a therapeutically inert carrier.
The invention relates in particular to the use of a compound of formula (I) for the preparation of a medicament for the treatment or prophylaxis of respiratory syncytial virus infection.
Said medicaments, e.g. in the form of pharmaceutical preparations, can be administered orally, e.g. in the form of tablets, coated tablets, dragees, hard and soft gelatine capsules, solutions, emulsions or suspensions. The administration can, however, also be effected rectally, e.g. in the form of suppositories, or parenterally, e.g. in the form of injection solutions with an effective amount of a compound as defined above.
The above-mentioned pharmaceutical composition can be obtained by processing the compounds according to this invention with pharmaceutically inert inorganic or organic carriers. For example, lactose, corn starch or derivatives thereof, talc, stearic acids or its salts and the like can be used, as such carriers for tablets, coated tablets, dragees and hard gelatine capsules.
Suitable carriers for soft gelatine capsules are, for example, vegetable oils, waxes, fats, semisolid and liquid polyols and the like. Depending on the nature of the active substance no carriers are, however, usually required in the case of soft gelatine capsules. Suitable carriers for the production of solutions and syrups are, for example, water, polyols, glycerol, vegetable oil and the like. Suitable carriers for suppositories are, for example, natural or hardened oils, waxes, fats, semi- liquid or liquid polyols and the like.
The pharmaceutical composition can, moreover, contain preservatives, solubilizers, stabilizers, wetting agents, emulsifiers, sweeteners, colorants, flavorants, salts for varying the osmotic pressure, buffers, masking agents or antioxidants. They can also contain still other therapeutically valuable substances.
The dosage depends on various factors such as manner of administration, species, age and/or individual state of health. The doses to be administered daily are about 5-400 mg/kg, preferably about 10-100 mg/kg, and can be taken singly or distributed over several
administrations .
A compound of formula (I) when manufactured according to the above process is also an object of the invention.
This invention relates to the use of a compound of formula (I) for the manufacture of a medicament for treatment or prophylaxis of RSV infection. The invention further relates to a method for the treatment or prophylaxis of respiratory syncytial virus infection, which method comprises administering an effective amount of a compound of formula (I).
The invention is illustrated by the following examples which have no limiting character. Unless explicitly otherwise stated, all reactions, reaction conditions, abbreviations and symbols have the meanings well known to a person of ordinary skill in organic chemistry.
Examples
Intermediates and final compounds were purified by flash chromatography using one of the following instruments: i) Biotage SP1 system and the Quad 12/25 Cartridge module, ii) ISCO combi-flash chromatography instrument. Silica gel Brand and pore size: i) KP-SIL 60 A, particle size: 40-60 μΜ; ii) CAS registry NO: Silica Gel: 63231-67-4, particle size: 47-60 micron silica gel; iii) ZCX from Qingdao Haiyang Chemical Co., Ltd, pore: 200-300 or 300-400. Intermediates and final compounds were purified by preparative HPLC on reversed phase column using X Bridge™ Perp Ci8 (5 μιη, OBD™ 30 100 mm) column or SunFire™ Perp Ci8 (5 μιη, OBD™ 30 100 mm) column.
LC/MS spectra were obtained using a MicroMass Plateform LC (WatersTM alliance 2795- ZQ2000). Standard LC/MS conditions were as follows (running time 6 minutes):
Acidic condition: A: 0.1% formic acid in H20; B: 0.1% formic acid in acetonitrile;
Basic condition: A: 0.01% ΝΗ3Ή20 in H20; B: acetonitrile;
Neutral condition: A: H20; B: acetonitrile.
Mass spectra (MS): generally only ions which indicate the parent mass are reported, and unless otherwise stated the mass ion quoted is the positive mass ion (M+H)+.
The microwave assisted reactions were carried out in a Biotage Initiator Sixty.
NMR Spectra were obtained using Bruker Avance 400MHz.
All reactions involving air-sensitive reagents were performed under an argon atmosphere. Reagents were used as received from commercial suppliers without further purification unless otherwise noted.
Intermediate 1-1
2,4-Dichloro-8-methylquinoline
Figure imgf000122_0001
To a three necks round bottom flask equipped with a reflux condenser and thermometer containing phosphoryl chloride (400 mL) was added 2-methylaniline (50 g, 0.47 mol) and propanedioic acid (73 g, 0.7 mol). The mixture was heated and stirred at 95 °C for 16 hours and then 145 °C for 1 hour. The volatiles were evaporated in vacuo and the residual black oil was poured onto crashed ice with stirring. The resulting mixture was extracted with dichloromethane (300 mL x 3). The combined organic layers were washed with a saturated aqueous solution of sodium bicarbonate until the water phase was pH 7-8, then washed with brine (300 mL), dried rwpr snHium sulfate filtered and concentrated in vacuo. The residue was purified by flash column chromatography (3% ethyl acetate in petroleum ether) to afford 65 g of the pure product (yield was 65.3%). MS obsd. (ESI+) [(M+H)+] 212.
Intermediate 1-2
2,4-Dichloro-6-(methylsulfanyl)quinoline
Figure imgf000123_0001
l-(Methylsulfanyl)-4-nitrobenzene
Figure imgf000123_0002
To a suspension of /?-nitrothiophenol (20 g, 0.129 mol) in water (150 mL) was added an aqueous solution of sodium hydroxide (75 mL, 2 N) at room temperature. After the mixture was stirred for 15 minutes and cooled to 10 °C, methyl iodide (57 g, 25 mL, 0.401 mol) was added slowly. The reaction mixture was allowed to warm to room temperature and stirred for 2.5 hours. The resulting mixture was extracted with diethyl ether (100 mL x 3). The organic layers were combined, washed with water (200 mL) and brine (200 mL), dried over calcium sulfate and concentrated in vacuo. The residue was purified by silica gel column chromatography to afford 11 g of l-(methylsulfanyl)-4-nitrobenzene as a yellow solid.
4-(Methylsulfanyl)aniline
Figure imgf000123_0003
A suspension of l-(methylsulfanyl)-4-nitrobenzene (10.5 g, 0.062 mol) and Raney nickel (5 g) in methanol (250 ml) was hydrogenated in a round flask equipped with a balloon filled with hydrogen at room temperature for 16 hours. The resulting mixture was filtered and concentrated in vacuo to afford 8.0 g of 4-(methylsulfanyl)aniline as colorless oil.
2,4-Dichloro-6-(methylsulfanyl)quinoline
Figure imgf000124_0001
Intermediate 1-2 can be prepared in analogy to Intermediate 1-1 by using 4- (methylsulfanyl)aniline. MS obsd. (ESI+) [(M+H)+] 244.
Intermediate 1-3 6-Bromo-2,4-dichloroquinoline
Figure imgf000124_0002
Intermediate 1-3 can be prepared in analogy to Intermediate 1-1 by using 4-bromoaniline. MS obsd. (ESI+) [(M+H)+] 276.
Intermediate 1-4
2,4-Dichloro-5-methylquinoline
Figure imgf000124_0003
Intermediate 1-4 can be prepared in analogy to intermediate 1-1 by using 3-methylaniline. MS obsd. (ESI+) [(M+H)+] 212.
Intermediate 1-5
2,4-Dichloro-7-methylquinoline
Figure imgf000124_0004
Intermediate 1-5 can be prepared in analogy to intermediate 1-1 by using 3-methylaniline. MS obsd. (ESI+) [(M+H)+] 212.
Intermediate 1-6 2,4-Dichloro-6-fluoro-quinoline
Figure imgf000125_0001
Intermediate 1-6 can be prepared in analogy to Intermediate 1-1 by using 4-fluoroaniline. MS obsd. (ESI+) [(M+H)+] 216.
Intermediate 1-8 2,4-Dichloro-6-trideuteriomethyl-quinoline
Figure imgf000125_0002
Intermediate 1-8 can be prepared in analogy to Intermediate 1-1 by using 4- trideuteriomethylaniline. MS obsd. (ESI+) [(M+H)+] 215.
Intermediate 1-9
Methyl 2,4-dichloro-quinoline-6-carboxylate
Figure imgf000125_0003
Intermediates 1-9 can be prepared in analogy to Intermediate 1-1 by using methyl 4- aminobenzoate. MS obsd. (ESI+) [(M+H)+] 256.
Intermediate 1-10
2,4-Dichloro-7,8-difluoro-6-methylquinoline
Figure imgf000125_0004
Intermediate 1-10 can be prepared in analogy to Intermediate 1-1 by using 2,3-difluoro-4- — + „I™ _ A ,C „ „A (ESI +) [(M+H)+] 248. Intermediate 1-11
2,4-Dichloro-6-(trifluoromethoxy)quinoline
Figure imgf000126_0001
Intermediate 1-11 can be prepared in analogy to Intermediate 1-1 by using 4- (trifluoromethoxy)aniline. MS obsd. (ESI+) [(M+H)+] 282.
Intermediate 1-12
2,4-Dichloro-6-(difluoromethoxy)quinoline
Figure imgf000126_0002
Intermediate 1-12 can be prepared in analogy to Intermediate 1-1 by using 4- (difluoromethoxy)aniline. MS obsd. (ESI+) [(M+H)+] 264.
Intermediate 1-13
2,4-Dichloro-5-fluoro-6-methylquinoline
Figure imgf000126_0003
Intermediate 1-13 can be prepared in analogy to Intermediate 1-1 by using 3-fluoro-4- methylaniline. MS obsd. (ESI+) [(M+H)+] 230.
Intermediate 1-14
2,4-Dichloro-7-fluoro-6-methylquinoline
Figure imgf000126_0004
Intermediate 1-14 can be prepared in analogy to Intermediate 1-1 by using 3-fluoro-4- methylaniline. MS obsd. (ESI+) [(M+H)+] 230.
Intermediate 1-15
2,4-Dibromo-6-methylquinoline
Figure imgf000127_0001
Intermediate 1-15 can be prepared in analogy to Intermediate 1-1 by using 4-methylaniline, propanedioic acid and phosphoryl bromide. MS obsd. (ESI+) [(M+H)+] 300, 1H NMR (400 MHz, CD3OD) δ ppm 7.92 (s, 1 H), 7.91 - 7.88 (d, J= 0.8 Hz, 1 H), 7.80 (s, 1 H), 7.62 -7.56 (dd, J = 2.0, 8.4 Hz, 1 H), 2.57 (s, 3 H).
Intermediate 1-16
2,4-Dichloro- 1 ,6-naphthyridine
Figure imgf000127_0002
Methyl 4-aminopyridine-3-carboxylate
Figure imgf000127_0003
A mixture of compound 4-aminopyridine-3-carboxylic acid (100 g, 0.7 mol) and concentrated sulfuric acid (400 g, 4.0 mol) in absolute methanol (1.5 L) was stirred under reflux for 24 hours. The reaction mixture was concentrated in vacuo. The residue was diluted with ice-water (800 mL), basified with 2 N of aqueous solution of sodium hydroxide to about pH 10 and then extracted with ethyl acetate (300 mL x 3). The combined organic layers were washed with water (500 mL), dried over sodium sulfate and concentrated in vacuo to afford the crude product, which was used for next step without further purification.
Methyl 4-(acetylamino)pyridine-3-carboxylate
Figure imgf000128_0001
A mixture of methyl 4-aminopyridine-3-carboxylate (100 g, 0.6 mol) and acetic anhydride (240 g, 2.4 mol) in anhydrous 1,4-dioxane (1.2 L) was stirred at room temperature overnight. The reaction mixture was concentrated in vacuo and diluted with water (800 mL). The mixture was neutralized with a saturated aqueous solution of sodium bicarbonate to pH 7. The formed solid was collected by filtration and dried in vacuo to afford 50 g of methyl 4-(acetylamino)pyridine- 3-carboxylate as a white solid. l-Benzyl-4-hydroxy-l,6-naphthyridin-2(lH)-one
Figure imgf000128_0002
A mixture of methyl 4-(acetylamino)pyridine-3-carboxylate (70 g, 0.36 mol) and sodium hydride (50 g, 1.25 mol, 60% in mineral oil) in anhydrous tetrahydrofuran (800 mL) was stirred at room temperature for 30 minutes. To the above mixture was added bromomethylbenzene (60 g, 0.36 mmol) and the resulting mixture was stirred at room temperature overnight. The reaction mixture was poured onto crashed ice (600 mL), concentrated in vacuo, and washed with ethyl acetate (400 mL). The aqueous layer was neutralized by addition of 3 N aqueous solution of hydrochloric acid to pH 7. The formed solid was collected by filtration and dried in vacuo to afford 24 g of l-benzyl-4-hydroxy-l,6-naphthyridin-2(lH)-one as a pale yellow solid. l,6-Naphthyridine-2,4(lH,3H)-dione
Figure imgf000128_0003
A mixture of l-benzyl-4-hydroxy-l,6-naphthyridin-2(lH)-one (21 g, 0.08 mol) and
trifluoromethanesulfonic acid (100 mL) was heated with stirring at 120 °C overnight. The reaction mixture was used for the next step directly. 2,4-Dichloro- 1 ,6-naphthyridine
Figure imgf000129_0001
A mixture of l,6-naphthyridine-2,4(lH,3H)-dione (10 g, 0.06 mol) and phosphoryl chloride (180 g) was heated with stirring at 100 °C for 3 hours. The reaction mixture was cooled to room temperature and concentrated in vacuo. The residue was poured into ice-water (200 g) and extracted with ethyl acetate (200 mL x 5). The combined organic layers were dried over sodium sulfate, concentrated in vacuo to afford the crude product. 1H NMR (400 MHz, CD3OD) δ ppm 9.57 (s, 1 H), 8.90 - 8.89 (d, J= 5.6 Hz, 1 H), 8.12 (s, 1 H), 7.94 - 7.93 (d, J= 6.0 Hz, 1 H).
Intermediate 1-17 2,4-Dichloro-6-difluoromethylquinoline
Figure imgf000129_0002
4-Aminobenzaldehyde
Figure imgf000129_0003
To a solution of 4-nitrobenzaldehyde (2.0 g, 0.133 mol) in acetic acid (150 mL) and water (15 mL) was added iron powder (1.48 g, 0.265 mol). The reaction was stirred overnight at room temperature. The mixture was filtered and extracted with dichloromethane (50 mL x 3). Then the organic layer was dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by flash column chromatography (eluting with 10% ethyl acetate in petroleum ether) to afford 1.2 g of the pure product (yield was 75%). 2,4-Dichloroquinoline-6-carbaldehyde o CI A mixture of 4-aminobenzaldehyde (14 g, 0.116 mol), propanedioic acid (14.4 g, 0.139 mol) and phosphoryl chloride (180 g) was heated with stirring at 95 °C for 16 hours. The reaction mixture was cooled to room temperature and concentrated in vacuo. The residue was purified by flash column chromatography afford 150 mg of the pure product (yield was 0.57%). 2,4-Dichloro-6-difluoromethylquinoline
Figure imgf000130_0001
A mixture of 2,4-dichloroquinoline-6-carbaldehyde (45.2 mg, 0.2 mmol) and diethylamino sulfur trifluoride (32.2 mg, 0.2 mmol) in 1,2-dichloroethane (15 mL) was refluxed overnight. The reaction mixture was cooled to room temperature and concentrated in vacuo. The residue was purified by thin layer chromatography to afford 20 mg of the desired product (yield was 40.3%>), MS obsd. (ESI+) [(M+H)+] 248, 1H NMR (400 MHz, CDC13) δ ppm 8.28 (s, 1 H), 8.10 - 8.05 (d, J= 8.8 Hz,l H), 7.90 - 7.82 (d, J= 8.4 Hz,l H), 7.53 (s, 1 H), 6.95 - 6.62 (t, J= 56 Hz ,1 H).
Intermediate 2-1
2,3,4,5-Tetrahydro-l,4-benzothiazepine
Figure imgf000130_0002
Methyl 2-sulfanylbenzoate
Figure imgf000130_0003
To a cooled solution of concentrated sulfuric acid (72 g) in methanol (1.5 L) at 0 °C, was added 2-sulfanylbenzoic acid (300 g, 1.95 mol) in portions under argon atmosphere. After being refluxed with stirring for 18 hours, the reaction mixture was concentrated in vacuo. The residue was diluted with water (800 mL), basified with a saturated aqueous solution of sodium bicarbonate to about pH 7, and extracted with dichloromethane (600 mL x 3). The combined organic layers were washed with brine (800 mL), dried over sodium sulfate, filtered and concentrated in vacuo to afford 300 g of methyl 2-sulfanylbenzoate (yield was 91%) as a light Ί for me nex{ w thout further purification. 3,4-Dihydro-l,4-benzothiazepin-5(2H)-one
Figure imgf000131_0001
To a cooled solution of methyl 2-sulfanylbenzoate (200 g, 1.19 mol) in tetrahydroiuran and N,N- dimethylformamide (2 L, V/V = 1/1) was added 2-chloroethanamine hydrochloride (138 g, 1.19 mol) at 0 °C followed by sodium hydride (143 g, 3.57 mol, 60% in mineral oil) in portions.
After being stirred at room temperature overnight, the reaction mixture was poured into ice- water and extracted with ethyl acetate (900 mL x 4). The organic layers were combined, washed with brine (900 mL x 3), dried over sodium sulfate and concentrated in vacuo. The residue was stirred in a mixture solution of ethyl acetate and petroleum ether (300 mL, V/V = 1/1) for 1 hour. The solid was collected by filtration and dried in vacuo to afford 100 g of 3,4-dihydro-l,4- benzothiazepin-5(2H)-one (yield was 47%).
2,3,4,5-Tetrahydro-l,4-benzothiazepine
Figure imgf000131_0002
To a bottle containing a cooled suspension of lithium aluminum hydride (44 g, 1.17 mol) in dry tetrahydrofuran (1.5 L) was added 3,4-dihydro-l,4-benzothiazepin-5(2H)-one (150 g, 0.84 mol) in portions at 0 °C. After being refluxed for 18 hours, the reaction mixture was cooled to 0 °C, followed by addition of water (25 mL) dropwise. The reaction mixture was then filtered through a pad of celite and washed with dichloromethane. The filtrate was dried over sodium sulfate and evaporated in vacuo to afford 125 g of 2,3,4, 5-tetrahydro-l,4-benzothiazepine (yield was 90%>), which was used for the next step without further purification.
Intermediate 2-2 and 2-3
8-Methoxy-2,3,4,5-tetrahydro-l,4-benzothiazepine (Intermediate 2-2) and 8-Fluoro-2,3,4,5- tetrahydro-l,4-benzothiazepine (Intermediate 2-3)
Figure imgf000131_0003
loic acid
Figure imgf000132_0001
To a cooled solution of 2-amino-4-fluoro-benzoic acid (0.93 g, 6 mmol) in water (3 mL) was added concentrated hydrochloric acid (1.2 mL), then a cold solution of sodium nitrite (0.41 g, 6 mmol) in water (2 mL) was added drop wise at 5 °C. After the addition, the mixture was stirred for 30 minutes at that temperature. A cooled solution of disodium disulphide prepared with boiled water (2 mL), sodium sulfide nonahydrate (1.57 g, 6.66 mmol), sulfur (0.2 g, 6.6 mmol) and a solution of sodium hydroxide (0.6 mL, 10 mol/ L) was added dropwise into the above mixture at 5 °C. After being stirred for 2 hours at room temperature, the mixture was acidified with hydrochloric acid. The formed precipitate was filtered, washed with water, and dried in vacuo to afford 1.4 g of the disulfide derivative as a yellow solid (yield was 70%). MS obsd. (EST) [(M-H) ] 341.
A mixture of disulfide (1.4 g, 4.1 mmol) and zinc powder (0.18 g, 2.76 mmol) in acetic acid (5 mL) was refluxed for 4 hours, and then cooled to room temperature. The formed precipitate was collected by filtration, and then boiled in an aqueous solution of sodium hydroxide (0.15 g in 1.2 mL of water) for 30 minutes. After being cooled to 0 °C, the mixture was acidified with hydrochloric acid. The formed solid was collected by filtration, washed with water, and dried in vacuo to afford 0.5 g of the product (yield was 36%). MS obsd. (EST) [(M-H)"] 171.
Methyl 4-fluoro-2-sulfanylbenzoate
Figure imgf000132_0002
A mixture of 4-fluoro-2-sulfanylbenzoic acid (6.0 g, 34.9 mmol), concentrated sulfuric acid (6 mL) in methanol (200 mL) was refluxed for 18 hours under argon atmosphere. The resulting mixture was concentrated in vacuo. The residue was diluted with ethyl acetate, washed with water, basified with a saturated aqueous solution of sodium bicarbonate to about pH 8. The organic layer was washed with brine, dried over sodium sulfate, and concentrated in vacuo to afford 4.54 g of the crude product as a brown oil (yield was 70%>), which was used directly for the next step without further purification. MS obsd. (EST) [(M-H) ~] 185. 8-Methoxy-3,4-dihydro-l,4-benzothiazepin-5(2H)-one and 8 - Fluoro-3,4-dihydro-l,4- benzothiazepin-5(2H)-one
Figure imgf000133_0001
To a solution of methyl 4-fluoro-2-sulfanylbenzoate (3.0 g, 16 mmol) and 2-chloroethanamine hydrochloride (1.88 g, 16 mmol) in N,N-dimethylformamide (30 mL), sodium hydride (1.94 g, 48 mmol, 60 % in mineral oil) was added in portions. The reaction mixture was stirred at 100 °C overnight. The solvent was removed under reduced pressure. The residue was diluted with water, then a mixture of ethyl acetate and petroleum ether (1/10, V/V). The resulting mixture was stirred for 1 hour. The resulting precipitate was collected by filtration, washed with diethyl ether and petroleum ether, dried in vacuo to afford a mixture of 8-methoxy-3,4-dihydro-l,4- benzothiazepin-5(2H)-one and 8-fluoro-3,4-dihydro-l,4-benzothiazepin-5(2H)-one. The above mixture was purified by flash column to afford 0.75 g of the product 8-methoxy-3,4-dihydro-l ,4- benzothiazepin-5(2H)-one as a pale white solid (yield was 22%), MS obsd. (ESI+) [(M+H)+] 210 , and 0.75 g of the product 8-fluoro-3,4-dihydro-l,4-benzothiazepin-5(2H)-one as a pale white solid (yield was 23%), MS obsd. (ESI+) [(M+H) +] 198.
Intermediate 2-2 8-Methoxy-2,3,4,5-tetrahydro-l,4-benzothiazepine
Figure imgf000133_0002
Intermediate 2-2 can be prepared in analogy to intermediate 2-1 by using 8-methoxy-3,4- dihydro-l ,4-benzothiazepin-5(2H)-one (yield was 90%). MS obsd. (ESI+) [(M+H)+] 196.
Intermediate 2-3
8-Fluoro-2,3,4,5-tetrahydro-l,4-benzothiazepine
Figure imgf000133_0003
Intermediate 2-3 can be prepared in analogy to intermediate 2-1 by using 8-fluoro-3,4-dihydro- l,4-benzothiazepin-5(2H)-one (yield was 96%). MS obsd. (ESI+) [(M+H)+] 184.
Intermediate 2-4
7-Fluoro-2,3,4,5-tetrahydro-l,4-benzothiazepine
Figure imgf000134_0001
Intermediate 2-4 can be prepared in analogy to intermediate 2-1 by using 5-fluoro-2- sulfanylbenzoic acid. MS obsd. (ESI+) [(M+H)+] 184.
Intermediate 2-5
9-Fluoro-2,3,4,5-tetrahydro-l,4-benzothiazepine
Figure imgf000134_0002
Intermediate 2-5 can be prepared in analogy to intermediate 2-1 by using 3-fluoro-2- sulfanylbenzoic acid. MS obsd. (ESI+) [(M+H)+] 184.
Intermediate 2-6
8-Methyl-2,3,4,5-tetrahydro-l,4-benzothiazepine
Figure imgf000134_0003
Methyl 2-hydroxy-4-methylbenzoate
Figure imgf000134_0004
A mixture of 2-hydroxy-4-methylbenzoic acid (100.0 g, 657.2 mmol), concentrated sulfuric acid (50 mL) in methanol (1000 mL) was refluxed for 20 hours under nitrogen atmosphere. The resulting mixture was concentrated in vacuo. The residue was poured into ice-water, extracted with ethyl acetate (1000 mL). The organic layer was washed with saturated sodium bicarbonate, brine, dried over sodium sulfate, concentrated in vacuo to afford 109 g of the crude product of methyl 2-hydroxy-4-methylbenzoate as light brown oil, which was used directly in the next step without further purification.
Methyl 2- [(dimethylcarbamothioyl)oxy] -4-methylbenzoate
Figure imgf000135_0001
To a solution of methyl 2-hydroxy-4-methylbenzoate (109 g, 657.2 mmol) and 1,4- diazabicyclo[2.2.2]octane (147.4 g, 1314.4 mmol) in N,N-dimethylformamide (300 mL) was added a solution of N,N-dimethylcarbamothioyl chloride (97.5 g, 788.6 mmol) w. N,N- dimethylformamide (100 mL) at room temperature. After being heated at 60 °C for 4 hours, the mixture was cooled and poured onto ice. The formed precipitate was collected by filtration, washed with water (300 mL x 3) and dried in vacuo to afford 137 g of methyl 2- [(dimethylcarbamothioyl)oxy]-4-methylbenzoate as an off-white solid (yield was 82%).
Methyl 2- [(dimethylcarbamoyl)sulfanyl] -4-methylbenzoate
Figure imgf000135_0002
Methyl 2-[(dimethylcarbamothioyl)oxy]-4-methylbenzoate (52.0 g, 205.5 mmol) in a round bottle flask which was vacuumed and backfilled with nitrogen, was heated at 210 °C for 4 hours. The mixture was then cooled to room temperature and used for next step without further purification.
4-Methyl-2-sulfanylbenzoic acid
Figure imgf000135_0003
A round bottle flask containing a mixture of methyl 2-[(dimethylcarbamoyl)sulfanyl]-4- methylbenzoate (50 g, 197.6 mmol) and an aqueous solution of sodium hydroxide (120 mL, 4 N) was vacuumed and backfilled with nitrogen 3 times. After being refluxed for 2 hours, the resulting mixture was cooled to 0 °C and acidified with an aqueous solution of hydrochloric acid (45 mL, 6 N). The formed precipitate was collected by filtration, and then dissolved in ethyl acetate (500 mL). The solution was dried over anhydrous sodium sulfate, and concentrated in vacuo to afford 4-methyl-2-sulfanylbenzoic acid as a light yellow solid.
8-Methyl-2,3,4,5-tetrahydro-l,4-benzothiazepine
Figure imgf000136_0001
Intermediate 2-6 can be prepared in analogy to intermediate 2-1 by using 4-methyl-2- sulfanylbenzoic acid. MS obsd. (ESI+) [(M+H)+] 180. Intermediate 2-7
8-Chloro-2,3,4,5-tetrahydro-l,4-benzothiazepine
Figure imgf000136_0002
4-Chloro-2-sulfanylbenzoic acid
Figure imgf000136_0003
To a cooled mixture of concentrated hydrochloric acid (6 mL) and ice (10 g) was added slowly a solution of 2-amino-4-chlorobenzoic acid ( 4 g, 23.3 mmol), sodium hydroxide (0.94 g, 23.5 mmol) and sodium nitrite ( 1.6 g, 23.3 mmol) in water (30 mL) in an ice bath. The resulting mixture was stirred at 0 °C for 1 hour. A solution of potassium ethoxymethanedithioate (20.8 g, 65.2 mmol) in water (40 mL) in a beaker was heated to 65 °C. The cold diazonium salt solution was added slowly to the above hot solution while evolution of gas was observed. After the addition the mixture was cooled to room temperature and acidified to about pH 3 with an aqueous solution of hydrochloric acid (4 N). The aqueous phase was decanted from the resulting semisolid and the sludge was dissolved in 10% aqueous sodium hydroxide (20 mL). The solution was heated for 2 hours at 100 °C followed by addition of sodium hydrosulfite (2 g). The resulting mixture was heated with stirring at 100 °C for an additional 10 minutes, then cooled to room temperature and filtered through a pad of celite. The filtrate was acidified to about pH 4 with concentrated hydrochloric acid. The formed solid was collected by filtration, washed with water, and dissolved in methanol (10 mL) and diethyl ether (150 mL). The solution was dried over sodium sulfate and concentrated in vacuo to afford 2.8 g of 4-chloro-2-sulfanylbenzoic acid as a yellow solid (yield was 63%).
8-Chloro-2,3,4,5-tetrahydro-l,4-benzothiazepine
Figure imgf000137_0001
Intermediate 2-7 can be prepared in analogy to intermediate 2-1 by using 4-chloro-2- sulfanylbenzoic acid. MS obsd. (ESI+) [(M+H)+] 200. Intermediate 3
5-Methyl-2,3,4,5-tetrahydro-l,4-benzothiazepine
Figure imgf000137_0002
l-(2-Sulfanylphenyl)ethanone
Figure imgf000137_0003
To a stirred suspension of aluminium chloride (10.50 g, 78.8 mmol) in dry benzene (200 mL) was added a solution of l-[2-(benzylsulfanyl)phenyl]ethan-l-one (11.93g, 49.2 mmol) in dry benzene (100 mL) dropwise in an ice bath under argon atmosphere. After the reaction mixture being stirred at room temperature overnight, the reaction was quenched by the cautious addition of ice-water. The separated organic layer was washed with water and extracted with 5% aqueous solution of sodium hydroxide (300 mL). The aqueous layer was acidified to about pH 3 with concentrated hydrochloric acid (12 N) and extracted with dichloromethane (300 mL x 3). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, concentrated in vacuo to afford 6.47 g of the crude product l-(2-sulfanylphenyl)ethanone.
5-Methyl-2,3-dihydro- 1 ,4-benzothiazepine
Figure imgf000138_0001
To a solution of l-(2-sulfanylphenyl)ethanone (6.40 g, 42.05 mmol) in ethanol (80 mL) was added an aqueous solution of potassium hydroxide (7.08 g, 126.14 mmol in 30 mL of water) and an aqueous solution of 2-bromoethanamine hydrobromide (9.48 g, 46.25 mmol in 30 mL of water). After being stirred at room temperature for 6 hours, the reaction mixture was
concentrated in vacuo to remove most of ethanol and extracted with dichloromethane (60 mL x 3). The combined organic layers were washed with brine (100 mL), dried over anhydrous sodium sulfate, and concentrated in vacuo. The residue was purified by flash column
chromatography to give 5.92 g of 5-methyl-2,3-dihydro-l,4-benzothiazepine. 5-Methyl-2,3,4,5-tetrahydro-l,4-benzothiazepine
Figure imgf000138_0002
To a solution of 5-methyl-2,3-dihydro-l,4-benzothiazepine (5.92 g, 33.40 mmol) in methanol (100 mL) was added a solution of sodium borohydride (3.16 g, 83.49 mmol) in water (60 mL). After being stirred at room temperature overnight, the reaction mixture was acidified with concentrated hydrochloric acid, and then stirred at room temperature for 30 minutes. After being adjusted to pH 9 with an aqueous solution of sodium hydroxide, the resulting mixture was extracted with ethyl acetate (60 mL x 3). The combined organic layers were washed by brine (100 mL), dried over anhydrous sodium sulfate, and concentrated in vacuo to afford 5.6 g of 5- methyl-2,3,4,5-tetrahydro-l,4-benzothiazepine, MS obsd. (ESI+) [(M+H)+] 180. Intermediate 4
1-(1 , l-Dioxido-2,3-dihydro- 1 ,4-benzothiazepin-4(5H)-yl)ethanone
Figure imgf000138_0003
l-(2,3-Dihydro-l,4-benzothiazepin-4(5H)-yl)ethanone
Figure imgf000139_0001
To a solution of 2,3,4, 5-tetrahydro-l,4-benzothiazepine (5 g, 30.3 mmol) in dry dichloromethane (100 mL) was added triethylamine (5.06 mL, 36.3 mmol) at room temperature, followed by the dropwise addition of acetic anhydride (3.43 mL, 36.3 mmol) at 0 °C under nitrogen. The resulting solution was stirred for 1 hour whilst allowing the temperature to rise slowly to room temperature. The mixture was washed with brine (50 mL x 2), dried over sodium sulfate, filtered and concentrated in vacuo to afford 6.28 g of product as yellow oil, which was used for next step without further purification.
1-(1 , l-Dioxido-2,3-dihydro- 1 ,4-benzothiazepin-4(5H)-yl)ethanone
Figure imgf000139_0002
To a cooled solution of l-(2,3-dihydro-l,4-benzothiazepin-4(5H)-yl)ethanone (6.27 g, 30.2 mmol) in dichloromethane (100 mL) was added a suspension of 3-chloroperoxybenzoic acid (20.9 g, 90.8 mmol, 75% purity) in dichloromethane (50 mL) at 10 °C. After the addition, the resulting mixture was stirred for 1 hour whilst allowing the temperature to rise slowly to room temperature. The mixture was washed with a saturated aqueous solution of sodium carbonate (100 mL x 2), a saturated aqueous solution of sodium sulfite (100 mL x 2) and brine (100 mL). The organic layer was dried over sodium sulfate, filtered and concentrated in vacuo. The residue was stirred in diethyl ether (50 mL) and the solid was collected by filtration and dried in vacuo to afford 6 g of l-(l,l-dioxido-2,3-dihydro-l,4-benzothiazepin-4(5H)-yl)ethanone as a white powder.
Intermediate 5
2,3,4,5-Tetrahydro- 1 ,4-benzothiazepine 1 , 1-dioxide
Figure imgf000139_0003
To a solution of l-( 1 , 1 -dioxido-2,3-dihydro-l ,4-benzothiazepin-4(5H)-yl)ethanone (240 g, 1.0 mol) in ethanol (1.0 L) was added sodium hydroxide (200 g, 5.0 mol) and water (700 mL). The mixture was re fluxed overnight and then concentrated in vacuo. The residue was extracted by ethyl acetate (1500 mL x 4). The combined organic layers were extracted by hydrochloric acid (2000 mL, 3 N). The acidic aqueous layer was washed with ethyl acetate (1500 mL x 2), then basified with a saturated aqueous solution of sodium bicarbonate to pH > 7, and extracted with ethyl acetate (1500 mL x 4). The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo to afford 151 g of 2,3,4, 5-tetrahydro-l ,4-benzothiazepine 1 , 1- dioxide (yield was 76%), MS obsd. (ESI+) [(M+H)+] 198, 1H NMR (400 MHz, DMSO-d6) δ ppm 7.89 (dd, J= 1.2, 7.6 Hz, 1 H), 7.56 (t, J= 7.6 Hz, 1 H), 7.47 (t, J= 7.6 Hz, 1 H), 7.42 (d, J = 7.6 Hz, 1 H), 4.04 (s, 2 H), 3.32 - 3.30 (m, 2 H), 3.30 - 3.25 (m, 2 H), 2.64 (s, 1 H).
Intermediate 6
2,3,4,5-Tetrahydro-l,4-benzothiazepine
Figure imgf000140_0001
l-(l-Oxido-2,3-dihydro-l,4-benzothiazepin-4(5H)-yl)ethanone
Figure imgf000140_0002
To a cooled solution of 1 -(2, 3-dihydro-l,4-benzothiazepin-4(5H)-yl)ethanone (70 g, 0.33 mol) in dichloromethane (700 mL) was added a solution of 3-chloroperoxybenzoic acid (67 g, 0.33 mol) in dichloromethane (800 mL) dropwise at 0 °C. After the addition, the reaction was stirred at the same temperature for 15 minutes. The resulting reaction mixture was washed with a saturated aqueous solution of sodium carbonate (500 mL x 2) and a saturated aqueous solution of sodium sulfite (500 mL x 2). The combined aqueous layers were extracted with dichloromethane (200 mL x 2), dried over sodium sulfate and concentrated in vacuo. The residue was purified by flash chromatography (eluting with 1~2% methanol in dichloromethane) to afford 57 g of the desired product (yield was 77%). 2,3,4,5-Tetrahydro-l,4-benzothiazepine 1-oxide
Figure imgf000141_0001
Intermediate 6 was prepared in analogy to intermediate 5 by using l-(l-oxido-2,3-dihydro-l ,4- benzothiazepin-4(5H)-yl)ethanone (yield was 66%), MS obsd. (ESI+) [(M+H)+] 181, 1H NMR (400 MHz, CD3OD) δ ppm 7.72 (dd, J = 1.6, 7.6 Hz, 1 H), 7.52 - 7.48 (m, 2 H), 7.33 (dd, J = 1.6, 7.2 Hz, 1 H), 4.21 - 4.1 l(m, 1 H), 3.82 - 3.80 (m, 1 H), 3.62 - 3.50 (m, 2 H), 3.22 - 3.19 (m, 2 H).
Intermediate 7
^Z -TV-Methoxy-ljl^^-tetrahydro-SH-l-benzazepin-S-imine
Figure imgf000141_0002
A mixture of l ,2,3,4-tetrahydro-l-benzazepin-5-one (500 mg, 2.530 mmol), O-methyl hydro xylamine hydrochloride (21 1 mg, 2.530 mmol), sodium acetate (208 mg, 2.530 mmol) and sodium carbonate (536 mg, 5.060 mmol) in ethanol was refluxed for 3 hours. The resulting mixture was concentrated in vacuo to remove ethanol and to the residue was added water (15 mL). The residue in water was extracted with dichloromethane (15 mL x 3). The organic layers were combined, dried over sodium sulfate, and concentrated in vacuo to afford 326 mg of the desired product (yield was 67%).
Intermediate 8
5,5-Difluoro-2,3,4,5-tetrahydro-lH-benzazepine
Figure imgf000141_0003
l-(5,5-Difluoro-l,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)-2,2,2-trifluoroethanone
Figure imgf000142_0001
To a cooled solution of l,2,3,4-tetrahydro-l-benzazepin-5-one hydrochloride (33.7 g, 0.17 mol) in dichloromethane (500 mL) at 0 °C, was added triethylamine (52 g, 0.51 mol) dropwise followed by trifluoro acetic anhydride (36 g, 0.17 mmol). After being stirred at room temperature for 3 hours, the resulting mixture was diluted with water (300 mL). The aqueous layer was extracted with dichloromethane (500 mL). The combined organic layers were washed with a saturated aqueous solution of sodium bicarbonate (500 mL) and brine (500 mL), dried over sodium sulfate and concentrated in vacuo. The residue was purified by flash chromatography (eluting with 16% ethyl acetate in petroleum ether) to afford 40 g of the desired product (yield was 89%). l-(5,5-Difluoro-l,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)-2,2,2-trifluoroethanone
Figure imgf000142_0002
A solution of 2-(trifluoroacetyl)-l,2,3,4-tetrahydro-5H-2-benzazepin-5-one (40 g, 0.156 mol) in N,N-diethylaminosuflur trifluoride (104 g, 0.468 mol) was heated at 70 °C for 3 hours. The reaction mixture was poured into ice-water (600 mL) and extracted with dichloromethane (800 mL). The organic layer was washed with a saturated aqueous solution of sodium bicarbonate (500 mL) and brine (500 mL), dried over sodium sulfate, and concentrated in vacuo. The residue was purified by flash chromatography (eluting with 16% ethyl acetate in petroleum ether) to give 33 g of the desired product (yield was 76%). 5,5-Difluoro-2,3,4,5-tetrahydro-lH-benzazepine
Figure imgf000142_0003
To a cooled solution of l-(5,5-difluoro-l,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)-2,2,2- trifluoroethanone (33 g, 0.184 mmol) in methanol was added an ammonia methanol solution (300 mL, 7 M) at 0 °C. After being stirred at 0 °C for 2 hours, the reaction mixture was concentrated in vacuo. The residue was purified by flash chromatography (eluting with 10-25% ethyl acetate in petroleum ether) to afford 18 g of the desired product as a purple oil (yield was 83.3%), MS obsd. (ESI+) [(M+H)+] 184, 1H NMR (400 MHz, CDC13) δ ppm 7.64 - 7.60 (m, 1 H), 7.34 - 7.25 (m, 2 H), 7.16 -7.14 (m, 1 H),7.01 (s, 2 H), 3.33 - 3.30 (m, 2 H), 2.33 - 2.24 (m, 2 H).
Intermediate 9-1 3-(Aminomethyl)- V, V-dibenzyltetrahydrofuran-3-amine
Figure imgf000143_0001
3-(Dibenzylamino)tetrahydrofuran-3-carbonitrile
Figure imgf000143_0002
To a cooled solution of dibenzylamine (31.9 g, 162 mmol) in acetic acid (100 mL) at 0 °C, dihydrofuran-3(2H)-one (7.0 g, 81 mmol) was added followed by trimethylsilyl-formonitrile (14.4 g, 145.8 mmol). After being stirred at room temperature for 16 hours, the reaction mixture was poured into water (100 mL), adjusted to pH 7 with sodium bicarbonate, exacted with ethyl acetate (100 mL x 2). The combined organic layers were washed with brine (150 mL), dried over sodium sulfate and concentrated in vacuo. The residue was purified by column chromatography to afford 2.2 g of the desired product (yield was 9.28%>).
3-(Aminomethyl)- V, V-dibenzyltetrahydrofuran-3-amine
Figure imgf000143_0003
To a cooled solution of 3-(dibenzylamino)tetrahydrofuran-3-carbonitrile (2.2 g, 7.5 mmol) in tetrahydrofuran (50 mL) at 0 °C, was added lithium aluminium hydride (855 mg, 22.5 mmol). Λ * +Vi^ mi'vt,,rp ^in rr ctirred for 16 hours at room temperature, the reaction was quenched by addition of water (5 mL). The resulting mixture was filtered and the filtrate was concentrated in vacuo to afford 1.3 g of the crude product (yield was 58%).
Intermediate 9-2
3-(Aminomethyl)- V, V-dibenzyloxetan-3-amine
Figure imgf000144_0001
Intermediate 9-2 can be prepared in analogy to intermediate 9-1 by using oxetan-3-one. MS obsd. (ESI+) [(M+H)+] 283.
Intermediate 9-3 l-(Aminomethyl)- V, V-dibenzylcyclobutanamine
Figure imgf000144_0002
Intermediate 9-3 can be prepared in analogy to intermediate 9-1 by using cyclobutanone. MS obsd. (ESI+) [(M+H)+] 281.
Intermediate 9-4 3-(Aminomethyl)- V, V-dibenzylthietan-3-amine
Figure imgf000144_0003
3,3-Dimethoxythietane
Figure imgf000144_0004
To a solution of l,3-dibromo-2,2-dimethoxy-propane (102 g, 389 mmol) in N,N- dimethylformamide (1200 mL) was added sodium sulfide (66.8 g, 506 mmol), the mixture was refluxed for 3 days. The mixture was cooled to room temperature, diluted with diethyl ether (1200 mL), washed with water (1200 mL) and brine (1200 mL), dried over sodium sulphate and concentrated in vacuo to afford 40 g of the product as a yellowish oil (yield was 77%).
Thietan-3-one
Figure imgf000145_0001
To a solution of 3,3-dimethoxythietane (40 g, 600 mmol) in dichloromethane (2500 mL) was added dioxosilane (160 g). The mixture was refluxed for 2 days. The mixture was cooled to room temperature and filtered through a pad of celite. The filtrate was concentrated in vacuo to afford the desired product.
3-(Aminomethyl)- V, V-dibenzylthietan-3-amine
Figure imgf000145_0002
Intermediate 9-4 can be prepared in analogy to intermediate 9-1 by using thietan-3-one. MS obsd. (ESI+) [(M+H)+] 299, 1H NMR (400 MHz, CD3OD) δ ppm 7.21 - 7.14 (m, 8 H), 7.11 7.08 (m, 2 H), 3.74 (s, 4 H), 3.48 - 3.45 (m, 2 H), 3.26 (s, 2 H), 2.66 - 2.64 (m, 2 H), 1.49 (s H).
Intermediate 9-5 l-(Aminomethyl)- V, V-dibenzylcyclohexanamine
Figure imgf000145_0003
Intermediate 9-5 can be prepared in analogy to intermediate 9-1 by using cyclohexanone. MS obsd. (ESI+) [(M+H)+] 309.
Intermediate 9-6 (4-Aminomethyl-tetrahydropyran-4-yl)-dibenzyl-amine
Figure imgf000146_0001
Intermediate 9-6 can be prepared in analogy to intermediate 9-1 by using tetrahydropyran-4-one. MS obsd. (ESI+) [(M+H)+] 311.
Intermediate 10 V-[(3-Aminooxetan-3-yl)methyl]-2,2,2-trifluoroacetamide
Figure imgf000146_0002
V-{[3-(Dibenzylamino)oxetan-3-yl]methyl}-2,2,2-trifluoroacetamide
Figure imgf000146_0003
To a solution of 3-(aminomethyl)-N,N-dibenzyloxetan-3-amine (3.0 g, 10.6 mmol) in
dichloromethane (30 mL) in an ice bath was added drop wise trifluro acetic anhydride (2.5 g, 11.7 mmol). After the mixture being stirred at room temperature overnight, the reaction was quenched by addition of a saturated aqueous solution of sodium bicarbonate at 0 °C. The resulting mixture was extracted with dichloromethane, dried over sodium sulfate and concentrated in vacuo to afford 4.0 g of the crude product as yellow oil. V-[(3-Aminooxetan-3-yl)methyl]-2,2,2-trifluoroacetamide
Figure imgf000147_0001
To a solution of N-{[3-(dibenzylamino)oxetan-3-yl]methyl}-2,2,2-trifluoroacetamide (4.0 g, 10.57 mmol) in methanol (80 mL) was added 20% palladium hydroxide on carbon (0.8 g) and trifluoro acetic acid (one drop). The mixture was stirred at room temperature under hydrogen overnight and then filtered. The filtrate was concentrated in vacuo to afford the crude product as a white solid.
Intermediate 11 terf-Butyl [(3-aminooxetan-3-yl)methyl] carbamate
Figure imgf000147_0002
terf-Butyl {[3-(dibenzylamino)oxetan-3-yl] methyl} carbamate
Figure imgf000147_0003
To a solution of 3-(aminomethyl)-N,N-dibenzyloxetan-3-amine (10. Og, 35.41 mmol) in tetrahydroiuran (100 mL) was added an aqueous solution of sodium bicarbonate (8.6 g, 102.4 mmol dissolved in 50 mL of water) and a solution of di-tert-butyl dicarbonate (8.9 g, 51.08 mmol) in tetrahydroiuran (30 mL). The mixture was stirred at room temperature overnight, concentrated in vacuo to remove most of the organic solvent, and the aqueous residue was extracted with dichloromethane (100 mL x 3). The organic layers were combined, washed with brine (150 mL), dried over sodium sulfate and concentrated in vacuo to afford 13.0 g of the crude product, which was used for the next step without any purification. terf-Butyl [(3-aminooxetan-3-yl)methyl] carbamate
Figure imgf000147_0004
A mixture of tert-butyl {[3-(dibenzylamino)oxetan-3-yl]methyl}carbamate (13.0 g, crude), 20% palladium hydroxide on carbon (2.0 g) and trifluoro acetic acid (0.5 mL) in methanol (20 mL) was stirred overnight under hydrogen atmosphere (1 bar). After being basified with ammonia solution in methanol, the resulting mixture was filtered and concentrated in vacuo to afford 5.8 g of the crude product, which was used for the next step without any purification.
Intermediate 12 tert-Buty\ [l-(2-aminoethyl)-cyclopropyl] carbamate
Figure imgf000148_0001
izyloxy)propanenitrile
Figure imgf000148_0002
To a mixture of benzyl alcohol (108 g, 1 mol) and 40% aqueous solution of sodium hydroxide (10 mL) was added prop-2-enenitrile (58.3 g, 1.1 mol) and the mixture was stirred for 6 hours at room temperature. The mixture was neutralized with 1 N hydrochloric acid, and extracted with dichloromethane (300 mL). The organic layer was washed with 5% solution of sodium hydroxide (300 mL) and brine (300 mL), dried over sodium sulfate and concentrated in vacuo to afford 150 g of the desired compound (yield was 93%>). l-[2-(benzyloxy)ethyl]cyclopropanamine
Figure imgf000148_0003
To a solution of 3-(benzyloxy)propanenitrile (16.9 g 105 mmol) in diethyl ether (400 mL) were added titanium isopropoxide (35.7 mL, 115 mmol) and ethyl magnesium bromide (210 mL, 1 M in diethyl ether) successively at room temperature. After being stirred for 0.5 hour, boron trifluoride etherate (27 mL, 525 mmol) was added. After stirring for another 0.5 hour, 10% aqueous solution of sodium hydroxide (ca. 5.5 mL) was introduced to the above mixture. The resulting mixture was acidified with IN hydrochloric acid to pH 3, and then washed with dichloromethane. The aqueous layer was basified with 5% aqueous solution of sodium hydroxide to pH 8~9 and extracted with dichloromethane (100 mL). The organic layer was washed with brine (100 mL), dried over sodium sulfate and concentrated in vacuo to afford 11 g of l-[2- (benzyloxy)ethyl]cyclopropanamine (yield was 55%). 2-(l-Aminocyclopropyl)ethanol hydrochloride
Figure imgf000149_0001
To a mixture of l-[2-(benzyloxy)ethyl]cyclopropanamine (13.2 g, 69 mmol), 10% palladium on carbon (3.0 g) and propan-2-ol (100 mL) was added a solution of hydrochloride in propan-2-ol (100 mL, 5-6 N). The mixture was shaken at 40 °C under hydrogen pressure of 4 atmospheres until hydrogen uptake ceased. The catalyst was removed by filtration and washed with propan-2- ol. The filtrate was concentrated in vacuo to afford 8.8 g of the salt as a viscous oil (yield was 84.6%). terf-Butyl [l-(2-hydroxyethyl)cyclopropyl] carbamate
Figure imgf000149_0002
To a solution of 2-(l-amino-cyclopropyl)-ethanol hydrochloride (1 : 1) (8.8 g, 64.4 mmol) in tetrahydrofuran (63 mL) was added water (1.5 mL), triethylamine (18.3 mL, 130 mmol) and a solution of di-tert-butyl dicarbonate (15.46 g, 70.9 mmol) in tetrahydrofuran (21 mL). The resulting mixture was stirred at room temperature for 16 hours. The mixture was concentrated in vacuo and the residue was dissolved in diethyl ether (100 mL). The organic solution was washed with an aqueous hydrochloric acid solution (0.1 N, 50 mL) and brine (50 mL), dried over sodium sulfate and concentrated in vacuo. The residue was triturated in water and filtered to afford 9.3 g of the pure product as a white solid (yield was 71%).
2-{l-[(terf-Butoxycarbonyl)amino]-cyclopropyl}ethyl methanesulfonate
Figure imgf000149_0003
To a cooled solution of tert-butyl [l-(2-hydroxyethyl)cyclopropyl] carbamate (8.0 g, 0.04 mol) and triethylamine (12.14 g) in anhydrous tetrahydrofuran (120 mL) at -20 °C was added a solution of mesyl chloride (17.8 g) in anhydrous tetrahydrofuran (30 mL). The resulting mixture was allowed to warm to room temperature and stirred at this temperature for 2 hours. The resulting mixture was poured into ice-water (50 mL) and the separated organic layer was washed with brine (100 mL), dried over sodium sulfate and concentrated in vacuo. The residue was triturated with petroleum ether and filtered to give 9.5 g of the pure product as an orange solid (yield was 95%). tert-Buty\ l-[2-(l,3-dioxo-l,3-dihydro-2H-isoindol-2-yl) ethyl] cyclopropylcarbamate
Figure imgf000150_0001
To a solution of 2-{l-[(tert-butoxycarbonyl)amino]-cyclopropyl}ethyl methanesulfonate (9.5 g, 344.3 mmol) in anhydrous N,N-dimethylformamide (20 ml) was added potassium 2,3-dihydro- lH-isoindole-l,3-dione (7.0 g, 37 mmol). After being stirred at 150 °C for 18 hours, the resulting mixture was then filtered and washed with diethyl ether (50 mL). The filtrate was washed with brine (50 mL x 3), dried over sodium sulfate and concentrated in vacuo. The residue was heated with stirring in water and the precipitate was collected by filtration and dried in vacuo to afford 6.0 g of the pure product as an orange solid (yield was 53%). tert-Buty\ [l-(2-aminoethyl)-cyclopropyl] carbamate
Figure imgf000150_0002
To a solution of tert-butyl l-[2-(l,3-dioxo-l,3-dihydro-2H-isoindol-2-yl)ethyl]
cyclopropylcarbamate (3.3 g, 2.4 mmol) in ethanol (100 mL) was added hydrazine hydrate (5 mL) and the resulting mixture was heated under reflux for 16 hours. The mixture was filtered and washed with diethyl ether. The filtrate was concentrated in vacuo to afford 1.5 g of the pure compound as an orange oil (yield was 75%>).
Intermediate 13 tert- utyl [2-(l-aminocyclopropyl)ethyl] carbamate
Figure imgf000151_0001
Methyl 1-aminocyclopropanecarboxylate
Figure imgf000151_0002
To a solution of 1-aminocyclopropanecarboxylic acid (1.0 g, 9.9 mmol) in methanol (30 mL) was added thionyl chloride (3.5 g, 29.7 mmol) at 0 °C. The mixture was heated under reflux for 2 hours and then concentrated in vacuo to afford 1.1 g of the crude product (yield was 100%).
Methyl l-[(terf-butoxycarbonyl)amino]cyclopropanecarboxylate
Figure imgf000151_0003
To a cooled mixture of methyl 1-aminocyclopropanecarboxylate (1.1 g, 9.6 mmol) and an aqueous solution of potassium bicarbonate (2.88 g, 28.8 mmol dissolved in 10 mL of water) in ethyl acetate (30 mL) was added a solution of di-tert-butyl dicarbonate (4.15 g, 19.2 mmol) in ethyl acetate (10 mL) at 0 °C. The reaction mixture was allowed to warm to room temperature and stirred at this temperature overnight. The separated aqueous layer was extracted with ethyl acetate (20 mL). The combined organic layers were dried over sodium sulfate and concentrated in vauco to afford 2.0 g of the product (yield was 97%). tert-Butyl [l-(hydroxymethyl)cyclopropyl] carbamate
Figure imgf000151_0004
To a cooled solution of methyl l-[(tert-butoxycarbonyl)amino]cyclopropanecarboxylate (1.2 g, 5.6 mmol) in tetrahydrofuran (10 mL) at 0 °C was added drop wise a solution of lithium borohydride (244 mg, 11.2 mmol) in tetrahydrofuran (10 mL) The reaction mixture was allowed to warm to room temperature and stirred at this temperature overnight. The reaction was quenched by addition of water (10 mL) and the resulting mixture was extracted with
dichloromethane. The organic layer was dried over sodium sulfate and concentrated in vacuo to afford 0.8 g of the product (yield was 76.2%). terf-Butyl [l-(azidomethyl)cyclopropyl] carbamate
Figure imgf000152_0001
To a solution of tert-butyl [1 -(hydro xymethyl)cyclopropyl] carbamate (1 g, 5.3 mmol) in N,N- dimethylformamide (20 mL) was added l,8-diazabicyclo[5.4.0]undec-7-ene (1.22 g, 8.0 mmol) and diphenylphosphoryl azide (2.33 g, 8.00 mmol). After the mixture was stirred at 80 °C for 3 hours, another batch of l,8-diazabicyclo[5.4.0]undec-7-ene (1.22 g, 8.0 mmol) and
diphenylphosphoryl azide (2.33 g, 8.00 mmol) was introduced and the mixture was stirred at 80 °C for another 2 hours. The resulting mixture was then diluted with water (20 mL) and extracted with ethyl acetate (30 mL x 2). The combined organic layers were used for next step directly. terf-Butyl [l-(aminomethyl)cyclopropyl] carbamate
Figure imgf000152_0002
A solution of tert-butyl [l-(azidomethyl)cyclopropyl]carbamate (60 mL, obtained from the above step) was hydrogenated in the presence of 10% palladium on carbon (60 mg) at room temperature overnight under hydrogen atmosphere with hydrogen balloon. The reaction was filtered and concentrated in vacuo to afford 40 mg of the crude product (yield was 40%>).
Intermediate 14
(l,l-Dioxidothietane-3,3-diyl)dimethanamine
Figure imgf000152_0003
3,3-Bis(azidomethyl)thietane
Figure imgf000153_0001
To a mixture of 3,3-bis(bromomethyl)thietane (15.0 g, 0.058 mol) and tetrabutylazanium bromide (0.93 g, 5%) in water (30 mL) was added sodium azide (9.0 g, 0.138 mol). The mixture was stirred at 70 °C overnight, then diluted with water (20 mL) and extracted with
dichloromethane (50 mL x 3). The combined organic layers were dried over sodium sulfate and concentrated in vacuo to remove most of dichloromethane. The residual solution (in 24 mL of dichloromethane) was used for the next step.
3,3-Bis-azidomethyl-thietane 1,1-dioxide
Figure imgf000153_0002
To a solution of 3,3-bis(azidomethyl)thietane (2.5 g, 13.59 mmol) in the mixture of formic acid (5 mL) and dichloromethane (6 mL) was added hydrogen peroxide (9.2 g, 81.54 mmol) slowly at 0 °C. After being warmed slowly to room temperature and stirred at room temperature overnight, the mixture was diluted with water (10 mL) and extracted with dichloromethane (15 mL x 3). The combined organic layers were dried over sodium sulfate and concentrated in vacuo. The residue was purified by flash column chromatography to afford 2.8 g of the desired product as a white solid (yield of two steps was 96%).
(l,l-Dioxidothietane-3,3-diyl)dimethanamine
Figure imgf000153_0003
A solution of 3,3-bis-azidomethyl-thietane 1,1-dioxide (1.0 g, 4.63 mmol) in methanol (10 mL) was stirred in the presence of 10% palladium on carbon (0.2 g) under hydrogen atmosphere overnight. The resulting reaction mixture was filtered and the filtrate was concentrated in vacuo to afford 720 mg of the desired product.
Intermediate 15
Thietane-3.3-divldimethanamine
Figure imgf000154_0001
A solution of 3,3-bis(azidomethyl)thietane (2.5 g, 13.59 mmol) in dichloromethane (6 mL) and methanol (50 mL) was stirred in the presence of 10% palladium on carbon (0.8 g) under 25 psi of hydrogen overnight. The resulting mixture was filtered and concentrated in vacuo to afford 1.8 g of the desired product.
Intermediate 16
(3,3-Difluorocyclobutane-l,l-diyl)dimethanamine
Figure imgf000154_0002
Dipropan-2-yl 3,3-dimethoxycyclobutane-l,l-dicarboxylate
Figure imgf000154_0003
To a stirred suspension of sodium hydride (96.5 g, 2.413 mol, 60%> in mineral oil) in dry N,N- dimethylformamide (900 ml) was added l,3-bis(propan-2-yl) propanedioate (363.3 g, 1.930 mo dropwise under nitrogen at a rate such that the temperature was maintained below 70 °C. On cessation of hydrogen evolution, the mixture was heated to 130 °C, to 3-dibromo-2,2- dimethoxypropane (252.8 g, 0.965 mol) was then introduced in one portion. The mixture was heated under reflux for 48 hours. The cooled mixture was poured into a saturated aqueous solution of ammonium chloride (300 mL) and extracted with methyl tert-butyl ether (300 mL). The organic layer was washed with a saturated aqueous solution of sodium bicarbonate and brine, dried over sodium sulfate, and concentrated in vacuo. The residue was distilled in vacuo
(oil pump) to afford 52.7 g of dipropan-2-yl 3,3-dimethoxycyclobutane-l,l-dicarboxylate as a colorless oil (yield was 58.2%). 1H NMR (400 MHz, CDC13) δ ppm 5.02 (mJ= 6.4 Hz, 2 H), 3.12 (s, 6 H), 2.66 (s, 4 H), 1.11 (d, J= 6.4 Hz, 12 H).
Di ropan-2-yl 3-oxocyclobutane- 1 , 1-dicarboxylate
Figure imgf000155_0001
A solution of dipropan-2-yl 3,3-dimethoxycyclobutane-l,l-dicarboxylate (10.0 g, 34.6 mmol) in hydrochloric acid (3 N, 55 mL) was heated at 50 °C for 4 hours. The resulting mixture was neutralized with a saturated aqueous solution of sodium bicarbonate and extracted with ethyl acetate (100 mL). The combined organic layers were dried over sodium sulfate and concentrated in vacuo to afford 6.073 g of dipropan-2-yl 3-oxocyclo butane- 1,1-dicarboxylate as a light brown oil (yield was 72.3%).
Dipropan-2-yl 3,3-difluorocyclobutane-l,l-dicarboxylate
Figure imgf000155_0002
To a cooled solution of dipropan-2-yl 3-oxocyclobutane- 1,1-dicarboxylate (5.657 g, 23.3 mmol) in dichloromethane (50 ml) at -78 °C, was added dropwise a solution of N,N-diethylaminosuflur trifluoride (9.25 ml, 70.05 mmol) in dichloromethane (25 ml) under nitrogen. After the addition, the mixture was allowed to warm up to room temperature and stirred for 24 hours. The mixture was diluted with dichloromethane (50 mL), and washed with 2 N aqueous solution of sodium hydroxide (50 mL) and brine (50 mL). The organic layer was dried over sodium sulfate, and concentrated in vacuo to afford dipropan-2-yl 3,3-difluorocyclobutane-l,l-dicarboxylate as a yellow oil (yield was 68.8%).
3,3-Difluorocyclobutane-l,l-dicarboxylic acid
Figure imgf000155_0003
A mixture of 3,3-difluoro-cyclobutane-l,l-dicarboxylic acid diisopropyl ester (5.00 g, 18.9 mmol) and sodium hydroxide (3.00 g, 75.7 mmol) in methanol (20 ml) was stirred at room temperature overnight. The formed off-white solid was collected by filtration, washed with ethyl „„ j A.' ~ .·.. water aqueous solution was acidified with hydrochloric acid (3 N) to H 3 - 4. The mixture was concentrated in vacuo to afford 6.293 g of the crude 3,3- difluorocyclo butane- 1,1-dicarboxylic acid as a white solid, which was used for next step without further purification.
3,3-Difluorocyclobutane-l,l-dicarboxamide
Figure imgf000156_0001
A solution of crude 3,3-difluorocyclobutane-l,l-dicarboxylic acid (6.293 g) in thionyl chloride (50 mL) was heated under reflux for 2 hours. Then the solution was concentrated in vacuo to remove thionyl chloride. To the residue was added dropwise ice-cold ammonium hydroxide (10 mL) and stirred for 0.5 hour. The formed off-white precipitate was collected by filtration. The filtrate was extracted with tetrahydrofuran (three times). The combined organic layers were dried over magnesium sulfate and concentrated in vacuo. The solids were combined to afford 1.858 g of 3,3-difluorocyclobutane-l,l-dicarboxamide as an off-white solid (yield of three steps was 55.2%).
(3,3-Difluorocyclobutane-l,l-diyl)dimethanamine
Figure imgf000156_0002
To a cooled solution of 3,3-difluorocyclobutane-l,l-dicarboxamide (1.858 g, 10.4 mmol) in tetrahydrofuran (25 mL) at -10 °C, was added slowly lithium aluminium hydride (2.375 g, 62.58 mmol). The reaction was stirred at 0 °C for 4 hours and then heated under reflux for 30 hours. The mixture was cooled and quenched at 0 °C by addition of water (2.5 mL), 15% aqueous solution of sodium hydroxide (7.5 mL) and water (2.5 mL) successively. The resulting mixture was stirred at room temperature for 0.5 hour. The mixture was filtered and the filtrate was concentrated in vacuo to afford 1.137 g of the crude product of (3,3-difluorocyclobutane-l,l- diyl)dimethanamine as a colorless oil (yield was 72.8%).
Intermediate 17 3-(l,3-Dioxo-l,3-dihydro-2H-isoindol-2-yl)-4,4,4-trifluorobutanoyl chloride
Figure imgf000157_0001
3-(l,3-Dioxo-l,3-dihydro-2H-isoindol-2-yl)-4,4,4-trifluorobutanoic acid
Figure imgf000157_0002
A solution of phthalic ahydride (378 mg, 2.54 mmol) and 3-amino-4,4,4-trifluorobutanoic acid (200 mg, 1.27 mmol) in N,N-dimethylformamide (5 mL) was heated at 160 °C under microwave irradiation for 1 hour. The resulting mixture was cooled to room temperature, diluted with water, and extracted with ethyl acetate (30 mL x 2). The combined organic layers were washed with brine (50 mL), dried over sodium sulfate and concentrated in vacuo. The residue was purified by flash chromatograph on silica gel (eluting with 50% ethyl acetate in hexane) to afford 270 mg of the product of 3-(l,3-dioxo-l,3-dihydro-2H-isoindol-2-yl)-4,4,4-trifluorobutanoic acid (yield was 37%). MS obsd. (ESI+) [(M+H)+] 288.
3-(l,3-Dioxo-l,3-dihydro-2H-isoindol-2-yl)-4,4,4-trifluorobutanoyl chloride
Figure imgf000157_0003
To a solution of 3-(l,3-dioxo-l,3-dihydro-2H-isoindol-2-yl)-4,4,4-trifluorobutanoic acid (270 mg, 0.94 mmol) in dichloromethane (10 mL) was added oxalyl chloride (0.16 mL, 1.8 8 mmol), followed by N,N-dimethylformamide (1 drop). After the gas ceased to produce, the reaction mixture was stirred at room temperature for 2 hours. After the mixture was concentrated in vacuo, the residue was diluted with dichloromethane and concentrated in vacuo again to afford 280 mg of the product (yield was 90%>), which was used for next step without purification. Intermediate 18
2-Fluorobutane- 1 ,4-diamine
F l,4-Dibromo-2-fluorobutane
Figure imgf000158_0001
To a solution of l,4-dibromobutan-2-ol (6.0 g, 25.64 mmol) in dichloromethane (80 mL) was added N,N-diethylaminosuflur trifluoride (6.25 mg, 38.79 mmol). The reaction mixture was stirred at room temperature overnight. The mixture was diluted with ethyl acetate (15 mL), washed with water (15 mL) and brine (15 mL), dried over sodium sulfate, and concentrated in vacuo to afford 4.0 g of l,4-dibromo-2-fluoro-butane as a yellow oil.
2,2'-(2-Fluorobutane-l,4-diyl)bis(lH-isoindole-l,3(2H)-dione)
Figure imgf000158_0002
To a solution of l,4-dibromo-2-fluoro-butane (4.0 g, 17.09 mmol) in N,N-dimethylformamide (60 mL) was added potassium 2,3-dihydro-lH-isoindole-l,3-dione (9.5 g, 51.27 mmol). The reaction mixture was stirred at 100 °C overnight. The mixture was cooled to room temperature, diluted with ethyl acetate (60 mL), washed with water (60 mL), brine (60 mL), dried over sodium sulfate, and concentrated in vacuo to afford 4.5 g of 2,2'-(2-fluorobutane-l,4- diyl)bis(lH-isoindole-l,3(2H)-dione) as a white solid.
2-Fluorobutane- 1 ,4-diamine
Figure imgf000158_0003
A mixture of 2,2'-(2-fluorobutane-l,4-diyl)bis(lH-isoindole-l,3(2H)-dione) (1.0 g, 2.73 mmol) and hydrazine hydrate (0.68 g, 13.6 mmol) in ethanol (20 mL) was heated under reflux for 16 hours. The resulting mixture was cooled to room temperature and concentrated in vacuo to afford the crude product, which was used for the next step.
Intermediate 19 terf-Butyl (4S)-4-(aminomethyl)-2,2-dimethyl-l,3-oxazolidine-3-carboxylate
Figure imgf000159_0001
tert-Buty\ (4S)-4-[(benzylamino)methyl]-2,2-dimethyl-l,3-oxazolidine-3-carboxylate
Figure imgf000159_0002
A mixture of tert-butyl (45)-4-formyl-2,2-dimethyl-l,3-oxazolidine-3-carboxylate (1.0 g, 4.36 mmol), phenylmethanamine (491 mg, 4.58 mmol) and toluene (8 mL) was heated under reflux with stirring for 2 hours. The mixture was concentrated in vacuo. The residue was dissolved in 1,2-dichloroethane (10 mL), to which sodium £zs(acetyloxy)boranuidyl acetate (2.31 g, 10.91 mmol) was added. The mixture was stirred at room temperature for two days, then diluted with water (25 mL), extracted with dichloromethane (25 mL x 3). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by flash column chromatography to afford 849 mg of the product. tert-Butyl (4S)-4-(aminomethyl)-2,2-dimethyl-l,3-oxazolidine-3-carboxylate
Figure imgf000159_0003
A mixture of tert-butyl (45)-4-[(benzylamino)methyl]-2,2-dimethyl-l,3-oxazolidine-3- carboxylate (810 mg, 2.53 mmol), palladium hydroxide on carbon (81 mg) and methanol (20 mL) was stirred at room temperature under hydrogen atmosphere overnight. The catalyst was removed by filtration. The filtrate was concentrated in vacuo. The residue was purified by SPE (12 mL tube, 2 gram of DSC-SCX) to afford the pure product.
Intermediate 20 tert-Butyl 2-oxa-6-azaspiro[3.4]oct-8-ylcarbamate
Figure imgf000160_0001
6-Benzyl-8-nitro-2-oxa-6-aza-spiro [3.4] octane
Figure imgf000160_0002
To a solution of benzyl-methoxymethyl-trimethylsilanylmethyl-amine (3.0 g, 12.6 mmol) and 3- nitromethylene-oxetane (1.38 g, 12.0 mmol) in dichloromethane (60 mL) was added
trifluoro acetic acid (0.93 mL, 12.6 mmol) dropwise. The mixture was stirred at room
temperature for 2 hours, quenched with sodium carbonate, extracted with dichloromethane. The organic layer was dried over sodium sulfate, concentrated in vacuo. The residue was purified by column chromatography on silica gel to give 2 g of product as colorless oil. It was used for next step without further purification.
6-Benzyl-2-oxa-6-aza-spiro [3.4] oct-8-ylamine
Figure imgf000160_0003
The mixture of 6-benzyl-8-nitro-2-oxa-6-aza-spiro[3.4]octane (2 g, 8.1 mmol), iron powder (2.3 g, 40.5 mmol), ammonium chloride (4.3 g, 81 mmol), methanol (40 mL) and 8 mL of water was heated with stirring for 2 hours at 80 °C. The reaction mixture was filtered by a pad of celite. The filtrate was concentrated under reduced pressure, and the residue was used for next step without further purification. terf-Butyl (6-benzyl-2-oxa-6-azaspiro[3.4]oct-8-yl)carbamate
Figure imgf000160_0004
To a mixture of 6-benzyl-2-oxa-6-azaspiro[3.4]oct-8-ylamine (prepared above), sodium carbonate (1.46 g, 13.74 mmol), dichloromethane (20 mL) and water (20 mL) was added άι-tert- butyl dicarbonate (1.8 g, 8.24 mmol) at room temperature. The mixture was stirred at room temperature overnight. The separated organic layer was dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography on silica gel to give 1.5 g of product as colorless oil, which was used for next step without further purification. terf-Butyl 2-oxa-6-azaspiro[3.4]oct-8-ylcarbamate
Figure imgf000161_0001
To a solution of 6-benzyl-2-oxa-6-azaspiro[3.4]oct-8-ylamine (1.5 g, 4.71 mmol) in methanol (50 mL) was added palladium hydroxide (20% on carbon, 300 mg). After being stirred at room temperature for 4 hours under a hydrogen atmosphere, the resulting mixture was filtered. The filtrate was concentrated in vacuo to give 900 mg of the product as colorless oil, which was used for next step without further purification.
Intermediate 21 V-(3-Methylpyrrolidin-3-yl)-acetamide
Figure imgf000161_0002
V-(l-Benzyl-3-methylpyrrolidin-3-yl)-acetamide
Figure imgf000161_0003
To a solution of l-benzyl-3-methylpyrrolidin-3-ol (1.0 g, 5.2 mmol) in acetonitrile (10 mL) at 0 °C, was added concentrated sulfuric acid (10 mL) slowly. After being stirred for 16 hours at room temperature, the reaction mixture was poured into ice-water. After the reaction mixture was adjusted to pH 7 with a saturated aqueous solution of potassium carbonate, the resulting mixture was exacted with dichloromethane (200 mL x 3). The combined organic layers were dried over sodium sulfate, and concentrated in vauo. The residue was purified by preparative HPLC to afford 600 mg of the product (yield was 50%). N-(3-Methylpyrrolidin-3-yl)-acetamide
Figure imgf000162_0001
A mixture of N-(l-benzyl-3-methylpyrrolidin-3-yl)-acetamide (600 mg, 2.6 mmol), palladium on carbon (400 mg, 10%) and ethanol (20 mL) was stirred at 40 °C under 50 Psi of hydrogen for 16 hours. The resulting mixture was filtrated. The filtrate was concentrated in vacuo to give 200 mg of the desired product (yield was 54%), which was used for next step without any purification.
Intermediate 22
2-Fluoropropane-l,3-diamine
Figure imgf000162_0002
2-Fluoropropanediamide
Figure imgf000162_0003
To a solution of 1,3-diethyl 2-difluoropropanedioate (25 g, 140.4 mmol) in methanol (100 mL) under a nitrogen atmosphere was added a solution of ammonia in methanol (80 mL, 7 N, 560 mmol). The resulting mixture was stirred at room temperature overnight and then concentrated in vacuo. The residue was triturated in petroleum ether to afford 16.3 g of 2-fluoropropanediamide as a white solid (yield was 97%). MS obsd. (ESI+) [(M+H)+] 121.
2-Fluoropropane-l,3-diamine
Figure imgf000162_0004
To a solution of 2-fluoropropanediamide (16.3 g, 136 mmol) in tetrahydrofuran (200 mL) was added a solution of boran-tetrahydrofuran complex (800 mL, 800 mmol, 1 M) in
tetrahydrofuran. The reaction mixture was heated at 70 °C with stirring overnight, then cooled in an ice bath, stirred with methanol (100 mL) further for 30 minutes, and concentrated in vacuo. The residue was dissolved in methanol (100 mL) and the solution was concentrated in vacuo. To + 0 ^ Ο Λ Λ ^Λ «™ter (10 mL), potassium hydroxide was added with cooling until the aqueous solution was saturated. The mixture was extracted by diethyl ether (20 mL x 2), and the combined organic layers was dried over potassium hydroxide and concentrated in vacuo to afford 7.5 g of 2-fiuoropropane-l,3-diamine (yield was 60%). MS obsd. (ESI+) [(M+H)+] 93.
Intermediate 23 Benzyl 6-oxa-3-azabicyclo[3.1.0]hexane-3-carboxylate
Figure imgf000163_0001
To a solution of l-benzyloxycarbonyl-3-pyrroline (2.5 g) in dichloromethane (60 mL) was added 3-chloroperoxybenzoic acid (6.08 g, 50-60% purity). The reaction was stirred at room temperature for 72 hours, and then a saturated sodium thiosulfate solution (50 mL) was added. After being stirred for additional 30 minutes, the mixture was extracted with chloroform (50 mL x 2). The combined organic layers were washed successively with 2 N aqueous solution of sodium hydroxide (50 mL x 2) and brine (50 mL), dried over magnesium sulfate and
concentrated in vacuo to afford 2.79 g of the crude benzyl 6-oxa-3-azabicyclo[3.1.0]hexane-3- carboxylate as an oil. MS obsd. (ESI+) [(M+H)+] 220. irans-(±)-Benzyl-3-amino-4-hydroxypyrrolidine-l-carboxylate
Figure imgf000163_0002
A mixture of the crude benzyl 6-oxa-3-azabicyclo[3.1.0]hexane-3-carboxylate obtained in the above step (2.79 g) and 28% aqueous solution of ammonia (20 mL) was stirred at 40 °C for 2 days in a sealed tube, then 2 N aqueous solution of sodium hydroxide (25 mL) was introduced and the mixture was extracted with chloroform (25 mL x 3). The combined organic layers were dried over anhydrous magnesium sulfate and concentrated in vacuo to afford 2.67 g of the crude tra/75-benzyl-3-amino-4-hydroxypyrrolidine-l-carboxylate as oil. MS obsd. (ESI ) [(M+H)+]
237. irans-(±)-Benzyl-3-[(tei"i-butoxycarbonyl)amino]-4-hydroxypyrrolidine-l-carboxylate
Figure imgf000164_0001
To a cooled solution of tra/75-benzyl-3-amino-4-hydroxypyrrolidine-l-carboxylate (2.67 g) in chloroform (25 mL) was added dropwise a solution of di-tert-butyl dicarbonate (3.7 g) in chloroform (10 mL) in an ice-water bath, and the mixture was stirred at room temperature for 19 hours. The reaction mixture was washed with water and the organic layer was dried over anhydrous magnesium sulfate and concentrated in vacuo. The residue was purified by a column chromatography on silica gel to afford 2.7 g of trans-benzyl-3-[(tert-butoxycarbonyl)amino]-4- hydroxypyrrolidine-l-carboxylate as crystals. MS obsd. (ESI+) [(M+H)+] 337. trans-(±)-tert- utyl [4-hydroxypyrrolidin-3-yl] carbamate
Figure imgf000164_0002
To a solution of tra/75-3-tert-butoxycarbonylamino-4-hydroxy-pyrrolidine-l-carboxylic acid benzyl ester (3.9 g) in methanol (31 mL) and tetrahydrofuran (7 mL) was added palladium hydroxide (20 wt% Pd on carbon, 500 mg) and the mixture was stirred at room temperature under 40 - 45 psi of hydrogen atmosphere overnight. The resulting mixture was filtered and the filtrate was concentrated in vacuo. The residue was triturated in the mixture of ethyl acetate and diisopropylether and filtered to remove the insoluable materials. The filtrate was concentrated in vacuo to afford 2.0 g of trans-tert-bvXy\ [4-hydroxypyrrolidin-3-yl]carbamate (yield was 94%) as a powder. MS obsd. (ESI+) [(M+H)+] 203.
Intermediate 24 frans-(±)-Benzyl 3-amino-4-fluoroypyrrolidne-l-carobxylate
Figure imgf000164_0003
frans-(±)-Benzyl 3-azido-4-fluoroypyrrolidne-l-carobxylate
Figure imgf000165_0001
In a solution of benzyl-6-oxa-3-azabicyclo[3.1.0]hexane-3-carboxylate (2.5 g) in methanol (20 mL) was added water (5 mL), ammonium chloride (550 mg) and sodium azide (1.5 g). The resulting mixture was heated at 65 °C for 21 hours. The solids were removed by filtration and the filtrate was concentrated in vacuo. The residue was poured into 15% aqueous solution of sodium hydroxide (30 mL) and extracted with dichloromethane (50 mL). The organic layers were washed with brine, dried over magnesium sulfate and concentrated in vacuo to afford 2.7 g of trans-{±) benzyl-3-azido-4-hydroxypyrrolidne-l-carobxylate. MS obsd. (ESI+) [(M+H)+] 250. frans-(±)-Benzyl 3-azido-4-fluoroypyrrolidne-l-carobxylate
Figure imgf000165_0002
To a cooled solution of trans-(±) benzyl-3-azido-4-hydroxypyrrolidne-l-carobxylate (6.5 g) in dichloromethane (110 mL) was added diethylamino sulfur trifluoride (6.8 mL) at -78 °C. The mixture was stirred at room temperature for 16 hours, and then concentrated in vacuo. The residue was dissolved in ethyl acetate (100 mL), and the solution was washed with a saturated sodium bicarbonate (100 mL) and brine (100 mL), dried over magnesium sulfate and
concentrated in vacuo. The residue was purified by column chromatography on silica gel (eluting with 1% methanol in dichloromethane) to yield 5.7 g of trans-(±) benzyl-3-azido-4- fluoroypyrrolidne- 1 -carobxylate. frans-(±)-Benzyl 3-amino-4-fluoroypyrrolidne-l-carobxylate
Figure imgf000165_0003
To a solution of trans-{±) benzyl-3-azido-4-fluoroypyrrolidne-l -carobxylate (4.33 g) in tetrahydrofuran (100 mL) and water (10 mL) was added triphenylphospine (4.5 g). The reaction mixture was heated under reflux for 2 hours. The reaction mixture was concentrated in vacuo and the residue was dissolved in ethyl acetate (50 mL). The solution was extracted with 15% aqueous solution of citric acid (30 mL x 2) and the aqueous layers were combined, basified with a concentrated aqueous ammonium hydroxide to about pH 9, then extracted with ethyl acetate (50 mL x 2). The combined organic layers were washed with brine (50 mL), dried over magnesium sulfate and concentrated in vacuo to afford tra/?s-(±)-benzyl 3-amino-4- fluoroypyrrolidne-l-carobxylate.
Intermediate 25 trans-(±)-tert-Buty\ (4-fluoropyrrolidin-3-yl)carbamate
Figure imgf000166_0001
irans-(±)-l-Benzyl-3-[(tei"i-butoxycarbonyl)amino]-4-fluoropyrrolidine-l-carboxylate
Figure imgf000166_0002
To a cooled solution of tra/75-(±)-benzyl-3-amino-4-fluoroypyrrolidne-l-carobxylate (2.39 g) in chloroform (25 mL) was added dropwise a solution of di-tert-butyl dicarbonate (3.7 g) in chloroform (10 mL) in an ice- water bath. The mixture was stirred at room temperature for 19 hours. The reaction mixture was washed with water and the organic layer was dried over anhydrous magnesium sulfate and concentrated in vacuo. The residue was purified by a column chromatography on silica gel to afford 2.9 g of trans-(±)-l-bQ zyl-3-[(tert- butoxycarbonyl)amino]-4-fluoropyrrolidine-l-carboxylate (yield was 90%) as crystals. trans-(±)-tert- utyl (4-fluoropyrrolidin-3-yl) carbamate
Figure imgf000166_0003
To a solution of tra/75-(±)-l-benzyl-3-[(tert-butoxycarbonyl)amino]-4-fluoropyrrolidine-l- carboxylate (3.39 g) in methanol (31 mL) and tetrahydrofuran (7 mL) was added palladium hydroxide (20 wt% on carbon, 500 mg) and the mixture was stirred at room temperature under 40 - 45 psi of hydrogen atmosphere overnight. The resulting mixture was filtered and the filtrate was concentrated in vacuo. The residue was triturated in the mixture of ethyl acetate and diisopropylether and filtered to remove the insoluable materials. The filtrate was concentrated in vacuo to afford 1.5 g of trans-{±)-tert- vXy\ (4-fluoropyrrolidin-3-yl) carbamate (yield was 74%) as a powder.
Intermediate 26 terf-Butyl (4S)-4-ethenyl-2,2-dimethyl-l,3-oxazolidine-3-carboxylate
Figure imgf000167_0001
3-terf-Butyl 4-methyl (4R)-2,2-dimethyl-l,3-oxazolidine-3,4-dicarboxylate
Figure imgf000167_0002
A solution of methyl (2i?)-2-{[(tert-butoxy)carbonyl]amino}-3-hydroxypropanoate (22 g, 0.1 mol), 2,2-dimethoxypropane (20.8 g, 0.2 mol) and 4-methylbenzene-l -sulfonic acid (0.5 g) in toluene was heated with stirring at 110 °C overnight. The solvent was removed under reduced pressure. The residue was treated with ethyl acetate, washed with water and brine. The organic layer was dried over sodium sulfate, concentrated under reduced pressure. The residue distilled at 0.6 mbar to give 16.5 g of 3-tert-butyl 4-methyl (4i?)-2,2-dimethyl-l,3-oxazolidine-3,4- dicarboxylate (yield was 63.6 %) as an amber oil. terf-Butyl (4R)-4-formyl-2,2-dimethyl-l,3-oxazolidine-3-carboxylate
Figure imgf000167_0003
To a cooled solution of 3-tert-butyl 4-methyl (4i?)-2,2-dimethyl-l,3-oxazolidine-3,4- dicarboxylate (16.5 g, 63.6 mmol) in dry dichloromethane (300 mL) at -78 °C, was added a cooled solution of 1.0 M diisobutylaluminium hydride in hexane (127.6 mL, 127.2 mmol) under argon. The rate of addition was adjusted so as to keep the internal temperature below -65 °C and take about 1 hour to complete. The reaction mixture was stirred for an additional 2 hours at -78 °C under argon. The reaction was quenched by slowly adding 60 mL of cold methanol (-78 °C) so as to keep the internal temperature below -65 °C. The resulting mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, concentrated under reduced pressure. The residue was distilled at 0.7 mbar to give tert-butyl (4i?)-4-formyl- 2,2-dimethyl-l,3-oxazolidine-3-carboxylate (10 g, 68.5 %) as colorless liquid. tert-Butyl (4S)-4-ethenyl-2,2-dimethyl-l,3-oxazolidine-3-carboxylate
Figure imgf000168_0001
To a solution of methyltriphenylphosphonium bromide (3.1 g, 8.64 mmol) in dry tetrahydrofuran (30 mL) was add a solution of sodium bis(trimethylsilyl)amide in hexane (1.0 M, 8.64 mL, 8.64 mmol) under argon. After the reaction was stirred for further 20 minutes, a solution of (4R)-4- formyl-2,2-dimethyl-l,3-oxazolidine-3-carboxylate (1.8 g, 7.86 mmol) in dry tetrahydrofuran (20 mL) was added dropwise. The resulting mixture was stirred at room temperature overnight. The solvent was removed under reduced pressure. The residue was purified by flash column to give tert-butyl (45)-4-ethenyl-2,2-dimethyl-l,3-oxazolidine-3-carboxylate (1.5 g, 83.9%) as colorless liquid.
Intermediate 27
Pyridazine-3-carboxamide
Figure imgf000168_0002
To a cooled solution of pyridazine-3-carboxylic acid (1.0 g, 8.06 mmol) in tetrahydrofuran (40 mL) in a dry-ice bath was added 4-methyl-morpholine (0.9 g, 8.87 mmol) and isopropyl chloroformate (1.1 g, 8.87 mmol) slowly. The reaction was stirred at -30 °C for 6 hours, then an aqueous solution of ammonia (8 mL, 10%> W/W) was added. The resulting mixture was stirred at room temperature overnight, washed with a saturated aqueous solution of potassium bisulfate (50 mL). The aqueous layer was extracted with ethyl acetate (30 mL x 3). The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo to afford 202.5 mg of the desired product (yield was 20.4%). MS obsd. (ESI+) [(M+H)+] 124, 1H NMR (400 MHz, CD3OD) δ ppm 9.45 - 9.35 (t, J= 1.6 Hz, 1 H), 8.58 (s, 1 H), 8.23 - 8.15 (d, J= 7.6 Hz, 1 H), 7.98 - 7.88 (m, 2 H).
Intermediate 28
Oxetane-3,3-diyldimethanamine
H2N''"^X^~ "NH2
3,3-Bis-azidomethyl-oxetane
Figure imgf000169_0001
A mixture of 3,3-bis(bromomethyl)oxetane (25 g, 100 mmol) and sodium azide (14.3 g, 220 mmol) in water (65 ml) was added tetrabutylazanium bromide (1.61 g, 5 mmol). The reaction mixture was heated with stirring at 70 °C overnight. The reaction mixture was cooled to room temperature and extracted with dichloromethane (50 mL x 3). The combined organic layers were washed with water, dried over sodium sulphate and concentrated in vacuo to afford 18.7 g of 3,3- bis-azidomethyl-oxetane as a light yellow oil. The crude product was used for next step without further purification.
Oxetane-3,3-diyldimethanamine
Figure imgf000169_0002
A solution of 3,3-bis-azidomethyl-oxetane (18.7 g) in methanol (15 ml ) was stirred in the presence of 10% palladium on carbon (1.8 g ) under hydrogen atmosphere at room temperature for 5 hours. The reaction mixture was filtered and the filtrate was concentrated in vacuo to afford oxetane-3,3-diyldimethanamine (12 g) as a light yellow solid.
Intermediate 29
Oxetan-3-ylidene-acetonitrile
Figure imgf000170_0001
To a solution of oxetan-3-one (5 g, 69.4 mmol ) in dry dichloromethane (150 ml ) was added (triphenylphosphoranylidene)acetonitrile (20.9 g, 69.4 mmol) at room temperature. After being stirred for 6 hours, the mixture was concentrated in vacuo and the residue was filtered through a pad of silica gel (eluting with 30-50% diethyl ether in pentanes) to afford 5.2 g of oxetan-3- ylidene-acetonitrile as a white solid (yield was 79%).
3-(Benzylamino)oxetan-3-acetonitrile
Figure imgf000170_0002
A mixture of oxetan-3-ylidene-acetonitrile (950 mg, 10 mmol) and phenylmethanamine (1.31 ml, 12 mmol) was heated with stirring at 60 °C for 5 hours under nitrogen. The mixture was concentrated in vacuo. The residue was purified by flash column (eluting with 0-50%> ethyl acetate in hexane) to afford 1.65 g of 3-(benzylamino)oxetan-3-acetonitrile as a colorless oil (yield was 81.7%).
3-(Aminoethyl)- V-benzyloxetan-3-amine
Figure imgf000170_0003
To a cooled slurry of lithium aluminium hydride (327 mg, 8.6 mmol) in anhydrous diethyl ether (40 mL), was added a solution of 3-(benzylamino)oxetan-3-acetonitrile (1.0 g, 4.3 mmol) in anhydrous diethyl ether (10 mL) dropwise at 0 °C. After being stirred at 0 °C for 2 hours, the reaction was quenched by introducing disodium sulfate decahydrate slowly. After being stirred for 30 minutes, the mixture was filtered, and the filter cake was washed with ethyl acetate. The filtrate was dried over sodium sulfate and concentrated in vacuo. The residue was purified by flash column to afford 800 mg of 3-(aminoethyl)-N-benzyloxetan-3- amine as a light yellow oil (yield was 79%).
Intermediate 30
Figure imgf000171_0001
The intermediate was prepared in analogy to l-(l,l-dioxido-2,3-dihydro-l ,4-benzothiazepin- 4(5H)-yl)ethanone in Intermediate 4 by oxidation of 3-(aminomethyl)-N,N-dibenzylthietan-3- amine ( Intermediate 9-4) with 3-chloroperoxybenzoic acid. The following examples were prepared by the general methods outlined in the schemes above. They are intended to illustrate the meaning of the present invention but should by no means represent a limitation within the meaning of the present invention.
Example 1-1
TV- [(3- Aminooxetan-3-yl)methyl] -2-(8-methoxy- 1 , l-dioxido-2,3-dihydro- 1 ,4-benzothiazepin- 4(5H)-yl)-6-methylquinolin-4-amine
Figure imgf000171_0002
4-(4-Chloro-6-methylquinolin-2-yl)-8-methoxy-2,3,4,5-tetrahydro-l,4-benzothiazepine
Figure imgf000171_0003
A mixture of 8-methoxy-2,3,4,5-tetrahydro-l ,4-benzothiazepine (0.63 g, 3.2 mmol), 2,4- dichloro-6-methylquinoline (0.68 g, 3.2 mmol) and n-butanol (4 mL) was heated with stirring in a 5 mL of microwave process vial for 2.5 hours at 160 °C under microwave irradiation. The solvent was removed by concentration in vacuo. The residue was dissolved in a mixture solvent of ethanol and dichloromethane and then concentrated in vacuo to remove dichloromethane. The formed precipitate was collected by filtration, which was washed with diethyl ether and petroleum ether, dried in vacuo to afford 0.59 g of the product as a pale white solid (yield was 50%). MS obsd. (ESI+) [(M+H)+] 371. 4-(4-Chloro-6-methylquinolin-2-yl)-8-methoxy-2,3,4,5-tetrahydro-l,4-benzothiazepine 1,1- dioxide
Figure imgf000172_0001
A mixture of 4-(4-chloro-6-methylquinolin-2-yl)-8-methoxy-2,3,4,5-tetrahydro-l,4- benzothiazepine (0.40 g, 1.1 mmol) and sodium metaperiodate (0.71 g, 3.3 mmol) in methanol (15 mL) and water (6 mL) was stirred for 12 hours at room temperature. After removal of the solvent by concentration in vacuo, the residue was dissolved in methanol (15 mL). A solution of potassium permanganate (0.17 g, 1.1 mmol) in water (6 mL) was added dropwise to the above solution which was cooled to 0 °C. After being stirred for 2 hours at 0 °C, the mixture was extracted with ethyl acetate (10 mL). The organic layer was filtered through a short silica gel column. The filtrate was concentrated in vacuo to afford 0.40 g of the product as a white solid (yield was 90%). MS obsd. (ESI+) [(M+H)+] 403.
TV- { [3-(Dibenzylamino)oxetan-3-yl] methyl}-2-(8-methoxy- 1 , l-dioxido-2,3-dihydro- 1 ,4- benzothiazepin-4(5H)-yl)-6-methylquinolin-4-amine
Figure imgf000172_0002
A mixture of 4-(4-chloro-6-methylquinolin-2-yl)-8-methoxy-2,3,4,5-tetrahydro-l,4- benzothiazepine 1,1 -dioxide (50 mg, 0.13 mmol), cesium carbonate (80 mg, 0.26 mmol), palladium acetate (2.8 mg, 0.013 mmol), 9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene (11 mg, 0.019 mmol) and 3-(aminomethyl)-N,N-dibenzyloxetan-3-amine (54 mg, 0.19 mmol) in toluene (5 mL) was heated with stirring for 4 hours at 120 °C. After being cooled to room temperature, the mixture was concentrated in vacuo. The residue was purified by flash chromatography (eluting with 0.5% triethylamine and 5% methanol in dichloromethane) to afford 50 mg of the product as a white powder (yield was 59%). MS obsd. (ESI+) [(M+H)+] 649. N- [(3- Aminooxetan-3-yl)methyl] -2-(8-methoxy- 1 , l-dioxido-2,3-dihydro- 1 ,4-benzothiazepin- 4(5H)-yl)-6-methylquinolin-4-amine
Figure imgf000173_0001
A mixture of N-{[3-(dibenzylamino)oxetan-3-yl]methyl}-2-(8-methoxy-l,l-dioxido-2,3- dihydro-l,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-amine (50 mg, 0.077 mmol), 10% palladium hydroxide on carbon (100 mg) and trifluoro acetic acid (0.2 mL) in methanol (20 mL) was stirred for 12 hours at room temperature under hydrogen atmosphere (1 bar). The resulting mixture was basified with a saturated aqueous solution of sodium bicarbonate to pH >9 and then extracted with dichloro methane (20 mL x 2). The combined organic layers were dried over anhydrous sodium sulfate, and then concentrated in vacuo. The residue was purified by preparative HPLC to afford 10 mg of the product (yield was 28%). MS obsd. (ESI+) [(M+H)+] 469, 1H NMR (400 MHz, CD3OD) δ ppm 7.82 (d, J= 8.34 Hz, 2 H), 7.56 (brs, 2 H), 7.44 (brs, 1 H), 7.18 (d, J= 8.59 Hz, 1 H), 6.22 (s, 1 H), 5.27 - 5.13 (m, 2 H), 4.74 - 4.55 (m, 4 H), 4.50 (brs, 2 H), 3.86 (s, 3 H), 3.81 - 3.72 (m, 2 H), 3.71 - 3.60 (m, 2 H), 2.46 (s, 3 H). Example 1-2
TV- [(3- Aminooxetan-3-yl)methyl] -2-(8-fluoro- 1 , l-dioxido-2,3-dihydro- 1 ,4-benzothiazepin- 4(5H)-yl)-6-methylquinolin-4-amine
Figure imgf000173_0002
The title compound was prepared in analogy to Example 1-1 in Scheme 4 by using 2,4-dichloro-
6-methylquinoline, 8-fluoro-2,3,4,5-tetrahydro-l,4-benzothiazepine and 3-(aminomethyl)-7V,7V- dibenzyloxetan-3-amine. MS obsd. (ESI+) [(M+H)+] 457, 1H NMR (400 MHz, CD3OD) δ ppm 7.95 (dd, J= 8.46, 5.18 Hz, 1 H), 7.77 - 7.64 (m, 2 H), 7.47 (d, J= 8.34 Hz, 1 H), 7.43 - 7.25 (m, 2 H), 6.20 (s, 1 H), 5.19 (brs, 2 H), 4.68 - 4.57 (m, 6 H), 3.70 (s, 2 H), 3.67 - 3.56 (m, 2 H), 2.44 (s, 3 H).
Example 1-3
TV- [(3- Aminooxetan-3-yl)methyl] -2-(7-fluoro- 1 , l-dioxido-2,3-dihydro- 1 ,4-benzothiazepin- 4(5H)-yl)-6-methylquinolin-4-amine
Figure imgf000174_0001
The title compound was prepared in analogy to Example 1-1 in Scheme 4 by using 2,4-dichloro- 6-methylquinoline, 7-fluoro-2,3,4,5-tetrahydro-l,4-benzothiazepine and 3-(aminomethyl)-N,N- dibenzyloxetan-3-amine. MS obsd. (ESI+) [(M+H)+] 457, 1H NMR (400 MHz, CD3OD) δ ppm 8.02 (dd, J= 8.72, 5.43 Hz, 1 H), 7.79 - 7.65 (m, 2 H), 7.46 (d, J = 8.34 Hz, 1 H), 7.33 (d, J = 8.84 Hz, 1 H), 7.17 (td, J = 8.40, 2.65 Hz, 1 H), 6.17 (s, 1 H), 5.17 (brs, 2 H), 4.68 - 4.41 (m, 6 H), 3.72 - 3.64 (m, 2 H), 3.64 - 3.53 (m, 2 H), 2.44 (s, 3 H).
Example 1-4
TV- [(3- Aminooxetan-3-yl)methyl] -2-(9-fluoro- 1 , l-dioxido-2,3-dihydro- 1 ,4-benzothiazepin- 4(5H)-yl)-6-methylquinolin-4-amine
Figure imgf000174_0002
The title compound was prepared in analogy to Example 1-1 in Scheme 4 by using 2,4-dichloro- 6-methylquinoline, 9-fluoro-2,3,4,5-tetrahydro-l,4-benzothiazepine and 3-(aminomethyl)-7V,7V- dibenzyloxetan-3-amine. MS obsd. (ESI+) [(M+H)+] 457, 1H NMR (400 MHz, CD3OD) δ ppm 7.75 - 7.65 (m, 2 H), 7.60 (td, J = 7.96, 4.80 Hz, 1 H), 7.46 (d, J = 8.34 Hz, 1 H), 7.32 (dd, J = 8.59, 1.77 Hz, 1 H), 7.17 (dd, J= 10.36, 8.34 Hz, 1 H), 6.15 (s, 1 H), 5.20 (s, 2 H), 4.68 - 4.53 (m, 4 H), 4.45 (brs, 2 H), 3.86 - 3.73 (m, 2 H), 3.65 (s, 2 H), 2.43 (s, 3 H). Example 1-5
TV- [(3- Aminooxetan-3-yl)methyl] -2-(7-methoxy- 1 , l-dioxido-2,3-dihydro- 1 ,4-benzothiazepin- 4(5H)-yl)-6-methylquinolin-4-amine
Figure imgf000175_0001
The title compound was prepared in analogy to Example 1-1 in Scheme 4 by using 2,4-dichloro- 6-methylquinoline, 7-methoxy-2,3,4,5-tetrahydro-l,4-benzothiazepine and 3-(aminomethyl)- N,N-dibenzyloxetan-3-amine. MS obsd. (ESI+) [(M+H)+] 469, 1H NMR (400 MHz, DMSO-d6) δ ppm 7.79 (d, J= 8.84 Hz, 1 H), 7.68 (s, 1 H), 7.57 (d, J= 2.53 Hz, 1 H), 7.34 (d, J= 8.59 Hz, 1 H), 7.30 - 7.21 (m, 1 H), 6.96 (dd, J= 8.72, 2.65 Hz, 1 H), 6.35 (t, J= 5.31 Hz, 1 H), 6.19 (s, 1 H), 5.04 (brs, 2 H), 4.45 - 4.39 (m, 6 H), 3.92 - 3.75 (m, 3 H), 3.62 - 3.45 (m, 4 H), 2.37 (s, 3 H).
Example 1-6
N- [(3- Aminooxetan-3-yl)methyl] -2-(8-chloro- 1 , l-dioxido-2,3-dihydro- 1 ,4-benzothiazepin- 4(5H)-yl)-6-methylquinolin-4-amine
Figure imgf000175_0002
The title compound was prepared in analogy to Example 1-1 in Scheme 4 by using 2,4-dichloro- 6-methylquinoline, 8-chloro-2,3,4,5-tetrahydro-l,4-benzothiazepine and 3-(aminomethyl)-7V,7V- dibenzyloxetan-3-amine. MS obsd. (ESI+) [(M+H)+] 473, 1H NMR (400 MHz, CD3OD) δ ppm 7.99 - 7.88 (m, 2 H), 7.77 (s, 1 H), 7.64 (dd, J= 8.08, 2.27 Hz, 1 H), 7.53 (d, J= 8.59 Hz, 1 H), 7.40 (d, J= 8.59 Hz, 1 H), 6.19 (s, 1 H), 5.21 (brs, 2 H), 4.84 - 4.56 (m, 4 H), 4.53 (brs, 2 H), 3.75 (s, 2 H), 3.68 (brs, 2 H), 2.45 (s, 3 H).
Example 1-7 N- [(3- Aminooxetan-3-yl)methyl] -2-(7-methoxy- 1 , l-dioxido-2,3-dihydro- 1 ,4-benzothiazepin- 4(5H)-yl)-quinolin-4-amine
Figure imgf000176_0001
The title compound was prepared in analogy to Example 1-1 in Scheme 4 by using 2,4- dichloroquinoline, 7-methoxy-2,3,4,5-tetrahydro-l,4-benzothiazepine and 3-(aminomethyl)-N,N- dibenzyloxetan-3-amine. MS obsd. (ESI+) [(M+H)+] 455, 1H NMR (400 MHz, CD3OD) δ ppm 7.79 (d, J= 8.84 Hz, 1 H), 7.68 (s, 1 H), 7.57 (d, J= 2.53 Hz, 1 H), 7.34 (d, J = 8.59 Hz, 1 H), 7.30 - 7.21 (m, 1 H), 6.96 (dd, J= 8.72, 2.65 Hz, 1 H), 6.35 (t, J= 5.31 Hz, 1 H), 6.19 (s, 1 H), 5.04 (brs, 2 H), 4.45 (d, J= 5.81 Hz, 2 H), 4.39 (d, J = 5.81 Hz, 2 H), 3.92 - 3.75 (m, 3 H), 3.62 - 3.45 (m, 4 H), 2.37 (s, 3 H).
Example 2-1 V-[(3-Aminotetrahydrofuran-3-yl)methyl]-2-(l,l-dioxido-2,3-dihydro-l,4-benzothiazepin- 4(5H)-yl)-6-methylquinolin-4-amine
Figure imgf000176_0002
7V-{[3-(Dibenzylamino) tetrahydrofuran-3-yl]methyl}-2-(l,l-dioxido-2,3-dihydro-l,4- benzothiazepin-4(5H)-yl)-6-methylquinolin-4-amine
Figure imgf000176_0003
To a mixture of 4-(4-chloro-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-l,4-benzothiazepine 1,1- dioxide (400 mg, 1.08 mmol, prepared in analogy to 4-(4-chloro-6-methylquinolin-2-yl)-2, 3,4,5- tetrahydro-l,4-benzothiazepine 1,1 -dioxide in Example 1-1 by using 2,3,4, 5-tetrahydro-l,4- benzothiazepine and 2,4-dichloro-6-methylquinoline), 3 -(amino methyl)- N,N-dibenzyl tetrahydrofuran-3-amine (385 mg, 1.3 mmol), sodium tert-butoxide (207 mg, 2.16 mmol), Ι,Γ- bis(diphenylphosphino)ferrocene-palladium(II)dichloride (50 mg) and Ι,Γ- bis(diphenylphosphino)ferrocene (200 mg) in 1,4-dioxane (5 mL) was heated with stirring in a sealed 10 mL of microwave process vial for 1 hour at 120 °C under microwave irradiation. The resulting mixture was concentrated in vacuo. The residue was purified by preparative HPLC to afford 270 mg of the desired product (yield was 39.7%). V-[(3-Aminotetrahydrofuran-3-yl)methyl]-2-(l,l-dioxido-2,3-dihydro-l,4-benzothiazepin- 4(5H)-yl)-6-methylquinolin-4-amine
Figure imgf000177_0001
A mixture ofN-{[3-(dibenzylamino) tetrahydrofuran-3-yl]methyl}-2-(l,l-dioxido-2,3-dihydro- l,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-amine (270 mg, 0.43 mmol), 10% palladium hydroxide on active carbon (300 mg) in methanol (20 mL) was stirred for 16 hours at room temperature under hydrogen atmosphere (1 bar). The resulting mixture was concentrated in vacuo. The residue was purified by preparative HPLC to afford 21 mg of the desired product
(yield was 10.8%). MS obsd. (ESI+) [(M+H)+] 453, 1H NMR (400 MHz, CD3OD) δ ppm 8.06 - 7.98 (m, 2 H), 7.89 - 7.87 (d, J= 7.6 Hz, 1 H), 7.75 - 7.66 (m, 2 H), 7.59 - 7.56 (m, 2 H), 6.22 - 6.20 (d, J= 8.4 Hz, 1 H), 5.35 (s, 2 H), 4.5 (s, 2 H), 4.08 - 3.97 (m, 4 H), 3.88 - 3.73 (m, 3 H), 2.81 (s, 2 H), 2.46 (s, 3 H), 2.31 (s, 2 H).
Example 2-2
N-f(3- Aminooxetan-3-yl)methyl] -2-(l , l-dioxido-2,3-dihydro- 1 ,4-benzothiazepin-4(5H)-yl)- 6-methylquinolin-4-amine
Figure imgf000178_0001
The title compound was prepared in analogy to Example 2-1 in Scheme 4 by using 4-(4-chloro- 6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-l,4-benzothiazepine 1 , 1-dioxide (prepared in analogy to the one in Example 2-1) and 3-(aminomethyl)-N,N-dibenzyloxetan-3-amine. MS obsd. (ESI ) [(M+H)+] 439, 1H NMR (400 MHz, CD3OD) δ ppm 7.98 (dd, J = 1.2, 7.6 Hz, 1 H), 7.90 (d, J = 6.8 Hz, 1 H), 7.66 (s, 1 H), 7.62 (td, J = 1.2, 7.6 Hz, 1 H), 7.47 - 7.43 (m, 2 H), 7.30 (dd, J = 1.6, 8.4 Hz, 1 H), 6.20 (s, 1 H), 5.18 (s, 2 H), 4.63 (d, J= 6.4 Hz, 2 H), 4.59 (d, J = 6.8 Hz, 2 H), 4.59 (brs , 2 H), 3.68 (s, 2 H), 3.59 (t, J = 4.4 Hz, 2 H), 2.42 (s, 3 H).
Example 2-3 N- [(4- Aminotetrahydro-2H-pyran-4-yl)methyl] -2-(l , l-dioxido-2,3-dihydro- 1 ,4- benzothiazepin-4(5H)-yl)-6-methylquinolin-4-amine
Figure imgf000178_0002
The title compound was prepared in analogy to Example 2-1 in Scheme 4 by using 4-(4-chloro- 6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-l,4-benzothiazepine 1 , 1-dioxide (prepared in analogy to the one in Example 2-1) and 4-(aminomethyl)-N,N-dibenzyltetrahydro-2H-pyran-4-amine. MS obsd. (ESI+) [(M+H)+] 467, 1H NMR (400 MHz, CD3OD) δ ppm 7.98 (d, J = 7.2 Hz, 1 H), 7.87 (d, J= 7.6 Hz, 1 H), 7.68 (s, 1 H), 7.64 - 7.60 (m, 1 H), 7.44 (m, 2 H), 7.29 (dd, J= 2.0, 8.4 Hz, 1 H), 6.14 (s, 1 H), 5.16 (s, 2 H), 4.54 (brs, 2 H), 3.86 - 3.74 (m, 4 H), 3.58 (t, J = 4.8 Hz, 2 H), 2.42 (s, 3 H), 2.18 (dd, J = 2.4, 4.8 Hz, 2 H), 1.88 - 1.81 (m, 2 H), 1.57 (m, 2 H). Example 2-4 V-[(3-Aminooxetan-3-yl)methyl]-2-(8-methyl-l,l-dioxido-2,3-dihydro-l,4-benzothiazepin- 4(5H)-yl)-quinolin-4-amine
Figure imgf000179_0001
The title compound was prepared in analogy to Example 2-1 in Scheme 4 by using 4-(4- chloroquinolin-2-yl)-8-methyl-2,3,4,5-tetrahydro-l,4-benzothiazepine 1,1-dioxide (prepared in analogy to 4-(4-chloro-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-l,4-benzothiazepine 1,1- dioxide in Example 2-1 by using 8-methyl-2,3,4,5-tetrahydro-l,4-benzothiazepine and 2,4- dichloroquinoline) and 3-(aminomethyl)-N,N-dibenzyloxetan-3-amine. MS (ESI ) [(M+H)+] 439, 1H NMR (400 MHz, CD3OD) δ ppm 7.91 (d, J= 8.34 Hz, 1 H), 7.84 (d, J= 7.58 Hz, 1 H), 7.72 - 7.60 (m, 1 H), 7.49 - 7.35 (m, 3 H), 7.09 (ddd, J= 8.21, 5.18, 3.03 Hz, 1 H), 6.52 (t, J = 5.43 Hz, 1 H), 6.22 (s, 1 H), 5.06 (brs, 2 H), 4.45 (d, J= 6.06 Hz, 3 H), 4.38 (d, J= 6.06 Hz, 3 H), 3.61 (t, J= 4.80 Hz, 2 H), 3.56 (d, J= 5.31 Hz, 2 H), 2.31 (s, 3 H).
Example 2-5
TV- [(3- Aminooxetan-3-yl)methyl] -6-methyl-2-(8-methyl- 1 , l-dioxido-2,3-dihydro- 1 ,4- benzothiazepin-4(5H)-yl)quinolin-4-amine
Figure imgf000179_0002
The title compound was prepared in analogy to Example 2-1 in Scheme 4 by using 4-(4-chloro- 6-methylquinolin-2-yl)-8-methyl-2,3,4,5-tetrahydro- 1 ,4-benzothiazepine 1 , 1 -dioxide (prepared in analogy to 4-(4-chloro-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-l,4-benzothiazepine 1,1- dioxide in Example 2-1 by using 8-methyl-2,3,4,5-tetrahydro-l,4-benzothiazepine and 2,4- dichloro-6-methylquinoline) and 3-(aminomethyl)-N,N-dibenzyloxetan-3-amine. MS obsd.
(ESI+) [(M+H)+] 453, 1H NMR (400 MHz, CD3OD) δ ppm 7.82 (d, J= 7.83 Hz, 1 H), 7.68 (d, J = 3.03 Hz, 2 H), 7.41 (d, J= 6.57 Hz, 1 H), 7.33 (d, J= 8.59 Hz, 1 H), 7.25 (dd, J= 8.59, 1.52 Hz, 1 H), 6.42 (t, J= 5.56 Hz, 1 H), 6.19 (s, 1 H), 5.05 (brs, 2 H), 4.45 (d, J= 5.81 Hz, 3 H), 4.39 (d, J= 6.06 Hz, 3 H), 3.60 (t, J= 4.55 Hz, 2 H), 3.55 (d, J= 5.31 Hz, 2 H), 2.37 (s, 3 H), 2.31 (s, 3 H). Example 2-6
2-(l , l-Dioxido-2,3-dihydro- 1 ,4-benzothiazepin-4(5H)-yl)-6-methyl-7V-(2-oxa-6- azaspiro [3.4] oct-8-yl)quinolin-4-amine
Figure imgf000180_0001
The title compound was prepared in analogy to Example 2-1 in Scheme 4 by using 4-(4-chloro- 6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-l,4-benzothiazepine 1,1-dioxide (prepared in analogy to the one in Example 2-1) and 6-benzyl-2-oxa-6-azaspiro[3.4]oct-8-ylamine. MS obsd. (ESI ) [(M+H)+] 465, 1H NMR (400 MHz, CD3OD) δ ppm 8.11 - 8.08 (m, 2 H), 7.90 - 7.88 ( d, J= 7.2, 1 H), 7.75 - 7.70 (m, 2 H), 7.65 - 7.59 (m, 2 H), 6.36 (s, 1 H), 5.38 - 5.36 (d, J = 8.8, 2 H), 5.20 - 5.10 (m, 1 H), 4.80 - 4.79 (m, 2 H), 4.74 - 4.72 (m, 2 H), 4.56 - 4.54 (d, J = 7.2, 2 H), 3.90 - 3.87 (m, 1 H), 3.81 - 3.75 (m, 4 H), 3.60 - 3.50 (m, 1 H), 2.48 (s, 3 H).
Example 2-7
TV- [2-(3- Aminooxetan-3-yl)ethyl] -2-(l , l-dioxido-2,3-dihydro- 1 ,4-benzothiazepin-4(5H)-yl)- 6-methylquinolin-4-amine
Figure imgf000180_0002
The title compound was prepared in analogy to Example 2-1 in Scheme 4 by using 4-(4-chloro- 6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-l,4-benzothiazepine 1,1-dioxide (prepared in analogy to the one in Example 2-1) and 3-(aminoethyl)-N-benzyloxetan-3-amine. MS obsd. (ESI )
[(M+H)+] 453, 1H NMR (400 MHz, DMSO- 6) δ ppm 7.95 - 7.89 (t, 1 H), 7.89 - 7.87 (t, 1 H), 7.64 - 7.60 (m, 2 H), 7.49 - 7.45 (m, 1 H), 7.31 (d, J= 8.4 Hz, 1 H), 7.24 - 7.21 (m, 1 H), 6.87 (t, J= 10.4 Hz, 1 H), 6.05 (s, 1 H), 5.08 (s, 2 H), 4.39 (m, 6 H), 3.63 (t, J= 9.2 Hz, 2 H), 3.41 - 3.36 (m, 2 H), 2.41 (s, 2 H), 2.35 (s, 3 H), 2.08 (t, J= 14.4 Hz, 2 H). Example 2-8
TV- [(3- Aminooxetan-3-yl)methyl] -6-methyl-2-(5-methyl- 1 , l-dioxido-2,3-dihydro- 1 ,4- benzothiazepin-4(5H)-yl)quinolin-4-amine
Figure imgf000181_0001
The title compound was prepared in analogy to Example 2-1 in Scheme 4 by using 4-(4-chloro- 6-methylquinolin-2-yl)-5-methyl-2,3,4,5-tetrahydro- 1 ,4-benzothiazepine 1 , 1 -dioxide (prepared in analogy to 4-(4-chloro-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-l,4-benzothiazepine 1,1- dioxide in Example 2-1 by using 5-methyl-2,3,4,5-tetrahydro-l,4-benzothiazepine and 2,4- dichloro-6-methylquinoline) and 3-(aminomethyl)-7Y,7V-dibenzyloxetan-3-amine. MS obsd. (ESI+) [(M+H)+] 453, 1H NMR (400 MHz, CD3OD) δ ppm 8.03 (dd, J= 7.96, 1.39 Hz, 1 H), 7.90 (d, J= 6.57 Hz, 1 H), 7.71 - 7.64 (m, 2 H), 7.46 (ddd, J= 8.15, 6.63, 1.64 Hz, 2 H), 7.33 (dd, J= 8.59, 1.77 Hz, 1 H), 6.15 (s, 1 H), 5.86 (d, J= 6.82 Hz, 1 H), 4.64 - 4.53 (m, 4 H), 4.40 - 4.25 (brs, 2 H), 3.70 (d, J= 8.59 Hz, 1 H), 3.62 - 3.58 (m, 2 H), 3.57 - 3.49 (m, 1 H), 2.43 (s, 3 H), 2.00 (d, J = 7.07 Hz, 3 H). Example 2-9
N- [(3- Aminooxetan-3-yl)methyl] -2-(8-methoxy- 1 , l-dioxido-2,3-dihydro- 1 ,4-benzothiazepin- 4(5H)-yl)quinolin-4-amine
Figure imgf000181_0002
The title compound was prepared in analogy to Example 2-1 in Scheme 4 by using 4-(4- chloroquinolin-2-yl)-8-methoxy-2,3 ,4,5-tetrahydro- 1 ,4-benzothiazepine 1 , 1 -dioxide (prepared analogy to 4-(4-chloro-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-l,4-benzothiazepine 1,1- dioxide in Example 2-1 by using 8-methoxy-2,3,4,5-tetrahydro-l,4-benzothiazepine and 2,4- dichloroquinoline) and 3-(aminomethyl)-7Y,7V-dibenzyloxetan-3-amine. MS obsd. (ESI ) [(M+H)+] 455, 1H NMR (400 MHz, CD3OD) δ ppm 7.91 - 7.74 (m, 2 H), 7.58 - 7.38 (m, 3 H), 7.22 - 7.03 (m, 2 H), 6.23 (s, 1 H), 5.12 (brs, 2 H), 4.70 - 4.46 (m, 6 H), 3.81 (s, 3 H), 3.70 (s, 2 H), 3.65 - 3.52 (m, 2 H).
Example 2-10 TV- [(3- Aminooxetan-3-yl)methyl] -2-(l , l-dioxido-2,3-dihydro- 1 ,4-benzothiazepin-4(5H)-yl)- 1 ,6-naphthyridin-4-amine
Figure imgf000182_0001
The title compound was prepared in analogy to Example 2-1 in Scheme 4 by using 4-(4-chloro- l,6-naphthyridin-2-yl) -2,3,4,5-tetrahydro-l,4-benzothiazepine 1,1-dioxide (prepared in analogy to 4-(4-chloro-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-l,4-benzothiazepine 1,1-dioxide in Example 2-1 by using 2,3,4,5-tetrahydro-l,4-benzothiazepine and 2,4-dichloro-l,6- naphthyridine) and 3-(aminomethyl)-7Y,7V-dibenzyloxetan-3-amine. MS obsd. (ESI ) [(M+H)+] 426, 1H NMR (400 MHz, CD3OD) δ ppm 9.15 (s, 1 H), 8.28 - 8.80 (d, J= 6.4 Hz, 1 H), 8.00 - 7.95 (d, J= 1.2 Hz, 1 H), 7.95 - 7.90 (d, J= 7.2 Hz, 1 H), 7.62 - 7.58 (t, J= 0.8 Hz, 1 H), 7.50 - 7.40 (m, 2 H), 6.31 (s, 1 H), 5.35 (s, 2 H), 4.65 - 4.58 (m, 6 H), 3.80 (s, 2 H), 3.60 - 3.50 (t, J = 2.8 Hz, 2 H).
Example 2-11 iV-[(l-Aminocyclohexyl)methyl]-2-(l,l-dioxido-2,3-dihydro-l,4-benzothiazepin-4(5H)-yl)-6- methylquinolin-4-amine
Figure imgf000182_0002
The title compound was prepared in analogy to Example 2-1 in Scheme 4 by using 4-(4-chloro- 6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-l,4-benzothiazepine 1,1-dioxide (prepared in analogy +^ +ν in «i0 anci l-(aminomethyl)-N,N-dibenzylcyclohexanamine. MS obsd. (ESI+) [(M+H)+] 465, 1H NMR (400 MHz, CDC13) δ ppm 8.02 - 7.99 (dd, J= 1.2 Hz, 8.0 Hz, 1 H), 7.65 - 7.63 (d, J= 7.6 Hz, 1 H), 7.48 - 7.46 (m, 2 H), 7.34 - 7.25 (m, 3 H), 5.86 (s, 1 H), 5.64 (s, 1 H), 5.10 (s, 2 H), 4.56 (s, 2 H), 3.55 (s, 2 H), 3.05 - 3.04 (d, J= 4.8 Hz, 2 H), 2.41 (s, 3 H), 1.98 (s, 4 H), 1.56 (m, 10 H).
Example 3-1
TV- { [3-(Aminomethyl)oxetan-3-yl] methyl}-2-(8-fluoro- 1 , l-dioxido-2,3-dihydro- 1 ,4- benzothiazepin-4(5H)-yl)-6-methylquinolin-4-amine
Figure imgf000183_0001
A mixture of 8-(4-chloro-6-methylquinolin-2-yl)-8-fluoro-2,3,4,5-tetrahydro- 1 ,4- benzothiazepine 1,1 -dioxide (200 mg, 0.51 mmol, prepared in analogy to 4-(4-chloro-6- methylquinolin-2-yl)-2,3,4,5-tetrahydro-l,4-benzothiazepine 1,1-dioxide in Example 2-1 by using 8-fluoro-2,3,4,5-tetrahydro-l,4-benzothiazepine and 2,4-dichloro-6-methylquinoline), sodium tert-butoxide (96 mg, 1.02 mmol), l, -bis(diphenylphosphino)ferrocene- palladium(II)dichloride (42 mg, 0.051 mmol), l, -bis(diphenylphosphino)ferrocene (29 mg, 0.051 mmol), and oxetane-3,3-diyldimethanamine (89 mg, 0.77 mmol) in 1,4-dioxane (2 mL) was heated with stirring in a sealed 5 mL of microwave process via for 1.5 hours at 120 °C under microwave irradiation. The resulting mixture was concentrated in vacuo. The residue was purified by preparative HPLC to afford 48 mg of the product as a white product (yield was 20%). MS obsd. (ESI+) [(M+H)+] 471, 1H NMR (400 MHz, CD3OD) δ ppm 7.95 (dd, J= 8.34, 5.05
Hz, 1 H), 7.74 (t, J= 5.56 Hz, 2 H), 7.54 (d, J= 8.59 Hz, 1 H), 7.46 - 7.29 (m, 2 H), 6.19 (s H), 5.23 (brs, 2 H), 4.69 - 4.58 (m, 8 H), 3.78 (s, 2 H), 3.69 (brs, 2 H), 3.41 (s, 2 H), 2.46 (s H).
Example 3-2 V-{[3-(Benzylamino)oxetan-3-yl]methyl}-6-chloro-2-(7-fluoro-l,l-dioxido-2,3-dihyd] benzothiazepin-4(5H)-yl)quinolin-4-amine
Figure imgf000184_0001
The title compound was prepared in analogy to Example 3-1 in Scheme 5 by using 4-(4,6- dichloroquinolin-2-yl)-7-fluoro-2,3,4,5-tetrahydro-l,4-benzothiazepine 1,1-dioxide (prepared in analogy to 4-(4-chloro-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-l,4-benzothiazepine 1,1- dioxide in Example 2-1 by using 7-fluoro-2,3,4,5-tetrahydro-l,4-benzothiazepine and 2,4,6- trichloroquinoline) and 3-(aminomethyl)-N-benzyloxetan-3-amine. MS obsd. (ESI ) [(M+H)+] 567, 1H NMR (400 MHz, CD3OD) δ ppm 7.98 (dd, J= 8.72, 5.43 Hz, 1 H), 7.82 (d, J= 2.27 Hz, 1 H), 7.71 (dd, J= 9.09, 2. 53 Hz, 1 H), 7.50 (d, J= 8.84 Hz, 1 H), 7.39 (dd, J = 8.84, 2.27 Hz, 1 H), 7.33 (d, J= 7.07 Hz, 2 H), 7.25 - 7.16 (m, 2 H), 7.16 - 7.04 (m, 2 H), 6.13 (s, 1 H), 5.15 (brs, 2 H), 4.71 (d, J= 6.57 Hz, 2 H), 4.54 (d, J= 6.57 Hz, 4 H), 3.77 (s, 2 H), 3.72 (s, 2 H), 3.56 (t, J = 4.93 Hz, 2 H).
Example 3-3
TV- [(3- Aminooxetan-3-yl)methyl] -6-chloro-2-(7-fluoro- 1 , l-dioxido-2,3-dihydro- 1 ,4- benzothiazepin-4(5H)-yl)quinolin-4-amine
Figure imgf000184_0002
The title compound was prepared in analogy to Example 3-1 in Scheme 5 by using 4-(4,6- dichloroquinolin-2-yl)-7-fluoro-2,3,4,5-tetrahydro-l,4-benzothiazepine 1,1-dioxide (prepared in analogy to the one in Example 3-2) and 3-(aminomethyl)oxetan-3-amine. MS obsd. (ESI )
[(M+H)+] 477, 1H NMR (400 MHz, CD3OD) δ ppm 8.07 - 7.94 (m, 2 H), 7.72 (dd, J= 8.97, 2.65 Hz, 1 H), 7.53 (d, J= 8.84 Hz, 1 H), 7.43 (dd, J= 8.84, 2.27 Hz, 1 H), 7.15 (td, J= 8.46, 2.53 Hz, 1 H), 6.23 (s, 1 H), 5.18 (brs, 2 H), 4.73 - 4.60 (m, 4 H), 4.51 (brs, 2 H), 3.75 (s, 2 H), 3.59 (t, J = 4.67 Hz, 2 H).
Example 3-4 N- { [3-(Aminomethyl)oxetan-3-yl] methyl}-2-(7-methoxy- 1 , l-dioxido-2,3-dihydro- 1 ,4- benzothiazepin-4(5H)-yl)-quinolin-4-amine
Figure imgf000185_0001
The title compound was prepared in analogy to Example 3-1 in Scheme 5 by using 4-(4- chloroquinolin-2-yl)-7-methoxy-2,3,4,5-tetrahydro-l,4-benzothiazepine 1,1-dioxide (prepared in analogy to 4-(4-chloro-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-l,4-benzothiazepine 1,1- dioxide in Example 2-1 by using 7-methoxy-2,3,4,5-tetrahydro-l,4-benzothiazepine and 2,4- dichloroquinoline) and oxetane-3,3-diyldimethanamine. MS obsd. (ESI ) [(M+H)+] 469, 1H NMR (400 MHz, CD3OD) δ ppm 8.41 (brs, 3 H), 8.02 (d, J= 8.08 Hz, 1 H), 7.97 (d, J= 8.84 Hz, 1 H), 7.68 (d, J= 8.08 Hz, 1 H), 7.60 (t, J = 7.71 Hz, 1 H), 7.44 (d, J = 2.53 Hz, 1 H), 7.3 l(t, J= 7.20 Hz, 1 H), 7.01 (dd, J= 8.59, 2.53 Hz, 1 H), 6.19 (s, 1 H), 5.20 (br. s,2 H), 4.64 (s, 4 H), 4.54 (brs, 2 H), 3.92 (s, 3 H), 3.81 (s, 2 H), 3.69 - 3.55 (m, 2 H), 3.47 (s, 2 H).
Example 3-5
TV- { [3-(Aminomethyl)oxetan-3-yl] methyl}-2-(7-methoxy- 1 , l-dioxido-2,3-dihydro- 1 ,4- benzothiazepin-4(5H)-yl)-6-methylquinolin-4-amine
Figure imgf000185_0002
The title compound was prepared in analogy to Example 3-1 in Scheme 5 by using 4-(4-chloro- 6-methylquinolin-2-yl)-7-methoxy-2,3,4,5-tetrahydro- 1 ,4-benzothiazepine 1 , 1 -dioxide (prepared in analogy to 4-(4-chloro-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-l,4-benzothiazepine 1,1- dioxide in Example 2-1 by using 7-methoxy-2,3,4,5-tetrahydro-l,4-benzothiazepine and 2,4- dichloro-6-methylquinoline) and oxetane-3,3-diyldimethanamine. MS obsd. (ESI ) [(M+H)+] 483, 1H NMR (400 MHz, CD3OD) δ ppm 7.89 (d, J= 8.59 Hz, 1 H), 7.64 (s, 1 H), 7.51 - 7.39 (m, 2 H), 7.31 (dd, J= 8.59, 1.77 Hz, 1 H), 6.91 (dd, J= 8.59, 2.53 Hz, 1 H), 6.14 (s, 1 H), 5.10 (brs, 2 H), 4.69 - 4.44 (m, 6 H), 3.90 (s, 3 H), 3.74 - 3.61 (m, 2 H), 3.57 - 3.52 (m, 2 H), 3.18 (s, 2 H), 2.42 (s, 3 H).
Example 3-6 V-{[3-({[2-(7-Methoxy-l,l-dioxido-2,3-dihydro-l,4-benzothiazepin-4(5H)-yl)-6- methylquinolin-4-yl] amino} methyl)oxetan-3-yl] methyl} acetamide
Figure imgf000186_0001
The title compound was prepared in analogy to Example 3-1 in Scheme 5 by using 4-(4-chloro- 6-methylquinolin-2-yl)-7-methoxy-2,3,4,5-tetrahydro- 1 ,4-benzothiazepine 1 , 1 -dioxide (prepared in analogy to 4-(4-chloro-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-l ,4-benzothiazepine 1 , 1- dioxide in Example 2-1 by using 7-methoxy-2,3,4,5-tetrahydro-l ,4-benzothiazepine and 2,4- dichloro-6-methylquinoline) and N- {[3-(aminomethyl)oxetan-3-yl]methyl} acetamide. MS obsd. (ESI+) [(M+H)+] 525, 1H NMR (400 MHz, CD3OD) δ ppm 7.91 (d, J = 8.59 Hz, 1 H), 7.70 (s, 1 H), 7.47 (d, J = 8.59 Hz, 1 H), 7.41 (d, J = 2.27 Hz, 1 H), 7.33 (dd, J = 8.46, 1.64 Hz, 1 H), 6.94 (d, J= 8.59 Hz, 1 H), 6.18 (s, 1 H), 5.12 (s, 2 H), 4.61 - 4.54 (m, 6 H), 3.90 (s, 3 H), 3.68 (s, 2 H), 3.67 - 3.63 (m, 2 H), 3.59 - 3.51 (m, 2 H), 2.44 (s, 3 H), 2.05 (s, 3 H).
Example 3-7
TV- { [3-(Aminomethyl)oxetan-3-yl] methyl}-2-(8-methyl- 1 , l-dioxido-2,3-dihydro- 1 ,4- benzothiazepin-4(5H)-yl)-6-methylquinolin-4-amine
Figure imgf000186_0002
The title compound was prepared in analogy to Example 3-1 in Scheme 5 by using 4-(4- chloroquinolin-2-yl)-8-methyl-2,3,4,5-tetrahydro-l,4-benzothiazepine 1 , 1-dioxide (prepared in
(Λ methylquinolin-2-yl)-2,3,4,5-tetrahydro-l ,4-benzothiazepine 1 , 1- dioxide in Example 2-1 by using 8-methyl-2,3,4,5-tetrahydro-l,4-benzothiazepine and 2,4- dichloroquinoline) and oxetane-3,3-diyldimethanamine. MS obsd. (ESI ) [(M+H)+] 453, 1H NMR (400 MHz, CD3OD) δ ppm 7.86 - 7.69 (m, 3 H), 7.57 - 7.49 (m, 1 H), 7.47 - 7.34 (m, 2 H), 7.19 - 7.06 (m, 1 H), 6.17 (s, 1 H), 5.11 (brs, 2 H), 4.68 - 4.39 (m, 6 H), 3.67 (s, 2 H), 3.63 (q, J = 7.07 Hz, 1 H), 3.55 (t, J= 4.55 Hz, 2 H), 3.15 (s, 2 H), 2.33 (s, 3 H).
Example 3-8 V-{[3-(Aminomethyl)oxetan-3-yl]methyl}-6-methyl-2-(8-methyl-l,l-dioxido-2,3-dihydro- l,4-benzothiazepin-4(5H)-yl)quinolin-4-amine
Figure imgf000187_0001
The title compound was prepared in analogy to Example 3-1 in Scheme 5 by using 4-(4-chloro- 6-methylquinolin-2-yl)-8-methyl-2,3,4,5-tetrahydro- 1 ,4-benzothiazepine 1 , 1 -dioxide (prepared in analogy to 4-(4-chloro-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-l,4-benzothiazepine 1,1- dioxide in Example 2-1 by using 8-methyl-2,3,4,5-tetrahydro-l,4-benzothiazepine and 2,4- dichloro-6-methylquinoline) and oxetane-3,3-diyldimethanamine. MS obsd. (ESI ) [(M+H)+] 467, 1H NMR (400 MHz, CD3OD) 7.74 - 7.62 (m, 2 H), 7.58 (s, 1 H), 7.43 (d, J= 8.59 Hz, 1 H), 7.32 - 7.20 (m, 2 H), 6.07 (s, 1 H), 4.99 (brs, 2 H), 4.62 - 4.48 (m, 4 H), 4.48 - 4.18 (m, 2 H), 3.65 - 3.60 (m, 2 H), 3.44 (brs, 2 H), 3.11 (s, 2 H), 2.43 - 2.26 (m, 3 H), 2.14 (s, 3 H).
Example 3-9
[3-({[2-(l,l-Dioxido-2,3-dihydro-l,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4- yl] amino} methyl)oxetan-3-yl] methanol
Figure imgf000187_0002
The title compound was prepared in analogy to Example 3-1 in Scheme 5 by using 4-(4-chloro- 6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-l,4-benzothiazepine 1,1-dioxide (prepared in analogy to the one in Example 2-1) and 3-(aminomethyl)oxetan-3-yl]methanol. MS obsd. (ESI )
[(M+H)+] 454, 1H NMR (400 MHz, CD3OD) δ ppm 8.02 - 7.96 (m, 1 H), 7.90 (d, J= 7.33 Hz, 1 H), 7.68 - 7.54 (m, 2 H), 7.45 (d, J= 8.34 Hz, 2 H), 7.35 - 7.20 (m, 1 H), 6.19 (s, 1 H), 5.14 (s, 2 H), 4.60 (d, J= 6.06 Hz, 3 H), 4.51 (d, J= 6.06 Hz, 3 H), 3.98 (s, 2 H), 3.67 (s, 2 H), 3.58 (t, J = 4.67 Hz, 2 H), 2.42 (s, 3 H).
Example 3-10
(25)-3- { [2-(l , l-Dioxido-2,3-dihydro- 1 ,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4- yl]amino}propane-l,2-diol
Figure imgf000188_0001
The title compound was prepared in analogy to Example 3-1 in Scheme 5 by using 4-(4-chloro- 6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-l,4-benzothiazepine 1,1-dioxide (prepared in analogy to the one in Example 2-1) and (25)-3-aminopropane-l,2-diol. MS obsd. (ESI+) [(M+H)+] 428, 1H NMR (400 MHz, CD3OD) δ ppm 7.98 (dd, J= 7.83, 1.26 Hz, 1 H), 7.89 (d, J= 7.33 Hz, 1 H), 7.63 (td, J= 7.45, 1.26 Hz, 1 H), 7.57 (s, 1 H), 7.50 - 7.35 (m, 2 H), 7.29 (dd, J= 8.59, 1.77 Hz, 1 H), 6.13 (s, 1 H), 5.14 (s, 2 H), 4.55 (brs, 2 H), 4.04 - 3.89 (m, 1 H), 3.69 (d, J= 5.56 Hz, 2 H), 3.64 - 3.49 (m, 4 H), 2.41 (s, 3 H).
Example 3-11 (2R)-3-{[2-(l,l-Dioxido-2,3-dihydro-l,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4- yl]amino}propane-l,2-diol
Figure imgf000189_0001
The title compound was prepared in analogy to Example 3-1 in Scheme 5 by using 4-(4-chloro- 6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-l,4-benzothiazepine 1,1-dioxide (prepared in analogy to the one in Example 2-1) and (2i?)-3-aminopropane-l,2-diol. MS obsd. (ESI+) [(M+H)+] 428, 1H NMR (400 MHz, CD3OD) δ ppm 7.98 (dd, J= 7.83, 1.26 Hz, 1 H), 7.89 (d, J= 7.33 Hz, 1 H), 7.63 (td, J= 7.45, 1.26 Hz, 1 H), 7.57 (s, 1 H), 7.50 - 7.35 (m, 2 H), 7.29 (dd, J= 8.59, 1.77 Hz, 1 H), 6.13 (s, 1 H), 5.14 (s, 2 H), 4.55 (brs, 2 H), 4.04 - 3.89 (m, 1 H), 3.69 (d, J= 5.56 Hz, 2 H), 3.64 - 3.49 (m, 4 H), 2.41 (s, 3 H).
Example 3-12 V-{[l-(Aminomethyl)-3,3-difluorocyclobutyl]methyl}-2-(l,l-dioxido-2,3-dihydro-l,4- benzothiazepin-4(5H)-yl)-6-methylquinolin-4-amine
Figure imgf000189_0002
The title compound was prepared in analogy to Example 3-1 in Scheme 5 by using 4-(4-chloro- 6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-l,4-benzothiazepine 1,1-dioxide (prepared in analogy to the one in Example 2-1) and (3, 3-difluorocyclo butane- l,l-diyl)dimethanamine. MS obsd. (ESI+) [(M+H)+] 487, 1H NMR (400 MHz, CD3OD) δ ppm 8.11 (dd, J= 7.83, 1.01 Hz, 1 H), 8.08 (s, 1 H), 7.89 (d, J= 7.07 Hz, 1 H), 7.80 - 7.68 (m, 2 H), 7.68 - 7.56 (m, 2 H), 6.15 (s, 1 H), 5.37 (s, 2 H), 4.55 (brs, 2 H), 3.80 (s, 2 H), 3.79 - 3.67 (m, 2 H), 3.44 (s, 2 H), 2.76 (t, J= 12.25 Hz, 4 H), 2.51 (s, 3 H).
Example 3-13 N- [(3- Aminooxetan-3-yl)methyl] -6-chloro-2-(8-methoxy- 1 , l-dioxido-2,3-dihydro- 1 ,4- benzothiazepin-4(5H)-yl)quinolin-4-amine
Figure imgf000190_0001
The title compound was prepared in analogy to Example 3-1 in Scheme 5 by using 4-(4,6- dichloroquinolin-2-yl)-8-methoxy-2,3,4,5-tetrahydro-l,4-benzothiazepine 1,1-dioxide (prepared in analogy to 4-(4-chloro-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-l,4-benzothiazepine 1,1- dioxide in Example 2-1 by using 8-methoxy-2,3,4,5-tetrahydro-l,4-benzothiazepine and 2,4,6- trichloroquinoline) and 3-(aminomethyl)oxetan-3-amine. MS obsd. (ESI+) [(M+H)+] 489, 1H NMR (400 MHz, CD3OD) δ ppm 7.95 (d, J= 2.27 Hz, 1 H), 7.83 - 7.74 (m, 1 H), 7.58 - 7.44 (m, 2 H), 7.44 - 7.33 (m, 1 H), 7.14 (dd, J= 8.34, 2.78 Hz, 1 H), 6.24 (s, 1 H), 5.11 (brs, 2 H), 4.61 (q, J= 6.74 Hz, 6 H), 3.82 (s, 3 H), 3.69 (s, 2 H), 3.63 - 3.50 (m, 2 H), 2.05 (s, 2 H).
Example 3-14 V-{[3-(Aminomethyl)oxetan-3-yl]methyl}-6-chloro-2-(8-methoxy-l,l-dioxido-2,3-dihydro- l,4-benzothiazepin-4(5H)-yl)quinolin-4-amine
Figure imgf000190_0002
The title compound was prepared in analogy to Example 3-1 in Scheme 5 by using 4-(4,6- dichloroquinolin-2-yl)-8-methoxy-2,3,4,5-tetrahydro- 1 ,4-benzothiazepine 1 , 1 -dioxide (prepared in analogy to the one in Example 3-13) and oxetane-3,3-diyldimethanamine. MS obsd. (ESI ) [(M+H)+] 503, 1H NMR (400 MHz, CD3OD) δ ppm 8.23 (s, 1 H), 7.88 (d, J= 8.59 Hz, 1 H), 7.73 (d, J= 8.84 Hz, 1 H), 7.65 - 7.51 (m, 2 H), 7.21 (dd, J= 8.34, 2.78 Hz, 1 H), 6.30 (s, 1 H), 5.26 (brs, 2 H), 4.76 - 4.60 (m, 6 H), 4.56 (brs, 1 H), 3.91 (s, 2 H), 3.85 (s, 3 H), 3.69 (brs, 2 H), 3.52 (s, 2 H). Example 3-15 irans- V-[2-(l,l-Dioxido-2,3-dihydro-l,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4- yl]cyclohexane -1,2-diamine
Figure imgf000191_0001
The title compound was prepared in analogy to Example 3-1 in Scheme 5 by using 4-(4-chloro- 6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-l,4-benzothiazepine 1,1-dioxide (prepared in analogy to the one in Example 2-1) and trans-cyclohexane- 1,2-diamine. MS obsd. (ESI ) [(M+H)+] 451, 1H NMR (400 MHz, CD3OD) δ ppm 8.06 - 7.96 (d, J= 7.8 Hz, 1 H), 7.83 (d, J= 7.33 Hz, 1 H), 7.70 (s, 1 H), 7.60 (td, J = 7.52, 1.14 Hz, 1 H), 7.50 - 7.38 (m, 2 H), 7.28 (dd, J= 8.46, 1.64 Hz, 1 H), 6.13 (s, 1 H), 5.20 - 5.11 (m, 2 H), 3.72 - 3.60 (m, 1 H), 3.58 - 3.49 (m, 1 H), 3.42 - 3.35 (m, 2 H), 3.35 - 3.30 (m, 1 H), 2.87 (td, J= 10.17, 3.92 Hz, 1 H), 2.42 (s, 3 H), 2.10 (d, J= 5.31 Hz, 1 H), 2.01 (d, J= 13.14 Hz, 1 H), 1.89 (d, J= 8.08 Hz, 2 H), 1.67 - 1.56 (m, 1 H), 1.51 - 1.41 (m, 2 H), 1.32 - 1.17 (m, 1 H).
Example 3-16 V-[2-(l,l-Dioxido-2,3-dihydro-l,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]- cyclohexane- 1 ,3-diamine
Figure imgf000191_0002
The title compound was prepared in analogy to Example 3-1 in Scheme 5 by using 4-(4-chloro- 6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-l,4-benzothiazepine 1,1-dioxide (prepared in analogy to the one in Example 2-1) and cyclohexane-l,3-diamine. MS obsd. (ESI+) [(M+H)+] 451, 1H NMR (400 MHz, CD3OD) δ ppm 8.04 (d, J= 7.8 Hz, 1 H), 7.57 (d, J= 7.3 Hz, 1 H ), 7.53 - 7.47 (m, 2 H), 7.37 (t, J= 7.7 Hz, 1 H), 7.32 - 7.26 (m, 2 H), 5.86 (s, 1 H), 5.16 - 5.00 (m, 2 H), 3.65 - 3.50 (brs, 4 H), 3.16 (brs, 1 H), 2.42 (s, 3 H), 2.45 - 2.38 (m, 1 H), 2.29 (d, J= 1 1.1 Hz, 1 H), 2.03 - 1.85 (m, 3 H), 1.54 - 1.42 (m, 1 H), 1.40 - 1.24 (m, 3 H).
Example 3-17
(R)-l-[2-(l,l-Dioxido-2,3-dihydro-l,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]-4,4- dimethyl-pyrrolidin-3-ol
Figure imgf000192_0001
The title compound was prepared in analogy to Example 3-1 in Scheme 5 by using 4-(4-chloro- 6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-l,4-benzothiazepine 1 , 1-dioxide (prepared in analogy to the one in Example 2-1) and (3R)-4,4-dimethylpyrrolidin-3-ol. MS obsd. (ESI+) [(M+H)+] 452, 1H NMR (400 MHz, CD3OD) δ ppm 7.94 (dd, J = 7.83, 1.01 Hz, 1 H), 7.83 - 7.73 (m, 2 H), 7.58 (td, J= 7.58, 1.26 Hz, 1 H), 7.47 - 7.37 (m, 2 H), 7.23 (dd, J = 8.59, 1.77 Hz, 1 H), 6.03 (s, 1 H), 5.1 1 (s, 2 H), 4.02 (dd, J = 10.36, 5.31 Hz, 1 H), 3.93 (dd, J = 5.05, 3.79 Hz, 1 H), 3.61 - 3.47 (m, 4 H), 2.37 (s, 3 H), 1.15 (s, 3 H), 1.10 - 1.05 (m, 3 H).
Example 3-18 cis- V-[2-(l,l-Dioxido-2,3-dihydro-l,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]- cyclohexane- 1 ,4-diamine
Figure imgf000192_0002
The title compound was prepared in analogy to Example 3-1 in Scheme 5 by using 4-(4-chloro- 6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-l,4-benzothiazepine 1 , 1-dioxide (prepared in analogy to the one in Example 2-1) and czs-cyclohexane-l ,4-diamine. MS obsd. (ESI ) [(M+H)+] 451 , 1H NMR (400 MHz, DMSO- d6) δ ppm 7.91 - 7.85 (m, 2 H), 7.79 (s, 1 H), 7.58 (td, J = 7.45, 1.26 Hz, 1 H), 7.51 - 7.44 (m, 1 H), 7.29 (d, J= 8.59 Hz, 1 H), 7.21 (dd, J= 8.59, 1.52 Hz, 1 H), 6.17 (d, J= 7.58 Hz, 1 H), 6.03 (s, 1 H), 5.06 (brs, 2 H), 4.50 (brs, 1 H), 4.11 (d, J= 4.55 Hz, 1 H), 3.67 (d, J= 4.80 Hz, 1 H), 3.64 - 3.56 (m, 2 H), 3.16 (m, 2 H), 3.06 (brs, 1 H), 2.35 (s, 3 H), 1.83 - 1.44 (m, 8 H). Example 3-19 V-[2-(l,l-Dioxido-2,3-dihydro-l,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]-2,2- difluoropropane-l,3-diamine
Figure imgf000193_0001
The title compound was prepared in analogy to Example 3-1 in Scheme 5 by using 4-(4-chloro- 6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-l,4-benzothiazepine 1,1-dioxide (prepared in analogy to the one in Example 2-1) and 2,2-difluoropropane-l,3-diamine. MS obsd. (ESI ) [(M+H)+] 447, 1H NMR (400 MHz, CD3OD) δ ppm 8.09 - 8.07 (d, 1 H), 7.95 (s, 1 H), 7.86 - 7.84 (d, 1 H), 7.77 - 7.69 (m, 2 H), 7.64 - 7.58 (m, 2 H), 6.26 (s, 1 H), 5.34 (s, 2 H), 4.53 (s, 2 H), 4.23 (t, 2 H), 3.74 - 3.66 (m, 4 H), 2.48 (s, 3 H). Example 3-20 V-[6-Chloro-2-(l,l-dioxido-2,3-dihydro-l,4-benzothiazepin-4(5H)-yl)quinolin-4-yl]-2,2- difluoropropane-l,3-diamine
Figure imgf000193_0002
The title compound was prepared in analogy to Example 3-1 in Scheme 5 by using 4-(4,6- dichloroquinolin-2-yl)-2,3,4,5-tetrahydro-l,4-benzothiazepine 1,1-dioxide (prepared in analogy to 4-(4-chloro-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-l,4-benzothiazepine 1,1-dioxide in Cvom",° 1 1^ "^'"" 1 3,4,5-tetrahydro-l,4-benzothiazepine and 2,4,6-trichloroquinoline) and 2,2-difluoropropane-l,3-diamine. MS obsd. (ESI+) [(M+H)+] 467, 1H NMR (400 MHz, DMSO- d6) δ ρρηι 8.17 - 8.08 (m, 1 H), 7.94 (d, J= 7.07 Hz, 1 H), 7.88 (dd, J= 7.83, 1.26 Hz, 1 H), 7.62 (td, J= 7.45, 1.26 Hz, 1 H), 7.54 - 7.39 (m, 3 H), 7.14 (brs, 1 H), 6.33 (s, 1 H), 5.77 (s, 1 H), 5.11 (brs, 2 H), 4.43 (brs, 2 H), 4.03 - 3.87 (m, 2 H), 3.61 (brs, 2 H), 3.13 - 3.29 (m, 2 H). Example 3-21 V-[2-(l,l-Dioxido-2,3-dihydro-l,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]-2- fluoropropane-l,3-diamine
Figure imgf000194_0001
The title compound was prepared in analogy to Example 3-1 in Scheme 5 by using 4-(4-chloro- 6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-l,4-benzothiazepine 1,1-dioxide (prepared in analogy to the one in Example 2-1) and 2-fluoropropane-l,3-diamine. MS obsd. (ESI+) [(M+H)+] 429, 1H NMR (400 MHz, CD3OD) δ ppm 7.98 (dd, J= 7.83, 1.01 Hz, 1 H), 7.84 (d, J= 7.58 Hz, 1 H), 7.65 - 7.57 (m, 2 H), 7.47 - 7.38 (m, 2 H), 7.29 (dd, J= 8.59, 1.77 Hz, 1 H), 6.10 (s, 1 H), 5.14 (s, 2 H), 4.69 (s, 2 H), 3.64 (d, J= 5.31 Hz, 1 H), 3.61 - 3.52 (m, 4 H), 3.04 - 2.91 (m, 2 H), 2.41 (s, 3 H).
Example 3-22 V-[(3-Aminooxetan-3-yl)methyl]-6-chloro-2-(l,l-dioxido-2,3-dihydro-l,4-benzothiazepin- 4(5H)-yl)quinolin-4-amine
Figure imgf000194_0002
The title compound was prepared in analogy to Example 3-1 in Scheme 5 by using 4-(4,6- dichloroquinolin-2-yl)-2,3,4,5-tetrahydro-l,4-benzothiazepine 1,1-dioxide (prepared in analogy to 4-(4-chloro-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-l,4-benzothiazepine 1,1-dioxide in Example 2-1 by using 2,3,4,5-tetrahydro-l,4-benzothiazepine and 2,4, 6-trichloroquino line) and 3-(aminomethyl)oxetan-3-amine. MS obsd. (ESI+) [(M+H)+] 459, 1H NMR (400 MHz, CD3OD) δ ppm 8.34 (s, 1 H), 8.02 - 8.00 (t, J = 4.0, 2.4 Hz, 2 H), 7.92 - 7.90 (d, J = 7.2 Hz, 1 H), 7.65 - 7.62 (m, 1 H), 7.56 - 7.54 ( d, J = 9.2 Hz, 1 H), 7.49 - 7.44 (m, 2 H), 6.27 (s, 1 H), 5.22 (s, 2 H), 4.67 - 4.63 (m, 4 H), 4.56 (s, 1 H), 3.78 (s, 2 H), 3.63 - 3.60 (t, J = 4.8 Hz, 2 H).
Example 3-23
[4- { [(3- Aminooxetan-3-yl)methyl] amino}-2-(l , l-dioxido-2,3-dihydro- 1 ,4-benzothiazepin- 4(5H)-yl)quinolin-6-yl] methanol
Figure imgf000195_0001
Methyl 4-chloro-2-(l,l-dioxido-2,3-dihydro-l,4-benzothiazepin-4(5H)-yl)quinoline-6- carboxylate
Figure imgf000195_0002
To a cooled solution of methyl 4-chloro-2-(2,3-dihydro-l ,4-benzothiazepin-4(5H)-yl)quinoline- 6-carboxylate (2.0 g, 5.2 mmol, prepared in analogy to 4-(4-chloro-6-methylquinolin-2-yl)-8- methoxy-2,3,4,5-tetrahydro-l,4-benzothiazepine in Example 1-1 by using methyl 2,4- dichoroquinoline-6-carboxylate and 2,3,4,5-tetrahydro-l ,4-benzothiazepine) in dichloromethane (30 mL) was added 3-chloroperoxybenzoic acid (2.63 g, 20.8 mmol) in an ice-bath. After being stirred for 1 hour at 0 °C, the reaction mixture was washed with brine, dried over sodium sulfate and concentrated in vacuo to afford 2.0 g of the crude product. 4-Chloro-2-(l,l-dioxido-2,3-dihydro-l,4-benzothiazepin-4(5H)-yl)-quinoline-6-methanol
Figure imgf000195_0003
To a solution of methyl 4-chloro-2-(l,l-dioxido-2,3-dihydro-l,4-benzothiazepin-4(5H)- yl)quinoline-6-carboxylate (2.0 g, 4.8 mmol) in tetrahydrofuran (50 mL) was added sodium borohydride (729 mg, 19.2 mmol). After being refluxed for 60 hours, the reaction mixture was diluted with water (30 mL) and extracted with dichloromethane (50 mL x 2). The combined organic layers were dried over sodium sulfate and concentrated in vacuo to afford 1.4 g of the crude product.
[4- { [(3- Aminooxetan-3-yl)methyl] amino}-2-(l , l-dioxido-2,3-dihydro- 1 ,4-benzothiazepin- 4(5H)-yl)quinolin-6-yl] methanol
Figure imgf000196_0001
The title compound was prepared in analogy to Example 3-1 in Scheme 5 by using 4-chloro-2- (1,1 -dioxido-2,3-dihydro- 1 ,4-benzothiazepin-4(5H)-yl)-quinoline-6-methanol and 3-
(aminomethyl)oxetan-3-amine. MS obsd. (ESI+) [(M+H)+] 455, 1H NMR (400 MHz, CD3OD) δ ppm 8.33 (s, 1 H), 8.08 - 8.05 (d, J= 11.2 Hz, 2 H), 7.94 - 7.92 (d, J= 7.2 Hz, 1 H), 7.74 - 7.68 (m, 3 H), 7.57 - 7.53 ( t, J= 7.6 Hz, 1 H), 6.26 (s, 1 H), 5.31 (s, 2 H), 4.72 (s, 2 H), 44.57 (s, 4 H), 4.44 (s, 1 H), 3.88 (s, 2 H), 3.77 - 3.71 (m, 2 H).
Example 3-24 V-[(3-Aminooxetan-3-yl)methyl]-2-(l,l-dioxido-2,3-dihydro-l,4-benzothiazepin-4(5H)-yl)- 7-fluoro-6-methylquinolin-4-amine
Figure imgf000196_0002
The title compound was prepared in analogy to Example 3-1 in Scheme 5 by using 4-(4-chloro- 7-fluoro-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-l,4-benzothiazepine 1,1-dioxide (prepared in analogy to 4-(4-chloro-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-l,4-benzothiazepine 1,1- dioxide in Example 2-1 by using 2,4-dichloro-7-fluoro-6-methylquinoline and 2,3,4,5- tetrahydro-l,4-benzothiazepine) and 3-(aminomethyl)oxetan-3-amine. MS obsd. (ESI )
[(M+H)+] 457, 1H NMR (400 MHz, CD3OD) δ ppm 8.05 - 8.03 (d, J= 8.0 Hz, 1 H), 7.92 - 7.88 (t, J= 8.8, 8.0 Hz, 2 H), 7.68 - 7.65 (m, 1 H), 7.53 - 7.49 ( t, J= 7.6 Hz, 1 H), 7.28 - 7.25 (d, J = 11.6 Hz, 1 H), 6.20 (s, 1 H), 5.24 (s, 2 H), 4.66 - 4.48 (m, 6 H), 3.82 (s, 2 H), 3.66 - 3.64 (m, 2 H), 2.68 (s, 3 H).
Example 3-25
TV- [(3- Aminooxetan-3-yl)methyl] -2-(l , l-dioxido-2,3-dihydro- 1 ,4-benzothiazepin-4(5H)-yl)- 5-fluoro-6-methylquinolin-4-amine
Figure imgf000197_0001
The title compound was prepared in analogy to Example 3-1 in Scheme 5 by using 4-(4-chloro- 5-fluoro-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-l,4-benzothiazepine 1,1-dioxide (prepared in analogy to 4-(4-chloro-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-l,4-benzothiazepine 1,1- dioxide in Example 2-1 by using 2,4-dichloro-5-fluoro-6-methylquinoline and 2,3,4,5- tetrahydro-l,4-benzothiazepine) and 3-(aminomethyl)oxetan-3-amine. MS obsd. (ESI )
[(M+H)+] 457, 1H NMR (400 MHz, DMSO- d6) δ ppm 7.99 - 7.97 (d, J= 7.2 Hz, 1 H), 7.90 - 7.88 (m, 1 H), 7.66 - 7.62 (m, 1 H), 7.51 - 7.47 ( t, J= 7.6 Hz, 1 H), 7.29 - 7.24 (t, J= 8.8, 8.4 Hz, 1 H), 7.20 - 7.18 (d, J = 8.4 Hz, 1 H), 6.61 - 6.57 (d, J= 16.0 Hz, 1 H), 6.12 (s, 1 H), 5.11 (s, 2 H), 4.44 - 4.43 (d, J= 6.0 Hz, 2 H), 4.38 - 4.37 (d, J= 6.0 Hz, 2 H), 3.63 - 3.61 (t, J= 4.8, 4.4 Hz, 2 H), 3.53 (s, 2 H), 2.68 - 2.67 (t, J= 2.0, 1.6 Hz, 1 H), 2.34 - 2.33 (t, J= 2.0, 1.6, 1 H), 1.92 (s, 3 H).
Example 3-26 V~l~-[6-Chloro-2-(l,l-dioxido-2,3-dihydro-l,4-benzothiazepin-4(5H)-yl)quinolin-4-yl]-2- methylpropane- 1 ,2-diamine
Figure imgf000198_0001
The title compound was prepared in analogy to Example 3-1 in Scheme 5 by using 4-(4,6- dichloroquinolin-2-yl)-2,3,4,5-tetrahydro-l,4-benzothiazepine 1,1-dioxide (prepared in analogy to 4-(4-chloro-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-l,4-benzothiazepine 1,1-dioxide in Example 2-1 by using 2,4, 6-trichloroquino line and 2,3,4,5-tetrahydro-l,4-benzothiazepine) and 2-methylpropane-l,2-diamine. MS obsd. (ESI+) [(M+H)+] 445, 1H NMR (400 MHz, CD3OD) δ ppm 7.98 (d, J= 8.0 Hz, 2 H), 7.87 (d, J= 7.2 Hz, 1 H), 7.61 (t, J= 7.2 Hz, 1 H), 7.49 -7.43 (m, 2 H), 7.38 (dd, J= 2.0, 8.8 Hz, 1 H), 6.13 (s, 1 H), 5.16 (s, 2 H), 4.54 (brs, 2 H), 3.57 (t, J= 4.4 Hz, 2 H), 3.27 (s, 2 H), 1.26 (s, 6 H). Example 3-27
2-(l , l-Dioxido-2,3-dihydro- 1 ,4-benzothiazepin-4(5H)-yl)-6-methyl-N-(tetrahydi
pyran-4-yl)quinolin-4-amine
Figure imgf000198_0002
The title compound was prepared in analogy to Example 3-1 in Scheme 5 by using 4-(4-chloro- 6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-l,4-benzothiazepine 1,1-dioxide (prepared in analogy to the one in Example 2-1) and tetrahydro-2H-pyran-4-ylamine. MS obsd. (ESI ) [(M+H)+] 438, 1H NMR (400 MHz, DMSO- d6) δ ppm 7.89 (dd, J= 6.95, 3.41 Hz, 2 H), 7.78 (s, 1 H), 7.59 (t, J = 7.07 Hz, 1 H), 7.47 (t, J= 7.58 Hz, 1 H), 7.31 (d, J= 8.59 Hz, 1 H), 7.23 (d, J= 8.59 Hz, 1 H), 6.33 (d, J= 8.08 Hz, 1 H), 6.09 (s, 1 H), 5.09 (brs, 2 H), 4.44 (brs, 1 H), 3.99 (d, J= 9.85 Hz, 2 H), 3.94 - 3.82 (m, 1 H), 3.69 - 3.52 (m, 4 H), 2.36 (s, 3 H), 1.85 (d, J= 11.87 Hz, 2 H), 1.69 - 1.44 (m, 2 H).
Example 3-28 2-(l , l-Dioxido-2,3-dihydro- 1 ,4-benzothiazepin-4(5H)-yl)-6-methykV- [2-(piperazin- 1- yl)ethyl] quinolin-4-amine
Figure imgf000199_0001
The title compound was prepared in analogy to Example 3-1 in Scheme 5 by using 4-(4-chloro- 6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-l,4-benzothiazepine 1,1-dioxide (prepared in analogy to the one in Example 2-1) and 2-(piperazin-l-yl)ethanamine. MS obsd. (ESI ) [(M+H)+] 466, 1H NMR (400 MHz, DMSO- 6) 5ppm 7.925 (d, J= 8.0 Hz, 1 H), 7.806 (d, J= 7.2 Hz, 1 H), 7.516 - 7.575 (m, 2 H), 7.359 - 7.395 (m, 2 H), 7.238 (m, 1 H), 5.98 (s, 1 H), 5.10 (s, 2 H), 4.49 (brs, 2 H), 3.538 (m, 2 H), 3.542 (m, 2 H), 3.44 (t, J= 6.57 Hz, 2 H), 3.32 (s, 2 H), 2.89 (t, J= 4.80 Hz, 4 H), 2.71 (t, J= 6.57 Hz, 2 H), 2.56 (brs, 4 H), 2.37 (s, 3 H).
Example 3-29
2-(l , l-Dioxido-2,3-dihydro- 1 ,4-benzothiazepin-4(5H)-yl)-6-methyl- V-(piperidin-4- ylmethyl)quinolin-4-amine
Figure imgf000199_0002
The title compound was prepared in analogy to Example 3-1 in Scheme 5 by using 4-(4-chloro- 6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-l,4-benzothiazepine 1,1-dioxide (prepared in analogy to the one in Example 2-1) and l-(piperidin-4-yl)methanamine. MS obsd. (ESI ) [(M+H)+] 451, 1H NMR (400 MHz, DMSO- d6) δ ppm 9.89 (brs, 2 H), 7.875 (t, J= 8.0 Hz, 2 H), 7.76 (s, 1 H), 7.625 (t, J= 6.8Hz, 1 H), 7.48 (d, J= 7.6Hz, 1 H), 7.30 (d, J= 8.4Hz, 1 H), 7.226 (d, J= 1.6Hz ,1 H), 6.73 (t, J= 5.43 Hz, 1 H), 5.07 (brs, 2 H), 4.42 (brs, 2 H), 4.10 (d, J= 12.63 Hz, 2 H), 3.63(m, 2 H), 3.23 - 3.05 (m, 2 H), 2.50 (s, 2 H), 2.05(s, 3 H), 1.76 - 1.66 (m, 3 H), 1.15 - 0.98 (m, 2 H). Example 3-30 V-[2-(l,l-Dioxido-2,3-dihydro-l,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4- yl] heptane- 1 ,7-diamine
Figure imgf000200_0001
The title compound was prepared in analogy to Example 3-1 in Scheme 5 by using 4-(4-chloro- 6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-l,4-benzothiazepine 1,1-dioxide (prepared in analogy to the one in Example 2-1) and heptane- 1,7-diamine. MS obsd. (ESI+) [(M+H)+] 467, 1H NMR (400 MHz, CD3OD) δ ppm 8.07 (dd, J= 1.2, 0.8 Hz, 1 H), 7.97 (s, 1 H), 7.92(d, J= 7.6 Hz, 1 H), 7.74 - 7.68 (m, 2 H), 7.61-7.56 (m, 2 H), 5.91 (s, 1 H), 5.32 (s, 2 H), 4.52 (brs, 2 H), 3.75 (d, J= 4.80 Hz, 2 H), 3.31 (d, J= 1.60 Hz, 2 H), 2.94(m, 2 H), 2.45 (s, 3 H), 1.72 (m, 4 H), 1.50 (m, 6 H).
Example 3-31 V-[2-(l,l-Dioxido-2,3-dihydro-l,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]- V'- methylethane- 1 ,2-diamine
Figure imgf000200_0002
The title compound was prepared in analogy to Example 3-1 in Scheme 5 by using 4-(4-chloro- 6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-l,4-benzothiazepine 1,1-dioxide (prepared in analogy to the one in Example 2-1) and N-methylethane-l,2-diamine. MS obsd. (ESI+) [(M+H)+] 411, 1H NMR (400 MHz, CD3OD) δ ppm 8.03 - 8.0 (m, 3 H), 7.87 - 7.84 (d, J= 8.8 Hz, 1 H), 7.71 - 7.70 (d, J= 1.2 Hz, 1 H), 7.57 - 7.53 (m, 2 H), 6.07 (s, 1 H), 5.40 (s, 2 H), 4.56 (s, 2 H), 3.96 - 3.93 (dd, J= 6.0, 6.4 Hz, 2 H), 3.75 - 3.73 (q, J= 4.4 Hz, 2 H), 3.43 - 3.40 (q, J= 6 Hz, 2 H), 2.80 (s, 3 H), 2.46 (s, 3 H).
Example 3-32 V'-[2-(l,l-Dioxido-2,3-dihydro-l,4-benzothiazepin-4(5/^-yl)-6-methylquinolin-4-yl]- V, V- dimethylethane- 1 ,2-diamine
Figure imgf000201_0001
The title compound was prepared in analogy to Example 3-1 in Scheme 5 by using 4-(4-chloro- 6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-l,4-benzothiazepine 1,1-dioxide (prepared in analogy to the one in Example 2-1) and N,N-dimethylethane-l,2-diamine. MS obsd. (ESI+) [(M+H)+] 425, 1H NMR (400 MHz, CD3OD) δ ppm 8.05 - 8.01 (m, 3 H), 7.88 - 7.86 (d, J= 8.8 Hz, 1 H), 7.70 - 7.68 (d, J= 1.2 Hz, 1 H), 7.56 - 7.52 (m, 2 H), 6.05 (s, 1 H), 5.41 (s, 2 H), 4.56 (s, 2 H), 3.96 - 3.93 (dd, J = 6.0, 6.4 Hz, 2 H), 3.75-3.73 (q, J= 4.4 Hz, 2 H), 3.43 - 3.40 (q, J= 6.0 Hz, 2 H), 3.01 (s, 3 H), 2.45 (s, 3 H).
Example 3-33
2-(l , l-Dioxido-2,3-dihydro- 1 ,4-benzothiazepin-4(5H)-yl)- V,6-dimethylquinolin-4-amine trifluoroacetate
Figure imgf000201_0002
The title compound was prepared in analogy to Example 3-1 in Scheme 5 by using 4-(4-chloro- 6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-l,4-benzothiazepine 1,1-dioxide (prepared in analogy to the one in Example 2-1) and methylamine. MS obsd. (ESI+) [(M+H)+] 368, 1H NMR (400 MHz, DMSO- 6) δ ppm 11.47 (s, 1 H), 8.45 (brs, 1 H), 7.99 (m, 3 H), 7.75 (m, 2 H), 7.60 (m, 2 H), 5.92 (s, 1 H), 5.33 (s, 2 H), 4.48 (s, 2 H), 3.91 (s, 2 H), 3.02 (s, 3 H), 2.33 (s, 3 H). Example 3-34
(3S,4S)-l-[2-(l,l-Dioxido-2,3-dihydro-l,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4- yl] pyrrolidine-3,4-diol
Figure imgf000202_0001
The title compound was prepared in analogy to Example 3-1 in Scheme 5 by using 4-(4-chloro- 6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-l,4-benzothiazepine 1,1-dioxide (prepared in analogy to the one in Example 2-1) and (3S,4S)-pyrrolidine-3,4-diol. MS obsd. (ESI+) [(M+H)+] 440, 1H NMR (400 MHz, CD3OD) δ ppm 8.03 (s, 1 H),8.01 (s, 1 H), 7.80 - 7.78 (d, J= 7.6 Hz, 1 H), 7.67 - 7.63 (m, 2 H), 7.54 - 7.50 (m, 2 H), 5.83 (s, 1 H), 5.21 (s, 2 H), 4.45 (s, 2 H), 4.22 (s, 2 H), 4.18 - 4.15 (m, 2 H), 3.67 - 3.60 (m, 4 H), 2.41 (s, 3 H).
Example 3-35
2-(l , l-Dioxido-2,3-dihydro- 1 ,4-benzothiazepin-4(5H)-yl)-6-methyl- V-(pyrrolidin-2- ylmethyl)quinolin-4-amine
Figure imgf000202_0002
The title compound was prepared in analogy to Example 3-1 in Scheme 5 by using 4-(4-chloro- 6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-l,4-benzothiazepine 1,1-dioxide (prepared in analogy to the one in Example 2-1) and l-(pyrrolidin-2-yl)methanamine. MS obsd. (ESI ) [(M+H)+] 437, 1H NMR (400 MHz, CD3OD) δ ppm 7.96 - 7.94 (m, 2 H), 7.90 (d, J= 7.6 Hz, 1 H), 7.70 (d, J = 8.4 Hz, 1 H), 7.61 (t, J= 7.6 Hz, 1 H), 7.47 - 7.45 (m, 2 H), 6.01 (s, 1 H), 5.33 - 5.25 (m, 2 H), 4.55 - 4.41 (m, 2 H), 3.96 - 3.73 (m, 3 H), 3.64 (s, 2 H), 3.38 - 3.31 (m, 1 H), 3.29 - 3.27 (m, 1 H), 2.37 (s, 3 H), 2.28 - 2.21 (m, 1 H), 2.13 - 1.96 (m, 2 H), 1.89 - 1.81 (m, 1 H).
Example 3-36 4-[4-(l,4-Diazepan-l-yl)-6-methylquinolin-2-yl]-2,3,4,5-tetrahydro-l,4-benzothiazepine 1,1- dioxide
Figure imgf000203_0001
The title compound was prepared in analogy to Example 3-1 1 in Scheme 5 by using 4-(4- chloro-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-l,4-benzothiazepine 1,1-dioxide (prepared in analogy to the one in Example 2-1) and 1,4-diazepine. MS obsd. (ESI+) [(M+H)+] 437, 1H NMR (400 MHz, CD3OD) δ ppm 7.99 (d, J= 7.2 Hz, 1 H), 7.86 (d, J= 7.2 Hz, 1 H), 7.81 (d, J= 8.8 Hz, 1 H), 7.72 - 7.68 (m, 2 H), 7.58 - 7.51 (m, 2 H), 6.31 (s, 1 H), 5.32 (s, 2 H), 4.54 (s, 2 H), 4.06 - 4.04 (m, 2 H), 3.90 - 3.87 (m, 2 H), 3.72 (s, 2 H), 3.63 - 3.61 (m, 2 H), 3.46 - 3.42 (m, 2 H), 2.45 (s, 3 H), 2.32 (s, 2 H).
Example 3-37 V-[2-(l,l-Dioxido-2,3-dihydro-l,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]- V- ethylethane- 1 ,2-diamine
Figure imgf000203_0002
The title compound was prepared in analogy to Example 3-1 in Scheme 5 by using 4-(4-chloro- 6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-l,4-benzothiazepine 1,1-dioxide (prepared in analogy to the one in Example 2-1) and N-ethylethane-l,2-diamine. MS obsd. (ESI+) [(M+H)+] 425, 1H NMR (400 MHz, CD3OD) δ ppm 8.05 (d, J= 7.2 Hz, 1 H), 7.99 - 7.97 (m, 2 H), 7.81 (d, J= 8.4 Hz, 1 H), 7.67 (t, J= 7.2 Hz, 1 H), 7.51 - 7.46 (m, 2 H), 6.08 (s, 1 H), 5.37 (s, 2 H), 4.57 (s, 2 H), 3.91 (t, J = 6.4 Hz, 2 H), 3.69 (t, J = 4.8 Hz, 2 H), 3.37 (t, J= 6.4 Hz, 2 H), 3.15 (q, J= 7.2 Hz, 2 H), 2.43 (s, 3 H), 1.35 (t, J = 7.2 Hz, 3 H). Example 3-38
2- { [2-(l , l-Dioxido-2,3-dihydro- 1 ,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4- yl] amino} ethanol
Figure imgf000204_0001
The title compound was prepared in analogy to Example 3-1 in Scheme 5 by using 4-(4-chloro- 6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-l,4-benzothiazepine 1,1-dioxide (prepared in analogy to the one in Example 2-1) and 2-aminoethanol. MS obsd. (ESI+) [(M+H)+] 398, 1H NMR (400 MHz, CD3OD) δ ppm 8.08 (d, J= 7.6 Hz, 1 H), 7.91 (s, 1 H), 7.85 (d, J= 7.6 Hz, 1 H), 7.74 - 7.67 (m, 2 H), 7.59 - 7.56 (m, 2 H), 6.09 (s, 1 H), 5.29 (s, 2 H), 4.51 (s, 2 H), 3.83 (t, J= 5.6 Hz, 2 H), 3.74 - 3.72 (m, 2 H), 3.62 (t, J = 5.6 Hz, 2 H), 2.47 (s, 3 H).
Example 3-39
2-(l , l-Dioxido-2,3-dihydro- 1 ,4-benzothiazepin-4(5H)-yl)-6-methyl- V-(piperidin-4- yl)quinolin-4-amine
Figure imgf000204_0002
The title compound was prepared in analogy to Example 3-1 in Scheme 5 by using 4-(4-chloro- 6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-l,4-benzothiazepine 1,1-dioxide (prepared in analogy to the one in Example 2-1) and piperidin-4-amine. MS obsd. (ESI+) [(M+H)+] 437, 1H NMR (400 MHz, CD3OD) δ ppm 8.05 (t, J= 8 Hz, 2 H), 7.88 (d, J= 8 Hz, 1 H), 7.73 - 7.69 (m, 2 H), 7.59 - 7.57 (m, 2 H), 6.04 (s, 1 H), 5.33 (s, 2 H), 4.52 (s, 2 H), 4.18 - 4.11 (m, 1 H), 3.74 (s, 2 H), 3.61 - 3.57 (m, 2 H), 3.33 - 3.26 (m, 2 H), 2.46 (s, 3 H), 2.24 - 2.19 (m, 2 H), 2.01 - 1.91 (m, 2 H).
Example 3-40 2-(l , l-Dioxido-2,3-dihydro- 1 ,4-benzothiazepin-4(5H)-yl)-6-methyl- V-(piperidin-3- yl)quinolin-4-amine
Figure imgf000205_0001
The title compound was prepared in analogy to Example 3-1 in Scheme 5 by using 4-(4-chloro- 6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-l,4-benzothiazepine 1,1-dioxide (prepared in analogy to the one in Example 2-1) and piperidin-3-amine. MS obsd. (ESI+) [(M+H)+] 437, 1H NMR (400 MHz, CD3OD) δ ppm 8.09 - 8.07 (d, J= 8 Hz, 1 H), 7.99 (s, 1 H), 7.89 - 7.87 (q, J= 7.2 Hz, 1 H), 7.73 - 7.68 (q, J= 14 Hz, 2 H), 7.62 - 7.55 (m, 2 H), 6.14 (s, 1 H), 5.36 (s, 2 H), 4.58 - 4.51 (m, 2 H), 4.34 (s, 1 H), 3.75 (s, 2 H), 3.63 - 3.60 (d, J= 11.6 Hz, 1 H), 3.47 - 3.44 (m, 1 H), 3.07 - 3.02 (d, J= 11.6 Hz, 2 H), 2.47 (s, 3 H), 2.17 - 2.14 (m, 2 H), 2.05 - 2.00 (m, 1 H), 1.85 - 1.84 (m, 1 H).
Example 3-41
2-(l , l-Dioxido-2,3-dihydro- 1 ,4-benzothiazepin-4(5H)-yl)-6-methyl- V-(piperidin-2- ylmethyl)quinolin-4-amine
Figure imgf000205_0002
The title compound was prepared in analogy to Example 3-1 in Scheme 5 by using 4-(4-chloro- 6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-l,4-benzothiazepine 1,1-dioxide (prepared in analogy to the one in Example 2-1) and l-(piperidin-2-yl)methanamine. MS obsd. (ESI ) [(M+H)+] 451, 1H NMR (400 MHz, CD3OD) δ ppm 8.07 (d, J= 7.6 Hz, 1 H), 7.93 (s, 1 H), 7.85 (d, J= 7.6 Hz, 1 H), 7.73 - 7.70 (m, 2 H), 7.62 - 7.58 (m, 2 H), 6.02 (s, 1 H), 5.35 (s, 2 H), 4.51 (s, 2 H), 3.75 - 3.71 (m, 4 H), 3.51 - 3.40 (m, 2 H), 2.98 - 2.92 (m, 1 H), 2.46 (s, 3 H), 2.11 - 2.05 (m, 1 H), 1.96 - 1.90 (m, 2 H), 1.78 - 1.56 (m, 3 H).
Example 3-42
2-[(2-{[2-(l,l-Dioxido-2,3-dihydro-l,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4- yll amino] eth v l)amino I ethanol
Figure imgf000206_0001
The title compound was prepared in analogy to Example 3-1 in Scheme 5 by using 4-(4-chloro- 6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-l,4-benzothiazepine 1,1-dioxide (prepared in analogy to the one in Example 2-1) and 2-[(2-aminoethyl)amino]ethanol. MS obsd. (ESI+) [(M+H)+] 441, 1H NMR (400 MHz, CD3OD) δ ppm 7.94 (d, J= 7.6 Hz, 1 H), 7.81 (d, J= 6.8 Hz, 1 H), 7.61 - 7.57 (m, 2 H), 7.43 - 7.38 (m, 2 H), 7.24 (d, J= 7.6 Hz, 1 H), 6.02 (s, 1 H), 5.12 (s, 2 H), 4.51 (brs, 2 H), 3.69 (t, J= 5.2 Hz, 2 H), 3.55 - 3.52 (m, 2 H), 3.49 (t, J= 6.0 Hz, 2 H), 3.01 (t, J= 6.0 Hz, 2 H), 2.83 (t, J= 5.6 Hz, 2 H), 2.38 (s, 3 H).
Example 3-43 V-[2-(l,l-Dioxido-2,3-dihydro-l,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]-2,2,3,3- tetrafluorobutane- 1 ,4-diamine
Figure imgf000206_0002
The title compound was prepared in analogy to Example 3-1 in Scheme 5 by using 4-(4-chloro- 6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-l,4-benzothiazepine 1,1-dioxide (prepared in analogy to the one in Example 2-1) and 2,2,3,3-tetrafluorobutane-l,4-diamine. MS obsd. (ESI )
[(M+H)+] 497, 1H NMR (400 MHz, CD3OD) δ ppm 7.99 (d, J= 6.8 Hz, 1 H), 7.78 (d, J= 6.4 Hz, 1 H), 7.58 - 7.62 (m, 2 H), 7.43 - 7.47 (m, 2 H), 7.30 - 7.32 (m, 1 H), 6.19 (s, 1 H), 5.13 (s, 2 H), 4.58 (brs, 2 H), 4.12 (t, J= 16 Hz, 2 H), 3.58 (t, J= 4.8 Hz 2 H), 3.34 - 3.20 (m, 2 H), 2.43 (s, 3 H). Example 3-44 V-[2-(l,l-Dioxido-2,3-dihydro-l,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]- V-(2- methoxyethyl)ethane- 1 ,2-diamine
Figure imgf000207_0001
The title compound was prepared in analogy to Example 3-1 1 in Scheme 5 by using 4-(4- chloro-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-l,4-benzothiazepine 1,1-dioxide (prepared in analogy to the one in Example 2-1) and N-(2-methoxyethyl)ethane-l,2-diamine. MS obsd. (ESI ) [(M+H)+] 455, 1H NMR (400 MHz, CD3OD) δ ppm 8.06 - 8.04 (d, J= 7.6 Hz, 1 H), 7.88 - 7.86 (m, 2 H), 7.73 - 7.70 (m, 2 H), 7.59 - 7.56 (m, 2 H), 6.01 (s, 1 H), 5.33 (s, 2 H), 4.55 (s, 2 H), 3.88 - 3.78 (m, 2 H), 3.72 (s, 2 H), 3.67 - 3.65 (t, J= 4.8 Hz, 2 H), 3.45 - 3.42 (t, J= 6 Hz, 2 H), 3.38 (s, 3 H), 3.30 - 3.28 (m, 2 H), 2.45 (s, 3 H).
Example 3-45 l-[2-(l,l-Dioxido-2,3-dihydro-l,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]-3- methylpyrrolidin-3-ol
Figure imgf000207_0002
The title compound was prepared in analogy to Example 3-1 in Scheme 5 by using 4-(4-chloro- 6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-l,4-benzothiazepine 1,1-dioxide (prepared in analogy to the one in Example 2-1) and 3-methylpyrrolidin-3-ol. MS obsd. (ESI+) [(M+H)+] 438, 1H NMR (400 MHz, CD3OD) δ ppm 8.06 - 8.01 (m, 2 H), 7.84 - 7.82 (d, J= 7.2 Hz, 1 H), 7.74 - 7.68 (m, 2 H), 7.57 - 7.53 (m, 2 H), 5.81 (s, 1 H), 5.26 (s, 2 H), 4.49 (s, 2 H), 4.12 -3.31 (m, 3 H), 3.27 -3.21 (m, 3 H), 2.44 (s, 3 H), 2.08 (s, 2 H), 1.50 (s, 3 H).
Example 3-46 V-[6-Chloro-2-(l,l-dioxido-2,3-dihydro-l,4-benzothiazepin-4(5H)-yl)quinolin-4-yl]ethane- 1,2-diamine
Figure imgf000208_0001
The title compound was prepared in analogy to Example 3-1 in Scheme 5 by using 4-(4,6- dichloroquinolin-2-yl)-2,3,4,5-tetrahydro-l,4-benzothiazepine 1,1-dioxide (prepared in analogy to 4-(4-chloro-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-l,4-benzothiazepine 1,1-dioxide in Example 2-1 by using 2,4, 6-trichloroquino line and 2,3,4,5-tetrahydro-l,4-benzothiazepine) and ethane- 1,2-diamine. MS obsd. (ESI+) [(M+H)+] 417, 1H NMR (400 MHz, CD3OD) δ ppm 8.01 - 7.99 (d, J= 8.8 Hz, 1 H), 7.90 (s, 1 H), 7.86 -7.84 (d, J= 7.2 Hz, 1 H), 7.53 - 7.38 (m, 4 H), 6.10 (s, 1 H), 5.18(s, 2 H), 3.59-3.40 (m, 4 H), 3.19 - 3.10 (m, 2 H).
.Example 3-47 2-(l , l-Dioxido-2,3-dihydro- 1 ,4-benzothiazepin-4(5H)-yl)-6-methyl- V-(oxetan-3-yl)quinolin- 4-amine
Figure imgf000208_0002
The title compound was prepared in analogy to Example 3-1 in Scheme 5 by using 4-(4-chloro- 6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-l,4-benzothiazepine 1,1-dioxide (prepared in analogy to the one in Example 2-1) and oxetan-3-amine. MS obsd. (ESI+) [(M+H)+] 410, 1H NMR (400 MHz, CD3OD) δ ppm 7.97 (d, J= 1.9 Hz, 1 H), 7.79 (d, J= 1.9 Hz, 1 H), 7.72 (s, 1 H), 7.63 (t, J = 3.8 Hz, 1 H), 7.44 (t, J= 4.3 Hz, 2 H), 7.29 (d, J= 2.1 Hz, 1 H), 5.72 (s, 1 H), 5.16 (t, J= 3.3 Hz, 2 H), 5.12 (s, 2 H), 4.86 (m, 1 H), 4.72 (t, J= 3.0 Hz, 2 H), 4.53 (brs, 2 H), 3.58 (t, J= 2.3 Hz, 2 H), 2.43 (s, 3 H). Example 3-48
TV- [(3- Aminooxetan-3-yl)methyl] -2-(l , l-dioxido-2,3-dihydro- 1 ,4-benzothiazepin-4(5H)- yl)quinolin-4-amine
Figure imgf000209_0001
The title compound was prepared in analogy to Example 3-1 in Scheme 5 by using 4-(4- chloroquinolin-2-yl)-2,3,4,5-tetrahydro-l,4-benzothiazepine 1,1-dioxide (prepared in analogy to 4-(4-chloro-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro- 1 ,4-benzothiazepine 1 , 1 -dioxide in Example 2-1 by using 2,4-dichloroquinoline and 2,3,4,5-tetrahydro-l,4-benzothiazepine) and 3- (aminomethyl)oxetan-3-amine. MS obsd. (ESI+) [(M+H)+] 425, 1H NMR (400 MHz, CD3OD) δ ppm 7.96 (d, J= 1.8 Hz, 1 H), 7.89 (m, J= 5.5 Hz, 2 H), 7.63 (m, J= 4.0 Hz, 1 H), 7.44 (m, J = 7.6 Hz, 3 H), 7.12 - 7.08 (m, J = 4.1 Hz, 1 H), 6.58 (d, J = 0.8 Hz, 1 H), 6.22 (s, 1 H), 5.11 (s, 2 H ), 4.48 - 4.39 (m, J= 9.0 Hz, 6 H), 3.65 - 3.58 (m, J = 6.1 Hz, 4 H). Example 3-49
2-(l , l-Dioxido-2,3-dihydro- 1 ,4-benzothiazepin-4(5H)-yl)-6-methy 1- V- [(3R)- tetrahydrofuran-3-yl]quinolin-4-amine
Figure imgf000209_0002
The title compound was prepared in analogy to Example 3-1 in Scheme 5 by using 4-(4-chloro- 6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-l,4-benzothiazepine 1,1-dioxide (prepared in analogy to the one in Example 2-1) and (3i?)-tetrahydrofuran-3-amine. MS obsd. (ESI+) [(M+H)+] 424, 1H NMR (400 MHz, CD3OD) δ ppm 7.89 (t, J= 4.4 Hz, 2 H), 7.83 (s, 1 H), 7.65 (t, J= 3.7 Hz, 1 H), 7.47 (t, J= 3.8 Hz, 1 H), 7.31 (d, J= 2.1 Hz, 1 H), 7.24 (d, J= 2.1 Hz, 1 H), 6.56 (d, J= 1.5 Hz, 1 H), 6.01 (s, 1 H), 5.08 (s, 2 H), 4.40 (brs, 2 H), 4.02 (t, J= 3.6 Hz, 1 H), 3.88 (m, J= 7.2 Hz, 1 H), 3.80 (m, J= 5.4 Hz, 1 H), 3.64 (d, J= 4.5 Hz, 3 H), 2.30 (t, J= 3.7 Hz, 4 H).
Example 3-50 N- { [3-(Aminomethyl)oxetan-3-yl] methyl}-2-(l , l-dioxido-2,3-dihydro- 1 ,4-benzothiazepin- 4(5H)-yl)-6-methylquinolin-4-amine
Figure imgf000210_0001
The title compound was prepared in analogy to Example 3-1 in Scheme 5 by using 4-(4-chloro- 6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-l,4-benzothiazepine 1,1-dioxide (prepared in analogy to the one in Example 2-1) and oxetane-3,3-diyldimethanamine. MS obsd. (ESI ) [(M+H)+] 453, 1H NMR (400 MHz, CD3OD) δ ppm 8.04 (d, J= 1.8 Hz, 1 H), 7.90 (d, J= 1.9 Hz, 1 H), 7.81 (s, 1 H), 7.67 (t, J= 3.6 Hz, 1 H), 7.57 (d, J= 2.1 Hz, 1 H), 7.52 (t, J= 3.8 Hz, 1 H),7.43 (d, J= 2.1 Hz, 1 H), 6.21 (s, 1 H), 5.26 (s, 2 H), 4.63 (s, 4 H), 4.55 (brs, 2 H), 3.82 (s, 2 H ), 3.67 (t, J= 2.4 Hz, 2 H ), 3.45 (brs, 2 H), 2.46 (s, 3 H).
Example 3-51
TV- { [3-(Aminomethyl)oxetan-3-yl] methyl}-6-chloro-2-(l , l-dioxido-2,3-dihydro- 1 ,4- benzothiazepin-4(5H)-yl)quinolin-4-amine
Figure imgf000210_0002
The title compound was prepared in analogy to Example 3-1 in Scheme 5 by using 4-(4,6- dichloroquinolin-2-yl)-2,3,4,5-tetrahydro-l,4-benzothiazepine 1,1-dioxide (prepared in analogy to 4-(4-chloro-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-l,4-benzothiazepine 1,1-dioxide in Example 2-1 by using 2,4, 6-trichloroquino line and 2,3,4,5-tetrahydro-l,4-benzothiazepine) and oxetane-3,3-diyldimethanamine. MS obsd. (ESI+) [(M+H)+] 473, 1H NMR (400 MHz, CD3OD) δ ppm 8.00 (m, J= 2.2 Hz, 1 H), 7.89 (t, J= 2.9 Hz, 2 H), 7.63 (m, J= 4.1, 1 H), 7.45 (m, J= 6.5 Hz, 2 H), 7.37 (m, J= 2.8 Hz, 1 H), 6.21 (d, 1 H), 5.18 (s, 2 H), 4.56 (m, J= 4.6 Hz, 6 H), 3.67 (s, 2 H), 3.58 (t, J= 2.4 Hz, 2 H ), 3.15 (s, 2 H).
Example 3-52 N- { [3-(Aminomethyl)oxetan-3-yl] methyl}-2-(l , l-dioxido-2,3-dihydro- 1 ,4-benzothiazepin- 4(5H)-yl)quinolin-4-amine
Figure imgf000211_0001
The title compound was prepared in analogy to Example 3-1 in Scheme 5 by using 4-(4- chloroquinolin-2-yl)-2,3,4,5-tetrahydro-l,4-benzothiazepine 1,1-dioxide (prepared in analogy to 4-(4-chloro-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro- 1 ,4-benzothiazepine 1 , 1 -dioxide in Example 2-1 by using 2,4-dichloroquinoline and 2,3,4,5-tetrahydro-l,4-benzothiazepine) and oxetane-3,3-diyldimethanamine. MS obsd. (ESI+) [(M+H)+] 439, 1H NMR (400 MHz, CD3OD) δ ppm 8.32 (d, J= 2.1 Hz, 1 H), 8.11 (t, J= 2.0 Hz, 1 H), 8.04 (d, J= 1.9 Hz, 1 H), 7.93 (d, J= 2.0 Hz, 1 H), 7.77 (m, J= 8.3 Hz, 2 H), 7.63 (t, J= 3.7 Hz, 1 H), 7.53 (d, J= 3.8 Hz, 1 H), 6.30 (s, 1 H), 5.45 (s, 2 H ), 4.65 (m, J= 5.5 Hz, 6 H), 4.01 (s, 2 H) , 3.83 (t, J= 2.4 Hz, 2 H ), 3.51 (s, 2 H).
Example 3-53
2-(l , l-Dioxido-2,3-dihydro- 1 ,4-benzothiazepin-4(5H)-yl)-6-methyl- V-(oxetan-3- ylmethyl)quinolin-4-amine
Figure imgf000211_0002
The title compound was prepared in analogy to Example 3-1 in Scheme 5 by using 4-(4-chloro- 6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-l,4-benzothiazepine 1,1-dioxide (prepared in analogy to the one in Example 2-1) and l-(oxetan-3-yl)methanamine. MS obsd. (ESI+) [(M+H)+] 424, 1H NMR (400 MHz, DMSO- 6) δ ppm 7.93 (d, 1 H), 7.89 - 7.87 (t, 1 H), 7.69 - 7.65 (m, 2 H), 7.50 - 7.46 (t, 1 H), 7.31 (d, 1 H), 7.24 - 7.21 (m, 1 H), 6.79 - 6.76 (t, 1 H), 6.04 (s, 1 H), 5.08 (s, 2 H), 4.74 - 4.70 (m, 2 H), 4.37 (t, 4 H), 3.61 (t, 4 H), 3.28 (m, 1 H), 2.35 (s, 3 H)
Example 3-54 N-[(l-Aminocyclobutyl)methyl]-2-(l,l-dioxido-2,3-dihydro-l,4-benzothiazepin-4(5H)-yl)-6- methylquinolin-4-amine
Figure imgf000212_0001
The title compound was prepared in analogy to Example 3-1 in Scheme 5 by using 4-(4-chloro- 6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-l,4-benzothiazepine 1,1-dioxide (prepared in analogy to the one in Example 2-1) and l-(aminomethyl)cyclobutanamine. MS obsd. (ESI ) [(M+H)+] 437, 1H NMR (400 MHz, CD3OD) δ ppm 7.97 (m, J= 2.0 Hz, 1 H), 7.86 (d, J= 1.8 Hz, 1 H), 7.70 (s, 1 H), 7.61 (t, J = 3.6 Hz, 1 H), 7.45 (m, J = 3.0 Hz, 2 H), 7.30 (m, J= 2.5 Hz, 1 H), 6.13 (s, 1 H), 5.18 (s, 2 H), 4.53 (br. s., 2 H), 3.59 (t, J= 2.3 Hz, 2 H), 3.46 (s, 2 H), 2.43 (s, 3 H), 2.28 - 2.22 (m, J= 6.3 Hz, 2 H ), 2.12 - 2.03 (m, J= 9.2 Hz, 2 H ), 1.97 - 1.82 (m, J= 14.7 Hz, 2 H).
Example 3-55 V-[2-(l,l-Dioxido-2,3-dihydro-l,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4- yl] pentane- 1 ,5-diamine
Figure imgf000212_0002
The title compound was prepared in analogy to Example 3-1 in Scheme 5 by using 4-(4-chloro- 6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-l,4-benzothiazepine 1,1-dioxide (prepared in analogy to the one in Example 2-1) and pentane- 1,5-diamine. MS obsd. (ESI+) [(M+H)+] 439, 1H NMR (400 MHz, CDC13) δ ppm 7.96 (d, J= 7.6 Hz, 1 H), 7.54 (d, J= 6.8 Hz 1 H), 7.42 (m, 2 H), 7.30 (d, J= 6.4 Hz, 1 H), 7.21 (m, 2 H), 5.81 (s, 1 H), 5.03 (s, 2 H), 4.61 (m, 2 H), 3.49 (brs, 2 H), 3.19 (m, 2 H), 2.71 (d, J= 6.40 Hz, 2 H), 2.94 (m, 2 H), 2.34 (s, 3 H), 1.61 (s, 2 H), 1.49 (m, 4 H).
Example 3-56 N-[2-(l,l-Dioxido-2,3-dihydro-l,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]hexane- 1,6-diamine
Figure imgf000213_0001
The title compound was prepared in analogy to Example 3-1 in Scheme 5 by using 4-(4-chloro- 6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-l,4-benzothiazepine 1,1-dioxide (prepared in analogy to the one in Example 2-1) and hexane-l,6-diamine. MS obsd. (ESI+) [(M+H)+] 453, 1H NMR (400 MHz, CD3OD) δ ppm 8.07 (dd, J= 1.2, 0.8 Hz, 1 H), 7.97 (s, 1 H), 7.92 (d, J= 7.6 Hz, 1 H), 7.80 (d, J= 8.8 Hz, 1 H), 7.70 (d, J= 1.2 Hz, 1 H), 7.57 (dd, J= 7.20, 1.6 Hz, 2 H), 5.91 (s, 1 H), 5.32 (s, 2 H), 4.52 (brs, 2 H), 3.75 (d, J= 4.80 Hz, 2 H), 3.31 (d, J= 1.60 Hz, 2 H), 2.94 (m, 2 H), 2.45 (s, 3 H), 1.72 (m, 4 H), 1.50 (m, 4 H).
Example 3-57 V-[2-(l,l-Dioxido-2,3-dihydro-l,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]-l,l,l- trifluoromethanesulfonamide hydrochloride
Figure imgf000213_0002
The title compound was prepared in analogy to Example 3-1 in Scheme 5 by using 4-(4-chloro- 6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-l,4-benzothiazepine 1,1-dioxide (prepared in analogy to the one in Example 2-1) and 1,1,1-trifluoromethanesulfonamide. MS obsd. (ESI ) [(M+H)+] 486, 1H NMR (400 MHz, DMSO- d6) δ ppm 7.99 - 7.92 (m, 2 H), 7.85 - 7.80 (d, J= 7.2 Hz, 1 H), 7.78 - 7.73 (d, J= 2 Hz, 1 H), 7.72 - 7.65 (t, J= 7.6 Hz, 1 H), 7.62 - 7.51 (m, 2 H), 7.13 (s, 1 H), 5.07 (s, 2 H), 4.60 - 4.40 (m, 2 H), 3.98 - 3.91 (t, J= 2.8 Hz, 2 H), 2.39 (s, 3 H).
Example 3-58 V-[2-(l,l-Dioxido-2,3-dihydro-l,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-
Figure imgf000214_0001
The title compound was prepared in analogy to Example 3-1 in Scheme 5 by using 4-(4-chloro- 6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-l,4-benzothiazepine 1,1-dioxide (prepared in analogy to the one in Example 2-1) and pyridazine-3-carboxamide. MS obsd. (ESI ) [(M+H)+] 460, 1H NMR (400 MHz, CD3OD) δ ppm 9.52 - 9.48 (d, J= 8 Hz, 1 H), 8.68 (s, 1 H), 8.62- 8.58 (d, J = 7.6 Hz ,1 H), 8.10 - 8.02 (m, 3 H), 7.94 (s, 1 H), 7.88 - 7.82 (d, J= 8 Hz ,1 H), 7.75 - 7.68 (t, J = 7.6 Hz , 2 H), 7.60 - 7.52 (t, J= 7.2 Hz, 1 H), 5.36 (s, 2 H), 4.80 - 4.55 (m, 2 H), 3.83 - 3.78 (t, J = 2.8 Hz , 2 H), 2.56 (s, 3 H).
Example 3-59 V-[2-(l,l-Dioxido-2,3-dihydro-l,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4- yl] benzamide
Figure imgf000214_0002
The title compound was prepared in analogy to Example 3-1 in Scheme 5 by using 4-(4-chloro- 6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-l,4-benzothiazepine 1,1-dioxide (prepared in analogy to the one in Example 2-1) and benzamide. MS obsd. (ESI+) [(M+H)+] 458, 1H NMR (400 MHz, CD3OD) δ ppm 8.64 (s, 1 H), 8.09 - 8.04 (m, 5 H), 7.89 - 7.87 (d, J = 8.4 Hz, 1 H), 7.75 - 7.67 (m, 3 H), 7.62 - 7.55 (m, 3 H), 5.34 (s, 2 H), 4.62 (s, 2 H), 3.76 (s, 2 H), 2.53 (s, 3 H).
Example 3-60 V-[2-(l,l-Dioxido-2,3-dihydro-l,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4- yljacetamide
Figure imgf000215_0001
The title compound was prepared in analogy to Example 3-1 in Scheme 5 by using 4-(4-chloro- 6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-l,4-benzothiazepine 1,1-dioxide (prepared in analogy to the one in Example 2-1) and acetamide. MS obsd. (ESI+) [(M+H)+] 396, 1H NMR (400 MHz, CD3OD) δ ppm 8.53 (s, 1 H), 8.10 - 8.06 (m, 2 H), 7.97 - 7.85 (d, J= 8.4 Hz, 1 H), 7.82 - 7.80 (d, J= 9.2 Hz, 1 H), 7.76 - 7.72 (m, 2 H), 7.58 - 7.54 (m, 2 H), 5.28 (s, 2 H), 4.60 (s, 2 H), 3.77 - 3.71 (m, 2 H), 2.52 (s, 3 H), 2.40 (s, 3 H).
Example 3-61 V-[2-(l,l-Dioxido-2,3-dihydro-l,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4- yl]piperidine-3-carboxamide
Figure imgf000215_0002
The title compound was prepared in analogy to Example 3-1 in Scheme 5 by using 4-(4-bromo- 6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-l,4-benzothiazepine 1,1-dioxide (prepared in analogy to 4-(4-chloro-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-l,4-benzothiazepine 1,1-dioxide in Example 2-1 by using 4,6-dibromoquinoline and 2,3,4,5-tetrahydro-l,4-benzothiazepine) and piperidine-3-carboxamide. MS obsd. (ESI+) [(M+H)+] 465, 1H NMR (400 MHz, CD3OD) δ ppm 8.47 (s, 1 H), 8.11 (s, 1 H), 8.07 - 8.05 (d, J= 1.2 Hz, 1 H), 7.98 - 7.96 (d, J= 7.2 Hz, 1 H), 7.83 - 7.80 (d, J= 8.4 Hz, 1 H), 7.70 - 7.64 (m, 2 H), 7.58 - 7.54 (m, 1 H), 5.29 (s, 1 H), 4.61 (s, 2 H), 3.76 (s, 2 H), 3.55 - 3.52 (m, 2 H), 3.43 - 3.34 (m, 3 H), 3.22 - 3.15 (m, 1 H), 2.52 (s, 3 H), 2.29 - 2.27 (m, 1 H), 2.06 - 2.02 (m, 1 H), 1.97 - 1.89 (m, 2 H).
Example 3-62 V-[2-(l,l-Dioxido-2,3-dihydro-l,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4- yl] piperidine-4-carboxamide
Figure imgf000216_0001
The title compound was prepared in analogy to Example 3-1 in Scheme 5 by using 4-(4-chloro- 6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-l,4-benzothiazepine 1,1-dioxide (prepared in analogy to the one in Example 2-1) and piperidine-4-carboxamide. MS obsd. (ESI ) [(M+H)+] 465, 1H NMR (400 MHz, CD3OD) δ ppm 8.50 (s, 1 H), 8.14 (s, 1 H), 8.01- 7.98 (d, J= 1.2 Hz, 1 H), 7.95 - 7.93 (d, J= 7.2 Hz, 1 H), 7.84 - 7.82 (d, J= 8.8 Hz, 1 H), 7.66 - 7.61 (m, 2 H), 7.52 - 7.51 (m, 1 H), 5.23 (s, 1 H), 4.59 (s, 2 H), 3.74 (s, 2 H), 3.57 - 3.54 (m, 2 H), 3.22 - 3.10 (m, 4 H), 2.50 (s, 3 H), 2.26 - 2.22 (m, 2 H), 2.14 - 2.08 (m, 2 H).
Example 3-63 3- [2-(l, l-Dioxido-2,3-dihydro- 1 ,4-benzothiazepin-4(5H yl)-6-methylquinolin-4-yl] -1,1- dimethylurea
Figure imgf000216_0002
The title compound was prepared in analogy to Example 3-1 in Scheme 5 by using 4-(4-chloro- 6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-l,4-benzothiazepine 1,1-dioxide (prepared in analogy to the one in Example 2-1) and 1,1-dimethylurea. MS obsd. (ESI+) [(M+H)+] 425, 1H NMR (400 MHz, CD3OD) δ ppm 7.83 (d, J= 7.6 Hz, 1 H), 7.68 (t, J= 3.6 Hz, 2 H), 7.42 (q, J= 7.2 Hz, 2 H), 7.23 - 7.20 (m, 2 H), 7.15 (s, 1 H), 5.00 (s, 2 H), 4.45 (brs, 2 H), 3.42 (s, 2 H), 3.02 (s, 6 H), 2.30 (s, 3 H).
Example 3-64 2-(l,l-Dioxido-2,3-dihydro-l,4-benzothiazepin-4(5H yl)-6-methyl- V-(l,2-oxazol-3- yl)quinolin-4-amine
Figure imgf000217_0001
The title compound was prepared in analogy to Example 3-1 in Scheme 5 by using 4-(4-bromo- 6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-l,4-benzothiazepine 1,1-dioxide (prepared in analogy to 4-(4-chloro-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-l,4-benzothiazepine 1,1-dioxide in Example 2-1 by using 4,6-dibromoquinoline and 2,3,4,5-tetrahydro-l,4-benzothiazepine) and l,2-oxazol-3-amine. MS obsd. (ESI+) [(M+H)+] 421, 1H NMR (400 MHz, CD3OD) δ ppm 8.72 (s, 1 H), 8.20 (s, 2 H), 8.14 (d, J= 7.2 Hz, 1 H), 8.07 (d, J= 7.6 Hz, 1 H), 7.83 (d, J= 8.8 Hz, 1 H), 7.63 -7.68 (m, 2 H), 7.56 (t, J= 7.6 Hz, 1 H), 6.65 (s, 1 H), 5.29 (s, 2 H), 4.61 (s, 2 H), 3.79 (s, 2 H), 2.54 (s, 3 H).
Example 3-65
TV- { [3-(Aminomethyl)oxetan-3-yl] methyl}-2-(l , l-dioxido-2,3-dihydro- 1 ,4-benzothiazepin- 4(5H)-yl)-6- trideuteriomethylquinolin-4-amine
Figure imgf000217_0002
The title compound was prepared in analogy to Example 3-1 in Scheme 5 by using 4-(4-chloro- 6- trideuteriomethylquinolin-2-yl)-2,3,4,5-tetrahydro-l,4-benzothiazepine 1,1-dioxide (prepared in analogy to 4-(4-chloro-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-l,4-benzothiazepine 1,1- dioxide in Example 2-1 by using 2,4-dichloro-6- trideuteriomethylquinoline and 2,3,4,5- tetrahydro-l,4-benzothiazepine) and oxetane-3,3-diyldimethanamine. MS obsd. (ESI ) [(M+H)+] 456, 1H NMR (400 MHz, CDC13) δ ppm 8.04 (d, 1 H), 7.68 (d, 1 H), 7.51 (m, 2 H), 7.36 (t, 1 H), 7.29 (s, 1 H), 7.22 (d, 1 H), 7.08 (s, 1 H), 5.92 (s, 1 H), 5.13 (s, 2 H), 4.57 (s, 6 H), 3.67 (s, 2 H ), 3.57 (s, 2 H ), 3.34 (s, 2 H).
Example 4-1 V-[(3-Aminooxetan-3-yl)methyl]-6-chloro-2-(2,3-dihydro-l,4-benzothiazepin- yl)quinolin-4-amine
Figure imgf000218_0001
The title compound was prepared in analogy to Example 3-1 in Scheme 5 by using 4-(4,6- dichloroquinolin-2-yl)-2,3,4,5-tetrahydro-l,4-benzothiazepine (prepared in analogy to 4-(4- chloro-6-methylquinolin-2-yl)-8-methoxy-2,3,4,5-tetrahydro-l,4-benzothiazepine in Example 1- 1) and 3-aminomethyl-oxetan-3-ylamine. MS obsd. (ESI+) [(M+H)+] 410, 1H NMR (400 MHz, CD3OD) δ ppm 7.94 (s, 1 H), 7.93 - 7.70 (m, 1 H), 7.50 - 7.48 (d, J= 8.4 Hz, 2 H), 7.40 - 7.37 (m, 1 H), 7.26 - 7.22 (m, 1 H), 7.15 - 7.11 (m, 1 H), 6.20 (s, 1 H), 4.99 (s, 2 H), 4.63 - 4.61 (d, J = 6.8 Hz, 2 H), 4.58 - 4.57 (d, J= 6.4 Hz, 2 H), 4.38 (s, 2 H), 3.65 (s, 2 H), 2.99 - 2.97 (t, J= 4.8 Hz, 2 H).
Example 4-2
TV- [6-Chloro-2-(2,3-dihydro- 1 ,4-benzothiazepin-4(5H)-yl)quinolin-4-yl] ethane- 1 ,2-diamine
Figure imgf000218_0002
The title compound was prepared in analogy to Example 4-1 in Scheme 5 by using 4-(4,6- dichloroquinolin-2-yl)-2,3,4,5-tetrahydro-l,4-benzothiazepine (prepared in analogy to the one in Example 4-1) and ethane- 1,2-diamine. MS obsd. (ESI+) [(M+H)+] 385, 1H NMR (400 MHz, CD3OD) δ ppm 7.901 (s, 1 H), 7.70 - 7.60 (m, 1 H), 7.55 - 7.42 (m, 2 H), 7.378 - 3.350 (dd, J = 8.8, 2.4 Hz, 1 H), 7.28 - 7.16 (m, 1 H), 7.14 - 7.12 (m , 1 H), 6.05 (s, 1 H), 5.51 (s, 1 H), 4.97 (s, 2 H), 4.38 (s, 2 H), 3.43 - 3.39 (t, J= 6.4 Hz, 2 H), 2.99 - 2.95 (m, 4 H).
Example 4-3
TV- [(3- Aminooxetan-3-yl)methyl] -2-(2,3-dihydro- 1 ,4-benzothiazepin-4(5H)-yl)-6-
Figure imgf000218_0003
Figure imgf000219_0001
The title compound was prepared in analogy to Example 4-1 in Scheme 5 by using 4-(4-chloro- 6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-l,4-benzothiazepine (prepared in analogy to 4-(4- chloro-6-methylquinolin-2-yl)-8-methoxy-2,3,4,5-tetrahydro-l,4-benzothiazepine in Example 1- 1) and 3-aminomethyl-oxetan-3-ylamine. MS obsd. (ESI+) [(M+H)+] 407, 1H NMR (400 MHz, CD3OD) δ ppm 7.97 (s, 1 H), 7.74 - 7.67 (t, 2 H), 7.61 (d, J= 8.4 Hz, 1 H), 7.55 (d, J= 7.6 Hz, 1 H), 7.32 (t, 1 H), 7.26 (t, 1 H), 6.27 (s, 1 H), 5.19 (s, 2 H), 4.77 - 4.70 (m, 4 H), 4.35 (s, 2 H), 4.12 (s, 2 H ), 3.16 (t, J= 9.6 Hz, 2 H ), 2.49 (s, 3 H).
Example 4-4 l-[2-(2,3-Dihydro-l,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]pyrrolidin-3-amine
Figure imgf000219_0002
The title compound was prepared in analogy to Example 4-1 in Scheme 5 by using 4-(4-chloro- 6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-l,4-benzothiazepine (prepared in analogy to 4-(4- chloro-6-methylquinolin-2-yl)-8-methoxy-2,3,4,5-tetrahydro-l,4-benzothiazepine in Example 1- 1) and pyrrolidin-3-amine. MS obsd. (ESI+) [(M+H)+] 391, 1H NMR (400 MHz, CD3OD) δ ppm 8.07 (s, 1 H), 7.79 (d, J= 8.4 Hz, 1 H), 7.67 - 7.57 (m, 3 H), 7.38 -7.30 (m, 2 H), 5.96 (s, 1 H), 5.17 (s, 2 H), 4.45 - 4.35 (m, 2 H), 4.30 - 4.25 (m, 1 H), 4.20 - 4.11 (m, 2 H), 4.05 - 3.91 (m, 2 H), 3.23 (t, J= 4.8 Hz, 2 H), 2.51 - 2.50 (m, 1 H), 2.53 (s, 3 H), 2.40 - 2.30 (m, 1 H).
Example 5-1 2-(l,l-Dioxido-2,3-dihydro-l,4-benzothiazepin-4(5H)-yl)- V-[2-(l,l-dioxidothiomorpholin-4- yl)ethyl]-6-methylquinolin-4-amine
Figure imgf000220_0001
To a solution of 4-(4-chloro-6-methylquinolin-2-yl)-2, 3,4, 5-tetrahydro-l,4-benzothiazepine 1,1- dioxide (150 mg, 0.40 mmol, prepared in analogy to the one in Example 2-1) in 1,4-dioxane (4 mL) was added tris(dibenzylideneacetone) dipalladium (0) (40 mg, 0.04 mmol), Ι,Γ- bis(diphenyphosphino)ferrocene (25 mg, 0.04 mmol), sodium tert-butoxide (77 mg, 0.80 mmol) and 2-(l,l-dioxidothio-morpholin-4-yl)ethanamine (107 mg, 0.60 mmol). The resulting mixture was evacuated and refilled with nitrogen, sealed and heated at 120 °C overnight. After being cooled to room temperature, the mixture was filtered and washed with ethyl acetate, the organic layers were combined and concentrated in vacuo, the residue was purified by flash
chromatography (eluenting with 2% methanol in dichloromethane) to afford 67 mg of the title compound as a light solid (yield was 40%). MS obsd. (ESI+) [(M+H)+] 515, 1H NMR (400 MHz, CDCls) 8.05 (d, J= 7.6Hz, 1 H), 7.66 (d, J= 7.2 Hz, 1 H), 7.53 - 7.48 (m, 2 H), 7.37 - 7.28 (m, 2 H), 7.21 (s, 1 H), 5.88 (s, 1 H), 5.26 (m, 1 H), 5.12 (s, 1 H), 4.6 (brs, 1 H), 3.56 (m, 1 H), 3.33 (m, 2 H), 3.14 (m, 8 H), 2.99 (t, J= 4.8 Hz, 2 H), 2.46 (s, 3 H), 2.0 (d, J= 4.5 Hz, 2 H). Example 5-2
TV- [2-(2- Aminoethoxy)ethyl] -2-(l , l-dioxido-2,3-dihydro- 1 ,4-benzothiazepin-4(5H)-yl)-6- methylquinolin-4-amine
Figure imgf000220_0002
The title compound was prepared in analogy to Example 5-1 in Scheme 5 by using 4-(4-chloro- 6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-l,4-benzothiazepine 1,1-dioxide (prepared in analogy to the one in Example 2-1) and 2,2'-oxydiethanamine. MS obsd. (ESI+) [(M+H)+] 441, 1H NMR (400 MHz, CD3OD) δ ppm 8.08 (dd, J= 1.2, 7.6 Hz, 1 H), 7.92 (s, 1 H), 7.83 (d, J= 7.2 Hz, 1 H), 7.70 - 7.67 (m, 2 H), 7.59 - 7.55 (m, 2 H), 5.96 (s, 1 H), 5.28 (s, 2 H), 4.49 (s, 2 H), 3.81 (t, J = 5.2 Hz, 2 H), 3.72 - 3.68 (m, 6 H), 3.13 (t, J= 4.8 Hz, 2 H), 2.45 (s, 3 H). Example 5-3 V~l~-[2-(l,l-Dioxido-2,3-dihydro-l,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]-2- methyl ropane- 1 ,2-diamine
Figure imgf000221_0001
The title compound was prepared in analogy to Example 5-1 in Scheme 5 by using 4-(4-chloro- 6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-l,4-benzothiazepine 1,1-dioxide (prepared in analogy to the one in Example 2-1) and 2-methylpropane-l ,2-diamine. MS obsd. (ESI ) [(M+H)+] 425, 1H NMR (400 MHz, CD3OD) δ ppm 7.97 (d, J= 7.83 Hz, 1 H), 7.85 (d, J= 7.58 Hz, 1 H), 7.70 (s, 1 H), 7.60 (t, J= 7.33 Hz, 1 H), 7.48 - 7.38 (m, 2 H), 7.29 - 7.27 (m, 1 H), 6.09 (s, 1 H), 5.15 (brs, 2 H), 3.57 (brs, 2 H), 3.26 (s, 2 H), 2.43 (s, 3 H), 1.34 - 1.20 (m, 6 H).
Example 5-4
7V~1~ [2-(l,l-Dioxido-2,3-dihydro-l,4-benzothiazepin-4(5H yl)quinolin-4-yl]-2- methylpropane- 1 ,2-diamine
Figure imgf000221_0002
The title compound was prepared in analogy to Example 5-1 in Scheme 5 by using 4-(4- chloroquinolin-2-yl)-2,3,4,5-tetrahydro-l,4-benzothiazepine 1,1-dioxide (prepared in analogy to 4-(4-chloro-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro- 1 ,4-benzothiazepine 1 , 1 -dioxide in Example 2-lby using and 2,4-dichloroquinoline 2,3,4,5-tetrahydro-l,4-benzothiazepine) and 2- methylpropane-l,2-diamine. MS obsd. (ESI+) [(M+H)+] 411, 1H NMR (400 MHz, CD3OD) δ ppm 8.02 - 7.93 (m, 1 H), 7.87 (s, 2 H), 7.64 - 7.57 (m, 1 H), 7.56 - 7.48 (m, 1 H), 7.42 (s, 2 H), 7.19 -7.09 (m, 1 H), 6.11 (s, 1 H), 5.23 - 5.07 (m, 2 H), 3.63 - 3.51 (m, 2 H), 3.37 (s, 2 H), 3.33 (m, 2 H), 3.28 (s, 2 H), 1.26 (s, 6 H).
Example 5-5 V~l~-[2-(l,l-Dioxido-2,3-dihydro-l,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4- yl] propane- 1 ,2-diamine
Figure imgf000222_0001
The title compound was prepared in analogy to Example 5-1 in Scheme 5 by using 4-(4-chloro- 6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-l,4-benzothiazepine 1,1-dioxide (prepared in analogy to the one in Example 2-1) and propane- 1,2-diamine. MS obsd. (ESI+) [(M+H)+] 411, 1H NMR (400 MHz, CD3OD) δ ppm 7.91 (dd, J= 7.83, 1.01 Hz, 1 H), 7.83(d, J= 7.33 Hz, 1 H), 7.69 (s, 1 H), 7.58 (d, J= 1.26 Hz, 1 H), 7.44 (d, J= 8.59 Hz, 1 H), 7.38 - 7.31 (m, 1 H), 7.28 (dd, J = 8.59, 1.77 Hz, 1 H), 6.04 (s, 1 H), 5.13(brs, 2 H), 3.56 (t, J= 4.67 Hz, 2 H), 3.52 - 3.41 (m, 4 H), 3.37 (s, 1 H), 2.41 (s, 3 H), 1.38 (d, J= 6.06 Hz, 3 H).
Example 5-6
4- [6-Methyl-4-(4-methylpiperazin- l-yl)quinolin-2-yl] -2,3,4,5-tetrahydro- 1 ,4- benzothiazepine 1,1-dioxide
Figure imgf000222_0002
The title compound was prepared in analogy to Example 5-1 in Scheme 5 by using 4-(4-chloro- 6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-l,4-benzothiazepine 1,1-dioxide (prepared in analogy to the one in Example 2-1) and 1-methylpiperazine. MS obsd. (ESI+) [(M+H)+] 437, 1H NMR (400 MHz, CD3OD) δ ppm 7.90 (dd, J= 7.83, 1.01 Hz, 1 H), 7.79 (d, J= 7.07 Hz, 1 H), 7.60 - 7.45 (m, 3 H), 7.34 (td, J= 7.64, 1.14 Hz, 1 H), 7.28 (dd, J= 8.59, 1.77 Hz, 1 H), 6.54 (s, 1 H), 5.11 (s, 2 H), 3.61 - 3.50 (m, 2 H), 3.37 (s, 2 H), 3.17 (brs, 4 H), 2.80 (brs, 4 H), 2.46 (s, 3 H), 2.39 (s, 3 H).
Example 5-7 1- { [2-(l , l-Dioxido-2,3-dihydro- 1 ,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4- yl] amino}propan-2-ol
Figure imgf000223_0001
The title compound was prepared in analogy to Example 5-1 in Scheme 5 by using 4-(4-chloro- 6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-l,4-benzothiazepine 1,1-dioxide (prepared in analogy to the one in Example 1-1) and l-aminopropan-2-ol. MS obsd. (ESI+) [(M+H)+] 412, 1H NMR (400 MHz, CD3OD) δ ppm 7.99 (dd, J= 7.71, 1.14 Hz, 1 H), 7.84 (d, J= 7.07 Hz, 1 H), 7.71 (s, 1 H), 7.64 (td, J= 7.58, 1.26 Hz, 1 H), 7.55 (d, J= 8.59 Hz, 1 H), 7.50 - 7.41 (m, 1 H), 7.37 (dd, J= 8.59, 1.52 Hz, 1 H), 6.03 (s, 1 H), 5.16 (s, 2 H), 4.08 (dd, J= 11.49, 6.44 Hz, 1 H), 3.62 (t, J = 4.80 Hz, 2 H), 3.44 - 3.35 (m, 4 H), 2.42 (s, 3 H), 1.33 (d, J= 6.06 Hz, 3 H).
Example 5-8
(25)- V~l-[2-(l,l-Dioxido-2,3-dihydro-l,4-benzothiazepin-4(5H yl)-6-methylquinolin-4- yl] propane- 1 ,2-diamine
Figure imgf000223_0002
The title compound was prepared in analogy to Example 5-1 in Scheme 5 by using 4-(4-chloro- 6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-l,4-benzothiazepine 1,1-dioxide (prepared in analogy to the one in Example 2-1) and (25)-propane-l,2-diamine. MS obsd. (ESI+) [(M+H)+] 411, 1H NMR (400 MHz, CD3OD) δ ppm 7.86 (d, J= 7.58 Hz, 1 H), 7.71 (d, J= 7.33 Hz, 1 H), 7.67 - 7.60 (m, 1 H), 7.49 (t, J= 7.33 Hz, 1 H), 7.42 (d, J= 8.59 Hz, 1 H), 7.28 - 7.19 (m, 2 H), 6.07 - 5.83 (m, 1 H), 5.02 (brs, 2 H), 3.62 (s, 1 H), 3.56 - 3.46 (m, 2 H), 3.37 (s, 2 H), 3.28 - 3.11 (m, 4 H), 2.36 (s, 3 H), 0.92 - 0.80 (m, 2 H).
Example 5-9 (2R)- V~l—[2-(l,l-Dioxido-2,3-dihydro-l,4-benzothiazepin-4(5H yl)-6-methylquinolin-4- yl] propane- 1 ,2-diamine
Figure imgf000224_0001
The title compound was prepared in analogy to Example 5-1 in Scheme 5 by using 4-(4-chloro- 6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-l,4-benzothiazepine 1,1-dioxide (prepared in analogy to the one in Example 2-1) and (2i?)-propane-l,2-diamine. MS obsd. (ESI+) [(M+H)+] 411, 1H NMR (400 MHz, CD3OD) δ ppm 7.97 (d, J= 7.83 Hz, 1 H), 7.82 (d, J= 7.58 Hz, 1 H), 7.70 - 7.55 (m, 2 H), 7.46 - 7.37 (m, 2 H), 7.33 - 7.22 (m, 2 H), 6.10 - 5.99 (m, 1 H), 5.13 (brs, 2 H), 3.65 - 3.52 (m, 3 H), 3.37 (m, 2 H), 3.31 - 3.20 (m, 2 H), 2.41 (s, 3 H), 1.32 - 1.22 (m, 2 H). Example 5-10
TV- [(3- Aminooxetan-3-yl)methyl] -2-(l , l-dioxido-2,3-dihydro- 1 ,4-benzothiazepin-4(5H)-yl)- 7,8-difluoro-6-methylquinolin-4-amine
Figure imgf000224_0002
The title compound was prepared in analogy to Example 5-1 in Scheme 5 by using 4-(4-chloro- 6-methyl-7,8-difluoroquinolin-2-yl)-2,3,4,5-tetrahydro- 1 ,4-benzothiazepine 1 , 1 -dioxide (prepared in analogy to 4-(4-chloro-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-l,4- benzothiazepine 1,1-dioxide in Example 2-1 by using 4-chloro-6-methyl-7,8-dichloroquinoline and 2,3,4,5-tetrahydro-l,4-benzothiazepine) and 3-(aminomethyl)oxetan-3-amine. MS obsd. (ESI+) [(M+H)+] 475, 1H NMR (400 MHz, DMSO- 6) δ ppm 8.04 (brs, 1 H), 7.88 (d, J= 7.83 Hz, 1 H), 7.62 (t, J= 6.82 Hz, 1 H), 7.47 (t, J= 7.58 Hz, 1 H), 7.18 (brs, 1 H), 6.31 (brs, 1 H),
5.16 (brs, 1 H), 4.60 (d, J= 8.34 Hz, 2 H), 4.05 - 3.97 (m, 2 H), 3.82 (brs, 2 H), 3.62 (brs, 2 H),
3.17 (m, 2 H), 2.33 (s, 1 H), 1.28 - 1.13 (m, 3 H). Example 5-11 V-(2,2-Difluoroethyl)- V-[2-(l,l-dioxido-2,3-dihydro-l,4-benzothiazepin-4(5H yl)-6- methylquinolin-4-yl] ethane- 1 ,2-diamine
Figure imgf000225_0001
The title compound was prepared in analogy to Example 5-1 in Scheme 5 by using 4-(4-chloro- 6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-l,4-benzothiazepine 1,1-dioxide (prepared in analogy to the one in Example 2-1) and N-(2,2-difluoroethyl)ethane-l,2-diamine. MS obsd. (ESI )
[(M+H)+] 461, 1H NMR (400 MHz, CD3OD) δ ppm 7.97 (dd, J = 7.83, 1.26 Hz, 1 H), 7.83 (d, J = 6.82 Hz, 1 H), 7.60 (td, J = 7.45, 1.26 Hz, 2 H), 7.46 - 7.38 (m, 2 H), 7.28 (dd, J = 8.59, 1.77 Hz, 1 H), 6.04 (s, 1 H), 5.13(s, 2 H), 3.58 (t, J = 4.80 Hz, 2 H), 3.46 (t, J = 6.19 Hz, 2 H), 3.37 (s, 3 H), 3.10 - 2.97 (m, 4 H), 2.41 (s, 3 H).
Example 5-12
3- { [2-(l , l-Dioxido-2,3-dihydro- 1 ,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4- yl] amino} oxetan-3-ethanol
Figure imgf000225_0002
The title compound was prepared in analogy to Example 5-1 in Scheme 5 by using 4-(4-chloro- 6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-l,4-benzothiazepine 1,1-dioxide (prepared in analogy to the one in Example 2-1) and 3-aminooxetan-3-ethanol. MS obsd. (ESI+) [(M+H)+] 454, 1H NMR (400 MHz, DMSO- 6) δ ppm 7.97 (d, 1 H), 7.89 (d, 1 H), 7.64 (t, 1 H), 7.55 (s, 1 H), 7.49 - 7.42 (m, 2 H), 7.35 - 7.32 (m, 1 H), 6.63 (s, 1 H), 5.15 (s, 2 H), 4.50 (d, 2 H), 4.41(brs, 2 H), 4.39 (d, 4 H), 3.66 (d, 2 H), 2.33 (s, 3 H ), 2.27 (t, 2 H).
Example 6-1 V-{[3-(Aminomethyl)thietan-3-yl]methyl}-2-(l,l-dioxido-2,3-dihydro-l,4-benzothiazepin- 4(5H)-yl)-6-methylquinolin-4-amine
Figure imgf000226_0001
A flask containing 4-(4-chloro-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-l,4-benzothiazepine 1,1-dioxide (250 mg, 0.67 mmol), thietane-3,3-diyldimethanamine (266 mg, 2.01 mmol ), tris(dibenzylideneacetone)dipalladium(0) ( 61.8 mg, 0.067 mmol ), 2,2'-bis(diphenylphosphino)- 1 , Γ-binaphthyl ( 42 mg, 0.067 mmol), sodium tert-butoxide (160 mg, 1.66 mmol ) and toluene (15 mL) was evacuated and then filled with nitrogen (balloon). After being stirred at 110 °C overnight, the resulting mixture was diluted with water (15 mL) and extracted with ethyl acetate (15 mL x 4). The combined organic layers were dried over sodium sulfate and concentrated in vacuo. The residue was purified by flash column chromatography and preparative HPLC to afford 63 mg of the product as a white solid (yield was 20%). MS obsd. (ESI+) [(M+H)+] 469, 1H
NMR (400 MHz, CD3OD) δ ppm 7.96 - 7.94 (m, 1 H), 7.68 - 7.66 (d, J= 7.2 Hz, 1 H), 7.47 - 7.43 (m, 2 H), 7.31 - 7.27 (m, 1 H), 7.22 - 7.21 (d, J= 1.6 Hz, 1 H), 7.19 (s, 1 H), 5.88 (s, 1 H), 5.07 (s, 2 H), 4.50 (s, 2 H), 3.55 - 3.49 (m, 4 H), 3.11 (s, 2 H), 3.06 - 3.03 (d, J= 9.6 Hz, 2 H), 2.94 - 2.91 (d, J= 9.6 Hz, 2 H), 2.31 (s, 3 H).
Example 6-2
TV- { [3-(Aminomethyl)- 1 , l-dioxidothietan-3-yl] methyl}-2-(l , l-dioxido-2,3-dihydro- 1 ,4- benzothiazepin-4(5H)-yl)-6-methylquinolin-4-amine
Figure imgf000226_0002
The title compound was prepared in analogy to Example 6-1 in Scheme 5 by using 4-(4-chloro- 6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-l,4-benzothiazepine 1,1-dioxide (prepared in analogy
^ ^ ^ j -dioxidothietane-3 ,3 -diyl)dimethanamine. MS obsd. (ESI ) [(M+H)+] 501, 1H NMR (400 MHz, CD3C1) δ ppm 7.958 - 7.939 (d, J= 7.6 Hz, 1 H), 7.651 - 7.633 (d, J= 7.2 Hz, 1 H), 7.482 - 7.415 (m, 2 H), 7.308 - 7.270 (t, J= 7.2 Hz, 1 H), 7.235 - 7.215 (d, J= 8.0 Hz, 1 H), 7.134 (s, 1 H), 6.646 (s, 1 H), 5.065 (s, 2 H), 4.701 - 1.250 (brs, 2 H), 3.924 - 3.890 (m, 4 H), 3.659 -3.646 (d, J= 5.2 Hz, 2 H), 3.491 (s, 2 H), 3.320 (s, 2 H), 2.323 (s, 3 H).
Example 7 V-(4,5-Dihydro-lH-imidazol-2-yl)-2-(l,l-dioxido-2,3-dihydro-l,4-benzothiazepin-4(5H)-yl)- 6-methylquinolin-4-amine
Figure imgf000227_0001
A mixture of 4-(4-chloro-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-l,4-benzothiazepine 1,1- dioxide (150 mg, 0.40 mmol, prepared in analogy to the one in Example 2-1), hydrogen iodide salt of 4,5-dihydro-lH-imidazol-2-amine (110 mg, 0.515 mmol), 4,5-bis(diphenylphosphino)- 9,9-dimethylxanthene (25 mg, 0.043 mmol), tris(dibenzylideneacetone)dipalladium(0) (35 mg, 0.038 mmol), cesium carbonate (525 mg, 1.6 mmol) and 1,4-dioxane (3 mL) was heated with stirring in a 5 mL of microwave process vial for 2 hours at 120 °C under microwave irradiation. The resulting mixture was filtered and washed with ethyl acetate. The filtrate was washed with brine, dried over sodium sulfate, and concentrated in vacuo. The residue was purified by preparative HPLC to afford the product as a solid. MS obsd. (ESI+) [(M+H)+] 422, 1H NMR (400 MHz, CD3OD) δ ppm 7.68 - 7.59 (m, 2 H), 7.56 (s, 1 H), 7.50 - 7.41 (m, 2 H), 7.08 (s,l H), 5.23 (brs, 2 H), 4.62 (s, 3 H), 3.76 (s, 3 H), 3.61 (t, J= 4.93 Hz, 2 H), 2.68 (s, 4 H), 2.45 (s, 2 H).
Example 8-1 irans-4-{[2-(l,l-Dioxido-2,3-dihydro-l,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4- yl] amino} cyclohexanol
Figure imgf000228_0001
A mixture of 4-(4-chloro-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-l,4-benzothiazepine 1,1- dioxide (140 mg, 0.38 mmol, prepared in analogy to the one in Example 2-1), trans-4- aminocyclohexanol (45 mg, 0.39 mmol), tris(dibenzylideneacetone)dipalladium(0) (35 mg, 0.038 mmol), 2-dicyclohexylphosphino-2'-(A ,N-dimethylamino)biphenyl (15 mg, 0.038 mmol), sodium tert-butoxide (38 mg, 0.39 mmol) and 1,4-dioxane (2 mL) was heated with stirring in a 5 mL of microwave process vial for 2 hours at 120 °C under microwave irradiation. The mixture was filtered and washed with ethyl acetate. The filtrate was washed with brine, dried over sodium sulfate, and concentrated in vacuo. The residue was purified by preparative HPLC to afford the product as a solid. MS obsd. (ESI+) [(M+H)+] 452, 1H NMR (400 MHz, DMSO- 6) δ ppm 7.98 - 7.83 (m, 2 H), 7.76 (s, 1 H), 7.64 - 7.44 (m, 2 H), 7.29 (d, J= 8.34 Hz, 1 H), 7.21 (d, J= 8.84 Hz, 1 H), 6.22 (d, J= 8.34 Hz, 1 H), 6.06 (s, 1 H), 5.09 (brs, 2 H), 4.68 (d, J= 4.29 Hz, 1 H), 3.62 (brs, 3 H), 3.49 (d, J= 4.55 Hz, 1 H), 2.34 (s, 3 H), 2.03 - 1.83 (m, 4 H), 1.63 - 1.45 (m, 2 H), 1.35 (brs, 2 H), 1.24 (brs, 1 H), 1.18 (brs, 1 H). Example 8-2
(25)-2-{[2-(l,l-Dioxido-2,3-dihydro-l,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4- yl]amino}propan-l-ol
Figure imgf000228_0002
The title compound was prepared in analogy to Example 8-1 in Scheme 5 by using 4-(4-chloro- 6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-l,4-benzothiazepine 1,1-dioxide (prepared in analogy to the one in Example 2-1) and (25)-2-aminopropan-l-ol. MS obsd. (ESI+) [(M+H)+] 412, 1H NMR (400 MHz, DMSO- 6) δ ppm 7.89 (t, J= 6.32 Hz, 2 H), 7.75 (s, 1 H), 7.64 (t, J= 7.20 Hz,
), 7.38 - 7.27 (m, l H), 7.27 - 7.14 (m, l H), 6.16 (d, J= 8.08 Hz, l H), 6.07 (s, 1 H), 5.07 (brs, 2 H), 4.85 (brs, 1 H), 4.42 (brs, 1 H), 3.85 (dt, J= 12.82, 6.35 Hz, 1 H), 3.70 - 3.47 (m, 3 H), 2.36 (s, 3 H), 1.23 (d, J= 6.32 Hz, 3 H).
Example 8-3 irans-l-[2-(l,l-Dioxido-2,3-dihydro-l,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]-4- methoxypyrrolidin-3-amine
Figure imgf000229_0001
The title compound was prepared in analogy to Example 8-1 in Scheme 5 by using 4-(4-chloro- 6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-l,4-benzothiazepine 1,1-dioxide (prepared in analogy to the one in Example 2-1) and tra/75-4-methoxy-3-methylpyrrolidin-3-amine. MS obsd. (ESI ) [(M+H)+] 453, 1H NMR (400 MHz, CD3OD) δ ppm 8.00 (dd, J= 7.83, 1.26 Hz, 1 H), 7.89 - 7.78 (m, 2 H), 7.63 (td, J= 7.45, 1.26 Hz, 1 H), 7.53 (d, J= 8.59 Hz, 1 H), 7.47 (td, J= 7.71, 1.01 Hz, 1 H), 7.35 (dd, J= 8.59, 1.52 Hz, 1 H), 6.19 (s, 1 H), 5.19 (s, 2 H), 4.53 (brs, 2 H), 4.12 (dd, J= 11.12, 5.05 Hz, 1 H), 3.99 - 3.81 (m, 2 H), 3.73 (brs, 1 H), 3.67 - 3.56 (m, 2 H), 3.55 - 3.41 (m, 5 H), 2.43 (s, 3 H). Example 8-4
2-(l,l-Dioxido-2,3-dihydro-l,4-benzothiazepin-4(5H)-yl)- V-[irans-4-methoxypyrrolidin-3- yl] -6-methylquinolin-4-amine
Figure imgf000229_0002
The title compound was prepared in analogy to Example 8-1 in Scheme 5 by using 4-(4-chloro- 6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-l,4-benzothiazepine 1,1-dioxide (prepared in analogy to the one in Example 2-1) and tra/75-4-methoxy-3-methylpyrrolidin-3-amine. MS obsd. (ESI ) [(M+H)+] 453, 1H NMR (400 MHz, CD3OD) δ ppm 8.14 (d, J= 7.83 Hz, 1 H), 8.08 (s, 1 H), 7.87 (d, J= 7.33 Hz, 1 H), 7.79 - 7.73 (m, 2 H), 7.69 - 7.63 (m, 2 H), 6.10 (s, 1 H), 5.36 (q, J = 16.67 Hz, 2 H), 4.60 (brs, 2 H), 4.28 (brs, 1 H), 3.93 (dd, J= 12.63, 6.82 Hz, 1 H), 3.82 (t, J = 4.80 Hz, 2 H), 3.75 - 3.68 (m, 1 H), 3.68 - 3.59 (m, 2 H), 3.56 (s, 3 H), 2.51 (s, 3 H). Example 8-5
4-{4-[(4aS,7aR)-Hexahydropyrrolo[3,4-b] [l,4]oxazin-6(2H)-yl]-6-methylquinolin-2-yl}- 2,3,4,5-tetrahydro- 1 ,4-benzothiazepine 1 , 1-dioxide
Figure imgf000230_0001
The title compound was prepared in analogy to Example 8-1 in Scheme 5 by using 4-(4-chloro- 6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-l,4-benzothiazepine 1,1-dioxide (prepared in analogy to the one in Example 2-1) and (4a5',7ai?)-octahydropyrrolo[3,4-b][l,4]oxazine. MS obsd. (ESI+) [(M+H)+] 465, 1H NMR (400 MHz, CD3OD) δ ppm 7.99 (dd, J= 7.83, 1.26 Hz, 1 H), 7.85 (d, J = 7.33 Hz, 1 H), 7.81 (s, 1 H), 7.63 (td, J= 7.52, 1.39 Hz, 1 H), 7.50 - 7.41 (m, 2 H), 7.28 (dd, J = 8.59, 1.77 Hz, 1 H), 6.09 (s, 1 H), 5.16 (s, 2 H), 4.51 (m, 2 H), 4.02 - 4.15 (m, 3 H), 3.86 (d, J = 10.8 Hz, 1 H), 3.68 - 3.47 (m, 6 H), 3.238 (m, 1 H), 2.72 (m, 1 H), 2.41 (s, 3 H).
Example 8-6
(3R,4R)-l-[2-(l,l-Dioxido-2,3-dihydro-l,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4- yl]-4-(4-methylpiperazin-l-yl)pyrrolidin-3-ol
Figure imgf000230_0002
The title compound was prepared in analogy to Example 8-1 in Scheme 5 by using 4-(4-chloro- 6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-l,4-benzothiazepine 1,1-dioxide (prepared in analogy to the one in Example 2-1) and (3i?,4i?)-4-(4-methylpiperazin-l-yl)pyrrolidin-3-ol. MS obsd.
(ESI+) [(M+H)+] 522, 1H NMR (400 MHz, CD3OD) δ ppm 7.99 - 7.86 (m, 1 H), 7.84 - 7.75 (m, 1 H), 7.73 (s, 1 H), 7.64 - 7.52 (m, 1 H), 7.47 (d, J= 8.59 Hz, 1 H), 7.43 - 7.32 (m, 1 H), 7.27 (d, J= 8.59 Hz, 1 H), 6.27 - 6.09 (m, 1 H), 5.10 (brs, 2 H), 4.50 (brs, 1 H), 4.43 - 4.33 (m, 1 H), 3.81 - 3.62 (m, 2 H), 3.56 (dd, J= 9.85, 4.55 Hz, 3 H), 3.45 - 3.35 (m, 1 H), 3.02 - 2.92 (m, 1 H), 2.84 (brs, 2 H), 2.76 - 2.62 (m, 3 H), 2.57 (brs, 3 H), 2.39 (s, 3 H), 2.32 (s, 3 H).
Example 8-7
TV- {2- [(2- Aminoethyl)sulfanyl] ethyl}-2-(l , l-dioxido-2,3-dihydro- 1 ,4-benzothiazepin- yl)-6-methylquinolin-4-amine
Figure imgf000231_0001
The title compound was prepared in analogy to Example 8-1 in Scheme 5 by using 4-(4-chloro- 6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-l,4-benzothiazepine 1,1-dioxide (prepared in analogy to the one in Example 2-1) and 2,2'-sulfanediyldiethanamine. MS obsd. (ESI ) [(M+H) ] 457, 1H NMR (400 MHz, CD3OD) δ ppm 8.00 (dd, J= 7.83, 1.26 Hz, 1 H), 7.84 (d, J= 7.33 Hz, 1 H), 7.65 (td, J= 7.58, 1.26 Hz, 1 H), 7.57 (s, 1 H), 7.51 - 7.39 (m, 2 H), 7.29 (dd, J= 8.59, 1.77 Hz, 1 H), 6.03 (s, 1 H), 5.14 (s, 2 H), 3.65 - 3.50 (m, 4 H), 2.92 - 2.79 (m, 4 H), 2.78 - 2.68 (m, 2 H), 2.42 (s, 3 H).
Example 9-1 l-{l-[2-(l,l-Dioxido-2,3-dihydro-l,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4- yl] piperidin-4-yl} methanamine
Figure imgf000231_0002
A mixture of 4-(4-chloro-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-l,4-benzothiazepine 1,1- dioxide (75 mg, 0.20 mmol, prepared in analogy to the one in Example 2-1), piperidin-4-yl- methylamine (3 mL) in a 2~5 mL of process vial was heated at 160 °C under microwave irradiation for 1 hour. After being cooled to room temperature, the mixture was concentrated in vacuo to remove the solvent. The residue was purified by preparative HPLC to afford the product as a solid. MS obsd. (ESI+) [(M+H)+] 451, 1H NMR (400 MHz, DMSO- 6) δ ppm 7.96 - 7.81 (m, 2 H), 7.66 (td, J= 7.58, 1.26 Hz, 1 H), 7.53 - 7.39 (m, 3 H), 7.28 (dd, J= 8.72, 1.89 Hz, 1 H), 6.58 (s, 1 H), 5.13 (brs, 2 H), 4.42 (brs, 2 H), 3.65 (t, J= 4.80 Hz, 2 H), 3.42 (d, J= 11.62 Hz, 2 H), 2.72 (t, J= 10.99 Hz, 2 H), 2.41 - 2.27 (m, 3 H), 1.95 - 1.74 (m, 2 H), 1.61 - 1.33 (m, 5 H).
Example 9-2
2- { [2-(8-Methoxy- 1 , l-dioxido-2,3-dihydro- 1 ,4-benzothiazepin-4(5H)-yl)quinolin-4- yl] amino} ethanol
Figure imgf000232_0001
The title compound was prepared in analogy to Example 9-1 in Scheme 5 by using 4-(4- chloroquinolin-2-yl)-2,3,4,5-tetrahydro-l,4-benzothiazepine 1,1-dioxide (prepared in analogy to 4-(4-chloro-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro- 1 ,4-benzothiazepine 1 , 1 -dioxide in Example 2-1 by using 2,4-dichloroquinoline and 2,3,4,5-tetrahydro-l,4-benzothiazepine) and 2- aminoethanol. MS obsd. (ESI+) [(M+H)+] 414, 1H NMR (400 MHz, CD3OD) δ ppm 7.82 (d, J = 8.08 Hz, 1 H), 7.76 (d, J= 8.34 Hz, 1 H), 7.53 (d, J= 2.78 Hz, 2 H), 7.51 - 7.41 (m, 1 H), 7.22 - 7.09 (m, 2 H), 6.10 (s, 1 H), 5.11 (s, 2 H), 4.62 (brs, 2 H), 3.83 (s, 3 H), 3.91 - 3.80 (m, 2 H), 3.61 (brs, 2 H), 3.52 (t, J= 5.81 Hz, 2 H).
Example 9-3 V-[2-(l,l-Dioxido-2,3-dihydro-l,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4- yl]propane-l,3-diamine
Figure imgf000233_0001
The title compound was prepared in analogy to Example 9-1 in Scheme 5 by using 4-(4-chloro- 6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-l,4-benzothiazepine 1,1-dioxide (prepared in analogy to the one in Example 2-1) and propane- 1,3-diamine. MS obsd. (ESI+) [(M+H)+] 411, 1H NMR (400 MHz, CD3OD) δ ppm 7.96 (dd, J= 7.83, 1.01 Hz, 1 H), 7.81(d, J= 7.07 Hz, 1 H), 7.64 - 7.54 (m, 2 H), 7.47 - 7.35 (m, 2 H), 7.26 (dd, J= 8.59, 1.77 Hz, 1 H), 5.98 (s, 1 H), 5.12 (s, 2 H), 3.56 (t, J= 4.93 Hz, 2 H), 3.39 (t, J= 6.82 Hz, 2 H), 2.82 (t, J= 6.95 Hz, 2 H), 2.39 (s, 3 H), 1.89 (t, J= 6.95 Hz, 2 H).
Example 9-4
4-[6-Methyl-4-(morpholin-4-yl)quinolin-2-yl]-2,3,4,5-tetrahydro-l,4-benzothiazepine dioxide
Figure imgf000233_0002
The title compound was prepared in analogy to Example 9-1 in Scheme 5 by using 4-(4-chloro- 6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-l,4-benzothiazepine 1,1-dioxide (prepared in analogy to the one in Example 2-1) and morpholine. MS obsd. (ESI+) [(M+H)+] 424, 1H NMR (400 MHz, CDCI3) δ ppm 8.06 (d, J= 8.0 Hz, 1 H), 7.62 - 7.53 (m, 4 H), 7.40 (t, J= 7.6 Hz, 1 H), 7.32 (d, J = 7.6 Hz, 1 H), 6.42 (s, 1 H), 5.51 (s, 2 H), 4.60 (brs, 2 H), 4.00 (t, J= 4.4 Hz, 4 H), 3.59 (s, 2 H), 3.10 (m, 4 H), 2.44 (s, 3 H).
Example 9-5 3- { [2-(l , l-Dioxido-2,3-dihydro- 1 ,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4- yl]amino}propan-l-ol
Figure imgf000234_0001
The title compound was prepared in analogy to Example 9-1 in Scheme 5 by using 4-(4-chloro- 6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-l,4-benzothiazepine 1,1-dioxide (prepared in analogy to the one in Example 2-1) and 3-propan-l-ol. MS obsd. (ESI+) [(M+H)+] 412, 1H NMR (400 MHz, CDCls) δ ppm 8.02 (d, J= 7.2 Hz, 1 H), 7.71 (m, 1 H), 7.53 - 7.49 (m, 2 H), 7.38 (t, J = 7.2 Hz, 1 H), 7.26 (m, 2 H), 5.31 (s, 1 H), 5.13 (s, 2 H), 4.60 (brs, 2 H), 3.92 (t, J= 4.2 Hz, 2 H), 3.52 (s, 2 H), 3.44 (m, 2 H), 2.40 (s, 3 H), 2.00 (m, 2 H).
Example 9-6
2-(l , l-Dioxido-2,3-dihydro- 1 ,4-benzothiazepin-4(5H)-yl)-6-methykV- [2-(piperidin- 1- yl)ethyl]quinolin-4-amine
Figure imgf000234_0002
The title compound was prepared in analogy to Example 9-1 in Scheme 5 by using 4-(4-chloro- 6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-l,4-benzothiazepine 1,1-dioxide (prepared in analogy to the one in Example 2-1) and 2-(piperidin-l-yl)ethanamine. MS obsd. (ESI+) [(M+H)+] 465, 1H NMR (400 MHz, CDC13) δ ppm 8.04 (d, J= 7.6 Hz, 1 H), 7.67 (d, J= 7.6 Hz, 1 H), 7.51 (m, 2 H), 7.38 (t, J= 7.6 Hz, 1 H), 7.30 (m, 2 H), 5.74 (m, 1 H), 5.12 (s, 2 H), 4.6 (brs, 2 H), 3.58 (s, 2 H), 3.28 (m, 2 H), 2.75 (t, J= 8.4 Hz, 2 H), 2.46 (m, 7 H), 1.62 (m, 4 H), 1.52 (m, 2 H).
Example 9-7 l-Amino-3-{[2-(l,l-dioxido-2,3-dihydro-l,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4- yl]amino}propan-2-ol
Figure imgf000234_0003
The title compound was prepared in analogy to Example 9-1 in Scheme 5 by using 4-(4-chloro- 6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-l,4-benzothiazepine 1,1-dioxide (prepared in analogy to the one in Example 2-1) and l,3-diaminopropan-2-ol. MS obsd. (ESI+) [(M+H)+] 427, 1H NMR (400 MHz, CD3OD) δ ppm 7.97 (d, J= 2.0 Hz, 1 H), 7.86 (d, J= 1.8 Hz, 1 H), 7.62 (t, J = 3.7 Hz, 1 H), 7.57 (s, 1 H), 7.44 (t, J= 3.8 Hz, 2 H), 7.30 - 7.27 (m, J= 2.5 Hz, 1 H), 6.09 (s, 1 H), 5.15 (s, 2 H), 4.53 (brs, 2 H), 3.97 - 3.91 (m, J= 5.8 Hz, 2 H ), 3.58 (t, J= 2.4 Hz, 2 H), 3.66 - 3.41 (m, J= 3.3 Hz, 2 H), 2.90 (dd, J= 4.2, 0.90 Hz, 1 H), 2.77 (dd, J= 5.2, 0.9 Hz, 1 H), 2.42 (s, 3 H).
Example 9-8 V-[2-(l,l-Dioxido-2,3-dihydro-l,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4- yl] glycine
Figure imgf000235_0001
The title compound was prepared in analogy to Example 9-1 in Scheme 5 by using 4-(4-chloro- 6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-l,4-benzothiazepine 1,1-dioxide (prepared in analogy to the one in Example 2-1) and glycine. MS obsd. (ESI+) [(M+H)+] 412, 1H NMR (400 MHz,
CD3OD) 5 ppm 8.01 (d, J= 1.8 Hz, 1 H), 7.89 (d, J= 1.9 Hz, 1 H), 7.68 (t, J = 2.9 Hz, 2 H), 7.54 (d, J= 2.1 Hz, 1 H), 7.48 (t, J= 2.2 Hz, 1 H), 7.40 (d, J= 0.9 Hz, 1 H), 5.73 (s, 1 H), 5.09 (s, 2 H), 4.36 (brs , 2 H), 3.3 (s, 2 H ), 3.58 (s, 2 H), 2.41 (s, 3 H).
Example 9-9 V-[2-(l,l-Dioxido-2,3-dihydro-l,4-benzothiazepin-4(5H)-yl)-6-fluoroquinolin-4-yl]ethane- 1,2-diamine
Figure imgf000235_0002
The title compound was prepared in analogy to Example 9-1 in Scheme 5 by using 4-(4-chloro- 6-fluoroquinolin-2-yl)-2,3,4,5-tetrahydro-l,4-benzothiazepine 1,1-dioxide (prepared in analogy to 4-(4-chloro-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-l,4-benzothiazepine 1,1-dioxide in Example 2-1 by using 2,4-dichloro-6-fluoroquinoline and 2,3,4,5-tetrahydro-l,4- benzothiazepine) and ethane- 1,2-diamine. MS obsd. (ESI+) [(M+H)+] 401, 1H NMR (400 MHz, CD3OD) δ ppm 7.98 (d, J= 7.6 Hz, 1 H), 7.84 (d, J= 7.6 Hz, 1 H), 7.64 (t, J = 7.6 Hz, 1 H), 7.58 (dd, J= 2.8, 10.8 Hz, 1 H), 7.52 (dd, J= 6.4, 8.8 Hz, 1 H), 7.45 (t, J= 8.0 Hz, 1 H), 7.22 (td, J = 2.8, 8.8 Hz, 1 H), 6.09 (s, 1 H), 5.16 (s, 2 H), 4.55 (brs, 2 H), 3.63 - 3.57 (m, 2 H), 3.43 (t, J = 6.4 Hz, 2 H), 2.97 (t, J= 6.4 Hz, 2 H).
Example 9-10 V-[2-(l,l-Dioxido-2,3-dihydro-l,4-benzothiazepin-4(5H)-yl)-6-ethylquinolin-4-yl] ethane- 1,2-diamine
Figure imgf000236_0001
The title compound was prepared in analogy to Example 9-1 in Scheme 5 by using 4-(4-chloro- 6-ethylquinolin-2-yl)-2,3,4,5-tetrahydro-l,4-benzothiazepine 1,1-dioxide (prepared in analogy to 4-(4-chloro-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro- 1 ,4-benzothiazepine 1 , 1 -dioxide in Example 2-1 by using 4-chloro-6-ehtylquinoline and 2,3,4,5-tetrahydro-l,4-benzothiazepine) and ethane- 1,2-diamine. MS obsd. (ESI+) [(M+H)+] 411, 1H NMR (400 MHz, CD3OD) δ ppm 7.98 (d, J= 7.6 Hz, 1 H), 7.84 (d, J= 7.6 Hz, 1 H), 7.62 (m, 2 H), 7.44 (t, J= 8.4 Hz, 2 H), 7.32 (dd, J = 1.6, 8.4 Hz, 1 H), 6.03 (s, 1 H), 5.14 (s, 2 H), 4.53 (brs, 2 H), 3.58 (s, 2 H), 3.44 (t, J= 6.0 Hz, 2 H), 2.97 (t, J= 6.4 Hz, 2 H), 2.72 (q, J= 7.6 Hz, 2 H), 1.27 (t, J= 7.6 Hz, 3 H).
Example 9-11 V-[7-Chloro-2-(l,l-dioxido-2,3-dihydro-l,4-benzothiazepin-4(5H)-yl)quinolin-4- yl] propane- 1 ,3-diamine
Figure imgf000237_0001
The title compound was prepared in analogy to Example 9-1 in Scheme 5 by using 4-(4,7- dichloroquinolin-2-yl)-2,3,4,5-tetrahydro-l,4-benzothiazepine 1,1-dioxide (prepared in analogy to 4-(4-chloro-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-l,4-benzothiazepine 1,1-dioxide in Example 2-1 by using 2,4, 7-trichloroquino line and 2,3,4,5-tetrahydro-l,4-benzothiazepine) and propane- 1,3-diamine. MS obsd. (ESI+) [(M+H)+] 431, 1H NMR (400 MHz, CD3OD) δ ppm 8.10 - 8.05 (m, 2 H), 7.91 -7.82 (m, 2 H), 7.80 - 7.69 (m, 1 H), 7.61 - 7.50 (m, 1 H), 7.43 - 7.41 (d, J = 7.6 Hz, 1 H), 5.95 (s, 1 H), 5.30 (s, 2 H), 4.5 (s, 2 H), 3.72 (s, 2 H), 3.59 - 3.56 (t, J= 6.4 Hz, 2 H), 3.10 - 3.06 (t, J= 7.6 Hz, 2 H), 2.70 - 2.10 (t, J= 7.2 Hz, 2 H). Example 9-12 V-[8-Chloro-2-(l,l-dioxido-2,3-dihydro-l,4-benzothiazepin-4(5H)-yl)quinolin-4- yl] propane- 1 ,3-diamine
Figure imgf000237_0002
The title compound was prepared in analogy to Example 9-1 in Scheme 5 by using 4-(4,8- dichloroquinolin-2-yl)-2,3,4,5-tetrahydro-l,4-benzothiazepine 1,1-dioxide (prepared in analog to 4-(4-chloro-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-l,4-benzothiazepine 1,1-dioxide in
Example 2-1 by using 2,4, 8-trichloroquino line and 2,3,4,5-tetrahydro-l,4-benzothiazepine) and propane- 1,3-diamine. MS obsd. (ESI+) [(M+H)+] 431, 1H NMR (400 MHz, CD3OD) δ ppm 8.08 - 8.05 (m, 2 H), 7.94 - 7.92 (d, J= 7.6 Hz, 1 H), 7.85 - 7.83 (d, J= 7.6 Hz, 1 H), 7.71 - 7.70 (m, 1 H), 7.57 -7.56 (m, 1 H), 7.41 - 7.38 (m, 1 H), 6.00 (s, 1 H), 5.39 (s, 2 H), 4.55 (s, 2 H), 3.74 (s, 2 H), 3.60 - 3.56 (t, J= 6.8 Hz, 2 H), 3.09 - 3.05 (t, J= 7.6 Hz, 2 H), 2.11 - 2.07 (m, 2 H).
Example 9-13 V-[5-Chloro-2-(l,l-dioxido-2,3-dihydro-l,4-benzothiazepin-4(5H)-yl)quinolin-4- yl] propane- 1 ,3-diamine
Figure imgf000238_0001
The title compound was prepared in analogy to Example 9-1 in Scheme 5 by using 4-(4,5- dichloroquinolin-2-yl)-2,3,4,5-tetrahydro-l,4-benzothiazepine 1,1-dioxide (prepared in analogy to 4-(4-chloro-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-l,4-benzothiazepine 1,1-dioxide in Example 2-1 by using 2,4, 5-trichloroquino line and 2,3,4,5-tetrahydro-l,4-benzothiazepine) and propane- 1,3-diamine. MS obsd. (ESI+) [(M+H)+] 431, 1H NMR (400 MHz, CD3OD) δ ppm 8.08 - 8.06 (d, J= 7.6 Hz, 1 H), 7.94 - 7.92 (m, 2 H), 7.41 - 7.26 (m, 5 H), 5.99 (s, 1 H), 5.35 (s, 2 H), 4.55 (s, 2 H), 3.74 (s, 2 H), 3.63-3.61 (m, 2 H), 3.15 - 3.11 (t, J= 7.6 Hz, 2 H), 2.16 - 2.13 (m, 2 H ). Example 9-14 V-[2-(l,l-Dioxido-2,3-dihydro-l,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]-2,2- dimethyl ropane- 1 ,3-diamine
Figure imgf000238_0002
The title compound was prepared in analogy to Example 9-1 in Scheme 5 by using 4-(4-chloro- 6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-l,4-benzothiazepine 1,1-dioxide (prepared in analogy to the one in Example 2-1) and 2,2-dimethylpropane- 1,3-diamine. MS obsd. (ESI ) [(M+H)+] 439, 1H NMR (400 MHz, CD3OD) δ ppm 8.07 (d, J= 1.2 Hz, 1 H), 7.99 (s, 1 H), 7.88 (d, J= 7.2 Hz, 1H), 7.73 -7.70 (m, 2 H), 7.61 - 7.57 (m, 2 H), 6.07 (s, 1 H), 5.31 (s, 2 H), 4.50 (s, 2 H), 3.73 (s, 2 H), 3.49 (s, 2 H), 2.99 (s, 2 H), 2.47 (s, 3 H), 1.10 (s, 6 H).
Example 9-15 V-[2-(l,l-Dioxido-2,3-dihydro-l,4-benzothiazepin-4(5H)-yl)quinolin-4-yl]ethane-l,2- diamine
Figure imgf000239_0001
The title compound was prepared in analogy to Example 9-1 in Scheme 5 by using 4-(4- chloroquinolin-2-yl)-2,3,4,5-tetrahydro-l,4-benzothiazepine 1,1-dioxide (prepared in analogy to 4-(4-chloro-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro- 1 ,4-benzothiazepine 1 , 1 -dioxide in Example 2-1 by using 2,4-dichloroquinoline and 2,3,4,5-tetrahydro-l,4-benzothiazepine) and ethane- 1,2-diamine. MS obsd. (ESI+) [(M+H)+] 383, 1H NMR (400 MHz, CD3OD) δ ppm 7.87 (m, 1 H), 7.81 (d, J= 7.83 Hz, 2 H), 7.55 (m, 1 H), 7.47 (m, 1 H), 7.33 (m, 2 H), 7.04 (m, 1 H), 5.94 (m,l H), 5.12 (s, 2 H), 3.57 (t, J= 4.55 Hz, 2 H), 3.43 (t, J= 6.32 Hz, 2 H), 3.33 (m, 2 H), 2.97 (t, J = 6.44 Hz, 2 H). Example 9-16
N-[2-(l,l-Dioxido-2,3-dihydro-l,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]ethane-
1,2-diamine
Figure imgf000239_0002
The title compound was prepared in analogy to Example 9-1 in Scheme 5 by using 4-(4-chloro- 6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-l,4-benzothiazepine 1,1-dioxide (prepared in analogy to the one in Example 2-1) and ethane- 1,2-diamine. MS obsd. (ESI+) [(M+H)+] 397, 1H NMR (400 MHz, CD3OD) δ ppm 7.86 (m, 2 H), 7.65 - 7.50 (m, 2 H), 7.42 - 7.30 (m, 2 H), 7.28 - 7.16 (m, 1 H), 6.10 - 5.95 (m, 1 H), 5.09 (brs, 2 H), 3.64 - 3.42 (m, 2 H), 3.15 - 2.98 (m, 2 H), 2.84 (s, 2 H), 2.35 (s, 3 H), 1.20 (s, 2 H). Example 9-17 V~2~- [2-(l , l-Dioxido-2,3-dihydro- 1 ,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl] -2- methylpropane- 1 ,2-diamine
Figure imgf000240_0001
The title compound was prepared in analogy to Example 9-1 in Scheme 5 by using 4-(4-chloro- 6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-l,4-benzothiazepine 1,1-dioxide (prepared in analogy to the one in Example 2-1) and 2-methylpropane-l ,2-diamine. MS obsd. (ESI ) [(M+H)+] 425, 1H NMR (400 MHz, CD3OD) δ ppm 7.98 (dd, J= 7.83, 1.26 Hz, 1 H), 7.86 (d, J= 6.82 Hz, 1 H), 7.70 (s, 1 H), 7.61 (td, J= 7.45, 1.26 Hz, 1 H), 7.47 - 7.42 (m, 2 H), 7.29 (dd, J= 8.59, 1.77 Hz, 1 H), 6.09 (s, 1 H), 5.16 (s, 2 H), 3.58 (t, J= 4.80 Hz, 2 H), 3.33 (m, 2 H), 3.27 (s, 2 H), 2.43 (s, 3 H), 1.27 (s, 6 H).
Example 9-18 V~2~- [2-(l , l-Dioxido-2,3-dihydro- 1 ,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4- yl] propane- 1 ,2-diamine
Figure imgf000240_0002
The title compound was prepared in analogy to Example 9-1 in Scheme 5 by using 4-(4-chloro- 6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-l,4-benzothiazepine 1,1-dioxide (prepared in analogy to the one in Example 2-1) and propane- 1,2-diamine. MS obsd. (ESI+) [(M+H)+] 411, 1H NMR (400 MHz, CD3OD) δ ppm 7.97 (dd, J= 7.83, 1.01 Hz, 1 H), 7.82 (d, J= 7.33 Hz, 1 H), 7.69 - 7.56 (m, 2 H), 7.46 - 7.38 (m, 2 H), 7.28 (dd, J= 8.46, 1.64 Hz, 1 H), 6.11 - 5.96 (m, 1 H), 5.13 (s, 2 H), 3.66 - 3.49 (m, 2 H), 3.30 - 3.20 (m, 3 H), 2.47 - 2.39 (m, 3 H), 2.24 - 2.19 (m, 2 H), 1.32 - 1.22 (m, 3 H). Example 9-19 V-[2-(l,l-Dioxido-2,3-dihydro-l,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]butane- 1,4-diamine
Figure imgf000241_0001
The title compound was prepared in analogy to Example 9-1 in Scheme 5 by using 4-(4-chloro- 6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-l,4-benzothiazepine 1,1-dioxide (prepared in analogy to the one in Example 2-1) and butane- 1,4-diamine. MS obsd. (ESI+) [(M+H)+] 425, 1H NMR (400 MHz, CD3OD) δ ppm 8.01 - 7.95 (m, 1 H), 7.92 -7.86 (m, 1 H), 7.83 - 7.76 (m, 1 H), 7.69 - 7.61 (m, 1 H), 7.61 - 7.54 (m, 1 H), 7.50 - 7.42 (m, 1 H), 7.39 - 7.31 (m, 1 H), 5.96 (s, 1 H), 5.20 (brs, 2 H), 3.63 (brs, 2 H), 3.47 (brs, 2 H), 3.37 (s, 2 H), 2.42 (s, 3 H), 2.27 - 2.24 (m, 4 H), 1.86 (d, J = 3.28 Hz, 2 H).
Example 9-20 N-[2-(l,l-Dioxido-2,3-dihydro-l,4-benzothiazepin-4(5H)-yl)-6-nitroquinolin-4-yl]ethane- 1,2-diamine
Figure imgf000241_0002
The title compound was prepared in analogy to Example 9-1 in Scheme 5 by using 4-(4-chloro- 6-nitroquinolin-2-yl)-2,3,4,5-tetrahydro-l,4-benzothiazepine 1,1-dioxide (prepared in analogy to 4-(4-chloro-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-l,4-benzothiazepine 1,1-dioxide in
Example 2-1 by using 2,4-dichloro-6-nitroquinoline and 2,3,4,5-tetrahydro-l,4-benzothiazepine) and ethane- 1,2-diamine. MS obsd. (ESI+) [(M+H)+] 428, 1H NMR (400 MHz, CD3OD) δ ppm 9.07 (d, J= 2.53 Hz, 1 H), 8.13 (dd, J = 9.35, 2.53 Hz, 1 H), 7.96 (d, J= 7.58 Hz, 1 H), 7.91 (dd, J= 7.71, 1.14 Hz, 1 H), 7.69 (t, J= 7.20 Hz, 1 H), 7.56 - 7.41 (m, 2 H), 6.09 (s, 1 H), 5.15 (brs, 2 H), 3.64 (brs, 2 H), 3.34 (brs, 4 H), 2.79 (t, J= 6.44 Hz, 2 H).
Example 9-21 V-[2-(l,l-Dioxido-2,3-dihydro-l,4-benzothiazepin-4(5H)-yl)-5-fluoro-6-methylquinolin-4- J! :
Figure imgf000242_0001
The title compound was prepared in analogy to Example 9-1 in Scheme 5 by using 4-(4-chloro- 5-fluoro-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-l,4-benzothiazepine 1,1-dioxide (prepared in analogy to 4-(4-chloro-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-l,4-benzothiazepine 1,1- dioxide in Example 2-1 by using 2,4-dichloro-5-fluoro-6-methylquinoline and 2,3,4,5- tetrahydro-l,4-benzothiazepine) and ethane- 1,2-diamine. MS obsd. (ESI+) [(M+H)+] 415, 1H NMR (400 MHz, CD3OD) δ ppm 7.98 - 7.83 (m, 2 H), 7.71 - 7.60 (m, 1 H), 7.53 - 7.43 (m, 1 H), 7.32 - 7.22 (m, 1 H), 7.21 - 7.11 (m, 1 H), 6.80 - 6.66 (m, 1 H), 6.01 (s, 1 H), 5.08 (brs, 2 H), 3.61 (t, J= 4.67 Hz, 2 H), 3.31 - 3.26 (m, 3 H), 2.87 (t, J= 6.19 Hz, 2 H), 2.22 (d, J= 2.53 Hz, 3 H).
Example 9-22
2- { [2-(l , l-Dioxido-2,3-dihydro- 1 ,4-benzothiazepin-4(5H)-yl)-5-fluoro-6-methylquinolin-4- yl] amino} ethanol
Figure imgf000242_0002
The title compound was prepared in analogy to Example 9-1 in Scheme 5 by using 4-(4-chloro- 5-fluoro-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-l,4-benzothiazepine 1,1-dioxide (prepared in analogy to the one in Example 9-21) and aminoethanol. MS obsd. (ESI+) [(M+H)+] 416, 1H NMR (400 MHz, DMSO- 6) δ ppm 7.94 - 7.84 (m, 2 H), 7.66 (td, J= 7.45, 1.26 Hz, 1 H), 7.49 (td, J= 7.71, 1.26 Hz, 1 H), 7.32 - 7.21 (m, 1 H), 7.21 - 7.11 (m, 1 H), 6.48 (dt, J= 16.93, 4.67 Hz, 1 H), 6.04 (s, 1 H), 5.08 (brs, 2 H), 4.98 (t, J= 5.18 Hz, 1 H), 3.67 (q, J= 5.31 Hz, 2 H), 3.61 (t, J= 4.80 Hz, 2 H), 3.43 (m, 2 H), 2.22 (d, J= 2.53 Hz, 3 H).
Example 9-23 2- { [2-(l , l-Dioxido-2,3-dihydro- 1 ,4-benzothiazepin-4(5H)-yl)-7-fluoro-6-methylquinolin-4- yl] amino} ethanol
Figure imgf000243_0001
The title compound was prepared in analogy to Example 9-1 in Scheme 5 by using 4-(4-chloro- 7-fluoro-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-l,4-benzothiazepine 1,1-dioxide (prepared in analogy to 4-(4-chloro-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-l,4-benzothiazepine 1,1- dioxide in Example 2-1 by using 2,4-dichloro-7-fluoro-6-methylquinoline and 2,3,4,5- tetrahydro-l,4-benzothiazepine) and aminoethanol. MS obsd. (ESI+) [(M+H)+] 416, 1H NMR
(400 MHz, DMSO- 6) δ ppm 7.93 - 7.87 (m, 2 H), 7.84 (d, J = 8.84 Hz, 1 H), 7.65 (td, J = 7.52, 1.14 Hz, 1 H), 7.53 - 7.43 (m, 1 H), 7.05 (d, J = 11.87 Hz, 1 H), 6.71 (t, J= 5.56 Hz, 1 H), 6.00 (s, 1 H), 5.07 (brs, 2 H), 4.83 (t, J = 5.56 Hz, 1 H), 3.67 - 3.55 (m, 4 H), 3.42 - 3.36 (m, 2 H), 2.27 (s, 3 H).
Example 9-24 V-[2-(l,l-Dioxido-2,3-dihydro-l,4-benzothiazepin-4(5H)-yl)-7-fluoro-6-methylquinolin-4- yl] ethane- 1,2-diamine
Figure imgf000243_0002
The title compound was prepared in analogy to Example 9-1 in Scheme 5 by using 4-(4-chloro- 7-fluoro-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-l,4-benzothiazepine 1,1-dioxide (prepared in analogy to 4-(4-chloro-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-l,4-benzothiazepine 1,1- dioxide in Example 2-1 by using 2,4-dichloro-7-fluoro-6-methylquinoline and 2,3,4,5- tetrahydro-l,4-benzothiazepine) and ethane- 1,2-diamine. MS obsd. (ESI+) [(M+H)+] 415, 1H
NMR (400 MHz, DMSO- 6) δ ppm 7.93 (d, J = 6.82 Hz, 1 H), 7.91 - 7.87 (m, 1 H), 7.82 (d, J = β o/i u~ 1 m n ^ A T = 7 52, 1.39 Hz, 1 H), 7.48 (td, J = 7.71, 1.01 Hz, 1 H), 7.09 - 7.03 (m, 1 H), 5.99 (s, 1 H), 5.09 (brs, 2 H), 3.61 (m, 2 H), 3.45 - 3.31 (m, 4 H), 2.90 (t, J= 6.32 Hz, 2 H), 2.27 (s, 3 H).
Example 9-25
N-[2-(l,l-Dioxido-2,3-dihydro-l,4-benzothiazepin-4(5H)-yl)-7,8-difluoro-6-methylquinolin- 4-yl] ethane- 1,2-diamine
Figure imgf000244_0001
The title compound was prepared in analogy to Example 9-1 in Scheme 5 by using 4-(4-chloro- 7,8-difluoro-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro- 1 ,4-benzothiazepine 1 , 1 -dioxide
(prepared in analogy to 4-(4-chloro-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-l,4- benzothiazepine 1 , 1 -dioxide in Example 2- 1 by using 2,4-dichloro-7,8-difluoro-6- methylquinoline and 2,3,4,5-tetrahydro-l,4-benzothiazepine) and ethane- 1,2-diamine. MS obsd. (ESI+) [(M+H)+] 433, 1H NMR (400 MHz, DMSO- 6) δ ppm 8.25 (m, 1 H), 8.08 (m, 1 H), 7.84 (m, 1 H), 7.76 (m, 1 H), 7.53 (m, 1 H), 5.99 (s, 1 H), 5.06 (brs, 2 H), 3.70 (m, 2 H), 3.49 - 3.30(m, 4 H), 3.01 (m, 2 H), 2.92 (s, 3 H). Example 9-26
2-(l , l-Dioxido-2,3-dihydro- 1 ,4-benzothiazepin-4(5H)-yl)- V-(2-methoxyethyl)-6- methylquinolin-4-amine
Figure imgf000244_0002
The title compound was prepared in analogy to Example 9-1 in Scheme 5 by using 4-(4-chloro- 6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-l,4-benzothiazepine 1,1-dioxide (prepared in analogy to the one in Example 2-1) and 2-methoxyethaneamine. MS obsd. (ESI ) [(M+H)+] 412, 1H
ΛΤ\/ΓΡ ^ nn MH, <^nr)) § ppm 8.12 - 8.08 (d, J= 7.6 Hz, 1 H), 7.90 (s, 1 H), 7.35 - 7.30 (d, J = 7.6 Hz, 1 H), 7.26 - 7.13 (m, 2 H), 7.11 - 7.05 (m, 2 H), 6.06 (s, 1 H), 5.27 (s, 2 H), 4.50 (s, 2 H), 4.78 - 4.62 (m, 6 H), 3.35 (s, 3 H), 2.45 (s, 3 H).
Example 9-27 l-[2-(l,l-Dioxido-2,3-dihydro-l,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4- yl]piperidin-4-amine
Figure imgf000245_0001
The title compound was prepared in analogy to Example 9-1 in Scheme 5 by using 4-(4-chloro- 6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-l,4-benzothiazepine 1,1-dioxide (prepared in analogy to the one in Example 2-1) and piperidin-4-amine. MS obsd. (ESI+) [(M+H)+] 437, 1H NMR (400 MHz, CD3OD) δ ppm 8.10 - 8.08 (m, 1 H), 7.84 - 7.71 (m, 3 H), 7.62 - 7.59 (m, 3 H), 6.50 (s, 1 H), 5.34 (s, 2 H), 4.57 - 4.55 (m, 2 H), 3.96 - 3.86 (m, 2 H), 3.78 - 3.76 (m, 2 H), 3.48 - 3.45 (m, 1 H), 3.13 - 3.08 (m, 2 H), 2.48 (s, 3 H), 2.27 - 2.23 (m, 2 H), 2.02 - 1.92 (m, 2 H).
Example 9-28 l-[2-(l,l-Dioxido-2,3-dihydro-l,4-benzothiazepin-4(5H)-yl)-l,6-naphthyridin-4- yl]pyrrolidin-3-amine
Figure imgf000245_0002
The title compound was prepared in analogy to Example 9-1 in Scheme 5 by using 4-(4-chloro- l,6-naphthyridin-2-yl)-2,3,4,5-tetrahydro-l,4-benzothiazepine 1,1-dioxide (prepared in analogy to 4-(4-chloro-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-l,4-benzothiazepine 1,1-dioxide in Example 2-1 by using 2,3,4,5-tetrahydro-l,4-benzothiazepine and 2,4-dichloro-l,6- naphthyridine) and pyrrolidin-3-amine. MS obsd. (ESI+) [(M+H)+] 410, 1H NMR (400 MHz,
' H), 8.28 - 8.20 (d, J= 6.4 Hz, 1 H), 8.05 - 7.98 (d, J= 8 Hz, 1 H), 7.90 - 7.82 (d, J= 7.2 Hz, 1 H), 7.70 - 7.60 (m, 2 H), 7.50 - 7.42 (t, J = 7.2 Hz, 1 H), 6.14 (s, 1 H), 5.26 (s, 2 H), 4.70 - 4.50 (m, 2 H), 4.20 - 4.10 (m, 2 H), 4.10 - 4.00 (m, 1 H), 3.90 - 3.78 (m, 2 H), 3.60 - 3.52 (t, J= 2.8 Hz, 2 H), 2.60 - 2.48 (m, 1 H), 2.35 - 2.25 (m, 1 H).
Example 9-29 N-[6-(Difluoromethyl)-2-(l,l-dioxido-2,3-dihydro-l,4-benzothiazepin-4(5H)-yl)quinolin-4- yl] propane- 1 ,3-diamine
Figure imgf000246_0001
The title compound was prepared in analogy to Example 9-1 in Scheme 5 by using 4-(4-chloro- 6-difluoromethylquinolin-2-yl)-2,3,4,5-tetrahydro-l,4-benzothiazepine 1,1-dioxide (prepared in analogy to 4-(4-chloro-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-l,4-benzothiazepine 1,1- dioxide in Example 2-1 by using 2,4-dichloro-6-difluoromethylquinoline and 2,3,4,5-tetrahydro- 1,4-benzothiazepine) and propane- 1,3-diamine. MS obsd. (ESI+) [(M+H)+] 447, 1H NMR (400 MHz, CD3OD) δ ppm 8.39 (s, 1 H), 8.12 - 8.08 (d, J= 7.6 Hz, 1 H), 7.95 - 7.85 (m, 3 H), 7.78 - 7.70 (t, J= 1.2 Hz, 1 H), 7.65 - 7.58 (t, J= 6.8 Hz, 1 H), 7.03 - 6.72 (t, J= 54.4 Hz, 1 H), 6.03 (s, 1 H), 5.35 (s, 2 H), 4.60 - 4.49 (m, 2 H), 3.80 - 3.72 (t, J= 2.8 Hz, 2 H), 3.68 - 3.60 (t, J= 6.8 Hz, 2 H), 3.15 - 3.09 (t, J= 7.6 Hz, 2 H), 2.16 - 2.05 (m, 2 H).
Example 9-30
6-Chloro-2-(l,l-dioxido-2,3-dihydro-l,4-benzothiazepin-4(5H)-yl)- V-ethylquinolin-4- amine
Figure imgf000246_0002
The title compound was prepared in analogy to Example 9-1 in Scheme 5 by using 4-(4,6- dichloroquinolin-2-yl)-2,3,4,5-tetrahydro-l,4-benzothiazepine 1,1-dioxide (prepared in analogy to 4-(4-chloro-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-l,4-benzothiazepine 1,1-dioxide in ~ * ' 1, 6-trichloroquino line and 2,3,4, 5-tetrahydro-l,4-benzothiazepine) and ethaneamine. MS obsd. (ESI+) [(M+H)+] 402, 1H NMR (400 MHz, DMSO- 6) δ ppm 8.07 (s, 1 H), 7.90 (t, J= 4.2 Hz, 2 H), 7.65 (t, J= 3.5 Hz, 1 H), 7.48 (t, J= 3.7 Hz, 1 H), 7.38 (t, J= 3.8 Hz, 2 H), 6.03 (s, 1 H), 5.09 (s, 2 H), 4.42 (brs, 2 H), 3.62 (t, J= 2.4 Hz, 2 H), 3.3 (m, 2 H), 1.24 (t, 3 H). Example 9-31
2- { [6-Chloro-2-(l , l-dioxido-2,3-dihydro- 1 ,4-benzothiazepin-4(5H)-yl)quinolin-4- yl] amino} ethanol
Figure imgf000247_0001
The title compound was prepared in analogy to Example 9-1 in Scheme 5 by using 4-(4,6- dichloroquinolin-2-yl)-2,3,4,5-tetrahydro-l,4-benzothiazepine 1,1-dioxide (prepared in analogy to 4-(4-chloro-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-l,4-benzothiazepine 1,1-dioxide in Example 2-1 by using 2,4, 6-trichloroquino line and 2,3,4,5-tetrahydro-l,4-benzothiazepine) and aminoethanol. MS obsd. (ESI+) [(M+H)+] 418, 1H NMR (400 MHz, DMSO- 6) δ ppm 8.06 (s, 1 H), 7.90 (t, J= 3.9 Hz, 2 H), 7.65 (t, J= 3.7 Hz, 1 H), 7.49 (t, J= 3.8 Hz, 1 H), 7.39 (t, J= 3.6 Hz, 2 H), 6.83 (t, J= 4.6 Hz, 1 H), 6.08 (s, 1 H), 5.08 (s, 2 H), 4.81 (t, J= 2.8 Hz, 1 H), 4.43 (brs, 2 H), 3.63 (m, 4 H), 3.85 (m, 2 H).
Example 9-32 V-[6-Chloro-2-(l,l-dioxido-2,3-dihydro-l,4-benzothiazepin-4(5H)-yl)quinolin-4-yl]- V- methylethane- 1 ,2-diamine
Figure imgf000247_0002
The title compound was prepared in analogy to Example 9-1 in Scheme 5 by using 4-(4,6- dichloroquinolin-2-yl)-2,3,4,5-tetrahydro-l,4-benzothiazepine 1,1-dioxide (prepared in analogy to 4-(4-chloro-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-l,4-benzothiazepine 1,1-dioxide in Example 2-1 by using 2,4, 6-trichloroquino line and 2,3,4,5-tetrahydro-l,4-benzothiazepine) and N-methylethane-l,2-diamine. MS obsd. (ESI+) [(M+H)+] 431, 1H NMR (400 MHz, CD3OD) δ ppm 7.98 (d, J= 2.0 Hz, 1 H), 7.90 (s, 1 H), 7.84 (d, J= 1.8 Hz, 1 H), 7.63 (t, J= 3.7 Hz, 1 H), 7.46 (t, J= 4.1 Hz, 2 H), 7.36 (m, J= 2.8 Hz, 1 H), 6.08 (s, 1 H), 5.17 (s, 2 H), 4.55 (brs, 2 H), 3.58 (t, J= 2.3 Hz, 2 H), 3.50 (t, J= 3.1 Hz, 2 H), 2.96 (t, J= 3.1 Hz, 2 H), 2.51 (s, 3 H).
Example 9-33 V-[2-(l,l-Dioxido-2,3-dihydro-l,4-benzothiazepin-4(5H)-yl)-6-(methylsulfanyl)quinolin-4- yl] propane- 1 ,3-diamine
Figure imgf000248_0001
The title compound was prepared in analogy to Example 9-1 in Scheme 5 by using 4-(4-chloro- 6-(methylsulfanyl)quinolin-2-yl)-2,3,4,5-tetrahydro- 1 ,4-benzothiazepine 1 , 1 -dioxide (prepared in analogy to 4-(4-chloro-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-l,4-benzothiazepine 1,1- dioxide in Example 2-1 by using 2,4-dichloro-6-(methylsulfanyl)quinoline and 2,3,4,5- tetrahydro-l,4-benzothiazepine) and propane- 1,3-diamine. MS obsd. (ESI ) [(M+H)+] 442, 1H NMR (400 MHz, CD3OD) δ ppm 8.07 (dd, J= 1.2, 8.0 Hz, 1 H), 7.92 (d, J= 2.0 Hz, 1 H), 7.84 (d, J= 7.6 Hz, 1 H), 7.74 - 7.69 (m, 2 H), 7.64 (dd, J= 2.0, 8.8 Hz, 1 H), 7.57 (t, J= 8.0 Hz, 1 H), 5.95 (s, 1 H), 5.30 (s, 2 H), 4.50 (brs, 2 H), 3.72 (t, J= 4.8 Hz, 2 H), 3.59 (t, J= 6.8 Hz, 2 H), 3.08 (t, J= 7.6 Hz, 2 H), 2.55 (s, 3 H), 2.14 - 2.05 (m, 2 H).
Example 9-34 V-[6-Bromo-2-(l,l-dioxido-2,3-dihydro-l,4-benzothiazepin-4(5H)-yl)quinolin-4- yl] propane- 1 ,3-diamine
Figure imgf000248_0002
The title compound was prepared in analogy to Example 9-1 in Scheme 5 by using 4-(6-bromo-
~ 3,4, 5-tetrahydro-l,4-benzothiazepine 1,1-dioxide (prepared in analogy to 4-(4-chloro-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-l ,4-benzothiazepine 1 , 1-dioxide in Example 2-1 by using 6-bromo-2,4-dichloroquinoline and 2,3,4,5-tetrahydro-l ,4- benzothiazepine) and propane- 1 ,3-diamine. MS obsd. (ESI+) [(M+H)+] 475, 1H NMR (400 MHz, CD3OD) δ ppm 8.34 (s, 1 H), 8.05 - 8.04 (d, J = 7.6 Hz, 1 H), 7.88 - 7.86 (d, J= 7.6 Hz, 1 H), 7.81 - 7.79 (d, J= 9.2 Hz, 1 H), 7.75 - 7.69 (m, 2 H), 7.58 - 7.55 (t, J = 7.6 Hz, 1 H), 5.98 (s, 2 H), 5.34 (s, 2 H),4.52 (s, 2 H), 3.72 (s, 2 H), 3.60 - 3.57 (t, J= 7.2 Hz, 2 H), 3.12 - 3.08 (t, J = 7.6 Hz, 2 H), 2.15 - 2.08 (m, 2 H).
Example 10
{4-[(2-Aminoethyl)amino]-2-(l,l-dioxido-2,3-dihydro-l,4-benzothiazepin- yl)quinolin-6-yl} methanol
Figure imgf000249_0001
4-Chloro-2-(2,3-dihydro-l,4-benzothiazepin-4(5H)-yl)-quinoline-6-methanol
Figure imgf000249_0002
The title compound was prepared in analogy to 4-chloro-2-(l , l-dioxido-2,3-dihydro-l ,4- benzothiazepin-4(5H)-yl)-quinoline-6-methanol in Example 3-23 in Scheme 5 by using methyl 4-chloro-2-(2,3-dihydro- 1 ,4-benzothiazepin-4(5H)-yl)quinoline-6-carboxylate (prepared in analogy to 4-(4-chloro-6-methylquinolin-2-yl)-8-methoxy-2,3,4,5-tetrahydro-l,4- benzothiazepine in Example 1-1 in Scheme 4 by using methyl 2,4-dichloro quinoline-6- carboxylate and 2,3,4,5-tetrahydro-l ,4-benzothiazepine) and sodium boro hydride. {4- [(2- Aminoethyl)amino] -2-(2,3-dihydro- 1 ,4-benzothiazepin-4(5H)-yl)quinolin-6- yl} methanol
Figure imgf000250_0001
The title compound was prepared in analogy to Example 9-1 in Scheme 5 by using [4-chloro-2- (2,3-dihydro- 1 ,4-benzothiazepin-4(5H)-yl)quinolin-6-yl]methanol and propane- 1 ,3-diamine.
{4-[(2-Aminoethyl)amino]-2-(l,l-dioxido-2,3-dihydro-l,4-benzothiazepin-4(5H)- yl)quinolin-6-yl} methanol
Figure imgf000250_0002
To a suspension of {4-[(2-aminoethyl)amino]-2-(2,3-dihydro-l ,4-benzothiazepin-4(5H)- yl)quinolin-6-yl} methanol (370 mg, 1.04 mmol) in dichloromethane (10 mL) was added 3- chloroperoxybenzoic acid (384 mg, 2.18 mmol). The resulting mixture was stirred at room temperature for 2 hours. To the mixture was added an aqueous solution of saturated sodium bicarbonate (1 mL) to quench the reaction, and resulting mixture was diluted with
dichloromethane (15 mL). The organic phase was separated, washed with saturated sodium bicarbonate and brine, dried over sodium sulfate, and concentrated in vacuo. The residue was purified by flash chromatography to afford 400 mg of the title compound as a yellow solid (yield was 98%). MS obsd. (ESI+) [(M+H)+] 413, 1H NMR (400 MHz, DMSO- 6) δ ppm 8.18 (s, 1 H), 7.93 (d, J= 7.6 Hz, 1 H), 7.87 - 7.84 (m, 2 H), 7.64 (m, 1 H), 7.45 (m, 1 H), 7.37 (s, 1 H), 7.33 (s, 1 H), 6.10 (s, 1 H), 5.09 (s, 2 H), 4.52 (brs, 2 H), 3.62 (s, 2 H), 3.37 - 3.28 (m, 4 H), 3.18 (m, 2 H).
Example 1 1-1 2- { [2-(l , l-Dioxido-2,3-dihydro- 1 ,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4- yl]amino}propane-l,3-diol
Figure imgf000251_0001
A solution of 4-(4-chloro-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-l,4-benzothiazepine 1,1- dioxide ( 200.0 mg, 0.54 mmol, prepared in analogy to the one in Example 2-1) and 2- aminopropane-l,3-diol ( 420.0 mg, 4.6 mmol) in l-methyl-2-pyrrolidinone (1.0 mL) was stirred at 160 °C for 16 hours. After being cooled to room temperature and diluted with water (50 mL), the resulting mixture was extracted with ethyl acetate (100 mL), washed with brine (50 mL x 2), dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by preparative HPLC to afford 34.6 mg of the product as a white solid (yield was 15%). MS obsd.
(ESI+) [(M+H)+] 428, 1H NMR (400 MHz, CD3OD) δ ppm 7.99 (dd, J= 7.83, 1.01 Hz, 1 H), 7.86 (d, J= 7.07 Hz, 1 H), 7.71 - 7.58 (m, 2 H), 7.51 - 7.40 (m, 2 H), 7.36 - 7.24 (m, 1 H), 6.16 (s, 1 H),5.16 (s, 2 H), 4.79 - 4.59 (m, 1 H), 4.54 (brs, 1 H), 3.81 (s, 5 H), 3.69 - 3.50 (m, 2 H), 2.42 (s, 3 H).
Example 11-2
2,2 '- { [2-(l, l-Dioxido-2,3-dihydro- 1 ,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4- yljimino} diethanol
Figure imgf000251_0002
The title compound was prepared in analogy to Example 11-1 in Scheme 5 by using 4-(4-chloro- 6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-l,4-benzothiazepine 1,1-dioxide (prepared in analogy to the one in Example 2-1) and 2,2*-iminodiethanol. MS obsd. (ESI+) [(M+H)+] 442, 1H NMR
(400 MHz, CD3OD) δ ppm 7.99 (dd, J= 7.83, 1.26 Hz, 1 H), 7.81 (s, 1 H), 7.83 (s, 1 H), 7.63 (td, J= 7.58, 1.26 Hz, 1 H), 7.56 - 7.39 (m, 2 H), 7.30 (dd, J= 8.46, 1.89 Hz, 1 H), 6.78 (s, 1 ] 5.18 (s, 2 H), 4.57 (brs, 2 H), 3.73 - 3.56 (m, 6 H), 3.56 - 3.43 (m, 4 H), 2.42 (s, 3 H).
Example 11-3 4- { [2-(l , l-Dioxido-2,3-dihydro- 1 ,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl] amino}- 3-hydroxybutanoic acid
Figure imgf000252_0001
The title compound was prepared in analogy to Example 11-1 in Scheme 5 by using 4-(4-chloro- 6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-l,4-benzothiazepine 1,1-dioxide (prepared in analogy to the one in Example 2-1) and 4-amino- 3-hydroxybutanoic acid. MS obsd. (ESI ) [(M+H)+] 456. 1H NMR (400 MHz, CD3OD) δ ppm 8.10 (dd, J= 7.83, 1.26 Hz, 1 H), 7.83 - 8.00 (m, 2 H), 7.80 - 7.67 (m, 2 H), 7.67 - 7.52 (m, 2 H), 6.32 (s, 1 H), 5.43 - 5.27 (m, 2 H), 4.55 (brs, 2 H), 4.39 - 4.23 (m, 1 H), 3.86 - 3.66 (m, 3 H), 3.57 - 3.40 (m, 1 H), 2.78 - 2.63 (m, 2 H), 2.50 (s, 3 H).
Example 11-4 l-Amino-3-{[2-(l,l-dioxido-2,3-dihydro-l,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4- yl] amino}-2-methylpropan-2-ol
Figure imgf000252_0002
The title compound was prepared in analogy to Example 11-1 in Scheme 5 by using 4-(4-chloro- 6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-l,4-benzothiazepine 1,1-dioxide (prepared in analogy to the one in Example 2-1) and l,3-diamino-2-methylpropan-2-ol. MS obsd. (ESI ) [(M+H)+] 441, 1H NMR (400 MHz, CD3OD) δ ppm 7.97 (d, J= 7.6 Hz, 1 H), 7.88 (d, J= 7.6 Hz, 1 H), 7.60 (t, J= 7.6 Hz, 1 H), 7.57 (s, 1 H), 7.43 (m, 2 H), 7.29 (dd, J= 1.2, 8.4 Hz, 1 H), 6.18 (s, 1 H), 5.15 (s, 2 H), 4.53 (brs, 2 H), 3.58 (t, J= 4.4 Hz, 2 H), 3.34 (m, 2 H), 2.85 - 2.76 (m, 2 H), 2.42 (s, 3 H), 1.32 (s, 3 H).
Example 12-1 2-(l , l-Dioxido-2,3-dihydro- 1 ,4-benzothiazepin-4(5H)-yl)-6-methyl- V- [2-(morpholin-4- yl)ethyl] quinolin-4-amine
Figure imgf000253_0001
A mixture of 4-(4-chloro-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-l,4-benzothiazepine 1,1- dioxide (50 mg, 0.134 mmol, prepared in analogy to the one in Example 2-1), 2-(morpholin-4- yl)ethanamine (78 mg, 0.67 mmol) and n-butanol (5 mL) was heated with stirring in a 10 mL of microwave process vial for 2 hours at 160 °C under microwave irradiation. After being cooled to room temperature, the mixture was diluted with dichloromethane and washed with brine. The organic layer was dried over sodium sulfate and concentrated in vacuo. The residue was purified by column chromatography on silica gel (eluting with 3% methanol in dichloromethane) to afford 35 mg of the product as a light oil (yield was 56%). MS obsd. (ESI+) [(M+H)+] 467, 1H NMR (400 MHz, CDC13) δ ppm 8.05 (d, 7.6 Hz, 1 H), 7.66 (d, 7.2 Hz, 1 H), 7.53 - 7.51 (m, 2 H), 7.38 (m, 1 H), 7.32 (m, 1 H), 5.88 (s, 1 H), 5.56 (s, 2 H), 5.09 (s, 2 H), 4.6 (brs, 2 H) 3.76 (t, 4.8 Hz, 4 H), 3.50 (brs, 2 H), 3.33 (m, 2 H), 2.82 (m, 2 H), 2.56 (m, 4 H), 2.29 (s, 3 H).
Example 12-2
2- { [2-(l , l-Dioxido-2,3-dihydro- 1 ,4-benzothiazepin-4(5H)-yl)- 1 ,6-naphth rid in-4- yl] amino} ethanol
Figure imgf000253_0002
The title compound was prepared in analogy to Example 12-1 in Scheme 5 by using 4-(4-chloro- l,6-naphthyridin-2-yl)-2,3,4,5-tetrahydro-l,4-benzothiazepine 1,1-dioxide (prepared in analogy to 4-(4-chloro-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-l,4-benzothiazepine 1,1-dioxide in Example 2-1 by using 2,3,4,5-tetrahydro-l,4-benzothiazepine and 2,4-dichloro-l,6- naphthyridine) and 2-aminoethanol. MS obsd. (ESI+) [(M+H)+] 385, 1H NMR (400 MHz, rn,nro Ά™™ (a 1 H), 8.66 - 8.64 (d, 6.8 Hz, 1 H), 8.26 - 8.24 (d, 6.8 Hz, 1 H), 8.05 - 8.03 (d, J= 7.6 Hz, 1 H), 7.97 - 7.95 (d, J= 7.2 Hz, 1 H), 7.71 - 7.69 (d, J= 7.2 Hz, 1 H), 7.56 - 7.54 (d, J= 7.6 Hz, 1 H), 6.30 (s, 1 H), 5.38 (s, 1 H), 4.72 - 4.60 (m, 2 H), 3.87 - 3.86 (m, 2 H), 3.71 - 3.67 (m, 4 H).
Example 12-3 V-[2-(l,l-Dioxido-2,3-dihydro-l,4-benzothiazepin-4(5H)-yl)-8-methylquinolin-4-yl]nonane- 1,9-diamine
Figure imgf000254_0001
The title compound was prepared in analogy to Example 12-1 in Scheme 5 by using 4-(4-chloro- 8-methylquinolin-2-yl)-2,3,4,5-tetrahydro-l,4-benzothiazepine 1,1-dioxide (prepared in analogy to 4-(4-chloro-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-l,4-benzothiazepine 1,1-dioxide in Example 2-1 by using 2,4-dichloro-8-methylquinoline and 2,3,4,5-tetrahydro-l,4- benzothiazepine) and nonane- 1,9-diamine. MS obsd. (ESI+) [(M+H)+] 495, 1H NMR (400 MHz, CD3OD) δ ppm 8.04 - 8.03 (m, 1 H), 7.93 - 7.91 (m, 1 H), 7.82 - 7.80 (m, 1 H), 7.68 - 7.70 (m, 1 H), 7.58 - 7.56 (m, 2 H), 7.40 - 7.30 (m, 1 H), 5.87 (s, 1 H), 5.30 (s, 2 H), 4.49 (s, 2 H), 3.76 - 3.75 (m, 2 H), 3.42 - 3.40 (m, 2 H), 2.90 - 2.85 (m, 2 H), 2.61 (s, 3 H), 1.70 - 1.58 (m, 4 H), 1.48 - 1.31 (m, 10 H).
Example 12-4 V-[2-(l,l-Dioxido-2,3-dihydro-l,4-benzothiazepin-4(5H)-yl)-8-methylquinolin-4-yl]decane- 1,10-diamine
Figure imgf000254_0002
The title compound was prepared in analogy to Example 12-1 in Scheme 5 by using 4-(4-chloro- 8-methylquinolin-2-yl)-2,3,4,5-tetrahydro-l,4-benzothiazepine 1,1-dioxide (prepared in analogy to 4-(4-chloro-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-l,4-benzothiazepine 1,1-dioxide in Example 2-1 by using 2,4-dichloro-8-methylquinoline and 2,3,4,5-tetrahydro-l,4- , -" - -ane.i o-diamine. MS obsd. (ESI+) [(M+H)+] 509, 1H NMR (400 MHz, CD3OD) δ ppm 8.08 - 8.06 (m, 1 H), 7.94 - 7.93 (m, 1 H), 7.82 - 7.81 (m, 1 H), 7.72 - 7.70 (m, 1 H), 7.59 - 7.57 (m, 2 H), 7.42 - 7.32 (m, 1 H), 5.89 (s, 1 H), 5.31 (s, 2 H), 4.50 (s, 2 H), 3.78 - 3.77 (m, 2 H), 3.44 - 3.42 (m, 2 H), 2.91 - 2.87 (m, 2 H), 2.63 (s, 3 H), 1.70 - 1.58 (m, 4 H), 1.48 - 1.31 (m, 12 H). Example 12-5 V-[2-(l,l-Dioxido-2,3-dihydro-l,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl] octane- 1,8-diamine
Figure imgf000255_0001
The title compound was prepared in analogy to Example 12-1 in Scheme 5 by using 4-(4-chloro- 6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-l,4-benzothiazepine 1,1-dioxide (prepared in analogy to the one in Example 2-1) and octane- 1,8-diamine. MS obsd. (ESI+) [(M+H)+] 481, 1H NMR (400 MHz, CD3OD) 5 ppm 8.10 - 8.08 (dd, J= 1.2 Hz, 1 H), 7.92 (s, 1 H), 7.86 - 7.84 (d, J= 7.6 Hz, 1 H), 7.71 - 7.67 (m, 2 H), 7.61 - 7.55 (m, 2 H), 5.92 (s, 1 H), 5.28 (s, 2 H), 4.52 (s, 2 H), 3.75 - 3.73 (m, 2 H), 3.50 - 3.46 (t, 2 H), 2.93 - 2.83 (t, 2 H), 2.46 (s, 3 H), 1.74 - 1.64 (m, 4 H), 1.51 - 1.40 (m, 8 H).
Example 12-6
9- { [2-(l , l-Dioxido-2,3-dihydro- 1 ,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4- yl]amino}nonan-l-ol
Figure imgf000255_0002
The title compound was prepared in analogy to Example 12-1 in Scheme 5 by using 4-(4-chloro- 6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-l,4-benzothiazepine 1,1-dioxide (prepared in analogy to the one in Example 2-1) and 9-aminononanol. MS obsd. (ESI+) [(M+H)+] 495, 1H NMR (400 MHz, CD3OD) 5 ppm 8.11 - 8.09 (dd, J= 1.2 Hz, 1 H), 7.92 (s, 1 H), 7.85 -7.83 (d, J= 7.6 Hz, 1 H), 7.71 - 7.67 (m, 2 H), 7.61 - 7.57 (m, 2 H), 5.92 (s, 1 H), 5.28 (s, 2 H), 4.52 (s, 2 H), 3.74 (s, 2 H), 3.50 - 3.46 (t, 2 H), 2.92 - 2.89 (t, 2 H), 2.46 (s, 3 H), 1.73 - 1.63 (m, 4 H), 1.50 - 1.38 (m, 10 H).
Example 12-7 V-[2-(l,l-Dioxido-2,3-dihydro-l,4-benzothiazepin-4(5H)-yl)-8-methylquinolin-4-yl] octane- 1,8-diamine
Figure imgf000256_0001
The title compound was prepared in analogy to Example 12-1 in Scheme 5 by using 4-(4-chloro- 8-methylquinolin-2-yl)-2,3,4,5-tetrahydro-l,4-benzothiazepine 1,1-dioxide (prepared in analogy to 4-(4-chloro-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-l,4-benzothiazepine 1,1-dioxide in Example 2-1 by using 2,4-dichloro-8-methylquinoline and 2,3,4,5-tetrahydro-l,4- benzothiazepine) and octane- 1,8-diamine. MS obsd. (ESI+) [(M+H)+] 481, 1H NMR (400 MHz, CD3OD) δ ppm 8.09 - 8.07 (d, J= 7.6 Hz, 1 H), 7.96 - 7.94 (d, J= 8.4 Hz, 1 H), 7.85 - 7.83 (d, J = 7.6 Hz, 1 H), 7.73 - 7.70 (m, 2 H), 7.36 - 7.32 (m, 2 H), 5.90 (s, 1 H), 5.33 (s, 2 H), 4.52 - 4.51 (m, 2 H), 3.81 - 3.78 (t, 2 H), 3.47 - 3.42 (t, 2 H), 2.91 - 2.89 (t, 2 H), 2.64 (s, 3 H), 1.67 - 1.63 (m, 4 H), 1.50 - 1.37 (m, 8 H).
Example 13 cis-4-amino-l-[2-(l,l-Dioxido-2,3-dihydro-l,4-benzothiazepin-4(5H)-yl)-6-methylquinolin- 4-yl] pyrrolidin-3-ol
Figure imgf000256_0002
A mixture of 4-(4-chloro-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-l,4-benzothiazepine 1,1- dioxide (740 mg, 2.0 mmol, prepared in analogy to the one in Example 2-1) and cis-4- aminopyrrolidin-3-ol (600 mg, 6.0 mmol) in n-butanol (0.2 mL) was heated at 180 °C for 3 days After being cooled to room temperature, the mixture was purified by preparative HPLC to afford the product as a solid. MS obsd. (ESI+) [(M+H)+] 439, 1H NMR (400 MHz, CD3OD) δ ppm 8.12 (dd, J= 7.83, 1.26 Hz, 1 H), 8.02 (s, 1 H), 7.87 (d, J= 7.07 Hz, 1 H), 7.82 - 7.71 (m, 2 H), 7.67 - 7.57 (m, 2 H), 5.93 (s, 1 H), 5.33 (s, 2 H), 4.66 (d, J= 2.02 Hz, 1 H), 4.56 (brs, 2 H), 4.28 - 4.17 (m, 2 H), 4.13 -3.99 (m, 2 H), 3.91 (s, 1 H), 3.76 (brs, 2 H), 3.37 (s, 3 H), 2.50 (s, 3 H).
Example 14-1 V-[2-(l,l-Dioxido-2,3-dihydro-l,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]-L- alanine
Figure imgf000257_0001
The mixture of 4-(4-chloro-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-l,4-benzothiazepine 1,1- dioxide (150 mg, 0.40 mmol, prepared in analogy to the one in Example 2-1) and Z-alanine (360 mg, 4.0 mmol) in phenol (360 mg) was heated at 150°C overnight. After being cooled to room temperature, the mixture was purified by preparative HPLC to afford the pure product as a solid. MS obsd. (ESI+) [(M+H)+] 426, 1H NMR (400 MHz, CD3OD) δ ppm 8.16 - 7.92 (m, 3 H), 7.84 (d, J= 8.34 Hz, 1 H), 7.78 - 7.62 (m, 1 H), 7.61 - 7.42 (m, 2 H), 5.86 (s, 1 H), 5.24 (brs, 2 H), 4.65 - 4.35 (m, 3 H), 3.69 (brs, 2 H), 3.37 (s, 3 H), 2.53 - 2.39 (m, 3 H), 1.76 - 1.57 (m, 3 H).
Example 14-2 V-[2-(l,l-Dioxido-2,3-dihydro-l,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-l]-beta- alanine
Figure imgf000257_0002
The title compound was prepared in analogy to Example 14-1 in Scheme 5 by using 4-(4-chloro- 6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-l,4-benzothiazepine 1,1-dioxide (prepared in analogy to the one in Example 2-1) and beta-alanine. MS obsd. (ESI+) [(M+H)+] 426, 1H NMR (400 MHz, CD3OD) δ ppm 8.14 - 8.08 (m, 1 H), 7.96 - 7.88 (m, 2 H), 7.77 - 7.68 (m, 2 H), 7.65 - 7.57 (m, 2 H), 6.09 (s, 1 H), 5.32 (s, 2 H), 4.56 (brs, 1 H), 3.84 - 3.71 (m, 4 H), 3.37 (s, 2 H), 2.76 (t, J = 6.95 Hz, 2 H), 2.48 (s, 3 H).
Example 15-1 V-[2-(l,l-Dioxido-2,3-dihydro-l,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4- yl] benzene- 1 ,3-diamine
Figure imgf000258_0001
A mixture of 4-(4-chloro-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-l,4-benzothiazepine 1,1- dioxide (150 mg, 0.40 mmol, prepared in analogy to the one in Example 2-1), benzene-1,3- diamine (86 mg, 0.80 mmol), palladium acetate (18 mg, 0.04 mmol), 2,2'- bis(diphenylphosphino)-l,l'-binaphthalene (50 mg, 0.04 mmol), potassium phosphate (169.6 mg, 0.8 mmol) and 1,4-dioxane (3 mL) in a 2~5 mL of process vial was heated at 140 °C under microwave irradiation for 1.5 hours. After being cooled to room temperature, the mixture was filtered and washed with ethyl acetate. The filtrate was washed with brine, dried over sodium sulfate, and concentrated in vacuo. The residue was purified by preparative HPLC to afford the pure product as a solid. MS obsd. (ESI+) [(M+H)+] 445, 1H NMR (400 MHz, DMSO- 6) δ ppm 8.31 (s, 1 H), 7.88 (dd, J = 6.06, 1.52 Hz, 2 H), 7.63 (td, J= 7.52, 1.14 Hz, 1 H), 7.54 - 7.46 (m, 1 H), 7.42 - 7.33 (m, 2 H), 7.33 - 7.27 (m, 1 H), 7.16 (t, J= 7.83 Hz, 1 H), 6.52 (t, J= 1.89 Hz, 1 H), 6.49 - 6.34 (m, 3 H), 5.23 (s, 2 H), 4.86 (s, 2 H), 3.60 (brs, 2 H), 2.38 (s, 3 H).
Example 15-2 V-[2-(l,l-Dioxido-2,3-dihydro-l,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4- yl] benzene- 1,4-diamine
Figure imgf000259_0001
The title compound was prepared in analogy to Example 15-1 in Scheme 5 by using 4-(4-chloro- 6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-l,4-benzothiazepine 1,1-dioxide (prepared in analogy to the one in Example 2-1 1) and benzene- 1,4-diamine. MS obsd. (ESI+) [(M+H)+] 445, 1H NMR (400 MHz, DMSO- 6) δ ppm 8.21 (s, 1 H), 7.92 - 7.83 (m, 2 H), 7.63 - 7.55 (m, 1 H), 7.53 - 7.46 (m, 1 H), 7.34 (d, J= 8.34 Hz, 1 H), 7.27 (dd, J= 8.59, 1.52 Hz, 1 H), 7.15 (d, J= 7.58 Hz, 1 H), 6.91 (m, J= 8.34 Hz, 2 H), 6.77 (m, J= 8.59 Hz, 2 H), 5.97 (s, 1 H), 5.20 - 5.12 (m, 2 H), 4.76 (brs, 2 H), 3.57 (brs, 2 H), 2.37 (s, 3 H).
Example 15-3 (35)- 1- [2-(l , l-Dioxido-2,3-dihydro- 1 ,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4- yl]pyrrolidin-3-ol
Figure imgf000259_0002
The title compound was prepared in analogy to Example 15-1 in Scheme 5 by using 4-(4-chloro- 6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-l,4-benzothiazepine 1,1-dioxide (prepared in analogy to the one in Example 2-1) and (35)-pyrrolidin-3-ol. MS obsd. (ESI+) [(M+H)+] 424, 1H NMR (400 MHz, CD3OD) δ ppm 7.90 (dd, J= 7.83, 1.26 Hz, 1 H), 7.80 - 7.72 (m, 2 H), 7.54 (td, J = 7.52, 1.39 Hz, 1 H), 7.43 (d, J= 8.59 Hz, 1 H), 7.34 (td, J= 7.71, 1.01 Hz, 1 H), 7.23 (dd, J = 8.59, 1.77 Hz, 1 H), 6.05 (s, 1 H), 5.06 (s, 2 H), 4.55 - 4.43 (m, 1 H), 3.84 (dd, J= 10.48, 4.42 Hz, 2 H), 3.58 - 3.43 (m, 4 H), 3.35 (s, 2 H), 2.35 (s, 3 H), 2.11 (dd, J= 8.84, 4.55 Hz, 1 H), 2.06 - 1.97 (m, 1 H).
Example 15-4 (3R) - 1- [2-(l , l-Dioxido-2,3-dihydro- 1 ,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4- yl]pyrrolidin-3-ol
Figure imgf000260_0001
The title compound was prepared in analogy to Example 15-1 in Scheme 5 by using 4-(4-chloro- 6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-l,4-benzothiazepine 1,1-dioxide (prepared in analogy to the one in Example 2-1) and (3R)-pyrrolidin-3-ol. MS obsd. (ESI+) [(M+H)+] 424, 1H NMR (400 MHz, CD3OD) δ ppm 7.88 (dd, J= 7.83, 1.01 Hz, 1 H), 7.79 - 7.69 (m, 2 H), 7.52 (td, J = 7.52, 1.14 Hz, 1 H), 7.44 (d, J= 8.59 Hz, 1 H), 7.33 - 7.27 (m, 1 H), 7.23 (dd, J= 8.59, 1.77 Hz, 1 H), 6.02 (s, 1 H), 5.04 (s, 2 H), 4.55 - 4.42 (m, 2 H), 3.89 - 3.76 (m, 2 H), 3.59 - 3.42 (m, 4 H), 3.37 (s, 2 H), 2.35 (s, 3 H), 2.16 - 1.97 (m, 2 H).
Example 15-5 irans- V-[2-(l,l-Dioxido-2,3-dihydro-l,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4- yl] cyclopentane- 1 ,2-diamine
Figure imgf000260_0002
The title compound was prepared in analogy to Example 15-1 in Scheme 5 by using 4-(4-chloro- 6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-l,4-benzothiazepine 1,1-dioxide (prepared in analogy to the one in Example 2-1) and trans-cyclopentane-l,2-diamine. MS obsd. (ESI ) [(M+H)+] 437, 1H NMR (400 MHz, CD3OD) δ ppm 8.03 (d, J= 7.83 Hz, 1 H), 7.93 - 7.81 (m, 2 H), 7.67 (t, J = 7.45 Hz, 1 H), 7.61 (d, J= 8.59 Hz, 1 H), 7.51 (t, J= 7.71 Hz, 1 H), 7.47 (d, J= 7.58 Hz, 1 H), 6.04 (s, 1 H), 5.25 (s, 2 H), 4.66 (brs, 1 H), 4.40 (brs, 1 H), 4.27 (d, J= 7.07 Hz, 1 H), 3.84 (q, J = 7.66 Hz, 1 H), 3.75 - 3.65 (m, 2 H), 2.45 (s, 3 H), 2.40 - 2.24 (m, 2 H), 2.08 -1.79 (m, 3 H), 1.58 (dd, J= 13.01, 7.71 Hz, 1 H). Example 16-1
Figure imgf000261_0001
A mixture of 4-(4-chloro-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-l,4-benzothiazepine 1,1- dioxide (0.2 g, 0.54 mmol, prepared in analogy to the one in Example 2-1), piperidin-3-ylamine hydrochloric acid salt (0.275 g, 1.6 mmol) and N,N-diisopropylethylamine (1 mL) was heated at 160 °C under microwave irradiation for 1 hour. After being cooled to room temperature, the mixture was purified by preparative HPLC and SPE. After SPE separation, the eluent was concentrated in vacuo to remove the organic solution. The residue was dried by lyophylization to give 52.3 mg of the desired product (yield was 22.3%). MS obsd. (ESI+) [(M+H)+] 437, 1H NMR (400 MHz, CD3OD) δ ppm 8.09 - 8.07 (d, J = 8 Hz, 1 H), 7.87 - 7.85 (q, J= 7.2 Hz, 1 H), 7.85 - 7.82 (m, 1 H), 7.73 - 7.68 (q, J= 14 Hz, 2 H), 7.62 - 7.55 (m, 2 H), 6.56 (s, 1 H), 5.37 (s, 2 H), 4.57 (s, 2 H), 3.90 - 3.88 (d, J= 9.6 Hz, 1 H), 3.75 (s, 2 H), 3.67-3.66 (m, 1 H), 3.51 - 3.48 (d, J = 11.6 Hz, 1 H), 3.26 - 3.24 (d, J= 9.6 Hz, 1 H), 3.24 -3.14 (m, 1 H), 2.49 (s, 3 H), 2.26 - 2.22 (m, 1 H), 2.14 - 2.10 (m, 1 H), 1.99 - 1.92 (m, 1 H), 1.91 - 1.78 (m, 1 H).
Example 16-2
2-(l , l-Dioxido-2,3-dihydro- 1 ,4-benzothiazepin-4(5H)-yl)- V V,6-trimethylquinolin-4-amine
Figure imgf000261_0002
The title compound was prepared in analogy to Example 16-1 in Scheme 5 by using 4-(4-chloro- 6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-l,4-benzothiazepine 1,1-dioxide (prepared in analogy to the one in Example 2-1) and dimethylamine. MS obsd. (ESI+) [(M+H)+] 382, 1H NMR (400 ,— - " Ί7 (d, J= 7.6 Hz, 1 H), 7.85 - 7.83 (m, 2 H), 7.73 - 7.70 (m, 2 H), 7.58 - 7.55 (m, 2 H), 6.14 (s, 1 H), 5.30 (s, 2 H), 4.51 (s, 2 H), 3.72 - 3.70 (m, 2 H), 3.29 (s, 6 H), 2.45 (s, 3 H).
Example 17-1
N-[2-(l,l-Dioxido-2,3-dihydro-l,4-benzothiazepin-4(5H)-yl)-6-(trifluoromethoxy)quinolin- 4-yl] propane- 1,3-diamine
Figure imgf000262_0001
4-(4-Chloro-6-(trifluoromethoxy)quinolin-2-yl)-2,3,4,5-tetrahydro-l,4-benzothiazepine 1,1- dioxide
Figure imgf000262_0002
A mixture of 2,4-dichloro-6-(trifluoromethoxy)quinoline (250 mg, 0.89 mmol), 2,3,4,5- tetrahydro-l ,4-benzothiazepine 1 , 1 -dioxide (210 mg, 1.06 mmol) and n-butanol (2 mL) was heated with stirring in a 5 mL of microwave process vial for 3 hours at 150 °C under microwave irradiation. The mixture was filtered. The formed solid was collected by filtration and washed with 10 mL of mixture solution of petroleum ether and ethyl acetate (V/V=10/l) to afford 0.3 g of the product (yield was 77%). V-[2-(l,l-Dioxido-2,3-dihydro-l,4-benzothiazepin-4(5H)-yl)-6-(trifluoromethoxy)quinolin- 4-yl] propane- 1 ,3-diamine
Figure imgf000262_0003
The title compound was prepared in analogy to Example 3-1 in Scheme 5 by using 4-(4-chloro- 6-(trifluoromethoxy)quinolin-2-yl)-2,3,4,5-tetrahydro- 1 ,4-benzothiazepine 1 , 1 -dioxide and propane- 1,3-diamine. MS obsd. (ESI+) [(M+H)+] 481, 1H NMR (400 MHz, CD3OD) δ ppm 8.16 - 8.15 (d, J= 2.4 Hz, 1 H), 8.09 - 8.07 (dd, J= 5.2, 8.0 Hz, 1 H), 7.94 - 7.92 (d, J= 10 Hz, 1 H), 7.90 - 7.88 (d, J= 8 Hz, 1 H), 7.72 - 7.70 (m, 2 H), 7.58 - 7.55 (m, 1 H), 6.03 (s, 1 H), 5.34 (s, 2 H), 4.55 (s, 2 H), 3.75 (s, 2 H), 3.62 - 3.59 (t, J= 6.8 Hz, 2 H), 3.14 - 3.10 (t, J= 8.0 Hz, 2 H), 2.15 - 2.11 (m, 2 H).
Example 17-2
N-[2-(l,l-Dioxido-2,3-dihydro-l,4-benzothiazepin-4(5H)-yl)-6-(trifluoromethyl)quinolin-4- yl]propane-l,3-diamine
Figure imgf000263_0001
The title compound was prepared in analogy to Example 17-1 in Scheme 6 by using 4-(4-chloro- 6-(trifluoromethyl)quinolin-2-yl)-2,3,4,5-tetrahydro- 1 ,4-benzothiazepine 1 , 1 -dioxide (prepared in analogy to 4-(4-chloro-6-(trifluoromethoxy)quinolin-2-yl)-2,3,4,5-tetrahydro-l,4- benzothiazepine 1,1 -dioxide in Example 17-1 by uisng 2,4-dichloro-6-(trifluoromethyl)quinoline and 2,3,4, 5-tetrahydro-l,4-benzothiazepine 1,1-dioxide) and propane- 1,3-diamine. MS obsd. (ESI+) [(M+H)+] 465, 1H NMR (400 MHz, CD3OD) δ ppm 8.57 (s, 1 H), 8.09 - 8.07 (dd, J= 6.4, 7.6 Hz, 1 H), 7.98 - 9.97 (d, J= 1.6 Hz, 2 H), 7.95 - 7.87 (d, J= 7.2 Hz, 1 H), 7.74 - 7.70 (m, 1 H), 7.60 - 7.58 (m, 1 H), 6.04 (s, 1 H), 5.34 (s, 2 H), 4.55 (s, 2 H), 3.75 (s, 2 H), 3.62 - 3.59 (t, J = 6.8 Hz, 2 H), 3.12 - 3.08 (t, J= 8 Hz, 2 H), 2.14 - 2.10 (t, J= 8 Hz, 2 H).
Example 17-3 V-[6-(Difluoromethoxy)-2-(l,l-dioxido-2,3-dihydro-l,4-benzothiazepin-4(5H)-yl)quinolin- 4-yl] propane- 1 ,3-diamine
Figure imgf000263_0002
The title compound was prepared in analogy to Example 17-1 in Scheme 6 by using 4-(4-chloro- 6-(difluoromethoxy)quinolin-2-yl)-2,3,4,5-tetrahydro- 1 ,4-benzothiazepine 1 , 1 -dioxide (prepared in analogy to 4-(4-chloro-6-(trifluoromethoxy)quinolin-2-yl)-2,3,4,5-tetrahydro-l,4- benzothiazepine 1,1 -dioxide in Example 17-1 by using 2,4-dichloro-6- (difluoromethoxy)quinoline and 2,3,4,5-tetrahydro-l,4-benzothiazepine 1,1-dioxide) and propane- 1,3-diamine. MS obsd. (ESI+) [(M+H)+] 463, 1H NMR (400 MHz, CD3OD) δ ppm 8.02 - 8.00 (d, J= 7.6 Hz, 1 H), 7.98 - 7.90 (d, J= 2 Hz, 1 H), 7.84 - 7.82 (d, J= 8.4 Hz, 2 H), 7.68 - 7.64 (t, J= 7.6 Hz, 1 H), 7.54 - 7.50 (m, 1 H), 7.05 - 6.68 (d, J= 73.6 Hz, 2 H), 5.95 (s, 1 H), 5.28 (s, 2 H), 4.48 (s, 2 H), 3.68 (s, 2 H), 3.57 - 3.54 (t, J= 6.8 Hz, 2 H), 3.08 - 3.04 (t, J= 7.6 Hz, 2 H), 2.11 - 2.04 (m, 2 H).
Example 17-4 V-[2-(l,l-Dioxido-2,3-dihydro-l,4-benzothiazepin-4(5H)-yl)-6-methoxyquinolin-4- yl] propane- 1 ,3-diamine
Figure imgf000264_0001
The title compound was prepared in analogy to Example 17-1 in Scheme 6 by using 4-(4-chloro- 6-methoxyquinolin-2-yl)-2,3,4,5-tetrahydro-l,4-benzothiazepine 1,1-dioxide (prepared in analogy to 4-(4-chloro-6-(trifluoromethoxy)quinolin-2-yl)-2,3,4,5-tetrahydro-l,4- benzothiazepine 1,1-dioxide in Example 17-1 by using 2,4-dichloro-6-methoxyquinoline and 2,3,4,5-tetrahydro-l,4-benzothiazepine 1,1-dioxide) and propane- 1,3-diamine. MS obsd. (ESI+) [(M+H)+] 427, 1H NMR (400 MHz, CD3OD) δ ppm 8.01 - 7.99 (d, J= 8 Hz, 1 H), 7.83 - 7.81 (d, J= 7.2 Hz, 1 H), 7.71 - 7.64 (m, 2 H), 7.52 - 7.50 (d, J= 7.6 Hz, 2 H), 7.30 - 7.27 (d, J= 9.2 Hz, 1 H), 5.90 (s, 1 H), 5.25 (s, 2 H), 4.46 (s, 2 H), 3.83 (s, 3 H), 3.66 (s, 2 H), 3.56 (s, 2 H), 3.08 - 3.07 (t, J= 7.2 Hz, 2 H), 2.09 - 2.06 (d, J= 5.2 Hz, 2 H).
Example 17-5 V-[2-(l,l-Dioxido-2,3-dihydro-l,4-benzothiazepin-4(5H)-yl)-8-methylquinolin-4- yl] propane- 1 ,3-diamine
Figure imgf000265_0001
The title compound was prepared in analogy to Example 17-1 in Scheme 6 by using 4-(4-chloro- 8-methylquinolin-2-yl)-2,3,4,5-tetrahydro-l,4-benzothiazepine 1 , 1-dioxide (prepared in analogy to 4-(4-chloro-6-(trifluoromethoxy)quinolin-2-yl)-2,3,4,5-tetrahydro- 1 ,4-benzothiazepine 1 , 1- dioxide in Example 17-1 by using 2,4-dichloro-8-methylquinoline and 2,3,4,5-tetrahydro-l ,4- benzothiazepine 1 , 1-dioxide) and propane- 1 ,3-diamine. MS obsd. (ESI+) [(M+H)+] 41 1 , 1H NMR (400 MHz, CD3OD) δ ppm 8.33 (s, 1 H), 8.08 - 8.02 (m, 2 H), 7.83 - 7.86 (d, J = 7.2 Hz, 1 H), 7.74 - 7.72 (t, J = 8.4 Hz, 1 H), 7.62 - 7.58 (q, J = 7.2 Hz, 2 H), 7.34 - 7.28 (t, J= 7.6 Hz, 1 H), 5.98 (s, 2 H), 5.40 (s, 2 H), 4.58 (s, 2 H), 3.79 (s, 2 H), 3.64 - 3.61 (t, J = 6.8 Hz, 2 H), 3.09 - 3.05 (dd, J= 7.6, 8.4 Hz, 2 H), 2.67 (s, 3 H), 2.10 - 2.06 (d, J = 7.2 Hz, 2 H).
Exampe 17-6 and 17-7 V-[2-(l,l-Dioxido-2,3-dihydro-l,4-benzothiazepin-4(5H)-yl)-5-methylquinolin-4- yl] ropane- 1 ,3-diamine and TV- [2-(l , l-Dioxido-2,3-dihydro- 1 ,4-benzothiazepin-4(5H)-yl)-7- methylquinolin-4-yl]propane-l,3-diamine
Figure imgf000265_0002
A mixture of the title compound prepared in analogy to Example 17-1 by using propane- 1 ,3- diamine and a mixture of 4-(4-chloro-5-methylquinolin- 2-yl)- 2,3,4,5-tetrahydro-l ,4- benzothiazepine 1 , 1-dioxide and 4-(4-chloro-7-methylquinolin-2-yl)- 2,3,4,5-tetrahydro-l ,4- benzothiazepine 1 , 1-dioxide (prepared in analogy to 4-(4-chloro-6-(trifluoromethoxy)quinolin-2- yl)-2,3,4,5-tetrahydro-l ,4-benzothiazepine 1 , 1-dioxide in Example 17-1 by using a mixture of 2,4-dichloro-5-methylquinoline and 2,4-dichloro-7-methylquinoline and propane- 1 ,3-diamine) was purified by preparative HPLC and SPE to give the pure title compounds N-[2-(l , l-dioxido- 2,3-dihydro- 1 ,4-benzothiazepin-4(5H)-yl)-5-methylquinolin-4-yl]propane- 1 ,3-diamine and N-[2- (1 , 1 -dioxido-2,3-dihydro- 1 ,4-benzothiazepin-4(5H)-yl)-7-methylquinolin-4-yl]propane- 1 ,3- diamine. N-[2-(l , 1 -Dioxido-2,3-dihydro- 1 ,4-benzothiazepin-4(5H)-yl)-5-methylquinolin-4-yl]propane- 1 ,3-diamine, MS obsd. (ESI+) [(M+H)+] 41 1, 1H NMR (400 MHz, CD3OD) δ ppm 8.15 - 7.98 (d, J = 7.6 Hz , 1 H), 7.85 - 7.80 (d, J= 7.2 Hz , 1 H), 7.70 - 7.60 (q, J= 6.4 Hz ,2 H), 7.55 - 7.48 (t, J = 7.6 Hz , 2 H), 7.21 - 7.18 (d, J = 6.8 Hz , 1 H), 5.87 (s, 1 H), 5.26 (s, 2 H), 4.70 - 4.40 (m, 2 H), 3.71 - 3.65 (t, J= 2.8 Hz , 2 H), 3.58 - 3.50 (t, J= 7.2 Hz ,2 H), 3.12 - 3.05 (t, J = 7.6 Hz, 2 H), 2.82 (s, 3 H), 2.12 - 2.03 (m, 2 H).
N-[2-(l , 1 -Dioxido-2,3-dihydro- 1 ,4-benzothiazepin-4(5H)-yl)-7-methylquinolin-4-yl]propane- 1 ,3-diamine, MS obsd. (ESI+) [(M+H)+] 41 1, 1H NMR (400 MHz, CD3OD) δ ppm 8.10 - 8.02 (m, 1 H), 8.00 - 7.95 (d, J= 8.8 Hz , l H), 7.88 - 7.81 (d, J = 7.2 Hz, 1 H), 7.70 - 7.65 (t, J= 1.2 Hz , 1 H), 7.57 (s, 1 H), 7.57 - 7.50 (t, J = 16 Hz , 1 H), 7.30 - 7.22 (d, J = 8.4 Hz , 1 H), 5.88 (s, 1 H), 5.29 (s, 2 H), 4.60 - 4.40 (m, 2 H), 3.72 - 3.68 (t, J = 1.2 Hz ,2 H), 3.60 - 3.50 (t, J= 2.8 Hz ,2 H), 3.10 - 3.02 (t, J = 7.6 Hz ,2 H), 2.45 (s, 3 H), 2.1 1 - 2.02 (m, 2 H).
Example 17-8 V-{[3-(Aminomethyl)oxetan-3-yl]methyl}-2-(l,l-dioxido-2,3-dihydro-l,4-benzothiazepin- 4(5H)-yl)-6-fluoroquinolin-4-amine
Figure imgf000266_0001
The title compound was prepared in analogy to Example 17-1 in Scheme 6 by using 4-(4-chloro- 8-fluoroquinolin-2-yl)-2,3,4,5-tetrahydro-l ,4-benzothiazepine 1 , 1-dioxide (prepared in analogy to 4-(4-chloro-6-(trifluoromethoxy)quinolin-2-yl)-2,3,4,5-tetrahydro- 1 ,4-benzothiazepine 1 , 1- dioxide in Example 17-1 by using 2,4-dichloro-8-fluoroquinoline and 2,3,4,5-tetrahydro-l ,4- benzothiazepine 1 , 1-dioxide) and oxetane-3,3-diyldimethanamine. MS obsd. (ESI ) [(M+H)+] 457, 1H NMR (400 MHz, CD3OD) δ ppm 8.08 (d, J = 7.2 Hz, 1 H), 8.03 (dd, J= 2.4, 9.6 Hz, 1
H), 7.91 - 7.84 (m, 2 H), 7.70 (t, J = 7.2 Hz, 1 H), 7.57 (t, J= 7.6 Hz, 2 H), 6.23 (s, 1 H), 5.35 (s, 2 H), 4.63 (d, J = 7.2 Hz, 2 H), 4.56 - 4.51 (m, 4 H), 3.92 (s, 2 H), 3.74 (s, 2 H), 3.47 (s, 2 H).
Example 18-1 V-[(3-Aminooxetan-3-yl)methyl]-6-methyl-2-(l-oxido-2,3-dihydro-l,4-benzothiazepin-
Ine
Figure imgf000267_0001
4-(4-Chloro-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-l,4-benzothiazepine
Figure imgf000267_0002
The title compound was prepared in analogy to 4-(4-chloro-6-(trifluoromethoxy)quinolin-2-yl)- 2,3,4,5-tetrahydro-l,4-benzothiazepine 1,1-dioxide in Example 17-1 in Scheme 6 by using 2,4- dichloro-6-methylquinoline and 2,3,4,5-tetrahydro-l,4-benzothiazepine 1-oxide. V-[(3-Aminooxetan-3-yl)methyl]-2-(l-oxido-2,3-dihydro-l,4-benzothiazepin-4(5H)-yl)-6- methylquinolin-4-amine
Figure imgf000267_0003
A mixture of 4-(4-chloro-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-l,4-benzothiazepine 1-oxide (2 g, 5.6 mmol), 3-aminomethyloxetan-3-ylamine (572 mg, 5.6 mmol),
tri(dibenzylideneacetone)dipalladium(0) (256 mg, 0.28 mmol), 2,2'-bis(diphenylphosphino)-l,l'- binaphthalene (348.7 mg, 0.56 mmol), sodium tert-butoxide (1.08 g, 11.2 mmol) and toluene (20 mL) was heated with stirring in a 30 mL of sealed tube for 20 hours at 110 °C under nitrogen. The resulting mixture was diluted with ethyl acetate and washed with water. The organic layer was dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography on silica gel to give 1.5 g of the product as off-white foam.
Example 18-2 and Example 18-3
(+)- V- [(3- Aminooxetan-3-yl)methyl] -6-methyl-2- [ l-oxido-2,3-dihydro- 1 ,4-benzothiazepin- 4(5H)-yl]quinolin-4-amine and (-)- V-[(3-Aminooxetan-3-yl)methyl]-6-methyl-2-[l-oxido-
" iiazepin-4(5H)-yl] quinolin-4-amine
Figure imgf000268_0001
The chiral separation of Example 18-1 (column: IA; flow rate: 15mL/min; gradient: 50% hexane in ethanol with 0.4% of triethylamine) gives (+)-N-[(3-aminooxetan-3-yl)methyl]-6-methyl-2-[l- oxido-2,3-dihydro-l,4-benzothiazepin-4(5H)-yl]quinolin-4-amine, MS obsd. (ESI+) [(M+H)+] 423, 1H NMR (400 MHz, CD3OD) δ ppm 7.74 (d, J = 7.6 Hz, 1 H), 7.70 - 7.66 (m, 2 H), 7.48 - 7.43 (m, 2 H), 7.39 (t, J = 7.2 Hz, 1 H), 7.29 (dd, J= 1.6, 8.4 Hz, 1 H), 6.16 (s, 1 H), 5.21 (d, J = 16.0 Hz, 1 H), 4.72 (brs, 2 H), 4.62 (d, J = 6.8 Hz, 2 H), 4.57 (dd, J = 2.4, 6.4 Hz, 2 H), 4.43 (brs, 1 H), 3.66 (s, 2 H), 3.42 (m, 2 H), 2.41 (s, 3 H); and (-)-N-[(3-aminooxetan-3-yl)methyl]-6- methyl-2-[l-oxido-2,3-dihydro-l ,4-benzothiazepin-4(5H)-yl]quinolin-4-amine, MS obsd. (ESI+) [(M+H)+] 423, 1H NMR (400 MHz, CD3OD) δ ppm 7.70 (d, J = 7.6 Hz, 1 H), 7.65 (m, 2 H), 7.47 - 7.38 (m, 2 H), 7.33 (t, J = 7.2 Hz, 1 H), 7.27 (dd, J = 1.6, 8.4 Hz, 1 H), 6.12 (s, 1 H), 5.15 (d, J= 16.0 Hz, 1 H), 4.64 (brs, 2 H), 4.60 (d, J = 6.4 Hz, 2 H), 4.55 (dd, J = 2.8, 6.4 Hz, 2 H), 4.43 (brs, 1 H), 3.63 (s, 2 H), 3.34 (m, 2 H), 2.38 (s, 3 H).
Example 18-4 V-[(3-Aminooxetan-3-yl)methyl]-6-chloro-2-(l-oxido-2,3-dihydro-l,4-benzothiazepin- 4(5H)-yl)quinolin-4-amine
Figure imgf000268_0002
The title compound was prepared in analogy to Example 18-1 in Scheme 6 by using 4-(4,6- dichloroquinolin-2-yl)-2,3,4,5-tetrahydro-l,4-benzothiazepine 1-oxide (prepared in analogy to 4- (4-chloro-6-methylquinolin-2-yl)- 2,3,4,5-tetrahydro-l ,4-benzothiazepine 1-oxide in Example 18-1 by using 2,4, 6-trichloroquino line and 2,3,4,5-tetrahydro-l ,4-benzothiazepine 1-oxide) and 3-aminomethyloxetan-3-ylamine. MS obsd. (ESI+) [(M+H)+] 443, 1H NMR (400 MHz, CD3OD) δ ppm 7.94 (d, J = 2.02 Hz, 1 H), 7.77 (d, J= 7.83 Hz, 1 H), 7.71 (d, J = 8.59 Hz, 1 H), 7.52 - 7.34 (m, 4 H), 6.22 (s, 1 H), 5.25 (d, J=15.92 Hz, 2 H), 4.78 (brs, 2 H), 4.65 - 4.52 (m, 4 H), 3.66 (s, 2 H), 3.47 - 3.38 (m, 2 H).
Example 18-5 V-[2-(l-Oxido-2,3-dihydro-l,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]-2,2- difluoropropane-l,3-diamine
Figure imgf000269_0001
The title compound was prepared in analogy to Example 18-1 in Scheme 6 by using 4-(4-chloro- 6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-l,4-benzothiazepine 1-oxide (prepared in analogy to the one in Example 18-1) and 2,2-difluoropropane-l,3-diamine. MS obsd. (EST) [(M+H)+] 431, 1H NMR (400 MHz, CD3OD) δ ppm 7.93 (s, 1 H), 7.81 - 7.79 (m, 1 H), 7.76 - 7.74 (d, 2 H), 7.62 - 7.52 (m, 3 H), 6.25 (s, 1 H), 5.45 - 5.41 (d, 1 H), 5.05 (d, 1 H), 4.75 (m, 1 H), 4.45 (m, 1 H), 4.23 - 4.16 (m, 2 H), 3.72 - 3.64 (t, 2 H), 3.50 (m, 2 H), 2.47 (s, 3 H).
Example 18-6 V-[6-Chloro-2-(l-oxido-2,3-dihydro-l,4-benzothiazepin-4(5H)-yl)quinolin-4-yl]-2,2- difluoropropane-l,3-diamine
Figure imgf000269_0002
The title compound was prepared in analogy to Example 18-1 in Scheme 6 by using 4-(4,6- dichloroquinolin-2-yl)-2,3,4,5-tetrahydro-l,4-benzothiazepine 1-oxide (prepared in analogy to 4- (4-chloro-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-l,4-benzothiazepine 1-oxide in Example 18- 1 by using 2,4, 6-trichloroquino line and 2,3,4,5-tetrahydro-l,4-benzothiazepine 1-oxide) and 2,2- difluoropropane-l,3-diamine. MS obsd. (ESI+) [(M+H)+] 451, 1H NMR (400 MHz, CD3OD) δ ppm 8.21 (s, 1 H), 7.86 - 7.81 (m, 2 H), 7.77 - 7.74 (m, 2 H), 7.58 (m, 2 H), 6.32 (s, 1 H), 5.45 (d, 1 H), 5.05 (d, 1 H), 4.75 (m, 1 H), 4.48 (m, 1 H), 4.20 (m, 2 H), 3.68 (t, 2 H), 3.50 (m, 2 H).
Example 18-7 V-[6-Chloro-2-(l-oxido-2,3-dihydro-l,4-benzothiazepin-4(5H)-yl)quinolin-4-yl]ethane-l,2- diamine
Figure imgf000270_0001
The title compound was prepared in analogy to Example 18-1 in Scheme 6 by using 4-(4,6- dichloroquinolin-2-yl)-2,3,4,5-tetrahydro-l,4-benzothiazepine 1-oxide (prepared in analogy to 4- (4-chloro-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-l,4-benzothiazepine 1-oxide in Example 18- 1 by using 2,4,6-trichloroquinoline and 2,3,4,5-tetrahydro-l,4-benzothiazepine 1-oxide) and ethane- 1,3-diamine. MS obsd. (ESI+) [(M+H)+] 401, 1H NMR (400 MHz, CD3OD) δ ppm 7.91 (d, J= 2.0 Hz, 1 H), 7.76 -7.74 (d, J= 7.8 Hz, 2 H), 7.53 - 7.38 (m, 4 H), 6.10 (s, 1 H), 5.29 - 5.25 (d, J= 15.2 Hz, 1 H), 4.62 (s, 3 H), 3.57 (m, 4 H), 3.19 - 3.10 (m, 2 H).
Example 18-8 V-{[3-(Aminomethyl)oxetan-3-yl]methyl}-6-methyl-2-(l-oxido-2,3-dihydro-l,4- benzothiazepin-4(5H)-yl)quinolin-4-amine
Figure imgf000270_0002
The title compound was prepared in analogy to Example 18-1 in Scheme 6 by using 4-(4-chloro- 6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-l,4-benzothiazepine 1-oxide (prepared in analogy to the one in Example 18-1) and oxetane-3,3-diyldimethanamine. MS obsd. (EST ) [(Μ+Η) ] 437, 1H NMR (400 MHz, CD3OD) δ ppm 8.11 (s, 1 H), 7.86 - 7 .75 (m, 3 H), 7.59 - 7.51 (m, 3 H), 7.67 (t, J= 3.6 Hz, 1 H), 7.57 (d, J= 2.1 Hz, 1 H), 6.22 (s, 1 H), 5.45 (d, J= 16.4 Hz, 1 H), 5.10 (brs, 1 H), 4.76 (brs, 1 H), 4.60 (m, 4 H), 3.94 (d, 2 H), 4.52 (s, 2 H), 3.47 (s, 2 H), 2.46 (s, 3 H).
Example 18-9 V-{[3-(Aminomethyl)oxetan-3-yl]methyl}-6-chloro-2-(l-oxido-2,3-dihydro-l,4- benzothiazepin-4(5H)-yl)quinolin-4-amine
Figure imgf000271_0001
The title compound was prepared in analogy to Example 18-1 in Scheme 6 by using 4-(4,6- dichloroquinolin-2-yl)-2,3,4,5-tetrahydro-l,4-benzothiazepine 1-oxide (prepared in analogy to 4- (4-chloro-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-l,4-benzothiazepine 1-oxide in Example 18- 1 by using 2,4,6-trichloroquinoline and 2,3,4,5-tetrahydro-l,4-benzothiazepine 1-oxide) and oxetane-3,3-diyldimethanamine. MS obsd. (ESI+) [(M+H)+] 457, 1H NMR (400 MHz, CD3OD) δ ppm 8.31 (d, 1 H), 7.85 - 7.74 (m, 4 H), 7.60 - 7.55 (m, 2 H), 6.22 (s, 1 H), 5.45 (d, 1 H), 5.1 l(d, 1 H), 4.68(brs, 1 H), 4.65 - 4.56 (m, 4 H), 4.47 (d, 1 H), 3.91 (m, 2 H ), 3.55( m, 2 H ), 3.47 (s, 2 H). Example 18-10 V-[6-Methyl-2-(l-oxido-2,3-dihydro-l,4-benzothiazepin-4(5H)-yl)quinolin-4-yl]ethane-l,2- diamine
Figure imgf000271_0002
The title compound was prepared in analogy to Example 18-1 in Scheme 6 by using 4-(4-chloro- 6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-l,4-benzothiazepine 1-oxide (prepared in analogy to the one in Example 18-1) and ethane- 1,2-amine. MS obsd. (ESI+) [(M+H)+] 381, 1H NMR (400 MHz, CD3OD) δ ppm 7.89 (s, 1 H), 7.81 - 7.76 (m, 2 H), 7.73 - 7.70 (m, 1 H), 7.59 - 7.49 (m, 3 H), 6.02 (s, 1 H), 5.44 - 5.40 (m, 1 H), 5.04 - 5.01 (m, 1 H), 4.75 - 4.71 (m, 1 H), 4.48 - 4.44 (m, 1 H), 3.84 - 3.81 (t, 2 H), 3.51 (s, 2 H), 3.33 - 3.28 (m, 2 H), 2.45 (s, 3 H).
Example 18-11
2-{[6-Methyl-2-(l-oxido-2,3-dihydro-l,4-benzothiazepin-4(5H)-yl)quinolin-4- yl] amino} ethanol
Figure imgf000272_0001
The title compound was prepared in analogy to Example 18-1 in Scheme 6 by using 4-(4-chloro- 6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-l,4-benzothiazepine 1-oxide (prepared in analogy to the one in Example 18-1) and 2-amino-ethanol. MS obsd. (ESI+) [(M+H)+] 382, 1H NMR (400 MHz, CD3OD) δ ppm 7.92 (s, 1 H), 7.85 - 7.80 (d, J= 8.4 Hz, 1 H), 7.80 - 7.75 (d, J= 7.6 Hz, 1 H), 7.75 - 7.70 (d, J= 7.2 Hz, 1 H), 7.61 - 7.50 (m, 3 H), 6.10 (s, 1 H), 5.48 - 5.39 (m, 1 H), 5.08 - 4.95 (m, 1 H), 4.80 - 4.70 (m, 1 H), 4.52 - 4.42 (m, 1 H), 3.88 - 3.80 (t, J= 5.6 Hz, 2 H), 3.65 - 3.60 (t, J= 5.6 Hz, 2 H), 3.59 - 3.40 (m, 2 H ), 2.46 (s, 3 H).
Example 19-1 irans-4-Amino-l-[6-methyl-2-(l-oxido-2,3-dihydro-l,4-benzothiazepin-4(5H)-yl)quinolin-4- yl]pyrrolidin-3-ol
Figure imgf000272_0002
tert-Buty\ {irans-l-[6-methyl-2-(l-oxido-2,3-dihydro-l,4-benzothiazepin-4(5H)-yl)quinolin- 4-yl] -4-hydroxypy rrolidin-3-yl} carboxylate
Figure imgf000273_0001
A mixture of 4-(4-chloro-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-l,4-benzothiazepine 1-oxide (200 mg, 0.56 mmol, prepared in analogy to the one in Example 18-1), tert-butyl [trans-4- hydroxypyrrolidin-3-yl] carbamate (125 mg, 0.62 mmol), tris(2-benzylidene acetone)
palladium(II) (50 mg, 0.055 mmol), 2-dicyclohexylphosphino-2-(N,N-dimethylamino)biphenyl (30 mg, 0.076 mmol), sodium tert-butoxide (60 mg, 0.625 mmol) and 1,4-dioxane (3 mL) in a 2~5 mL of process vial was heated at 120°C under microwave irradiation for 2 hours. After being cooled to room temperature, the mixture was filtered and washed with ethyl acetate. The filtrate was washed with brine, dried over sodium sulfate, and concentrated in vacuo. The residue was purified by flash column chromatography (eluting with 10% methanol in dichloromethane) to afford 230 mg of the product as a white solid (yield was 80%). irans-4-Amino-l-[6-methyl-2-(l-oxido-2,3-dihydro-l,4-benzothiazepin-4(5H)-yl)quinolin-4- yl]pyrrolidin-3-ol
Figure imgf000273_0002
To a solution of tert-butyl {tra/75-l-[6-methyl-2-(l-oxido-2,3-dihydro-l,4-benzothiazepin-4(5H)- yl)quinolin-4-yl]-4-hydroxypyrrolidin-3-yl}carboxylate (230 mg, 0.54 mmol) in
dichloromethane (5 mL) was added trifluoro acetic acid (2 mL). After being stirred at room temperature for 3 hours, the resulting mixture was concentrated in vacuo. The residue was purified by preparative HPLC to afford the pure product as a solid. MS obsd. (ESI+) [(M+H)+] 423, 1H NMR (400 MHz, CD3OD) δ ppm 7.95 (s, 1 H), 7.80 - 7.76 (d, J= 7.2 Hz, 1 H), 7.76 - 7.70 (m, 2 H), 7.60 - 7.52 (m, 2 H), 7.52 - 7.43 (m, 1 H), 5.91 (s, 1 H), 5.42 - 5.30 (m, 1 H), 5.02 - 4.90 (m, 1 H), 4.80 - 4.68 (m, 1 H), 4.56 - 4.50 (m, 1 H), 4.50 - 4.20 (m, 3 H), 3.96 - 3.88 (m, 1 H), 3.86 - 3.80 (m, 1 H), 3.80 - 3.70 (m, 1 H), 3.56 - 3.38 (m, 2 H), 2.43 (s, 3 H ). Example 19-2
(lR,5S,6S)-3-[2-(l,l-Dioxido-2,3-dihydro-l,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4- yl] -3-azabicyclo [3.1.0] hexan-6-amine
Figure imgf000274_0001
The title compound was prepared in analogy to Example 19-1 in Scheme 7 by using 4-(4-chloro- 6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-l,4-benzothiazepine 1,2-dioxide (prepared in analogy to 4-(4-chloro-6-(trifluoromethoxy)quinolin-2-yl)-2,3,4,5-tetrahydro- 1 ,4-benzothiazepine 1,1- dioxide in Example 17-1 by using 2,4-dichloro-6-methylquinoline and 2,3,4,5-tetrahydro-l,4- benzothiazepine 1,2-dioxide ) and tert-butyl (li?,55',65)-3-azabicyclo[3.1.0]hex-6-ylcarbamate. MS obsd. (ESI+) [(M+H)+] 435, 1H NMR (400 MHz, CD3OD) δ ppm 7.98 (dd, J= 7.83, 1.01 Hz, 1 H), 7.82 (d, J= 7.07 Hz, 1 H), 7.71 - 7.56 (m, 2 H), 7.51 - 7.39 (m, 2 H), 7.27 (dd, J = 8.59, 1.77 Hz, 1 H), 6.31 (s, 1 H), 5.15 (s, 2 H), 4.56(brs, 2 H), 3.83(d, J= 9.60 Hz, 2 H), 3.58 (t, J= 4.93 Hz, 2 H), 3.38 (d, J= 9.60 Hz, 2 H), 2.55 (s, 1 H), 2.40 (s, 3 H), 1.76 - 1.62 (m, 2 H).
Example 19-3 irans-4-Amino-l-[2-(l,l-dioxido-2,3-dihydro-l,4-benzothiazepin-4(5H)-yl)-6- methylquinolin-4-yl]pyrrolidin-3-ol
Figure imgf000274_0002
The title compound was prepared in analogy to Example 19-1 in Scheme 7 by using 4-(4-chloro- 6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-l,4-benzothiazepine 1,1-dioxide (prepared in analogy to 4-(4-chloro-6-(trifluoromethoxy)quinolin-2-yl)-2,3,4,5-tetrahydro- 1 ,4-benzothiazepine 1,1- dioxide in Example 17-1 by using 2,4-dichloro-6-methylquinoline and 2,3,4,5-tetrahydro-l,4- ben nthia enine 1 .2-dinxide) and tert-butyl trans-(4-hydroxypyrrolidin-3-yl)carbamate. MS obsd. (ESI+) [(M+H)+] 439, 1H NMR (400 MHz, CD3OD) δ ppm 7.92 - 7.83 (m, 2 H), 7.76 (s, 1 H), 7.67 - 7.59 (m, 1 H), 7.47 (t, J= 7.45 Hz, 1 H), 7.37 (d, J= 8.59 Hz, 1 H), 7.23 (dd, J= 8.46, 1.39 Hz, 1 H), 6.03 (s, 1 H), 5.18 - 4.96 (m, 3 H), 4.41(brs, 2 H), 4.04 - 3.83 (m, 3 H), 3.62 (t, J = 4.80 Hz, 2 H), 3.35 - 3.25 (d, J= 9.85 Hz, 2 H), 2.35 (s, 3 H). Example 19-4 l-[6-Methyl-2-(l-oxido-2,3-dihydro-l,4-benzothiazepin-4(5H)-yl)quinolin-4-yl]pyrrolidin- 3-amine
Figure imgf000275_0001
The title compound was prepared in analogy to Example 19-1 in Scheme 7 by using 4-(4-chloro- 6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-l,4-benzothiazepine 1-oxide (prepared in analogy to the one in Example 18-1) and tert-butyl pyrrolidin-3-ylcarbamate. MS obsd. (ESI ) [(Μ+Η) ] 407, 1H NMR (400 MHz, CD3OD) δ ppm 7.81 (s, 1 H), 7.71 (t, J= 8.21 Hz, 2 H), 7.57 - 7.36 (m, 3 H), 7.27 (dd, J= 8.59, 1.77 Hz, 1 H), 6.11 (s, 1 H), 5.21 (d, J= 16.17 Hz, 1 H), 4.76 (d, J = 15.92 Hz, 2 H), 4.50 (brs, 1 H), 3.88 - 3.71 (m, 2 H), 3.71 - 3.53 (m, 2 H), 3.53 - 3.36 (m, 3 H), 2.40 (s, 3 H), 2.26 (dq, J= 12.63, 6.23 Hz, 1 H), 1.98 - 1.78 (m, 1 H).
Example 19-5 irans-l-[6-Chloro-2-(l,l-dioxido-2,3-dihydro-l,4-benzothiazepin-4(5H)-yl)quinolin-4-yl]-4- fluoropyrrolidin-3-amine
Figure imgf000275_0002
The title compound was prepared in analogy to Example 19-1 in Scheme 7 by using 4-(4,6- dichloroquinolin-2-yl)-2,3,4,5-tetrahydro-l,4-benzothiazepine 1,1-dioxide (prepared in analogy to 4-(4-chloro-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-l,4-benzothiazepine 1,1-dioxide in Example 2-1) and tert-butyl trans-(4-fluoropyrrolidin-3-yl) carbamate. MS obsd. (ESI )
[(M+H)+] 461, 1H NMR (400 MHz, CD3OD) δ ppm 8.03 - 7.96 (m, 2 H), 7.86 (d, J= 7.58 Hz, 1 H), 7.63 (td, J= 7.45, 1.26 Hz, 1 H), 7.54 (d, J= 9.09 Hz, 1 H), 7.46 (td, J = 7.71, 1.01 Hz, 1 H), 7.39 (dd, J= 9.09, 2.27 Hz, 1 H), 6.25 (s, 1 H), 5.14 - 5.25 (m, 2 H), 5.05 (brs, 1 H), 4.55 (brs, 2 H), 4.18 - 4.27 (dd, J= 12.25, 3.92 Hz, 1 H), 4.01 (dd, J= 8.97, 5.18 Hz, 1 H), 3.78 - 3.55 (m, 4 H), 3.40 - 3.30 (m, 1 H).
Example 19-6 trans-4- Amino- 1- [6-chloro-2-(l , l-dioxido-2,3-dihydro- 1 ,4-benzothiazepin-4(5H)- yl)quinolin-4-yl]pyrrolidin-3-ol
Figure imgf000276_0001
The title compound was prepared in analogy to Example 19-1 in Scheme 7 by using 4-(4,6- dichloroquinolin-2-yl)-2,3,4,5-tetrahydro-l,4-benzothiazepine 1,1-dioxide (prepared in analogy to 4-(4-chloro-6-(trifluoromethoxy)quinolin-2-yl)-2,3,4,5-tetrahydro- 1 ,4-benzothiazepine 1,1- dioxide in Example 17-1 by using 2,4, 6-trichloro-quino line and 2,3,4,5-tetrahydro-l,4- benzothiazepine 1,2-dioxide) and tert-butyl (trans-4-hydroxypyrrolidin-3-yl) carbamate. MS obsd. (ESI+) [(M+H)+] 459, 1H NMR (400 MHz, CD3OD) δ ppm 8.03 - 7.96 (m, 2 H), 7.85 (d, J = 7.33 Hz, 1 H), 7.66 - 7.60 (m, 1 H), 7.53 (d, J= 9.09 Hz, 1 H), 7.49 - 7.42 (m, 1 H), 7.38 (dd, J = 8.97, 2.15 Hz, 1 H), 6.20 (s, 1 H), 5.18 (brs, 2 H), 4.70 - 4.40 (b, 2 H), 4.21 (brs, 1 H), 4.10 (dd, J= 10.74, 4.93 Hz, 1 H), 3.97 (dd, J= 9.60, 5.56 Hz, 1 H), 3.59 (d, J= 3.28 Hz, 2 H), 3.54 - 3.49 (m, 1 H), 3.48 - 3.39 (m, 2 H).
Example 19-7 irans-l-[6-Chloro-2-(l-oxido-2,3-dihydro-l,4-benzothiazepin-4(5H)-yl)quinolin-4-yl]-4- fluoropyrrolidin-3-amine
Figure imgf000277_0001
The title compound was prepared in analogy to Example 19-1 in Scheme 7 by using 4-(4,6- dichloroquinolin-2-yl)-2,3,4,5-tetrahydro-l,4-benzothiazepine 1-oxide (prepared in analogy to 4- (4-chloro-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-l,4-benzothiazepine 1-oxide in Example 18- 1) and tert-butyl (trarcs-4-fluoropyrrolidin-3-yl) carbamate. MS obsd. (ESI+) [(M+H)+] 445, 1H NMR (400 MHz, CD3OD) δ ppm 7.98 (d, J= 2.27 Hz, 1 H), 7.78 - 7.68 (m, 2 H), 7.55 (dd, J = 9.09, 1.52 Hz, 1 H), 7.52 - 7.42 (m, 2 H), 7.39 (dd, J= 9.09, 2.27 Hz, 1 H), 6.28 - 6.21 (m, 1 H), 5.25 (d, J= 15.66 Hz, 1 H), 5.10 - 4.95 (m, 1 H), 4.90 - 4.54 (m, 2 H), 4.65 - 4.40 (m, 1 H), 4.30 - 4.10 (m, 1 H), 4.05 - 3.59 (m, 1 H), 3.55 - 3.51 (m, 2 H), 3.40 - 3.35 (m, 3 H). Example 19-8
2-[2-(l,l-Dioxido-2,3-dihydro-l,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]-2- azabicyclo [2.1.1] hexan-5-amine
Figure imgf000277_0002
The title compound was prepared in analogy to Example 19-1 in Scheme 7 by using 4-(4-chloro- 6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-l,4-benzothiazepine 1,1-dioxide (prepared in analogy to 4-(4-chloro-6-(trifluoromethoxy)quinolin-2-yl)-2,3,4,5-tetrahydro- 1 ,4-benzothiazepine 1,1- dioxide in Example 17-1 by using 2,4-dichloro-6-methylquinoline and 2,3,4,5-tetrahydro-l,4- benzothiazepine 1,2-dioxide) and tert-butyl 2-azabicyclo[2.1.1]hex-5-ylcarbamate. MS obsd. (ESI+) [(M+H)+] 435, 1H NMR (400 MHz, CD3OD) δ ppm 7.99 (dd, J= 7.83, 1.01 Hz, 1 H), 7.86 - 7.74 (m, 2 H), 7.61 (td, J= 7.58, 1.26 Hz, 1 H), 7.54 - 7.39 (m, 2 H), 7.33 (dd, J= 8.59, 1.77 Hz, 1 H), 6.43 (s, 1 H), 5.22 - 5.06 (m, 2 H), 4.38 (d, J= 6.32 Hz, 1 H), 3.95 (d, J= 8.59 Hz, 1 H), 3.67 - 3.52 (m, 2 H), 3.42 - 3.35 (m, 1 H), 3.05 (d, J= 8.59 Hz, 1 H), 2.91 - 2.77 (m, 1 H), 2.45 (s, 3 H), 1.67 (d, J= 7.83 Hz, 1 H), 1.39 - 1.26 (m, 2 H), 1.19 (d, J= 7.83 Hz, 1 H). Example 20-1
2-(8-Methoxy- 1 , l-dioxido-2,3-dihydro- 1 ,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4- amine
Figure imgf000278_0001
tert-Butyl [2-(8-Methoxy- 1 , l-dioxido-2,3-dihydro- 1 ,4-benzothiazepin-4(5H)-yl)-6- methylquinolin-4-yl] carbamate
Figure imgf000278_0002
A mixture solution of 4-(4-chloro-6-methylquinolin-2-yl)-8-methoxy-2,3,4,5-tetrahydro-l,4- benzothiazepine 1,1 -dioxide (60.0 mg, 0.15 mmol, prepared in analogy to 4-(4-chloro-6- (trifluoromethoxy)quinolin-2-yl)-2,3,4,5-tetrahydro-l,4-benzothiazepine 1,1-dioxide in Example 17-1 by using 2,4-dichloro-6-methylquinoline and 8-methoxy-2,3,4,5-tetrahydro-l,4- benzothiazepine 1,2-dioxide), tert-butyl carbamate (45.0 mg, 0.37 mmol), Ι,Γ- bis(diphenylphosphino)ferrocene (11.2 mg, 0.02 mmol), Ι,Γ- bis(diphenylphosphino)ferrocenedichloropalladium(II) (15.0 mg, 0.02 mmol), and sodium tert- butoxide (75.0 mg, 0.72 mmol) in 1,4-dioxane (2.0 mL) was heated with stirring at 120 °C for 2 hours. After being cooled to room temperature, the reaction mixture was extracted with ethyl acetate (100 mL), washed with brine (50 mL x 2), dried over anhydrous sodium sulfate and concentrated in vacuo to afford 59.9 mg of the crude product as yellow oil. MS obsd. (ESI+) [(M+H)+] 484. 2-(8-Methoxy- 1 , l-dioxido-2,3-dihydro- 1 ,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4- amine
Figure imgf000279_0001
A mixture solution of tert-butyl [2-(8-methoxy-l,l-dioxido-2,3-dihydro-l,4-benzothiazepin- 4(5H)-yl)-6-methylquinolin-4-yl] carbamate (59.0 mg, 0.12 mmol) and trifluoro acetic acid (0.5 mL) in dichloromethane (2.0 mL) was stirred at room temperature for 6 hours. Then the reaction mixture was extracted with ethyl acetate (100 mL). The organic layer was washed with brine (50 mL x 2), dried over anhydrous sodium sulfate and then concentrated in vacuo. The residue was purified by preparative HPLC to afford 10.2 mg of the product as a white solid (yield was 21.5%). MS obsd. (ESI+) [(M+H)+] 384, 1H NMR (400 MHz, CD3OD) δ ppm 7.72 (d, J= 8.34 Hz, 1 H), 7.58 (s, 1 H), 7.50 (d, J= 2.78 Hz, 1 H), 7.43 (d, J= 8.34 Hz, 1 H), 7.29 (dd, J= 8.46, 1.89 Hz, 1 H), 7.12 (dd, J= 8.34, 2.78 Hz, 1 H), 6.27 (s, 1 H), 5.02 (s, 2 H), 4.47 (brs, 2 H), 3.82 (s, 3 H), 3.56 (t, J= 4.80 Hz, 2 H), 2.42 (s, 3 H).
Example 20-2
2-(7-Methoxy- 1 , l-dioxido-2,3-dihydro- 1 ,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4- amine
Figure imgf000279_0002
The title compound was prepared in analogy to Example 20-1 in Scheme 7 by using 4-(4-chloro- 6-methylquinolin-2-yl)-7-methoxy-2,3,4,5-tetrahydro- 1 ,4-benzothiazepine 1 , 1 -dioxide (prepared in analogy to 4-(4-chloro-6-(trifluoromethoxy)quinolin-2-yl)-2,3,4,5-tetrahydro-l,4- benzothiazepine 1,1 -dioxide in Example 17-1 by using 2,4-dichloro-6-methylquinoline and 7- methoxy-2,3,4,5-tetrahydro-l,4-benzothiazepine 1,2-dioxide) and tert-butyl carbamate. MS obsd. (ESI+) [(M+H)+] 384, 1H NMR (400 MHz, CD3OD) δ ppm 7.87 (d, J= 8.84 Hz, 1 H), 7.59 (s, 1 H), 7.44 (d, J= 8.59 Hz, 1 H), 7.35 (d, J= 2.53 Hz, 1 H), 7.30 (dd, J= 8.59, 1.77 Hz, 1 H), 6.88 (dd, J= 8.72, 2.65 Hz, 1 H), 6.27 (s, 1 H), 5.04 (s, 2 H), 4.46 (brs, 2 H), 3.89 (s, 3 H), 3.52 (t, J= 4.67 Hz, 2 H), 2.42 (s, 3 H).
Example 20-3 [2-(l-Amino-cyclopropyl)-ethyl]-[2-(l,l-dioxido-2,3-dihydro-l,4-benzothiazepin-4(5H)-yl)- 6-methylquinolin-4-yl] -amine
Figure imgf000280_0001
The title compound was prepared in analogy to Example 20-1 in Scheme 7 by using 4-(4- chloro-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-l,4-benzothiazepine 1,1-dioxide (prepared in analogy to 4-(4-chloro-6-(trifluoromethoxy)quinolin-2-yl)-2,3,4,5-tetrahydro-l,4- benzothiazepine 1,1-dioxide in Example 17-1 by using 2,4-dichloro-6-methylquinoline and 2,3,4,5-tetrahydro-l,4-benzothiazepine 1,2-dioxide) and tert-butyl l-(2-aminoethyl)- cyclopropylcarbamate. MS obsd. (ESI+) [(M+H)+] 437, 1H NMR (400 MHz, CDC13) δ ppm 7.95 - 7.93 (dd, J= 1.2 , 8.0 Hz, 1 H), 7.59 - 7.57 (d, J= 6 Hz, 1 H), 7.42 - 7.38 (m, 2 H), 7.29 - 7.25 (m, 1 H), 7.21 - 7.18 (m, 2 H), 6.40 (s, 1 H), 5.79 (s, 1 H), 4.5 (s, 2 H), 3.48 (s, 2 H), 3.35 (s, 2 H), 2.44 (s, 3 H), 2.31 (s, 3 H), 1.77 - 1.74 (d, J = 6 Hz, 2 H), 1.54 (s, 2 H), 0.56 - 0.50 (m, 2 H).
Example 21-1
2-(l , l-Dioxido-2,3-dihydro- 1 ,4-benzothiazepin-4(5H)-yl)-6-methyl- V-(morpholin-2- ylmethyl)quinolin-4-amine
Figure imgf000280_0002
tert-Buty\ 2-{[2-(l,l-dioxido-2,3-dihydro-l,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4- ylamino]-methyl}-morpholine-4-carboxylate
Figure imgf000281_0001
A mixture of 4-(4-chloro-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-l,4-benzothiazepine 1,1- dioxide (682 mg, 1.83 mmol, prepared in analogy to 4-(4-chloro-6-(trifluoromethoxy)quinolin-2- yl)-2,3,4,5-tetrahydro-l,4-benzothiazepine 1,1 -dioxide in Example 17-1 by using 2,4-dichloro-6- methylquinoline and 2,3,4,5-tetrahydro-l,4-benzothiazepine 1,2-dioxide) in 1,4-dioxane (5 mL) was added tert-butyl 2-(aminomethyl)morpholine-4-carboxylate (395 mg, 1.83 mmol), Ι,Γ- bis(diphenylphosphino)ferrocenedichloropalladium(II) (146 mg, 0.18 mmol), Ι,Γ- bis(diphenylphosphino)ferrocene (100 mg, 0.18 mmol) and sodium tert-butoxide (350 mg, 3.66 mmol) under Argon protection. The mixture was heated with stirring under microwave irridiation at 120 °C for 1.5 hours. The reaction mixture was concentrated in vacuo and the residue was purified by preparative HPLC to give 100 mg of the desired product (yield was
10%).
2-(l , l-Dioxido-2,3-dihydro- 1 ,4-benzothiazepin-4(5H)-yl)-6-methyl- V-(morpholin-2- ylmethyl)quinolin-4-amine
Figure imgf000281_0002
To a solution of tert-butyl 2-{[2-(l,l-dioxido-2,3-dihydro-l,4-benzothiazepin-4(5H)-yl)-6- methylquinolin-4-ylamino]-methyl}-morpholine-4-carboxylate (100 mg, 0.18 mmol) in ethyl acetate (10 mL) was added a solution of hydrochloride in ethyl acetate (4 N, 30 mL) in an ice- water bath dropwise. After being stirred at room temperature for 4 hours, the mixture was concentrated in vacuo. The residue was purified by preparative HPLC to afford trifluoro acetic acid salt of the desired product. The trifluoro acetic acid salt was flashed through SPE column with methanol to remove the trifluoro acetic acid. The solution was concentrated in vacuo and then dried by lyopylization to give 46.94 mg of the desired product (yield was 60%). MS obsd. (ESI+) [(M+H)+] 453, 1H NMR (400 MHz, CD3OD) δ ppm 8.04 (d, J= 7.6 Hz, 1 H), 7.90 - 7.86 (m, 2 H), 7.72 - 7.68 (m, 2 H), 7.56 - 7.50 (m, 2 H), 6.11 (s, 1 H), 5.29 (s, 2 H), 4.55 - 4.49 (m, 2 H), 4.11 - 4.01 (m, 2 H), 3.88 - 3.81 (m, 1 H), 3.71 - 3.62 (m, 4 H), 3.42 - 3.39 (m, 1 H), 3.33 - 3.21 (s, 1 H), 3.28 - 3.01 (m, 2 H), 2.45 (s, 3 H).
Example 21-2 V-[2-(l,l-Dioxido-2,3-dihydro-l,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]- V- methylethane- 1 ,2-diamine
Figure imgf000282_0001
The title compound was prepared in analogy to Example 21-1 in Scheme 7 by using 4-(4-chloro- 6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-l,4-benzothiazepine 1,1-dioxide (prepared in analogy to 4-(4-chloro-6-(trifluoromethoxy)quinolin-2-yl)-2,3,4,5-tetrahydro- 1 ,4-benzothiazepine 1,1- dioxide in Example 17-1 by using 2,4-dichloro-6-methylquinoline and 2,3,4,5-tetrahydro-l,4- benzothiazepine 1,2-dioxide) and tert-butyl N-[2-(methylamino)ethyl]carbamate. MS obsd.
(ESI+) [(M+H)+] 411, 1H NMR (400 MHz, CD3OD) δ ppm 7.92 (dd, J= 1.6, 7.6 Hz, 1 H), 7.86 (d, J= 7.6 Hz, 2 H), 7.74 (s, 1 H), 7.61 (t, J= 7.6 Hz, 1 H), 7.54 (d, J= 8.4 Hz, 1 H), 7.40 (t, J = 7.6 Hz, 1 H), 7.33 (dd, J= 2.0, 8.8 Hz, 1 H), 6.66 (s, 1 H), 5.20 (s, 2 H), 4.51 (brs, 2 H), 3.59 - 3.53 (m, 4 H), 3.24 (t, J= 6.4 Hz, 2 H), 2.93 (s, 3 H), 2.42 (s, 3 H). Example 21-3 V-(Azetidin-2-ylmethyl)-2-(l,l-dioxido-2,3-dihydro-l,4-benzothiazepin-4(5H)-yl)-6- methylquinolin-4-amine
Figure imgf000282_0002
The title compound was prepared in analogy to Example 21-1 in Scheme 7 by using 4-(4-chloro- 6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-l,4-benzothiazepine 1,1-dioxide (prepared in analogy to 4-(4-chloro-6-(trifluoromethoxy)quinolin-2-yl)-2,3,4,5-tetrahydro- 1 ,4-benzothiazepine 1,1- dioxide in Example 17-1 by using 2,4-dichloro-6-methylquinoline and 2,3,4,5-tetrahydro-l,4- benzodiazepine 1,2-dioxide) and tert-butyl 2-(aminomethyl)azetidine-l-carboxylate. MS obsd. (ESI+) [(M+H)+] 423, 1H NMR (400 MHz, CD3OD) δ ppm 8.09 - 8.02 (d, J = 4 Hz, 1 H), 7.89 (s, 1 H), 7.85 - 7.79 (d, J = 4 Hz, 1 H), 7.72 - 7.65 (m, 2 H), 7.60 - 7.50 (m, 2 H), 6.00 (s, 1 H), 5.31 (s, 2 H), 4.85 - 4.75 (m, 1 H), 4.60 - 4.40 (m, 2 H), 4.13 - 3.95 (m, 3 H), 3.92 - 3.85 (dd, J = 2.8, 12.8 Hz, 1 H), 3.75 - 3.66 (t, J= 2.8 Hz, 2 H), 2.72 - 2.60 (m, 1 H), 2.52 - 2.42 (m, 1 H), 2.42 (s, 3 H).
Example 21-4
2-(l , l-Dioxido-2,3-dihydro- 1 ,4-benzothiazepin-4(5H)-yl)-6-methyl- V-(pyrrolidin-3- yl)quinolin-4-amine
Figure imgf000283_0001
The title compound was prepared in analogy to Example 21-1 in Scheme 7 by using 4-(4-chloro- 6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-l,4-benzothiazepine 1,1-dioxide (prepared in analogy to 4-(4-chloro-6-(trifluoromethoxy)quinolin-2-yl)-2,3,4,5-tetrahydro- 1 ,4-benzothiazepine 1,1- dioxide in Example 17-1 by using 2,4-dichloro-6-methylquinoline and 2,3,4,5-tetrahydro-l,4- benzothiazepine 1,2-dioxide) and tert-butyl 3-aminopyrrolidine-l-carboxylate. MS obsd. (ESI ) [(M+H)+] 423, 1H NMR (400 MHz, CD3OD) δ ppm 8.16 (s, 1 H), 8.12 - 8.10 (q, J= 1.2 Hz, 1 H), 7.96 - 7.94 (d, J= 7.6 Hz, 1 H), 7.80 - 7.74 (m, 2 H), 7.74 - 7.60 (m, 2 H), 6.04 (s, 1 H), 5.39 (s, 2 H), 4.84 - 4.82 (m, 2 H), 4.58 (s, 2 H), 3.81 - 3.77 (dd, J= 6.4, 4.4 Hz, 2 H), 3.62 - 3.52 (m, 3 H), 2.67 - 2.30 (m, 1 H), 2.61 - 2.54 (m, 1 H), 2.50 (s, 3 H).
Example 21-5 (l-Amino-c clo ro lmeth l)-[2-(5,5-dioxo-5,6,7,9-tetrah dro-5λ6-thia-8-aza- benzocyclohepten-8-yl)-6-methyl-quinolin-4-yl]-amine
Figure imgf000284_0001
The title compound was prepared in analogy to Example 21-1 in Scheme 7 by using 4-(4-chloro-
6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-l,4-benzothiazepine 1,1-dioxide (prepared in analog to 4-(4-chloro-6-(trifluoromethoxy)quinolin-2-yl)-2,3,4,5-tetrahydro- 1 ,4-benzothiazepine 1,1- dioxide in Example 17-1 by using 2,4-dichloro-6-methylquinoline and 2,3,4,5-tetrahydro-l,4- benzothiazepine 1,2-dioxide) and tert-butyl l-(aminomethyl)cyclopropane carbamate. MS obsd. (ESI+) [(M+H)+] 423, 1H NMR (400 MHz, CD3OD) δ ppm 7.98 - 7.90 (d, J = 8 Hz, 1 H), 7.82 - 7.78 (d, J= 7.6 Hz, 1 H), 7.69 (s, 1 H), 7.60 - 7.52 (t, J= 1.2 Hz, 1 H), 7.42 - 7.36 (m, 2 H), 7.29 - 7.22 (d, J= 7.2 Hz, 1 H), 6.00 (s, 1 H), 5.11 (s, 2 H), 4.65 - 4.50 (m, 2 H), 3.60 - 3.50 (t, J= 2.8 Hz, 2 H), 3.40 - 3.30 (d, J= 4.4 Hz, 2 H), 2.39 (s, 3 H ), 0.70 - 0.60 (m, 4 H).
Example 22 V-(Azetidin-3-yl)-6-chloro-2-(l,l-dioxido-2,3-dihydro-l,4-benzothiazepin-4(5H)- yl)quinolin-4-amine
Figure imgf000284_0002
tert- uty\ 3-[6-chloro-2-(l,l-dioxido-2,3-dihydro-l,4-benzothiazepin-4(5H)-yl)-quinolin ylamino]-azetidine-l-carboxylate
Figure imgf000284_0003
The title compound was prepared in analogy to tert-butyl 2-{[2-(l,l-dioxido-2,3-dihydro-l,4- benzothiazepin-4(5H)-yl)-6-methylquinolin-4-ylamino]-methyl}-morpholine-4-carboxylate in Example 21-1 by using 4-(4,6-dichloroquinolin-2-yl)-2,3,4,5-tetrahydro-l,4-benzothiazepine 1,1 -dioxide and tert-butyl 3-aminoazetidine-l-carboxylate. V-(Azetidin-3-yl)-6-chloro-2-(l,l-dioxido-2,3-dihydro-l,4-benzothiazepin-4(5H)- yl)quinolin-4-amine
Figure imgf000285_0001
A mixture of tert-butyl 3-[6-chloro-2-(l,l-dioxido-2,3-dihydro-l,4-benzothiazepin-4(5H)-yl)- quinolin-4-ylamino]-azetidine-l-carboxylate (120 mg, 0.2 mmol) and a solution of hydrochloride in 1,4-dioxane (4 N, 20 mL) was stirred at room temperature for 16 hours. The resulting mixture was concentrated in vacuo. The residue was purified by preparative HPLC to afford 50 mg of the desired product (yield was 51%). MS obsd. (ESI+) [(M+H)+] 429, 1H NMR (400 MHz, CD3OD) δ ppm 8.31 (s, 1 H), 8.08 - 8.06 (d, J= 8 Hz, 1 H), 7.87 - 7.80 (m, 2 H), 7.73 - 7.68 (m, 2 H), 7.55 - 7.53 (m, 1 H), 5.84 (s, 1 H), 5.30 (s, 2 H), 4.99 - 4.96 (m, 1 H), 4.59 - 4.52 (m, 4 H), 4.32 - 4.27 (m, 2 H), 3.72 (s, 2 H).
Example 23 6-[2-(l,l-Dioxido-2,3-dihydro-l,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]-2-oxa-6- azaspiro [3.4] octan-8-amine
Figure imgf000285_0002
tert-Buty\ 6-[2-(l,l-dioxido-2,3-dihydro-l,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4- yl] -2-oxa-6-azaspiro [3.4] octan-8-carbamate
Figure imgf000286_0001
A mixture of tert-butyl 2-oxa-6-azaspiro[3.4]oct-8-ylcarbamate (459 mg, 2.0 mmol), 4-(4- chloro-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-l,4-benzothiazepine 1,1-dioxide (500 mg, 1.34 mmol, prepared in analogy to 4-(4-chloro-6-(trifluoromethoxy)quinolin-2-yl)-2,3,4,5-tetrahydro- 1 ,4-benzothiazepine 1,1-dioxide in Example 17-1 by using 2,4-dichloro-6-methylquinoline and 2,3,4,5-tetrahydro-l,4-benzothiazepine 1,2-dioxide), tri(dibenzylideneacetone)dipalladium(0) (61.3 mg, 0.067 mmol), 2'-(dicyclohexylphosphino)-A ,N-dimethyl[l, -biphenyl]-2-amine (52.7 mg, 0.134 mmol), sodium tert-butoxide (192.2 mg, 2.0 mmol) and 1,4-dioxane (6 mL) was heated with stirring in a 20 mL of microwave process vial for 3 hours at 100 °C. The mixture was diluted with ethyl acetate and washed with water. The organic layer was dried over sodium sulfate and concentrated in vacuo. The residue was purified by column chromatography on silica gel to give 700 mg of the product as a white solid, which was used for next step without further purification.
6-[2-(l,l-Dioxido-2,3-dihydro-l,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]-2-oxa-6- azaspiro[3.4]octan-8-amine
Figure imgf000286_0002
To a solution of tert-butyl 6-[2-(l,l-dioxido-2,3-dihydro-l,4-benzothiazepin-4(5H)-yl)-6- methylquinolin-4-yl]-2-oxa-6-azaspiro[3.4]octan-8-carbamate (700 mg, 1.24 mmol) in dichloromethane (10 mL) was added trifluoro acetic acid (5 mL) at 0 °C. The resulting mixture was stirred at room temperature for further 30 minutes. The reaction was quenched with a saturated aqueous solution of sodium carbonate, and the mixture was extracted with
dichloromethane. The organic layer was dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by preparative HPLC to give 80 mg of the product as a white solid. MS obsd. (ESI+) [(M+H)+] 465, 1H NMR (400 MHz, CD3OD) δ ppm 7.97 (d, J= 7.6 Hz, 1 H), 7.83 (d, J= 7.6 Hz, 1 H), 7.79 (s, 1 H), 7.63 (m, 1 H), 7.52 (d, J= 8.4 Hz, 1 H), 7.44 (m, 1 H), 7.35 (m, 1 H), 6.10 (s, 1 H), 5.17 (s, 2 H), 4.95 (d, J= 6.8 Hz, 1 H), 4.68 - 4.62 (m, 3 H), 4.50 (brs, 2 H), 4.10 (d, J= 8.8 Hz, 1 H), 3.91 - 3.81 (m, 3 H), 3.60 (m, 2 H), 3.45 (m 1 H), 2.41 (s, 3 H).
Example 24 trans-4- Amino- 1- [2-(l, l-dioxido-2,3-dihydro- 1 ,4-benzothiazepin-4(5H)-yl)- 1,6- naphthyridin-4-yl]pyrrolidin-3-ol
Figure imgf000287_0001
tert-Buty\ trans- 1- [2-(l , l-dioxido-2,3-dihydro- 1 ,4-benzothiazepin-4(5H)-yl)- 1,6- naphthyridin-4-yl] -3-hydroxypyrrolidin-4-carbamate
Figure imgf000287_0002
To a solution of -(4-chloro-l,6-naphthyridin-2-yl)-2,3,4,5-tetrahydro-l,4-benzothiazepine 1,1- dioxide (300 mg, 0.84 mmol, prepared in analogy to 4-(4-chloro-6-methylquinolin-2-yl)-2, 3,4,5- tetrahydro-l,4-benzothiazepine 1,1-dioxide in Example 2-1 by using 2,3,4,5-tetrahydro-l,4- benzothiazepine and 2,4-dichloro-l,6-naphthyridine) in 1,4-dioxane (5 mL) was added tert-butyl (trans-4-hydroxypyrrolidin-3-yl)carbamate (204 mg, 1.02 mmol),
tri(dibenzylideneacetone)dipalladium(0) (39 mg, 0.042 mmol), (2'-dicyclohexylphosphanyl- biphenyl-2-yl)-dimethyl-amine (24 mg, 0.063 mmol) and sodium tert-butoxide (114 mg, 1.17 mmol) under Ar protection. The reaction mixture was heated with stirring in a 10 mL of microwave process vial for 2 hours at 120 °C. The reaction mixture was concentrated in vacuo. The residue was purified by preparative HPLC to give 45 mg of the desired product (yield was 10%). trans-4- Amino- 1- [2-(l, l-dioxido-2,3-dihydro- 1 ,4-benzothiazepin-4(5H)-yl)- 1,6- naphthyridin-4-yl]pyrrolidin-3-ol
Figure imgf000288_0001
To a solution of tert-butyl tra«5-l-[2-(l,l-dioxido-2,3-dihydro-l,4-berizothiazepin-4(5H)-yl)- l,6-naphthyridin-4-yl]-3-hydroxypyrrolidin-4-carbamate (45 mg, 0.08 mmol) in ethyl acetate (10 mL) was added a solution of hydrochloride in ethyl acetate (4 N, 30 mL) in an ice- water bath dropwise. After being stirred at room temperature for 4 hours, the mixture was concentrated in vacuo. The residue was purified by preparative HPLC to give the trifluoro acetic acid salt of the desired product. The trifluoro acetic acid salt was flashed through SPE column with methanol. The solution was concentrated in vacuo and dried by lyopylization to afford 10.9 mg of the desired product (yield was 30%). MS obsd. (ESI+) [(M+H)+] 426, 1H NMR (400 MHz, CD3OD) δ ppm 9.23 (s, 1 H), 8.23 (d, J= 7.2 Hz, 1 H), 7.99 (d, J= 7.6 Hz, 1 H), 7.87 (d, J= 7.2 Hz, 1 H), 7.66 - 7.64 (m, 2 H), 7.48 (t, J= 7.6 Hz, 1 H), 6.16 (s, 1 H), 5.25 (s, 2 H), 4.70 - 4.40 (m, 3 H), 4.26 - 4.18 (m, 2 H), 3.87 - 3.85 (m, 1 H), 3.81 - 3.78 (m, 1 H), 3.71 - 3.68 (m, 1 H), 3.55 (t, J = 4.8 Hz, 2 H).
Example 25 l-[2-(l,l-Dioxido-2,3-dihydro-l,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4- yl] py rrolidin-3-amine
Figure imgf000288_0002
A mixture of 4-(4-chloro-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-l,4-benzothiazepine 1,1- dioxide (0.3 g, 0.8 mmol, prepared in analogy to 4-(4-chloro-6-(trifluoromethoxy)quinolin-2-yl)- 2,3,4,5-tetrahydro-l,4-benzothiazepine 1,1 -dioxide in Example 17-1 by using 2,4-dichloro-6- methylquinoline and 2,3,4,5-tetrahydro-l,4-benzothiazepine 1,2-dioxide) and tert-butyl pyrrolidine-3-carbamate (0.3 g, 1.6 mmol) was heated with stirring in a 10 mL of microwave process vial for 1 hour at 140 °C. The resuting mixture was purified by preparative HPLC and SPE. After SPE separation, the eluent was concentrated in vacuo to remove the organic solution. The residue was dried by lyophylization to afford 82.9 mg of the desired product (yield was 25 %). MS obsd. (ESI+) [(M+H)+] 423, 1H NMR (400 MHz, CD3OD) δ ppm 8.09 - 8.08 (dd, J = 4.0, 8.0 Hz, 1 H), 8.02 (s, 1 H), 7.85 - 7.83 (q, J= 7.6 Hz, 1 H), 7.77 - 7.70 (m, 2 H), 7.61 - 7.56 (m, 2 H), 5.90 (s, 1 H), 5.30 (s, 2 H), 4.52 (s, 2 H), 4.30 - 4.26 (m, 1 H), 4.17 - 4.11 (m, 2 H) 3.99 - 3.96 (m, 2 H), 3.74 (s, 2 H), 2.57-2.52 (m, 1 H), 2.47 (s, 3 H), 2.35 - 2.28 (m, 1 H). Example 26-1 V-(Azetidin-3-yl)-2-(l,l-dioxido-2,3-dihydro-l,4-benzothiazepin-4(5H)-yl)-6- methylquinolin-4-amine
Figure imgf000289_0001
tert-Buty\ 3-[l,l-dioxido-2,3-dihydro-l,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4- ylamino]-azetidine-l-carboxylate
Figure imgf000289_0002
A mixture of 8-(4-bromo-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-l,4-benzothiazepine 1,1- dioxide (900 mg, 2.16 mmol, prepared in analogy to the one in Example 2-1) and tert-butyl 3- aminoazetidine-l-carboxylate (1.86 g, 10.77 mmol) was heated with stirring in a 10 mL of microwave process vial for 1 hour at 150 °C. The resuting mixture was purified by preparative HPLC to afford 110 mg of the desired product (yield was 7%). V-(Azetidin-3-yl)-2-(l,l-dioxido-2,3-dihydro-l,4-benzothiazepin-4(5H)-yl)-6- methylquinolin-4-amine
Figure imgf000290_0001
To a solution of tert-butyl 3-[l,l-dioxido-2,3-dihydro-l,4-benzothiazepin-4(5H)-yl)-6- methylquinolin-4-ylamino]-azetidine-l-carboxylate (110 mg, 0.22 mmol) in ethyl acetate (10 mL) was added a solution of hydrochloride in ethyl acetate (4 N, 30 mL) in an ice- water bath dropwise. After being stirred at room temperature for 4 hours, the mixture was concentrated in vacuo. The residue was purified by preparative HPLC to give the trifluoro acetic acid salt of the desired product. The trifluoro acetic acid salt was flashed through SPE column with methanol. The solution was concentrated in vacuo and dried by lyopylization to afford 29 mg of the desired product (yield was 33%). MS obsd. (ESI+) [(M+H)+] 409, 1H NMR (400 MHz, CD3OD) δ ppm 8.09 (d, J= 7.2 Hz, 1 H), 8.02 (s, 1 H), 7.84 - 7.82 (m, 1 H), 7.76 - 7.72 (m, 2 H), 7.65 - 7.60 (m, 2 H), 5.79 (s, 1 H), 5.33 (s, 2 H), 4.96 - 4.92 (m, 1 H), 4.55 - 4.50 (m, 4 H), 4.31 - 4.28 (m, 2 H), 3.76 (s, 2 H), 2.49 (s, 3 H).
Example 26-2 l-[2-(l,l-Dioxido-2,3-dihydro-l,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]azetidin- 3-amine
Figure imgf000290_0002
The title compound was prepared in analogy to Example 26-1 in Scheme 7 by using 4-(4-chloro- 6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-l,4-benzothiazepine 1,1-dioxide (prepared in analogy to the one in Example 2-1) and tert-butyl azetidin-3-ylcarbamate. MS obsd. (ESI ) [(M+H)+] 409, 1H NMR (400 MHz, CD3OD) δ ppm 8.03 - 8.00 (d, J= 7.6 Hz, 1 H), 7.87 (s, 1 H), 7.80 - 7.78 (d, J= 7.6 Hz, 1 H), 7.67 - 7.62 (m, 2 H), 7.56 - 7.50 (m, 2 H), 6.00 (s, 1 H), 5.29 (s, 2 H), 4.47 (s, 2 H), 3.97 - 3.89 (m, 3 H), 3.82 - 3.69 (m, 4 H), 2.40 (s, 3 H).
Example 27 V-[2-(l,l-Dioxido-2,3-dihydro-l,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4- yljprolinamide
Figure imgf000291_0001
tert-Buty\ 2-{[2-(l,l-dioxido-2,3-dihydro-l,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4- yl]carbamoyl}pyrrolidine-l-carboxylate
Figure imgf000291_0002
To a solution of 4-(4-chloro-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro- 1 ,4-benzothiazepine 1,1- dioxide (0.60 g, 1.6 mmol, prepared in analogy to the one in Example 2-1), tert-butyl 2- carbamoylpyrrolidine-l-carboxylate (0.34 g, 1.6 mmol), l,l'-bis(diphenylphosphino)ferrocene- palladium(II)dichloride (0.13 g, 0.16 mmol), l,l'-bis(diphenylphosphino)ferrocene (0.089 g, 0.16 mmol) and sodium tert-butoxide (0.307 g, 3.2 mmol) in 1,4-dioxane (25 mL) was heated with stirring for 1.5 hours at 120 °C under microwave irradiation. The reaction mixture was filtered and concentrated in vacuo. The residue was purified by preparative TLC (eluting with 50% ethyl acetate in petroleum ether, V/V=l : 1) to give 250 mg of the desired product (yield was
29%). V-[2-(l,l-Dioxido-2,3-dihydro-l,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4- yljprolinamide
Figure imgf000292_0001
To a solution of tert-butyl 2-{[2-(l,l-dioxido-2,3-dihydro-l,4-benzothiazepin-4(5H)-yl)-6- methylquinolin-4-yl]carbamoyl}pyrrolidine-l-carboxylate (250 mg, 0.44 mmol) in ethyl acetate (5 mL) was added a solution of hydrochloride in ethyl acetate (4 N, 20 mL) dropwise in an ice- water bath. After being stirred at room temperature for 14 hours, the reaction mixture was concentrated in vacuo. The residue was purified by preparative TLC to give 104.8 mg of the desired product (yield was 48%). MS obsd. (ESI+) [(M+H)+] 451, 1H NMR (400 MHz, DMSO- d6) δ ppm 7.96 (s, 1 H), 7.88 - 7.84 (m, 2 H), 7.63 - 7.59 (m, 1 H), 7.54 (s, 1 H) 7.49 - 7.44 (m, 2 H), 7.39 - 7.37 (m, 2 H), 7.00 (s, 1 H), 5.04 (s, 2 H), 4.40 (s, 2 H), 4.16 - 4.12 (t, J= 5.2 Hz, 1 H), 3.64 (s, 2 H) 3.15 - 3.01 (m, 3 H), 2.39 (s, 3 H), 2.23 - 2.20 (m, 1 H), 1.95 - 1.90 (m, 1 H), 1.80 - 1.75 (m, 1 H).
Example 28-1
2-(l,l-Dioxido-2,3-dihydro-l,4-benzothiazepin-4(5H)-yl)-N-irans-(4-fluoropyrrolidin-3-yl)- 6-methylquinolin-4-amine
Figure imgf000292_0002
Benzyl trans-3- { [2-(l , l-dioxido-2,3-dihydro- 1 ,4-benzothiazepin-4(5H)-yl)-6-methylquinolin- 4-yl]amino}-4-fluoropyrrolidine-l-carboxylate
Figure imgf000292_0003
The title compound was prepared in analogy to Example 8-1 in Scheme 7 by using 4-(4-chloro- 6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-l,4-benzothiazepine 1,1-dioxide (prepared in analogy to the one in Example 2-1) and benzyl tra/75-3-amino-4-fluoropyrrolidine-l-carboxylare.
2-(l,l-Dioxido-2,3-dihydro-l,4-benzothiazepin-4(5H)-yl)-N-(irans-4-fluoropyrrolidin-3-yl)- 6-methylquinolin-4-amine
Figure imgf000293_0001
To a suspension of benzyl tra/?5-3-{[2-(l,l-dioxido-2,3-dihydro-l,4-benzothiazepin-4(5H)-yl)-6- methylquinolin-4-yl]amino}-4-fluoropyrrolidine-l-carboxylate (320 mg, 0.557 mmol) in methanol (5 mL) was added an aqueous solution of potassium hydroxide (40%, 5 mL). The suspension was heated under reflux for 30 minutes. The organic solvent was removed by concentration in vacuo. The residue was purified by preparative HPLC to afford the pure product as a solid. MS obsd. (ESI+) [(M+H)+] 441, 1H NMR (400 MHz, CD3OD) δ ppm 8.01 (d, J = 6.57 Hz, 1 H), 7.85 (d, J= 7.33 Hz, 1 H), 7.67 (s, 1 H), 7.63 (t, J= 7.07 Hz, 1 H), 7.53 - 7.40 (m, 2 H), 7.30 (d, J= 8.84 Hz, 1 H), 6.18 (s, 1 H), 5.15 (s, 2 H), 5.10 (brs, 1 H), 4.97 (brs, 1 H), 3.60 (dd, J= 12.00, 6.44 Hz, 3 H), 3.28 (brs, 1 H), 3.23 (dd, J= 8.84, 5.31 Hz, 1 H), 3.18 - 3.12 (m, 1 H), 3.04 (dd, J= 12.00, 4.67 Hz, 1 H), 2.42 (s, 3 H).
Example 28-2 irans-4-{[2-(l,l-Dioxido-2,3-dihydro-l,4-benzothiazepin-4(5H)-yl)quinolin-4- yl] amino}pyrrolidin-3-ol
Figure imgf000293_0002
The title compound was prepared in analogy to Example 28-1 in Scheme 8 by using 4-(4- bromoquinolin-2-yl)-2,3,4,5-tetrahydro-l,4-benzothiazepine 1,1-dioxide (prepared in analog 4-(4-chloro-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro- 1 ,4-benzothiazepine 1 , 1 -dioxide in Example 2-1) and benzyl tra/75-3-amino-4-hydroxypyrrolidine-l-carboxylate. MS obsd. (ESI ) [(M+H)+] 439, 1H NMR (400 MHz, CD3OD) δ ppm 8.29 - 8.22 (d, J= 7.6 Hz, 1 H), 8.12 - 8.08 (d, J= 1.2 Hz, 1 H), 7.98 - 7.92 (d, J= 7.6 Hz, 1 H), 7.88- 7.82 (d, J= 0.8 Hz, 1 H), 7.80 - 7.71 (m, 2 H), 7.62 - 7.58 (t, J= 1.2 Hz, 1 H), 7.50 - 7.42 (t, J= 6.8 Hz, 1 H), 6.20 (s, 1 H), 5.45 - 5.30 (q, J= 7.2 Hz , 2 H), 4.62 - 4.52 (m, 2 H), 4.52 - 4.45 (m, 2 H), 4.05 - 3.95 (q, J= 4.4 Hz, 1 H), 3.80 - 3.75 (t, J= 2.8 Hz, 2 H), 3.75 - 3.68 (m, 1 H), 3.62 - 3.55 (dd, J= 2.8, 12.8 Hz,l H), 3.48 - 3.40 (d, J= 7.6 Hz, 1 H).
Example 28-3 irans-4-{[2-(l,l-Dioxido-2,3-dihydro-l,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4- yl]amino}pyrrolidin-3-ol
Figure imgf000294_0001
The title compound was prepared in analogy to Example 28-1 in Scheme 8 by using 4-(4-bromo- 6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-l,4-benzothiazepine 1,1-dioxide (prepared in analogy to the one in Example 2-1) and benzyl (35',45)-3-amino-4-hydroxypyrrolidine-l-carboxylate. MS obsd. (ESI+) [(M+H)+] 439, 1H NMR (400 MHz, CD3OD) δ ppm 8.13 - 8.10 (d, J= 7.6 Hz ,1 H), 8.06 (s, 1 H), 7.95 - 7.90 (d, J= 7.2 Hz ,1 H), 7.78 - 7.70 (m, 2 H), 7.65 - 7.58 (m, 2 H), 6.16 (s, 1 H), 5.3 (q, J= 1.2 Hz , 2 H), 4.65 - 4.40 (m, 2 H), 4.50 - 4.40 (m, 2 H), 4.12 - 3.95 (m, 1 H), 3.80 - 3.68 (m, 3 H), 3.60 - 3.50 (m, 1 H), 3.48 - 3.40 (d, J= 7.2 Hz ,1 H), 2.47 (s, 3 H).
Example 28-4 cis-4- { [2-(l , l-Dioxido-2,3-dihydro- 1 ,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4- yl] amino}pyrrolidin-3-ol
Figure imgf000294_0002
The title compound was prepared in analogy to Example 28-1 in Scheme 8 by using 4-(4-bromo- 6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-l,4-benzothiazepine 1 , 1-dioxide (prepared in analogy to the one in Example 2-1) and benzyl czs-3-amino-4-hydroxypyrrolidine-l-carboxylate. MS obsd. (ESI+) [(M+H)+] 439, 1H NMR (400 MHz, CD3OD) δ ppm 8.12 - 8.07 (m, 2 H), 7.98 - 7.90 (d, J= 7.6 Hz, 1 H), 7.78 - 7.70 (m, 2 H), 7.63 - 7.58 (m, 2 H), 6.16 (s, 1 H), 5.41 - 5.28 (m, 2 H), 4.61 - 4.50 (m, 2 H), 4.48 (s, 2 H), 4.02 - 3.93 (q, J = 6 Hz, 1 H), 3.78 - 3.68 (m, 3 H), 3.60 - 3.50 (dd, J= 2.8, 12.8 Hz, 1 H), 3.48 - 3.40 (d, J= 3.6 Hz, 1 H), 2.46 (s, 3 H).
Example 28-5 V-[irans-4-Fluoropyrrolidin-3-yl]-6-methyl-2-(l-oxido-2,3-dihydro-l,4-benzothiazepin- 4(5H)-yl)quinolin-4-amine
Figure imgf000295_0001
The title compound was prepared in analogy to Example 28-1 in Scheme 8 by using 4-(4-chloro- 6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-l,4-benzothiazepine 1-oxide (prepared in analogy to the one in Example 18-1) and benzyl tra/75-3-amino-4-fluoropyrrolidine-l-carboxylare. MS obsd. (ESI+) [(M+H)+] 425, 1H NMR (400 MHz, CD3OD) δ ppm 7.75 (m, 3 H), 7.50 (m, 3 H), 7.35 (d, J= 8.4 Hz, 1 H), 6.16 (brs, 1 H), 5.28 - 4.97 (m, 3 H), 4.61 (s, 1 H), 4.28 (m, 1 H), 3.64 (m, l H), 3.47 (s, 2 H), 3.30 - 3.08 (m, 2 H), 2.43 (s, 3 H).
Example 29
4- [(3- Aminopropyl)amino] -2-(l , l-dioxido-2,3-dihydro- 1 ,4-benzothiazepin-4(5H)- yl)quinolin-6-ol
Figure imgf000295_0002
4-Chloro-2-(l,l-dioxido-2,3-dihydro-l,4-benzothiazepin-4(5H)-yl)-quinolin-6-ol
Figure imgf000296_0001
A mixture of 4-(4-chloro-6-methoxyquinolin-2-yl)-2,3,4,5-tetrahydro-l,4-benzothiazepine 1 , 1- dioxide (5.0 g, 12.85 mmol, prepared in analogy to 4-(4-chloro-6-methylquinolin-2-yl)-2, 3,4,5- tetrahydro-l ,4-benzothiazepine 1 , 1 -dioxide in Example 2-1 by using 2,4-dichloro-6- methoxyquinoline and 2,3,4,5-tetrahydro-l ,4-benzothiazepine) and hydrobromic acid (350 mL, 48%) was refluxed for 2 days. The resulting mixture was basified with an aqueous solution of sodium hydroxide (4 N) to about pH 9 and extracted with ethyl acetate (250 mL x 3). The combined organic layers were dried over sodium sulfate and concentrated in vacuo. The residue was purified by preparative HPLC to afford 3.0 g of the desired product (yield was 62.2%). 4- [(3- Aminopropyl)amino] -2-(l , l-dioxido-2,3-dihydro- 1 ,4-benzothiazepin-4(5H)- yl)quinolin-6-ol
Figure imgf000296_0002
A mixture of 4-chloro-2-(l , l-dioxido-2,3-dihydro-l ,4-benzothiazepin-4(5H)-yl)-quinolin-6-ol (400 mg, 1.067 mmol) and propane- 1 ,3-diamine (158 mg, 2.134 mmol) was heated with stirring for 1.5 hours at 150 °C under microwave irradiation. The reacting mixture was purified by preparative HPLC and SPE to give 1 18.8 mg of the desired product (yield was 27%>). MS obsd. (ESI+)[(M+H)+] 413, 1H NMR (400 MHz, CD3OD) δ ppm 8.10 - 8.05 (d, J = 7.6 Hz, 1 H), 7.85 - 7.80 (d, J= 8 Hz, 1 H), 7.71 - 7.62 (m, 2 H), 7.60 - 7.52 (t, J = 7.2 Hz, 1 H), 7.40- 7.35 (m, 1 H), 7.26 - 7.20 (dd, J= 2.8 Hz, 12.8 Hz, 1 H), 5.91 (s, 1 H), 5.27 (s, 2 H), 4.52 - 4.42 (m, 2 H), 3.72 - 3.68 (t, J= 2.8 Hz, 2 H), 3.60 - 3.52 (t, J = 6.8 Hz, 2 H),3.10 - 3.02 (t, J = 7.2 Hz, 2 H), 2.10 - 2.00 (m, 2 H);
Example 30-1
2-({4- [(3- Aminopropyl)amino] -2-(l , l-dioxido-2,3-dihydro- 1 ,4-benzothiazepin- yl)quinolin-6-yl}oxy)ethanol
Figure imgf000297_0001
2-[4-Chloro-2-(l,l-dioxido-2,3-dihydro-l,4-benzothiazepin-4(5H)-yl)-quinolin-6-yloxy]- ethanol
Figure imgf000297_0002
A mixture of 4-chloro-2-(l , l-dioxido-2,3-dihydro-l ,4-benzothiazepin-4(5H)-yl)-quinolin-6-ol (250 mg, 0. 67 mmol, prepared in analogy to the one in Example 29), 2-bromo-ethanol (166.7 mg, 1.33 mmol), and potassium carbonate (277 mg, 2.01 mmol) in acetone (30 mL) was stirred at room temperature overnight and then refluxed for 12 hours. The reacting mixture was filtered and concentrated in vacuo. The residue was purified by preparative TLC to afford 230 mg of the desired product (yield was 82%).
2-({4- [(3- Aminopropyl)amino] -2-(l , l-dioxido-2,3-dihydro- 1 ,4-benzothiazepin- yl)quinolin-6-yl}oxy)ethanol
Figure imgf000297_0003
A mixture of 2- {[4-chloro-2-(l , l-dioxido-2,3-dihydro-l ,4-benzothiazepin-4(5H)-yl)quinolin-6- yl]oxy}ethanol (250 mg, 0.6 mmol) and propane- 1,3-diamine (88.8 mg, 1.2 mmol) was heated for 1.5 hours at 150 °C under microwave irradiation. The reacting mixture was purified by preparative HPLC and SPE to afford 98.2 mg of the desired product (yield was 35.8%). MS obsd. (ESI+) [(M+H)+] 457, 1H NMR (400 MHz, CD3OD) δ ppm 8.10 - 8.02 (d, J= 8 Hz, 1 H), 7.88 - 7.80 (d, J= 7.6 Hz, 1 H), 7.77 - 7.68 (q, J= 9.6 Hz, 2 H), 7.60 - 7.50 (m, 2 H), 7.42 - 7.38 (m, 1 H), 5.94 (s, 1 H), 5.29 (s, 2 H), 4.55 - 4.42 (m, 2 H), 4.18 - 4.10 (t, J= 4.4 Hz, 2 H), 3.90 - 3.85 (t, J= 4.4 Hz, 2 H), 3.76 - 3.68 (t, J= 4.4 Hz, 2 H), 3.62 - 3.55 (t, J= 6.8 Hz, 2 H), 3.12 - - - ~ 2.15 - 2.00 (m, 2 H). Example 30-2 V-[2-(l,l-Dioxido-2,3-dihydro-l,4-benzothiazepin-4(5H)-yl)-6-(2-methoxyethoxy)quinolin- 4-yl] propane- 1 ,3-diamine
Figure imgf000298_0001
The title compound was prepared in analogy to Example 30-1 by using 4-chloro-2-(l , l-dioxido- 2,3-dihydro-l ,4-benzothiazepin-4(5H)-yl)quinolin-6-ol (prepared in analogy to the one in Example 29), l-bromo-2-methoxyethane and propane- 1 ,3-diamine. MS obsd. (ESI ) [(M+H)+] 471 , 1H NMR (400 MHz, CD3OD) δ ppm 8.10 - 8.05 (d, J = 8 Hz, 1 H), 7.90 - 7.83 (d, J = 7.6 Hz, 1 H), 7.77 - 7.68 (q, J = 9.2 Hz, 2 H), 7.60 - 7.52 (m, 2 H), 7.42 - 7.36 (m, 1 H), 5.95 (s, 1 H), 5.30 (s, 2 H), 4.56 - 4.45 (m, 2 H), 4.22 - 4.18 (t, J= 2.8 Hz, 2 H), 3.80 - 3.75 (t, J = 2.8 Hz, 2 H), 3.75 - 3.70 (t, J = 4.4 Hz, 2 H), 3.65 - 3.58 (t, J = 6.8 Hz, 2 H), 3.42 (s, 3 H), 3.15 - 3.09 (t, J = 7.6 Hz, 2 H), 2.16 - 2.05 (m, 2 H).
Example 31 V-[2-(l,l-Dioxido-2,3-dihydro-l,4-benzothiazepin-4(5H)-yl)-6-(pyridin-2-yloxy)quinolin-4- yl]propane-l,3-diamine
Figure imgf000298_0002
8-[4-Chloro-6-(pyridin-2-yloxy)-quinolin-2-yl]- 2,3,4,5-tetrahydro-l,4-benzothiazepine 1,1- dioxide
Figure imgf000298_0003
A mixture of 4-chloro-2-(l,l-dioxido-2,3-dihydro-l,4-benzothiazepin-4(5H)-yl)quinolin-6-ol (400 mg, 1.067 mmol), 2-bromo-pyridine (337 mg, 2.134 mmol, prepared in analogy to the one in Example 29), copper(I) iodide (40 mg, 0.107 mmol), N,N'-dimethyl-cyclohexane-l,2-diamine (2.0 mg, 0.107 mmol) and potassium carbonate (250 mg, 2.134 mmol) in 1 ,2-dimethoxyethane (5 mL) was heated at 120 °C for 1 hour under microwave irridiation. The resulting mixture was filtered and concentrated in vacuo. The residue was purified by preparative HPLC to afford 300 mg of the desired product (yield was 62.2%).
N-[2-(l,l-Dioxido-2,3-dihydro-l,4-benzothiazepin-4(5H)-yl)-6-(pyridin-2-yloxy)quinolin-4- yl] propane- 1 ,3-diamine
Figure imgf000299_0001
The title compound was prepared in analogy to Example 30-1 in Scheme 9 by using 8-[4-chloro- 6-(pyridin-2-yloxy)-quinolin-2-yl]-2,3,4,5-tetrahydro- 1 ,4-benzothiazepine 1 , 1 -dioxide and propane- 1,3-diamine. MS obsd. (ESI+) [(M+H)+] 490, 1H NMR (400 MHz, CD3OD) δ ppm 8.10 - 8.02 (m, 2 H), 7.92 - 7.90 (m, 1 H), 7.88 - 7.80 (m, 3 H), 7.71 - 7.65 (t, J= 7.2 Hz, 1 H), 7.60- 7.48 (m, 2 H), 7.15 - 7.09 (t, J= 0.8 Hz, 1 H), 7.06 - 7.00 (d, J= 8.4 Hz, 1 H), 5.96 (s, 1 H), 5.31 (s, 2 H), 4.55 - 4.42 (m, 2 H), 3.78 - 3.69 (t, J= 2.8 Hz, 2 H), 3.60 - 3.50 (t, J= 6.8 Hz, 2 H), 3.08 - 3.00 (t, J= 7.6 Hz, 2 H), 2.10 - 2.00 (m, 2 H).
Example 32-1
3- { [2-(l , l-Dioxido-2,3-dihydro- 1 ,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4- yl]amino}propane-l,2-diol
Figure imgf000299_0002
A mixture of 4-(4-chloro-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-l,4-benzothiazepine 1,1- dioxide (200.0 mg, 0.54 mmol, prepared in analogy to the one in Example 2-1) and l-(2,2- dimethyl-l,3-dioxolan-4-yl)methanamine (0.5 mL, 3.8 mmol) was heated with stirring at 160 °C for 16 hours. After being cooled to room temperature, the resulting reaction mixture was diluted with methanol (2.0 mL). Concentrated hydrochloric acid (12.0 N, 0.5 mL) was introduced to the above mixture. The resulting mixture was stirred at room temperature for 1 hour, and then extracted with ethyl acetate (100 mL). The organic layer was washed with brine (50 mL x 2), dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by preparative HPLC to afford 69.2 mg of the product as a white solid (yield was 30%). MS obsd. (ESI+) [(M+H)+] 428, 1H NMR (400 MHz, CD3OD) δ ppm 7.98 (dd, J = 7.83, 1.26 Hz, 1 H), 7.89 (d, J= 7.33 Hz, 1 H), 7.63 (td, J= 7.45, 1.26 Hz, 1 H), 7.57 (s, 1 H), 7.50 - 7.35 (m, 2 H), 7.29 (dd, J= 8.59, 1.77 Hz, 1 H), 6.13 (s, 1 H), 5.14 (s, 2 H), 4.55 (brs, 2 H), 4.04 - 3.89 (m, 1 H), 3.69 (d, J= 5.56 Hz, 2 H), 3.64 - 3.49 (m, 4 H), 2.41 (s, 3 H).
Example 32-2
3- { [6-Chloro-2-(l , l-dioxido-2,3-dihydro- 1 ,4-benzothiazepin-4(5H)-yl)quinolin-4- yl]amino}propane-l,2-diol
Figure imgf000300_0001
The title compound was prepared in analogy to Example 32-1 in Scheme 10 by using 4-(4,6- dichloroquinolin-2-yl)-2,3,4,5-tetrahydro-l,4-benzothiazepine 1,1-dioxide (prepared in analogy to 4-(4-chloro-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-l,4-benzothiazepine 1,1-dioxide in Example 2-1 by using 2,4, 6-triochloroquino line and 2,3,4,5-tetrahydro-l,4-benzothiazepine) and l-(2,2-dimethyl-l,3-dioxolan-4-yl)methanamine. MS obsd. (ESI+) [(M+H)+] 448. 1H NMR (400 MHz, CD3OD) δ ppm 8.23 (d, J= 2.02 Hz, 1 H), 8.12 (dd, J= 7.83, 1.01 Hz, 1 H), 7.97 (d, J = 6.82 Hz, 1 H), 7.87 - 7.80 (m, 1 H), 7.80 - 7.68 (m, 2 H), 7.66 - 7.54 (m, 1 H), 6.30 (s, 1 H), 5.32 (s, 2 H), 4.56 (brs, 2 H), 4.04 - 3.83 (m, 1 H), 3.83 - 3.60 (m, 5 H), 3.54 (dd, J= 14.27, 7.20 Hz, 1 H).
Example 32-3 3- { [2-(8-Chloro- 1 , l-dioxido-2,3-dihydro- 1 ,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4- yl]amino}propane-l,2-diol
Figure imgf000301_0001
The title compound was prepared in analogy to Example 32-1 in Scheme 10 by using 4-(4- chloro-6-methylquinolin-2-yl)-8-chloro-2,3,4,5-tetrahydro- 1 ,4-benzothiazepine 1 , 1 -dioxide (prepared in analogy to 4-(4-chloro-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-l ,4- benzothiazepine 1 , 1 -dioxide in Example 2-1 by using 2,4-dichloro-6-methylquinoline and 8- chloro-2,3,4,5-tetrahydro- 1 ,4-benzothiazepine) and 1 -(2,2-dimethyl- 1 ,3-dioxolan-4- yl)methanamine. MS obsd. (ESI+) [(M+H)+] 462. 1H NMR (400 MHz, CD3OD) δ ppm 8.04 (d, J = 2.27 Hz, 1 H), 7.94 (d, J = 10.36 Hz, 2 H), 7.67 - 7.82 (m, 2 H), 7.61 (dd, J = 8.59, 1.26 Hz, 1 H), 6.21 (s, 1 H), 5.28 (s, 2 H), 4.54 (brs, 2 H), 4.02 - 3.90 (m, 1 H), 3.80 (brs, 2 H), 3.76 - 3.61 (m, 3 H), 3.54 (dd, J = 14.15, 7.33 Hz, 1 H), 2.50 (s, 3 H).
Example 32-4
3-{[6-Methyl-2-(l-oxido-2,3-dihydro-l,4-benzothiazepin-4(5H)-yl)quinolin-4- yl]amino}propane-l,2-diol
Figure imgf000301_0002
The title compound was prepared in analogy to Example 32-1 in Scheme 5 by using 4-(4-chloro- 6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-l,4-benzothiazepine 1-oxide (prepared in analogy to the one in Example 18-1) and 1 -(2,2-dimethyl- l ,3-dioxolan-4-yl)methanamine. MS obsd. (ESI ) [(M+H)+] 412, 1H NMR (400 MHz, CD3OD) δ ppm 7.78 (d, J = 7.33 Hz, 1 H), 7.74 (dd, J =
7.58, 1.26 Hz, 1 H), 7.62 (s, 1 H), 7.55 - 7.39 (m, 3 H), 7.33 (dd, J = 8.34, 1.52 Hz, 1 H), 6.13 (s, m ^ A SA A τ - Λ ^ Λ 2.91 Hz, 2 H), 4.82 (d, J= 7.58 Hz, 1 H), 4.76 (d, J = 14.15 Hz, 2 H), 4.06 - 3.83 (m, 1 H), 3.75 - 3.63 (m, 2 H), 3.63 - 3.52 (m, 1 H), 3.45 (d, J = 3.79 Hz, 2 H), 3.37 (td, J = 6.88, 4.42 Hz, 1 H), 2.43 (s, 3 H).
Example 32-5
3- { [6-Methyl-2-(5-methyl- 1 , l-dioxido-2,3-dihydro- 1 ,4-benzothiazepin-4(5H)-yl)quinolin-4- yl]amino}propane-l,2-diol
Figure imgf000302_0001
4-(4-Chloro-6-methylquinolin-2-yl)-5-methyl-2,3,4,5-tetrahydro-l,4-benzothiazepine
Figure imgf000302_0002
A mixture of 5-methyl-2,3,4,5-tetrahydro-l,4-benzothiazepine (1.0 g, 5.58 mmol) and 2,4- dichloro-6-methylquinoline (1.7 g, 8.02 mmol) was heated with stirring in a 2 mL of microwave process vial for 5 hours at 170 °C under microwave irradiation. The solvent was removed by concentration in vacuo. The residue was purified by flash column chromatography to give 560 mg of the mixture of 5-methyl-2,3,4,5-tetrahydro-l,4-benzothiazepine and 4-(4-chloro-6- methylquinolin-2-yl)-5-methyl-2,3,4,5-tetrahydro-l,4-benzothiazepine. 4-(4-Chloro-6-methylquinolin-2-yl)-5-methyl-2,3,4,5-tetrahydro-l,4-benzothiazepine 1,1- dioxide
Figure imgf000302_0003
To a solution of the above mixture of 5-methyl-2,3,4,5-tetrahydro-l,4-benzothiazepine and 4-(4- chloro-6-methylquinolin-2-yl)-5-methyl-2,3,4,5-tetrahydro-l,4-benzothiazepine (427 mg) in ^ i^-^ o^„,o ^ A A Q^ a soiution of 3-chloroperbenzoic acid (693 mg, 3.01 mmol) in dichloromethane in an ice bath. After being stirred for 1.5 hours in an ice bath, the reaction mixture was washed with a saturated aqueous solution of sodium bicarbonate and brine. The organic layer was dried over anhydrous sodium sulfate, and concentrated in vacuo. The residue was purified by flash column chromatography to give 130 mg of the product. 3- { [6-Methyl-2-(5-methyl- 1 , l-dioxido-2,3-dihydro- 1 ,4-benzothiazepin-4(5H)-yl)quinolin-4- yl]amino}propane-l,2-diol
Figure imgf000303_0001
The title compound was prepared in analogy to Example 32-1 in Scheme 10 by using 4-(4- chloro-6-methylquinolin-2-yl)-5-methyl-2,3,4,5-tetrahydro- 1 ,4-benzothiazepine 1 , 1 -dioxide and l-(2,2-dimethyl-l,3-dioxolan-4-yl)methanamine. MS obsd. (ESI+) [(M+H)+] 453, 1H NMR (400 MHz, CD3OD) δ ppm 8.03 (dd, J= 7.96, 1.39 Hz, 1 H), 7.90 (d, J= 6.57 Hz, 1 H), 7.71 - 7.64 (m, 2 H), 7.46 (ddd, J= 8.15, 6.63, 1.64 Hz, 2 H), 7.33 (dd, J= 8.59, 1.77 Hz, 1 H), 6.15 (s, 1 H), 5.86 (d, J= 6.82 Hz, 1 H), 4.64 - 4.53 (m, 4 H), 3.70 (d, J= 8.59 Hz, 1 H), 3.62 - 3.58 (m, 2 H), 3.57 - 3.49 (m, 1 H), 2.43 (s, 3 H), 2.00 (d, J= 7.07 Hz, 3 H). Example 33-1
TV- [(3- Aminooxetan-3-yl)methyl] -2-(7-morpholin-4-yl- 1 , l-dioxido-2,3-dihydro- 1 ,4- benzothiazepin-4(5H)-yl)-6-methylquinolin-4-amine
Figure imgf000303_0002
V-{[3-(Dibenzylamino)oxetan-3-yl]methyl}-6-methyl-2-[7-(morpholin-4-yl)-l,l-dioxido-2,3- dihydro- 1 ,4-benzothiazepin-4(5H)-yl] quinolin-4-amine
Figure imgf000304_0001
A mixture of N-{[3-(dibenzylamino)oxetan-3-yl]methyl}-6-methyl-2-[7-fluoro-l,l-dioxido-2,3- dihydro-l,4-benzothiazepin-4(5H)-yl]quinolin-4-amine (100 mg, 0.16 mmol, prepared in analogy to N- {[3-(dibenzylamino)oxetan-3-yl]methyl} -2-(8-methoxy- 1 , 1 -dioxido-2,3-dihydro- l,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-amine in Example 1-1 by using 2,4-dichloro- 6-methylquinoline, 7-fluoro-2,3,4,5-tetrahydro-l,4-benzothiazepine and 3-(aminomethyl)-N,N- dibenzyloxetan-3-amine) and morpholine (0.5 mL) was heated with stirring in a sealed 2 mL of microwave process via for 3 hours at 120 °C under microwave irradiation. The resulting mixture was concentrated in vacuo to afford 111 mg of the crude product which was used in next step without purification. MS obsd. (ESI+) [(M+H)+] 704.
TV- [(3- Aminooxetan-3-yl)methyl] -2- [(7-morpholin-4-yl)- 1 , l-dioxido-2,3-dihydro- 1 ,4- benzothiazepin-4(5H)-yl]-6-methylquinolin-4-amine
Figure imgf000304_0002
A mixture of N-{[3-(dibenzylamino)oxetan-3-yl]methyl}-6-methyl-2-[7-(morpholin-4-yl)-l,l- dioxido-2,3-dihydro-l,4-benzothiazepin-4(5H)-yl]quinolin-4-amine (100 mg, 0.14 mmol), 10% palladium hydroxide on active carbon (100 mg) and trifluoro acetic acid (0.5 mL) in methanol (20 mL) was stirred for 12 hours under hydrogen (1 bar). Then the mixture was basified with a saturated aqueous solution of sodium bicarbonate, and extracted with dichloromethane. The organic layer was dried over anhydrous sodium sulfate, and concentrated in vacuo. The residue was purified by preparative HPLC to afford 30 mg of the product (yield was 40%). MS obsd. (ESI+) [(M+H)+] 524, 'HNMR ((400 MHz, CD3OD) δ ppm 7.72 - 7.60 (m, 2 H), 7.56 (d, J = 2.27 Hz, 1 H), 7.33 (d, J = 8.34 Hz, 1 H), 7.25 (dd, J= 8.46, 1.39 Hz, 1 H), 6.85 (dd, J= 8.84, 2.53 Hz, 1 H), 6.30 - 6.03 (m, 2 H), 5.00 (brs, 2 H), 4.53 - 4.31 (m, 4 H), 3.86 - 3.68 (m, 4 H), 3.51 (d, J= 14.40 Hz, 4 H), 3.33 - 3.19 (m, 6 H), 2.41 (brs, 1 H), 2.37 (s, 3 H).
Example 33-2
TV- [(3- Aminooxetan-3-yl)methyl] -2- { 1 , l-dioxido-7- [4-(propan-2-yl)piperazin- 1-yl] -2,3- dihydro-l,4-benzothiazepin-4(5H)-yl}-6-methylquinolin-4-amine
Figure imgf000305_0001
The title compound was prepared in analogy to Example 33-1 in Scheme 11 by using N- {[3- (dibenzylamino)oxetan-3-yl]methyl} -6-methyl-2-[7-fluoro- 1 , 1 -dioxido-2,3-dihydro- 1 ,4- benzothiazepin-4(5H)-yl]quinolin-4-amine (prepared in analogy to the one in Example 33-1) and 4-(propan-2-yl)piperazine. MS obsd. (ESI+) [(M+H)+] 565, !HNMR ((400 MHz, CD3OD) δ ppm 7.82 - 7.67 (m, 2 H), 7.58 (d, J= 8.59 Hz, 1 H), 7.46 (d, J = 2.53 Hz, 1 H), 7.35 (dd, J= 8.59, 1.52 Hz, 1 H), 6.72 (dd, J = 8.97, 2.15 Hz, 1 H), 6.14 (s, 1 H), 5.11 (brs, 2 H), 4.62 (q, J= 6.57 Hz, 4 H), 4.56 - 4.36 (m, 2 H), 3.82 - 3.65 (m, 2 H), 3.54 (brs, 2 H), 3.50 - 3.39 (m, 4 H), 2.90 - 2.88 (m, 1 H), 2.88 - 2.72 (m, 4 H), 2.50 - 2.40 (m, 3 H), 1.26 - 1.11 (m, 6 H). Example 34
3-{[4-(4-Aminoquinolin-2-yl)-l,l-dioxido-2,3,4,5-tetrahydro-l,4-benzothiazepin-8- yl]oxy}propan-l-ol
Figure imgf000305_0002
4-(4-Chloroquinolin-2-yl)-2,3,4,5-tetrahydro-l,4-benzothiazepin-8-ol 1,1-dioxide
Figure imgf000305_0003
To a stirred solution of 4-(4-chloroquinolin-2-yl)-8-methoxy-2,3,4,5-tetrahydro-l,4- benzothiazepine 1,1-dioxide (2.0 g, 5.15 mmol, prepared in analogy to 4-(4-chloro-6- methylquinolin-2-yl)-2,3,4,5-tetrahydro-l,4-benzothiazepine 1,1-dioxide in Example 2-1) in dry methylene chloride (70.0 mL) was added a solution of boron tribromide (2.5 ml, 25.7 mmol) in dry methylene chloride (10 ml) at 0 °C. After being stirred at 0 °C for 1 hour, the reaction was quenched by addition of a saturated aqueous sodium bicarbonate solution (30 mL). The mixture was extracted with ethyl acetate (100 mL x 2). The combined organic layers were washed with a saturated aqueous sodium bicarbonate solution (20 mL x 3) and brine (20 mL x 3), dried over anhydrous sodium sulfate and concentrated in vacuo to afford 1.95 g of the crude product as a white solid. MS obsd. (ESI+) [(M+H)+] 375.
3-{[4-(4-Chloroquinolin-2-yl)- l,l-dioxido-2,3,4,5-tetrahydro-l,4-benzothiazepin-8- yl]oxy}propan-l-ol
Figure imgf000306_0001
A mixture of 4-(4-chloroquinolin-2-yl)-2,3,4,5-tetrahydro-l,4-benzothiazepin-8-ol 1,1-dioxide (374.0 mg, 1.0 mmol), 3-bromo-propan-l-ol (0.37 mL, 3.0 mmol) and potassium carbonate
(415.0 mg, 3.0 mmol) in N, N-dimethylformamide (1.5 mL) was heated with stirring at 70 °C for 2 hours. After being cooled to room temperature, the resulting mixture was extracted with ethyl acetate (150 mL x 2). The combined organic layers were washed with water (50 mL x 2) and a saturated aqueous ammonium chloride solution (50 mL x 2), dried over anhydrous sodium sulfate and then concentrated in vacuo to afford 421.6 mg of the crude product as a yellow oil which was used for next step without further purification. MS obsd. (ESI+) [(M+H)+] 433. terf-Butyl {2- [8-(3-hydroxy ropoxy)- 1 , l-dioxido-2,3-dihydro- 1 ,4-benzothiazepin- yl] quinolin-4-yl} carbamate
Figure imgf000306_0002
A mixture solution of 3- {[4-(4-chloroquinolin-2-yl)-l , l-dioxido-2,3,4,5-tetrahydro-l ,4- benzothiazepin-8-yi]oxy}propan-l-ol (300.0 mg, 0.70 mmol), tert-butyl carbamate (175.0 mg, 1.5 mmol), l, -bis(diphenylphosphino)ferrocene (70.0 mg, 0.1 13 mmol), Ι , Γ- bis(diphenylphosphino)ferrocenedichloropalladium(II) (70.0 mg, 0.075 mmol) and sodium tert- butoxide (232.0 mg, 2.25 mmol) in 1 ,4-dioxane (2.0 mL) was heated with stirring at 120 °C for 2 hours under microwave irridiation. After being cooled to room temperature, the reaction mixture was extracted with ethyl acetate (100 mL). The organic layer was washed with brine (50 mL x 2), dried over anhydrous sodium sulfate and concentrated in vacuo to afford 359.1 mg of the crude product as yellow oil which was used for next step without further purification. MS obsd. (ESI+) [(M+H)+] 514.
3-{[4-(4-Aminoquinolin-2-yl)-l,l-dioxido-2,3,4,5-tetrahydro-l,4-benzothiazepin-8- yl]oxy}propan-l-ol
Figure imgf000307_0001
A mixture solution of tert-butyl {2-[8-(3-hydroxypropoxy)-l , l-dioxido-2,3-dihydro-l ,4- benzothiazepin-4(5H)-yl]quinolin-4-yl} carbamate (359.1 mg, the crude product of the above step) and trifluoro acetic acid (1.0 mL) in dichloromethane (2.0 mL) was stirred at room temperature for 6 hours. The reaction mixture was diluted with water (10 mL) and extracted with ethyl acetate (100 mL). The organic layer was washed with brine (50 mL x 2), dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by preparative HPLC to afford 14.2 mg of the desired product as a white solid (yield was 4.9%). MS obsd.
(ESI+) [(M+H)+] 414, 1HNMR ((400 MHz, CD3OD) δ ppm 7.82 - 7.67 (m, 2 H), 7.54 - 7.48 (m, 2 H), 7.48 - 7.39 (m, 1 H), 7.19 - 7.06 (m, 2 H), 6.30 (s, 1 H), 5.04 (s, 2 H), 4.78 - 4.34 (m, 2 H), 4.1 1 (t, J= 6.32 Hz, 2 H), 3.71 (t, J = 6.19 Hz, 2 H), 3.62 - 3.49 (m, 2 H), 2.1 1 - 1.78 (m, 2 H).
Example 35 TV- [(3- Aminooxetan-3-yl)methyl] -2-(l , l-dioxido-8-phenoxy-2,3-dihydro- 1 ,4-benzothiazepin- 4(5H)-yl)-6-methylquinolin-4-amine
Figure imgf000308_0001
4-(4-Chloro-6-methylquinolin-2-yl)-8-phenoxy-2,3,4,5-tetrahydro-l,4-benzothiazepine 1,1- dioxide
Figure imgf000308_0002
A mixture of 4-(4-chloro-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-l,4-benzothiazepin-8-ol 1,1- dioxide (250.0 mg, 0.65 mmol, prepared in analogy to 4-(4-chloroquinolin-2-yl)-2, 3,4,5- tetrahydro-l,4-benzothiazepin-8-ol 1,1 -dioxide in Example 34), iodo-benzene (0.1 mL, 0.089 mmol), copper(I) iodide (74.0 mg, 0.35 mmol), N, N-dimethylglycine hydrochloride (72.0 mg, 0.52 mmol) and potassium carbonate (267.0 mg, 1.9 mmol) in dimethyl sulfoxide (1.5 mL). The reaction mixture was heated with stirring at 120 °C for 6 hours. After being cooled to room temperature, the reaction mixture was extracted with ethyl acetate (150 mL x 2), washed with water (50 mL x 2) and a saturated aqueous ammonium chloride solution (50 mL x 2), dried over anhydrous sodium sulfate and then concentrated in vacuo to afford 298.0 mg of the crude product as a yellow oil which was used for next step without further purification. MS obsd. (ESI+) [(M+H)+] 465. V-{[3-(Dibenzylamino)oxetan-3-yl]methyl}-2-(l,l-dioxido-8-phenoxy-2,3-dihydro-l,4- benzothiazepin-4(5H)-yl)-6-methylquinolin-4-amine
Figure imgf000308_0003
A mixture solution of 4-(4-chloro-6-methylquinolin-2-yl)-8-phenoxy-2,3,4,5-tetrahydro-l,4- benzothiazepine 1,1 -dioxide ( 167.0 mg, 0.36 mmol), (3-(aminomethyl)-N,N-dibenzyloxetan-3- amine ( 609.0 mg, 2.16 mmol), l, -bis(diphenylphosphino)-ferrocenedichloropalladium(II) (15.0 mg, 0.02 mmol), l, -bis(diphenylphosphino)-ferrocene (11.2 mg, 0.02 mmol) and sodium tert-butoxide (75.0 mg, 0.72 mmol) in 1,4-dioxane (2.0 mL) was heated with stirring at 120 °C for 2 hours under microwave irridiation. After being cooled to room temperature, the reaction mixture was extracted with ethyl acetate (100 mL). The organic layer was washed with brine (50 mL x 2), dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by ISCO combi- flash chromatography (gradient elution, 20 - 60% ethyl acetate in petroleum ether) to afford 134.6 mg of the desired product as a light yellow solid (yield was 52.6%). MS obsd. (ESI+) [(M+H)+] 711.
TV- [(3- Aminooxetan-3-yl)methyl] -2-(l , l-dioxido-8-phenoxy-2,3-dihydro- 1 ,4-benzothiazepin- 4(5H)-yl)-6-methylquinolin-4-amine
Figure imgf000309_0001
A mixture of 7V-{[3-(dibenzylamino)oxetan-3-yl]methyl}-2-(l,l-dioxido-8-phenoxy-2,3-dihydro- l,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-amine (90 mg, 0.13 mmol), palladium hydroxide on carbon (40 mg) and trifluoro acetic acid (0.1 mL) in methanol (30.0 mL) was stirred at room temperature under hydrogen (2 bar) for 14 hours. Then the reaction mixture was filtered and concentrated in vacuo. The residue was purified by preparative HPLC to afford 10.5 mg of the desired product as a white solid (yield was 15.2%). MS obsd. (ESI+) [(M+H)+] 531 , 1H NMR (400 MHz, CD3OD) δ ppm 7.86 (d, J= 8.34 Hz, 1 H), 7.69 (s, 1 H), 7.52 (d, J= 2.53 Hz, 1 H), 7.45 (d, J= 8.59 Hz, 1 H), 7.42 - 7.35 (m, 2 H), 7.31 (dd, J= 8.46, 1.64 Hz, 1 H), 7.25 - 7.13 (m, 2 H), 7.06 - 6.97 (m, 2 H), 6.21 (s, 1 H), 5.14 (brs, 2 H), 4.70 - 4.46 (m, 6 H), 3.68 (s, 2 H), 3.60 (brs, 2 H), 2.44 (s, 3 H).
Example 36-1
7V~3~- [2-(l , l-Dioxido-2,3-dihydro- 1 ,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl] -
I pta-alaninamirlp
Figure imgf000310_0001
Methyl V-[2-(l,l-dioxido-2,3-dihydro-l,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]- beta-alaninate
Figure imgf000310_0002
To a solution of N-[2-(l,l-dioxido-2,3-dihydro-l,4-benzothiazepm^
4-yl]-beta-alanine (85 mg, 0.2 mmol, prepared in analogy to the one in Example 14-2) in methanol (10 mL) at 0 °C was added thionyl chloride (1.5 mL) carefully. The mixture was stirred at room temperature for 20 minutes, and then refluxed at 80 °C for 2 hours. After being cooled to room temperature, the mixture was concentrated in vacuo. The residue was dissolved in dichloromethane, washed with a saturated aqueous solution of sodium bicarbonate, water and brine, then dried over sodium sulfate, and concentrated in vacuo to afford the crude product which was directly used for the next step without further purification.
N~3~- [2-(l , l-Dioxido-2,3-dihydro- 1 ,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl] - beta-alaninamide
Figure imgf000310_0003
A mixture of methyl N-[2-(l, l-dioxido-2, 3-dihydro-l,4-benzothiazepin-4(5H)-yl)-6- methylquinolin-4-yl] -beta-alaninate and a solution of ammonia in methanol (7 N, 10 mL) was heated with stirring at 85 °C in a sealed tube overnight. The resulting mixture was concentrated in vacuo. The residue was purified by preparative HPLC to afford 59.2 mg of the desired product as a solid. MS obsd. (ESI+) [(M+H)+] 425, 1H NMR (400 MHz, DMSO- 6) δ ppm 7.95 (d, J = 6.82 Hz, 1 H), 7.88 (dd, J = 7.83, 1.26 Hz, 1 H), 7.66 - 7.60 (m, 2 H), 7.50 - 7.42 (m, 2 H), 7.31 (d, J= 8.59 Hz, 1 H), 7.22 (dd, J = 8.46, 1.64 Hz, 1 H), 6.97 (brs, 1 H), 6.73 (t, J= 5.68 Hz, 1 H), 6.06 (s, 1 H), 5.06 (brs, 2 H), 4.40 (brs, 2 H), 3.68 - 3.56 (m, 2 H), 3.51 (q, J= 6.65 Hz, 2 H), 2.42 (t, J= 7.07 Hz, 2 H), 2.34 (s, 3 H).
Example 36-2
3- { [2-(l , l-Dioxido-2,3-dihydro- 1 ,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4- yl] amino] butanamide
Figure imgf000311_0001
The title compound was prepared in analogy to Example 36-1 in Scheme 13 by using 3- {[2-(l , l- dioxido-2,3-dihydro-l ,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]amino}butanoic acid (prepared in analogy to N-[2-(l , l-dioxido-2,3-dihydro-l ,4-benzothiazepin-4(5H)-yl)-6- methylquinolin-4-yl]-beta-alanine in Example 14-2). MS obsd. (ESI+) [(M+H)+] 439, 1H NMR (400 MHz, CD3OD) δ ppm 8.07 (dd, J = 7.83, 1.26 Hz, 1 H), 7.98 (d, J= 7.6 Hz, 1 H), 7.95 (brs, 1 H), 7.74 - 7.66 (m, 2 H), 7.62 - 7.51 (m, 2 H), 6.14 (s, 1 H), 5.29 (s, 2 H), 4.43 - 4.64 (m, 2 H), 4.38 (q, J= 8Hz, 1 H), 3.72 (brs, 2 H), 2.68 (dd, J= 14.65, 5.56 Hz, 1 H), 2.54 (dd, J = 14.65, 7.07 Hz, 1 H), 2.46 (s, 3 H), 1.41 (d, J = 6.32 Hz, 3 H).
Example 36-3 3- { [2-(l , l-Dioxido-2,3-dihydro- 1 ,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl] amino}- 2-methylpropanamide
Figure imgf000312_0001
The title compound was prepared in analogy to Example 36-1 by using 3-{[2-(l,l-dioxido-2,3- dihydro-l,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]amino}-2-methylpropanoic acid (prepared in analogy to N-[2-(l,l-dioxido-2,3-dihydro-l,4-benzothiazepin-4(5H)-yl)-6- methylquinolin-4-yl]-beta-alanine in Example 14-2). MS obsd. (ESI+) [(M+H)+] 439, 1H NMR (400 MHz, DMSO- 6) δ ppm 8.17 (s, 1 H), 7.99 - 7.82 (m, 2 H), 7.72 - 7.57 (m, 2 H), 7.54 - 7.43 (m, 1 H), 7.38 (brs, 1 H), 7.32 (d, J = 8.34 Hz, 1 H), 7.23 (dd, J = 8.59,1.52 Hz, 1 H), 6.94 (s, 1 H), 6.03 (s, 1 H), 5.08 (brs, 2 H), 4.52 (brs, 3 H), 4.30 (brs, 1 H), 3.70 - 3.55 (m, 2 H), 3.50 (dt, J= 13.26, 6.51 Hz, 2 H), 3.25 - 3.15 (m, 2 H), 2.67 (q, J= 6.91 Hz, 1 H), 2.41 - 2.26 (m, 3 H), 1.13 (d, J = 7.07 Hz, 3 H).
Example 36-4 \r2~-[2-(l,l-dioxido-2,3-dihydro-l,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]-L- alaninamide
Figure imgf000312_0002
The title compound was prepared in analogy to Example 36-1 by using N-[2-(l,l-dioxido-2,3- dihydro-l,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]-Z-alanine (prepared in analogy to N-[2-(l , 1 -dioxido-2,3-dihydro- 1 ,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]-beta- alanine in Example 14-2). MS obsd. (ESI+) [(M+H)+] 425, 1H NMR (400 MHz, DMSO- 6) δ ppm 7.91 - 7.81 (m, 3 H), 7.68 (s, 1 H), 7.54 (brs, 1 H), 7.48 (d, J= 7.33 Hz, 1 H), 7.33 (d, J = 8.34 Hz, 1 H), 7.26 (d, J = 8.08 Hz, 1 H), 7.18 (brs, 1 H), 6.61 (d, J= 6.32 Hz, 1 H), 5.89 (s, 1 H), 4.99 (brs, 2 H), 4.08 (brs, 2 H), 3.59 (brs, 3 H), 2.35 (brs, 3 H), 1.49 (d, J= 6.82 Hz, 3 H).
Example 36-5 N~2~- [2-(l , l-Dioxido-2,3-dihydro- 1 ,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4- yl]glycinamide
Figure imgf000313_0001
The title compound was prepared in analogy to Example 36-1 by using N~2~-[2-(l , l-Dioxido- 2,3-dihydro- 1 ,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl] glycine (prepared in analogy to N-[2-(l , 1 -dioxido-2,3-dihydro- 1 ,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]-beta- alanine in Example 14-2). MS obsd. (ESI+) [(M+H)+] 41 1, 1H NMR (400 MHz, DMSO- 6) δ ppm 7.87 (d, J = 7.83 Hz, 1 H), 7.82 (d, J= 7.33 Hz, 1 H), 7.74 - 7.64 (m, 2 H), 7.52 - 7.41 (m, 2 H), 7.36 - 7.30 (m, 1 H), 7.30 - 7.19 (m, 2 H), 7.10 (t, J = 5.56 Hz, 1 H), 5.87 (s, 1 H), 5.00 (brs, 2 H), 3.86 (d, J = 5.81 Hz, 2 H), 3.59 (brs, 2 H), 3.32 (s, 2 H), 2.41 - 2.32 (s, 3 H).
Example 36-6 V~2~- [2-(l , l-Dioxido-2,3-dihydro- 1 ,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl] -N- methylglycinamide
Figure imgf000313_0002
The title compound was prepared in analogy to Example 36-1 by using AT2~-[2-(l , l-dioxido-2,3- dihydro-l ,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]glycine (prepared in analogy to N- [2-(l , 1 -dioxido-2,3-dihydro- 1 ,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]-beta-alanine in Example 14-2) and a solution of methylamine in ethanol. MS obsd. (ESI ) [(M+H)+] 425, 1H NMR (400 MHz, DMSO- 6) δ ppm 7.90 - 7.82 (m, 2 H), 7.77 (d, J = 7.58 Hz, 1 H), 7.70 (s, 1 H), 7.61 (td, J = 7.45, 1.52 Hz, 1 H), 7.51 - 7.46 (m, 1 H), 7.34 (d, J= 8.34 Hz, 1 H), 7.26 (dd, J = 8.46, 1.64 Hz, 1 H), 7.15 (t, J = 5.94 Hz, 1 H), 5.86 (s, 1 H), 5.00 (brs, 2 H), 3.90 (d, J = 5.81 Hz, 2 H), 3.59 (brs, 2 H), 3.32 (s, 2 H), 2.62 (d, J = 4.55 Hz, 3 H), 2.37 (s, 3 H).
Example 37-1 (2S)-2-Amino-3-{[2-(l,l-dioxido-2,3-dihydro-l,4-benzothiazepin-4(5H)-yl)-6- methylquinolin-4-yl]amino}propan-l-ol
Figure imgf000314_0001
teri-Butyl (2S)-4-({[2-(l,l-dioxido-2,3-dihydro-l,4-benzothiazepin-4(5H)-yl)-6- methylquinolin-4-yl] amino} methyl)-2,2-dimethyl- 1 ,3-oxazolidine-3-carboxylate
Figure imgf000314_0002
A mixture of 4-(4-chloro-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-l,4-benzothiazepine 1,1- dioxide (332 mg, 0.890 mmol), tert-butyl (25)-4-aminomethyl-2,2-dimethyl-l,3-oxazolidine-3- carboxylate (205 mg, 0.890 mmol), l,l'-bis(diphenylphosphino)ferrocene- palladium(II)dichloride (73 mg, 0.089 mmol), l, -bis(diphenylphosphino)ferrocene (49 mg, 0.089 mmol), sodium tert-butoxide (171.1 mg, 1.780 mmol) and 1,4-dioxane (4 mL) was heated at 120 °C for 1.5 hours under microwave irradiation. The reaction mixture was concentrated in vacuo. The residue was purified by flash column chromatography to afford 251 mg of the desired product. (25)-2-Amino-3-{[2-(l,l-dioxido-2,3-dihydro-l,4-benzothiazepin-4(5H)-yl)-6- methylquinolin-4-yl]amino}propan-l-ol
Figure imgf000315_0001
A mixture of tert-butyl 4-({[2-(l,l-dioxido-2,3-dihydro-l,4-benzothiazepin-4(5H)-yl)-6- methylquinolin-4-yl]amino}methyl)-2,2-dimethyl-l,3-oxazolidine-3-carboxylate (251 mg) and a solution of hydrochloride in ethyl acetate (13 mL, 4 N) was stirred at room temperature overnight. The reaction mixture was concentrated in vacuo. The residue was dissolved in water, and basified with a saturated aqueous solution of sodium bicarbonate to about pH 9, and extracted with ethyl acetate ( 20 mL x 3). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, concentrated in vacuo. The residue was purified by preparative HPLC to give 74.6 mg of the desired product as a white solid. MS obsd. (ESI+)
[(M+H)+] 427, 1H NMR (400 MHz, CD3OD) δ ppm 8.04 (dd, J= 1.2, 8.0 Hz, 1 H), 7.98 (d, J = 7.2 Hz, 1 H), 7.86 (s, 1 H), 7.72 - 7.66 (m, 2 H), 7.55 - 7.46 (m, 2 H), 6.20 (s, 1 H), 5.31 (s, 2 H), 4.57 (s, 2 H), 3.93 - 3.62 (m, 7 H), 2.47 (s, 3 H).
Example 37-2
(2R)-2-Amino-3-{[2-(l,l-dioxido-2,3-dihydro-l,4-benzothiazepin-4(5H)-yl)-6- methylquinolin-4-yl] amino}propan-l-ol
Figure imgf000315_0002
The title compound was prepared in analogy to Example 37-1 in Scheme 14 by using 4-(4- chloro-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro- 1 ,4-benzothiazepine 1 , 1 -dioxide, tert-butyl (2i?)-4-aminomethyl-2,2-dimethyl-l,3-oxazolidine-3-carboxylate. MS obsd. (ESI+) [(M+H)+] 427, 1H NMR (400 MHz, CD3OD) δ ppm 8.02 (d, J= 6.8 Hz, 1 H), 7.96 (d, J= 8.4 Hz, 1 H), 7.80 (s, 1 H), 7.68 (dd, J= 6.0, 7.6 Hz, 1 H), 7.58 (d, J= 8.4 Hz, 1 H), 7.50 (m, 1 H), 7.41 (d, J 8.4 Hz. 1 HI 6.19 is. 1 H), 5.27 (s, 2 H), 4.57 (s, 2 H), 3.92 - 3.60 (m, 7 H), 2.45 (s, 3 H). Example 38-1
TV- [(2- Amino-4,5-dihydro- 1 ,3-oxazol-5-yl)methyl] -2-(l , l-dioxido-2,3-dihydro- 1 ,4- benzothiazepin-4(5H)-yl)-6-methylquinolin-4-amine
Figure imgf000316_0001
A mixture of l-amino-3- {[2-(l , l-dioxido-2,3-dihydro-l ,4-benzothiazepin-4(5H)-yl)-6- methylquinolin-4-yl]amino}propan-2-ol (80 mg, 0.18 mmol, prepared in analogy to Example 9- 7) and potassium acetate (89 mg, 0.91 mmol ) in a mixture solution of methanol and water (7 ml, V/V = 6/1) was added cyanogen bromide (89 mg, 0.84 mmol ) at 0 °C. After being stirred at room temperature for 3 hours, the mixture was stirred further with concentrated hydrochloric acid (3 mL) for 1 hour, and then concentrated in vacuo. The residue was dissolved in a saturated aqueous solution of sodium bicarbonate (10 mL) and extracted with dichloromethane (15 mL x 3). The combined organic layers were dried over sodium sulfate and concentrated in vacuo. The residue was purified by flash column (10% methanol in dichloromethane) to afford 32 mg of the desired product as a white solid. MS obsd. (ESI+) [(M+H)+] 452, 1H NMR (400 MHz, DMSO- d6) δ ppm 7.92 - 7.87 (m, J = 4.6 Hz, 2 H), 7.72 (s, 1 H), 7.65 - 7.62 (t, J = 3.7 Hz, 1 H), 7.49 - 7.45 (t, J= 3.9 Hz, 1 H), 7.32 (d, J = 2.1 Hz, 1 H), 7.23 (d, J= 2.1 Hz, 1 H), 6.85 (t, J = 2.6 Hz, 1 H), 6.46 (brs, 2 H), 6.10 (s, 1 H), 5.10 (s, 2 H), 4.82 - 4.77 (m, J = 4.8 Hz, 1 H), 4.49 (brs, 2 H), 3.75 (m, 1 H), 3.63(s, 2 H), 3.52 (m, 3 H), 2.35 (s, 3 H).
Example 38-2 N- [(2- Amino-5-methyl-4,5-dihydro- 1 ,3-oxazol-5-yl)methyl] -2-(l , l-dioxido-2,3-dihydro- 1 ,4- benzothiazepin-4(5H)-yl)-6-methylquinolin-4-amine
Figure imgf000316_0002
To a mixture of l-amino-3-{[2-(l,l-dioxido-2,3-dihydro-l,4-benzothiazepin-4(5H)-yl)-6- methylquinolin-4-yl]amino}-2-methylpropan-2-ol (200 mg, 0.45 mmol, prepared in analogy to Example 11-4) and potassium acetate (240 mg, 2.4 mmol) in methanol (8 mL) and water (2 mL) which was cooled to 0 °C, a cooled solution of cyanogen bromide (52.3 mg, 0.5 mmol) in methanol (2 mL) was added. After being stirred at room temperature for 4 hours, the reaction mixture was concentrated in vacuo. The residue was diluted with ethyl acetate (50 mL), washed with water (50 mL), dried over sodium sulfate, and concentrated in vacuo. The residue was purified by column chromatography on silica gel to give 80 mg of the product as a white powder.
MS obsd. (ESI+) [(M+H)+] 466, 1H NMR (400 MHz, CD3OD) δ ppm 7.95 (d, J= 7.6 Hz, 1 H), 7.83 (d, J= 7.2 Hz, 1 H), 7.60 (m, 2 H), 7.46 - 7.39 (m, 2 H), 7.29 (dd, J= 1.6, 8.8 Hz, 1 H), 6.19 (s, 1 H), 5.18 - 5.09 (m, 2 H), 4.51 (brs, 2 H), 3.82 (d, J= 11.2 Hz, 1 H), 3.65 (s, 2 H), 2.57 (m, 3 H), 2.41 (s, 3 H), 1.62 (s, 3 H).
Example 38-3 V-{[(4R)-2-Amino-4,5-dihydro-l,3-oxazol-4-yl]methyl}-2-(l,l-dioxido-2,3-dihydro-l,4- benzothiazepin-4(5H)-yl)-6-methylquinolin-4-amine
Figure imgf000317_0001
The title compound was prepared in analogy to Example 38-1 in Scheme 15 by using (2i?)-2- amino-3- {[2-(l , l-dioxido-2,3-dihydro-l ,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4- yl]amino}propan-l-ol (prepared in analogy to Example 37-2). MS obsd. (ESI ) [(M+H)+] 452, 1H NMR (400 MHz, CD3OD) δ ppm 7.98 (d, J= 7.2 Hz, 1 H), 7.87 (d, J= 7.2 Hz, 1 H), 7.64 - 7.58 (m, 2 H), 7.47 - 7.41 (m, 2 H), 7.28 (dd, J= 2.0, 8.8 Hz, 1 H), 6.09 (s, 1 H), 5.16 (s, 2 H), 4.58 (brs, 2 H), 4.40 (t, J= 8.0 Hz, 1 H), 4.29 (td, J= 5.6, 12.8 Hz, 1 H), 4.20 (dd, J= 6.0, 8.0 Hz, 1 H), 3.58 (t, J= 4.8 Hz, 2 H), 3.45 - 3.35 (m, 2 H), 2.42 (s, 3 H).
Example 38-4 V-{[(4S)-2-Amino-4,5-dihydro-l,3-oxazol-4-yl]methyl}-2-(l,l-dioxido-2,3-dihydro-l,4- benzothiazepin-4(5H)-yl)-6-methylquinolin-4-amine
Figure imgf000318_0001
The title compound was prepared in analogy to Example 38-1 in Scheme 15 by using (2S)-2- amino-3- {[2-(l , l-dioxido-2,3-dihydro-l ,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4- yl]amino}propan-l-ol (prepared in analogy to Example 37-1). MS obsd. (ESI ) [(M+H)+] 452, 1H NMR (400 MHz, CD3OD) δ ppm 7.98 (d, J= 7.2 Hz, 1 H), 7.87 (d, J= 7.2 Hz, 1 H), 7.64 - 7.58 (m, 2 H), 7.47 - 7.41 (m, 2 H), 7.28 (dd, J= 2.0, 8.8 Hz, 1 H), 6.09 (s, 1 H), 5.16 (s, 2 H), 4.58 (brs, 2 H), 4.40 (t, J= 8.0 Hz, 1 H), 4.29 (td, J= 5.6, 12.8 Hz, 1 H), 4.20 (dd, J= 6.0, 8.0 Hz, 1 H), 3.58 (t, J= 4.8 Hz, 2 H), 3.45 - 3.35 (m, 2 H), 2.42 (s, 3 H).
Example 38-5 c/s-5-[2-(l,l-Dioxido-2,3-dihydro-l,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]- 4,5,6,6a-tetrahydro-3aH-pyrrolo[3,4-d] [l,3]oxazol-2-amine
Figure imgf000318_0002
To a mixture of cz5-4-amino-l-[2-(l,l-dioxido-2,3-dihydro-l,4-benzothiazepin-4(5H)-yl)-6- methylquinolin-4-yl]pyrrolidin-3-ol (90 mg 0.20 mmol, prepared in analogy to Example 19-3 in Scheme 7 by using 4-(4-chloro-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-l,4-benzothiazepine 1,1 -dioxide and tert-butyl [cz's-4-hydroxypyrrolidin-3-yl] carbamate) and sodium acetate (82 mg, 1.0 mmol) in methanol (10 mL) at 0 °C was added cyanogen bromide (105 mg, 1 mmol). The mixture was stirred overnight gradually from 0 °C to room temperature, and then concentrated in vacuo. The residue was purified by preparative HPLC to afford the pure product as a solid. MS obsd. (ESI+) [(M+H)+] 464, 1H NMR (400 MHz, CD3OD) δ ppm 8.09 (d, J = 7.33 Hz, 1 H), 7.98 (d, J= 7.58 Hz, 1 H), 7.89 (brs, 1 H), 7.79 - 7.70 (m, 2 H), 7.66 - 7.56 (m, 2 H), 6.50 (s, 1 H), 5.89 - 5.84 (m, 1 H), 5.41 (brs, 2 H), 4.97-5.02 (m, 1 H), 4.63 (brs, 2 H), 4.31 (brs, 1 H), 4.12 (brs, 1 H), 3.77 (brs, 2 H), 3.62 - 3.42 (b, 2 H), 2.54 - 2.48 (m, 3 H).
Example 39
2-(l , l-Dioxido-2,3-dihydro- 1 ,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-amine
Figure imgf000319_0001
2-{[(l£)-l-(l,l-Dioxido-2,3-dihydro-l,4-benzothiazepin-4(5H)-yl)ethylidene]amino}-5- methylbenzonitrile
Figure imgf000319_0002
To a stirred solution of l-(l , l-dioxido-2,3-dihydro-l ,4-benzothiazepin-4(5H)-yl)ethanone (6.0 g, 25.0 mmol) in dry dichloromethane (100 mL) was added phosphorus oxychloride (2.5 mL, 27.3 mmol) at 10 °C. After being stirred for 20 minutes at room temperature, a solution of 2-amino-5- methylbenzonitrile (3.3 g, 25.0 mmol) in dry dichloromethane (40 mL) was added and the resulting suspension was heated under reflux for 24 hours. After being cooled to room
temperature, the reaction mixture was diluted with water (50 mL), basified with a saturated aqueous solution of sodium bicarbonate to about pH 8. The separated aqueous layer was extracted with dichloromethane (100 mL). The combined organic layers were washed with brine, dried over sodium sulfate and concentrated in vacuo. The residue was purified by column chromatography on silica gel (eluting with 16% ethyl acetate in petroleum ether) to give 1.5 g of the product as a white solid.
2-(l , l-Dioxido-2,3-dihydro- 1 ,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-amine
Figure imgf000320_0001
A mixture of 2- { [(IE)- 1 -( 1 , 1 -dioxido-2,3-dihydro- 1 ,4-benzothiazepin-4(5H)- yl)ethylidene]amino}-5-methylbenzonitrile (1.5 g, 4.24 mmol), zinc chloride (578 mg, 4.24 mmol) and N,N-dimethylacetamide (4 mL) was heated with stirring at 160 °C for 3 hours under argon. After the reaction mixture was cooled to about 40 °C, an aqueous solution of sodium hydroxide (2 N, 20 mL) was introduced. After being stirred for 10 minutes at room temperature, the reaction mixture was poured into water. The formed solid was collected by filtration, and dried in vacuo to give 1.5 g of the product as a brown powder. MS obsd. (ESI+) [(M+H)+] 354, 1H NMR (400 MHz, DMSO- 6) δ ppm 7.90 - 7.84 (m, 2 H), 7.66 - 7.62 (m, 2 H), 7.48 (t, J= 7.2 Hz, 1 H), 7.32 (d, J= 8.4 Hz, 1 H), 7.23 (dd, J= 1.6, 8.8 Hz, 1 H), 6.29 (s, 2 H), 6.23 (s, 1 H), 4.97 (s, 2 H), 4.36 (brs, 2 H), 3.60 (t, J= 4.8 Hz, 2 H), 2.34 (s, 3 H).
Example 40-1 V-[2-(l,l-Dioxido-2,3-dihydro-l,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4- yl]glycinamide
Figure imgf000320_0002
2-Chloro- V-[2-(l,l-dioxido-2,3-dihydro-l,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4- yljacetamide
Figure imgf000320_0003
To a solution of 2-(l,l-dioxido-2,3-dihydro-l,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4- amine (500 mg, 1.4 mmol) in chloroform (10 mL) was added l,8-diazabicyclo[5.4.0]undec-7- ene (0.41 mL, 2.8 mmol) followed by chloroacetyl chloride (0.17 mL, 2.1 mmol) at room temnerature. The resulting solution was heated with stirring at 70 °C for 2 hours under nitrogen. After being cooled to room temperature, the reaction was diluted with ethyl acetate (50 mL), washed with water (50 mL x 3), dried over sodium sulfate and concentrated in vacuo. The residue was purified by column chromatography on silica gel (eluting with 25% ethyl acetate in petroleum ether) to give 120 mg of the product as an off-white solid. 2-Azido-N-[2-(l,l-dioxido-2,3-dihydro-l,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4- yljacetamide
Figure imgf000321_0001
To a solution of 2-chloro-N-[2-(l , l-dioxido-2,3-dihydro-l ,4-benzothiazepin-4(5H)-yl)-6- methylquinolin-4-yl]acetamide (120 mg, 0.28 mmol) in acetonitrile (3 mL) was added sodium azide (72 mg, 1.1 mmol). The resulting mixture was stirred at room temperature for 6 hours. The reaction was diluted with ethyl acetate (20 mL), washed with water (10 mL), dried over sodium sulfate, and concentrated in vacuo. The residue was purified by column chromatography on silica gel (20% ethyl acetate in petroleum ether) to give 1 10 mg of the product as a white powder. V-[2-(l,l-Dioxido-2,3-dihydro-l,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4- ylj lycinamide
Figure imgf000321_0002
To a solution of 2-azido-N-[2-(l, l-dioxido-2,3-dihydro-l ,4-benzothiazepin-4(5H)-yl)-6- methylquinolin-4-yl]acetamide (1 10 mg, 0.25 mmol) in methanol was added 10% palladium on carbon (507 mg). After being stirred at room temperature overnight under a hydrogen
atmosphere, the resulting mixture was filtered. The filtrate was concentrated in vacuo. The residue was purified by preparative HPLC to afford 30 mg of the product as a white powder. MS obsd. (ESI+) [(M+H)+] 41 1, 1H NMR (400 MHz, CD3OD) δ ppm 8.51 (s, 1 H), 8.12 (s, 1 H), 8.07 (d, J= 7.6 Hz, 1 H), 8.00 (d, J = 7.6 Hz, 1 H), 7.87 (d, J = 8.8 Hz, 1 H), 7.67 - 7.12 (m, 2 H), 7.57 (t, J = 8.0 Hz, 1 H), 5.31 (s, 2 H), 4.66 (brs, 2 H), 4.25 (s, 2 H), 3.78 (s, 2 H), 2.52 (s, 3 r I \ Example 40-2 V-[2-(l,l-Dioxido-2,3-dihydro-l,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]-2- methylalaninamide
Figure imgf000322_0001
2-Bromo-7V- [2-(l , l-dioxido-2,3-dihydro- 1 ,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4- yl]-2-methylpropanamide
Figure imgf000322_0002
To a solution of 2-(l , l-dioxido-2,3-dihydro-l ,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4- amine (200 mg, 0.566 mmol) in chloroform (10 mL) was added triethylamine (0.124 mL), followed by 2-bromo-2-methylpropionyl chloride (286 mg, 1.30 mmol). The resulting mixture was heated at 1 10 °C for 2 hours under microwave irradiation. After being cooled to room temperature, the mixture was concentrated in vacuo. The residue was diluted with ethyl acetate (35 mL), washed with brine and dried over sodium sulfate, and concentrated in vacuo. The residue was purified by flash chromatography to afford 180 mg of the title compound as a light solid (yield was 63%).
2-Azido- V-[2-(l,l-dioxido-2,3-dihydro-l,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4- yl]-2-methylpropanamide
Figure imgf000322_0003
To a solution of 2-bromo-N-[2-(l,l-dioxido-2,3-dihydro-l,4-benzothiazepin-4(5H)-yl)-6- methylquinolin-4-yl]-2-methylpropanamide (160 mg, 0.319 mmol) in actonitrile (15 mL) was added sodium azide (62 mg, 0.958 mmol). After being refluxed overnight, the resulting mixture was concentrated in vacuo. The residue was diluted with ethyl acetate (40 mL), washed with brine, dried over sodium sulfate, and concentrated in vacuo to afford 160 mg of the crude product. V-[2-(l,l-Dioxido-2,3-dihydro-l,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]-2- methylalaninamide
Figure imgf000323_0001
To a solution 2-azido-N-[2-(l,l-dioxido-2,3-dihydro-l,4-benzothiazepin-4(5H)-yl)-6- methylquinolin-4-yl]-2-methylpropanamide (160 mg, 0.345 mmol) in ethyl acetate (25 mL) was added 10% palladium on carbon (100 mg), the flask was degassed and refilled with hydrogen (repeated for three times). After being stirred at room temperature overnight under a hydrogen atmosphere, the resulting mixture was filtered. The filtrate was concentrated in vacuo. The residue was purified by flash chromatography to afford 110 mg of the title compound (yield was
73%). MS obsd. (ESI+) [(M+H)+] 439, 1H NMR (400 MHz, CDC13) δ ppm 11.05 (s, 1 H), 8.30 (s, 1 H), 8.02 (dd, J= 0.8, 7.6 Hz, 1 H), 7.89 (d, J= 7.2 Hz, 1 H), 7.59 (d, J= 8.8 Hz, 1 H), 7.53 (t, J= 7.6 Hz, 1 H), 7.37 (m, 3 H), 5.17 (s, 2 H), 4.6 (brs., 2 H), 3.56 (s, 2 H), 2.48 (s, 3 H), 1.56
(s, 6 H).
Example 40-3 V-[2-(l,l-Dioxido-2,3-dihydro-l,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4- yl]alaninamide
Figure imgf000323_0002
The title compound was prepared in analogy to Example 40-2 in Scheme 18 by using 2-(l,l- dioxido-2,3-dihydro- 1 ,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-amine, 2-bromopropionyl chloride and sodium azide. MS obsd. (ESI+) [(M+H)+] 425, 1H NMR (400 MHz, CD3OD) δ ppm 8.07 - 7.85 (m, 3 H), 7.64 - 7.51 (m, 2 H), 7.46 - 7.35 (m, 2 H), 5.22 - 5.08 (m, 2 H), 4.51 - 4.42 (m, 1 H), 3.65 - 3.53 (m, 2 H), 3.37 (s, 3 H), 2.51 - 2.40 (m, 3 H), 1.73 (d, J= 7.07 Hz, 1 H), 1.30 (d, J= 2.78 Hz, 2 H).
Example 40-4
2-Amino-N-[2-(l,l-dioxido-2,3-dihydro-l,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4- yl]butanamide
Figure imgf000324_0001
The title compound was prepared in analogy to Example 40-2 in Scheme 18 by using 2-(l,l- dioxido-2,3-dihydro- 1 ,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-amine, 2-bromobutyryl chloride and sodium azide. MS obsd. (ESI+) [(M+H)+] 439, 1H NMR (400 MHz, CD3OD) δ ppm 8.07 (m, 3 H), 7.53 (m, 2 H), 7.45 (m, 2 H), 5.33 (m, 2 H), 4.32 (m, 1 H), 3.59 (m, 2 H), 3.37 (s, 3 H), 2.44 (m, 2 H), 1.70 (d, J = 8.02 Hz, 1 H), 1.38 (d, J = 2.56 Hz, 2 H), 1.22 (m, 3 H).
Example 41
N- [2-(l , l-Dioxido-2,3-dihydro- 1 ,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl] -2- methoxy-2-methylpropanamide
Figure imgf000324_0002
To a solution of 2-bromo-N-[2-(l,l-dioxido-2,3-dihydro-l,4-benzothiazepin-4(5H)-yl)-6- methylquinolin-4-yl]-2-methylpropanamide (80 mg, 0.159 mmol, prepared in Example 40-2) in methanol (5 mL) was added ethylamine (1 mL), the resulting mixture was heated under reflux oled to room temperature, the resulting mixture was concentrated in vacuo. The residue was purified by preparative TLC (eluting with 33% ethyl acetate in hexanes) to afford 15 mg of the title compound as a light powder (yield was 21%). MS obsd. (ESI+)
[(M+H)+] 454, 1H NMR (400 MHz, CD3OD) δ ppm 7.94 -7.89 (m, 3 H), 7.58 (m, 2 H), 7.43 - 7.39 (m, 3 H), 5.17 (s, 2 H), 4.50 (brs, 2 H), 3.59 (m, 2 H), 3.50 (s, 3 H), 2.46 (s, 3 H), 1.56 (s, 6 H).
Example 42-1
TV" 1 - [2-(l , l-Dioxido-2,3-dihydro- 1 ,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl] - 4,4,4-trifluorobutane-l,3-diamine
Figure imgf000325_0001
V-[2-(l,l-Dioxido-2,3-dihydro-l,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]-3-(l,3- dioxo-l,3-dihydro-2H-isoindol-2-yl)-4,4,4-trifluorobutanamide
Figure imgf000325_0002
To a solution of 2-(l,l-dioxido-2,3-dihydro-l,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4- amine (200 mg, 0.565 mmol, prepared in analogy to the one in Example 2-1) in N,N- dimethylformamide (6 mL) was added a solution of 3-(l,3-dioxo-l,3-dihydro-2H-isoindol-2-yl)- 4,4,4-trifluorobutanoyl chloride (670 mg, 2.3 mmol) in dichloromethane (4 mL) followed by N,N-diisopropylethylamine (0.3 mL). The resulting mixture was stirred at room temperature for 1 hour and heated at 85 °C for additional 2 hours. After being cooled to room temperature, the resulting mixture was evaporated in vacuo. The residue was diluted with water and extracted with ethyl acetate (20 mL x 2). The combined organic layers were washed with brine, dried over sodium sulfate and concentrated in vacuo. The residue was purified by flash chromatography to afford 230 mg of the product as a solid (yield was 66%).
3-Amino-N-[2-(l,l-dioxido-2,3-dihydro-l,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4- yl] -4,4,4-trifluorobutanamide
Figure imgf000326_0001
To a solution ofN-[2-(l,l-dioxido-2,3-dihydro-l,4-benzothiazepin-4(5H)-yl)-6-methylquinolin- 4-yl]-3-(l,3-dioxo-l,3-dihydro-2H-isoindol-2-yl)-4,4,4-trifluorobutanamide (25 mg, 0.04 mmol) in ethanol (3 mL) was added a solution of methylamine (30% in ethanol, 0.3 mL). The resulting mixture was heated at 90 °C for 2 hours. After being cooled to room temperature, the mixture was concentrated in vacuo. The residue was purified by flash chromatography (eluting with 50%> ethyl acetate in hexanes) to afford 15 mg of the title compound as light solid (yield was 80%). \rl~-[2-(l,l-Dioxido-2,3-dihydro-l,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]- 4,4,4-trifluorobutane-l,3-diamine
Figure imgf000326_0002
To a solution of 3-amino-N-[2-(l,l-dioxido-2,3-dihydro-l,4-benzothiazepin-4(5H)-yl)-6- methylquinolin-4-yl]-4,4,4-trifluorobutanamide (120 mg, 0.245 mmol) was added a solution of borane-methyl sulfide complex in methyl sulfide (5 M, 1.0 mL). The resulting solution was heated at 85 °C for 2 hours. After being cooled to room temperature, the mixture was acidified by careful addition of an aqueous solution of hydrochloric acid (1 M) to about pH 4, and then stirred at room temperature overnight. The resulting mixture was concentrated in vacuo. The residue was neutralized with a 10%> aqueous solution of sodium hydroxide to pH >9, and then extracted with dichloromethane (20 mL x 3). The combined organic layers were washed with brine, dried over sodium sulfate, and concentrated in vacuo. The residue was purified by flash
I 60 mg of the title product as a solid (yield was 65%>). MS obsd. (ESI+) [(M+H)+] 479, 1H NMR (400 MHz, CDC13) δ ppm 8.04 (d, J= 7.6 Hz, 1 H), 7.65(d, J= 7.6 Hz, 1 H), 7.50 - 7.49 (m, 2 H), 7.38 (t, J= 7.2 Hz, 1 H), 7.30 (m, 1 H), 6.06 (s, 1 H), 5.93 (s, 1 H), 5.12 (s, 1 H), 3.63 (m, 3 H), 4.62 (brs, 2 H), 3.45 (m, 1 H), 3.33 (m, 1 H), 2.42 (s, 3 H), 2.22 (m, 1 H), 2.03 (s, 1 H), 1.82 (m, 1 H). Example 42-2 V-[2-(l,l-Dioxido-2,3-dihydro-l,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]-beta- alaninamide
Figure imgf000327_0001
The title compound was prepared in analogy to 3-amino-N-[2-(l,l-dioxido-2,3-dihydro-l,4- benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]-4,4,4-trifluorobutanamide in Example 42-1 in Scheme 19 by using 2-(l,l-dioxido-2,3-dihydro-l,4-benzothiazepin-4(5H)-yl)-6-methylquinolin- 4-amine and 3-(l,3-dioxo-l,3-dihydro-2H-isoindol-2-yl)propanoyl chloride. MS obsd. (ESI+) [(M+H)+] 425, 1H NMR (400 MHz, CDC13) δ ppm 8.00 (d, J= 7.83 Hz, 1 H), 8.29 (s, 1 H), 7.85 (d, J= 7.33 Hz, 1 H), 7.61 - 7.47 (m, 4 H), 7.34 (d, J= 12.13 Hz, 2 H), 5.12 (s, 2 H), 3.55 (brs, 2 H), 3.23 (d, J= 5.56 Hz, 2 H), 2.62 (brs, 2 H), 2.44 (brs, 3 H), 1.66 - 2.10 (m, 2 H).
Example 43
2-(l,l-Dioxido-2,3-dihydro-l,4-benzothiazepin-4(5H)-yl)- V-{[3-(ethylamino)oxetan-3- yl]methyl}-6-methylquinolin-4-amine
Figure imgf000327_0002
To a stirred solution of N-[(3-aminooxetan-3-yl)methyl]-2-(l,l-dioxido-2,3-dihydro-l,4- benzothiazepin-4(5H)-yl)-6-methylquinolin-4-amine (200 mg, 0.46 mmol, prepared in analogy to Examole 2-21 acetaldehyde (25.6 μί, 0.46 mmol) and acetic acid (270 μί) in methanol (8 mL) was added dropwize a solution of sodium cyanoborohydride (34 mg, 0.54 mmol) in tetrahydrofuran (0.5 mL). After being stirred for 12 hours at room temperature, the reaction mixture was diluted with ethyl acetate, washed with water and a saturated aqueous solution of sodium bicarbonate, dried over sodium sulfate, and concentrated in vacuo. The residue was purified by preparative HPLC to afford 42 mg of the desired product as a white solid (yield was 20%). MS obsd. (ESI+) [(M+H)+] 467, 1H NMR(400 MHz, DMSO- 6) δ ppm 7.95 (d, J= 1.9 Hz, 1 H), 7.89 - 7.87 (t, J= 2.2 Hz, 1 H), 7.64 - 7.58 (m, J= 6.0 Hz, 2 H),7.49 - 7.45 (m, J = 4.0 Hz, 1 H), 7.35 (d, J= 2.1 Hz, 1 H), 7.27 - 7.24 (m, J = 2.5 Hz, 1 H), 6.17 (s, 1 H), 5.11 (s, 2 H), 4.52 (d, 2 H), 4.37 (d, 4 H), 3.62 - 3.45 (t, J= 2.4 Hz, 2 H ), 3.58 (d, 2 H ), 2.53 (m, 2 H), 2.37 (s, 3 H), 1.07 -1.03 (t, J= 3.6 Hz, 3 H ).
Example 44-1
2-(l , l-Dioxido-2,3-dihydro- 1 ,4-benzothiazepin-4(5H)-yl)-6-methykV- [ l-(oxetan-3- yl)pyrrolidin-3-yl]quinolin-4-amine
Figure imgf000328_0001
To a solution of [2-(l,l-dioxido-2,3-dihydro-l,4-benzothiazepin-4(5H)-yl)-6-methyl-N-
(pyrrolidin-3-yl)quinolin-4-amine (21 mg, 0.05 mmol, prepared in analogy to Example 21-4) and oxetan-3-one (7.2 mg, 0.10 mmol) in tetrahydrofuran (2 mL) was added acetic acid (8.6 μί, 0.15 mmol). After the mixture being stirred at 55 °C for 1 hour, sodium triacetoxyborohydride (21 mg, 0.10 mmol) was added to the mixture. After being stirred for 2 hours at 65 °C, the reaction mixture was concentrated in vacuo. The residue was portioned between ethyl acetate and a saturated aqueous solution of sodium carbonate. The separated organic layer was washed with water, dried over sodium sulfate, and concentrated in vacuo. The residue was purified by preparative HPLC to afford 10 mg of the product as a white solid. MS obsd. (ESI+) [(M+H)+] 479, 1H NMR (400 MHz, CD3OD) δ ppm 8.30 (d, J= 1.9 Hz, 1 H), 7.84 (d, J= 1.8Hz, 1 H), 7.78 (s, 1 H), 7.68 - 7.64 (t, J= 3.7 Hz, 1 H), 7.53 - 7.49 (t, J= 3.7 Hz, 2 H), 7.39 (d, J= 1.7 Hz, 1 H), 5.98 (s, 1 H), 5.20 (s, 2 H), 4.83 - 4.78 (m, J= 4.7 Hz, 2 H), 4.69 - 4.60 (m, J= 8.4 Hz, 2 H), 4.55 (brs, 2 H), 4.37 (s, 1 H), 3.80 - 3.74 (m, J= 4.1 Hz, 1 H), 3.65 - 3.61 (m, J= 4.2 Hz, 2 H), 2.96 - 2.89 (m, J = 6.6 Hz, 2 H), 2.75 - 2.72 (m, J = 3.3 Hz, 1 H), 2.63 - 2.47 (m, J = 15.9 Hz, 2 H), 2.45(s, 3 H), 1.95 (m, 1 H).
Example 44-2
N1-[2-(l,l-Dioxido-2,3-dihydro-l,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]- V- ethyl- V-(oxetan-3-yl)ethane-l,2-diamine
Figure imgf000329_0001
The title compound was prepared in analogy to Example 44-1 in Scheme 20 by using N-[2-(l , l- dioxido-2,3-dihydro- 1 ,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]-N'-ethylethane- 1 ,2- diamine (prepared in analogy to Example 3-37) and oxetan-3-one. MS obsd. (ESI ) [(M+H)+] 481 , 1H NMR (400 MHz, CD3OD) δ ppm 8.02 (d, J = 7.6 Hz, 1 H), 7.87 (d, J= 7.2 Hz, 1 H), 7.66 (t, 2 H), 7.50 (t, 2 H), 7.36 (d, J = 7.6 Hz, 1 H), 6.04 (s, 1 H), 5.20 (s, 2 H), 4.68 - 4.50 (m, 6 H), 4.07 - 4.00 (m, 1 H), 3.65 (s, 2 H), 3.45 (t, J = 12.4 Hz, 2 H), 2.84 (t, J = 12.8 Hz, 2 H), 2.73 - 2.67 (m, 2 H), 2.45 (s, 3 H), 1.07 (t, 3 H).
Example 45-1 V-[2-(l,l-Dioxido-2,3-dihydro-l,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]- V- (oxetan-3-yl)propane- 1 ,3-diamine
Figure imgf000329_0002
To a stirred ofN-[2-(l, l-dioxido-2,3-dihydro-l,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4- yl]propane-l ,3-diamine (84 mg, 0.2 mmol, prepared in analogy to Example 9-3), oxetan-3-one (15 mg, 0.21 mmol ) and ethyldiisopropylamine (43 μί, 0.25 mmol ) in dichloromethane (10 mL) was added molecular sieves (4A, 84 mg) followed by sodium triacetoxyborohydride (63.6 mg, 0.3 mmol). After being stirred at room temperature overnight, another batch of sodium triacetoxyborohydride (63.6 mg, 0.3 mmol) was added and the mixture was heated under reflux for 2 hours. The reaction mixture was cooled, washed with brine, dried over sodium sulfate and concentrated in vacuo. The residue was purified by preparative HPLC to afford 26 mg of N-[2- (1 , 1 -dioxido-2,3-dihydro- 1 ,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]-N'-(oxetan-3- yl)propane-l ,3-diamine as a white solid. MS obsd. (ESI+) [(M+H)+] 467, 1H NMR (400 MHz, CD3OD) δ ppm 8.05 (d, J= 7.6 Hz, 1 H), 7.87 (d, J = 7.6 Hz, 1 H), 7.34 (s, 1 H), 7.68 (t, J = 14.8 Hz, 1 H), 7.58 - 7.51 (m, 2 H), 7.45 (d, 1 H), 5.99 (s, 1 H), 5.24 (s, 2 H), 4.85 (t, J = 3.3 Hz, 2 H), 4.85 (t, J= 13.6 Hz, 2 H), 4.55 (m, 4 H), 4.06 - 4.00 (m, 1 H), 3.67 (s, 2 H), 3.50 (t, J = 13.2 Hz, 2 H), 2.74 (t, J = 13.6 Hz, 2 H), 2.45 (s, 3 H), 1.98 - 1.91 (m, 2 H).
Example 45-2 l-[2-(l,l-Dioxido-2,3-dihydro-l,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]- V- (oxetan-3-yl)pyrrolidin-3-amine
Figure imgf000330_0001
The title compound was prepared in analogy to Example 45-1 in Scheme 20 by using l-[2-(l , 1- dioxido-2,3-dihydro-l ,4-benzothiazepin-4(5H)-yl)-6-m
and oxetan-3-one (prepared in analogy to Example 25) and oxetan-3-one. MS obsd. (ESI )
[(M+H)+] 479, 1H NMR (400 MHz, CD3OD) δ ppm 7.99 - 7.97 (m, J = 2.2 Hz, 1 H), 7.83 - 7.80 (t, J= 2.9 Hz, 2 H), 7.64 - 7.60 (m, J = 4.1 Hz, 1 H), 7.47 - 7.43 (m, J = 4.5 Hz, 2 H), 7.29 - 7.26 (m, J = 2.5 Hz, 1 H), 6.12 (s, 1 H), 5.15 (s, 2 H), 4.85 (m, 2 H), 4.56 (m, 4 H), 4.14 (m, 1 H ), 3.73 (m, 2 H), 3.60 (m, 3 H), 3.42 (m, 2 H), 2.40 (s, 3 H), 2.21 (m, 1 H), 1.87 (m, 1 H). Example 45-3 V-[2-(l,l-Dioxido-2,3-dihydro-l,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]- V- (oxetan-3-yl)ethane- 1 ,2-diamine
Figure imgf000330_0002
The title compound was prepared in analogy to Example 45-1 in Scheme 20 by using N-[2-(l , l- dioxido-2,3-dihydro-l ,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]-A '-(oxetan- yl)ethane-l ,2-diamine (prepared in analogy to Example 9-16) and oxetan-3-one. MS obsd. (ESI ) [(M+H)+] 453, 1H NMR (400 MHz, CD3OD) δ ppm 8.09 (t, J = 2.0 Hz, 1 H), 7.87 (d, J = 1.7 Hz, 2 H), 7.74 - 7.70 (m, J = 4.0 Hz, 1 H), 7.64 (d, J = 2.1 Hz, 1 H), 7.61 - 7.54 (m, J = 6.8 Hz, 2 H), 6.03 (s, 1 H), 5.29 (s, 2 H), 4.85 (t, J = 3.3 Hz, 2 H), 4.51 (t, J = 3.1 Hz, 4 H), 4.06 (brs, 1 H), 3.73 (s, 2 H), 3.57 (t, J = 3.0 Hz, 2 H), 2.93 (brs, 2 H), 2.48 (s, 3 H).
Example 46
N-[2-(l,l-Dioxido-2,3-dihydro-l,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]- V'- (pyridin-2-yl)ethane- 1 ,2-diamine
Figure imgf000331_0001
A mixture of N-[2-(l , l-dioxido-2,3-dihydro-l ,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4- yl] ethane- 1 ,2-diamine (150 mg, 0.38 mol, prepared in analogy to Example 9-16), 2-bromo- pyridine (60 mg, 0.38 mol), tri(dibenzylideneacetone)dipalladium(0) (17.4 mg, 0.019 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthe (22 mg, 0.038 mmol), cesium carbonate (247.6 mg, 0.76 mmol) and N-methylpyrolidinone (3 mL) was heated with stirring at 150 °C for 6 hours under nitrogen. The mixture was diluted with ethyl acetate, washed with water, dried over sodium sulfate, filtered, concentrated in vacuo. The residue was purified by preparative HPLC to give 10 mg of produce as an off-white solid. MS obsd. (ESI+) [(M+H)+] 474, 1H NMR (400 MHz, DMSO-<i(5) δ ppm 8.1 (d, J = 6.4 Hz, 1 H), 7.96 (dd, J= 1.2, 8.0 Hz, 1 H), 7.81 (d, J= 6.8 Hz, 1 H), 7.54 - 7.39 (m, 5 H), 7.27 (dd, J = 2.0, 8.8 Hz, 1 H), 6.63 - 6.56 (m, 2 H), 6.07 (s, 1 H), 5.10 (s, 2 H), 4.52 (brs, 2 H), 3.69 (t, J= 6.4 Hz, 2 H), 3.55 (m, 4 H), 2.40 (s, 3 H).
Example 47-1
(4R)- 1- [2-(l , l-Dioxido-2,3-dihydro- 1 ,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl] -4- hydroxypyrrolidin-2-one
Figure imgf000332_0001
A mixture of 4-(4-bromo-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-l,4-benzothiazepine 1,1- dioxide (400 mg, 0.96 mol, prepared in analogy to 4-(4-chloro-6-(trifluoromethoxy)quinolin-2- yl)-2,3,4,5-tetrahydro-l,4-benzothiazepine 1,1-dioxide in Example 17-1), (4R)-4- hydro xypyrrolidin-2-one (116.3 mg, 1.15 mmol), copper(I) iodide (90 mg, 0.47 mmol), potassium carbonate (265 mg, 1.92 mmol), trans-N,N'-dimethylcyclohexane-l,2-diamine (0.1 mL, 0.63 mmol) and diethylene glycol dimethyl ether (10 mL) was heated with stirring in a 10 mL of microwave process vial for 2 hours at 140 °C. The mixture was diluted with
dichloromethane, washed with water. The aqueous was back extracted with dichloromethane. The combined organic layer was dried over sodium sulfate, filtered, concentrated in vacuo. The residue was purified by column chromatography on silica gel to give 160 mg of produce as a gray solid. MS obsd. (ESI+) [(M+H)+] 438, 1H NMR (400 MHz, DMSO- 6) δ ppm 7.96 (d, J = 7.2 Hz, 1 H), 7.88 (dd, J= 1.2, 8.0 Hz, 1 H), 7.64 (td, J= 1.2, 7.6 Hz, 1 H), 7.56 (d, J= 8.8 Hz, 1 H), 7.48 (dd, J= 6.8, 7.6 Hz, 1 H), 7.40 (m, 2 H), 7.24 (s, 1 H), 5.51 (d, J= 3.6 Hz, 1 H), 5.13 (s, 2 H), 5.55 (d, J= 2.4 Hz, 1 H), 4.41 (brs, 2 H), 4.08 (dd, J= 4.8, 10.0 Hz, 1 H), 3.66 (s, 2 H), 3.52 (d, J= 9.6 Hz, 1 H), 2.87 (dd, J= 6.4, 16.8 Hz, 1 H), 2.36 (dd, J= 2.0, 16.8 Hz, 1 H), 2.36 (s, 3 H).
Example 47-2 V-[2-(l,l-Dioxido-2,3-dihydro-l,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]-5- oxopyrrolidine-3-carboxamide
Figure imgf000332_0002
A mixture of 4-(4-bromo-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-l,4-benzothiazepine 1,1- dioxide (500 mg, 1.19 mol, prepared in analogy to 4-(4-chloro-6-(trifluoromethoxy)quinolin-2- yl)-2,3,4,5-tetrahydro-l,4-benzothiazepine 1,1-dioxide in Example 17-1), 5-oxopyrrolidine-3- carboxamide (307 mg, 2.39 mmol), copper(I) iodide (23 mg, 0.12 mmol), potassium carbonate (497 mg, 3.60 mmol), tra/75-N,N'-dimethylcyclohexane-l,2-diamine (0.038 mL, 0.24 mmol) and diethylene glycol dimethyl ether (10 mL) was heated with stirring in a 10 mL microwave process vial for 3 hours at 140 °C under microwave irridiation. The mixture was diluted with
dichloromethane, washed with water. The aqueous layer was back extracted with
dichloromethane. The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by column chromatography on silica gel to give 40 mg of N-[2-(l,l-dioxido-2,3-dihydro-l,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]-5- oxopyrrolidine-3-carboxamide as light brown solid. MS obsd. (ESI+) [(M+H)+] 451, 1H NMR (400 MHz, DMSO- 6) δ ppm 9.98 (s, 1 H), 7.88 (m, 3 H), 7.81 (s, 1 H), 7.70 (s, 1 H), 7.64 (td, J = 1.2, 7.6 Hz, 1 H), 7.47 (d, J= 8.8 Hz, 1 H), 7.46 (dd, J= 0.8, 7.6 Hz, 1 H), 7.38 (dd, J= 1.6, 8.4 Hz, 1 H), 5.08 (s, 2 H), 4.42 (brs, 2 H), 3.73 - 3.57 (m, 4 H), 3.43 (dd, J= 6.0, 9.6 Hz, 1 H), 3.32 (s, 1 H), 2.48 (m, 1 H), 2.42 (s, 3 H). Example 47-3
2-(l,l-Dioxido-2,3-dihydro-l,4-benzothiazepin-4(5H)-yl)-6-methyl- V-(lH-pyrazol-3- yl)quinolin-4-amine
Figure imgf000333_0001
The title compound was prepared in analogy to Example 47-1 in Scheme 5 by using 4-(4-bromo- 6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-l,4-benzothiazepine 1,1-dioxide (prepared in analogy to 4-(4-chloro-6-(trifluoromethoxy)quinolin-2-yl)-2,3,4,5-tetrahydro- 1 ,4-benzothiazepine 1,1- dioxide in Example 17-1) and lH-pyrazol-3-amine. MS obsd. (ESI+) [(M+H)+] 420, 1H NMR (400 MHz, CD3OD) δ ppm 8.22 (s, 1 H), 8.15 - 8.14 (d, J= 2.8 Hz, 1 H), 8.04 - 8.02 (d, J= 8 Hz, 1 H), 7.90 - 7.88 (d, J= 7.2 Hz, 1 H), 7.85 -7.83 (d, J= 8.8 Hz, 1 H), 7.71 - 7.70 (m, 1 H), 7.64 - 7.61 (d, J= 8.4 Hz, 1 H), 7.60 - 7.51 (t, J= 8 Hz, 1 H), 7.30 (s, 1 H), 6.27 (s, 1 H), 5.34 (s, 2 H), 4.59 (s, 2 H), 3.74 (s, 2 H), 2.45 (s, 3 H).
Example 47-4 V-[2-(l,l-Dioxido-2,3-dihydro-l,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4- yl] py ridine-3-carboxamide
Figure imgf000334_0001
The title compound was prepared in analogy to Example 47-1 in Scheme 5 by using 4-(4-bromo- 6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-l,4-benzothiazepine 1,1-dioxide (prepared in analogy to 4-(4-chloro-6-(trifluoromethoxy)quinolin-2-yl)-2,3,4,5-tetrahydro- 1 ,4-benzothiazepine 1,1- dioxide in Example 17-1) and pyridine-3-carboxamide. MS obsd. (ESI+) [(M+H)+] 459, 1H NMR (400 MHz, CD3OD) δ ppm 9.17 (s, 1 H), 8.80 (s, 1 H), 8.52 (s, 1 H), 8.44 - 8.42 (d, J= 8 Hz, 1 H), 8.08 - 8.06 (d, J= 8 Hz, 1 H), 7.99 - 7.96 (d, J= 9.6 Hz, 2 H), 7.90 - 7.88 (d, J= 8.4 Hz, 1 H), 7.70 - 7.48 (m, 4 H), 5.29 (s, 2 H), 4.72 (s, 2 H), 3.64 (s, 2 H), 2.49 (s, 3 H).
Example 47-5 V-[2-(l,l-Dioxido-2,3-dihydro-l,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4- yl] piperidine-2-carboxamide
Figure imgf000334_0002
The title compound was prepared in analogy to Example 47-1 in Scheme 5 by using 4-(4-bromo- 6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-l,4-benzothiazepine 1,1-dioxide (prepared in analogy to 4-(4-chloro-6-(trifluoromethoxy)quinolin-2-yl)-2,3,4,5-tetrahydro- 1 ,4-benzothiazepine 1,1- dioxide in Example 17-1) and piperidine-2-carboxamide. MS obsd. (ESI ) [(M+H)+] 465, 1H NMR (400 MHz, CD3OD) δ ppm 8.33 (s, 1 H), 8.07 - 8.05 (d, J= 6.8 Hz, 1 H), 8.02 (s, 1 H), 7.95 - 7.93 (d, J= 7.6 Hz, 1 H), 7.80 - 7.78 (d, J= 8.4 Hz, 1 H), 7.66 - 7.62 (q, J= 8.8 Hz, 2 H), 7.56 - 7.52 (dd, J= 7.2, 15.6 Hz, 1 H), 5.28 (s, 2 H), 4.61 (s, 2 H), 4.34 - 4.31 (dd, J= 2.4, 12.8 Hz, 1 H), 3.74 (s, 2 H), 3.56 - 3.53 (d, J= 12.8 Hz, 1 H), 3.18 - 3.11 (m, 1 H), 2.51 (s, 3 H), 2.46 - 2.43 (d, J= 14 Hz, 1 H), 2.07 - 1.99 (m, 2 H), 1.88 - 1.76 (m, 1 H).
Example 47-6 V-[2-(l,l-Dioxido-2,3-dihydro-l,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]-2- (pyridin-2-yl)acetamide
Figure imgf000335_0001
The title compound was prepared in analogy to Example 47-1 in Scheme 5 by using 4-(4-bromo- 6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-l,4-benzothiazepine 1,1-dioxide (prepared in analogy to 4-(4-chloro-6-(trifluoromethoxy)quinolin-2-yl)-2,3,4,5-tetrahydro- 1 ,4-benzothiazepine 1,1- dioxide in Example 17-1) and 2-(pyridin-2-yl)acetamide. MS obsd. (ESI+) [(M+H)+] 473, 1H NMR (400 MHz, CD3OD) δ ppm 8.53 (s, 1 H), 8.15 (s, 2 H), 8.06 - 8.04 (d, J= 7.6 Hz, 1 H), 7.85 - 7.54 (m, 8 H), 5.26 (s, 2 H), 4.61 (s, 2 H), 3.57 (s, 2 H), 2.56 (s, 3 H).
Example 47-7 V-[2-(l,l-Dioxido-2,3-dihydro-l,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4- yljmethanesulfonamide trifluoroacetate
Figure imgf000335_0002
The title compound was prepared in analogy to Example 47-1 in Scheme 5 by using 4-(4-bromo- 6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-l,4-benzothiazepine 1,1-dioxide (prepared in analogy to 4-(4-chloro-6-(trifluoromethoxy)quinolin-2-yl)-2,3,4,5-tetrahydro- 1 ,4-benzothiazepine 1,1- dioxide in Example 17-1) and methanesulfonamide. MS obsd. (ESI+) [(M+H)+] 432, 1H NMR (400 MHz, DMSO- 6) δ ppm 7.98 - 7.90 (m, 2 H), 7.88 - 7.82 (d, J= 7.2 Hz, 1 H), 7.72 - 7.65 (\ τ= π7 1 m 7 *s . 7.58 (d, J= 7.6 Hz, 1 H), 7.58 - 7.51 (t, J= 2.4 Hz, 1 H), 7.48 - 7.42 (d, J= 7.6 Hz, 1 H), 7.01 (s, 1 H), 5.10 (s, 2 H), 4.60 - 4.40 (m, 2 H), 3.82 - 3.75 (t, J= 2.8 Hz, 2 H), 3.10 (s, 3 H), 2.38 (s, 3 H).
Example 47-8 V-[2-(l,l-Dioxido-2,3-dihydro-l,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4- yl]pyrazine-2-carboxamide
Figure imgf000336_0001
The title compound was prepared in analogy to Example 47-1 in Scheme 5 by using 4-(4-bromo- 6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-l,4-benzothiazepine 1,1-dioxide (prepared in analogy to 4-(4-chloro-6-(trifluoromethoxy)quinolin-2-yl)-2,3,4,5-tetrahydro- 1 ,4-benzothiazepine 1,1- dioxide in Example 17-1) and pyrazine-2-carboxamide. MS obsd. (ESI ) [(M+H)+] 460, 1H NMR (400 MHz, CD3OD) δ ppm 9.53 (s, 1 H), 8.97 (s, 1 H), 8.86 (s, 1 H), 8.72 (s, 1 H), 8.10 - 8.08 (dd, J= 5.2, 11.2 Hz, 2 H), 7.94 - 7.90 (dd, J= 8.8, 14.8 Hz, 2 H), 7.76 - 7.72 (d, J= 7.6 Hz, 2 H), 7.60 - 7.56 (d, J= 8 Hz, 1 H), 5.37 (s, 2 H), 4.70 (s, 2 H), 3.81 (s, 2 H), 2.56 (s, 3 H).
Example 47-9 V-[2-(l,l-Dioxido-2,3-dihydro-l,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]-2- hydroxyacetamide
Figure imgf000336_0002
The title compound was prepared in analogy to Example 47-1 in Scheme 5 by using 4-(4-bromo- 6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-l,4-benzothiazepine 1,1-dioxide (prepared in analogy to 4-(4-chloro-6-(trifluoromethoxy)quinolin-2-yl)-2,3,4,5-tetrahydro-l,4-benzothiazepine 1,1- dioxide in Example 17-1) and 2-hydroxyacetamide. MS obsd. (ESI+) [(M+H)+] 412, 1H NMR (400 MHz, CD3OD) δ ppm 8.54 (s, 1 H), 8.05 (dd, J= 1.2, 7.6 Hz, 1 H), 7.97 (d, J= 7.2 Hz, 1 H), 7.81 (s, 2 H), 7.70 - 7.66 (m, 2 H), 7.54 (t, J= 7.6 Hz, 1 H), 5.27 (s, 2 H), 4.62 (s, 2 H), 4.36 (s, 2 H), 3.76 (s, 2 H), 2.51 (s, 3 H).
Example 48 V-[2-(l,l-Dioxido-2,3-dihydro-l,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4- yl] py ridine-2-carboxamide
Figure imgf000337_0001
A mixture of pyridine-2-carboxylic acid amide (99 mg, 0.8 mmol), 4-(4-chloro-6- methylquinolin-2-yl)-2,3,4,5-tetrahydro-l,4-benzothiazepine 1,1-dioxide (300 mg, 0.8 mmol, prepared in analogy to 4-(4-chloro-6-(trifluoromethoxy)quinolin-2-yl)-2,3,4,5-tetrahydro-l,4- benzothiazepine 1,1-dioxide in Example 17-1), cyclohexane-l,3-diamine (90 mg, 0.08 mmol), copper(I) iodide (1.5 mg, 0.008 mmol) and potassium phosphate (340 mg, 1.6 mmol) in 1,4- dioxane (3 mL) was heated in a 5 mL of microwave process vial for 3 hours at 150 °C. The reaction mixture was concentrated in vacuo. The residue was purified by preparative HPLC and SPE to give 26 mg of the desired product (yield was 7.1 %). MS obsd. (ESI+) [(M+H)+] 451 , 1H NMR (400 MHz, CD3OD) δ ppm 8.90 - 8.82 (d, J= 8 Hz, 1 H), 8.77 (s, 1 H), 8.47 - 8.40 (d, J = 7.6 Hz, 1 H), 8.20 - 8.13 (t, J= 6.4 Hz, 1 H), 8.13 - 8.08 (d, J= 7.6 Hz, 2 H), 7.92 - 7.85 (m, 2 H), 7.80 - 7.70 (q, J= 8.4 Hz, 3 H), 7.62 - 7.56 (t, J= 7.2 Hz, 1 H), 5.37 (s, 2 H), 4.80 - 4.50 (m, 2 H), 3.82 - 3.78 (t, J= 2.8 Hz , 2 H), 2.60 (s, 3 H).
Example 49 V-[2-(l,l-Dioxido-2,3-dihydro-l,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4- yl] azetidine-2-carboxamide
Figure imgf000338_0001
tert-Buty\ 2-{[2-(l,l-dioxido-2,3-dihydro-l,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4- yl] carbamoyl} azetidine- 1-carboxylate
Figure imgf000338_0002
The title compound was prepared in analogy to Example 48-1 in Scheme 5 by using 4-(4- bromo-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-l,4-benzothiazepine 1,1-dioxide (prepared in analogy to 4-(4-chloro-6-(trifluoromethoxy)quinolin-2-yl)-2,3,4,5-tetrahydro-l,4- benzothiazepine 1,1-dioxide in Example 17-1) and tert-butyl 2-carbamoylazetidine-l- carboxylate. V-[2-(l,l-Dioxido-2,3-dihydro-l,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4- yl] azetidine-2-carboxamide
Figure imgf000338_0003
To a solution of tert-butyl 2-{[2-(l,l-dioxido-2,3-dihydro-l,4-benzothiazepin-4(5H)-yl)-6- methylquinolin-4-yl] carbamoyl} azetidine- 1-carboxylate (80 mg, 0.15 mmol) in ethyl acetate (10 mL) was added a solution of hydrochloride in ethyl acetate (4 N, 30 mL) drop wise in an ice- water bath. After being stirred at room temperature for 4 hours, the resulting mixture was concentrated in vacuo and purified by preparative HPLC to give the trifluoro acetic acid salt of the desired product. The trifluoro acetic acid salt was flashed through SPE column with methanol. The eluent was concentrated in vacuo and dried by lyopylization to give 30.79 mg of the desired product (yield was 47%). MS obsd. (ESI+) [(M+H)+] 437, 1H NMR (400 MHz, CD3OD) δ ppm 8.35 (s, 1 H), 8.04 (dd, J = 1.2, 7.6 Hz, 1 H), 7.98 (d, J= 7.6 Hz, 1 H), 7.93 (s, 1 H), 7.75 (d, J = 8.8 Hz, 1 H), 7.67 (t, J= 7.6 Hz, 1 H), 7.59 (d, J= 9.6 Hz, 1 H), 7.53 (t, J= 8.8 Hz, 1 H), 5.47 - 5.43 (m, 1 H), 5.28 (s, 2 H), 4.61 (brs, 2 H), 4.25 - 4.18 (m, 1 H), 4.14 - 4.10 (m, 1 H), 3.73 (s, 2 H), 3.04 - 2.98 (m, 1 H), 2.76 - 2.72 (m, 1 H), 2.49 (s, 3 H).
Example 50-1 l-[2-(l,l-Dioxido-2,3-dihydro-l,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]-3- phenylurea
Figure imgf000339_0001
To a solution of 2-(l,l-dioxido-2,3-dihydro-l,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4- amine (180 mg, 0.5 mmol, prepared in analogy to 4-(4-chloro-6-(trifluoromethoxy)quinolin-2- yl)-2,3,4,5-tetrahydro-l,4-benzothiazepine 1,1 -dioxide in Example 17-1) and triethylamine (103 mg) in tetrahydrofuran (15 mL) was added a solution of isocyanato-benzene (59.6 mg, 0.5 mmol) in tetrahydrofuran (5 mL) at 0 °C. The reaction was stirred at room temperature overnight and then heated at 50 °C for additional 5 hours. The reaction mixture was concentrated in vacuo and the residue was purified by preparative HPLC and SPE to give 17.6 mg of the desired product (yield was 7.5%). MS obsd. (ESI+) [(M+H)+] 473, 1H NMR (400 MHz, CD3OD) δ ppm 8.55 (s, 1 H), 8.12 - 8.03 (m, 2 H), 7.92 (s, 1 H), 7.86 - 7.81 (d, J= 8.4 Hz, 1 H), 7.76 - 7.68 (m, 2 H), 7.66 - 7.57 (m, 3 H), 7.45 - 7.38 (t, J= 7.6 Hz, 2 H), 7.20 - 7.12 (t, J= 2.0 Hz, 1 H), 5.32 (s, 2 H), 4.61 - 4.40 (m, 2 H), 3.82 - 3,75 (t, J= 2.8 Hz, 2 H), 2.56 (s, 3 H).
Example 50-2 l-[2-(l,l-Dioxido-2,3-dihydro-l,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]-3- ethylurea
Figure imgf000340_0001
The title compound was prepared in analogy to Example 50-1 by using 2-(l,l-dioxido-2,3- dihydro-l,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-amine (prepared in analogy to 4-(4- chloro-6-(trifluoromethoxy)quinolin-2-yl)-2,3,4,5-tetrahydro- 1 ,4-benzothiazepine 1 , 1 -dioxide in Example 17-1) and ethylisocyanate. MS obsd. (ESI+) [(M+H)+] 425, 1H NMR (400 MHz,
CD3OD) δ ppm 8.44 (s, 1 H), 8.09 - 8.03 (d, J = 8 Hz, 1 H), 7.99 - 7.93 (d, J= 7.6 Hz, 1 H), 7.86 (s, 1 H), 7.80 - 7.74 (d, J= 8.8 Hz, 1 H), 7.72 - 7.62 (m, 2 H), 7.60 - 7.51 (t, J= 8.4 Hz, 1 H), 5.24 (s, 2 H), 4.62 - 4.50 (m, 2 H), 3.78 - 3.70 (m, 2 H), 3.40 - 3.32 (q, J= 7.2 Hz, 2 H), 2.49 (s, 3 H), 1.28 - 1.20 (t, J= 7.2 Hz, 3 H). Example 51 V-[6-Cyclopropyl-2-(l,l-dioxido-2,3-dihydro-l,4-benzothiazepin-4(5H)-yl)quinolin-4- yl] propane- 1 ,3-diamine
Figure imgf000340_0002
4-(4-Chloro-6-cyclopropylquinolin-2-yl)-2,3,4,5-tetrahydro-l,4-benzothiazepine 1,1-dioxide
Figure imgf000340_0003
To a solution of 4-(6-bromo-4-chloroquinolin-2-yl)-2, 3,4, 5-tetrahydro-l,4-benzothiazepine 1,1- dioxide (1.0 g, 2.3 mmol, prepared in analogy to 4-(4-chloro-6-(trifluoromethoxy)quinolin-2-yl)- 2,3,4,5-tetrahydro-l,4-benzothiazepine 1,1-dioxide in Example 17-1) in toluene (150 mL) was added cyclopropylboronic acid (200 mg, 2.3 mmol), palladium acetate (52 mg, 0. 23 mmol), 2,2'- bis(diphenylphosphino)-l, -binaphthyl (143 mg, 0.23 mmol) and potassium carbonate (320 mg, 2.3 mmol) under argon protection. After being heated at 90 °C for 16 hours, the reaction mixture was concentrated in vacuo. The residue was dissolved in dichloromethane (100 mL), and the solution was washed with water (50 mL x 3), dried over sodium sulfate, filtered and
concentrated in vacuo. The residue was purified by column chromatography (eluting with 16% ethyl acetate in petroleum ether) to afford 300 mg of the desired product (yield was 33%). V-[6-Cyclopropyl-2-(l,l-dioxido-2,3-dihydro-l,4-benzothiazepin-4(5H)-yl)quinolin-4- yl] propane- 1 ,3-diamine
Figure imgf000341_0001
A mixture of 4-(4-chloro-6-cyclopropylquinolin-2-yl)-2,3,4,5-tetrahydro-l,4-benzothiazepine 1,1 -dioxide (300 mg, 0.75 mmol) and propane- 1,3-diamine (700 mg, 7.5 mmol) was heated with stirring in a 10 mL of microwave process vial for 1.5 hours at 150 °C under microwave irradiation. The reaction mixture was purified by preparative HPLC to give the trifluoro acetic acid salt of the desired product. The trifluoro acetic acid salt was flashed through SPE column with methanol. The eluent was concentrated in vacuo and dried by lyopylization to give 119.4 mg of the desired product (yield was 36%). MS obsd. (ESI+) [(M+H)+] 437, 1H NMR (400 MHz, CD3OD) δ ppm 8.05 (d, J= 7.6 Hz, 1 H), 7.84 (d, J= 7.2 Hz, 1 H), 7.81 (d, J= 1.2 Hz, 1 H), 7.67 - 7.69 (m, 2 H), 7.55 (t, J= 7.6 Hz, 1 H), 7.46 (d, J= 8.8 Hz, 1 H), 5.92 (s, 1 H), 5.29 (s, 2 H), 4.48 (brs, 2 H), 3.70 (s, 2 H), 3.59 (t, J= 6.8 Hz, 2 H), 3.08 (t, J= 8.0 Hz, 2 H), 2.12 - 2.07 (m, 2 H), 2.05 - 1.98 (m,l H), 1.03 (dd, J= 2.0 Hz, 8.4 Hz, 2 H), 0.78 - 0.76 (m, 2 H).
Example 52
4- [(3- Aminopropyl)amino] -2-(l , l-dioxido-2,3-dihydro- 1 ,4-benzothiazepin- yl)quinoline-6-carbonitrile
Figure imgf000341_0002
4-(4-Chloro-6-ethynylquinolin-2-yl)-2,3,4,5-tetrahydro-l,4-benzothiazepine 1,1-dioxide
Figure imgf000342_0001
To a degassed solution of 4-(6-bromo-4-chloroquinolin-2-yl)-2,3,4,5-tetrahydro-l,4- benzothiazepine 1,1 -dioxide (880 mg, 2 mmol, prepared in analogy to 4-(4-chloro-6- (trifluoromethoxy)quinolin-2-yl)-2,3,4,5-tetrahydro-l,4-benzothiazepine 1,1-dioxide in Example 17-1) in N,N-dimethylformamide (50 mL), zinc cyanide (280 mg, 2.4 mmol) and
tetrakis(triphenylphosphine)palladium(0) (232 mg, 0.2 mmol) was added under argon. After being refluxed for 2 hours, the reaction mixture was concentrated in vacuo and the residue was portioned in ethyl acetate (100 mL) and water (100 mL). After being stirred vigorously for 1 hour, the separated aqueous layer was extracted with ethyl acetate (100 mL x 2). The combined organic layers were dried over sodium sulfate and concentrated in vacuo to afford 0.6 g of the crude product.
4- [(3- Aminopropyl)amino] -2-(l , l-dioxido-2,3-dihydro- 1 ,4-benzothiazepin- yl)quinoline-6-carbonitrile
Figure imgf000342_0002
A mixture of 4-(4-chloro-6-ethynylquinolin-2-yl)-2,3,4,5-tetrahydro-l,4-benzothiazepine 1,1- dioxide (300 mg, 0.7 mmol), propane- 1,3-diamine (64 mg, 0.8 mmol), Ι,Γ- bis(diphenylphosphino)ferrocene-palladium(II)dichloride (65 mg, 0.08 mmol), Ι,Γ- bis(diphenylphosphino)ferrocene (45 mg, 0.08 mmol) and sodium tert-butoxide (307 mg, 3.2 mmol) in 1,4-dioxane (3 mL) was heated with stirring in a sealed 5 mL of microwave process vial for 1.5 hours at 120 °C under microwave irradiation. The resulting mixture was concentrated in vacuo. The residue was purified by preparative HPLC and SPE. After SPE separation, the eluent was concentrated in vacuo and the residue was dried by lyophylization to afford 65.2 mg of the desired product (yield was 20 %). MS obsd. (ESI+) [(M+H)+] 422, 1H NMR (400 MHz,
CD3OD) δ ppm 8.60 (s, 1 H), 8.10 - 8.08 (d, J= 8 Hz, 1 H), 7.99 - 7.86 (m, 3 H), 7.74 - 7.70 (t, J = 7.2 Hz, 1 H), 7.61 - 7.57 (t, J= 7.6 Hz, 1 H), 6.05 (s, 2 H), 5.35 (s, 2 H), 4.56 (s, 2 H), 3.75 (s, 2 H), 3.62 - 3.59 (t, J= 6.8 Hz, 2 H), 3.14 - 3.10 (t, J= 8 Hz, 2 H), 2.15 - 2.11 (t, J= 7.6 Hz, 2 H).
Example 53 V-[2-(l,l-Dioxido-2,3-dihydro-l,4-benzothiazepin-4(5H)-yl)-6-ethenylquinolin-4- yl]propane-l,3-diamine
Figure imgf000343_0001
4-(4-Chloro-6-ethenylquinolin-2-yl)-2,3,4,5-tetrahydro-l,4-benzothiazepine 1,1-dioxide
Figure imgf000343_0002
To a degassed solution of 4-(6-bromo-4-chloroquinolin-2-yl)-2,3,4,5-tetrahydro-l,4- benzothiazepine 1,1-dioxide (880 mg, 2 mmol, prepared in analogy to 4-(4-chloro-6-
(trifluoromethoxy)quinolin-2-yl)-2,3,4,5-tetrahydro-l,4-benzothiazepine 1,1-dioxide in Example 17-1) in N,N-dimethylformamide (50 mL), tributyl(vinyl)tin (760 mg, 2.4 mmol) and tetrakis(triphenylphosphine)palladium(0) (232 mg, 0.2 mmol) was added under argon. After being refluxed for 2 hours, the reaction mixture was concentrated in vacuo and the residue was portioned in ethyl acetate (100 mL) and a saturated aqueous solution of potassium fluoride (100 mL). After the mixture being stirred vigorously for 1 hour, the separated aqueous layer was extracted with ethyl acetate (100 mL x 2). The combined organic layers were dried over sodium sulfate and concentrated in vacuo to afford 0.4 g of the crude product. V-[2-(l,l-Dioxido-2,3-dihydro-l,4-benzothiazepin-4(5H)-yl)-6-ethenylquinolin-4- yl]propane-l,3-diamine
Figure imgf000343_0003
The title compound was prepared in analogy to Example 52 in Scheme 22 by using 4-(4-chloro- 6-ethenylquinolin-2-yl)-2,3,4,5-tetrahydro-l,4-benzothiazepine 1,1-dioxide and propane-1,3- diamine. MS obsd. (ESI+) [(M+H)+] 423, 1H NMR (400 MHz, CD3OD) δ ppm 8.12 (s, 1 H), 8.05 - 8.02 (q, J= 8 Hz, 1 H), 7.89 - 7.81 (m, 2 H), 7.77 - 7.70 (m, 2 H), 7.56 - 7.54 (t, J= 4.4 Hz, 1 H), 6.80 - 6.74 (m, 1 H), 5.95 - 5.90 (m, 2 H), 5.36 - 5.30 (m, 3 H), 4.51 (s, 2 H), 3.71 (s, 2 H), 3.61 - 3.60 (t, J= 3.2 Hz, 2 H), 3.11 - 3.10 (t, J= 5.2 Hz, 2 H), 2.13 - 2.11 (t, J= 5.6 Hz, 2 H).
Example 54 V-[2-(l,l-Dioxido-2,3-dihydro-l,4-benzothiazepin-4(5H)-yl)-6-ethynylquinolin-4- yl] propane- 1 ,3-diamine
Figure imgf000344_0001
4-(4-chloro-6-ethynylquinolin-2-yl)-2,3,4,5-tetrahydro-l,4-benzothiazepine 1,1-dioxide
Figure imgf000344_0002
To a degassed solution of 4-(6-bromo-4-chloroquinolin-2-yl)-2,3,4,5-tetrahydro-l,4- benzothiazepine 1,1-dioxide (880 mg, 2 mmol, prepared in analogy to 4-(4-chloro-6- (trifiuoromethoxy)quinolin-2-yl)-2,3,4,5-tetrahydro-l,4-benzothiazepine 1,1-dioxide in Example 17-1) in N,N-dimethylformamide (50 mL), tributyl(ethynyl)tin (760 mg, 2.4 mmol) and tetrakis(triphenylphosphine)palladium(0) (232 mg, 0.2 mmol) was added under argon. After being refluxed for 2 hours, the reaction mixture was concentrated in vacuo and the residue was portioned in a mixture of ethyl acetate (100 mL) and a saturated aqueous solution of potassium fluoride (100 mL). After the mixture being stirred vigorously for 1 hour, the separated aqueous layer was extracted with ethyl acetate (100 mL x 2). The combined organic layers were dried over sodium sulfate and concentrated in vacuo to afford 0.45 g of the crude product. V-[2-(l,l-Dioxido-2,3-dihydro-l,4-benzothiazepin-4(5H)-yl)-6-ethynylquinolin-4- yl] propane- 1 ,3-diamine
Figure imgf000345_0001
The title compound was prepared in analogy to Example 52 in Scheme 22 by using 4-(4-chloro- 6-ethynylquinolin-2-yl)-2,3,4,5-tetrahydro-l,4-benzothiazepine 1,1-dioxide and propane- 1,3- diamine. MS obsd. (ESI+) [(M+H)+] 421, 1H NMR (400 MHz, CD3OD) δ ppm 8.25 (s, 1 H), 8.01
- 7.99 (d, J= 7.6 Hz, 1 H), 7.94 - 7.92 (d, J= 7.2 Hz, 1 H), 7.87 - 7.85 (d, J= 8.8 Hz, 1 H), 7.82
- 7.79 (m, 1 H), 7.65 - 7.61 (m, 1 H), 7.50 - 7.47 (m, 1 H), 7.32 (s, 1 H), 5.30 (s, 2 H), 3.65 - 3.60 (m, 6 H), 2.70 (s, 3 H), 2.14 - 2.11 (t, J = 5.2 Hz, 2 H). Example 55-1 V-[(3-Aminooxetan-3-yl)methyl]-6-methyl-2-(l-oxido-2,3-dihydro-l,4-benzothiazepin- 4(5H)-yl)quinazolin-4-amine
Figure imgf000345_0002
V-(3-Aminooxetan-3-ylmethyl)-2-chloro-6-methylquinazolin-4-amine
Figure imgf000345_0003
A solution of 2,4-dichloro-6-methylquinazoline (645 mg, 3 mmol) and 3-(aminomethyl)oxetan- 3-amine (340 mg, 3.3 mmol) in methanol (15 mL) was stirred at room temperature overnight. After the resulting mixture was concentrated in vacuo, the residue was purified by column chromatography (eluting with 10% methanol in dichloromethane) to afford the desired product. V-[(3-Aminooxetan-3-yl)methyl]-6-methyl-2-(l-oxido-2,3-dihydro-l,4-benzothiazepin- 4i5H)-vl)a uinazolin-4-amine
Figure imgf000346_0001
A mixture ofN-(3-aminooxetan-3-ylmethyl)-2-chloro-6-methylquinazolin-4-amine (140 mg, 0.5 mmol) and 2,3,4,5-tetrahydro-l,4-benzothiazepine 1-oxide (270 mg, 1.5 mmol) in n-butanol (10 mL) was heated at 160 °C for 30 minutes. After the resulting mixture was concentrated in vacuo, the residue was purified by preparative HPLC to afford the pure product as a solid. MS obsd. (ESI+) [(M+H)+] 424, 1H NMR (400 MHz, CD3OD) δ ppm 8.01 (s, 1 H), 7.83 - 7.79 (m, 2 H), 7.66 - 7.52 (m, 4 H), 5.45 - 5.41 (d, 1 H), 5.10 (brs, 1 H), 4.80 - 4.72 (m, 6 H), 4.39 (s, 2 H), 3.51 (s, 2 H), 2.45 (s, 3 H).
Example 55-2 V-{[3-(Benzylamino)oxetan-3-yl]methyl}-6-methyl-2-(l-oxido-2,3-dihydro-l,4- benzothiazepin-4(5H)-yl)quinazolin-4-amine
Figure imgf000346_0002
The title compound was prepared in analogy to Example 55-1 in Scheme 23 by using 2,4- dichloro-6-methylquinazoline, 3-(aminomethyl)-N-benzyloxetan-3-amine and 2,3,4,5-tetrahydro- 1,4-benzothiazepine 1-oxide. MS obsd. (ESI+) [(M+H)+] 514, 1H NMR (400 MHz, CD3OD) δ ppm 8.06 (s, 1 H), 7.81 - 7.77 (m, 2 H), 7.66 - 7.56 (m, 4 H), 7.47 - 7.45 (m, 2 H), 7.31 - 7.29 (m, 3 H), 5.45 - 5.35 (d, 1 H), 5.10 (brs, 1 H), 4.82 - 4.80 (m, 6 H), 4.71 - 4.69 (m, 2 H), 4.16 (s, 2 H), 3.51 (m, 2 H), 2.46 (s, 3 H).
Example 55-3 2-Fluoro- V-[6-methyl-2-(l-oxido-2,3-dihydro-l,4-benzothiazepin-4(5H)-yl)quinazolin-4- yl] propane- 1 ,3-diamine
Figure imgf000347_0001
The title compound was prepared in analogy to Example 55-1 in Scheme 23 by using 2,4- dichloro-6-methylquinazoline, 2-fluoropropane-l,3-diamine and 2,3,4,5-tetrahydro-l,4- benzothiazepine 1-oxide. MS obsd. (ESI+) [(M+H)+] 414, 1H NMR (400 MHz, CD3OD) δ ppm (d, J= 7.6 Hz, 1 H), 7.79 (s, 1 H), 7.70 - 7.20 (m, 6 H), 5.56 (m, 1 H), 4.85 - 4.55 (m, 3 H), 4.48 - 4.32 (brs, 1 H), 3.91 - 3.71 (brs, 2 H), 3.40 - 3.11 (m, 2 H), 2.93 - 2.72 (m, 2 H), 2.24 (s, 3 H), 1.68 (s, 2 H).
Example 55-4
TV- [2-(2,3-Dihydro- 1 ,4-benzothiazepin-4(5H)-yl)-6-methylquinazolin-4-yl] -2,2- difluoropropane-l,3-diamine
Figure imgf000347_0002
The title compound was prepared in analogy to Example 55-1 in Scheme 23 by using 2,4- dichloro-6-methylquinazoline, 2,2-difluoropropane-l,3-diamine and 2,3,4,5-tetrahydro-l,4- benzothiazepine. MS obsd. (ESI+) [(M+H)+] 416, 1H NMR (400 MHz, CD3OD) δ ppm 7.96 (s, 1 H), 7.80 -7.68 (m, 1 H), 7.60 -7.58 (m, 2 H), 7.51 - 7.49 (m, 1 H), 7.30 - 7.27 (t, 1 H), 7.24 - 7.20 (t, 1 H), 5.15 (s, 2 H), 4.37 - 4.31 (m, 4 H), 3.51 - 3.49 (m, 4 H), 3.14 (s, 2 H), 2.45 (s, 3 H).
Example 56-1 V-{[3-(Aminomethyl)oxetan-3-yl]methyl}-2-(l,l-dioxido-2,3-dihydro-l,4-benzothiazepin- 4(5H)-yl)-6-methylquinazolin-4-amine
Figure imgf000347_0003
V-{[3-(Aminomethyl)oxetan-3-yl]methyl}-2-chloro-6-methylquinazolin-4-amine
Figure imgf000348_0001
To a mixture of oxetane-3,3-diyldimethanamine (1.16 g, 10.0 mmol) and triethylamine (1.4 mL, 10 mol) in dichloromethane (15 mL) was added dropwise of a solution of 2,4-dichloro-6- methylquinazoline (500 mg, 2.36 mmol) in dichloromethane (5 mL). After being stirred at room temperature overnight, the resulting mixture was diluted with water (50 mL), and extracted with dichloromethane. The organic layer was washed with brine, dried over anhydrous sodium sulfate, and concentrated in vacuo. The residue was purified by flash column chromatography (eluting with 10% methanol in dichloromethane) to afford 300 mg of the desired product as a white solid. V-{[3-(Aminomethyl)oxetan-3-yl]methyl}-2-(l,l-dioxido-2,3-dihydro-l,4-benzothiazepin- 4(5H)-yl)-6-methylquinazolin-4-amine
Figure imgf000348_0002
The title compound was prepared in analogy to Example 55-1 in Scheme 23 by using N-{[3- (aminomethyl)oxetan-3-yl]methyl}-2-chloro-6-methylquinazolin-4-amine and 2,3,4,5- tetrahydro-l,4-benzothiazepine 1,2-dioxide. MS obsd. (ESI+) [(M+H)+] 454, 1H NMR (400 MHz, CD3OD) δ ppm 7.99 (dd, J= 7.83, 1.26 Hz, 1 H), 7.88 (d, J = 7.33 Hz, 1 H), 7.67 (s, 1 H), 7.62 (td, J= 7.58, 1.26 Hz, 1 H), 7.50 - 7.37 (m, 2 H), 7.37 - 7.30 (m, 1 H), 5.21 (brs, 2 H), 4.66 (d, J= 6.06 Hz, 2 H), 4.57 (d, J= 6.06 Hz, 1 H), 4.51 (d, J= 6.32 Hz, 2 H), 4.06 (s, 2 H), 3.53 (t, J= 5.05 Hz, 2 H), 3.05 (s, 2 H), 2.40 (s, 3 H).
Example 56-2
2,2-Difluoro- V-[6-methyl-2-(l-oxido-2,3-dihydro-l,4-benzothiazepin-4(5H)-yl)quinazolin-4- yl] propane- 1 ,3-diamine
Figure imgf000349_0001
The title compound was prepared in analogy to Example 56-1 in Scheme 23 by using 2,4- dichloro-6-methylquinazoline, 2,2-difluoropropane-l,3-diamine and 2,3,4,5-tetrahydro-l,4- benzothiazepine 1-oxide. MS obsd. (ESI+) [(M+H)+] 432, 1H NMR (400 MHz, CD3OD) δ ppm 7.98 (s, 1 H), 7.82 - 7.80 (d, 1 H), 7.74 - 7.69 (m, 2 H), 7.63 - 7.53 (m, 3 H), 5.40 (d, 1 H), 5.10 (m, 1 H), 4.75 (m, 1 H), 4.60 - 4.33 (m, 3 H), 3.63 (m, 4 H), 2.45 (s, 3 H).
Example 56-3 V-{[3-(aminomethyl)oxetan-3-yl]methyl}-6-chloro-2-(l,l-dioxido-2,3-dihydro-l,4- benzothiazepin-4(5H)-yl)quinazolin-4-amine
Figure imgf000349_0002
The title compound was prepared in analogy to Example 56-1 in Scheme 23 by using 2,4,6- trichloroquinazoline, oxetane-3,3-diyldimethanamine and 2,3,4,5-tetrahydro-l,4-benzothiazepine 1,1 -dioxide. MS obsd. (ESI+) [(M+H)+] 474, 1H NMR (400 MHz, CD3OD) δ ppm 7.99 (d, J = 6.82 Hz, 1 H), 7.94 (d, J= 2.53 Hz, 1 H), 7.88 (d, J= 7.07 Hz, 1 H), 7.66 - 7.59 (m, 1 H), 7.52 - 7.42 (m, 2 H), 7.42 - 7.36 (m, 1 H), 5.21 (brs, 2 H), 4.69 - 4.56 (m, 5 H), 4.51 (d, J= 6.32 Hz, 2 H), 4.05 (brs, 2 H), 3.52 (t, J= 5.05 Hz, 2 H), 3.04 (s, 2 H).
Example 56-4 V-[2-(l,l-Dioxido-2,3-dihydro-l,4-benzothiazepin-4(5H)-yl)-6-methylquinazolin-4-yl]-2,2- difluoropropane-l,3-diamine
Figure imgf000350_0001
The title compound was prepared in analogy to Example 56-1 in Scheme 23 by using 2,4- dichloro-6-methylquinazoline, 2,2-difluoropropane-l,3-diamine and 2,3,4,5-tetrahydro-l,4- benzothiazepine 1,1-dioxide. MS obsd. (ESI+) [(M+H)+] 448, 1H NMR (400 MHz, CD3OD) δ ppm 8.06 - 8.04 (dd, J= 1.2, 7.6 Hz, 1 H), 7.99 (s, 1 H), 7.84 - 7.82 (d, J= 7.6 Hz, 1 H), 7.72 - 7.67 (m, 2 H), 7.63 - 7.58 (m, 1 H), 7.56 - 7.54 (dd, J= 1.2, 8 Hz, 1 H), 5.35 (s, 2 H), 4.54 (s, 2 H), 4.44 - 4.37 (t, J=14 Hz, 2 H), 3.72 - 3.64 (m, 4 H), 2.46 (s, 3 H).
Example 56-5 V-[2-(l,l-Dioxido-2,3-dihydro-l,4-benzothiazepin-4(5H)-yl)-6-methylquinazolin-4-yl]-2- fluoropropane-l,3-diamine
Figure imgf000350_0002
The title compound was prepared in analogy to Example 56-1 in Scheme 23 by using 2,4- dichloro-6-methylquinazoline, 2-fluoropropane-l,3-diamine and 2,3,4,5-tetrahydro-l,4- benzothiazepine 1,1-dioxide. MS obsd. (ESI+) [(M+H)+] 430, 1H NMR (400 MHz, CD3OD) δ ppm 8.06 - 8.04 (d, J= 7.6 Hz, 1 H), 7.93 (s, 1 H), 7.81 - 7.79 (d, J= 7.6 Hz, 1 H), 7.69 - 7.65 (t, J= 8 Hz, 2 H), 7.60 - 7.53 (m, 2 H), 5.32 (s, 2 H), 5.17 - 5.03 (d, J= 28 Hz, 1 H), 4.52 (s, 2 H), 4.20 - 3.92 (m, 2 H), 3.67 (s, 2 H), 3.47 - 3.36 (m, 2 H), 2.44 (s, 3 H).
Example 56-6 V-[6-Methyl-2-(l-oxido-2,3-dihydro-l,4-benzothiazepin-4(5H)-yl)quinazolin-4-yl]propane- 1,3-diamine
Figure imgf000351_0001
The title compound was prepared in analogy to Example 56-1 in Scheme 23 by using 2,4- dichloro-6-methylquinazoline, propane- 1,3-diamine and 2,3,4,5-tetrahydro-l,4-benzothiazepine 1 -oxide. MS obsd. (ESI+) [(M+H)+] 396, 1H NMR (400 MHz, CD3OD) δ ppm 7.92 (s, 1 H), 7.81 - 7.79 (d, J= 7.6 Hz, 1 H), 7.74 - 7.72 (d, J= 7.6 Hz, 1 H), 7.64 - 7.50 (m, 4 H), 5.43 - 5.39 (d, J= 15.6 Hz, 1 H), 5.12 - 5.05 (m, 1 H), 4.81 - 4.72 (m, 1 H), 4.53 - 4.46 (m, 2 H), 3.84 - 3.82 (m, 2 H), 3.52 - 3.48 (m, 2 H), 3.31 - 3.29 (m, 2 H), 2.43 (s, 3 H), 2.17 - 2.11 (m, 2 H).
Example 57-1
N- [(3- Aminooxetan-3-yl)methyl] -2-(2,3-dihydro- 1 ,4-benzothiazepin-4(5H)-yl)quinazolin-4- amine
Figure imgf000351_0002
N- [(3-Aminooxetan-3-yl)methyl] -2-chloroquinazolin-4-amine
Figure imgf000351_0003
To a solution of 2,4-dichloroquinazoline (1.0 g, 5.024 mmol) in methanol (15 mL) was added 3- (aminomethyl)oxetan-3 -amine (855 mg, 60%, 5.024 mmol) and triethylamine (101 mg, 1.005 mmol). After being stirred at room temperature overnight, the mixture was concentrated in vacuo. The residue was purified by flash column chromatography to afford 1.2 g of the desired product as a white solid (yield was 92%).
N- [(3- Aminooxetan-3-yl)methyl] -2-(2,3-dihydro- 1 ,4-benzothiazepin-4(5H)-yl)quinazolin-4- amine
Figure imgf000352_0001
To a solution ofN-[(3-aminooxetan-3-yl)methyl]-2-chloroquinazolin-4-amine (200 mg, 0.756 mmol) in N,N-dimethylformamide (4 mL) was added 2,3,4,5-tetrahydro-l,4-benzothiazepine (125 mg, 0.756 mmol) and triethylamine (230 mg, 2.268 mmol). After being heated at 130 °C for 4 hours under microwave irradiation, the reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was dried with sodium sulfate, and concentrated in vacuo. The residue was purified by preparative HPLC to afford 42 mg of the desired product as a white solid (yield was 14%). MS obsd. (ESI+) [(M+H)+] 394, 1H NMR (400 MHz, CD3OD) δ ppm 7.75 - 7.73 (t, J= 6.4, 1.2 Hz, 1 H), 7.56 - 7.53 (m, 1 H), 7.52 - 7.47 (m, 2 H), 7.43 - 7.41 (d, J= 8.0 Hz, 1 H), 7.24 - 7.20 (m, 1 H), 7.15 - 7.08 (m, 2 H), 5.06 (s, 2 H), 4.69 - 4.67 (d, J= 6.8 Hz, 2 H), 4.55 - 4.53 (d, J= 6.4 Hz, 2 H), 4.42 (s, 2 H), 4.09 (s, 2 H), 2.97 - 2.95 (t, J= 4.8, 4.4 Hz, 2 H).
Example 57-2 V-[(3-Aminooxetan-3-yl)methyl]-2-(l-oxido-2,3-dihydro-l,4-benzothiazepin- yl)quinazolin-4-amine
Figure imgf000352_0002
The title compound was prepared in analogy to Example 57-1 in Scheme 23 by using
dichloroquinazoline, 3 -(amino methyl)oxetan-3 -amine and 2,3,4,5-tetrahydro-l,4- benzodiazepine 1-oxide. MS obsd. (ESI+) [(M+H)+] 410, 1H NMR (400 MHz, CD3OD) δ ppm 7.91 - 7.90 (t, J= 7.2, 0.8 Hz, 1 H), 7.81 - 7.74 (m, 2 H), 7.58 - 7.54 (m, 1 H), 7.51 - 7.43 (m, 3 H), 7.16 - 7.12 (m, 1 H), 5.32 - 5.28 (d, J= 15.2 Hz, 2 H), 4.68 - 4.53 (m, 6 H), 4.10 (s, 2 H), 3.37 - 3.34 (m, 2 H).
Example 57-3
TV- [(3- Aminooxetan-3-yl)methyl] -2-(l , l-dioxido-2,3-dihydro- 1 ,4-benzothiazepin-4(5H)-
Figure imgf000353_0001
The title compound was prepared in analogy to Example 57-1 in Scheme 23 by using 2,4- dichloroquinazoline, 3 -(amino methyl)oxetan-3 -amine and 2,3,4,5-tetrahydro-l ,4- benzothiazepine 1 , 1-dioxide. MS obsd. (ESI+) [(M+H)+] 426, 1H NMR (400 MHz, CD3OD) δ ppm 7.98 - 7.93 (m, 1 H), 7.91 - 7.88 (m, 2 H), 7.64 - 7.60 (m, 1 H), 7.57 - 7.51 (m, 1 H), 7.48 - 7.41 (m, 2 H), 7.15 - 7.1 1 (m, 1 H), 5.24 (s, 2 H), 4.67 - 4.54 (m, 6 H), 4.09 (s, 2 H), 3.55 - 3.50 (m, 2 H).
Example 57-4 V-[(3-Aminooxetan-3-yl)methyl]-6-chloro-2-(2,3-dihydro-l,4-benzothiazepin-4(5H)- yl)quinazolin-4-amine
Figure imgf000353_0002
The title compound was prepared in analogy to Example 57-1 in Scheme 23 by using 2,4,6- trichloroquinazoline, 3 -(amino methyl)oxetan-3 -amine and 2,3,4,5-tetrahydro-l ,4- benzothiazepine. MS obsd. (ESI+) [(M+H)+] 428, 1H NMR (400 MHz, DMSO- 6) δ ppm 8.18 (s, 1 H), 7.97 (s, 1 H), 7.70 (s, 1 H), 7.51 - 7.44 (m, 2 H), 7.27 - 7.21 (m, 2 H), 7.16 - 7.12 (t, J = 7.2 Hz, 1 H), 4.93 (s, 2 H), 4.50 - 4.35 (m, 5 H), 3.97 - 3.80 (m, 2 H), 2.96 - 2.87 (m, 2 H), 2.69 - 2.67 (m, 1 H), 2.35 - 2.33 (m, 1 H), 2.10 (s, 2 H).
Example 57-5 V-[(3-Aminooxetan-3-yl)methyl]-6-chloro-2-(l-oxido-2,3-dihydro-l,4-benzothiazepin- 4(5H)-yl)quinazolin-4-amine
Figure imgf000353_0003
The title compound was prepared in analogy to Example 57-1 in Scheme 23 by using 2,4,6- trichloroquinazoline, 3 -(amino methyl)oxetan-3 -amine and 2,3,4,5-tetrahydro-l,4- benzothiazepine 1-oxide. MS obsd. (ESI+) [(M+H)+] 444, 1H NMR (400 MHz, CD3OD) δ ppm 8.57 (s, 1 H), 8.01 - 7.73 (m, 2 H), 7.52 - 7.40 (m, 4 H), 5.31 - 5.28 (d, J= 15.2 Hz, 1 H), 4.66 - 4.53 (m, 6 H), 4.08 (s, 2 H), 3.51 - 3.50 (m, 2 H), 1.36 - 1.31 (m, 1 H).
Example 57-6 V-[(3-Aminooxetan-3-yl)methyl]-6-chloro-2-(l,l-dioxido-2,3-dihydro-l,4-benzothiazepin- 4(5H)-yl)quinazolin-4-amine
Figure imgf000354_0001
The title compound was prepared in analogy to Example 57-1 in Scheme 23 by using 2,4,6- trichloroquinazoline, 3 -(amino methyl)oxetan-3 -amine and 2,3,4,5-tetrahydro-l,4- benzothiazepme 1,1-dioxide. MS obsd. (ESI+) [(M+H)+] 460, 1H NMR (400 MHz, CD3OD) δ ppm 8.00 - 7.98 (t, J= 2.0, 4.8 Hz, 2 H), 7.91 - 7.89 (d, J= 7.2 Hz, 1 H), 7.64 - 7.60 (t, J= 7.2 Hz , 1 H), 7.51 - 7.44 (m, 2 H), 7.40 - 7.38 (d, J= 9.2 Hz, 1 H), 5.22 (s, 2 H), 4.65 - 4.62 (t, J = 6.4, 5.6 Hz, 4 H), 4.56 - 4.54 (d, J= 6.4 Hz, 2 H), 4.08 (s, 2 H), 3.54 - 3.51 (t, J= 5.2, 4.8 Hz, 2
H).
Example 57-7
2- { [2-(l , l-Dioxido-2,3-dihydro- 1 ,4-benzothiazepin-4(5H)-yl)-6-methylquinazolin-4- yl] amino} ethanol
Figure imgf000354_0002
The title compound was prepared in analogy to Example 57-1 in Scheme 23 by using 2,4- diichloro-6-methylquinazoline, 2-aminoethanol and 2,3,4,5-tetrahydro-l,4-benzothiazepine 1,1- dioxide. MS obsd. (ESI+) [(M+H)+] 410, 1H NMR (400 MHz, CD3OD) δ ppm 7.98 (dd, J= 1.2, 7.6 Hz, 1 H), 7.83 (d, J= 6.8 Hz, 1 H), 7.63 - 7.59 (m, 2 H), 7.44 (td, J= 0.8, 7.6 Hz, 1 H), 7.38 (dd, J= 1.6, 8.4 Hz, 1 H), 7.31 (d, J= 8.4 Hz, 1 H), 5.20 (s, 2 H), 4.58 (brs, 2 H), 3.82 - 3.78 (m, 4 H), 3.53 (t, J = 5.2 Hz, 2 H), 2.39 (s, 3 H).
Example 58 2-(2,3-Dihydro- 1 ,4-benzothiazepin-4(5H)-yl)-6-methylquinazolin-4-amine
Figure imgf000355_0001
2-Chloro-6-methylquinazolin-4-amine
Figure imgf000355_0002
A mixture of 2,4-dichloro-6-methylquinazoline (500 mg, 2.348 mmol) and a solution of ammonia in tetrahydrofuran (20 mL, 3.0 M) was stirred in an ice-bath for 2 hours. The resulting mixture was concentrated in vauco to afford 454 mg of the crude product as a white solid.
2-(2,3-Dihydro-l,4-benzothiazepin-4(5H)-yl)-6-methylquinazolin-4-amine
Figure imgf000355_0003
To a solution of 2-chloro-6-methylquinazolin-4-amine (454 mg, 2.345 mmol) in n-butanol (5 mL) was added 2,3,4,5-tetrahydro-l,4-benzothiazepine (388 mg, 2.345 mmol). After being heated at 150 °C for 1.5 hours under microwave irradiation, the reaction mixture was filtered and the collected solid was washed with ether to afford 756 mg of the product as a white solid. MS obsd. (ESI+) [(M+H)+] 323, 1H NMR (400 MHz, DMSO- 6) δ ppm 7.92 (s, 1 H), 7.83 - 7.81 (d, J= 8.0 Hz, 1 H), 7.62 - 7.60 (d, J= 8.0 Hz, 1 H), 7.53 - 7.49 (m, 2 H), 7.29 - 7.25 (m, 1 H), 7.22 - 7.19 (m, 1 H), 4.98 (s, 2 H), 4.25 (s, 2 H), 2.98 (s, 2 H), 2.35 (s, 3 H).
Example 59
2-(l , l-Dioxido-2,3-dihydro- 1 ,4-benzothiazepin-4(5H)-yl)-6-methylquinazolin-4-amine
Figure imgf000356_0001
To a solution of oxone (670 mg, 1.117 mmol) in water (2.5 mL), which was cooled below 0 °C in an ice-bath, was added a solution of 2-(2,3-dihydro-l,4-benzothiazepin-4(5H)-yl)-6- methylquinazolin-4-amine (300 mg, 0.930 mmol) in methanol (15 mL) and tetrahydrofuran (3 mL) dropwise. The resulting mixture was stirred below 0 °C for 2 hours. The formed precipitate was collected by filtration, washed with water and dried in vacuo to afford the desired product as a white solid. MS obsd. (ESI+) [(M+H)+] 355, 1H NMR (400 MHz, DMSO- 6) δ ppm 7.91 -7.86 (m, 2 H), 7.77 (s, 1 H), 7.64 - 7.60 (t, J= 16.0 Hz, 1 H), 7.51 - 7.48 (m, 2 H), 7.37 - 7.35 (d, J = 8.0 Hz, 1 H), 5.06 (s, 2 H), 4.37 (s, 2 H), 3.59 (s, 2 H), 2.31 (s, 3 H). Example 60 \rl~-[2-(l,l-Dioxido-2,3-dihydro-l,4-benzothiazepin-4(5H)-yl)-6-methylquinazolin-4-yl]-2- methyl ropane- 1 ,2-diamine
Figure imgf000356_0002
V~l~-(2-Chloro-6-methylquinazolin-4-yl)-2-methylpropane-l,2-diamine
Figure imgf000356_0003
A solution of 2,4-dichloro-6-methylquinazoline (500 mg, 2.35 mmol) and 2-methylpropane-l,2- diamine (365 μί, 3.52 mmol) in methanol (10 mL) was stirred at room temperature for 1 hour. The reaction mixture was diluted with ethyl acetate (30 mL) and stirred for 30 minutes. The formed solid was collected by filtration and dried in vacuo to afford 500 mg of the desired product as a white solid (yield was 80.6%). \rl~-[2-(l,l-Dioxido-2,3-dihydro-l,4-benzothiazepin-4(5H)-yl)-6-methylquinazolin-4-yl]-2- methylpropane- 1 ,2-diamine
Figure imgf000357_0001
A mixture ofA i~-(2-chloro-6-methylquinazolin-4-yl)-2-methylpropane-l,2-diamine (300 mg, 1.14 mmol) and 2,3,4,5-tetrahydro-l,4-benzothiazepine (226 mg, 1.25 mmol) in n-butanol (3 mL) was heated in the microwave at 160 °C for 2 hours. The resulting mixture was concentrated in vacuo. The residue was purified by flash column chromatography (eluting with 0 - 10% methanol in dichloromethane) to afford 300 mg of the desired product as a white solid (yield was
67%). \rl~-[2-(l,l-Dioxido-2,3-dihydro-l,4-benzothiazepin-4(5H)-yl)-6-methylquinazolin-4-yl]-2- methyl ropane- 1 ,2-diamine
Figure imgf000357_0002
To a stirred solution ofATl~-[2-(l,l-dioxido-2,3-dihydro-l,4-benzothiazepin-4(5H)-yl)-6- methylquinazolin-4-yl]-2-methylpropane-l,2-diamine (240 mg, 0.61 mmol ) in dichloromethane (15 mL) was added 3-chloroperoxybenzoic acid (263 mg, 1.53 mmol) at 0 °C. After being stirred at 0 °C for 20 minutes, the reaction mixture was washed with a saturated aqueous solution of sodium carbonate and brine, dried over sodium sulfate, and concentrated in vacuo. The residue was purified by flash column chromatography (eluting with 10% methanol in dichloromethane) to afford 100 mg of the desired product as a white solid (yield was 38.6%>). MS obsd. (ESI+)
[(M+H)+] 426, 1H NMR (400 MHz, CD3OD) δ ppm 7.99 (d, J= 1.9 Hz, 1 H), 7.86 (d, J= 1.8 Hz, 1 H), 7.73 (s, 1 H), 7.60 (t, J= 2.7 Hz, 1 H), 7.47 - 7.40 (m, J= 6.9 Hz, 2 H), 7.36 -7.33 (m, 1 H), 5.20 (s, 2 H), 4.58 (brs, 2 H), 3.72 (s, 2 H ), 3.52 (m, 2 H ), 2.41 (s, 3 H), 1.30 (s, 6 H).
Example 61-1
TV- [(3- Aminooxetan-3-yl)methyl] -2-(l , l-dioxido-2,3-dihydro- 1 ,4-benzothiazepin-4(5H)-yl)- 6-methylquinazolin-4-amine
Figure imgf000358_0001
V-{[3-(Dibenzylamino)oxetan-3-yl]methyl}-2-(2,3-dihydro-l,4-benzothiazepin-4(5H)-yl)-6- methylquinazolin-4-amine
Figure imgf000358_0002
A mixture of (2-chloro-6-methylquinazolin-4-yl)-[3-(dibenzylamino)oxetan-3-ylmethyl]-amine (2 g, 4.4 mmol, prepared in analogy to N-(3-aminooxetan-3-ylmethyl)-2-chloro-6- methylquinazolin-4-amine in Example 55-1), 2,3,4,5-tetrahydro-l,4-benzothiazepine (720 mg, 4.4 mmol), triethylamine (1.2 mL, 8.6 mmol) in N,N-dimethylformamide (20 mL) was heated with stirring in a 30 mL of microwave process vial for 2 hours at 150 °C. The reaction mixture was diluted with ethyl acetate, washed with water and brine. The organic layer was dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography on silica gel to give 1.7 g of the product as a white solid. V-{[3-(Dibenzylamino)oxetan-3-yl]methyl}-2-(l,l-dioxido-2,3-dihydro-l,4-benzothiazepin- 4(5H)-yl)-6-methylquinazolin-4-amine
Figure imgf000358_0003
To a solution ofN-{[3-(dibenzylamino)oxetan-3-yl]methyl}-2-(2,3-dihydro-l,4-benzothiazepin- 4(5H)-yl)-6-methylquinazolin-4-amine (1.7 g, 2.89 mmol) in dichloromethane (30 mL) was added -r,h1n nne beri7nic acid (75%, 1.33 g, 5.8 mmol) at 0 °C. The resulting mixture was stirred for 1 hour whilst allowing the temperature to rise slowly to room temperature. The reaction mixture was then washed with a saturated aqueous solution of sodium carbonate, a saturated aqueous solution of sodium sulfite and brine. The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by column chromatography on silica gel to give 1.4 g of the product as a white solid.
TV- [(3- Aminooxetan-3-yl)methyl] -2-(l , l-dioxido-2,3-dihydro- 1 ,4-benzothiazepin-4(5H)-yl)- 6-methylquinazolin-4-amine
Figure imgf000359_0001
To a solution ofN- {[3-(dibenzylamino)oxetan-3-yl]methyl}-2-(l , l-dioxido-2,3-dihydro-l ,4- benzothiazepin-4(5H)-yl)-6-methylquinazolin-4-amine (1.4 g, 2.26 mmol) in methanol was added palladium hydroxide (20% on carbon, 200 mg). After being stirred at room temperature overnight under a hydrogen atmosphere, the resulting mixture was filtered. The filtrate was concentrated in vacuo. The residue was purified by column chromatography on silica gel to afford 300 mg of the product as off-white foam. MS obsd. (ESI+) [(M+H)+] 440, 1H NMR (400 MHz, CD3OD) δ ppm 7.97 (d, J = 7.6 Hz, 1 H), 7.86 (d, J = 7.2 Hz, 1 H), 7.69 (s, 1 H), 7.58 (t, J = 7.2 Hz, 1 H), 7.44 - 7.34 (m, 3 H), 5.21 (s, 2 H), 4.66 (d, J= 6.4 Hz, 2 H), 4.60 (br.s., 2 H), 4.56 (d, J= 6.4 Hz, 2 H), 4.10 (s, 2 H), 3.52 (t, J = 5.2 Hz, 2 H), 2.39 (s, 3 H).
Example 61-2 V-[(l-Aminocyclobutyl)methyl]-2-(l,l-dioxido-2,3-dihydro-l,4-benzothiazepin-4(5H)-yl)-6- methylquinazolin-4-amine
Figure imgf000359_0002
V-[(l-Benzylamino-cyclobutyl)methyl]-2-(l,l-dioxido-2,3-dihydro-l,4-benzothiazepin- 4(5H)-yl)-6-methylquinazolin-4-amine
Figure imgf000360_0001
The title compound was prepared in analogy to N-{[3-(dibenzylamino)oxetan-3-yl]methyl}-2- (l,l-dioxido-2,3-dihydro-l,4-benzothiazepin-4(5H)-yl)-6-methylquinazolin-4-amine in Example 61-1 in Scheme 24 by using 2,4-dichloro-6-methylquinazoline, l-(aminomethyl)-N- dibenzylcyclobutanamine and 2,3,4,5-tetrahydro-l,4-benzothiazepine. V-[(l-Aminocyclobutyl)methyl]-2-(l,l-dioxido-2,3-dihydro-l,4-benzothiazepin-4(5H)yl)-6- methylquinazolin-4-amine
Figure imgf000360_0002
A mixture of N-[(l-benzylamino-cyclobutyl)methyl]-2-(l,l-dioxido-2,3-dihydro-l,4- benzothiazepin-4(5H)-yl)-6-methylquinazolin-4-amine (220 mg, 0.417 mmol), 10% of palladium hydroxide on carbon (30 mg), and trifluoro acetic acid (160 μί) in methanol (20 mL) was stirred at room temperature for 24 hours under a hydrogen atmosphere. The resulting mixture was filtered, and the filtrate was adjusted to pH 8-9 by the addition of a solution of ammonia in methanol (7 M), and concentrated in vacuo. The residue was purified by preparative HPLC to give 105 mg of the product as a white solid. MS obsd. (ESI+) [(M+H)+] 438, 1H NMR (400 MHz, CD3OD) δ ppm 7.98 (d, J= 7.6 Hz, 1 H), 7.86 (d, J= 7.6 Hz, 1 H), 7.73 (s, 1 H), 7.60 (t, J = 7.6 Hz, 1 H), 7.47 - 7.32 (m, 3 H), 5.33 (s, 2 H), 4.58 (brs, 2 H), 3.84 (s, 2 H), 3.53 (t, J= 4.8 Hz, 2 H), 2.41 (s, 3 H), 2.21 (m, 2 H), 2.04 - 1.97 (m, 2 H), 1.91 - 1.82 (m, 2 H).
Example 62-1 V-{[3-(Aminomethyl)oxetan-3-yl]methyl}-6-methyl-2-(l-oxido-2,3-dihydro-l,4- benzothiazepin-4(5H)-yl)quinazolin-4-amine
Figure imgf000361_0001
2-Chloro-6-methylquinazolin-4(3H)-one
Figure imgf000361_0002
To a solution of 2,4-dichloro-6-methylquinazoline (2.13 g, 10 mmol ) in tetrahydrofuran (20 mL) was added sodium hydroxide (2 N, 20 mL). After being stirred at room temperature for 4 hours, the reaction mixture was chilled and acidified to pH 5 with acetic acid. The formed solid was collected by filtration, washed with water, and dried in vacuo to afford 1.7 g of the desired product as a white solid (yield was 87.6%).
6-Methyl-2-(l-oxido-2,3-dihydro-l,4-benzothiazepin-4(5H)-yl)quinazolin-4(3H)-one
Figure imgf000361_0003
To a stirred solution of 2-chloro-6-methylquinazolin-4(3H)-one (15 g, 77.3 mmol) and 2,3,4,5- tetrahydro-l ,4-benzothiazepine 1-oxide (16.8 g, 103 mmol) in toluene ( 200 mL) was added triethylamine (16.1 mL, 1 16 mmol). After being refluxed overnight, the reaction mixture was cooled to room temperature. The formed solid was collected by filtration, washed with ethanol (50 mL ) and ethyl acetate( 100 mL), and then dried in vacuo to afford 21.0 g of the desired product as a white solid (yield was 80%). V-{[3-(Aminomethyl)oxetan-3-yl]methyl}-6-methyl-2-(l-oxido-2,3-dihydro-l,4- benzothiazepin-4(5H)-yl)quinazolin-4-amine
Figure imgf000362_0001
To a solution of 6-methyl-2-(l-oxido-2,3-dihydro-l ,4-benzothiazepin-4(5H)-yl)quinazolin- 4(3H)-one (10 g, 29.5 mmol) and benzotriazol-l-yloxytris(dimethylamino)phosphonium hexafluorophosphate (16.9 g, 38.3 mmol) in N,N-dimethylformamide (140 mL) was added 1 ,8- diazabicyclo[5.4.0]undec-7-ene (6.7 g, 44.2 mmol) at room temperature. After being stirred for 10 minutes, (3-aminomethyl-oxetan-3-yl)-methylamine (5.1 g, 44.2 mmol) was added. The mixture was stirred for 4 hours at room temperature and diluted with water (150 mL). The separated aqueous layer was extracted with ethyl acetate (100 mL x 6 ). The organic layers were combined and washed with brine, dried over sodium sulfate, and then concentrated in vacuo. The residue was purified by flash column chromatography (eluting with 10% methanol in
dichloromethane) to afford 9.0 g of the impure product (purity was 90%>). The impure product was purified by preparative HPLC to afford 6.0 g of the desired product as a white solid. MS obsd. (ESI+) [(M+H)+] 438, 1H NMR (400 MHz, CD3OD) δ ppm 8.02 (s, 1 H), 7.82 - 7.79 (m, 2 H), 7.64 (d, J = 1.6 Hz, 1H), 7.60 - 7.57 (m, 3 H), 5.44 (d, 1 H), 5.13 (brs, 1 H), 4.77 (brs, 1 H), 4.66 - 4.59 (m, 4 H), 4.51 (brs, 1 H), 4.24 (s, 2 H), 3.55 (brs, 2 H), 3.44 (s, 2 H ), 2.44(s, 3 H).
Example 62-2 and Example 62-3
(-)- V-{[3-(Aminomethyl)oxetan-3-yl]methyl}-6-methyl-2-[(l-oxido-2,3-dihydro-l,4- benzothiazepin-4(5H)-yl]quinazolin-4-amine and (+)- V-{[3-(Aminomethyl)oxetan-3- yl]methyl}-6-methyl-2-[l-oxido-2,3-dihydro-l,4-benzothiazepin-4(5H)-yl]quinazolin-4- amine
Figure imgf000362_0002
(-) (+)
The chiral separation of Example 62-1 (column: IA; flow rate: 15 mL/min; gradient: 50% hexane in ethanol with 0.4% of triethylamine) affords (-)- N- {[3-(aminomethyl)oxetan-3-yl]methyl}-6- i_ _n ¾- ihydro-l ,4-benzothiazepin-4(5H)-yl]quinazolin-4-amine, MS obsd. (ESI+) [(M+H)+] 438, and (+)-N- {[3-(aminomethyl)oxetan-3-yl]methyl}-6-methyl-2-[l-oxido- 2,3-dihydro-l ,4-benzothiazepin-4(5H)-yl]quinazolin-4-amine, MS obsd. (ESI+) [(M+H)+] 438.
Example 62-4 and Example 62-5 \r4~-[2-(l,l-Dioxido-2,3-dihydro-l,4-benzothiazepin-4(5H)-yl)-6-methylquinazolin-4-yl]-2- fluorobutane-l,4-diamine and V~l~-[2-(l,l-Dioxido-2,3-dihydro-l,4-benzothiazepin-4(5H)- yl)-6-methylquinazolin-4-yl]-2-fluorobutane-l,4-diamine
Figure imgf000363_0001
A
The title compound was prepared in analogy to Example 62-1 in Scheme 23 by using 2-chloro-6- methylquinazolin-4(3H)-one, 2,3,4,5-tetrahydro-l,4-benzothiazepine 1 , 1-dioxide and 2- fluorobutane-l ,4-diamine. 8.65 mg of compound A and 3.54 mg of compound B were obtained.
A: MS obsd. (ESI+) [(M+H)+] 444, 1H NMR (400 MHz, CD3OD) δ ppm 8.03 - 7.90 (d, J = 3 Hz,
1 H), 7.65 (s, 1 H), 7.50 - 7.40 (t, 1 H), 7.40 - 7.30 (m, 3 H), 7.15 (s, 1 H), 5.95 (s, 1 H), 5.10 (s,
2 H), 4.75 - 4.50 (d, J = 52 Hz, 2 H), 3.75 (s, 2 H), 3.40 (s, 2 H), 2.97 - 2.87 (m, 2 H), 2.34 (s, 3 H), 1.90 (s, 2 H). B: MS obsd. (ESI+) [(M+H)+] 444, 1H NMR (400 MHz, CD3OD) δ ppm 8.03 - 7.90 (d, J = 4 Hz, 1 H), 7.70 (s, 1 H), 7.45 - 7.35 (t, 1 H), 7.33 - 7.25 (m, 3 H), 6.10 (s, 1 H), 5.15 (s, 2 H), 4.90 - 4.50 (m, 3 H), 4.00 - 3.65 (m, 2 H), 3.40 (s, 2 H), 2.95 - 2.70 (m, 2 H), 2.30 (s, 3 H), 2.1 1 - 1.65 (m, 2 H).
Example 62-6 V-{[3-(Aminomethyl)oxetan-3-yl]methyl}-2-(2,3-dihydro-l,4-benzothiazepin-4(5H)-yl)-6- methylquinazolin-4-amine
Figure imgf000364_0001
The title compound was prepared in analogy to Example 62-1 in Scheme 23 by using 2-chloro-6- methylquinazolin-4(3H)-one, 2,3,4,5-tetrahydro-l,4-benzothiazepine and oxetane-3,3- diyldimethanamine. MS obsd. (ESI+) [(M+H)+] 422. 1H NMR (400 MHz, CD3OD) δ ppm 7.66 (dd, J = 1.6, 7.2 Hz, 1 H), 7.62 (s, 1 H), 7.44 (dd, J = 1.2, 7.6 Hz, 1 H), 7.34 - 7.29 (m, 2 H), 7.18 (m, 1 H), 7.08 (m, 1 H), 4.99 (s, 2 H), 4.63 (d, J = 6.4 Hz, 2 H), 4.45 (d, J = 6.4 Hz, 2 H), 4.34 (s, 2 H), 4.02 (s, 2 H), 2.98 (s, 2 H), 2.90 (m, 2 H), 2.36 (s, 3 H).
Example 62-7 irans-4-Fluoro-l-[6-methyl-2-(l-oxido-2,3-dihydro-l,4-benzothiazepin-4(5H)-yl)quinazolin- 4-yl]pyrrolidin-3-amine
Figure imgf000364_0002
The title compound was prepared in analogy to Example 62-1 in Scheme 23 by using 2-chloro-6- methylquinazolin-4(3H)-one, 2,3,4,5-tetrahydro-l,4-benzothiazepine 1-oxide and trans-4- fluoropyrrolidin-3-amine. MS obsd. (ESI+) [(M+H)+] 426. 1H NMR (400 MHz, CD3OD) 7.82 (s, 1 H), 7.71 (d, J = 6.8 Hz, 1 H), 7.42 (m, 4 H), 5.26 (d, J = 15.2 Hz, 1 H), 5.07 (d, J= 51.2 Hz, 1 H), 4.78 (brs, 1 H), 4.43 (m, 2 H), 4.29 (m, 1 H), 4.06 (t, J= 1 1.2 Hz, 1 H), 3.86 (d, J = 12 Hz, 1 H), 3.75 (m, 1 H), 3.40 (m, 2 H), 2.40 (s, 3 H).
Example 63-1 V-(2-{[2-(l,l-Dioxido-2,3-dihydro-l,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4- yl] amino} ethyl)acetamide
Figure imgf000365_0001
To a solution ofN-[2-(l,l-dioxido-2,3-dihydro-l,4-benzothiazepm^
4-yl] ethane- 1,2-diamine (39 mg, 0.1 mmol, prepared in analogy to Example 9-11) in
dichloromethane (5 mL) was added acetic anhydride (12 mg, 0.12 mmol) at 0 °C. The reaction mixture was stirred at room temperature for 2 hours and then concentrated in vacuo. The residue was diluted with a saturated aqueous solution of sodium bicarbonate (5 mL), and extracted with dichloromethane (10 mL x 2). The combined organic layers were washed with brine (10 mL), dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by flash column chromatography (eluting with 10% methanol in dichloromethane) to afford 21 mg of the desired product as a white solid (yield was 48%). MS obsd. (ESI+) [(M+H)+] 439, 1H NMR (400 MHz, CD3OD) δ ppm 8.16 (s, 1 H), 7.95 (d, J= 1.8 Hz, 2 H), 7.86 (d, J = 1.9 Hz, 1 H), 7.62 (t, J = 3.6 Hz, 2 H), 7.46 (t, J= 3.8 Hz, 1 H), 7.31 (d, J= 2.1 Hz, 1 H), 7.22 (d, J= 2.1 Hz, 1 H), 6.84 (s, 1 H), 6.20 (s, 1 H), 5.10 (s, 2 H), 4.43 (brs, 2 H), 3.62 (s, 2 H), 3.32 (m, 4 H), 2.34 (s, 3 H), 1.89 (s, 3 H). Example 63-2
TV- { [3-({ [2-(l , l-Dioxido-2,3-dihydro- 1 ,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4- yl] amino} methyl)oxetan-3-yl] methyl} acetamide
Figure imgf000365_0002
The title compound was prepared in analogy to Example 63-1 in Scheme 25 by using 7V-{[3- (aminomethyl)oxetan-3-yl]methyl} -2-(l , 1 -dioxido-2,3-dihydro- 1 ,4-benzothiazepin-4(5H)-yl)-6- methylquinolin-4-amine (prepared in analogy to Example 3-50) and acetic anhydride. MS obsd.
(ESI+) [(M+H)+] 495, 1H NMR (400 MHz, CD3OD) δ ppm 8.00 (d, J= 7.6 Hz, 1 H), 7.89 (d, J = 7.2 Hz, 1 H), 7.66 (t, 2 H), 7.46 (t, 2 H), 7.32 - 7.30 (m, 1 H), 6.22 (s, 1 H), 5.17 (s, 2 H), 4.56 - 4.51 (m, 6 H), 3.67 (d, 4 H), 3.60 (t, J= 9.6 Hz, 2 H ), 2.43 (s, 3 H), 2.06 (s, 3 H). Example 63-3 V-(3-{[2-(l,l-Dioxido-2,3-dihydro-l,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4- yl] amino}propyl)acetamide
Figure imgf000366_0001
The title compound was prepared in analogy to Example 63-1 in Scheme 25 by using N-[2-(l,l- dioxido-2,3-dihydro- 1 ,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]propane- 1 ,3-diamine (prepared in analogy to Example 9-3) and acetic anhydride. MS obsd. (ESI+) [(M+H)+] 453, 1H NMR (400 MHz, CD3OD) δ ppm 8.00 - 7.97 (m, 1 H), 7.81 (d, J= 7.2 Hz, 1 H), 7.76 - 7.64 (m, 2 H), 7.46 - 7.42 (m, 2 H), 7.30 - 7.28 (m, 1 H), 5.99 (s, 1 H), 5.14 (s, 2 H), 4.54 (brs, 2 H), 3.58 (t, 2 H), 3.36 (m, 4 H), 2.42 (s, 3 H), 2.00 (s, 3 H), 1.94 - 1.87 (m, 2 H).
Example 63-4 V-[2-(l,l-Dioxido-2,3-dihydro-l,4-benzothiazepin-4(5H)-yl)-6-methylquinazolin-4- yljacetamide
Figure imgf000366_0002
A mixture of 2-(l,l-dioxido-2,3-dihydro-l,4-benzothiazepin-4(5H)-yl)-6-methylquinazolin-4- amine (50 mg, 0.14 mmol, prepared in analogy to Example 59) and acetic anhydride (2 mL) was heated with stirring at 110 °C for 2 hours under nitrogen. The reaction mixture was diluted with ethyl acetate, washed with a saturated aqueous solution of sodium carbonate and brine, dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography on silica gel to give 30 mg of the product as a white powder. MS obsd. (ESI+) [(M+H)+] 397, 1H NMR (400 MHz, CD3OD) δ ppm 7.87 (d, J= 7.6 Hz, 1 H), 7.80 (s, 1 H), 7.56 (m, 3 H), 7.28 (m, 1 H), 7.21 (m, 1 H), 5.11 (s, 2 H), 4.48 (s, 2 H), 2.99 (s, 2 H), 2.47 (s, 6 H). Example 64 l-[2-(l,l-Dioxido-2,3-dihydro-l,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]-3- methylpyrrolidin-3-amine
Figure imgf000367_0001
TV- { 1- [2-(l , l-Dioxido-2,3-dihydro- 1 ,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl] -3- methylpy rrolidin-3-yl} acetamide
Figure imgf000367_0002
The title compound was prepared in analogy to Example 3-1 in Scheme 26 by using 4-(4-chloro- 6-methylquinolin-2-yl)-2-methyl-2,3,4,5-tetrahydro- 1 ,4-benzothiazepine 1 , 1 -dioxide (prepared in analogy to the one in Example 2-1) and 7V-(3-methylpyrrolidin-3-yl)acetamide. l-[2-(l,l-Dioxido-2,3-dihydro-l,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]-3- methylpyrrolidin-3-amine
Figure imgf000367_0003
A mixture of N-{l-[2-(l,l-dioxido-2,3-dihydro-l,4-benzothiazepin-4(5H)-yl)-6-methylquinolin- 4-yl]-3-methylpyrrolidin-3-yl}acetamide (102 mg, 0.21 mmol) and hydrochloric acid (2 N, 120 mL) was heated with stirring at 100 °C for 16 hours. After being cooled to room temperature, the reaction mixture was adjusted to pH 9 with a saturated aqueous solution of potassium carbonate and exacted with dichloromethane (200 mL x 3). The combined organic layers were dried over sodium sulfate, and concentrated in vacuo. The residue was purified by preparative HPLC to afford 2.6 mg of the product (yield was 2.8%). MS obsd. (ESI+) [(M+H)+] 437, 1H NMR (400 MHz, CD3OD) 5 ppm 8.10 - 8.08 (d, J= 7.6 Hz, 1 H), 8.01 (s, 1 H), 7.85 - 7.83 (d, J= 7.6 Hz, 1 H), 7.76 - 7.71 (m, 2 H), 7.60- 7.58 (m, 2 H), 5.92 (s, 1 H), 5.31 (s, 2 H), 4.51 (s, 2 H), 4.22 - 3.97 (m, 4 H), 3.75 - 3.73 (d, J= 8 Hz, 2 H), 2.47 (s, 3 H), 3.11- 3.08 (m, 2 H), 2.47 - 2.31 (m, 2 H), 1.63 (s, 3 H).
Example 65
TV- [(3- Aminooxetan-3-yl)methyl] -2-(9-methoxy- 1 , l-dioxido-2,3-dihydro- 1 ,4-benzothiazepin- 4(5H)-yl)-6-methylquinolin-4-amine
Figure imgf000368_0001
A mixture of 7V-[(3-aminooxetan-3-yl)methyl]-2-(9-fluoro-l,l-dioxido-2,3-dihydro-l,4- benzothiazepin-4(5H)-yl)-6-methylquinolin-4-amine (20 mg, 0.044 mmol, prepared in analogy to Example 1-4) and sodium methoxide (24 mg, 0.44 mmol) in methanol (2 mL) was heated with stirring in a sealed 5 mL of microwave process via for 20 minutes at 100 °C under microwave irradiation. The resulting mixture was concentrated in vacuo. The residue was purified by preparative HPLC to afford 6 mg of the product (yield was 29%). MS obsd. (ESI ) [(M+H)+] 469, !HNMR (400 MHz, CD3OD) δ ppm 7.67 (s, 1 H), 7.62 - 7.52 (m, 1 H), 7.47 (d, J= 8.59 Hz, 1 H), 7.41 (d, J= 7.07 Hz, 1 H), 7.31 (dd, J= 8.46, 1.89 Hz, 1 H), 7.16 (d, J= 7.83 Hz, 1 H), 5.99 (s, 1 H), 5.08 (s, 2 H), 4.63 - 4.49 (m, 4 H), 4.31 (t, J= 5.56 Hz, 2 H), 3.98 - 3.81 (m, 5 H), 3.54 (s, 2 H), 2.43 (s, 3 H).
Example 66
4-(4-{[(3-Aminooxetan-3-yl)methyl]amino}-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-l,4- benzothiazepin-7-ol 1,1-dioxide
Figure imgf000369_0001
A mixture of N-[(3-aminooxetan-3-yl)methyl]-2-(7-methoxy-l,l-dioxido-2,3-dihydro-l,4- benzothiazepin-4(5H)-yl)-6-methylquinolin-4-amine (20 mg, 0.044 mmol, prepared in analogy to Example 1-5), potassium hydroxide (24 mg, 0.44 mmol) in dimethylsulfoxide (2 mL) was heated with stirring in a sealed 5 mL of microwave process via for 20 minutes at 100 °C under microwave irradiation. The resulting mixture was purified by preparative HPLC to afford 6 mg of the product (yield was 30%). MS obsd. (ESI+) [(M+H)+] 455, 1HNMR (400 MHz, CD3OD) δ ppm 7.77 (d, J= 8.59 Hz, 1 H), 7.67 (s, 1 H), 7.45 (d, J= 8.59 Hz, 1 H), 7.31 (dd, J= 8.46, 1.64 Hz, 1 H), 7.18 (d, J= 2.53 Hz, 1 H), 6.72 (dd, J= 8.59, 2.27 Hz, 1 H), 6.19 (s, 1 H), 5.03 (s, 2 H), 4.68 (d, J= 6.57 Hz, 2 H), 4.61 (d, J= 6.57 Hz, 2 H), 3.66 (s, 2 H), 3.50 (brs, 2 H), 3.30 (m, 2 H), 2.43 (s, 3 H).
Example 67
3- { [2-(l , l-Dioxido-2,3-dihydro- 1 ,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl] amino}- 2-methyl ropane- 1 ,2-diol
Figure imgf000369_0002
2-(l , l-Dioxido-2,3-dihydro- 1 ,4-benzothiazepin-4(5H)-yl)-6-methyl- V-(2-methylprop-2-en- 1- yl)quinolin-4-amine
Figure imgf000369_0003
A solution of 4-(4-chloro-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-l,4-benzothiazepine 1,1- dioxide (372.0 mg, 1.0 mmol, prepared in analogy to 4-(4-chloro-6-(trifluoromethoxy)quinolin- 2- yl)-2,3,4,5-tetrahydro-l,4-benzothiazepine 1,1-dioxide in Example 17-1) and 2-methylprop-2- en-1 -amine (213.0 mg, 3.0 mmol) in l-methyl-2-pyrrolidinone ( 1.0 mL) was heated with stirring at 160 °C for 36 hours. The reaction mixture was cooled to room temperature, diluted with water (10 mL) and extracted with ethyl acetate (100 mL). The organic layer was washed with brine (50 mL x 2), dried over anhydrous sodium sulfate and then concentrated in vacuo to afford 407.0 mg of the product as a light yellow solid. MS obsd. (ESI+) [(M+H)+] 408.
3- { [2-(l , l-Dioxido-2,3-dihydro- 1 ,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl] amino}- 2-methyl ropane- 1 ,2-diol
Figure imgf000370_0001
A mixture solution of 2-(l,l-dioxido-2,3-dihydro-l,4-benzothiazepin-4(5H)-yl)-6-methyl-N-(2- methylprop-2-en-l-yl)quinolin-4-amine (200.0 mg, 0.49 mmol), 4-methylmorpholine N-oxide monohydrate (67.2 mg, 0.58 mmol) and osmium tetroxide (6.4 mg, 0.024 mmol) in acetone ( 10 mL) was stirred at room temperature for 1 hour. After being quenched by adding sodium bisulfite, the resulting mixture was extracted with ethyl acetate (100 mL). The organic layer was washed with brine (50 mL x 2), dried over anhydrous sodium sulfate and then concentrated in vacuo. The residue was purified by preparative HPLC to afford 25.1 mg of the desired product as a light yellow solid (yield was 11.6%), MS obsd. (ESI+) [(M+H)+] 442, 1H NMR (400 MHz, CD3OD) δ ppm 7.96 (dd, J= 7.83, 1.01 Hz, 1 H), 7.89 (d, J= 7.33 Hz, 1 H), 7.60 (td, J = 7.45, 1.26 Hz, 1 H), 7.54 (s, 1 H), 7.50 - 7.34 (m, 2 H), 7.28 (dd, J= 8.59, 1.77 Hz, 1 H), 6.22 (s, 1 H), 5.13 (brs, 2 H), 4.52 (brs, 2 H), 3.66 - 3.46 (m, 4 H), 3.40 (s, 2 H), 3.33 (dt, J= 3.28, 1.64 Hz, 2 H), 2.41 (s, 3 H), 1.31 (s, 3 H).
Example 68
4- { [2-(l , l-Dioxido-2,3-dihydro- 1 ,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4- yl]amino}butane-l,3-diol
Figure imgf000371_0001
A solution of 4-{[2-(l,l-dioxido-2,3-dihydro-l,4-b^
yl]amino}-3-hydroxybutanoic acid (50.0 mg, 0.11 mmol, prepared in analogy to Example 11-3), sodium borohydride (100.0 g, 2.6 mmol) and iodine (300.0 mg, 1.2 mmol) in
tetrahydroiuran (10.0 mL) was stirred at room temperature for 16 hours. The reaction mixture was diluted with water (20 mL) and extracted with ethyl acetate (100 mL). The organic layer was washed with brine (50 mL x 2), dried over anhydrous sodium sulfate and then concentrated in vacuo. The residue was purified by preparative HPLC to afford 20.0 mg of the desired product as a light yellow solid (yield was 41.2%). MS obsd. (ESI+) [(M+H)+] 442, 1H NMR (400 MHz, CD3OD) δ ppm 8.04 (d, J= 7.58 Hz, 1 H), 7.90 (d, J= 7.58 Hz, 1 H), 7.81 (brs, 1 H), 7.75 - 7.59 (m, 2 H), 7.59 - 7.41 (m, 2 H), 6.10 (s, 1 H), 5.25 (brs, 2 H), 4.53 (brs, 2 H), 4.12 (brs, 1 H), 3.82 (t, J= 5.94 Hz, 2 H), 3.68 (brs, 2 H), 3.55 (dd, J= 13.77, 4.17 Hz, 1 H), 3.44 (dd, J= 13.64, 7.33 Hz, 1 H), 2.45 (s, 3 H), 1.97 - 1.73 (m, 2 H).
Example 69-1 N- [6-Methyl-2-(2-methyl- 1 , l-dioxido-2,3-dihydro- 1 ,4-benzothiazepin-4(5H)-yl)quinolin-4- yl] ethane- 1 ,2-diamine
Figure imgf000371_0002
4-(4-Chloro-6-methylquinolin-2-yl)-2-methyl-2,3,4,5-tetrahydro-l,4-benzothiazepine 1,1- dioxide
Figure imgf000371_0003
To a cooled solution of 4-(4-chloro-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-l,4- ^e (186 mg^ 0.5 mmol, prepared in analogy to 4-(4-chloro-6- (trifluoromethoxy)quinolin-2-yl)-2,3,4,5-tetrahydro-l,4-benzothiazepine 1,1-dioxide in Example 17-1) in dry tetrahydrofuran (10 mL) was added n-butyllithium (0.47 mL, 1.6 N) at -78 °C under argon. After being stirred at -78 °C for 1 hour, a solution of methyl iodide in dry tetrahydrofuran (5 mL) was added to the reaction mixture dropwise at -78°C. Then the mixture was stirred overnight whilst allowing the temperature to rise slowly to room temperature. The resulting reaction mixture was poured into a saturated aqueous solution of ammonium chloride (20 mL) and extracted with ethyl acetate (50 mL). The organic layer was dried over sodium sulfate and concentrated in vacuo. The residue was purified by flash column chromatography (eluting with 20% ethyl acetate in petroleum ether) to afford the desired product. TV- [6-Methyl-2-(2-methyl- 1 , l-dioxido-2,3-dihydro- 1 ,4-benzothiazepin-4(5H)-yl)quinolin-4- yl] ethane- 1 ,2-diamine
Figure imgf000372_0001
The title compound was prepared in analogy to Example 9-1 in Scheme 30 by using 4-(4-chloro- 6-methylquinolin-2-yl)-2-methyl-2,3,4,5-tetrahydro-l,4-benzothiazepine 1,1-dioxide and ethane
1,2-diamine. MS obsd. (ESI+) [(M+H)+] 411, 1H NMR (400 MHz, CD3OD) δ ppm 8.01 (d, J = 7.83 Hz, 1 H), 7.85 (brs, 1 H), 7.70 - 7.60 (m, 2 H), 7.52 - 7.40 (m, 2 H), 7.30 (dd, J= 8.59, 1.77 Hz, 1 H), 6.03 (s, 1 H), 5.13 (brs, 2 H), 3.67 - 3.57 (m, 1 H), 3.56 - 3.48 (m, 2 H), 3.31 - 3.30 (m, 3 H), 3.15 - 3.04 (m, 2 H), 2.42 (s, 3 H), 1.51 (brs, 2 H).
Example 69-2
N- [(3- Aminooxetan-3-yl)methyl] -6-methyl-2-(2-methyl- 1 , l-dioxido-2,3-dihydi
benzothiazepin-4(5H)-yl)quinolin-4-amine
Figure imgf000372_0002
The title compound was prepared in analogy to Example 69-1 in Scheme 30 by using 4-(4- chloro-6-methylquinolin-2-yl)-2-methyl-2,3,4,5-tetrahydro- 1 ,4-benzothiazepine 1 , 1 -dioxide and 3-(aminomethyl)oxetan-3-amine. MS obsd. (ESI+) [(M+H)+] 453, 1H NMR (400 MHz, CD3OD) δ ppm 8.01 (d, J= 7.83 Hz, 1 H), 7.92 (brs, 1 H), 7.66 (s, 2 H), 7.52 - 7.41 (m, 2 H), 7.30 (dd, J = 8.59, 1.77 Hz, 1 H), 6.19 (s, 1 H), 5.18 (brs, 1 H), 5.10 (brs, 1 H), 4.66 - 4.55 (m, 4 H), 3.68 (d, J= 2.02 Hz, 2 H), 3.65 - 3.57 (m, 1 H), 3.35 - 3.30 (m, 3 H), 2.43 (s, 3 H), 1.60 - 1.40 (brs, 2 H). Example 70 V-[(3-{[2-(l,l-Dioxido-2,3-dihydro-l,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4- yl]amino}oxetan-3-yl)methyl]-2,2,2-trifluoroacetamide
Figure imgf000373_0001
A solution of 4-(4-chloro-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-l,4-benzothiazepine 1,1- dioxide (500 mg, 1.341 mmol, prepared in analogy to 4-(4-chloro-6-(trifluoromethoxy)quinolin-
2- yl)-2,3,4,5-tetrahydro-l,4-benzothiazepine 1,1-dioxide in Example 17-1), N-[(3-aminooxetan-
3- yl)methyl]-2,2,2-trifluoroacetamide (570 mg, 70%, 2.01 mmol), Ι,Γ- bis(diphenylphosphino)ferrocene-palladium(II)dichloride (99 mg, 0.134 mmol), Ι,Γ- bis(diphenylphosphino)ferrocene (75 mg, 0.134 mmol), and sodium tert-butoxide (258 mg, 2.682 mmol) in 1,4-dioxane (8 mL) was heated with stirring in a sealed 10 mL of microwave process vial for 1.5 hours at 120 °C under microwave irradiation. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was dried over sodium sulfate and concentrated in vacuo. The residue was purified by flash column chromatography (eluting with 1 - 10% methanol in dichloromethane) to afford 190 mg of the desired product (yield was 26%). MS obsd. (ESI+) [(M+H)+] 535, 1H NMR (400 MHz, CD3OD) δ ppm 7.98 (m, 1 H), 7.82 (d, J= 6.8 Hz, 1 H), 7.66 (s, 1 H), 7.59 (td, J= 0.8, 7.6 Hz, 1 H), 7.47 - 7.42 (m, 2 H), 7.32 (dd, J= 1.6, 8.8 Hz, 1 H), 5.70 (s, 1 H), 5.18 (s, 2 H), 4.86 (m, 4 H), 4.52 (s, 2 H), 3.87 (s, 2 H), 3.60 (t, J= 4.8 Hz, 2 H), 2.43 (s, 3 H).
Example 71 TV- [3-(Aminomethyl)oxetan-3-yl] -2-(l , l-dioxido-2,3-dihydro- 1 ,4-benzothiazepin-4(5H)-yl)- 6-methylquinolin-4-amine
Figure imgf000374_0001
To a solution ofN-[(3-{[2-(l,l-dioxido-2,3-dihydro-l,4-benzothiazepin-4(5H)-yl)-6- methylquinolin-4-yl]amino}oxetan-3-yl)methyl]-2,2,2-trifluoroacetamide (190 mg, 0.355 mmol) in methanol (15 mL) was added an aqueous solution of potassium carbonate (197 mg, 1.42 mmol, dissolved in 2 mL of water). After being stirred at room temperature overnight, the resulting mixture was concentrated in vacuo to remove methanol. The residue was diluted with water (5 mL) and extracted with dichloromethane (15 mL). The organic layer was dried over sodium sulfate and concentrated in vacuo. The residue was purified by preparative HPLC to give 23 mg of the desired product as a white solid (yield was 14.8%). MS obsd. (ESI+) [(M+H)+] 439, 1H NMR (400 MHz, CD3OD) δ ppm 7.98 - 7.96 (m, 1 H), 7.58 - 7.56 (d, J= 6.8 Hz, 1 H), 7.44 - 7.40 (m, 2 H), 7.32 - 7.30 (t, 1 H), 7.19 (m, 2 H), 5.99 (s, 1 H), 5.54 (s, 1 H), 4.98 - 4.97 (d, J = 6.0, 4 H), 4.64 - 4.63 (m, 3 H), 3.51 (s, 2 H), 3.30 (s, 2 H), 2.34 (s, 3 H).
Example 72
2-(Aminomethyl)-2- { [2-(l , l-dioxido-2,3-dihydro- 1 ,4-benzothiazepin-4(5H)-yl)-6- methylquinolin-4-yl] amino}propane- 1 ,3-diol
Figure imgf000374_0002
A mixture of N-[(3-{[2-(l,l-dioxido-2,3-dihydro-l,4-benzothiazepin-4(5H)-yl)-6- methylquinolin-4-yl]amino}oxetan-3-yl)methyl]-2,2,2-trifluoroacetamide (269 mg, 0.503 mmol) and a solution of ammonia in methanol (7 M, 10 mL,) was stirred at room temperature overnight.
The resulting mixture was concentrated in vacuo and the residue was purified by preparative HPLC to afford 58 mg of the product as a white solid (yield was 25%). MS obsd. (ESI+)
[(M+H)+] 457, 1H NMR (400 MHz, CD3OD) δ ppm 8.11 - 8.09 (t, J = 6.4, 1.2 Hz, 1 H), 8.00 - 7.96 (m, 1 H), 7.86 (s, 1 H), 7.76 - 7.73 (m, 2 H), 7.64 - 7.60 (m, 2 H), 6.49 (s, 1 H), 5.33 (s, 2 H), 4.55 (s, 2 H), 3.82 (s, 2 H), 3.77 - 3.75 (m, 6 H), 2.49 (s, 3 H). Example 73
4- Amino- 1- [2-(l , l-dioxido-2,3-dihydro- 1 ,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4- yl] py rrolidin-2-one
Figure imgf000375_0001
To a solution of l-[2-(l,l-dioxido-2,3-dihydro-l,4-benzothiazepin-4(5H)-yl)-6-methylquinolin- 4-yl]-5-oxopyrrolidine-3-carboxamide (100 mg, 0.22 mmol, byproduct of Example 47-2) in acetonitrile (2 mL) and water (2 mL) was added (diacetoxyiodo)benzene (91 mg, 0.28 mmol). The mixture was stirred at room temperature overnight. The reaction mixture was diluted with water, acidified with concentrated hydrochloride acid (12 N), and extracted with
dichloromethane. The organic layer was dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography on silica gel (eluting with 1 - 10% methanol in dichloromethane) to give 10 mg of the product as a white solid. MS obsd. (ESI ) [(M+H)+] 437, 1H NMR (400 MHz, DMSO- 6) δ ppm 7.94 - 7.87 (m, 2 H), 7.60 (td, J= 1.2, 7.2
Hz, 1 H), 7.55 (d, J= 8.8 Hz, 1 H), 7.47 - 7.43 (m, 2 H), 7.37 (dd, J= 2.0, 8.8 Hz, 1 H), 7.22 (s, 1 H), 5.13 (s, 2 H), 4.42 (brs, 2 H), 4.02 (dd, J= 2.0, 9.6 Hz, 1 H), 3.87 (td, J= 3.6, 6.8 Hz, 1 H), 3.62 (dd, J= 4.8, 9.6 Hz, 2 H), 3.45 (dd, J= 3.2, 9.6 Hz, 1 H), 3.14 - 3.13 (m, 1 H), 2.85 (dd, J = 7.2, 16.8 Hz, 1 H), 2.36 (s, 3 H).
Example 74
2-(l , l-Dioxido-2,3-dihydro- 1 ,4-benzothiazepin-4(5H)-yl)-6-methy 1- V- [2- (methylsulfinyl)ethyl] quinolin-4-amine
Figure imgf000375_0002
2-(l , l-Dioxido-2,3-dihydro- 1 ,4-benzothiazepin-4(5H)-yl)-6-methy 1- V- [2- uinolin-4-amine
Figure imgf000376_0001
A dried microwave process vial capped with a rubber septum was purged with argon and charged with tris(dibenzylideneacetone)dipalladium(0) (2.88 mg, 0.005 mmol), 1-(N,N- dimethylamino)- -(dicyclohexylphosphino)biphenyl (5.90 mg, 0.015 mmol) and sodium tert- butoxide (134 mg, 1.4 mmol). The tube was purged with argon, and a solution of 4-(4-chloro-6- methylquinolin-2-yl)-2,3,4,5-tetrahydro-l ,4-benzothiazepine 1 , 1-dioxide (370 mg, 1.0 mmol, prepared in analogy to 4-(4-chloro-6-(trifluoromethoxy)quinolin-2-yl)-2,3,4,5-tetrahydro-l,4- benzothiazepine 1 , 1-dioxide in Example 17-1) and 2-(methylthio)ethylamine (128 mg, 1.4 mmol) in 1 ,4-dioxane (2.0 mL) was added. The mixture was heated with stirring in a sealed 5 mL of microwave process vial for 2 hour at 120 °C under microwave irradiation. After being cooled to room temperature, the reaction mixture was diluted with ethyl acetate, filtered through celite and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (eluting with 1 - 10% methanol in dichloromethane) to afford 341 mg of the desired product (yield was 80%). MS obsd. (ESI+) [(M+H)+] 428. 2-(l , l-Dioxido-2,3-dihydro- 1 ,4-benzothiazepin-4(5H)-yl)-6-methy 1- V- [2- (methylsulfinyl)ethyl]quinolin-4-amine
Figure imgf000376_0002
To a solution of 2-(l , l-dioxido-2,3-dihydro-l ,4-benzothiazepin-4(5H)-yl)-6-methyl-N-[2- (methylsulfanyl)ethyl]quinolin-4-amine (300 mg, 0.70 mmol) in acetic acid (2 mL) was added hydrogen peroxide (0.5 mL) at room temperature. The mixture was stirred at room temperature for 2 hours. The resulting mixture was diluted with ethyl acetate (10 mL), washed with a saturated aqueous solution of sodium bicarbonate, dried over sodium sulfate, and concentrated in vacuo. The residue was purified by preparative HPLC to afford the desired product. MS obsd.
" 1 _~ NMR (400 MHz, DMSO-<i(5) δ ppm 7.99 (d, J = 7.07 Hz, 1 H), 7.88 (dd, J= 7.83, 1.26 Hz, 1 H), 7.70 - 7.60 (m, 2 H), 7.47 (td, J= 7.64, 1.14 Hz, 1 H), 7.34 (d, J = 8.34 Hz, 1 H), 7.25 (dd, J= 8.34, 1.52 Hz, 1 H), 6.98 (t, J= 5.56 Hz, 1 H), 6.14 (s, 1 H), 5.09 (brs, 2 H), 4.5(brs, 2 H), 3.81 - 3.56 (m, 4 H), 3.20 - 3.07 (m, 1 H), 3.04 - 2.92 (m, 1 H), 2.65 (s, 3 H), 2.35 (s, 3 H).
Example 75
TV- {2- [(2- Aminoethyl)sulfonyl] ethyl}-2-(l , l-dioxido-2,3-dihydro- 1 ,4-benzothiazepin- yl)-6-methylquinolin-4-amine
Figure imgf000377_0001
To a solution of7V-{2-[(2-aminoethyl)sulfanyl]ethyl}-2-(l,l-dioxido-2,3-dihydro-l,4- benzothiazepin-4(5H)-yl)-6-methylquinolin-4-amine (40 mg, 0.087 mmol, prepared in analogy to Example 3-1 by using 4-(4-chloro-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-l,4- benzothiazepine 1,1 -dioxide and 2-[(2-aminoethyl)sulfanyl]ethylamine) in acetic acid (2 mL), potassiumpermanganate (15 mg, 0.08 mmol) was added. After being stirred at room temperature for 30 minutes, the mixture was concentrated in vacuo. The residue was purified by preparative HPLC to afford the pure product as a solid. MS obsd. (ESI+) [(M+H)+] 489, 1H NMR (400 MHz, CD3OD) δ ppm 7.99 (dd, J= 7.83, 1.26 Hz, 1 H), 7.93 (d, J= 7.58 Hz, 1 H), 7.65 (td, J= 7.45, 1.26 Hz, 1 H), 7.54 (s, 1 H), 7.49 - 7.41 (m, 2 H), 7.30 (dd, J= 8.46, 1.64 Hz, 1 H), 6.13 (s, 1 H), 5.16 (s, 2 H), 4.63 (brs, 1 H), 4.56 (brs, 1 H), 3.91 (t, J= 6.82 Hz, 2 H), 3.60 (t, J= 4.67 Hz, 2 H), 3.55 - 3.45 (m, 2 H), 3.31 - 3.27 (m, 2 H), 3.20 - 3.06 (m, 2 H), 2.41 (s, 3 H). Example 76 V-[2-(l-Imino-l-oxido-l,2,3,5-tetrahydro-4H-llambda~4~,4-benzothiazepin-4-yl)-6- methylquinolin-4-yl] ethane- 1 ,2-diamine
Figure imgf000377_0002
V-[4-(4-Chloro-6-methylquinolin-2-yl)-l-oxido-2,3,4,5-tetrahydro-lH-llambda~4~,4- benzothiazepin-l-ylidene]-2,2,2-trifluoroacetamide
Figure imgf000378_0001
To a suspension of 4-(4-chloro-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-l,4-benzothiazepine 1-oxide (357 mg, 1.0 mmol, prepared in analogy to the one in Example 18-1), trifluoroacetamide (226 mg, 2.0 mmol), magnesium oxide (160 mg, 4.0 mmol) and rhodium(II) acetate (11 mg, 2.5 mol) in dichloromethane (10 mL) was added (diacetoxyiodo)benzene (483 mg, 1.5 mmol). After being stirred at room temperature overnight, the resulting mixture was concentrated in vacuo. The residue was purified by flash column chromatography (eluting with 20 - 33% ethyl acetate in petroleum ether) to afford 234 mg of the pure product (yield was 50%). MS obsd. (ESI+) [(M+H)+] 468.
4-(4-Chloro-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-lH-llambda~4~,4-benzothiazepin-l- imine 1-oxide
Figure imgf000378_0002
To a solution of N-[4-(4-chloro-6-methylquinolin-2-yl)-l-oxido-2,3,4,5-tetrahydro-lH- llambda~4~,4-benzothiazepin-l-ylidene]-2,2,2-trifluoroacetamide (234 mg, 0.50 mmol) in methanol (10 mL) was added potassium carbonate (690 mg, 5.0 mmol). After being stirred at room temperature for 30 minutes, the reaction mixture was concentrated in vacuo. The residue was purified by column chromatography (eluting with 20 - 33% ethyl acetate in petroleum ether) to afford the N-unsubstituted sulfoximines. MS obsd. (ESI+) [(M+H)+] 372. V-[2-(l-Imino-l-oxido-l,2,3,5-tetrahydro-4H-llambda~4~,4-benzothiazepin-4-yl)-6- methylquinolin-4-yl] ethane- 1 ,2-diamine
Figure imgf000379_0001
The title compound was prepared in analogy to Example 9-1 in Scheme 35 by using 4-(4-chloro- 6-methylquinolin-2-yl)-2,3,4,5-tetrahydro- 1H- 1 lambda~4~,4-benzothiazepin- 1 -imine 1 -oxide and ethane 1,2-diamine. MS obsd. (ESI+) [(M+H)+] 396, 1H NMR (400 MHz, DMSO- 6) δ ppm 7.91 (d, J= 8.08 Hz, 1 H), 7.83 (d, J= 7.58 Hz, 1 H), 7.70 (s, 1 H), 7.58 -7.52 (m, 1 H), 7.44 - 7.37 (m, 1 H), 7.30 (d, J= 8.59 Hz, 1 H), 7.21 (dd, J= 8.46, 1.64 Hz, 1 H), 6.63 (t, J= 5.43 Hz, 1 H), 6.01 (s, 1 H), 5.11 (brs, 2 H), 4.61 (brs,l H), 4.10 (brs, 1 H), 3.49 - 3.36 (m, 2 H), 3.31 (q, J = 6.23 Hz, 3 H), 2.86 - 2.76 (m, 3 H), 2.34 (s, 3 H).
Example 77 2-(l,l-Dioxido-2,3-dihydro-l,4-benzothiazepin-4(5H)-yl)-6-methyl- V-[2-(S- methylsulfonimidoyl)ethyl]quinolin-4-amine
Figure imgf000379_0002
The title compound was prepared in analogy to Example 76 in Scheme 33 by using 2-(l,l- dioxido-2,3-dihydro- 1 ,4-benzothiazepin-4(5H)-yl)-6-methyl-N-[2- (methylsulfinyl)ethyl]quinolin-4-amine (prepared in analogy to Example 74) and
trifluoroacetamide. MS obsd. (ESI+) [(M+H)+] 459, 1H NMR (400 MHz, CD3OD) δ ppm 8.04 (d, J= 7.33 Hz, 1 H), 7.96 (d, J= 7.33 Hz, 1 H), 7.73 - 7.66 (m, 2 H), 7.60 - 7.55 (m, 1 H), 7.52 (s, 1 H), 7.46 - 7.40 (m, 1 H), 6.17 (s, 1 H), 5.26 (brs, 2 H), 4.50 (brs, 2 H), 3.98 (t, J= 6.69 Hz, 2 H), 3.68 (brs, 2 H), 3.59 (t, J= 6.82 Hz, 2 H), 3.14 (s, 3 H), 2.45 (s, 3 H). Example 78-1 irans-4-Amino-l-[2-(l-imino-l-oxido-l,2,3,5-tetrahydro-4H-llambda~4~,4-benzothiazepin- 4-yl)-6-methylquinolin-4-yl]pyrrolidin-3-ol
Figure imgf000380_0001
A mixture of 4-(4-chloro-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-lH-llambda~4~,4- benzothiazepin-l-imine 1-oxide (100 mg, 0.27 mmol), tert-butyl (trans-4-hydroxypyiroiidin-3- yl)carbamate (164 mg, 0.81 mmol) and n-butanol (0.2 mL) was stirred at 160 °C overnight. After the mixture being cooled to room temperature, to the above mixture was added dichloromethane (10 mL) and trifluoro acetic acid (10 mL). The mixture was stirred further until the reaction finished monitoring by TLC, and then concentrated in vacuo. The residue was dissolved in dichloromethane and the solution was washed with an aqueous solution of sodium hydroxide (10% WAV) and brine, dried over sodium sulfate, and concentrated in vacuo. The residue was purified by preparative HPLC to afford the product as a solid. MS obsd. (ESI+) [(M+H)+] 438, 1H NMR (400 MHz, CD3OD) δ ppm 8.05 (d, J= 7.83 Hz, 1 H), 7.84 (s, 1 H), 7.81 (s, 1 H), 7.61 (t, J= 7.45 Hz, 1 H), 7.52 (d, J= 8.59 Hz, 1 H), 7.49 - 7.43 (m, 1 H), 7.36 - 7.30 (m, 1 H), 6.14 (s, 1 H), 5.31 - 5.16 (m, 2 H), 4.25 (brs, 1 H), 4.17 - 4.05 (m, 1 H), 4.05 - 3.94 (m, 1 H), 3.62 (d, J= 10.61 Hz, 2 H), 3.70 - 3.58 (m, 2 H), 3.57 - 3.41 (m, 3 H), 2.43 (s, 3 H). Example 78-2 irans-l-[2-(l,l-Dioxido-2,3-dihydro-l,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]-4- fluoropyrrolidin-3-amine
Figure imgf000380_0002
The title compound was prepared in analogy to Example 78-1 in Scheme 7 by using 4-(4-chloro-
6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-l,4-benzothiazepine 1,1-dioxide and tert-butyl (trans- 4-fiuoropyrrolidin-3-yl)carbamate. MS obsd. (ESI+) [(M+H)+] 441, 1H NMR (400 MHz, CD3OD) δ ppm 7.98 (dd, J= 7.71, 1.89 Hz, 1 H), 7.91 - 7.75 (m, 2 H), 7.62 (t, J= 7.45 Hz, 1 H), 7.52 (d, J= 8.59 Hz, 1 H), 7.45 (td, J= 7.58, 3.28 Hz, 1 H), 7.32(d, J= 8.59 Hz, 1 H), 6.19 (s, 1 H), 5.18 (brs, 2 H), 5.06 (m, 1 H), 4.53 (brs, 2 H), 4.17 (m, 1 H), 4.03 (dd, J= 9.98, 5.43 Hz, 1 H), 3.81 - 3.54 (m, 4 H), 3.45 - 3.35 (m, 1 H), 2.42 (s, 3 H).
Example 79 l-[2-(l,l-Dioxido-2,3-dihydro-l,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4- yl]pyrrolidine-3-carboxamide
Figure imgf000381_0001
l-[2-(l,l-Dioxido-2,3-dihydro-l,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4- yl]pyrrolidine-3-carboxylic acid
Figure imgf000381_0002
A mixture of 4-(4-chloro-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-l,4-benzothiazepine 1,1- dioxide (500 mg, 1.34 mmol, prepared in analogy to 4-(4-chloro-6-(trifluoromethoxy)quinolin-2- yl)-2,3,4,5-tetrahydro-l,4-benzothiazepine 1,1 -dioxide in Example 17-1) and methyl pyrrolidine- 3-carboxylate (173 mg, 1.34 mmol) and N,N-diisopropylethylamine (346 mg, 2.68 mmol) was heated with stirring in a sealed 10 mL of microwave process vial for 1.5 hours at 140 °C under microwave irradiation. The resulting mixture was purified by preparative HPLC to afford 120 mg of the pure product (yield was 19.8%). l-[2-(l,l-Dioxido-2,3-dihydro-l,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4- yl]pyrrolidine-3-carbonyl chloride
Figure imgf000382_0001
To a cooled solution of l-[2-(l,l-dioxido-2,3-dihydro-l,4-benzothiazepin-4(5H)-yl)-6- methylquinolin-4-yl]pyrrolidine-3-carboxylic acid (120 mg, 0.26 mmol) in dichloromethane (20 mL) was added two drops of N,N-dimethylformamide followed by oxalyl chloride (30.6 μί, 0.39 mmol) at 0 °C. After being stirred for 16 hours at room temperature, the reaction mixture was concentrated in vacuo to afford 100 mg of the crude product which was used for the next step without any further purification. l-[2-(l,l-Dioxido-2,3-dihydro-l,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4- yl] py rrolidine-3-carboxamide
Figure imgf000382_0002
To a cooled solution of l-[2-(l,l-dioxido-2,3-dihydro-l,4-benzothiazepin-4(5H)-yl)-6- methylquinolin-4-yl]pyrrolidine-3-carbonyl chloride (100 mg, 0.21 mmol) in dichloromethane (20 mL) was added a saturated solution of ammonia in dichloromethane (10 mL) slowly at 0 °C. After being stirred for 16 hours at room temperature, the mixture was concentrated in vacuo. The residue was purified by preparative HPLC to afford 13 mg of the desired product (yield was 13.5%). MS obsd. (ESI+) [(M+H)+] 451, 1H NMR (400 MHz, CD3OD) δ ppm 8.08 - 8.05 (m, 2 H), 7.33 - 7.31 (d, J= 7.6 Hz, 1 H), 7.70 - 7.67 (m, 2 H), 7.57 - 7.55 (m, 2 H), 5.85 (s, 1 H), 5.25 (s, 2 H), 4.5 (s, 2 H), 4.03 - 3.94 (m, 4 H), 3.71 (s, 2 H), 3.29 - 3.21 (m, 1 H), 2.45 (s, 3 H), 2.41 - 2.32 (m, 1 H), 2.31 - 2,21 (m, 1 H).
Example 80 V-[2-(l,l-Dioxido-2,3-dihydro-l,4-benzothiazepin-4(5H)-yl)-6-(methylsulfinyl)quinolin-4- yl] propane- 1 ,3-diamine
Figure imgf000383_0001
4-[4-Chloro-6-(methylsulfinyl)quinolin-2-yl]-2,3,4,5-tetrahydro-l,4-benzothiazepine 1,1- dioxide
Figure imgf000383_0002
To a cooled solution of 4-[4-Chloro-6-(methylsulfanyl)quinolin-2-yl]-2,3,4,5-tetrahydro-l,4- benzothiazepine 1,1 -dioxide (800 mg, 1.98 mmol, prepared in analogy to 4-(4-chloro-6- methylquinolin-2-yl)-2,3,4,5-tetrahydro-l,4-benzothiazepine 1,1-dioxide in Example 17-1) in dichloromethane (70 mL) was added a solution of 3-chloroperoxybenzoic acid (400 mg, 198 mmol, purity 85%) in dichloromethane (30 mL) dropwise at 0 °C. After being stirred at 0 °C for 20 minutes, the reaction mixture was washed with a saturated aqueous solution of sodium bicarbonate (100 mL), a saturated aqueous solution of sodium thiosulphate (100 mL x 3) and brine (100 x 2). The organic layer was dried over sodium sulfate, filtered and concentrated in vacuo to afford 500 mg of the desired product (yield was 60%). V-[2-(l,l-Dioxido-2,3-dihydro-l,4-benzothiazepin-4(5H)-yl)-6-(methylsulfinyl)quinolin-4- yl]propane-l,3-diamine
Figure imgf000383_0003
A mixture of 4-[4-chloro-6-(methylsulfinyl)quinolin-2-yl]-2,3,4,5-tetrahydro-l,4- benzothiazepine 1,1-dioxide (300 mg, 0.71 mmol) and propane- 1,3-diamine (67525 mg, 7.1 mmol) was heated with stirring in a sealed 10 mL of microwave process vial for 1 hour at 150 °C under microwave irradiation. The reaction mixture was purified by preparative HPLC to afford the trifluoro acetic acid salt of the desired product. The trifluoro acetic acid salt was flashed through SPE column with methanol. The eluent was concentrated in vacuo and dried by
I nn liyfltinn in affnrH 756.8 mg of the desired product (yield was 78%). MS obsd. (ESI+) [(M+H)+] 459, 1H NMR (400 MHz, CD3OD) δ ppm 8.44 (s, 1 H), 8.05 - 7.96 (m, 3 H), 7.88 (d, J = 7.6 Hz, 1 H), 7.71 (t, J= 7.6 Hz, 1 H), 7.55 (t, J= 7.6 Hz, 1 H), 6.02 (s, 1 H), 5.33 (s, 2 H), 4.54 (s, 2 H), 3.74 (s, 2 H), 3.61 (t, J= 6.0 Hz, 2 H), 3.11 (t, J= 8.0 Hz, 2 H), 2.82 (s, 3 H), 2.16 - 2.09 (m, 2 H). Example 81
4- [(3- Aminopropyl)amino] -2-(l , l-dioxido-2,3-dihydro- 1 ,4-benzothiazepin- yl)quinoline-6-carboxamide
Figure imgf000384_0001
4-Chloro-2-(2,3-dihydro-l,4-benzothiazepin-4(5H)-yl)quinoline-6-carboxamide
Figure imgf000384_0002
To a mixture of methyl 4-chloro-2-(2,3-dihydro-l,4-benzothiazepin-4(5H)-yl)quinoline-6- carboxylate (400 mg, 1.04 mmol, prepared in analogy to 4-(4-chloro-6-methylquinolin-2-yl)-8- methoxy-2,3,4,5-tetrahydro-l,4-benzothiazepine in Example 1-1) in tetrahydrofuran (5 mL) and a saturated solution of ammonia in methanol (30 mL) was heated with stirring for 16 hours at 120 °C in a sealed tube. The reaction mixture was concentrated in vacuo to afford 300 mg of the product (yield was 78%).
4-Chloro-2-(l,l-dioxido-2,3-dihydro-l,4-benzothiazepin-4(5H)-yl)quinoline-6-carboxamide
Figure imgf000384_0003
To a cooled solution of 4-chloro-2-(2,3-dihydro-l,4-benzothiazepin-4(5H)-yl)quinoline-6- carboxamide (300 mg, 0.81 mmol) in dichloromethane (50 mL) was added 3- chloroperoxybenzoic acid (418 mg, 70% purity, 1.70 mmol) at 0 °C. After being stirred for 2 Vi ii c at n °r t p
Figure imgf000384_0004
mixture was washed with a saturated aqueous solution of sodium thiosulphate (50 mL), dried over sodium sulfate, and concentrated in vacuo to afford 300 the crude product.
4- [(3- Aminopropyl)amino] -2-(l , l-dioxido-2,3-dihydro- 1 ,4-benzothiazepin-4(5H)- yl)quinoline-6-carboxamide
Figure imgf000385_0001
A mixture of 4-chloro-2-(l,l-dioxido-2,3-dihydro-l,4-benzothiazepin-4(5H)-yl)quinoline-6- carboxamide (300 mg, 0.75 mmol) and propane- 1,3 -diamine (306 mg, 4.14 mmol) was heated with stirring in a sealed 10 mL of microwave process vial for 1 hour at 120 °C under microwave irradiation. The reaction mixture was purified by preparative HPLC to afford 23.5 mg of the desired product (yield was 7.2%). MS obsd. (ESI+) [(M+H)+] 440, 1H NMR (400 MHz, CD3OD) δ ppm 8.70 - 8.69 (d, J= 1.6 Hz, 1 H), 8.18 - 8.15 (m, 1 H), 8.10 - 8.08 (dd, J= 1.2, 7.6 Hz, 1 H), 7.88 - 7.84 (t, J= 6.8 Hz, 2 H), 7.73 - 7.72 (m, 1 H), 7.60 - 7.59 (m, 1 H), 6.01 (s, 1 H), 5.34 (s, 2 H), 4.55 (s, 2 H), 3.75 (s, 2 H), 3.64 - 3.60 (t, J= 6.8 Hz, 1 H), 3.11 - 3.09 (m, 2 H), 2.18 - 2.09 (m, 2 H). Example 82
1- {4- [(3- Aminopropyl)amino] -2-(l , l-dioxido-2,3-dihydro- 1 ,4-benzothiazepin-4(5H)- yl)quinolin-6-yl}ethanol
Figure imgf000385_0002
4-Chloro-2-(l,l-dioxido-2,3-dihydro-l,4-benzothiazepin-4(5H)-yl)quinoline-6-carbaldehyde
Figure imgf000385_0003
To a solution of oxalyl dichloride (36.3 mg, 0.29 mmol) in dichloromethane (10 mL) was added a solution of dimethyl sulphoxide (0.1 mL, 0.57 mmol) in dichloromethane (10 mL) at -78 °C dropwise. After the mixture being stirred for 10 minutes at -78 °C, a solution of 4-chloro-2-(l, l- dioxido-2,3-dihydro-l ,4-benzothiazepin-4(5H)-yl)-quinoline-6-methanol (100 mg, 0.26 mmol, prepared in analogy to the one in Example 3-23) in dichloromethane (5 mL) was added dropwise. After the mixture being stirred for further 1 hour at -78 °C, triethylamine (0.2 mL, 1.3 mmol) was. The resulting mixture was stirred at -78 °C for 1 hour and then at room temperature for further 1 hour. The reaction was washed with brine, dried over sodium sulfate and concentrated in vacuo to afford 70 mg of the product. l-[4-Chloro-2-(l,l-dioxido-2,3-dihydro-l,4-benzothiazepin-4(5H)-yl)quinolin-6-yl]ethanol
Figure imgf000386_0001
To a cooled solution of 4-chloro-2-(l, l-dioxido-2,3-dihydro-l,4-benzothiazepin-4(5H)-yl)- quinoline-6-carbaldehyde (100 mg, 0.26 mmol) in tetrahydrofuran (20 mL) was added a solution of methyl magnesium bromide in tetrahydrofuran (0.13 mL, 0.39 mmol, 3 M) at 0 °C dropwise. After being stirred for 20 minutes at the temperature below 12 °C, the mixture was concentrated in vacuo. The residue was purified by preparative TLC to give 100 mg of the desired product (yield was 96%).
1- {4- [(3- Aminopropyl)amino] -2-(l , l-dioxido-2,3-dihydro- 1 ,4-benzothiazepin- yl)quinolin-6-yl}ethanol
Figure imgf000386_0002
A mixture of l-[4-chloro-2-(l , l-dioxido-2,3-dihydro-l ,4-benzothiazepin-4(5H)-yl)quinolin-6- yljethanol (150 mg, 0.387 mmol) and propane- 1 ,3-diamine (55 mg, 0.74 mmol) was heated with stirring in a sealed 0.5 mL of microwave process vial for 1.5 hours at 150 °C under microwave irradiation. The reaction mixture was purified by preparative HPLC and SPE to afford 70.2 mg of the desired product (yield was 41.2%). MS obsd. (ESI+) [(M+H)+] 441 , 1H NMR (400 MHz, CD3OD) δ ppm 8.10 - 8.05 (m, 2 H), 7.86 - 7.80 (d, J= 7.6 Hz, 1 H), 7.78 - 7.75 (m, 2 H), 7.72- 7.62 (t, J= 1.2 Hz, 1 H), 7.60 - 7.50 (t, J= 1.2 Hz, 1 H), 5.94 (s, 1 H), 5.30 (s, 2 H), 4.98 - 4.92 (m, 1 H), 4.58 - 4.45 (m, 2 H), 3.78 - 3.70 (t, J= 2.8 Hz, 2 H), 3.62 - 3.53 (t, J= 4.4 Hz, 2 H), 3.10 - 3.02 (t, J= 6.8 Hz, 2 H), 2.12 - 2.02 (m, 2 H), 1.50 - 1.40 (d, J= 6.4 Hz, 3 H). Example 83
3- { [2-(l , l-Dioxido-2,3-dihydro- 1 ,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4- yl] amino] propanenitrile
Figure imgf000387_0001
A flask containing 4-(4-chloro-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-l,4-benzothiazepine 1,1 -dioxide (500 mg, 1.34 mmol, prepared in analogy to 4-(4-chloro-6-
(trif uoromethoxy)quinolin-2-yl)-2,3,4,5-tetrahydro-l,4-benzothiazepine 1,1-dioxide in Example 17-1), 3-aminopropionitrile (140 mg, 2.01 mmol ), tris(dibenzylideneacetone)dipalladium(0) ( 61.8 mg, 0.068 mmol ), 2,2'-bis(diphenylphosphino)-l, -binaphthyl ( 83.3 mg, 0.134 mmol ), sodium tert-butoxide (257 mg, 2.68 mmol) and toluene (15 ml ) was evacuated and then filled with nitrogen (balloon). After being stirred at 110 °C overnight, the resulting mixture was diluted with water (15 mL), and extracted with ethyl acetate (15 mL x 4). The combined organic layers were dried over sodium sulfate and concentrated in vacuo. The residue was purified by flash column chromatography (eluting with 10% methanol in dichloromethane) to afford 380 mg of the product as a white solid (yield was 70%). MS obsd. (ESI+) [(M+H)+] 407, 1H NMR (400 MHz, CD3OD) δ ppm 8.02 - 8.00 (m, 1 H), 7.90 (d, J= 7.2 Hz, 1 H), 7.69 - 7.63 (m, 2 H), 7.51 - 7.45 (m, 2 H), 7.34 - 7.31 (m, 1 H), 6.10 (s, 1 H), 5.19 (s, 2 H), 4.55 (brs, 2 H), 3.73 (t, J= 13.2 Hz, 2 H), 3.63 (t, J= 10 Hz, 2 H ), 2.85 (t, 2 H), 2.44 (s, 3 H).
Example 84
2-(l,l-Dioxido-2,3-dihydro-l,4-benzothiazepin-4(5H)-yl)-6-methyl- V-[2-(lH-tetrazol-5- yl)ethyl]quinolin-4-amine
Figure imgf000388_0001
A mixture of 3- {[2-(l , l-dioxido-2,3-dihydro-l ,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4- yl] amino }propanenitrile (100 mg, 0.25 mmol), sodium azide (48 mg, 0.98 mmol), dimethyl formamide (2 ml) and ammonium chloride (52.6 mg, 0.98 mmol) was heated at 80 °C in an oil bath overnight. The resulting mixture was diluted with water and extracted with dichloromethane (10 mL x 3). The combined organic layers were washed with brine, dried over sodium sulfate and concentrated in vacuo. The residue was purified by flash column chromatography (eluting with 10% methanol in dichloromethane) to afford 20 mg of the desired product as a white solid. MS obsd. (ESI+) [(M+H)+] 450, 1H NMR (400 MHz, CD3OD) δ ppm 8.06 (m, 1 H), 7.92 (t, 1 H), 7.86 (s, 1 H), 7.60 (m, 1 H), 7.58 - 7.52 (m, 3 H), 5.89 (s, 1 H), 5.27 (s, 2 H), 4.52 (brs, 2 H), 3.86 (t, 2 H), 3.72 (t, 2 H ), 3.33 (t, 2 H), 2.47 (s, 3 H).
Example 85
N~4~-(2-Aminoethyl)-2-(l,l-dioxido-2,3-dihydro-l,4-benzothiazepin-4(5H)-yl)quinoline-4,6- diamine
Figure imgf000388_0002
To a solution ofN-[2-(l,l-dioxido-2,3-dihydro-l,4-benzothiazepin-4(5H)-yl)-6-nitroquinolin-4- yl] ethane- 1,2-diamine (50 mg, 0.11 mmol, prepared in analogy to N-[2-(l,l-dioxido-2,3- dihydro-l,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]ethane-l,2-diamine in Example 9- 11) in methanol (20 mL) was added tin(II) chloride (102.8 mg, 0.55 mmol). After being re fluxed overnight, the resulting mixture was cooled to room temperature, diluted with dichloromethane, washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by preparative HPLC to afford 11 mg of the desired product (yield was 25%). MS obsd. (ESI+) [(M+H)+] 398, 1H NMR (400 MHz, CD3OD) δ ppm 7.95 (d, J= 8.08 Hz, 1 H), 7.79 (d, J= 7.58 Hz, 1 H), 7.60 (t, J= 7.45 Hz, 1 H), 7.47 - 7.37 (m, 1 H), 7.35 (d, J= 8.84 Hz, 1 H), 7.06 - 6.95 (m, 2 H), 6.00 (s, 1 H), 5.10 (s, 2 H), 3.56 (brs, 2 H), 3.41 (t, J= 6.44 Hz, 2 H), 2.96 (t, J= 6.44 Hz, 2 H), 1.29 (brs, 2 H).
Example 86
5-[2-(l,l-Dioxido-2,3-dihydro-l,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]-2-oxa- 5,7-diazaspiro[3.4]octan-6-one
Figure imgf000389_0001
A mixture of 4-(4-chloro-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-l,4-benzothiazepine 1,1- dioxide (372 mg, 1.0 mmol, prepared in analogy to the one in Example 17-1), tert-butyl [(3- aminooxetan-3-yl)methyl] carbamate (202 mg, 1.0 mmol),
tris(dibenzylideneacetone)dipalladium(0) (91 mg, 0.10 mmol), 2,2'-bis(diphenylphosphino)-l,l'- binaphthyl (62 mg, 0.10 mmol) and sodium tert-buoxide (192 mg, 2.0 mmol) in toluene (10 mL) was heated at 110 °C overnight. The resulting mixture was diluted with water (20 mL), and extracted with dichloromethane (20 mL x 3). The combined organic layers were washed with brine (50 mL), dried over sodium sulfate, and concentrated in vacuo. The residue was purified by preparative HPLC to afford 15 mg of the title compound. MS obsd. (ESI+) [(M+H)+] 465, 1H NMR (400 MHz, DMSO- 6) δ ppm 8.15 (s, 1 H), 7.98 - 7.96 (d, J= 7.2 Hz, 1 H), 7.90 - 7.87 (m, 1 H), 7.68 - 7.64 (m, 1 H), 7.53 -7.46 (m, 2 H), 7.37 - 7.34 (m, 2 H), 7.17 (s, 1 H), 5.14 (s, 2 H), 4.80 - 4.74 (m, 4 H), 4.44 (s, 2 H), 4.27 (s, 2 H), 3.66 - 3.64 (t, J= 4.8, 4,4 Hz, 2 H), 2.36 (s, 3 H).
Example 87-1
3- { [2-(l , l-Dioxido-2,3-dihydro- 1 ,4-benzothiazepin-4(5H)-yl)-6-methylquinazolin-4- yl]amino}propane-l,2-diol
Figure imgf000390_0001
2-Chloro- V-[(2,2-dimethyl-l,3-dioxolan-4-yl)methyl]-6-methylquinazolin-4-amine
Figure imgf000390_0002
A solution of 2,4-dichloro-6-methylquinazoline (300.0 mg, 1.4 mmol), triethylamine ( 0.5 mL) and 2,2-dimethyl-l,3-dioxolane-4-methanamine (0.2 mL, 1.5 mmol) in methanol ( 2.0 mL) was stirred at room temperature for 16 hours. The reaction mixture was diluted with ethyl acetate (100 mL), washed with brine (50 mL x 2), dried over anhydrous sodium sulfate and then concentrated in vacuo to afford 431 mg of the crude product as a white solid. MS obsd. (ESI+) [(M+H)+] 308. 3- { [2-(l , l-Dioxido-2,3-dihydro- 1 ,4-benzothiazepin-4(5H)-yl)-6-methylquinazolin-4- yl]amino}propane-l,2-diol
Figure imgf000390_0003
A solution of 2-chloro-N-[(2,2-dimethyl- 1 ,3-dioxolan-4-yl)methyl]-6-methylquinazolin-4-amine (431.2 mg, 1.4 mmol) and triethylamine (0.8 mL), 2,3,4,5-tetrahydro-l,4-benzothiazepine 1,1- dioxide (296.1 mg, 1.5 mmol) in N,N-dimethyl-formamide (1.0 mL) was stirred at 160 °C for 4 hours. After being cooled to room temperature, the reaction mixture was dissolved in methanol (2.0 mL). To the above mixture, concentrated hydrochloric acid (0.5 mL) was added, and the resulting mixture was stirred at room temperature for 1 hour, and then extracted with ethyl acetate (100 mL). The organic layer was washed with brine (50 mL x 2), dried over anhydrous ntrated in vacuo. The residue was purified by preparative HPLC to afford 59.2 mg of the product as a white solid (yield was 10%). MS obsd. (ESI ) [(M+H)+] 429, 1H NMR (400 MHz, CD3OD) δ ppm 7.98 (dd, J= 7.83, 1.01 Hz, 1 H), 7.90 (d, J= 7.58 Hz, 1 H), 7.66 - 7.55 (m, 2 H), 7.50 - 7.35 (m, 2 H), 7.35 - 7.28 (m, 1 H), 5.21 (brs, 2 H), 4.56 (brs, 2 H), 4.05 - 3.95 (m, 1 H), 3.86 (dd, J= 13.26, 4.42 Hz, 1 H), 3.73 - 3.56 (m, 3 H), 3.53 (t, J = 5.05 Hz, 2 H), 2.39 (s, 3 H).
Example 87-2
3-[6-Chloro-2-(l,l-Dioxido-2,3-dihydro-l,4-benzothiazepin-4(5H)-yl))-quinazolin-4- ylamino] -propane- 1 ,2-diol
Figure imgf000391_0001
The title compound was prepared in analogy to Example 87-1 in Scheme 41 by using 2,4,6- trichloroquinazoline, 2,2-dimethyl-l,3-dioxolane-4-methanamine and 2,3,4,5-tetrahydro-l,4- benzothiazepine 1,1-dioxide. MS obsd. (ESI+) [(M+H)+] 449, 1H NMR (400 MHz, CD3OD) δ ppm 7.98 (d, J= 7.83 Hz, 1 H), 7.95 - 7.84 (m, 2 H), 7.62 (t, J= 7.33 Hz, 1 H), 7.53 - 7.41 (m, 2 H), 7.37 (d, J= 8.84 Hz, 1 H), 5.21 (brs, 2 H), 4.61 (brs, 2 H), 4.01 (brs, 1 H), 3.85 (brs, 1 H), 3.65 (brs, 3 H), 3.52 (t, J= 4.67 Hz, 3 H).
Example 88-1
TV- [2-(2,3-Dihydro- 1 ,4-benzothiazepin-4(5H)-yl)-6-methylquinazolin-4-yl] ethane- 1 ,2- diamine
Figure imgf000391_0002
tert-Buty\ {2- [(2-chloro-6-methylquinazolin-4-yl)amino] ethyl} carbamate
Figure imgf000392_0001
A mixture of 2,4-dichloro-6-methylquinazoline (700 mg, 3.29 mmol), tert-butyl N-(2- aminoethyl)carbamate (2.6 g, 16.4 mmol) and methanol (35 mL) was stirred at room temperature for 1 hour. The resulting mixture was concentrated in vacuo and the residue was purified by flash column chromatography to afford 1.0 g of the product as a white solid (yield was 91%). tert-Butyl {2- [2-(2,3-dihydro- 1 ,4-benzothiazepin-4(5H)-yl)-6-methylquinazolin-4- yljaminoethyl} carbamate
Figure imgf000392_0002
To a solution of tert-butyl {2-[(2-chloro-6-methylquinazolin-4-yl)amino]ethyl} carbamate (460 mg, 1.366 mmol) in n-butanol (6 mL) was added 2,3,4,5-tetrahydro-l,4-benzothiazepine (248 mg, 1.50 mmol) and triethylamine (276 mg, 2.732 mmol). The mixture was heated with stirring at 100 °C in a sealed tube for 4 hours, and then concentrated in vacuo. The residue was purified by flash column chromatography to afford 350 mg of the desired product as a white solid (yield was 55%). N- [2-(2,3-Dihydro- 1 ,4-benzothiazepin-4(5H)-yl)-6-methylquinazolin-4-yl] ethane- 1 ,2- diamine
Figure imgf000392_0003
To a cooled solution of trifluoro acetic acid in dichloromethane (2 mL, V/V = 1/4) was added tert-butyl {2-[2-(2,3-dihydro- 1 ,4-benzothiazepin-4(5H)-yl)-6-methylquinazolin-4- yl] amino ethyl} carbamate (120 mg, 0.258 mmol) in an ice bath. The mixture was stirred for 3 hours whilst allowing the temperature of the mixture rising naturally to room temperature, and then concentrated in vacuo. The residue was dissolved in water (10 mL), and washed with dichloromethane (10 mL). The aqueous layer was adjusted to pH 10 with a saturated aqueous solution of sodium carbonate and extracted with ethyl acetate (20 mL x 2). The organic extracts were dried with sodium sulfate, concentrated in vacuo to afford 68 mg of the product as a white solid (yield was 72%). MS obsd. (ESI+) [(M+H)+] 366, 1H NMR (400 MHz, CD3OD) δ ppm 7.67 - 7.64 (t, J= 12.0 Hz, 2 H), 7.49 - 7.47 (d, J = 8.4 Hz, 1 H), 7.38 - 7.30 (m, 2 H), 7.23 - 7.19 (dd, J = 8.4, 7.6 Hz, 2 H), 7.13 - 7.09 (dd, J = 8.8 Hz, 1 H), 5.04 (s, 2 H), 4.38 (s, 2 H), 3.75 - 3.72 (m, 2 H), 2.98 - 2.92 (m, 4 H), 2.39 (s, 3 H).
Example 88-2
(l-Amino-cyclopropylmethyl)-[6-methyl-2-(l-oxido-2,3-dihydro-l,4-benzothiazepin- yl)-quinolin-4-yl] -amine
Figure imgf000393_0001
The title compound was prepared in analogy to Example 88-1 in Scheme 42 by using 2,4- dichloro-6-methylquinazoline, tert-butyl [l-(aminomethyl)cyclopropyl]carbamate and 2,3,4,5- tetrahydro-l ,4-benzothiazepine 1 -oxide. MS obsd. (ESI+) [(M+H)+] 408, 1H NMR (400 MHz, CDC13) δ ppm 7.766 - 7.748 (d, J= 7.2 Hz, 1 H),7.632 (s, 1 H), 7.410 - 7.328 (m, 5 H), 5.936 (s,
1 H), 5.333 - 5.295 (d, J = 15.2 Hz, 1 H), 4.924 (m, 2 H), 4.400 (s, 1 H), 3.644 (s, 2 H), 3.332 (s,
2 H), 2.398 (s, 3 H), 0.740 - 0.678 (m, 4 H).
Example 89 V-[6-Methyl-2-(l-oxido-2,3-dihydro-l,4-benzothiazepin-4(5H)-yl)quinazolin-4-yl] ethane- 1,2-diamine
Figure imgf000394_0001
tert-Buty\ {2-[2-(l-oxido-2,3-dihydro-l,4-benzothiazepin-4(5H)-yl)-6-methylquinazolin-4- yljaminoethyl} carbamate
Figure imgf000394_0002
To a solution of oxone (120 mg, 0.200 mmol) in water (0.7 mL) which was cooled below 0 °C in an ice bath, was added a solution of tert-butyl {2-[2-(2,3-dihydro-l,4-benzothiazepin-4(5H)-yl)- 6-methylquinazolin-4-yl]aminoethyl}carbamate (155 mg, 0.333 mmol) in methanol (3 mL) dropwise. The mixture was stirred below 0 °C about 20 minutes. The formed precipitate was collected by filtration, washed with water and purified by flash column chromatography to afford 124 mg of the product as a white solid (yield was 77%). V-[6-Methyl-2-(l-oxido-2,3-dihydro-l,4-benzothiazepin-4(5H)-yl)quinazolin-4-yl]ethane- 1,2-diamine
Figure imgf000394_0003
The title compound was prepared in analogy to Example 88-1 in Scheme 42 by using tert-butyl {2-[2-(l-oxido-2,3-dihydro-l,4-benzothiazepin-4(5H)-yl)-6-methylquinazolin-4- yl]aminoethyl} carbamate (150 mg, yield was 86%). MS obsd. (ESI+) [(M+H)+] 382, 1H NMR (400 MHz, CD3OD) δ ppm 7.74 - 7.72 (t, J= 8.0 Hz, 2 H), 7.66 - 7.62 (d, J= 16.0 Hz, 1 H), 7.49 - 7.44 (m, 2 H), 7.42 - 7.40 (m, 1 H), 7.38 - 7.33 (m, 1 H), 5.29 - 5.25 (d, J= 16.0 Hz, 1 H ), 4.81 - 4.70 (m, 1 H), 4.58 - 4.51 (m, 1 H), 3.79 - 3.70 (m, 2 H), 3.53 - 3.34 (m, 4 H), 3.03 - 3.00 (m, 2 H), 2.40 (s, 3 H).
Example 90 V-[2-(l,l-Dioxido-2,3-dihydro-l,4-benzothiazepin-4(5H)-yl)-6-methylquinazolin-4- yl] ethane- 1,2-diamine
Figure imgf000395_0001
tert-Buty\ {2-[2-(l,l-dioxido-2,3-dihydro-l,4-benzothiazepin-4(5H)-yl)-6-methylquinazolin- 4-yl] aminoethyl} carbamate
Figure imgf000395_0002
To a solution of tert-butyl {2-[2-(2,3-dmydro-l,4-benzothiazepin-4(5H)-yl)-6-methylquinazolin- 4-yl]aminoethyl} carbamate (190 mg, 0.408 mmol) in dichloromethane (10 mL) was added dropwise a solution of 3-chloroperbenzoic acid (228.6 mg, 1.02 mmol) in dichloromethane (6 mL) in an ice bath. After the mixture being stirred in an ice bath for 2 hours, the reaction was quenched by the addition of a saturated aqueous solution of sodium thiosulphate. The separated organic layer was washed by a saturated aqueous solution of sodium bicarbonate and brine, dried over anhydrous sodium sulfate, and concentrated in vacuo. The residue was purified by flash column chromatography (eluting with 20 - 40% ethyl acetate in petroleum ether) to give 170 mg of the product. V-[2-(l,l-Dioxido-2,3-dihydro-l,4-benzothiazepin-4(5H)-yl)-6-methylquinazolin-4- yl] ethane- 1,2-diamine
Figure imgf000396_0001
The title compound was prepared in analogy to Example 88-1 in Scheme 42 by using tert-butyl {2-[2-(l , 1 -dioxido-2,3-dihydro- 1 ,4-benzothiazepin-4(5H)-yl)-6-methylquinazolin-4- yl]aminoethyl} carbamate. MS obsd. (ESI+) [(M+H)+] 398, 1H NMR (400 MHz, CD3OD) δ ppm 7.98 (d, J= 6.8 Hz, 1 H), 7.83 (d, J = 7.6 Hz, 1 H), 7.65 (s, 1 H), 7.61 (dd, J = 6.8, 7.6 Hz, 1 H), 7.44 (t, J= 7.2 Hz, 1 H), 7.38 (dd, J = 1.6, 8.4 Hz, 1 H), 7.31 (d, J = 8.4 Hz, 1 H), 5.20 (s, 2 H), 4.58 (brs, 2 H), 3.73 (t, J = 6.4 Hz, 2 H), 3.54 - 3.48 (m, 2 H), 2.97 (t, J= 6.4 Hz, 2 H), 2.39 (s, 3 H).
Example 91 V-[3-(Aminomethyl)oxetan-3-yl]-6-methyl-2-(l-oxido-2,3-dihydro-l,4-benzothiazepin- 4(5H)-yl)quinazolin-4-amine
Figure imgf000396_0002
2,2,2-Trifluoro- V-[(3-{[6-methyl-2-(l-oxido-2,3-dihydro-l,4-benzothiazepin- yl)quinazolin-4-yl] amino} oxetan-3-yl)methyl] acetamide
Figure imgf000396_0003
The title compound was prepared as a light white solid in analogy to Example 62-1 in Scheme 23 by using 2-chloro-6-methylquinazolin-4(3H)-one, 2,3,4,5-tetrahydro-l ,4-benzothiazepine 1- oxide and N-[(3-aminooxetan-3-yl)methyl]-2,2,2-trifluoroacetamide (yield was 80%). V-[3-(Aminomethyl)oxetan-3-yl]-6-methyl-2-(l-oxido-2,3-dihydro-l,4-benzothiazepin- mine
Figure imgf000397_0001
To a stirred of 2,2,2-trifluoro-N-[(3-{[6-methyl-2-(l-oxido-2,3-dihydro-l,4-benzothiazepin- 4(5H)-yl)quinazolin-4-yl] amino }oxetan-3-yl)methyl]acetamide (70 mg, 0.135 mmol) in ethanol (5 mL) was added an aqueous solution of sodium hydroxide (5 N, 1 mL). After being stirred at room temperature overnight, the resulting mixture was diluted with water (15 mL), and extracted with dichloromethane (15 mL x 3). The organic layers were combined, washed with brine, dried over sodium sulfate, and concentrated in vacuo. The residue was purified by preparative HPLC to afford 7 mg of the desired product as a white solid. MS obsd. (ESI+) [(M+H)+] 424, 1H NMR
(400 MHz, CD3OD) δ ppm 7.97 (s, 1 H), 7.83 - 7.78 (m, 2 H), 7.71 - 7.68 (m, 1 H), 7.61 - 7.54 (m, 3 H), 5.45 (d, 1 H), 5.15 (brs, 1 H), 4.81 - 4.74 (m, 5 H), 4.51 (brs, 3 H), 3.54 (brs, 2 H), 2.45 (s, 3 H).
Example 92-1 V-(irans-4-Fluoropyrrolidin-3-yl)-6-methyl-2-(l-oxido-2,3-dihydro-l,4-benzothiazepin- 4(5H)-yl)quinazolin-4-amine
Figure imgf000397_0002
Benzyl irans-3-fluoro-4-{[6-methyl-2-(l-oxido-2,3-dihydro-l,4-benzothiazepin- yl)quinazolin-4-yl]amino}pyrrolidine-l-carboxylate
Figure imgf000397_0003
A suspension of 6-methyl-2-(l-oxido-2,3-dihydro-l,4-benzothiazepin-4(5H)-yl)quinazolin- Ai~kU\-nne> ( ήππ mrr 1 77 mmol, prepared in analogy to the one in Example 91), benzotriazol-1- yloxytris(dimethylamino)phosphonium hexafluorophosphate (1.02 g, 2.3 mmol), and 1 ,8- diazabicyclo[5.4.0]undec-7-ene (400 mg, 2.6 mmol) in anhydrous N,N-dimethylformamide (10 mL) was stirred at room temperature for 10 minutes. Then a solution of benzyl trans-3-ammo-4- fluoropyrrolidine-l-carboxylate (500 mg, 2.1 mmol) in N,N-dimethylformamide (5 mL) was added dropwise. After being heated at 60 °C overnight, the mixture was diluted with water (50 mL), extracted with dichloromethane (50mL). The organic layer was washed with brine, dried over anhydrous sodium sulfate, and concentrated in vacuo. The residue was purified by flash column chromatography (gradient eluting with 10% to 25% ethyl acetate in dichloromethane) to afford 415 mg of the desired product as a yellow solid (yield was 41.8%). V-(irans-4-Fluoropyrrolidin-3-yl)-6-methyl-2-(l-oxido-2,3-dihydro-l,4-benzothiazepin- 4(5H)-yl)quinazolin-4-amine
Figure imgf000398_0001
A mixture of benzyl tra/75-3-fluoro-4- {[6-methyl-2-(l-oxido-2,3-dihydro-l ,4-benzothiazepin- 4(5H)-yl)quinazolin-4-yl] amino }pyrrolidine-l-carboxylate (200 mg, 0.35 mmol) and an aqueous solution of hydrochloric acid (5 mL, 6 N) was refluxed for 6 hours. The resulting mixture was basified by adding an aqueous solution of sodium hydroxide (1 N) to pH 10, and then extracted with dichloromethane (50 mL). The organic layer was washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by preparative HPLC to afford the desired compound as a yellow solid. MS obsd. (ESI+) [(M+H)+] 426, 1H NMR (400 MHz, CD3OD) δ ppm 7.76 (m, 3 H), 7.45 (m, 4 H), 5.32 (m, 3 H), 4.61(s, 3 H), 3.70 - 3.1 1 (m, 6 H), 2.41 (s, 3 H).
Example 92-2 V-(irans-4-Fluoropyrrolidin-3-yl)-6-methyl-2-(l,l-dioxido-2,3-dihydro-l,4-benzothiazepin- 4(5H)-yl)quinazolin-4-amine
Figure imgf000399_0001
The title compound was prepared in analogy to Example 92-1 in Scheme 44 by using 6-methyl- 2-(l,l-dioxido-2,3-dihydro-l,4-benzothiazepin-4(5H)-yl)quinazolin-4(3H)-one (prepared in analogy to 6-methyl-2-(l-oxido-2,3-dihydro-l,4-benzothiazepin-4(5H)-yl)quinazolin-4(3H)-one in Example 91) and benzyl tra/75-3-amino-4-fluoropyrrolidine-l-carboxylate. MS obsd. (ESI ) [(M+H)+] 442, 1H NMR (400 MHz,CDCl3) δ ppm 8.40 - 8.02 (d, J= 7.6 Hz , 1 H), 7.83 - 7.81 (d, J= 7.2 Hz ,1 H), 7.52 - 7.49 (m, 1 H), 7.37 - 7.35 (d, J= 10.8 Hz, 3 H), 7.22 (s, 1 H), 5.41 (s, 1 H), 5.30 - 5.00 (brs, 2 H), 4.90 - 4.55 (brs, 2 H), 3.70 - 3.68 (d, J= 5.2 Hz, 1 H), 3.48 (s, 2 H), 3.31 - 3.25 (brs, 2 H) 2.95 (s, 1 H), 2.38 (s, 3 H), 2.20- 2.18 (d, J= 8.8 Hz, 1 H). Example 93-1 l-[6-Methyl-2-(l-oxido-2,3-dihydro-l,4-benzothiazepin-4(5H)-yl)quinazolin-4- yl] py rrolidin-3-amine
Figure imgf000399_0002
tert-Buty\ {l-[6-methyl-2-(l-oxido-2,3-dihydro-l,4-benzothiazepin-4(5H)-yl)quinazolin-4- yl]pyrrolidin-3-yl} carbamate
Figure imgf000399_0003
The title compound was prepared in analogy to benzyl (35',45)-3-fluoro-4-{[6-methyl-2-(l- oxido-2,3-dihydro- 1 ,4-benzothiazepin-4(5H)-yl)quinazolin-4-yl] amino} pyrrolidine- 1 - carboxylate in Example 92 by using 6-methyl-2-(l-oxido-2,3-dihydro-l,4-benzothiazepin-4(5H)- yl)quinazolin-4(3H)-one and tert-butyl (pyrrolidin-3-yl)carbamate. l-[6-Methyl-2-(l-oxido-2,3-dihydro-l,4-benzothiazepin-4(5H)-yl)quinazolin-4- yl] py rrolidin-3-amine
Figure imgf000400_0001
The title compound was prepared in analogy to Example 90 in Scheme 44 by using tert-butyl {1- [6-methyl-2-(l-oxido-2,3-dihydro-l,4-benzothiazepin-4(5H)-yl)quinazolin-4-yl]pyrrolidm^ yl} carbamate. MS obsd. (ESI+) [(M+H)+] 408, 1H NMR (400 MHz, CD3OD) δ ppm 7.73 (s, 1 H), 7.64 (dd, J= 7.2, 1.6 Hz, 2 H), 7.41 - 7.28 (m, 4 H), 5.16 (d, J= 15.2 Hz, 1 H), 4.70 (m, 2 H), 4.39 (s, 1 H), 3.86 (m, 2 H), 3.59 (m, 2 H), 3.37 (brs, 1 H), 2.31 (s, 3 H), 2.15 (m, 1 H), 1.82 (m, 1 H), 1.24 (brs, 1 H).
Example 93-2 V-(Azetidin-3-yl)-6-methyl-2-(l , l-dioxido-2,3-dihydro- 1 ,4-benzothiazepin-4(5H)-yl) quinazolin-4-amine
Figure imgf000400_0002
The title compound was prepared in analogy to Example 93-1 in Scheme 44 by using 6-methyl- 2-(l,l-dioxido-2,3-dihydro-l,4-benzothiazepin-4(5H)-yl)quinazolin-4(3H)-one and tert-butyl 3- aminoazetidine-l-carboxylate. MS obsd. (ESI+) [(M+H)+] 410.1, 1H NMR (400 MHz, DMSO- d6) δ ppm 8.24 (s, 1 H), 7.87 (s, 2 H), 7.79 (s, 1 H), 7.62 (brs, 1 H), 7.45 (s, 1 H), 7.34 (d, J= 8.4 Hz, 1 H), 7.22 (brs, 1 H), 5.06 - 4.42 (m, 5 H), 3.85 (brs, 1 H), 3.59 (m, 5 H), 2.32 (s, 3 H).
Example 94 (4R)-4- {2- [2-(l , l-Dioxido-2,3-dihydro- 1 ,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4- yl]ethyl}-4,5-dihydro-l,3-oxazol-2-amine
Figure imgf000401_0001
tert-Butyl (4R)-4-{(2J-i)-[2-(l,l-dioxido-2,3-dihydro-l,4-benzothiazepin-4(5H)-yl)-6- methylquinolin-4-yl]-vinyl}-2,2-dimethyl-l,3-oxazolidine-3-carboxylate
Figure imgf000401_0002
To a vial containing a mixture of 4-(4-chloro-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-l,4- benzothiazepine 1,1 -dioxide (200 mg, 0.536 mmol, prepared in analogy to 4-(4-chloro-6- (trifluoromethoxy)quinolin-2-yl)-2,3,4,5-tetrahydro-l,4-benzothiazepine 1,1-dioxide in Example 17-1), tert-butyl (4i?)-4-ethenyl-2,2-dimethyl-l,3-oxazolidine-3-carboxylate (146 mg, 0.643 mmol), triethylamine (0.5 mL) and N,N-dimethylformamide (1 mL), which was evacuated and filled with argon, di(tri-tert-butylphosphine)palladium(0) (13.7 mg, 0.0268 mmol) was added. The vial was caped and heated at 110 °C for 30 minutes under microwave irradiation. The reaction mixture was poured into water (30 mL) and extracted with ethyl acetate (20 mL x 3). The organic layers were combined, washed with brine, dried over sodium sulfate and
concentrated in vacuo. The residue was purified by flash column chromatography (eluting with 50% ethyl acetate in hexanes) to afford 180 mg of the desired product as a white solid (yield was 60%).
(3R)-2-Amino-4-[2-(l,l-dioxido-2,3-dihydro-l,4-benzothiazepin-4(5H)-yl))-6-methyl- quinolin-4-yl]-butan-l-ol
Figure imgf000402_0001
A solution of tert-butyl (4i?)-4-{(2E) 2 l,l-dioxido-2,3-dihydro-l,4-benzothiazepin-4(5H)-yl)- 6-methylquinolin-4-yl]-vinyl}-2,2-dimethyl-l,3-oxazolidine-3-carboxylate (180 mg, 0.32 mmol) in methanol was hydrogenated over 10% palladium on carbon (30 mg) under atmospheric pressure for 2 hours at room temperature. The reaction mixture was filtered and the filtrate was concentrated in vacuo. The residue was dissolved in a solution of hydrochloride in ethyl acetate (2 N, 10 mL) and the solution was stirred at room temperature for 2 hours. The reaction mixture was basified with an aqueous solution of sodium bicarbonate (2 N) to pH 8 and then extracted with ethyl acetate (15 mL x 3). The combined layers was dried over sodium sulfate and concentrated in vacuo. The residue was purified by flash column chromatography (eluting with 10% methanol in dichloromethane) to afford 90 mg of the desired product as a white solid (yield was 66.2%).
(4R)-4-{2-[2-(l,l-Dioxido-2,3-dihydro-l,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4- yl]ethyl}-4,5-dihydro-l,3-oxazol-2-amine
Figure imgf000402_0002
The title compound was prepared in analogy to Example 38-1 in Scheme 45 by using (3i?)-2- amino-4-[2-(l,l-dioxido-2,3-dihydro-l,4-benzothiazepin-4(5H)-yl))-6-methyl-quinolin-4-yl]- butan-l-ol and cyanogen bromide. MS obsd. (ESI+) [(M+H)+] 451, 1H NMR (400 MHz, DMSO- d6) δ ppm 7.89 (m, J= 4.7 Hz, 2 H), 7.72 (s, 1 H), 7.63 (t, J= 3.7 Hz, 1 H), 7.47 (t, J= 3.9 Hz, 1 H), 7.32 (d, J= 2.1 Hz, 1 H), 7.23 (d, J= 2.1 Hz, 1 H), 6.85 (t, J= 2.6 Hz, 1 H), 6.10 (s, 1 H), 5.15 (s, 2 H), 4.53 (brs, 2 H), 3.97 - 3.91 (m, J= 5.8 Hz, 2 H ), 3.58 (t, J= 2.4 Hz, 2 H), 3.66 - 3.41 (m, J= 3.3 Hz, 2 H), 2.90 (dd, J= 4.2, 0.9, Hz, 1 H), 2.77 (dd, J= 5.2, 0.9 Hz, 1 H), 2.42 (s, 3 H). Example 95
3-[2-(l,l-Dioxido-2,3-dihydro-l,4-benzothiazepin-4(5H)-yl)-6-ethylquinolin-4-yl]propanoic acid
Figure imgf000403_0001
Ethyl (2E)-3- [2-(l , l-dioxido-2,3-dihydro- 1 ,4-benzothiazepin-4(5H)-yl)-6-ethylquinolin-4- yl]prop-2-enoate
Figure imgf000403_0002
A mixture of 4-(4-chloro-6-ethylquinolin-2-yl)-2,3,4,5-tetrahydro-l,4-benzothiazepine 1,1- dioxide (300 mg, 0.78 mmmol), ethyl prop-2-enoate (170 mg, 1.70 mmol), triethylamine (1 mL) and N,N-dimethylformamide (2 mL), bis(tri-tert-butylphosphine)palladium(0) (15 mg, 0.02 mmol) was heated with stirring in a 10 mL of microwave process vial for 30 minutes at 100 °C under microwave irradiation. The reaction mixture was poured into water (5 mL) and extracted with ethyl acetate (10 mL x 3). The organic layers were combined, washed with brine, dried over sodium sulfate and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (eluting with 20 - 40% ethyl acetate in petroleum ether) to afford 280 mg of the product as a white solid (yield was 80%). MS obsd. (ESI+) [(M+H)+] 451.
Ethyl 3-[2-(l,l-dioxido-2,3-dihydro-l,4-benzothiazepin-4(5H)-yl)-6-ethylquinolin-4- yl]propanoate
Figure imgf000403_0003
To a 25 mL of dry round bottom flask containing a solution of ethyl (2E)-3-[2-(l,l-dioxido-2,3- dihydro-l,4-benzothiazepin-4(5H)-yl)-6-ethylquinolin-4-yl]prop-2-enoate (300 mg, 0.67 mmol) in dichloromethane (5 mL) was added 2-nitrophenylsulfonylhydrazide (2.91 g, 13.4 mmol) followed by a solution of triethylamine (5 mL) in dichloromethane (10 mL) under nitrogen. The suspension was gently stirred for 6 hour at room temperature under nitrogen, and then concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (eluting with 20 - 40% ethyl acetate in petroleum ether) to afford 151 mg of the desired product (yield was 50%). MS obsd. (ESI+) [(M+H)+] 453.
3-[2-(l,l-dioxido-2,3-dihydro-l,4-benzothiazepin-4(5H)-yl)-6-ethylquinolin-4-yl]propanoic acid
Figure imgf000404_0001
To a solution of ethyl 3-[2-(l,l-dioxido-2,3-dihydro-l,4-benzothiazepin-4(5H)-yl)-6- ethylquinolin-4-yl]propanoate (100 mg, 0.22 mmol) in methanol (2 mL) was added an aqueous solution of lithium hydroxide (20.6 mg in 2 mL of water) and the resulting mixture was stirred at room temperature for 4 hours. The reacting mixture was acidified to pH 4 with an aqueous solution of hydrochloric acid (5 N), and then extracted with ethyl acetate (10 mL x 3). The organic layers were dried over sodium sulfate and concentrated in vacuo. The residue was purified by flash column chromatography (eluting with 1 - 10% methanol in dichlorometane) to afford 50 mg of the product as a white solid. MS (ESI+) [(M+H)+] 425, 1H NMR (400 MHz, DMSO- 6) δ ppm 8.08 (brs, 2 H), 7.94 (d, J= 7.58 Hz, 1 H), 7.80 (brs, 1 H), 7.72 (t, J= 7.07 Hz, 1 H), 7.57 (d, J= 7.33 Hz, 2 H), 7.37 (brs, 1 H), 5.38 (m, 2 H), 4.56 (brs, 2 H), 3.94 - 3.69 (m, 2 H), 3.26 (brs, 2 H), 2.81 - 2.64 (m, 4 H), 1.22 (t, J= 7.58 Hz, 3 H).
Example 96
3-[2-(l,l-Dioxido-2,3-dihydro-l,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]propan- 1-amine
Figure imgf000405_0001
3-[2-(l,l-Dioxido-2,3-dihydro-l,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]- propionitrile
Figure imgf000405_0002
The title compound was prepared in analogy to ethyl 3-[2-(l,l-dioxido-2,3-dihydro-l,4- benzothiazepin-4(5H)-yl)-6-ethylquinolin-4-yl]propanoate in Example 95 in Scheme 46 by using 4-(4-chloro-6-ethylquinolin-2-yl)-2,3,4,5-tetrahydro- 1 ,4-benzothiazepine 1 , 1 -dioxide and acrylonitrile.
3-[2-(l,l-dioxido-2,3-dihydro-l,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4- yl]propanamide
Figure imgf000405_0003
A solution of 3-[2-(l , 1 -dioxido-2,3-dihydro- 1 ,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4- yl]-propionitrile (150 mg, 0.38 mmol), and powdered potassium hydroxide (172 mg, 3.07 mmol) in tert-butanol (8 mL) was heated with stirring under reflux for 1.5 hours. After being cooled to room temperature, the reaction mixture was diluted with water (15 mL) and extracted with ethyl acetate (15 mL x 3). The combined organic layers were dried over sodium sulfate and concentrated in vacuo. The residue was purified by flash column (eluting with 5% methanol in dichloromethane) to afford 125 mg of the product as a white solid. 3-[2-(l,l-Dioxido-2,3-dihydro-l,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]propan- 1-amine
Figure imgf000406_0001
To a solution of 3-[2-(l , l-dioxido-2,3-dihydro-l,4-benzothiazepin-4(5H)-yl)-6-methylquinolin- 4-yl]-propionamide (30 mg, 0.073 mmol) in tetrahydrofuran (2 mL) was added a solution of borane in tetrahydrofuran (1 mL, 2 M) in an ice bath. The mixture was stirred at 65 °C for 3 hours and then cooled naturally to room temperature. The reaction was quenched with methanol and the mixture was concentrated in vacuo. The residue was purified by preparative HPLC to afford 6.3 mg of the desired product. MS obsd. (ESI+) [(M+H)+] 396, 1H NMR (400 MHz,
CD3OD) δ ppm 7.99 (dd, J= 1.2, 8.0 Hz, 1 H), 7.88 (d, J = 7.2 Hz, 1 H), 7.64 - 7.56 (m, 3 H), 7.45 (dd, J= 6.8, 7.6 Hz, 1 H), 7.37 (dd, J= 1.6, 8.4 Hz, 1 H), 7.06 (s, 1 H), 5.22 (s, 2 H), 4.57 (brs, 2 H), 3.61 (t, J= 4.8 Hz, 2 H), 3.07 (t, J = 8.0 Hz, 2 H), 2.94 (t, J= 7.6 Hz, 2 H), 2.45 (s, 3 H), 2.04 - 1.96 (m, 2 H).
Example 97 2- { [2-(l , l-Dioxido-2,3-dihydro- 1 ,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4- yl]oxy}ethanamine
Figure imgf000406_0002
V-(2-{[2-(l,l-Dioxido-2,3-dihydro-l,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4- yl] oxy}ethyl)acetamide
Figure imgf000407_0001
A mixture of N-(2-hydroxyethyl)-acetamide (247 mg, 2.4 mmol), 4-(4-bromo-6-methylquinolin- 2-yl)-2,3,4,5-tetrahydro-l,4-benzothiazepine 1,1-dioxide (1000 mg, 2.4 mmol, prepared in analogy to 4-(4-chloro-6-(trifluoromethoxy)quinolin-2-yl)-2,3,4,5-tetrahydro-l,4- benzothiazepine 1,1-dioxide in Example 17-1), l, -bis(diphenylphosphino)ferrocene- palladium(II)dichloride (190.4 mg, 0.24 mmol), l, -bis(diphenylphosphino)ferrocene (129.3 mg, 0.24 mmol) and sodium tert-butoxide (460.8 mg, 4.8 mmol) in 1,4-dioxane (5 mL) was heated with stirring in a sealed 10 mL of microwave process vial for 1 hour at 130 °C under microwave irradiation. The reaction mixture was concentrated in vacuo and the residue was purified by preparative HPLC to afford 20 mg of the desired product (yield was 1.9%).
2- { [2-(l , l-Dioxido-2,3-dihydro- 1 ,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4- yl]oxy}ethanamine
Figure imgf000407_0002
A mixture of N-(2-{[2-(l,l-dioxido-2,3-dihydro-l,4-benzothiazepin-4(5H)-yl)-6-methylquinolin- 4-yl]oxy}ethyl)acetamide (15 mg, 0.03 mmol) and an aqueous solution of hydrochloric acid (10 mL, 37% W/W) was heated with stirring at 80 °C for 3 hours. The reaction mixture was purified by preparative HPLC and SPE to give 9.3 mg of the desired product (yield was 68.5%>). MS obsd. (ESI+) [(M+H)+] 398, 1H NMR (400 MHz, CD3OD) δ ppm 8.11 (s, 1 H), 8.10 - 8.06 (d, J = 7.6 Hz , 1 H), 7.93 - 7.88 (d, J= 7.2 Hz ,1 H), 7.82 - 7.76 (d, J = 8 Hz, 1 H), 7.73 - 7.68 (t, J = 7.6 Hz, 1 H), 7.65 - 7.60 (d, J= 6.8 Hz ,1 H), 7.60 - 7.53 (t, J= 7.2 Hz ,1 H), 6.68 (s, 1 H), 5.41 (s, 2 H), 4.70 - 4.65 (m, 2 H), 4.65 - 4.45 (m, 2 H), 3.80 - 3.72 (t, J= 2.8 Hz , 2 H), 3.62 - 3.58 (t, J = 4.4 Hz , 2 H), 2.47 (s, 3 H).
Example 98-1 4- [6-Methyl-4-(pyrrolidin-3-yloxy)quinolin-2-yl] -2,3,4,5-tetrahydro- 1 ,4-benzothiazepine 1,1-dioxide
Figure imgf000408_0001
terf-Butyl 3-{[2-(l,l-dioxido-2,3-dihydro-l,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4- yl]oxy}pyrrolidine-l-carboxylate
Figure imgf000408_0002
A mixture of tert-butyl 3-hydroxypyrrolidine-l-carboxylate (134.7 mg, 0.72 mmol), 4-(4-bromo- 6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-l,4-benzothiazepine 1,1-dioxide (300 mg, 0.72 mmol, prepared in analogy to 4-(4-chloro-6-(trifluoromethoxy)quinolin-2-yl)-2,3,4,5-tetrahydro-l,4- benzodiazepine 1,1-dioxide in Example 17-1), l, -bis(diphenylphosphino)ferrocene- palladium(II)dichloride (57.12 mg, 0.07 mmol), l, -bis(diphenylphosphino)ferrocene (38.78 mg, 0.07 mmol) and sodium tert-butoxide (138.24 mg, 1.44 mmol) in 1,4-dioxane (5 mL) was heated with stirring in a sealed 10 mL of microwave process vial for 1 hour at 130 °C under microwave irradiation. The reaction mixture was concentrated in vacuo and the residue was purified by preparative HPLC to afford 20 mg of the desired product (yield was 5.3%).
4- [6-Methyl-4-(pyrrolidin-3-yloxy)quinolin-2-yl] -2,3,4,5-tetrahydro- 1 ,4-benzothiazepine 1,1-dioxide
Figure imgf000408_0003
A mixture of tert-butyl 3-{[2-(l,l-dioxido-2,3-dihydro-l,4-benzothiazepin-4(5H)-yl)-6- methylquinolin-4-yl]oxy}pyrrolidine-l-carboxylate (50 mg, 0.096 mmol) and a solution of hydrochloride in ethyl acetate (30 mL, 4 M) was stirred at room temperature for 8 hours. The resulting mixture was concentrated in vacuo and the residue was purified by preparative HPLC and SPE to afford 18.4 mg of the desired product (yield was 45.3%). MS obsd. (ESI+) [(M+H)+] 424, 1H NMR (400 MHz, CD3OD) δ ppm 8.11 - 8.08 (d, J= 6.4 Hz, 1 H), 7.95 - 7.88 (m, 2 H), 7.78 - 7.70 (m, 2 H), 7.68 - 7.56 (m, 2 H), 6.62 (s, 1 H), 5.75 - 5.70 (m, 1 H), 5.40 (s, 2 H), 4.70 - 4.50 (m, 2 H), 3.80 - 3.70 (m, 4 H), 3.65 - 3.48 (m, 2 H), 2.60 - 2.50 (m, 1 H), 2.46 (s, 3 H), 2.46 - 2.35 (m, 1 H). Example 98-2
8-[6-Methyl-4-(piperidin-4-yloxy)-quinolin-2-yl]-2,3,4,5-tetrahydro-l,4-benzothiazepine 1,1-dioxide
Figure imgf000409_0001
The title compound was prepared in analogy to Example 98-1 in Scheme 47 by using 4-(4- bromo-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-l,4-benzothiazepine 1,1-dioxide (prepared in analogy to 4-(4-chloro-6-(trifluoromethoxy)quinolin-2-yl)-2,3,4,5-tetrahydro-l,4- benzothiazepine 1,1-dioxide in Example 17-1) and tert-butyl 4-hydroxypiperidine-l-carboxylate.
MS obsd. (ESI+) [(M+H)+] 438, 1H NMR (400 MHz, CD3OD) δ ppm 8.10 - 8.05 (d, J= 8 Hz, 1 H), 7.92 (s, 1 H), 7.90 - 7.85 (d, J= 7.6 Hz ,1 H), 7.80 - 7.75 (d, J= 8.8 Hz, 1 H), 7.75 - 7.68 (t, J= 7.6 Hz, 1 H), 7.68 - 7.62 (d, J= 9.2 Hz,l H), 7.60 -7.55 (t, J= 7.6 Hz,l H), 6.64 (s, 1 H), 5.38 (s, 2 H), 5.32 - 5.26 (m, 1 H),4.65 - 4.40 (m, 2 H), 3.82 - 3.72 (t, J= 2.8 Hz , 2 H), 3.52 - 3.40 (m, 2 H), 3.40 - 3.30 (m, 2 H), 2.47 (s, 3 H), 3.36 - 3.28 (m, 2 H), 3.20 - 3.10 (m, 2 H).
Example 99
4-(4,6-Dimethylquinolin-2-yl)-2,3,4,5-tetrahydro-l,4-benzothiazepine 1,1-dioxide
Figure imgf000410_0001
Diethyl (2-chloro-6-methylquinolin-4-yl)propanedioate
Figure imgf000410_0002
To a solution of 2,4-dichloro-6-methylquinoline (2.11 g, 10 mmol) and 1,3-diethyl propanedioate (2.64 g, 20 mmol) in N,N-dimethylformamide (40 mL) was added anhydrous potassium carbonate (2.8 g, 20 mmol). The mixture was stirred at 70 °C for 3 hours, then poured into ice/water (100 mL) and extracted with ethyl acetate (100 mL x 3). The combined organic layers were washed with brine (150 mL x 2), dried over sodium sulfate. The residue was purified by flash column chromatography on silica gel (eluting with 20 - 30% ethyl acetate in petroleum ether) to afford 1.34 g of the desired product (yield was 40%). MS obsd. (ESI+) [(M+H)+] 336.
(2-Chloro-6-methylquinolin-4-yl)acetic acid
Figure imgf000410_0003
To a solution of diethyl (2-chloro-6-methylquinolin-4-yl)propanedioate (100 mg, 0.30 mmol) in methanol (2 mL) was added an aqueous solution of sodium hydroxide (2 N, 2 mL) and the resulting mixture was stirred at room temperature overnight. The reaction was then acidified to pH 4 with an aqueous solution of hydrochloric acid (5 N), and extracted with ethyl acetate (10 mL x 3). The organic layer was dried over sodium sulfate and concentrated in vacuo to afford the desired product as a white solid. MS (ESI+) [(M+H)+] 236.
4-(4,6-Dimethylquinolin-2-yl)-2,3,4,5-tetrahydro-l,4-benzothiazepine
Figure imgf000410_0004
A solution of (2-chloro-6-methylquinolin-4-yl)acetic acid (118 mg, 0.5 mmol ) and 2,3,4,5- tetrahydro-l,4-benzothiazepine (247 mg, 1.5 mmol) in n-butanol (0.2 mL) was heated with stirring in a sealed 0.5 mL of microwave process vial for 2 hours at 160 °C. After being cooled to room temperature, the reaction mixture was diluted with dichloromethane (50 mL), washed with a saturated aqueous solution of sodium carbonate (50 mL) and brine (50 mL), dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (eluting with 20 - 30% ethyl acetate in petroleum ether) to afford 100 mg of the desired product (yield was 62%). MS (ESI+) [(M+H)+] 321.
4-(4,6-Dimethylquinolin-2-yl)-2,3,4,5-tetrahydro-l,4-benzothiazepine 1,1-dioxide
Figure imgf000411_0001
To a solution of 4-(4,6-dimethylquinolin-2-yl)-2,3,4,5-tetrahydro-l,4-benzothiazepine (100 mg, 0.31 mmol) in dichloromethane (10 mL) was added 3-chloroperbenzoic acid (167 mg, 70% purity, 0.78 mmol) at room temperature for 4 hours. The resulting mixture was washed with a saturated aqueous solution of sodium carbonate (10 mL), dried over sodium sulfate and concentrated in vacuo. The residue was purified by preparative HPLC to afford the desired product. MS (ESI+) [(M+H)+] 353, 1H NMR (400 MHz, DMSO- 6) δ ppm 7.99 (d, J= 7.58 Hz, 1 H), 7.88 (d, J= 7.33 Hz, 1 H), 7.65 (t, J= 7.20 Hz, 1 H), 7.60 - 7.42 (m, 3 H), 7.35 (d, J= 8.34 Hz, 1 H), 7.18 (s, 1 H), 5.12 (brs, 2 H), 4.43 (brs, 2 H), 3.65 (brs, 2 H), 2.53 (s, 3 H), 2.39 (s, 3
H).
Example 100
[2-(l,l-Dioxido-2,3-dihydro-l,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl](piperidin- 4-yl)methanone
Figure imgf000411_0002
tert-Buty\ 4- { [2-(2,3-dihydro- 1 ,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4- yl](hydroxy)methyl}piperidine-l-carboxylate
Figure imgf000412_0001
To a solution of 4-(4-bromo-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-l,4-benzothiazepine (385 mg, 1.0 mmol, prepared in analogy to 4-(4-chloro-6-(trifluoromethoxy)quinolin-2-yl)-2, 3,4,5- tetrahydro-l,4-benzothiazepine 1,1-dioxide in Example 17-1) in tetrafiydrofuran (10 mL) which was cooled to -78 °C, butyl lithium (0.8 mL, 1.3 mmol) was added slowly and the mixture was stirred for 5 minutes, followed by the addition of a solution of tert-butyl 4-formylpiperidine-l- carboxylate (153 mg, 1.3 mmol ) in tetrahydrofuran (5 mL) slowly. After being stirred further at -78 °C for 2 hours, the reaction mixture was diluted with a saturated aqueous solution of ammonium chloride (10 mL) and extracted with dichloro methane (20 mL x 2). The organic layers were combined, dried over sodium sulfate and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (eluting with 20 - 40% ethyl acetate in petroleum ether) to afford 360 mg of the desired product (yield was 70%>). MS (ESI+) [(M+H)+]
520. tert-Buty\ 4-{[2-(l,l-dioxido-2,3-dihydro-l,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4- yl](hydroxy)methyl}piperidine-l-carboxylate
Figure imgf000412_0002
To a solution of tert-butyl 4-{[2-(2,3-dihydro-l,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4- yl](hydroxy)methyl}piperidine-l-carboxylate (519 mg, 1.0 mmol) in dichloromethane (10 mL) was added 3-chloroperbenzoic acid (537 mg, 70%> purity, 2.2 mmol). After being stirred at room temperature for 4 hours, to the above mixture was added a saturated aqueous solution of sodium thiosulfate (3 mL). The separated organic layer was washed with a saturated aqueous solution of sodium carbonate (5 mL) and brine (5 mL), dried over sodium sulfate and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (eluting with 20 - 50% ethyl acetate in petroleum ether) to afford 300 mg of the desired product. MS (ESI ) [(M+H)+]
552. tert-Buty\ 4-{[2-(l,l-dioxido-2,3-dihydro-l,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4- yl]carbonyl}piperidine-l-carboxylate
Figure imgf000413_0001
To a solution of tert-butyl 4-{[2-(l,l-dioxido-2,3-dihydro-l,4-benzothiazepin-4(5H)-yl)-6- methylquinolin-4-yl](hydroxy)methyl}piperidine-l-carboxylate (200 mg, 0.36 mmol) in dichloromethane (10 mL) was added Dess-Martin reagents (226 mg, 0.54 mmol). The resulting mixture was stirred at room temperature until the reaction was complete monitoring by LC/MS and then concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (eluting with 20 - 30% ethyl acetate in petroleum ether) to afford 150 mg of the desired product. MS (ESI+) [(M+H)+] 550.
[2-(l,l-Dioxido-2,3-dihydro-l,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl](piperidin- 4-yl)methanone
Figure imgf000413_0002
To a solution of tert-butyl 4-{[2-(l,l-dioxido-2,3-dihydro-l,4-benzothiazepin-4(5H)-yl)-6- methylquinolin-4-yl]carbonyl}piperidine-l-carboxylate (100 mg, 0.18 mmol) in
dichloromethane (1 mL) was added trifluoro acetic acid (1 mL). The resulting mixture was stirred at room temperature until the reaction was complete monitoring by LC/MS and then
concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (eluting with 1 - 10% methanol in dichloromethane) to afford 60 mg of the desired product. MS (ESI+) [(M+H)+] 450, 1H NMR (400 MHz, CD3OD) δ ppm 8.01 (dd, J= 7.83, 1.26 Hz, 1 H),
"), 7.68 - 7.56 (m, 2 H), 7.51 - 7.38 (m, 3 H), 7.34 (s, 1 H), 5.26 (brs, 2 H), 4.5 (brs, 2 H), 3.70 - 3.58 (m, 2 H), 3.37 (s, 2 H), 3.35 - 3.32 (m, 1 H), 3.14 - 3.03 (m, 2 H), 2.71 (td, J= 12.25, 2.78 Hz, 2 H), 2.40 (s, 3 H), 1.79 (m, 2 H), 1.69 - 1.51 (m, 2 H).
Example 101
4-[6-Methyl-4-(lH-pyrazol-3-yl)quinolin-2-yl]-2,3,4,5-tetrahydro-l,4-benzothiazepine 1,1- dioxide
Figure imgf000414_0001
To a solution of 8-(4-bromo-6-methylquinolin-2-yl)-2, 3,4, 5-tetrahydro-l,4-benzothiazepine 1,1- dioxide (115 mg, 0.28 mmol, prepared in analogy to 4-(4-chloro-6-(trifluoromethoxy)quinolin-2- yl)-2,3,4,5-tetrahydro-l,4-benzothiazepine 1,1 -dioxide in Example 17-1) in dimethoxyethane (8 mL) was added (triphenylphosphine) palladium (20 mg). After the mixture was stirred for 10 minutes, lH-pyrazole-3-boric acid (107 mg, 0.84 mmol) was added followed by an aqueous solution of sodium carbonate (1 M, 0.5 mL). The resulting mixture was sealed and heated with stirring in a sealed 10 mL of microwave process vial for 1 hour at 80 °C under microwave irradiation. The reaction mixture was then purified by preparative HPLC to afford 36.5 mg of the desired product (yield was 10.8%). MS (ESI+) [(M+H)+] 405, 1H NMR (400 MHz, CD3OD) δ ppm 8.41 (s, 1 H), 8.09 - 8.02 (m, 2 H), 7.95 (s, 2 H), 7.69 - 7.53 (m, 4 H), 6.99 (s, 1 H), 5.48 (s, 2 H), 4.67 (s, 2 H), 3.81 (s, 2 H), 3.34 (s, 1 H), 2.44 (s, 3 H).
Example 102
4-[6-Methyl-4-(phenylsulfonyl)quinolin-2-yl]-2,3,4,5-tetrahydro-l,4-benzothiazepine dioxide
Figure imgf000414_0002
4-[6-Methyl-4-(phenylsulfanyl)quinolin-2-yl]-2,3,4,5-tetrahydro-l,4-benzothiazepine 1,1- dioxide
Figure imgf000415_0001
A mixture of 4-(4-chloro-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-l,4-benzothiazepine 1,1- dioxide (1.8 g, 5.0 mmol, prepared in analogy to the one in Example 17-1), benzenethiol (0.66 g, 6.0 mmol) and N,N-dimethylpyridin-4-amine (0.74 g, 6 mmol) in dry ethanol (40 mL) was stirred at room temperature for 3 days. The reaction mixture was filtered and concentrated in vacuo. The residue was purified by silica gel column (gradient eluting with 10 - 20 % ethyl acetate in hexanes) to afford 1.0 g of the desired product (yield was 45%). 4-[6-Methyl-4-(phenylsulfonyl)quinolin-2-yl]-2,3,4,5-tetrahydro-l,4-benzothiazepine 1,1- dioxide
Figure imgf000415_0002
A mixture solution of 4-[6-methyl-4-(phenylsulfanyl)quinolin-2-yl]-2,3,4,5-tetrahydro-l,4- benzothiazepine 1,1 -dioxide (223 mg, 0.5 mmol) and 3-chloroperbenzoic acid (340 mg, 2 mmol) in dry dichloromethane (30 mL) was stirred at 0 °C for 2 hours. After the reaction was quenched with a saturated aqueous solution of sodium thiosulphate (15 mL), the resulting mixture was stirred further at room temperature for 15 minutes. The separated organic layer was washed with a saturated aqueous solution of sodium bicarbonate (15 mL) and a saturated aqueous solution of sodium thiosulphate (15 mL), dried over sodium sulfate and concentrated in vacuo. The residue was purified by preparative HPLC to afford 168 mg of the desired product (yield was 70%). MS (ESI+) [(M+H)+] 479, 1H NMR (400 MHz, CDC13) δ ppm 8.11 - 8.08 (dd, J= 1.2, 8 Hz, 1 H), 8.05 (s, 1 H), 7.91 - 7.89 (t, J= 3.6 Hz, 3 H), 7.75 - 7.38 (d, J= 6.8 Hz, 1 H), 7.65 - 7.58 (m, 3 H), 7.53 - 7.45 (m, 3 H), 7.41 - 7.39 (dd, J= 1.6, 8.4 Hz, 1 H), 5.25 (s, 2 H), 5.15 - 4.20 (brs, 2 H), 3.58 (s, 2 H), 2.42 (s, 3 H). Example 103 V-(2-Aminoethyl)-2-(l,l-dioxido-2,3-dihydro-l,4-benzothiazepin-4(5H)-yl)-6- methylquinoline-4-sulfonamide
Figure imgf000416_0001
2-(l , l-Dioxido-2,3-dihydro- 1 ,4-benzothiazepin-4(5H)-yl)-6-methylquinoline-4-thiol
Figure imgf000416_0002
To a solution of 4-(4-chloro-6-methylquinolin-2-yl)-2, 3,4, 5-tetrahydro-l,4-benzothiazepine 1,1- dioxide (1.5 g, 4 mmol, prepared in analogy to the one in Example 17-1) in dry N,N- dimethylformamide (100 mL) was added sodium methanethiolate (1.4 g, 20 mmol) under argon protection. The reaction was stirred at 130 °C for 16 hours. The reaction mixture was cooled to 50 °C and concentrated in vacuo. The residue was dissolved in cooled water (150 mL) and carefully acidified with 20% of hydrochloric acid to pH 4 ~ 5 under argon atmosphere. The resultant solution was extracted with cooled dichloromethane (150 mL x 3). The combined organic layer was washed with cooled brine (100 mL x 2) and concentrated in vacuo at room temperature to afford the crude product, which was used for next step without further purification.
2-(l , l-Dioxido-2,3-dihydro- 1 ,4-benzothiazepin-4(5H)-yl)-6-methylquinoline-4-sulfonyl chloride
Figure imgf000416_0003
Gaseous chlorine was passed through a well stirred solution of 2-(l,l-dioxido-2,3-dihydro-l,4- benzothiazepin-4(5H)-yl)-6-methylquinoline-4-thiol (the crude product from the above step) in concentrated hydrochloric acid (10 mL) at -10 °C at such a rate that temperature was maintained between -5 °C ~ -10 °C. After been stirred for 30 minutes, the passage of chlorine was discontinued and the mixture was poured onto ice (10 g) followed by the addition of sodium bicarbonate (8 g) in small portions. The resulting mixture was extracted with cooled
dichloromethane (100 mL x 3). The combined organic layer was washed with cooled water (100 mL), dried over sodium sulfate and filtered. The filtrate was used for the next step without further purification. V-(2-Aminoethyl)-2-(l,l-dioxido-2,3-dihydro-l,4-benzothiazepin-4(5H)-yl)-6- methylquinoline-4-sulfonamide
Figure imgf000417_0001
To a cooled solution of ethane- 1,2-diamine (320 mg, 5.4 mmol) in dichloromethane (50 mL) was added triethylamine (3 drops) followed by 2-(l,l-dioxido-2,3-dihydro-l,4-benzothiazepin- 4(5H)-yl)-6-methylquinoline-4-sulfonyl chloride (the filtrate from the above step) at 0 °C. The resulting mixture was stirred at room temperature for 16 hours and concentrated in vacuo. The residue was purified by preparative HPLC to afford 56.38 mg of the desired product (yield of three steps was 3.1%). MS (ESI+) [(M+H)+] 461, 1H NMR (400 MHz, CD3OD) δ ppm 8.11 (s, 1 H), 7.99 - 7.97 (d, J= 8.4 Hz, 1 H), 7.85 - 7.83 (d, J= 7.6 Hz, 1 H), 7.67 - 7.63 (m, 3 H), 7.49 - 7.45 (m, 2 H), 5.25 (s, 2 H), 4.76 - 4.03 (m, 2 H), 3.63 - 3.59 (t, 2 H), 3.03 - 3.00 (m, 4 H), 2.46 (s, 3 H).
Example 104
Methyl 4-({[3-(aminomethyl)oxetan-3-yl]methyl}amino)-2-(l,l-dioxido-2,3-dihydro-l,4- benzothiazepin-4(5H)-yl)quinoline-6-carboxylate
Figure imgf000418_0001
Methyl 4-chloro-2-(l,l-dioxido-2,3-dihydro-l,4-benzothiazepin-4(5H)-yl)quinoline-6- carboxylate
Figure imgf000418_0002
To a stirred solution of methyl 4-chloro-2-(2,3-dihydro-l,4-benzothiazepin-4(5H)-yl)quinoline- 6-carboxylate (1.5 g, 3.9 mmol) in dichloromethane (20 ml) was added 3-chloroperbenzoic acid (1.68 g, 9.7 mmol) at 0 °C. The reaction mixture was stirred at 0 °C for 20 minutes and the reaction was quenched with a saturated aqueous solution of sodium carbonate (10 mL). The separated organic layer was washed with a saturated aqueous solution of sodium carbonate (10 mL) and brine (10 mL), dried over sodium sulfate and concentrated in vacuo. The residue was purified by flash column chromatography (eluting with 5% methanol in dichloromethane) to afford 1.38 g of the desired product as a white solid (yield was 85%).
Methyl 4-({[3-(aminomethyl)oxetan-3-yl]methyl}amino)-2-(l,l-dioxido-2,3-dihydro-l,4- benzothiazepin-4(5H)-yl)quinoline-6-carboxylate
Figure imgf000418_0003
The title compound was prepared in analogy to Example 6-1 in Scheme 52 by using methyl 4- chloro-2-( 1 , 1 -dioxido-2,3-dihydro- 1 ,4-benzothiazepin-4(5H)-yl)quinoline-6-carboxylate and oxetane-3,3-diyldimethanamine. MS obsd. (ESI+) [(M+H)+] 497, 1H NMR (400 MHz, DMSO- d6) δ ppm 8.57 (d, 1 H), 7.95 (d, 1 H), 7.85 (m, 2 H), 7.71 (t, 1 H), 7.61 (m, 1 H), 7.46 - 7.38 (m, 2 H), 6.18 (s, 1 H), 5.07 (s, 2 H), 4.32 (m, 6 H), 3.80 (s, 3 H), 3.55 (m, 4 H), 2.95 (s, 2 H).
Example 105 4-({[3-(Aminomethyl)oxetan-3-yl]methyl}amino)-2-(l,l-dioxido-2,3-dihydro-l,4- benzothiazepin-4(5H)-yl)quinoline-6-carboxylic acid
Figure imgf000419_0001
To a stirred solution of methyl 4-({[3-(aminomethyl)oxetan-3-yl]methyl} amino)-2-(l , l-dioxido- 2,3-dihydro-l ,4-benzothiazepin-4(5H)-yl)quinoline-6-carboxylate (100 mg, 0.2 mmol) in tetrahydrofuran and water (4 mL, V/V = 3/1) was added sodium hydroxide (40 mg, 1.0 mmol). After being stirred at room temperature overnight, the resulting mixture was concentrated in vacuo to remove the organic solvent. The residual aqueous solution was acidified with an aqueous solution of citric acid (5 mL, 20%) and extracted with dichloromethane (15 mL x 3). The combined organic layers were dried over anhydrous sodium sulfate and concentrated in vacuo to afford a sticky solid, which was purified by flash column chromatography (eluting with 5% methanol in dichloromethane) to afford 20 mg of the desire product as a solid. MS obsd. (ESI+) [(M+H)+] 483, 1H NMR (400 MHz, DMSO- 6) δ ppm 8.78 (s, 1 H), 8.01 (d, 1 H), 7.90
(m, 2 H), 7.61 (t, 1 H), 7.47 (t, 1 H), 7.32 (d, 1 H), 6.29 (s, 1 H), 5.76 (s, 2 H), 4.40 (m, 6 H), 3.78 (s, 2 H), 3.62 (s, 2 H), 3.17 (m, 2 H) .
Example 106
[4-({[3-(Aminomethyl)oxetan-3-yl]methyl}amino)-2-(l,l-dioxido-2,3-dihydro-l,4- benzothiazepin-4(5H)-yl)quinolin-6-yl]methanol
Figure imgf000419_0002
[4-Chloro-2-(l,l-dioxido-2,3-dihydro-l,4-benzothiazepin-4(5H)-yl)quinolin-6-yl]methanol
Figure imgf000419_0003
To a slurry of lithium aluminum hydride (46 mg, 1.21 mmol) in tetrahydrofuran (5 mL) was added a solution of methyl 4-chloro-2-(l,l-dioxido-2,3-dihydro-l,4-benzothiazepin-4(5H)- yl)quinoline-6-carboxylate (400 mg, 0.96 mmol) in tetrahydrofuran (10 mL) at 0 °C under a nitrogen atmosphere. After being allowed to warm to room temperature and stirred for 2 hours, the reaction mixture was cooled to 0 °C and treated with water (0.2 mL) to quench the reaction. The resulting mixture was stirred for 30 minutes, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to afford 321 mg of the desired product as a white solid (yield was
86%).
[4-({[3-(Aminomethyl)oxetan-3-yl]methyl}amino)-2-(l,l-dioxido-2,3-dihydro-l,4- benzothiazepin-4(5H)-yl)quinolin-6-yl] methanol
Figure imgf000420_0001
The title compound was prepared in analogy to Example 6-1 in Scheme 52 by using [4-chloro-2- (l,l-dioxido-2,3-dihydro-l,4-benzothiazepin-4(5H)-yl)quinolin-6-yl]methanol and oxetane-3,3- diyldimethanamine. MS obsd. (ESI+) [(M+H)+] 469, 1H NMR (400 MHz, DMSO- 6) δ ppm 7.93 (d, 1 H), 7.83 (m, 1 H), 7.75 (s, 1 H), 7.59 (m, 1 H), 7.42 (m, 1 H), 7.34 (s, 2 H), 7.25 (t, 1 H), 6.13 (s, 1 H), 5.10 (t, 1 H), 5.04 (s, 2 H), 4.47 (d, 2 H), 4.34 (m, 6 H), 3.58 (d, 2 H), 3.52 (d, 2 H), 2.96 (t, 2 H), 1.79 (m, 2 H).
Example 107 V-{[3-(Aminomethyl)oxetan-3-yl]methyl}-6-trideuteriomethyl-2-(l-oxido-2,3-dihyd] benzothiazepin-4(5H)-yl)quinazolin-4-amine
Figure imgf000420_0002
izyloxy)-6-bromo-2-chloroquinazoline
Figure imgf000421_0001
To a cooled solution of 6-bromo-2,4-dichloroquinazoline (1.39g, 5 mmol) in tetrahydrofuran (50 mL) was added a solution of benzyl alcohol (0.52 mL, 5 mmol) and sodium hydride (210 mg, 5.25 mmol, 60% in mineral oil) in tetrahydrofuran (15 mL) dropwise at 0 °C. After being stirred at room temperature for 2 hours, the reaction mixture was poured into cold water (10 mL) and then extracted with ethyl acetate (50 mL). The organic layer was dried over magnesium sulfate and concentrated in vacuo to afford 1.73 g of the desired product as a yellow solid ( yield was 99%).
4-[4-(Benzyloxy)-6-bromoquinazolin-2-yl]-2,3,4,5-tetrahydro-l,4-benzothiazepine
Figure imgf000421_0002
A mixture of 4-(benzyloxy)-6-bromo-2-chloroquinazoline (700 mg, 2.0 mmol) and 2,3,4,5- tetrahydro-l,4-benzothiazepine (990 mg, 6.0 mmol) was heated at 80 °C for 10 minutes. The resulting reaction mixture was cooled to room temperature and purified by silica gel column chromatography (eluting with dichloromethane) to afford 600 mg of the desired product as a white solid (yield was 62.7%>).
4-[4-(Benzyloxy)-6-trideuteriomethylquinazolin-2-yl]-2,3,4,5-tetrahydro-l,4- benzothiazepine
Figure imgf000421_0003
To a cooled solution of 4-[4-(benzyloxy)-6-bromoquinazolin-2-yl]-2,3,4,5-tetrahydro-l,4- benzothiazepine (239 mg, 0.50 mmol) in anhydrous tetrahydrofuran (10 mL) was added n- butyllithium (0.5 mL, 0.80 mmol) in tetrahydrofuran dropwise over 5 minutes under a nitrogen atmosphere at -78 °C, followed by addition of methyl-<i3 trifluoromethanesulfonate(134 mg, 0.80 mmol) dropwise at -78 °C over 5 minutes. After being stirred for 1 hour at -78 °C, the reaction ^,, +,,^ +^ -varm to room temperature and stirred for another 1 hour. The reaction was quenched with deuterated water (5 mL). The resulting mixture was extracted with ethyl acetate (20 mL). The organic layer was dried over sodium sulfate and concentrated in vacuo to afford the desired compound.
4-[4-(Benzyloxy)-6-trideuteriomethylquinazolin-2-yl]-2,3,4,5-tetrahydro-l,4- benzothiazepine 1-oxide
Figure imgf000422_0001
To a solution of 4-[4-(benzyloxy)-6-trideuteriomethylquinazolin-2-yl]-2,3,4,5-tetrahydro-l,4- benzothiazepine (417 mg, 1.0 mmol) in dichloromethane (10 mL) was added 3- chloroperoxybenzoic acid (233 mg, 1.0 mmol, 75%). After being stirred for 1 hour, the mixture was washed with a saturated aqueous solution of sodium thiosulphate (3 mL), 10% aqueous solution of sodium hydroxide (5 mL) and brine (5 mL). The organic layer was dried over sodium sulfate and concentrated in vacuo. The residue was purified by silica gel column chromatography (eluting with 10% ethyl acetate in dichloromethane) to afford the desired product as a white solid. V-{[3-(aminomethyl)oxetan-3-yl]methyl}-6-trideuteriomethyl-2-(l-oxido-2,3-dihydro-l,4- benzothiazepin-4(5H)-yl)quinazolin-4-amine
Figure imgf000422_0002
A mixture of 4-[4-(benzyloxy)-6-trideuteriomethylquinazolin-2-yl]-2,3,4,5-tetrahydro-l,4- benzothiazepine 1-oxide (700 mg, 1.62 mmol) and oxetane-3,3-diyldimethanamine (752 mg, 6.5 mmol) was heated at 170 °C for 20 minutes, then the mixture was cooled to room temperature and then purified by preparative HPLC to afford 60 mg of the desired product as a white solid (yield was 8.4%). MS obsd. (ESI+) [(M+H)+] 441, 1H NMR (400 MHz, CD3OD) δ ppm 7.78 - 7.73 (m, 2 H), 7.69 - 7.67 (m,l H), 7.62 - 7.45 (m, 2 H), 7.44 - 7.40 (m, 1 H), 7.38 - 7.34 (m, 1 H), 5.27 (d, J= 16 Hz, 1H), 4.77 (brs, 1 H), 4.68 - 4.64 (m, 2 H), 4.52 - 4.47 (m, 2 H), 4.11 - 4.01 (m, 2 H), 3.49 - 3.35 (m, 2 H), 3.50 - 3.40 (m, 1 H), 3.40 - 3.34 (m, 1H), 3.04 (s, 2 H). Example 108-1
4-({[3-(Aminomethyl)oxetan-3-yl]methyl}amino)-2-(l-oxido-2,3-dihydro-l,4- benzothiazepin-4(5H)-yl)quinazoline-6-carboxylic acid
Figure imgf000423_0001
Methyl 4-(benzyloxy)-2-(2,3-dihydro- 1 ,4-benzothiazepin-4(5H)-yl)quinazoline-6- carboxylate
Figure imgf000423_0002
To a solution of 4-(4-benzyloxy-6-bromoquinazolin-2-yl)-2,3,4,5-tetrahydro-l,4- benzothiazepine (239 mg, 0.5 mmol) in anhydrous tetrahydrofuran (10 mL) was added n- butyllithium (0.5 mL, 0.8 mmol) in tetrahydrofuran dropwise at -78 °C under nitrogen atmosphere over 5 minutes followed by addition of dry ice ( 2.5 mmol) at -78 °C. After being stirred for 1 hour at -78 °C, the reaction mixture was allowed to warm to room temperature and stirred for another 1 hour. The reaction was quenched by addition of a saturated solution of ammonium chloride (10 mL) and extracted with ethyl acetate (25 mL). The organic layer was dried over sodium sulfate and concentrated in vacuo to afford the crude product of the acid. To a solution of the above crude acid in methanol (15 mL) was added sulfmyl chloride (2 mL) at 0 °C, then the mixture was heat at 70 °C for 1 hour. The reaction mixture was cooled to room temperature and concentrated in vacuo. The residue was dissolved in ethyl acetate, and the solution was washed with a saturated aqueous solution of sodium bicarbonate, dried over sodium sulfate and concentrated in vacuo. The residue was purified by flash column chromatography (eluting with 10% ethyl acetate in dichloromethane) to afford the desired methyl ester.
Methyl 4-(benzyloxy)-2-(l-oxido-2,3-dihydro-l,4-benzothiazepin-4(5H)-yl)quinazoline-6- carboxylate and Methyl 4-(benzyloxy)-2-(l,l-dioxido-2,3-dihydro-l,4-benzothiazepin 4(5H)-yl)quinazoline-6-carboxylate
Figure imgf000424_0001
To a solution of methyl 4-(benzyloxy)-2-(2,3-dihydro-l,4-benzothiazepin-4(5H)-yl)quinazoline- 6-carboxylate (800 mg, 1.75 mmol) in dichloromethane was added m-chloroperoxybenzoic acid (602 mg, 2.625 mmol, 75% purity) slowly, then the mixture was stirred at room temperature for 1 hour. The reaction mixture was washed with a saturated aqueous solution of sodium
thiosulphate, and 10%> aqueous solution of sodium hydroxide, and brine. The resulting organic layer was dried over sodium sulfate and concentrated in vacuo. The residue was purified by flash column chromatography (eluting with 10% ethyl acetate in dichloromethane) to afford 350 mg of methyl 4-(benzyloxy)-2-(l-oxido-2,3-dihydro-l,4-benzothiazepin-4(5H)-yl)quinazoline-6- carboxylate and 400 mg of methyl 4-(benzyloxy)-2-(l,l-dioxido-2,3-dihydro-l,4- benzothiazepin-4(5H)-yl)quinazoline-6-carboxylate.
4-(Benzyloxy)-2-(l-oxido-2,3-dihydro-l,4-benzothiazepin-4(5H)-yl)quinazoline-6- carboxylic acid
Figure imgf000424_0002
To the solution of methyl 4-(benzyloxy)-2-(l-oxido-2,3-dihydro-l,4-benzothiazepin-4(5H)- yl)quinazoline-6-carboxylate (350 mg, 0.74 mmol) in the mixture of tetrahydrofuran and water (10 mL, V/V = 4: 1) was added lithium hydroxide (178 mg, 7.4 mmol). The resulting mixture was stirred at room temperature overnight and then acidified with hydrochloric acid (2 N), extracted with ethyl acetate. The organic layer was dried over sodium sulfate and concentrated in vacuo. The residue was purified by flash column chromatography (eluting with 10%> ethyl acetate in dichloromethane) to afford 4-(benzyloxy)-2-(l-oxido-2,3-dihydro-l,4-benzothiazepin- 4(5H)-yl)quinazoline-6-carboxylic MS obsd. (ESI+) [(M+H)+] 460.
4-({[3-(Aminomethyl)oxetan-3-yl]methyl}amino)-2-(l-oxido-2,3-dihydro-l,4- benzothiazepin-4(5H)-yl)quinazoline-6-carboxylic acid
Figure imgf000425_0001
A mixture of 4-(benzyloxy)-2-(l-oxido-2,3-dihydro-l,4-benzothiazepin-4(5H)-yl)quinazoline-6- carboxylic acid (170 mg, 0.37 mmol) and oxetane-3,3-diyldimethanamine (128 mg, 1.1 1 mmol) was heated at 170 °C for 30 minutes. Then the reaction mixture was cooled to room temperature and purified by preparative HPLC to afford 4-({[3-(Aminomethyl)oxetan-3-yl]methyl}amino)-2- (l-oxido-2,3-dihydro-l ,4-benzothiazepin-4(5H)-yl)quinazoline-6-carboxylic acid, MS obsd. (ESI+) [(M+H)+] 468, 1H NMR (400 MHz, DMSO- 6) δ ppm 8.91 - 8.61 (m, 2 H), 8.09 - 8.00 (m, 1 H), 7.77 - 7.74 (m, 1 H), 7.68 - 7.65 (m, 1 H), 7.51 - 7.42 (m, 2 H), 7.27 -7.13 (m, 1 H), 5.26 - 5.17 (m. 2 H), 4.89 - 4.68 (m, 4 H), 452 - 4.45 (m, 2 H), 4.40 - 4.31 (m, 2 H), 4.10 - 3.84 (m, 2 H), 3.20 - 3.01 (m, 2 H).
Example 108-2
4-({[3-(Aminomethyl)oxetan-3-yl]methyl}amino)-2-(l,l-dioxido-2,3-dihydro-l,4- benzothiazepin-4(5H)-yl)quinazoline-6-carboxylic acid
Figure imgf000425_0002
The title compound was prepared in analogy to Example 108-1 in Scheme 54 by using 4-
(benzyloxy)-2-(l , 1 -dioxido-2,3-dihydro- 1 ,4-benzothiazepin-4(5H)-yl)quinazoline-6-carboxylic acid and oxetane-3,3-diyldimethanamine, MS obsd. (ESI+) [(M+H)+] 484, 1H NMR (400 MHz, DMSO- 6) δ ppm 8.95 (brs, 1 H), 8.68 (m, 1H), 8.04 (d, J = 9.1 Hz, 1 H), 7.77 - 7.73 (m, 2 H), 7.68 - 7.63 (m, 1 H), 7.48 - 7.43 (m, 1 H), 7.24 - 7.19 (m, 1 H), 5.1 1 (brs, 2 H), 4.59-4.30 (brs, 6 H), 4.20 (m, 1H), 4.0 (m, 1H), 3.58 (brs, 2 H), 3.12 (m, 2 H).
Example 109-1 and Example 109-2
[4-({ [3-(Aminomethyl)oxetan-3-yl] methyl} amino)-2-(l-oxido-2,3-dihydro- 1 ,4- benzothiazepin-4(5H)-yl)quinazolin-6-yl] methanol and [4-({ [3-(Aminomethyl)oxetan-3- yl] methyl} amino)-2-(l , l-dioxido-2,3-dihydro- 1 ,4-benzothiazepin-4(5H)-yl)quinazolin-6- yl] methanol
Figure imgf000426_0001
izyloxy)-2-(2,3-dihydro-l,4-benzothiazepin-4(5H)-yl)quinazoline-6-carbaldehyde
Figure imgf000426_0002
To a cooled solution of 4-(4-benzyloxy-6-bromoquinazolin-2-yl)-2,3,4,5-tetrahydro-l,4- benzothiazepine (500 mg, 1.048 mmol) in anhydrous tetrahydrofuran (10 mL) was added anhydrous N,N-dimethylformamide (150 μί, 1.94 mmol) at -78 °C. After being stirred at -78 °C for 30 minutes, the mixture was warmed to room temperature, diluted with water (10 mL) and extracted with ethyl acetate (20 mL x 3). The combined organic layers were washed with a saturated aqueous solution of ammonium chloride (40 mL) and brine (40 mL), dried over anhydrous sodium sulfate, and concentrated in vacuo to afford 410 mg of the crude product as a yellow solid. MS obsd. (ESI+) [(M+H)+] 428. izyloxy)-2-(2,3-dihydro- 1 ,4-benzothiazepin-4(5H)-yl)quinazolin-6-yl] methanol
Figure imgf000426_0003
To a solution of 4-(benzyloxy)-2-(2,3-dihydro-l,4-benzothiazepin-4(5H)-yl)quinazoline-6- carbaldehyde (3.0 g, 7.0 mmol) in methanol (20 mL) and tetrahydrofuran (20 mL) was added sodium borohydride (270 mg, 7.13 mmol) at 0 °C. After being stirred at 0 °C for 15 minutes, the resulting mixture was warmed to room temperature, diluted with water (10 mL) and extracted with ethyl acetate (20 mL x 3). The combined organic layers were washed with a saturated aqueous solution of ammonium chloride (40 mL) and brine (40 mL), dried over anhydrous sodium sulfate, and concentrated in vacuo to afford 2.85 g of the desired product as a yellow solid (yield was 95%), MS obsd. (ESI+) [(M+H)+] 430.
[4-(Benzyloxy)-2-(l-oxido-2,3-dihydro-l,4-benzothiazepin-4(5H)-yl)quinazolin-6- yl] methanol and [4-(Benzyloxy)-2-(l,l-dioxido-2,3-dihydro-l,4-benzothiazepin-4(5H)- yl)quinazolin-6-yl] methanol
Figure imgf000427_0001
To a solution of [4-(benzyloxy)-2-(2,3-dihydro-l ,4-benzothiazepin-4(5H)-yl)quinazolin-6- yljmethanol (1.0 g, 2.33 mmol) in dichloromethane (20 mL) was added 3-chloroperoxybenzoic acid (536 mg, 2.33 mmol, 75% purity) at 0 °C. After being stirred at 0 °C for 15 minutes, the mixture was warmed to room temperature, diluted with water, extracted with dichloromethane (20 mL x 3). The combined organic layers were washed with a saturated aqueous solution of sodium bicarbonate (40 mL) and brine (40 mL), dried over anhydrous sodium sulfate, and concentrated in vacuo to afford 0.90 g of the mixture of [4-(benzyloxy)-2-(l-oxido-2,3-dihydro- l ,4-benzothiazepin-4(5H)-yl)quinazolin-6-yl]methanol and [4-(benzyloxy)-2-(l , l-dioxido-2,3- dihydro-l ,4-benzothiazepin-4(5H)-yl)quinazolin-6-yl]methanol as a yellow solid.
[4-({ [3-(Aminomethyl)oxetan-3-yl] methyl} amino)-2-(l-oxido-2,3-dihydro- 1 ,4- benzothiazepin-4(5H)-yl)quinazolin-6-yl] methanol and [4-({ [3-(Aminomethyl)oxetan-3- yl] methyl} amino)-2-(l , l-dioxido-2,3-dihydro- 1 ,4-benzothiazepin-4(5H)-yl)quinazolin-6- yl] methanol
Figure imgf000427_0002
A mixture of [4-(benzyloxy)-2-(l-oxido-2,3-dihydro-l ,4-benzothiazepin-4(5H)-yl)quinazolin-6- yljmethanol and [4-(benzyloxy)-2-(l , 1 -dioxido-2,3-dihydro- 1 ,4-benzothiazepin-4(5H)- yl)quinazolin-6-yl]methanol (700 mg, about 1.57 mmol) and oxetane-3,3-diyldimethanamine (700 mg, 6.03 mmol) was heated at 160 °C for 30 minutes. After being cooled to room temperature, the reaction mixture was diluted with water (10 mL), extracted with dichloromethane (20 mL x 3). The organic layers were washed with brine (40 mL), dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by preparative HPLC to afford [4-({[3-(aminomethyl)oxetan-3-yl]methyl}amino)-2-(l-oxido-2,3-dihydro-l,4- benzothiazepin-4(5H)-yl)quinazolin-6-yl]methanol, MS obsd. (ESI+) [(M+H)+] 454, 1H NMR (400 MHz, DMSO- 6) δ ppm 8.139 (s, 1 H), 7.918 (s, 1 H), 7.71 (m, 2 H), 7.48 (m, 3 H), 7.316 (d, J= 8 Hz, 1 H), 5.21 (m, 2 H), 4.75 (m, 2 H), 4.51 (m, 4 H), 4.369 (s, 3 H), 3.93 (brs, 1 H), 3.15 (brs, 2 H), 2.989 (s, 2 H), and [4-({[3-(aminomethyl)oxetan-3-yl]methyl}amino)-2-(l,l- dioxido-2,3-dihydro-l,4-benzothiazepin-4(5H)-yl)quinazolin-6-yl]methanol, MS obsd. (ESI+) [(M+H)+] 470, 1H NMR (400 MHz, DMSO- 6) δ ppm 8.197(s, 1 H), 7.789 (m, 3 H), 7.62 (t, J = 7.2 Hz, 1 H), 7.48 (m, 2 H), 7.316 (s, 1 H), 5.12 (m, 3 H), 4.48 (m, 8 H), 3.917 (s, 2 H), 3.569 (brs, 2 H), 2.951 (brs, 2 H).
Example 110-1 V-[(3-Aminooxetan-3-yl)methyl]-2-(5,5-difluoro-l,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)- 6-methylquinolin-4-amine
Figure imgf000428_0001
2-(4-Chloro-6-methylquinolin-2-yl)-5,5-difluoro-2,3,4,5-tetrahydro-lH-benzo[c]azepine
Figure imgf000428_0002
A solution of 2,4-dichloro-6-methylquinoline (500 mg, 2.358 mmol) and 5,5-difluoro-2,3,4,5- tetrahydro-lH-benzazepine (432 mg, 2.358 mmol) in n-butanol (10 mL) was heated at 160 °C for 5 hours under microwave irradiation. The resulting reaction mixture was poured into water (10 mL) and extracted with ethyl acetate (20 mL x 3). The combined organic layers were dried over sodium sulfate and concentrated in vacuo. The residue was purified by flash column chromatography (eluting with 20% ethyl acetate in petroleum ether) to afford 550 mg of the desired product as a solid (yield was 65 %). V-[(3-Aminooxetan-3-yl)methyl]-2-(5,5-difluoro-l,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)- 6-methylquinolin-4-amine
Figure imgf000429_0001
A solution of 2-(4-chloro-6-methylquinolin-2-yl)-5,5-difluoro-2,3,4,5-tetrahydro-lH- benzazepine (250 mg, 0.697 mmol), 3 -(amino methyl)oxetan-3 -amine (119 mg, 0.697 mmol, purity: 60 %), l,l'-bis(diphenylphosphino)ferrocene (39 mg, 0.0697 mmol), Ι,Γ- bis(diphenylphosphino)ferrocene-palladium(II)dichloride (51 mg, 0.0697 mmol), sodium tert- butoxide (134 mg, 1.394 mmol). in 1,4-dioxane (10 mL) was heated at 120 °C for 1.5 hours under microwave irradiation. The resulting reaction mixture was poured into water (10 mL) and extracted with dichloromethane (20 mL x 3), the combined organic layers were dried over sodium sulfate and concentrated in vacuo. The residue was purified by flash column
chromatography (eluting with 0 - 10% methanol in dichloromethane) and preparative HPLC to afford 14 mg of the product as a white solid (yield was 4.4%). MS obsd. (ESI+) [(M+H)+] 425, 1H NMR (400 MHz, CD3OD) δ ppm 7.67 - 7.65 (d, J= 6.8 Hz, 2 H), 7.61 - 7.59 (d, J= 7.6 Hz , 1 H), 7.46 - 7.39 (m, 2 H), 7.33 - 7.29 (m, 2 H), 6.15 (s, 1 H), 4.91 (s, 2 H), 4.63 - 4.61 (d, J = 6.4 Hz, 2 H), 4.58 - 4.56 (d, J= 6.4 Hz, 2 H), 4.32 - 4.29 (t, J= 5.5, 5.6 Hz, 2 H), 3.64 (s, 2 H), 2.55 - 2.45 (m, 2 H), 2.42 (s, 3 H). Example 110-2 V-[2-(2-Aminoethoxy)ethyl]-2-(5,5-difluoro-l,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)-6- methylquinolin-4-amine
Figure imgf000429_0002
The title compound was prepared in analogy to Example 110-1 in Scheme 56 by using 2-(4- chloro-6-methylquinolin-2-yl)-5,5-difluoro-2,3,4,5-tetrahydro-lH-benzazepine and 2-(2- aminoethoxy)ethan-l -amine. MS obsd. (ESI+) [(M+H)+] 427, 1H NMR (400 MHz, CD3OD) δ ppm 7.60 -7.50 (d, J= 7.2 Hz 1 H), 7.50 - 7.40 (d, J= 9.2 Hz , 1 H), 7.40 - 7.30 (d, J= 7.6 Hz ,1 H), 7.30 - 7.15 (m, 5 H), 5.85 (s, 1 H), 5.05 (s, 1 H), 4.75 (s, 2 H), 4.30 (s, 2 H), 3.75 - 3.65 (m, 2 H), 3.55 - 3.45 (m, 2 H), 3.40 - 3.30 (m, 2 H), 2.90 - 2.80 (t, 2 H), 2.50 - 2.40 (m, 2 H), 2.35 (s, 3 H).
Example 110-3 V-[2-(5,5-Difluoro-l,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)-6-methylquinolin-4-yl]- V- methylethane-l,2-diamine
Figure imgf000430_0001
The title compound was prepared in analogy to Example 110-1 in Scheme 56 by using 2-(4- chloro-6-methylquinolin-2-yl)-5,5-difluoro-2,3,4,5-tetrahydro-lH-benzazepine and (2- aminoethyl)(methyl)amine. MS obsd. (ESI+) [(M+H)+] 397, 1H NMR (400 MHz, CD3OD) δ ppm
7.60 - 7.50 (d, J= 7.2 Hz, 1 H), 7.45 - 7.30 (m, 2 H), 7.30 - 7.10 (m, 5 H), 5.85 (s, 1 H), 5.25 (s, 1 H), 4.80 (s, 2 H), 4.30 (s, 2 H), 3.35 - 3.20 (m, 2 H), 2.97 - 2.85 (m, 2 H), 2.50 - 2.40 (m, 5 H), 2.35 (s, 3 H).
Example 110-4 l-Amino-3-{[2-(5,5-difluoro-l,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)-6-methylquinolin-4- yl]amino}propan-2-ol
Figure imgf000430_0002
The title compound was prepared in analogy to Example 110-1 in Scheme 56 by using 2-(4- chloro-6-methylquinolin-2-yl)-5,5-difluoro-2,3,4,5-tetrahydro-lH-benzazepine and 1,3- diaminopropan-2-ol. MS obsd. (ESI+) [(M+H)+] 413, 1H NMR (400 MHz, CD3OD) δ ppm 7.60 - 7.50 (d, J= 7.6 Hz, 1 H), 7.45 - 7.35 (m, 2 H), 7.30 - 7.10 (m, 5 H), 5.85 (s, 1 H), 5.20 (s, 1 H), 4.78 (s, 2 H), 4.30 (s, 2 H), 3.85 - 3.75 (m, 1 H), 3.35 - 3.20 (m, 1 H), 3.20 - 3.10 (m, 1 H), 3.00 - 2.90 (m, 1 H), 2.75 - 2.65 (m,l H), 2.45 - 2.35 (m, 2 H), 2.32 (s, 3 H). Example 110-5
3-{[2-(5,5-Difluoro-l,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)-6-methylquinolin-4- yl]amino}propane-l,2-diol
Figure imgf000431_0001
The title compound was prepared in analogy to Example 110-1 in Scheme 56 by using 2-(4- chloro-6-methylquinolin-2-yl)-5,5-difluoro-2,3,4,5-tetrahydro-lH-benzazepine and 3- aminopropane-l,2-diol. MS obsd. (ESI+) [(M+H)+] 414, 1H NMR (400 MHz, CDC13) δ ppm 7.60
- 7.50 (d, J= 7.6 Hz, 1 H), 7.50 - 7.40 (d, J= 8.4 Hz, 2 H), 7.35 - 7.25 (d, J= 8.4 Hz, 2 H), 7.25
- 7.10 (m, 2 H) 5.85 (s, 1 H), 5.20 (s, 1 H), 4.78 (s, 2 H), 4.20 (s, 2 H), 3.95 - 3.85 (m, 1 H), 3.70
- 3.50 (m, 2 H), 3.20 - 3.10 (m, 2 H), 2.50 - 2.40 (m, 2 H), 2.32 (s, 3 H). Example 110-6
3-{[2-(5,5-Difluoro-l,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)-6-methylquinolin-4- yl]amino}propan-l-ol
Figure imgf000431_0002
The title compound was prepared in analogy to Example 110-1 in Scheme 56 by using 2-(4- chloro-6-methylquinolin-2-yl)-5,5-difluoro-2,3,4,5-tetrahydro-lH-benzazepine and 3- aminopropane-l-ol. MS obsd. (ESI+) [(M+H)+] 398, 1H NMR (400 MHz, CD3C1) δ ppm 7.60 - 7.40 (m, 3 H), 7.35 - 7.25 (m, 4 H), 5.85 (s, 1 H), 4.80 (s, 2 H), 4.30 (s, 2 H), 3.90 - 3.80 (m, 2 H), 3.45 - 3.30 (m, 2 H), 2.55 - 2.45 (m, 2 H), 2.38 (s, 3 H). Example 110-7
2-(5,5-Difluoro-l,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)-6-methyl- V-[2-(piperazin-l- yl)ethyl] quinolin-4-amine
Figure imgf000432_0001
The title compound was prepared in analogy to Example 110-1 in Scheme 56 by using 2-(4- chloro-6-methylquinolin-2-yl)-5,5-difluoro-2,3,4,5-tetrahydro-lH-benzazepine and 2-(piperazin- l-yl)ethan-l -amine. MS obsd. (ESI+) [(M+H)+] 452, 1H NMR (400 MHz, CD3C1) δ ppm 7.52 - 7.44 (d, J= 8.8 Hz, 1 H), 7.41 - 7.40 (m, 2 H), 7.25 - 7.10 (m, 4 H), 5.80 (s, 1 H), 5.51 (s, 1 H), 4.79 (s, 2 H), 4.26 (s, 2 H), 3.21 - 3.17 (m, 2 H), 2.86 - 2.84 (m, 4 H), 2.70 - 2.67 (m, 2 H), 2.44 - 2.42 (m, 6 H), 2.35 (s, 3 H).
Example 110-8 V~l~-[2-(5,5-Difluoro-l,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)-6-methylquinolin-4- yl] propane- 1 ,2-diamine
Figure imgf000432_0002
The title compound was prepared in analogy to Example 110-1 in Scheme 56 by using 2-(4- chloro-6-methylquinolin-2-yl)-5,5-difluoro-2,3,4,5-tetrahydro-lH-benzazepine and propane- 1,2- diamine. MS obsd. (ESI+) [(M+H)+] 397, 1H NMR (400 MHz, CD3C1) δ ppm 7.54 - 7.52 (d, J = 7.6 Hz, 1 H), 7.47 - 7.45 (d, J= 8.4 Hz, 1 H), 7.40 - 7.38 (d, J= 7.6 Hz, 1 H), 7.25 - 7.16 (m, 4 H) 5.85 (s, 1 H), 5.25 (s, 1 H), 4.78 (s, 2 H), 4.29 - 4.24 (m, 2 H), 3.22 - 3.17 (m, 2 H), 2.91 - 2.89 (m, 1 H), 2.46 - 2.33 (m, 2 H), 2.32 (s, 3 H) , 1.20 - 1.18 (m, 3 H).
Example 110-9 cis- V-[2-(5,5-Difluoro-l,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)-6-methylquinolin-4- yl] cyclohexane- 1 ,4-diamine
Figure imgf000433_0001
The title compound was prepared in analogy to Example 110-1 in Scheme 56 by using 2-(4- chloro-6-methylquinolin-2-yl)-5,5-difluoro-2,3,4,5-tetrahydro-lH-benzazepine and cis- cyclohexane-l,4-diamine. MS obsd. (ESI+) [(M+H)+] 437, 1H NMR (400 MHz, CD3OD) δ ppm 7.60 - 7.50 (d, J= 7.6 Hz, 1 H), 7.50 - 7.40 (d, J= 8.4 Hz, 1 H), 7.40 - 7.30 (d, J= 7.6 Hz, 1 H), 7.30 - 7.15 (m, 5 H), 5.95 (s, 1 H), 4.80 - 4.70 (d, J= 4.0 Hz, 2 H), 4.60 (s, 2 H), 4.05 (s, 1 H), 3.10 (s, 1 H), 2.70 - 2.60 (m, 1 H), 2.50 - 2.40 (m, 2 H), 2.35 (s, 3 H), 2.05 (s, 2 H), 1.80 (s, 2 H), 1.50 - 1.30 (m, 4 H).
Example 110-10
2-(9,9-Difluoro-6,7,8,9-tetrahydro-5H-benzo[7] annulen-6-yl)-6-methyl- V-(pyrrolidin-3- yl)quinolin-4-amine
Figure imgf000433_0002
The title compound was prepared in analogy to Example 110-1 in Scheme 56 by using 2-(4- chloro-6-methylquinolin-2-yl)-5,5-difluoro-2,3,4,5-tetrahydro-lH-benzazepine and pyrrolidin-3- amine. MS obsd. (ESI+) [(M+H)+] 409, 1H NMR (400 MHz, CD3OD) δ ppm 7.60 - 7.50 (d, J = 7.6 Hz, 1 H), 7.50 - 7.40 (d, J= 8.8 Hz, 1 H), 7.40 - 7.30 (d, J= 7.2 Hz, 1 H), 7.30 - 7.20 (m, 4 H), 5.85 (s, 1 H), 4.75 (s, 2 H), 4.30 (s, 2 H), 4.05 (s, 1 H), 3.65 (s, 1 H), 3.30 - 3.20 (m, 1 H), 3.20 - 2.90 (m, 3 H) , 2.50 - 2.40 (m, 2 H), 2.35 (s, 3 H), 2.20 - 2.10 (m, 2 H).
Example 110-11 2,2 '- { [2-(5,5-Difluoro- 1 ,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)-6-methylquinolin-4- yl] imino} diethanol
Figure imgf000434_0001
The title compound was prepared in analogy to Example 110-1 in Scheme 56 by using 2-(4- chloro-6-methylquinolin-2-yl)-5,5-difluoro-2,3,4,5-tetrahydro-lH-benzazepine and 2,2'- iminodiethanol. MS obsd. (ESI+) [(M+H)+] 428, 1H NMR (400 MHz, CD3OD) δ ppm 7.90 - 7.70 (m, 2 H), 7.70 - 7.60 (m, 2 H), 7.50 - 7.30 (m, 3 H), 6.40 (s, 1 H), 5.85 (s, 2 H), 4.65 (s, 2 H), 4.15 (s, 2 H), 3.85 (s, 3 H), 3.58 (s, 2 H), 3.25 (s, 2 H), 2.60 - 2.50 (m, 3 H) , 2.35 (s, 3 H).
Example 110-12 V~l—[2-(5,5-Difluoro-l,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)-6-methylquinolin-4-yl]-2- methylpropane- 1 ,2-diamine
Figure imgf000434_0002
The title compound was prepared in analogy to Example 110-1 in Scheme 56 by using 2-(4- chloro-6-methylquinolin-2-yl)-5,5-difluoro-2,3,4,5-tetrahydro-lH-benzazepine and 2- methylpropane-l,2-diamine. MS obsd. (ESI+) [(M+H)+] 411, 1H NMR (400 MHz, CD3OD) δ ppm 8.06 (s, 1 H), 7.79 - 7.69 (m, 3 H), 7.61 - 7.58 (dd, J= 8.8, 1.6 Hz, 1 H), 7.53 - 7.49 (t, J 7.6 Hz, 1 H), 7.46 - 7.42 (t, J= 7.6 Hz, 1 H), 6.13 (s, 1 H), 5.12 (s, 2 H), 4.24 - 4.21 (t, J= 5.( Hz, 2 H), 3.76 (s, 2 H), 2.73 - 2.64 (m, 2 H), 2.48 (s, 3 H), 1.42 (s, 6 H).
Example 110-13 5,5-Difluoro-2-[6-methyl-4-(4-methylpiperazin-l-yl)quinolin-2-yl]-2,3,4,5-tetrahydro-lH-2- benzazepine
Figure imgf000435_0001
The title compound was prepared in analogy to Example 110-1 in Scheme 56 by using 2-(4- chloro-6-methylquinolin-2-yl)-5,5-difluoro-2,3,4,5-tetrahydro-lH-benzazepine and 1- methylpiperazine. MS obsd. (ESI+) [(M+H)+] 423, 1H NMR (400 MHz, CD3OD) δ ppm 7.93 - 7.91 (d, J= 8.4 Hz, 1 H), 7.77 - 7.75 (d, J= 7.6 Hz, 1 H), 7.71 - 7.69 (d, J= 7.6 Hz, 1 H), 7.69 (s, 1 H), 7.62 - 7.60 (d, J= 7.6 Hz, 1 H), 7.56 - 7.52 (t, J = 8 Hz, 1 H), 7.49 - 7.45 (t, J = 8 Hz, 1 H), 6.58 (s, 1 H), 5.18 (s, 2 H), 4.32 - 4.29 (t, J= 6 Hz, 2 H), 3.97 - 3.89 (m, 2 H), 3.77 - 3.68 (m, 2 H), 3.61 - 3.51 (m, 2 H), 3.50 - 3.39 (m, 2 H), 3.03 (s, 3 H), 2.79 - 2.67 (m, 2 H), 2.49 (s, 3 H).
Example 110-14 1- [2-(9,9-Difluoro-6,7,8,9-tetrahydro-5H-benzo [7] annulen-6-yl)-6-methylquinolin-4-yl] -3- ethylurea
Figure imgf000435_0002
The title compound was prepared in analogy to Example 110-1 in Scheme 56 by using 2-(4- chloro-6-methylquinolin-2-yl)-5,5-difluoro-2,3,4,5-tetrahydro-lH-benzazepine and ethylurea. MS obsd. (ESI+) [(M+H)+] 411, 1H NMR (400 MHz, CDC13) δ ppm 12.30 (s, 1 H), 9.62 - 9.55 (m, 1 H), 8.40 - 8.20 (m, 1 H), 7.82 - 7.70 (m, 2 H), 7.60 - 7.38 (m, 4 H), 7.12 (s, 1 H), 5.00 - 4.80 (m, 2 H), 4.50 - 4.10 (m, 2 H), 3.42 - 3.30 (m, 2 H), 2.70 - 2.50 (m, 2 H), 1.92 (s, 3 H), 1.31 - 1.20 (t, J = 7.2 Hz, 3 H).
Example 110-15 V-{[3-(Aminomethyl)oxetan-3-yl]methyl}-2-(5,5-difluoro-l,3,4,5-tetrahydro-2H-2- benzazepin-2-yl)-6-methylquinolin-4-amine
Figure imgf000436_0001
The title compound was prepared in analogy to Example 110-1 in Scheme 56 by using 2-(4- chloro-6-methylquinolin-2-yl)-5,5-difluoro-2,3,4,5-tetrahydro-lH-benzazepine and oxetane-3,3- diyldimethanamine. MS obsd. (ESI+) [(M+H)+] 439, 1H NMR (400 MHz, CDC13) δ ppm 8.08 (s, 1 H), 7.80 (m, 3 H), 7.67 (d, 1 H), 7.60 (t, 1 H), 7.54 (t, 1 H), 6.18 (s, 1 H), 5.16 (s, 2 H), 4.68 - 4.62 (m, 4 H), 4.32 (t, 2 H), 3.94 (s, 2 H), 3.54 (s, 2 H), 2.78 (m, 2 H), 2.54 (s, 3 H).
Example 111-1
5,5-Difluoro-2-[6-methyl-4-(piperazin-l-yl)quinolin-2-yl]-2,3,4,5-tetrahydro-lH-2- benzazepine
Figure imgf000436_0002
A mixture of 2-(4-chloro-6-methylquinolin-2-yl)-5,5-difluoro-2,3,4,5-tetrahydro-lH- benzazepine (100 mg, 0.279 mmol) and piperazine (300 mg, 3.488 mmol) was heated at 150 °C for 2 hours under microwave irradiation. The resulting reaction mixture was purified by preparative HPLC followed by SPE. The eluent was concentrated in vacuo and the residue was dried by lyophilization to afford 38.87 mg of the desired product (yield was 34.1%). MS obsd. (ESI+) [(M+H)+] 409, 1H NMR (400 MHz, CD3OD) δ ppm 7.65 - 7.58 (d, J = 7.6 Hz, 1 H ), 7.55 - 7.45 (t, 2 H), 7.40 - 7.30 (d, J= 7.6 Hz, 1 H), 7.38 - 7.25 (m, 2 H), 7.28 - 7.20 (m, 1 H), 6.35 (s, 1 H), 4.75 (s, 2 H), 4.34 (s, 2 H), 3.20 - 3.00 (m, 8 H), 2.60 - 2.45 (m, 2 H), 2.43 (s, 3 H).
Example 111-2 2-[4-(l,4-Diazepan-l-yl)-6-methylquinolin-2-yl]-5,5-difluoro-2,3,4,5-tetrahydro-lH-2- benzazepine
Figure imgf000437_0001
The title compound was prepared in analogy to Example 111-1 in Scheme 56 by using 2-(4- chloro-6-methylquinolin-2-yl)-5,5-difluoro-2,3,4,5-tetrahydro-lH-benzazepine and
[l,4]diazepane. MS obsd. (ESI+) [(M+H)+] 423, 1H NMR (400 MHz, CD3C1) δ ppm 7.60 - 7.58 (d, J= 6.8 Hz, 1 H), 7.55 - 7.53 (m, 2 H), 7.45 - 7.43 (d, J= 7.2 Hz, 1 H), 7.34 - 7.24 (m, 3 H), 6.41 (s, 1 H), 4.85 (s, 2 H), 4.33 - 4.32 (d, J= 5.2 Hz ,2 H), 3.43 - 3.40 (m, 4 H), 3.17 - 3.14 (m, 4 H), 2.51 - 2.47 (m, 2 H), 2.41 (s, 3 H), 2.20 (brs, 1H), 2.04 -2.01 (m, 2 H).
Example 111-3 V-[2-(5,5-Difluoro-l,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)-6-methylquinolin-4-yl]-N- methylethane-l,2-diamine
Figure imgf000437_0002
The title compound was prepared in analogy to Example 111-1 in Scheme 56 by using 2-(4- chloro-6-methylquinolin-2-yl)-5,5-difluoro-2,3,4,5-tetrahydro-lH-benzazepine and (2- aminoethyl)(methyl)amine. MS obsd. (ESI+) [(M+H)+] 397, 1H NMR (400 MHz, CD3OD) δ ppm 7.60 - 7.50 (d, J= 7.2 Hz, 1 H), 7.45 - 7.35 (m, 2 H), 7.30 - 7.10 (m, 5 H), 5.85 (s, 1 H), 5.25 (s, 1 H), 4.78 (s, 2 H), 4.30 (s, 2 H), 3.35 - 3.20 (m, 2 H), 2.97 - 2.80 (m, 2 H), 2.50 - 2.35 (m, 5 H), 2.40 - 2.30 (s, 3 H).
Example 111-4 l-[2-(5,5-Difluoro-l,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)-6-methylquinolin-4- yl]pyrrolidin-3-amine
Figure imgf000438_0001
The title compound was prepared in analogy to Example 111-1 in Scheme 56 by using 2-(4- chloro-6-methylquinolin-2-yl)-5,5-difluoro-2,3,4,5-tetrahydro-lH-benzazepine and pyrrolidin-3- amine. MS obsd. (ESI+) [(M+H)+] 409, 1H NMR (400 MHz, CD3OD) δ ppm 7.65 (s, 1 H), 7.62 - 7.55 (d, J= 7.6 Hz, 1 H), 7.55 - 7.45 (d, J= 8.8 Hz, 1 H), 7.45 - 7.40 (d, J= 7.2 Hz, 1 H), 7.40 - 7.30 (t, 1 H), 7.30 - 7.20 (m, 3 H), 5.85 (s, 1 H), 4.85 (s, 2 H), 4.30 (s, 2 H), 3.80 - 3.70 (m, 3 H), 3.60 - 3.50 (m, 2 H), 3.40 - 3.30 (m, 1 H), 2.50 - 2.40 (m, 2 H), 2.35 (s, 3 H), 2.30 - 2.10 (m, 1 H).
Example 111-5 2-{[2-(5,5-Difluoro-l,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)-6-methylquinolin-4- yl] amino} ethanol
Figure imgf000438_0002
The title compound was prepared in analogy to Example 111-1 in Scheme 56 by using 2-(4- chloro-6-methylquinolin-2-yl)-5,5-difluoro-2,3,4,5-tetrahydro-lH-benzazepine and 2- aminoethanol. MS obsd. (ESI+) [(M+H)+] 384, 1H NMR (400 MHz, CD3OD) δ ppm 7.60 - 7.40 (m, 3 H), 7.35 - 7.20 (m, 4 H), 5.87 (s, 1 H), 4.88 - 4.87 (d, J= 16.4 Hz, 2 H), 4.33 (s, 2 H), 3.90 - 3.87 (m, 2 H), 3.41 - 3.37 (m, 2 H), 2.52 - 2.47 (m, 2 H), 2.38 (s, 3 H), 2.00 - 1.97 (m, 2 H).
Example 111-6 V-[2-(5,5-Difluoro-l,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)-6-methylquinolin-4-yl]ethane- 1,2-diamine
Figure imgf000439_0001
The title compound was prepared in analogy to Example 111-1 in Scheme 56 by using 2-(4- chloro-6-methylquinolin-2-yl)-5,5-difluoro-2,3,4,5-tetrahydro-lH-benzazepine and ethane- 1,2- diamine. MS obsd. (ESI+) [(M+H)+] 383, 1H NMR (400 MHz, CD3OD) δ ppm 7.89 (s, 1 H), 7.72 - 7.70 (d, J= 6.8 Hz, 1 H), 7.70 - 7.67 (d, J= 6.8 Hz, 2 H), 7.65 - 7.42 (m, 3 H), 6.00 (s, 1 H), 5.02 (s, 2 H), 4.23 - 4.20 (t, 2 H), 3.88 - 3.78 (t, 2 H), 3.58 - 3.55 (t, 2 H), 2.71 - 2.61 (m, 2 H), 2.46 (s, 3 H).
Example 111-7 V-[2-(5,5-Difluoro-l,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)-6-methylquinolin-4- yl]cyclohexane-l,3-diamine
Figure imgf000439_0002
The title compound was prepared in analogy to Example 111-1 in Scheme 56 by using 2-(4- chloro-6-methylquinolin-2-yl)-5,5-difluoro-2,3,4,5-tetrahydro-lH-benzazepine and cyclohexane- 1,3-diamine. MS obsd. (ESI+) [(M+H)+]437, 1H NMR (400 MHz, CD3OD) δ ppm 8.01 - 7.97 (d, J = 15.2 Hz, 1 H), 7.69 - 7.65 (m, 3 H), 7.55 - 7.41 (m, 3 H), 5.92 - 5.91 (d, J= 2.4 Hz, 2 H), 5.02 - 4.92 (m, 2 H), 4.31 - 4.10 (m, 2 H), 3.83 - 3.60 (m, 1 H), 3.41 - 3.32 (m, 1 H), 2.69 - 2.63 (m, 2 H), 2.45 - 2.43 (m, 3 H), 2.38 - 2.32 (m, 1 H), 2.19 - 2.11 (m, 1 H), 2.10 - 1.98 (m, 2 H), 1.70 - 1.65 (m, 2 H), 1.44 - 1.29 (m, 2 H).
Example 111-8 V'-[2-(5,5-Difluoro-l,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)-6-methylquinolin-4-yl]- V, V- dimethylethane- 1 ,2-diamine
Figure imgf000440_0001
The title compound was prepared in analogy to Example 111-1 in Scheme 56 by using 2-(4- chloro-6-methylquinolin-2-yl)-5,5-difluoro-2,3,4,5-tetrahydro-lH-benzazepine and N,N- dimethylethane-l,2-diamine. MS obsd. (ESI+) [(M+H)+] 411, 1H NMR (400 MHz, CDC13) δ ppm 7.61 (s, 2 H), 7.59 (s, 1 H), 7.46 - 7.44 (d, J= 8.4 Hz, 1 H), 7.37 - 7.42 (m, 1 H), 7.31 - 7.29 (m, 2 H), 5.93 (s, 1 H), 4.88 (s, 2 H), 4.25 (m, 2 H), 3.45 - 3.41 (t, J= 6.4 Hz, 2 H), 2.69 - 2.65 (t, J= 6.4 Hz, 2 H), 2.53 - 2.44 (m, 2 H), 2.39 (s, 3 H), 2.34 (s, 3 H).
Example 111-9 V-[2-(5,5-Difluoro-l,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)-6-methylquinolin-4- yl]propane-l,3-diamine
Figure imgf000440_0002
The title compound was prepared in analogy to Example 111-1 in Scheme 56 by using 2-(4- chloro-6-methylquinolin-2-yl)-5,5-difluoro-2,3,4,5-tetrahydro-lH-benzazepine and propane-1,3- diamine. MS obsd. (ESI+) [(M+H)+] 397, 1H NMR (400 MHz, CD3OD) δ ppm 7.60 - 7.52 (m, 3 H), 7.40 - 7.32 (t, J= 2.4 Hz, 2 H), 7.30 - 7.20 (m, 2 H), 5.92 (s, 1 H), 4.30 - 4.20 (m, 2 H), 3.38 - 3.30 (t, J= 6.8 Hz, 2 H), 2.81 - 2.74 (t, J= 7.2 Hz, 2 H), 2.51 - 2.40 (m, 2 H), 2.37 (s, 3 H), 1.90 - 1.80 (m, 2 H), 1.32 - 1.25 (m, 2 H).
Example 111-10 V-[2-(5,5-Difluoro-l,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)-6-methylquinolin-4-yl]butane- 1,4-diamine
Figure imgf000441_0001
The title compound was prepared in analogy to Example 111-1 in Scheme 56 by using 2-(4- chloro-6-methylquinolin-2-yl)-5,5-difluoro-2,3,4,5-tetrahydro-lH-benzazepine and butane- 1,4- diamine. MS obsd. (ESI+) [(M+H)+] 411, 1H NMR (400 MHz, CD3OD) δ ppm 7.60 - 7.52 (m, 3 H), 7.40 - 7.35 (t, J= 2.4 Hz, 2 H), 7.32 - 7.20 (m, 2 H), 5.90 (s, 1 H), 4.30 - 4.20 (m, 2 H), 3.35 - 3.25 (m, 2 H), 2.78 - 2.68 (t, J= 7.2 Hz, 2 H), 2.51 - 2.40 (m, 2 H), 2.37 (s, 3 H), 1.78 - 1.68 (m, 2 H), 1.68 - 1.58 (m, 2 H), 1.32 - 1.25 (m, 2 H).
Example 111-11 irans-4-Amino-l-[2-(5,5-difluoro-l,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)-6- methylquinolin-4-yl] py rrolidin-3-ol
Figure imgf000441_0002
The title compound was prepared in analogy to Example 111-1 in Scheme 56 by using 2-(4- chloro-6-methylquinolin-2-yl)-5,5-difluoro-2,3,4,5-tetrahydro-lH-benzazepine and tert-butyl [(3lS,45)-4-hydroxypyrrolidin-3-yl]carbamate. MS obsd. (ESI+) [(M+H)+] 425, 1H NMR (400 MHz, CD3OD) δ ppm 7.75 (s, 1 H ), 7.65 - 7.55 (m, 2 H), 7.50 - 7.40 (d, J= 7.6 Hz, 1 H), 7.42 - 7.35 (t, 1 H), 7.35 - 7.25 (m, 2 H), 5.60 (s, 1 H), 4.80 (s, 2 H), 4.60 - 4.50 (m, 1 H), 4.25 - 4.15 (m, 1 H), 4.15 - 4.00 (m, 3 H), 3.90 - 3.80 (m, 1 H), 3.80 - 3.70(m, 1 H), 3.65 - 3.55 (m, 1 H), 3.30 (s, 2 H), 2.60 - 2.40 (m, 2 H), 2.30 (s, 3 H).
Example 112-1 TV- { [3-(Aminomethyl)- 1 , l-dioxidothietan-3-yl] methyl}-2-(5,5-difluoro- 1 ,3,4,5-tetrahydro- 2H-2-benzazepin-2-yl)-6-methylquinolin-4-amine
Figure imgf000442_0001
A mixture solution of 2-(4-chloro-6-methyl-quinolin-2-yl)-5,5-difluoro-2,3,4,5-tetrahydro-lH- benzazepine (218 mg, 0.609 mmol), (l,l-dioxidothietane-3,3-diyl)dimethanamine (110 mg, 0.670 mmol), (tris(dibenzylideneacetone) dipalladium(0) (56 mg, 0.061 mmol), 2,2'- bis(diphenylphosphino)-l, -binaphthalene (38 mg, 0.061 mmol) and sodium tert-butoxide (117 mg, 1.218 mmol) in toluene (5 mL) was heated at 110 °C overnight. The resulting reaction mixture was poured into water (10 mL) and extracted with dichloromethane (20 mL x 3), The combined organic layers were dried over sodium sulfate and concentrated in vacuo. The residue was purified by flash column chromatography and preparative HPLC to afford 50 mg of the product as a white solid (yield was 17%). MS obsd. (ESI+) [(M+H)+] 487, 1H NMR (400 MHz, CD3OD) δ ppm 7.970 (s, 1 H), 7.751 - 7.703 (m, 3 H), 7.618 - 7.593 (dd, J= 8.8, 1.2 Hz, 1 H), 7.533 - 7.497 (m, 2 H), 6.377 (s, 1 H), 5.107 (s, 1 H), 4.315 - 4.106 (m, 6 H), 3.993 (s, 1 H), 3.569 (s, 1 H), 2.708 - 2.645 (m, 2 H), 2.479 (s, 3 H).
Example 112-2
TV- [(3- Aminooxetan-3-yl)methyl] -2- [(5£)-5-(methoxyimino)- 1 ,3,4,5-tetrahydi
benzazepin-2-yl]-6-methylquinolin-4-amine
Figure imgf000442_0002
(5£)-2-(4-Chloro-6-methylquinolin-2-yl)- V-methoxy-l,2,3,4-tetrahydro-5H-2-benzazepin-5- imine
Figure imgf000443_0001
The title compound was prepared in analogy to 2-(4-chloro-6-methylquinolin-2-yl)-5,5-difluoro- 2,3,4,5-tetrahydro-lH-benzazepine in Example 110-1 in Scheme 56 by using 2,4-dichoro-6- methylquinoline and N-methoxy-l,2,3,4-tetrahydro-5H-2-benzazepin-5-imine. TV- [(3- Aminooxetan-3-yl)methyl] -2- [(5£)-5-(methoxyimino)- 1 ,3,4,5-tetrahydro-2H-2- benzazepin-2-yl]-6-methylquinolin-4-amine
Figure imgf000443_0002
The title compound was prepared in analogy to Example 112-1 in Scheme 56 by using (5E)-2-(4- chloro-6-methylquinolin-2-yl)-N-methoxy-l,2,3,4-tetrahydro-5H-2-benzazepin-5-imine and 3- (aminomethyl)oxetan-3-amine. MS obsd. (ESI+) [(M+H)+] 432, 1H NMR (400 MHz, CD3OD) δ ppm 7.965 (s, 1 H), 7.706 - 7.684 (d, J= 8.8 Hz, 1 H), 7.609 - 7.586 (m, 3 H), 7.453 - 7.376 (m, 2 H), 6.100 (s, 1 H), 5.035 (s, 2 H), 4.695 - 4.623 (m, 4 H), 4.014 - 3.987 (m, 4 H), 3.928 (s, 3 H), 3.258 - 3.242 (m, 2 H), 2.471 (s, 3 H).
Example 113 V-{2-[(2-Aminoethyl)sulfonyl]ethyl}-2-(5,5-difluoro-l,3,4,5-tetrahydro-2H-2-benzazepin-2- yl)-6-methylquinolin-4-amine
Figure imgf000443_0003
V-{2-[(2-Aminoethyl)sulfanyl]ethyl}-2-(5,5-difluoro-l,3,4,5-tetrahydro-2H-2-benzazepin-2- yl)-6-methylquinolin-4-amine
Figure imgf000444_0001
A mixture of 2-(4-chloro-6-methylquinolin-2-yl)-5,5-difluoro-2,3,4,5-tetrahydro-lH- benzazepine (160 mg, 0.447 mmol) and 2-[(2-aminoethyl)sulfanyl]ethan-l -amine (1.5 mL) was heated at 150 °C for 8 hours. The resulting reaction mixture was concentrated in vacuo. The residue was dissolved in dichloromethane (20 mL), washed with a saturated aqueous solution of sodium bicarbonate (20 mL) and brine (20 mL), dried over sodium sulfate and concentrated in vacuo. The residue was purified by flash column chromatography (eluting with 10 - 20% methanol in dichloromethane) to afford 180 mg of the desired product as oil (yield was 91.1%), MS obsd. (ESI+) [(M+H)+] 443. V-{2-[(2-Aminoethyl)sulfonyl]ethyl}-2-(5,5-difluoro-l,3,4,5-tetrahydro-2H-2-benzazepin-2- yl)-6-methylquinolin-4-amine
Figure imgf000444_0002
To a solution of N-{2-[(2-aminoethyl)sulfanyl]ethyl}-2-(5,5-difluoro-l,3,4,5-tetrahydro-2H-2- benzazepin-2-yl)-6-methylquinolin-4-amine (120 mg, 0.271 mmol) in acetic acid (2 mL) was added potassium permanganate (60 mg, 0.38 mmol). After being stirred at room temperature for 30 minutes, the resulting mixture was concentrated in vacuo. The residue was purified by preparative HPLC to afford 5 mg of the desired product as a solid. MS obsd. (ESI+) [(M+H)+] 475, 1H NMR (400 MHz, CD3OD) δ ppm 7.81 (s, 1 H), 7.77 - 7.68 (m, 2 H), 7.676 (s, 1 H), 7.56 (dd, J= 7.2, 1.2 Hz, 2 H), 7.47 (t, J= 7.6 Hz, 1 H), 6.08 (s, 1 H), 5.07 (brs, 2 H), 4.60 (brs, 2 H), 4.27 (t, J= 5.6 Hz, 2 H), 4.01 (t, J= 6.4 Hz, 2 H), 3.62 (t, J= 6.8 Hz, 2 H), 3.53 (m, 2 H), 3.42 (m, 2 H), 2.48 (s, 3 H).
Example 114-1 2-(4-{[(3-Aminooxetan-3-yl)methyl]amino}-6-methylquinazolin-2-yl)-l,2,3,4-tetrahydro- 5H-2-benzazepin-5-one
Figure imgf000445_0001
2-(4-Hydroxy-6-methylquinazolin-2-yl)-l,2,3,4-tetrahydro-5H-2-benzazepin-5-one
Figure imgf000445_0002
To a stirred solution of 2-chloro-4(3H)-quinazolinone (580 mg, 3.0 mmol ) and 1,2,3,4- tetrahydro-5H-2-benzazepin-5-one (591 mg, 3.0 mmol ) in toluene (20 mL) was added triethylamine (626 μί, 4.5 mmol ). After being re fluxed overnight, the resulting reaction mixture was cooled and the formed solid was collected by filtration, washed with ethanol (10 mL) and ethyl acetate (10 mL), and dried in vacuo to afford 775 mg of the desired product as a white solid (yield was 81%).
2-(4-{[(3-Aminooxetan-3-yl)methyl]amino}-6-methylquinazolin-2-yl)-l,2,3,4-tetrahydro- 5H-2-benzazepin-5-one
Figure imgf000445_0003
The title compound was prepared in analogy to Example 62-1 in Scheme 23 by using 2-(4- hydroxy-6-methylquinazolin-2-yl)-l,2,3,4-tetrahydro-5H-2-benzazepin-5-one and 3- (aminomethyl)oxetan-3-amine. MS obsd. (ESI+) [(M+H)+] 404, 1H NMR (400 MHz, CD3OD) δ ppm 7.94 (s, 1 H), 7.90 (d, 1 H), 7.75 (d, 1 H), 7.65 - 7.55 (m, 3 H), 7.45 (t, 1 H), 5.40 (s, 2 H), 4.77 - 7.72 (m, 4 H), 4.40 (s, 2 H), 4.05 (brs, 2 H), 3.35 (t, 2 H), 2.43 (s, 3 H). Example 114-2 V-{[3-(Aminomethyl)thietan-3-yl]methyl}-2-(5,5-difluoro-l,3,4,5-tetrahydro-2H-2- benzazepin-2-yl)-6-methylquinazolin-4-amine
Figure imgf000446_0001
The title compound was prepared in analogy to Example 114-1 in Scheme 23 by using 2- 4(3H)-quinazolinone, 5,5-difluoro-2,3,4,5-tetrahydro-lH-benzazepine and thietane-3,3- diyldimethanamine. MS obsd. (ESI+) [(M+H)+] 456, 1H NMR (400 MHz, CD3OD) δ ppm 7.701 - 7.683 (d, J= 7.2 Hz, 1 H), 7.605 (s, 1 H), 7.574 - 7.554 (d, J= 8.0 Hz, 1 H), 7.392 - 7.336 (m, 2 H), 7.298 - 7.251 (t, J= 8.4, 10.4 Hz, 2 H), 4.990 (s, 2 H), 4.309 - 4.283 (t, J= 4.8, 5.6 Hz, 2 H), 4.035 (s, 2 H), 3.119 - 3.095 (d, J= 9.6 Hz, 2 H), 3.016 - 2.992 (d, J= 9.6 Hz, 2 H), 2.849 (s: 2 H), 2.478 - 2.413 (m, 2 H), 2.356 (s, 3 H).
Example 114-3 V-{[3-(Aminomethyl)oxetan-3-yl]methyl}-2-(5,5-difluoro-l,3,4,5-tetrahydro-2H-2- benzazepin-2-yl)-6-methylquinazolin-4-amine
Figure imgf000446_0002
The title compound was prepared in analogy to Example 114-1 in Scheme 23 by using 2- 4(3H)-quinazolinone, 5,5-difluoro-2,3,4,5-tetrahydro-lH-benzazepine and oxetane-3,3- diyldimethanamine. MS obsd. (ESI+) [(M+H)+] 440, 1H NMR (400 MHz, CD3OD) δ ppm 8.00 (s, 1 H), 7.67 (m, 3 H), 7.56 (d, 1 H), 7.45 (m, 2 H), 5.14 (s, 2 H), 4.64 (d, 2 H), 4.58 (d, 2 H ), 4.21 (s, 4 H), 3.41 (s, 2 H), 2.63 (brs, 2 H), 2.44 (s, 3 H).
Example 114-4 2-(Aminomethyl)-2-({[2-(5,5-difluoro-l,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)-6- methylquinazolin-4-yl] amino} methyl)propane- 1 ,3-diol
Figure imgf000447_0001
The title compound was formed when purification of Examle 114-3 by preparative HPLC in acid condition. MS obsd. (ESI+) [(M+H)+] 458, 1H NMR (400 MHz, CD3OD) δ ppm 7.96 (s, 1 H), 7.63 - 7.75 (m, 4 H), 7.50 (t, 1 H), 7.43 (t, 1 H), 5.17 (s, 2 H), 4.27 (s, 2 H), 3.94 (s, 2 H), 3.76 (m, 4 H), 3.25 (s, 2 H), 2.68 (s, 2 H), 2.45 (s, 3 H).
Example 115
2-(4-{[(3-Aminooxetan-3-yl)methyl]amino}-6-methylquinazolin-2-yl)-5-methyl-2,3,4,5- tetrahydro- lH-2-benzazepin-5-ol
Figure imgf000447_0002
2-(5-Hydroxy-5-methyl-l,3,4,5-tetrahydro-benzoazepin-2-yl)-6-methyl-3H-quinazolin-4- one
Figure imgf000447_0003
To a suspension of 2-(4-hydroxy-6-methylquinazolin-2-yl)- 1 ,2,3 ,4-tetrahydro-5H-2-benzazepin- 5-one (500 mg, 1.57 mmol) in tetrahydroiuran (15 mL), a solution of methyl magnesium bromide in tetrahydroiuran (3 M, 0.57 ml, 1.72 mmol) was added at 0 °C. The reaction mixture was heated at 50 °C for 4 hours, and then poured into a saturated aqueous solution of ammonium chloride (10 mL) and stirred for 10 minutes. The resulting mixture was extracted with dichloromethane (15 mL x 3). The combined organic layers were dried over sodium sulfate and concentrated in vacuo. The residue was purified by flash column chromatography (eluting with 50% ethyl acetate in hexanes) to afford 350 mg of the desired product as a white solid (yield was 66.5%).
2-(4-{[(3-Aminooxetan-3-yl)methyl]amino}-6-methylquinazolin-2-yl)-5-methyl-2,3,4,5- tetrahydro- lH-2-benzazepin-5-ol
Figure imgf000448_0001
The title compound was prepared in analogy to Example 114-1 in Scheme 57 by using 2-(5- hydroxy-5-methyl-l,3,4,5-tetrahydro-benzoazepin-2-yl)-6-methyl-3H-quinazolin-4-one and 3- (aminomethyl)oxetan-3-amine. MS obsd. (ESI+) [(M+H)+] 420, 1H NMR (400 MHz, CD3OD) δ ppm 7.95 (s, 1 H), 7.66 (d, 2 H), 7.57 (d, 1 H), 7.51 (d, 1 H), 7.30 (m, 2 H), 5.31 (d, 2 H), 4.80 (m, 4 H), 4.73 (d, 2 H), 4.39 (brs, 2 H), 3.97 (brs, 2 H), 2.45(s, 3 H), 1.64 (s, 3 H).
Example 116-1 V-[(3-Aminooxetan-3-yl)methyl]-2-(5,5-difluoro-l,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)- 6-methylquinazolin-4-amine
Figure imgf000448_0002
2-Chloro- V-{[3-(dibenzylamino)oxetan-3-yl]methyl}-6-ethylquinazolin-4-amine
Figure imgf000449_0001
A solution of 2,4-dichloro-6-methylquinazoline (1.0 g, 4.69 mmol) in methanol (10 mL) was added 3-(aminomethyl)-N,N-dibenzyloxetan-3-amine (1.4 g, 5.16 mmol, 60% purity) and triethylamine (0.1 g, 1 mmol). After being stirred at room temperature overnight, the mixture was concentrated in vacuo. The residue was purified by flash column chromatography (eluting with 20% ethyl acetate in petroleum ether) to afford 1.6 g of the product as a white solid (yield was 76%)). V-{[3-(Dibenzylamino)oxetan-3-yl]methyl}-2-(5,5-difluoro-l,3,4,5-tetrahydro-2H-2- benzazepin-2-yl)-6-methylquinazolin-4-amine
Figure imgf000449_0002
To a solution of 2-chloro-N-{[3-(dibenzylamino)oxetan-3-yl]methyl}-6-methylquinazolin-4- amine (200 mg, 0.436 mmol) in N,N-dimethylformamide (3 mL) was added 5,5-difluoro-l,3,4,5- tetrahydro-2H-2-benzazepine (80 mg, 0.436 mmol) and triethylamine (89 mg, 0.872 mmol). The mixture was heated at 120 °C for 30 minutes under microwave irradiation. The reaction was poured into water (10 mL) and extracted with dichloromethane (15 mL x 3). The combined organic layers were dried over sodium sulfate and concentrated in vacuo. The residue was purified by flash column chromatography (eluting with 20% ethyl acetate in petroleum ether) to afford 190 mg of the product as a brown solid (yield was 72%). V-[(3-Aminooxetan-3-yl)methyl]-2-(5,5-difluoro-l,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)- 6-methylquinazolin-4-amine
Figure imgf000450_0001
A solution of N-{[3-(dibenzylamino)oxetan-3-yl]methyl}-2-(5,5-difluoro-l,3,4,5-tetrahydro-2H- 2-benzazepin-2-yl)-6-methylquinazolin-4-amine (190 mg, 0.314 mmol) and trifluororacetic acid (1 drop) in methanol was stirred in the presence of palladium hydroxide on carbon (50 mg) at room temperature under hydrogen atmosphere overnight. The resulting mixture was filtered, concentrated in vacuo. The residue was purified by preparative HPLC to afford 32 mg of the product as a white solid (yield was 24%). MS obsd. (ESI+) [(M+H)+] 426, 1H NMR (400 MHz, CD3OD) δ ppm 7.696 (s, 1 H), 7.654 - 7.636 (d, J= 7.2 Hz, 1 H), 7.607 - 7.588 ( d, J= 7.6 Hz, 1 H), 7.404 - 7.367 (m, 2 H), 7.341 - 7.283 (m, 2 H), 5.011 (s, 2 H), 4.683 - 4.626 (m, 2 H), 4.556 - 4.540 (d, J= 6.4 Hz, 2 H), 4.335 - 4.307 ( t, J= 5.6 Hz, 2 H), 4.084 (s, 2 H), 5.528 - 2.432 (m, 2 H), 2.398 (s, 3 H).
Example 116-2 V-[(3-Amino-l,l-dioxidothietan-3-yl)methyl]-2-(5,5-difluoro-l,3,4,5-tetrahydro-2H-2- benzazepin-2-yl)-6-methylquinazolin-4-amine
Figure imgf000450_0002
The title compound was prepared in analogy to Example 116-1 in Scheme 57 by using 2,4- dichloro-6-methylquinazoline, 3-(aminomethyl)-N,N-dibenzyl(l,l-dioxido)thietan-3-amine and 5,5-difluoro-l,3,4,5-tetrahydro-2H-2-benzazepine. MS obsd. (ESI+) [(M+H)+] 474, 1H NMR (400 MHz, CD3OD) δ ppm 7.73 (s, 1 H), 7.65(d, 1 H), 7.60 (d, 1 H), 7.29- 7.45 (m, 4 H), 5.02 (s 2 H), 4.04 - 4.62 (m, 2 H), 4.34 (t, 2 H ), 4.12 (t, 2 H ), 4.01 - 4.04 (m, 2 H), 2.47 (m, 2 H), 2.41 (s, 3 H).
Example 117 V-[2-(5,5-Difluoro-l,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)-6-methylquinazolin-4-yl]-2,2- difluoropropane-l,3-diamine
Figure imgf000451_0001
V-(2-Chloro-6-methylquinazolin-4-yl)-2,2-difluoropropane-l,3-diamine
Figure imgf000451_0002
To a solution of 2,2-difluoropropane-l,3-diamine (1.1 g,10 mmol) and triethylamine (1.4 mL, 10 mol) in dichloromethane (15 mL) was added a solution of 2,4-dichloro-6-methylquinazoline (500 mg, 2.36 mmol) in dichloromethane (5 mL) dropwise. After being stirred at room temperature overnight, the resulting mixture was poured into water (50 mL) and extracted with dichloromethane (50 mL x 2). The combined organic layers were washed with brine (50 mL), dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by flash column chromatography (eluting with 10 - 25% methanol in dichloromethane) to afford 41.8 mg of the desired product as a white solid (yield was 62%). MS obsd. (ESI+) [(M+H)+] 287. V-[2-(5,5-Difluoro-l,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)-6-methylquinazolin-4-yl]-2,2- difluoropropane-l,3-diamine
Figure imgf000451_0003
A solution ofN-(2-chloro-6-methylquinazolin-4-yl)-2,2-difluoropropane-l,3-diamine (97 mg, 0.34 mmol) and 5,5-difluoro-2,3,4,5-tetrahydro-lH-benzazepine (310 mg, 1.70 mmol) in n- butanol (1 mL) was heated at 160 °C for 30 minutes. The resulting reaction mixture was purified by preparative HPLC to afford 24.3 mg of the desired compound as a white solid. MS obsd. (ESI+) [(M+H)+] 434, 1H NMR (400 MHz, CD3OD) δ ppm 7.96 (s, 1 H), 7.68 (d, J= 7.2 Hz, 2 H), 7.58 (m, 2 H), 7.46 (m, 2 H), 5.12 (s, 2 H), 4.36 (t, J= 13.6 Hz, 2 H), 4.23 (s, 2 H), 3.58 (t, J = 16 Hz, 2 H), 2.67 (brs, 2 H), 2.44 (s, 3 H).
Example 118-1
TV- [2-(7-Bromo- 1 ,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)-6-chloroquinolin-4-yl] ethane- 1 ,2- diamine
Figure imgf000452_0001
7-Bromo- 1 ,2,4,5-tetrahydro-3H-2-benzazepin-3-one
Figure imgf000452_0002
To a cooled solution of 6-bromo-3,4-dihydro-lH-naphthalen-2-one (100 g, 0.44 mol) in toluene was added sodium azide (150 g, 2.2 mol) followed by addition of trifluoromethanesulfonic acid (200 mL) dropwise. When the addition was completed, the ice bath was removed and the mixture was stirred at room temperature overnight. The reaction was poured into ice-water, basified with potassium carbonate to pH>10 slowly, and then extracted with dichloro methane (1000 mL x 3). The organic layers were combined and dried over sodium sulfate, and then concentrated under reduced pressure to give a residue which was separated by column chromatography on silica gel to give 35 g of crude product. It was used for next step without further purification. MS obsd. (ESI+) [(M+H)+] 240.
7-Bromo-2,3,4,5-tetrahydro-lH-2-benzazepine
Figure imgf000452_0003
To a solution of 7-bromo- 1,2,4, 5-tetrahydro-3H-2-benzazepin-3-one (35 g, 146 mmol) in 1,2- dimethoxyethane (400 mL) was added a solution of borane dimethyl sulfide complex (1.0 M in tetrahydrofuran, 40 mL) under nitrogen and the resulting mixture was stirred under reflux overnight. The reaction was quenched with methanol, acidified with 2 M hydrochloric acid and then stirred for further 2 hours. The resulting mixture was concentrated in vacuo and the residue was purified by preparative HPLC to give 4.6 g of product. MS obsd. (ESI+) [(M+H)+] 226. 1H NMR (400 MHz, CDC13) δ ppm 7.21 (d, J = 5 Hz, 1 H), 7.15 - 7.13 (dd, J= 2.0, 8.0 Hz, 1 H), 6.89 (d, J= 8 Hz, 1 H), 3.79 (s, 2 H), 3.11 - 3.08 (m, 2 H), 2.82 - 2.79 (m, 2 H), 2.38 (brs, 1 H), 1.63 - 1.61 (m, 2 H).
7-Bromo-2-(4,6-dichloroquinolin-2-yl)-2,3,4,5-tetrahydro-lH-2-benzazepine
Figure imgf000453_0001
The mixture of 2,4, 6-trichloroquino line (300 mg, 1.29 mmol), 7-bromo-2,3,4,5-tetrahydro-lH-2- benzazepine (291 mg, 1.29 mmol) and n-butanol (3 mL) was heated with stirring in a 10 mL microwave process vial for 1 hour at 160 °C under microwave irradiation. The mixture was cooled to room temperature and diluted with ethyl acetate (10 mL), and then washed with water (10 mL). The organic layer was dried over sodium sulfate and evaporated to give a residue which was purified by column chromatography on silica gel to give 222 mg of product as a white solid (yield was 41%). MS obsd. (ESI+) [(M+H)+] 421. TV- [2-(7-Bromo- 1 ,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)-6-chloroquinolin-4-yl] ethane- 1 ,2- diamine
Figure imgf000453_0002
The mixture of 7-bromo-2-(4,6-dichloroquinolin-2-yl)-2,3,4,5-tetrahydro-lH-2-benzazepine (200 mg, 0.47 mmol) and ethane- 1,2-diamine (0.5 mL) was heated with stirring in a 5 mL microwave process vial for 2 hours at 160 °C under microwave irradiation. The solvent was removed under reduced pressure, and the residue was purified by preparative HPLC to give 38 mg of product (yield was 18%). MS obsd. (ESI+) [(M+H)+] 445, 1H NMR (400 MHz, CD3OD) δ ppm 7.90 (d, J= 2.4 Hz, 1 H), 7.49 (d, J= 8.8 Hz, 1 H), 7.41(m, 1 H) , 7.35 (m, 1 H), 7.31 (m, 2 H), 5.99 (s, 1 H), 4.80 (s, 2 H), 4.13 (m, 2 H), 3.40 (m, 2 H), 3.00 (m, 4 H), 1.90 (m, 2 H). Example 118-2
2-{4-[(2-Aminoethyl)amino]quinolin-2-yl}-2,3,4,5-tetrahydro-lH-2-benzazepin-8-ol
Figure imgf000454_0001
The title compound was prepared in analogy to Example 118-1 in Scheme 59 by using 2,3,4,5- tetrahydro-lH-2-benzazepine-8-ol (commercial available) and 2,4-dichloroquinoline
(commercial available) instead of 7-bromo-2,3,4,5-tetrahydro-lH-2-benzazepine and 2,4,6- trichloroquinoline respectively. MS obsd. (ESI+) [(M+H)+] 349. 1H NMR (400 MHz, CD3OD) δ ppm 7.82 (d, J= 8.0 Hz, 1 H), 7.55 (d, J= 8.0 Hz, 1 H), 7.43 (m, 1 H), 7.13 (m, 1 H), 6.96 (m, 2 H), 6.56 (m, 1 H), 6.00 (s, 1 H), 4.72 (s, 2 H), 4.13 (m, 2 H), 3.43 (t, J= 6.4 Hz, 2 H), 2.96 (m, 4 H), 1.87 (m, 2 H).
Example 118-3 V-[6-Methyl-2-(l,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)quinolin-4-yl]ethane-l,2 diamine
Figure imgf000454_0002
The title compound was prepared in analogy to Example 118-1 in Scheme 59 by using 2,3,4,5- tetrahydro-lH-2-benzazepine (commercial available) and 2,4-dichloro-6-methylquinoline (commercial available) instead of 7-bromo-2,3,4,5-tetrahydro-lH-2-benzazepine and 2,4,6- trichloroquinoline respectively. MS obsd. (ESI+) [(M+H)+] 347. 1H NMR (400 MHz, DMSO- 6) δ ppm 7.68 (s, 1 H), 7.55 (d, J= 6.8 Hz, 1 H), 7.29 (d, J= 8.4 Hz, 1 H), 7.21 (d, J= 6.8 Hz, 1 H), 7.13 - 7.05 (m, 3 H), 6.67 (brs, 1 H), 6.00 (s, 1 H), 4.79 (s, 2 H), 4.11 (brs, 2 H), 3.52 (s, 2 H), 3.05 - 2.99 (m, 4 H), 2.35 (s, 3 H), 1.77 (s, 2 H).
Example 118-4 V-[2-(8-Fluoro-l,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)-6-methylquinolin-4-yl]ethane-l,2- diamine
Figure imgf000455_0001
The title compound was prepared in analogy to Example 118-1 in Scheme 59 by using 8-fluoro- 2,3,4,5-tetrahydro-lH-2-benzazepine (commercial available) and 2,4-dichloro-6-methylquinoline (commercial available) instead of 7-bromo-2,3,4,5-tetrahydro-lH-2-benzazepine and 2,4,6- trichloroquinoline respectively. MS obsd. (ESI+) [(M+H)+] 365. 1H NMR (400 MHz, CD3OD) δ ppm 7.68 (s, 1 H), 7.48 (d, J= 8.4 Hz, 1 H), 7.28 (m, 2 H), 7.12 (m, 1 H), 6.83 (m, 1 H), 5.93 (s, 1 H), 4.80 (s, 2 H), 4.09 (s, 2 H), 3.46 (t, J= 6.0 Hz, 2 H), 3.00 (m, 4 H), 2.40 (s, 3 H), 1.90 (m, 2 H).
Example 118-5 V-[6-Chloro-2-(l,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)quinolin-4-yl]ethane-l,2-diamine
Figure imgf000455_0002
The title compound was prepared in analogy to Example 118-1 in Scheme 59 by using 2,3,4,5- tetrahydro- lH-2-benzazepine (commercial available) instead of 7-bromo-2,3,4,5-tetrahydro- 1H- 2-benzazepine. MS obsd. (ESI+) [(M+H)+] 367. 1H NMR (400 MHz, CD3OD) δ ppm 7.87 (d, J = 2.4 Hz, 1 H), 7.47 - 7.42 (m, 2 H), 7.34 (dd, J= 9.0, 2.2 Hz, 1 H), 7.15 - 7.09 (m, 3 H), 5.99 (s, 1 H), 4.76 (s, 2 H), 4.11 (brs, 2 H), 3.38 - 3.32 (m, 2 H), 3.00 - 2.93 (m, 4 H), 1.87 (t, J= 5.2 Hz, 2 H). Example 118-6 V-[6-Chloro-2-(9-fluoro-l,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)quinolin-4-yl]ethane-l,2- diamine
Figure imgf000456_0001
The title compound was prepared in analogy to Example 118-1 in Scheme 59 by using 9-fluoro- 2,3,4,5-tetrahydro-lH-2-benzazepine (commercial available) instead of 7-bromo-2, 3,4,5- tetrahydro-lH-2-benzazepine. MS obsd. (ESI+) [(M+H)+] 385. 1H NMR (400 MHz, CD3OD) δ ppm 7.90 (d, J= 2.0 Hz, 1 H), 7.47 (d, J= 8.8 Hz, 1 H), 7.36 (dd, J = 8.8, 2.4 Hz, 1 H), 7.13 (m,
1 H), 7.00 (m, 2 H), 6.11 (s, 1 H), 4.91 (s, 2 H), 4.21 (s, 2 H), 3.45 (t, J= 6.0 Hz, 2 H), 3.10 (m,
2 H), 3.00 (t, J= 6.0 Hz, 2 H), 1.89 (m, 2 H).
Example 118-7 V-[2-(8-Fluoro-l,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)quinolin-4-yl]ethane-l,2-diamine
Figure imgf000456_0002
The title compound was prepared in analogy to Example 118-1 in Scheme 59 by using 8-fluoro- 2,3,4,5-tetrahydro-lH-2-benzazepine (commercial available) and 2,4-dichloroquinoline
(commercial available) instead of 7-bromo-2,3,4,5-tetrahydro-lH-2-benzazepine and 2,4,6- trichloroquinoline respectively. MS obsd. (ESI+) [(M+H)+] 351. 1H NMR (400 MHz, CD3OD) δ ppm 7.90 (d, J= 7.6 Hz, 1 H), 7.58 (d, J= 8.0 Hz, 1 H), 7.52 (t, J= 6.8, 1.2 Hz, 1 H), 7.19 (m, 2 H), 7.02 (m, 2 H), 6.07 (s, 1 H), 4.21 (s, 2 H), 3.52 (t, J= 6.0 Hz, 2 H), 4.91 (s, 2 H), 3.12 (m, 2 H), 3.06 (m, 2 H), 1.94 (m, 2 H).
Example 118-8 l-Amino-3-{[2-(l,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)quinolin-4-yl]amino}propan-2-ol trifluoroacetate (salt)
Figure imgf000457_0001
The title compound was prepared in analogy to Example 118-1 in Scheme 59 by using 2,3,4,5- tetrahydro-lH-2-benzazepine (commercial available), 2,4-dichloroquinoline (commercial available) and l,3-diamino-propan-2-ol (commercial available) instead of 7-bromo-2, 3,4,5- tetrahydro-lH-2-benzazepine, 2,4, 6-trichloroquino line and ethane- 1,2-diamine respectively. MS obsd. (ESI+) [(M+H)+] 363. 1H NMR (400 MHz, CD3OD CD3OD) δ ppm 8.05 - 8.03 (d, J= 7.6 Hz, 1 H), 7.78 - 7.76 (d, J= 7.6 Hz, 1 H), 7.72 - 7.68 (m, 1 H), 7.52 - 7.50 (m, 1 H), 7.44 - 7.40 (m, 1 H), 7.23 - 7.19 (m, 3 H), 6.12 (s, 1 H), 4.97 (s, 2 H), 4.16 - 4.11 (m, 3 H), 3.56 - 3.55 (d, J = 6 Hz, 2 H), 3.20 - 3.16 (dd, J= 2.8, 12.8 Hz, 1 H), 3.11 - 3.08 (m, 2 H), 2.99 - 2.94 (m, 1 H), 1.99 - 1.98 (m, 2 H).
Example 118-9 V-[2-(l,3,4,5-Tetrahydro-2H-2-benzazepin-2-yl)quinolin-4-yl]ethane-l,2-diamine
Figure imgf000457_0002
The title compound was prepared in analogy to Example 118-1 in Scheme 59 by using 2,3,4,5- tetrahydro-lH-2-benzazepine (commercial available) and 2,4-dichloroquinoline (commercial available) instead of 7-bromo-2,3,4,5-tetrahydro-lH-2-benzazepine and 2,4, 6-trichloroquino line respectively. MS obsd. (ESI+) [(M+H)+] 333. 1H NMR (400 MHz, CD3OD) δ ppm 7.91 - 7.89 (m, 1 H), 7.62 - 7.60 (m, 1 H), 7.52 - 7.45 (m, 2 H), 7.21 - 7.12 (m, 3 H), 5.96 (s, 1 H), 4.10 (s, 2 H), 3.51 - 3.47 (t, J= 6.0 Hz, 1 H), 3.04 - 2.98 (m, 5 H), 2.84 (s, 2 H), 1.94 - 1.91 (m, 2 H). Example 118-10 V-[6-Bromo-2-(l,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)quinolin-4-yl]ethane-l,2-diamine
Figure imgf000458_0001
The title compound was prepared in analogy to Example 118-1 in Scheme 59 by using 2,3,4,5- tetrahydro-lH-2-benzazepine (commercial available) and 6-bromo-2,4-dichloroquinoline (commercial available) instead of 7-bromo-2,3,4,5-tetrahydro-lH-2-benzazepine and 2,4,6- trichloroquinoline respectively. MS obsd. (ESI+) [(M+H)+] 411. 1H NMR (400 MHz, CD3OD) δ ppm 8.05 (d, J= 2.0 Hz, 1 H), 7.52 - 7.42 (m, 3 H), 7.16 - 7.12 (m, 3 H), 6.03 (s, 1 H), 4.83 (s, 2 H), 4.15 (brs, 2 H), 3.48 (t, J= 6.0 Hz, 2 H), 3.07 - 3.03 (m, 4 H), 1.94 (t, J = 5.2 Hz, 2 H).
Example 118-11 V-[6-Methoxy-2-(l,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)quinolin-4-yl]ethane-l,2- diamine
Figure imgf000458_0002
The title compound was prepared in analogy to Example 118-1 in Scheme 59 by using 2,3,4,5- tetrahydro-lH-2-benzazepine (commercial available) and 2,4-dichloro-6-methoxyquinoline (commercial available) instead of 7-bromo-2,3,4,5-tetrahydro-lH-2-benzazepine and 2,4,6- trichloroquinoline respectively. MS obsd. (ESI+) [(M+H)+] 363. 1H NMR (400 MHz, CD3OD) δ ppm 7.60 (d, J= 9.2 Hz, 1 H), 7.50 (d, J= 6.4 Hz, 1 H), 7.42 (d, J= 2.4 Hz, 1 H), 7.25 - 7.18 (m, 4 H), 6.01 (s, 1 H), 4.93 (s, 2 H), 4.13 (brs, 2 H), 3.89 (s, 3 H), 3.53 (t, J= 6.4 Hz, 2 H), 3.10 - 3.01 (m, 4 H), 1.96 (s, 2 H).
Example 118-12 V-[2-(6-Chloro-l,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)quinolin-4-yl]ethane-l,2-diamine
Figure imgf000459_0001
The title compound was prepared in analogy to Example 118-1 in Scheme 59 by using 5-chloro- 3,4-dihydro-lH-naphthalen-2-one (commercial available) and 2,4-dichloroquinoline
(commercial available) instead of 6-bromo-3,4-dihydro-lH-naphthalen-2-one and 2,4,6- trichloroquinoline respectively. MS obsd. (ESI+) [(M+H)+] 367. 1H NMR (400 MHz, CD3OD) δ ppm 7.82 (d, J= 8.0 Hz, 1 H), 7.53 (d, J= 8.4 Hz, 1 H), 7.43 (m, 2 H), 7.25 (d, J= 8.4 Hz, 1 H), 7.12 (m, 2 H), 5.96 (s, 1 H), 4.87 (s, 2 H), 4.10 (s, 2 H), 3.41 (m, 2 H), 3.25 (m, 2 H), 2.95 (m, 2 H), 1.94 (m, 2 H).
Example 118-13 V-[2-(7-Fluoro-l,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)-6-methylquinolin-4-yl]ethane-l,2- diamine
Figure imgf000459_0002
The title compound was prepared in analogy to Example 118-1 in Scheme 59 by using 6-fluoro- 3,4-dihydro-lH-naphthalen-2-one (commercial available) and 2,4-dichloro-6-methylquinoline (commercial available) instead of 6-bromo-3,4-dihydro-lH-naphthalen-2-one and 2,4,6- trichloroquinoline respectively. MS obsd. (ESI+) [(M+H)+] 365. 1H NMR (400 MHz, CD3OD) δ ppm 7.82 (s, 1H), 7.58 (d, J= 8.4 Hz, 1 H), 7.45 (m, 1 H), 7.17 (m, 1 H), 6.94 (m, 1 H), 6.84 (m, 1 H), 6.03 (d, J= 4.0 Hz, 1 H), 4.87 (s, 2 H), 3.95 (m, 4 H), 3.56 (t, J= 6.4 Hz, 2 H), 3.10 (m, 4 H), 2.48 (s, 3 H). Example 118-14 V-Methyl- V'-[2-(l,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)quinolin-4-yl]ethane-l,2-diamine
Figure imgf000460_0001
The title compound was prepared in analogy to Example 118-1 in Scheme 59 by using 2,3,4,5- tetrahydro-lH-2-benzazepine (commercial available), 2,4-dichloroquinoline (commercial available) and N-methyl-ethane- 1,2-diamine (commercial available) instead of 7-bromo-2, 3,4,5- tetrahydro-lH-2-benzazepine, 2,4, 6-trichloroquino line and ethane- 1,2-diamine respectively. MS obsd. (ESI+) [(M+H)+] 347. 1H NMR (400 MHz, DMSO- 6) δ ppm 8.42 (brs, 2 H), 7.88 (s, 1 H), 7.55 (d, J= 6.4 Hz, 1 H), 7.47 (s, 2 H), 7.16 - 7.11 (m, 4 H), 6.01 (s, 1 H), 4.87 (s, 2 H), 4.14 (s, 2 H), 3.63 (s, 2 H), 3.20 (t, J= 5.6 Hz, 2 H), 3.02 (s, 2 H), 2.67 (s, 3 H), 1.80 (s, 2 H).
Example 118-15 TV- [2-(7-Methoxy- 1 ,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)quinolin-4-yl] ethane- 1 ,2- diamine
Figure imgf000460_0002
The title compound was prepared in analogy to Example 118-1 in Scheme 59 by using 7- methoxy-2,3,4,5-tetrahydro-lH-2-benzazepine (commercial available) and 2,4-dichloroquinoline (commercial available) instead of 7-bromo-2,3,4,5-tetrahydro-lH-2-benzazepine and 2,4,6- trichloroquinoline respectively. MS obsd. (ESI+) [(M+H)+] 363. 1H NMR (400 MHz, CD3OD) δ ppm 8.00 (d, J= 6.0 Hz, 1 H), 7.70 (d, J= 8.0 Hz, 1 H), 7.63 (t, J= 6.0 Hz, 1 H), 7.43 (d, J= 8.0 Hz, 1 H), 7.34 (m, 1 H), 6.80 (m, 1 H), 6.76 (m, 1 H), 6.00 (s, 1 H), 4.87 (s, 2 H), 4.13 (m, 2 H), 3.76 (s, 3 H), 3.59 (m, 2 H), 3.09 (m, 4 H), 1.97 (m, 2 H). Example 118-16 V-[2-(7-Fluoro-l,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)quinolin-4-yl]ethane-l,2-diamine
Figure imgf000461_0001
The title compound was prepared in analogy to Example 118-1 in Scheme 59 by using 6-fluoro- 3,4-dihydro-lH-naphthalen-2-one (commercial available) and 2,4-dichloroquinoline
(commercial available) instead of 6-bromo-3,4-dihydro-lH-naphthalen-2-one and 2,4,6- trichloroquinoline respectively. MS obsd. (ESI+) [(M+H)+] 351. 1H NMR (400 MHz, CD3OD) δ ppm 7.92 (d, J= 8.4 Hz, 1 H), 7.63 (d, J= 8.0 Hz, 1 H), 7.55 - 7.49 (m, 2 H), 7.24 (m, 1 H), 6.96 - 6.91 (m, 2 H), 5.97 (s, 1 H), 4.86 (s, 2 H), 4.12 (s, 2 H), 3.55 (t, J= 6.0 Hz, 2 H), 3.08 (m, 4 H), 1.95 (m, 2 H).
Example 118-17 TV- [2-(8-Methoxy- 1 ,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)quinolin-4-yl] ethane- 1 ,2- diamine
Figure imgf000461_0002
The title compound was prepared in analogy to Example 118-1 in Scheme 59 1 by using 8- methoxy-2,3,4,5-tetrahydro-lH-2-benzazepine (commercial available) and 2,4-dichloroquinoline (commercial available) instead of 7-bromo-2,3,4,5-tetrahydro-lH-2-benzazepine and 2,4,6- trichloroquinoline respectively. MS obsd. (ESI+) [(M+H)+] 363. 1H NMR (400 MHz, CD3OD) δ ppm 8.08 (d, J= 8.4 Hz, 1 H), 7.82 (d, J= 8.0 Hz, 1 H), 7.75 (t, J= 7.2 Hz, 1 H), 7.46 (t, J= 8.0 Hz, 1 H), 7.19 (m, 1 H), 7.13 (m, 1 H), 6.81 (m, 1 H), 6.05 (s, 1 H), 4.96 (s, 2 H), 4.15 (m, 2 H), 3.82 (m, 5 H), 3.29 (m, 2 H), 3.07 (m, 2 H), 1.99 (m, 2 H). Example 118-18 V-[6-(Difluoromethoxy)-2-(l,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)quinolin-4-yl]ethane- 1,2-diamine
Figure imgf000462_0001
The title compound was prepared in analogy to Example 118-1 in Scheme 59 by using 2,3,4,5- tetrahydro-lH-2-benzazepine (commercial available) and 2,4-dichloro-6- difluoromethoxyquinoline (commercial available) instead of 7-bromo-2,3,4,5-tetrahydro-lH-2- benzazepine and 2,4,6-trichloroquinoline respectively. MS obsd. (ESI+) [(M+H)+] 399. 1H NMR (400 MHz, CD3OD) δ ppm 7.63 (d, J= 2.4 Hz, 1 H), 7.55 (d, J= 9.2 Hz, 1 H), 7.47 (d, J= 6.8 Hz, 1 H), 7.27 (dd, J= 8.8, 2.4 Hz, 1 H), 7.18 - 7.12 (m, 3 H), 6.79 (t, J = 74.4 Hz, 1 H, HCF20- ), 6.03 (s, 1 H), 4.82 (s, 2 H), 4.15 (brs, 2 H), 3.46 (t, J= 6.2 Hz, 2 H), 3.06 - 3.00 (m, 4 H), 1.91 (t, J= 5.2 Hz, 2 H). Example 118-19 V-[2-(l,3,4,5-Tetrahydro-2H-2-benzazepin-2-yl)-6-(trifluoromethyl)quinolin-4-yl]ethane- 1,2-diamine
Figure imgf000462_0002
The title compound was prepared in analogy to Example 118-1 in Scheme 59 by using 2,3,4,5- tetrahydro-lH-2-benzazepine (commercial available) and 2,4-dichloro-6- trifluoromethylquinoline (commercial available) instead of 7-bromo-2, 3,4, 5-tetrahydro-lH-2- benzazepine and 2,4,6-trichloroquinoline respectively. MS obsd. (ESI+) [(M+H)+] 401. 1H NMR (400 MHz, DMSO- 6) δ ppm 8.36 (s, 1 H), 7.57 - 7.45 (m, 3 H), 7.12 (brs, 3 H), 6.99 (s, 1 H), 6.03 (s, 1 H), 4.81 (s, 2 H), 4.15 (brs, 2 H), 3.29 (brs, 2 H), 3.01 (s, 2 H), 2.82 (s, 2 H), 1.77 (s, 2 H).
Example 118-20 V-[8-Chloro-2-(l,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)quinolin-4-yl]ethane-l,2-diamine
The title compound was prepared in analogy to Example 118-1 in Scheme 59 by using 2,3,4,5- tetrahydro-lH-2-benzazepine (commercial available) and 2,4, 8-trichloroquino line (commercial available) instead of 7-bromo-2,3,4,5-tetrahydro-lH-2-benzazepine and 2,4, 6-trichloroquino line respectively. MS obsd. (ESI+) [(M+H)+] 367. 1H NMR (400 MHz, CD3OD) δ ppm 7.24 (d, J = 8.0 Hz, 1 H), 7.60 (d, J= 6.8 Hz, 1 H), 7.55 (d, J= 7.6 Hz, 1 H), 7.13 - 7.09 (m, 3 H), 6.98 (t, J = 8.0 Hz, 1 H), 6.03 (s, 1 H), 4.89 (s, 2 H), 4.20 (brs, 2 H), 3.46 (t, J= 6.0 Hz, 2 H), 3.07 - 3.02 (m, 4 H), 1.92 (t, J = 5.2 Hz, 2 H).
Example 118-21 V-[6-Fluoro-2-(l,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)quinolin-4-yl]ethane-l,2-diamine
Figure imgf000463_0002
The title compound was prepared in analogy to Example 118-1 in Scheme 59 by using 2,3,4,5- tetrahydro-lH-2-benzazepine (commercial available) and 2,4-dichloro-6-fluoroquinoline
(commercial available) instead of 7-bromo-2,3,4,5-tetrahydro-lH-2-benzazepine and 2,4,6- trichloroquinoline respectively. MS obsd. (ESI+) [(M+H)+] 351. 1H NMR (400 MHz, CD3OD) δ ppm 7.60 - 7.52 (m, 2 H), 7.47 (d, J = 6.8 Hz, 1 H), 7.26 - 7.21 (m, 1 H), 7.17 - 7.12 (m, 3 H), 6.04 (s, 1 H), 4.82 (s, 2 H), 4.15 (brs, 2 H), 3.45 (t, J= 6.4 Hz, 2 H), 3.06 - 2.99 (m, 4 H), 1.91 (t, J= 5.4 Hz, 2 H).
Example 118-22 V^V-Dimethyl- V'-[2-(l,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)quinolin-4-yl]ethane-l,2- diamine
Figure imgf000464_0001
The title compound was prepared in analogy to Example 118-1 in Scheme 59 by using 2,3,4,5- tetrahydro-lH-2-benzazepine (commercial available), 2,4-dichloroquinoline (commercial available) and N,N-dimethyl-ethane-l,2-diamine (commercial available) instead of 7-bromo- 2,3,4,5-tetrahydro-lH-2-benzazepine, 2,4,6-trichloroquinoline and ethane- 1,2-diamine respectively. MS obsd. (ESI+) [(M+H)+] 361. 1H NMR (400 MHz, DMSO- 6) δ ppm 7.90 (d, J = 3.6 Hz, 1 H), 7.56 - 7.46 (m, 3 H), 7.15 - 7.11 (m, 4 H), 5.89 (s, 1 H), 4.87 (s, 2 H), 4.14 (s, 2 H), 3.53 (s, 2 H), 3.05 (s, 2 H), 2.91 (s, 2 H), 2.53 (s, 6 H), 1.80 (s, 2 H).
Example 118-23 V-[2-(l,3,4,5-Tetrahydro-2H-2-benzazepin-2-yl)-6-(trifluoromethoxy)quinolin-4-yl]ethane- 1,2-diamine
Figure imgf000464_0002
The title compound was prepared in analogy to Example 118-1 in Scheme 59 by using 2,3,4,5- tetrahydro-lH-2-benzazepine (commercial available) and 2,4-dichloro-6- trifluoromethoxyquinoline (commercial available) instead of 7-bromo-2,3,4,5-tetrahydro-lH-2- benzazepine and 2,4,6-trichloroquinoline respectively. MS obsd. (ESI+) [(M+H)+] 417. 1H NMR (400 MHz, CD3OD) δ ppm 7.80 (d, J= 2.0 Hz, 1 H), 7.56 (d, J= 9.2 Hz, 1 H), 7.48 (d, J= 6.8 Hz, 1 H), 7.33 (d, J= 10.0 Hz, 1 H), 7.18 - 7.12 (m, 3 H), 6.06 (s, 1 H), 4.83 (s, 2 H), 4.16 (brs, 2 H), 3.46 (t, J= 6.2 Hz, 2 H), 3.06 - 3.00 (m, 4 H), 1.91 (t, J= 5.2 Hz, 2 H).
Example 118-24 V-[6-(Methylsulfonyl)-2-(l,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)quinolin-4-yl]ethane-l,2- diamine
Figure imgf000465_0001
The title compound was prepared in analogy to Example 118-1 in Scheme 59 by using 2,3,4,5- tetrahydro-lH-2-benzazepine (commercial available) and 2,4-dichloro-6- methanesulfonylquinoline (commercial available) instead of 7-bromo-2,3,4,5-tetrahydro-lH-2- benzazepine and 2,4,6-trichloroquinoline respectively. MS obsd. (ESI+) [(M+H)+] 411. 1H NMR (400 MHz, DMSO- 6) δ ppm 8.518 (s, 0.5 H), 8.514 (s, 0.5 H), 7.76 - 7.73 (m, 1 H), 7.61 (d, J = 6.4 Hz, 0.5 H), 7.52 (d, J= 6.8 Hz, 0.5 H), 7.47 - 7.34 (m, 1 H), 7.13 - 7.07 (m, 3 H), 6.23 (s, 0.5 H), 6.04 (s, 0.5 H). 4.83 (d, J= 6.4 Hz, 2 H), 4.34 (brs, 2 H), 3.15 (brs, 4 H), 3.00 (s, 2 H), 2.81 (t, J= 6.4 Hz, 1 H), 1.76 (brs, 2 H). Example 118-25
2-{4-[(2-Aminoethyl)amino]quinolin-2-yl}-2,3,4,5-tetrahydro-lH-2-benzazepine-8- carboxylic acid
Figure imgf000465_0002
The title compound was prepared in analogy to Example 118-1 in Scheme 59 by using 2,3,4,5- tetrahydro-lH-2-benzazepine-8-carboxylic acid (commercial available) and 2,4- dichloroquinoline (commercial available) instead of 7-bromo-2,3,4,5-tetrahydro-lH-2- benzazepine and 2,4,6-trichloroquinoline respectively. MS obsd. (ESI+) [(M+H)+] 377. 1H NMR (400 MHz, CD3OD) δ ppm 8.57 (s, 1 H), 8.07 (s, 1 H), 7.84 (d, J= 7.6 Hz, 1 H), 7.74 (dd, J = 6.0 Hz, 1 H), 7.58 (d, J= 8.4 Hz, 1 H), 7.47 (m, 1 H), 7.18 (m, 2 H), 6.10 (s, 1 H), 4.24 (brs, 2 H), 3.62 (m, 2 H), 3.26 (m, 2 H), 3.16 (m, 4 H), 1.91 (m, 2 H).
Example 118-26
2-(4-Chloroquinolin-2-yl)-2,3,4,5-tetrahydro-lH-2-benzazepine
Figure imgf000466_0001
The title compound was prepared in Scheme 1 by using 2,3,4,5-tetrahydro-lH-2-benzazepine (commercial available) and 2,4-dichloroquinoline (commercial available) instead of 7-bromo- 2,3,4,5-tetrahydro-lH-2-benzazepine and 2,4, 6-trichloroquino line respectively. MS obsd. (ESI+) [(M+H)+] 309. 1H NMR (400 MHz, CDC13) δ ppm 7.92 - 7.88 (dd, J= 1.2, 8.0 Hz, 1 H), 7.65 (d, J= 8 Hz, 1 H), 7.53 - 7.45 (m, 2 H), 7.24 - 7.10 (m, 5 H), 4.81 (s, 2 H), 4.09 (brs, 2 H), 3.02 - 2.97 (m, 2 H), 1.94 - 1.88 (m, 2 H).
Example 119 V-[5-Chloro-2-(l,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)quinolin-4-yl]ethane-l,2-diamine
Figure imgf000466_0002
l-(l,3,4,5-Tetrahydro-2H-2-benzazepin-2-yl)ethanone
Figure imgf000466_0003
A suspension of 2,3,4, 5-tetrahydro-lH-2-benzazepine hydrochloride (10 g, 54.4 mmol) in dry dichloromethane (450 mL) was stirred at 0 °C. Triethylamine (18.21 mL, 130.6 mmol) was added followed by the dropwise addition of acetic anhydride (6.18 mL, 65.3 mmol) in dry dichloromethane (50 mL). The reaction was then stirred for 1 hour whilst allowing the temperature to rise slowly to room temperature. The resulting mixture was washed with 1 N hydrochloric acid (200 mL) and brine (200 mL), dried over sodium sulfate and concentrated in vacuo to give 10 g of product as colorless oil (yield was 97%). It was used in next step without further purification. MS obsd. (ESI ) [(M+H)+] 190.
2-Chloro-6-{[l-(l,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)ethylidene]amino}benzonitrile
Figure imgf000467_0001
Phosphorus oxychloride (2.93 mL, 32.0 mmol) was added to a stirred solution of 1-(1, 3,4,5- tetrahydro-2H-2-benzazepin-2-yl)ethanone (5.5 g, 29.0 mmol) in dry dichloromethane (100 mL) at 10 °C. After that, the mixture was stirred for 20 minutes at room temperature. Then a solution of 2-amino-6-chloro-benzonitrile (4.43 g, 29.0 mmol) in dry dichloromethane (40 mL) was added and the resulting suspension was heated under reflux for 24 hours. After the reaction mixture was cooled to room temperature, water (50 mL) was added followed by saturated sodium bicarbonate to pH 8. The organic layer was separated and the aqueous was extracted with dichloromethane (100 mL). The organic fraction was washed with brine and dried over sodium sulfate, and then evaporated in vacuo to give a residue which was precipitated in ether. The solid was collected by filtration and dried in vacuo to give 6 g of product as a brown powder (yield was 63.7%). It was used in the next step without further purification. MS obsd. (ESI+) [(M+H)+] 324.
5-Chloro-2-(l,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)quinolin-4-amine
Figure imgf000467_0002
The mixture of 2-chloro-6- { [ 1 -( 1 ,3 ,4,5-tetrahydro-2H-2-benzazepin-2- yl)ethylidene] amino }benzonitrile (6 g, 18.5 mmol), zinc chloride (2.52 g, 18.5 mmol) and N,N- dimethyl-acetamide (18 mL) was heated with stirring at 160 °C for 3 hours under argon. After the reaction was allowed to cool to about 40 °C, sodium hydroxide (2 N, 20 mL) was added and then stirred for 10 minutes at room temperature. The reaction mixture was poured into water and the solid was collected by filtration, washed with water and dried in vacuo to give 5 g of product as an off-white powder (yield was 83.3%). MS obsd. (ESI+) [(M+H)+] 324.
2-(4,5-Dichloroquinolin-2-yl)-2,3,4,5-tetrahydro-lH-2-benzazepine
Figure imgf000467_0003
To the suspension of 5-chloro-2-(l,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)quinolin-4-amine (1.5 g, 4.6 mmol) in concentrated hydrochloric acid (10 mL) was added a solution of sodium nitrite (390 mg, 5.6 mmol) in water at -10 °C. After the addition, the reaction mixture was stirred for further 30 minutes, and then sodium chloride (2 g) was added. The resulting mixture was stirred at room temperature overnight and neutralized with saturated sodium bicarbonate, extracted with dichloromethane (50 mL x 2). The organic layers were combined and dried over sodium sulfate, and then concentrated under reduced pressure to give the crude product. It was used in next step without further purification. V-[5-Chloro-2-(l,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)quinolin-4-yl]ethane-l,2-diamine
Figure imgf000468_0001
The mixture of 2-(4,5-dichloroquinolin-2-yl)-2,3,4,5-tetrahydro-lH-2-benzazepine prepared above and ethane- 1,2-diamine (2 mL) was heated with stirring in a 10 mL microwave process vial for 2 hours at 150 °C under microwave irradiation. The reaction mixture was diluted with ethyl acetate (20 mL), and then washed with water (20 mL). The organic fraction was dried over sodium sulfate, and concentrated under reduced pressure to give a residue which was purified by preparative HPLC to give 20 mg of product as a white powder. MS obsd. (ESI+) [(M+H)+] 367. 1H NMR (400 MHz, CD3OD) δ ppm 7.46 - 7.42 (m, 2 H), 7.27 - 7.23 (m, 1 H), 7.16 - 7.11 (m, 3 H), 7.02 (66, J= 7.6, 1.2 Hz, 1 H), 5.97 (s, 1 H), 4.79 (s, 2 H), 4.13 (brs, 2 H), 3.38 - 3.21 (m, 2 H), 3.04 - 3.02 (m, 2 H), 2.96 (t, J= 6.0 Hz, 2 H), 1.91 - 1.86 (m, 2 H).
Example 120-1
TV- {2- [7-(Methylsulfonyl)- 1 ,3,4,5-tetrahydro-2H-2-benzazepin-2-yl] quinolin-4-yl} ethane- 1,2-diamine
Figure imgf000468_0002
7-(Methylsulfonyl)-2,3,4,5-tetrahydro-lH-2-benzazepine
Figure imgf000469_0001
The mixture of 7-bromo-2,3,4,5-tetrahydro-lH-2-benzazepine (226 mg, 1.0 mmol), sodium methanesulfmate (120 mg, 1.2 mmol), copper(I) iodide (19 mg, 0.1 mmol), Z-proline (23 mg, 0.2 mmol), sodium hydroxide (8.0 mg, 0.2 mmol) and dimethyl sulfoxide (2 mL) was heated in a sealed tube for 20 hours at 95 °C. The resulting mixture was diluted with water, and extracted with ethyl acetate (30 mL x 3). The organic layers were combined and washed with brine (40 mL x 3), and then dried over sodium sulfate. The solvent was removed under reduced pressure and the residue was purified by column chromatography on silica gel
(methanol/dichloromethane, 1 :20) to give 144 mg of product as a light-brown viscous oil (yield was 63.9%). MS obsd. (ESI+) [(M+H)+] 226.
2-(4-Chloroquinolin-2-yl)-7-(methylsulfonyl)-2,3,4,5-tetrahydro-lH-2-benzazepine
Figure imgf000469_0002
The mixture of 2,4-dichloroquinoline (126 mg, 0.637 mmol), 7-(methylsulfonyl)-2, 3,4,5- tetrahydro-lH-2-benzazepine (144 mg, 0.637 mmol), triethylamine (0.106 mL, 0.765 mmol) and N-methyl-2-pyrrolidone (2 mL) was heated with stirring in a sealed tube for 4 hours at 100 °C. The resulting mixture was diluted with water and extracted with ethyl acetate (15 mL x 3). The organic layers were combined and washed with brine (15 mL x 3), and then dried over sodium sulfate. The solvent was removed under reduced pressure and the residue was purified by column chromatography on silica gel (ethyl acetate/petroleum ether, 1 :5) to afford 55.6 mg of product as a white solid (yield was 22.5%). MS obsd. (ESI+) [(M+H)+] 387.
TV- {2- [7-(Methylsulfonyl)- 1 ,3,4,5-tetrahydro-2H-2-benzazepin-2-yl] quinolin-4-yl} ethane- 1,2-diamine
Figure imgf000470_0001
The mixture of 2-(4-chloroquinolin-2-yl)-7-(methylsulfonyl)-2,3,4,5-tetrahydro-lH-2- benzazepine (55.6 mg, 0.144 mmol) and ethane- 1,2-diamine (1 mL) was heated with stirring in a 10 mL microwave process vial for 2 hours at 150 °C under microwave irradiation. The solvent was removed in vacuo and the residue was purified by preparative HPLC to give 27.5 mg of product as a light-yellow solid (yield was 46.5%). MS obsd. (ESI+) [(M+H)+] 411. 1H NMR (400 MHz, CD3OD) δ ppm 7.82 - 7.73 (m, 4 H), 7.53 (d, J= 7.6 Hz, 1 H), 7.45 - 7.40 (m, 1 H), 7.12 - 7.08 (m, 1 H), 5.98 (s, 1 H), 4.96 (s, 2 H), 4.16 (s, 2 H), 3.41 (t, J= 6.4 Hz, 2 H), 3.16 (brs, 2 H), 3.06 (s, 3 H), 2.97 (t, J= 6.4 Hz, 2 H), 1.96 (brs, 2 H).
Example 120-2
TV- {2- [7-(Ethylsulfonyl)- 1 ,3,4,5-tetrahydro-2H-2-benzazepin-2-yl] quinolin-4-yl} ethane- 1 ,2- diamine
Figure imgf000470_0002
The title compound was prepared in analogy to Example 120-1 by using sodium ethanesulfmate (commercial available) instead of sodium methanesulfmate. MS obsd. (ESI ) [(M+H)+] 424. 1H NMR (400 MHz, CD3OD) δ ppm 7.81 - 7.76 (m, 2 H), 7.70 - 7.67 (m, 2 H), 7.53 (d, J= 7.6 Hz, 1 H), 7.43 - 7.39 (m, 1 H), 7.10 - 7.06 (m, 1 H), 5.97 (s, 1 H), 4.93 (s, 2 H), 4.14 (s, 2 H), 3.39 (t, J = 6.4 Hz, 2 H), 3.16 - 3.10 (m, 4 H), 2.95 (t, J= 6.4 Hz, 2 H), 1.94 (brs, 2 H), 1.16 (t, J= 7.2 Hz, 3 H).
Example 121
N- [2-(8-Ethoxy- 1 ,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)quinolin-4-yl] ethane- 1 ,2-diamine
Figure imgf000471_0001
2-(4-Chloroquinolin-2-yl)-8-ethoxy-2,3,4,5-tetrahydro-lH-2-benzazepine
Figure imgf000471_0002
To a solution of 2-(4-chloroquinolin-2-yl)-2,3,4,5-tetrahydro-iH-2-benzazepin-8-ol (36 mg, 0.11 mmol) in 5 mL of dry N,N-dimethylformamide was added sodium hydride (8 mg, 0.17 mmol), then bromoethane (18.5 mg, 0.17 mmol) was added dropwise under nitrogen. After the addition, the reaction was stirred at room temperature for further 1 hour. The resulting mixture was diluted with dichloromethane (10 mL), washed with brine and then dried over sodium sulfate. The solvent was removed in vacuo and the residue was purified by column chromatography on silica gel to give 28 mg of product. MS obsd. (EST ) [(M+H)+] 353.
TV- [2-(8-Ethoxy- 1 ,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)quinolin-4-yl] ethane- 1 ,2-diamine
Figure imgf000471_0003
The mixture of 2-(4-chloroquinolin-2-yl)-8-ethoxy-2,3,4,5-tetrahydro-lH-2-benzazepine (28 mg, 0.79 mmol) and ethane- 1,2-diamine (0.5 mL) was heated with stirring in a 5 mL microwave process vial for 2 hours at 160 °C under microwave irradiation. The solvent was removed under reduced pressure and the residue was purified by preparative HPLC to give 12 mg of product
(yield was 40%). MS obsd. (ESI+) [(M+H)+] 377. 1H NMR (400 MHz, CD3OD) δ ppm 7.88 (d, J = 7.6 Hz, 1 H,), 7.62 (d, J= 8.0 Hz, 1 H), 7.57 (m, 1 H), 7.51 (d, J= 8.4 Hz, 1 H), 7.38 (m, 1 H), 7.19 (m, 2 H), 6.00 (s, 1 H), 4.78 (s, 2 H), 4.12 (m, 2 H), 3.99 (q, J= 6.8 Hz, 2 H), 3.48 (m, 2 H), 2.98 (m, 4 H), 1.94 (m, 2 H), 1.34 (t, J= 6.8 Hz, 3 H).
Example 122 V-[6-(Pyridin-2-yloxy)-2-(l,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)quinolin-4-yl]ethane- 1,2-diamine
Figure imgf000472_0001
4-Chloro-2-(l,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)quinolin-6-ol
Figure imgf000472_0002
To a solution of 2-(4-chloro-6-methoxy-quinolin-2-yl)-2,3,4,5-tetrahydro-lH-2-benzazepine (800 mg, 2.37 mmol) in 15 mL of dichloromethane was added slowly a solution of boron tribromide (0.558 mL, 5.9 mmol). The resulting mixture was stirred at room temperature for 30 minutes, followed by stirring at 40 °C for 2 hours. After cooled to room temperature, the reaction mixture was carefully quenched with sodium bicarbonate (20 mL), and then extracted with dichloromethane (10 mL x 3). The organic layers were combined and washed with brine (20 ml), then dried over sodium sulfate. The solvent was removed in vacuo and the residue was purified by flash column chromatography on silica gel (ethyl acetate/hexane, 1 :5) to give 500 mg of product (yield was 65%). 2-[4-Chloro-6-(pyridin-2-yloxy)quinolin-2-yl]-2,3,4,5-tetrahydro-lH-2-benzazepine
Figure imgf000472_0003
The mixture of 4-chloro-2-(l,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)quinolin-6-ol (200 mg, 0.617 mmol), 2-fluoro-pyridine (180 mg, 1.85 mmol), potassium carbonate (73 mg, 0.53 mmol) and dry dimethylsulfoxide was heated with stirring in a sealed tube for 40 minutes at 130 °C under microwave irradiation. The resulting mixture was cooled to room temperature, then diluted „„·+ν, ί (\ TVIT Λ « xtracted with ethyl acetate (10 mL x 2). The combined organic layer was washed with brine (10 mL x 3), and then dried over sodium sulfate. The solvent was removed in vacuo and the residue was purified by column chromatography on silica gel (ethyl acetate/petroleum ether, 1 :5) to give 110 mg of product as a yellow solid (yield was 45%). V-[6-(Pyridin-2-yloxy)-2-(l,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)quinolin-4-yl]ethane- 1,2-diamine
Figure imgf000473_0001
The mixture of 2-[4-chloro-6-(pyridin-2-yloxy)quinolin-2-yl]-2,3,4,5-tetrahydro-lH-2- benzazepine (40 mg, 0.1 mmol) and ethane- 1,2-diamine (2 mL) was heated with stirring in a 5 mL microwave process vial for 3 hours at 180 °C under microwave irradiation. The solvent was removed under reduced pressure and the residue was purified by preparative HPLC to give 7 mg of product as a yellow powder. MS obsd. (ESI+) [(M+H)+] 426. 1H NMR (400 MHz, CD3OD) δ ppm 8.12 (d, J= 3.2 Hz, 1 H), 7.82 - 7.78 (m, 1 H), 7.66 (d, J= 2.8 Hz, 1 H), 7.61 (d, J= 8.8 Hz, 1 H), 7.48 (d, J= 6.8 Hz, 1 H), 7.23 (dd, J= 5.2, 2.4 Hz, 1 H), 7.16 - 7.08 (m, 4 H), 6.90 (d, J = 8.4 Hz, 1 H), 6.04 (s, 1 H), 4.83 (s, 2 H), 4.16 (brs, 2 H), 3.41 (t, J= 6.2 Hz, 2 H), 3.05 (t, J= 4.8 Hz, 2 H), 2.94 (t, J= 6.2 Hz, 2 H), 1.96 - 1.91 (m, 2 H).
Example 123
2-{4-[(2-Aminoethyl)amino]-6-chloroquinolin-2-yl}- V^V-dimethyl-2,3,4,5-tetrahyd] benzazepine-7-carboxamide
Figure imgf000473_0002
Methyl 2-(4,6-dichloroquinolin-2-yl)-2,3,4,5-tetrahydro-lH-2-benzazepine-7-carboxylate
Figure imgf000474_0001
7-Bromo-2-(4,6-dichloroquinolin-2-yl)-2,3,4,5-tetrahydro-lH-benzazepine (200 mg, 0.47 mmol), triethylamine ( 94 mg, 0.94 mmol) and tetrakis(triphenylphosphine)palladium(0) (49.2 mg, 0.047 mmol) were added into 10 mL of dry methanol. The resulting mixture was stirred under reflux overnight under carbon monoxide. After cooled to room temperature, the reaction was diluted with ethyl acetate (30 mL), and then washed with water. The organic fraction was dried over sodium sulfate and concentrated in vacuo to give a residue which was purified by column chromatography on silica gel (ethyl acetate/petroleum ether, 1 :5) to give 156 mg of product (yield was 83%). MS obsd. (ESI+) [(M+H)+] 401. 2-(4,6-Dichloroquinolin-2-yl)-2,3,4,5-tetrahydro-lH-2-benzazepine-7-carboxylic acid
Figure imgf000474_0002
Methyl 2-(4,6-dichloroquinolin-2-yl)-2,3,4,5-tetrahydro-lH-2-benzazepine-7-carboxylate (156 mg, 0.39 mmol) was added into the mixture of methanol (5 mL) and sodium hydroxide (5 M, 2 mL). The reaction mixture was stirred at room temperature overnight. After that, the reaction was diluted with 20 mL of water, acidified with 2 M of hydrochloric acid to pH 6 and diluted with ethyl acetate (30 mL). The organic layer was separated and washed with water. The solvent was dried over sodium sulfate and concentrated in vacuo to give a residue which was purified by column chromatography on silica gel to give 135 mg of product. MS obsd. (ESI+) [(M+H)+] 387.
2-(4,6-Dichloroquinolin-2-yl)- V^V-dimethyl-2,3,4,5-tetrahydro-lH-2-benzazepine-7- carboxamide
Figure imgf000474_0003
The mixture of 2-(4,6-dichloroquinolin-2-yl)-2,3,4,5-tetrahydro-lH-2-benzazepine-7-carboxylic acid (135 mg, 0.35 mmol), dimethylamine hydrochloride (34.2 mg, 0.42 mmol), triethylamine (105 mg, 1.05 mmol), O-(7-azabenzotriazol-l-yl)-N,N,N',N'-tetramethyluronium
hexafluorophosphate (159 mg, 0.42 mmol) and 5 mL of dichloromethane was stirred at room temperature overnight under nitrogen. The reaction was diluted with ethyl acetate (20 mL), washed with water and dried over sodium sulfate. The solvent was removed in vacuo and the residue was purified by column chromatography to give 133 mg of product as a white solid, (yield was 92%). MS obsd. (ESI+) [(M+H)+] 414.
2-{4-[(2-Aminoethyl)amino]-6-chloroquinolin-2-yl}- V^V-dimethyl-2,3,4,5-tetrahyd] benzazepine-7-carboxamide
Figure imgf000475_0001
The mixture of 2-(4,6-dichloroquinolin-2-yl)-N,N-dimethyl-2,3,4,5-tetrahydro-lH-2- benzazepine-7-carboxamide (133 mg, 0.32 mmol) and ethane- 1,2-diamine (2 mL) was heated with stirring in a 5 mL microwave process vial for 3 hours at 180 °C under microwave irradiation. The solvent was removed under reduced pressure and the residue was purified by preparative HPLC to give 11 mg of product as a white solid. MS obsd. (ESI+) [(M+H)+] 438. 1H NMR (400 MHz, CD3OD) δ ppm 7.89 (s, 1 H), 7.60 (d, J= 8.0 Hz, 1 H), 7.49 (d, J= 8.8 Hz, 1 H), 7.38 (m, 1 H), 7.22 (m, 2 H), 6.01 (s, 1 H), 4.80 (s, 2 H), 4.16 (m, 2 H), 3.44 (t, J= 6.4 Hz, 2 H), 3.11 - 2.97 (m, 10 H), 1.93 (m, 2 H). Example 124
2-{4-[(2-Aminoethyl)amino]quinolin-2-yl}-7-bromo-l,2,4,5-tetrahydro-3H-2-benzazepin-3- one
Figure imgf000476_0001
7-Bromo-2-(4-chloroquinolin-2-yl)-l,2,4,5-tetrahydro-3H-2-benzazepin-3-one
Figure imgf000476_0002
To a solution of 2,4-dichloroquinoline (196 mg, 1.0 mmol) in dioxane (4 mL) was added 7- bromo-l,2,4,5-tetrahydro-3H-2-benzazepin-3-one (161 mg, 1.0 mmol), followed by
tris(dibenzylideneacetone)dipalladium(0) (28 mg, 0.03 mmol), 9,9-dimethyl-4,5- bis(diphenylphosphino)xanthene (65 mg, 0.11 mmol), and potassium phosphate tribasic (212 mg, 1.0 mmol). The resultant mixture was refilled with nitrogen and heated at 130 °C overnight. After cooled to room temperature, the mixture was diluted with acetonitrile (10 mL), filtered, and washed with acetonitrile. The filtrate was concentrated under reduced pressure to give a residue which was purified by column chromatography on silica gel (hexane/ethyl
acetate/ammonium hydroxide solution, 80: 19: 1) to give 165 mg of product as a white solid (yield was 42%). MS obsd. (ESI+) [(M+H)+] 401.
2-{4-[(2-Aminoethyl)amino]quinolin-2-yl}-7-bromo-l,2,4,5-tetrahydro-3H-2-benzazepin-3- one
Figure imgf000476_0003
To a solution of 7-bromo-2-(4-chloroquinolin-2-yl)- 1,2,4, 5-tetrahydro-3H-2-benzazepin-3-one (40 mg, 0.1 mmol) was added ethane- 1,2-diamine (0.5 mL) in a microwave vessel, which was degassed and refilled with nitrogen. The resultant mixture was heated at 170 °C under microwave irradiation for 30 minutes. After cooled to room temperature, the mixture was diluted i+Vi an(j concentrated under reduced pressure to give a residue which was purified by preparative HPLC to afford 42 mg of product as a solid (yield was 98%). MS obsd. (ESI+) [(M+H)+] 424. 1H NMR (400 MHz, CD3OD) δ ppm 7.99 (d, J= 8.0 Hz, 1H), 7.73 (d, J = 8.0 Hz, 1 H), 7.58 (m, 2 H), 7.47 (s, 2 H), 7.32 (td, J= 1.2, 8.8 Hz, 1 H), 6.04 (s, 1 H), 5.48 (s, 2 H), 3.42 (t, J= 6.4 Hz, 2 H), 3.11 (t, J= 7.6 Hz, 2 H), 2.98 (t, J= 6.0 Hz, 2 H), 2.86 (t, J= 7.2 Hz, 2 H).
Example 125 l-(2-{[2-(l,3,4,5-Tetrahydro-2H-2-benzazepin-2-yl)quinolin-4-yl]amino}ethyl)guanidine trifluoroacetate
Figure imgf000477_0001
To a solution of N-[2-(l,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)quinolin-4-yl]ethane-l,2- diamine (200 mg, 0.6 mmol) and 3,5-dimethyl-lH-pyrazole-l-carboximidamide nitrate (122 mg, 0.6 mmol) in ethanol (15 mL) was refluxed by heating for overnight. After cooled to room temperature, the reaction mixture was concentrated under reduced pressure, diluted with water (15 mL), and then extracted with dichloromethane (50 mL x 2). The dichloromethane fractions were combined and dried over sodium sulfate, and then concentrated under reduced pressure to give a residue which was purified by preparative HPLC to give 35.78 mg of product as a white solid. MS obsd. (ESI+) [(M+H)+] 375. 1H NMR (400 MHz, CD3OD) δ ppm 8.07 - 8.04 (brs, 1 H), 7.80 - 7.69 (m, 2 H), 7.51 - 7.41 (m, 2 H), 7.26 - 7.20 (m, 3 H), 6.00 (s, 1 H), 4.98 (s, 2 H), 4.14 (s, 2 H), 3.71 - 3.67 (m, 2 H), 3.58 - 3.55 (t, J= 6.4 Hz, 2 H), 3.13 - 3.10 (m, 2 H), 2.01 (s, 2 H).
Example 126-1 V-[(2-Amino-4,5-dihydro-l,3-oxazol-5-yl)methyl]-2-(l,3,4,5-tetrahydro-2H-2-benzazepin-2- yl)quinolin-4-amine trifluoroacetate
Figure imgf000478_0001
The mixture of l-amino-3-{[2-(l,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)quinolin-4- yl]amino}propan-2-ol (690 mg, 1.9 mmol) and potassium acetate (490 mg, 5 mmol) in methanol (7 mL) and water (1.75 mL) was stirred at 0 °C. A cooled solution of cyanogen bromide (212 mg, 2 mmol) in methanol (1 mL) was added to the above mixture and the resultant mixture was stirred at room temperature for 4 hours. The reaction mixture was concentrated and diluted with ethyl acetate (50 mL), and then washed with water (50 mL). The organic fraction was dried over sodium sulfate, and concentrated under reduced pressure to give a residue which was purified by preparative HPLC to give 73 mg of product as a white powder (yield was 10%). MS obsd. (ESI+) [(M+H)+] 388. 1H NMR (400 MHz, CD3OD) δ ppm 8.06 - 8.04 (dd, J= 8.4, 1.2 Hz, 1 H), 7.80 - 7.78 (d, J= 8.4 Hz, 1 H), 7.72 (m, 1 H), 7.50 (m, 1 H), 7.42 (m, 1 H), 7.23 (m, 3 H), 6.11 (s, 1 H), 5.42 (m, 1 H), 4.99 (s, 2 H), 4.11 (m, 3 H), 3.93 (d, J= 5.6 Hz, 2 H), 3.77 (dd, J= 9.6, 6.8 Hz, 1 H), 3.09 (m, 2 H), 2.00 (d, J= 5.6 Hz, 2 H).
Example 126-2 V-[(2-Amino-4,5-dihydro-l,3-oxazol-5-yl)methyl]-6-chloro-2-(l,3,4,5-tetrahydro-2H-2- benzazepin-2-yl)quinolin-4-amine
Figure imgf000478_0002
The title compound was prepared in analogy to Example 9-1 by using l-amino-3-{6-chloro-[2- (l,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)quinolin-4-yl]amino}propan-2-ol [It was prepared in Scheme 1 by using 2,3,4,5-tetrahydro-lH-2-benzazepine (commercial available) and 1,3- diamino-propan-2-ol (commercial available) instead of 7-bromo-2,3,4,5-tetrahydro-lH-2- benzazepine and ethane- 1,2-diamine respectively.] instead of l-amino-3-{[2-(l,3,4,5-tetrahydro- 2H-2-benzazepin-2-yl)quinolin-4-yl]amino}propan-2-ol. MS obsd. (ESI+) [(M+H)+] 422. 1H NMR (400 MHz, CD3OD) δ ppm 8.17 (s, 1 H), 7.82 (d, J= 8.8 Hz, 1 H), 7.69 (m, 1 H), 7.52 (s,
1 H), 7.22 (m, 3 H), 6.15 (s, 1 H), 5.42 (m, 1 H), 4.99 (s, 2 H), 4.11 (m, 3 H), 3.94 (d, J= 5.6 Hz,
2 H), 3.77 (dd, J= 9.6, 6.8 Hz, 1 H), 3.09 (m, 2 H), 2.00 (d, J= 5.6 Hz, 2 H).
Example 127 V-[2-(l,3,4,5-Tetrahydro-2H-2-benzazepin-2-yl)quinolin-4-yl]glycinamide
Figure imgf000479_0001
2-Chloro- V-[2-(l,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)quinolin-4-yl]acetamide
Figure imgf000479_0002
To the solution of 2-(l,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)quinolin-4-amine (500 mg, 1.73 mmol) was added l,8-diazabicyclo[5.4.0]undec-7-ene (0.52 mL, 3.48 mmol) followed by chloroacetyl chloride (0.21 mL, 2.64 mmol) at room temperature. The resulting solution was heated with stirring at 70 °C for 2 hours under nitrogen. After cooled to room temperature, the reaction was diluted with ethyl acetate (50 mL), and then washed with water (50 mL x 3). The organic phase was dried over sodium sulfate and concentrated under reduced pressure to give a residue which was purified by column chromatography on silica gel (ethyl acetate/petroleum ether, 1 :4) to give 140 mg of product as an off-white solid (yield was 22.1%). MS obsd. (ESI+) [(M+H)+] 366.
2-Azido- V-[2-(l,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)quinolin-4-yl]acetamide
Figure imgf000480_0001
To a solution of 2-chloro-N-[2-(l,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)quinolin-4- yljacetamide (70 mg, 0.19 mmol) in acetonitrile (2 mL) was added sodium azide (62 mg, 0.95 mmol). The resulting mixture was stirred at room temperature for 6 hours. The reaction was diluted with ethyl acetate (20 mL), and then washed with water (10 mL). The ethyl acetate fraction was dried over sodium sulfate, and then concentrated under reduced pressure to give a residue which was purified by column chromatography on silica gel (ethyl acetate/petroleum ether, 1 :4) to give 65 mg of product as a white powder (yield was 91.8%). MS obsd. (ESI+) [(M+H)+] 373. V-[2-(l,3,4,5-Tetrahydro-2H-2-benzazepin-2-yl)quinolin-4-yl]glycinamide
Figure imgf000480_0002
To a solution of 2-azido-N-[2-(l,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)quinolin-4-yl]acetamide (65 mg, 0.17 mmol) in methanol was added palladium (10% on carbon, 7 mg). After being stirred at room temperature overnight under a hydrogen atmosphere, the resulting mixture was filtered. The filtrate was concentrated in vacuo and the residue was purified by preparative HPLC to afford 30 mg of product as a white powder (yield was 60.5%>). MS obsd. (ESI+)
[(M+H)+] 347. 1H NMR (400 MHz, DMSO- 6) δ ppm 8.08 (s, 1 H), 7.78 (d, J= 8.0 Hz, 1 H), 7.55 - 7.49 (m, 3 H), 7.23 - 7.20 (m, 1 H), 7.15 - 7.08 (m, 3 H), 4.79 (s, 2 H), 4.13 (brs, 2 H), 3.45 (brs, 2 H), 3.04 (brs, 2 H), 1.79 (brs, 2 H).
Example 128
3-[2-(l,3,4,5-Tetrahydro-2H-2-benzazepin-2-yl)quinolin-4-yl]propan-l-amine
Figure imgf000481_0001
Methyl (2JE)-3-[2-(l,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)quinolin-4-yl]prop-2-enoate
Figure imgf000481_0002
The mixture of 2-(4-chloroquinolin-2-yl)-2,3,4,5-tetrahydro-lH-2-benzazepine (1.5 g, 4.86 mmol), acrylic acid methyl ester (0.88 ml, 9.7 mmol), triethylamine (6 mL) and N,N- dimethylformamide (6 mL), bis(tri-tert-butylphosphine)palladium(0) (124 mg, 0.243 mmol) was heated with stirring in a 20 mL of microwave process vial for 30 minutes at 100 °C under argon. The reaction mixture was poured into water (30 mL) and extracted with ethyl acetate (20 mL x 3). The organic layers were combined, washed with brine, dried over sodium sulfate and concentrated in vacuo to give a residue which was purified by flash column to afford 1.41 g of product as a white solid (yield was 81%). MS obsd. (ESI+) [(M+H)+] 359.
Methyl 3- [2-(l,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)quinolin-4-yl] propanoate
Figure imgf000481_0003
To a solution of methyl (2E)-3-[2-(l,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)quinolin-4-yl]prop- 2-enoate (1.4 g, 3.91 mmol) in 30 mL of methanol was added 10% palladium on carbon (70 mg). After being vigorously stirred under hydrogen (balloon) for 3 hours, the reaction was filtered and the filtrate was concentrated in vacuo to give 1.4 g of product as a white solid (yield was 98%>). MS obsd. (ESI+) [(M+H)+] 361.
3- [2-(l,3,4,5-Tetrahydro-2H-2-benzazepin-2-yl)quinolin-4-yl] propanoic acid
Figure imgf000482_0001
To a solution of methyl 3-[2-(l,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)quinolin-4-yl]propanoate (1.4 g, 3.89 mmol) in methanol (10 mL) was added an aqueous solution of sodium hydroxide (4 N, 16 mL) and the resulting mixture was stirred at room temperature for 4 hours. The reaction was acidified to pH 4 with 5 N hydrochloric acid, and then extracted with ethyl acetate (10 mL x 3). The organic layer was dried over sodium sulfate and concentrated in vacuo to give a residue which was purified by flash column chromatography to afford 1.1 g of product as a white solid (yield was 82%). MS obsd. (ESI+) [(M+H)+] 347.
3-[2-(l,3,4,5-Tetrahydro-2H-2-benzazepin-2-yl)quinolin-4-yl]propanamide
Figure imgf000482_0002
To a solution of 3-[2-(l, 3,4, 5-tetrahydro-2H-2-benzazepin-2-yl)quinolin-4-yl]propanoic acid (300 mg, 0.867 mmol) in dichloromethane (10 mL) was added oxalyl chloride (0.123 mL, 1.3 mmol ) and one drop of N,N-dimethylformamide at 0 °C. The resulting mixture was warmed to room temperature and stirred for further 2 hours. The solvent was removed under reduced pressure and the residue was dissolved in dichloromethane (5 mL), to which a tetrahydrofuran solution of ammonia (4 N, 5 mL) was added at 0 °C, followed by stirring at room temperature overnight. The reaction was concentrated in vacuo to dryness and purified by flash column to afford 50 mg of product as a white solid. It was used in next step without further purification. MS obsd. (ESI+) [(M+H)+] 346. 3-[2-(l,3,4,5-Tetrahydro-2H-2-benzazepin-2-yl)quinolin-4-yl]propan-l-amine
Figure imgf000483_0001
To the mixture of 3-[2-(l,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)quinolin-4-yl]propanamide (50 mg, 0.145 mmol ) in tetrahydrofuran (5 mL) was added a tetrahydrofuran solution of borane (1.5 mL, 1.5 mmol) at 0 °C, followed by stirring at 70 °C for 4 hours. After being quenched with methanol (5 mL) at 0 °C, the resulting mixture was concentrated in vacuo to give a residue which was purified by flash column (ethyl acetate/hexane, 3:7) to afford 10 mg of product as a white solid. MS obsd. (ESI+) [(M+H)+] 332. 1H NMR (400 MHz, DMSO- 6) δ ppm 7.79 (d, J= 7.2 Hz, 1 H), 7.57 - 7.52 (m, 2 H), 7.47 - 7.43 (m, 1 H), 7.18 - 7.04 (m, 5 H), 5.24 (brs, 2 H), 4.85 (s, 2 H), 4.14 (brs, 2 H), 3.03 (brs, 2 H), 2.93 (t, J= 7.2 Hz, 2 H), 1.89 - 1.82 (m, 4 H). Example 129
[2-(l,3,4,5-Tetrahydro-2H-2-benzazepin-2-yl)quinolin-4-yl]methanol
Figure imgf000483_0002
Methyl 2-(l,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)quinoline-4-carboxylate
Figure imgf000483_0003
The mixture of 2-chloroquinoline-4-carboxylic acid methyl ester (3 g, 13.5 mmol), 2,3,4,5- tetrahydro-lH-2-benzazepine hydrochloride (3 g, 16.3 mmol), potassium carbonate (4.5 g, 32.6 mmol), tetrabutylammonium iodide (300 mg) and toluene (60 mL) was heated with stirring at 110 °C for 5 days. The solvent was removed under reduced pressure to give a residue which was purified by column chromatography on silica gel (ethyl acetate/petroleum ether, 1 :4) to give 1.97 g of product as a yellow solid. MS obsd. (ESI+) [(M+H)+] 333. -2-benzazepin-2-yl)quinolin-4-yl] methanol
Figure imgf000484_0001
To the mixture of methyl 2-(l,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)quinoline-4-carboxylate (30 mg, 0.087 mmol ) in tetrahydrofuran (2 mL) was added a tetrahydrofuran solution of borane (1.5 mL, 1.5 mmol) at 0 °C. After being stirred at 70 °C for 4 hours, the mixture was quenched with methanol (5 mL) at 0 °C. The solvent was removed in vacuo to give a residue which was purified by flash column (ethyl acetate/hexane, 3:7) to afford 16 mg of product as a white solid. MS obsd. (ESI+) [(M+H)+] 305. 1H NMR (400 MHz, DMSO- 6) δ ppm 7.70 (d, J= 8.0 Hz, 1 H), 7.56 - 7.44 (m, 3 H), 7.25 (s, 1 H), 7.16 - 7.07 (m, 4 H), 5.44 (t, J= 4.2 Hz, 1 H), 4.86 (s, 2 H), 4.85 (s, 2 H), 4.18 (brs, 2 H), 3.04 (brs, 2 H), 1.80 (brs, 2 H). Example 130-1
2-(6-Chloroquinolin-2-yl)-2,3,4,5-tetrahydro-lH-2-benzazepine
Figure imgf000484_0002
2-[6-Chloro-4-(prop-2-en-l-yl)quinolin-2-yl]-2,3,4,5-tetrahydro-lH-2-benzazepine
Figure imgf000484_0003
The mixture of 2-(4,6-dichloroquinolin-2-yl)-2,3,4,5-tetrahydro-lH-2-benzazepine (200 mg, 0.58 mmol), 2-allyl-4,4,5,5-tetramethyl-[l,3,2]dioxaborolane (0.164 mL, 0.87 mmol), tetrakis(triphenylphosphine)palladium(0) (68 mg, 0.058 mmol), potassium carbonate (241 mg, 1.74 mmol), 1 ,2-dimethoxyethane (3 mL) and water (1 mL) was heated with stirring in a 10 mL of microwave process vial for 3 hours at 120 °C under microwave irradiation. The resulting mixture was diluted with ethyl acetate (20 mL), and then washed with water (20 mL). The ethyl acetate fraction was dried over sodium sulfate, and then concentrated under reduced pressure to give a residue which was separated by column chromatography on silica gel (ethyl
Q pptQtp/nptmipnTn ^+ 0.1 :5) to afford 2-[6-chloro-4-(prop-2-en- 1 -yl)quinolin-2-yl]-2, 3 ,4,5- tetrahydro-iH-2-benzazepine (20 mg) and 2-(6-chloroquinolin-2-yl)-2,3,4,5-tetrahydro-lH-2- benzazepine (50 mg).
2-[6-chloro-4-(prop-2-en-l-yl)quinolin-2-yl]-2,3,4,5-tetrahydro-iH-2-benzazepine MS obsd. (ESI+) [(M+H)+] 349. 2-(6-chloroquinolin-2-yl)-2,3,4,5-tetrahydro-lH-2-benzazepine
MS obsd. (ESI+) [(M+H)+] 309. 1H NMR (400 MHz, DMSO- 6) δ ppm 7.93 (d, J= 9.2 Hz, 1 H), 7.72 (brs, 1 H), 7.56 - 7.51 (m, 2 H), 7.47 - 7.44 (m, 1 H), 7.29 (d, J= 9.6 Hz, 1 H), 7.14 - 7.08 (m, 3 H), 4.85 (brs, 2 H), 4.14 (brs, 2 H), 3.03 (brs, 2 H), 1.78 (brs, 2 H).
Example 130-2 3-[6-Chloro-2-(l,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)quinolin-4-yl]propane-l,2-diol
Figure imgf000485_0001
To a solution of 2-[6-chloro-4-(prop-2-en-l-yl)quinolin-2-yl]-2,3,4,5-tetrahydro-lH-2- benzazepine (20 mg, 0.057 mmol) in acetone (2 mL) and water (1 mL) was added N-methyl morpholine-N-oxide (50 % in water, 15.5 mg, 0.057 mmol) followed by osmium tetroxide (0.14 mg, 0.0005 mmol). The resulting mixture was stirred at room temperature overnight. The solvent was removed under reduced pressure and the residue was purified by column chromatography on silica gel (ethyl acetate/petroleum ether, 3:2) to give 14 mg of product as colorless oil. MS obsd.
(ESI+) [(M+H)+] 383. 1H NMR (400 MHz, CD3OD) δ ppm 7.82 (d, J= 2.0 Hz, 1 H), 7.58 (d, J = 8.8 Hz, 1 H), 7.50 (d, J= 6.8 Hz, 1 H), 7.40 (dd, J= 9.2, 2.4 Hz, 1 H), 7.14 - 7.08 (m, 4 H), 4.84 (brs, 2 H), 4.21 (brs, 1 H), 4.10 (brs, 1 H), 3.91 - 3.88 (m, 1 H), 3.58 - 3.55 (m, 2 H), 3.21 (dd, J = 14.0, 4.4 Hz, 1 H), 3.04 (d, J= 6.4 Hz, 2 H), 2.87 (dd, J= 14.0, 8.4 Hz, 1 H), 1.91 - 1.86 (m, 2 H).
Example 131 (4S)-4-{2-[2-(l,3,4,5-Tetrahydro-2H-2-benzazepin-2-yl)quinolin-4-yl]ethyl}-4,5-dihydro-
1 ,3-oxazol-2-amine
Figure imgf000486_0001
tei-i-Butyl (4S)-2,2-dimethyl-4-{(£)-2-[2-(l,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)quinolin- 4-yl]ethenyl}-l,3-oxazolidine-3-carboxylate
Figure imgf000486_0002
The mixture of 2-(4-chloroquinolin-2-yl)-2,3,4,5-tetrahydro-lH-2-benzazepine (310 mg, 1.0 mmol), (S)-2,2-dimethyl-4-vinyl-oxazolidine-3-carboxylic acid tert-butyl ester (273 mg, 1.2 mmol), bis(tri-tert-butylphosphine)palladium(0) (51 mg, 0.1 mmol), methyl dicyclohexylamine (293 mg, 1.5 mmol) and N,N-dimethylformamide (6 mL) was heated with stirring in a 20 mL microwave process vial for 2.5 hours at 120 °C under microwave irradiation. The reaction mixture was diluted with ethyl acetate and washed with brine. The organic layer was dried over sodium sulfate, and then concentrated under reduced pressure to give a residue which was purified by flash column to give 380 mg of product as a white solid (yield was 76%). MS obsd. (ESI+) [(M+H)+] 500. tert-Butyl (4S)-2,2-dimethyl-4-{2-[2-(l,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)quinolin-4- yl] ethyl}- 1 ,3-oxazolidine-3-carboxylate
Figure imgf000486_0003
The mixture of tert-butyl (45)-2,2-dimethyl-4-{(E)-2-[2-(l,3,4,5-tetrahydro-2H-2-benzazepin-2- yl)quinolin-4-yl]ethenyl}-l,3-oxazolidine-3-carboxylate (380 mg, 0.76 mmol), palladium hydroxide (20 % on carbon, 50 mg) and ethanol (15 mL) was stirred at room temperature for 4 hours under hydrogen. The solid was filtered by a pad of silica gel and the filtrate was concentrated in vacuo to give 340 mg of product as a white solid (yield was 89%). MS obsd. (ESI+) [(M+H)+] 502.
(2S)-2-Amino-4-[2-(l,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)quinolin-4-yl]butan-l-ol
Figure imgf000487_0001
To the solution of tert-butyl (45)-2,2-dimethyl-4-{2-[2-(l,3,4,5-tetrahydro-2H-2-benzazepin-2- yl)quinolin-4-yl]ethyl}-l,3-oxazolidine-3-carboxylate (340 mg, 0.68 mmol) in ethyl acetate was introduced hydrochloric acid gas for 30 minutes. After being stirred at room temperature overnight, the reaction was poured into ice-water then neutralized with saturated sodium carbonate. The organic layer was separated, dried over sodium sulfate, and then concentrated in vacuo to give the product. It was used in next step without further purification. MS obsd. (ESI+) [(M+H)+] 362.
(45)-4-{2-[2-(l,3,4,5-Tetrahydro-2H-2-benzazepin-2-yl)quinolin-4-yl]ethyl}-4,5-dihydro- 1 ,3-oxazol-2-amine
Figure imgf000487_0002
To the stirred mixture of (25)-2-amino-4-[2-(l,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)quinolin- 4-yl]butan-l-ol (110 mg, 0.3 mmol), potassium acetate (90 mg, 0.91 mmol), methanol (8 mL) and water (2 mL) was added a solution of cyanogen bromide (32.3 mg, 0.3 mmol) in cold methanol (2 mL) at 0 °C. After the addition, the resulting mixture was stirred at room temperature for 24 hours. The solvent was removed under reduced pressure to give a residue which was purified by preparative HPLC to give 40 mg of product as a white solid (yield was 34.5%). MS obsd. (ESI+) [(M+H)+] 387. 1H NMR (400 MHz, DMSO- 6) δ ppm 7.77 (d, J= 7.2 Hz, 1 H), 7.56 - 7.43 (m, 3 H), 7.17 - 7.04 (m, 4 H), 5.91 (brs, 1 H), 4.84 (s, 2 H), 4.21 (t, J= 8.0 Hz, 2 H), 4.13 (brs, 2 H), 3.87 (t, J= 7.2 Hz, 1 H), 3.77 (t, J= 7.2 Hz, 1 H), 3.01 (brs, 2 H), 2.94 - 2.89 (m, 1 H), 1.78 (brs, 2 H), 1.72 - 1.67 (m, 2 H).
Example 132 V-(2-Aminoethyl)-2-(l,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)quinoline-4-sulfonamide trifluoroacetate
Figure imgf000488_0001
2-(l,3,4,5-Tetrahydro-2H-2-benzazepin-2-yl)quinoline-4-thiol
Figure imgf000488_0002
A mixture of 2-(4-chloroquinolin-2-yl)-2,3,4,5-tetrahydro-lH-2-benzazepine (2 g, 6.47 mmol) and sodium thiomethoxide (2.4 g, 34 mmol) in dry N,N-dimethylformamide (20 mL) was heated with stirring overnight under reflux. The reaction mixture was cooled to 50 °C and the volatile components were evaporated under reduced pressure to give a residue which was dissolved in 30 mL of chilled water and carefully acidified with 20% hydrochloride aid to pH 4-5 under argon. The resultant solution was extracted with chilled dichloromethane (30 mL x 3). The
dichloromethane fractions were combined and washed with chilled brine (30 mL x 2) and then concentrated under reduced pressure at room temperature to give the crude product. It was used in next step without further purification.
2-(l,3,4,5-Tetrahydro-2H-2-benzazepin-2-yl)quinoline-4-sulfonyl chloride
Figure imgf000489_0001
Gaseous chlorine was passed through a well stirred solution of 2-(l,3,4,5-tetrahydro-2H-2- benzazepin-2-yl)quinoline-4-thiol (2 g, 6.5 mmol) in concentrated hydrochloric acid (17 mL) at - 10 °C at such a rate that temperature was maintained between -5 and -10 °C. The passage of chlorine was discontinued after 30 minutes. The mixture was poured into ice (30 g) followed by addition of sodium bicarbonate (4 g) in small portions. The resultant mixture was extracted with chilled dichloromethane (30 mL x 3). The dichloromethane fractions were combined and washed with chilled water (20 mL), and then dried over sodium sulfate, filtered and the filtrate was used in next step without further purification. V-(2-Aminoethyl)-2-(l,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)quinoline-4-sulfonamide trifluoroacetate
Figure imgf000489_0002
To a solution of ethane- 1,2-diamine (500 mg, 8.3 mmol) in dichloromethane (20 mL) was added a cold triethylamine (5 drops) in an ice-water bath, followed by the addition of the solution of 2- (l,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)quinoline-4-sulfonyl chloride (400 mg, 0.9 mmol) in dichloromethane (20 mL) prepared above slowly. After being stirred overnight, the solvent was removed under reduced pressure, and the residue was purified by preparative HPLC to give 43.6 mg of product (yield was 12.2%). MS obsd. (ESI+) [(M+H)+] 397. 1H NMR (400 MHz, CD3OD) δ ppm 8.37 - 8.35 (m, 1 H), 7.88 - 7.82 (m, 2 H), 7.71 (m, 1 H), 7.48 - 7.42 (m, 2 H), 7.18 - 7.17 (m, 3 H), 5.02 (s, 2 H), 4.23 (s, 2 H), 3.09 - 3.03 (m, 6 H), 1.98 (s, 2 H).
Example 133-1
4- {4- [(2- Aminoethyl)amino] -6-methylquinolin-2-yl}- 1 ,3,4,5-tetrahydro-2H- 1 ,4- benzodiazepin-2-one
Figure imgf000490_0001
4-(4-Chloro-6-methylquinolin-2-yl)-l,3,4,5-tetrahydro-2H-l,4-benzodiazepin-2-one
Figure imgf000490_0002
The mixture of 2,4-dichloro-6-methyl-quinoline (422 mg, 2 mmol), l,3,4,5-tetrahydro-2H-l,4- benzodiazepin-2-one (298 mg, 2 mmol) and n-butyl alcohol (15 mL) was heated with stirring in a 20 mL microwave process vial for 3 hours at 160 °C under microwave irradiation. After cooling, the solvent was removed in vacuo and the residue was purified by column
chromatography on silica gel (methanol/dichloromethane, 1 :20) to give the product. MS obsd. (ESI+) [(M+H)+] 338. 4- {4- [(2- Aminoethyl)amino] -6-methylquinolin-2-yl}- 1 ,3,4,5-tetrahydro-2H- 1 ,4- benzodiazepin-2-one
Figure imgf000490_0003
The mixture of 4-(4-chloro-6-methylquinolin-2-yl)-l,3,4,5-tetrahydro-2H-l,4-benzodiazepin-2- one (60 mg, 1 mmol), [l, -bis(diphenylphosphino)ferrocene]dichloropalladium(II), (8.2 mg, 0.01 mmol), bis(diphenylphosphino)ferrocene (6 mg, 0.01 mmol) and sodium tert-butoxide (20 mg, 0.2 mmol) and 1,4-dioxane (2 mL) was heated with stirring in a 10 mL microwave process vial for 1 hour at 120 °C under microwave irradiation. After cooling, the mixture was filtered and washed with ethyl acetate. The filtrate was washed with brine, dried over sodium sulfate, and concentrated in vacuo to give a residue which was purified by preparative HPLC to afford the product as a solid. MS obsd. (ESI+) [(M+H)+] 362. 1H NMR (400 MHz, CD3OD) δ ppm 7.64 (s, — - > > ~ 7.28 (dd, J= 1.6, 8.4 Hz, 1 H), 7.18 (dd, J= 1.6, 8.0 Hz, 1 H), 7.09 (dd, J= 0.8, 8.0 Hz, 1 H), 6.98 (dd, J= 0.8, 8.0 Hz, 1 H), 6.00 (s, 1 H), 4.87 (s, 2 H), 4.72 (s, 2 H), 3.40 (t, J= 6.4 Hz, 2 H), 2.95 (t, J= 6.4 Hz, 2 H), 2.40 (s, 3 H).
Example 133-2 V-[6-Methyl-2-(l,2,3,5-tetrahydro-4H-l,4-benzodiazepin-4-yl)quinolin-4-yl]ethane-l,2- diamine
Figure imgf000491_0001
The title compound was prepared in analogy to Example 16-1 by using 2,3,4,5-tetrahydro-lH- 1,4-benzodiazepine (commercial available) instead of 1,3,4, 5-tetrahydro-2H-l,4-benzodiazepin- 2-one. MS obsd. (ESI+) [(M+H)+] 348. 1H NMR (400 MHz, CD3OD) δ ppm 7.90 (s, 1 H), 7.67 (d, J= 8.4 Hz, 1 H), 7.58 (d, J = 8.4 Hz, 1 H), 7.42 (d, J = 7.2 Hz, 1 H), 7.12 (t, J= 8.0 Hz, 1 H), 6.88 (t, J= 7.2 Hz, 1 H), 6.82 (d, J= 8.0 Hz, 1 H), 5.95 (s, 1 H), 4.87 (s, 2 H), 4.00 (t, J= 4.8 Hz, 2 H), 3.72 (t, J= 6.0 Hz, 2 H), 3.46 (t, J= 4.8 Hz, 2 H), 3.18 (t, J = 6.0 Hz, 2 H), 2.49 (s, 3 H).
Example 134 TV- [2-(2,3-Dihydro- 1 ,4-benzoxazepin-4(5H)-yl)quinolin-4-yl] ethane- 1 ,2-diamine
Figure imgf000491_0002
Methyl (2-cyanophenoxy)acetate
Figure imgf000491_0003
To the mixture of 2-hydroxybenzonitrile (40 g, 0.34 mol) and potassium carbonate (51.6 g, 0.374 mol) in 850 mL of acetone was added methyl bromoacetate (51.7 g, 0.34 mol) slowly at room temperature. After being stirred at room temperature overnight, the solid was filtered off. The filtrate was concentrated under reduced pressure and the residue was dissolved in ethyl acetate. The organic layer was washed with water then brine, dried over sodium sulfate, filtered and concentrated under reduced pressure to give a residue which was recrystallized in methanol to give 40 g of product as a white solid.
4,5-Dihydro- 1 ,4-benzoxazepin-3(2H)-one
Figure imgf000492_0001
The methanol solution of methyl (2-cyanophenoxy)acetate (40 g, 0.209 mol) was added to the mixture of Raney Ni (80 g) in 500 mL of methanol. The reaction mixture was stirred at room temperature overnight under hydrogen atmosphere. Raney Ni was removed by filtration, and the filtrated was concentrated under reduced pressure to give a residue which was purified by column chromatography on silica gel (methanol/dichloro methane, 1 :50) to give 23 g of product. MS obsd. (ESI+) [(M+H)+] 164.
2,3,4,5-Tetrahydro- 1 ,4-benzoxazepine
Figure imgf000492_0002
To the suspension of lithium aluminium hydride (15.2 g, 0.4 mol) in 600 mL of ether was added a solution of 4,5-dihydro-l,4-benzoxazepin-3(2H)-one (16.3 g, 0.1 mol) in 60 mL of tetrahydrofuran at room temperature. After being heated with stirring under reflux overnight, water was added drop wise to quench the reaction at 0 °C, The resulting mixture was diluted with ethyl acetate, and then filtered by a pad of celite. The filtrate was concentrated under reduced pressure, followed by the addition of hydrochloric acid ethyl acetate solution. The hydrochloride was collected by filtration, washed with ethyl acetate then ether, and then dried in vacuo to give 13.5 g of product. MS obsd. (ESI+) [(M+H)+] 150.
4-(4-Chloroquinolin-2-yl)-2,3,4,5-tetrahydro-l,4-benzoxazepine
Figure imgf000492_0003
The mixture of 2,4-dichloroquinoline (198 mg, 0.1 mmol), 2,3,4,5-tetrahydro-l,4-benzoxazepine hydrochloride (186 mg, 0.1 mmol), diisopropylethylamine (0.4 mL) and 5 mL of N-methyl-2- pyrrolidone was heated with stirring at 100 °C overnight. The mixture was cooled to room temperature, diluted with brine, and extracted with ethyl acetate (30 mL x 3). The organic layers were combined and washed with brine. The solvent was dried over sodium sulfate and removed under reduced pressure to give a residue which was purified by column chromatography on silica gel to give 119 mg of product as a white solid. MS obsd. (ESI+) [(M+H)+] 311.
TV- [2-(2,3-Dihydro- 1 ,4-benzoxazepin-4(5H)-yl)quinolin-4-yl] ethane- 1 ,2-diamine
Figure imgf000493_0001
The mixture of 4-(4-chloroquinolin-2-yl)-2,3,4,5-tetrahydro-l,4-benzoxazepine (100 mg, 0.32 mmol) and 1.6 mL of ethane- 1,2-diamine was heated with stirring in a 5 mL microwave process vial for 3 hours at 150 °C under microwave irradiation. The mixture was concentrate in vacuo to give a residue which was purified by preparative HPLC to give 31 mg of product as a white solid. MS obsd. (ESI+) [(M+H)+] 335. 1H NMR (400 MHz, CD3OD) δ ppm 8.61 (s, 1 H), 7.90 (d, J= 7.6 Hz, 1 H), 7.60 - 7.51 (m, 3 H), 7.23 (brs, 2 H), 7.09 - 6.98 (m, 2 H), 6.05 (s, 1 H), 4.89 (s, 2 H), 4.27 (s, 2 H), 4.25 (s, 2 H), 3.61 (s, 2 H), 3.15 (s, 2 H).
Example 135-1
N-[(l-Aminocyclopropyl)methyl]-2-(l,l-dioxido-2,3-dihydro-l,4-benzothiazepin-4(5H)-yl)- 6-methylquinazolin-4-amine
Figure imgf000493_0002
tert-Buty\ (l-{[(2-chloro-6-methylquinazolin-4-yl)amino]methyl}cyclopropyl)carbamate
Figure imgf000494_0001
To a solution of tert-butyl [1 -(amino methyl)cyclopropyl] carbamate (0.92 g, 4.9 mmol) in tetrahydrofuran (50 mL) was added triethylamine (1.3 mL, 9.4 mmol) followed by 2,4-dichloro- 6-methylquinazoline (1.0 g, 4.7 mmol) in portions at room temperature. After being stirred at room temperature overnight, the resultant mixture was concentrated in vacuo to remove 20 mL of solvent and then stirred vigorously with water (200 mL). The formed solid was collected by filtration and washed with water and ether, then dried in vacuo to afford 1.5 g of the product as a white powder. tert-Butyl [({2-[2-(l,l-dioxido-2,3-dihydro-l,4-benzothiazepin-4(5H)-yl)-6- methylquinazolin-4-yl] amino}methyl)cyclopropyl] carbamate
Figure imgf000494_0002
A mixture of tert-butyl (l-{[(2-chloro-6-methylquinazolin-4-yl)amino]methyl}cyclopropyl) carbamate (1.5 g, 4.1 mmol), 2,3,4,5-tetrahydro-l,4-benzothiazepine 1,1-dioxide (0.82 g, 4.1 mmol) and catalystic amount of ammonium chloride in ethanol (40 mL) was heated with stirring at 70 °C overnight. The reaction mixture was then cooled to room temperature. The formed solid was collected by filtration, then washed with ethanol and dried in vacuo. The crude solid (1.5 g) was suspended in dichloromethane (50 mL) and basified with 1 N of sodium hydroxide. The organic phase was separated and used for the next step directly.
(l-Amino-cyclopropylmethyl)-[2-(5,5-dioxo-5,6,7,9-tetrahydro-51ambda*6*-thia-8-aza- benzocyclohepten-8-yl)-6-methyl-quinazolin-4-yl] -amine
Figure imgf000495_0001
To the solution obtained above was added trifluoroacetic acid (10 mL) and the mixture was stirred at room temperature for 30 minutes. The reaction was quenched with saturated aqueous solution of sodium carbonate. The organic layer was separated and dried over sodium sulfate, filtrated and concentrated in vacuo. The residue was stirred with methanol. The produced white solid was collected by filtration and dried in vacuo to afford 400 mg of the product as a white powder. MS obsd. (ESI+) [(M+H)+] 424, 1H NMR (400 MHz, DMSO-d6) δ ppm 7.95 - 7.85 (m, 2 H), 7.74 (br. s., 2 H), 7.62 (t, J= 7.00 Hz, 1 H), 7.47 (t, J= 8.30 Hz, 1 H), 7.35 (dd, J= 8.53, 1.51 Hz, 1 H), 7.23 (d, J= 7.78 Hz, 1 H), 5.07 (br. s., 2 H), 4.44 (br. s., 2 H), 3.32 (s, 2 H), 2.35 (s, 3 H), 2.04 (s, 2 H), 0.52 (d, J= 30.62 Hz, 4 H).
Example 135-2
2-(l , l-Dioxido-2,3-dihydro- 1 ,4-benzothiazepin-4(5H)-yl)-6-methyl- V-(pyrrolidin-3- yl)quinazolin-4-amine
Figure imgf000495_0002
The title compound was prepared in analogy to Example 135-1 in Scheme 70 by using 2,4- dichloro-6-methylquinazoline, tert-butyl 3-aminopyrrolidine-l-carboxylate, 2,3,4,5-tetrahydro- 1 ,4-benzothiazepine 1,1 -dioxide and trifluoroacetic acid instead of 2,4-dichloro-6- methylquinazoline, tert-butyl [1 -(amino methyl)cyclopropyl] carbamate, 2,3,4,5-tetrahydro-l,4- benzothiazepme 1,1 -dioxide and trifluoroacetic acid. MS obsd. (ESI+) [(M+H)+] 424, 1H NMR (400 MHz, DMSO-dg) δ ppm 7.92 - 7.82 (m, 2 H), 7.78 (br. s., 1 H), 7.69 - 7.56 (m, 2 H), 7.48 (t, J= 7.53 Hz, 1 H), 7.34 (dd, J= 8.53, 1.25 Hz, 1 H), 7.22 (d, J= 6.78 Hz, 1 H), 5.08 (br. s., 2 H), 4.47 (br. s., 2 H), 3.48 - 2.54 (m, 7 H), 2.33 (s, 3 H), 2.25 - 2.00 (m, 1 H), 1.81 - 1.68 (m, 1 Example 136
Viral cytopathic effect (CPE) assay: To measure anti-RSV activity of compounds, 96- well plates are seeded with 6xl03 cells per well in Dulbecco's modified Eagle's medium
(DMEM) containing 10% fetal bovine serum (FBS). Cells are infected the next day with sufficient RSV Long strain (ATCC) to produce an approximately 80-90% cytopathic effect after 6 days, in the presence of serial half-log diluted compound in a total volume of 200 per well. The viability of cells is assessed after 6 days using Cell Counting kit-8 (Dojindo Molecular Technologies). The absorbance at 450 nm and referenced at 630 nm is measured to determine 50%) effective concentration (EC50).
The compounds of the present invention were tested for their anti-RSV activity, and the activation as described herein. The Examples were tested in the above assay and found to have EC50 of about 0.0001 μΜ to about 10 μΜ. Particular compound of formula (I) were found to have EC50 of about 0.0001 μΜ to about 1 μΜ. Further particular compound of formula (I) were found to have EC50 of about 0.0001 μΜ to about 0.1 μΜ.
Results of CPE assays are given in Table 1.
Table 1 :
Example EC50 (μΜ, Example EC50 (μΜ, Example EC50 (μΜ,
Long Strain) Long Strain) Long Strain)
1-1 0.002 11-4 0.004 62-5 0.017
1-2 0.007 12-1 0.536 62-6 0.006
1-3 0.072 12-2 0.315 62-7 0.186
1-4 0.004 12-3 6.256 63-1 3.133
1-5 0.004 12-4 0.764 63-2 2.021
1-6 0.022 12-5 0.448 63-3 0.007
1-7 0.022 12-6 9.214 63-4 0.797
2-1 0.024 12-7 0.226 64 0.035
2-2 0.002 13 0.026 65 0.322
2-3 2.805 14-1 2.194 66 0.002
2-4 0.081 14-2 8.792 67 0.585
2-5 0.006 15-1 7.892 68 2.012
2-6 0.021 15-2 7.994 69-1 0.007 -7 0.234 15-3 2.697 69-2 0.007-8 0.055 15-4 0.257 70 0.071-9 0.007 15-5 0.740 71 0.005-10 0.005 16-1 2.567 72 0.002-11 0.008 16-2 9.642 73 6.978-1 0.006 17-1 5.538 74 1.936-2 3.051 17-2 0.616 75 0.002-3 3.552 17-3 2.17 76 0.006-4 0.006 17-4 0.071 77 8.78-5 0.002 17-5 1.504 78-1 0.016-6 0.058 17-6 0.086 78-2 0.25-7 0.009 17-7 0.642 79 2.791-8 0.002 17-8 0.021 80 5.479-9 0.248 18-1 0.003 81 0.353-10 0.053 18-2 0.024 82 0.014-11 0.054 18-3 0.014 83 0.662-12 1.654 18-4 0.061 84 2.965-13 0.099 18-5 0.057 85 0.008-14 0.017 18-6 0.061 86 2.222-15 0.482 18-7 0.023 87-1 0.096-16 0.075 18-8 0.0007 87-2 9.31-17 5.053 18-9 0.005 88 0.007-18 0.024 18-10 0.011 89 0.007-19 0.009 18-11 0.619 90 0.005-20 0.507 19-1 0.043 91 0.004-21 0.006 19-2 0.011 92-1 0.009-22 0.032 19-3 0.006 92-2 0.019-23 0.002 19-4 0.02 93-1 0.005-24 0.021 19-5 3.073 93-2 0.009-25 0.022 19-6 0.054 94 6.527-26 0.876 19-7 6.856 95 3.039-27 1.394 19-8 2.749 96 2.833-28 0.149 20-1 0.073 97 0.177-29 0.022 20-2 0.31 98-1 0.778-30 7.81 20-3 0.093 98-2 3.163-31 0.014 21-1 0.023 99 2.999-32 0.037 21-2 0.161 100 9.191-33 0.426 21-3 0.015 101 8.579-34 0.085 21-4 0.004 102 9.76-35 0.013 21-5 0.007 103 0.202 -36 0.092 22 0.036 104 0.89-37 0.017 23 5.185 105 1.084-38 0.0439 24 0.016 106 0.002-39 0.030 25 0.002 107 0.001-40 0.022 26-1 0.005 108-1 0.488-41 0.071 26-2 0.179 108-2 2.474-42 0.007 27 2.393 109-1 0.00088-43 2.394 28-1 0.007 109-2 0.0015-44 0.012 28-2 0.007 110-1 0.017-45 5.229 28-3 0.001 110-2 2.607-46 0.053 28-4 0.001 110-3 0.161-47 0.101 28-5 0.003 110-4 0.06-48 0.023 29 0.042 110-5 1.655-49 0.099 30-1 0.317 110-6 4.278-50 0.0004 30-2 0.218 110-7 1.178-51 0.004 31 0.702 110-8 0.081-52 0.005 32-1 0.019 110-9 1.367-53 0.261 32-2 2.454 110-10 0.099-54 0.114 32-3 1.991 110-11 6.753-55 0.027 32-4 0.272 110-12 0.072-56 0.716 32-5 2.58 110-13 3.679-57 7.534 33-1 0.044 110-14 0.648-58 0.184 33-2 0.627 110-15 0.004-59 1.083 34 2.086 111-1 2.007-60 0.617 35 2.791 111-2 1.345-61 0.118 36-1 0.073 111-3 0.0768-62 0.589 36-2 1.474 111-4 0.066-63 9.899 36-3 2.153 111-5 1.64-64 0.874 36-4 0.138 111-6 0.062-65 0.002 36-5 0.026 111-7 0.873-1 0.269 36-6 0.264 111-8 0.283-2 0.098 37-1 0.005 111-9 0.047-3 0.026 37-2 0.043 111-10 0.107-4 0.208 38-1 0.01 111-11 0.588-5 5.258 38-2 0.302 112-1 3.739-1 9.197 38-3 0.074 112-2 0.092-2 0.211 38-4 0.064 113 0.733-3 0.015 38-5 6.652 114-1 0.007-4 0.326 39 0.092 114-2 0.975-5 0.014 40-1 0.039 114-3 0.004 -6 2.062 40-2 4.655 114-4 0.186-7 0.941 40-3 0.917 115 0.01-8 0.022 40-4 2.646 116-1 0.005-9 0.018 41 2.629 116-2 0.309-10 0.397 42-1 8.947 117 5.97-11 0.526 42-2 0.037 118-1 1.975-12 6.249 43 0.017 118-2 0.048-1 0.025 44-1 0.084 118-3 0.063-2 0.908 44-2 1.547 118-4 0.104
7 1.418 45-1 0.021 118-5 0.178-1 5.513 45-2 0.253 118-6 0.173-2 0.817 45-3 0.031 118-7 0.166-3 0.9 46 0.682 118-8 0.223-4 0.064 47-1 7.881 118-9 0.202-5 0.074 47-2 5.822 118-10 0.289-6 3.767 47-3 5.692 118-11 0.323-7 0.322 47-4 0.993 118-12 0.448-1 2.35 47-5 0.835 118-13 0.463-2 4.77 47-6 2.312 118-14 0.616-3 0.001 47-7 3.4107 118-15 0.626-4 8.874 47-8 0.432 118-16 0.695-5 0.179 47-9 0.192 118-17 0.806-6 0.275 48 0.009 118-18 0.973-7 0.002 49 0.721 118-19 1.236-8 3.478 50-1 0.931 118-20 1.129-9 0.157 50-2 2.423 118-21 1.382-10 0.037 51 0.056 118-22 2.227-11 0.953 52 0.419 118-23 2.641-12 2.663 53 0.094 118-24 6.451-13 0.701 54 4.798 118-25 7.623-14 0.025 55-1 0.007 118-26 7.754-15 0.012 55-2 0.202 119 6.656-16 0.005 55-3 0.006 120-1 2.193-17 0.025 56-1 0.002 120-2 1.785-18 0.01 56-2 0.023 121 1.103-19 0.0007 56-3 0.004 122 3.125-20 0.760 56-4 0.027 123 3.144-21 0.021 56-5 0.022 124 6.102-22 0.872 56-6 0.002 125 2.521-23 3.022 57-1 0.067 126-1 0.790 9-24 0.024 57-2 0.018 126-2 0.638
9-25 4.084 57-3 0.023 127 6.249
9-26 7.204 57-4 0.239 128 7.174
9-27 0.797 57-5 0.027 129 7.875
9-28 0.003 57-6 0.037 130-1 6.836
9-29 0.024 57-7 0.081 130-2 7.269
9-30 8.591 58 2.772 131 2.523
9-31 2.427 59 0.746 132 7.814
9-32 0.063 60 0.018 133-1 0.31
9-33 0.057 61-1 0.005 133-2 0.186
9-34 0.024 61-2 0.097 134 0.25
10 0.003 62-1 0.0003 135-1 0.006
11-1 0.069 62-2 0.0017 135-2 0.018
11-2 7.022 62-3 0.0013
11-3 0.922 62-4 0.019
Example A
A compound of formula (I) can be used in a manner known per se as the active ingredient for the production of tablets of the following composition:
Per tablet
Active ingredient 200 mg
Micro crystalline cellulose 155 mg
Corn starch 25 mg
Talc 25 mg
Hydro xypropylmethylcellulose 20 mg
425 mg
Example B
A compound of formula (I) can be used in a manner known per se as the active ingredient for the production of capsules of the following composition: Per capsule
Active ingredient 100.0 mg
Corn starch 20.0 mg
Lactose 95.0 mg
~ * 4.5 mg Magnesium stearate 0.5 mg
220.0 mg

Claims

Claims
Figure imgf000502_0001
Wherein
R1 is hydrogen, halogen, or Ci_6alkyl;
R2 is hydrogen, halogen, or Ci_6alkyl;
R3 is hydrogen, halogen, or Ci_6alkyl;
R4 is hydrogen, or Ci_6alkyl;
R5 is hydrogen, or halogen;
R6 is hydrogen, halogen, hydroxy, Ci_6alkoxy, carboxy, morpholinyl, or 4-C0.
6alkylpiperazin- 1 -yl;
R7 is hydrogen, halogen, Ci_6alkyl, Ci_6alkoxy, Ci_6alkylaminocarbonyl, diCi_6 alkylaminocarbonyl, Ci_6alkylsulfonyl, phenoxy, or hydroxy(CH2)2-6-0-; R8 is hydrogen, halogen, or Ci_6alkoxy;
R9 is hydrogen, Ci_6alkyl, or =0;
R10 is hydrogen, or =0, provided that R9 and R10 are not =0 simultaneously;
A is nitrogen, or -C-R11, wherein R11 is hydrogen, halogen, Chalky!, cycloalkyl, Ci_ 6alkoxy, trifluoromethyl, trifluoromethoxy, pyridinyloxy, Ci_6alkoxy(CH2)i_6-0-,
difluoromethoxy, cyano, nitro, amino, vinyl, acetylenyl, amino carbonyl, hydroxy(CH2)2-6-0-, Ci_ 6alkylsulfmyl, Ci_6alkylsulfonyl, hydroxy(CH2)i_6, deuteratedCi_6alkyl, carboxyl, Ci_
6alkoxycarbonyl, hydroxy, difluoromethyl, -CH(hydroxy) Ci_6alkyl, or Ci_6alkylsulfanyl; X is -CH2-, -0-, -NH-, -CF2-, -C(Ci_6alkyl)(OH)-, -S-, -C(=0)-, -C(=NOC0-6alkyl)-, - =0)-, -S(02)- or -S(=0)(NH)-;
Y is -CH-, or nitrogen;
Q is hydrogen; halogen; Ci_6alkyl, unsubstituted or once or twice substituted by amino or hydroxy, provided that di-substitution is not on the same carbon; amino(CH2)2_
6aminosulfonyl; 2-amino-4,5-dihydro- 1 ,3-oxazol-4-yl(CH2)i_6; carboxy(CH2)i_6;
phenylsulfonyl; piperidin-4-yl-carbonyl; lH-pyrazol-3-yl; pyrrolidin-3-yloxy; piperidin-4- yloxy; amino(CH2)2_6-0-; or
12 13 12 13
NR R , wherein one of R and R is hydrogen, Ci_6alkyl, or hydroxy(CH2)2_6, and the other one is { l-[amino(CH2)o-6]-3,3-difluorocyclobutyl}(CH2)i_6; guanidino(CH2)2_6; (S-Ci. 6alkylsulfonimidoyl)(CH2)2_6; 2-oxa-6-aza-spiro[3.4]oct-8-yl; {3-[amino(CH2)0_
6]tetrahydrofuran-3-yl} (CH2)i_6; 3 -amino methyl- 1 , 1 -dioxidothietan-3 -ylmethyl; 3-amino- 1 , 1 -dioxidothietan-3 -ylmethyl; 3 -(amino methyl)thietan-3 -ylmethyl; (1 , 1- dioxidothiomorpholin-4-yl)ethyl; Co-6alkyl(oxetanyl)N(CH2)2_6; 4,5-dihydro- lH-imidazol- 2-yl; amino(CH2)2_6-0-(CH2)2_6; amino(CH2)2_i0; amino(CH2)i_6difluoromethyl(CH2)i_6; amino (CH2) i _6difluoromethy ldifluoromethy 1(CH2) i _6 ; amino (CH2) i _6 fluoromethy 1(CH2) i _6 ; amino (CH2) i _6oxetany 1(CH2)0_6 ; amino (CH2)0_6Oxetanyl(CH2) i _6 ; amino (CH2)2_
6Sulfanyl(CH2)2_6; amino(CH2)2_6sulfonyl(CH2)2_6; amino(CH2)o-6carbonyl(CH2)0- 6; aminocycloalkyl(CH2)o-6; 2-aminodihydrooxazol-4-yl(CH2)i_6; 2-aminodihydrooxazol-5- yl(CH2)i_6; (2-amino-5-methyl-4,5-dihydro-l ,3-oxazol-5-yl)methyl; aminophenyl; 4- aminotetrahydropyran-4-yl(CH2) i _6; azetidin-2-yl(CH2) i _6; azetidin-3 -yl(CH2)0_6 ;
azetidinylcarbonyl; Ci_6alkoxy(CH2)2_6; Ci_6alkoxy(CH2)2_6amino(CH2)2_6; Ci_6alkyl; Ci_ 6alkylamino(CH2)2_6; Ci_6alkylaminocarbonyl(CH2)0-6; Ci_6alkylaminooxetanyl(CH2)i_6; Ci_ 6alkylcarbonyl; Ci_6alkylcarbonylamino(CH2)2_6; Ci_6alkylcarbonylamino(CH2)i_
6oxetanyl(CH2)o_6; Ci_6alkylsulfinyl(CH2)2_6; Ci_6alkylsulfonyl; carboxy(CH2)i_6;
cyano(CH2)i_6; diCi_6alkylamino(CH2)2_6; diCi_6alkylaminocarbonyl; difluoromethyl(CH2)i_ 6amino(CH2)2_6; hydrogen; hydroxy(CH2)2_i0; hydroxy(CH2)2_6amino(CH2)2_6;
hydro xy(CH2) i _6carbonyl; hydro xy(CH2)0_6Oxetanyl(CH2) i _6 ; hydro xy(CH2) i _
6oxetanyl(CH2)o_6; hydroxycycloalkyl; isoxazolyl; morpholin-2-yl(CH2)i_6; morpholin-4- yl(CH2)2_6; oxetanyl(CH2)0_6; N-oxetanylpyrrolidin-3-yl; oxo-pyrrolidinylcarbonyl;
phenylaminocarbonyl; phenyl(CH2)o_6aminooxetanyl(CH2) i _6 ; phenylcarbonyl;
piperazinyl(CH2)2_6; piperidin-l-yl(CH2)2_6; piperidin-2-yl(CH2)i_6; piperidin-3-yl(CH2)o-6; piperidin-4-yl(CH2)o_6; piperidinylcarbonyl; pyrazinylcarbonyl; pyrazol-3-yl;
pyridazinylcarbonyl; pyridinyl(CH2)0-6carbonyl; pyridinylamino(CH2)2_6; pyrrolidin-3-yl, unsubstituted or 4-substituted by halogen; pyrrolidin-4-yl, unsubstituted or 3-substituted by hydroxy or Ci_6alkoxy; pyrrolidin-2-yl(CH2)i_6; pyrrolidinylcarbonyl; tetrahydrofuran-3-yl; tetrahydropyran-4-yl; tetrazolyl(CH2)2-6; trifluoromethylcarbonylamino(CH2)1_60xetanyl;
R14
-(CH -C-R15
trifiuoromethylsulfonyl; R , wherein R14 is hydrogen, Ci_6alkyl or
hydroxy(CH2)i_6; R15 is hydroxy, Ci_6alkyl, hydroxy(CH2)i_6 or amino; and R16 is Ci_6alkyl, trifluoromethyl, hydroxy(CH2)i_6, amino (CH2)i_6, aminocarboxy or carboxy(CH2)i_6;
R17 R , wherein R17 is hydrogen, Ci_6alkyl or hydroxy(CH2)i_6; R18 is hydroxy(CH2)i_6 or
Figure imgf000504_0001
or amino;
R12 and R13, with the nitrogen atom to which they are attached, may form a pyrrolidinyl, piperazinyl, piperidinyl, morpholinyl, azetidinyl, diazepanyl or oxopyrrolidinyl ring; which may be unsubstituted, once or twice substituted by a group selected from halogen, Ci_ 6alkyl, Ci_6alkoxy, gemdimethyl, amino, aminocarbonyl, hydroxy, oxetanylamino, Ci_ 6alkylpiperazinyl, and amino (CH2)i_6 ;
R12 and R13, with the nitrogen atom to which they are attached may form a bridge ring or a spiral ring selected from 2-oxa-6-aza-spiro[3.4]octan-6-yl, 2-oxa-5,7-diazaspiro[3.4]octan- 6-one-5-yl, (4aS,7aR)-hexahydropyrrolo[3,4-b][l,4]oxazin-6(2H)-yl, 4,5,6,6a-tetrahydro- 3aH-pyrrolo[3,4-d][l,3]oxazol-5-yl, 2-aza-bicyclo[2.1.1]hexan-2-yl, and 3-aza- bicyclo[3.1.0]hexan-3-yl; which may be unsubstituted or further substituted by amino; and pharmaceutically acceptable salt and stereoisomers thereof.
A compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein
R1 is hydrogen, halogen or Ci_6alkyl;
R2 is hydrogen, halogen or Ci_6alkyl;
R3 is hydrogen, halogen or Ci_6alkyl;
R4 is hydrogen or Ci_6alkyl;
R5 is hydrogen;
R6 is hydrogen, halogen, hydroxy, Ci. 6alkoxy, morpholinyl or 4-Co-6alkylpiperazin-l-yl;
Ώ 7 i o U Ar-n r,^ ½logen, Ci_6alkyl, Ci _6alkoxy, phenoxy or hydroxy(CH2)2-6-0-; R is hydrogen, halogen or Ci_6alkoxy; R9 is hydrogen or Ci_6alkyl; R10 is hydrogen;
A is nitrogen or -C-R1 1, wherein R1 1 is hydrogen, halogen, Ci_6 alkyl, cycloalkyl, Ci_ 6alkoxy, trifluoromethyl, trifluoromethoxy, pyridinyloxy, Ci_6alkoxy(CH2)i_6-0-,
difiuoromethoxy, cyano, nitro, amino, vinyl, acetylenyl, amino carbonyl, hydroxy(CH2)2_6-0-, Ci_ 6alkylsulfinyl, hydroxy(CH2)i_6, deuteratedCi_6alkyl, carboxyl, alkoxycarbonyl, hydroxy, difiuoromethyl, -CH(hydroxy)Ci_6alkyl or Ci_6alkylsulfanyl;
X is S, S=0, S02 or S(0)NH; Y is -CH- or nitrogen;
Q is Ci_6alkyl, unsubstituted or once substituted by amino; amino(CH2)2_6aminosulfonyl; 2-amino-4,5-dihydro-l ,3-oxazol-4-ylethyl; carboxy(CH2)i_6; phenylsulfonyl; piperidin-4-yl- carbonyl; lH-pyrazol-3-yl; pyrrolidin-3-yloxy; piperidin-4-yloxy; amino(CH2)2_6-0-; or
12 13 12 13
NR R , wherein one of R and R is hydrogen, Ci_6alkyl or hydroxy(CH2)2_6, and the other one is { l-[amino(CH2)o-6]-3,3-difluorocyclobutyl}(CH2)i_6; (S-Ci.
6alkylsulfonimidoyl)(CH2)2_6; {3-[amino(CH2)0_6]tetrahydrofuran-3-yl} (CH2)i_6; (2-amino-5- methyl-4,5-dihydro- 1 ,3-oxazol-5-yl)methyl; 3 -amino methyl- 1 , 1 -dioxidothietan-3-ylmethyl; 3- (aminomethyl)thietan-3-ylmethyl; (1 , 1 -dioxidothiomorpholin-4-yl)ethyl; C0- 6alkyl(oxetanyl)N(CH2)2_6; 4,5-dihydro- lH-imidazol-2-yl; amino(CH2)2_6-0-(CH2)2_6;
amino(CH2)2_i0; amino(CH2)o-6carbonyl(CH2)0-6; amino(CH2)i_6difluoromethyl(CH2)i_6;
amino (CH2) i _6difluoromethy ldifluoromethy 1(CH2) i _6 ; amino (CH2) i _6 fiuoromethy 1(CH2) i _6 ;
amino (CH2) i _6oxetany 1(CH2)0_6 ; amino (CH2)0_6Oxetanyl(CH2) i _6 ; amino (CH2)2_6sulfany 1(CH2)2_6 ; amino(CH2)2_6sulfonyl(CH2)2_6; 1 -amino eye lobutylmethyl; 2-aminocyclohexyl; 3- aminocyclohexyl; 4-aminocyclohexyl; 1-aminocyclohexylmethyl; 2-aminocyclopentyl; 1- aminocyclopropylethyl; 1-aminocyclopropylmethyl; (2-amino-4,5-dihydro-oxazol-5-yl)(CH2)i_6; (2-amino-4,5-dihydro-oxazol-4-yl)(CH2)i_6; aminophenyl; 4-aminotetrahydropyran-4-yl(CH2)i_6; azetidin-2-yl(CH2)i_6; azetidin-3-yl(CH2)0_6; azetidin-3-ylcarbonyl; Ci_6alkoxy(CH2)2_6; Ci_ 6alkoxy(CH2)2_6amino(CH2)2_6; Ci_6alkyl; Ci_6alkylamino(CH2)2_6; Ci_
6alkylaminooxetanyl(CH2)i_6; Ci_6alkylcarbonyl; Ci_6alkylaminocarbonyl(CH2)o_6; Ci_
6alkylcarbonylamino(CH2)2_6; Ci_6alkylcarbonylamino(CH2)i_6oxetanyl(CH2)o-6; Ci_
6alkylsulfinyl(CH2)2_6; Ci_6alkylsulfonyl; carboxy(CH2)i_6; cyano (CH2)i_6; diCi_
6alky lamino (CH2)2_6 ; diC i _6alkylamino carbonyl; difluoromethy 1(CH2) i _6amino (CH2)2_6 ;
hydrogen; hydroxy(CH2)2_i0; hydroxy(CH2)2_6amino(CH2)2_6; hydroxy(CH2)i_6carbonyl; hydroxy(CH2) i _6Oxetanyl(CH2)0_6; hydro xy(CH2)0_6Oxetanyl(CH2) i _6 ; 4-hydroxycyclohexyl; isoxazol-3-yl; morpholin-2-yl(CH2)i_6; morpholin-4-yl(CH2)2_6; 2-oxa-6-aza-spiro[3.4]oct-8-yl; oxetanyl(CH2)o_6; N-oxetanylpyrrolidin-3-yl; oxo-pyrrolidinylcarbonyl; phenylaminocarbonyl; phenyl(CH2)0-6aminooxetanyl(CH2)i_6; phenylcarbonyl; piperazinyl(CH2)2_6; piperidin-1- yl(CH2)2_6; piperidin-2-yl(CH2)i_6; piperidin-3-yl(CH2)o-6; piperidin-4-yl(CH2)o-6;
piperidinylcarbonyl; pyrazinylcarbonyl; pyrazol-3-yl; pyridazinylcarbonyl; pyridinyl(CH2)0-
6carbonyl; pyridinylamino(CH2)2_6; pyrrolidin-3-yl, unsubstituted or 4-substituted by halogen; pyrrolidin-4-yl, unsubstituted or 3-substituted by hydroxy or Ci_6alkoxy; pyrrolidin-2-yl(CH2)i_6; pyrrolidinylcarbonyl; tetrahydrofuran-3-yl; tetrahydropyran-4-yl; tetrazolyl(CH2)2_6;
Figure imgf000506_0001
, wherein
R14 is hydrogen or Ci_6alkyl; R15 is hydroxy, Ci_6alkyl or amino; and R16 is Ci_6alkyl, trifluoromethyl, hydroxy(CH2)i_6, amino (CH2)i_6, aminocarbonyl or carboxy(CH2)i_6;
Figure imgf000506_0002
, wherein R17 is hydrogen, Ci_6alkyl or hydroxy(CH2)i_6; R18 is hydroxy(CH2)i_6 or Ci_6alkyl; R19 o _22
is hydroxy(CH2)i_6, amino (CH2)i_6, carboxy or amino carbonyl(CH2)0_6; or K , wherein R 20 21 Ci 22
is hydrogen or Ci_6alkyl; R is _6alkyl; R is Ci_6alkoxy or amino;
R12 and R13, with the nitrogen atom to which they are attached, may form a pyrrolidinyl, piperazinyl, piperidinyl, morpholinyl, azetidinyl, diazepanyl or oxopyrrolidinyl ring; which may be unsubstituted, once or twice substituted by a group selected from halogen, Ci_6alkyl, Ci_ 6alkoxy, gemdimethyl, amino, aminocarbonyl, hydroxy, oxetanylamino, Ci_6alkylpiperazinyl, and amino (CH2)i_6;
R12 and R13, with the nitrogen atom to which they are may form a bridge ring or a spiral ring selected from 2-oxa-6-aza-spiro[3.4]octan-6-yl, 2-oxa-5,7-diazaspiro[3.4]octan-6-one-5-yl, (4aS, 7ai?)-hexahydropyrrolo [3 ,4-b] [ 1 ,4]oxazin-6(2H)-yl, 4,5 ,6,6a-tetrahydro-3aH-pyrrolo [3 ,4- d] [ l,3]oxazol-5-yl, 2-aza-bicyclo[2.1.1]hexan-2-yl and 3-aza-bicyclo[3.1.0]hexan-3-yl; which may be unsubstituted or further substituted by amino.
3. A compound according to claim 1 or 2 or a pharmaceutically acceptable salt thereof, wherein
R1, R2 or R3 are hydrogen, fluoro, chloro or methyl;
R4 is hydrogen or methyl; R5 is hydrogen;
R6 is hydrogen, fluoro, hydroxy, methoxy, morpholinyl or 4-(propan-2-yl)piperazin-l-yl; R7 is hydrogen, fluoro, chloro, methyl, methoxy, ethoxy, hydroxyethoxy or phenoxy; R8 is hydrogen, fluoro or methoxy; R9 is hydrogen or methyl; R10 is hydrogen;
A is nitrogen or -C-R11, wherein R11 is hydrogen, fluoro, chloro, bromo, methyl, ethyl, cyclopropyl, methoxy, trifluoromethyl, trifluoromethoxy, pyridinyloxy, methoxyethoxy, difluoromethoxy, cyano, nitro, amino, vinyl, acetylenyl, amino carbonyl, hydroxyethoxy, methylsulfanyl, methylsulfmyl, hydroxymethyl, deuteratedmethyl, carboxyl, methoxycarbonyl, hydroxy, difluoromethyl, methylCH(hydroxy)- or methylsulfonyl;
X is S, S=0, S02 or S(0)NH;
Y is -CH- or nitrogen;
Q is 2-amino-4,5-dihydro-l,3-oxazol-4-ylethyl; aminoethoxy; aminoethylaminosulfonyl; aminopropyl; carboxyethyl; methyl; phenylsulfonyl; piperidin-4-yl-carbonyl; piperidin-4- yloxy; lH-pyrazol-3-yl; pyrrolidin-3-yloxy; or
NR 112ZR13 , wherein one of R 12 and R 13 is hydrogen, methyl or hydro xyethyl, and the other one is amino butyl; amino carbonylethyl; amino carbonylmethyl; 1-aminocyclobutylmethyl;
2- aminocyclohexyl; 3-aminocyclohexyl; 4-aminocyclohexyl; 1-aminocyclohexylmethyl; 2- aminocyclopentyl; 1-aminocyclopropylethyl; 1-aminocyclopropylmethyl; aminodecyl; (2- amino-4,5-dihydro-oxazol-5-yl)methyl; (2-amino-4,5-dihydro-oxazol-4-yl)methyl;
aminoethoxyethyl; aminoethyl; amino ethylcarbonyl; amino ethylfluoromethylmethyl;
amino ethylsulfanylethyl; aminoethylsulfonylethyl; aminoheptyl; aminohexyl;
aminomethylcarbonyl; (l-aminomethyl-3,3-difluorocyclobutyl)methyl;
aminomethyldifluoromethyldifluoromethylmethyl; ammomethyldifluoromethylmethyl; (2- amino-5-methyl-4,5-dihydro- 1 ,3-oxazol-5-yl)methyl; 3 -amino methyl- 1 , 1 -dioxidothietan-3- ylmethyl; aminomethylfluoromethylethyl; aminomethylfluoromethylmethyl;
aminomethyloxetanyl; ammomethyloxetanylmethyl; 3-(aminomethyl)thietan-3-ylmethyl; aminononyl; aminooctyl; aminooxetanylethyl; aminooxetanylmethyl; aminopentyl;
aminophenyl; aminopropyl; 4-aminotetrahydropyran-4-ylmethyl; 3-aminotetrahydrofuran-
3- ylmethyl; azetidin-3-yl; azetidin-3-ylcarbonyl; azetidin-2-ylmethyl; azetidin-3-ylmethyl; carboxyethyl; carboxymethyl; cyanoethyl; difluoromethylmethylamino ethyl; 4,5-dihydro- lH-imidazol-2-yl; dimethylaminocarbonyl; dimethylamino ethyl; (1,1- dioxidothiomorpholin-4-yl)ethyl; ethyl; ethylaminocarbonyl; ethylamino ethyl;
ethylammooxetanylmethyl; ethyl (oxetanyl)amino ethyl; hydrogen; 4-hydroxycyclohexyl; hydroxyethyl; hydroxyethylammoethyl; hydroxyethyloxetanyl; hydroxymethylcarbonyl; hydroxymethyloxetanylmethyl; hydroxynonyl; hydroxypropyl; isoxazol-3-yl;
methoxyethyl; methoxyethylaminoethyl; methyl; methylaminocarbonylmethyl;
methylamino ethyl; methylcarbonyl; methylcarbonylaminoethyl;
methylcarbonylaminomethyloxetanylmethyl; methylcarbonylaminopropyl;
methylsulfinylethyl; 2-(S'-methylsulfonimidoyl)ethyl; methylsulfonyl; morpholin-4-ylethyl; morpholin-2-ylmethyl; 2-oxa-6-aza-spiro[3.4]oct-8-yl; oxetanyl; oxetanylaminoethyl; oxetanylaminopropyl; oxetanylmethyl; N-oxetanylpyrrolidin-3-yl; oxo-pyrrolidin-4- ylcarbonyl; phenylaminocarbonyl; phenylcarbonyl; phenylmethylaminooxetanylmethyl; piperazin-l-ylethyl; piperidin-2-ylcarbonyl; piperidin-3-ylcarbonyl; piperidin-4-ylcarbonyl; piperidin-3-yl; piperidin-4-yl; piperidin-l-ylethyl; piperidin-2-ylmethyl; pyrazin-2- ylcarbonyl; pyrazol-3-yl; pyridazin-3-ylcarbonyl; pyridine-2-ylmethylcarbonyl; pyridine-2- ylaminoethyl; pyridine-2-ylcarbonyl; pyridine-3-ylcarbonyl; pyrrolidin-3-yl, unsubstituted or 4-substituted by fluoro; pyrrolidin-4-yl, unsubstituted or 3-substituted by hydroxy or methoxy; pyrrolidin-2-ylmethyl; pyrrolidin-2-ylcarbonyl; tetrahydrofuran-3-yl;
tetrahydropyran-4-yl; tetrazolylethyl; trifluoromethylsulfonyl; trifiuoromethylcarbonylaminomethyloxetanyl;
Figure imgf000508_0001
, wherein R is hydrogen or methyl; R15 is hydroxy, methyl or amino; and R16 is methyl, trifluoromethyl, hydroxymethyl, hydroxyethyl, aminomethyl, aminocarbonyl or carboxymethyl;
Figure imgf000508_0002
, wherein R17 is hydrogen, methyl or hydroxymethyl; R18 is hydroxymethyl or methyl; R19 is hydroxymethyl, aminomethyl, carboxy, aminocarbonyl or amino carbonylmethyl;
or
Figure imgf000508_0003
, wherein R is hydrogen or methyl; R is methyl or ethyl; R is methoxy or amino;
R12 and R13, with the nitrogen atom to which they are attached, may form a pyrrolidinyl, piperazinyl, piperidinyl, morpholinyl, azetidinyl, diazepanyl or oxopyrrolidinyl ring; which may be unsubstituted, once or twice substituted by a group selected from fluoro, methyl, methoxy, gemdimethyl, amino, aminocarbonyl, hydroxy, oxetanylamino,
methylpiperazinyl and aminomethyl; R12 and R13, with the nitrogen atom to which they are attached may form a bridge ring or a spiral ring selected from 2-oxa-6-aza-spiro[3.4]octan-6-yl, 2-oxa-5,7-diazaspiro[3.4]octan- 6-one-5-yl, (4a5',7ai?)-hexahydropyrrolo[3,4-b][l,4]oxazin-6(2H)-yl, 4,5,6,6a-tetrahydro- 3aH-pyrrolo[3,4-d][l,3]oxazol-5-yl, 2-aza-bicyclo[2.1.1]hexan-2-yl or 3-aza- bicyclo[3.1.0]hexan-3-yl; which may be unsubstituted or further substituted by amino.
4. A compound according to any one of claims 1 to 3 or a pharmaceutically acceptable salt thereof, wherein
R1, R2, R3, R4, R5, R6, R7, R8, R9 and R10 are hydrogen;
A is -C-R11 , wherein R11 is hydrogen, halogen or Ci_6alkyl;
X is S;
Y is -CH- or nitrogen;
12 13 12 13
Q is NR R , wherein one of R and R is hydrogen, and the other one is
amino (CH2)2-6; amino(CH2)i-6difluoromethyl(CH2)i-6; amino(CH2)o-60xetanyl(CH2)i-6 or hydrogen;
R12 and R13, with the nitrogen atom to which they are attached, may form a pyrrolidinyl ring, which may be once substituted by amino.
5. A compound according to claim 4 or a pharmaceutically acceptable salt thereof, wherein R1, R2, R3, R4, R5, R6, R7, R8, R9 and R10 are hydrogen;
A is -C-R11 , wherein R11 is hydrogen, chloro or methyl;
12 13 , wherein one of R 12 and R 13
u is NR1ZR is hydrogen, and the other one is amino ethyl; ammomethyldifluoromethylmethyl; ammomethyloxetanylmethyl; aminooxetanylmethyl or hydrogen;
R12 and R13, with the nitrogen atom to which they are attached, may form a pyrrolidinyl ring, which may be once substituted by amino.
6. A compound according to any one of claims 1 to 5 or a pharmaceutically acceptable salt thereof, wherein
R1, R2, R3, R4, R5, R6, R7, R8, R9 and R10 are hydrogen;
A is -C-R11, wherein R11 is hydrogen, halogen, Ci_6alkyl, hydro xy(CH2)i_6,
-oxyl; X is S=0;
Y is -CH- or nitrogen;
12 13 12 13
Q is NR R , wherein one of R and R is hydrogen; and the other one is
amino (CH2)2-6 ; amino (CH2) i _6difluoromethy 1(CH2) i _6 ; amino (CH2) i _6 fluoromethy 1(CH2) i _6 ; amino(CH2)i_60xetanyl; amino(CH2)i-60xetanyl(CH2)i-6; aminooxetanyl(CH2)i_6; hydroxy(CH2)2- io; phenyl(CH2)i-6aminooxetanyl(CH2)i-6; pyrrolidin-3-yl, 4-substituted by halogen;
Figure imgf000510_0001
R15 is hydroxy, and R16 is hydroxy(CH2)i_6;
R12 and R13, with the nitrogen atom to which they are attached, may form a pyrrolidinyl ring, which may be once or twice substituted by a group selected from halogen, amino and hydroxyl.
7. A compound according to claim 6 or a pharmaceutically acceptable salt thereof, wherein
R1, R2, R3, R4, R5, R6, R7, R8, R9 and R10 are hydrogen;
A is -C-R11, wherein R11 is hydrogen, chloro, methyl, hydro xymethyl, deuteratedmethyl or carboxyl; s NR 112ZR13 , wherein one of R 12 and R 13
u i is hydrogen, and the other one is amino ethyl; ammomethyldifluoromethylmethyl; ammomethylfluoromethylmethyl; aminomethyloxetanyl; aminomethyloxetanylmethyl; aminooxetanylmethyl; aminopropyl; hydroxyethyl; phenylmethylaminooxetanylmethyl; pyrrolidin-3-yl,
Figure imgf000510_0002
, wherein R14 is hydrogen, R15 is hydroxy, and R16 is hydroxymethyl;
R12 and R13, with the nitrogen atom to which they are attached, may form a pyrrolidinyl ring, which may be once or twice substituted by a group selected from fluoro, amino and hydroxyl.
8. A compound according to any one of claims 1 to 7 or a pharmaceutically acceptable salt thereof, wherein
R1, R2, and R3 are hydrogen, halogen or Ci_6alkyl;
R4 is hydrogen or Ci_6alkyl; R5 is hydrogen;
R6 is hydrogen, halogen, hydroxy, Ci_6alkoxy, morpholinyl or 4-(propan-2-yl)piperazin-
1 ,,1. R7 is hydrogen, halogen, Ci_6alkyl, Ci_6alkoxy, hydroxy(CH2)2-6-0-, or phenoxy; R8 is hydrogen, halogen or Ci_6alkoxy; R9 is hydrogen or Ci_6alkyl; R10 is hydrogen; A is nitrogen or -C-R1 1, wherein R1 1 is hydrogen, halogen, Chalky!, Ci_6alkoxy, trifluoromethyl, trifluoromethoxy, pyridinyloxy, Ci_6alkoxy(CH2)i_6-0-, difluoromethoxy, nitro, cycloalkyl, cyano, amino, vinyl, acetylenyl, amino carbonyl, hydroxy(CH2)2-6-0-, Ci_
6alkylsulfanyl, Ci_6alkylsulfinyl, hydroxy(CH2)i_6, deuteratedmethyl, carboxyl, Ci_
6alkoxycarbonyl, hydroxy, difluoromethyl or methylCH(hydroxy)-; X is S02;
Y is -CH- or nitrogen;
Q is 2-amino-4,5-dihydro-l ,3-oxazol-4-ylethyl; amino(CH2)2_6-0-; amino(CH2)2_ 6aminosulfonyl; Ci_6alkyl, unsubstituted or once substituted by amino; carboxy(CH2)i_6;
phenylsulfonyl; piperidin-4-yl-carbonyl; piperidin-4-yloxy; lH-pyrazol-3-yl; pyrrolidin-3-yloxy; or
12 13 12 13
NR R , wherein one of R and R is hydrogen, Ci_6alkyl or hydro xy(CH2)2_6; and the other one is { l-[amino(CH2)o-6]-3,3-difluorocyclobutyl}(CH2)i_6; (S-Ci.
6alkylsulfonimidoyl)(CH2)2_6 ; 3 -aminotetrahydro furan-3 -yl(CH2) i _6 ; (2-amino-5 -methyl-4,5 - dihydro- 1 ,3-oxazol-5-yl)methyl; 3 -amino methyl- 1 , 1 -dioxidothietan-3-ylmethyl; 3- (aminomethyl)thietan-3-ylmethyl; (l , l-dioxidothiomorpholin-4-yl)ethyl; C0-
6alkyl(oxetanyl)N(CH2)2_6; 4,5-dihydro- lH-imidazol-2-yl; amino(CH2)2_6-0-(CH2)2_6;
amino(CH2)2_i0; amino(CH2)i_6carbonyl; amino carbonyl(CH2)i_6; amino(CH2)i_
6difluoromethy 1(CH2) i _6 ; amino (CH2) i _6difluoromethyldifluoromethy 1(CH2) i _6 ; amino (CH2) i _ 6fluoromethyl(CH2) i _6; amino(CH2) i _6oxetanyl(CH2)0_6; amino(CH2)0_6Oxetanyl(CH2) i _6 ;
amino(CH2)2_6sulfanyl(CH2)2_6; amino(CH2)2_6sulfonyl(CH2)2_6; 1-aminocyclobutylmethyl; 2- aminocyclohexyl; 3-aminocyclohexyl; 4-aminocyclohexyl; 1-aminocyclohexylmethyl; 2- aminocyclopentyl; 1-aminocyclopropylethyl; 1-aminocyclopropylmethyl; (2-amino-4,5-dihydro- oxazol-5-yl)(CH2)i_6; (2-amino-4,5-dihydro-oxazol-4-yl) (CH2)i_6; aminophenyl; 4- aminotetrahydropyran-4-yl(CH2)i_6; azetidin-2-yl(CH2)i_6; azetidin-3-yl(CH2)0_6; azetidin-3- ylcarbonyl; Ci_6alkoxy(CH2)2_6; Ci_6alkoxy(CH2)2_6amino(CH2)2_6; Ci_6alkyl; Ci_
6alkylamino(CH2)2_6; Ci_6alkylaminooxetanyl(CH2)i_6; Ci_6alkylcarbonyl; Ci_
6alkylcarbonylamino(CH2)2_6; C i _6alkylcarbonylamino(CH2) i _6oxetanyl(CH2)0_6 ; C i _ 6alkylsulfinyl(CH2)2-6; Ci_6alkylsulfonyl; carboxy(CH2)i_6; cyano(CH2)i_6; Ci_
6alkylaminocarbonyl(CH2)o-6; diCi_6alkylamino(CH2)2-6; diCi_6alkylaminocarbonyl;
difluoromethyl(CH2)i-6amino(CH2)2-6; hydrogen; hydroxy(CH2)2-io; hydroxy(CH2)2- 6amino(CH2)2-6; hydroxy(CH2)i_6carbonyl; hydroxy(CH2)i_60xetanyl(CH2)o-6; 4- hydroxycyclohexyl; isoxazol-3-yl; morpholin-2-yl(CH2)i-6; morpholin-4-yl(CH2)2-6; 2-oxa-6- aza-spiro[3.4]oct-8-yl; oxetanyl(CH2)o-6; N-oxetanylpyrrolidin-3-yl; oxo-pyrrolidin-4- ylcarbonyl; phenylaminocarbonyl; phenyl(CH2)i-6aminooxetanyl(CH2)i-6; phenylcarbonyl;
piperazinyl(CH2)2-6; piperidin-l-yl(CH2)2-6; piperidin-2-yl(CH2)i-6; piperidin-3-yl(CH2)o-6;
piperidin-4-yl(CH2)o-6; piperidin-2-ylcarbonyl; piperidin-3-ylcarbonyl; piperidin-4-ylcarbonyl; pyrazin-2-ylcarbonyl; pyrazol-3-yl; pyridazin-3-ylcarbonyl; pyridine-2-yl(CH2)o-6carbonyl; pyridine-3-yl(CH2)o-6carbonyl; pyridine-2-ylamino(CH2)2-6; pyrrolidin-3-yl, unsubstituted or 4- substituted by halogen; pyrrolidin-4-yl, unsubstituted or 3-substituted by hydroxy or Ci_6alkoxy; pyrrolidin-2-yl(CH2)i-6; pyrrolidin-2-ylcarbonyl; tetrahydrofuran-3-yl; tetrahydropyran-4-yl;
_
Figure imgf000512_0001
R12 and R13, with the nitrogen atom to which they are attached, may form a pyrrolidinyl, piperazinyl, piperidinyl, morpholinyl, azetidinyl, diazepanyl or oxopyrrolidinyl ring; which may be unsubstituted, once or twice substituted by a group selected from halogen, Ci_6alkyl, Ci_ 6alkoxy, gemdimethyl, amino, aminocarbonyl, hydroxy, oxetanylamino, Ci_6alkylpiperazinyl and amino(CH2)i-6; R12 and R13, with the nitrogen atom to which they are attached may form a bridge ring or a spiral ring selected from 2-oxa-6-aza-spiro[3.4]octan-6-yl, 2-oxa-5,7-diazaspiro[3.4]octan-6-one-5-yl, (4aS, 7ai?)-hexahydropyrrolo [3 ,4-b] [ 1 ,4]oxazin-6(2H)-yl, 4,5 ,6,6a-tetrahydro-3aH-pyrrolo [3 ,4- d][l,3]oxazol-5-yl, 2-aza-bicyclo[2.1.1]hexan-2-yl or 3-aza-bicyclo[3.1.0]hexan-3-yl; which may be unsubstituted or further substituted by amino.
9. A compound according to claim 8 or a pharmaceutically acceptable salt thereof, wherein R2, and R3 are hydrogen, fluoro, chloro or methyl; R4 is hydrogen or methyl;
R5 is hydrogen;
R6 is hydrogen, fluoro, hydroxy, methoxy, morpholinyl or 4-(propan-2-yl)piperazin-l-yl;
R7 is hydrogen, fluoro, chloro, methyl, methoxy, hydroxyethoxy, or phenoxy;
R8 is hydrogen, fluoro or methoxy;
R9 is hydrogen or methyl;
R10 is hydrogen;
A is nitrogen or -C-R11, wherein R11 is hydrogen, fluoro, chloro, bromo, methyl, ethyl, methoxy, trifluoromethyl, trifiuoromethoxy, pyridinyloxy, methoxyethoxy, difluoromethoxy, nitro, cyclopropyl, cyano, amino, vinyl, acetylenyl, amino carbonyl, hydroxyethoxy,
methylsulfanyl, methylsulfinyl, hydroxymethyl, deuteratedmethyl, carboxyl, methoxycarbonyl, hydroxy, difluoromethyl or methylCH(hydroxy)-;
Y is -CH- or nitrogen;
Q is 2-amino-4,5-dihydro-l,3-oxazol-4-ylethyl; aminoethoxy; aminoethylaminosulfonyl; aminopropyl; carboxyethyl; methyl; phenylsulfonyl; piperidin-4-yl-carbonyl; piperidin-4-
12 13 12 13 yloxy; lH-pyrazol-3-yl; pyrrolidin-3-yloxy; or NR R , wherein one of R1Z and R1J is hydrogen, methyl or hydroxyethyl, and the other one is aminobutyl; amino carbonylethyl; amino carbonylmethyl; 1-aminocyclobutylmethyl; 2-aminocyclohexyl; 3-aminocyclohexyl; 4-aminocyclohexyl; 1-aminocyclohexylmethyl; 2-aminocyclopentyl; 1- aminocyclopropylethyl; 1-aminocyclopropylmethyl; aminodecyl; (2-amino-4,5-dihydro- oxazol-5-yl)methyl; (2-amino-4,5-dihydro-oxazol-4-yl)methyl; aminoethoxyethyl;
aminoethyl; aminoethylcarbonyl; ammoethylfluoromethylmethyl; ammoethylsulfanylethyl; aminoethylsulfonylethyl; amino heptyl; amino hexyl; aminomethylcarbonyl; (1- aminomethyl-3,3-difluorocyclobutyl)methyl;
aminomethyldifluoromethyldifluoromethylmethyl; aminomethyldifluoromethylmethyl; (2- amino-5-methyl-4,5-dihydro- 1 ,3-oxazol-5-yl)methyl; 3 -amino methyl- 1 , 1 -dioxidothietan-3- ylmethyl; aminomethylfluoromethylethyl; aminomethylfluoromethylmethyl;
aminomethyloxetanyl; ammomethyloxetanylmethyl; 3-(aminomethyl)thietan-3-ylmethyl; aminononyl; aminooctyl; aminooxetanylethyl; aminooxetanylmethyl; aminopentyl;
aminophenyl; aminopropyl; 4-aminotetrahydropyran-4-ylmethyl; 3-aminotetrahydrofuran- 3-ylmethyl; azetidin-3-yl; azetidin-3-ylcarbonyl; azetidin-2-ylmethyl; azetidin-3-ylmethyl; carboxyethyl; carboxymethyl; cyanoethyl; difluoromethylmethylamino ethyl; 4,5-dihydro- lH-imidazol-2-yl; dimethylaminocarbonyl; dimethylamino ethyl; (1,1- dioxidothiomorpholin-4-yl)ethyl; ethyl; ethylaminocarbonyl; ethylamino ethyl;
ethylammooxetanylmethyl; ethyl (oxetanyl)amino ethyl; hydrogen; 4-hydroxycyclohexyl; hydroxyethyl; hydroxyethylaminoethyl; hydroxyethyloxetanyl; hydroxymethylcarbonyl; hydroxymethyloxetanylmethyl; hydroxynonyl; hydroxypropyl; isoxazol-3-yl;
methoxyethyl; methoxyethylaminoethyl; methyl; methylaminocarbonylmethyl;
methylamino ethyl; methylcarbonyl; methylcarbonylaminoethyl;
methylcarbonylaminomethyloxetanylmethyl; methylcarbonylaminopropyl;
methylsulfmylethyl; 2-(S'-methylsulfonimidoyl)ethyl; methylsulfonyl; morpholin-4-ylethyl; morpholin-2-ylmethyl; 2-oxa-6-aza-spiro[3.4]oct-8-yl; oxetanyl; oxetanylaminoethyl; oxetanylaminopropyl; oxetanylmethyl; N-oxetanylpyrrolidin-3-yl; oxo-pyrrolidin-4- ylcarbonyl; phenylaminocarbonyl; phenylcarbonyl; phenylmethylaminooxetanylmethyl; piperazin-l-ylethyl; piperidin-2-ylcarbonyl; piperidin-3-ylcarbonyl; piperidin-4- ylcarbonyl; piperidine-3-yl; piperidine-4-yl; piperidin-l-ylethyl; piperidin-2-ylmethyl; pyrazin-2-ylcarbonyl; pyrazol-3-yl; pyridazin-3-ylcarbonyl; pyridine-2-ylmethylcarbonyl; pyridine-2-ylaminoethyl; pyridine-2-ylcarbonyl; pyridine-3-ylcarbonyl; pyrrolidin-3-yl, unsubstituted or 4-substituted by fluoro; pyrrolidin-4-yl, unsubstituted or 3-substituted by hydroxy or methoxy; pyrrolidin-2-ylmethyl; pyrrolidin-2-ylcarbonyl; tetrahydrofuran-3-yl;
Figure imgf000514_0001
wherein R 14 is hydrogen or methyl; R15 is hydroxy, methyl or amino; and R16 is methyl, trifluoromethyl,
R17 ^C- R18 hydroxymethyl, hydroxyethyl, aminomethyl, aminocarbonyl or carboxymethyl; R K19 , wherein R17 is hydrogen, methyl or hydroxymethyl; R18 is hydroxymethyl or methyl; R19 is
Figure imgf000514_0002
or amino;
R12 and R13, with the nitrogen atom to which they are attached, may form a pyrrolidinyl, piperazinyl, piperidinyl, morpholinyl, azetidinyl, diazepanyl or oxopyrrolidinyl ring; which may be unsubstituted, once or twice substituted by a group selected from fluoro, methyl, methoxy, gemdimethyl, amino, aminocarbonyl, hydroxy, oxetanylamino,
methylpiperazinyl and aminomethyl; R12 and R13, with the nitrogen atom to which they are attached may form a bridge ring or a spiral ring selected from 2-oxa-6-aza-spiro[3.4]octan-6-yl, 2-oxa-5,7-diazaspiro[3.4]octan- 6-one-5-yl, (4a5',7ai?)-hexahydropyrrolo[3,4-b][l,4]oxazin-6(2H)-yl, 4,5,6,6a-tetrahydro- 3aH-pyrrolo[3,4-d][l,3]oxazol-5-yl, 2-aza-bicyclo[2.1.1]hexan-2-yl or 3-aza- bicyclo[3.1.0]hexan-3-yl; which may be unsubstituted or further substituted by amino.
10. A compound according to any one of claims 1 to 9 or a pharmaceutically acceptable salt thereof, wherein
R1, R2, R3, R4, R5, R6, R7, R8, R9, and R10 are hydrogen;
Ais -C-R11, wherein R11 is Ci_6alkyl;
X is S(0)NH;
Y is -CH-;
12 13 12 13
Q is NR R , wherein one of R and R is hydrogen; and the other one is
amino(CH2)2-6;
R12 and R13, with the nitrogen atom to which they are attached, may form a pyrrolidinyl ring, which may be twice substituted by a group selected from amino and hydro xyl.
11. A compound according to claim 10 or a pharmaceutically acceptable salt thereof, wherein R1, R2, R3, R4, R5, R6, R7, R8, R9, and R10 are hydrogen;
A is -C-R11 , wherein R11 is methyl;
12 13 12 13
u is NR1ZR , wherein one of R and R is hydrogen; and the other one is amino ethyl;
R12 and R13, with the nitrogen atom to which they are attached, may form a pyrrolidinyl ring, which may be twice substituted by a group selected from amino and hydro xyl.
12. A compound according to any one of claims 1 to 11 or a pharmaceutically acceptable salt thereof, selected from
N-[(3-aminooxetan-3-yl)methyl]-2-(8-methoxy- 1 , 1 -dioxido-2,3-dihydro- 1 ,4-benzothiazepin- 4(5H)-yl)-6-methylquinolin-4-amine; N-[(3-aminooxetan-3-yl)methyl]-2-(8-fluoro- 1 , 1 -dioxido- 2,3-dihydro- 1 ,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-amine; N-[(3-aminooxetan-3- yl)methyl]-2-(7-fluoro- 1 , 1 -dioxido-2,3-dihydro- 1 ,4-benzothiazepin-4(5H)-yl)-6-methylquinolin- 4-amine; N-[(3-aminooxetan-3-yl)methyl]-2-(9-fluoro- 1 , l-dioxido-2,3-dihydro- 1 ,4- K^ + /iz-^ tn -iV6-methylquinolin-4-amine; N-[(3-aminooxetan-3-yl)methyl]-2-(7- methoxy- 1 , 1 -dioxido-2,3-dihydro- 1 ,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-amine; N- [(3-aminooxetan-3-yl)methyl]-2-(8-chloro- 1 , 1 -dioxido-2,3-dihydro- 1 ,4-benzothiazepin-4(5H)- yl)-6-methylquinolin-4-amine; N-[(3-aminooxetan-3-yl)methyl]-2-(7-methoxy- 1 , 1 -dioxido-2,3- dihydro- 1 ,4-benzothiazepin-4(5H)-yl)quinolin-4-amine; N-[(3-aminotetrahydrofuran-3- yl)methyl]-2-(l , 1 -dioxido-2,3-dihydro- 1 ,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-amine; N-[(3-aminooxetan-3-yl)methyl]-2-(l , 1 -dioxido-2,3-dihydro- 1 ,4-benzothiazepin-4(5H)-yl)-6- methylquinolin-4-amine; N-[(4-aminotetrahydro-2H-pyran-4-yl)methyl]-2-(l,l-dioxido-2,3- dihydro- 1 ,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-amine; N-[(3-aminooxetan-3- yl)methyl]-2-(8-methyl- 1 , 1 -dioxido-2,3-dihydro- 1 ,4-benzothiazepin-4(5H)-yl)quinolin-4-amine; N-[(3-aminooxetan-3-yl)methyl]-6-methyl-2-(8-methyl- 1 , 1 -dioxido-2,3-dihydro- 1 ,4- benzothiazepin-4(5H)-yl)quinolin-4-amine; 2-(l , 1 -dioxido-2,3-dihydro- 1 ,4-benzothiazepin- 4(5H)-yl)-6-methyl-N-(2-oxa-6-azaspiro[3.4]oct-8-yl)quinolin-4-amine; N-[2-(3-aminooxetan-3- yl)ethyl]-2-(l , 1 -dioxido-2,3-dihydro- 1 ,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-amine; N- [(3 -aminooxetan-3-yl)methyl]-6-methyl-2-(5 -methyl- 1 , 1 -dioxido-2,3-dihydro- 1 ,4- benzothiazepin-4(5H)-yl)quinolin-4-amine; N-[(3-aminooxetan-3-yl)methyl]-2-(8-methoxy- 1,1- dioxido-2,3-dihydro- 1 ,4-benzothiazepin-4(5H)-yl)quinolin-4-amine; N-[(3-aminooxetan-3- yl)methyl]-2-(l , 1 -dioxido-2,3-dihydro- 1 ,4-benzothiazepin-4(5H)-yl)- 1 ,6-naphthyridin-4-amine; N-[(l -aminocyclohexyl)methyl]-2-(l , 1 -dioxido-2,3-dihydro- 1 ,4-benzothiazepin-4(5H)-yl)-6- methylquinolin-4-amine; N-{[3-(aminomethyl)oxetan-3-yl]methyl}-2-(8-fluoro-l,l-dioxido-2,3- dihydro-l,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-amine; N-{[3-(benzylamino)oxetan-3- yljmethyl} -6-chloro-2-(7-fluoro- 1 , 1 -dioxido-2,3-dihydro- 1 ,4-benzothiazepin-4(5H)-yl)quinolin- 4-amine; N-[(3-aminooxetan-3-yl)methyl]-6-chloro-2-(7-fluoro- 1 , 1 -dioxido-2,3-dihydro- 1 ,4- benzothiazepin-4(5H)-yl)quinolin-4-amine; N-{[3-(aminomethyl)oxetan-3-yl]methyl}-2-(7- methoxy- 1 , 1 -dioxido-2,3-dihydro- 1 ,4-benzothiazepin-4(5H)-yl)quinolin-4-amine; N- {[3- (aminomethyl)oxetan-3-yl]methyl} -2-(7-methoxy- 1 , 1 -dioxido-2,3-dihydro- 1 ,4-benzothiazepin- 4(5H)-yl)-6-methylquinolin-4-amine; N- {[3-( {[2-(7-methoxy- 1 , 1 -dioxido-2,3-dihydro- 1 ,4- benzothiazepin-4(5H)-yl)-6-methylquino lin-4-yl] amino } methyl)oxetan-3 -yl]methyl}acetamide; N- {[3-(aminomethyl)oxetan-3-yl]methyl} -2-(8-methyl- 1 , 1 -dioxido-2,3-dihydro- 1 ,4- benzothiazepin-4(5H)-yl)quinolin-4-amine; N-{[3-(aminomethyl)oxetan-3-yl]methyl}-6-methyl- 2-(8-methyl- 1 , 1 -dioxido-2,3-dihydro- 1 ,4-benzothiazepin-4(5H)-yl)quinolin-4-amine; [3-( {[2- (1,1 -dioxido-2,3-dihydro- 1 ,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4- yl]amino}methyl)oxetan-3-yl]methanol; (2S)-3- {[2-(l , l-dioxido-2,3-dihydro-l ,4- benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl] amino} propane- 1,2-diol; (2i?)-3- {[2-(l, 1- dioxido-2,3-dihydro-l,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]amino}propane- diol; N- { [ 1 -(aminomethyl)-3 ,3-difluorocyclobutyl]methyl} -2-( 1 , 1 -dioxido-2,3-dihydro- 1 ,4- benzothiazepin-4(5H)-yl)-6-methylquino lin-4-amine; N- [(3 -aminooxetan-3 -yl)methyl] -6-chloro- 2-(8-methoxy- 1 , 1 -dioxido-2,3-dihydro- 1 ,4-benzothiazepin-4(5H)-yl)quinolin-4-amine; N- {[3- (aminomethyl)oxetan-3-yl]methyl} -6-chloro-2-(8-methoxy- 1 , 1 -dioxido-2,3-dihydro- 1 ,4- benzothiazepin-4(5H)-yl)quinolin-4-amine; trans-N-[2-(l , 1 -dioxido-2,3-dihydro- 1 ,4- benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]cyclohexane-l,2-diamine; N-[2-(l,l-dioxido-
2.3- dihydro-l,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]cyclohexane-l,3-dk
(3R)- 1 -[2-(l , l-dioxido-2,3-dihydro- 1 ,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]-4,4- dimethylpyrrolidin-3-ol; cz5-N-[2-(l,l-dioxido-2,3-dihydro-l,4-benzothiazepin-4(5H)-yl)-6- methylquinolin-4-yl]cyclohexane-l ,4-diamine; N-[2-(l , l-dioxido-2,3-dihydro-l ,4- benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]-2,2-difluoropropane- 1 ,3-diamine; N-[6-chloro- 2-(l,l-dioxido-2,3-dihydro-l,4-benzothiazepin-4(5H)-yl)quinolin-4-yl]-2,2-difluoropropane diamine; N-[2-(l,l-dioxido-2,3-dihydro-l,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]-2- fluoropropane- 1 ,3-diamine; N-[(3-aminooxetan-3-yl)methyl]-6-chloro-2-(l , 1 -dioxido-2,3- dihydro-l,4-benzothiazepin-4(5H)-yl)quinolin-4-amine; [4-{[(3-aminooxetan-3- yl)methyl] amino } -2-(l , 1 -dioxido-2,3-dihydro- 1 ,4-benzothiazepin-4(5H)-yl)quinolin-6- yljmethanol; N-[(3-aminooxetan-3-yl)methyl]-2-(l , 1 -dioxido-2,3-dihydro- 1 ,4-benzothiazepin- 4(5H)-yl)-7-fluoro-6-methylquinolin-4-amine; N-[(3-aminooxetan-3-yl)methyl]-2-(l,l-dioxido- 2,3-dihydro-l,4-benzothiazepin-4(5H)-yl)-5-fluoro-6-methylquinolin-4-amine; N~l— [6-chloro- 2-(l,l-dioxido-2,3-dihydro-l,4-benzothiazepin-4(5H)-yl)quinolin-4-yl]-2-methylpropane-l,2- diamine; 2-( 1 , 1 -dioxido-2,3-dihydro- 1 ,4-benzothiazepin-4(5H)-yl)-6-methyl-N-(tetrahydro-2H- pyran-4-yl)quinolin-4-amine; 2-(l , 1 -dioxido-2,3-dihydro- 1 ,4-benzothiazepin-4(5H)-yl)-6- methyl-N-[2-(piperazin- 1 -yl)ethyl]quinolin-4-amine; 2-(l , 1 -dioxido-2,3-dihydro- 1 ,4- benzothiazepin-4(5H)-yl)-6-methyl-N-(piperidin-4-ylmethyl)quinolin-4-amine; N-[2-(l,l- dioxido-2,3-dihydro- 1 ,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]heptane- 1 ,7-diamine; N-[2-(l , 1 -dioxido-2,3-dihydro- 1 ,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]-N'- methylethane- 1 ,2-diamine; N-[2-(l , 1 -dioxido-2,3-dihydro- 1 ,4-benzothiazepin-4(5H)-yl)-6- methylquinolin-4-yl]-N,N-dimethylethane- 1 ,2-diamine; 2-(l , 1 -dioxido-2,3-dihydro- 1 ,4- benzothiazepin-4(5H)-yl)-N,6-dimethylquinolin-4-amine trifluoroacetate; (3S,4S)-\-\2-(\,\- dioxido-2,3-dihydro-l,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]pyrrol
2-(l,l-dioxido-2,3-dihydro-l,4-benzothiazepin-4(5H)-yl)-6-methyl-N-(pyrrolidin-2- ylmethyl)quinolin-4-amine; 4-[4-(l,4-diazepan-l-yl)-6-methylquinolin-2-yl]-2,3,4,5-tetrahydro-
1.4- benzothiazepine 1 , 1 -dioxide; N-[2-(l , 1 -dioxido-2,3-dihydro- 1 ,4-benzothiazepin-4(5H)-yl)-6- methylquinolin-4-yl]-N'-ethylethane- 1 ,2-diamine; 2- {[2-(l , 1 -dioxido-2,3-dihydro- 1 ,4- benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl] amino }ethanol; 2-(l,l-dioxido-2,3-dihydro-l,4- benzothiazepin-4(5H)-yl)-6-methyl-N-(piperidin-4-yl)quinolin-4-amine; 2-(l,l-dioxido-2,3- dihydro- 1 ,4-benzothiazepin-4(5H)-yl)-6-methyl-N-(piperidin-3-yl)quinolin-4-amine; 2-(l , 1 - dioxido-2,3-dihydro-l,4-benzothiazepin-4(5H)-yl)-6-methyl-N-(piperidin-2-ylmethyl)qum^ 4-amine; 2-[(2- {[2-(l , 1 -dioxido-2,3-dihydro- 1 ,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4- yljamino} ethyl)amino]ethanol; N-[2-(l , l-dioxido-2,3-dihydro-l ,4-benzothiazepin-4(5H)-yl)-6- methylquinolin-4-yl]-2,2,3,3-tetrafluorobutane- 1 ,4-diamine; N-[2-(l , 1 -dioxido-2,3-dihydro- 1 ,4- benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]-N'-(2-methoxyethyl)ethane- 1 ,2-diamine; 1 -[2- (1,1 -dioxido-2,3-dihydro- 1 ,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]-3- methylpyrrolidin-3-ol; N-[6-chloro-2-(l,l-dioxido-2,3-dihydro-l,4-benzothiazepin-4(5H)- yl)quinolin-4-yl] ethane- 1 ,2-diamine; 2-(l , 1 -dioxido-2,3-dihydro- 1 ,4-benzothiazepin-4(5H)-yl)- 6-methyl-N-(oxetan-3 -yl)quino lin-4-amine; N- [(3 -aminooxetan-3 -yl)methyl] -2-( 1 , 1 -dioxido-2,3 - dihydro- 1 ,4-benzothiazepin-4(5H)-yl)quinolin-4-amine; 2-( 1 , 1 -dioxido-2,3-dihydro- 1 ,4- benzothiazepin-4(5H)-yl)-6-methyl-N- [( Ji?)-tetrahydrofuran-3 -yl] quino lin-4-amine; N- { [3 - (aminomethyl)oxetan-3-yl]methyl} -2-(l , 1 -dioxido-2,3-dihydro- 1 ,4-benzothiazepin-4(5H)-yl)-6- methylquinolin-4-amine; N-{[3-(aminomethyl)oxetan-3-yl]methyl}-6-chloro-2-(l,l-dioxido-2,3- dihydro-l,4-benzothiazepin-4(5H)-yl)quinolin-4-amine; N-{[3-(aminomethyl)oxetan-3- yljmethyl} -2-( 1 , 1 -dioxido-2,3-dihydro- 1 ,4-benzothiazepin-4(5H)-yl)quinolin-4-amine; 2-(l,l- dioxido-2,3-dihydro-l,4-benzothiazepin-4(5H)-yl)-6-m
amine; N-[(l-aminocyclobutyl)methyl]-2-(l,l-dioxido-2,3-dihydro-l,4-benzothiazepin-4(5H)- yl)-6-methylquinolin-4-amine; N-[2-(l,l-dioxido-2,3-dihydro-l,4-benzothiazepin-4(5H)-yl)-6- methylquinolin-4-yl]pentane- 1 ,5-diamine; N-[2-(l , 1 -dioxido-2,3-dihydro- 1 ,4-benzothiazepin- 4(5H)-yl)-6-methylquinolin-4-yl]hexane- 1 ,6-diamine; N-[2-(l , 1 -dioxido-2,3-dihydro- 1 ,4- benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]- 1 ,1,1 -trifluoromethanesulfonamide
hydrochloride; N-[2-(l , 1 -dioxido-2,3-dihydro- 1 ,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4- yl]pyridazine-3-carboxamide; N-[2-(l,l-dioxido-2,3-dihydro-l,4-benzothiazepin-4(5H)-yl)-6- methylquinolin-4-yl]benzamide; N-[2-(l,l-dioxido-2,3-dihydro-l,4-benzothiazepin-4(5H)-yl)-6- methylquinolin-4-yl]acetamide; N-[2-(l,l-dioxido-2,3-dihydro-l,4-benzothiazepin-4(5H)-yl)-6- methylquinolin-4-yl]piperidine-3-carboxamide; N-[2-(l,l-dioxido-2,3-dihydro-l,4- benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]piperidine-4-carboxamide; 3-[2-(l , 1-dioxido- 2,3-dihydro- 1 ,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]- 1 , 1 -dimethylurea; 2-(l,l- dioxido-2,3-dihydro-l,4-benzothiazepin-4(5H)-yl)-6-methyl-N-(l,2-oxazol-3-yl)quinolm^ amine; N- {[3-(aminomethyl)oxetan-3-yl]methyl}-2-(l , l-dioxido-2,3-dihydro-l ,4- benzothiazepin-4(5H)-yl)-6-(~2~H_3_)methylquinolin-4-amine; N- [(3 -aminooxetan-3 - yl)methyl]-6-chloro-2-(2,3-dihydro- 1 ,4-benzothiazepin-4(5H)-yl)quinolin-4-amine; N-[6-chloro- 2-(2,3-dihydro- 1 ,4-benzothiazepin-4(5H)-yl)quinolin-4-yl]ethane- 1 ,2-diamine; N-[(3- aminooxetan-3-yl)methyl]-2-(2,3-dihydro-l,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4- amine; 1 -[2-(2,3-dihydro- 1 ,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]pyrrolidin-3- amine; N-[2-(2,3-dihydro- 1 ,4-benzothiazepin-4(5H)-yl)-6-methylquinazolin-4-yl]-2,2- difluoropropane- 1 ,3-diamine; 2-(l , 1 -dioxido-2,3-dihydro- 1 ,4-benzothiazepin-4(5H)-yl)-N-[2- (l,l-dioxidothiomorpholin-4-yl)ethyl]-6-methylquinolin-4-amine; N-[2-(2-aminoethoxy)ethyl]- 2-(l,l-dioxido-2,3-dihydro-l,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-amine; N~l— [2- (1,1 -dioxido-2,3-dihydro- 1 ,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]-2- methylpropane- 1 ,2-diamine; N~ 1 ~-[2-( 1 , 1 -dioxido-2,3-dihydro- 1 ,4-benzothiazepin-4(5H)- yl)quinolin-4-yl]-2-methylpropane-l,2-diamine; N~l~- [2-(l,l-dioxido-2,3-dihydro-l,4- benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]propane- 1 ,2-diamine; 4-[6-methyl-4-(4- methylpiperazin- 1 -yl)quinolin-2-yl]-2,3,4,5-tetrahydro- 1 ,4-benzothiazepine 1 , 1 -dioxide; 1 - {[2- ( 1 , 1 -dioxido-2,3-dihydro- 1 ,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl] amino }propan-2- ol; (25)-N~l~-[2-(l,l-dioxido-2,3-dihydro-l,4^
yl]propane- 1 ,2-diamine; (2R)-N~ 1 ~-[2-( 1 , 1 -dioxido-2,3-dihydro- 1 ,4-benzothiazepin-4(5H)-yl)- 6-methylquinolin-4-yl]propane- 1 ,2-diamine; N-[(3-aminooxetan-3-yl)methyl]-2-(l , 1 -dioxido- 2,3-dihydro- 1 ,4-benzothiazepin-4(5H)-yl)-7,8-difluoro-6-methylquinolin-4-amine; N-(2,2- difluoroethyl)-N-[2-(l,l-dioxido-2,3-dihydro-l,4-benzothiazepin-4(5H)-yl)-6-meth^
yljethane- 1 ,2-diamine; 3- { [2-( 1 , 1 -dioxido-2,3-dihydro- 1 ,4-benzothiazepin-4(5H)-yl)-6- methylquino lin-4-yl] amino } oxetan-3 -ethano 1; N- { [3 -(amino methyl)thietan-3 -yljmethyl} -2-( 1 , 1 - dioxido-2,3-dihydro-l,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-amine; N-{[3-
(aminomethyl)- 1 , 1 -dioxidothietan-3-yl]methyl} -2-( 1 , 1 -dioxido-2,3-dihydro- 1 ,4-benzothiazepin- 4(5H)-yl)-6-methylquinolin-4-amine; N-(4,5-dihydro-lH-imidazol-2-yl)-2-(l,l-dioxido-2,3- dihydro- 1 ,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-amine; trans-4- { [2-( 1 , 1 -dioxido-2,3- dihydro-l,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]amino}cyclohexanol; (2S)-2-{[2- (1,1 -dioxido-2,3-dihydro- 1 ,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl] amino }propan- 1 - ol; tran5-l-[2-(l,l-dioxido-2,3-dihydro-l,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]-4- methoxypyrrolidin-3-amine; 2-(l , 1 -dioxido-2,3-dihydro- 1 ,4-benzothiazepin+D 154-4(5H)-yl)-N- [tra/75-4-methoxypyrrolidin-3-yl]-6-methylquinolin-4-amine; 4- {4-[(4aS, 7aR)- hexahydropyrrolo [3 ,4-b] [ 1 ,4]oxazin-6(2H)-yl]-6-methylquinolin-2-yl} -2,3 ,4,5-tetrahydro- 1 ,4- benzothiazepine 1,1-dioxide; (Ji?,4i?)-l-[2-(l,l-dioxido-2,3-dihydro-l,4-benzothiazepin-4(5H)- yl)-6-methylquinolin-4-yl]-4-(4-methylpiperazin- 1 -yl)pyrrolidin-3-ol; N- {2-[(2- aminoethyl)sulfanyl]ethyl} -2-(l , 1 -dioxido-2,3-dihydro- 1 ,4-benzothiazepin-4(5H)-yl)-6- methylquinolin-4-amine; 1 - { 1 -[2-(l , 1 -dioxido-2,3-dihydro- 1 ,4-benzothiazepin-4(5H)-yl)-6- methylquinolin-4-yl]piperidin-4-yl}methanamine; 2-{[2-(8-methoxy-l,l-dioxido-2,3-dihydro- 1 ,4-benzothiazepin-4(5H)-yl)quino lin-4-yl] amino} ethano 1; N-[2-(l , l-dioxido-2,3-dihydro-l ,4- benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]propane- 1 ,3-diamine; 4-[6-methyl-4- (morpholin-4-yl)quino lin-2-yl]-2, 3,4, 5-tetrahydro-l ,4-benzothiazepine 1 , 1-dioxide; 3- {[2-(l , 1- dioxido-2,3-dihydro-l,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]amino}propan-l-ol; 2- (1,1 -dioxido-2,3-dihydro- 1 ,4-benzothiazepin-4(5H)-yl)-6-methyl-N-[2-(piperidin- 1 - yl)ethyl]quinolin-4-amine; 1 -amino-3- {[2-(l , 1 -dioxido-2,3-dihydro- 1 ,4-benzothiazepin-4(5H)- yl)-6-methylquinolin-4-yl]amino}propan-2-ol; N-[2-(l,l-dioxido-2,3-dihydro-l,4- benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]glycine; N-[2-(l , 1 -dioxido-2,3-dihydro- 1 ,4- benzothiazepin-4(5H)-yl)-6-fluoroquinolin-4-yl]ethane- 1 ,2-diamine; N-[2-(l , 1 -dioxido-2,3- dihydro- 1 ,4-benzothiazepin-4(5H)-yl)-6-ethylquinolin-4-yl]ethane- 1 ,2-diamine; N-[7-chloro-2- (1,1 -dioxido-2,3-dihydro- 1 ,4-benzothiazepin-4(5H)-yl)quinolin-4-yl]propane- 1 ,3-diamine; N-[8- chloro-2-(l , 1 -dioxido-2,3-dihydro- 1 ,4-benzothiazepin-4(5H)-yl)quinolin-4-yl]propane- 1 ,3- diamine; N-[5-chloro-2-(l,l-dioxido-2,3-dihydro-l,4-benzothiazepin-4(5H)-yl)quinolin-4- yl]propane- 1 ,3-diamine; N-[2-(l , 1 -dioxido-2,3-dihydro- 1 ,4-benzothiazepin-4(5H)-yl)-6- methylquinolin-4-yl]-2,2-dimethylpropane-l,3-diamine; N-[2-(l,l-dioxido-2,3-dihydro-l,4- benzothiazepin-4(5H)-yl)quinolin-4-yl]ethane-l,2-diamine; N-[2-(l,l-dioxido-2,3-dihydro-l,4- benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]ethane-l,2-diamine; N~2— [2-(l,l-dioxido-2,3- dihydro- 1 ,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]-2-methylpropane- 1 ,2-diamine; N~2~-[2-(l,l-dioxido-2,3-dihydro-l,4-benzothia^
yl]propane- 1 ,2-diamine; N-[2-( 1 , 1 -dioxido-2,3-dihydro- 1 ,4-benzothiazepin-4(5H)-yl)-6- methylquinolin-4-yl]butane-l,4-diamine; N-[2-(l,l-dioxido-2,3-dihydro-l,4-benzothiazepin- 4(5H)-yl)-6-nitroquinolin-4-yl]ethane-l,2-diamine; N-[2-(l,l-dioxido-2,3-dihydro-l,4- benzothiazepin-4(5H)-yl)-5-fluoro-6-methylquinolin-4-yl]ethane-l,2-diamine; 2-{[2-(l,l- dioxido-2,3-dihydro- 1 ,4-benzothiazepin-4(5H)-yl)-5-fluoro-6-methylquinolin-4- yljamino } ethanol; 2- { [2-( 1 , 1 -dioxido-2,3-dihydro- 1 ,4-benzothiazepin-4(5H)-yl)-7-fluoro-6- methylquinolin-4-yl]amino}ethanol; N-[2-(l,l-dioxido-2,3-dihydro-l,4-benzothiazepin-4(5H)- yl)-7-fluoro-6-methylquinolin-4-yl]ethane-l,2-diamine; N-[2-(l,l-dioxido-2,3-dihydro-l,4- benzothiazepin-4(5H)-yl)-7,8-difluoro-6-methylquinolin-4-yl]ethane-l,2-diamine; 2-(l,l- dioxido-2,3-dihydro- 1 ,4-benzothiazepin-4(5H)-yl)-N-(2-methoxyethyl)-6-methylquinolin-4- amine; l-[2-(l,l-dioxido-2,3-dihydro-l,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4- yl]piperidin-4-amine; 1 -[2-(l , 1 -dioxido-2,3-dihydro- 1 ,4-benzothiazepin-4(5H)-yl)- 1 ,6- naphthyridin-4-yl]pyrrolidin-3-amine; N-[6-(difluoromethyl)-2-(l , 1 -dioxido-2,3-dihydro- 1 ,4- benzothiazepin-4(5H)-yl)quinolin-4-yl]propane- 1 ,3-diamine; 6-chloro-2-(l , 1 -dioxido-2,3- dihydro- 1 ,4-benzothiazepin-4(5H)-yl)-N-ethylquinolin-4-amine; 2- { [6-chloro-2-( 1 , 1 -dioxido-
2.3- dihydro-l,4-benzothiazepin-4(5H)-yl)quinolin-4-yl]amino} ethanol; N-[6-chloro-2-(l,l- dioxido-2,3-dihydro- 1 ,4-benzothiazepin-4(5H)-yl)quinolin-4-yl]-N'-methylethane- 1 ,2-diamine; N-[2-(l , 1 -dioxido-2,3-dihydro- 1 ,4-benzothiazepin-4(5H)-yl)-6-(methylsulfanyl)quinolin-4- yl]propane- 1 ,3-diamine; N-[6-bromo-2-(l , 1 -dioxido-2,3-dihydro- 1 ,4-benzothiazepin-4(5H)- yl)quinolin-4-yl]propane-l,3-diamine; {4-[(2-aminoethyl)amino]-2-(l,l-dioxido-2,3-dihydro-
1.4- benzothiazepin-4(5H)-yl)quinolin-6-yl} methanol; 2-{[2-(l,l-dioxido-2,3-dihydro-l,4- benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]amino}propane-l,3-diol; 2,2'-{[2-(l,l-dioxido- 2,3 -dihydro- 1 ,4-benzothiazepin-4(5H)-yl)-6-methylquino lin-4-yl] imino } diethano l; 4-{[2-(l,l- dioxido-2,3-dihydro-l,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]amino}-3- hydroxybutanoic acid; l-amino-3-{[2-(l,l-dioxido-2,3-dihydro-l,4-benzothiazepin-4(5H)-yl)-6- methylquinolin-4-yl] amino } -2-methylpropan-2-ol; 2-( 1 , 1 -dioxido-2,3-dihydro- 1 ,4- benzothiazepin-4(5H)-yl)-6-methyl-N-[2-(morpholin-4-yl)ethyl]quinolin-4-amine; 2-{[2-(l,l- dioxido-2,3-dihydro- 1 ,4-benzothiazepin-4(5H)-yl)- 1 ,6-naphthyridin-4-yl]amino} ethanol; N-[2- (1,1 -dioxido-2,3-dihydro- 1 ,4-benzothiazepin-4(5H)-yl)-8-methylquinolin-4-yl]nonane- 1 ,9- diamine; N-[2-(l,l-dioxido-2,3-dihydro-l,4-benzothiazepin-4(5H)-yl)-8-methylquinolin-4- yl]decane- 1 , 10-diamine; N-[2-(l , 1 -dioxido-2,3-dihydro- 1 ,4-benzothiazepin-4(5H)-yl)-6- methylquinolin-4-yl]octane- 1 ,8-diamine; 9- {[2-(l , 1 -dioxido-2,3-dihydro- 1 ,4-benzothiazepin- 4(5H)-yl)-6-methylquinolin-4-yl]amino}nonan-l-ol; N-[2-(l,l-dioxido-2,3-dihydro-l,4- benzothiazepin-4(5H)-yl)-8-methylquinolin-4-yl]octane- 1 ,8-diamine; czs-4-amino- 1 -[2-(l , 1 - dioxido-2,3-dihydro- 1 ,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]pyrrolidin-3-ol; N-[2- (1,1 -dioxido-2,3-dihydro- 1 ,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]-L-alanine; N-[2- (1,1 -dioxido-2,3-dihydro- 1 ,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]-beta-alanine; N- [2-(l , 1 -dioxido-2,3-dihydro- 1 ,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]benzene- 1 ,3- diamine; N-[2-(l,l-dioxido-2,3-dihydro-l,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4- yljbenzene- 1 ,4-diamine; (3S)- 1 -[2-(l , 1 -dioxido-2,3-dihydro- 1 ,4-benzothiazepin-4(5H)-yl)-6- methylquinolin-4-yl]pyrrolidin-3-ol; (3R)- 1 -[2-(l , 1 -dioxido-2,3-dihydro- 1 ,4-benzothiazepin- 4(5H)-yl)-6-methylquinolin-4-yl]pyrrolidin-3-ol; trans-N-[2-{\ , 1 -dioxido-2,3-dihydro- 1 ,4- benzothiazepin-4(5H)-yl)-6-methylquino lin-4-yl] cyclopentane- 1 ,2-diamine; 1 - [2-( 1 , 1 -dioxido- 2,3-dihydro- 1 ,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]piperidin-3-amine; 2-(l , 1 - dioxido-2,3-dihydro- 1 ,4-benzothiazepin-4(5H)-yl)-N,N,6-trimethylquinolin-4-amine; N-[2-(l , 1 - dioxido-2,3-dihydro-l,4-benzothiazepin-4(5H)-yl)-6-(trifluoromethoxy)quinolin^
1.3- diamine; N-[2-(l , 1 -dioxido-2,3-dihydro- 1 ,4-benzothiazepin-4(5H)-yl)-6- (trifluoromethyl)quinolin-4-yl]propane- 1 ,3-diamine; N-[6-(difluoromethoxy)-2-(l , 1 -dioxido-2,3- dihydro- 1 ,4-benzothiazepin-4(5H)-yl)quinolin-4-yl]propane- 1 ,3-diamine; N-[2-(l , 1 -dioxido-2,3- dihydro- 1 ,4-benzothiazepin-4(5H)-yl)-6-methoxyquinolin-4-yl]propane- 1 ,3-diamine; N-[2-(l , 1 - dioxido-2,3-dihydro- 1 ,4-benzothiazepin-4(5H)-yl)-8-methylquinolin-4-yl]propane- 1 ,3-diamine; N-[2-(l , 1 -dioxido-2,3-dihydro- 1 ,4-benzothiazepin-4(5H)-yl)-5-methylquinolin-4-yl]propane- 1 ,3-diamine; N-[2-(l , 1 -dioxido-2,3-dihydro- 1 ,4-benzothiazepin-4(5H)-yl)-7-methylquinolin-4- yl]propane- 1 ,3-diamine; N- {[3-(aminomethyl)oxetan-3-yl]methyl} -2-(l , 1 -dioxido-2,3-dihydro-
1.4- benzothiazepin-4(5H)-yl)-6-fluoroquinolin-4-amine; N-[(3-aminooxetan-3-yl)methyl]-6- methyl-2-(l-oxido-2,3-dihydro-l,4-benzothiazepin-4(5H)-yl)quinolin-4-amine; (+)-N-[(3- aminooxetan-3-yl)methyl]-6-methyl-2-[ 1 -oxido-2,3-dihydro- 1 ,4-benzothiazepin-4(5H)- yl]quinolin-4-amine; (-)-N-[(3-aminooxetan-3-yl)methyl]-6-methyl-2-[ 1 -oxido-2,3-dihydro- 1 ,4- benzothiazepin-4(5H)-yl] quino lin-4-amine; N- [(3 -aminooxetan-3 -yl)methyl] -6-chloro-2-( 1 - oxido-2,3-dihydro- 1 ,4-benzothiazepin-4(5H)-yl)quinolin-4-amine; 2,2-difluoro-N-[6-methyl-2- (1 -oxido-2,3-dihydro- 1 ,4-benzothiazepin-4(5H)-yl)quinolin-4-yl]propane- 1 ,3-diamine; N-[6- chloro-2-(l-oxido-2,3-dihydro-l,4-benzothiazepin-4(5H)-yl)quinolin-4-yl]-2,2-difluoropro 1,3-diamine; N-[6-chloro-2-(l-oxido-2,3-dihydro-l,4-benzothiazepin-4(5H)-yl)quinolin-4- yl]ethane-l,2-diamine; N-{[3-(aminomethyl)oxetan-3-yl]methyl}-6-methyl-2-(l-oxido-2,3- dihydro-l,4-benzothiazepin-4(5H)-yl)quinolin-4-amine; N-{[3-(aminomethyl)oxetan-3- yl]methyl}-6-chloro-2-(l-oxido-2,3-dihydro-l,4-benzothiazepin-4(5H)-yl)quinolin-4-amine; N- [6-methyl-2-(l -oxido-2,3-dihydro- 1 ,4-benzothiazepin-4(5H)-yl)quinolin-4-yl] ethane- 1 ,2- diamine; 2-{[6-methyl-2-(l-oxido-2,3-dihydro-l,4-benzothiazepin-4(5H)-yl)quinolin-4- yl] amino }ethanol; tra/75-4-amino-l-[6-methyl-2-(l-oxido-2,3-dihydro-l,4-benzothiazepin- 4(5H)-yl)quinolin-4-yl]pyrrolidin-3-ol; (7R,JS, S)-3-[2-(1 -dioxido-2,3-dihydro-l,4- benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]-3-azabicyclo[3.1.0]hexan-6-amine; trans-4- amino- 1 -[2-( 1 , 1 -dioxido-2,3-dihydro- 1 ,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4- yl]pyrrolidin-3-ol; l-[6-methyl-2-(l-oxido-2,3-dihydro-l,4-benzothiazepin-4(5H)-yl)quinolin-4- yl]pyrrolidin-3-amine; tran5-l-[6-chloro-2-(l,l-dioxido-2,3-dihydro-l,4-benzothiazepin-4(5H)- yl)quinolin-4-yl]-4-fluoropyrrolidin-3-amine; trans-4-ammo- 1 -[6-chloro-2-(l , 1 -dioxido-2,3- dihydro- 1 ,4-benzothiazepin-4(5H)-yl)quinolin-4-yl]pyrrolidin-3-ol; trans- 1 -[6-chloro-2-(l - oxido-2,3-dihydro- 1 ,4-benzothiazepin-4(5H)-yl)quinolin-4-yl]-4-fluoropyrrolidin-3-amine; 2-[2- (1,1 -dioxido-2,3-dihydro- 1 ,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]-2- azabicyclo[2.1.1 ]hexan-5-amine; 2-(8-methoxy- 1 , 1 -dioxido-2,3-dihydro- 1 ,4-benzothiazepin- 4(5H)-yl)-6-methylquinolin-4-amine; 2-(7-methoxy- 1 , 1 -dioxido-2,3-dihydro- 1 ,4- benzothiazepin-4(5H)-yl)-6-methylquinolin-4-amine; N-[2-(l-aminocyclopropyl)ethyl]-2-(l,l- dioxido-2,3-dihydro- 1 ,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-amine; 2-(l , 1 -dioxido-
2.3- dihydro-l,4-benzothiazepin-4(5H)-yl)-6-methyl-N-(morpholin-2-ylm
N-[2-(l , 1 -dioxido-2,3-dihydro- 1 ,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]-N- methylethane- 1 ,2-diamine; N-(azetidin-2-ylmethyl)-2-( 1 , 1 -dioxido-2,3-dihydro- 1 ,4- benzothiazepin-4(5H)-yl)-6-methylquinolin-4-amine; 2-(l , 1 -dioxido-2,3-dihydro- 1 ,4- benzothiazepin-4(5H)-yl)-6-methyl-N-(pyrrolidin-3-yl)quinolin-4-amine; N-[(l- aminocyclopropyl)methyl]-2-(l , 1 -dioxido-2,3-dihydro- 1 ,4-benzothiazepin-4(5H)-yl)-6- methylquinolin-4-amine; N-(azetidin-3-yl)-6-chloro-2-(l , 1 -dioxido-2,3-dihydro- 1 ,4- benzothiazepin-4(5H)-yl)quinolin-4-amine; 6-[2-(l , 1 -dioxido-2,3-dihydro- 1 ,4-benzothiazepin- 4(5H)-yl)-6-methylquinolin-4-yl]-2-oxa-6-azaspiro[3.4]octan-8-amine; tra/?5-4-amino-l-[2-(l,l- dioxido-2,3-dihydro- 1 ,4-benzothiazepin-4(5H)-yl)- 1 ,6-naphthyridin-4-yl]pyrrolidin-3-ol; 1 -[2- (1,1 -dioxido-2,3-dihydro- 1 ,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]pyrrolidin-3- amine; N-(azetidin-3-yl)-2-(l , 1 -dioxido-2,3-dihydro- 1 ,4-benzothiazepin-4(5H)-yl)-6- methylquinolin-4-amine; 1 -[2-(l , 1 -dioxido-2,3-dihydro- 1 ,4-benzothiazepin-4(5H)-yl)-6- methylquinolin-4-yl]azetidin-3-amine; N-[2-(l,l-dioxido-2,3-dihydro-l,4-benzothiazepin-4(5H)- yl)-6-methylquinolin-4-yl]prolinamide; 2-(l , 1 -dioxido-2,3-dihydro- 1 ,4-benzothiazepin-4(5H)- yl)-N-(tran5-4-fluoropyrrolidin-3-yl)-6-methylquinolin-4-amine; trans-4- { [2-( 1 , 1 -dioxido-2,3- dihydro- 1 ,4-benzothiazepin-4(5H)-yl)quino lin-4-yl] amino } pyrro lidin-3 -o 1; trans-4- { [2-( 1 , 1 - dioxido-2,3-dihydro- 1 ,4-benzothiazepin-4(5H^
cz'5-4-{[2-(l,l-dioxido-2,3-dihydro-l,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4- yl] amino} pyrro lidin-3 -ol; N-[tra/75-4-fluoropyrrolidin-3-yl]-6-methyl-2-(l-oxido-2,3-dihydro-
1.4- benzothiazepin-4(5H)-yl)quinolin-4-amine; 4-[(3-aminopropyl)amino]-2-(l,l-dioxido-2,3- dihydro- 1 ,4-benzothiazepin-4(5H)-yl)quinolin-6-ol; 2-( {4-[(3-aminopropyl)amino]-2-(l , 1 - dioxido-2,3-dihydro-l,4-benzothiazepin-4(5H)-yl)quinolin-6-yl}oxy)ethanol; N-[2-(l,l-dioxido- 2,3-dihydro- 1 ,4-benzothiazepin-4(5H)-yl)-6-(2-methoxyethoxy)quinolin-4-yl]propane- 1,3- diamine; N-[2-(l,l-dioxido-2,3-dihydro-l,4-benzothiazepin-4(5H)-yl)-6-(pyridin-2- yloxy)quinolin-4-yl]propane- 1 ,3-diamine; 3- {[2-(l , 1 -dioxido-2,3-dihydro- 1 ,4-benzothiazepin- 4(5H)-yl)-6-methylquinolin-4-yl] amino} propane- 1 ,2-diol; 3-{[6-chloro-2-(l,l-dioxido-2,3- dihydro- 1 ,4-benzothiazepin-4(5H)-yl)quino lin-4-yl] amino } ropane- 1 ,2-dio 1; 3 - { [2-(8-chloro- 1 , 1 -dioxido-2,3-dihydro- 1 ,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]amino}propane- 1 ,2-dio 1; 3-{[6-methyl-2-(l-oxido-2,3-dihydro-l,4-benzothiazepin-4(5H)-yl)quinolin-4- yl] amino} propane- 1 ,2-dio 1; 3- {[6-methyl-2-(5 -methyl- 1 , 1 -dioxido-2,3-dihydro- 1 ,4- benzothiazepin-4(5H)-yl)quino lin-4-yl] amino } propane- 1 ,2-dio 1; N- [(3 -aminooxetan-3 - yl)methyl]-6-methyl-2-[7-(morpholin-4-yl)- 1 , 1 -dioxido-2,3-dihydro- 1 ,4-benzothiazepin-4(5H)- yl]quinolin-4-amine; N- [(3 -aminooxetan-3 -yl)methyl] -2- {1,1 -dioxido-7-[4-(propan-2- yl)piperazin- 1 -yl]-2,3-dihydro- 1 ,4-benzothiazepin-4(5H)-yl} -6-methylquinolin-4-amine; 3- {[4- (4-aminoquinolin-2-yl)- 1 , 1 -dioxido-2,3,4,5-tetrahydro- 1 ,4-benzothiazepin-8-yl]oxy}propan- 1 - ol; N- [(3 -aminooxetan-3 -yl)methyl] -2-( 1 , 1 -dioxido-8-phenoxy-2,3-dihydro- 1 ,4-benzothiazepin- 4(5H)-yl)-6-methylquinolin-4-amine; N~3— [2-(l , 1 -dioxido-2,3-dihydro- 1 ,4-benzothiazepin- 4(5H)-yl)-6-methylquinolin-4-yl]-beta-alaninamide; 3-{[2-(l,l-dioxido-2,3-dihydro-l,4- benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl] amino } butanamide; 3- { [2-( 1 , 1 -dioxido-2,3- dihydro-l,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]amino}-2-methylpropanamide; N~2~-[2-(l,l-dioxido-2,3-dihydro-l,4-benzothk^
alaninamide; N~2— [2-(l , 1 -dioxido-2,3-dihydro- 1 ,4-benzothiazepin-4(5H)-yl)-6-methylquinolin- 4-yl]glycinamide; N~2~- [2-(l , 1 -dioxido-2,3-dihydro- 1 ,4-benzothiazepin-4(5H)-yl)-6- methylquinolin-4-yl]-N-methylglycinamide; (25)-2-amino-3-{[2-(l,l-dioxido-2,3-dihydro-l,4- benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]amino}propan-l-ol; (2i?)-2-amino-3-{[2-(l,l- dioxido-2,3-dihydro-l,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]amino}prop
N-[(2-amino-4,5-dihydro- 1 ,3-oxazol-5-yl)methyl]-2-(l , l-dioxido-2,3-dihydro- 1 ,4- benzothiazepin-4(5H)-yl)-6-methylquinolin-4-amine; N-[(2-amino-5-methyl-4,5-dihydro- 1,3- oxazol-5-yl)methyl]-2-(l , 1 -dioxido-2,3-dihydro- 1 ,4-benzothiazepin-4(5H)-yl)-6-methylquinolin- 4-amine; N- {[(4i?)-2-amino-4,5-dihydro- 1 ,3-oxazol-4-yl]methyl} -2-(l , 1 -dioxido-2,3-dihydro- l,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-amine; N-{[(45)-2-amino-4,5-dihydro-l,3- oxazol-4-yl]methyl} -2-( 1 , 1 -dioxido-2,3-dihydro- 1 ,4-benzothiazepin-4(5H)-yl)-6- methylquinolin-4-amine; cz5-5-[2-(l,l-dioxido-2,3-dihydro-l,4-benzothiazepin-4(5H)-yl)-6- methylquinolin-4-yl]-4,5,6,6a-tetrahydro-3aH-pyrrolo[3,4-d][l,3]oxazol-2-amine; 2-(l,l- dioxido-2,3-dihydro- 1 ,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-amine; N-[2-(l , 1 - dioxido-2,3-dihydro- 1 ,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]glycinamide; N-[2- (1,1 -dioxido-2,3-dihydro- 1 ,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]-2- methylalaninamide; N-[2-(l , 1 -dioxido-2,3-dihydro- 1 ,4-benzothiazepin-4(5H)-yl)-6- methylquinolin-4-yl]alaninamide; 2-amino-N-[2-(l,l-dioxido-2,3-dihydro-l,4-benzothiazepin- 4(5H)-yl)-6-methylquinolin-4-yl]butanamide; N-[2-(l,l-dioxido-2,3-dihydro-l,4- benzothiazepin-4(5H)-yl)-6-methylquino lin-4-yl] -2-methoxy-2-methylpropanamide; N~ 1— [2- (1,1 -dioxido-2,3-dihydro- 1 ,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]-4,4,4- trifluorobutane- 1 ,3-diamine; N-[2-(l , 1 -dioxido-2,3-dihydro- 1 ,4-benzothiazepin-4(5H)-yl)-6- methylquinolin-4-yl]-beta-alaninamide; 2-(l , 1 -dioxido-2,3-dihydro- 1 ,4-benzothiazepin-4(5H)- yl)-N-{[3-(ethylamino)oxetan-3-yl]methyl}-6-methylquinolin-4-amine; 2-(l,l-dioxido-2,3- dihydro- 1 ,4-benzothiazepin-4(5H)-yl)-6-methyl-N-[ 1 -(oxetan-3-yl)pyrrolidin-3-yi]quinolin-4- amine; N-[2-(l , 1 -dioxido-2,3-dihydro- 1 ,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]-N- ethyl-N-(oxetan-3-yl)ethane- 1 ,2-diamine; N-[2-(l , 1 -dioxido-2,3-dihydro- 1 ,4-benzothiazepin- 4(5H)-yl)-6-methylquinolin-4-yl]-N'-(oxetan-3-yl)propane- 1 ,3-diamine; 1 -[2-(l , 1 -dioxido-2,3- dihydro-l,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]-N-(oxetan-3-yl)pyrrolidm amine; N-[2-(l , 1 -dioxido-2,3-dihydro- 1 ,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]-N'- (oxetan-3-yl)ethane-l,2-diamine; N-[2-(l,l-dioxido-2,3-dihydro-l,4-benzothiazepin-4(5H)-yl)- 6-methylquinolin-4-yl]-N'-(pyridin-2-yl)ethane-l,2-diamine; (4i?)-l-[2-(l,l-dioxido-2,3-dihydro- l,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]-4-hydroxypyrrolidin-2-one; N-[2-(l,l- dioxido-2,3-dihydro-l,4-berizothiazepin-4(5H)-^^
carboxamide; 2-( 1 , 1 -dioxido-2,3-dihydro- 1 ,4-benzothiazepin-4(5H)-yl)-6-methyl-N-( 1H- pyrazol-3-yl)quinolin-4-amine; N-[2-(l,l-dioxido-2,3-dihydro-l,4-benzothiazepin-4(5H)-yl)-6- methylquinolin-4-yl]pyridine-3-carboxamide; N-[2-(l,l-dioxido-2,3-dihydro-l,4- benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]piperidine-2-carboxamide; N-[2-(l,l-dioxido- 2,3-dihydro- 1 ,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]-2-(pyridin-2-yl)acetamide; N- [2-(l , 1 -dioxido-2,3-dihydro- 1 ,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4- yljmethanesulfonamide trifluoroacetate; N-[2-(l , l-dioxido-2,3-dihydro-l ,4-benzothiazepin- 4(5H)-yl)-6-methylquinolin-4-yl]pyrazine-2-carboxamide; N-[2-(l , 1 -dioxido-2,3-dihydro- 1 ,4- benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]-2-hydroxyacetamide; N-[2-(l , l-dioxido-2,3- dihydro- 1 ,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]pyridine-2-carboxamide; N-[2- (1,1 -dioxido-2,3-dihydro- 1 ,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl] azetidine-2- carboxamide; l-[2-(l,l-dioxido-2,3-dihydro-l,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4- yl]-3-phenylurea; 1 -[2-(l , 1 -dioxido-2,3-dihydro- 1 ,4-benzothiazepin-4(5H)-yl)-6- methylquinolin-4-yl]-3-ethylurea; N-[6-cyclopropyl-2-(l , 1 -dioxido-2,3-dihydro- 1 ,4- benzothiazepin-4(5H)-yl)quino lin-4-yl]propane- 1 ,3-diamine; 4- [(3 -aminopropyl)amino] -2-( 1,1- dioxido-2,3-dihydro- 1 ,4-benzothiazepin-4(5H)-yl)quinoline-6-carbonitrile; N-[2-(l , 1 -dioxido- 2,3-dihydro- 1 ,4-benzothiazepin-4(5H)-yl)-6-ethenylquinolin-4-yl]propane- 1 ,3-diamine; N-[2- (1,1 -dioxido-2,3-dihydro- 1 ,4-benzothiazepin-4(5H)-yl)-6-ethynylquinolin-4-yl]propane- 1,3- diamine; N-[(3-aminooxetan-3-yl)methyl]-6-methyl-2-(l-oxido-2,3-dihydro-l,4-benzothiazepin- 4(5H)-yl)quinazolin-4-amine; N-{[3-(benzylamino)oxetan-3-yl]methyl}-6-methyl-2-(l-oxido- 2,3-dihydro-l,4-benzothiazepin-4(5H)-yl)quinazolin-4-amine; 2-fluoro-N-[6-methyl-2-(l-oxido- 2,3-dihydro- 1 ,4-benzothiazepin-4(5H)-yl)quinazolin-4-yl]propane- 1 ,3-diamine; N- {[3- (aminomethyl)oxetan-3-yl]methyl} -2-(l , 1 -dioxido-2,3-dihydro- 1 ,4-benzothiazepin-4(5H)-yl)-6- methylquinazolin-4-amine; 2,2-difluoro-N-[6-methyl-2-(l-oxido-2,3-dihydro-l,4- benzothiazepin-4(5H)-yl)quinazolin-4-yl]propane-l,3-diamine; N-{[3-(aminomethyl)oxetan-3- yl]methyl}-6-chloro-2-(l,l-dioxido-2,3-dihydro-l,4-benzothiazepin-4(5H)-yl)quinazolin-4- amine; N-[2-(l , 1 -dioxido-2,3-dihydro- 1 ,4-benzothiazepin-4(5H)-yl)-6-methylquinazolin-4-yl]-
2.2- difluoropropane-l,3-diamine; N-[2-(l,l-dioxido-2,3-dihydro-l,4-benzothiazepin-4(5H)-yl)- 6-methylquinazolin-4-yl]-2-fluoropropane-l,3-diamine; N-[6-methyl-2-(l-oxido-2,3-dihydro-
1 ,4-benzothiazepin-4(5H)-yl)quinazolin-4-yl]propane- 1 ,3-diamine; N-[(3-aminooxetan-3- yl)methyl]-2-(2,3-dihydro- 1 ,4-benzothiazepin-4(5H)-yl)quinazolin-4-amine; N-[(3-aminooxetan- 3-yl)methyl]-2-(l-oxido-2,3-dihydro-l,4-benzom^ N-[(3- aminooxetan-3-yl)methyl]-2-(l , 1 -dioxido-2,3-dihydro- 1 ,4-benzothiazepin-4(5H)-yl)quinazolin- 4-amine; N-[(3-aminooxetan-3-yl)methyl]-6-chloro-2-(2,3-dihydro- 1 ,4-benzothiazepin-4(5H)- yl)quinazolin-4-amine; N-[(3-aminooxetan-3-yl)methyl]-6-chloro-2-(l-oxido-2,3-dihydro-l,4- benzothiazepin-4(5H)-yl)quinazolin-4-amine; N-[(3-aminooxetan-3-yl)methyl]-6-chloro-2-(l , 1- dioxido-2,3-dihydro- 1 ,4-benzothiazepin-4(5H)-yl)quinazolin-4-amine; 2- {[2-(l , 1 -dioxido-2,3- dihydro-l,4-benzothiazepin-4(5H)-yl)-6-methylquinazolin-4-yl]amino}ethanol; 2-(2,3-dihydro- 1 ,4-benzothiazepin-4(5H)-yl)-6-methylquinazolin-4-amine; 2-(l , 1 -dioxido-2,3-dihydro- 1 ,4- benzothiazepin-4(5H)-yl)-6-methylquinazolin-4-amine; N~l— [2-(l,l-dioxido-2,3-dihydro-l,4- benzothiazepin-4(5H)-yl)-6-methylquinazolin-4-yl]-2-methylpropane- 1 ,2-diamine; N-[(3- aminooxetan-3-yl)methyl]-2-(l , 1 -dioxido-2,3-dihydro- 1 ,4-benzothiazepin-4(5H)-yl)-6- methylquinazolin-4-amine; N-[(l-aminocyclobutyl)methyl]-2-(l,l-dioxido-2,3-dihydro-l,4- benzothiazepin-4(5H)-yl)-6-methylquinazolin-4-amine; N-{[3-(aminomethyl)oxetan-3- yljmethyl} -6-methyl-2-(l -oxido-2,3-dihydro- 1 ,4-benzothiazepin-4(5H)-yl)quinazolin-4-amine; (-)-N- {[3-(aminomethyl)oxetan-3-yl]methyl} -6-methyl-2-[ 1 -oxido-2,3-dihydro- 1 ,4- benzothiazepin-4(5H)-yl]quinazolin-4-amine; (+)-N-{[3-(aminomethyl)oxetan-3-yl]methyl}-6- methyl-2-[l-oxido-2,3-dihydro-l,4-benzothiazepin-4(5H)-yl]quinazolin-4-amin^ N~4— [2-(l,l- dioxido-2,3-dihydro- 1 ,4-benzothiazepin-4(5H)-yl)-6-methylquinazolin-4-yl]-2-fluorobutane- 1 ,4- diamine; N~l— [2-(l,l-dioxido-2,3-dihydro-l,4-benzothiazepin-4(5H)-yl)-6-methylquinazolin-4- yl]-2-fluorobutane- 1 ,4-diamine; N- {[3-(aminomethyl)oxetan-3-yl]methyl} -2-(2,3-dihydro- 1 ,4- benzothiazepin-4(5H)-yl)-6-methylquinazolin-4-amine; tra/75-4-fluoro-l-[6-methyl-2-(l-oxido-
2.3- dihydro- 1 ,4-benzothiazepin-4(5H)-yl)quinazolin-4-yl]pyrrolidin-3-amine; N-(Azetidin-3-yl)- 6-methyl-2-(l , 1 -dioxido-2,3-dihydro- 1 ,4-benzothiazepin-4(5H)-yl) quinazolin-4-amine; N-(2- {[2-(l,l-dioxido-2,3-dihydro-l,4-benzothiazepin-4(5H)-yl)-6-methylquinolm^
yljamino } ethyl)acetamide; N- { [3-( { [2-( 1 , 1 -dioxido-2,3-dihydro- 1 ,4-benzothiazepin-4(5H)-yl)-6- methylquino lin-4-yl] amino } methyl)oxetan-3 -yljmethyl} acetamide; N-(3 - { [2-( 1 , 1 -dioxido-2,3 - dihydro-l,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]amino}propyl)acetamide; N-[2- (1,1 -dioxido-2,3-dihydro- 1 ,4-benzothiazepin-4(5H)-yl)-6-methylquinazolin-4-yl]acetamide; 1 - [2-(l , 1 -dioxido-2,3-dihydro- 1 ,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]-3- methylpyrrolidin-3-amine; N-[(3-aminooxetan-3-yl)methyl]-2-(9-methoxy- 1 , 1 -dioxido-2,3- dihydro-l,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-amine; 4-(4-{[(3-aminooxetan-3- yl)methyl]amino}-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-l,4-benzothiazepin-7-ol 1,1- dioxide; 3-{[2-(l,l-dioxido-2,3-dihydro-l,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4- yljamino } -2-methylpropane- 1 ,2-diol; 4- { [2-( 1 , 1 -dioxido-2,3-dihydro- 1 ,4-benzothiazepin-4(5H)- yl)-6-methylquino lin-4-yl] amino } butane- 1 ,3 -dio 1; N- [6-methyl-2-(2-methyl- 1 , 1 -dioxido-2,3 - dihydro- 1 ,4-benzothiazepin-4(5H)-yl)quinolin-4-yl] ethane- 1 ,2-diamine; N-[(3-aminooxetan-3- yl)methyl]-6-methyl-2-(2-methyl- 1 , 1 -dioxido-2,3-dihydro- 1 ,4-benzothiazepin-4(5H)- yl)quinolin-4-amine; N-[(3-{[2-(l,l-dioxido-2,3-dihydro-l,4-benzothiazepin-4(5H)-yl)-6- methylquinolin-4-yl]amino}oxetan-3-yl)methyl]-2,2,2-trifluoroacetamide; N-[3-
(aminomethyl)oxetan-3-yl]-2-(l , 1 -dioxido-2,3-dihydro- 1 ,4-benzothiazepin-4(5H)-yl)-6- methylquinolin-4-amine; 2-(aminomethyl)-2- {[2-(l , 1 -dioxido-2,3-dihydro- 1 ,4-benzothiazepin- 4(5H)-yl)-6-methylquinolin-4-yl]amino}propane-l ,3-diol; 4-amino-l-[2-(l,l-dioxido-2,3- dihydro- 1 ,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]pyrrolidin-2-one; 2-(l , 1 -dioxido- 2,3-dihydro- 1 ,4-benzothiazepin-4(5H)-yl)-6-methyl-N-[2-(methylsulfinyl)ethyl]quinolin-4- amine; N- {2-[(2-aminoethyl)sulfonyl]ethyl} -2-(l , 1 -dioxido-2,3-dihydro- 1 ,4-benzothiazepin- 4(5H)-yl)-6-methylquinolin-4-amine; N-[2-(l-imino-l-oxido- 1,2,3, 5-tetrahydro-4H- 1 /am¾(ia~4~,4-benzothiazepin-4-yl)-6-methylquinolin-4-yl]ethane- 1 ,2-diamine; 2-( 1 , 1 -dioxido-
2.3- dihydro- 1 ,4-benzothiazepin-4(5H)-yl)-6-methyl-N-[2-(5*- methylsulfonimidoyl)ethyl]quinolin-4-amine; trans-4-ammo- 1 -[2-(l -imino- 1 -oxido- 1 ,2,3,5- tetrahydro-4H- 1 lamb <ia~4~,4-benzothiazepin-4-yl)-6-methylquinolin-4-yl]pyrrolidin-3-ol; trans- 1 -[2-(l , 1 -dioxido-2,3-dihydro- 1 ,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]-4- fluoropyrrolidin-3-amine; 1 -[2-(l , 1 -dioxido-2,3-dihydro- 1 ,4-benzothiazepin-4(5H)-yl)-6- methylquinolin-4-yl]pyrrolidine-3-carboxamide; N-[2-(l , 1 -dioxido-2,3-dihydro- 1 ,4- benzothiazepin-4(5H)-yl)-6-(methylsulfinyl)quinolin-4-yl]propane- 1 ,3-diamine; 4-[(3- aminopropyl)amino]-2-(l , 1 -dioxido-2,3-dihydro- 1 ,4-benzothiazepin-4(5H)-yl)quinoline-6- carboxamide; l-{4-[(3-aminopropyl)amino]-2-(l,l-dioxido-2,3-dihydro-l,4-benzothiazepin- 4(5H)-yl)quinolin-6-yl} ethanol; 3- {[2-(l , 1 -dioxido-2,3-dihydro- 1 ,4-benzothiazepin-4(5H)-yl)-6- methylquinolin-4-yl]amino}propanenitrile; 2-(l,l-dioxido-2,3-dihydro-l,4-benzothiazepin- 4(5H)-yl)-6-methyl-N-[2-(lH-tetrazol-5-yl)ethyl]quinolin-4-amine; N~4~-(2-aminoethyl)-2 dioxido-2,3-dihydro- 1 ,4-benzothiazepin-4(5H)-yl)quinoline-4,6-diamine; 5-[2-(l , 1 -dioxido-2,3- dihydro-l,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]-2-oxa-5,7-diazaspiro[3.4]octan-6- one; 3-{[2-(l,l-dioxido-2,3-dihydro-l,4-benzothiazepin-4(5H)-yl)-6-methylquinazolin-4- yl] amino} propane- 1,2-diol; 3-{[6-chloro-2-(l,l-dioxido-2,3-dihydro-l,4-benzothiazepin-4(5H)- yl)quinazolin-4-yl] amino} propane- 1,2-diol; N-[2-(2,3-dihydro-l,4-benzothiazepin-4(5H)-yl)-6- methylquinazolin-4-yl] ethane- 1 ,2-diamine; N-[6-methyl-2-(l -oxido-2,3-dihydro- 1 ,4- benzothiazepin-4(5H)-yl)quinazolin-4-yl] ethane- 1 ,2-diamine; N-[2-(l , 1 -dioxido-2,3-dihydro-
1.4- benzothiazepin-4(5H)-yl)-6-methylquinazolin-4-yl] ethane- 1 ,2-diamine; N-[3- (aminomethyl)oxetan-3-yl]-6-methyl-2-(l-oxido-2,3-dihydro-l,4-benzothiazepin-4(5H)- yl)quinazolin-4-amine; N-(tra/75-4-fluoropyrrolidin-3-yl)-6-methyl-2-(l-oxido-2,3-dihydro-l,4- benzothiazepin-4(5H)-yl)quinazolin-4-amine; N-(tra/75-4-fluoropyrrolidin-3-yl)-6-methyl-2-(l,l- dioxido-2,3-dihydro-l,4-benzothiazepin-4(5H)-yl)quinazolin-4-amine; l-[6-methyl-2-(l-oxido- 2,3-dihydro- 1 ,4-benzothiazepin-4(5H)-yl)quinazolin-4-yl]pyrrolidin-3-amine; N-(azetidin-3-yl)- 6-methyl-2-(l , 1 -dioxido-2,3-dihydro- 1 ,4-benzothiazepin-4(5H)-yl)quinazolin-4-amine; (4R)-4- {2-[2-(l , 1 -dioxido-2,3-dihydro- 1 ,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl] ethyl} -4,5- dihydro- 1 ,3-oxazol-2-amine; 3-[2-(l , 1 -dioxido-2,3-dihydro- 1 ,4-benzothiazepin-4(5H)-yl)-6- ethylquinolin-4-yl]propanoic acid; 3-[2-(l,l-dioxido-2,3-dihydro-l,4-benzothiazepin-4(5H)-yl)- 6-methylquinolin-4-yl]propan- 1 -amine; 2- { [2-( 1 , 1 -dioxido-2,3-dihydro- 1 ,4-benzothiazepin- 4(5H)-yl)-6-methylquinolin-4-yl]oxy}ethanamine; 4-[6-methyl-4-(pyrrolidin-3-yloxy)quinolin- 2-yl]-2,3,4,5-tetrahydro- 1 ,4-benzothiazepine 1 , 1 -dioxide; 4-[6-methyl-4-(piperidin-4- yloxy)quinolin-2-yl]-2,3,4,5-tetrahydro- 1 ,4-benzothiazepine 1 , 1 -dioxide; 4-(4,6- dimethylquinolin-2-yl)-2,3,4,5-tetrahydro- 1 ,4-benzothiazepine 1 , 1 -dioxide; [2-(l , 1 -dioxido-2,3- dihydro- 1 ,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl](piperidin-4-yl)methanone; 4-[6- methyl-4-(lH-pyrazol-3-yl)quinolin-2-yl]-2,3,4,5-tetrahydro-l,4-benzothiazepine 1,1 -dioxide; 4- [6-methyl-4-(phenylsulfonyl)quinolin-2-yl]-2,3,4,5-tetrahydro- 1 ,4-benzothiazepine 1 , 1 -dioxide; N-(2-aminoethyl)-2-( 1 , 1 -dioxido-2,3-dihydro- 1 ,4-benzothiazepin-4(5H)-yl)-6-methylquinoline- 4-sulfonamide; methyl 4-({[3-(aminomethyl)oxetan-3-yl]methyl}amino)-2-(l,l-dioxido-2,3- dihydro- 1 ,4-benzothiazepin-4(5H)-yl)quino line-6-carboxylate; 4-( { [3 -(amino methyl)oxetan-3 - yljmethyl} amino)-2-(l , 1 -dioxido-2,3-dihydro- 1 ,4-benzothiazepin-4(5H)-yl)quinoline-6- carboxylic acid; [4-({[3-(aminomethyl)oxetan-3-yl]methyl}amino)-2-(l,l-dioxido-2,3-dihydro- l,4-benzothiazepin-4(5H)-yl)quinolin-6-yl]methanol; N-{[3-(aminomethyl)oxetan-3-yl]methyl}- 6-(~2~H_3_)methyl-2-(l-oxido-2,3-dihydro-l,4-benzothiazepin-4(5H)-yl)quinazolin-4-amine; 4-({[3-(aminomethyl)oxetan-3-yl]methyl}amino)-2-(l,l-dioxido-2,3-dihydro-l,4- benzothiazepin-4(5H)-yl)quinazoline-6-carboxylic acid; 4-({[3-(aminomethyl)oxetan-3- yl]methyl}amino)-2-(l-oxido-2,3-dihydro-l,4-benzothiazepin-4(5H)-yl)quinazoline-6- carboxylic acid; [4-( { [3-(aminomethyl)oxetan-3-yl]methyl} amino)-2-( 1 -oxido-2,3-dihydro- 1 ,4- benzothiazepin-4(5H)-yl)quinazo lin-6-yl]methano 1; [4-( { [3 -(amino methyl)oxetan-3 - yljmethyl} amino)-2-(l , 1 -dioxido-2,3-dihydro- 1 ,4-benzothiazepin-4(5H)-yl)quinazolin-6- yljmethanol; N-[(l-aminocyclopropyl)methyl]-2-(l,l-dioxido-2,3-dihydro-l,4-benzothiazepin- 4(5H)-yl)-6-methylquinazolin-4-amine; and 2-(l,l-dioxido-2,3-dihydro-l,4-benzothiazepin- 4(5H)-yl)-6-methyl-N-(pyrrolidin-3-yl)quinazolin-4-amine.
13. A compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R1 is hydrogen or halogen;
R2 and R4 are hydrogen;
R3 is hydrogen or halogen;
R5 is hydrogen or halogen;
R6 is hydrogen, halogen, hydroxy, Ci_6alkoxy or carboxy; R7 is hydrogen, halogen, Ci_6alkoxy, Ci_6alkylaminocarbonyl, diCi_6
alkylaminocarbonyl or Ci_6alkylsulfonyl;
R8 is hydrogen or halogen;
R9 is hydrogen or =0;
R10 is hydrogen or =0, provided that R9 and R10 are not =0 simultaneously;
A is -C-R11, wherein R11 is hydrogen, halogen, Chalky!, Ci_6alkoxy, trifluoromethyl, trifluoromethoxy, pyridinyloxy, difluoromethoxy or Ci_6alkylsulfonyl;
X is -CH2-, -0-, -NH-, -CF2, -C(CH3)(OH)-, C=0, or -C(=N-Ci_6alkoxy)-;
Y is -CH- or nitrogen;
Q is hydrogen; halogen; Ci_6alkyl, once or twice substituted by hydroxy provided that disubstitution of hydroxy is not on the same carbon; amino(CH2)2_6aminosulfonyl; 2- amino-4,5-dihydro-l,3-oxazol-4-ylethyl; or NR 12 R13 , wherein one of R 112Z and R 113J is hydrogen, Ci_6alkyl or hydroxy(CH2)2_, and the other one is guanidino(CH2)2_6; 3- aminomethyl- 1 , 1 -dioxidothietan-3-ylmethyl; 3-amino- 1 , 1 -dioxidothietan-3-ylmethyl; 3- (aminomethyl)thietan-3-ylmethyl; amino(CH2)2_6-0-(CH2)2_6; amino(CH2)2_io;
amino (CH2) i _6carbony 1; amino (CH2) i _6difluoromethy 1(CH2) i _6 ; amino (CH2) i _
6oxetanyl(CH2)i_6; amino(CH2)2_6sulfonyl(CH2)2_6; 3-aminocyclohexyl; 4- aminocyclohexyl; 2-amino-4,5-dihydro-oxazol-5-yl(CH2)i_6; aminooxetanyl(CH2)i_6; Ci_
Figure imgf000528_0001
or hydroxy(CH2)i_6; R15 is hydroxy, hydroxy(CH2)i_6 or amino; and R16 is Ci_6alkyl, hydroxy(CH2)i_6 or amino (CH2)i_6;
R12 and R13, with the nitrogen atom to which they are attached, may form a pyrrolidinyl, piperazinyl or diazepanyl ring; which may be unsubstituted, once or twice substituted by a group selected from Ci_6alkyl, amino or hydroxy.
14. A compound according to claim 13 or a pharmaceutically acceptable salt thereof, wherein
R1 is hydrogen or chloro;
R2 and R4 are hydrogen; R5 is hydrogen or fluoro;
R6 is hydrogen, fluoro, hydroxy, methoxy, ethoxy or carboxy;
R7 is hydrogen, fluoro, bromo, methoxy, dimethylaminocarbonyl, methylsulfonyl or ethylsulfonyl; R8 is hydrogen or chloro.
A is CR11, wherein R11 is hydrogen, fluoro, chloro, bromo, methyl, methoxy,
trifluoromethyl, trifluoromethoxy, pyridinyloxy, difluoromethoxy or methylsulfonyl;
Q is hydrogen; chloro; hydroxymethyl; hydroxymethyl(hydroxy)ethyl;
aminoethylaminosulfonyl; 2-amino-4,5-dihydro-l,3-oxazol-4-ylethyl; or NR12R13, wherein one of R12 and R13 is hydrogen, methyl or hydroxyethyl;and the other one is aminobutyl; 3-aminocyclohexyl; 4-aminocyclohexyl; 2-amino-4,5-dihydro-oxazol-5- ylmethyl; 3-amino-l,l-dioxidothietan-3-ylmethyl; aminoethoxyethyl; aminoethyl;
aminoethylsulfonylethyl; aminomethylcarbonyl; aminomethyldifluoromethylmethyl; 3- amino methyl- 1 , 1 -dioxidothietan-3 -ylmethyl; 3 -(amino methyl)thietan-3 -ylmethyl;
aminomethyloxetanylmethyl; aminooxetanylmethyl; aminopropyl; dimethylamino ethyl; ethylaminocarbonyl; guanidino ethyl; hydroxyethyl; hydroxypropyl; methylamino ethyl; piperazin- 1 -ylethyl; pyrro lidin-3 -yl;
or
Figure imgf000529_0001
, wherein R14 is hydrogen, methyl or hydroxymethyl; R15 is hydroxy, hydroxymethyl or amino; and R16 is methyl, hydroxymethyl or aminomethyl;R12 and R13, with the nitrogen atom to which they are attached, may form a pyrrolidinyl, piperazinyl or diazepanyl ring; which may be unsubstituted, once or twice substituted by a group selected from methyl, amino or hydroxy.
15. A compound according to any one of claims 13 to 14 or a pharmaceutically acceptable salt thereof, selected from N-[(3-aminooxetan-3-yl)methyl]-2-(5,5-difluoro- 1,3,4, 5-tetrahydro-2H-2-benzazepin-2-yl)-6- methylquinolin-4-amine; N-[2-(2-aminoethoxy)ethyl]-2-(5,5-difluoro- 1,3,4, 5-tetrahydro-2H-2- benzazepin-2-yl)-6-methylquinolin-4-amine; N-[2-(5,5-difluoro- 1,3,4, 5-tetrahydro-2H-2- benzazepin-2-yl)-6-methylquinolin-4-yl]-N'-methylethane-l,2-diamine; l-amino-3-{[2-(5,5- difluoro-l,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)-6-methylquinolin-4-yl]amino}propan-2-ol; 3- {[2-(5,5-difluoro-l,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)-6-methylquinolin-4- yl] amino} propane- 1,2-diol; 3-{[2-(5,5-difluoro-l,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)-6- methylquinolin-4-yl]amino}propan-l-ol; 2-(5,5-difluoro-l,3,4,5-tetrahydro-2H-2-benzazepin-2- yl)-6-methyl-N-[2-(piperazin-l-yl)ethyl]quinolin-4-amine; N~l~- [2-(5,5-difluoro-l,3,4,5- tetrahydro-2H-2-benzazepin-2-yl)-6-methylquinolin-4-yl]propane-l,2-diamine; c«-N-[2-(5,5- difluoro-l,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)-6-methylquinolin-4-yl]cyclohexane-l,4- diamine; 2-(9,9-difluoro-6,7,8,9-tetrahydro-5H-benzo[7]annulen-6-yl)-6-methyl-N-(pyrrolidin-3- yl)quinolin-4-amine; 2,2'-{[2-(5,5-difluoro-l,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)-6- methylquinolin-4-yl]imino}diethanol; N~l— [2-(5,5-difluoro- 1,3,4, 5-tetrahydro-2H-2- benzazepin-2-yl)-6-methylquinolin-4-yl]-2-methylpropane-l,2-diamine; 5,5-difluoro-2-[6- methyl-4-(4-methylpiperazin- 1 -yl)quinolin-2-yl]-2,3,4,5-tetrahydro- lH-2-benzazepine; 1 -[2- (9,9-difluoro-6,7,8,9-tetrahydro-5H-benzo[7]annulen-6-yl)-6-methylquinolin-4-yl]-3-ethylurea; N-{[3-(aminomethyl)oxetan-3-yl]methyl}-2-(5,5-difluoro-l,3,4,5-tetrahydro-2H-2-benzazepin-
2- yl)-6-methylquinolin-4-amine; 5,5-difluoro-2-[6-methyl-4-(piperazin-l-yl)quinolin-2-yl]- 2,3,4,5-tetrahydro-lH-2-benzazepine; 2-[4-(l,4-diazepan-l-yl)-6-methylquinolin-2-yl]-5,5- difluoro-2,3,4,5-tetrahydro-lH-2-benzazepine; N-[2-(5,5-difluoro-l,3,4,5-tetrahydro-2H-2- benzazepin-2-yl)-6-methylquinolin-4-yl]-N-methylethane-l,2-diamine; l-[2-(5,5-difluoro-
1 ,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)-6-methylquinolin-4-yl]pyrrolidin-3-amine; 2- {[2-(5,5- difluoro-l,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)-6-methylquinolin-4-yl]amino}ethanol; N-[2- (5,5-difluoro-l,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)-6-methylquinolin-4-yl]ethane-l,2- diamine; N-[2-(5,5-difluoro- 1,3,4, 5-tetrahydro-2H-2-benzazepin-2-yl)-6-methylquinolin-4- yl]cyclohexane-l,3-diamine; N'-[2-(5,5-difluoro-l,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)-6- methylquinolin-4-yl]-N,N-dimethylethane-l,2-diamine; N-[2-(5,5-difluoro-l,3,4,5-tetrahydro- 2H-2-benzazepin-2-yl)-6-methylquinolin-4-yl]propane-l,3-diamine; N-[2-(5,5-difluoro-l, 3,4,5- tetrahydro-2H-2-benzazepin-2-yl)-6-methylquinolin-4-yl]butane- 1 ,4-diamine; trans-4-ammo- 1 - [2-(5,5-difluoro-l,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)-6-methylquinolin-4-yl]pyrrolidin-3 N-{[3-(aminomethyl)-l,l-dioxidothietan-3-yl]methyl}-2-(5,5-difluoro-l,3,4,5-tetrahydro-2H-2- benzazepin-2-yl)-6-methylquinolin-4-amine; N-{2-[(2-aminoethyl)sulfonyl]ethyl}-2-(5,5- difluoro-l,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)-6-methylquinolin-4-amine; N-{[3- (aminomethyl)thietan-3-yl]methyl}-2-(5,5-difluoro-l,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)-6- methylquinazolin-4-amine; N-{[3-(aminomethyl)oxetan-3-yl]methyl}-2-(5,5-difluoro- 1,3,4,5- tetrahydro-2H-2-benzazepin-2-yl)-6-methylquinazolin-4-amine; 2-(aminomethyl)-2-({[2-(5,5- difluoro-l,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)-6-methylquinazolin-4- yl] amino } methyl)propane- 1 ,3 -dio 1; 2-(4- { [(3 -aminooxetan-3 -yl)methyl] amino } -6- methylquinazolin-2-yl)-5-methyl-2,3,4,5-tetrahydro-lH-2-benzazepin-5-ol; N-[(3-aminooxetan-
3- yl)methyl]-2-(5,5-difluoro-l,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)-6-methylquinazolin-4- amine; N-[(3-amino- 1 , 1 -dioxidothietan-3-yl)methyl]-2-(5,5-difluoro- 1 ,3,4,5-tetrahydro-2H-2- benzazepin-2-yl)-6-methylquinazolin-4-amine; N-[2-(5,5-difluoro- 1,3,4, 5-tetrahydro-2H-2- benzazepin-2-yl)-6-methylquinazolin-4-yl]-2,2-difluoropropane- 1 ,3-diamine; N-[2-(7-bromo- l,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)-6-chloroquinolin-4-yl]ethane-l,2-diamine; 2-{4-[(2- aminoethyl)amino]quinolin-2-yl}-2,3,4,5-tetrahydro-lH-2-benzazepin-8-ol; N-[6-methyl-2- (l,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)quinolin-4-yl]ethane-l,2-diamine; N-[2-(8-fiuoro- l,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)-6-methylquinolin-4-yl]ethane-l,2-diamine; N-[6- chloro-2-(l,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)quinolin-4-yl]ethane-l,2-diamine; N-[6- chloro-2-(9-fluoro-l,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)quinolin-4-yl]ethane-l,2-diamm^ N-[2-(8-fluoro- 1 ,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)quinolin-4-yl]ethane- 1 ,2-diamine; 1 - amino-3-{[2-(l,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)quinolin-4-yl]amino}propan-2-ol trifluoroacetate; N-[2-(l,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)quinolin-4-yl]ethane-l,2- diamine; N-[6-bromo-2-(l,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)quinolin-4-yl]ethane-l,2- diamine; N-[6-methoxy-2-(l,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)quinolin-4-yl]ethane-l,2- diamine; N-[2-(6-chloro- 1 ,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)quinolin-4-yl]ethane- 1 ,2- diamine; N-[2-(7-fluoro-l,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)-6-methylquinolin-4- yl]ethane-l,2-diamine; N-methyl-N'-[2-(l,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)quinolin-4- yl]ethane-l,2-diamine; N-[2-(7-methoxy- 1,3,4, 5-tetrahydro-2H-2-benzazepin-2-yl)quinolin-4- yljethane- 1 ,2-diamine; N-[2-(7-fiuoro- 1 ,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)quinolin-4- yl]ethane-l,2-diamine; N-[2-(8-methoxy- 1,3,4, 5-tetrahydro-2H-2-benzazepin-2-yl)quinolin-4- yl]ethane-l,2-diamine; N-[6-(difluoromethoxy)-2-(l,3,4,5-tetrahydro-2H-2-benzazepin-2- yl)quinolin-4-yl]ethane-l,2-diamine; N-[2-(l,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)-6- (trifluoromethyl)quinolin-4-yl]ethane-l,2-diamine; N-[8-chloro-2-(l,3,4,5-tetrahydro-2H-2- benzazepin-2-yl)quinolin-4-yl]ethane-l,2-diamine; N-[6-fluoro-2-(l,3,4,5-tetrahydro-2H-2- benzazepin-2-yl)quinolin-4-yl]ethane-l,2-diamine; N,N-dimethyl-N'-[2-(l,3,4,5-tetrahydro-2H- 2-benzazepin-2-yl)quinolin-4-yl]ethane-l,2-diamine; N-[2-(l,3,4,5-tetrahydro-2H-2-benzazepin- 2-yl)-6-(trifluoromethoxy)quinolin-4-yl]ethane-l,2-diamine; N-[6-(methylsulfonyl)-2-(l, 3,4,5- tetrahydro-2H-2-benzazepin-2-yl)quinolin-4-yl]ethane- 1 ,2-diamine; 2- {4-[(2- aminoethyl)amino]quinolin-2-yl}-2,3,4,5-tetrahydro-lH-2-benzazepine-8-carboxylic acid; 2-(4- chloroquinolin-2-yl)-2,3,4,5-tetrahydro-lH-2-benzazepine; N-[5-chloro-2-(l,3,4,5-tetrahydro- 2H-2-benzazepin-2-yl)quinolin-4-yl] ethane- 1 ,2-diamine; N- (2-[7-(methylsulfonyl)- 1 ,3,4,5- tetrahydro-2H-2-benzazepin-2-yl]quinolin-4-yl} ethane- 1 ,2-diamine; N- (2-[7-(ethylsulfonyl)- l,3,4,5-tetrahydro-2H-2-benzazepin-2-yl]quinolin-4-yl} ethane- 1,2-diamine; N-[2-(8-ethoxy- l,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)quinolin-4-yl]ethane- 1,2-diamine; N-[6-(pyridin-2- yloxy)-2-(l, 3,4, 5-tetrahydro-2H-2-benzazepin-2-yl)quinolin-4-yl]ethane- 1,2-diamine; 2-{4-[(2- aminoethyl)amino]-6-chloroquinolin-2-yl}-N,N-dimethyl-2,3,4,5-tetrahydro-lH-2-benzazepine- 7-carboxamide; 2- {4-[(2-aminoethyl)amino]quinolin-2-yl} -7-bromo- 1 ,2,4,5-tetrahydro-3H-2- benzazepin-3-one; l-(2-{[2-(l,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)quinolin-4- yl] amino }ethyl)guanidine trifluoroacetate; N-[(2-amino-4,5-dihydro-l,3-oxazol-5-yl)methyl]-2- (1 ,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)quinolin-4-amine trifluoroacetate; N-[(2-amino-4,5- dihydro- l,3-o xazol-5-yl)methyl]-6-chloro-2-(l,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)quinolin- 4-amine; N-[2-(l ,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)quinolin-4-yl]glycinamide; 3-[2- (l,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)quinolin-4-yl]propan-l-amine; [2-(l,3,4,5-tetrahydro- 2H-2-benzazepin-2-yl)quinolin-4-yl]methanol; 2-(6-chloroquinolin-2-yl)-2,3,4,5-tetrahydro-lH- 2-benzazepine; 3-[6-chloro-2-(l,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)quinolin-4-yl]propane- 1,2-diol; (45)-4-{2-[2-(l,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)quinolin-4-yl]ethyl}-4,5- dihydro-l,3-oxazol-2-amine; N-(2-aminoethyl)-2-(l,3,4,5-tetrahydro-2H-2-benzazepin-2- yl)quinoline-4-sulfonamide trifluoroacetate; 4- {4-[(2-aminoethyl)amino]-6-methylquinolin-2- yl} - 1 ,3 ,4,5-tetrahydro-2H- 1 ,4-benzodiazepin-2-one; N-[6-methyl-2-( 1 ,2,3 ,5-tetrahydro-4H- 1 ,4- benzodiazepin-4-yl)quinolin-4-yl]ethane- 1 ,2-diamine; N-[2-(2,3-dihydro- 1 ,4-benzoxazepin- 4(5H)-yl)quinolin-4-yl] ethane- 1 ,2-diamine; N-[(3-aminooxetan-3-yl)methyl]-2-[(5E)-5- (methoxyimino)-l,3,4,5-tetrahydro-2H-2-benzazepin-2-yl]-6-methylquinolin-4-amine and 2-(4- {[(3-aminooxetan-3-yl)methyl]amino}-6-methylquinazolin-2-yl)-l,2,3,4-tetrahydro-5H-2- benzazepin-5-one.
16. A compound according to any one of claims 1 to 15 for use as a therapeutically active substance.
17. A pharmaceutical composition comprising a compound in accordance with any one of claims 1 to 15 and a therapeutically inert carrier.
18. The use of a compound according to any one of claims 1 to 15 for the treatment or prophylaxis of respiratory syncytial virus infection.
19. The use of a compound according to any one of claims 1 to 15 for the preparation of a medicament for the treatment or prophylaxis of respiratory syncytial virus infection.
20. A compound according to any one of claims 1 to 15 for the treatment or prophylaxis of respiratory syncytial virus infection.
21. A method for the treatment or prophylaxis of respiratory syncytial virus infection, which method comprisis administering an effective amount of a compound as defined in any one of claims 1 to 15.
22. The invention as hereinbefore described.
PCT/EP2012/065499 2011-08-11 2012-08-08 Compounds for the treatment and prophylaxis of respiratory syncytial virus disease WO2013020993A1 (en)

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