NZ620079B2 - 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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NZ620079B2
NZ620079B2 NZ620079A NZ62007912A NZ620079B2 NZ 620079 B2 NZ620079 B2 NZ 620079B2 NZ 620079 A NZ620079 A NZ 620079A NZ 62007912 A NZ62007912 A NZ 62007912A NZ 620079 B2 NZ620079 B2 NZ 620079B2
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dihydro
benzothiazepin
dioxido
methyl
amino
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NZ620079A
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NZ620079A (en
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Li Chen
Lichun Feng
Song Feng
Lu Gao
Tao Guo
Mengwei Huang
Chungen Liang
Yongfu Liu
Lisha Wang
Jason Christopher Wong
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F Hoffmann La Roche Ag
F Hoffmannla Roche Ag
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Priority claimed from PCT/EP2012/065499 external-priority patent/WO2013020993A1/en
Publication of NZ620079A publication Critical patent/NZ620079A/en
Publication of NZ620079B2 publication Critical patent/NZ620079B2/en

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    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
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    • 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
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    • 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
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    • C07—ORGANIC CHEMISTRY
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    • 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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    • C07—ORGANIC CHEMISTRY
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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
    • C07D471/04—Ortho-condensed systems
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    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • 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
    • C07D487/04—Ortho-condensed systems
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/10—Spiro-condensed systems
    • C07D491/107—Spiro-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
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    • 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
    • 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

Abstract

Provided are heteroaryl substituted benzazepine, benzoxazepine and benzothiazepine derivatives of the general formula (I), where the variables are as defined in the specification. Examples of the compounds include 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 and 2-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methyl-N-(pyrrolidin-3-yl)quinazolin-4-amine. The compounds are useful in the treatment of respiratory syncytial virus (RSV). -4(5H)-yl)-6-methylquinolin-4-amine and 2-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methyl-N-(pyrrolidin-3-yl)quinazolin-4-amine. The compounds are useful in the treatment of respiratory syncytial virus (RSV).

Description

Case 30569 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 laxis of RSV disease.
The ion relates in particular to (i) a compound of formula (I) R3 Q A Y R4 R6 R2 N N R7 R10 X R8 R9 (I) Wherein R1 is hydrogen, halogen, or C1-6alkyl; R2 is hydrogen, halogen, or C1-6alkyl; R3 is hydrogen, halogen, or C1-6alkyl; R4 is hydrogen, or C1-6alkyl; R5 is hydrogen, or halogen; R6 is en, halogen, hydroxy, C1-6alkoxy, carboxy, morpholinyl, or 4-C0- 6alkylpiperazinyl; R7 is hydrogen, n, C1-6alkyl, C1-6alkoxy, C1-6alkylaminocarbonyl, diC1-6 alkylaminocarbonyl, C1-6alkylsulfonyl, phenoxy, or hydroxy(CH2)2O-; R8 is hydrogen, halogen, or C1-6alkoxy; R9 is hydrogen, C1-6alkyl, or =O; R10 is hydrogen, or =O, ed that R9 and R10 are not =O simultaneously; JZ / 21.05.2012 A is nitrogen, or -C-R11 , wherein R11 is en, halogen, kyl, cycloalkyl, C1- 6alkoxy, trifluoromethyl, trifluoromethoxy, pyridinyloxy, C1-6alkoxy(CH 2)1O-, difluoromethoxy, cyano, nitro, amino, vinyl, acetylenyl, aminocarbonyl, hydroxy(CH2)2O-, C1- 6alkylsulfinyl, C1-6alkylsulfonyl, y(CH2)1-6, deuteratedC1-6alkyl, carboxyl, C1- 6alkoxycarbonyl, hydroxy, difluoromethyl, droxy) C1-6alkyl, or C1-6alkylsulfanyl; X is -CH2-, -O-, -NH-, -CF2-, -C(C1-6alkyl)(OH)-, -S-, -, -C(=NOC0-6alkyl)-, - S(=O)-, -S(O2)- or -S(=O)(NH)-; Y is -CH-, or nitrogen; Q is en; halogen; C1-6alkyl, unsubstituted or once or twice substituted by amino or hydroxy, provided that stitution is not on the same carbon; amino(CH2)2- 6aminosulfonyl; 2-amino-4,5-dihydro-1,3-oxazolyl(CH 2)1-6; carboxy(CH2)1-6; phenylsulfonyl; piperidinyl-carbonyl; 1H-pyrazolyl; pyrrolidinyloxy; piperidin yloxy; amino(CH2)2O-; orNR12R13 , wherein one of R12 and R13 is hydrogen, C1-6alkyl, or hydroxy(CH 2)2-6; and the other one is {1-[amino(CH2)0-6]-3,3-difluorocyclobutyl}(CH 2)1-6; guanidino(CH2)2-6; (S-C1- 6alkylsulfonimidoyl)(CH 2)2-6; 2-oxaaza-spiro[3.4]octyl; {3-[amino(CH2)0- 6]tetrahydrofuranyl}(CH 2)1-6; 3-aminomethyl-1,1-dioxidothietanylmethyl; 3-amino- 1,1-dioxidothietanylmethyl; 3-(aminomethyl)thietanylmethyl; (1,1- dioxidothiomorpholinyl)ethyl; C0-6alkyl(oxetanyl)N(CH 2)2-6; 4,5-dihydro-1H-imidazol- 2-yl; amino(CH2)2O-(CH 2)2-6; amino(CH2)2-10 ; amino(CH2)1-6difluoromethyl(CH 2)1-6; amino(CH 2)1-6difluoromethyldifluoromethyl(CH 2)1-6; amino(CH2)1-6fluoromethyl(CH 2)1-6; amino(CH 2)1-6oxetanyl(CH 2)0-6; amino(CH2)0-6oxetanyl(CH 2)1-6; amino(CH2)2- 6sulfanyl(CH 2)2-6; amino(CH2)2-6sulfonyl(CH 2)2-6; CH2)0-6carbonyl(CH 2)0- 6; aminocycloalkyl(CH2)0-6; 2-aminodihydrooxazolyl(CH2)1-6; odihydrooxazol yl(CH 2)1-6; (2-aminomethyl-4,5-dihydro-1,3-oxazolyl)methyl; aminophenyl; 4- aminotetrahydropyranyl(CH 2)1-6; inyl(CH2)1-6; azetidinyl(CH2)0-6; azetidinylcarbonyl; C1-6alkoxy(CH 2)2-6; C1-6alkoxy(CH 2)2-6amino(CH 2)2-6; C1-6alkyl; C1- 6alkylamino(CH 2)2-6; C1-6alkylaminocarbonyl(CH 2)0-6; C1-6alkylaminooxetanyl(CH 2)1-6; C1- 6alkylcarbonyl; C1-6alkylcarbonylamino(CH 2)2-6; C1-6alkylcarbonylamino(CH 2)1- 6oxetanyl(CH 2)0-6; C1-6alkylsulfinyl(CH 2)2-6; C1-6alkylsulfonyl; carboxy(CH2)1-6; cyano(CH 2)1-6; diC1-6alkylamino(CH 2)2-6; diC1-6alkylaminocarbonyl; difluoromethyl(CH2)1- 6amino(CH 2)2-6; hydrogen; hydroxy(CH2)2-10 ; hydroxy(CH2)2-6amino(CH 2)2-6; y(CH 2)1-6carbonyl; hydroxy(CH2)0-6oxetanyl(CH 2)1-6; hydroxy(CH2)1- nyl(CH 2)0-6; hydroxycycloalkyl; isoxazolyl; morpholinyl(CH2)1-6; morpholin yl(CH2)2-6; oxetanyl(CH2)0-6; N-oxetanylpyrrolidinyl; oxo-pyrrolidinylcarbonyl; phenylaminocarbonyl; phenyl(CH2)0-6aminooxetanyl(CH2)1-6; phenylcarbonyl; piperazinyl(CH2)2-6; piperidinyl(CH2)2-6; piperidinyl(CH2)1-6; piperidinyl(CH2)0-6; piperidinyl(CH2)0-6; piperidinylcarbonyl; pyrazinylcarbonyl; pyrazolyl; pyridazinylcarbonyl; pyridinyl(CH2)0-6carbonyl; pyridinylamino(CH2)2-6; pyrrolidinyl, unsubstituted or 4-substituted by halogen; pyrrolidinyl, unsubstituted or 3-substituted by hydroxy or C1-6alkoxy; pyrrolidinyl(CH2)1-6; pyrrolidinylcarbonyl; tetrahydrofuranyl; tetrahydropyranyl; tetrazolyl(CH2)2-6; trifluoromethylcarbonylamino(CH2)1-6oxetanyl; -(CH2)1-6 C R15 trifluoromethylsulfonyl; R16 , wherein R14 is hydrogen, C1-6alkyl or hydroxy(CH2)1-6; R15 is hydroxy, C1-6alkyl, hydroxy(CH2)1-6 or amino; and R16 is C1-6alkyl, trifluoromethyl, hydroxy(CH2)1-6, amino(CH2)1-6, aminocarboxy or carboxy(CH2)1-6; C R18 R19 , n R17 is hydrogen, C 18 is hydroxy(CH 1-6alkyl or hydroxy(CH2)1-6; R 2)1-6 or C1-6alkyl; R19 is y(CH2)1-6, amino(CH2)1-6, carboxy or aminocarboxy(CH2)0-6; C R21 or R22 , wherein R20 is hydrogen or C1-6alkyl; R21 is C1-6alkyl; R22 is C1-6alkoxy or amino; R12 and R13, with the nitrogen atom to which they are ed, may form a pyrrolidinyl, zinyl, piperidinyl, morpholinyl, azetidinyl, diazepanyl or oxopyrrolidinyl ring; which may be unsubstituted, once or twice substituted by a group selected from halogen, C1- 6alkyl, koxy, gemdimethyl, amino, aminocarbonyl, hydroxy, oxetanylamino, C1- 6alkylpiperazinyl, and amino(CH2)1-6; R12 and R13, with the nitrogen atom to which they are attached may form a bridge ring or a spiral ring selected from 2-oxaaza-spiro[3.4]octanyl, 2-oxa-5,7-diazaspiro[3.4]octan- 6-oneyl, aR)-hexahydropyrrolo[3,4-b][1,4]oxazin-6(2H)-yl, 4,5,6,6a-tetrahydro- 3aH-pyrrolo[3,4-d][1,3]oxazolyl, 2-aza-bicyclo[2.1.1]hexanyl, and 3-aza- bicyclo[3.1.0]hexanyl; which may be unsubstituted or further substituted by amino; and pharmaceutically acceptable salt and stereoisomers thereof.
Respiratory ial Virus (RSV) belongs to the family of Paramyxoviridae, ily of Pneumovirinae. The human RSV is a major cause of acute upper and lower respiratory tract ion in infants and en. 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. isk factors for lower respiratory track infections include premature birth, congenital heart disease, chronic ary 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 ing 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 ion. However, it is rarely used clinically, due to limited efficacy and potential side effects. Two marketed prophalyxis antibodies were developed by une (CA, USA).
RSV-IGIV (brand name RespiGam) is polyclonal-concentrated RSV neutralizing antibody administered through monthly on of 750 mg/kg in hospital (Wandstrat TL, Ann cother. 1997 Jan;31(1):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 laxis in high-risk s in 1998. When administered intramuscularly at 15 mg/kg once a month for the duration of RSV season, palivizumab demonstrated 45 – 55% ion of hospitalization rate caused by RSV infection in selected infants (Pediatrics. 1998 Sep;102(3):531-7; Feltes TF et al, J r. 2003 Oct;143(4):532-40).
Unfortunately, zumab is not effective in the treatment of established RSV infection. A newer version monoclonal dy, motavizumab, was designed as potential replacement of palivizumab but failed to show additional t 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 ry 2010 (www.clinicaltrials.gov), but has not released the final results. Most of other small molecules were put on hold for s reasons.
RNAi therapeutics against RSV have also been thoroughly studied. ALN-RSV01 (Alnylam ceuticals, 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 IIb clinical trials in similar patient population for ALN-RSV01 are on-going (www.clinicaltrials.gov).
Nevertheless, safe and effective treatment for RSV disease is needed urgently.
It has been found that the compounds of the t 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 “C0-6alkyl” alone or in combination signifies a chemical bond, or hydrogen, or saturated, linear- or ed chain alkyl group ning 1 to 6, preferably 1 to 4 carbon atoms, for example methyl, ethyl, propyl, pyl, 1-butyl, 2-butyl, tert -butyl and the like. red “C0-6alkyl” groups are chemical bond, hydrogen, methyl, ethyl, isopropyl, tert - butyl.
As used herein, the term “C1-6alkyl” alone or in combination signifies a saturated, linear- or ed chain alkyl group containing 1 to 6, preferably 1 to 4 carbon atoms, for example methyl, ethyl, propyl, isopropyl, 1-butyl, l, tert -butyl and the like. Preferred “C1-6alkyl” groups are methyl, ethyl, isopropyl, tert -butyl.
As used herein, the term lkyl” alone or in ation 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 lkyl” groups are ethyl, isopropyl, tert -butyl.
As used herein, the term “-(CH2)0” signifies a chemical link, hydrogen, or a saturated, linear alkyl chain containing from 1 to 6 carbon atoms, preferably, the term signifies hydrogen or -(CH2)1.
As used herein, the term “-(CH2)1” 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” signifies a saturated, linear alkyl chain containing from 2 to 6 carbon atoms, ably from 2 to 4 carbon atoms.
As used herein, the term “-(CH2)2-10 -” ies 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, ropyl, utyl, cyclopentyl, exyl, cycloheptyl and the like. Preferred cycloalkyl groups are ropyl, cyclopentyl and exyl.
The term “C1-6alkoxy” alone or in combination signifies a group C1-6alkyl-O-, n the “C1-6alkyl” is as defined above; for example methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, i- butoxy, xy, t-butoxy and the like. Preferred C1-6alkoxy groups are methoxy and ethoxy and more preferably methoxy.
The term “C2-6alkoxy” alone or in combination signifies a group C2-6alkyl-O-, wherein the “C2-6alkyl” is as defined above; for example ethoxy, propoxy, isopropoxy, n-butoxy, xy, 2- butoxy, t-butoxy and the like. Preferred koxy 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 ( N ).
The term “sulfonyl” alone or in combination refers to the group -S(O)2-.
The term “C1-6alkylsulfanyl” alone or in combination refers to the group -S-C1-6alkyl.
The term “C1-6alkylsulfinyl” alone or in ation refers to the group -S(O) -C1-6alkyl.
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 ical 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 derived from inorganic acids such as hloric acid, hydrobromic acid, hydroiodic 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 d from ammonium, potassium, sodium and, quaternary um hydroxides, such as for example, ethyl ammonium hydroxide. The chemical cation of a pharmaceutical compound into a salt is a que well known to ceutical chemists in order to obtain improved physical and chemical ity, hygroscopicity, ility and solubility of compounds. It is for example described in Bastin R.J., et. al., Organic Process Research & Development 2000, 4, 5; 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 tives 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 e, propionate and isobutyrate.
Additionally, any physiologically able equivalents of the compounds of general formula (I), similar to the metabolically labile esters, which are e 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 s 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 R1 is hydrogen, halogen or C1-6alkyl; R2 is hydrogen, halogen or C1-6alkyl; R3 is hydrogen, halogen or C1-6alkyl; R4 is hydrogen or C1-6alkyl; R5 is hydrogen; R6 is hydrogen, halogen, hydroxy, C1-6 alkoxy, linyl or alkylpiperazinyl; R7 is hydrogen, halogen, C1-6alkyl, C1-6alkoxy, phenoxy or hydroxy(CH2)2O-; R8 is hydrogen, halogen or C1-6alkoxy; R9 is en or C1-6alkyl; R10 is hydrogen; A is nitrogen or -C-R11 , wherein R11 is hydrogen, halogen, C1-6 alkyl, cycloalkyl, C1- 6alkoxy, trifluoromethyl, trifluoromethoxy, pyridinyloxy, C1-6alkoxy(CH O-, romethoxy, cyano, nitro, amino, vinyl, acetylenyl, aminocarbonyl, hydroxy(CH2)2O-, C1- 6alkylsulfinyl, hydroxy(CH2)1-6, deuteratedC1-6alkyl, carboxyl, carbonyl, hydroxy, difluoromethyl, -CH(hydroxy)C1-6alkyl or C1-6alkylsulfanyl; X is S, S=O, SO2 or S(O)NH; Y is -CH- or nitrogen; Q is C1-6alkyl, unsubstituted or once substituted by amino; amino(CH 2)2-6aminosulfonyl; 2-amino-4,5-dihydro-1,3-oxazolylethyl; carboxy(CH2)1-6; phenylsulfonyl; piperidinyl- carbonyl; 1H-pyrazolyl; pyrrolidinyloxy; piperidinyloxy; amino(CH2)2O-; NR 12 R13 , wherein one of R12 and R13 is hydrogen, C 1-6alkyl or hydroxy(CH2)2-6; and the other one is {1-[amino(CH2)0-6]-3,3-difluorocyclobutyl}(CH 2)1-6; (S-C1-6alkylsulfonimidoyl)(CH 2)2-6; {3-[amino(CH 2)0-6]tetrahydrofuranyl}(CH 2)1-6; (2-aminomethyl-4,5-dihydro-1,3- oxazolyl)methyl; 3-aminomethyl-1,1-dioxidothietanylmethyl; 3- (aminomethyl)thietanylmethyl; (1,1-dioxidothiomorpholinyl)ethyl; C0- 6alkyl(oxetanyl)N(CH 2)2-6; 4,5-dihydro-1H-imidazolyl; amino(CH2)2O-(CH 2)2-6; amino(CH 2)2-10 ; amino(CH2)0-6carbonyl(CH 2)0-6; amino(CH2)1-6difluoromethyl(CH 2)1-6; amino(CH 2)1-6difluoromethyldifluoromethyl(CH 2)1-6; CH2)1-6fluoromethyl(CH 2)1-6; amino(CH 2)1-6oxetanyl(CH 2)0-6; amino(CH2)0-6oxetanyl(CH 2)1-6; amino(CH2)2- nyl(CH 2)2-6; amino(CH2)2-6sulfonyl(CH 2)2-6; 1-aminocyclobutylmethyl; 2- aminocyclohexyl; 3-aminocyclohexyl; 4-aminocyclohexyl; 1-aminocyclohexylmethyl; 2- aminocyclopentyl; ocyclopropylethyl; 1-aminocyclopropylmethyl; (2-amino-4,5- dihydro-oxazolyl)(CH 2)1-6; (2-amino-4,5-dihydro-oxazolyl)(CH2)1-6; aminophenyl; 4- aminotetrahydropyranyl(CH2)1-6; azetidinyl(CH2)1-6; azetidinyl(CH2)0-6; azetidin- rbonyl; C1-6alkoxy(CH2)2-6; C1-6alkoxy(CH2)2-6amino(CH2)2-6; C1-6alkyl; C1- 6alkylamino(CH2)2-6; C1-6alkylaminooxetanyl(CH2)1-6; C1-6alkylcarbonyl; C1- 6alkylaminocarbonyl(CH2)0-6; C1-6alkylcarbonylamino(CH2)2-6; C1- 6alkylcarbonylamino(CH2)1-6oxetanyl(CH2)0-6; C1-6alkylsulfinyl(CH2)2-6; kylsulfonyl; carboxy(CH2)1-6; cyano(CH2)1-6; alkylamino(CH2)2-6; diC1-6alkylaminocarbonyl; difluoromethyl(CH2)1-6amino(CH2)2-6; hydrogen; hydroxy(CH2)2-10; hydroxy(CH2)2- 6amino(CH2)2-6; hydroxy(CH2)1-6carbonyl; hydroxy(CH2)1-6oxetanyl(CH2)0-6; hydroxy(CH2)0-6oxetanyl(CH2)1-6; 4-hydroxycyclohexyl; isoxazolyl; morpholin yl(CH2)1-6; morpholinyl(CH2)2-6; 2-oxaaza-spiro[3.4]octyl; oxetanyl(CH2)0-6; N- oxetanylpyrrolidinyl; oxo-pyrrolidinylcarbonyl; phenylaminocarbonyl; phenyl(CH2)0- 6aminooxetanyl(CH2)1-6; phenylcarbonyl; piperazinyl(CH2)2-6; piperidinyl(CH2)2-6; piperidinyl(CH2)1-6; piperidinyl(CH2)0-6; piperidinyl(CH2)0-6; piperidinylcarbonyl; pyrazinylcarbonyl; pyrazolyl; pyridazinylcarbonyl; pyridinyl(CH2)0-6carbonyl; nylamino(CH2)2-6; pyrrolidinyl, unsubstituted or 4-substituted by halogen; pyrrolidinyl, unsubstituted or 3-substituted by hydroxy or C1-6alkoxy; pyrrolidin yl(CH2)1-6; pyrrolidinylcarbonyl; tetrahydrofuranyl; tetrahydropyranyl; tetrazolyl(CH2)2-6; trifluoromethylcarbonylamino(CH2)1-6oxetanyl; trifluoromethylsulfonyl; -(CH2)1-6 C R15 R16 , wherein R14 is hydrogen or C1-6alkyl; R15 is hydroxy, kyl or amino; and R16 is C1-6alkyl, oromethyl, hydroxy(CH2)1-6, amino(CH2)1-6, arbonyl or C R18 carboxy(CH2)1-6; R19 , wherein R17 is hydrogen, C 18 is 1-6alkyl or hydroxy(CH2)1-6; R hydroxy(CH2)1-6 or C1-6alkyl; R19 is hydroxy(CH2)1-6, amino(CH2)1-6, carboxy or C R21 aminocarbonyl(CH2)0-6; or R22 , wherein R20 is hydrogen or C1-6alkyl; R21 is C1- 22 is C 6alkyl; R 1-6alkoxy 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 tuted by a group selected from n, C1- 6alkyl, C1-6alkoxy, gemdimethyl, amino, aminocarbonyl, hydroxy, oxetanylamino, C1- 6alkylpiperazinyl, and amino(CH2)1-6; R12 and R13, with the nitrogen atom to which they are may form a bridge ring or a spiral ring selected from 6-aza-spiro[3.4]octanyl, 5,7-diazaspiro[3.4]octanone- -yl, (4aS,7aR)-hexahydropyrrolo[3,4-b][1,4]oxazin-6(2H)-yl, 4,5,6,6a-tetrahydro-3aH- pyrrolo[3,4-d][1,3]oxazolyl, 2-aza-bicyclo[2.1.1]hexanyl and 3-azabicyclo [3.1.0]hexanyl; which may be unsubstituted or further tuted by amino.
Further embodiment of present invention is (iii) a compound of formula (I) or a pharmaceutically able 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-(propanyl)piperazinyl; 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, nyloxy, methoxyethoxy, difluoromethoxy, cyano, nitro, amino, vinyl, acetylenyl, aminocarbonyl, yethoxy, sulfanyl, sulfinyl, hydroxymethyl, atedmethyl, carboxyl, methoxycarbonyl, hydroxy, difluoromethyl, methylCH(hydroxy)- or methylsulfonyl; X is S, S=O, SO2 or S(O)NH; Y is -CH- or en; Q is 2-amino-4,5-dihydro-1,3-oxazolylethyl; aminoethoxy; aminoethylaminosulfonyl; aminopropyl; carboxyethyl; methyl; phenylsulfonyl; dinyl-carbonyl; piperidin yloxy; 1H-pyrazolyl; pyrrolidinyloxy; or NR 12 R13 , wherein one of R12 and R13 is hydrogen, methyl or hydroxyethyl; and the other one is aminobutyl; aminocarbonylethyl; aminocarbonylmethyl; 1-aminocyclobutylmethyl; 2- aminocyclohexyl; 3-aminocyclohexyl; 4-aminocyclohexyl; 1-aminocyclohexylmethyl; 2- aminocyclopentyl; 1-aminocyclopropylethyl; 1-aminocyclopropylmethyl; aminodecyl; (2- amino-4,5-dihydro-oxazolyl)methyl; (2-amino-4,5-dihydro-oxazolyl)methyl; aminoethoxyethyl; aminoethyl; aminoethylcarbonyl; aminoethylfluoromethylmethyl; aminoethylsulfanylethyl; aminoethylsulfonylethyl; aminoheptyl; aminohexyl; aminomethylcarbonyl; (1-aminomethyl-3,3-difluorocyclobutyl)methyl; aminomethyldifluoromethyldifluoromethylmethyl; ethyldifluoromethylmethyl; (2- aminomethyl-4,5-dihydro-1,3-oxazolyl)methyl; 3-aminomethyl-1,1-dioxidothietan ylmethyl; aminomethylfluoromethylethyl; aminomethylfluoromethylmethyl; aminomethyloxetanyl; aminomethyloxetanylmethyl; 3-(aminomethyl)thietanylmethyl; aminononyl; aminooctyl; aminooxetanylethyl; aminooxetanylmethyl; aminopentyl; aminophenyl; aminopropyl; 4-aminotetrahydropyranylmethyl; 3-aminotetrahydrofuran- 3-ylmethyl; azetidinyl; azetidinylcarbonyl; azetidinylmethyl; azetidinylmethyl; carboxyethyl; carboxymethyl; cyanoethyl; difluoromethylmethylaminoethyl; 4,5-dihydro- 1H-imidazolyl; dimethylaminocarbonyl; dimethylaminoethyl; (1,1- dioxidothiomorpholinyl)ethyl; ethyl; ethylaminocarbonyl; ethylaminoethyl; minooxetanylmethyl; ethyl (oxetanyl)aminoethyl; en; 4-hydroxycyclohexyl; hydroxyethyl; hydroxyethylaminoethyl; hydroxyethyloxetanyl; hydroxymethylcarbonyl; hydroxymethyloxetanylmethyl; hydroxynonyl; ypropyl; isoxazolyl; methoxyethyl; methoxyethylaminoethyl; methyl; methylaminocarbonylmethyl; methylaminoethyl; methylcarbonyl; methylcarbonylaminoethyl; methylcarbonylaminomethyloxetanylmethyl; carbonylaminopropyl; methylsulfinylethyl; 2-(S-methylsulfonimidoyl)ethyl; methylsulfonyl; linylethyl; morpholinylmethyl; 2-oxaaza-spiro[3.4]octyl; oxetanyl; oxetanylaminoethyl; oxetanylaminopropyl; oxetanylmethyl; N-oxetanylpyrrolidinyl; oxo-pyrrolidin ylcarbonyl; phenylaminocarbonyl; carbonyl; phenylmethylaminooxetanylmethyl; piperazinylethyl; piperidinylcarbonyl; piperidinylcarbonyl; piperidinylcarbonyl; piperidinyl; piperidinyl; piperidinylethyl; dinylmethyl; pyrazin ylcarbonyl; pyrazolyl; pyridazinylcarbonyl; pyridineylmethylcarbonyl; ne ylaminoethyl; pyridineylcarbonyl; pyridineylcarbonyl; pyrrolidinyl, unsubstituted or 4-substituted by fluoro; idinyl, unsubstituted or 3-substituted by hydroxy or methoxy; pyrrolidinylmethyl; pyrrolidinylcarbonyl; tetrahydrofuranyl; tetrahydropyranyl; olylethyl; trifluoromethylsulfonyl; -(CH2)1-6 C R15 oromethylcarbonylaminomethyloxetanyl; R16 , wherein R14 is hydrogen or methyl; R15 is hydroxy, methyl or amino; and R16 is methyl, trifluoromethyl, C R18 hydroxymethyl, hydroxyethyl, aminomethyl, aminocarbonyl or carboxymethyl; R19 , wherein R17 is hydrogen, methyl or hydroxymethyl; R18 is ymethyl or methyl; R19 is hydroxymethyl, aminomethyl, carboxy, aminocarbonyl or aminocarbonylmethyl; C R21 or R22 , wherein R20 is hydrogen or ; 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, arbonyl, 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-oxaaza-spiro[3.4]octanyl, 2-oxa-5,7-diazaspiro[3.4]octan- 6-oneyl, aR)-hexahydropyrrolo[3,4-b][1,4]oxazin-6(2H)-yl, 4,5,6,6a-tetrahydro- 3aH-pyrrolo[3,4-d][1,3]oxazolyl, 2-aza-bicyclo[2.1.1]hexanyl or 3-azabicyclo [3.1.0]hexanyl; 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 ceutically acceptable salt f, wherein R1, R2, R3, R4, R5, R6, R7, R8, R9 and R10 are hydrogen; A is -C-R11, wherein R11 is en, n or C1-6alkyl; X is S; Y is -CH- or nitrogen; Q is NR12R13, n one of R12 and R13 is hydrogen; and the other one is amino(CH2)2-6, amino(CH2)1-6difluoromethyl(CH2)1-6, amino(CH2)0-6oxetanyl(CH2)1-6 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 R1, R2, R3, R4, R5, R6, R7, R8, R9 and R10 are hydrogen; A is -C-R11, wherein R11 is hydrogen, chloro or methyl; Q is NR12R13, wherein one of R12 and R13 is hydrogen; and the other one is aminoethyl, aminomethyldifluoromethylmethyl, ethyloxetanylmethyl, aminooxetanylmethyl or hydrogen; R12 and R13, with the nitrogen atom to which they are ed, 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, n, C1-6alkyl, hydroxy(CH2)1-6, deuteratedmethyl or carboxyl; X is S=O; Y is -CH- or nitrogen; Q is NR12R13, wherein one of R12 and R13 is hydrogen; and the other one is amino(CH2)2-6; CH2)1-6difluoromethyl(CH2)1-6; amino(CH2)1-6fluoromethyl(CH2)1-6; amino(CH2)1-6oxetanyl; amino(CH2)1-6oxetanyl(CH2)1-6; xetanyl(CH2)1-6; hydroxy(CH2)2- ; phenyl(CH2)1-6aminooxetanyl(CH2)1-6; pyrrolidinyl, 4-substituted by n; -(CH2)1-6 C R15 or R16 , wherein R14 is hydrogen, R15 is hydroxy, and R16 is hydroxy(CH2)1-6; R12 and R13, with the nitrogen atom to which they are ed, may form a pyrrolidinyl ring, which may be once or twice substituted by a group selected from halogen, amino and yl; and all the ing 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, hydroxymethyl, deuteratedmethyl or carboxyl; Q is NR12R13, wherein one of R12 and R13 is hydrogen; and the other one is thyl; aminomethyldifluoromethylmethyl; aminomethylfluoromethylmethyl; ethyloxetanyl; aminomethyloxetanylmethyl; aminooxetanylmethyl; aminopropyl; yethyl; -(CH2)1-6 C R15 phenylmethylaminooxetanylmethyl; pyrrolidinyl, tituted by fluoro; or R16 , 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 ed 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 C1-6alkyl; R4 is hydrogen or C1-6alkyl; R5 is hydrogen; R6 is hydrogen, halogen, hydroxy, C1-6alkoxy, morpholinyl or 4-(propanyl)piperazin- 1-yl; R7 is hydrogen, halogen, C1-6alkyl, koxy, hydroxy(CH2)2O-, or phenoxy; R8 is hydrogen, n or C1-6alkoxy; R9 is hydrogen or C1-6alkyl; R10 is hydrogen; A is nitrogen or -C-R11, wherein R11 is hydrogen, halogen, C1-6alkyl, C1-6alkoxy, trifluoromethyl, oromethoxy, pyridinyloxy, koxy(CH2)1O-, difluoromethoxy, nitro, cycloalkyl, cyano, amino, vinyl, acetylenyl, aminocarbonyl, hydroxy(CH2)2O-, C1- 6alkylsulfanyl, C1-6alkylsulfinyl, hydroxy(CH2)1-6, deuteratedmethyl, carboxyl, C1- 6alkoxycarbonyl, hydroxy, difluoromethyl or methylCH(hydroxy)-; X is SO2; Y is -CH- or nitrogen; Q is 2-amino-4,5-dihydro-1,3-oxazolylethyl; amino(CH2)2O-; amino(CH2)2- 6aminosulfonyl; C1-6alkyl, unsubstituted or once substituted by amino; carboxy(CH2)1-6; phenylsulfonyl; piperidinyl-carbonyl; dinyloxy; 1H-pyrazolyl; idinyloxy; or NR12R13, wherein one of R12 and R13 is hydrogen, C1-6alkyl or y(CH2)2-6; and the other one is {1-[amino(CH2)0-6]-3,3-difluorocyclobutyl}(CH2)1-6; (S-C1-6alkylsulfonimidoyl)(CH2)2-6; 3-aminotetrahydrofuranyl(CH2)1-6; (2-aminomethyl-4,5-dihydro-1,3-oxazolyl)methyl; 3- aminomethyl-1,1-dioxidothietanylmethyl; 3-(aminomethyl)thietanylmethyl; (1,1- dioxidothiomorpholinyl)ethyl; kyl(oxetanyl)N(CH2)2-6; 4,5-dihydro-1H-imidazolyl; amino(CH2)2O-(CH2)2-6; CH2)2-10; amino(CH2)1-6carbonyl; aminocarbonyl(CH2)1-6; amino(CH2)1-6difluoromethyl(CH2)1-6; amino(CH2)1-6difluoromethyldifluoromethyl(CH2)1-6; amino(CH2)1-6fluoromethyl(CH2)1-6; amino(CH2)1-6oxetanyl(CH2)0-6; amino(CH2)0- 6oxetanyl(CH2)1-6; amino(CH2)2-6sulfanyl(CH2)2-6; amino(CH2)2-6sulfonyl(CH2)2-6; 1- aminocyclobutylmethyl; 2-aminocyclohexyl; 3-aminocyclohexyl; 4-aminocyclohexyl; 1- yclohexylmethyl; 2-aminocyclopentyl; 1-aminocyclopropylethyl; 1- aminocyclopropylmethyl; (2-amino-4,5-dihydro-oxazolyl)(CH2)1-6; (2-amino-4,5-dihydrooxazolyl ) (CH2)1-6; aminophenyl; otetrahydropyranyl(CH2)1-6; azetidinyl(CH2)1-6; azetidinyl(CH2)0-6; azetidinylcarbonyl; C1-6alkoxy(CH2)2-6; C1-6alkoxy(CH2)2- 6amino(CH2)2-6; kyl; C1-6alkylamino(CH2)2-6; C1-6alkylaminooxetanyl(CH2)1-6; C1- 6alkylcarbonyl; kylcarbonylamino(CH2)2-6; C1-6alkylcarbonylamino(CH2)1-6oxetanyl(CH2)0- 6; C1-6alkylsulfinyl(CH2)2-6; C1-6alkylsulfonyl; carboxy(CH2)1-6; cyano(CH2)1-6; C1- 6alkylaminocarbonyl(CH2)0-6; diC1-6alkylamino(CH2)2-6; diC1-6alkylaminocarbonyl; difluoromethyl(CH2)1-6amino(CH2)2-6; hydrogen; hydroxy(CH2)2-10; hydroxy(CH2)2- (CH2)2-6; hydroxy(CH2)1-6carbonyl; hydroxy(CH2)1-6oxetanyl(CH2)0-6; 4- hydroxycyclohexyl; isoxazolyl; morpholinyl(CH2)1-6; morpholinyl(CH2)2-6; 2-oxa aza-spiro[3.4]octyl; oxetanyl(CH2)0-6; N-oxetanylpyrrolidinyl; oxo-pyrrolidin ylcarbonyl; phenylaminocarbonyl; phenyl(CH2)1-6aminooxetanyl(CH2)1-6; phenylcarbonyl; piperazinyl(CH2)2-6; piperidinyl(CH2)2-6; dinyl(CH2)1-6; piperidinyl(CH2)0-6; piperidinyl(CH2)0-6; piperidinylcarbonyl; piperidinylcarbonyl; piperidinylcarbonyl; pyrazinylcarbonyl; pyrazolyl; pyridazinylcarbonyl; pyridineyl(CH2)0-6carbonyl; pyridineyl(CH2)0-6carbonyl; pyridineylamino(CH2)2-6; pyrrolidinyl, unsubstituted or 4- substituted by halogen; pyrrolidinyl, tituted or tituted by hydroxy or C1-6alkoxy; pyrrolidinyl(CH2)1-6; pyrrolidinylcarbonyl; tetrahydrofuranyl; tetrahydropyranyl; tetrazolyl(CH2)2-6; trifluoromethylcarbonylamino(CH2)1-6oxetanyl; trifluoromethylsulfonyl; -(CH2)1-6 C R15 R16 , wherein R14 is hydrogen or C1-6alkyl; R15 is hydroxy, C1-6alkyl or amino; and R16 is C1-6alkyl, trifluoromethyl, hydroxy(CH2)1-6, amino(CH2)1-6, aminocarbonyl or carboxy(CH2)1- C R18 R19 , wherein R17 is hydrogen, C 18 is hydroxy(CH 6; 1-6alkyl or hydroxy(CH2)1-6; R 2)1-6 or C1-6alkyl; R19 is hydroxy(CH2)1-6, amino(CH2)1-6, y or aminocarbonyl(CH2)0-6; C R21 or R22 , wherein R20 is hydrogen or kyl; R21 is C1-6alkyl; R22 is C1-6alkoxy 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, C1-6alkyl, C1- 6alkoxy, gemdimethyl, amino, aminocarbonyl, hydroxy, ylamino, C1-6alkylpiperazinyl and amino(CH2)1-6; R12 and R13, with the nitrogen atom to which they are attached may form a bridge ring or a spiral ring selected from 2-oxaaza-spiro[3.4]octanyl, 5,7-diazaspiro[3.4]octanone- 5-yl, (4aS,7aR)-hexahydropyrrolo[3,4-b][1,4]oxazin-6(2H)-yl, 4,5,6,6a-tetrahydro-3aH- pyrrolo[3,4-d][1,3]oxazolyl, 2-aza-bicyclo[2.1.1]hexanyl or 3-aza-bicyclo[3.1.0]hexan 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-(propanyl)piperazinyl; R7 is hydrogen, fluoro, , methyl, methoxy, hydroxyethoxy, or phenoxy; R8 is hydrogen, fluoro or methoxy; R9 is en or ; R10 is hydrogen; A is nitrogen or -C-R11, wherein R11 is en, fluoro, chloro, bromo, methyl, ethyl, methoxy, trifluoromethyl, trifluoromethoxy, pyridinyloxy, methoxyethoxy, difluoromethoxy, nitro, ropyl, cyano, amino, vinyl, acetylenyl, aminocarbonyl, hydroxyethoxy, methylsulfanyl, methylsulfinyl, hydroxymethyl, deuteratedmethyl, carboxyl, ycarbonyl, hydroxy, difluoromethyl or methylCH(hydroxy)-; Y is -CH- or nitrogen; Q is 2-amino-4,5-dihydro-1,3-oxazolylethyl; aminoethoxy; aminoethylaminosulfonyl; aminopropyl; carboxyethyl; methyl; phenylsulfonyl; piperidinyl-carbonyl; piperidinyloxy; 1H-pyrazolyl; pyrrolidinyloxy; or NR12 R13 , wherein one of R12 and R13 is hydrogen, methyl or hydroxyethyl, and the other one is aminobutyl; aminocarbonylethyl; aminocarbonylmethyl; 1-aminocyclobutylmethyl; 2-aminocyclohexyl; 3-aminocyclohexyl; 4- aminocyclohexyl; 1-aminocyclohexylmethyl; 2-aminocyclopentyl; 1-aminocyclopropylethyl; 1- aminocyclopropylmethyl; aminodecyl; (2-amino-4,5-dihydro-oxazolyl)methyl; no-4,5- dihydro-oxazolyl)methyl; aminoethoxyethyl; aminoethyl; aminoethylcarbonyl; aminoethylfluoromethylmethyl; aminoethylsulfanylethyl; aminoethylsulfonylethyl; aminoheptyl; exyl; aminomethylcarbonyl; (1-aminomethyl-3,3- difluorocyclobutyl)methyl; ethyldifluoromethyldifluoromethylmethyl; aminomethyldifluoromethylmethyl; (2-aminomethyl-4,5-dihydro-1,3-oxazolyl)methyl; 3- aminomethyl-1,1-dioxidothietanylmethyl; aminomethylfluoromethylethyl; aminomethylfluoromethylmethyl; aminomethyloxetanyl; aminomethyloxetanylmethyl; 3- (aminomethyl)thietanylmethyl; onyl; aminooctyl; aminooxetanylethyl; aminooxetanylmethyl; entyl; aminophenyl; aminopropyl; 4-aminotetrahydropyran ylmethyl; 3-aminotetrahydrofuranylmethyl; azetidinyl; azetidinylcarbonyl; azetidin ylmethyl; azetidinylmethyl; carboxyethyl; carboxymethyl; cyanoethyl; difluoromethylmethylaminoethyl; 4,5-dihydro-1H-imidazolyl; dimethylaminocarbonyl; dimethylaminoethyl; (1,1-dioxidothiomorpholinyl)ethyl; ethyl; ethylaminocarbonyl; minoethyl; ethylaminooxetanylmethyl; ethyl (oxetanyl)aminoethyl; en; 4- hydroxycyclohexyl; hydroxyethyl; hydroxyethylaminoethyl; hydroxyethyloxetanyl; hydroxymethylcarbonyl; hydroxymethyloxetanylmethyl; hydroxynonyl; ypropyl; olyl; methoxyethyl; methoxyethylaminoethyl; methyl; methylaminocarbonylmethyl; methylaminoethyl; methylcarbonyl; methylcarbonylaminoethyl; methylcarbonylaminomethyloxetanylmethyl; methylcarbonylaminopropyl; methylsulfinylethyl; 2-(S-methylsulfonimidoyl)ethyl; methylsulfonyl; morpholinylethyl; morpholinylmethyl; 2- oxaaza-spiro[3.4]octyl; oxetanyl; oxetanylaminoethyl; ylaminopropyl; oxetanylmethyl; N-oxetanylpyrrolidinyl; oxo-pyrrolidinylcarbonyl; phenylaminocarbonyl; phenylcarbonyl; phenylmethylaminooxetanylmethyl; piperazinylethyl; piperidin ylcarbonyl; piperidinylcarbonyl; piperidinylcarbonyl; piperidineyl; piperidineyl; piperidinylethyl; piperidinylmethyl; pyrazinylcarbonyl; pyrazolyl; pyridazin ylcarbonyl; pyridineylmethylcarbonyl; neylaminoethyl; pyridineylcarbonyl; pyridineylcarbonyl; pyrrolidinyl, unsubstituted or tituted by fluoro; pyrrolidinyl, unsubstituted or 3-substituted by y or methoxy; pyrrolidinylmethyl; pyrrolidin ylcarbonyl; tetrahydrofuranyl; tetrahydropyranyl; tetrazolylethyl; trifluoromethylsulfonyl; -(CH2)1-6 C R15 trifluoromethylcarbonylaminomethyloxetanyl; R16 , wherein R14 is hydrogen or methyl; R15 is y, methyl or amino; and R16 is methyl, trifluoromethyl, hydroxymethyl, C R18 yethyl, aminomethyl, aminocarbonyl or carboxymethyl; R19 , wherein R17 is hydrogen, methyl or ymethyl; R18 is hydroxymethyl or methyl; R19 is hydroxymethyl, C R21 aminomethyl, y, arbonyl or aminocarbonylmethyl; or R22 , 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, dinyl, 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, ylamino, methylpiperazinyl and ethyl; R12 and R13, with the nitrogen atom to which they are attached may form a bridge ring or a spiral ring selected from 2-oxaaza-spiro[3.4]octanyl, 2-oxa-5,7-diazaspiro[3.4]octanone- -yl, (4aS,7aR)-hexahydropyrrolo[3,4-b][1,4]oxazin-6(2H)-yl, 4,5,6,6a-tetrahydro-3aH- pyrrolo[3,4-d][1,3]oxazolyl, 2-aza-bicyclo[2.1.1]hexanyl or 3-aza-bicyclo[3.1.0]hexan 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; A is -C-R11, wherein R11 is C1-6alkyl; X is S(O)NH; Y is -CH-; Q is NR12R13, wherein one of R12 and R13 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 yl; and all the remaining substituents are as defined above in embodiment (i) to (ix).
Still another ular embodiment of invention is (xi) a compound of formula (I) or a pharmaceutically acceptable salt thereof, n R1, R2, R3, R4, R5, R6, R7, R8, R9, and R10 are hydrogen; A is -C-R11 , wherein R11 is methyl; Q is NR12 R13 , wherein one of R12 and R13 is hydrogen; and the other one is aminoethyl; 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 hydroxyl; and all the remaining substituents are as defined above in ment (x). ular embodiment of present invention is a compound of formula (I) or a pharmaceutically acceptable salt thereof, selected from: N-[(3-aminooxetanyl)methyl](8-methoxy-1,1-dioxido-2,3-dihydro-1,4-benzothiazepin- 4(5 H)-yl)methylquinolinamine; N-[(3-aminooxetanyl)methyl](8-fluoro-1,1-dioxido- 2,3-dihydro-1,4-benzothiazepin-4(5 H)-yl)methylquinolinamine; N-[(3-aminooxetan yl)methyl](7-fluoro-1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5 H)-yl)methylquinolin- 4-amine; N-[(3-aminooxetanyl)methyl](9-fluoro-1,1-dioxido-2,3-dihydro-1,4- benzothiazepin-4(5 H)-yl)methylquinolinamine; N-[(3-aminooxetanyl)methyl](7- methoxy-1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5 H)-yl)methylquinolinamine; N- inooxetanyl)methyl](8-chloro-1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5 H)- yl)methylquinolinamine; N-[(3-aminooxetanyl)methyl](7-methoxy-1,1-dioxido-2,3- o-1,4-benzothiazepin-4(5 H)-yl)quinolinamine; N-[(3-aminotetrahydrofuran yl)methyl](1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5 H)-yl)methylquinolinamine; N-[(3-aminooxetanyl)methyl](1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5 H)-yl) methylquinolinamine; N-[(4-aminotetrahydro-2H-pyranyl)methyl](1,1-dioxido-2,3- dihydro-1,4-benzothiazepin-4(5 H)-yl)methylquinolinamine; N-[(3-aminooxetan yl)methyl](8-methyl-1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5 H)-yl)quinolinamine; N-[(3-aminooxetanyl)methyl]methyl(8-methyl-1,1-dioxido-2,3-dihydro-1,4- benzothiazepin-4(5 H)-yl)quinolinamine; 2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin- 4(5 H)-yl)methyl-N-(2-oxaazaspiro[3.4]octyl)quinolinamine; N-[2-(3-aminooxetan yl)ethyl](1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5 methylquinolinamine; N-[(3-aminooxetanyl)methyl]methyl(5-methyl-1,1-dioxido-2,3-dihydro-1,4- benzothiazepin-4(5 H)-yl)quinolinamine; aminooxetanyl)methyl](8-methoxy-1,1- dioxido-2,3-dihydro-1,4-benzothiazepin-4(5 H)-yl)quinolinamine; N-[(3-aminooxetan yl)methyl](1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5 H)-yl)-1,6-naphthyridinamine; N-[(1-aminocyclohexyl)methyl](1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5 H)-yl) methylquinolinamine; N-{[3-(aminomethyl)oxetanyl]methyl}(8-fluoro-1,1-dioxido-2,3- o-1,4-benzothiazepin-4(5 H)-yl)methylquinolinamine; N-{[3-(benzylamino)oxetan yl]methyl}chloro(7-fluoro-1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5 H)-yl)quinolin- 4-amine; N-[(3-aminooxetanyl)methyl]chloro(7-fluoro-1,1-dioxido-2,3-dihydro-1,4- benzothiazepin-4(5 H)-yl)quinolinamine; N-{[3-(aminomethyl)oxetanyl]methyl}(7- methoxy-1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5 H)-yl)quinolinamine; N-{[3- (aminomethyl)oxetanyl]methyl}(7-methoxy-1,1-dioxido-2,3-dihydro-1,4-benzothiazepin- 4(5 H)-yl)methylquinolinamine; N-{[3-({[2-(7-methoxy-1,1-dioxido-2,3-dihydro-1,4- hiazepin-4(5 H)-yl)methylquinolinyl]amino}methyl)oxetanyl]methyl}acetamide; (aminomethyl)oxetanyl]methyl}(8-methyl-1,1-dioxido-2,3-dihydro-1,4- hiazepin-4(5 H)-yl)quinolinamine; N-{[3-(aminomethyl)oxetanyl]methyl}methyl- 2-(8-methyl-1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5 H)-yl)quinolinamine; [3-({[2- (1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5 H)-yl)methylquinolin yl]amino}methyl)oxetanyl]methanol; (2S ){[2-(1,1-dioxido-2,3-dihydro-1,4- benzothiazepin-4(5 methylquinolinyl]amino}propane-1,2-diol; (2R ){[2-(1,1- dioxido-2,3-dihydro-1,4-benzothiazepin-4(5 H)-yl)methylquinolinyl]amino}propane-1,2- diol; N-{[1-(aminomethyl)-3,3-difluorocyclobutyl]methyl}(1,1-dioxido-2,3-dihydro-1,4- benzothiazepin-4(5 H)-yl)methylquinolinamine; N-[(3-aminooxetanyl)methyl]chloro- 2-(8-methoxy-1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5 H)-yl)quinolinamine; N-{[3- (aminomethyl)oxetanyl]methyl}chloro(8-methoxy-1,1-dioxido-2,3-dihydro-1,4- benzothiazepin-4(5H)-yl)quinolinamine; trans-N-[2-(1,1-dioxido-2,3-dihydro-1,4- benzothiazepin-4(5 H)-yl)methylquinolinyl]cyclohexane-1,2-diamine; N-[2-(1,1-dioxido- 2,3-dihydro-1,4-benzothiazepin-4(5 H)-yl)methylquinolinyl]cyclohexane-1,3-diamine; (3R )[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5 H)-yl)methylquinolinyl]-4,4- dimethylpyrrolidinol; cis-N-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl) methylquinolinyl]cyclohexane-1,4-diamine; N-[2-(1,1-dioxido-2,3-dihydro-1,4- benzothiazepin-4(5 H)-yl)methylquinolinyl]-2,2-difluoropropane-1,3-diamine; N-[6-chloro- 2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5 H)-yl)quinolinyl]-2,2-difluoropropane-1,3- diamine; N-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)methylquinolinyl] fluoropropane-1,3-diamine; N-[(3-aminooxetanyl)methyl]chloro(1,1-dioxido-2,3- dihydro-1,4-benzothiazepin-4(5 H)-yl)quinolinamine; [4-{[(3-aminooxetan yl)methyl]amino}(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5 quinolin yl]methanol; N-[(3-aminooxetanyl)methyl](1,1-dioxido-2,3-dihydro-1,4-benzothiazepin- 4(5 H)-yl)fluoromethylquinolinamine; aminooxetanyl)methyl](1,1-dioxido- 2,3-dihydro-1,4-benzothiazepin-4(5 H)-yl)fluoromethylquinolinamine; 6-chloro- 2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5 H)-yl)quinolinyl]methylpropane-1,2- diamine; 2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5 H)-yl)methyl-N-(tetrahydro-2H- pyranyl)quinolinamine; 2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5 H)-yl) methyl-N-[2-(piperazinyl)ethyl]quinolinamine; 2-(1,1-dioxido-2,3-dihydro-1,4- benzothiazepin-4(5 H)-yl)methyl-N-(piperidinylmethyl)quinolinamine; N-[2-(1,1- dioxido-2,3-dihydro-1,4-benzothiazepin-4(5 H)-yl)methylquinolinyl]heptane-1,7-diamine; 1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)methylquinolinyl]-N'- methylethane-1,2-diamine; N'-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5 H)-yl) methylquinolinyl]-N,N-dimethylethane-1,2-diamine; -dioxido-2,3-dihydro-1,4- benzothiazepin-4(5 H)-yl)-N,6-dimethylquinolinamine trifluoroacetate; (3S ,4S )[2-(1,1- dioxido-2,3-dihydro-1,4-benzothiazepin-4(5 H)-yl)methylquinolinyl]pyrrolidine-3,4-diol; 2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5 H)-yl)methyl-N-(pyrrolidin ylmethyl)quinolinamine; 4-[4-(1,4-diazepanyl)methylquinolinyl]-2,3,4,5-tetrahydro- 1,4-benzothiazepine 1,1-dioxide; N-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl) methylquinolinyl]-N'-ethylethane-1,2-diamine; 2-{[2-(1,1-dioxido-2,3-dihydro-1,4- benzothiazepin-4(5 H)-yl)methylquinolinyl]amino}ethanol; -dioxido-2,3-dihydro-1,4- benzothiazepin-4(5 methyl-N-(piperidinyl)quinolinamine; 2-(1,1-dioxido-2,3- dihydro-1,4-benzothiazepin-4(5 H)-yl)methyl-N-(piperidinyl)quinolinamine; 2-(1,1- dioxido-2,3-dihydro-1,4-benzothiazepin-4(5 H)-yl)methyl-N-(piperidinylmethyl)quinolin- 4-amine; 2-[(2-{[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5 H)-yl)methylquinolin no}ethyl)amino]ethanol; N-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl) methylquinolinyl]-2,2,3,3-tetrafluorobutane-1,4-diamine; N-[2-(1,1-dioxido-2,3-dihydro-1,4- benzothiazepin-4(5 H)-yl)methylquinolinyl]-N'-(2-methoxyethyl)ethane-1,2-diamine; 1-[2- (1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5 H)-yl)methylquinolinyl] methylpyrrolidinol; N-[6-chloro(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5 H)- nolinyl]ethane-1,2-diamine; 2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5 H)-yl)- 6-methyl-N-(oxetanyl)quinolinamine; N-[(3-aminooxetanyl)methyl](1,1-dioxido-2,3- dihydro-1,4-benzothiazepin-4(5 H)-yl)quinolinamine; 2-(1,1-dioxido-2,3-dihydro-1,4- benzothiazepin-4(5 H)-yl)methyl-N-[( 3R )-tetrahydrofuranyl]quinolinamine; N-{[3- methyl)oxetanyl]methyl}(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5 H)-yl) methylquinolinamine; N-{[3-(aminomethyl)oxetanyl]methyl}chloro(1,1-dioxido-2,3- dihydro-1,4-benzothiazepin-4(5 H)-yl)quinolinamine; N-{[3-(aminomethyl)oxetan yl]methyl}(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5 H)-yl)quinolinamine; 2-(1,1- dioxido-2,3-dihydro-1,4-benzothiazepin-4(5 H)-yl)methyl-N-(oxetanylmethyl)quinolin amine; N-[(1-aminocyclobutyl)methyl](1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5 H)- yl)methylquinolinamine; N-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl) methylquinolinyl]pentane-1,5-diamine; N-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin- 4(5 H)-yl)methylquinolinyl]hexane-1,6-diamine; 1,1-dioxido-2,3-dihydro-1,4- benzothiazepin-4(5 H)-yl)methylquinolinyl]-1,1,1-trifluoromethanesulfonamide hydrochloride; N-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)methylquinolin yl]pyridazinecarboxamide; N-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl) methylquinolinyl]benzamide; N-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl) methylquinolinyl]acetamide; N-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl) methylquinolinyl]piperidinecarboxamide; N-[2-(1,1-dioxido-2,3-dihydro-1,4- benzothiazepin-4(5 H)-yl)methylquinolinyl]piperidinecarboxamide; 3-[2-(1,1-dioxido- 2,3-dihydro-1,4-benzothiazepin-4(5 H)-yl)methylquinolinyl]-1,1-dimethylurea; 2-(1,1- dioxido-2,3-dihydro-1,4-benzothiazepin-4(5 H)-yl)methyl-N-(1,2-oxazolyl)quinolin amine; N-{[3-(aminomethyl)oxetanyl]methyl}(1,1-dioxido-2,3-dihydro-1,4- hiazepin-4(5 H)-yl)(~2~ H_3_)methylquinolinamine; N-[(3-aminooxetan yl)methyl]chloro(2,3-dihydro-1,4-benzothiazepin-4(5 H)-yl)quinolinamine; N-[6-chloro- 2-(2,3-dihydro-1,4-benzothiazepin-4(5 H)-yl)quinolinyl]ethane-1,2-diamine; N-[(3- aminooxetanyl)methyl](2,3-dihydro-1,4-benzothiazepin-4(5 H)-yl)methylquinolin amine; 2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)methylquinolinyl]pyrrolidin amine; N-[2-(2,3-dihydro-1,4-benzothiazepin-4(5 H)-yl)methylquinazolinyl]-2,2- ropropane-1,3-diamine; 2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-N-[2- (1,1-dioxidothiomorpholinyl)ethyl]methylquinolinamine; N-[2-(2-aminoethoxy)ethyl]- 2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5 methylquinolinamine; N~1~-[2- (1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5 H)-yl)methylquinolinyl] methylpropane-1,2-diamine; N~1~-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5 H)- yl)quinolinyl]methylpropane-1,2-diamine; N~1~-[2-(1,1-dioxido-2,3-dihydro-1,4- benzothiazepin-4(5 H)-yl)methylquinolinyl]propane-1,2-diamine; 4-[6-methyl(4- piperazinyl)quinolinyl]-2,3,4,5-tetrahydro-1,4-benzothiazepine oxide; 1-{[2- (1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5 H)-yl)methylquinolinyl]amino}propan ol; (2S )-N~1~-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5 H)-yl)methylquinolin yl]propane-1,2-diamine; (2R )-N~1~-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5 H)-yl)- 6-methylquinolinyl]propane-1,2-diamine; N-[(3-aminooxetanyl)methyl](1,1-dioxido- 2,3-dihydro-1,4-benzothiazepin-4(5 H)-yl)-7,8-difluoromethylquinolinamine; N-(2,2- difluoroethyl)-N'-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5 methylquinolin yl]ethane-1,2-diamine; 3-{[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5 H)-yl) methylquinolinyl]amino}oxetanethanol; (aminomethyl)thietanyl]methyl}(1,1- dioxido-2,3-dihydro-1,4-benzothiazepin-4(5 H)-yl)methylquinolinamine; N-{[3- (aminomethyl)-1,1-dioxidothietanyl]methyl}(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin- 4(5 H)-yl)methylquinolinamine; N-(4,5-dihydro-1H-imidazolyl)(1,1-dioxido-2,3- dihydro-1,4-benzothiazepin-4(5 H)-yl)methylquinolinamine; trans {[2-(1,1-dioxido-2,3- dihydro-1,4-benzothiazepin-4(5 H)-yl)methylquinolinyl]amino}cyclohexanol; (2S ){[2- (1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5 H)-yl)methylquinolinyl]amino}propan ol; trans [2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5 H)-yl)methylquinolinyl] methoxypyrrolidinamine; 2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin+D154-4(5 H)-yl)-N- [trans methoxypyrrolidinyl]methylquinolinamine; 4-{4-[(4aS ,7aR )- hexahydropyrrolo[3,4-b][1,4]oxazin-6(2 methylquinolinyl}-2,3,4,5-tetrahydro-1,4- benzothiazepine 1,1-dioxide; (3R ,4R )[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5 H)- yl)methylquinolinyl](4-methylpiperazinyl)pyrrolidinol; N-{2-[(2- aminoethyl)sulfanyl]ethyl}(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5 H)-yl) quinolinamine; 1-{1-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5 H)-yl) methylquinolinyl]piperidinyl}methanamine; 2-{[2-(8-methoxy-1,1-dioxido-2,3-dihydro- 1,4-benzothiazepin-4(5 H)-yl)quinolinyl]amino}ethanol; N-[2-(1,1-dioxido-2,3-dihydro-1,4- benzothiazepin-4(5 H)-yl)methylquinolinyl]propane-1,3-diamine; ethyl (morpholinyl)quinolinyl]-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide; 3-{[2-(1,1- dioxido-2,3-dihydro-1,4-benzothiazepin-4(5 H)-yl)methylquinolinyl]amino}propanol; 2- (1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5 H)-yl)methyl-N-[2-(piperidin yl)ethyl]quinolinamine; 1-amino{[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5 H)- yl)methylquinolinyl]amino}propanol; N-[2-(1,1-dioxido-2,3-dihydro-1,4- benzothiazepin-4(5 methylquinolinyl]glycine; N-[2-(1,1-dioxido-2,3-dihydro-1,4- benzothiazepin-4(5 H)-yl)fluoroquinolinyl]ethane-1,2-diamine; N-[2-(1,1-dioxido-2,3- dihydro-1,4-benzothiazepin-4(5 H)-yl)ethylquinolinyl]ethane-1,2-diamine; N-[7-chloro (1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5 H)-yl)quinolinyl]propane-1,3-diamine; N-[8- chloro(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5 H)-yl)quinolinyl]propane-1,3- diamine; N-[5-chloro(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5 H)-yl)quinolin yl]propane-1,3-diamine; N-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl) methylquinolinyl]-2,2-dimethylpropane-1,3-diamine; N-[2-(1,1-dioxido-2,3-dihydro-1,4- benzothiazepin-4(5 H)-yl)quinolinyl]ethane-1,2-diamine; N-[2-(1,1-dioxido-2,3-dihydro-1,4- benzothiazepin-4(5 H)-yl)methylquinolinyl]ethane-1,2-diamine; N~2~-[2-(1,1-dioxido-2,3- o-1,4-benzothiazepin-4(5 methylquinolinyl]methylpropane-1,2-diamine; N~2~-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5 H)-yl)methylquinolin yl]propane-1,2-diamine; 1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl) methylquinolinyl]butane-1,4-diamine; N-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin- 4(5 H)-yl)nitroquinolinyl]ethane-1,2-diamine; N-[2-(1,1-dioxido-2,3-dihydro-1,4- benzothiazepin-4(5H)-yl)fluoromethylquinolinyl]ethane-1,2-diamine; 2-{[2-(1,1- dioxido-2,3-dihydro-1,4-benzothiazepin-4(5 H)-yl)fluoromethylquinolin yl]amino}ethanol; 2-{[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5 H)-yl)fluoro methylquinolinyl]amino}ethanol; N-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)- yl)fluoromethylquinolinyl]ethane-1,2-diamine; 1,1-dioxido-2,3-dihydro-1,4- benzothiazepin-4(5 H)-yl)-7,8-difluoromethylquinolinyl]ethane-1,2-diamine; 2-(1,1- dioxido-2,3-dihydro-1,4-benzothiazepin-4(5 H)-yl)-N-(2-methoxyethyl)methylquinolin amine; 1-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5 H)-yl)methylquinolin yl]piperidinamine; 1-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5 H)-yl)-1,6- naphthyridinyl]pyrrolidinamine; N-[6-(difluoromethyl)(1,1-dioxido-2,3-dihydro-1,4- hiazepin-4(5 H)-yl)quinolinyl]propane-1,3-diamine; 6-chloro(1,1-dioxido-2,3- dihydro-1,4-benzothiazepin-4(5 H)-yl)-N-ethylquinolinamine; 2-{[6-chloro(1,1-dioxido- 2,3-dihydro-1,4-benzothiazepin-4(5 H)-yl)quinolinyl]amino}ethanol; N-[6-chloro(1,1- dioxido-2,3-dihydro-1,4-benzothiazepin-4(5 H)-yl)quinolinyl]-N'-methylethane-1,2-diamine; N-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)(methylsulfanyl)quinolin yl]propane-1,3-diamine; N-[6-bromo(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5 H)- yl)quinolinyl]propane-1,3-diamine; {4-[(2-aminoethyl)amino](1,1-dioxido-2,3-dihydro- 1,4-benzothiazepin-4(5 H)-yl)quinolinyl}methanol; 2-{[2-(1,1-dioxido-2,3-dihydro-1,4- benzothiazepin-4(5 H)-yl)methylquinolinyl]amino}propane-1,3-diol; 2,2'-{[2-(1,1-dioxido- 2,3-dihydro-1,4-benzothiazepin-4(5 H)-yl)methylquinolinyl]imino}diethanol; 4-{[2-(1,1- dioxido-2,3-dihydro-1,4-benzothiazepin-4(5 H)-yl)methylquinolinyl]amino} hydroxybutanoic acid; 1-amino{[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5 H)-yl) methylquinolinyl]amino}methylpropanol; 2-(1,1-dioxido-2,3-dihydro-1,4- benzothiazepin-4(5 H)-yl)methyl-N-[2-(morpholinyl)ethyl]quinolinamine; 2-{[2-(1,1- dioxido-2,3-dihydro-1,4-benzothiazepin-4(5 H)-yl)-1,6-naphthyridinyl]amino}ethanol; N-[2- (1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5 H)-yl)methylquinolinyl]nonane-1,9- diamine; N-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)methylquinolin ane-1,10-diamine; N-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl) methylquinolinyl]octane-1,8-diamine; (1,1-dioxido-2,3-dihydro-1,4-benzothiazepin- 4(5 H)-yl)methylquinolinyl]amino}nonanol; N-[2-(1,1-dioxido-2,3-dihydro-1,4- benzothiazepin-4(5 H)-yl)methylquinolinyl]octane-1,8-diamine; cis amino[2-(1,1- dioxido-2,3-dihydro-1,4-benzothiazepin-4(5 H)-yl)methylquinolinyl]pyrrolidinol; N-[2- (1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5 H)-yl)methylquinolinyl]-L-alanine; N-[2- (1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5 methylquinolinyl]-beta-alanine; N- [2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5 methylquinolinyl]benzene-1,3- diamine; N-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)methylquinolin yl]benzene-1,4-diamine; (3S )[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5 H)-yl) methylquinolinyl]pyrrolidinol; (3R )[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin- 4(5 H)-yl)methylquinolinyl]pyrrolidinol; trans -N-[2-(1,1-dioxido-2,3-dihydro-1,4- benzothiazepin-4(5 H)-yl)methylquinolinyl]cyclopentane-1,2-diamine; 1-[2-(1,1-dioxido- 2,3-dihydro-1,4-benzothiazepin-4(5 methylquinolinyl]piperidinamine; 2-(1,1- o-2,3-dihydro-1,4-benzothiazepin-4(5 H)-yl)-N,N,6-trimethylquinolinamine; N-[2-(1,1- dioxido-2,3-dihydro-1,4-benzothiazepin-4(5 H)-yl)(trifluoromethoxy)quinolinyl]propane- amine; N-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl) (trifluoromethyl)quinolinyl]propane-1,3-diamine; N-[6-(difluoromethoxy)(1,1-dioxido-2,3- dihydro-1,4-benzothiazepin-4(5 H)-yl)quinolinyl]propane-1,3-diamine; N-[2-(1,1-dioxido-2,3- dihydro-1,4-benzothiazepin-4(5 H)-yl)methoxyquinolinyl]propane-1,3-diamine; N-[2-(1,1- dioxido-2,3-dihydro-1,4-benzothiazepin-4(5 H)-yl)methylquinolinyl]propane-1,3-diamine; 1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)methylquinolinyl]propane- amine; N-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)methylquinolin yl]propane-1,3-diamine; N-{[3-(aminomethyl)oxetanyl]methyl}(1,1-dioxido-2,3-dihydro- 1,4-benzothiazepin-4(5 H)-yl)fluoroquinolinamine; N-[(3-aminooxetanyl)methyl] methyl(1-oxido-2,3-dihydro-1,4-benzothiazepin-4(5 H)-yl)quinolinamine; (+)-N-[(3- xetanyl)methyl]methyl[1-oxido-2,3-dihydro-1,4-benzothiazepin-4(5 H)- yl]quinolinamine; (-)-N-[(3-aminooxetanyl)methyl]methyl[1-oxido-2,3-dihydro-1,4- hiazepin-4(5 H)-yl]quinolinamine; aminooxetanyl)methyl]chloro(1- oxido-2,3-dihydro-1,4-benzothiazepin-4(5 H)-yl)quinolinamine; 2,2-difluoro-N-[6-methyl (1-oxido-2,3-dihydro-1,4-benzothiazepin-4(5 H)-yl)quinolinyl]propane-1,3-diamine; N-[6- chloro(1-oxido-2,3-dihydro-1,4-benzothiazepin-4(5 H)-yl)quinolinyl]-2,2-difluoropropane- 1,3-diamine; N-[6-chloro(1-oxido-2,3-dihydro-1,4-benzothiazepin-4(5 H)-yl)quinolin yl]ethane-1,2-diamine; N-{[3-(aminomethyl)oxetanyl]methyl}methyl(1-oxido-2,3- dihydro-1,4-benzothiazepin-4(5 H)-yl)quinolinamine; N-{[3-(aminomethyl)oxetan yl]methyl}chloro(1-oxido-2,3-dihydro-1,4-benzothiazepin-4(5 H)-yl)quinolinamine; N- hyl(1-oxido-2,3-dihydro-1,4-benzothiazepin-4(5 H)-yl)quinolinyl]ethane-1,2- diamine; methyl(1-oxido-2,3-dihydro-1,4-benzothiazepin-4(5 H)-yl)quinolin yl]amino}ethanol; trans amino[6-methyl(1-oxido-2,3-dihydro-1,4-benzothiazepin- 4(5 H)-yl)quinolinyl]pyrrolidinol; (1R ,5S ,6S )[2-(1,1-dioxido-2,3-dihydro-1,4- benzothiazepin-4(5 H)-yl)methylquinolinyl]azabicyclo[3.1.0]hexanamine; trans amino[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5 H)-yl)methylquinolin yl]pyrrolidinol; 1-[6-methyl(1-oxido-2,3-dihydro-1,4-benzothiazepin-4(5 H)-yl)quinolin yl]pyrrolidinamine; trans [6-chloro(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5 H)- yl)quinolinyl]fluoropyrrolidinamine; trans amino[6-chloro(1,1-dioxido-2,3- dihydro-1,4-benzothiazepin-4(5 H)-yl)quinolinyl]pyrrolidinol; trans [6-chloro(1- oxido-2,3-dihydro-1,4-benzothiazepin-4(5 H)-yl)quinolinyl]fluoropyrrolidinamine; 2-[2- (1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5 H)-yl)methylquinolinyl] azabicyclo[2.1.1]hexanamine; 2-(8-methoxy-1,1-dioxido-2,3-dihydro-1,4-benzothiazepin- 4(5 methylquinolinamine; 2-(7-methoxy-1,1-dioxido-2,3-dihydro-1,4- benzothiazepin-4(5 H)-yl)methylquinolinamine; N-[2-(1-aminocyclopropyl)ethyl](1,1- dioxido-2,3-dihydro-1,4-benzothiazepin-4(5 H)-yl)methylquinolinamine; 2-(1,1-dioxido- 2,3-dihydro-1,4-benzothiazepin-4(5 H)-yl)methyl-N-(morpholinylmethyl)quinolinamine; N-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)methylquinolinyl]-N- methylethane-1,2-diamine; N-(azetidinylmethyl)(1,1-dioxido-2,3-dihydro-1,4- benzothiazepin-4(5 H)-yl)methylquinolinamine; 2-(1,1-dioxido-2,3-dihydro-1,4- benzothiazepin-4(5 H)-yl)methyl-N-(pyrrolidinyl)quinolinamine; N-[(1- aminocyclopropyl)methyl](1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5 H)-yl) methylquinolinamine; N-(azetidinyl)chloro(1,1-dioxido-2,3-dihydro-1,4- benzothiazepin-4(5 H)-yl)quinolinamine; 6-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin- 4(5 H)-yl)methylquinolinyl]oxaazaspiro[3.4]octanamine; trans amino[2-(1,1- dioxido-2,3-dihydro-1,4-benzothiazepin-4(5 -1,6-naphthyridinyl]pyrrolidinol; 1-[2- (1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5 H)-yl)methylquinolinyl]pyrrolidin amine; N-(azetidinyl)(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5 H)-yl) methylquinolinamine; 1-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5 H)-yl) methylquinolinyl]azetidinamine; N-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)- yl)methylquinolinyl]prolinamide; 2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5 H)- yl)-N-(trans fluoropyrrolidinyl)methylquinolinamine; trans {[2-(1,1-dioxido-2,3- dihydro-1,4-benzothiazepin-4(5 quinolinyl]amino}pyrrolidinol; trans {[2-(1,1- dioxido-2,3-dihydro-1,4-benzothiazepin-4(5 H)-yl)methylquinolinyl]amino}pyrrolidinol; cis {[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5 H)-yl)methylquinolin yl]amino}pyrrolidinol; N-[trans fluoropyrrolidinyl]methyl(1-oxido-2,3-dihydro- 1,4-benzothiazepin-4(5 H)-yl)quinolinamine; 4-[(3-aminopropyl)amino](1,1-dioxido-2,3- dihydro-1,4-benzothiazepin-4(5 H)-yl)quinolinol; 2-({4-[(3-aminopropyl)amino](1,1- dioxido-2,3-dihydro-1,4-benzothiazepin-4(5 H)-yl)quinolinyl}oxy)ethanol; N-[2-(1,1-dioxido- 2,3-dihydro-1,4-benzothiazepin-4(5 H)-yl)(2-methoxyethoxy)quinolinyl]propane-1,3- diamine; 1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)(pyridin quinolinyl]propane-1,3-diamine; 3-{[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin- 4(5 H)-yl)methylquinolinyl]amino}propane-1,2-diol; 3-{[6-chloro(1,1-dioxido-2,3- dihydro-1,4-benzothiazepin-4(5 H)-yl)quinolinyl]amino}propane-1,2-diol; 3-{[2-(8-chloro- oxido-2,3-dihydro-1,4-benzothiazepin-4(5 H)-yl)methylquinolinyl]amino}propane- 1,2-diol; 3-{[6-methyl(1-oxido-2,3-dihydro-1,4-benzothiazepin-4(5 H)-yl)quinolin yl]amino}propane-1,2-diol; 3-{[6-methyl(5-methyl-1,1-dioxido-2,3-dihydro-1,4- benzothiazepin-4(5 H)-yl)quinolinyl]amino}propane-1,2-diol; aminooxetan hyl]methyl[7-(morpholinyl)-1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5 H)- yl]quinolinamine; N-[(3-aminooxetanyl)methyl]{1,1-dioxido[4-(propan yl)piperazinyl]-2,3-dihydro-1,4-benzothiazepin-4(5 H)-yl}methylquinolinamine; 3-{[4- (4-aminoquinolinyl)-1,1-dioxido-2,3,4,5-tetrahydro-1,4-benzothiazepinyl]oxy}propan ol; N-[(3-aminooxetanyl)methyl](1,1-dioxidophenoxy-2,3-dihydro-1,4-benzothiazepin- 4(5 H)-yl)methylquinolinamine; 2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin- 4(5 H)-yl)methylquinolinyl]-beta-alaninamide; 3-{[2-(1,1-dioxido-2,3-dihydro-1,4- benzothiazepin-4(5 H)-yl)methylquinolinyl]amino}butanamide; 3-{[2-(1,1-dioxido-2,3- dihydro-1,4-benzothiazepin-4(5 H)-yl)methylquinolinyl]amino}methylpropanamide; N~2~-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5 H)-yl)methylquinolinyl]-L- alaninamide; N~2~-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5 H)-yl)methylquinolin- 4-yl]glycinamide; N~2~-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5 H)-yl) methylquinolinyl]-N-methylglycinamide; (2S )amino{[2-(1,1-dioxido-2,3-dihydro-1,4- hiazepin-4(5 H)-yl)methylquinolinyl]amino}propanol; (2R )amino{[2-(1,1- dioxido-2,3-dihydro-1,4-benzothiazepin-4(5 methylquinolinyl]amino}propanol; N-[(2-amino-4,5-dihydro-1,3-oxazolyl)methyl](1,1-dioxido-2,3-dihydro-1,4- benzothiazepin-4(5 H)-yl)methylquinolinamine; N-[(2-aminomethyl-4,5-dihydro-1,3- oxazolyl)methyl](1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5 H)-yl)methylquinolin- 4-amine; N-{[(4R )amino-4,5-dihydro-1,3-oxazolyl]methyl}(1,1-dioxido-2,3-dihydro- 1,4-benzothiazepin-4(5 H)-yl)methylquinolinamine; N-{[( 4S )amino-4,5-dihydro-1,3- oxazolyl]methyl}(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5 H)-yl) methylquinolinamine; cis [2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5 H)-yl) methylquinolinyl]-4,5,6,6a-tetrahydro-3a H-pyrrolo[3,4-d][1,3]oxazolamine; 2-(1,1- dioxido-2,3-dihydro-1,4-benzothiazepin-4(5 H)-yl)methylquinolinamine; N-[2-(1,1- dioxido-2,3-dihydro-1,4-benzothiazepin-4(5 H)-yl)methylquinolinyl]glycinamide; N-[2- (1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5 H)-yl)methylquinolinyl] methylalaninamide; N-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl) methylquinolinyl]alaninamide; 2-amino-N-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin- 4(5 methylquinolinyl]butanamide; 1,1-dioxido-2,3-dihydro-1,4- benzothiazepin-4(5 H)-yl)methylquinolinyl]methoxymethylpropanamide; N~1~-[2- (1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5 H)-yl)methylquinolinyl]-4,4,4- trifluorobutane-1,3-diamine; 1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl) methylquinolinyl]-beta-alaninamide; 2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5 H)- yl)-N-{[3-(ethylamino)oxetanyl]methyl}methylquinolinamine; 2-(1,1-dioxido-2,3- dihydro-1,4-benzothiazepin-4(5 H)-yl)methyl-N-[1-(oxetanyl)pyrrolidinyl]quinolin amine; (1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5 H)-yl)methylquinolinyl]-N- ethyl-N-(oxetanyl)ethane-1,2-diamine; N-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin- 4(5 H)-yl)methylquinolinyl]-N'-(oxetanyl)propane-1,3-diamine; 1-[2-(1,1-dioxido-2,3- dihydro-1,4-benzothiazepin-4(5 H)-yl)methylquinolinyl]-N-(oxetanyl)pyrrolidin amine; N-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)methylquinolinyl]-N'- (oxetanyl)ethane-1,2-diamine; N-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)- ylquinolinyl]-N'-(pyridinyl)ethane-1,2-diamine; (4R )[2-(1,1-dioxido-2,3-dihydro- 1,4-benzothiazepin-4(5 H)-yl)methylquinolinyl]hydroxypyrrolidinone; N-[2-(1,1- dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)methylquinolinyl]oxopyrrolidine carboxamide; 2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5 H)-yl)methyl-N-(1 H- pyrazolyl)quinolinamine; N-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl) methylquinolinyl]pyridinecarboxamide; N-[2-(1,1-dioxido-2,3-dihydro-1,4- benzothiazepin-4(5 H)-yl)methylquinolinyl]piperidinecarboxamide; N-[2-(1,1-dioxido- 2,3-dihydro-1,4-benzothiazepin-4(5 H)-yl)methylquinolinyl](pyridinyl)acetamide; N- [2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5 H)-yl)methylquinolin yl]methanesulfonamide trifluoroacetate; N-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin- 4(5 H)-yl)methylquinolinyl]pyrazinecarboxamide; N-[2-(1,1-dioxido-2,3-dihydro-1,4- benzothiazepin-4(5 H)-yl)methylquinolinyl]hydroxyacetamide; N-[2-(1,1-dioxido-2,3- dihydro-1,4-benzothiazepin-4(5 H)-yl)methylquinolinyl]pyridinecarboxamide; N-[2- (1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5 H)-yl)methylquinolinyl]azetidine carboxamide; 1-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5 H)-yl)methylquinolin yl]phenylurea; 1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5 H)-yl) methylquinolinyl]ethylurea; N-[6-cyclopropyl(1,1-dioxido-2,3-dihydro-1,4- benzothiazepin-4(5 H)-yl)quinolinyl]propane-1,3-diamine; 4-[(3-aminopropyl)amino](1,1- dioxido-2,3-dihydro-1,4-benzothiazepin-4(5 H)-yl)quinolinecarbonitrile; N-[2-(1,1-dioxido- hydro-1,4-benzothiazepin-4(5 H)-yl)ethenylquinolinyl]propane-1,3-diamine; N-[2- (1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5 H)-yl)ethynylquinolinyl]propane-1,3- diamine; N-[(3-aminooxetanyl)methyl]methyl(1-oxido-2,3-dihydro-1,4-benzothiazepin- 4(5 H)-yl)quinazolinamine; N-{[3-(benzylamino)oxetanyl]methyl}methyl(1-oxido- 2,3-dihydro-1,4-benzothiazepin-4(5 H)-yl)quinazolinamine; 2-fluoro-N-[6-methyl(1-oxido- 2,3-dihydro-1,4-benzothiazepin-4(5 H)-yl)quinazolinyl]propane-1,3-diamine; N-{[3- (aminomethyl)oxetanyl]methyl}(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5 H)-yl) methylquinazolinamine; 2,2-difluoro-N-[6-methyl(1-oxido-2,3-dihydro-1,4- benzothiazepin-4(5 H)-yl)quinazolinyl]propane-1,3-diamine; N-{[3-(aminomethyl)oxetan yl]methyl}chloro(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5 quinazolin amine; N-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)methylquinazolinyl]- 2,2-difluoropropane-1,3-diamine; N-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)- 6-methylquinazolinyl]fluoropropane-1,3-diamine; N-[6-methyl(1-oxido-2,3-dihydro- 1,4-benzothiazepin-4(5 H)-yl)quinazolinyl]propane-1,3-diamine; aminooxetan yl)methyl](2,3-dihydro-1,4-benzothiazepin-4(5 H)-yl)quinazolinamine; N-[(3-aminooxetan- 3-yl)methyl](1-oxido-2,3-dihydro-1,4-benzothiazepin-4(5 quinazolinamine; N-[(3- aminooxetanyl)methyl](1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5 quinazolin- 4-amine; N-[(3-aminooxetanyl)methyl]chloro(2,3-dihydro-1,4-benzothiazepin-4(5 H)- yl)quinazolinamine; N-[(3-aminooxetanyl)methyl]chloro(1-oxido-2,3-dihydro-1,4- benzothiazepin-4(5 quinazolinamine; N-[(3-aminooxetanyl)methyl]chloro(1,1- dioxido-2,3-dihydro-1,4-benzothiazepin-4(5 H)-yl)quinazolinamine; 2-{[2-(1,1-dioxido-2,3- dihydro-1,4-benzothiazepin-4(5 H)-yl)methylquinazolinyl]amino}ethanol; 2-(2,3-dihydro- 1,4-benzothiazepin-4(5 H)-yl)methylquinazolinamine; 2-(1,1-dioxido-2,3-dihydro-1,4- hiazepin-4(5 H)-yl)methylquinazolinamine; N~1~-[2-(1,1-dioxido-2,3-dihydro-1,4- benzothiazepin-4(5 H)-yl)methylquinazolinyl]methylpropane-1,2-diamine; N-[(3- aminooxetanyl)methyl](1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5 H)-yl) methylquinazolinamine; N-[(1-aminocyclobutyl)methyl](1,1-dioxido-2,3-dihydro-1,4- benzothiazepin-4(5 H)-yl)methylquinazolinamine; N-{[3-(aminomethyl)oxetan yl]methyl}methyl(1-oxido-2,3-dihydro-1,4-benzothiazepin-4(5 H)-yl)quinazolinamine; (-)-N-{[3-(aminomethyl)oxetanyl]methyl}methyl[1-oxido-2,3-dihydro-1,4- benzothiazepin-4(5 H)-yl]quinazolinamine; (+)-N-{[3-(aminomethyl)oxetanyl]methyl} methyl[1-oxido-2,3-dihydro-1,4-benzothiazepin-4(5 H)-yl]quinazolinamine; N~4~-[2-(1,1- dioxido-2,3-dihydro-1,4-benzothiazepin-4(5 H)-yl)methylquinazolinyl]fluorobutane-1,4- diamine; N~1~-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5 H)-yl)methylquinazolin yl]fluorobutane-1,4-diamine; N-{[3-(aminomethyl)oxetanyl]methyl}(2,3-dihydro-1,4- benzothiazepin-4(5 H)-yl)methylquinazolinamine; trans fluoro[6-methyl(1-oxido- 2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinazolinyl]pyrrolidinamine; N-(Azetidinyl)- 6-methyl(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl) quinazolinamine; N-(2- {[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)methylquinolin yl]amino}ethyl)acetamide; ({[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5 H)-yl) methylquinolinyl]amino}methyl)oxetanyl]methyl}acetamide; N-(3-{[2-(1,1-dioxido-2,3- dihydro-1,4-benzothiazepin-4(5 H)-yl)methylquinolinyl]amino}propyl)acetamide; N-[2- (1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5 H)-yl)methylquinazolinyl]acetamide; 1- [2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5 H)-yl)methylquinolinyl] methylpyrrolidinamine; N-[(3-aminooxetanyl)methyl](9-methoxy-1,1-dioxido-2,3- dihydro-1,4-benzothiazepin-4(5 H)-yl)methylquinolinamine; 4-(4-{[(3-aminooxetan yl)methyl]amino}methylquinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepinol 1,1- dioxide; 3-{[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5 H)-yl)methylquinolin yl]amino}methylpropane-1,2-diol; (1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5 H)- yl)methylquinolinyl]amino}butane-1,3-diol; N-[6-methyl(2-methyl-1,1-dioxido-2,3- dihydro-1,4-benzothiazepin-4(5 quinolinyl]ethane-1,2-diamine; N-[(3-aminooxetan yl)methyl]methyl(2-methyl-1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5 H)- yl)quinolinamine; N-[(3-{[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5 H)-yl) quinolinyl]amino}oxetanyl)methyl]-2,2,2-trifluoroacetamide; N-[3- (aminomethyl)oxetanyl](1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5 H)-yl) quinolinamine; 2-(aminomethyl){[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin- 4(5 H)-yl)methylquinolinyl]amino}propane-1,3-diol; 4-amino[2-(1,1-dioxido-2,3- dihydro-1,4-benzothiazepin-4(5 H)-yl)methylquinolinyl]pyrrolidinone; 2-(1,1-dioxido- 2,3-dihydro-1,4-benzothiazepin-4(5 H)-yl)methyl-N-[2-(methylsulfinyl)ethyl]quinolin amine; N-{2-[(2-aminoethyl)sulfonyl]ethyl}(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin- 4(5 methylquinolinamine; N-[2-(1-iminooxido-1,2,3,5-tetrahydro-4H- 1lambda ~4~,4-benzothiazepinyl)methylquinolinyl]ethane-1,2-diamine; -dioxido- 2,3-dihydro-1,4-benzothiazepin-4(5 methyl-N-[2-(S- methylsulfonimidoyl)ethyl]quinolinamine; trans amino[2-(1-iminooxido-1,2,3,5- tetrahydro-4H-1lambda ~4~,4-benzothiazepinyl)methylquinolinyl]pyrrolidinol; trans - 1-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5 H)-yl)methylquinolinyl] fluoropyrrolidinamine; 1-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5 H)-yl) methylquinolinyl]pyrrolidinecarboxamide; N-[2-(1,1-dioxido-2,3-dihydro-1,4- benzothiazepin-4(5 H)-yl)(methylsulfinyl)quinolinyl]propane-1,3-diamine; 4-[(3- ropyl)amino](1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5 H)-yl)quinoline amide; 1-{4-[(3-aminopropyl)amino](1,1-dioxido-2,3-dihydro-1,4-benzothiazepin- 4(5 H)-yl)quinolinyl}ethanol; 3-{[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5 H)-yl) methylquinolinyl]amino}propanenitrile; 2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin- 4(5 H)-yl)methyl-N-[2-(1 H-tetrazolyl)ethyl]quinolinamine; N~4~-(2-aminoethyl)(1,1- dioxido-2,3-dihydro-1,4-benzothiazepin-4(5 H)-yl)quinoline-4,6-diamine; 5-[2-(1,1-dioxido-2,3- dihydro-1,4-benzothiazepin-4(5 H)-yl)methylquinolinyl]oxa-5,7-diazaspiro[3.4]octan one; 3-{[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5 H)-yl)methylquinazolin yl]amino}propane-1,2-diol; 3-{[6-chloro(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5 H)- yl)quinazolinyl]amino}propane-1,2-diol; N-[2-(2,3-dihydro-1,4-benzothiazepin-4(5 H)-yl) methylquinazolinyl]ethane-1,2-diamine; N-[6-methyl(1-oxido-2,3-dihydro-1,4- benzothiazepin-4(5 H)-yl)quinazolinyl]ethane-1,2-diamine; N-[2-(1,1-dioxido-2,3-dihydro- 1,4-benzothiazepin-4(5 H)-yl)methylquinazolinyl]ethane-1,2-diamine; N-[3- (aminomethyl)oxetanyl]methyl(1-oxido-2,3-dihydro-1,4-benzothiazepin-4(5 H)- yl)quinazolinamine; N-(trans fluoropyrrolidinyl)methyl(1-oxido-2,3-dihydro-1,4- benzothiazepin-4(5 H)-yl)quinazolinamine; N-(trans fluoropyrrolidinyl)methyl(1,1- dioxido-2,3-dihydro-1,4-benzothiazepin-4(5 H)-yl)quinazolinamine; 1-[6-methyl(1-oxido- hydro-1,4-benzothiazepin-4(5 H)-yl)quinazolinyl]pyrrolidinamine; N-(azetidinyl)- 6-methyl(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5 H)-yl)quinazolinamine; (4R ) {2-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5 H)-yl)methylquinolinyl]ethyl}-4,5- o-1,3-oxazolamine; 3-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5 H)-yl) ethylquinolinyl]propanoic acid; 3-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5 H)-yl)- 6-methylquinolinyl]propanamine; 2-{[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin- 4(5 H)-yl)methylquinolinyl]oxy}ethanamine; 4-[6-methyl(pyrrolidinyloxy)quinolin- 2-yl]-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide; 4-[6-methyl(piperidin yloxy)quinolinyl]-2,3,4,5-tetrahydro-1,4-benzothiazepine oxide; 4-(4,6- dimethylquinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide; [2-(1,1-dioxido-2,3- dihydro-1,4-benzothiazepin-4(5 H)-yl)methylquinolinyl](piperidinyl)methanone; 4-[6- methyl(1 H-pyrazolyl)quinolinyl]-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide; 4- [6-methyl(phenylsulfonyl)quinolinyl]-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide; minoethyl)(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5 H)-yl)methylquinoline- 4-sulfonamide; methyl 4-({[3-(aminomethyl)oxetanyl]methyl}amino)(1,1-dioxido-2,3- dihydro-1,4-benzothiazepin-4(5 H)-yl)quinolinecarboxylate; 4-({[3-(aminomethyl)oxetan hyl}amino)(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5 H)-yl)quinoline carboxylic acid; [4-({[3-(aminomethyl)oxetanyl]methyl}amino)(1,1-dioxido-2,3-dihydro- 1,4-benzothiazepin-4(5 H)-yl)quinolinyl]methanol; N-{[3-(aminomethyl)oxetanyl]methyl}- 6-(~2~ ethyl(1-oxido-2,3-dihydro-1,4-benzothiazepin-4(5 H)-yl)quinazolinamine; 4-({[3-(aminomethyl)oxetanyl]methyl}amino)(1,1-dioxido-2,3-dihydro-1,4- benzothiazepin-4(5 quinazolinecarboxylic acid; 4-({[3-(aminomethyl)oxetan yl]methyl}amino)(1-oxido-2,3-dihydro-1,4-benzothiazepin-4(5 H)-yl)quinazoline carboxylic acid; [4-({[3-(aminomethyl)oxetanyl]methyl}amino)(1-oxido-2,3-dihydro-1,4- benzothiazepin-4(5 H)-yl)quinazolinyl]methanol; [4-({[3-(aminomethyl)oxetan yl]methyl}amino)(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5 H)-yl)quinazolin yl]methanol; aminocyclopropyl)methyl](1,1-dioxido-2,3-dihydro-1,4-benzothiazepin- 4(5 H)-yl)methylquinazolinamine; and 2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin- 4(5 H)-yl)methyl-N-(pyrrolidinyl)quinazolinamine.
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 en; R3 is en or halogen; R5 is hydrogen or halogen; R6 is hydrogen, halogen, hydroxy, C1-6alkoxy or carboxy; R7 is hydrogen, halogen, C1-6alkoxy, C1-6alkylaminocarbonyl, diC1-6 alkylaminocarbonyl or C1-6alkylsulfonyl; R8 is hydrogen or halogen; R9 is hydrogen or =O; R10 is hydrogen or =O, ed that R9 and R10 are not =O simultaneously; A is -C-R11 , wherein R11 is hydrogen, halogen, C1-6alkyl, C1-6alkoxy, trifluoromethyl, trifluoromethoxy, pyridinyloxy, difluoromethoxy or C ylsulfonyl; X is -CH2-, -O-, –NH-, -CF2, -C(CH3)(OH)-, C=O, or -C(=N-C1-6alkoxy)-; Y is -CH- or nitrogen; Q is hydrogen; halogen; C1-6alkyl, once or twice tuted by hydroxy provided that disubstitution of hydroxy is not on the same carbon; amino(CH2)2-6aminosulfonyl; 2-amino-4,5- dihydro-1,3-oxazolylethyl; or NR12 R13 , wherein one of R12 and R13 is hydrogen, C1-6alkyl or hydroxy(CH2)2-6, and the other one is guanidino(CH2)2-6; 3-aminomethyl-1,1-dioxidothietan ylmethyl; 3-amino-1,1-dioxidothietanylmethyl; 3-(aminomethyl)thietanylmethyl; amino(CH2)2O-(CH2)2-6; amino(CH2)2-10; amino(CH2)1-6carbonyl; amino(CH2)1- 6difluoromethyl(CH2)1-6; amino(CH2)1-6oxetanyl(CH2)1-6; amino(CH2)2-6sulfonyl(CH2)2-6; 3- aminocyclohexyl; 4-aminocyclohexyl; 2-amino-4,5-dihydro-oxazolyl(CH2)1-6; aminooxetanyl(CH2)1-6; C1-6alkylamino(CH2)2-6; kylaminocarbonyl; diC1- -C1-6alkyl C R15 6alkylamino(CH2)2-6; hydroxy(CH2)2-6; zinyl(CH2)2-6; pyrrolidinyl; or , n R14 is hydrogen, C1-6alkyl or hydroxy(CH2)1-6; R15 is hydroxy, hydroxy(CH2)1-6 or amino; and R16 is C1-6alkyl, y(CH2)1-6 or amino(CH2)1-6; 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 C1-6alkyl, amino or hydroxy.
Another ular 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 en, fluoro, bromo, methoxy, dimethylaminocarbonyl, methylsulfonyl or ulfonyl; R8 is hydrogen or chloro.
A is CR11, wherein R11 is hydrogen, fluoro, chloro, bromo, methyl, methoxy, trifluoromethyl, trifluoromethoxy, nyloxy, difluoromethoxy or methylsulfonyl; Q is hydrogen; ; hydroxymethyl; hydroxymethyl(hydroxy)ethyl; aminoethylaminosulfonyl; 2-amino-4,5-dihydro-1,3-oxazolylethyl; or NR12R13, wherein one of R12 and R13 is hydrogen, methyl or yethyl, and the other one is aminobutyl; 3- aminocyclohexyl; 4-aminocyclohexyl; 2-amino-4,5-dihydro-oxazolylmethyl; 3-amino-1,1- dioxidothietanylmethyl; aminoethoxyethyl; aminoethyl; aminoethylsulfonylethyl; aminomethylcarbonyl; aminomethyldifluoromethylmethyl; 3-aminomethyl-1,1-dioxidothietan ylmethyl; nomethyl)thietanylmethyl; aminomethyloxetanylmethyl; aminooxetanylmethyl; aminopropyl; dimethylaminoethyl; ethylaminocarbonyl; guanidinoethyl; hydroxyethyl; hydroxypropyl; methylaminoethyl; piperazinylethyl; pyrrolidinyl; or -C1-6alkyl C R15 R16 , wherein R14 is en, 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; and all the remaining substituents are as defined above in embodiment (xii).
A particular embodiment of present invention is a compound of formula (I) or a pharmaceutically able salt thereof, selected from: N-[(3-aminooxetanyl)methyl](5,5-difluoro-1,3,4,5-tetrahydro-2Hbenzazepinyl) quinolinamine; N-[2-(2-aminoethoxy)ethyl](5,5-difluoro-1,3,4,5-tetrahydro-2H benzazepinyl)methylquinolinamine; N-[2-(5,5-difluoro-1,3,4,5-tetrahydro-2H benzazepinyl)methylquinolinyl]-N'-methylethane-1,2-diamine; 1-amino{[2-(5,5- difluoro-1,3,4,5-tetrahydro-2Hbenzazepinyl)methylquinolinyl]amino}propanol; 3- {[2-(5,5-difluoro-1,3,4,5-tetrahydro-2Hbenzazepinyl)methylquinolin no}propane-1,2-diol; 3-{[2-(5,5-difluoro-1,3,4,5-tetrahydro-2Hbenzazepinyl) methylquinolinyl]amino}propanol; 2-(5,5-difluoro-1,3,4,5-tetrahydro-2Hbenzazepin yl)methyl-N-[2-(piperazinyl)ethyl]quinolinamine; N~1~-[2-(5,5-difluoro-1,3,4,5- tetrahydro-2Hbenzazepinyl)methylquinolinyl]propane-1,2-diamine; cis-N-[2-(5,5- difluoro-1,3,4,5-tetrahydro-2Hbenzazepinyl)methylquinolinyl]cyclohexane-1,4- diamine; 2-(9,9-difluoro-6,7,8,9-tetrahydro-5H-benzo[7]annulenyl)methyl-N-(pyrrolidin nolinamine; 2,2'-{[2-(5,5-difluoro-1,3,4,5-tetrahydro-2Hbenzazepinyl) methylquinolinyl]imino}diethanol; N~1~-[2-(5,5-difluoro-1,3,4,5-tetrahydro-2H benzazepinyl)methylquinolinyl]methylpropane-1,2-diamine; 5,5-difluoro[6- methyl(4-methylpiperazinyl)quinolinyl]-2,3,4,5-tetrahydro-1Hbenzazepine; 1-[2- (9,9-difluoro-6,7,8,9-tetrahydro-5H-benzo[7]annulenyl)methylquinolinyl]ethylurea; N-{[3-(aminomethyl)oxetanyl]methyl}(5,5-difluoro-1,3,4,5-tetrahydro-2Hbenzazepin- 2-yl)methylquinolinamine; 5,5-difluoro[6-methyl(piperazinyl)quinolinyl]- 2,3,4,5-tetrahydro-1Hbenzazepine; 2-[4-(1,4-diazepanyl)methylquinolinyl]-5,5- difluoro-2,3,4,5-tetrahydro-1Hbenzazepine; N-[2-(5,5-difluoro-1,3,4,5-tetrahydro-2H benzazepinyl)methylquinolinyl]-N-methylethane-1,2-diamine; 5,5-difluoro- 1,3,4,5-tetrahydro-2Hbenzazepinyl)methylquinolinyl]pyrrolidinamine; 2-{[2-(5,5- difluoro-1,3,4,5-tetrahydro-2Hbenzazepinyl)methylquinolinyl]amino}ethanol; N-[2- (5,5-difluoro-1,3,4,5-tetrahydro-2Hbenzazepinyl)methylquinolinyl]ethane-1,2- diamine; N-[2-(5,5-difluoro-1,3,4,5-tetrahydro-2Hbenzazepinyl)methylquinolin yl]cyclohexane-1,3-diamine; N'-[2-(5,5-difluoro-1,3,4,5-tetrahydro-2Hbenzazepinyl) methylquinolinyl]-N,N-dimethylethane-1,2-diamine; N-[2-(5,5-difluoro-1,3,4,5-tetrahydro- 2Hbenzazepinyl)methylquinolinyl]propane-1,3-diamine; N-[2-(5,5-difluoro-1,3,4,5- tetrahydro-2Hbenzazepinyl)methylquinolinyl]butane-1,4-diamine; trans amino [2-(5,5-difluoro-1,3,4,5-tetrahydro-2Hbenzazepinyl)methylquinolinyl]pyrrolidinol; N-{[3-(aminomethyl)-1,1-dioxidothietanyl]methyl}(5,5-difluoro-1,3,4,5-tetrahydro-2H benzazepinyl)methylquinolinamine; N-{2-[(2-aminoethyl)sulfonyl]ethyl}(5,5- difluoro-1,3,4,5-tetrahydro-2Hbenzazepinyl)methylquinolinamine; N-{[3- (aminomethyl)thietanyl]methyl}(5,5-difluoro-1,3,4,5-tetrahydro-2Hbenzazepinyl) methylquinazolinamine; N-{[3-(aminomethyl)oxetanyl]methyl}(5,5-difluoro-1,3,4,5- tetrahydro-2Hbenzazepinyl)methylquinazolinamine; nomethyl)({[2-(5,5- ro-1,3,4,5-tetrahydro-2Hbenzazepinyl)methylquinazolin yl]amino}methyl)propane-1,3-diol; 2-(4-{[(3-aminooxetanyl)methyl]amino} methylquinazolinyl)methyl-2,3,4,5-tetrahydro-1Hbenzazepinol; N-[(3-aminooxetan- 3-yl)methyl](5,5-difluoro-1,3,4,5-tetrahydro-2Hbenzazepinyl)methylquinazolin amine; N-[(3-amino-1,1-dioxidothietanyl)methyl](5,5-difluoro-1,3,4,5-tetrahydro-2H benzazepinyl)methylquinazolinamine; N-[2-(5,5-difluoro-1,3,4,5-tetrahydro-2H benzazepinyl)methylquinazolinyl]-2,2-difluoropropane-1,3-diamine; N-[2-(7-bromo- 1,3,4,5-tetrahydro-2Hbenzazepinyl)chloroquinolinyl]ethane-1,2-diamine; 2-{4-[(2- aminoethyl)amino]quinolinyl}-2,3,4,5-tetrahydro-1Hbenzazepinol; ethyl (1,3,4,5-tetrahydro-2Hbenzazepinyl)quinolinyl]ethane-1,2-diamine; N-[2-(8-fluoro- 1,3,4,5-tetrahydro-2Hbenzazepinyl)methylquinolinyl]ethane-1,2-diamine; N-[6- chloro(1,3,4,5-tetrahydro-2Hbenzazepinyl)quinolinyl]ethane-1,2-diamine; N-[6- chloro(9-fluoro-1,3,4,5-tetrahydro-2Hbenzazepinyl)quinolinyl]ethane-1,2-diamine; N-[2-(8-fluoro-1,3,4,5-tetrahydro-2Hbenzazepinyl)quinolinyl]ethane-1,2-diamine; 1- amino{[2-(1,3,4,5-tetrahydro-2Hbenzazepinyl)quinolinyl]amino}propanol trifluoroacetate; N-[2-(1,3,4,5-tetrahydro-2Hbenzazepinyl)quinolinyl]ethane-1,2- diamine; N-[6-bromo(1,3,4,5-tetrahydro-2Hbenzazepinyl)quinolinyl]ethane-1,2- e; N-[6-methoxy(1,3,4,5-tetrahydro-2Hbenzazepinyl)quinolinyl]ethane-1,2- e; N-[2-(6-chloro-1,3,4,5-tetrahydro-2Hbenzazepinyl)quinolinyl]ethane-1,2- diamine; N-[2-(7-fluoro-1,3,4,5-tetrahydro-2Hbenzazepinyl)methylquinolin yl]ethane-1,2-diamine; N-methyl-N'-[2-(1,3,4,5-tetrahydro-2Hbenzazepinyl)quinolin yl]ethane-1,2-diamine; 7-methoxy-1,3,4,5-tetrahydro-2Hbenzazepinyl)quinolin yl]ethane-1,2-diamine; N-[2-(7-fluoro-1,3,4,5-tetrahydro-2Hbenzazepinyl)quinolin yl]ethane-1,2-diamine; N-[2-(8-methoxy-1,3,4,5-tetrahydro-2Hbenzazepinyl)quinolin ane-1,2-diamine; N-[6-(difluoromethoxy)(1,3,4,5-tetrahydro-2Hbenzazepin nolinyl]ethane-1,2-diamine; N-[2-(1,3,4,5-tetrahydro-2Hbenzazepinyl) (trifluoromethyl)quinolinyl]ethane-1,2-diamine; N-[8-chloro(1,3,4,5-tetrahydro-2H benzazepinyl)quinolinyl]ethane-1,2-diamine; N-[6-fluoro(1,3,4,5-tetrahydro-2H epinyl)quinolinyl]ethane-1,2-diamine; N,N-dimethyl-N'-[2-(1,3,4,5-tetrahydro-2H- 2-benzazepinyl)quinolinyl]ethane-1,2-diamine; N-[2-(1,3,4,5-tetrahydro-2Hbenzazepin- 2-yl)(trifluoromethoxy)quinolinyl]ethane-1,2-diamine; N-[6-(methylsulfonyl)(1,3,4,5- tetrahydro-2Hbenzazepinyl)quinolinyl]ethane-1,2-diamine; 2-{4-[(2- aminoethyl)amino]quinolinyl}-2,3,4,5-tetrahydro-1Hbenzazepinecarboxylic acid; 2-(4- chloroquinolinyl)-2,3,4,5-tetrahydro-1Hbenzazepine; N-[5-chloro(1,3,4,5-tetrahydro- enzazepinyl)quinolinyl]ethane-1,2-diamine; N-{2-[7-(methylsulfonyl)-1,3,4,5- tetrahydro-2Hbenzazepinyl]quinolinyl}ethane-1,2-diamine; N-{2-[7-(ethylsulfonyl)- 1,3,4,5-tetrahydro-2Hbenzazepinyl]quinolinyl}ethane-1,2-diamine; N-[2-(8-ethoxy- 1,3,4,5-tetrahydro-2Hbenzazepinyl)quinolinyl]ethane-1,2-diamine; N-[6-(pyridin yloxy)(1,3,4,5-tetrahydro-2Hbenzazepinyl)quinolinyl]ethane-1,2-diamine; (2- aminoethyl)amino]chloroquinolinyl}-N,N-dimethyl-2,3,4,5-tetrahydro-1Hbenzazepine- 7-carboxamide; 2-{4-[(2-aminoethyl)amino]quinolinyl}bromo-1,2,4,5-tetrahydro-3H benzazepinone; 1-(2-{[2-(1,3,4,5-tetrahydro-2Hbenzazepinyl)quinolin yl]amino}ethyl)guanidine trifluoroacetate; N-[(2-amino-4,5-dihydro-1,3-oxazolyl)methyl] (1,3,4,5-tetrahydro-2Hbenzazepinyl)quinolinamine trifluoroacetate; N-[(2-amino-4,5- dihydro-1,3-oxazolyl)methyl]chloro(1,3,4,5-tetrahydro-2Hbenzazepinyl)quinolin- 4-amine; N-[2-(1,3,4,5-tetrahydro-2Hbenzazepinyl)quinolinyl]glycinamide; 3-[2- (1,3,4,5-tetrahydro-2Hbenzazepinyl)quinolinyl]propanamine; [2-(1,3,4,5-tetrahydro- 2Hbenzazepinyl)quinolinyl]methanol; 2-(6-chloroquinolinyl)-2,3,4,5-tetrahydro-1H- 2-benzazepine; 3-[6-chloro(1,3,4,5-tetrahydro-2Hbenzazepinyl)quinolinyl]propane- ol; (4S ){2-[2-(1,3,4,5-tetrahydro-2Hbenzazepinyl)quinolinyl]ethyl}-4,5- dihydro-1,3-oxazolamine; minoethyl)(1,3,4,5-tetrahydro-2Hbenzazepin yl)quinolinesulfonamide trifluoroacetate; 4-{4-[(2-aminoethyl)amino]methylquinolin yl}-1,3,4,5-tetrahydro-2H-1,4-benzodiazepinone; N-[6-methyl(1,2,3,5-tetrahydro-4H-1,4- iazepinyl)quinolinyl]ethane-1,2-diamine; N-[2-(2,3-dihydro-1,4-benzoxazepin- 4(5 H)-yl)quinolinyl]ethane-1,2-diamine; N-[(3-aminooxetanyl)methyl][(5 E) (methoxyimino)-1,3,4,5-tetrahydro-2Hbenzazepinyl]methylquinolinamine and 2-(4- {[(3-aminooxetanyl)methyl]amino}methylquinazolinyl)-1,2,3,4-tetrahydro-5H benzazepinone.
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. rmore, 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 DMSO-d6: deuterated dimethylsulfoxide FBS: fetal bovine serum g: gram µg: microgram EC50: the concentration of a compound where 5 0% of its l protection effect against viral induced CPE is observed HPLC: high performance liquid chromatography Hz: Hertz CDCl3 deuterated form CD3OD: deuterated methanol mg: milligram MHz: rtz mL: milliliter mmol: millimole obsd. Observed µL: microliter µm: micrometer µM: micromoles per liter mm: millimeter MS (ESI): mass spectroscopy (electron spray tion) NMR: nuclear magnetic resonance TLC: thin layer chromatography General synthetic route for 2,4-dihalogen quinolines IIIa (Scheme 1) Scheme 1 OH O O OH R3 E POE3 A VI A R2 N E R2 NH2 VII IIIa E is Cl or Br nds of st of formula IIIa 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-quinolines IIIa. The reaction can be d 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-1,4-benzothiazepines (Scheme 2) Scheme 2 O O OH NH2.HCl R6 H R6 R6 O N SH R7 SH R7 S R7 R8 R8 VIIIa X IXa H H N R6 N R6 N R6 S R7 S R7 S R7 R8 R8 O R8 N R6 S R7 O O R8 Compounds of interest IVa, IVb, IVc and IVd can be ed ing to Scheme 2.
Starting with 2-sulfanylbenzoic acids X, fication with methanol gives methyl 2- sulfanylbenzoates IXa. Annulation of esters IXa with 2-bromo ethylamine affords 3,4-dihydro- 1,4-benzothiazepin-5(2H)-ones VIIIa. ion of VIIIa affords 2,3,4,5-tetrahydro-1,4- 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-1,4-benzothiazepin-5(2 H)-ones VIIIa can be ed from methyl 2- sulfanylbenzoates IXa by tion 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 le organic solvent such as tetrahydrofuran, 1,4-dioxane, N,N -dimethylformamide or mixtures thereof, lly at 0 ºC, followed by stirring at room temperature overnight. 2,3,4,5-Tetrahydro-1,4-benzothiazepines IVa can be prepared by reduction of 3,4- dihydro-1,4-benzothiazepin-5(2 H)-ones VIIIa . The reaction can be d 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 ºC, followed by stirring at a temperature between ºC and 70 ºC 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 ºC, ed 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 lents of 3-chloroperoxybenzoic acid, in a suitable t such as dichloromethane, chloroform, 1,2-dichloroethane, or the mixture thereof, lly at 0 ºC, 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 l and water under reflux overnight.
Compounds IVd can be prepared by oxidation of IVb followed by deacylation. Oxidation can be d out with 4 equivalents of roperoxybenzoic acid, in a suitable solvent such as dichloromethane, chloroform, 1,2-dichloroethane, or the mixture thereof, typically at 0 ºC, followed by stirring at room ature for 1 to 2 hours. Deacylation can be ed 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-1,4-benzothiazepines (Scheme 3) Scheme 3 R6 N R6 H O NH2.HCl N R6 SH R7 S R7 S R7 R8 R8 IXb VIIIb IVe Compounds of st IVe can be ed ing to Scheme 3. Starting from 1-(2- sulfanylphenyl)ethanones IXb, annulation of esters IXb with 2-bromo ethylamine hydrochloride affords 5-methyl-2,3-dihydro-1,4-benzothiazepines VIIIb. Reduction of VIIIb affords 5-methyl- 2,3,4,5-tetrahydro-1,4-benzothiazepines IVe.
-Methyl-2,3-dihydro-1,4-benzothiazepine VIIIb can be prepared from 1-(2- sulfanylphenyl)ethanones IXb by tion 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, oxane, N,N-dimethylformamide or mixtures thereof, typically at 0 ºC, followed by ng at room temperature overnight.
-Methyl-2,3,4,5-tetrahydro-1,4-benzothiazepines IVe can be prepared from reduction of -methyl-2,3-dihydro-1,4-benzothiazepines VIIIb. 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 ght, 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 R4 R6 R3 E R3 E NH R7 A R4 R6 S R8 R2 N N IVf R7 R2 N E R1 IIac R1 S IIIa R8 N L1 N R3 E R3 NH W1 NH W1 2 A R4 R6 A R4 R6 Va R2 N N R2 N N R7 R7 R1 R1 IIaa IIab S O R8 O R3 NH W1 A R6 R2 N N E is Cl or Br, W1 is (oxetanyl)C1-4 alkyl, (tetrahydrofuranyl)C1-4alkyl, hydro-2H-pyranyl)C1-4alkyl, or (C3-6cycloalkyl)C1-4alkyl L1 is H or benzyl, or L1 and W1 with the nitrogen atom to which they are attached form 2-Oxaaza-spiro[3.4]octyl Compounds of interest Iaa can be prepared ing to Scheme 4. Coupling of 2,4- dihalogen quinolines IIIa with benzothiazepines IVf followed by oxidation gives 4-halogen quinolines IIab. Coupling of 4-halogen quinolines IIab with various benzyl diamines Va followed by debenzylation generates Iaa.
Quinolines IIac can be ed by ng of 2,4-dihalogen ines IIIa with benzothiazepines IVf. The reaction can be carried out with or t a solvent such as isopropanol, n-butanol, tert-butanol or the mixture thereof at a temperature between 120 oC and 180 oC, typically at 160 ºC under microwave irradiation for several hours.
Sulfones IIab can be prepared by oxidation of sulfides IIac. 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 ºC, followed by stirring at room temperature for several hours. Alternatively, the reaction can be d out with a suitable oxidant such as hydrogen peroxide, sodium periodate or potassium permanganate, in a suitable solvent such as methanol, tetrahydrofuran, water or the e thereof, typically at 0 ºC, followed by stirring at a temperature between room temperature and 70 ºC for several hours. 4-Benzyl diamino quinolines IIaa can be prepared by coupling of quinolines IIab with various benzyl es Va . The on can be carried out in the presence of a palladium catalyst such as 1,1'-bis(diphenylphosphino)ferrocene-palladium (II), palladium (II) acetate, tri(dibenzylideneacetone)dipalladium(0), or ium (II) chloride in the presence of a phosphine ligand such as triphenyl phosphane, 1,1'-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 utoxide or potassium tert -butoxide, in a suitable inert organic solvent such as toluene, 1,4-dioxane, tetrahydrofuran or N,N -dimethylformamide at a temperature between 100 ºC and 160 ºC for 1 to 3 hours under microwave irradiation. Alternatively, the reactions can be carried out at a heated ature such as between 100 ºC and 140 ºC for a longer reaction time without microwave irradiation.
Compounds of interest Iaa can be prepared by standard debenzylation of IIaa . The reaction can be carried out in the ce of palladium on carbon, palladium ide on carbon or platinum oxide, typically with an acid such as hydrochloric acid, acetic acid or trifluoroacetic acid in a suitable solvent such as methanol, ethanol, tetrahydrofuran, ethyl acetate or the mixture thereof, at room temperature for several hours under hydrogen atmosphere.
General synthetic route for formula Iab and Iac (Scheme 5) Scheme 5 R3 E R12 R13 R12 R13 R3 N A R4 R6 N H A R4 R6 R2 N N XI R1 R2 N N IIac R7 S R8 R1 Iab R12 R13 R3 E R12 R13 R3 N A R4 R6 H A R4 R6 R2 N N R7 R2 N N R1 R1 IIab S O Iac R8 S O O O E is Cl or Br Compounds of interest Iab and Iac can be prepared according to Scheme 5. Coupling of 4-halogen quinolines IIac with various amines XI affords Iab. Coupling of 4-halogen quinolines IIab and various amines XI affords 4-amino quinolines Iac. Alternatively, Iac can be obtained by oxidation of the es Iab. 4-Amino ines Iab can be prepared by coupling of 4-halogen quinolines IIac 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 1,1'- phenylphosphino)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)-1,1’-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 ave irradiation. atively, palladium-catalyzed coupling reaction can be carried out at an ed temperature such as 110 °C or 120 °C without microwave irradiation for a longer on time. Coupling of 4-halogen quinolines IIac with various amines XI in the absence of a ium 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, 1-methylpyrrolidinone 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 t microwave irradiation for a longer reaction time. Alternatively, the reaction can also be carried out without any base and without any t at 160 °C for one to several hours under microwave irradiation. 4-Amino quinolines Iac can be prepared by coupling of 4-halogen quinolines IIab 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 quinolines IIab with various amines XI in the presence of a palladium catalyst or in the e of any metal catalyst can be carried out in analogy to coupling of 4-halogen quinolines IIac with various amines XI .
Copper(I) iodide catalyzed coupling of 4-halogen quinolines IIab with various amines XI can be carried out in the ce of copper(I) iodide with a ligand such as N,N' -dimethylcyclohexane- 1,2-diamine or cyclohexane-1,3-diamine, and a base such as potassium ate 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 d out at an elevated temperature without microwave ation for a longer reaction time.
Alternatively, 4-Amino quinolines Iac can be prepared from oxidation of sulfides Iab .
The reaction can be d out in analogy to oxidation of ines IIac in Scheme 4.
General synthetic route for formula Iad (Scheme 6) Scheme 6 R4 R6 R3 E R3 E S R8 O A R4 R6 A m IVg R2 N N R2 N E R7 R1 IIIa IIad S R12 R13 R12 R13 R3 N A R4 R6 E is Cl or Br; R2 N N m is 1 or 2. R1 Iad S Compounds of interest Iad can be prepared according to Scheme 6. Coupling of 2,4- halogen quinolines IIIa with benzothiazepines IVg affords 2-benzothiazepinhalogen ines IIad. Coupling of IIad with various amines XI affords compounds of interest Iad. 2-Benzothiazepinhalogen quinolines IIad can be prepared from coupling of 2,4- halogen quinolines IIIa with benzothiazepines IVg. The reaction can be carried out in the absence of t or in a suitable solvent such as isopropanol, n-butanol, tert-butanol or the mixtures thereof at a temperature between 120 oC and 180 oC, typically at 160 ºC under microwave irradiation for several hours.
Compounds of interest of formula Iad can be prepared from coupling of 2- benzothiazepinhalogen quinolines IIad with s amines XI. The on can be carried out in the ce of a metal catalyst or in the absence of a metal catalyst in analogy to coupling of 4-halogen ines IIab with various amines XI in Scheme 5.
General synthetic route for formula Iae, Iaf and Iag (Scheme 7) Scheme 7 R3 NH2 R3 NH O A R4 R6 A R4 R6 R2 N N R2 N N R1 R7 X R1 Iae R8 IIaf X R8 NH O L3 N 2 O H L2 L3 N O R3 E L2 O R3 N A R4 R6 H A R4 R6 R2 N N R7 XII R2 N N R1 R7 IIae X R1 R8 IIag X R8 L5 O L4 N N W2 H O XIII L3 NH R3 N N O A R4 R6 L4 W2 R3 N R2 N N A R4 R6 R1 Iaf X R8 R2 N N R7 L5 R1 NH IIah X L4 R8 W2 R3 N A R4 R6 R2 N N Iag X E is Cl or Br; L2 is hydrogen; L3 is hydrogen, hydroxy or fluoro; L2 and L3 are attached to form 3-oxetanyl; L4 is hydrogen,or ; L5 is hydrogen; W2 is ethyl, methylcyclopropyl, ethylcyclopropyl, or (morpholinyl)methyl L4 and W2 with nitrogen they are attached to form azetidinyl, 2-azabicyclo[2.1.1]hexanyl or (1R,5S,6S)azabicyclo[3,1,0]hexanyl L5 and W2 with nitrogen they are attached to form pyrrolindinyl, azetidinyl, methylazetidinyl, azetidinyl-carbonyl or pyrrolindinyl-carbonyl. nds of st Iae, Iaf and Iag can be prepared according to Scheme 7. Coupling of 4-halogen quinolines IIae with various protected amines affords intermediates IIaf, IIag and IIah. Deprotection of IIaf, IIag and IIah affords compounds of interest Iae, Iaf and Iag.
Compounds of interest IIaf, IIag and IIah can be prepared from ng of 4-halogen quinolines IIae with various protected amines. Coupling of 4-halogen quinolines IIae 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 gen quinolines IIab with various amines XI in Scheme 5.
Compounds of interest Iae, Iaf and Iag can be prepared from deprotection of tertbutyloxycarbonyl of IIaf, IIag and IIah. The reaction can be carried out with a suitable acid such as oroacetic 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 tic route for formula Iah (Scheme 8) Scheme 8 L6 N Cbz R3 E R3 NH N Cbz A R4 R6 NH 2 A R4 R6 R2 N N R7 R2 N N IIae R1 X IIai R8 X R8 R3 NH A R4 R6 Q is Cl or Br, R2 N N L6 is hydroxy or fluoro X R8 Compounds of st Iah can be prepared according to Scheme 8. Coupling of 4- halogen quinolines IIae with s protected amines XIV affords intermediates IIai.
Deprotection of benzyloxycarbonyl of IIai affords compounds of interest Iah.
Compounds IIai can be prepared from coupling of 4-halogen quinolines IIae with various amines XIV. The reaction can be carried out in the ce of a metal catalyst or in the absence of a metal catalyst in analogy to coupling of 4-halogen quinolines IIab with s amines XI in Scheme 5. Typically, the reaction can be carried out in the presence of tris(dibenzylideneacetone)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 IIai. The conversion can be achieved under strong acidic conditions, under basic conditions or by hydrogenation. ng IIai with a mixture of aqueous solution of potassium hydroxide and methanol under reflux for 30 minutes to several hours can generate Iah. Treating IIai under strong acidic conditions such as reflux in 6 N hydrochloride in ol for several hours can also generate Iah. Hydrogenation of IIai 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 ol or ethanol, at a temperature between room ature and 80 ºC for 15 minutes to several hours.
General synthetic route for formula Iai and Iaj (Scheme 9) Scheme 9 R3 E O R5 R4 R6 R2 N N IIaj X R8 R3 E R3 NH NH OH R5 R4 R6 OH R5 R4 R6 NH NH 2 2 R2 N N R7 R2 N N R1 IIak R1 X R8 Iai X R8 L7 Br L7 R3 E L7 R3 N NH2 O R5 R4 R6 O R5 NH R4 R6 R2 N N R7 R2 N N R1 R7 IIam R1 X R8 Iaj X R8 E is Cl or Br, L7 is hydroxyethyl, methoxyethyl or pyridinyl Compounds of interest Iai and Iaj can be prepared according to Scheme 8. Demethylation of 6-methoxy quinolines IIaj affords 6-hydroxy ines IIak. Reaction of IIak with bromides XV s IIam. ng of 6-hydroxy quinolines IIak with propane-1,3-diamine affords compounds of interest Iai. Coupling of IIam with e-1,3-diamine affords compounds of interest Iaj. 6-Hydroxy quinolines IIak can be prepared by ylation of 6-methoxy quinolines IIaj. The reaction can be carried out in an aqueous solution of hydrobromic acid by heating under reflux for 2 days.
IIam can be prepared by reaction of IIak with bromides XV. When L7 is pyridinyl, the reaction can be carried out in the presence of a metal catalyst such as Copper(I) iodide with a ligand such as imethylcyclohexane-1,2-diamine and with a suitable base such as potassium carbonate in a suitable solvent such as methoxyethane at 120 °C for 1 hours under microwave irradiation. When L7 is substituted alkyl such as hydroxyethyl 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 Iai and Iaj can be prepared by coupling of IIak and IIam with propane-1,3-diamine tely. 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 O O R3 E R3 NH A R4 R6 NH 2 A R4 R6 R2 N N R7 R2 N N R1 R7 IIae X R1 R8 IIan X R8 R3 NH A R4 R6 R2 N N E is Cl or Br, R7 Iak X R8 Compounds of interest Iak can be prepared according to Scheme 10. Coupling of 4- halogen quinolines IIae with C-(2,2-dimethyl-[1,3]dioxolanyl)-methylamine ed by deprotection s 4-(2,3-diol-propylamino)-quinolines Iak.
IIan can be obtained by coupling of 4-halogen quinolines IIae with C-(2,2-dimethyl- [1,3]dioxolanyl)-methylamine. The reaction can be carried out in y to coupling of 4- n quinolines IIab with various amines XI in Scheme 5. Typically the reaction can be carried out by heating a mixture of 4-halogen quinolines IIae and C-(2,2-dimethyl- [1,3]dioxolanyl)-methylamine at 160 oC for 16 hours. 4-(2,3-Diol-propylamino)-quinolines Iak can be prepared by ection of IIan. 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 11) Scheme 11 O N O N R3 NH N R3 NH W3 A R4 F XVI A R4 N R2 N N R7 R2 N N IIao R1 S O IIap R8 S O O O O NH R3 NH W3 A R4 N R2 N N W3 is O or NCH(CH3) R7 2 R1 O Compounds of interest Ial can be prepared according to Scheme 11. Coupling of fluorides IIao with amines XVI followed by debenzylation affords compounds of interest Ial .
Quinolines IIap can be prepared from coupling of fluorides IIao (which can be prepared in analogy to 4-benzyl o quinolines IIaa in Scheme 4) with amines XVI. The reaction can be carried out by heating a mixture of fluorides IIao and amines XVI with a suitable solvent such as N,N -dimethyl ide, N,N -dimethyl acetamide, N-methylpyrrolidinone, dimethyl ide or the mixtures thereof, or without any solvent at a temperature between 100 oC and 150 oC, typically at 120 ºC under ave irradiation for several hours.
Compounds of interest Ial can be prepared by standard benzyl deprotection of IIap . The reaction can be d out in analogy to debenzylation of IIaa in Scheme 4.
General synthetic route for formula Iam and Ian (Scheme 12) Scheme 12 R3 E A R4 R6 R2 N N IIaq S O R3 E A R4 R6 R2 N N IIar S O R3 E R3 E A R4 R6 A R4 R6 R2 N N O R2 N N R1 O IIas S O R8 IIau S O O R8 N O R3 NH R3 NH O R4 R6 A R4 R6 R2 N N R2 N N O O R1 R1 IIat S O IIav S O R8 R8 O O R3 NH R3 NH A R4 R6 A R4 R6 R2 N N O R2 N N R1 O Iam S O R1 R8 Ian S O O R8 E is Cl or Br, Compounds of interest Iam and Ian can be prepared according to Scheme 12.
Demethylation of IIaq affords IIar. Coupling of IIar with iodobenzene affords 4-phenoxy benzothiazepines IIas. ng of IIas with (3-aminomethyl-oxetanyl)-dibenzylamine followed by debenzylation provides 4-[(3-amino-oxetanylmethyl)-amino]quinolines Iam .
Coupling of IIar with 3-bromo-propanol affords IIau . Coupling of 4-halogen quinolines IIau with carbamic acid tert -butyl ester followed by deprotection of tert -butyloxycarbonyl s 4- amino quinolines Ian .
IIar can be ed by demethylation of IIaq . The reaction can be carried out by treating IIaq 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, lly at 0 oC, for a period of 5 minutes to 3 hours, typically for 1 hour.
IIas can be obtained by coupling of IIar with iodobenzene. The reaction can be carried out by heating in the ce of copper(I) iodide or copper(I) bromide, with a ligand such as N,N -dimethylglycine hydrochloride, (2-pyridyl)acetone or tris(hydroxymethyl)ethane, and a base such as cesium ate, potassium carbonate, or potassium phosphate, in an organic solvent such as dimethyl sulfoxide, N,N -dimethylformamide, acetonitrile or 1,4-dioxane at a ature between 80 oC and 120 oC for 4 to 24 hours. Typically, the reaction can be d out by g in the presence of copper(I) iodide, N,N -dimethylglycine hydrochloride and potassium carbonate in dimethyl sulfoxide at 120 oC for 6 hours.
Iam can be obtained by coupling of IIas with (3-aminomethyl-oxetanyl)-dibenzylamine followed by debenzylation. The reactions can be conducted in analogy to preparation of Iaa from IIab in Scheme 4. Typically, coupling of IIas with (3-aminomethyl-oxetanyl)-dibenzylamine can be carried out in the presence of bis(diphenylphosphino)-ferrocenedichloropalladium(II), 1,1'-bis(diphenylphosphino)-ferrocene and sodium-tert -butoxide in 1,4-dioxane at 120 oC for 2 hours under microwave irradiation. Debenzylation of IIat can be achieved by stirring a solution of IIat in methanol in the presence of palladium hydroxide on carbon and oroacetic acid at room temperature under 2 bar of hydrogen atmosphere for 14 hours.
IIau can be prepared by coupling of IIar with 3-bromo-propanol. The reaction can be d out with a suitable base such as potassium ate, cesium carbonate, sodium tert - butoxide, potassium tert -butoxide, sodium hydride or 1,8-diazabicyclo[5.4.0]undecene in an inert organic solvent such as dichloromethane, N,N -dimethylformamide, dimethyl sulfoxide or 1- methyl-pyrrolidinone at a temperature between room temperature and 100 oC, typically at 70 oC for several hours.
IIav can be prepared by coupling of 4-halogen quinolines IIau 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 quinolines IIab with various amines XI in Scheme 5. Typically the reaction can be carried out by heating a mixture of 4-halogen quinolines IIau and carbamic acid tert-butyl ester in the presence of bis(diphenylphosphino)ferrocenedichloropalladium(II), with 1,1'-bis(diphenylphosphino)ferrocene and sodium-tert-butoxide in 1,4-dioxane at 120 oC for 2 hours. 4-Amine quinolines Ian can be obtained by standard deprotection of tyloxycarbonyl of IIav. The reaction can be carried out by treating IIav with a suitable acid such as hydrochloric acid, oroacetic acid, or ic acid in a suitable t such as methanol, ethyl acetate, romethane, 1,4-dioxane, water or the mixtures f at a temperature between 0 ºC and room temperature for 30 minutes to several hours. Typically the reaction can be carried out by treating IIav with trifluoroacetic acid in dichloromethane at room temperature for 6 hours.
General synthetic route for formula Iao (Scheme 12) Scheme 12 O OH O OH R3 E W4 W4 R3 NH R4 R6 NH A 2 XVII A R4 R6 R2 N N R7 R2 N N R1 R7 IIab S O R1 R8 IIaw O S O O N O O W4 W4 R3 NH R3 NH A R4 R6 A R4 R6 R2 N N R2 N N R7 R7 R1 R1 Iao IIax S O S O R8 R8 O O E is Cl 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 quinolines IIab with various amino acids XVII gives acids IIaw . Esterification of acids IIaw followed by aminolysis affords amides Iao .
Acids IIaw can be prepared by coupling of 4-halogen-quinolines IIab with amino acids XVII . The reaction can be carried out in phenol, preferably at 150 °C in a sealed tube overnight.
Esters IIax can be ed by esterification of carboxylic acids IIaw . The reaction can be carried out by heating IIaw 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 d out by g IIaw and methanol in the presence of thionyl chloride under reflux for 2 hours.
Amides Iao can be prepared by aminolysis of methyl esters IIax . The on can be carried out by heating methyl esters IIax with various concentrated amines in alcohol, such as 7N ammonia in ol or 33% (wt%) methyl amine in absolute ethanol. The reaction can be preferably carried out at 85 °C in a sealed tube overnight.
General tic route for formula Iap (Scheme 14) Scheme 14 O N R3 E O R3 NH A R4 R6 NH A R4 R6 R2 N N R7 R2 N N R1 R7 IIab S O R1 O IIay S O R3 NH A R4 R6 R2 N N Iap S O Compounds of interest Iap can be prepared according to Scheme 14. Coupling of 4- halogen quinolines IIab with 4-aminomethyl-2,2-dimethyl-oxazolidinecarboxylic acid tertbutyl ester affords IIay. Cleavage of utyloxycarbonyl and acetal tes amino alcohols Iap.
Oxazolidines can be prepared by coupling of 4-halogen quinolines IIab with 4- aminomethyl-2,2-dimethyl-oxazolidinecarboxylic acid utyl ester. The reaction can be carried out in the presence of a palladium catalyst in analogy to coupling of 4-halogen quinolines IIab with various amines XI in Scheme 5. Typically the reaction can be carried out by heating a mixture of 4-halogen quinolines IIab and 4-aminomethyl-2,2-dimethyl-oxazolidinecarboxylic acid utyl ester in the presence of bis(diphenylphosphino)ferrocenedichloropalladium(II), with 1,1'-bis(diphenylphosphino)ferrocene and sodium-tert-butoxide in 1,4-dioxane at 120 oC for 1.5 hours.
Amino ls Iap can be prepared by acid catalyzed cleavage of tert-butyloxycarbonyl and acetal of acetonides IIay. The reaction is typically carried out in a solution of hydrochloride in ethyl e for several hours at room temperature.
General synthetic route for formula Iar (Scheme 15) Scheme 15 NH 2 2 N R3 NH R3 NH A R4 R6 R5 A R4 R6 R2 N N R7 R2 N N R1 R7 Iaq X R8 Iar X L9 is H or CH3, Compounds of interest Iar can be ed according to Scheme 15. Starting with amino alcohols Iaq (prepared in ue to Idj in Scheme 56), ring closure with cyanogen bromide gives oxazoles Iar. The reaction can be carried out with a suitable base such as sodium acetate, sodium carbonate, potassium acetate or ium carbonate, in a suitable solvent such as methanol, water, or the mixtures thereof, typically at 0 ºC, followed by stirring at room temperature for several hours.
General synthetic route for formula Iat (Scheme 16) Scheme 16 2 W5 N W5 R3 N R3 N A R4 R6 A R4 R6 R2 N N R7 R2 N N R1 R7 Ias S O R1 R8 Iat O R8 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 Ias (prepared in analogue to Iap in Scheme 14 and Iaf in Scheme 7), ation with cyanogen e affords oxazoles Iat. Compounds of interest Iat can be prepared by cyclization of amino ls Ias 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 ate, potassium acetate or potassium carbonate, in a suitable solvent such as methanol, water, or the mixtures thereof, typically at 0 ºC, followed by stirring at room temperature for several hours.
General synthetic route for formula Iau (Scheme 17) Scheme 17 O R6 O R6 N R7 S R8 R8 O IVb IVh R2 NH XVIII R3 NH R3 2 N A R6 A R6 R2 N N R2 N N R7 R7 R1 R1 S O S O R8 R8 Iau O IIaz O Compounds of interest Iau 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 IIaz. Ring closure of imines IIaz gives 4-amino quinolines Iau. es IVh can be prepared by oxidation of IVb. The reaction can be carried out with a suitable t 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 f, lly at 0 ºC, followed by stirring at room temperature for several hours.
Imines IIaz 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 ºC, followed by stirring at reflux for 24 hours.
Compounds of interest Iau can be ed by ring e of imines IIaz. The reaction can be achieved by treatment of IIaz with Lewis acid such as zinc chloride in N,N- dimethylacetamide at 120-180 ºC for several hours in an inert atmosphere.
General tic route for formula Iav and Iaw (Scheme 18) Scheme 18 R3 NH A R4 R6 R2 N N Iae X R8 L11 L12 R3 NH L11 L12 A R4 R6 R2 N N IIba X R8 O O N O R3 NH R3 NH L11 L12 L12 R5 L11 R5 A R4 R6 A R4 R6 R2 N N R2 N N R7 R7 R1 R1 IIbb X Iav X R8 R8 R3 NH L11 R5 A R4 R6 R2 N N E is Cl or Br, R7 L11 is H, or CH3, Iaw X L12 is H, CH3 or CH2CH3 Compounds of st Iaw and Iav can be ed according to Scheme 18. Staring from 4-amino quinolines Iae, acylation of Iae with acyl chlorides XIX gives amides IIba. Reaction of IIba with methanol affords methyl ethers Iav. Reaction of IIba with sodium azide followed by hydrogenation of azides generates compounds of formula Iaw.
Amides IIba can be prepared from 4-amino quinolines Iae 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 1,8-diazabicyclo[5.4.0]undecene in an inert organic t such as dichloromethane, tetrahydrofuran or N,N-dimethylformamide, lly at room temperature, followed by stirring at 50-100 ºC for several hours.
Methyl ethers Iav can be prepared by on of IIba with methanol. The reaction can be realized by refluxing IIba in methanol in the presence of ethylamine overnight.
Azides IIbb can be prepared by reaction of amides IIba 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 ºC for several hours.
Amines Iaw can be prepared by enation of azides IIbb. 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, lly at room ature for several hours.
General synthetic route for formula Iax and Iay (Scheme 19) Scheme 19 O L13O O L13O Cl N R3 NH2 R3 NH N R4 R6 XX O A R4 O R6 R2 N N R7 R2 N N R1 R7 X R1 R8 IIbc X R8 L13 L13 R3 NH NH2 R3 NH NH A R4 R6 A R4 R6 R2 N N R7 R2 N N R1 R1 Iay X R8 Iax X R8 L13 is H or CF3 Compounds of interest Iax and Iay can be prepared according to Scheme 19. Starting from 4-aminoquinolines Iae, acylation of Iae with acyl chlorides XX gives IIbc. Cleavage of phthalic protecting group from IIbc generates amides Iax. Reduction of amides of Iax generates Iay.
IIbc can be prepared by acylation of 4-aminoquinolines Iae. The reaction can be d out by stirring a mixture of Iae and acyl chlorides XX with a suitable base such as N,N- diisopropylethylamine or cesium carbonate, in a suitable organic solvent such as romethane, N,N-dimethylformamide or the mixtures f, at room temperature for several hours.
Amides Iax can be prepared by cleavage of phthalic protecting group from IIbc. The reaction can be d out with a suitable base such as hydrazine, hydrazine e or low alkyl amine such as methylamine or n-butylamine in an alcohol solvent such as ol or ethanol at a ature between room temperature and 90 ºC for several hours. Typically, the reaction can be carried out by heating IIbc with methylamine in ethanol, at 90 ºC for 2 hours.
Iay can be obtained by reduction of amides of Iax. The reaction can be carried out by heating Iax in a solution of -methyl sulfide complex in diethyl ether at 80 ºC for several hours.
General synthetic route for formula Iba (Scheme 20) Scheme 20 L14 W6 L15 L14 R3 N N W6 L16 H R3 N N A R4 R6 L15 A R4 R6 R2 N N R7 R2 N N Iaz R1 R8 Iba X L14 is H, L15 is H or ethyl, L16 is CH2CH3 ,oxetanyl, or pyridinyl, W6 is (CH2)2, (CH2)3, or methyl-oxetanyl, L14 and W6 with nitrogen they are attached to form pyrrolidinyl, L15 and W6 with nitrogen they are ed to form pyrrolidiny, Compounds of interest Iba can be prepared according to Scheme 20. Starting with amines Iaz (prepared in ue to Iac in Scheme 5 and Iaf, Iag in Scheme 7), reductive amination with various aldehydes or ketones provides substituted amines Iba when L16 is ethyl or oxetanyl; coupling of amines Iaz with 2-bromo-pyridine tes Iba when L16 is pyridineyl.
Compounds of interest Iba can be prepared by reductive amination of Iaz 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 oC 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 oC and 150 oC for several hours under inert atmosphere. l synthetic route for formula Ibb (Scheme 21) Scheme 21 R3 NH2 R3 NH N L17 A R4 R6 O N L17 A R4 R6 R2 N N R7 R2 N N R1 R1 Iae X Ibb R8 X L17 is phenyl or ethyl Compounds of a Ibb can be prepared as shown in Scheme 21. Ureas Ibb can be prepared by reaction of 4-amino-quinolines Iae with isocyanides XXI. The reaction can be d out by ng 4-amino-quinolines Iae with various isocyanide XXI in the presence of a suitable base such as triethylamine in an organic solvent such as tetrahydrofuran at a ature between 0 oC to 50 oC for several hours.
General synthetic route for formula Ibc (Scheme 22) Scheme 22 R3 Cl R3 Cl R4 R6 L18 R4 R6 R2 N N R7 R2 N N R1 R7 IIbd R1 R8 IIbe X 2NH NH2 R3 NH NH R4 R6 R2 N N L18 is cyclopropyl, cyano, ethenyl, or ethynyl R1 X R8 Compounds of interest of formula Ibc can be prepared according to Scheme 22. on of es IIbd with various organoboronic acids or various organometallic reagents affords compounds IIbe. Coupling of IIbe with propane-1,3-diamine affords compounds of interest of formula Ibc.
Compounds IIbe can be prepared from reaction of bromides IIbd with s organoboronic acids or various metal reagents such as zinc cyanide or organostannic ts.
Reaction of bromides IIbd with various organoboronic acids can be d 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)-1,1’-binaphthalene and a base such as potassium carbonate in a suitable solvent such as toluene at 90 oC for 16 hours under argon atmosphere. on of bromides IIbd with s 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 methylformamide under reflux for 1 to 2 hours under argon atmosphere.
Coupling of halogens IIbe with propane-1,3-diamine can be carried out in analogy to coupling of 4-halogen quinolines IIab 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 1,1'- bis(diphenylphosphino)ferrocene, and a suitable base such as sodium-tert-butoxide in a suitable solvent such as 1,4-dioxane, heated at 120 oC for 2 hours under microwave irradiation. l synthetic route for formula Ibd, Ibe and Ibf (Scheme 23) Scheme 23 R4 R6 R3 OH R3 OH NH A N R4 R6 A N X R2 N N IVi R8 R7 R2 N Cl R1 IIbg R1 R8 IIIc R12 R13 R3 Cl A N R3 N R2 N Cl A N R4 R6 R1 IIIb R2 N N R12 R13 R8 H R4 R6 R12 NH R13 R7 R3 N A N IVi R2 N Cl IIbf R4 R6 IVf R12 R12 R13 R13 R3 N R3 N A N R4 R6 A N R4 R6 R2 N N R2 N N R7 R7 R1 Ibe Ibf S O S R8 R8 O Compounds of interest Ibd, Ibe and Ibf can be prepared ing to Scheme 23.
Hydrolysis of 2,4-dichloro-quinozalines IIIb affords 2-chlorohydroxy-quinozalines IIIc.
Coupling of 2,4-dichloro-quinozalines IIIb with various amines XI affords IIbf. Coupling of IIIc with benzoazapines IVi followed by coupling with various amines XI affords compounds of interest Ibd. Coupling of IIbf with benzoazapines IVi affords compounds of interest Ibd.
Coupling of IIbf with benzothioazapines IVf s compounds of st Ibe. Oxidation of sulfides of Ibe affords compounds of interest Ibf. 2-Chlorohydroxy-quinozalines IIIc can be prepared by ysis of 2,4-dichloroquinozalines IIIb . The reaction can be carried out in the presence of a le base such as sodium hydroxide in a suitable solvent such as tetrahydrofuran, water or mixtures f at room temperature for several hours. 4-Hydroxy quinozalines IIbg can be prepared by coupling of IIIc with zapines IVi . The on 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 n 110 °C and 160 °C under microwave irradiation for 30 minutes to 2 hours. Alternatively, the reaction can be carried out at an ed temperature such as under reflux overnight without microwave irradiation. 2-Chloroamino quinozalines IIbf can be prepared by coupling of IIIb 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 es thereof at a temperature between 0 oC to room temperature for several hours.
Compounds of interest Ibd can be prepared by coupling of IIbg 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]undecene with a suitable ng reagents such as benzotriazol 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 IIbf 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, lly at 100 °C for 4 hours.
Compounds of interest Ibe can be prepared by coupling of IIbf with hioazapines 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 ature 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 roperoxybenzoic acid in dichloromethane or oxone in a mixture solvent such as ol and tetrahydrofuran at a temperature between 0 °C and room temperature for several hours.
General synthetic route for formula Ibj (Scheme 24) Scheme 24 L19 L19 W7 N W7 N R3 NH R3 NH A N R4 R6 A N R4 R6 R2 N N R2 N N R7 R7 R1 R1 Ibh S R8 Ibi S O R8 W7 NH2 R3 NH A N R4 R6 W7 is O or CH2; R2 N N L19 is H or benzyl R1 Ibj S O R8 O 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 de, sodium periodate or ium permanganate, in a suitable t such as dichloromethane, acetic acid, water or the e thereof, typically at 0 ºC, 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 ium on carbon, palladium ide on carbon or platinum oxide, typically with an acid such as acetic acid or trifluoroacetic acid in a suitable solvent such as methanol, ethanol, tetrahydrofuran, ethyl acetate or the mixtures thereof, at room temperature under hydrogen atmosphere for several hours.
General synthetic route for formula Ibl (Scheme 25) Scheme 25 R3 NH NH2 W8 R3 NH N A Y R4 R6 A Y R4 R6 R2 N N R7 R2 N N Ibk R1 X Ibl R8 X W8 is (CH2)2, (CH2)3 or oxetanylmethyl, Compounds of interest Ibl can be prepared according to Scheme 25. Starting with amines Ibk (prepared in analogue to Iac in Scheme 5 and Ibf in Scheme 23), acylation with acetic ide 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 t such as dichloromethane, tetrahydrofuran or pyridine at 0 ºC, followed by stirring at room temperature for several hours.
General tic route for formula Ibm (Scheme 26) Scheme 26 O H R3 E N R3 N A R4 R6 N A R4 R6 R2 N N R7 R2 N N R1 R7 IIab S O R1 R8 IIbh S O O R8 R3 N A R4 R6 R2 N N E is Cl or Br R7 Ibm S O Compounds of interest Ibm can be prepared according to Scheme 26. Coupling of 4- halogen-quinolines IIab with N-(3-methyl-pyrrolidinyl)-acetamide affords compounds IIbh.
Deactylation of IIbh affords compounds of interest Ibm.
Compounds IIbh can be prepared by ng of 4-halogen-quinolines IIab with N-(3- methyl-pyrrolidinyl)-acetamide. The reaction can be d out in the presence of a metal st or in the absence of a metal catalyst in analogy to coupling of 4-halogen quinolines IIab with various amines XI in Scheme 5. Typically, the reaction can be carried out with 1,1'- bis(diphenylphosphino)ferrocene, is(diphenylphosphino)ferrocenedichloropalladium(II), and sodium-tert-butoxide in 1,4-dioxane at 120 oC for 1.5 hours under microwave irradiation.
Compounds of interest Ibm can be prepared by lation of IIbh. The reaction can be d out in 2 N hydrochloric acid at 100 oC for 16 hours.
General tic route for formula Ibo (Scheme 27) Scheme 27 R12 R13 R12 R13 R3 N R3 N A R4 R6 A R4 R6 R2 N N R2 N N R7 R7 R1 Ib R1 Ibo S O S O F O O O 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 ºC for 20 minutes under microwave irradiation.
General synthetic route for formula Ibq (Scheme 28) Scheme 28 R12 R13 R12 R13 R3 N R3 N A R4 O A R4 OH R2 N N R2 N N R7 R7 R1 R1 Ibp S O R8 Ibq S O O O 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 ium hydroxide in dimethylsulfoxide, typically at 100 ºC for 20 minutes under microwave irradiation.
General synthetic route for formula Ibr and Ibs (Scheme 29) Scheme 29 R3 Cl R3 NH A R4 R6 A R4 R6 R2 N N R7 R2 N N R1 R7 IIbi S O R1 R8 IIbk O S O R8 OH OH OH R3 NH R3 NH A R4 R6 A R4 R6 R2 N N R7 R2 N N R1 R1 IIbj S Ibs O R8 S O O R8 OH OH R3 NH A R4 R6 R2 N N R1 Ibr O R8 Compounds of interest Ibr and Ibs can be ed according to Scheme 29. Coupling of 4-chloroquinolines IIbi with 4-aminohydroxy-butyric acid followed by ion of acids IIbj affords 1,3-diols Ibr. Coupling of 4-chloroquinolines IIbi with 2-methyl-allyl1amine followed by dihydroxylation of alkenes IIbk s 1,2-diols Ibs.
Acids IIbj can be obtained by coupling of 4-chloroquinolines IIbi with 4-amino hydroxy-butyric acid. Alkenes IIbk can be obtained by ng of 4-chloro quinolines IIbi with 2-methyl-allylamine. ng reaction can be carried out by heating 4-chloroquinolines IIbi with amines in a suitable organic solvent such as 1-methylpyrrolidinone at an elevated temperature, typically at 160 oC for 16 hours. 1,3-Diols Ibr can be prepared by reduction of acids IIbj. The on can be carried out by treating acids with sodium borohydride in the presence of iodine in tetrahydrofuran, typically at 0 oC, followed by stirring at room temperature for 16 hours. 1,2-Diols Ibs can be prepared by dihydroxylation of alkenes IIbk. 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 tic route for formula Ibt (Scheme 30) Scheme 30 R3 Cl R3 Cl A R4 R6 A R4 R6 R2 N N R7 R2 N N R1 R1 IIbi S O IIbl R8 S O O O R12 R13 R3 N A R4 R6 R2 N N Ibt S O Compounds of interest Ibt can be prepared according to Scheme 30. Starting with IIbi, tion with methyl iodide followed by coupling with various amines affords compounds of interest Ibt. nds IIbl can be prepared by alkylation of IIbi with methyl . ably, compounds can be obtained by deprotonation of α-H of sulfone followed by reaction with methyl iodide. Deprotonation of α-H of sulfone can be carried out by treating sulfone IIbi with n-butyl lithium in ydrofuran at -78 °C under argon here for 1 hour. on with methyl iodide can be accomplished by addition of methyl iodide to the above reaction e at -78 oC, followed by stirring at room temperature overnight.
Compounds of interest Ibt can be prepared by coupling of IIbl with s amines. The reaction can be carried out in analogy to coupling of 4-halogen quinolines IIab with various amines XI in Scheme 5. The reaction preferably can be achieved by heating a mixture of IIbl and various amines with or without organic solvent such as N,N-dimethylformamide, 1- methylpyrrolidinone or n-butyl alcohol, under microwave irradiation at 140-160 ºC for 1-3 hours.
General tic route for formula Ibu, Ibv and Ibw (Scheme 31) Scheme 31 H N CF3 N CF3 R3 Cl O O R3 NH NH O A R4 R6 2 O A R4 R6 R2 N N R7 R2 N N R1 R7 IIbi S O R1 R8 Ibu O R8 NH NH 2 OH 2 R3 NH OH R3 NH A R4 R6 A R4 R6 R2 N N R2 N N R7 R7 R1 R1 Ibw S O Ibv R8 R8 O O Compounds of interest Ibu, Ibv and Ibw can be ed according to Scheme 31.
Coupling of 4-chloroquinolines IIbi with N-(3-amino-oxetanylmethyl)-2,2,2-trifluoro- acetamide affords Ibu. Standard trifluoroacetyl deprotection of Ibu generates compounds Ibv.
Trifluoroacetyl deprotection and hydrolysis of Ibu affords Ibw.
Compounds Ibu can be prepared by coupling of 4-chloroquinolines IIbi with N-(3-aminooxetanylmethyl )-trifluoro-acetamide. The reaction can be carried out 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 combination of a phosphine ligand such as bis(diphenylphosphino)ferrocene, tricyclohexylphosphine, or 9,9-dimethyl-4,5- bis(diphenylphosphino)xanthene, with a le base such as sodium tert ide, in a le inert organic solvent such as 1,4-dioxane, or N,N -dimethylformamide, at 100-150 ºC for 1-3 hours under microwave irradiation. Alternatively, the reactions can be d out at an elevated temperature such as 100-140 ºC for a longer reaction time without microwave irradiation.
Compounds Ibv can be prepared by standard trifluoroacetyl deprotection of Ibu . The reaction can be d 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 trifluoroacetyl deprotection and hydrolysis of Ibu .
The reaction is typically carried out with ammonia solution in methanol for several hours at room temperature.
General tic route for formula Ibx and Iby (Scheme 32) Scheme 32 O OH R3 E A R4 R6 R3 N R2 N N A R4 R6 IIab N N X R2 R8 R7 R9 R1 IIbn X R8 O O NH Cl R3 N O R3 N A R4 R6 A R4 R6 R2 N N R2 N N R7 R7 R1 R1 IIbm IIbo X X R8 R8 R9 R9 2 NH R3 N O R3 N A R4 R6 A R4 R6 R2 N N R7 R2 N N R1 R7 Ibx X R8 Iby X R9 R8 nds of interest Ibx and Iby can be prepared according to Scheme 32. Standard coupling of IIab with 5-oxo-pyrrolidinecarboxylic acid amide generates IIbm, followed by rearrangement of amides IIbm gives aminopyrrolidines Ibx. Coupling of halogens IIab with pyrrolidinecarboxylic acid methyl ester affords compounds IIbn. Conversion of IIbn to acylchlorides IIbo followed by treatment with ammonia affords compounds of interest Iby.
Amides IIbm can be prepared by copper-mediated coupling reaction of IIab with 5-oxopyrrolidinecarboxylic acid amide. The on can be d out in the presence of a copper source such as copper(I) iodide and a ligand such as 2,2'-bipyridine, L-proline, N,N-dimethyl glycine, ethylene glycol or N,N'-dimethylcyclohexane-1,2-diamine, with a suitable base such as triethylamine, sodium carbonate, ium carbonate, cesium carbonate, sodium tert - butoxide, ium tert -butoxide, sodium hydride or 1,8-diazabicyclo[5.4.0]undecene. The reaction can be carried out in a suitable organic t such as diethylene glycol dimethyl ether, toluene, 1,4-dioxane, N,N -dimethylformamide, dimethyl sulfoxide or 1-methyl-pyrrolidinone at a temperature n 100 ºC and 180 ºC for several hours under microwave irradiation.
Alternatively, the reactions can be carried out at a temperature such as 130 ºC for a longer reaction time without microwave irradiation.
Aminopyrrolidines Ibx can be prepared by rearrangement of amides IIbm. 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 IIbn can be ed by coupling of halogens IIab with idinecarboxylic 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 IIbo can be ed by chlorination of IIbn . 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 oC to room ature for 16 hours.
Compounds of interest Iby can be prepared by reaction of IIbo with ammonia. The reaction can be carried out in suitable solvent such as dichloromethane at 0 oC to room temperature for 16 hours.
General synthetic route for formula Ibz and Ica (Scheme 33) Scheme 33 R3 Cl R3 NH A R4 R6 A R4 R6 R2 N N R7 R2 N N R1 R7 IIbi S O R1 R8 IIbp S O O R8 S NH S R3 NH R3 NH A R4 R6 A R4 R6 R2 N N R2 N N R7 R7 R1 R1 Ica S O Ibz S O R8 R8 O O nds of interest Ibz and Ica can be prepared according to Scheme 33. Starting with IIbi, coupling with 2-methylsulfanyl-ethylamine gives sulfides IIbp. Selective oxidation of sulfides IIbi gives sulfoxides Ibz. Imination of sulfoxides, ed by hydrolyzation affords nds of interest Ica. es IIbp can be prepared from coupling of 2-benzoazapinchloroquinolines IIbi with 2-methylsulfanyl-ethylamine. The reaction can be carried out in the presence of a palladium catalyst in analogy to coupling of 4-halogen quinolines IIab with s amines XI in Scheme . 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 oC for 1.5 hours.
Sulfoxides Ibz can be prepared by oxidation of sulfides IIbp. The reaction preferably can be carried out with a standard oxidant agent such as hydrogen de in a suitable organic solvent such as acetic acid at room temperature for several hours.
Compounds of interest Ica can be prepared by metal-catalyzed imination of sulfoxides ed by hydrolysis. Imination of sulfoxides can be carried out by treating ides with rhodium (II) acetate and trifluoroacetamide or sulfonylamides in combination with iodobenzene diacetate and magnesium oxide in dichloromethane at room temperature overnight, preferably oroacetamide 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 Icc (Scheme 34) Scheme 34 O O R3 NH NH2 S R3 NH NH2 A R4 R6 KMnO4 A R4 R6 R2 N N R7 R2 N N R1 R1 Icb S O Icc R8 S O O O Compounds of interest Icc can be prepared according to Scheme 34. ng with sulfides Icb (prepared in analogue to Iac in Scheme 5), oxidation of sulfides s compounds of st Icc.
Compounds of interest Icc can be prepared by oxidation of sulfides Icb. The reaction can be carried out in analogy to oxidation of quinolines IIac in Scheme 4. Typically the reaction can be carried out by treating sufides with potassium permanganate in acetic acid at room ature for 30 minutes to several hours.
General synthetic route for formula Icd (Scheme 35) Scheme 35 R3 Cl R3 Cl A R4 R6 A R4 R6 R2 N N R7 R2 N N IIbq R1 S IIbr R8 S NH O R8 R3 NH A R4 R6 R2 N N Icd S NH Compounds of st Icd can be prepared according to Scheme 35. Starting with sulfoxides IIbq, metal-catalyzed imination of sulfoxides followed by hydrolysis gives sulfoximines IIbr. Coupling of IIbr with various amines affords nds of interest Icd.
Sulfoximines can be prepared from imination of sulfoxides IIbq followed by hydrolysis.
Imination of ides 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 d 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 Icd can be prepared by coupling of IIbr with 1,2- nediamine.
The reaction can be carried out in analogy to coupling of 4-halogen quinolines IIac with various amines XI in Scheme 5. Typically the reaction can be carried out with or without an organic solvent such as methylformamide, 1-methylpyrrolidinone or n-butyl alcohol at a ature between 140 ºC and 160 ºC under microwave irradiation for 1 to 3 hours.
General synthetic route for formula Ice e 36) Scheme 36 R3 Cl R3 Cl R4 R6 S O R4 R6 R2 N N R7 R2 N N R1 R7 IIbs S O R1 R8 IIbt S O O R8 R3 NH NH O R4 R6 R2 N N Ice S O Compounds of interest Ice can be prepared according to Scheme 36. Oxidation of sulfides IIbs followed by coupling of IIbt with propane-1,3-diamine s compounds of interest Ice.
Sulfoxides IIbt can be prepared by ion of sulfides IIbs . The reaction can be carried out with a le oxidation reagent such as m-chloroperbenzoic acid in a suitable solvent such as dichloromethane at 0 oC for 20 minutes.
Compounds of interest Ice can be prepared by coupling of IIbt with propane-1,3- diamine. The reaction can be carried out in analogy to coupling of 4-halogen quinolines IIac with various amines XI in Scheme 5. Typically, the reaction can be carried out by treating a mixture of IIbt and propane-1,3-diamine without any base and without any solvent at 150 oC for 1 hour under microwave irradiation.
General tic route for a Icf and Icg (Scheme 37) Scheme 37 O R3 Cl O R3 Cl O R4 R6 O R4 R6 R2 N N R7 R2 N N R1 R1 IIbu S R9 IIbv S O R8 O R3 Cl NH2 R3 Cl H R4 R6 O R4 R6 R2 N N R2 N N R7 R7 R1 IIby S IIbw S O R8 R8 O NH R3 OH R3 Cl 2 Cl O R4 R6 R4 R6 R2 N N R2 N N R7 R7 R1 R1 IIbz S S O R8 IIbx O R8 O O NH NH NH R3 2 R3 OH NH NH 2 2 O R4 R6 R4 R6 R2 N N R2 N N R7 R7 R1 R1 Icg S Icf S O R8 O R8 O O Compounds of st Icg and Icf can be prepared according to Scheme 37. Amination of IIbu affords amides IIby. Oxidation of sulfides IIby affords sulfones IIbz. Coupling of IIbz with propane-1,3-diamine affords compounds of interest Icg. Oxidation of sulfides IIbu affords sulfones IIbv. ion of carboxylic acid esters IIbv followed by Swern-oxidation affords aldehydes IIbw. Methylation of IIbw followed by ng with propane-1,3-diamine affords compounds of interest Icf.
Amides IIby can be prepared by amination of IIbu . The reaction can be carried out in a solution of ammonia in a le solvent such as methanol, tetrahydrofuran or mixture thereof in a sealed tube at a temperature between 100 oC and 150 oC for several hours, typically at 120 oC for 16 hours.
Sulfones IIbz can be prepared by oxidation of sulfides IIby . The reaction can be d out in y to oxidation of quinolines IIac in Scheme 4. Typically, the reaction can be carried out with m-chloroperbenzoic acid in dichloromethane at 0 oC for 2 hours.
Compounds of interest Icg can be ed by coupling of IIbz with propane-1,3- diamine. The reaction can be carried out in y to coupling of 4-halogen- quinolines IIac with various amines XI in Scheme 5. Typically, the reaction can be carried out by treating a mixture of IIbz and propane-1,3-diamine without any base and without any solvent at 120 oC for 1 hour under microwave irradiation.
Sulfones IIbv can be prepared by oxidation of es IIbu . The reaction can be carried out in analogy to oxidation of quinolines IIac in Scheme 4. Typically, the reaction can be d out with m-chloroperbenzoic acid in dichloromethane at 0 oC for 1 hour.
Aldehydes IIbw can be prepared by reduction of carboxylic acid esters IIbv followed by Swern oxidation. Reduction can be carried out with a rd reducing agent such as sodium ydride in a suitable solvent such as tetrahydrofuran, 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 oC, then at room temperature for 1 to several hours. 6-(1-Hydroxyethyl)quinolines IIbx can be prepared by methylation of IIbw . The reaction can be carried out with a methylation reagent such as methyl magnesium bromide in tetrahydrofuran at a temperature below 12 oC for 10 minutes to l hours.
Compounds of st Icg can be prepared by coupling of IIbw with propane-1,3- diamine. The reaction can be carried out in analogy to coupling of 4-halogen quinolines IIac with various amines XI in Scheme 5. Typically, the reaction can be carried out without any metal catalyst and without any t at 150 oC for 1.5 hours under microwave irradiation.
General synthetic route for formula Ich and Ici (Scheme 38) Scheme 38 R3 Cl R3 NH A R4 R6 A R4 R6 R2 N N R2 N N R7 R7 R1 R1 IIbi S O Ich S O R8 R8 O O R3 NH N A R4 R6 R2 N N Compounds of interest Ici can be prepared according to Scheme 38. Standard coupling of IIbi 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 IIbi with 3-aminopropionitrile.
The reaction can be carried out in analogy to coupling of 4-halogen quinolines IIac with various amines XI in Scheme 5. Typically, the on 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 ºC overnight.
Tetrazoles Ici can be prepared by cyclization of es 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 ature n 60 oC and 100 oC, lly at 80 oC for several hours.
General synthetic route for formula Ick (Scheme 39) Scheme 39 NH2 NH O R3 NH R3 NH 2 N NH2 O R4 R6 R4 R6 R2 N N R2 N N R7 R7 R1 R1 Icj S Ick O S R8 O R8 O O Compounds of formula Ick can be prepared according to Scheme 39. ion of o quinolines Icj generates 6-amino-quinolines 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 H N NH N R3 Cl 2 O O R3 N A R4 R6 A R4 R6 R2 N N R7 R2 N N IIbi R1 S O Icl R8 S O O R8 Compounds of interest Icl can be prepared according to Scheme 40. Starting with IIbi, coupling with (3-amino-oxetanylmethyl)-carbamic acid tert-butyl ester gives spiral compounds Icl. This reaction can be carried out in the presence of a palladium st such as (triphenylphosphine)dichloropalladium(II), [1,1'- bis(diphenylphosphino)ferrocene]dichloropalladium(II), palladium(II) acetate, or benzylideneacetone)dipalladium(0), with a ine 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, e, or N,N-dimethylformamide, at a temperature between 100 ºC and 150 ºC for 1 to 3 hours under microwave irradiation. Alternatively, the reactions can be carried out at a temperature such as 100 ºC to 140 ºC for a longer reaction time without microwave irradiation.
General synthetic route for formula Icm (Scheme 41) Scheme 41 R3 Cl H N O R3 NH A N O A N R2 N Cl R2 N Cl IIIb R1 IIca N R6 S R7 O R8 IVd O OH O R3 NH R3 NH A N A N R2 N N R6 R2 N N R6 R1 R1 S R7 S R7 Icm O IIcb O R8 O O R8 Compounds of interest Icm can be prepared according to Scheme 41. ng of 2,4- roquinazolines IIIb with C-(2,2-dimethyl-[1,3]dioxolanyl)-methylamine affords IIca.
Reaction of 2-chloroaminoquinazolines IIca with 6,7,8,9-tetrahydrothiaaza- benzocycloheptene oxides IVd followed by deprotection affords 4-(2,3-diol-propylamino)- quinolines Iak.
IIca can be obtained by coupling of 2,4-dichloroquinazolines IIIb with C-(2,2-dimethyl- [1,3]dioxolanyl)-methylamine. The on can be carried out with a base such as triethylamine in a suitable solvent such as methanol or romethane at room temperature for several hours.
Intermediates IIcb can be prepared by coupling of 2-chloroamino quinazolines IIca with 6,7,8,9-tetrahydrothiaaza-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 oC and 180 oC, typically at 160 oC for several hours. 4-(2,3-Diol-propylamino)-quinazolines Icm can be prepared by deprotection of IIcb. The reaction can be carried out in the presence of an acid such as hydrochloric acid in a suitable solvent such as ol, ethanol, water or mixtures thereof at room ature for several hours.
General synthetic route for formula Icn (Scheme 42) Scheme 42 O NH N 2 R3 NH R3 NH A N A N R4 R4 R6 R2 N N R2 N N R1 R7 R1 IIcc Icn S S R8 H O NH2 R3 NH R3 NH A N A N R4 R4 R6 R2 N N R2 N N R7 R1 R1 Ico IIcd S S R8 R8 O m m m is 1 or 2 Compounds of st Icn and Ico can be prepared ing to Scheme 42. Starting with IIcc, cleavage of tert-butoxycarbonyl gives compounds of interest Icn. Oxidation of sulfides IIcc generates oxides IIcd, followed by cleavage of tert-butoxycarbonyl generates nds of interest Ico.
IIcd can be prepared by oxidation of thio group of compounds IIcc. The reaction can be carried out with a suitable oxidant such as oxone, meta-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 ºC, followed by stirring at room temperature for several hours.
Amines Icn and Ico can be prepared by cleavage of tert-butoxycarbonyl of IIcc and IIcd respectively. The reaction can be typically carried out with trifluoroacetic acid in dichloromethane, or hydrogen chloride in methanol for several hours at room temperature.
General synthetic route for formula Icp (Scheme 43) Scheme 43 O O N CF NH R3 NH 3 R3 NH 2 A N R4 R6 A N R4 R6 R2 N N R2 N N R7 R7 R1 R1 IIce S Icp R8 S O O Compounds of interest Icp can be ed according to Scheme 43. Starting with IIce, removal of trifluoroacetyl generates amines Icp. The reaction can be carried out with ium carbonate or sodium hydroxide, in a suitable solvent such as the mixture of ethanol and water, at room ature for l hours.
General synthetic route for formula Icq and Icr (Scheme 44) Scheme 44 H O H O O R3 OH N O R3 N A N R4 R6 H A N R4 R6 R2 N N R1 R2 N N IIbg R7 R8 R1 IIcf X N Cbz F NH N Cbz R3 NH R3 N A N R4 R6 A N R4 R6 R2 N N R2 N N R7 R7 R1 R1 IIcg X X R8 Icq R8 R3 NH A N R4 R6 R2 N N Icr X Compounds of interest Icq and Icr can be prepared according to Scheme 44. Starting with quinazolinones IIbg, coupling reaction with amine gives IIcf, followed by cleavage of tertbutoxycarbonyl of IIcf affords compounds of interest Icq. Starting with quinazolinones IIbg, ng reaction with amine gives IIcg, followed by cleavage of benzoxycarbonyl of IIcg affords nds of interest Icr.
IIcf and IIcg can be prepared from ng reaction of IIbg with 3-( tert-butoxycarbonyl- amino)pyrrolidine and transaminofluoro-pyrrolidinecarboxylic acid benzyl ester separately. The reaction can be carried out in the presence of benzotriazolyloxytris (dimethylamino)phosphonium hexafluorophosphate, with a suitable base such as 1,8- diazabicyclo[5.4.0]undecene, or yl amine, in a solvent such as N,N-dimethylformamide or acetonitrile at room temperature overnight. nds of interest Icq can be prepared by standard cleavage of tert-butoxycarbonyl of IIcf. The on can be carried out by treating tert-butyl carbamates IIcf with a suitable acid such as hloric acid, trifluoroacetic 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 ºC and room temperature for 30 minutes to several hours. Typically the reaction can be carried out by ng tert-butyl carbamates IIaf with trifluoroacetic acid in dichloromethane at room temperature for 6 hours.
Compounds of interest Icr can be prepared by cleavage of benzyl carbomates IIcg. The sion can be achieved by hydrogenolysis or under strong acidic conditions. Hydrogenolysis of IIcg 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 le t such as methanol or ethanol, at a temperature between room temperature and 80 ºC for 15 minutes to several hours. Alternatively the conversion can also be achieved by treating IIcg 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 O O R3 Cl R5 O O R3 A R4 R6 N R5 O A R4 R6 R2 N N R7 R2 N N R1 R7 IIbi X R1 R8 IIch X A R4 R6 R5 A R4 R6 R2 N N R7 R2 N N R1 R7 Ics X R1 R8 IIci X Compounds of interest Ics can be prepared according to Scheme 45. Starting with 4- chloro-quinolines IIbi , coupling with (R)-2,2-dimethylvinyl-oxazolidinecarboxylic acid tert -butyl ester gives vinyl quinolines IIch . Subsequent reduction and deprotection of tert - butyloxycarbonyl and acetal of IIch generates amino alcohols IIci , which are then cyclized to compounds of interest Ics .
Vinyl ines IIch can be prepared by coupling of 4-chloro-quinolines IIbi with (R)- 2,2-dimethylvinyl-oxazolidinecarboxylic acid tert -butyl ester. The reaction can be lly conducted in deoxygenated N,N hylformamide with triethylamine, bis(tri-tert - butylphosphine)palladium(0), at a temperature between 100 ºC and 160 ºC for several hours under microwave irradiation. Alternatively, the reactions can be carried out at an elevated temperature such as between 100 and 140 ºC for a longer reaction time without microwave irradiation.
Amino alcohols IIci can be prepared from vinyl quinolines IIch by hydrogenolysis and deprotection of tert -butyloxycarbonyl and . 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, ol, or ethanol, typically at room temperature for several hours. ection of ides is typically d out in a solution of hydrochloric acid in ethyl acetate for several hours at room temperature.
Compounds Ics can be prepared from amino alcohols IIci by ring closure with cyanogen bromide. The on 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 ºC, followed by stirring at room temperature for several hours.
General synthetic route for formula Ict, Icu and Icv (Scheme 46) Scheme 46 R3 Cl A R4 R6 R5 A R4 R6 R2 N N R7 R2 N N R1 R7 IIbi X R1 R8 IIck O O O NH R3 R3 R5 R5 A R4 R6 A R4 R6 R2 N N R2 N N R7 R7 R1 R1 IIcj R8 X Icu R8 O OH 2 R5 A R4 R6 A R4 R6 R2 N N R2 N N R7 R7 R1 R1 Icv X Ict X R8 n is 0 or 1 Compounds of interest Ict, Icu and Icv can be prepared according to Scheme 46. Starting with 4-chloro quinolines IIbi, coupling with ethyl acrylate gives alkenes IIcj. ion of alkenes IIcj followed by hydrolysis of esters affords compounds of interest Ict. Heck reaction coupling with acrylonitrile gives alkenes IIck. Hydrogenation of alkenes followed by hydrolysis of nitriles affords amides Icu. atively, amides Icu can be formed by aminolysis of esters IIcj. ion of amides Icu affords compounds of interest Icv.
Alkenes IIcj and IIck can be prepared by Heck coupling of 4-chloro-quinolines IIbi with ethyl te 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 ature between 100 ºC and 160 ºC for 30 minutes to several hours under microwave irradiation. Alternatively, the reactions can be carried out at an elevated ature such as between 100 ºC and 140 ºC for a longer reaction time t microwave irradiation. nds of interest Ict can be prepared by reduction of s IIcj followed by hydrolysis. Reduction can be achieved by treating alkenes IIcj with 2- enzenesulfonylhydrazide 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 IIck followed by hydrolysis of nitriles. Hydrogenation reaction can be carried out in the ce 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 aminolysis of esters IIcj . The reaction can be typically conducted in an ammonia on in tetrahydrofuran at a temperature between 25 ºC to 70 ºC for several hours.
Amines Icv 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 Icw and Icx (Scheme 47) Scheme 47 R3 E NHAc R3 O A R4 R6 A R4 R6 R2 N N R2 N N R7 R7 R1 R1 IIab S O IIcl S O R8 R8 O O O R3 O 2 m A R4 R6 R2 N N XXII R1 Icw S O N H R3 O R3 O A R4 R6 A R4 R6 R2 N N R7 R2 N N R1 R1 IIcm S O R8 Icx S O O R8 E is Br or cl, m is 1 or 2 Compounds of interest Icw and Icx can be prepared according to Scheme 47. Coupling of 4- halogen quinolines IIab with N-(2-hydroxyethyl)acetamide followed by deacylation of IIcl affords compounds of interest Icw. Coupling of IIab with protected alcohol XXII followed by cleavage of tert-butyloxycarbonyl affords compounds of interest Icx.
Ethers IIcl and IIcm can be prepared by coupling of 4-halogen quinolines IIab with N- roxyethyl)acetamide and XXII separately. The reaction can be carried out with a palladium st such as 1,1'-bis(diphenylphosphino)ferrocene-palladium(II)dichloride in combination with 1,1'-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 ed temperature such as 130 ºC under microwave ation for 1 to several hours. 2-Aminoethyl ethers Icw can be prepared by ation of IIcl. The reaction can be carried out in an aqueous solution of hydrochloric acid at an elevated ature such as 80 ºC for several hours.
Compounds of interest Icx can be prepared by cleavage of tert- butyloxycarbonyl. The reaction can be carried out with trifluoroacetic acid in romethane or hloride in ethyl acetate at room temperature for several hours.
General synthetic route for formula Icy (Scheme 48) Scheme 48 O O R3 Cl R3 O O R2 N Cl R2 N Cl IIId IIcn R3 OH A R4 R6 R2 N N R7 R2 N Cl IIcp S R8 R1 IIco A R4 R6 R2 N N R7 Icy S O R8 Compounds of interest Icy can be prepared according to Scheme 48. Starting with 2,4- dichloro-quinolines IIId, regioselective phillic ement with diethyl malonate followed by hydrolysis affords carboxylic acids IIco. Coupling of IIco with benzothiazepines and decarboxylation in a tandem reaction affords 4-methyl-quinolines IIcp. Oxidation of sulfides IIcp affords sulfones Icy.
IIcn can be prepared from regioselective nucleophillic replacement with diethyl malonate.
The reaction can be carried out in the presence of a suitable base such as sodium hydride or potassium ate, 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 IIcn. The on 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-chloroquinolines IIco with benzothiazepines and decarboxylation in a tandem reaction. The reaction ably can be carried out with or without an c solvent such as n-butanol under microwave irradiation at a temperature between 150 ºC and 170 ºC 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 quinolines IIac in Scheme 4.
General synthetic route for formula Icz (Scheme 49) Scheme 49 N O R3 Br N O OH O R3 A R4 R6 H A R4 R6 R2 N N R7 R2 N N R1 R7 IIcq S R1 R8 IIcr S N O R3 O A R4 R6 A R4 R6 R2 N N R7 R2 N N R1 R7 Icz S O R8 IIcs S O O R8 O Compounds of interest Icz can be prepared according to Scheme 49. Starting with 4- uinolines IIcq, on with a lithium alkylide followed by reaction with butoxycarbonylpiperidinecarboxaldehyde provides the secondary alcohols IIcr. Dess-Martin oxidation of IIcr followed by cleavage of tert-butyl carbamates affords compounds of interest Icz.
IIcr can be obtained by reaction of oquinolines IIcq with a lithium alkylide followed by reaction with 1-tert-butoxycarbonylpiperidinecarboxaldehyde. The conversion can be achieved by ng 4-bromo-quinolines IIcq with llithium and 1-tertbutoxycarbonylpiperidinecarboxaldcehyde in an inert c t such as tetrahydrofuran at -78 °C, then at room temperature overnight.
Compounds of interest Icz can be obtained by Dess-Martin ion of IIcr followed by cleavage of tert-butyl carbamates. Oxidation of IIcr 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 IIcs with a suitable acid such as hydrochloric acid, trifluoroacetic acid, or sulfuric acid in a le solvent such as methanol, ethyl acetate, dichloromethane, 1,4-dioxane, water or the mixture thereof at a temperature between 0 ºC and room temperature for 30 minutes to several hours. Typically the reaction can be carried out by treating utyl carbamates IIcs with trifluoroacetic acid in dichloromethane at room temperature for 6 hours.
General synthetic route for formula Ida (Scheme 50) Scheme 50 OH N B OH N R3 Br R3 A R4 R6 N N A R4 R6 R2 N N R7 R2 N N R1 R1 IIct S O R8 Ida S O O O Compounds of interest Ida can be prepared according to Scheme 50. Coupling of bromides IIct with 1H-pyrazoleboronic acid affords Ida. The reaction can be carried out in the ce of a palladium catalyst such as (triphenylphosphine)palladium with sodium carbonate in a suitable c solvent such as benzene or oxyethane, at a temperature between 80 ºC and 120 ºC, typically at 80 ºC for 1 hour under microwave irradiation General synthetic route for formula Ida (Scheme 51) Scheme 51 R3 S R3O S A R4 R6 R5 A R4 R6 R2 N N R7 R2 N N R1 R7 IIcu X R1 R8 Idb X R3 Cl R3 SH R5 R5 A R4 R6 A R4 R6 R2 N N R2 N N R7 R7 R1 R1 IIbi X IIcv X R8 R8 NH 2 Cl R3O S O R3O S O R5 R5 A R4 R6 A R4 R6 R2 N N R2 N N R7 R7 R1 R1 Idc X R8 IIcw X Compounds of interest Idb and Idc can be prepared according to Scheme 51. Coupling of chlorides IIbi with ethiol affords IIcu. Oxidation of IIcu affords compounds of interest Idb. Coupling of chlorides IIbi with sodium methanethiolate affords IIcv. Oxidation and chlorination of IIcv affords sulfonyl chlorides IIcw. Coupling of sulfonyl chlorides IIcw with 1,2-diamine affords compounds of interest Idc. nds of interest of a IIcu can be prepared by coupling of chlorides IIbi with benzenethiol. The reaction can be carried out with a le base such as N,N- dimethylpyridinamine in a le 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 ºC and room temperature for 1 to several hours.
Thiols IIcv can be prepared by coupling of chlorides IIbi with sodium methanethiolate.
The reaction can be carried out in a suitable solvent such as N,N-dimethylformamide under reflux overnight.
Sulfonyl chlorides IIcw can be prepared by oxidation-chlorination of IIcv. The reaction can be carried out in a le solvent such as hloric acid by bubbling of chlorine at a temperature between 0 ºC and 10 ºC 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 ethyldiisopropyl-amine in a suitable solvent such as dichloromethane at a temperature n 0 ºC and room temperature overnight.
General synthetic route for a Idd, Ide and Idf (Scheme 52) Scheme 52 O R3 Cl NH NH 2 2 O R3 NH NH O R4 R6 O O O R4 R6 R2 N N R7 R2 N N R1 R7 IIbv S R1 O R8 Idd O O R8 OH R3 Cl OH R3 NH NH2 R4 R6 O O R4 R6 R2 N N R1 R2 N N IIcx S O R8 R1 O S O R8 NH NH 2 2 OH R3 NH NH2 O R4 R6 R2 N N Idf S O R8 nds of interest Idd , Ide and Idf can be prepared according to Scheme 52.
Coupling of des IIbv with C-(3-aminomethyl-oxetanyl)-methylamine generates Idd .
Hydrolysis of esters affords carboxylic acids Ide . Reduction of esters IIbv followed by coupling with C-(3-aminomethyl-oxetanyl)-methylamine generates compounds Idf .
Compounds Idd can be prepared by coupling of chlorides IIbv with C-(3-aminomethyloxetanyl )-methylamine. The reaction can be carried in y to coupling of 4-halogen quinolines IIab with various amines XI in Scheme 5. Typically the reaction can be carried out with tris(dibenzylideneacetone)dipalladium(0), 2,2'-bis(diphenylphosphino)-1,1'-binaphthyl and sodium tert -butoxide in e at 110 ºC overnight under nitrogen atmosphere.
Acids Ide can be prepared from hydrolysis of methyl esters Idd . The reaction can be carried out with a le base such as sodium hydroxide or lithium hydroxide in a mixture solvent of tetrahydrofuran and water at a temperature between room temperature and 60 ºC, typically at room temperature for several hours or ght.
Hydroxides IIcx can be prepared by reduction of esters IIbv . The reaction can be carried out with a standard reduction agent such as m ium hydride in a suitable solvent such as tetrahydrofuran, at a temperature between 0 ºC and room temperature for several hours, typically at room temperature for 2 hours.
Compounds Idf can be prepared by coupling of IIcx with C-(3-aminomethyl-oxetan yl)-methylamine. The reaction can be carried out in analogy to coupling of IIbv with C-(3- aminomethyl-oxetanyl)-methylamine in this scheme.
General synthetic route for formula Idg (Scheme 53) Scheme 53 Cl O Br Br N N N Cl N Cl R4 R6 IIId IIcy S R8 O Br CD N R6 3 N R6 CD O S CF R4 R4 3 3 O N N N N R7 IIcz S S R8 IIda R8 NH NH 2 2 NH NH2 O CD CD3 N O R6 N R6 R4 N N N N R7 Idg R8 IIdb S R8 O Compounds of interest Idg can be prepared according to Scheme 53. Starting with 2,4- dichloro-quinazolines IIId, reaction with benzyl alcohol followed by coupling with benzothiazepines IVf affords benzyloxy compounds IIcz. Substitution of bromo with -d3 followed by oxidation affords 6-methyl-d3-quinazolines IIdb. ng of IIdb with C-(3- aminomethyl-oxetanyl)-methylamine affords compounds of interest Idg. 2-Chlorobenzoxy quinazolines IIcy can be prepared by reaction of 2,4-dichloroquinazolines IIId 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 IIcy with hiazepines IVf. The reaction can be carried out t 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-d3-quinazolines IIda can be prepared by substitution of bromo with methyl-d3.
The reaction can be carried out by treating IIcy with n-butyllithium in ous tetrahydrofuran at -78 °C for several minutes under nitrogen followed by stirring with methyl-d3 trifluoromethanesulfonate at -78 °C and then at room temperature for 1 to several hours.
Sulfoxides IIdb can be prepared by oxidation of IIda. The reaction can be carried out by treating IIda with 1-2 equivalents of 3-chloroperoxybenzoic acid in a le c solvent such as dichloromethane, chloroform, 1,2-dichloroethane or the mixtures thereof, typically at 0 ºC, followed by stirring at room temperature for 10 to 20 minutes.
Compounds of interest Idg can be prepared by coupling of IIdb with C-(3-aminomethyloxetanyl )-methylamine. The reaction can be carried out without any t and t any base at an elevated temperature such as 170 °C for 20 minutes.
General synthetic route for formula Idh (Scheme 54) Scheme 54 O O O N R6 O N R6 R4 R4 N N N N R7 R7 IIda S IIdc S R8 R8 O O OH O O N R6 O N R6 R4 N N N N R7 IIde S IIdd R8 R8 O O m NH NH 2 2 O NH NH O N O R6 N N Idh S R8 m is 1 or 2 Compounds of interest Idh can be prepared according to Scheme 54. Starting with 6- bromo-quinazolines IIda , carbonylation ed by esterification, oxidation and hydrolysis affords acids IIde . Coupling of IIde with C-(3-aminomethyl-oxetanyl)-methylamine generates compounds of interest Idh . 6-Methoxycarbonyl quinazolines IIdc can be prepared by carbonylation of 6-bromoquinazolines IIda followed by esterification. ylation 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 d out in methanol in the presence of sulfinyl chloride or concentrated sulfuric acid at a temperature n room temperature and 70 °C for 1 to several hours Compounds IIdd can be prepared by oxidation of IIdc . Oxidation can be carried out by treating IIdc with 1-2 lent(s) of 3-chloroperoxybenzoic acid in a suitable organic solvent such as dichloromethane, form, 1,2-dichloroethane or mixtures thereof, typically at 0 ºC, followed by stirring at room temperature for 10 s to several hours.
Acids IIde can be prepared by hydrolysis of methyl esters IIdd . The reaction can be d 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 ºC, typically at room ature for several hours or overnight.
Compounds of interest Idh can be ed by couplin, g of IIde with C-(3- aminomethyl-oxetanyl)-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 O H O N R6 O N R6 R4 R4 N N N N R7 R7 IIdf IIda S S R8 R8 OH O OH O N R6 N R6 R4 R4 N N R7 N N IIdh S R8 IIdg S NH NH 2 2 OH NH NH N O R6 N N Idi S O m is 1 or 2 Compounds of Idi can be prepared according to Scheme 55. Starting with 6-bromo quinazolines IIda, Bouveault formylation followed by ion of aldehyde and ion of sulfide affords 4-benzyloxyhydroxymethyl-quinazolines IIdh. Coupling of IIdh with C-(3- aminomethyl-oxetanyl)-methylamine generates compounds of interest Idi.
Aldehydes IIdf can be prepared by ult formylation. The reaction can be carried out by treating bromide with n-butyllithium in anhydrous tetrahydrofuran at -78 oC followed by stirring with anhydrous N,N-dimethylformamide at -78 oC for 30 minutes to several hours . 6-Hydroxymethyl-quinazolines IIdg can be prepared by reduction of aldehydes. The reaction can be carried out with sodium borohydride in a suitable organic solvent such as methanol, tetrahydrofuran or the mixture thereof at 0 oC for 15 s to several hours.
IIdh can be ed 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, chloroethane or mixtures thereof, typically at 0 ºC, ed by stirring at room temperature for 10 minutes to several hours.
Compounds of interest Idi can be prepared by coupling IIdh with C-(3-aminomethyloxetanyl )-methylamine. The on can be d out without any solvent and without any base at 160 °C for 30 minutes. l synthetic route for formula Idj (Scheme 56) Scheme 56 R4 R6 R3 E NH R3 E A A R4 R6 R2 N E R2 N N R1 R1 IIIa IIdi R8 R12 R13 R12 R13 R3 N A R4 R6 R2 N N E is Cl or Br R1 Idj R8 Compounds of interest Idj can be prepared according to Scheme 56. Starting with 2,4- dihalogen-quinolines IIIa, coupling with benzoazepines IVi affords 2-benzoazepinhalogenqunolines IIdi. Coupling of IIdi with various amines generates compounds of interest Idj. 2-Benzoazepinhalogen-qunolines IIdi can be prepared by ng of halogenquinolines IIIa with benzoazepines IVi. The reaction can be carried out with or without a solvent such as n-butanol at 160 oC for several hours under microwave irradiation.
Compounds of interest Idj can be prepared by ng of IIdi with various amines. The reaction can be carried out in analogy to coupling of 4-halogen-quinolines IIab with various amines XI in Scheme 5. Typically the reaction can be carried out in the presence of 1,1'- bis(diphenylphosphino)ferrocene, 1,1'-bis(diphenylphosphino)ferrocene-palladium(II)dichloride and sodium tert-butoxide in 1,4-dioxane at 120 oC for 1.5 hours under microwave irradiation. l synthetic route for formula Idk (Scheme 57) Scheme 57 NH R3 OH R3 OH A N A N O R2 N N R2 N Cl R1 IIdj IIIc O NH2 R3 OH R3 NH A N A N O R2 N N R2 N N R1 OH Idk OH IIdk Compounds of interest Idk can be prepared according to Scheme 57. Starting with IIIc, coupling with 1,2,3,4-tetrahydro-benzo[c]azepinone followed by reaction with methyl magnesium bromide affords 5-methylhydroxy benzothiazepines IIdk. Coupling of IIdk with omethyl-oxetanylamine generates compounds of st Idk. 2-Benzoazepin-quinolines IIdj can be prepared by coupling of IIIc with 1,2,3,4- tetrahydro-benzo[c]azepinone. The reaction can be d out in the presence of an organic base such as triethylamine in toluene under reflux overnight. ylhydroxy benzothiazepines IIdk can be prepared by reaction of ketones IIdj with methyl magnesium bromide. The conversion can be achieved by stirring of IIdj with methyl magnesium bromide in tetrahydrofuran at 50 oC for several hours.
Compounds of interest Idk can be prepared by ng of IIdj with 3-aminomethyloxetanylamine.
The reaction can be carried out in the presence of a suitable base such as 1,8- diazabicyclo[5.4.0]undecene with a suitable phosphine ligand such as benzotriazol yloxytris(dimethylamino)-phosphonium hexafluorophosphate, in a suitable t such as N,N- dimethylformamide at room temperature for several hours.
General synthetic route for formula Idl (Scheme 58) Scheme 58 W9 N W9 N 2NH R3 Cl R3 NH A N A N XXIII R2 N Cl R2 N Cl R1 R1 IIIb IIdl W9 NH W9 N R3 NH R3 NH A N A N R2 N N R1 R2 N N Idl R1 F IIdm W9 is O or SO2 Compounds of interest Idl can be prepared according to Scheme 58. Starting with IIIb, reaction with various benzylamino mines XXIII affords IIdl. Substitution of 2-chloro with ,5-difluoro-2,3,4,5-tetrahydro-1H-benzo[c]azepine followed by deprotection of benzyl generates compounds of st Idl. 2-Chloro-quinazolines IIdl can be prepared by coupling of IIIb with various amines XXIII. The reaction can be carried out in the presence of a le base such as triethylamine in a suitable t such as methanol, tetrahydrofuran, dichloromethane or mixtures thereof at a temperature between 0 oC and room temperature for several hours or overnight.
Compounds Idl can be prepared by standard benzyl deprotection of IIdm. The reaction can be carried out with palladium on carbon, palladium hydroxide on carbon or platinum oxide, typically with on of acetic acid or trifluoroacetic acid in a suitable solvent such as methanol, ethanol, tetrahydrofuran, ethyl acetate or the mixture thereof, at room temperature for l hours under hydrogen atmosphere.
A. General synthetic route for formula Idm (Scheme 59) Scheme 59 R5 R5 R5 H H R6 O R6 N R6 N R7 R7 R7 R8 R8 R8 XXIV IVj IVk R3 E R2 N E IIIa R3 N R12 R13 R3 E R5 H R5 A A R6 R6 R2 N N R2 N N R7 R7 R1 R1 Idm R8 IIdn R8 E is chloro or bromo Compounds of interest Idm can be prepared according to Scheme 59. ng with naphthalenones XXIV, ring expansion with hydrazoic acid gives benzoazepinones IVj.
Reduction of lactams IVj to benzoazepines IVk followed by coupling of IVk with 2,4-dihalogen quinolines IIIa gives 4-halogen quinolines IIdn. Coupling of IIdn with s amines XI affords compounds of interest Idm. zepinones IVj can be prepared from ring expansion of naphthalenones XXIV by using sodium azide. The reaction can be carried out in toluene with a suitable acid such as trifluoromethanesulfonic acid, trifluoroacetic acid or hydrochloric acid, typically at 0 ºC, followed by ng at room temperature for several hours.
Benzoazepines IVk can be prepared from benzoazepinones IVj by reduction of lactams.
The reaction can be d 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 ºC, followed by ng at a temperature between 25 ºC and 70 ºC for several hours. gen quinolines IIdn can be prepared from coupling of zepines IVk and 2,4- dihalogen quinolines IIIa. The reaction can be carried out with a suitable acid such as hydrochloric acid or p-toluenesulfonic acid in a suitable organic solvent such as toluene, dioxane, n-butyl alcohol or 2-methylpentanol at a temperature between 100 ºC and 120 ºC for several hours. Alternatively, the reaction can be carried out without acid at a ature between 100 ºC and 160 ºC for 1 to 3 hours under microwave irradiation.
Compounds of interest Idm can be prepared by coupling of 4-halogen quinolines IIdn with various amines XI. The reaction can be achieved by microwave irradiation at a temperature between 140 ºC and 160 ºC for 1 to 3 hours with or without organic solvent such as N,N- dimethylformamide, 1-methylpyrrolidinone or l alcohol.
B. General tic route for formula Idm (Scheme 60) Scheme 60 R5 R2 NH2 H R6 R6 N N R1 XVIII IVk IVm R3 N R3 NH2 R5 R5 A R6 A R6 R2 N N R2 N N R7 R7 R1 R1 IIdo R8 IIdp R8 R3 N R12 R13 R3 Cl R5 H R5 A A R6 R6 R2 N N R2 N N R7 R7 R1 R1 Idm R8 IIdq R8 Compounds of interest Idm can be prepared according to Scheme 60. Acylation of benzoazepines IVk, followed by ng with 2-aminobenzonitriles XVIII provides imines IIdo. Ring closure of imines IIdo gives oquinolines IIdp. Sandmeyer reaction of 4- aminoquinolines IIdp provides 4-halogen quinolines IIdq . ng of IIdq with various amines XI generates compounds of st Idm .
Acetyl benzoazepines IVm can be prepared by acylation of benzoazepines IVk with acetyl chloride or acetic ide. 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 ºC, followed by stirring at room temperature for 30 minutes.
Imines IIdo can be prepared by g a mixture of IVm , 2-aminobenzonitriles XVIII and phosphorous oxychloride. The reaction can be d out in a suitable inert c solvent such as dichloromethane, chloroform or the mixtures thereof, lly at a temperature between 0 ºC and 10 ºC, followed by stirring under reflux for 24 hours.
Ring closure of imines IIdo to give 4-aminoquinolines IIdp can be achieved by treatment of IIdo with Lewis acid such as zinc chloride in N,N -dimethyl-acetamide at a temperature between 120 ºC and 180 ºC for several hours in an inert atmosphere.
Intermediates IIdq can be prepared from oquinolines IIdp 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 ºC, followed by ng at room temperature for several hours.
Compounds of interest Idm can be prepared by coupling of IIdq with various amines XI .
The reaction can be achieved by microwave irradiation at a temperature between 140 ºC and 160 ºC for 1-3 hours with or t organic solvent such as N,N -dimethylformamide, 1-methylpyrrolidinone or n-butyl alcohol.
General synthetic route for formula Idn (Scheme 61) Scheme 61 R3 E H L20 S O Na H N R2 N E XXV O R1 IIIa Br L20 IVn O IVo R12 R13 H R12 R13 R3 E R3 N A A O O R2 N N R2 N N S S R1 L20 R1 L20 IIdr O Idn O L20 is C1-6 alkyl; E is chloro or bromo. nds of interest Idn can be prepared according to Scheme 61. Starting with 7- bromo-2,3,4,5-tetrahydro-1H-benzo[c]azepine IVn, copper-catalyzed coupling with sodium sulfinates XXV gives sulfonyls IVo. Coupling of IVo with 2,4-dihalogen quinolines IIIa gives gen quinolines IIdr. ng of IIdr with various amines XI s compounds of interest Idn.
The copper-mediated coupling reaction of 7-bromo-2,3,4,5-tetrahydro-1H-benzo[c]azepine IVn with sodium sulfinates XXV illustrated above can be carried out in the presence of a copper source such as (I) iodide (CuI), and a ligand such as 2,2'-bipyridine, L-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 tertbutoxide , sodium hydride or 1,8-diazabicyclo[5.4.0]undecene. The reaction can be carried out in a le organic t such as acetonitrile, toluene, 1,4-dioxane, N,N-dimethylformamide, dimethyl sulfoxide or 1-methyl-pyrrolidinone at a temperature between 100 ºC and 180 ºC for 15 to 60 minutes under microwave irradiation. Alternatively, the reactions can be carried out at a temperature such as 130 ºC for a longer reaction time without the use of microwave irradiation.
Compounds IIdr can be ed from coupling of benzoazepine IVo and halogen quinolines IIIa. The reaction can be carried out with a suitable acid such as hydrochloric acid or p-toluenesulfonic acid in a suitable organic solvent such as toluene, dioxane, n-butyl alcohol or 2-methylpentanol at a temperature between 100 ºC and 120 ºC for several hours.
Alternatively, the reaction can be carried out t acid at a temperature between 100 ºC and 160 ºC for 1-3 hours under microwave irradiation.
Compounds of interest Idn can be prepared by coupling of IIdr with various amines XI.
The reaction can be achieved by microwave irradiation at 140-160 ºC for 1-3 hours with or without organic solvent such as N,N-dimethylformamide, 1-methyl-pyrrolidinone or n-butyl alcohol.
D. General synthetic route for formula Ido (Scheme 62) Scheme 62 R3 Cl R3 Cl L21E A OH XXVI A OL21 R2 N N R2 N N R1 R1 IIds IIdt R12 R13 R3 N A OL21 R2 N N L21 is C1-6 alkyl; E is chloro or bromo. Ido Compounds of interest Ido can be prepared according to Scheme 62. Starting with phenols IIds, tion with various XXVI provides IIdt. ng of IIdt with various amines XI affords compounds of interest Ido. nds IIdt can be prepared by alkylation of phenols IIds with XXVI. The reaction can be carried out with a le base such as cesium carbonate, sodium tert-butoxide, potassium tert-butoxide, sodium hydride or azabicyclo[5.4.0]undecene in an inert organic solvent such as dichloromethane, N,N-dimethylformamide, dimethyl sulfoxide or 1- methyl-pyrrolidinone, typically at room temperature for several hours.
Compounds of interest Ido can be prepared by coupling of IIdt with various amines XI.
The reaction can be achieved by microwave irradiation at a temperature between 140 ºC and 160 ºC for 1 to 3 hours with or without organic solvent such as N,N-dimethylformamide, ylpyrrolidinone or n-butyl alcohol.
F. General synthetic route for a Idp (Scheme 63) Scheme 63 R3 Cl R3 Cl A A R2 N N R2 N N O R1 R1 IIdu IIdv O L22 L23 R3 Cl H R3 Cl XXVII L22 A R2 N N N L23 R2 N N O IIdx O R1 IIdw OH R12 R13 R3 N R2 N N N L23 L22 is hydrogen or C1-6 alkyl; R1 L23 is hydrogen or C1-6 alkyl.
Idp O Compounds of st Idp can be prepared according to Scheme 63. Starting with IIdu, palladium-catalyzed carbonylation gives carboxylic acid methyl esters IIdv. Basic hydrolysis of esters IIdv to acids IIdw ed by coupling with various amines XXVII to furnishes amides IIdx. Coupling of IIdx with various amines XI affords compounds of interest Idp.
Palladium-catalyzed carbonylation of IIdu to the corresponding methyl esters IIdv 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 ce or absence of a phosphine ligand such as tricyclohexylphosphine or nylphosphine, and a suitable base such as triethylamine, sodium carbonate or ium carbonate at a temperature between 60 ºC and 120 ºC for several hours.
Hydrolysis of the methyl esters IIdv to acids IIdw can be d 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 IIdx can be prepared by coupling various amines XXVII with carboxylic acids IIdw . The reaction is typically conducted with standard peptide coupling reagents such as 1- ethyl(3-dimethylaminopropyl)carbodiimide and 1-hydroxybenzotriazole, bromo-tris - pyrrolidino-phosphoniumhexafluorophosphate and diisopropylethylamine, or O-(7- azabenzotriazolyl)-N,N,N',N' methyluronium hexafluorophosphate and a base such as triethylamine, or diisopropylethylamine in a suitable inert t such as dichloromethane or N,N -dimethylformamide or mixtures f at room temperature for several hours.
Compounds of interest Idp can be prepared by coupling of amides IIdx with various amines XI . The reaction can be conducted by ave irradiation at a temperature between 140 ºC and 160 ºC for 1 to 3 hours with or without organic solvent such as N,N - dimethylformamide, 1-methyl-pyrrolidinone or n-butyl alcohol.
G. General synthetic route for formula Idq (Scheme 64) Scheme 64 R6 N R3 E R3 E R7 R5 A R6 A R8 IVp R2 N N R2 N E R1 R1 R8 IIIa IIdy R12 R13 R3 N A R6 R2 N N Compounds of interest Idq can be prepared according to Scheme 64. Palladium-catalyzed coupling of lactams IVp with 2,4-dihalogenquinolines IIIa gives intermediates IIdy. ng of IIdy with various amines XI generates nds of interest Idq.
Intermediates IIdy can be prepared from lactams IVp by coupling with 2,4- dihhalogenquinolines IIIa. The reaction can be carried out typically in the presence of a palladium catalyst such as iphenylphosphine)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 methyl-4,5- bis(diphenylphosphino)xanthene, with a suitable base such as potassium ate tribasic, sodium carbonate or potassium carbonate, in a suitable inert organic solvent such as dioxane, or N,N-dimethylformamide, at a temperature between 100 ºC and 150 ºC for several hours.
Compounds of interest Idq can be prepared by coupling of IIdy with various amines XI.
The reaction can be achieved by microwave irradiation at a ature between 140 ºC and 160 ºC for 1 to 3 hours with or without organic solvent such as N,N-dimethylformamide, ylpyrrolidinone or n-butyl alcohol.
H. General synthetic route for formula Ids(Scheme 65) Scheme 65 O O 2NH NH NH2 NH NH NH2 R3 NH N R3 NH R5 R5 A R6 A R6 R2 N N R2 N N R7 R7 R1 R1 R8 R8 Idr Ids 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-1H-pyrazolecarboximidamide e gives guanidines Ids. The reaction can be carried out in a suitable solvent such as ethanol, typically at a temperature between 70 ºC and 90 ºC for several hours.
L. General tic route for formula Idt (Scheme 66) Scheme 66 CO Me CO Me H N Cl R5 R6 N XXVIII N N R8 IIdz R8 N N Idt R8 Compounds of interest Idt can be prepared according to Scheme 66. Starting with benzoazepines IVk, coupling with 2-chloro-quinolinecarboxylic acid methyl ester XXVIII gives compounds IIdz, which are in turn reduced to compounds of interest Idt.
Esters IIdz can be ed from benzoazepines IVk by coupling with 2-chloro-quinoline- oxylic acid methyl ester XXVIII. The reaction can be carried out with a suitable acid such as hydrochloric acid or p-toluenesulfonic acid in a suitable organic solvent such as toluene, dioxane, n-butyl alcohol or 2-methylpentanol at a temperature n 100 ºC and 120 ºC for several hours. Alternatively, the reaction can be d out without acid at a temperature between 100 ºC and 160 ºC for 1 to 3 hours under microwave irradiation.
Alcohols Idt can be prepared from methyl esters IIdz by reduction. The reaction is typically conducted in a tetrahydrofuran solution of borane at 0 ºC, followed by stirring at reflux temperature for several hours.
M. General synthetic route for formulas Idu and Idv (Scheme 67) Scheme 67 A R6 R2 N N O O R7 R3 E B R1 R5 R8 A R6 R2 N N IIdn R8 A R6 R2 N N IIea R3 OH A R6 R2 N N R8 Compounds of interest Idu and Idv can be prepared ing to Scheme 67. Starting with 4-halogen quinolines IIdn, Suzuki reaction coupling with 2-allyl-4,4,5,5-tetramethyl- ]dioxaborolane gives 4-allyl-quinolines IIea and compounds Idv as a byproduct. 4-Allylquinolines IIea are then converted to nds of interest Idu by Upjohn dihydroxylation. 4-Allyl-quinolines IIea and compounds Idv can be prepared from 4-halogen quinolines IIdn by Suzuki coupling with 2-allyl-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane. The reaction is typically conducted in 1,2-dimethoxyethane and water with potassium carbonate, tetrakis(triphenylphosphine)palladium(0), at a temperature between 80 ºC and 140 ºC for several hours under microwave irradiation. Alternatively, the reactions can be d out at a heated temperature such as a temperature n 100 ºC and 140 ºC for a longer reaction time without the use of microwave irradiation. nds of interest Idu can be prepared from 4-allyl-quinolines IIea by Upjohn oxylation. 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 e 68) Scheme 68 R3 E A R3 E R2 N E R5 R8 A R6 H L24 R1 IIIa R7 N R2 N N R6 N N H IIeb H R8 R5 L24 R12 R13 R3 N A R6 R2 N N Idw N H R8 L24 is hydrogen or oxygen. L24 Compounds of interest Idw can be prepared according to Scheme 68. Starting with diazepines IVq, coupling of 2,4-dihalogen quinolines IIIa with IVq furnishes IIeb. Subsequent coupling of IIeb with various amines XI generates compounds of interest Idw.
Compounds IIeb can be prepared from coupling of 2,4-dihalogen ines IIIa with diazepines IVq . The reaction can be carried out with a suitable acid such as hloric acid or p-toluenesulfonic acid in a suitable organic solvent such as toluene, dioxane, n-butyl l or 2-methylpentanol at a temperature between 100 ºC and 120 ºC for several hours.
Alternatively, the on can be carried out without acid at a temperature between 100 ºC and 160 ºC for 1 to 3 hours under microwave irradiation.
Compounds of interest Idw can be prepared by coupling of compounds IIeb 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 e, or N,N -dimethylformamide, at a ature between 100 ºC and 150 ºC for 1 to 3 hours under microwave irradiation. Alternatively, the reactions can be carried out at a heated temperature such as a temperature n 100 ºC and 140 ºC for a longer reaction time without the use of microwave irradiation.
R. General synthetic route for formula Idx (Scheme 69) Scheme 69 R5 R5 R6 CN R6 CN R7 OH R7 O CO Me R8 XXIX R8 XXX R3 E R5 R5 H H R2 N E R6 N R6 N R1 IIIa R7 O R7 O R8 R8 IVr IVs R3 E R12 R13 R13 N R3 N R5 H A R6 XI R5 A R6 R2 N N R7 R2 N N R1 R7 IIec O R8 Idx O Compounds of interest Idx can be prepared ing to Scheme 69. Starting with hydroxybenzonitriles XXIX, alkylation with methyl bromoacetate gives esters XXX.
Intramolecular cyclization of compounds XXX gives benzooxazepinones IVr, which are in turn converted to benzooxazepines IVs by reduction. Coupling of IVs with 2,4-dihalogen quinolines IIIa furnishes IIec. Subsequent coupling of IIec 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 ium carbonate at room temperature for several hours.
Benzooxazepinones 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 en.
Benzooxazepines IVs can be prepared from benzooxazepinones IVr by reduction of lactam. The on is typically conducted in an inert solvent such as tetrahydrofuran, diethyl ether or mixtures thereof with lithium aluminium hydride, typically at 0 ºC, followed by ng at reflux temperature for several hours.
Substituted quinolines IIec can be prepared from coupling of benzooxazepines IVs with 2,4-dihalogen quinolines IIIa. The reaction can be carried out with a suitable base such as potassium carbonate, cesium ate, diisopropylethylamine, triethylamine, or 1,8- diazabicyclo[5.4.0]undecene in an inert organic t such as toluene, ydrofuran, 1- methyl-pyrrolidinone or N,N-dimethylformamide, typically at a temperature between 100 ºC and 180 ºC for 1 to 3 hours under microwave irradiation.
Compounds of interest Idx can be prepared by coupling of substituted quinolines IIec with various amines XI. The reaction can be achieved by microwave irradiation at a temperature between 140 ºC and 180 ºC for 1 to 3 hours with or t organic solvent such as N,N- dimethylformamide, 1-methyl-pyrrolidinone or n-butyl alcohol.
General synthetic route for formula Idy (Scheme 70) Scheme 70 O R6 O L25 L25 N N N O O W10 R7 W10 R3 NH S R3 Cl NH 2 O R8 XXXI A N IVd A N R2 N Cl R2 N Cl R1 IIIb IIed L25 L25 N NH R3 NH W10 R3 NH A N A N R6 R6 R2 N N R2 N N R1 R7 R1 R7 IIef S O Idy S R8 O R8 O O .W10 is methylcyclopropyl and L25 is hydrogen, or W10 and L25 with nitrogen they are attached with form pyrrolindi nyl. nds of interest of formula Idy can be prepared according to Scheme 70.
Coupling of chloro-quinozalines IIIb with various amines XXXI followed by reaction with 6,7,8,9-tetrahydrothiaaza-benzocycloheptene 5,5-dioxides IVd affords 2,4 - disubstituted quinozalines IIef. Deprotection of utyloxycarbonyl of IIef generates the target compounds Idy. 2-Chloroamino quinozalines IIed can be prepared by coupling of IIIb 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, ydrofuran, romethane or mixture thereof at a temperature between 0 °C to room temperature for several hours. 4 - Disubstituted quinozalines IIef can be obtained by the coupling of IIed with 6,7,8,9- ydrothiaaza-benzocycloheptene 5,5-dioxides IVd . The reaction can be carried out with or without an acid such as 4-methylbenzenesulfonic acid and ammonium chloride, in a le solvent such as ethanol or N,N -dimethylformamide at an elevated temperature between 50 oC and 120 oC for several hours, typically at 70 °C overnight.
Compounds of interest of formula Idy can be prepared from ection of tert - butyloxycarbonyl of 4 – disubstituted quinozalines IIef . The reaction can be carried out with a suitable acid such as trifluoroacetic acid or hydrochloric acid in a suitable solvent such as dichloromethane, ethyl acetate or 1,4-dioxane, at 0 °C to room ature for 30 minutes to 16 hours.
The invention also s 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 ceutical ations, can be stered orally, e.g. in the form of tablets, coated tablets, dragées, hard and soft ne capsules, solutions, emulsions or sions. 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, e, corn starch or derivatives thereof, talc, stearic acids or its salts and the like can be used, as such carriers for tablets, coated tablets, dragées and hard gelatine capsules.
Suitable rs 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 ne 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 re, buffers, masking agents or antioxidants. They can also contain still other therapeutically valuable substances.
The dosage depends on various factors such as manner of stration, 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 ing to the above process is also an embodiment of the invention.
This invention relates to the use of a compound of a (I) for the manufacture of a medicament for treatment or prophylaxis of RSV infection.
Also described herein is a method for the treatment or prophylaxis of respiratory syncytial virus ion, which method ses administering an effective amount of a nd of formula (I).
The invention is illustrated by the following examples which have no ng character.
Unless explicitly otherwise stated, all reactions, reaction conditions, abbreviations and symbols have the meanings well known to a person of ry 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 . ii) ISCO combi-flash chromatography instrument. Silica gel Brand and pore size: i) KP-SIL 60 Å, particle size: 40-60 µM; ii) CAS registry NO: Silica Gel: 632314, particle size: 47-60 micron silica gel; iii) ZCX from Qingdao Haiyang Chemical Co., Ltd, pore: 0 or 300-400.
Intermediates and final compounds were ed by ative HPLC on reversed phase column using X BridgeTM Perp C18 (5 µm, OBDTM 30 × 100 mm) column or SunFireTM Perp C18 (5 µm, OBDTM 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 H2O; B: 0.1% formic acid in acetonitrile; Basic condition: A: 0.01% O in H2O; B: acetonitrile; Neutral condition: A: H2O; 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 d 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 r purification unless otherwise noted.
Intermediate 1-1 chloromethylquinoline N Cl To a three necks round bottom flask equipped with a reflux condenser and thermometer containing phosphoryl chloride (400 mL) was added ylaniline (50 g, 0.47 mol) and propanedioic acid (73 g, 0.7 mol). The mixture was heated and stirred at 95 oC for 16 hours and then 145 oC for 1 hour. The volatiles were evaporated in vacuo and the residual black oil was poured onto d ice with stirring. The resulting mixture was extracted with dichloromethane (300 mL × 3). The combined organic layers were washed with a ted aqueous solution of sodium bicarbonate until the water phase was pH 7~8, then washed with brine (300 mL), dried over sodium 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 t (yield was 65.3%). MS obsd. (ESI+) [(M+H)+] 212.
Intermediate 1-2 2,4-Dichloro(methylsulfanyl)quinoline N Cl 1-(Methylsulfanyl)nitrobenzene To a suspension of p-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 oC, methyl iodide (57 g, 25 mL, 0.401 mol) was added .
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 × 3). The organic layers were combined, washed with water (200 mL) and brine (200 mL), dried over m sulfate and trated in vacuo. The residue was purified by silica gel column chromatography to afford 11 g of 1-(methylsulfanyl)nitrobenzene as a yellow solid. 4-(Methylsulfanyl)aniline A sion of 1-(methylsulfanyl)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(methylsulfanyl)quinoline N Cl 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 N Cl Intermediate 1-3 can be prepared in analogy to Intermediate 1-1 by using oaniline. MS obsd. (ESI+) [(M+H)+] 276.
Intermediate 1-4 2,4-Dichloromethylquinoline N Cl Intermediate 1-4 can be prepared in y to intermediate 1-1 by using 3-methylaniline. MS obsd. (ESI+) [(M+H)+] 212.
Intermediate 1-5 2,4-Dichloromethylquinoline N Cl ediate 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-Dichlorofluoro-quinoline N Cl 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-Dichlorotrideuteriomethyl-quinoline D Cl N Cl 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 chloro-quinolinecarboxylate O Cl N Cl Intermediates 1-9 can be ed 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-difluoromethylquinoline F N Cl ediate 1-10 can be prepared in analogy to Intermediate 1-1 by using 2,3-difluoro methylaniline. MS obsd. (ESI+) [(M+H)+] 248.
Intermediate 1-11 2,4-Dichloro(trifluoromethoxy)quinoline F O N Cl Intermediate 1-11 can be prepared in analogy to Intermediate 1-1 by using 4- (trifluoromethoxy)aniline. MS obsd. (ESI+) +] 282.
Intermediate 1-12 2,4-Dichloro(difluoromethoxy)quinoline H O N Cl 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 chlorofluoromethylquinoline F Cl N Cl Intermediate 1-13 can be prepared in analogy to Intermediate 1-1 by using 3-fluoro methylaniline. MS obsd. (ESI+) [(M+H)+] 230.
Intermediate 1-14 2,4-Dichlorofluoromethylquinoline F N Cl Intermediate 1-14 can be prepared in analogy to Intermediate 1-1 by using 3-fluoro methylaniline. MS obsd. (ESI+) [(M+H)+] 230.
Intermediate 1-15 bromomethylquinoline N Br Intermediate 1-15 can be prepared in analogy to Intermediate 1-1 by using 4-methylaniline, propanedioic acid and oryl 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 N Cl Methyl 4-aminopyridinecarboxylate N O A mixture of compound 4-aminopyridinecarboxylic 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), ed with 2 N of aqueous solution of sodium hydroxide to about pH 10 and then extracted with ethyl acetate (300 mL × 3). The combined organic layers were washed with water (500 mL), dried over sodium sulfate and concentrated in vacuo to afford the crude t, which was used for next step without r purification.
Methyl 4-(acetylamino)pyridinecarboxylate N O A mixture of methyl 4-aminopyridinecarboxylate (100 g, 0.6 mol) and acetic ide (240 g, 2.4 mol) in ous 1,4-dioxane (1.2 L) was stirred at room ature 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. 1-Benzylhydroxy-1,6-naphthyridin-2(1H)-one N O A mixture of methyl 4-(acetylamino)pyridinecarboxylate (70 g, 0.36 mol) and sodium hydride (50 g, 1.25 mol, 60% in mineral oil) in anhydrous ydrofuran (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 e was stirred at room temperature ght. 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 1-benzylhydroxy-1,6-naphthyridin-2(1H)-one as a pale yellow solid. 1,6-Naphthyridine-2,4(1H,3H)-dione N O A mixture of 1-benzylhydroxy-1,6-naphthyridin-2(1 H)-one (21 g, 0.08 mol) and trifluoromethanesulfonic acid (100 mL) was heated with stirring at 120 oC overnight. The reaction mixture was used for the next step directly. 2,4-Dichloro-1,6-naphthyridine N Cl A mixture of 1,6-naphthyridine-2,4(1H,3H)-dione (10 g, 0.06 mol) and oryl chloride (180 g) was heated with stirring at 100 oC for 3 hours. The reaction mixture was cooled to room temperature and concentrated in vacuo. The residue was poured into ter (200 g) and extracted with ethyl acetate (200 mL × 5). The combined organic layers were dried over sodium sulfate, trated 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-Dichlorodifluoromethylquinoline F Cl N Cl 4-Aminobenzaldehyde H O 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 × 3). Then the organic layer was dried over sodium e, 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-Dichloroquinolinecarbaldehyde O Cl N Cl A e 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 oC for 16 hours. The reaction mixture was cooled to room temperature and concentrated in vacuo. The residue was purified by flash column tography afford 150 mg of the pure product (yield was 0.57%). 2,4-Dichlorodifluoromethylquinoline F Cl N Cl A mixture of 2,4-dichloroquinolinecarbaldehyde (45.2 mg, 0.2 mmol) and diethylaminosulfur trifluoride (32.2 mg, 0.2 mmol) in 1,2-dichloroethane (15 mL) was refluxed overnight. The reaction e 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, CDCl3) δ ppm 8.28 (s, 1 H), 8.10 - 8.05 (d, J = 8.8 Hz,1 H), 7.90 - 7.82 (d, J = 8.4 Hz,1 H), 7.53 (s, 1 H), 6.95 - 6.62 (t, J = 56 Hz ,1 H).
Intermediate 2-1 2,3,4,5-Tetrahydro-1,4-benzothiazepine S Methyl 2-sulfanylbenzoate To a cooled solution of trated sulfuric acid (72 g) in methanol (1.5 L) at 0 oC, 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 ted aqueous solution of sodium bicarbonate to about pH 7, and extracted with dichloromethane (600 mL × 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 yellow oil, which was used for the next step without further purification. 3,4-Dihydro-1,4-benzothiazepin-5(2H)-one To a cooled on of methyl 2-sulfanylbenzoate (200 g, 1.19 mol) in tetrahydrofuran and N,N- dimethylformamide (2 L, V/V = 1/1) was added 2-chloroethanamine hydrochloride (138 g, 1.19 mol) at 0 oC followed by sodium hydride (143 g, 3.57 mol, 60% in mineral oil) in ns.
After being stirred at room temperature overnight, the reaction mixture was poured into icewater and extracted with ethyl acetate (900 mL × 4). The c layers were combined, washed with brine (900 mL × 3), dried over sodium sulfate and concentrated in vacuo. The residue was stirred in a e 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 hydro-1,4- benzothiazepin-5(2H)-one (yield was 47%). 2,3,4,5-Tetrahydro-1,4-benzothiazepine To a bottle ning a cooled suspension of lithium aluminum hydride (44 g, 1.17 mol) in dry tetrahydrofuran (1.5 L) was added 3,4-dihydro-1,4-benzothiazepin-5(2H)-one (150 g, 0.84 mol) in portions at 0 oC. After being refluxed for 18 hours, the reaction mixture was cooled to 0 oC, 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-1,4-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-1,4-benzothiazepine (Intermediate 2-2) and 8-Fluoro-2,3,4,5- tetrahydro-1,4-benzothiazepine (Intermediate 2-3) H H N N S O S F 4-Fluorosulfanylbenzoic acid SH F To a cooled on of 2-aminofluoro-benzoic acid (0.93 g, 6 mmol) in water (3 mL) was added trated hydrochloric acid (1.2 mL), then a cold solution of sodium nitrite (0.41 g, 6 mmol) in water (2 mL) was added dropwise at 5 oC. After the addition, the mixture was stirred for 30 minutes at that temperature. A cooled solution of um disulphide prepared with boiled water (2 mL), sodium sulfide drate (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 e at 5 oC. 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.
(ESI-) [(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 itate 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 oC, 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. (ESI-) [(M-H)-] 171.
Methyl 4-fluorosulfanylbenzoate SH F A mixture of 4-fluorosulfanylbenzoic 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 s 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. (ESI-) [(M-H) -]185. 8-Methoxy-3,4-dihydro-1,4-benzothiazepin-5(2H)-one and 8- Fluoro-3,4-dihydro-1,4- benzothiazepin-5(2H)-one O O N H S O S F To a solution of methyl 4-fluorosulfanylbenzoate (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 l oil) was added in portions. The reaction mixture was stirred at 100 oC overnight. The solvent was removed under reduced pressure. The e was diluted with water, then a mixture of ethyl e 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-1,4- benzothiazepin-5(2H)-one and 8-fluoro-3,4-dihydro-1,4-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-1,4- 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-1,4-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-1,4-benzothiazepine S O ediate 2-2 can be prepared in analogy to intermediate 2-1 by using 8-methoxy-3,4- dihydro-1,4-benzothiazepin-5(2H)-one (yield was 90%). MS obsd. (ESI+) [(M+H)+] 196.
Intermediate 2-3 8-Fluoro-2,3,4,5-tetrahydro-1,4-benzothiazepine S F Intermediate 2-3 can be prepared in analogy to intermediate 2-1 by using 8-fluoro-3,4-dihydro- 1,4-benzothiazepin-5(2H)-one (yield was 96%). MS obsd. (ESI+) [(M+H)+] 184.
Intermediate 2-4 7-Fluoro-2,3,4,5-tetrahydro-1,4-benzothiazepine N F S Intermediate 2-4 can be prepared in analogy to intermediate 2-1 by using 5-fluoro sulfanylbenzoic acid. MS obsd. (ESI+) [(M+H)+] 184.
Intermediate 2-5 9-Fluoro-2,3,4,5-tetrahydro-1,4-benzothiazepine F Intermediate 2-5 can be ed in analogy to intermediate 2-1 by using 3-fluoro sulfanylbenzoic acid. MS obsd. (ESI+) [(M+H)+] 184.
Intermediate 2-6 8-Methyl-2,3,4,5-tetrahydro-1,4-benzothiazepine S Methyl 2-hydroxymethylbenzoate A mixture of 2-hydroxymethylbenzoic acid (100.0 g, 657.2 mmol), trated sulfuric acid (50 mL) in ol (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-hydroxymethylbenzoate as light brown oil, which was used directly in the next step without further purification.
Methyl 2-[(dimethylcarbamothioyl)oxy]methylbenzoate To a solution of methyl 2-hydroxymethylbenzoate (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) in N,N- dimethylformamide (100 mL) at room temperature. After being heated at 60 oC for 4 hours, the mixture was cooled and poured onto ice. The formed itate was collected by filtration, washed with water (300 mL × 3) and dried in vacuo to afford 137 g of methyl 2- [(dimethylcarbamothioyl)oxy]methylbenzoate as an off-white solid (yield was 82%).
Methyl methylcarbamoyl)sulfanyl]methylbenzoate Methyl 2-[(dimethylcarbamothioyl)oxy]methylbenzoate (52.0 g, 205.5 mmol) in a round bottle flask which was vacuumed and backfilled with nitrogen, was heated at 210 oC for 4 hours.
The mixture was then cooled to room temperature and used for next step without further purification. 4-Methylsulfanylbenzoic acid SH A round bottle flask ning a mixture of methyl 2-[(dimethylcarbamoyl)sulfanyl] 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 oC and acidified with an aqueous solution of hydrochloric acid (45 mL, 6 N). The formed itate 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-methylsulfanylbenzoic acid as a light yellow solid. 8-Methyl-2,3,4,5-tetrahydro-1,4-benzothiazepine Intermediate 2-6 can be prepared in analogy to ediate 2-1 by using 4-methyl sulfanylbenzoic acid. MS obsd. (ESI+) [(M+H)+] 180.
Intermediate 2-7 8-Chloro-2,3,4,5-tetrahydro-1,4-benzothiazepine S Cl 4-Chlorosulfanylbenzoic acid SH Cl To a cooled mixture of concentrated hydrochloric acid (6 mL) and ice (10 g) was added slowly a solution of 2-aminochlorobenzoic 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 oC 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 oC. The cold ium salt solution was added slowly to the above hot solution while evolution of gas was ed. After the addition the mixture was cooled to room temperature and acidified to about pH 3 with an aqueous on of hloric acid (4 N). The aqueous phase was decanted from the resulting semisolid and the sludge was dissolved in 10% aqueous sodium ide (20 mL). The solution was heated for 2 hours at 100 oC followed by addition of sodium hydrosulfite (2 g). The resulting mixture was heated with stirring at 100 oC for an additional 10 minutes, then cooled to room ature and filtered through a pad of celite. The filtrate was acidified to about pH 4 with trated 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-chlorosulfanylbenzoic acid as a yellow solid (yield was 63%). 8-Chloro-2,3,4,5-tetrahydro-1,4-benzothiazepine S Cl Intermediate 2-7 can be prepared in analogy to intermediate 2-1 by using 4-chloro sulfanylbenzoic acid. MS obsd. (ESI+) [(M+H)+] 200.
Intermediate 3 -Methyl-2,3,4,5-tetrahydro-1,4-benzothiazepine ulfanylphenyl)ethanone To a stirred suspension of aluminium chloride (10.50 g, 78.8 mmol) in dry benzene (200 mL) was added a solution of 1-[2-(benzylsulfanyl)phenyl]ethanone (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 ter. The separated organic layer was washed with water and extracted with 5% aqueous solution of sodium hydroxide (300 mL). The aqueous layer was ied to about pH 3 with concentrated hydrochloric acid (12 N) and extracted with dichloromethane (300 mL × 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 ulfanylphenyl)ethanone.
-Methyl-2,3-dihydro-1,4-benzothiazepine To a solution of 1-(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 e was concentrated in vacuo to remove most of ethanol and ted with dichloromethane (60 mL × 3). The combined organic layers were washed with brine (100 mL), dried over anhydrous sodium sulfate, and concentrated in vacuo. The residue was ed by flash column chromatography to give 5.92 g of 5-methyl-2,3-dihydro-1,4-benzothiazepine. 5-Methyl-2,3,4,5-tetrahydro-1,4-benzothiazepine To a solution of 5-methyl-2,3-dihydro-1,4-benzothiazepine (5.92 g, 33.40 mmol) in methanol (100 mL) was added a on of sodium dride (3.16 g, 83.49 mmol) in water (60 mL).
After being stirred at room temperature ght, 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 × 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-1,4-benzothiazepine, MS obsd. (ESI+) [(M+H)+] 180.
Intermediate 4 1-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)ethanone O O 1-(2,3-Dihydro-1,4-benzothiazepin-4(5H)-yl)ethanone To a on of 2,3,4,5-tetrahydro-1,4-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 oC 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 × 2), dried over sodium sulfate, ed and concentrated in vacuo to afford 6.28 g of product as yellow oil, which was used for next step without further purification. 1-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)ethanone O O To a cooled solution of 1-(2,3-dihydro-1,4-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 oC. After the on, 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 × 2), a ted aqueous solution of sodium e (100 mL × 2) and brine (100 mL).
The organic layer was dried over sodium sulfate, ed 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 1-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)ethanone as a white powder.
Intermediate 5 2,3,4,5-Tetrahydro-1,4-benzothiazepine 1,1-dioxide To a solution of 1-(1,1-dioxido-2,3-dihydro-1,4-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 refluxed overnight and then concentrated in vacuo. The e was extracted by ethyl acetate (1500 mL × 4). The combined organic layers were extracted by hydrochloric acid (2000 mL, 3 N). The acidic s layer was washed with ethyl acetate (1500 mL × 2), then basified with a saturated aqueous solution of sodium bicarbonate to pH > 7, and extracted with ethyl acetate (1500 mL × 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-1,4-benzothiazepine1,1- 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-1,4-benzothiazepine 1-oxide 1-(1-Oxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)ethanone To a cooled solution of 1-(2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)ethanone (70 g, 0.33 mol) in dichloromethane (700 mL) was added a on of roperoxybenzoic acid (67 g, 0.33 mol) in dichloromethane (800 mL) se at 0 oC. After the addition, the reaction was stirred at the same temperature for 15 s. The resulting reaction mixture was washed with a saturated aqueous solution of sodium carbonate (500 mL × 2) and a saturated aqueous solution of sodium sulfite (500 mL × 2). The combined aqueous layers were extracted with dichloromethane (200 mL × 2), dried over sodium sulfate and concentrated in vacuo. The residue was purified by flash chromatography (eluting with 1~2% ol in dichloromethane) to afford 57 g of the desired product (yield was 77%). 2,3,4,5-Tetrahydro-1,4-benzothiazepine 1-oxide Intermediate 6 was prepared in analogy to intermediate 5 by using 1-(1-oxido-2,3-dihydro-1,4- benzothiazepin-4(5H)-yl)ethanone (yield was 66%), MS obsd. (ESI+) +] 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 - 4.11(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 (5Z)-N-Methoxy-1,2,3,4-tetrahydro-5Hbenzazepinimine A mixture of 4-tetrahydrobenzazepinone (500 mg, 2.530 mmol), O-methyl hydroxylamine hydrochloride (211 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 × 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 fluoro-2,3,4,5-tetrahydro-1H-benzazepine 1-(5,5-Difluoro-1,3,4,5-tetrahydro-2Hbenzazepinyl)-2,2,2-trifluoroethanone N F O F F To a cooled solution of 1,2,3,4-tetrahydrobenzazepinone hydrochloride (33.7 g, 0.17 mol) in dichloromethane (500 mL) at 0 oC, was added ylamine (52 g, 0.51 mol) dropwise followed by oroacetic 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 e was purified by flash chromatography (eluting with 16% ethyl acetate in eum ether) to afford 40 g of the desired product (yield was 89%). 1-(5,5-Difluoro-1,3,4,5-tetrahydro-2Hbenzazepinyl)-2,2,2-trifluoroethanone N F O F F A on of 2-(trifluoroacetyl)-1,2,3,4-tetrahydro-5Hbenzazepinone (40 g, 0.156 mol) in N,N-diethylaminosuflur trifluoride (104 g, 0.468 mol) was heated at 70 oC 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-1H-benzazepine To a cooled solution of 1-(5,5-difluoro-1,3,4,5-tetrahydro-2Hbenzazepinyl)-2,2,2- trifluoroethanone (33 g, 0.184 mmol) in methanol was added an ammonia methanol solution (300 mL, 7 M) at 0 oC. After being stirred at 0 oC 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 t as a purple oil (yield was 83.3%), MS obsd. (ESI+) [(M+H)+] 184, 1H NMR (400 MHz, CDCl3) 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)-N,N-dibenzyltetrahydrofuranamine NH2 O 3-(Dibenzylamino)tetrahydrofurancarbonitrile To a cooled solution of dibenzylamine (31.9 g, 162 mmol) in acetic acid (100 mL) at 0 oC, ofuran-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, d with ethyl acetate (100 mL × 2). The combined organic layers were washed with brine (150 mL), dried over sodium sulfate and concentrated in vacuo. The residue was ed by column chromatography to afford 2.2 g of the desired product (yield was 9.28%). 3-(Aminomethyl)-N,N-dibenzyltetrahydrofuranamine NH2 O To a cooled solution of 3-(dibenzylamino)tetrahydrofurancarbonitrile (2.2 g, 7.5 mmol) in tetrahydrofuran (50 mL) at 0 oC, was added lithium aluminium hydride (855 mg, 22.5 mmol).
After the mixture being stirred 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)-N,N-dibenzyloxetanamine Intermediate 9-2 can be prepared in y to intermediate 9-1 by using oxetanone. MS obsd. (ESI+) [(M+H)+] 283.
Intermediate 9-3 1-(Aminomethyl)-N,N-dibenzylcyclobutanamine ediate 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)-N,N-dibenzylthietanamine 3,3-Dimethoxythietane O O To a solution of 1,3-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%).
Thietanone 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. nomethyl)-N,N-dibenzylthietanamine ediate 9-4 can be ed in analogy to intermediate 9-1 by using thietanone. 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, 2 Intermediate 9-5 1-(Aminomethyl)-N,N-dibenzylcyclohexanamine 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-tetrahydropyranyl)-dibenzyl-amine Intermediate 9-6 can be ed in analogy to intermediate 9-1 by using tetrahydropyranone.
MS obsd. (ESI+) [(M+H)+] 311.
Intermediate 10 Aminooxetanyl)methyl]-2,2,2-trifluoroacetamide O O NH H 2 F F N-{[3-(Dibenzylamino)oxetanyl]methyl}-2,2,2-trifluoroacetamide N H To a solution of 3-(aminomethyl)-N,N-dibenzyloxetanamine (3.0 g, 10.6 mmol) in romethane (30 mL) in an ice bath was added dropwise trifluroacetic 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 onate at 0 oC. 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.
N-[(3-Aminooxetanyl)methyl]-2,2,2-trifluoroacetamide O O H F To a solution of (dibenzylamino)oxetanyl]methyl}-2,2,2-trifluoroacetamide (4.0 g, .57 mmol) in methanol (80 mL) was added 20% palladium hydroxide on carbon (0.8 g) and trifluoroacetic acid (one drop). The mixture was stirred at room temperature under hydrogen overnight and then filtered. The te was concentrated in vacuo to afford the crude t as a white solid.
Intermediate 11 tert-Butyl [(3-aminooxetanyl)methyl]carbamate 2NH O tert-Butyl {[3-(dibenzylamino)oxetanyl]methyl}carbamate N N To a solution of 3-(aminomethyl)-N,N-dibenzyloxetanamine (10.0g, 35.41 mmol) in tetrahydrofuran (100 mL) was added an aqueous solution of sodium onate (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 tetrahydrofuran (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 × 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 cation. tert-Butyl [(3-aminooxetanyl)methyl]carbamate 2NH O A mixture of tert-butyl ibenzylamino)oxetanyl]methyl}carbamate (13.0 g, crude), 20% palladium ide on carbon (2.0 g) and oroacetic 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-Butyl [1-(2-aminoethyl)-cyclopropyl]carbamate O N H NH 3-(Benzyloxy)propanenitrile To a e of benzyl alcohol (108 g, 1 mol) and 40% aqueous solution of sodium hydroxide (10 mL) was added propenenitrile (58.3 g, 1.1 mol) and the mixture was stirred for 6 hours at room ature. The mixture was neutralized with 1 N hydrochloric acid, and extracted with dichloromethane (300 mL). The organic layer was washed with 5% on 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%). 1-[2-(benzyloxy)ethyl]cyclopropanamine 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 ature. 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 1N hydrochloric acid to pH 3, and then washed with dichloromethane. The s 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 1-[2- loxy)ethyl]cyclopropanamine (yield was 55%). 2-(1-Aminocyclopropyl)ethanol hydrochloride NH.HCl To a mixture of 1-[2-(benzyloxy)ethyl]cyclopropanamine (13.2 g, 69 mmol), 10% palladium on carbon (3.0 g) and propanol (100 mL) was added a solution of hydrochloride in propanol (100 mL, 5-6 N). The mixture was shaken at 40 oC under hydrogen pressure of 4 atmospheres until hydrogen uptake ceased. The catalyst was removed by filtration and washed with propan ol. The filtrate was concentrated in vacuo to afford 8.8 g of the salt as a viscous oil (yield was 84.6%). tert-Butyl hydroxyethyl)cyclopropyl]carbamate O H OH To a solution of 2-(1-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 e was ved 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 ed to afford 9.3 g of the pure product as a white solid (yield was 71%). 2-{1-[(tert-Butoxycarbonyl)amino]-cyclopropyl}ethyl methanesulfonate N S O H O To a cooled solution of tert-butyl [1-(2-hydroxyethyl)cyclopropyl]carbamate (8.0 g, 0.04 mol) and triethylamine (12.14 g) in ous tetrahydrofuran (120 mL) at -20 oC was added a solution of mesyl chloride (17.8 g) in anhydrous tetrahydrofuran (30 mL). The ing 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 ted organic layer was washed with brine (100 mL), dried over sodium sulfate and concentrated in vacuo. The e was triturated with petroleum ether and filtered to give 9.5 g of the pure product as an orange solid (yield was 95%). tert-Butyl 1-[2-(1,3-dioxo-1,3-dihydro-2H-isoindolyl) ethyl] cyclopropylcarbamate O N H N To a solution of 2-{1-[(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- 1H-isoindole-1,3-dione (7.0 g, 37 mmol). After being d at 150 oC for 18 hours, the resulting mixture was then filtered and washed with diethyl ether (50 mL). The filtrate was washed with brine (50 mL × 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%). utyl [1-(2-aminoethyl)-cyclopropyl]carbamate O N H NH To a solution of tert-butyl 1-[2-(1,3-dioxo-1,3-dihydro-2H-isoindolyl)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 trated in vacuo to afford 1.5 g of the pure compound as an orange oil (yield was 75%).
Intermediate 13 tert-Butyl [2-(1-aminocyclopropyl)ethyl]carbamate 2 N H O Methyl 1-aminocyclopropanecarboxylate 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 oC. 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 1-[(tert-butoxycarbonyl)amino]cyclopropanecarboxylate O N To a cooled mixture of methyl 1-aminocyclopropanecarboxylate (1.1 g, 9.6 mmol) and an aqueous solution of potassium onate (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 oC. The reaction mixture was allowed to warm to room temperature and stirred at this ature overnight. The separated aqueous layer was extracted with ethyl acetate (20 mL). The combined organic layers were dried over sodium sulfate and trated in vauco to afford 2.0 g of the product (yield was 97%). tert-Butyl [1-(hydroxymethyl)cyclopropyl]carbamate O N To a cooled solution of methyl 1-[(tert-butoxycarbonyl)amino]cyclopropanecarboxylate (1.2 g, 5.6 mmol) in tetrahydrofuran (10 mL) at 0 oC was added dropwise a solution of lithium borohydride (244 mg, 11.2 mmol) in tetrahydrofuran (10 mL) The on e was allowed to warm to room temperature and stirred at this temperature overnight. The reaction was quenched by on of water (10 mL) and the resulting mixture was extracted with dichloromethane. The organic layer was dried over sodium e and concentrated in vacuo to afford 0.8 g of the product (yield was 76.2%). tert-Butyl [1-(azidomethyl)cyclopropyl]carbamate O + N O N To a solution of tert-butyl [1-(hydroxymethyl)cyclopropyl]carbamate (1 g, 5.3 mmol) in N,N- dimethylformamide (20 mL) was added azabicyclo[5.4.0]undecene (1.22 g, 8.0 mmol) and diphenylphosphoryl azide (2.33 g, 8.00 mmol). After the mixture was stirred at 80 oC for 3 hours, another batch of azabicyclo[5.4.0]undecene (1.22 g, 8.0 mmol) and diphenylphosphoryl azide (2.33 g, 8.00 mmol) was introduced and the mixture was stirred at 80 oC for another 2 hours. The resulting mixture was then diluted with water (20 mL) and extracted with ethyl acetate (30 mL × 2). The combined organic layers were used for next step directly. tert-Butyl [1-(aminomethyl)cyclopropyl]carbamate O N 2 A solution of tert-butyl idomethyl)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 (1,1-Dioxidothietane-3,3-diyl)dimethanamine NH NH2 O O 3,3-Bis(azidomethyl)thietane + N N + N N N N 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 oC ght, then diluted with water (20 mL) and extracted with romethane (50 mL × 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 + N N + N N N N O O To a solution of 3,3-bis(azidomethyl)thietane (2.5 g, 13.59 mmol) in the mixture of formic acid (5 mL) and romethane (6 mL) was added en peroxide (9.2 g, 81.54 mmol) slowly at 0 oC. 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 × 3). The combined organic layers were dried over sodium sulfate and concentrated in vacuo. The e was purified by flash column tography to afford 2.8 g of the desired product as a white solid (yield of two steps was 96%). (1,1-Dioxidothietane-3,3-diyl)dimethanamine NH NH 2 2 O O 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-diyldimethanamine NH NH 2 2 A solution of 3,3-bis(azidomethyl)thietane (2.5 g, 13.59 mmol) in romethane (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 d product.
Intermediate 16 ifluorocyclobutane-1,1-diyl)dimethanamine F NH F NH2 Dipropanyl 3,3-dimethoxycyclobutane-1,1-dicarboxylate O O O O 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 1,3-bis(propanyl) propanedioate (363.3 g, 1.930 mol) dropwise under nitrogen at a rate such that the ature was ined below 70 ºC. On cessation of hydrogen evolution, the mixture was heated to 130 ºC, 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 dipropanyl 3,3-dimethoxycyclobutane-1,1-dicarboxylate as a ess oil (yield was 58.2%). 1H NMR (400 MHz, CDCl3) δ ppm 5.02 (m J = 6.4 Hz, 2 H), 3.12 (s, 6 H), 2.66 (s, 4 H), 1.11 (d, J = 6.4 Hz, 12 H).
Dipropanyl 3-oxocyclobutane-1,1-dicarboxylate A solution of dipropanyl methoxycyclobutane-1,1-dicarboxylate (10.0 g, 34.6 mmol) in hydrochloric acid (3 N, 55 mL) was heated at 50 ºC for 4 hours. The ing mixture was neutralized with a saturated aqueous solution of sodium bicarbonate and extracted with ethyl acetate (100 mL). The ed organic layers were dried over sodium e and concentrated in vacuo to afford 6.073 g of dipropanyl 3-oxocyclobutane-1,1-dicarboxylate as a light brown oil (yield was 72.3%).
Dipropanyl 3,3-difluorocyclobutane-1,1-dicarboxylate F O F O To a cooled solution of dipropanyl 3-oxocyclobutane-1,1-dicarboxylate (5.657 g, 23.3 mmol) in dichloromethane (50 ml) at -78 ºC, 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 ide (50 mL) and brine (50 mL). The organic layer was dried over sodium sulfate, and concentrated in vacuo to afford dipropanyl 3,3-difluorocyclobutane-1,1-dicarboxylate as a yellow oil (yield was 68.8%). 3,3-Difluorocyclobutane-1,1-dicarboxylic acid F OH F OH A mixture of 3,3-difluoro-cyclobutane-1,1-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 ature overnight. The formed off-white solid was collected by filtration, washed with ethyl acetate, and dissolved in water. The aqueous solution was acidified with hydrochloric acid (3 N) to pH 3 - 4. The mixture was concentrated in vacuo to afford 6.293 g of the crude 3,3- rocyclobutane-1,1-dicarboxylic acid as a white solid, which was used for next step without further purification. 3,3-Difluorocyclobutane-1,1-dicarboxamide F NH F NH2 O A solution of crude 3,3-difluorocyclobutane-1,1-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 ite 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-1,1-dicarboxamide as an off-white solid (yield of three steps was 55.2%). (3,3-Difluorocyclobutane-1,1-diyl)dimethanamine F NH F NH To a cooled solution of fluorocyclobutane-1,1-dicarboxamide (1.858 g, 10.4 mmol) in tetrahydrofuran (25 mL) at -10 ºC, was added slowly lithium ium hydride (2.375 g, 62.58 mmol). The reaction was stirred at 0 ºC for 4 hours and then heated under reflux for 30 hours.
The mixture was cooled and quenched at 0 ºC by on 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 ature 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-1,1- diyl)dimethanamine as a colorless oil (yield was 72.8%).
Intermediate 17 -Dioxo-1,3-dihydro-2H-isoindolyl)-4,4,4-trifluorobutanoyl chloride O F F N Cl 3-(1,3-Dioxo-1,3-dihydro-2H-isoindolyl)-4,4,4-trifluorobutanoic acid O F F N OH A solution of phthalic de (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 ºC under microwave irradiation for 1 hour. The resulting mixture was cooled to room temperature, diluted with water, and extracted with ethyl acetate (30 mL × 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 e in hexane) to afford 270 mg of the product of 3-(1,3-dioxo-1,3-dihydro-2H-isoindolyl)-4,4,4-trifluorobutanoic acid (yield was 37%). MS obsd. (ESI+) [(M+H)+] 288. 3-(1,3-Dioxo-1,3-dihydro-2H-isoindolyl)-4,4,4-trifluorobutanoyl chloride O F F N Cl To a solution of 3-(1,3-dioxo-1,3-dihydro-2H-isoindolyl)-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), ed by N,N-dimethylformamide (1 drop). After the gas ceased to produce, the reaction mixture was stirred at room ature for 2 hours. After the mixture was concentrated in vacuo, the e 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 NH 2 1,4-Dibromofluorobutane To a solution of 1,4-dibromobutanol (6.0 g, 25.64 mmol) in dichloromethane (80 mL) was added ethylaminosuflur trifluoride (6.25 mg, 38.79 mmol). The on 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 e, and concentrated in vacuo to afford 4.0 g of 1,4-dibromofluoro-butane as a yellow oil. 2,2'-(2-Fluorobutane-1,4-diyl)bis(1H-isoindole-1,3(2H)-dione) O F To a solution of 1,4-dibromofluoro-butane (4.0 g, 17.09 mmol) in N,N-dimethylformamide (60 mL) was added potassium 2,3-dihydro-1H-isoindole-1,3-dione (9.5 g, 51.27 mmol). The reaction mixture was stirred at 100 ºC 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-1,4- diyl)bis(1H-isoindole-1,3(2H)-dione) as a white solid. 2-Fluorobutane-1,4-diamine A mixture of 2,2'-(2-fluorobutane-1,4-diyl)bis(1H-isoindole-1,3(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 utyl (4S)(aminomethyl)-2,2-dimethyl-1,3-oxazolidinecarboxylate N O tert-Butyl -[(benzylamino)methyl]-2,2-dimethyl-1,3-oxazolidinecarboxylate N O A mixture of tert-butyl (4S)formyl-2,2-dimethyl-1,3-oxazolidinecarboxylate (1.0 g, 4.36 mmol), phenylmethanamine (491 mg, 4.58 mmol) and toluene (8 mL) was heated under reflux with ng for 2 hours. The mixture was concentrated in vacuo. The residue was dissolved in 1,2-dichloroethane (10 mL), to which sodium etyloxy)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 × 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)(aminomethyl)-2,2-dimethyl-1,3-oxazolidinecarboxylate N O A mixture of tert-butyl (4S)[(benzylamino)methyl]-2,2-dimethyl-1,3-oxazolidine carboxylate (810 mg, 2.53 mmol), palladium hydroxide on carbon (81 mg) and methanol (20 mL) was stirred at room temperature under hydrogen atmosphere ght. The catalyst was removed by filtration. The filtrate was concentrated in vacuo. The residue was ed by SPE (12 mL tube, 2 gram of DSC-SCX) to afford the pure product.
Intermediate 20 tert-Butyl 2-oxaazaspiro[3.4]octylcarbamate O H 6-Benzylnitrooxaaza-spiro[3.4]octane 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 trifluoroacetic acid (0.93 mL, 12.6 mmol) dropwise. The e was d at room temperature for 2 hours, ed with sodium carbonate, ted 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-Benzyloxaaza-spiro[3.4]octylamine The mixture of 6-benzylnitrooxaaza-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 ºC. The reaction mixture was filtered by a pad of celite. The filtrate was trated under reduced pressure, and the residue was used for next step without further purification. tert-Butyl (6-benzyloxaazaspiro[3.4]octyl)carbamate To a mixture of 6-benzyloxaazaspiro[3.4]octylamine (prepared above), sodium carbonate (1.46 g, 13.74 mmol), dichloromethane (20 mL) and water (20 mL) was added di-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, ed 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. tert-Butyl 2-oxaazaspiro[3.4]octylcarbamate O H To a solution of 6-benzyloxaazaspiro[3.4]octylamine (1.5 g, 4.71 mmol) in methanol (50 mL) was added ium 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 t further purification.
Intermediate 21 N-(3-Methylpyrrolidinyl)-acetamide N O N-(1-Benzylmethylpyrrolidinyl)-acetamide N O To a solution of 1-benzylmethylpyrrolidinol (1.0 g, 5.2 mmol) in acetonitrile (10 mL) at 0 ºC, was added concentrated sulfuric acid (10 mL) slowly. After being stirred for 16 hours at room temperature, the on mixture was poured into ice-water. After the on mixture was adjusted to pH 7 with a ted aqueous solution of potassium carbonate, the resulting mixture was d with dichloromethane (200 mL × 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-Methylpyrrolidinyl)-acetamide N O A mixture of N-(1-benzylmethylpyrrolidinyl)-acetamide (600 mg, 2.6 mmol), palladium on carbon (400 mg, 10%) and ethanol (20 mL) was stirred at 40 ºC under 50 Psi of hydrogen for 16 hours. The resulting mixture was ted. 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-1,3-diamine NH NH2 2-Fluoropropanediamide NH NH2 O O 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 ing e 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-1,3-diamine NH NH 2 2 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 ol (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 the residue was added water (10 mL), ium hydroxide was added with cooling until the aqueous solution was ted. The mixture was extracted by l ether (20 mL × 2), and the combined organic layers was dried over potassium hydroxide and concentrated in vacuo to afford 7.5 g of ropropane-1,3-diamine (yield was 60%). MS obsd. (ESI+) [(M+H)+] 93.
Intermediate 23 Benzyl 6-oxaazabicyclo[3.1.0]hexanecarboxylate N O To a solution of 1-benzyloxycarbonylpyrroline (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 e was extracted with chloroform (50 mL × 2). The combined organic layers were washed successively with 2 N aqueous solution of sodium hydroxide (50 mL × 2) and brine (50 mL), dried over magnesium sulfate and concentrated in vacuo to afford 2.79 g of the crude benzyl 6-oxaazabicyclo[3.1.0]hexane carboxylate as an oil. MS obsd. (ESI+) [(M+H)+] 220. trans-(±)-Benzylaminohydroxypyrrolidinecarboxylate O 2 A mixture of the crude benzyl 6-oxaazabicyclo[3.1.0]hexanecarboxylate 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 × 3). The combined organic layers were dried over anhydrous magnesium sulfate and concentrated in vacuo to afford 2.67 g of the crude benzylaminohydroxypyrrolidinecarboxylate as oil. MS obsd. (ESI+) [(M+H)+] 237. trans-(±)-Benzyl[(tert-butoxycarbonyl)amino]hydroxypyrrolidinecarboxylate O OH O NH O O To a cooled solution of trans-benzylaminohydroxypyrrolidinecarboxylate (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[(tert-butoxycarbonyl)amino] hydroxypyrrolidinecarboxylate as crystals. MS obsd. (ESI+) [(M+H)+] 337. trans-(±)-tert-Butyl [4-hydroxypyrrolidinyl]carbamate H O OH N H To a solution of 3-tert-butoxycarbonylaminohydroxy-pyrrolidinecarboxylic acid benzyl ester (3.9 g) in methanol (31 mL) and tetrahydrofuran (7 mL) was added palladium hydroxide (20 wt% Pd on , 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 te was concentrated in vacuo. The e was triturated in the mixture of ethyl acetate and diisopropylether and filtered to remove the insoluable materials. The te was trated in vacuo to afford 2.0 g of trans-tert-butyl [4-hydroxypyrrolidinyl]carbamate (yield was 94%) as a powder. MS obsd. (ESI+) [(M+H)+] 203.
Intermediate 24 trans-(±)-Benzyl 3-aminofluoroypyrrolidnecarobxylate O NH trans-(±)-Benzyl 3-azidofluoroypyrrolidnecarobxylate O N + In a solution of benzyloxaazabicyclo[3.1.0]hexanecarboxylate (2.5 g) in methanol (20 mL) was added water (5 mL), ammonium de (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 on of sodium hydroxide (30 mL) and ted 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-(±) benzylazidohydroxypyrrolidnecarobxylate. MS obsd. (ESI+) +] 250. trans-(±)-Benzyl 3-azidofluoroypyrrolidnecarobxylate O N + N To a cooled solution of trans-(±) benzylazidohydroxypyrrolidnecarobxylate (6.5 g) in dichloromethane (110 mL) was added diethylaminosulfur trifluoride (6.8 mL) at -78 °C. The mixture was stirred at room temperature for 16 hours, and then trated 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 e 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-(±) benzylazido fluoroypyrrolidnecarobxylate. trans-(±)-Benzyl 3-aminofluoroypyrrolidnecarobxylate O NH2 To a solution of trans-(±) benzylazidofluoroypyrrolidnecarobxylate (4.33 g) in tetrahydrofuran (100 mL) and water (10 mL) was added triphenylphospine (4.5 g). The reaction e 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 × 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 × 2). The combined organic layers were washed with brine (50 mL), dried over magnesium sulfate and concentrated in vacuo to afford trans-(±)-benzyl 3-amino fluoroypyrrolidnecarobxylate.
Intermediate 25 trans-(±)-tert-Butyl oropyrrolidinyl)carbamate H O F N trans-(±)Benzyl[(tert-butoxycarbonyl)amino]fluoropyrrolidinecarboxylate O O To a cooled solution of trans-(±)-benzylaminofluoroypyrrolidnecarobxylate (2.39 g) in chloroform (25 mL) was added dropwise a on of di-tert-butyl dicarbonate (3.7 g) in chloroform (10 mL) in an ice-water bath. The mixture was stirred at room ature for 19 hours. The on 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 tography on silica gel to afford 2.9 g of (±)benzyl[(tertbutoxycarbonyl )amino]fluoropyrrolidinecarboxylate (yield was 90%) as crystals. trans-(±)-tert-Butyl (4-fluoropyrrolidinyl) carbamate H O F N To a solution of trans-(±)benzyl[(tert-butoxycarbonyl)amino]fluoropyrrolidine 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 ght. 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 als. The filtrate was concentrated in vacuo to afford 1.5 g of trans-(±)-tert-butyl (4-fluoropyrrolidinyl) carbamate (yield was 74%) as a powder.
Intermediate 26 utyl (4S)ethenyl-2,2-dimethyl-1,3-oxazolidinecarboxylate N O 3-tert-Butyl 4-methyl (4R)-2,2-dimethyl-1,3-oxazolidine-3,4-dicarboxylate N O A solution of methyl (2R){[(tert-butoxy)carbonyl]amino}hydroxypropanoate (22 g, 0.1 mol), 2,2-dimethoxypropane (20.8 g, 0.2 mol) and 4-methylbenzenesulfonic acid (0.5 g) in toluene was heated with stirring at 110 oC overnight. The solvent was removed under reduced pressure. The e was treated with ethyl acetate, washed with water and brine. The organic layer was dried over sodium sulfate, concentrated under reduced re. The residue distilled at 0.6 mbar to give 16.5 g of 3-tert-butyl 4-methyl (4R)-2,2-dimethyl-1,3-oxazolidine-3,4- dicarboxylate (yield was 63.6 %) as an amber oil. tert-Butyl (4R)formyl-2,2-dimethyl-1,3-oxazolidinecarboxylate N O To a cooled solution of 3-tert-butyl 4-methyl (4R)-2,2-dimethyl-1,3-oxazolidine-3,4- dicarboxylate (16.5 g, 63.6 mmol) in dry dichloromethane (300 mL) at -78 oC, 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 oC and take about 1 hour to complete. The reaction mixture was d for an additional 2 hours at -78 oC under argon. The reaction was quenched by slowly adding 60 mL of cold methanol (-78 oC) so as to keep the internal temperature below -65 oC. The ing 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 (4R)formyl- 2,2-dimethyl-1,3-oxazolidinecarboxylate (10 g, 68.5 %) as colorless liquid. tert-Butyl (4S)ethenyl-2,2-dimethyl-1,3-oxazolidinecarboxylate N O To a solution of methyltriphenylphosphonium bromide (3.1 g, 8.64 mmol) in dry ydrofuran (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 - -2,2-dimethyl-1,3-oxazolidinecarboxylate (1.8 g, 7.86 mmol) in dry ydrofuran (20 mL) was added dropwise. The resulting mixture was stirred at room temperature ght.
The solvent was removed under reduced pressure. The residue was purified by flash column to give tert-butyl (4S)ethenyl-2,2-dimethyl-1,3-oxazolidinecarboxylate (1.5 g, 83.9%) as colorless liquid.
Intermediate 27 Pyridazinecarboxamide O NH N To a cooled solution of pyridazinecarboxylic 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 oC 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 ate (50 mL). The aqueous layer was extracted with ethyl acetate (30 mL × 3). The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo to afford 202.5 mg of the d 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 NH2 NH 3,3-Bis-azidomethyl-oxetane N + + N N N N N 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 oC overnight. The reaction mixture was cooled to room temperature and extracted with romethane (50 mL × 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 NH NH 2 2 A solution of s-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 ature 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 Oxetanylidene-acetonitrile To a on of oxetanone (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 d 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 es) to afford 5.2 g of oxetan ylidene-acetonitrile as a white solid (yield was 79%). zylamino)oxetanacetonitrile N CN A mixture of oxetanylidene-acetonitrile (950 mg, 10 mmol) and phenylmethanamine (1.31 ml, 12 mmol) was heated with stirring at 60 oC for 5 hours under nitrogen. The mixture was concentrated in vacuo. The e was purified by flash column (eluting with 0-50% ethyl acetate in hexane) to afford 1.65 g of 3-(benzylamino)oxetanacetonitrile as a colorless oil (yield was 81.7%). 3-(Aminoethyl)-N-benzyloxetanamine H NH 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)oxetanacetonitrile (1.0 g, 4.3 mmol) in anhydrous diethyl ether (10 mL) dropwise at 0 oC. After being stirred at 0 oC for 2 hours, the reaction was quenched by introducing disodium sulfate drate 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 amine as a light yellow oil (yield was 79%).
Intermediate 30 O O The intermediate was prepared in analogy to 1-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin- 4(5H)-yl)ethanone in Intermediate 4 by oxidation of nomethyl)-N,N-dibenzylthietan 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 g of the t invention.
Example 1-1 N-[(3-Aminooxetanyl)methyl](8-methoxy-1,1-dioxido-2,3-dihydro-1,4-benzothiazepin- 4(5H)-yl)methylquinolinamine O NH N N 4-(4-Chloromethylquinolinyl)methoxy-2,3,4,5-tetrahydro-1,4-benzothiazepine N N A mixture of 8-methoxy-2,3,4,5-tetrahydro-1,4-benzothiazepine (0.63 g, 3.2 mmol), 2,4- dichloromethylquinoline (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 oC under microwave irradiation. The t was removed by tration 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-Chloromethylquinolinyl)methoxy-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1- dioxide N N A mixture of 4-(4-chloromethylquinolinyl)methoxy-2,3,4,5-tetrahydro-1,4- 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 d 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 oC. After being stirred for 2 hours at 0 oC, the mixture was extracted with ethyl acetate (10 mL). The organic layer was filtered through a short silica gel . The filtrate was concentrated in vacuo to afford 0.40 g of the product as a white solid (yield was 90%). MS obsd. (ESI+) +] 403.
N-{[3-(Dibenzylamino)oxetanyl]methyl}(8-methoxy-1,1-dioxido-2,3-dihydro-1,4- benzothiazepin-4(5H)-yl)methylquinolinamine O N N N O A mixture of 4-(4-chloromethylquinolinyl)methoxy-2,3,4,5-tetrahydro-1,4- 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-dibenzyloxetanamine (54 mg, 0.19 mmol) in toluene (5 mL) was heated with stirring for 4 hours at 120 oC. After being cooled to room temperature, the mixture was concentrated in vacuo. The residue was purified by flash chromatography (eluting with 0.5% ylamine 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-Aminooxetanyl)methyl](8-methoxy-1,1-dioxido-2,3-dihydro-1,4-benzothiazepin- 4(5H)-yl)methylquinolinamine O NH N N A e of N-{[3-(dibenzylamino)oxetanyl]methyl}(8-methoxy-1,1-dioxido-2,3- dihydro-1,4-benzothiazepin-4(5H)-yl)methylquinolinamine (50 mg, 0.077 mmol), 10% palladium hydroxide on carbon (100 mg) and trifluoroacetic acid (0.2 mL) in methanol (20 mL) was d for 12 hours at room temperature under hydrogen here (1 bar). The resulting mixture was basified with a saturated aqueous solution of sodium bicarbonate to pH >9 and then extracted with dichloromethane (20 mL × 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 N-[(3-Aminooxetanyl)methyl](8-fluoro-1,1-dioxido-2,3-dihydro-1,4-benzothiazepin- 4(5H)-yl)methylquinolinamine O NH N N The title compound was prepared in y to Example 1-1 in Scheme 4 by using 2,4-dichloro- 6-methylquinoline, 8-fluoro-2,3,4,5-tetrahydro-1,4-benzothiazepine and 3-(aminomethyl)-N,N- dibenzyloxetanamine. 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). e 1-3 N-[(3-Aminooxetanyl)methyl](7-fluoro-1,1-dioxido-2,3-dihydro-1,4-benzothiazepin- 4(5H)-yl)methylquinolinamine O NH N N The title compound was prepared in analogy to Example 1-1 in Scheme 4 by using 2,4-dichloro- ylquinoline, 7-fluoro-2,3,4,5-tetrahydro-1,4-benzothiazepine and 3-(aminomethyl)-N,N- dibenzyloxetanamine. 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 N-[(3-Aminooxetanyl)methyl](9-fluoro-1,1-dioxido-2,3-dihydro-1,4-benzothiazepin- 4(5H)-yl)methylquinolinamine O NH N N S O 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-1,4-benzothiazepine and 3-(aminomethyl)-N,N- dibenzyloxetanamine. 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 N-[(3-Aminooxetanyl)methyl](7-methoxy-1,1-dioxido-2,3-dihydro-1,4-benzothiazepin- 4(5H)-yl)methylquinolinamine O NH N N The title nd 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-1,4-benzothiazepine and 3-(aminomethyl)- N,N-dibenzyloxetanamine. 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-Aminooxetanyl)methyl](8-chloro-1,1-dioxido-2,3-dihydro-1,4-benzothiazepin- yl)methylquinolinamine O NH N N 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-1,4-benzothiazepine and 3-(aminomethyl)-N,N- dibenzyloxetanamine. MS obsd. (ESI+) [(M+H)+] 473, 1H NMR (400 MHz, CD 3OD) 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-Aminooxetanyl)methyl](7-methoxy-1,1-dioxido-2,3-dihydro-1,4-benzothiazepin- 4(5H)-yl)-quinolinamine O NH N N The title nd was prepared in analogy to Example 1-1 in Scheme 4 by using 2,4- dichloroquinoline, 7-methoxy-2,3,4,5-tetrahydro-1,4-benzothiazepine and 3-(aminomethyl)-N,N- dibenzyloxetanamine. 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), .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 N-[(3-Aminotetrahydrofuranyl)methyl](1,1-dioxido-2,3-dihydro-1,4-benzothiazepin- 4(5H)-yl)methylquinolinamine N N N-{[3-(Dibenzylamino) tetrahydrofuranyl]methyl}(1,1-dioxido-2,3-dihydro-1,4- benzothiazepin-4(5H)-yl)methylquinolinamine N N To a mixture of 4-(4-chloromethylquinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1- dioxide (400 mg, 1.08 mmol, prepared in analogy to 4-(4-chloromethylquinolinyl)-2,3,4,5- tetrahydro-1,4-benzothiazepine 1,1-dioxide in Example 1-1 by using 2,3,4,5-tetrahydro-1,4- hiazepine and chloromethylquinoline), 3-(aminomethyl)- N,N-dibenzyl ydrofuranamine (385 mg, 1.3 mmol), sodium tert-butoxide (207 mg, 2.16 mmol), 1,1'- bis(diphenylphosphino)ferrocene-palladium(II)dichloride (50 mg) and 1,1'- 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 ºC 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%).
N-[(3-Aminotetrahydrofuranyl)methyl](1,1-dioxido-2,3-dihydro-1,4-benzothiazepin- 4(5H)-yl)methylquinolinamine N N A mixture of N-{[3-(dibenzylamino) tetrahydrofuranyl]methyl}(1,1-dioxido-2,3-dihydro- 1,4-benzothiazepin-4(5H)-yl)methylquinolinamine (270 mg, 0.43 mmol), 10% palladium hydroxide on active carbon (300 mg) in methanol (20 mL) was stirred for 16 hours at room ature under hydrogen atmosphere (1 bar). The resulting mixture was concentrated in vacuo. The residue was purified by ative 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-[(3-Aminooxetanyl)methyl](1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)- 6-methylquinolinamine O NH N N The title compound was prepared in analogy to Example 2-1 in Scheme 4 by using 4-(4-chloro- 6-methylquinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide (prepared in analogy to the one in e 2-1) and 3-(aminomethyl)-N,N-dibenzyloxetanamine. 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-pyranyl)methyl](1,1-dioxido-2,3-dihydro-1,4- hiazepin-4(5H)-yl)methylquinolinamine N N The title compound was prepared in analogy to Example 2-1 in Scheme 4 by using 4-(4-chloro- 6-methylquinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide (prepared in analogy to the one in Example 2-1) and 4-(aminomethyl)-N,N-dibenzyltetrahydro-2H-pyranamine. 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). e 2-4 N-[(3-Aminooxetanyl)methyl](8-methyl-1,1-dioxido-2,3-dihydro-1,4-benzothiazepin- 4(5H)-yl)-quinolinamine O NH N N The title compound was prepared in analogy to Example 2-1 in Scheme 4 by using 4-(4- chloroquinolinyl)methyl-2,3,4,5-tetrahydro-1,4-benzothiazepine oxide red in analogy to 4-(4-chloromethylquinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1- dioxide in Example 2-1 by using 8-methyl-2,3,4,5-tetrahydro-1,4-benzothiazepine and 2,4- dichloroquinoline) and 3-(aminomethyl)-N,N-dibenzyloxetanamine. MS (ESI+) [(M+H)+] 439, 1H NMR (400 MHz, CD 3OD) 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 N-[(3-Aminooxetanyl)methyl]methyl(8-methyl-1,1-dioxido-2,3-dihydro-1,4- benzothiazepin-4(5H)-yl)quinolinamine O NH2 N N The title compound was prepared in analogy to Example 2-1 in Scheme 4 by using 4-(4-chloro- 6-methylquinolinyl)methyl-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide (prepared in analogy to 4-(4-chloromethylquinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1- dioxide in e 2-1 by using 8-methyl-2,3,4,5-tetrahydro-1,4-benzothiazepine and 2,4- dichloromethylquinoline) and 3-(aminomethyl)-N,N-dibenzyloxetanamine. 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-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)methyl-N-(2-oxa azaspiro[3.4]octyl)quinolinamine N N The title compound was prepared in analogy to Example 2-1 in Scheme 4 by using hloro- 6-methylquinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide (prepared in analogy to the one in Example 2-1) and yloxaazaspiro[3.4]octylamine. 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 N-[2-(3-Aminooxetanyl)ethyl](1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)- 6-methylquinolinamine NH NH N N O The title compound was prepared in analogy to Example 2-1 in Scheme 4 by using 4-(4-chloro- 6-methylquinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide (prepared in analogy to the one in Example 2-1) and 3-(aminoethyl)-N-benzyloxetanamine. MS obsd. (ESI+) +] 453, 1H NMR (400 MHz, DMSO-d6) 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). e 2-8 N-[(3-Aminooxetanyl)methyl]methyl(5-methyl-1,1-dioxido-2,3-dihydro-1,4- benzothiazepin-4(5H)-yl)quinolinamine N N The title compound was prepared in analogy to Example 2-1 in Scheme 4 by using 4-(4-chloro- 6-methylquinolinyl)methyl-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide (prepared in analogy to 4-(4-chloromethylquinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1- dioxide in Example 2-1 by using 5-methyl-2,3,4,5-tetrahydro-1,4-benzothiazepine and 2,4- dichloromethylquinoline) and 3-(aminomethyl)-N,N-dibenzyloxetanamine. 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). e 2-9 N-[(3-Aminooxetanyl)methyl](8-methoxy-1,1-dioxido-2,3-dihydro-1,4-benzothiazepin- 4(5H)-yl)quinolinamine 2NH O N N The title compound was prepared in analogy to Example 2-1 in Scheme 4 by using 4-(4- chloroquinolinyl)methoxy-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide (prepared in analogy to 4-(4-chloromethylquinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1- dioxide in Example 2-1 by using oxy-2,3,4,5-tetrahydro-1,4-benzothiazepine and 2,4- dichloroquinoline) and 3-(aminomethyl)-N,N-dibenzyloxetanamine. 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 N-[(3-Aminooxetanyl)methyl](1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)- 1,6-naphthyridinamine N N The title compound was ed in analogy to Example 2-1 in Scheme 4 by using 4-(4-chloro- 1,6-naphthyridinyl) ,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide (prepared in analogy to 4-(4-chloromethylquinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide in e 2-1 by using 2,3,4,5-tetrahydro-1,4-benzothiazepine and 2,4-dichloro-1,6- naphthyridine) and 3-(aminomethyl)-N,N-dibenzyloxetanamine. 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 N-[(1-Aminocyclohexyl)methyl](1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl) methylquinolinamine N N O The title compound was prepared in analogy to Example 2-1 in Scheme 4 by using 4-(4-chloro- 6-methylquinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide (prepared in analogy to the one in Example 2-1) and 1-(aminomethyl)-N,N-dibenzylcyclohexanamine. MS obsd.
(ESI+) [(M+H)+] 465, 1H NMR (400 MHz, CDCl3) 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 N-{[3-(Aminomethyl)oxetanyl]methyl}(8-fluoro-1,1-dioxido-2,3-dihydro-1,4- benzothiazepin-4(5H)-yl)methylquinolinamine N N A mixture of 8-(4-chloromethylquinolinyl)fluoro-2,3,4,5-tetrahydro-1,4- benzothiazepine 1,1-dioxide (200 mg, 0.51 mmol, prepared in analogy to 4-(4-chloro methylquinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide in Example 2-1 by using 8-fluoro-2,3,4,5-tetrahydro-1,4-benzothiazepine and 2,4-dichloromethylquinoline), sodium tert-butoxide (96 mg, 1.02 mmol), is(diphenylphosphino)ferrocenepalladium (II)dichloride (42 mg, 0.051 mmol), 1,1'-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 ºC under microwave irradiation. The resulting mixture was concentrated in vacuo. The residue was ed by ative 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, 1 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, 3 Example 3-2 N-{[3-(Benzylamino)oxetanyl]methyl}chloro(7-fluoro-1,1-dioxido-2,3-dihydro-1,4- benzothiazepin-4(5H)-yl)quinolinamine O N N N The title compound was prepared in analogy to Example 3-1 in Scheme 5 by using 4-(4,6- dichloroquinolinyl)fluoro-2,3,4,5-tetrahydro-1,4-benzothiazepine oxide (prepared in analogy to 4-(4-chloromethylquinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1- dioxide in Example 2-1 by using 7-fluoro-2,3,4,5-tetrahydro-1,4-benzothiazepine and 2,4,6- trichloroquinoline) and 3-(aminomethyl)-N-benzyloxetanamine. 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 Aminooxetanyl)methyl]chloro(7-fluoro-1,1-dioxido-2,3-dihydro-1,4- benzothiazepin-4(5H)-yl)quinolinamine O NH2 N N O The title compound was prepared in analogy to Example 3-1 in Scheme 5 by using 4-(4,6- dichloroquinolinyl)fluoro-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide (prepared in analogy to the one in Example 3-2) and 3-(aminomethyl)oxetanamine. 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)oxetanyl]methyl}(7-methoxy-1,1-dioxido-2,3-dihydro-1,4- benzothiazepin-4(5H)-yl)-quinolinamine N N The title compound was prepared in analogy to Example 3-1 in Scheme 5 by using 4-(4- chloroquinolinyl)methoxy-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide (prepared in analogy to 4-(4-chloromethylquinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1- dioxide in Example 2-1 by using 7-methoxy-2,3,4,5-tetrahydro-1,4-benzothiazepine and 2,4- dichloroquinoline) and e-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), 7.31(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 N-{[3-(Aminomethyl)oxetanyl]methyl}(7-methoxy-1,1-dioxido-2,3-dihydro-1,4- benzothiazepin-4(5H)-yl)methylquinolinamine N N The title compound was prepared in analogy to Example 3-1 in Scheme 5 by using 4-(4-chloro- 6-methylquinolinyl)methoxy-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide (prepared in analogy to hloromethylquinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1- dioxide in Example 2-1 by using 7-methoxy-2,3,4,5-tetrahydro-1,4-benzothiazepine and 2,4- dichloromethylquinoline) 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 N-{[3-({[2-(7-Methoxy-1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl) methylquinolinyl]amino}methyl)oxetanyl]methyl}acetamide N N The title compound was prepared in analogy to e 3-1 in Scheme 5 by using 4-(4-chloro- 6-methylquinolinyl)methoxy-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide (prepared in analogy to 4-(4-chloromethylquinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1- dioxide in Example 2-1 by using 7-methoxy-2,3,4,5-tetrahydro-1,4-benzothiazepine and 2,4- dichloromethylquinoline) and N-{[3-(aminomethyl)oxetanyl]methyl}acetamide. MS obsd.
(ESI+) +] 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 N-{[3-(Aminomethyl)oxetanyl]methyl}(8-methyl-1,1-dioxido-2,3-dihydro-1,4- benzothiazepin-4(5H)-yl)methylquinolinamine N N The title compound was prepared in analogy to e 3-1 in Scheme 5 by using 4-(4- chloroquinolinyl)methyl-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide (prepared in analogy to 4-(4-chloromethylquinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1- dioxide in Example 2-1 by using 8-methyl-2,3,4,5-tetrahydro-1,4-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 N-{[3-(Aminomethyl)oxetanyl]methyl}methyl(8-methyl-1,1-dioxido-2,3-dihydro- 1,4-benzothiazepin-4(5H)-yl)quinolinamine N N The title compound was prepared in analogy to Example 3-1 in Scheme 5 by using 4-(4-chloro- 6-methylquinolinyl)methyl-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide (prepared in analogy to 4-(4-chloromethylquinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1- dioxide in Example 2-1 by using 8-methyl-2,3,4,5-tetrahydro-1,4-benzothiazepine and 2,4- dichloromethylquinoline) 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). e 3-9 [3-({[2-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)methylquinolin yl]amino}methyl)oxetanyl]methanol N N The title compound was prepared in analogy to Example 3-1 in Scheme 5 by using 4-(4-chloro- 6-methylquinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide (prepared in analogy to the one in Example 2-1) and 3-(aminomethyl)oxetanyl]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 -{[2-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)methylquinolin yl]amino}propane-1,2-diol N N The title compound was prepared in analogy to Example 3-1 in Scheme 5 by using hloro- 6-methylquinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide (prepared in analogy to the one in Example 2-1) and (2S)aminopropane-1,2-diol. MS obsd. (ESI+) [(M+H)+] 428, 1H NMR (400 MHz, CD 3OD) 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). e 3-11 (2R){[2-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)methylquinolin yl]amino}propane-1,2-diol N N The title compound was prepared in analogy to Example 3-1 in Scheme 5 by using 4-(4-chloro- 6-methylquinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide (prepared in analogy to the one in e 2-1) and (2R)aminopropane-1,2-diol. MS obsd. (ESI+) [(M+H)+] 428, 1H NMR (400 MHz, CD 3OD) 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 N-{[1-(Aminomethyl)-3,3-difluorocyclobutyl]methyl}(1,1-dioxido-2,3-dihydro-1,4- benzothiazepin-4(5H)-yl)methylquinolinamine N N The title compound was prepared in analogy to Example 3-1 in Scheme 5 by using 4-(4-chloro- 6-methylquinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide red in analogy to the one in Example 2-1) and (3,3-difluorocyclobutane-1,1-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), .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-Aminooxetanyl)methyl]chloro(8-methoxy-1,1-dioxido-2,3-dihydro-1,4- hiazepin-4(5H)-yl)quinolinamine O NH2 N N The title compound was prepared in analogy to Example 3-1 in Scheme 5 by using 4-(4,6- dichloroquinolinyl)methoxy-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide (prepared in analogy to 4-(4-chloromethylquinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1- dioxide in Example 2-1 by using 8-methoxy-2,3,4,5-tetrahydro-1,4-benzothiazepine and 2,4,6- trichloroquinoline) and 3-(aminomethyl)oxetanamine. 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 N-{[3-(Aminomethyl)oxetanyl]methyl}chloro(8-methoxy-1,1-dioxido-2,3-dihydro- 1,4-benzothiazepin-4(5H)-yl)quinolinamine N N O The title compound was ed in y to Example 3-1 in Scheme 5 by using 4-(4,6- dichloroquinolinyl)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), .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 trans-N-[2-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)methylquinolin yl]cyclohexane -1,2-diamine N N The title compound was prepared in analogy to Example 3-1 in Scheme 5 by using 4-(4-chloro- 6-methylquinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide (prepared in analogy to the one in Example 2-1) and trans-cyclohexane-1,2-diamine. MS obsd. (ESI+) +] 451, 1H NMR (400 MHz, CD 3OD) 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 N-[2-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)methylquinolinyl]- cyclohexane-1,3-diamine N N The title compound was ed in analogy to Example 3-1 in Scheme 5 by using 4-(4-chloro- 6-methylquinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide (prepared in analogy to the one in Example 2-1) and exane-1,3-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 = 11.1 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 [2-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)methylquinolinyl]-4,4- dimethyl-pyrrolidinol N N The title compound was prepared in analogy to e 3-1 in Scheme 5 by using 4-(4-chloro- 6-methylquinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide (prepared in analogy to the one in Example 2-1) and (3R)-4,4-dimethylpyrrolidinol. 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), 5.11 (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-N-[2-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)methylquinolinyl]- cyclohexane-1,4-diamine N N The title compound was prepared in analogy to e 3-1 in Scheme 5 by using 4-(4-chloro- 6-methylquinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide (prepared in analogy to the one in Example 2-1) and cis-cyclohexane-1,4-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 N-[2-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)methylquinolinyl]-2,2- difluoropropane-1,3-diamine F NH2 N N The title compound was prepared in analogy to Example 3-1 in Scheme 5 by using 4-(4-chloro- 6-methylquinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide (prepared in analogy to the one in Example 2-1) and fluoropropane-1,3-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 N-[6-Chloro(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinolinyl]-2,2- difluoropropane-1,3-diamine F NH N N The title compound was prepared in y to e 3-1 in Scheme 5 by using 4-(4,6- dichloroquinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide (prepared in analogy to 4-(4-chloromethylquinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide in Example 2-1 by using 2,3,4,5-tetrahydro-1,4-benzothiazepine and 2,4,6-trichloroquinoline) and 2,2-difluoropropane-1,3-diamine. MS obsd. (ESI+) [(M+H)+] 467, 1H NMR (400 MHz, DMSO- d6) δ ppm 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), .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 N-[2-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)methylquinolinyl] fluoropropane-1,3-diamine N N The title compound was prepared in analogy to e 3-1 in Scheme 5 by using 4-(4-chloro- 6-methylquinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide (prepared in analogy to the one in Example 2-1) and 2-fluoropropane-1,3-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 N-[(3-Aminooxetanyl)methyl]chloro(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin- 4(5H)-yl)quinolinamine O NH2 N N The title compound was prepared in analogy to Example 3-1 in Scheme 5 by using - dichloroquinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide red in analogy to 4-(4-chloromethylquinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide in Example 2-1 by using 2,3,4,5-tetrahydro-1,4-benzothiazepine and 2,4,6-trichloroquinoline) and 3-(aminomethyl)oxetanamine. 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-Aminooxetanyl)methyl]amino}(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin- 4(5H)-yl)quinolinyl]methanol O NH OH NH N N Methyl 4-chloro(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinoline carboxylate O Cl N N To a cooled solution of methyl ro(2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinoline- 6-carboxylate (2.0 g, 5.2 mmol, prepared in analogy to 4-(4-chloromethylquinolinyl) methoxy-2,3,4,5-tetrahydro-1,4-benzothiazepine in e 1-1 by using methyl 2,4- dichoroquinolinecarboxylate and 2,3,4,5-tetrahydro-1,4-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 e and concentrated in vacuo to afford 2.0 g of the crude product. 4-Chloro(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-quinolinemethanol OH Cl N N To a solution of methyl 4-chloro(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)- yl)quinolinecarboxylate (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 ted with dichloromethane (50 mL × 2). The combined c layers were dried over sodium sulfate and concentrated in vacuo to afford 1.4 g of the crude product. [4-{[(3-Aminooxetanyl)methyl]amino}(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin- 4(5H)-yl)quinolinyl]methanol O NH2 OH NH N N The title compound was prepared in analogy to Example 3-1 in Scheme 5 by using 4-chloro (1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-quinolinemethanol and 3- (aminomethyl)oxetanamine. 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 N-[(3-Aminooxetanyl)methyl](1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)- 7-fluoromethylquinolinamine O NH F N N The title compound was prepared in analogy to Example 3-1 in Scheme 5 by using 4-(4-chloro- 7-fluoromethylquinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide red in analogy to 4-(4-chloromethylquinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1- dioxide in e 2-1 by using 2,4-dichlorofluoromethylquinoline and 2,3,4,5- tetrahydro-1,4-benzothiazepine) and 3-(aminomethyl)oxetanamine. 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 N-[(3-Aminooxetanyl)methyl](1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)- -fluoromethylquinolinamine O NH2 F NH N N O The title compound was prepared in analogy to Example 3-1 in Scheme 5 by using 4-(4-chloro- -fluoromethylquinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide (prepared in analogy to 4-(4-chloromethylquinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1- dioxide in Example 2-1 by using 2,4-dichlorofluoromethylquinoline and 2,3,4,5- tetrahydro-1,4-benzothiazepine) and nomethyl)oxetanamine. MS obsd. (ESI+) +] 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 N~1~-[6-Chloro(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinolinyl] methylpropane-1,2-diamine N N The title nd was prepared in analogy to Example 3-1 in Scheme 5 by using 4-(4,6- dichloroquinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide (prepared in analogy to 4-(4-chloromethylquinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide in Example 2-1 by using 2,4,6-trichloroquinoline and 5-tetrahydro-1,4-benzothiazepine) and 2-methylpropane-1,2-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-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)methyl-N-(tetrahydro-2H- pyranyl)quinolinamine N N The title compound was prepared in analogy to Example 3-1 in Scheme 5 by using 4-(4-chloro- 6-methylquinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine oxide (prepared in analogy to the one in Example 2-1) and tetrahydro-2H-pyranylamine. 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-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)methyl-N-[2-(piperazin yl)ethyl]quinolinamine N N The title compound was prepared in analogy to Example 3-1 in Scheme 5 by using 4-(4-chloro- 6-methylquinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide red in analogy to the one in Example 2-1) and 2-(piperazinyl)ethanamine. MS obsd. (ESI+) [(M+H)+] 466, 1H NMR (400 MHz, DMSO-d6) δppm 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). e 3-29 2-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)methyl-N-(piperidin ylmethyl)quinolinamine N N The title compound was prepared in analogy to Example 3-1 in Scheme 5 by using 4-(4-chloro- 6-methylquinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide red in analogy to the one in Example 2-1) and 1-(piperidinyl)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 N-[2-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)methylquinolin yl]heptane-1,7-diamine NH NH N N The title compound was prepared in analogy to Example 3-1 in Scheme 5 by using 4-(4-chloro- 6-methylquinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide (prepared in analogy to the one in e 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 N-[2-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)methylquinolinyl]-N'- methylethane-1,2-diamine N N O The title compound was prepared in analogy to Example 3-1 in Scheme 5 by using hloro- 6-methylquinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide (prepared in y to the one in Example 2-1) and N-methylethane-1,2-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 N'-[2-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)methylquinolinyl]-N,N- dimethylethane-1,2-diamine N N The title compound was prepared in analogy to Example 3-1 in Scheme 5 by using 4-(4-chloro- 6-methylquinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide (prepared in analogy to the one in Example 2-1) and N,N-dimethylethane-1,2-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-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-N,6-dimethylquinolinamine trifluoroacetate NH F F N N The title compound was prepared in y to Example 3-1 in Scheme 5 by using 4-(4-chloro- 6-methylquinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine oxide (prepared in analogy to the one in Example 2-1) and amine. MS obsd. (ESI+) [(M+H)+] 368, 1H NMR (400 MHz, DMSO-d6) 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)[2-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)methylquinolin yl]pyrrolidine-3,4-diol OH OH N N The title nd was prepared in analogy to Example 3-1 in Scheme 5 by using 4-(4-chloro- 6-methylquinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide (prepared in analogy to the one in e 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-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)methyl-N-(pyrrolidin ylmethyl)quinolinamine N N The title compound was prepared in analogy to Example 3-1 in Scheme 5 by using 4-(4-chloro- 6-methylquinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide (prepared in analogy to the one in Example 2-1) and 1-(pyrrolidinyl)methanamine. MS obsd. (ESI+) [(M+H)+] 437, 1H NMR (400 MHz, CD 3OD) 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-(1,4-Diazepanyl)methylquinolinyl]-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1- dioxide N N The title compound was ed in analogy to e 3-1 1 in Scheme 5 by using 4-(4- chloromethylquinolinyl)-2,3,4,5-tetrahydro-1,4-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 N-[2-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)methylquinolinyl]-N'- ethylethane-1,2-diamine N N The title compound was prepared in analogy to Example 3-1 in Scheme 5 by using 4-(4-chloro- 6-methylquinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide (prepared in analogy to the one in Example 2-1) and N-ethylethane-1,2-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-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)methylquinolin yl]amino}ethanol N N The title compound was prepared in y to Example 3-1 in Scheme 5 by using 4-(4-chloro- 6-methylquinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide (prepared in y 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-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)methyl-N-(piperidin yl)quinolinamine N N S O The title nd was prepared in analogy to Example 3-1 in Scheme 5 by using 4-(4-chloro- 6-methylquinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide (prepared in analogy to the one in Example 2-1) and piperidinamine. 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 Example 3-40 2-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)methyl-N-(piperidin yl)quinolinamine N N The title compound was prepared in analogy to Example 3-1 in Scheme 5 by using 4-(4-chloro- 6-methylquinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide (prepared in analogy to the one in e 2-1) and dinamine. 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-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)methyl-N-(piperidin ylmethyl)quinolinamine N N The title compound was prepared in analogy to Example 3-1 in Scheme 5 by using 4-(4-chloro- 6-methylquinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide red in analogy to the one in Example 2-1) and 1-(piperidinyl)methanamine. MS obsd. (ESI+) [(M+H)+] 451, 1H NMR (400 MHz, CD 3OD) 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-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)methylquinolin yl]amino}ethyl)amino]ethanol NH OH N N The title compound was prepared in analogy to Example 3-1 in Scheme 5 by using 4-(4-chloro- ylquinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide red 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, CD 3OD) 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 N-[2-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)methylquinolinyl]-2,2,3,3- tetrafluorobutane-1,4-diamine N N S O The title compound was prepared in analogy to Example 3-1 in Scheme 5 by using 4-(4-chloro- 6-methylquinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide (prepared in analogy to the one in Example 2-1) and 2,2,3,3-tetrafluorobutane-1,4-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). e 3-44 N-[2-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)methylquinolinyl]-N'-(2- methoxyethyl)ethane-1,2-diamine NH O N N The title compound was prepared in analogy to Example 3-1 1 in Scheme 5 by using 4-(4- chloromethylquinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide (prepared in analogy to the one in Example 2-1) and N-(2-methoxyethyl)ethane-1,2-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 1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5 methylquinolinyl] methylpyrrolidinol N N The title compound was prepared in analogy to e 3-1 in Scheme 5 by using 4-(4-chloro- 6-methylquinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide (prepared in analogy to the one in Example 2-1) and 3-methylpyrrolidinol. 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 N-[6-Chloro(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinolinyl]ethane- 1,2-diamine N N The title compound was prepared in analogy to Example 3-1 in Scheme 5 by using 4-(4,6- dichloroquinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide (prepared in analogy to 4-(4-chloromethylquinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide in Example 2-1 by using 2,4,6-trichloroquinoline and 2,3,4,5-tetrahydro-1,4-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-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)methyl-N-(oxetanyl)quinolin- 4-amine N N The title compound was prepared in analogy to Example 3-1 in Scheme 5 by using 4-(4-chloro- 6-methylquinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine oxide (prepared in y to the one in Example 2-1) and 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 N-[(3-Aminooxetanyl)methyl](1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)- yl)quinolinamine O NH N N The title compound was prepared in analogy to Example 3-1 in Scheme 5 by using 4-(4- chloroquinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide (prepared in analogy to 4-(4-chloromethylquinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine oxide in Example 2-1 by using 2,4-dichloroquinoline and 2,3,4,5-tetrahydro-1,4-benzothiazepine) and 3- (aminomethyl)oxetanamine. 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-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)methyl-N-[(3R)- tetrahydrofuranyl]quinolinamine N N The title compound was prepared in y to Example 3-1 in Scheme 5 by using 4-(4-chloro- 6-methylquinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide (prepared in analogy to the one in Example 2-1) and (3R)-tetrahydrofuranamine. MS obsd. (ESI+) [(M+H)+] 424, 1H NMR (400 MHz, CD 3OD) 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)oxetanyl]methyl}(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin- 4(5H)-yl)methylquinolinamine N N The title compound was prepared in analogy to Example 3-1 in Scheme 5 by using 4-(4-chloro- 6-methylquinolinyl)-2,3,4,5-tetrahydro-1,4-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, CD 3OD) 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 N-{[3-(Aminomethyl)oxetanyl]methyl}chloro(1,1-dioxido-2,3-dihydro-1,4- benzothiazepin-4(5H)-yl)quinolinamine N N The title compound was prepared in analogy to e 3-1 in Scheme 5 by using 4-(4,6- dichloroquinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide (prepared in y to hloromethylquinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide in Example 2-1 by using 2,4,6-trichloroquinoline and 2,3,4,5-tetrahydro-1,4-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 (Aminomethyl)oxetanyl]methyl}(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin- 4(5H)-yl)quinolinamine N N The title compound was prepared in analogy to Example 3-1 in Scheme 5 by using 4-(4- chloroquinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide (prepared in analogy to 4-(4-chloromethylquinolinyl)-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-1,4-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 Example 3-53 2-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)methyl-N-(oxetan ylmethyl)quinolinamine N N S O The title compound was ed in analogy to Example 3-1 in Scheme 5 by using 4-(4-chloro- 6-methylquinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide (prepared in analogy to the one in Example 2-1) and tanyl)methanamine. MS obsd. (ESI+) [(M+H)+] 424, 1H NMR (400 MHz, DMSO-d6) 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-[(1-Aminocyclobutyl)methyl](1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl) methylquinolinamine N N The title compound was prepared in analogy to e 3-1 in Scheme 5 by using 4-(4-chloro- 6-methylquinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide (prepared in analogy to the one in Example 2-1) and nomethyl)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 Example 3-55 N-[2-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)methylquinolin yl]pentane-1,5-diamine NH NH N N O The title compound was prepared in analogy to Example 3-1 in Scheme 5 by using 4-(4-chloro- 6-methylquinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine oxide (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, CDCl3) 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 Example 3-56 N-[2-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)methylquinolinyl]hexane- 1,6-diamine N N The title compound was prepared in analogy to Example 3-1 in Scheme 5 by using 4-(4-chloro- 6-methylquinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide (prepared in analogy to the one in Example 2-1) and hexane-1,6-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 N-[2-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)methylquinolinyl]-1,1,1- trifluoromethanesulfonamide hydrochloride O F NH F HCl N N The title compound was prepared in analogy to e 3-1 in Scheme 5 by using hloro- 6-methylquinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide (prepared in y 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 N-[2-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)methylquinolin yl]pyridazinecarboxamide NH N N N The title compound was prepared in analogy to Example 3-1 in Scheme 5 by using 4-(4-chloro- 6-methylquinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide (prepared in analogy to the one in Example 2-1) and pyridazinecarboxamide. 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). e 3-59 1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)methylquinolin yl]benzamide N N S O The title compound was prepared in analogy to Example 3-1 in Scheme 5 by using 4-(4-chloro- 6-methylquinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide (prepared in analogy to the one in Example 2-1) and ide. 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 N-[2-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)methylquinolin yl]acetamide N N The title compound was prepared in analogy to Example 3-1 in Scheme 5 by using 4-(4-chloro- 6-methylquinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine oxide red 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 N-[2-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)methylquinolin yl]piperidinecarboxamide NH NH N N The title compound was prepared in analogy to Example 3-1 in Scheme 5 by using 4-(4-bromo- 6-methylquinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide (prepared in analogy to 4-(4-chloromethylquinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide in Example 2-1 by using 4,6-dibromoquinoline and 2,3,4,5-tetrahydro-1,4-benzothiazepine) and dinecarboxamide. 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 N-[2-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)methylquinolin yl]piperidinecarboxamide N N The title compound was prepared in analogy to Example 3-1 in Scheme 5 by using 4-(4-chloro- 6-methylquinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide (prepared in y to the one in Example 2-1) and piperidinecarboxamide. 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-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5 H)-yl)methylquinolinyl]-1,1- ylurea NH N N N The title compound was prepared in analogy to Example 3-1 in Scheme 5 by using 4-(4-chloro- 6-methylquinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide (prepared in analogy to the one in Example 2-1) and 1,1-dimethylurea. MS obsd. (ESI+) +] 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-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)methyl-N-(1,2-oxazol yl)quinolinamine NH N N N The title compound was prepared in analogy to Example 3-1 in Scheme 5 by using 4-(4-bromo- 6-methylquinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide (prepared in analogy to 4-(4-chloromethylquinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide in Example 2-1 by using 4,6-dibromoquinoline and 2,3,4,5-tetrahydro-1,4-benzothiazepine) and 1,2-oxazolamine. 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 N-{[3-(Aminomethyl)oxetanyl]methyl}(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin- 4(5H)-yl) trideuteriomethylquinolinamine D NH NH D 2 N N The title compound was prepared in analogy to Example 3-1 in Scheme 5 by using 4-(4-chloro- 6- trideuteriomethylquinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide (prepared in y to 4-(4-chloromethylquinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1- dioxide in Example 2-1 by using chloro trideuteriomethylquinoline and 5- tetrahydro-1,4-benzothiazepine) and oxetane-3,3-diyldimethanamine. MS obsd. (ESI+) [(M+H)+] 456, 1H NMR (400 MHz, CDCl 3) 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 N-[(3-Aminooxetanyl)methyl]chloro(2,3-dihydro-1,4-benzothiazepin-4(5H)- yl)quinolinamine O NH N N The title compound was prepared in analogy to Example 3-1 in Scheme 5 by using 4-(4,6- roquinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine (prepared in y to 4-(4- chloromethylquinolinyl)methoxy-2,3,4,5-tetrahydro-1,4-benzothiazepine in Example 1- 1) and 3-aminomethyl-oxetanylamine. 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 hloro(2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinolinyl]ethane-1,2-diamine N N The title compound was prepared in analogy to Example 4-1 in Scheme 5 by using 4-(4,6- dichloroquinolinyl)-2,3,4,5-tetrahydro-1,4-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 N-[(3-Aminooxetanyl)methyl](2,3-dihydro-1,4-benzothiazepin-4(5H)-yl) methylquinolinamine O NH N N The title compound was prepared in analogy to Example 4-1 in Scheme 5 by using 4-(4-chloro- ylquinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine (prepared in analogy to 4-(4- chloromethylquinolinyl)methoxy-2,3,4,5-tetrahydro-1,4-benzothiazepine in Example 1- 1) and 3-aminomethyl-oxetanylamine. 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 1-[2-(2,3-Dihydro-1,4-benzothiazepin-4(5H)-yl)methylquinolinyl]pyrrolidinamine N N The title compound was prepared in analogy to Example 4-1 in Scheme 5 by using 4-(4-chloro- 6-methylquinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine (prepared in y to 4-(4- chloromethylquinolinyl)methoxy-2,3,4,5-tetrahydro-1,4-benzothiazepine in Example 1- 1) and pyrrolidinamine. 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), .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-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-N-[2-(1,1-dioxidothiomorpholin yl)ethyl]methylquinolinamine N N To a solution of 4-(4-chloromethylquinolinyl)-2,3,4,5-tetrahydro-1,4-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), 1,1'- bis(diphenyphosphino)ferrocene (25 mg, 0.04 mmol), sodium tert-butoxide (77 mg, 0.80 mmol) and 2-(1,1-dioxidothio-morpholinyl)ethanamine (107 mg, 0.60 mmol). The resulting mixture was evacuated and refilled with nitrogen, sealed and heated at 120 oC ght. After being cooled to room temperature, the mixture was filtered and washed with ethyl e, 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, CDCl3) 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 N-[2-(2-Aminoethoxy)ethyl](1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl) methylquinolinamine NH NH2 N N The title compound was prepared in y to Example 5-1 in Scheme 5 by using 4-(4-chloro- 6-methylquinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide (prepared in analogy to the one in e 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 N~1~-[2-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)methylquinolinyl] methylpropane-1,2-diamine NH 2 N N The title compound was prepared in analogy to Example 5-1 in Scheme 5 by using 4-(4-chloro- 6-methylquinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide (prepared in analogy to the one in Example 2-1) and 2-methylpropane-1,2-diamine. MS obsd. (ESI+) +] 425, 1H NMR (400 MHz, CD 3OD) 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 N~1~-[2-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinolinyl] methylpropane-1,2-diamine N N S O The title compound was prepared in analogy to e 5-1 in Scheme 5 by using 4-(4- chloroquinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide (prepared in analogy to 4-(4-chloromethylquinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide in Example 2-1by using and 2,4-dichloroquinoline 2,3,4,5-tetrahydro-1,4-benzothiazepine) and 2- methylpropane-1,2-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 N~1~-[2-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)methylquinolin yl]propane-1,2-diamine N N The title nd was prepared in analogy to Example 5-1 in Scheme 5 by using 4-(4-chloro- 6-methylquinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine oxide (prepared in y 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-methylpiperazinyl)quinolinyl]-2,3,4,5-tetrahydro-1,4- benzothiazepine 1,1-dioxide N N The title compound was prepared in analogy to Example 5-1 in Scheme 5 by using 4-(4-chloro- 6-methylquinolinyl)-2,3,4,5-tetrahydro-1,4-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-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)methylquinolin yl]amino}propanol N N The title compound was prepared in analogy to Example 5-1 in Scheme 5 by using 4-(4-chloro- 6-methylquinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide (prepared in analogy to the one in Example 1-1) and 1-aminopropanol. MS obsd. (ESI+) +] 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 ~1~-[2-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)methylquinolin yl]propane-1,2-diamine NH 2 N N The title compound was ed in analogy to Example 5-1 in Scheme 5 by using 4-(4-chloro- 6-methylquinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide (prepared in analogy to the one in Example 2-1) and (2S)-propane-1,2-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)-N~1~-[2-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)methylquinolin yl]propane-1,2-diamine NH 2 N N The title compound was prepared in analogy to Example 5-1 in Scheme 5 by using 4-(4-chloro- 6-methylquinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide (prepared in y to the one in Example 2-1) and (2R)-propane-1,2-diamine. MS obsd. (ESI+) +] 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 N-[(3-Aminooxetanyl)methyl](1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)- 7,8-difluoromethylquinolinamine O NH2 F N N The title compound was prepared in analogy to Example 5-1 in Scheme 5 by using 4-(4-chloro- 6-methyl-7,8-difluoroquinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide (prepared in analogy to 4-(4-chloromethylquinolinyl)-2,3,4,5-tetrahydro-1,4- benzothiazepine 1,1-dioxide in Example 2-1 by using romethyl-7,8-dichloroquinoline and 2,3,4,5-tetrahydro-1,4-benzothiazepine) and 3-(aminomethyl)oxetanamine. MS obsd.
(ESI+) [(M+H)+] 475, 1H NMR (400 MHz, DMSO-d6) 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), .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 N-(2,2-Difluoroethyl)-N'-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5 H)-yl) methylquinolinyl]ethane-1,2-diamine N N The title compound was prepared in analogy to Example 5-1 in Scheme 5 by using 4-(4-chloro- ylquinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide (prepared in analogy to the one in Example 2-1) and N-(2,2-difluoroethyl)ethane-1,2-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-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)methylquinolin yl]amino}oxetanethanol NH OH N N O The title compound was prepared in y to Example 5-1 in Scheme 5 by using hloro- 6-methylquinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide (prepared in analogy to the one in Example 2-1) and 3-aminooxetanethanol. MS obsd. (ESI+) [(M+H)+] 454, 1H NMR (400 MHz, DMSO-d6) 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 N-{[3-(Aminomethyl)thietanyl]methyl}(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin- 4(5H)-yl)methylquinolinamine N N A flask containing 4-(4-chloromethylquinolinyl)-2,3,4,5-tetrahydro-1,4-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)- 1,1'-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 ºC overnight, the resulting e was d with water (15 mL) and extracted with ethyl acetate (15 mL × 4). The combined organic layers were dried over sodium sulfate and concentrated in vacuo. The residue was purified by flash column tography 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 N-{[3-(Aminomethyl)-1,1-dioxidothietanyl]methyl}(1,1-dioxido-2,3-dihydro-1,4- benzothiazepin-4(5H)-yl)methylquinolinamine O NH N N O The title compound was prepared in analogy to Example 6-1 in Scheme 5 by using 4-(4-chloro- 6-methylquinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide (prepared in y to the one in Example 2-1) and (1,1-dioxidothietane-3,3-diyl)dimethanamine. MS obsd. (ESI+) [(M+H)+] 501, 1H NMR (400 MHz, CD3Cl) 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 N-(4,5-Dihydro-1H-imidazolyl)(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)- ylquinolinamine N N N N A mixture of 4-(4-chloromethylquinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1- dioxide (150 mg, 0.40 mmol, prepared in y to the one in Example 2-1), hydrogen iodide salt of 4,5-dihydro-1H-imidazolamine (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 oC under microwave irradiation.
The resulting e 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,1 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 trans{[2-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)methylquinolin yl]amino}cyclohexanol N N A e of 4-(4-chloromethylquinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1- dioxide (140 mg, 0.38 mmol, prepared in analogy to the one in Example 2-1), trans aminocyclohexanol (45 mg, 0.39 mmol), tris(dibenzylideneacetone)dipalladium(0) (35 mg, 0.038 mmol), 2-dicyclohexylphosphino-2'-(N,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 oC under ave irradiation. The mixture was filtered and washed with ethyl e. 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-d6) 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 (2S){[2-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)methylquinolin yl]amino}propanol N N The title compound was prepared in analogy to Example 8-1 in Scheme 5 by using 4-(4-chloro- 6-methylquinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide (prepared in analogy to the one in Example 2-1) and (2S)aminopropanol. MS obsd. (ESI+) [(M+H)+] 412, 1H NMR (400 MHz, DMSO-d6) δ ppm 7.89 (t, J = 6.32 Hz, 2 H), 7.75 (s, 1 H), 7.64 (t, J = 7.20 Hz, 1 H), 7.55 - 7.43 (m, 1 H), 7.38 - 7.27 (m, 1 H), 7.27 - 7.14 (m, 1 H), 6.16 (d, J = 8.08 Hz, 1 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 trans[2-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)methylquinolinyl] methoxypyrrolidinamine NH O N N S O The title compound was prepared in y to Example 8-1 in Scheme 5 by using 4-(4-chloro- ylquinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide (prepared in analogy to the one in Example 2-1) and transmethoxymethylpyrrolidinamine. 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-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-N-[transmethoxypyrrolidin yl]methylquinolinamine N N S O The title compound was prepared in analogy to Example 8-1 in Scheme 5 by using 4-(4-chloro- 6-methylquinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide (prepared in analogy to the one in Example 2-1) and transmethoxymethylpyrrolidinamine. 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][1,4]oxazin-6(2H)-yl]methylquinolinyl}- 2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide O NH H H N N The title compound was prepared in analogy to Example 8-1 in Scheme 5 by using 4-(4-chloro- 6-methylquinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide red in y to the one in Example 2-1) and (4aS,7aR)-octahydropyrrolo[3,4-b][1,4]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)[2-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)methylquinolin yl](4-methylpiperazinyl)pyrrolidinol N OH N N The title compound was prepared in analogy to Example 8-1 in Scheme 5 by using hloro- 6-methylquinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide (prepared in analogy to the one in Example 2-1) and )(4-methylpiperazinyl)pyrrolidinol. MS obsd.
(ESI+) [(M+H)+] 522, 1H NMR (400 MHz, CD 3OD) 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 N-{2-[(2-Aminoethyl)sulfanyl]ethyl}(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)- yl)methylquinolinamine S NH2 N N The title compound was prepared in analogy to e 8-1 in Scheme 5 by using 4-(4-chloro- 6-methylquinolinyl)-2,3,4,5-tetrahydro-1,4-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, CD 3OD) 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 1-{1-[2-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)methylquinolin yl]piperidinyl}methanamine N N A e of 4-(4-chloromethylquinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1- dioxide (75 mg, 0.20 mmol, prepared in analogy to the one in e 2-1), piperidinylmethylamine (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 ature, 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-d6) 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-1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinolin yl]amino}ethanol N N The title compound was prepared in analogy to Example 9-1 in Scheme 5 by using 4-(4- chloroquinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide (prepared in analogy to 4-(4-chloromethylquinolinyl)-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-1,4-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 1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)methylquinolin yl]propane-1,3-diamine N N The title nd was prepared in analogy to Example 9-1 in Scheme 5 by using 4-(4-chloro- 6-methylquinolinyl)-2,3,4,5-tetrahydro-1,4-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(morpholinyl)quinolinyl]-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1- dioxide N N The title compound was prepared in analogy to Example 9-1 in Scheme 5 by using hloro- 6-methylquinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide (prepared in y to the one in Example 2-1) and morpholine. MS obsd. (ESI+) [(M+H)+] 424, 1H NMR (400 MHz, CDCl3) 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-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)methylquinolin yl]amino}propanol NH OH N N S O The title compound was prepared in analogy to e 9-1 in Scheme 5 by using 4-(4-chloro- 6-methylquinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide (prepared in analogy to the one in Example 2-1) and 3-propanol. MS obsd. (ESI+) [(M+H)+] 412, 1H NMR (400 MHz, CDCl3) 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-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)methyl-N-[2-(piperidin yl)ethyl]quinolinamine N N The title compound was prepared in analogy to Example 9-1 in Scheme 5 by using 4-(4-chloro- 6-methylquinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide (prepared in analogy to the one in Example 2-1) and eridinyl)ethanamine. MS obsd. (ESI+) [(M+H)+] 465, 1H NMR (400 MHz, CDCl3) 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 o{[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)methylquinolin yl]amino}propanol NH NH N N The title compound was prepared in analogy to Example 9-1 in Scheme 5 by using hloro- 6-methylquinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide (prepared in analogy to the one in e 2-1) and aminopropanol. 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 N-[2-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)methylquinolin yl]glycine O OH N N The title compound was prepared in analogy to Example 9-1 in Scheme 5 by using 4-(4-chloro- 6-methylquinolinyl)-2,3,4,5-tetrahydro-1,4-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) δ 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 N-[2-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)fluoroquinolinyl]ethane- 1,2-diamine N N The title compound was prepared in analogy to Example 9-1 in Scheme 5 by using 4-(4-chloro- 6-fluoroquinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide (prepared in analogy to 4-(4-chloromethylquinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide in Example 2-1 by using 2,4-dichlorofluoroquinoline and 2,3,4,5-tetrahydro-1,4- 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 N-[2-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)ethylquinolinyl]ethane- 1,2-diamine N N The title compound was prepared in analogy to Example 9-1 in Scheme 5 by using 4-(4-chloro- 6-ethylquinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide (prepared in analogy to 4-(4-chloromethylquinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide in Example 2-1 by using roehtylquinoline and 5-tetrahydro-1,4-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 hloro(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinolin yl]propane-1,3-diamine NH NH Cl N N The title compound was prepared in analogy to Example 9-1 in Scheme 5 by using 4-(4,7- dichloroquinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide (prepared in analogy to 4-(4-chloromethylquinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide in Example 2-1 by using trichloroquinoline and 2,3,4,5-tetrahydro-1,4-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 N-[8-Chloro(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinolin yl]propane-1,3-diamine NH NH N N The title compound was prepared in analogy to Example 9-1 in Scheme 5 by using 4-(4,8- dichloroquinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide red in analogy to 4-(4-chloromethylquinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide in Example 2-1 by using 2,4,8-trichloroquinoline and 2,3,4,5-tetrahydro-1,4-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 N-[5-Chloro(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinolin yl]propane-1,3-diamine Cl NH NH N N The title compound was prepared in y to Example 9-1 in Scheme 5 by using 4-(4,5- dichloroquinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide (prepared in y to 4-(4-chloromethylquinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide in Example 2-1 by using 2,4,5-trichloroquinoline and 2,3,4,5-tetrahydro-1,4-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 N-[2-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)methylquinolinyl]-2,2- dimethylpropane-1,3-diamine NH NH N N The title compound was prepared in analogy to Example 9-1 in Scheme 5 by using 4-(4-chloro- 6-methylquinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide (prepared in y 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 N-[2-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinolinyl]ethane-1,2- diamine N N The title nd was prepared in analogy to Example 9-1 in Scheme 5 by using 4-(4- chloroquinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide (prepared in analogy to 4-(4-chloromethylquinolinyl)-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-1,4-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), .94 (m,1 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-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)methylquinolinyl]ethane- amine N N The title compound was prepared in analogy to Example 9-1 in Scheme 5 by using 4-(4-chloro- 6-methylquinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide red 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 N~2~-[2-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)methylquinolinyl] methylpropane-1,2-diamine N N The title compound was prepared in analogy to Example 9-1 in Scheme 5 by using 4-(4-chloro- ylquinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide (prepared in analogy to the one in Example 2-1) and 2-methylpropane-1,2-diamine. MS obsd. (ESI+) [(M+H)+] 425, 1H NMR (400 MHz, CD 3OD) 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 N~2~-[2-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)methylquinolin pane-1,2-diamine N N The title compound was prepared in analogy to Example 9-1 in Scheme 5 by using 4-(4-chloro- 6-methylquinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine oxide (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 N-[2-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)methylquinolinyl]butane- 1,4-diamine NH 2 N N The title compound was prepared in analogy to Example 9-1 in Scheme 5 by using 4-(4-chloro- 6-methylquinolinyl)-2,3,4,5-tetrahydro-1,4-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 1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)nitroquinolinyl]ethane- 1,2-diamine O NH N N The title compound was prepared in analogy to e 9-1 in Scheme 5 by using 4-(4-chloro- 6-nitroquinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide (prepared in analogy to hloromethylquinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide in Example 2-1 by using 2,4-dichloronitroquinoline and 2,3,4,5-tetrahydro-1,4-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 N-[2-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)fluoromethylquinolin yl]ethane-1,2-diamine F NH N N The title compound was prepared in analogy to Example 9-1 in Scheme 5 by using 4-(4-chloro- -fluoromethylquinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine oxide (prepared in analogy to 4-(4-chloromethylquinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1- dioxide in Example 2-1 by using 2,4-dichlorofluoromethylquinoline and 5- tetrahydro-1,4-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-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)fluoromethylquinolin yl]amino}ethanol F NH N N The title compound was prepared in analogy to Example 9-1 in Scheme 5 by using 4-(4-chloro- -fluoromethylquinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide (prepared in y to the one in Example 9-21) and aminoethanol. MS obsd. (ESI+) [(M+H)+] 416, 1H NMR (400 MHz, DMSO-d6) 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-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)fluoromethylquinolin no}ethanol F N N The title compound was prepared in analogy to Example 9-1 in Scheme 5 by using 4-(4-chloro- 7-fluoromethylquinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide (prepared in analogy to 4-(4-chloromethylquinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1- dioxide in Example 2-1 by using 2,4-dichlorofluoromethylquinoline and 2,3,4,5- tetrahydro-1,4-benzothiazepine) and aminoethanol. MS obsd. (ESI+) [(M+H)+] 416, 1H NMR (400 MHz, DMSO-d6) 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 1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)fluoromethylquinolin ane-1,2-diamine F N N The title compound was prepared in analogy to Example 9-1 in Scheme 5 by using 4-(4-chloro- 7-fluoromethylquinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide (prepared in analogy to 4-(4-chloromethylquinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1- dioxide in Example 2-1 by using 2,4-dichlorofluoromethylquinoline and 2,3,4,5- tetrahydro-1,4-benzothiazepine) and -1,2-diamine. MS obsd. (ESI+) [(M+H)+] 415, 1H NMR (400 MHz, DMSO-d6) δ ppm 7.93 (d, J = 6.82 Hz, 1 H), 7.91 - 7.87 (m, 1 H), 7.82 (d, J = 8.84 Hz, 1 H), 7.66 (td, J = 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-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-7,8-difluoromethylquinolin- 4-yl]ethane-1,2-diamine F N N The title compound was prepared in analogy to Example 9-1 in Scheme 5 by using 4-(4-chloro- fluoromethylquinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide (prepared in analogy to 4-(4-chloromethylquinolinyl)-2,3,4,5-tetrahydro-1,4- benzothiazepine 1,1-dioxide in e 2-1 by using 2,4-dichloro-7,8-difluoro methylquinoline and 2,3,4,5-tetrahydro-1,4-benzothiazepine) and ethane-1,2-diamine. MS obsd.
(ESI+) [(M+H)+] 433, 1H NMR (400 MHz, DMSO-d6) 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-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-N-(2-methoxyethyl) methylquinolinamine N N The title compound was prepared in analogy to Example 9-1 in Scheme 5 by using 4-(4-chloro- 6-methylquinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide (prepared in analogy to the one in Example 2-1) and 2-methoxyethaneamine. MS obsd. (ESI+) [(M+H)+] 412, 1H NMR (400 MHz, CD3OD) δ 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 1-[2-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5 H)-yl)methylquinolin yl]piperidinamine N N The title nd was prepared in analogy to Example 9-1 in Scheme 5 by using 4-(4-chloro- 6-methylquinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide (prepared in analogy to the one in Example 2-1) and dinamine. 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 1-[2-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5 H)-yl)-1,6-naphthyridin yl]pyrrolidinamine N N The title compound was prepared in analogy to Example 9-1 in Scheme 5 by using 4-(4-chloro- phthyridinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide (prepared in analogy to 4-(4-chloromethylquinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide in Example 2-1 by using 2,3,4,5-tetrahydro-1,4-benzothiazepine and 2,4-dichloro-1,6- naphthyridine) and pyrrolidinamine. MS obsd. (ESI+) [(M+H)+] 410, 1H NMR (400 MHz, CD3OD) δ ppm 9.26 (s, 1 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), .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)(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinolin yl]propane-1,3-diamine F NH NH N N The title compound was prepared in analogy to Example 9-1 in Scheme 5 by using 4-(4-chloro- 6-difluoromethylquinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide (prepared in analogy to 4-(4-chloromethylquinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1- dioxide in Example 2-1 by using 2,4-dichlorodifluoromethylquinoline 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(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-N-ethylquinolin amine N N O The title compound was prepared in y to Example 9-1 in Scheme 5 by using 4-(4,6- dichloroquinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine oxide red in analogy to 4-(4-chloromethylquinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide in Example 2-1 by using 2,4,6-trichloroquinoline and 2,3,4,5-tetrahydro-1,4-benzothiazepine) and ethaneamine. MS obsd. (ESI+) [(M+H)+] 402, 1H NMR (400 MHz, DMSO-d6) 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 Chloro(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinolin yl]amino}ethanol N N The title compound was prepared in analogy to Example 9-1 in Scheme 5 by using 4-(4,6- dichloroquinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide (prepared in analogy to 4-(4-chloromethylquinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide in Example 2-1 by using 2,4,6-trichloroquinoline and 5-tetrahydro-1,4-benzothiazepine) and aminoethanol. MS obsd. (ESI+) [(M+H)+] 418, 1H NMR (400 MHz, DMSO-d6) 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 N-[6-Chloro(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinolinyl]-N'- methylethane-1,2-diamine N N O The title compound was prepared in analogy to Example 9-1 in Scheme 5 by using - dichloroquinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide (prepared in analogy to 4-(4-chloromethylquinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide in Example 2-1 by using 2,4,6-trichloroquinoline and 2,3,4,5-tetrahydro-1,4-benzothiazepine) and N-methylethane-1,2-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 N-[2-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)(methylsulfanyl)quinolin yl]propane-1,3-diamine NH NH2 N N The title compound was ed in analogy to Example 9-1 in Scheme 5 by using 4-(4-chloro- 6-(methylsulfanyl)quinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide (prepared in analogy to hloromethylquinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1- dioxide in Example 2-1 by using 2,4-dichloro(methylsulfanyl)quinoline and 2,3,4,5- tetrahydro-1,4-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 N-[6-Bromo(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinolin yl]propane-1,3-diamine NH NH N N The title compound was prepared in analogy to Example 9-1 in Scheme 5 by using 4-(6-bromo- roquinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide (prepared in analogy to hloromethylquinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide in Example 2-1 by using 6-bromo-2,4-dichloroquinoline and 2,3,4,5-tetrahydro-1,4- 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](1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)- yl)quinolinyl}methanol OH NH N N 4-Chloro(2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-quinolinemethanol OH Cl N N The title compound was prepared in analogy to 4-chloro(1,1-dioxido-2,3-dihydro-1,4- benzothiazepin-4(5H)-yl)-quinolinemethanol in Example 3-23 in Scheme 5 by using methyl 4-chloro(2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinolinecarboxylate (prepared in analogy to 4-(4-chloromethylquinolinyl)methoxy-2,3,4,5-tetrahydro-1,4- benzothiazepine in Example 1-1 in Scheme 4 by using methyl 2,4-dichloro quinoline carboxylate and 5-tetrahydro-1,4-benzothiazepine) and sodium borohydride. {4-[(2-Aminoethyl)amino](2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinolin yl}methanol OH NH N N The title compound was prepared in analogy to Example 9-1 in Scheme 5 by using [4-chloro ihydro-1,4-benzothiazepin-4(5H)-yl)quinolinyl]methanol and propane-1,3-diamine. {4-[(2-Aminoethyl)amino](1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)- yl)quinolinyl}methanol OH NH N N To a suspension of {4-[(2-aminoethyl)amino](2,3-dihydro-1,4-benzothiazepin-4(5H)- nolinyl}methanol (370 mg, 1.04 mmol) in dichloromethane (10 mL) was added 3- chloroperoxybenzoic acid (384 mg, 2.18 mmol). The resulting mixture was d 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 tography 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-d6) 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 11-1 2-{[2-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)methylquinolin yl]amino}propane-1,3-diol N N A solution of 4-(4-chloromethylquinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1- dioxide ( 200.0 mg, 0.54 mmol, prepared in analogy to the one in Example 2-1) and 2- aminopropane-1,3-diol ( 420.0 mg, 4.6 mmol) in 1-methylpyrrolidinone (1.0 mL) was stirred at 160 oC for 16 hours. After being cooled to room temperature and diluted with water (50 mL), the resulting mixture was ted with ethyl acetate (100 mL), washed with brine (50 mL × 2), dried over ous sodium sulfate and concentrated in vacuo. The e 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-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)methylquinolin yl]imino} diethanol OH OH N N The title compound was prepared in analogy to Example 11-1 in Scheme 5 by using 4-(4-chloro- ylquinolinyl)-2,3,4,5-tetrahydro-1,4-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 H), .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-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)methylquinolinyl]amino}- 3-hydroxybutanoic acid OH OH N N The title nd was ed in analogy to Example 11-1 in Scheme 5 by using 4-(4-chloro- 6-methylquinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide (prepared in analogy to the one in Example 2-1) and 4-aminohydroxybutanoic 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 1-Amino{[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)methylquinolin no}methylpropanol N N The title compound was prepared in analogy to Example 11-1 in Scheme 5 by using 4-(4-chloro- 6-methylquinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide (prepared in analogy to the one in Example 2-1) and 1,3-diaminomethylpropanol. 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-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)methyl-N-[2-(morpholin yl]quinolinamine N N S O A mixture of 4-(4-chloromethylquinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1- dioxide (50 mg, 0.134 mmol, prepared in analogy to the one in Example 2-1), 2-(morpholin anamine (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 ºC 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+) +] 467, 1H NMR (400 MHz, CDCl3) δ ppm 8.05 (d, J = 7.6 Hz, 1 H), 7.66 (d, J = 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, J = 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 (1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-1,6-naphthyridin yl]amino}ethanol N N The title compound was prepared in analogy to Example 12-1 in Scheme 5 by using 4-(4-chloro- 1,6-naphthyridinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine oxide (prepared in analogy to 4-(4-chloromethylquinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide in Example 2-1 by using 2,3,4,5-tetrahydro-1,4-benzothiazepine and 2,4-dichloro-1,6- naphthyridine) and 2-aminoethanol. MS obsd. (ESI+) [(M+H)+] 385, 1H NMR (400 MHz, CD3OD) δ ppm 9.66 (s, 1 H), 8.66 - 8.64 (d, J = 6.8 Hz, 1 H), 8.26 - 8.24 (d, J = 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 N-[2-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)methylquinolinyl]nonane- 1,9-diamine NH NH N N The title compound was prepared in analogy to e 12-1 in Scheme 5 by using 4-(4-chloro- 8-methylquinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide (prepared in analogy to 4-(4-chloromethylquinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide in Example 2-1 by using 2,4-dichloromethylquinoline and 2,3,4,5-tetrahydro-1,4- 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 N-[2-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)methylquinolinyl]decane- 1,10-diamine NH 2 N N O The title compound was prepared in analogy to Example 12-1 in Scheme 5 by using hloro- 8-methylquinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine oxide red in analogy to 4-(4-chloromethylquinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide in Example 2-1 by using 2,4-dichloromethylquinoline and 2,3,4,5-tetrahydro-1,4- benzothiazepine) and decane-1,10-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 N-[2-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)methylquinolinyl]octane- 1,8-diamine N N The title compound was prepared in analogy to Example 12-1 in Scheme 5 by using 4-(4-chloro- ylquinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide (prepared in analogy to the one in Example 2-1) and octane-1,8-diamine. MS obsd. (ESI+) +] 481, 1H NMR (400 MHz, CD3OD) δ 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-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)methylquinolin yl]amino}nonanol NH OH N N The title compound was ed in analogy to Example 12-1 in Scheme 5 by using 4-(4-chloro- 6-methylquinolinyl)-2,3,4,5-tetrahydro-1,4-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) δ 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 Example 12-7 N-[2-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)methylquinolinyl]octane- 1,8-diamine N N The title compound was prepared in y to Example 12-1 in Scheme 5 by using 4-(4-chloro- 8-methylquinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide (prepared in analogy to 4-(4-chloromethylquinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide in Example 2-1 by using 2,4-dichloromethylquinoline and 2,3,4,5-tetrahydro-1,4- 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 cisamino[2-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)methylquinolin- 4-yl]pyrrolidinol 2NH OH N N A e of 4-(4-chloromethylquinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1- dioxide (740 mg, 2.0 mmol, prepared in y to the one in Example 2-1) and cis aminopyrrolidinol (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). e 14-1 N-[2-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)methylquinolinyl]-L- alanine N N The mixture of 4-(4-chloromethylquinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1- dioxide (150 mg, 0.40 mmol, prepared in analogy to the one in Example 2-1) and L-alanine (360 mg, 4.0 mmol) in phenol (360 mg) was heated at 150°C ght. 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 N-[2-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)methylquinolinl]-beta- alanine N N O The title compound was prepared in analogy to Example 14-1 in Scheme 5 by using 4-(4-chloro- 6-methylquinolinyl)-2,3,4,5-tetrahydro-1,4-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 N-[2-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)methylquinolin yl]benzene-1,3-diamine N N O A mixture of 4-(4-chloromethylquinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1- e (150 mg, 0.40 mmol, prepared in analogy to the one in Example 2-1), benzene-1,3- e (86 mg, 0.80 mmol), palladium acetate (18 mg, 0.04 mmol), 2,2'- bis(diphenylphosphino)-1,1'-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 ed and washed with ethyl acetate. The filtrate was washed with brine, dried over sodium sulfate, and concentrated in vacuo. The residue was ed by preparative HPLC to afford the pure product as a solid. MS obsd. (ESI+) [(M+H)+] 445, 1H NMR (400 MHz, DMSO-d6) 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 N-[2-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)methylquinolin yl]benzene-1,4-diamine N N The title compound was prepared in analogy to Example 15-1 in Scheme 5 by using 4-(4-chloro- 6-methylquinolinyl)-2,3,4,5-tetrahydro-1,4-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-d6) 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 -[2-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)methylquinolin yl]pyrrolidinol N N The title compound was prepared in analogy to Example 15-1 in Scheme 5 by using 4-(4-chloro- 6-methylquinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide (prepared in analogy to the one in Example 2-1) and yrrolidinol. 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) [2-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)methylquinolin yl]pyrrolidinol N N The title nd was prepared in analogy to Example 15-1 in Scheme 5 by using 4-(4-chloro- 6-methylquinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide (prepared in analogy to the one in Example 2-1) and (3R)-pyrrolidinol. 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 trans-N-[2-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)methylquinolin yl]cyclopentane-1,2-diamine N N The title compound was prepared in analogy to Example 15-1 in Scheme 5 by using 4-(4-chloro- 6-methylquinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide red in analogy to the one in Example 2-1) and trans-cyclopentane-1,2-diamine. MS obsd. (ESI+) [(M+H)+] 437, 1H NMR (400 MHz, CD 3OD) 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 1-[2-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5 H)-yl)methylquinolin yl]piperidinamine N N A e of 4-(4-chloromethylquinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1- dioxide (0.2 g, 0.54 mmol, prepared in analogy to the one in Example 2-1), piperidinylamine 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 e 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). e 16-2 2-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-N,N,6-trimethylquinolinamine N N The title compound was prepared in analogy to Example 16-1 in Scheme 5 by using 4-(4-chloro- 6-methylquinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide (prepared in y to the one in Example 2-1) and dimethylamine. MS obsd. (ESI+) [(M+H)+] 382, 1H NMR (400 MHz, CD3OD) δ ppm 8.07 (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-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)(trifluoromethoxy)quinolin- ropane-1,3-diamine NH NH2 F O N N 4-(4-Chloro(trifluoromethoxy)quinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1- dioxide F O N N A mixture of 2,4-dichloro(trifluoromethoxy)quinoline (250 mg, 0.89 mmol), 2,3,4,5- tetrahydro-1,4-benzothiazepine 1,1-dioxide (210 mg, 1.06 mmol) and n-butanol (2 mL) was heated with stirring in a 5 mL of ave process vial for 3 hours at 150 oC 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=10/1) to afford 0.3 g of the product (yield was 77%).
N-[2-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)(trifluoromethoxy)quinolin- 4-yl]propane-1,3-diamine NH NH F 2 F O N N The title compound was prepared in analogy to Example 3-1 in Scheme 5 by using hloro- 6-(trifluoromethoxy)quinolinyl)-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-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)(trifluoromethyl)quinolin yl]propane-1,3-diamine F NH NH2 N N The title compound was ed in analogy to Example 17-1 in Scheme 6 by using 4-(4-chloro- 6-(trifluoromethyl)quinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide (prepared in analogy to 4-(4-chloro(trifluoromethoxy)quinolinyl)-2,3,4,5-tetrahydro-1,4- benzothiazepine 1,1-dioxide in Example 17-1 by uisng 2,4-dichloro(trifluoromethyl)quinoline and 2,3,4,5-tetrahydro-1,4-benzothiazepine oxide) 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 N-[6-(Difluoromethoxy)(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinolin- 4-yl]propane-1,3-diamine NH NH2 F O N N The title compound was prepared in y to Example 17-1 in Scheme 6 by using 4-(4-chloro- 6-(difluoromethoxy)quinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide (prepared in analogy to 4-(4-chloro(trifluoromethoxy)quinolinyl)-2,3,4,5-tetrahydro-1,4- benzothiazepine 1,1-dioxide in Example 17-1 by using 2,4-dichloro (difluoromethoxy)quinoline and 2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide) and propane-1,3-diamine. MS obsd. (ESI+) +] 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), .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 N-[2-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)methoxyquinolin pane-1,3-diamine NH NH N N The title compound was prepared in analogy to Example 17-1 in Scheme 6 by using 4-(4-chloro- 6-methoxyquinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide (prepared in analogy to 4-(4-chloro(trifluoromethoxy)quinolinyl)-2,3,4,5-tetrahydro-1,4- benzothiazepine 1,1-dioxide in e 17-1 by using 2,4-dichloromethoxyquinoline and 2,3,4,5-tetrahydro-1,4-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 N-[2-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)methylquinolin yl]propane-1,3-diamine NH NH N N The title compound was prepared in analogy to Example 17-1 in Scheme 6 by using hloro- 8-methylquinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide (prepared in analogy to 4-(4-chloro(trifluoromethoxy)quinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1- dioxide in Example 17-1 by using 2,4-dichloromethylquinoline and 2,3,4,5-tetrahydro-1,4- benzothiazepine 1,1-dioxide) and propane-1,3-diamine. MS obsd. (ESI+) [(M+H)+] 411, 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 N-[2-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)methylquinolin yl]propane-1,3-diamine and N-[2-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl) methylquinolinyl]propane-1,3-diamine NH NH NH NH 2 2 N N N N S O S O O O A mixture of the title compound prepared in y to Example 17-1 by using propane-1,3- e and a mixture of 4-(4-chloromethylquinolin- 2-yl)- 2,3,4,5-tetrahydro-1,4- benzothiazepine 1,1-dioxide and 4-(4-chloromethylquinolinyl)- 2,3,4,5-tetrahydro-1,4- benzothiazepine 1,1-dioxide (prepared in analogy to 4-(4-chloro(trifluoromethoxy)quinolin yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine oxide in Example 17-1 by using a mixture of 2,4-dichloromethylquinoline and 2,4-dichloromethylquinoline and propane-1,3-diamine) was purified by preparative HPLC and SPE to give the pure title compounds N-[2-(1,1-dioxido- hydro-1,4-benzothiazepin-4(5H)-yl)methylquinolinyl]propane-1,3-diamine and N-[2- (1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)methylquinolinyl]propane-1,3- diamine. 1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)methylquinolinyl]propane- 1,3-diamine, MS obsd. (ESI+) [(M+H)+] 411, 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-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)methylquinolinyl]propane- 1,3-diamine, MS obsd. (ESI+) [(M+H)+] 411, 1H NMR (400 MHz, CD3OD) δ ppm 8.10 - 8.02 (m, 1 H), 8.00 - 7.95 (d, J = 8.8 Hz ,1 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), 2.11 - 2.02 (m, 2 H).
Example 17-8 N-{[3-(Aminomethyl)oxetanyl]methyl}(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin- 4(5H)-yl)fluoroquinolinamine NH NH2 N N The title compound was ed in analogy to Example 17-1 in Scheme 6 by using 4-(4-chloro- 8-fluoroquinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide (prepared in analogy to 4-(4-chloro(trifluoromethoxy)quinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1- dioxide in Example 17-1 by using 2,4-dichlorofluoroquinoline and 2,3,4,5-tetrahydro-1,4- 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). e 18-1 N-[(3-Aminooxetanyl)methyl]methyl(1-oxido-2,3-dihydro-1,4-benzothiazepin- 4(5H)-yl)quinolinamine N N 4-(4-Chloromethylquinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1-oxide N N The title compound was prepared in analogy to 4-(4-chloro(trifluoromethoxy)quinolinyl)- 2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide in Example 17-1 in Scheme 6 by using 2,4- romethylquinoline and 2,3,4,5-tetrahydro-1,4-benzothiazepine 1-oxide.
N-[(3-Aminooxetanyl)methyl](1-oxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl) methylquinolinamine N N A e of 4-(4-chloromethylquinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1-oxide (2 g, 5.6 mmol), 3-aminomethyloxetanylamine (572 mg, 5.6 mmol), tri(dibenzylideneacetone)dipalladium(0) (256 mg, 0.28 mmol), 2,2'-bis(diphenylphosphino)-1,1'- binaphthalene (348.7 mg, 0.56 mmol), sodium tert-butoxide (1.08 g, 11.2 mmol) and toluene (20 mL) was heated with ng in a 30 mL of sealed tube for 20 hours at 110 oC under nitrogen.
The resulting e 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 (+)-N-[(3-Aminooxetanyl)methyl]methyl[1-oxido-2,3-dihydro-1,4-benzothiazepin- 4(5H)-yl]quinolinamine and (-)-N-[(3-Aminooxetanyl)methyl]methyl[1-oxido- 2,3-dihydro-1,4-benzothiazepin-4(5H)-yl]quinolinamine NH NH NH 2 NH 2 O O N N N N S S O O (+) (-) The chiral separation of Example 18-1 (column: IA; flow rate: 15mL/min; gradient: 50% hexane in l with 0.4% of triethylamine) gives (+)-N-[(3-aminooxetanyl)methyl]methyl[1- oxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl]quinolinamine, 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-aminooxetanyl)methyl] methyl[1-oxido-2,3-dihydro-1,4-benzothiazepin-4(5 H)-yl]quinolinamine, MS obsd. (ESI+) +] 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 N-[(3-Aminooxetanyl)methyl]chloro(1-oxido-2,3-dihydro-1,4-benzothiazepin- 4(5H)-yl)quinolinamine N N The title compound was prepared in analogy to Example 18-1 in Scheme 6 by using 4-(4,6- dichloroquinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1-oxide (prepared in analogy to 4- (4-chloromethylquinolinyl)- 2,3,4,5-tetrahydro-1,4-benzothiazepine 1-oxide in Example 18-1 by using trichloroquinoline and 2,3,4,5-tetrahydro-1,4-benzothiazepine 1-oxide) and 3-aminomethyloxetanylamine. 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 N-[2-(1-Oxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)methylquinolinyl]-2,2- ropropane-1,3-diamine F 2 N N The title compound was prepared in analogy to Example 18-1 in Scheme 6 by using 4-(4-chloro- 6-methylquinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1-oxide (prepared in y to the one in Example 18-1) and 2,2-difluoropropane-1,3-diamine. MS obsd. (ESI+) [(M+H)+] 431, 1H NMR (400 MHz, CD 3OD) 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 N-[6-Chloro(1-oxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinolinyl]-2,2- ropropane-1,3-diamine F 2 N N The title compound was prepared in analogy to Example 18-1 in Scheme 6 by using 4-(4,6- dichloroquinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1-oxide (prepared in analogy to 4- (4-chloromethylquinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1-oxide in Example 18- 1 by using 2,4,6-trichloroquinoline and 2,3,4,5-tetrahydro-1,4-benzothiazepine 1-oxide) and 2,2- difluoropropane-1,3-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). e 18-7 N-[6-Chloro(1-oxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinolinyl]ethane-1,2- diamine N N The title compound was prepared in analogy to Example 18-1 in Scheme 6 by using 4-(4,6- dichloroquinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1-oxide (prepared in analogy to 4- (4-chloromethylquinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1-oxide in Example 18- 1 by using 2,4,6-trichloroquinoline and 2,3,4,5-tetrahydro-1,4-benzothiazepine e) and -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 - .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 N-{[3-(Aminomethyl)oxetanyl]methyl}methyl(1-oxido-2,3-dihydro-1,4- benzothiazepin-4(5H)-yl)quinolinamine N N The title compound was prepared in analogy to Example 18-1 in Scheme 6 by using 4-(4-chloro- 6-methylquinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1-oxide (prepared in analogy to the one in Example 18-1) and oxetane-3,3-diyldimethanamine. MS obsd. (ESI+) [(M+H)+] 437, 1H NMR (400 MHz, CD 3OD) 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 N-{[3-(Aminomethyl)oxetanyl]methyl}chloro(1-oxido-2,3-dihydro-1,4- benzothiazepin-4(5H)-yl)quinolinamine N N The title compound was prepared in analogy to Example 18-1 in Scheme 6 by using 4-(4,6- roquinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1-oxide (prepared in analogy to 4- (4-chloromethylquinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1-oxide in e 18- 1 by using 2,4,6-trichloroquinoline and 2,3,4,5-tetrahydro-1,4-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), 5.11(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 Example 18-10 N-[6-Methyl(1-oxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinolinyl]ethane-1,2- diamine N N The title compound was prepared in analogy to Example 18-1 in Scheme 6 by using 4-(4-chloro- 6-methylquinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1-oxide (prepared in y 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(1-oxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinolin yl]amino}ethanol N N The title compound was prepared in analogy to Example 18-1 in Scheme 6 by using 4-(4-chloro- 6-methylquinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1-oxide (prepared in y 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 transAmino[6-methyl(1-oxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinolin yl]pyrrolidinol OH NH N N tert-Butyl [6-methyl(1-oxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinolin- 4-yl]hydroxypyrrolidinyl} carboxylate H O OH N N N A mixture of 4-(4-chloromethylquinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1-oxide (200 mg, 0.56 mmol, ed in analogy to the one in Example 18-1), utyl hydroxypyrrolidinyl]carbamate (125 mg, 0.62 mmol), tris(2-benzylidene acetone) palladium(II) (50 mg, 0.055 mmol), 2-dicyclohexylphosphino(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 ed 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%). transAmino[6-methyl(1-oxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinolin yl]pyrrolidinol OH NH2 N N To a solution of tert-butyl {trans[6-methyl(1-oxido-2,3-dihydro-1,4-benzothiazepin-4(5H)- yl)quinolinyl]hydroxypyrrolidinyl}carboxylate (230 mg, 0.54 mmol) in dichloromethane (5 mL) was added trifluoroacetic acid (2 mL). After being stirred at room temperature for 3 hours, the resulting mixture was concentrated in vacuo. The residue was ed 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 (1R,5S,6S)[2-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)methylquinolin yl]azabicyclo[3.1.0]hexanamine H H N N The title compound was prepared in analogy to Example 19-1 in Scheme 7 by using 4-(4-chloro- 6-methylquinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,2-dioxide (prepared in analogy to 4-(4-chloro(trifluoromethoxy)quinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1- dioxide in Example 17-1 by using 2,4-dichloromethylquinoline and 2,3,4,5-tetrahydro-1,4- benzothiazepine 1,2-dioxide ) and tert-butyl ,6S)azabicyclo[3.1.0]hexylcarbamate.
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), rs, 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 transAmino[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl) methylquinolinyl]pyrrolidinol H N OH N N The title compound was prepared in analogy to Example 19-1 in Scheme 7 by using 4-(4-chloro- 6-methylquinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide (prepared in analogy to 4-(4-chloro(trifluoromethoxy)quinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1- dioxide in Example 17-1 by using 2,4-dichloromethylquinoline and 2,3,4,5-tetrahydro-1,4- benzothiazepine 1,2-dioxide) and utyl trans-(4-hydroxypyrrolidinyl)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 1-[6-Methyl(1-oxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinolinyl]pyrrolidin- 3-amine N N The title compound was prepared in analogy to Example 19-1 in Scheme 7 by using 4-(4-chloro- 6-methylquinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine e (prepared in analogy to the one in Example 18-1) and utyl pyrrolidinylcarbamate. MS obsd. (ESI+) [(M+H)+] 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 = .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 trans[6-Chloro(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinolinyl] fluoropyrrolidinamine F NH N N The title compound was prepared in analogy to Example 19-1 in Scheme 7 by using 4-(4,6- dichloroquinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide (prepared in y to 4-(4-chloromethylquinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide in e 2-1) and tert-butyl trans-(4-fluoropyrrolidinyl) 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).
Example19-6 transAmino[6-chloro(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)- yl)quinolinyl]pyrrolidinol H N OH N N O The title compound was prepared in y to Example 19-1 in Scheme 7 by using - dichloroquinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide (prepared in analogy to 4-(4-chloro(trifluoromethoxy)quinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1- dioxide in Example 17-1 by using 2,4,6-trichloro-quinoline and 2,3,4,5-tetrahydro-1,4- benzothiazepine 1,2-dioxide) and tert-butyl (transhydroxypyrrolidinyl) 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 trans[6-Chloro(1-oxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinolinyl] fluoropyrrolidinamine NH F N N The title compound was prepared in analogy to Example 19-1 in Scheme 7 by using - roquinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1-oxide (prepared in analogy to 4- (4-chloromethylquinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1-oxide in Example 18- 1) and tert-butyl (transfluoropyrrolidinyl) 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), .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-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5 H)-yl)methylquinolinyl] azabicyclo[2.1.1]hexanamine N N The title compound was prepared in analogy to Example19-1 in Scheme 7 by using 4-(4-chloro- 6-methylquinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide red in analogy to 4-(4-chloro(trifluoromethoxy)quinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1- dioxide in Example 17-1 by using 2,4-dichloromethylquinoline and 2,3,4,5-tetrahydro-1,4- benzothiazepine 1,2-dioxide) and tert-butyl 2-azabicyclo[2.1.1]hexylcarbamate. 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-1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)methylquinolin amine N N tert-Butyl [2-(8-Methoxy-1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl) methylquinolinyl] carbamate NH O N N A mixture solution of 4-(4-chloromethylquinolinyl)methoxy-2,3,4,5-tetrahydro-1,4- benzothiazepine oxide (60.0 mg, 0.15 mmol, prepared in analogy to 4-(4-chloro (trifluoromethoxy)quinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide in Example 17-1 by using 2,4-dichloromethylquinoline and 8-methoxy-2,3,4,5-tetrahydro-1,4- benzothiazepine 1,2-dioxide), tert-butyl carbamate (45.0 mg, 0.37 mmol), 1,1'- bis(diphenylphosphino)ferrocene (11.2 mg, 0.02 mmol), 1,1'- 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 oC for 2 hours. After being cooled to room temperature, the reaction mixture was ted with ethyl acetate (100 mL), washed with brine (50 mL × 2), dried over anhydrous sodium e 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-1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)methylquinolin amine N N A mixture on of tert-butyl [2-(8-methoxy-1,1-dioxido-2,3-dihydro-1,4-benzothiazepin- 4(5H)-yl)methylquinolinyl] carbamate (59.0 mg, 0.12 mmol) and trifluoroacetic 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 e (100 mL). The organic layer was washed with brine (50 mL × 2), dried over anhydrous sodium sulfate and then concentrated in vacuo. The e 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). e 20-2 2-(7-Methoxy-1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)methylquinolin amine N N O The title compound was prepared in analogy to Example 20-1 in Scheme 7 by using 4-(4-chloro- 6-methylquinolinyl)methoxy-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide (prepared in analogy to 4-(4-chloro(trifluoromethoxy)quinolinyl)-2,3,4,5-tetrahydro-1,4- benzothiazepine 1,1-dioxide in Example 17-1 by using 2,4-dichloromethylquinoline and 7- methoxy-2,3,4,5-tetrahydro-1,4-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-(1-Amino-cyclopropyl)-ethyl]-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)- 6-methylquinolinyl]-amine NH 2NH N N The title compound was prepared in analogy to Example 20-1 in Scheme 7 by using 4-(4- chloromethylquinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide (prepared in analogy to 4-(4-chloro(trifluoromethoxy)quinolinyl)-2,3,4,5-tetrahydro-1,4- benzothiazepine 1,1-dioxide in Example 17-1 by using 2,4-dichloromethylquinoline and 2,3,4,5-tetrahydro-1,4-benzothiazepine 1,2-dioxide) and tert-butyl 1-(2-aminoethyl)- cyclopropylcarbamate. MS obsd. (ESI+) [(M+H)+] 437, 1H NMR (400 MHz, CDCl3) 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). e 21-1 2-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)methyl-N-(morpholin yl)quinolinamine N N tert-Butyl 2-{[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)methylquinolin ylamino]-methyl}-morpholinecarboxylate N O N N A mixture of 4-(4-chloromethylquinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1- dioxide (682 mg, 1.83 mmol, prepared in analogy to 4-(4-chloro(trifluoromethoxy)quinolin yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide in Example 17-1 by using 2,4-dichloro methylquinoline and 2,3,4,5-tetrahydro-1,4-benzothiazepine 1,2-dioxide) in 1,4-dioxane (5 mL) was added tert-butyl nomethyl)morpholinecarboxylate (395 mg, 1.83 mmol), 1,1'- bis(diphenylphosphino)ferrocenedichloropalladium(II) (146 mg, 0.18 mmol), 1,1'- 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 oC 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 d product (yield was %). 2-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)methyl-N-(morpholin ylmethyl)quinolinamine N N O To a solution of tert-butyl 2-{[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl) methylquinolinylamino]-methyl}-morpholinecarboxylate (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 icewater 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 oroacetic acid salt of the d t. The trifluoroacetic acid salt was flashed through SPE column with methanol to remove the trifluoroacetic acid. The solution was concentrated in vacuo and then dried by ization 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 N-[2-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)methylquinolinyl]-N- methylethane-1,2-diamine N 2 N N O The title compound was prepared in analogy to e 21-1 in Scheme 7 by using 4-(4-chloro- 6-methylquinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide (prepared in analogy to 4-(4-chloro(trifluoromethoxy)quinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1- dioxide in Example 17-1 by using 2,4-dichloromethylquinoline and 2,3,4,5-tetrahydro-1,4- 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 tidinylmethyl)(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl) methylquinolinamine NH N N N The title compound was prepared in analogy to Example 21-1 in Scheme 7 by using 4-(4-chloro- ylquinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide (prepared in analogy to 4-(4-chloro(trifluoromethoxy)quinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1- dioxide in Example 17-1 by using 2,4-dichloromethylquinoline and 2,3,4,5-tetrahydro-1,4- benzothiazepine 1,2-dioxide) and tert-butyl 2-(aminomethyl)azetidinecarboxylate. MS obsd.
(ESI+) +] 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), .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-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)methyl-N-(pyrrolidin yl)quinolinamine N N The title compound was prepared in analogy to Example 21-1 in Scheme 7 by using 4-(4-chloro- 6-methylquinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide (prepared in analogy to 4-(4-chloro(trifluoromethoxy)quinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1- dioxide in Example 17-1 by using 2,4-dichloromethylquinoline and 2,3,4,5-tetrahydro-1,4- benzothiazepine oxide) and tert-butyl 3-aminopyrrolidinecarboxylate. MS obsd. (ESI+) +] 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 (1-Amino-cyclopropylmethyl)-[2-(5,5-dioxo-5,6,7,9-tetrahydro-5λ6-thiaazabenzocycloheptenyl )methyl-quinolinyl]-amine N N The title compound was prepared in analogy to Example 21-1 in Scheme 7 by using 4-(4-chloro- 6-methylquinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine oxide red in analogy to 4-(4-chloro(trifluoromethoxy)quinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1- dioxide in Example 17-1 by using 2,4-dichloromethylquinoline and 2,3,4,5-tetrahydro-1,4- benzothiazepine 1,2-dioxide) and tert-butyl 1-(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). e 22 N-(Azetidinyl)chloro(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)- yl)quinolinamine N N tert-Butyl 3-[6-chloro(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-quinolin ylamino]-azetidinecarboxylate N O N N The title compound was prepared in analogy to tert-butyl 2-{[2-(1,1-dioxido-2,3-dihydro-1,4- benzothiazepin-4(5H)-yl)methylquinolinylamino]-methyl}-morpholinecarboxylate in Example 21-1 by using 4-(4,6-dichloroquinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide and utyl 3-aminoazetidinecarboxylate.
N-(Azetidinyl)chloro(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)- yl)quinolinamine N N O A mixture of tert-butyl 3-[6-chloro(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)- quinolinylamino]-azetidinecarboxylate (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 e 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-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5 H)-yl)methylquinolinyl]oxa ro[3.4]octanamine O NH N N tert-Butyl 6-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)methylquinolin yl]oxaazaspiro[3.4]octancarbamate O H O N N A mixture of tert-butyl 2-oxaazaspiro[3.4]octylcarbamate (459 mg, 2.0 mmol), 4-(4- chloromethylquinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide (500 mg, 1.34 mmol, prepared in analogy to 4-(4-chloro(trifluoromethoxy)quinolinyl)-2,3,4,5-tetrahydro- 1,4-benzothiazepine 1,1-dioxide in Example 17-1 by using 2,4-dichloromethylquinoline and 2,3,4,5-tetrahydro-1,4-benzothiazepine 1,2-dioxide), tri(dibenzylideneacetone)dipalladium(0) (61.3 mg, 0.067 mmol), 2'-(dicyclohexylphosphino)-N,N-dimethyl[1,1'-biphenyl]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 ng in a 20 mL of microwave process vial for 3 hours at 100 oC. 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-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5 H)-yl)methylquinolinyl]oxa azaspiro[3.4]octanamine O NH2 N N To a solution of tert-butyl 1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl) methylquinolinyl]oxaazaspiro[3.4]octancarbamate (700 mg, 1.24 mmol) in dichloromethane (10 mL) was added trifluoroacetic acid (5 mL) at 0 oC. The resulting mixture was d at room temperature for further 30 minutes. The reaction was ed with a saturated aqueous solution of sodium carbonate, and the e 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 transAmino[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-1,6- naphthyridinyl]pyrrolidinol OH NH N N tert-Butyl trans[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-1,6- naphthyridinyl]hydroxypyrrolidincarbamate OH N N N S O To a solution of -(4-chloro-1,6-naphthyridinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1- dioxide (300 mg, 0.84 mmol, prepared in analogy to 4-(4-chloromethylquinolinyl)-2,3,4,5- tetrahydro-1,4-benzothiazepine 1,1-dioxide in Example 2-1 by using 2,3,4,5-tetrahydro-1,4- benzothiazepine and chloro-1,6-naphthyridine) in 1,4-dioxane (5 mL) was added tert-butyl (transhydroxypyrrolidinyl)carbamate (204 mg, 1.02 mmol), benzylideneacetone)dipalladium(0) (39 mg, 0.042 mmol), (2'-dicyclohexylphosphanylbiphenylyl thyl-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 oC. The reaction mixture was concentrated in vacuo.
The residue was purified by preparative HPLC to give 45 mg of the desired product (yield was %). transAmino[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-1,6- naphthyridinyl]pyrrolidinol HO NH N N To a on of tert-butyl trans[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)- phthyridinyl]hydroxypyrrolidincarbamate (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 ative HPLC to give the trifluoroacetic acid salt of the desired product. The trifluoroacetic 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 d 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 1-[2-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5 H)-yl)methylquinolin yl]pyrrolidinamine N N A mixture of 4-(4-chloromethylquinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1- dioxide (0.3 g, 0.8 mmol, prepared in analogy to 4-(4-chloro(trifluoromethoxy)quinolinyl)- 2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide in Example 17-1 by using 2,4-dichloro methylquinoline and 2,3,4,5-tetrahydro-1,4-benzothiazepine 1,2-dioxide) and tert-butyl pyrrolidinecarbamate (0.3 g, 1.6 mmol) was heated with stirring in a 10 mL of microwave process vial for 1 hour at 140 oC. The resuting mixture was purified by ative HPLC and SPE. After SPE separation, the eluent was trated in vacuo to remove the c 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 N-(Azetidinyl)(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl) methylquinolinamine N N S O tert-Butyl 3-[1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)methylquinolin ylamino]-azetidinecarboxylate N O N N A mixture of 8-(4-bromomethylquinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1- dioxide (900 mg, 2.16 mmol, prepared in analogy to the one in Example 2-1) and tert-butyl 3- aminoazetidinecarboxylate (1.86 g, 10.77 mmol) was heated with stirring in a 10 mL of microwave s vial for 1 hour at 150 oC. The resuting mixture was purified by preparative HPLC to afford 110 mg of the desired product (yield was 7%).
N-(Azetidinyl)(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl) methylquinolinamine N N S O To a solution of tert-butyl 3-[1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl) methylquinolinylamino]-azetidinecarboxylate (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 ature for 4 hours, the mixture was concentrated in vacuo. The residue was purified by preparative HPLC to give the trifluoroacetic acid salt of the desired product. The trifluoroacetic acid salt was flashed h SPE column with methanol.
The solution was trated in vacuo and dried by lyopylization to afford 29 mg of the desired t (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 1-[2-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5 H)-yl)methylquinolinyl]azetidin- 3-amine N N The title compound was prepared in analogy to Example 26-1 in Scheme 7 by using 4-(4-chloro- 6-methylquinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide (prepared in analogy to the one in Example 2-1) and tert-butyl azetidinylcarbamate. 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 N-[2-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)methylquinolin yl]prolinamide N N tert-Butyl 2-{[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)methylquinolin yl]carbamoyl}pyrrolidinecarboxylate O O N N To a solution of 4-(4-chloromethylquinolinyl)-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- carbamoylpyrrolidinecarboxylate (0.34 g, 1.6 mmol), 1,1'-bis(diphenylphosphino)ferrocenepalladium (II)dichloride (0.13 g, 0.16 mmol), 1,1'-bis(diphenylphosphino)ferrocene (0.089 g, 0.16 mmol) and sodium tert-butoxide (0.307 g, 3.2 mmol) in oxane (25 mL) was heated with ng for 1.5 hours at 120 ºC under microwave irradiation. The reaction mixture was filtered and concentrated in vacuo. The residue was ed by preparative TLC (eluting with 50% ethyl acetate in petroleum ether, V/V=1:1) to give 250 mg of the desired product (yield was 29%).
N-[2-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)methylquinolin yl]prolinamide N N To a solution of tert-butyl 2-{[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl) methylquinolinyl]carbamoyl}pyrrolidinecarboxylate (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 ative TLC to give 104.8 mg of the d 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-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-N-trans-(4-fluoropyrrolidinyl)- 6-methylquinolinamine N N O Benzyl trans{[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)methylquinolin- 4-yl]amino}fluoropyrrolidinecarboxylate F O N O N N The title nd was prepared in analogy to Example 8-1 in Scheme 7 by using 4-(4-chloro- 6-methylquinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide (prepared in y to the one in Example 2-1) and benzyl transaminofluoropyrrolidinecarboxylare. 2-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-N-(transfluoropyrrolidinyl)- 6-methylquinolinamine N N To a suspension of benzyl trans{[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl) methylquinolinyl]amino}fluoropyrrolidinecarboxylate (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 s. The organic solvent was removed by concentration in vacuo. The residue was ed 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 trans{[2-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinolin yl]amino}pyrrolidinol N N O The title compound was prepared in analogy to Example 28-1 in Scheme 8 by using 4-(4- bromoquinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide (prepared in analogy to 4-(4-chloromethylquinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide in Example 2-1) and benzyl transaminohydroxypyrrolidinecarboxylate. 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,1 H), 3.48 - 3.40 (d, J = 7.6 Hz, 1 H).
Example 28-3 trans{[2-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)methylquinolin yl]amino}pyrrolidinol N N The title nd was prepared in analogy to Example 28-1 in Scheme 8 by using 4-(4-bromo- 6-methylquinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine oxide (prepared in analogy to the one in Example 2-1) and benzyl (3S,4S)aminohydroxypyrrolidinecarboxylate. 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{[2-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)methylquinolin yl]amino}pyrrolidinol N N The title compound was prepared in y to e 28-1 in Scheme 8 by using 4-(4-bromo- 6-methylquinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide (prepared in analogy to the one in Example 2-1) and benzyl cisaminohydroxypyrrolidinecarboxylate. 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 N-[transFluoropyrrolidinyl]methyl(1-oxido-2,3-dihydro-1,4-benzothiazepin- 4(5H)-yl)quinolinamine N N The title compound was prepared in analogy to Example 28-1 in Scheme 8 by using 4-(4-chloro- 6-methylquinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1-oxide red in analogy to the one in Example 18-1) and benzyl transaminofluoropyrrolidinecarboxylare. 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,1 H), 3.47 (s, 2 H), 3.30 - 3.08 (m, 2 H), 2.43 (s, 3 H).
Example 29 4-[(3-Aminopropyl)amino](1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)- yl)quinolinol NH NH2 N N 4-Chloro(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-quinolinol N N A mixture of 4-(4-chloromethoxyquinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1- dioxide (5.0 g, 12.85 mmol, prepared in analogy to 4-(4-chloromethylquinolinyl)-2,3,4,5- tetrahydro-1,4-benzothiazepine 1,1-dioxide in Example 2-1 by using 2,4-dichloro methoxyquinoline and 2,3,4,5-tetrahydro-1,4-benzothiazepine) and hydrobromic acid (350 mL, 48%) was refluxed for 2 days. The resulting e was basified with an aqueous solution of sodium hydroxide (4 N) to about pH 9 and extracted with ethyl acetate (250 mL × 3). The combined organic layers were dried over sodium sulfate and concentrated in vacuo. The residue was ed by preparative HPLC to afford 3.0 g of the desired product (yield was 62.2%). 4-[(3-Aminopropyl)amino](1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)- nolinol NH NH N N A mixture of ro(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-quinolinol (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 ºC under microwave irradiation. The reacting mixture was purified by preparative HPLC and SPE to give 118.8 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 0 - 3.02 (t, J = 7.2 Hz, 2 H), 2.10 - 2.00 (m, 2 H); Example 30-1 2-({4-[(3-Aminopropyl)amino](1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)- yl)quinolinyl}oxy)ethanol NH NH N N 2-[4-Chloro(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-quinolinyloxy]- ethanol N N A mixture of 4-chloro(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-quinolinol (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 trated in vacuo. The residue was ed by preparative TLC to afford 230 mg of the d product (yield was 82%). 2-({4-[(3-Aminopropyl)amino](1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)- yl)quinolinyl}oxy)ethanol NH NH2 N N A mixture of 2-{[4-chloro(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinolin 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 ºC under microwave ation. 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 - 3.05 (t, J = 7.6 Hz, 2 H), 2.15 - 2.00 (m, 2 H).
Example 30-2 N-[2-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)(2-methoxyethoxy)quinolin- 4-yl]propane-1,3-diamine NH NH N N The title compound was prepared in analogy to Example 30-1 by using 4-chloro(1,1-dioxido- 2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinolinol red in analogy to the one in Example 29), 1-bromomethoxyethane and propane-1,3-diamine. MS obsd. (ESI+) +] 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 N-[2-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)(pyridinyloxy)quinolin yl]propane-1,3-diamine NH NH2 N N 8-[4-Chloro(pyridinyloxy)-quinolinyl]- 2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1- dioxide N N A mixture of ro(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinolinol (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-1,2-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 e was purified by preparative HPLC to afford 300 mg of the desired product (yield was 62.2%).
N-[2-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)(pyridinyloxy)quinolin yl]propane-1,3-diamine NH NH2 N N O The title compound was prepared in analogy to e 30-1 in Scheme 9 by using 8-[4-chloro- 6-(pyridinyloxy)-quinolinyl]-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-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)methylquinolin yl]amino}propane-1,2-diol N N A mixture of 4-(4-chloromethylquinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1- dioxide (200.0 mg, 0.54 mmol, prepared in analogy to the one in Example 2-1) and 1-(2,2- dimethyl-1,3-dioxolanyl)methanamine (0.5 mL, 3.8 mmol) was heated with stirring at 160 oC 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 × 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(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinolin yl]amino}propane-1,2-diol N N O The title compound was prepared in analogy to e 32-1 in Scheme 10 by using 4-(4,6- roquinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine oxide (prepared in analogy to 4-(4-chloromethylquinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide in Example 2-1 by using 2,4,6-triochloroquinoline and 5-tetrahydro-1,4-benzothiazepine) and 1-(2,2-dimethyl-1,3-dioxolanyl)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-1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)methylquinolin yl]amino}propane-1,2-diol N N The title compound was prepared in analogy to e 32-1 in Scheme 10 by using 4-(4- chloromethylquinolinyl)chloro-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide (prepared in analogy to 4-(4-chloromethylquinolinyl)-2,3,4,5-tetrahydro-1,4- benzothiazepine 1,1-dioxide in e 2-1 by using 2,4-dichloromethylquinoline and 8- chloro-2,3,4,5-tetrahydro-1,4-benzothiazepine) and 1-(2,2-dimethyl-1,3-dioxolan 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(1-oxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinolin no}propane-1,2-diol N N The title compound was prepared in analogy to Example 32-1 in Scheme 5 by using 4-(4-chloro- 6-methylquinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1-oxide (prepared in analogy to the one in Example 18-1) and 1-(2,2-dimethyl-1,3-dioxolanyl)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, 1 H), 5.24 (dd, J = 16.04, 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(5-methyl-1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinolin yl]amino}propane-1,2-diol N N hloromethylquinolinyl)methyl-2,3,4,5-tetrahydro-1,4-benzothiazepine N N A mixture of 5-methyl-2,3,4,5-tetrahydro-1,4-benzothiazepine (1.0 g, 5.58 mmol) and 2,4- dichloromethylquinoline (1.7 g, 8.02 mmol) was heated with stirring in a 2 mL of microwave process vial for 5 hours at 170 oC under microwave irradiation. The t 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-1,4-benzothiazepine and hloro methylquinolinyl)methyl-2,3,4,5-tetrahydro-1,4-benzothiazepine. 4-(4-Chloromethylquinolinyl)methyl-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1- dioxide N N To a solution of the above mixture of 5-methyl-2,3,4,5-tetrahydro-1,4-benzothiazepine and 4-(4- chloromethylquinolinyl)methyl-2,3,4,5-tetrahydro-1,4-benzothiazepine (427 mg) in dichloromethane was added a solution of 3-chloroperbenzoic acid (693 mg, 3.01 mmol) in dichloromethane in an ice bath. After being d 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 ed by flash column chromatography to give 130 mg of the product. 3-{[6-Methyl(5-methyl-1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinolin yl]amino}propane-1,2-diol N N The title compound was prepared in analogy to Example 32-1 in Scheme 10 by using 4-(4- chloromethylquinolinyl)methyl-2,3,4,5-tetrahydro-1,4-benzothiazepine oxide and 1-(2,2-dimethyl-1,3-dioxolanyl)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), .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 N-[(3-Aminooxetanyl)methyl](7-morpholinyl-1,1-dioxido-2,3-dihydro-1,4- benzothiazepin-4(5H)-yl)methylquinolinamine O NH NH O N N N-{[3-(Dibenzylamino)oxetanyl]methyl}methyl[7-(morpholinyl)-1,1-dioxido-2,3- dihydro-1,4-benzothiazepin-4(5H)-yl]quinolinamine O N N O N N A mixture of N-{[3-(dibenzylamino)oxetanyl]methyl}methyl[7-fluoro-1,1-dioxido-2,3- dihydro-1,4-benzothiazepin-4(5H)-yl]quinolinamine (100 mg, 0.16 mmol, prepared in analogy to N-{[3-(dibenzylamino)oxetanyl]methyl}(8-methoxy-1,1-dioxido-2,3-dihydro- 1,4-benzothiazepin-4(5H)-yl)methylquinolinamine in Example 1-1 by using 2,4-dichloro- ylquinoline, 7-fluoro-2,3,4,5-tetrahydro-1,4-benzothiazepine and nomethyl)-N,N- dibenzyloxetanamine) and morpholine (0.5 mL) was heated with stirring in a sealed 2 mL of microwave process via for 3 hours at 120 ºC 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.
N-[(3-Aminooxetanyl)methyl][(7-morpholinyl)-1,1-dioxido-2,3-dihydro-1,4- benzothiazepin-4(5H)-yl]methylquinolinamine O NH NH O N N A mixture of N-{[3-(dibenzylamino)oxetanyl]methyl}methyl[7-(morpholinyl)-1,1- dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl]quinolinamine (100 mg, 0.14 mmol), 10% palladium hydroxide on active carbon (100 mg) and trifluoroacetic 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 romethane. The organic layer was dried over anhydrous sodium e, and concentrated in vacuo. The e was purified by preparative HPLC to afford 30 mg of the product (yield was 40%). MS obsd.
(ESI+) [(M+H)+] 524, 1HNMR ((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 N-[(3-Aminooxetanyl)methyl]{1,1-dioxido[4-(propanyl)piperazinyl]-2,3- dihydro-1,4-benzothiazepin-4(5H)-yl}methylquinolinamine O NH2 N N The title compound was prepared in analogy to Example 33-1 in Scheme 11 by using N-{[3- (dibenzylamino)oxetanyl]methyl}methyl[7-fluoro-1,1-dioxido-2,3-dihydro-1,4- benzothiazepin-4(5H)-yl]quinolinamine (prepared in analogy to the one in Example 33-1) and 4-(propanyl)piperazine. MS obsd. (ESI+) [(M+H)+] 565, 1HNMR ((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). e 34 3-{[4-(4-Aminoquinolinyl)-1,1-dioxido-2,3,4,5-tetrahydro-1,4-benzothiazepin yl]oxy}propanol N N 4-(4-Chloroquinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepinol 1,1-dioxide N N O To a stirred solution of 4-(4-chloroquinolinyl)methoxy-2,3,4,5-tetrahydro-1,4- benzothiazepine 1,1-dioxide (2.0 g, 5.15 mmol, prepared in analogy to 4-(4-chloro methylquinolinyl)-2,3,4,5-tetrahydro-1,4-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 oC. After being stirred at 0 oC 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 × 2). The combined organic layers were washed with a saturated aqueous sodium bicarbonate solution (20 mL × 3) and brine (20 mL × 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-Chloroquinolinyl)- 1,1-dioxido-2,3,4,5-tetrahydro-1,4-benzothiazepin yl]oxy}propanol N N A mixture of 4-(4-chloroquinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepinol 1,1-dioxide (374.0 mg, 1.0 mmol), 3-bromo-propanol (0.37 mL, 3.0 mmol) and ium carbonate (415.0 mg, 3.0 mmol) in N, N-dimethylformamide (1.5 mL) was heated with ng at 70 oC for 2 hours. After being cooled to room ature, the ing mixture was extracted with ethyl e (150 mL × 2). The combined organic layers were washed with water (50 mL × 2) and a saturated aqueous ammonium chloride solution (50 mL × 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 cation. MS obsd. (ESI+) [(M+H)+] 433. tert-Butyl {2-[8-(3-hydroxypropoxy)-1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)- yl]quinolinyl}carbamate NH O N N A mixture solution of 3-{[4-(4-chloroquinolinyl)-1,1-dioxido-2,3,4,5-tetrahydro-1,4- benzothiazepinyl]oxy}propanol (300.0 mg, 0.70 mmol), tert-butyl ate (175.0 mg, 1.5 mmol), 1,1'-bis(diphenylphosphino)ferrocene (70.0 mg, 0.113 mmol), 1,1'- 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 oC for 2 hours under microwave irridiation. After being cooled to room temperature, the on mixture was extracted with ethyl acetate (100 mL). The organic layer was washed with brine (50 mL × 2), dried over anhydrous sodium e 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-Aminoquinolinyl)-1,1-dioxido-2,3,4,5-tetrahydro-1,4-benzothiazepin yl]oxy}propanol N N A mixture solution of tert-butyl {2-[8-(3-hydroxypropoxy)-1,1-dioxido-2,3-dihydro-1,4- benzothiazepin-4(5H)-yl]quinolinyl}carbamate (359.1 mg, the crude product of the above step) and oroacetic 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 e (100 mL). The organic layer was washed with brine (50 mL × 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), 4.11 (t, J = 6.32 Hz, 2 H), 3.71 (t, J = 6.19 Hz, 2 H), 3.62 - 3.49 (m, 2 H), 2.11 - 1.78 (m, 2 H).
Example 35 N-[(3-Aminooxetanyl)methyl](1,1-dioxidophenoxy-2,3-dihydro-1,4-benzothiazepin- 4(5H)-yl)methylquinolinamine 2 O N N 4-(4-Chloromethylquinolinyl)phenoxy-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1- dioxide N N A mixture of 4-(4-chloromethylquinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepinol 1,1- dioxide (250.0 mg, 0.65 mmol, prepared in analogy to 4-(4-chloroquinolinyl)-2,3,4,5- tetrahydro-1,4-benzothiazepinol 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 yl sulfoxide (1.5 mL). The reaction mixture was heated with stirring at 120 oC for 6 hours. After being cooled to room temperature, the reaction e was extracted with ethyl acetate (150 mL × 2), washed with water (50 mL × 2) and a ted aqueous ammonium chloride solution (50 mL × 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 r purification. MS obsd.
(ESI+) [(M+H)+] 465.
N-{[3-(Dibenzylamino)oxetanyl]methyl}(1,1-dioxidophenoxy-2,3-dihydro-1,4- benzothiazepin-4(5H)-yl)methylquinolinamine N O N N A mixture solution of 4-(4-chloromethylquinolinyl)phenoxy-2,3,4,5-tetrahydro-1,4- benzothiazepine 1,1-dioxide ( 167.0 mg, 0.36 mmol), (3-(aminomethyl)-N,N-dibenzyloxetan amine ( 609.0 mg, 2.16 mmol), 1,1'-bis(diphenylphosphino)-ferrocenedichloropalladium(II) (15.0 mg, 0.02 mmol), 1,1'-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 oC 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 × 2), dried over ous 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.
N-[(3-Aminooxetanyl)methyl](1,1-dioxidophenoxy-2,3-dihydro-1,4-benzothiazepin- 4(5H)-yl)methylquinolinamine 2 O N N A mixture of N-{[3-(dibenzylamino)oxetanyl]methyl}(1,1-dioxidophenoxy-2,3-dihydro- 1,4-benzothiazepin-4(5H)-yl)methylquinolinamine (90 mg, 0.13 mmol), palladium hydroxide on carbon (40 mg) and oroacetic 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 ed and trated in vacuo. The residue was ed 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 N~3~-[2-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)methylquinolinyl]- beta-alaninamide N N Methyl N-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)methylquinolinyl]- beta-alaninate N N To a solution of N-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)methylquinolin- 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 ature for 20 minutes, and then refluxed at 80 °C for 2 hours. After being cooled to room ature, the mixture was concentrated in vacuo. The residue was dissolved in dichloromethane, washed with a saturated s solution of sodium onate, 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-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)methylquinolinyl]- beta-alaninamide N N O A mixture of methyl N-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl) methylquinolinyl]-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 d product as a solid. MS obsd. (ESI+) [(M+H)+] 425, 1H NMR (400 MHz, DMSO-d6) 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 (1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)methylquinolin yl]amino}butanamide N N O The title compound was prepared in analogy to Example 36-1 in Scheme 13 by using 3-{[2-(1,1- dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)methylquinolinyl]amino}butanoic acid (prepared in analogy to N-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl) methylquinolinyl]-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-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)methylquinolinyl]amino}- 2-methylpropanamide N N The title compound was prepared in analogy to Example 36-1 by using 3-{[2-(1,1-dioxido-2,3- dihydro-1,4-benzothiazepin-4(5H)-yl)methylquinolinyl]amino}methylpropanoic acid (prepared in analogy to N-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl) methylquinolinyl]-beta-alanine in e 14-2). MS obsd. (ESI+) [(M+H)+] 439, 1H NMR (400 MHz, DMSO-d6) 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 N~2~-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)methylquinolinyl]-L- alaninamide N N The title compound was prepared in analogy to Example 36-1 by using 1,1-dioxido-2,3- dihydro-1,4-benzothiazepin-4(5H)-yl)methylquinolinyl]-L-alanine (prepared in analogy to N-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)methylquinolinyl]-beta- alanine in Example 14-2). MS obsd. (ESI+) +] 425, 1H NMR (400 MHz, DMSO-d6) 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-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)methylquinolin yl]glycinamide N N The title nd was prepared in analogy to e 36-1 by using N~2~-[2-(1,1-Dioxido- 2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)methylquinolinyl]glycine (prepared in analogy to N-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)methylquinolinyl]-beta- alanine in Example 14-2). MS obsd. (ESI+) [(M+H)+] 411, 1H NMR (400 MHz, DMSO-d6) 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 N~2~-[2-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)methylquinolinyl]-N- methylglycinamide N N The title compound was prepared in analogy to Example 36-1 by using 2-(1,1-dioxido-2,3- dihydro-1,4-benzothiazepin-4(5H)-yl)methylquinolinyl]glycine (prepared in analogy to N- [2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)methylquinolinyl]-beta-alanine in Example 14-2) and a solution of methylamine in ethanol. MS obsd. (ESI+) [(M+H)+] 425, 1H NMR (400 MHz, DMSO-d6) 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)Amino{[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl) methylquinolinyl]amino}propanol N N tert-Butyl (2S)({[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl) methylquinolinyl]amino}methyl)-2,2-dimethyl-1,3-oxazolidinecarboxylate N N A mixture of 4-(4-chloromethylquinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1- dioxide (332 mg, 0.890 mmol), tert-butyl (2S)aminomethyl-2,2-dimethyl-1,3-oxazolidine carboxylate (205 mg, 0.890 mmol), 1,1'-bis(diphenylphosphino)ferrocene- palladium(II)dichloride (73 mg, 0.089 mmol), 1,1'-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 ºC for 1.5 hours under microwave irradiation. The reaction mixture was concentrated in vacuo. The residue was purified by flash column tography to afford 251 mg of the desired t. (2S)Amino{[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl) methylquinolinyl]amino}propanol N N A mixture of tert-butyl 4-({[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl) methylquinolinyl]amino}methyl)-2,2-dimethyl-1,3-oxazolidinecarboxylate (251 mg) and a solution of hloride in ethyl acetate (13 mL, 4 N) was d at room temperature overnight. The reaction mixture was concentrated in vacuo. The residue was dissolved in water, and basified with a saturated s solution of sodium bicarbonate to about pH 9, and extracted with ethyl acetate ( 20 mL × 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)Amino{[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl) methylquinolinyl]amino}propanol N N The title compound was prepared in analogy to e 37-1 in Scheme 14 by using 4-(4- chloromethylquinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide, tert-butyl (2R)aminomethyl-2,2-dimethyl-1,3-oxazolidinecarboxylate. 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 H), 6.19 (s, 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 N-[(2-Amino-4,5-dihydro-1,3-oxazolyl)methyl](1,1-dioxido-2,3-dihydro-1,4- benzothiazepin-4(5H)-yl)methylquinolinamine N N A mixture of 1-amino{[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl) methylquinolinyl]amino}propanol (80 mg, 0.18 mmol, prepared in analogy to Example 9- 7) and potassium e (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 ºC. After being stirred at room temperature for 3 hours, the mixture was stirred further with concentrated hloric 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 romethane (15 mL × 3). The combined organic layers were dried over sodium e 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-Aminomethyl-4,5-dihydro-1,3-oxazolyl)methyl](1,1-dioxido-2,3-dihydro-1,4- benzothiazepin-4(5H)-yl)methylquinolinamine N 2 N N To a mixture of 1-amino{[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl) methylquinolinyl]amino}methylpropanol (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 ºC, 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 e 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 R)Amino-4,5-dihydro-1,3-oxazolyl]methyl}(1,1-dioxido-2,3-dihydro-1,4- hiazepin-4(5H)-yl)methylquinolinamine N N The title compound was prepared in analogy to Example 38-1 in Scheme 15 by using (2R) amino{[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)methylquinolin yl]amino}propanol red in analogy to Example 37-2). MS obsd. (ESI+) [(M+H)+] 452, 1H NMR (400 MHz, CD 3OD) 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 N-{[(4S)Amino-4,5-dihydro-1,3-oxazolyl]methyl}(1,1-dioxido-2,3-dihydro-1,4- benzothiazepin-4(5H)-yl)methylquinolinamine N N The title compound was prepared in analogy to Example 38-1 in Scheme 15 by using (2S) amino{[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)methylquinolin yl]amino}propanol (prepared in y to Example 37-1). MS obsd. (ESI+) [(M+H)+] 452, 1H NMR (400 MHz, CD 3OD) 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 cis[2-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)methylquinolinyl]- 4,5,6,6a-tetrahydro-3aH-pyrrolo[3,4-d][1,3]oxazolamine N O N N To a mixture of cisamino[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl) methylquinolinyl]pyrrolidinol (90 mg 0.20 mmol, ed in analogy to Example 19-3 in Scheme 7 by using 4-(4-chloromethylquinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide and tert-butyl [cishydroxypyrrolidinyl]carbamate) and sodium acetate (82 mg, 1.0 mmol) in ol (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), .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-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)methylquinolinamine N N 2-{[(1E)(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)ethylidene]amino} methylbenzonitrile N N To a d solution of 1-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)ethanone (6.0 g, .0 mmol) in dry dichloromethane (100 mL) was added phosphorus oxychloride (2.5 mL, 27.3 mmol) at 10 ºC. After being stirred for 20 minutes at room temperature, a solution of 2-amino 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 ature, the reaction mixture was diluted with water (50 mL), ed with a saturated aqueous solution of sodium bicarbonate to about pH 8. The ted 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-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)methylquinolinamine N N A mixture of 2-{[(1E)(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)- yl)ethylidene]amino}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 ºC for 3 hours under argon. After the reaction e was cooled to about 40 ºC, 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+) +] 354, 1H NMR (400 MHz, DMSO-d6) 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 N-[2-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)methylquinolin yl]glycinamide N N O 2-Chloro-N-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)methylquinolin yl]acetamide N N To a on of 2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)methylquinolin amine (500 mg, 1.4 mmol) in chloroform (10 mL) was added 1,8-diazabicyclo[5.4.0]undec ene (0.41 mL, 2.8 mmol) followed by chloroacetyl chloride (0.17 mL, 2.1 mmol) at room temperature. The resulting on was heated with stirring at 70 ºC 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 × 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 ite solid. 2-Azido-N-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)methylquinolin yl]acetamide NH 3 N N To a on of 2-chloro-N-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl) methylquinolinyl]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 d with ethyl acetate (20 mL), washed with water (10 mL), dried over sodium sulfate, and trated in vacuo. The residue was purified by column chromatography on silica gel (20% ethyl acetate in petroleum ether) to give 110 mg of the product as a white powder.
N-[2-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)methylquinolin yl]glycinamide N N To a solution of 2-azido-N-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl) methylquinolinyl]acetamide (110 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)+] 411, 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 H).
Example 40-2 N-[2-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)methylquinolinyl] alaninamide N N 2-Bromo-N-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)methylquinolin yl]methylpropanamide N N To a solution of 2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)methylquinolin amine (200 mg, 0.566 mmol) in chloroform (10 mL) was added triethylamine (0.124 mL), followed by 2-bromomethylpropionyl chloride (286 mg, 1.30 mmol). The resulting mixture was heated at 110 ºC for 2 hours under microwave irradiation. After being cooled to room temperature, the mixture was trated 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-N-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)methylquinolin yl]methylpropanamide O N N N To a solution of 2-bromo-N-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl) methylquinolinyl]methylpropanamide (160 mg, 0.319 mmol) in actonitrile (15 mL) was added sodium azide (62 mg, 0.958 mmol). After being refluxed ght, the ing 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.
N-[2-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)methylquinolinyl] methylalaninamide N N To a on 2-azido-N-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl) methylquinolinyl]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 here, 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, CDCl3) 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 N-[2-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)methylquinolin yl]alaninamide N N The title compound was prepared in analogy to e 40-2 in Scheme 18 by using 2-(1,1- dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)methylquinolinamine, 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-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)methylquinolin yl]butanamide N N O The title compound was prepared in analogy to Example 40-2 in Scheme 18 by using 2-(1,1- dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)methylquinolinamine, 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). e 41 N-[2-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)methylquinolinyl] methoxymethylpropanamide N N To a solution of 2-bromo-N-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl) methylquinolinyl]methylpropanamide (80 mg, 0.159 mmol, prepared in e 40-2) in methanol (5 mL) was added ethylamine (1 mL), the resulting mixture was heated under reflux overnight. After being cooled to room temperature, the resulting mixture was concentrated in vacuo. The e was purified by preparative TLC (eluting with 33% ethyl e 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 N~1~-[2-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)methylquinolinyl]- 4,4,4-trifluorobutane-1,3-diamine NH NH2 N N N-[2-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)methylquinolinyl](1,3- dioxo-1,3-dihydro-2H-isoindolyl)-4,4,4-trifluorobutanamide O N O NH O N N To a solution of 2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)methylquinolin 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-(1,3-dioxo-1,3-dihydro-2H-isoindolyl)- 4,4,4-trifluorobutanoyl chloride (670 mg, 2.3 mmol) in dichloromethane (4 mL) followed by isopropylethylamine (0.3 mL). The resulting mixture was stirred at room temperature for 1 hour and heated at 85 ºC for onal 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 × 2). The combined organic layers were washed with brine, dried over sodium sulfate and concentrated in vacuo. The residue was purified by flash tography to afford 230 mg of the product as a solid (yield was 66%). 3-Amino-N-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)methylquinolin yl]-4,4,4-trifluorobutanamide NH O N N O To a solution of N-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)methylquinolin- 4-yl](1,3-dioxo-1,3-dihydro-2H-isoindolyl)-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 ºC for 2 hours. After being cooled to room temperature, the mixture was trated 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%).
N~1~-[2-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)methylquinolinyl]- 4,4,4-trifluorobutane-1,3-diamine NH NH N N To a solution of 3-amino-N-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl) quinolinyl]-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 ing solution was heated at 85 ºC 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 ght. 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 romethane (20 mL × 3). 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 60 mg of the title product as a solid (yield was 65%). MS obsd. (ESI+) [(M+H)+] 479, 1H NMR (400 MHz, CDCl3) 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), .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 N-[2-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)methylquinolinyl]-beta- alaninamide NH O N N The title compound was ed in analogy to 3-amino-N-[2-(1,1-dioxido-2,3-dihydro-1,4- benzothiazepin-4(5H)-yl)methylquinolinyl]-4,4,4-trifluorobutanamide in Example 42-1 in Scheme 19 by using 2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)methylquinolin- 4-amine and 3-(1,3-dioxo-1,3-dihydro-2H-isoindolyl)propanoyl chloride. MS obsd. (ESI+) [(M+H)+] 425, 1H NMR (400 MHz, CDCl3) 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-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-N-{[3-(ethylamino)oxetan yl]methyl}methylquinolinamine O N N N To a stirred solution of N-[(3-aminooxetanyl)methyl](1,1-dioxido-2,3-dihydro-1,4- hiazepin-4(5H)-yl)methylquinolinamine (200 mg, 0.46 mmol, prepared in analogy to Example 2-2), acetaldehyde (25.6 µL, 0.46 mmol) and acetic acid (270 µL) 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 on 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 %). MS obsd. (ESI+) [(M+H)+] 467, 1H NMR(400 MHz, 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-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)methyl-N-[1-(oxetan yl)pyrrolidinyl]quinolinamine N O N N To a solution of [2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)methyl-N- (pyrrolidinyl)quinolinamine (21 mg, 0.05 mmol, prepared in analogy to Example 21-4) and oxetanone (7.2 mg, 0.10 mmol) in tetrahydrofuran (2 mL) was added acetic acid (8.6 µL, 0.15 mmol). After the mixture being stirred at 55 ºC for 1 hour, sodium triacetoxyborohydride (21 mg, 0.10 mmol) was added to the mixture. After being stirred for 2 hours at 65 ºC, the reaction mixture was concentrated in vacuo. The residue was portioned between ethyl acetate and a saturated aqueous solution of sodium carbonate. The ted organic layer was washed with water, dried over sodium sulfate, and concentrated in vacuo. The residue was purified by ative HPLC to afford 10 mg of the t 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 N'-[2-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5 H)-yl)methylquinolinyl]-N- ethyl-N-(oxetanyl)ethane-1,2-diamine N N The title compound was prepared in analogy to Example 44-1 in Scheme 20 by using N-[2-(1,1- dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)methylquinolinyl]-N'-ethylethane-1,2- diamine (prepared in analogy to Example 3-37) and oxetanone. 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 N-[2-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)methylquinolinyl]-N'- (oxetanyl)propane-1,3-diamine NH N N N To a stirred of N-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)methylquinolin yl]propane-1,3-diamine (84 mg, 0.2 mmol, prepared in y to Example 9-3), oxetanone (15 mg, 0.21 mmol ) and ethyldiisopropylamine (43 µL, 0.25 mmol ) in dichloromethane (10 mL) was added molecular sieves (4Å, 84 mg) followed by sodium triacetoxyborohydride (63.6 mg, 0.3 mmol). After being stirred at room temperature overnight, r 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)methylquinolinyl]-N'-(oxetan yl)propane-1,3-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 1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5 H)-yl)methylquinolinyl]-N- (oxetanyl)pyrrolidinamine N N The title compound was prepared in analogy to e 45-1 in Scheme 20 by using 1-[2-(1,1- dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)methylquinolinyl]pyrrolidinamine and oxetanone (prepared in analogy to e 25) and oxetanone. 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 N-[2-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)methylquinolinyl]-N'- (oxetanyl)ethane-1,2-diamine N N The title compound was prepared in analogy to Example 45-1 in Scheme 20 by using N-[2-(1,1- dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)methylquinolinyl]-N'-(oxetan yl)ethane-1,2-diamine (prepared in analogy to Example 9-16) and oxetanone. MS obsd. (ESI+) +] 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-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)methylquinolinyl]-N'- (pyridinyl)ethane-1,2-diamine N N A e of N-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)methylquinolin yl]ethane-1,2-diamine (150 mg, 0.38 mol, prepared in analogy to Example 9-16), 2-bromopyridine (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 ate (247.6 mg, 0.76 mmol) and N-methylpyrolidinone (3 mL) was heated with stirring at 150 ºC 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-d6) 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), .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). e 47-1 (4R)[2-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)methylquinolinyl] hydroxypyrrolidinone O N N N A mixture of 4-(4-bromomethylquinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1- dioxide (400 mg, 0.96 mol, prepared in analogy to 4-(4-chloro(trifluoromethoxy)quinolin yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide in Example 17-1), (4R) hydroxypyrrolidinone (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-1,2-diamine (0.1 mL, 0.63 mmol) and diethylene glycol dimethyl ether (10 mL) was heated with stirring in a 10 mL of microwave s vial for 2 hours at 140 ºC. The mixture was diluted with dichloromethane, washed with water. The aqueous was back extracted with romethane.
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-d6) 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). e 47-2 N-[2-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)methylquinolinyl] oxopyrrolidinecarboxamide O H NH O N N A mixture of 4-(4-bromomethylquinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1- dioxide (500 mg, 1.19 mol, prepared in analogy to 4-(4-chloro(trifluoromethoxy)quinolin yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide in Example 17-1), 5-oxopyrrolidine carboxamide (307 mg, 2.39 mmol), copper(I) iodide (23 mg, 0.12 mmol), potassium carbonate (497 mg, 3.60 mmol), trans-N,N'-dimethylcyclohexane-1,2-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 oC under microwave irridiation. The e was d with dichloromethane, washed with water. The aqueous layer was back extracted with romethane. The combined c 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-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)methylquinolinyl] oxopyrrolidinecarboxamide as light brown solid. MS obsd. (ESI+) [(M+H)+] 451, 1H NMR (400 MHz, DMSO-d6) 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-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)methyl-N-(1H-pyrazol yl)quinolinamine N N The title compound was prepared in analogy to Example 47-1 in Scheme 5 by using 4-(4-bromo- ylquinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide (prepared in analogy to 4-(4-chloro(trifluoromethoxy)quinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1- dioxide in Example 17-1) and 1H-pyrazolamine. 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 N-[2-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)methylquinolin yl]pyridinecarboxamide NH O N N The title compound was ed in analogy to e 47-1 in Scheme 5 by using 4-(4-bromo- 6-methylquinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide (prepared in analogy to 4-(4-chloro(trifluoromethoxy)quinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1- dioxide in Example 17-1) and pyridinecarboxamide. 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). e 47-5 N-[2-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)methylquinolin yl]piperidinecarboxamide NH O N N The title compound was prepared in analogy to Example 47-1 in Scheme 5 by using 4-(4-bromo- 6-methylquinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide (prepared in analogy to 4-(4-chloro(trifluoromethoxy)quinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1- dioxide in Example 17-1) and piperidinecarboxamide. 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 N-[2-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)methylquinolinyl] inyl)acetamide O NH N N The title compound was prepared in analogy to Example 47-1 in Scheme 5 by using 4-(4-bromo- ylquinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide (prepared in analogy to 4-(4-chloro(trifluoromethoxy)quinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1- dioxide in Example 17-1) and 2-(pyridinyl)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 N-[2-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)methylquinolin yl]methanesulfonamide trifluoroacetate O F NH F O O N N The title compound was prepared in analogy to Example 47-1 in Scheme 5 by using 4-(4-bromo- 6-methylquinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide (prepared in analogy to 4-(4-chloro(trifluoromethoxy)quinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1- e in Example 17-1) and methanesulfonamide. MS obsd. (ESI+) [(M+H)+] 432, 1H NMR (400 MHz, DMSO-d6) δ ppm 7.98 - 7.90 (m, 2 H), 7.88 - 7.82 (d, J = 7.2 Hz, 1 H), 7.72 - 7.65 (t, J = 2 Hz, 1 H), 7.65 - 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 N-[2-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)methylquinolin azinecarboxamide NH O N N The title nd was prepared in y to Example 47-1 in Scheme 5 by using 4-(4-bromo- 6-methylquinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide (prepared in analogy to 4-(4-chloro(trifluoromethoxy)quinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1- dioxide in Example 17-1) and pyrazinecarboxamide. 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 N-[2-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)methylquinolinyl] hydroxyacetamide NH O N N The title compound was prepared in analogy to Example 47-1 in Scheme 5 by using 4-(4-bromo- 6-methylquinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide (prepared in analogy to 4-(4-chloro(trifluoromethoxy)quinolinyl)-2,3,4,5-tetrahydro-1,4-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). e 48 N-[2-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)methylquinolin yl]pyridinecarboxamide N N A mixture of pyridinecarboxylic acid amide (99 mg, 0.8 mmol), hloro methylquinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide (300 mg, 0.8 mmol, prepared in analogy to 4-(4-chloro(trifluoromethoxy)quinolinyl)-2,3,4,5-tetrahydro-1,4- benzothiazepine 1,1-dioxide in Example 17-1), cyclohexane-1,3-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 oC. The reaction mixture was concentrated in vacuo. The e 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 N-[2-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)methylquinolin yl]azetidinecarboxamide NH O N N utyl 2-{[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)methylquinolin yl]carbamoyl}azetidinecarboxylate NH O N N S O The title compound was prepared in analogy to Example 48-1 in Scheme 5 by using 4-(4- bromomethylquinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide (prepared in analogy to hloro(trifluoromethoxy)quinolinyl)-2,3,4,5-tetrahydro-1,4- benzothiazepine oxide in Example 17-1) and tert-butyl 2-carbamoylazetidine carboxylate.
N-[2-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)methylquinolin yl]azetidinecarboxamide NH O N N To a solution of tert-butyl 2-{[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl) methylquinolinyl]carbamoyl}azetidinecarboxylate (80 mg, 0.15 mmol) in ethyl e (10 mL) was added a solution of hydrochloride in ethyl acetate (4 N, 30 mL) dropwise in an icewater 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 trifluoroacetic acid salt of the desired product. The trifluoroacetic 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). e 50-1 1-[2-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5 H)-yl)methylquinolinyl] urea NH N N N O To a solution of 2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)methylquinolin amine (180 mg, 0.5 mmol, prepared in analogy to 4-(4-chloro(trifluoromethoxy)quinolin yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide in Example 17-1) and triethylamine (103 mg) in ydrofuran (15 mL) was added a solution of isocyanato-benzene (59.6 mg, 0.5 mmol) in tetrahydrofuran (5 mL) at 0 oC. The reaction was stirred at room temperature overnight and then heated at 50 oC 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 d 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 1-[2-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5 H)-yl)methylquinolinyl] ethylurea NH N N N The title compound was prepared in analogy to Example 50-1 by using 2-(1,1-dioxido-2,3- dihydro-1,4-benzothiazepin-4(5H)-yl)methylquinolinamine (prepared in analogy to 4-(4- (trifluoromethoxy)quinolinyl)-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), .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 N-[6-Cyclopropyl(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinolin yl]propane-1,3-diamine NH NH2 N N 4-(4-Chlorocyclopropylquinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide N N O To a solution of 4-(6-bromochloroquinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1- e (1.0 g, 2.3 mmol, prepared in analogy to 4-(4-chloro(trifluoromethoxy)quinolinyl)- 2,3,4,5-tetrahydro-1,4-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)-1,1'-binaphthyl (143 mg, 0.23 mmol) and potassium carbonate (320 mg, 2.3 mmol) under argon protection. After being heated at 90 oC for 16 hours, the reaction mixture was concentrated in vacuo. The e was dissolved in dichloromethane (100 mL), and the solution was washed with water (50 mL × 3), dried over sodium e, ed 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%).
N-[6-Cyclopropyl(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinolin yl]propane-1,3-diamine NH NH2 N N A mixture of 4-(4-chlorocyclopropylquinolinyl)-2,3,4,5-tetrahydro-1,4-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 oC under microwave irradiation. The reaction mixture was purified by preparative HPLC to give the oroacetic acid salt of the desired product. The trifluoroacetic 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,1 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](1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)- yl)quinolinecarbonitrile NH NH2 N N 4-(4-Chloroethynylquinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide N N To a degassed solution of 4-(6-bromochloroquinolinyl)-2,3,4,5-tetrahydro-1,4- benzothiazepine 1,1-dioxide (880 mg, 2 mmol, prepared in analogy to 4-(4-chloro (trifluoromethoxy)quinolinyl)-2,3,4,5-tetrahydro-1,4-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 × 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](1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)- yl)quinolinecarbonitrile NH NH2 N N A mixture of 4-(4-chloroethynylquinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1- dioxide (300 mg, 0.7 mmol), propane-1,3-diamine (64 mg, 0.8 mmol), 1,1'- bis(diphenylphosphino)ferrocene-palladium(II)dichloride (65 mg, 0.08 mmol), 1,1'- phenylphosphino)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 s vial for 1.5 hours at 120 ºC under microwave irradiation. The resulting e 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 lization 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 Example 53 N-[2-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)ethenylquinolin yl]propane-1,3-diamine NH NH N N 4-(4-Chloroethenylquinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide N N To a degassed solution of romochloroquinolinyl)-2,3,4,5-tetrahydro-1,4- benzothiazepine 1,1-dioxide (880 mg, 2 mmol, prepared in analogy to 4-(4-chloro uoromethoxy)quinolinyl)-2,3,4,5-tetrahydro-1,4-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 s layer was ted with ethyl acetate (100 mL × 2). The combined organic layers were dried over sodium sulfate and concentrated in vacuo to afford 0.4 g of the crude product.
N-[2-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)ethenylquinolin yl]propane-1,3-diamine NH NH N N The title compound was prepared in analogy to Example 52 in Scheme 22 by using 4-(4-chloro- 6-ethenylquinolinyl)-2,3,4,5-tetrahydro-1,4-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 N-[2-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)ethynylquinolin pane-1,3-diamine NH NH2 N N O hloroethynylquinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide N N To a degassed solution of 4-(6-bromochloroquinolinyl)-2,3,4,5-tetrahydro-1,4- benzothiazepine 1,1-dioxide (880 mg, 2 mmol, prepared in analogy to 4-(4-chloro (trifluoromethoxy)quinolinyl)-2,3,4,5-tetrahydro-1,4-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 ed for 2 hours, the reaction mixture was trated 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 d vigorously for 1 hour, the separated aqueous layer was extracted with ethyl acetate (100 mL × 2). The combined organic layers were dried over sodium sulfate and concentrated in vacuo to afford 0.45 g of the crude product.
N-[2-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)ethynylquinolin yl]propane-1,3-diamine NH NH N N The title compound was prepared in analogy to Example 52 in Scheme 22 by using 4-(4-chloro- 6-ethynylquinolinyl)-2,3,4,5-tetrahydro-1,4-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 N-[(3-Aminooxetanyl)methyl]methyl(1-oxido-2,3-dihydro-1,4-benzothiazepin- 4(5H)-yl)quinazolinamine NH 2 N N N-(3-Aminooxetanylmethyl)chloromethylquinazolinamine N Cl A solution of chloromethylquinazoline (645 mg, 3 mmol) and 3-(aminomethyl)oxetan- 3-amine (340 mg, 3.3 mmol) in ol (15 mL) was d 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.
N-[(3-Aminooxetanyl)methyl]methyl(1-oxido-2,3-dihydro-1,4-benzothiazepin- 4(5H)-yl)quinazolinamine NH 2 N N A mixture of N-(3-aminooxetanylmethyl)chloromethylquinazolinamine (140 mg, 0.5 mmol) and 2,3,4,5-tetrahydro-1,4-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 (Benzylamino)oxetanyl]methyl}methyl(1-oxido-2,3-dihydro-1,4- benzothiazepin-4(5H)-yl)quinazolinamine N N The title compound was prepared in analogy to Example 55-1 in Scheme 23 by using 2,4- romethylquinazoline, 3-(aminomethyl)-N-benzyloxetanamine 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-N-[6-methyl(1-oxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinazolin yl]propane-1,3-diamine N N The title compound was prepared in analogy to Example 55-1 in Scheme 23 by using 2,4- romethylquinazoline, 2-fluoropropane-1,3-diamine and 2,3,4,5-tetrahydro-1,4- 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 N-[2-(2,3-Dihydro-1,4-benzothiazepin-4(5H)-yl)methylquinazolinyl]-2,2- ropropane-1,3-diamine NH NH N N The title compound was prepared in analogy to Example 55-1 in Scheme 23 by using 2,4- dichloromethylquinazoline, 2,2-difluoropropane-1,3-diamine and 2,3,4,5-tetrahydro-1,4- 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 N-{[3-(Aminomethyl)oxetanyl]methyl}(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin- 4(5H)-yl)methylquinazolinamine N N O N-{[3-(Aminomethyl)oxetanyl]methyl}chloromethylquinazolinamine N Cl To a mixture of oxetane-3,3-diyldimethanamine (1.16 g, 10.0 mmol) and ylamine (1.4 mL, mol) in dichloromethane (15 mL) was added dropwise of a solution of 2,4-dichloro methylquinazoline (500 mg, 2.36 mmol) in romethane (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.
N-{[3-(Aminomethyl)oxetanyl]methyl}(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin- 4(5H)-yl)methylquinazolinamine N N The title compound was prepared in analogy to e 55-1 in Scheme 23 by using N-{[3- (aminomethyl)oxetanyl]methyl}chloromethylquinazolinamine and 2,3,4,5- ydro-1,4-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-N-[6-methyl(1-oxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinazolin yl]propane-1,3-diamine N N The title compound was prepared in analogy to Example 56-1 in Scheme 23 by using 2,4- romethylquinazoline, 2,2-difluoropropane-1,3-diamine and 2,3,4,5-tetrahydro-1,4- 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 (aminomethyl)oxetanyl]methyl}chloro(1,1-dioxido-2,3-dihydro-1,4- benzothiazepin-4(5H)-yl)quinazolinamine N N O 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-1,4-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 N-[2-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)methylquinazolinyl]-2,2- difluoropropane-1,3-diamine N N The title compound was prepared in analogy to Example 56-1 in Scheme 23 by using 2,4- dichloromethylquinazoline, 2,2-difluoropropane-1,3-diamine and 2,3,4,5-tetrahydro-1,4- 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 1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)methylquinazolinyl] fluoropropane-1,3-diamine NH NH N N The title compound was prepared in analogy to e 56-1 in Scheme 23 by using 2,4- dichloromethylquinazoline, 2-fluoropropane-1,3-diamine and 2,3,4,5-tetrahydro-1,4- 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 N-[6-Methyl(1-oxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinazolinyl]propane- 1,3-diamine NH NH N N The title compound was ed in analogy to Example 56-1 in Scheme 23 by using 2,4- dichloromethylquinazoline, propane-1,3-diamine and 5-tetrahydro-1,4-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 - .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-Aminooxetanyl)methyl](2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinazolin amine N N N-[(3-Aminooxetanyl)methyl]chloroquinazolinamine N Cl To a solution of 2,4-dichloroquinazoline (1.0 g, 5.024 mmol) in methanol (15 mL) was added 3- (aminomethyl)oxetanamine (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-Aminooxetanyl)methyl](2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinazolin amine N N To a solution of N-[(3-aminooxetanyl)methyl]chloroquinazolinamine (200 mg, 0.756 mmol) in N,N-dimethylformamide (4 mL) was added 2,3,4,5-tetrahydro-1,4-benzothiazepine (125 mg, 0.756 mmol) and triethylamine (230 mg, 2.268 mmol). After being heated at 130 oC for 4 hours under microwave ation, the reaction mixture was poured into water and extracted with ethyl e. 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 Example 57-2 N-[(3-Aminooxetanyl)methyl](1-oxido-2,3-dihydro-1,4-benzothiazepin-4(5H)- nazolinamine N N The title compound was prepared in analogy to Example 57-1 in Scheme 23 by using 2,4- dichloroquinazoline, 3-(aminomethyl)oxetanamine and 2,3,4,5-tetrahydro-1,4- benzothiazepine 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 N-[(3-Aminooxetanyl)methyl](1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)- yl)quinazolinamine N N The title compound was prepared in analogy to Example 57-1 in Scheme 23 by using 2,4- dichloroquinazoline, 3-(aminomethyl)oxetanamine and 2,3,4,5-tetrahydro-1,4- 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 - 7.11 (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 N-[(3-Aminooxetanyl)methyl]chloro(2,3-dihydro-1,4-benzothiazepin-4(5H)- yl)quinazolinamine Cl O N N The title compound was prepared in analogy to Example 57-1 in Scheme 23 by using 2,4,6- trichloroquinazoline, nomethyl)oxetanamine and 5-tetrahydro-1,4- benzothiazepine. MS obsd. (ESI+) [(M+H)+] 428, 1H NMR (400 MHz, DMSO-d6) 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 N-[(3-Aminooxetanyl)methyl]chloro(1-oxido-2,3-dihydro-1,4-benzothiazepin- 4(5H)-yl)quinazolinamine Cl O N N The title compound was prepared in analogy to Example 57-1 in Scheme 23 by using 2,4,6- trichloroquinazoline, 3-(aminomethyl)oxetanamine and 2,3,4,5-tetrahydro-1,4- 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 N-[(3-Aminooxetanyl)methyl]chloro(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin- 4(5H)-yl)quinazolinamine Cl O N N The title compound was prepared in analogy to e 57-1 in Scheme 23 by using 2,4,6- trichloroquinazoline, nomethyl)oxetanamine and 2,3,4,5-tetrahydro-1,4- hiazepine 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 Example 57-7 2-{[2-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)methylquinazolin yl]amino}ethanol N N O The title compound was prepared in analogy to Example 57-1 in Scheme 23 by using 2,4- diichloromethylquinazoline, 2-aminoethanol and 2,3,4,5-tetrahydro-1,4-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)methylquinazolinamine N N 2-Chloromethylquinazolinamine N Cl A mixture of 2,4-dichloromethylquinazoline (500 mg, 2.348 mmol) and a solution of ammonia in tetrahydrofuran (20 mL, 3.0 M) was d 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-1,4-benzothiazepin-4(5H)-yl)methylquinazolinamine N N To a solution of 2-chloromethylquinazolinamine (454 mg, 2.345 mmol) in nol (5 mL) was added 2,3,4,5-tetrahydro-1,4-benzothiazepine (388 mg, 2.345 mmol). After being heated at 150 oC for 1.5 hours under microwave irradiation, the reaction mixture was filtered and the ted 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-d6) 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-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)methylquinazolinamine N N To a solution of oxone (670 mg, 1.117 mmol) in water (2.5 mL), which was cooled below 0 oC in an ice-bath, was added a solution of 2-(2,3-dihydro-1,4-benzothiazepin-4(5H)-yl) methylquinazolinamine (300 mg, 0.930 mmol) in methanol (15 mL) and tetrahydrofuran (3 mL) dropwise. The resulting mixture was d below 0 oC for 2 hours. The formed precipitate was ted 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-d6) 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 2-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)methylquinazolinyl] methylpropane-1,2-diamine N N S O 2-Chloromethylquinazolinyl)methylpropane-1,2-diamine NH 2 N Cl A solution of 2,4-dichloromethylquinazoline (500 mg, 2.35 mmol) and 2-methylpropane-1,2- diamine (365 µL, 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%).
N~1~-[2-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)methylquinazolinyl] methylpropane-1,2-diamine NH 2 N N A mixture of 2-chloromethylquinazolinyl)methylpropane-1,2-diamine (300 mg, 1.14 mmol) and 2,3,4,5-tetrahydro-1,4-benzothiazepine (226 mg, 1.25 mmol) in n-butanol (3 mL) was heated in the microwave at 160 oC for 2 hours. The resulting mixture was concentrated in vacuo. The residue was purified by flash column chromatography (eluting with 0 - 10% ol in dichloromethane) to afford 300 mg of the desired product as a white solid (yield was 67%).
N~1~-[2-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)methylquinazolinyl] methylpropane-1,2-diamine N N S O O To a stirred solution of 2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl) methylquinazolinyl]methylpropane-1,2-diamine (240 mg, 0.61 mmol ) in dichloromethane (15 mL) was added 3-chloroperoxybenzoic acid (263 mg, 1.53 mmol) at 0 oC. After being stirred at 0 oC for 20 minutes, the reaction mixture was washed with a saturated aqueous solution of sodium ate 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 N-[(3-Aminooxetanyl)methyl](1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)- 6-methylquinazolinamine O NH N N N-{[3-(Dibenzylamino)oxetanyl]methyl}(2,3-dihydro-1,4-benzothiazepin-4(5H)-yl) methylquinazolinamine O N N N A mixture of (2-chloromethylquinazolinyl)-[3-(dibenzylamino)oxetanylmethyl]-amine (2 g, 4.4 mmol, prepared in analogy to N-(3-aminooxetanylmethyl)chloro methylquinazolinamine in Example 55-1), 2,3,4,5-tetrahydro-1,4-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 oC. The reaction mixture was d with ethyl acetate, washed with water and brine. The c layer was dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by column tography on silica gel to give 1.7 g of the product as a white solid.
N-{[3-(Dibenzylamino)oxetanyl]methyl}(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin- 4(5H)-yl)methylquinazolinamine O N N N O To a solution of N-{[3-(dibenzylamino)oxetanyl]methyl}(2,3-dihydro-1,4-benzothiazepin- 4(5H)-yl)methylquinazolinamine (1.7 g, 2.89 mmol) in dichloromethane (30 mL) was added 3-chloroperbenzoic acid (75%, 1.33 g, 5.8 mmol) at 0 oC. The resulting mixture was stirred for 1 hour whilst ng the temperature to rise slowly to room ature. The reaction mixture was then washed with a ted aqueous solution of sodium carbonate, a saturated aqueous solution of sodium sulfite and brine. The organic layer was dried over sodium e, filtered, and trated in vacuo. The residue was purified by column chromatography on silica gel to give 1.4 g of the product as a white solid.
N-[(3-Aminooxetanyl)methyl](1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)- 6-methylquinazolinamine O NH N N To a solution of N-{[3-(dibenzylamino)oxetanyl]methyl}(1,1-dioxido-2,3-dihydro-1,4- benzothiazepin-4(5H)-yl)methylquinazolinamine (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 N-[(1-Aminocyclobutyl)methyl](1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl) methylquinazolinamine N N Benzylamino-cyclobutyl)methyl](1,1-dioxido-2,3-dihydro-1,4-benzothiazepin- 4(5H)-yl)methylquinazolinamine N N The title compound was prepared in analogy to N-{[3-(dibenzylamino)oxetanyl]methyl} (1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)methylquinazolinamine in e 61-1 in Scheme 24 by using 2,4-dichloromethylquinazoline, 1-(aminomethyl)-N- dibenzylcyclobutanamine and 5-tetrahydro-1,4-benzothiazepine.
N-[(1-Aminocyclobutyl)methyl](1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)yl) methylquinazolinamine N N O A mixture of N-[(1-benzylamino-cyclobutyl)methyl](1,1-dioxido-2,3-dihydro-1,4- benzothiazepin-4(5H)-yl)methylquinazolinamine (220 mg, 0.417 mmol), 10% of palladium hydroxide on carbon (30 mg), and trifluoroacetic acid (160 µL) in methanol (20 mL) was stirred at room temperature for 24 hours under a en 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 (Aminomethyl)oxetanyl]methyl}methyl(1-oxido-2,3-dihydro-1,4- benzothiazepin-4(5H)-yl)quinazolinamine NH NH N N 2-Chloromethylquinazolin-4(3H)-one N Cl To a solution of 2,4-dichloromethylquinazoline (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(1-oxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinazolin-4(3H)-one N N To a stirred solution of 2-chloromethylquinazolin-4(3H)-one (15 g, 77.3 mmol) and 2,3,4,5- tetrahydro-1,4-benzothiazepine e (16.8 g, 103 mmol) in toluene ( 200 mL) was added triethylamine (16.1 mL, 116 mmol). After being refluxed overnight, the reaction e 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%).
(Aminomethyl)oxetanyl]methyl}methyl(1-oxido-2,3-dihydro-1,4- benzothiazepin-4(5H)-yl)quinazolinamine NH NH N N To a solution of 6-methyl(1-oxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinazolin- 4(3H)-one (10 g, 29.5 mmol) and benzotriazolyloxytris(dimethylamino)phosphonium hexafluorophosphate (16.9 g, 38.3 mmol) in N,N-dimethylformamide (140 mL) was added 1,8- diazabicyclo[5.4.0]undecene (6.7 g, 44.2 mmol) at room temperature. After being stirred for minutes, (3-aminomethyl-oxetanyl)-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 ted aqueous layer was extracted with ethyl acetate (100 mL × 6 ). The organic layers were ed 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 t 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 (-)-N-{[3-(Aminomethyl)oxetanyl]methyl}methyl[(1-oxido-2,3-dihydro-1,4- benzothiazepin-4(5H)-yl]quinazolinamine and (+)-N-{[3-(Aminomethyl)oxetan yl]methyl}methyl[1-oxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl]quinazolin amine NH NH 2 NH NH N O N O N N N N S S O O (-) (+) The chiral separation of Example 62-1 n: IA; flow rate: 15 mL/min; gradient: 50% hexane in ethanol with 0.4% of triethylamine) affords (-)- (aminomethyl)oxetanyl]methyl} methyl[1-oxido-2,3-dihydro-1,4-benzothiazepin-4(5 H)-yl]quinazolinamine, MS obsd.
(ESI+) [(M+H)+] 438, and (+)-N-{[3-(aminomethyl)oxetanyl]methyl}methyl[1-oxido- 2,3-dihydro-1,4-benzothiazepin-4(5H)-yl]quinazolinamine, MS obsd. (ESI+) [(M+H)+] 438.
Example 62-4 and e 62-5 N~4~-[2-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)methylquinazolinyl] fluorobutane-1,4-diamine and N~1~-[2-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)- yl)methylquinazolinyl]fluorobutane-1,4-diamine 2 NH NH NH 2 N N N N N N S O S O O O A B The title compound was ed in analogy to Example 62-1 in Scheme 23 by using 2-chloro methylquinazolin-4(3H)-one, 2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide and 2- fluorobutane-1,4-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), 2.11 - 1.65 (m, 2 H).
Example 62-6 N-{[3-(Aminomethyl)oxetanyl]methyl}(2,3-dihydro-1,4-benzothiazepin-4(5H)-yl) methylquinazolinamine N N The title compound was prepared in analogy to Example 62-1 in Scheme 23 by using 2-chloro methylquinazolin-4(3H)-one, 2,3,4,5-tetrahydro-1,4-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 transFluoro[6-methyl(1-oxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinazolin- 4-yl]pyrrolidinamine F NH N N The title compound was prepared in analogy to Example 62-1 in Scheme 23 by using ro methylquinazolin-4(3H)-one, 5-tetrahydro-1,4-benzothiazepine 1-oxide and trans fluoropyrrolidinamine. 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 = 11.2 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 N-(2-{[2-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)methylquinolin yl]amino}ethyl)acetamide N N To a solution of N-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)methylquinolin- 4-yl]ethane-1,2-diamine (39 mg, 0.1 mmol, prepared in analogy to Example 9-11) in romethane (5 mL) was added acetic anhydride (12 mg, 0.12 mmol) at 0 oC. 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 × 2). The combined organic layers were washed with brine (10 mL), dried over sodium sulfate, filtered and trated in vacuo. The e 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 N-{[3-({[2-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)methylquinolin yl]amino}methyl)oxetanyl]methyl}acetamide NH N N N The title compound was prepared in analogy to Example 63-1 in Scheme 25 by using N-{[3- (aminomethyl)oxetanyl]methyl}(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl) methylquinolinamine (prepared in y 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 N-(3-{[2-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)methylquinolin yl]amino}propyl)acetamide NH N N N The title nd was prepared in analogy to Example 63-1 in Scheme 25 by using N-[2-(1,1- dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)methylquinolinyl]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 N-[2-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)methylquinazolin tamide N N A mixture of 2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)methylquinazolin amine (50 mg, 0.14 mmol, prepared in analogy to Example 59) and acetic anhydride (2 mL) was heated with stirring at 110 oC for 2 hours under nitrogen. The on mixture was diluted with ethyl acetate, washed with a saturated s 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 1-[2-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5 H)-yl)methylquinolinyl] methylpyrrolidinamine N N N-{1-[2-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)methylquinolinyl] methylpyrrolidinyl}acetamide N O N N The title compound was prepared in analogy to Example 3-1 in Scheme 26 by using 4-(4-chloro- 6-methylquinolinyl)methyl-2,3,4,5-tetrahydro-1,4-benzothiazepine oxide (prepared in analogy to the one in Example 2-1) and N-(3-methylpyrrolidinyl)acetamide. 1-[2-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5 H)-yl)methylquinolinyl] methylpyrrolidinamine N N A mixture of N-{1-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)methylquinolin- 4-yl]methylpyrrolidinyl}acetamide (102 mg, 0.21 mmol) and hydrochloric acid (2 N, 120 mL) was heated with stirring at 100 oC 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 romethane (200 mL × 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) δ 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 N-[(3-Aminooxetanyl)methyl](9-methoxy-1,1-dioxido-2,3-dihydro-1,4-benzothiazepin- 4(5H)-yl)methylquinolinamine O NH2 N N S O O O A mixture of N-[(3-aminooxetanyl)methyl](9-fluoro-1,1-dioxido-2,3-dihydro-1,4- benzothiazepin-4(5H)-yl)methylquinolinamine (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 ng in a sealed 5 mL of microwave process via for 20 minutes at 100 ºC under microwave irradiation. The resulting mixture was concentrated in vacuo. The residue was purified by preparative HPLC to afford 6 mg of the t (yield was 29%). MS obsd. (ESI+) [(M+H)+] 469, 1HNMR (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), .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-Aminooxetanyl)methyl]amino}methylquinolinyl)-2,3,4,5-tetrahydro-1,4- hiazepinol 1,1-dioxide O NH N N S O A mixture of N-[(3-aminooxetanyl)methyl](7-methoxy-1,1-dioxido-2,3-dihydro-1,4- benzothiazepin-4(5H)-yl)methylquinolinamine (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 ng in a sealed 5 mL of microwave process via for 20 minutes at 100 ºC under microwave irradiation. The resulting e 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-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)methylquinolinyl]amino}- 2-methylpropane-1,2-diol N N O 2-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)methyl-N-(2-methylpropen yl)quinolinamine N N A solution of 4-(4-chloromethylquinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1- dioxide (372.0 mg, 1.0 mmol, ed in analogy to 4-(4-chloro(trifluoromethoxy)quinolin- 2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide in Example 17-1) and 2-methylprop enamine (213.0 mg, 3.0 mmol) in 1-methylpyrrolidinone ( 1.0 mL) was heated with stirring at 160 oC 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 × 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-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)methylquinolinyl]amino}- 2-methylpropane-1,2-diol N N A mixture solution of 2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)methyl-N-(2- propenyl)quinolinamine (200.0 mg, 0.49 mmol), 4-methylmorpholine N-oxide monohydrate (67.2 mg, 0.58 mmol) and osmium ide (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 c layer was washed with brine (50 mL × 2), dried over anhydrous sodium sulfate and then concentrated in vacuo. The e 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-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)methylquinolin yl]amino}butane-1,3-diol OH OH N N A solution of 4-{[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)methylquinolin yl]amino}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 tetrahydrofuran (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 × 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). e 69-1 N-[6-Methyl(2-methyl-1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinolin yl]ethane-1,2-diamine N N 4-(4-Chloromethylquinolinyl)methyl-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1- dioxide N N O To a cooled solution of 4-(4-chloromethylquinolinyl)-2,3,4,5-tetrahydro-1,4- benzothiazepine 1,1-dioxide (186 mg, 0.5 mmol, prepared in analogy to 4-(4-chloro (trifluoromethoxy)quinolinyl)-2,3,4,5-tetrahydro-1,4-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 e (50 mL). The organic layer was dried over sodium sulfate and concentrated in vacuo. The residue was purified by flash column chromatography (eluting with % ethyl acetate in petroleum ether) to afford the desired t.
N-[6-Methyl(2-methyl-1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinolin yl]ethane-1,2-diamine N N The title nd was prepared in analogy to Example 9-1 in Scheme 30 by using 4-(4-chloro- 6-methylquinolinyl)methyl-2,3,4,5-tetrahydro-1,4-benzothiazepine oxide 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 Aminooxetanyl)methyl]methyl(2-methyl-1,1-dioxido-2,3-dihydro-1,4- benzothiazepin-4(5H)-yl)quinolinamine NH 2 N N The title compound was prepared in analogy to Example 69-1 in Scheme 30 by using 4-(4- chloromethylquinolinyl)methyl-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide and 3-(aminomethyl)oxetanamine. MS obsd. (ESI+) [(M+H)+] 453, 1H NMR (400 MHz, CD 3OD) 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 N-[(3-{[2-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)methylquinolin yl]amino}oxetanyl)methyl]-2,2,2-trifluoroacetamide H F N F NH O N N A solution of 4-(4-chloromethylquinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1- dioxide (500 mg, 1.341 mmol, prepared in y to 4-(4-chloro(trifluoromethoxy)quinolin- 2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide in Example 17-1), aminooxetan- 3-yl)methyl]-2,2,2-trifluoroacetamide (570 mg, 70%, 2.01 mmol), 1,1'- bis(diphenylphosphino)ferrocene-palladium(II)dichloride (99 mg, 0.134 mmol), 1,1'- phenylphosphino)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 ºC 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+) +] 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 N-[3-(Aminomethyl)oxetanyl](1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)- 6-methylquinolinamine N N To a solution of N-[(3-{[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl) methylquinolinyl]amino}oxetanyl)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 ing 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, CD 3OD) 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-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl) methylquinolinyl]amino}propane-1,3-diol NH OH N N A mixture of N-[(3-{[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl) methylquinolinyl]amino}oxetanyl)methyl]-2,2,2-trifluoroacetamide (269 mg, 0.503 mmol) and a on of ammonia in methanol (7 M, 10 mL,) was stirred at room temperature ght.
The resulting mixture was concentrated in vacuo and the residue was ed 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[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)methylquinolin yl]pyrrolidinone O N N N To a solution of 1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)methylquinolin- 4-yl]oxopyrrolidinecarboxamide (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, ied 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 ed 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+) +] 437, 1H NMR (400 MHz, DMSO-d6) 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-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)methyl-N-[2- (methylsulfinyl)ethyl]quinolinamine N N 2-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)methyl-N-[2- (methylsulfanyl)ethyl]quinolinamine N N A dried microwave process vial capped with a rubber septum was purged with argon and charged with ibenzylideneacetone)dipalladium(0) (2.88 mg, 0.005 mmol), 1-(N,N- dimethylamino)-1′-(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 methylquinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide (370 mg, 1.0 mmol, prepared in y to 4-(4-chloro(trifluoromethoxy)quinolinyl)-2,3,4,5-tetrahydro-1,4- benzothiazepine oxide 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 ºC under ave 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-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)methyl-N-[2- (methylsulfinyl)ethyl]quinolinamine N N To a solution of 2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)methyl-N-[2- (methylsulfanyl)ethyl]quinolinamine (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 s solution of sodium bicarbonate, dried over sodium sulfate, and trated in vacuo. The residue was purified by preparative HPLC to afford the desired product. MS obsd.
(ESI+) [(M+H)+] 444, 1H NMR (400 MHz, DMSO-d6) 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 N-{2-[(2-Aminoethyl)sulfonyl]ethyl}(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)- yl)methylquinolinamine S NH NH 2 N N To a solution of N-{2-[(2-aminoethyl)sulfanyl]ethyl}(1,1-dioxido-2,3-dihydro-1,4- benzothiazepin-4(5H)-yl)methylquinolinamine (40 mg, 0.087 mmol, prepared in analogy to Example 3-1 by using hloromethylquinolinyl)-2,3,4,5-tetrahydro-1,4- benzothiazepine 1,1-dioxide and 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), .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 N-[2-(1-Iminooxido-1,2,3,5-tetrahydro-4H-1lambda~4~,4-benzothiazepinyl) methylquinolinyl]ethane-1,2-diamine NH 2 N N N-[4-(4-Chloromethylquinolinyl)oxido-2,3,4,5-tetrahydro-1H-1lambda~4~,4- benzothiazepinylidene]-2,2,2-trifluoroacetamide N N N F To a suspension of 4-(4-chloromethylquinolinyl)-2,3,4,5-tetrahydro-1,4-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 d at room ature 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-Chloromethylquinolinyl)-2,3,4,5-tetrahydro-1H-1lambda~4~,4-benzothiazepin imine 1-oxide N N To a solution of N-[4-(4-chloromethylquinolinyl)oxido-2,3,4,5-tetrahydro-1H- 1lambda~4~,4-benzothiazepinylidene]-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 e was concentrated in vacuo. The residue was ed by column tography (eluting with 20 - 33% ethyl acetate in petroleum ether) to afford the N-unsubstituted sulfoximines. MS obsd. (ESI+) [(M+H)+] 372.
N-[2-(1-Iminooxido-1,2,3,5-tetrahydro-4H-1lambda~4~,4-benzothiazepinyl) methylquinolinyl]ethane-1,2-diamine NH 2 N N The title compound was ed in analogy to Example 9-1 in Scheme 35 by using 4-(4-chloro- 6-methylquinolinyl)-2,3,4,5-tetrahydro-1H-1lambda~4~,4-benzothiazepinimine 1-oxide and ethane 1,2-diamine. MS obsd. (ESI+) [(M+H)+] 396, 1H NMR (400 MHz, DMSO-d6) 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,1 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-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)methyl-N-[2-(S- methylsulfonimidoyl)ethyl]quinolinamine S NH N N The title compound was prepared in analogy to Example 76 in Scheme 33 by using 2-(1,1- dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)methyl-N-[2- (methylsulfinyl)ethyl]quinolinamine (prepared in y 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 transAmino[2-(1-iminooxido-1,2,3,5-tetrahydro-4H-1lambda~4~,4-benzothiazepin- 4-yl)methylquinolinyl]pyrrolidinol H2N OH N N S NH A mixture of 4-(4-chloromethylquinolinyl)-2,3,4,5-tetrahydro-1H-1lambda~4~,4- benzothiazepinimine 1-oxide (100 mg, 0.27 mmol), tert-butyl (transhydroxypyrrolidin 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 trifluoroacetic acid (10 mL). The mixture was stirred further until the on finished monitoring by TLC, and then trated in vacuo. The residue was dissolved in dichloromethane and the solution was washed with an aqueous on of sodium hydroxide (10% W/W) 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, CD 3OD) 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 trans[2-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)methylquinolinyl] fluoropyrrolidinamine F NH2 N N The title compound was prepared in analogy to Example 78-1 in Scheme 7 by using 4-(4-chloro- 6-methylquinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine oxide and tert-butyl (trans- 4-fluoropyrrolidinyl)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). e 79 1-[2-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5 H)-yl)methylquinolin yl]pyrrolidinecarboxamide N N 1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5 H)-yl)methylquinolin yl]pyrrolidinecarboxylic acid N N A mixture of 4-(4-chloromethylquinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1- dioxide (500 mg, 1.34 mmol, prepared in analogy to 4-(4-chloro(trifluoromethoxy)quinolin yl)-2,3,4,5-tetrahydro-1,4-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 ºC under microwave irradiation. The resulting mixture was purified by ative HPLC to afford 120 mg of the pure product (yield was 19.8%). 1-[2-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5 H)-yl)methylquinolin yl]pyrrolidinecarbonyl chloride N N To a cooled solution of 1-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl) methylquinolinyl]pyrrolidinecarboxylic acid (120 mg, 0.26 mmol) in dichloromethane (20 mL) was added two drops of N,N-dimethylformamide followed by oxalyl chloride (30.6 µL, 0.39 mmol) at 0 oC. After being stirred for 16 hours at room temperature, the reaction mixture was concentrated in vacuo to afford 100 mg of the crude t which was used for the next step without any further purification. 1-[2-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5 H)-yl)methylquinolin yl]pyrrolidinecarboxamide N N O To a cooled solution of 1-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl) methylquinolinyl]pyrrolidinecarbonyl chloride (100 mg, 0.21 mmol) in dichloromethane (20 mL) was added a saturated solution of ammonia in dichloromethane (10 mL) slowly at 0 oC.
After being stirred for 16 hours at room ature, the mixture was concentrated in vacuo. The residue was purified by ative HPLC to afford 13 mg of the desired product (yield was 13.5%). MS obsd. (ESI+) +] 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 N-[2-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)(methylsulfinyl)quinolin yl]propane-1,3-diamine O NH NH N N 4-[4-Chloro(methylsulfinyl)quinolinyl]-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1- O Cl N N To a cooled solution of 4-[4-Chloro(methylsulfanyl)quinolinyl]-2,3,4,5-tetrahydro-1,4- benzothiazepine 1,1-dioxide (800 mg, 1.98 mmol, prepared in analogy to 4-(4-chloro quinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine oxide in e 17-1) in dichloromethane (70 mL) was added a solution of 3-chloroperoxybenzoic acid (400 mg, 198 mmol, purity 85%) in romethane (30 mL) dropwise at 0 oC. After being stirred at 0 oC 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 × 3) and brine (100 × 2). The organic layer was dried over sodium sulfate, filtered and trated in vacuo to afford 500 mg of the desired product (yield was 60%).
N-[2-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)(methylsulfinyl)quinolin yl]propane-1,3-diamine O NH NH N N A mixture of 4-[4-chloro(methylsulfinyl)quinolinyl]-2,3,4,5-tetrahydro-1,4- 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 ºC under microwave irradiation. The reaction mixture was purified by preparative HPLC to afford the trifluoroacetic acid salt of the desired product. The trifluoroacetic acid salt was flashed through SPE column with methanol. The eluent was concentrated in vacuo and dried by lyopylization to afford 256.8 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](1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)- nolinecarboxamide O NH NH N N 4-Chloro(2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinolinecarboxamide O Cl N N S To a mixture of methyl 4-chloro(2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinoline carboxylate (400 mg, 1.04 mmol, prepared in y to 4-(4-chloromethylquinolinyl) methoxy-2,3,4,5-tetrahydro-1,4-benzothiazepine in Example 1-1) in ydrofuran (5 mL) and a saturated solution of ammonia in methanol (30 mL) was heated with stirring for 16 hours at 120 ºC in a sealed tube. The reaction mixture was concentrated in vacuo to afford 300 mg of the product (yield was 78%). 4-Chloro(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinolinecarboxamide O Cl N N To a cooled solution of 4-chloro(2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinoline carboxamide (300 mg, 0.81 mmol) in dichloromethane (50 mL) was added 3- chloroperoxybenzoic acid (418 mg, 70% purity, 1.70 mmol) at 0 oC. After being stirred for 2 hours at 0 oC, the reaction mixture was washed with a saturated aqueous solution of sodium thiosulphate (50 mL), dried over sodium sulfate, and concentrated in vacuo to afford 300 mg of the crude product. 4-[(3-Aminopropyl)amino](1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)- yl)quinolinecarboxamide O NH NH2 N N O A mixture of 4-chloro(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinoline 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 ºC under ave irradiation. The reaction mixture was purified by preparative HPLC to afford 23.5 mg of the desired t (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](1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)- yl)quinolinyl}ethanol OH NH NH N N 4-Chloro(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinolinecarbaldehyde O Cl N N O 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(1,1- dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-quinolinemethanol (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 r 1 hour. The reaction was washed with brine, dried over sodium sulfate and concentrated in vacuo to afford 70 mg of the product. 1-[4-Chloro(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinolinyl]ethanol OH Cl N N To a cooled solution of 4-chloro(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)- inecarbaldehyde (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 s at the temperature below 12 °C, the mixture was concentrated in vacuo. The residue was ed by preparative TLC to give 100 mg of the desired product (yield was 96%). 1-{4-[(3-Aminopropyl)amino](1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)- yl)quinolinyl}ethanol OH NH NH N N O A mixture of 1-[4-chloro(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinolin yl]ethanol (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 ºC under microwave irradiation. The on mixture was ed by preparative HPLC and SPE to afford 70.2 mg of the desired t (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-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)methylquinolin yl]amino}propanenitrile N N A flask containing 4-(4-chloromethylquinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide (500 mg, 1.34 mmol, prepared in analogy to 4-(4-chloro (trifluoromethoxy)quinolinyl)-2,3,4,5-tetrahydro-1,4-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)-1,1'-binaphthyl ( 83.3 mg, 0.134 mmol ), sodium tert-butoxide (257 mg, 2.68 mmol) and e (15 ml ) was evacuated and then filled with nitrogen (balloon). After being stirred at 110 ºC overnight, the ing mixture was diluted with water (15 mL), and extracted with ethyl acetate (15 mL × 4). The ed organic layers were dried over sodium e 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-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)methyl-N-[2-(1H-tetrazol yl)ethyl]quinolinamine NH N N N A mixture of 3-{[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)methylquinolin yl]amino}propanenitrile (100 mg, 0.25 mmol), sodium azide (48 mg, 0.98 mmol), dimethyl formamide (2 ml) and um chloride (52.6 mg, 0.98 mmol) was heated at 80 ºC in an oil bath overnight. The resulting mixture was diluted with water and ted with romethane (10 mL × 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+) +] 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)(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinoline-4,6- diamine NH 2 N N O To a solution of N-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)nitroquinolin yl]ethane-1,2-diamine (50 mg, 0.11 mmol, prepared in analogy to N-[2-(1,1-dioxido-2,3- dihydro-1,4-benzothiazepin-4(5H)-yl)methylquinolinyl]ethane-1,2-diamine in Example 9- 11) in methanol (20 mL) was added tin(II) chloride (102.8 mg, 0.55 mmol). After being refluxed overnight, the resulting mixture was cooled to room temperature, diluted with dichloromethane, washed with brine, dried over anhydrous sodium e 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). e 86 -[2-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5 H)-yl)methylquinolinyl]oxa- 5,7-diazaspiro[3.4]octanone N O N N A mixture of 4-(4-chloromethylquinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1- e (372 mg, 1.0 mmol, ed in analogy to the one in Example 17-1), tert-butyl [(3- aminooxetanyl)methyl]carbamate (202 mg, 1.0 mmol), tris(dibenzylideneacetone)dipalladium(0) (91 mg, 0.10 mmol), 2,2'-bis(diphenylphosphino)-1,1'- binaphthyl (62 mg, 0.10 mmol) and sodium tert-buoxide (192 mg, 2.0 mmol) in toluene (10 mL) was heated at 110 oC overnight. The resulting mixture was diluted with water (20 mL), and extracted with dichloromethane (20 mL × 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-d6) 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-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)methylquinazolin yl]amino}propane-1,2-diol N N 2-Chloro-N-[(2,2-dimethyl-1,3-dioxolanyl)methyl]methylquinazolinamine N Cl A solution of 2,4-dichloromethylquinazoline (300.0 mg, 1.4 mmol), triethylamine ( 0.5 mL) and methyl-1,3-dioxolanemethanamine (0.2 mL, 1.5 mmol) in methanol ( 2.0 mL) was stirred at room temperature for 16 hours. The on mixture was diluted with ethyl acetate (100 mL), washed with brine (50 mL × 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-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)methylquinazolin yl]amino}propane-1,2-diol N N A solution of 2-chloro-N-[(2,2-dimethyl-1,3-dioxolanyl)methyl]methylquinazolinamine (431.2 mg, 1.4 mmol) and triethylamine (0.8 mL), 5-tetrahydro-1,4-benzothiazepine 1,1- dioxide (296.1 mg, 1.5 mmol) in N,N-dimethyl-formamide (1.0 mL) was stirred at 160 oC 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 ted with ethyl acetate (100 mL). The organic layer was washed with brine (50 mL × 2), dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by preparative HPLC to afford 59.2 mg of the t as a white solid (yield was 10%). MS obsd. (ESI+) [(M+H)+] 429, 1H NMR (400 MHz, CD 3OD) 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(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl))-quinazolin ylamino]-propane-1,2-diol N N The title compound was prepared in analogy to Example 87-1 in Scheme 41 by using 2,4,6- trichloroquinazoline, 2,2-dimethyl-1,3-dioxolanemethanamine and 2,3,4,5-tetrahydro-1,4- benzothiazepine oxide. 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 N-[2-(2,3-Dihydro-1,4-benzothiazepin-4(5H)-yl)methylquinazolinyl]ethane-1,2- diamine N N tert-Butyl {2-[(2-chloromethylquinazolinyl)amino]ethyl}carbamate O O N Cl A mixture of 2,4-dichloromethylquinazoline (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 ature 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 t as a white solid (yield was 91%). tert-Butyl {2-[2-(2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)methylquinazolin yl]aminoethyl}carbamate O O N N To a solution of tert-butyl {2-[(2-chloromethylquinazolinyl)amino]ethyl}carbamate (460 mg, 1.366 mmol) in n-butanol (6 mL) was added 2,3,4,5-tetrahydro-1,4-benzothiazepine (248 mg, 1.50 mmol) and triethylamine (276 mg, 2.732 mmol). The mixture was heated with stirring at 100 oC in a sealed tube for 4 hours, and then trated 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)methylquinazolinyl]ethane-1,2- diamine N N To a cooled solution of trifluoroacetic acid in romethane (2 mL, V/V = 1/4) was added tert-butyl {2-[2-(2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)methylquinazolin yl]aminoethyl}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 ed to pH 10 with a saturated aqueous solution of sodium carbonate and extracted with ethyl acetate (20 mL × 2). The organic extracts were dried with sodium sulfate, trated 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 (1-Amino-cyclopropylmethyl)-[6-methyl(1-oxido-2,3-dihydro-1,4-benzothiazepin-4(5H)- yl)-quinolinyl]-amine N N The title compound was prepared in analogy to Example 88-1 in Scheme 42 by using 2,4- dichloromethylquinazoline, tert-butyl inomethyl)cyclopropyl]carbamate and 2,3,4,5- tetrahydro-1,4-benzothiazepine 1-oxide. MS obsd. (ESI +) [(M+H)+] 408, 1H NMR (400 MHz, CDCl3) 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 N-[6-Methyl(1-oxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinazolinyl]ethane- 1,2-diamine N N tert-Butyl {2-[2-(1-oxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)methylquinazolin noethyl}carbamate N O N N O To a solution of oxone (120 mg, 0.200 mmol) in water (0.7 mL) which was cooled below 0 oC in an ice bath, was added a solution of tert-butyl {2-[2-(2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)- 6-methylquinazolinyl]aminoethyl}carbamate (155 mg, 0.333 mmol) in methanol (3 mL) dropwise. The mixture was stirred below 0 oC 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%).
N-[6-Methyl(1-oxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinazolinyl]ethane- 1,2-diamine N N The title compound was prepared in analogy to Example 88-1 in Scheme 42 by using tert-butyl {2-[2-(1-oxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)methylquinazolin 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 N-[2-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)methylquinazolin yl]ethane-1,2-diamine N N tert-Butyl {2-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)methylquinazolin- 4-yl]aminoethyl}carbamate O O N N To a solution of tert-butyl {2-[2-(2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)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 ted organic layer was washed by a saturated s 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 t.
N-[2-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)methylquinazolin yl]ethane-1,2-diamine N N The title compound was prepared in analogy to Example 88-1 in Scheme 42 by using tert-butyl {2-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)methylquinazolin 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 Example 91 N-[3-(Aminomethyl)oxetanyl]methyl(1-oxido-2,3-dihydro-1,4-benzothiazepin- 4(5H)-yl)quinazolinamine NH NH N N Trifluoro-N-[(3-{[6-methyl(1-oxido-2,3-dihydro-1,4-benzothiazepin-4(5H)- yl)quinazolinyl]amino}oxetanyl)methyl]acetamide NH N N O N N O The title compound was prepared as a light white solid in analogy to Example 62-1 in Scheme 23 by using 2-chloromethylquinazolin-4(3H)-one, 2,3,4,5-tetrahydro-1,4-benzothiazepine 1- oxide and aminooxetanyl)methyl]-2,2,2-trifluoroacetamide (yield was 80%).
N-[3-(Aminomethyl)oxetanyl]methyl(1-oxido-2,3-dihydro-1,4-benzothiazepin- 4(5H)-yl)quinazolinamine NH NH N N To a stirred of 2,2,2-trifluoro-N-[(3-{[6-methyl(1-oxido-2,3-dihydro-1,4-benzothiazepin- 4(5H)-yl)quinazolinyl]amino}oxetanyl)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 × 3). The organic layers were combined, washed with brine, dried over sodium sulfate, and concentrated in vacuo. The residue was ed by ative 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 N-(transFluoropyrrolidinyl)methyl(1-oxido-2,3-dihydro-1,4-benzothiazepin- 4(5H)-yl)quinazolinamine N N S Benzyl transfluoro{[6-methyl(1-oxido-2,3-dihydro-1,4-benzothiazepin-4(5H)- yl)quinazolinyl]amino}pyrrolidinecarboxylate N N A suspension of 6-methyl(1-oxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinazolin- 4(3H)-one (600 mg, 1.77 mmol, prepared in analogy to the one in Example 91), benzotriazol yloxytris(dimethylamino)phosphonium hexafluorophosphate (1.02 g, 2.3 mmol), and 1,8- diazabicyclo[5.4.0]undecene (400 mg, 2.6 mmol) in anhydrous N,N-dimethylformamide (10 mL) was stirred at room ature for 10 minutes. Then a solution of benzyl transamino fluoropyrrolidinecarboxylate (500 mg, 2.1 mmol) in N,N-dimethylformamide (5 mL) was added dropwise. After being heated at 60 oC overnight, the mixture was diluted with water (50 mL), extracted with dichloromethane (50mL). The c layer was washed with brine, dried over anhydrous sodium sulfate, and concentrated in vacuo. The residue was purified by flash column tography (gradient eluting with 10% to 25% ethyl acetate in romethane) to afford 415 mg of the desired product as a yellow solid (yield was 41.8%).
N-(transFluoropyrrolidinyl)methyl(1-oxido-2,3-dihydro-1,4-benzothiazepin- 4(5H)-yl)quinazolinamine N N A mixture of benzyl transfluoro{[6-methyl(1-oxido-2,3-dihydro-1,4-benzothiazepin- 4(5H)-yl)quinazolinyl]amino}pyrrolidinecarboxylate (200 mg, 0.35 mmol) and an aqueous solution of hloric acid (5 mL, 6 N) was ed 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 - 3.11 (m, 6 H), 2.41 (s, 3 H).
Example 92-2 N-(transFluoropyrrolidinyl)methyl(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin- 4(5H)-yl)quinazolinamine N N The title compound was prepared in analogy to Example 92-1 in Scheme 44 by using yl- 2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinazolin-4(3H)-one (prepared in analogy to 6-methyl(1-oxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinazolin-4(3H)-one in Example 91) and benzyl transaminofluoropyrrolidinecarboxylate. 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 1-[6-Methyl(1-oxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinazolin yl]pyrrolidinamine N N tert-Butyl methyl(1-oxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinazolin yl]pyrrolidinyl}carbamate N N The title compound was prepared in analogy to benzyl (3S,4S)fluoro{[6-methyl(1- oxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinazolinyl]amino}pyrrolidine carboxylate in Example 92 by using 6-methyl(1-oxido-2,3-dihydro-1,4-benzothiazepin-4(5H)- yl)quinazolin-4(3H)-one and tert-butyl (pyrrolidinyl)carbamate. 1-[6-Methyl(1-oxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinazolin yl]pyrrolidinamine N N O The title nd was prepared in analogy to Example 90 in Scheme 44 by using tert-butyl {1- [6-methyl(1-oxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinazolinyl]pyrrolidin 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 N-(Azetidinyl)methyl(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl) quinazolinamine N N O The title nd was prepared in analogy to Example 93-1 in Scheme 44 by using 6-methyl- 2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinazolin-4(3H)-one and tert-butyl 3- aminoazetidinecarboxylate. 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){2-[2-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)methylquinolin yl]ethyl}-4,5-dihydro-1,3-oxazolamine N N tert-Butyl (4R){(2E)-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5 H)-yl) methylquinolinyl]-vinyl}-2,2-dimethyl-1,3-oxazolidinecarboxylate N N To a vial containing a mixture of 4-(4-chloromethylquinolinyl)-2,3,4,5-tetrahydro-1,4- benzothiazepine 1,1-dioxide (200 mg, 0.536 mmol, prepared in analogy to 4-(4-chloro uoromethoxy)quinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide in Example 17-1), tert-butyl (4R)ethenyl-2,2-dimethyl-1,3-oxazolidinecarboxylate (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 oC for 30 minutes under ave ation. The reaction mixture was poured into water (30 mL) and extracted with ethyl acetate (20 mL × 3).
The c 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)Amino[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl))methyl- quinolinyl]-butanol N N A solution of tert-butyl (4R){(2E)-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5 H)-yl)- 6-methylquinolinyl]-vinyl}-2,2-dimethyl-1,3-oxazolidinecarboxylate (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 ed 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 ature for 2 hours. The reaction mixture was basified with an aqueous on of sodium bicarbonate (2 N) to pH 8 and then extracted with ethyl acetate (15 mL × 3). The combined layers was dried over sodium sulfate and concentrated in vacuo. The residue was purified by flash column chromatography (eluting with % methanol in dichloromethane) to afford 90 mg of the desired t as a white solid (yield was 66.2%). (4R){2-[2-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)methylquinolin yl]ethyl}-4,5-dihydro-1,3-oxazolamine N N O The title compound was prepared in analogy to Example 38-1 in Scheme 45 by using (3R) amino[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl))methyl-quinolinyl]- butanol and cyanogen e. 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), .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). e 95 3-[2-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5 H)-yl)ethylquinolinyl]propanoic acid O OH N N Ethyl (2E)[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)ethylquinolin yl]propenoate O O N N A mixture of 4-(4-chloroethylquinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1- dioxide (300 mg, 0.78 mmmol), ethyl propenoate (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 ng 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 × 3). The organic layers were combined, washed with brine, dried over sodium sulfate and concentrated in vacuo. The residue was purified by flash tography 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-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)ethylquinolin yl]propanoate O O N N To a 25 mL of dry round bottom flask containing a solution of ethyl (2E)[2-(1,1-dioxido-2,3- o-1,4-benzothiazepin-4(5H)-yl)ethylquinolinyl]propenoate (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 ature under nitrogen, and then trated 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 t (yield was 50%). MS obsd. (ESI+) [(M+H)+] 453. 3-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5 H)-yl)ethylquinolinyl]propanoic acid O OH N N To a solution of ethyl 3-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl) ethylquinolinyl]propanoate (100 mg, 0.22 mmol) in methanol (2 mL) was added an aqueous solution of m 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 × 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 t as a white solid. MS (ESI +) [(M+H)+] 425, 1H NMR (400 MHz, DMSO-d6) 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-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5 H)-yl)methylquinolinyl]propan- 1-amine N N O O 3-[2-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5 H)-yl)methylquinolinyl]- propionitrile N N O O The title compound was prepared in analogy to ethyl 3-[2-(1,1-dioxido-2,3-dihydro-1,4- benzothiazepin-4(5H)-yl)ethylquinolinyl]propanoate in e 95 in Scheme 46 by using 4-(4-chloroethylquinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide and acrylonitrile. 3-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)methylquinolin yl]propanamide O NH N N O O A solution of 3-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)methylquinolin 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 ature, the reaction mixture was diluted with water (15 mL) and extracted with ethyl acetate (15 mL × 3). The combined organic layers were dried over sodium sulfate and concentrated in vacuo. The e was purified by flash column (eluting with 5% methanol in dichloromethane) to afford 125 mg of the product as a white solid. 3-[2-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5 H)-yl)methylquinolinyl]propan- 1-amine N N O O To a solution of 3-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)methylquinolin- 4-yl]-propionamide (30 mg, 0.073 mmol) in tetrahydrofuran (2 mL) was added a solution of borane in ydrofuran (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 e 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-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)methylquinolin yl]oxy}ethanamine N N O O N-(2-{[2-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)methylquinolin yl]oxy}ethyl)acetamide N O N N O O A mixture of N-(2-hydroxyethyl)-acetamide (247 mg, 2.4 mmol), 4-(4-bromomethylquinolin- 2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide (1000 mg, 2.4 mmol, prepared in analogy to 4-(4-chloro(trifluoromethoxy)quinolinyl)-2,3,4,5-tetrahydro-1,4- benzothiazepine 1,1-dioxide in Example 17-1), 1,1'-bis(diphenylphosphino)ferrocenepalladium (II)dichloride (190.4 mg, 0.24 mmol), 1,1'-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 ºC under microwave irradiation. The reaction mixture was trated in vacuo and the residue was purified by preparative HPLC to afford 20 mg of the desired t (yield was 1.9%). 2-{[2-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)methylquinolin yl]oxy}ethanamine N N O O A mixture of N-(2-{[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)methylquinolin- 4-yl]oxy}ethyl)acetamide (15 mg, 0.03 mmol) and an s solution of hydrochloric acid (10 mL, 37% W/W) was heated with stirring at 80 ºC 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(pyrrolidinyloxy)quinolinyl]-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide N N tert-Butyl 3-{[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)methylquinolin yl]oxy}pyrrolidinecarboxylate N N A mixture of tert-butyl 3-hydroxypyrrolidinecarboxylate (134.7 mg, 0.72 mmol), 4-(4-bromo- 6-methylquinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide (300 mg, 0.72 mmol, prepared in analogy to 4-(4-chloro(trifluoromethoxy)quinolinyl)-2,3,4,5-tetrahydro-1,4- benzothiazepine 1,1-dioxide in Example 17-1), is(diphenylphosphino)ferrocenepalladium (II)dichloride (57.12 mg, 0.07 mmol), 1,1'-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 ºC under ave irradiation. The reaction mixture was concentrated in vacuo and the residue was purified by ative HPLC to afford 20 mg of the desired product (yield was 5.3%). 4-[6-Methyl(pyrrolidinyloxy)quinolinyl]-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide N N A mixture of tert-butyl (1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl) quinolinyl]oxy}pyrrolidinecarboxylate (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+) +] 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). e 98-2 8-[6-Methyl(piperidinyloxy)-quinolinyl]-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide N N The title compound was prepared in analogy to Example 98-1 in Scheme 47 by using 4-(4- bromomethylquinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide (prepared in analogy to 4-(4-chloro(trifluoromethoxy)quinolinyl)-2,3,4,5-tetrahydro-1,4- benzothiazepine 1,1-dioxide in Example 17-1) and tert-butyl 4-hydroxypiperidinecarboxylate.
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,1 H), 7.60 -7.55 (t, J = 7.6 Hz,1 H), 6.64 (s, 1 H), .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-Dimethylquinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide N N Diethyl (2-chloromethylquinolinyl)propanedioate O O O O N Cl To a solution of 2,4-dichloromethylquinoline (2.11 g, 10 mmol) and 1,3-diethyl propanedioate (2.64 g, 20 mmol) in N,N-dimethylformamide (40 mL) was added ous potassium carbonate (2.8 g, 20 mmol). The mixture was stirred at 70 °C for 3 hours, then poured into ter (100 mL) and extracted with ethyl acetate (100 mL × 3). The combined organic layers were washed with brine (150 mL × 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-Chloromethylquinolinyl)acetic acid N Cl To a solution of diethyl (2-chloromethylquinolinyl)propanedioate (100 mg, 0.30 mmol) in methanol (2 mL) was added an s solution of sodium hydroxide (2 N, 2 mL) and the resulting mixture was d at room temperature overnight. The reaction was then acidified to pH 4 with an s solution of hydrochloric acid (5 N), and extracted with ethyl acetate (10 mL × 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-Dimethylquinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine N N S A on of (2-chloromethylquinolinyl)acetic acid (118 mg, 0.5 mmol ) and 2,3,4,5- tetrahydro-1,4-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 ted 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 t (yield was 62%). MS (ESI+) [(M+H)+] 321. 4-(4,6-Dimethylquinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide N N O To a solution of 4-(4,6-dimethylquinolinyl)-2,3,4,5-tetrahydro-1,4-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 e was purified by preparative HPLC to afford the desired product. MS (ESI+) [(M+H)+] 353, 1H NMR (400 MHz, 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 Example 100 [2-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)methylquinolinyl](piperidin- 4-yl)methanone N N tert-Butyl 4-{[2-(2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)methylquinolin yl](hydroxy)methyl}piperidinecarboxylate N O N N To a solution of 4-(4-bromomethylquinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine (385 mg, 1.0 mmol, ed in analogy to 4-(4-chloro(trifluoromethoxy)quinolinyl)-2,3,4,5- tetrahydro-1,4-benzothiazepine 1,1-dioxide in Example 17-1) in tetrahydrofuran (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 carboxylate (153 mg, 1.3 mmol ) in ydrofuran (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 dichloromethane (20 mL × 2). The organic layers were combined, dried over sodium e 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-Butyl 4-{[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)methylquinolin yl](hydroxy)methyl}piperidinecarboxylate N O N N To a solution of tert-butyl 4-{[2-(2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)methylquinolin yl](hydroxy)methyl}piperidinecarboxylate (519 mg, 1.0 mmol) in romethane (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 s 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-Butyl 4-{[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)methylquinolin yl]carbonyl}piperidinecarboxylate N O N N To a solution of tert-butyl 4-{[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl) methylquinolinyl](hydroxy)methyl}piperidinecarboxylate (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 on 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 t. MS (ESI+) +] 550. [2-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)methylquinolinyl](piperidin- 4-yl)methanone N N To a solution of utyl 4-{[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl) methylquinolinyl]carbonyl}piperidinecarboxylate (100 mg, 0.18 mmol) in dichloromethane (1 mL) was added trifluoroacetic acid (1 mL). The resulting mixture was stirred at room temperature until the reaction was te monitoring by LC/MS and then concentrated in vacuo. The residue was purified by flash column tography 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), 7.90 (d, J = 7.07 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). e 101 4-[6-Methyl(1H-pyrazolyl)quinolinyl]-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1- dioxide N N To a solution of 8-(4-bromomethylquinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1- dioxide (115 mg, 0.28 mmol, prepared in analogy to 4-(4-chloro(trifluoromethoxy)quinolin yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide in Example 17-1) in dimethoxyethane (8 mL) was added enylphosphine) palladium (20 mg). After the mixture was stirred for 10 minutes, azoleboric 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 ºC under microwave ation. 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(phenylsulfonyl)quinolinyl]-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1- dioxide O S O N N ethyl(phenylsulfanyl)quinolinyl]-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1- dioxide N N A mixture of hloromethylquinolinyl)-2,3,4,5-tetrahydro-1,4-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-dimethylpyridinamine (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 s) to afford 1.0 g of the desired product (yield was 45%). 4-[6-Methyl(phenylsulfonyl)quinolinyl]-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1- dioxide O S O N N A mixture solution of 4-[6-methyl(phenylsulfanyl)quinolinyl]-2,3,4,5-tetrahydro-1,4- benzothiazepine 1,1-dioxide (223 mg, 0.5 mmol) and roperbenzoic acid (340 mg, 2 mmol) in dry dichloromethane (30 mL) was stirred at 0 ºC for 2 hours. After the reaction was quenched with a saturated aqueous on of sodium thiosulphate (15 mL), the resulting mixture was d 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, CDCl3) 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 N-(2-Aminoethyl)(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl) methylquinolinesulfonamide O S O N N 2-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)methylquinolinethiol N N To a solution of 4-(4-chloromethylquinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1- e (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 ºC for 16 hours. The reaction e was cooled to 50 ºC 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 romethane (150 mL × 3). The combined organic layer was washed with cooled brine (100 mL × 2) and concentrated in vacuo at room temperature to afford the crude product, which was used for next step without further purification. 2-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)methylquinolinesulfonyl chloride O S O N N Gaseous chlorine was passed through a well stirred solution of 2-(1,1-dioxido-2,3-dihydro-1,4- benzothiazepin-4(5H)-yl)methylquinolinethiol (the crude product from the above step) in concentrated hydrochloric acid (10 mL) at -10 ºC at such a rate that temperature was maintained between -5 ºC ~ -10 ºC. After been stirred for 30 minutes, the passage of ne 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 × 3). The combined organic layer was washed with cooled water (100 mL), dried over sodium sulfate and filtered. The te was used for the next step without r purification.
N-(2-Aminoethyl)(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl) methylquinolinesulfonamide O S O N N 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-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin- yl)methylquinolinesulfonyl de (the filtrate from the above step) at 0 ºC. 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). e 104 Methyl 4-({[3-(aminomethyl)oxetanyl]methyl}amino)(1,1-dioxido-2,3-dihydro-1,4- benzothiazepin-4(5H)-yl)quinolinecarboxylate O NH NH2 O O N N Methyl 4-chloro(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinoline carboxylate O Cl N N To a d solution of methyl 4-chloro(2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinoline- oxylate (1.5 g, 3.9 mmol) in dichloromethane (20 ml) was added 3-chloroperbenzoic acid (1.68 g, 9.7 mmol) at 0 oC. The reaction e was stirred at 0 oC 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)oxetanyl]methyl}amino)(1,1-dioxido-2,3-dihydro-1,4- hiazepin-4(5H)-yl)quinolinecarboxylate O NH NH2 O O N N O The title compound was prepared in analogy to Example 6-1 in Scheme 52 by using methyl 4- chloro(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinolinecarboxylate 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)oxetanyl]methyl}amino)(1,1-dioxido-2,3-dihydro-1,4- benzothiazepin-4(5H)-yl)quinolinecarboxylic acid OH NH NH2 O O N N To a stirred solution of methyl 4-({[3-(aminomethyl)oxetanyl]methyl}amino)(1,1-dioxido- hydro-1,4-benzothiazepin-4(5H)-yl)quinolinecarboxylate (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 ature 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 × 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 % methanol in dichloromethane) to afford 20 mg of the desire t as a solid. MS obsd.
(ESI+) [(M+H)+] 483, 1H NMR (400 MHz, DMSO-d6) 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)oxetanyl]methyl}amino)(1,1-dioxido-2,3-dihydro-1,4- benzothiazepin-4(5H)-yl)quinolinyl]methanol OH NH NH2 N N [4-Chloro(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinolinyl]methanol OH Cl N N To a slurry of lithium aluminum e (46 mg, 1.21 mmol) in tetrahydrofuran (5 mL) was added a solution of methyl 4-chloro(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)- yl)quinolinecarboxylate (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)oxetanyl]methyl}amino)(1,1-dioxido-2,3-dihydro-1,4- benzothiazepin-4(5H)-yl)quinolinyl]methanol OH NH NH2 N N The title compound was prepared in analogy to Example 6-1 in Scheme 52 by using [4-chloro (1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinolinyl]methanol and oxetane-3,3- diyldimethanamine. MS obsd. (ESI+) [(M+H)+] 469, 1H NMR (400 MHz, 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). e 107 (Aminomethyl)oxetanyl]methyl}trideuteriomethyl(1-oxido-2,3-dihydro-1,4- benzothiazepin-4(5H)-yl)quinazolinamine D NH NH D 2 N N 4-(Benzyloxy)bromochloroquinazoline N Cl 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, .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 e 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)bromoquinazolinyl]-2,3,4,5-tetrahydro-1,4-benzothiazepine N N S A mixture of 4-(benzyloxy)bromochloroquinazoline (700 mg, 2.0 mmol) and 2,3,4,5- ydro-1,4-benzothiazepine (990 mg, 6.0 mmol) was heated at 80 °C for 10 s. 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 . 4-[4-(Benzyloxy)trideuteriomethylquinazolinyl]-2,3,4,5-tetrahydro-1,4- benzothiazepine D O N N To a cooled solution of 4-[4-(benzyloxy)bromoquinazolinyl]-2,3,4,5-tetrahydro-1,4- benzothiazepine (239 mg, 0.50 mmol) in anhydrous tetrahydrofuran (10 mL) was added nbutyllithium (0.5 mL, 0.80 mmol) in tetrahydrofuran se over 5 minutes under a nitrogen atmosphere at -78 °C, followed by addition of methyl-d3 trifluoromethanesulfonate(134 mg, 0.80 mmol) dropwise at -78 °C over 5 minutes. After being stirred for 1 hour at -78 °C, the reaction mixture was allowed to warm to room ature 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)trideuteriomethylquinazolinyl]-2,3,4,5-tetrahydro-1,4- benzothiazepine e D O N N To a solution of 4-[4-(benzyloxy)trideuteriomethylquinazolinyl]-2,3,4,5-tetrahydro-1,4- 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 trated in vacuo. The residue was purified by silica gel column tography (eluting with 10% ethyl acetate in dichloromethane) to afford the desired product as a white solid.
N-{[3-(aminomethyl)oxetanyl]methyl}trideuteriomethyl(1-oxido-2,3-dihydro-1,4- benzothiazepin-4(5H)-yl)quinazolinamine D NH NH D 2 N N A e of 4-[4-(benzyloxy)trideuteriomethylquinazolinyl]-2,3,4,5-tetrahydro-1,4- hiazepine 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,1 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)oxetanyl]methyl}amino)(1-oxido-2,3-dihydro-1,4- benzothiazepin-4(5H)-yl)quinazolinecarboxylic acid OH NH NH O N O N N Methyl 4-(benzyloxy)(2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinazoline carboxylate O O O N N N To a solution of 4-(4-benzyloxybromoquinazolinyl)-2,3,4,5-tetrahydro-1,4- benzothiazepine (239 mg, 0.5 mmol) in anhydrous tetrahydrofuran (10 mL) was added n- butyllithium (0.5 mL, 0.8 mmol) in ydrofuran 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 ted with ethyl acetate (25 mL). The organic layer was dried over sodium e 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 sulfinyl 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 e and trated in vacuo. The residue was purified by flash column chromatography ng with 10% ethyl acetate in dichloromethane) to afford the desired methyl ester.
Methyl 4-(benzyloxy)(1-oxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinazoline carboxylate and Methyl 4-(benzyloxy)(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin 4(5H)-yl)quinazolinecarboxylate O O O O O N O N N N N N O S O To a solution of methyl 4-(benzyloxy)(2,3-dihydro-1,4-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 e was stirred at room temperature for 1 hour. The reaction mixture was washed with a saturated aqueous on of sodium thiosulphate, and 10% aqueous solution of sodium ide, and brine. The resulting organic layer was dried over sodium sulfate and concentrated in vacuo. The residue was purified by flash column tography (eluting with 10% ethyl acetate in dichloromethane) to afford 350 mg of methyl 4-(benzyloxy)(1-oxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinazoline carboxylate and 400 mg of methyl 4-(benzyloxy)(1,1-dioxido-2,3-dihydro-1,4- benzothiazepin-4(5H)-yl)quinazolinecarboxylate. 4-(Benzyloxy)(1-oxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinazoline ylic acid OH O O N N N To the solution of methyl 4-(benzyloxy)(1-oxido-2,3-dihydro-1,4-benzothiazepin-4(5H)- yl)quinazolinecarboxylate (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 tography (eluting with 10% ethyl acetate in dichloromethane) to afford 4-(benzyloxy)(1-oxido-2,3-dihydro-1,4-benzothiazepin- 4(5H)-yl)quinazolinecarboxylic MS obsd. (ESI+) [(M+H)+] 460. 4-({[3-(Aminomethyl)oxetanyl]methyl}amino)(1-oxido-2,3-dihydro-1,4- benzothiazepin-4(5H)-yl)quinazolinecarboxylic acid OH NH NH O N O N N A mixture of 4-(benzyloxy)(1-oxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinazoline carboxylic acid (170 mg, 0.37 mmol) and oxetane-3,3-diyldimethanamine (128 mg, 1.11 mmol) was heated at 170 °C for 30 minutes. Then the reaction mixture was cooled to room temperature and ed by ative HPLC to afford 4-({[3-(Aminomethyl)oxetanyl]methyl}amino) (1-oxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinazolinecarboxylic acid, MS obsd.
(ESI+) [(M+H)+] 468, 1H NMR (400 MHz, DMSO-d6) 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), .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)oxetanyl]methyl}amino)(1,1-dioxido-2,3-dihydro-1,4- benzothiazepin-4(5H)-yl)quinazolinecarboxylic acid OH NH NH2 O N O N N The title compound was prepared in analogy to Example 108-1 in Scheme 54 by using 4- (benzyloxy)(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinazolinecarboxylic acid and oxetane-3,3-diyldimethanamine, MS obsd. (ESI +) [(M+H)+] 484, 1H NMR (400 MHz, DMSO-d6) 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), 5.11 (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). e 109-1 and Example 109-2 [4-({[3-(Aminomethyl)oxetanyl]methyl}amino)(1-oxido-2,3-dihydro-1,4- benzothiazepin-4(5H)-yl)quinazolinyl]methanol and [4-({[3-(Aminomethyl)oxetan yl]methyl}amino)(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinazolin yl]methanol OH NH NH2 OH NH NH2 N O N O N N N N S S O zyloxy)(2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinazolinecarbaldehyde H O O N N N S To a cooled on of 4-(4-benzyloxybromoquinazolinyl)-2,3,4,5-tetrahydro-1,4- benzothiazepine (500 mg, 1.048 mmol) in anhydrous tetrahydrofuran (10 mL) was added anhydrous N,N-dimethylformamide (150 µL, 1.94 mmol) at -78 oC. After being stirred at -78 oC for 30 minutes, the mixture was warmed to room temperature, diluted with water (10 mL) and extracted with ethyl e (20 mL × 3). The combined organic layers were washed with a ted 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+) +] 428. [4-(Benzyloxy)(2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinazolinyl]methanol OH O N N S To a solution of 4-(benzyloxy)(2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinazoline 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 oC. After being stirred at 0 oC for 15 minutes, the resulting mixture was warmed to room temperature, diluted with water (10 mL) and extracted with ethyl acetate (20 mL × 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 trated in vacuo to afford 2.85 g of the desired product as a yellow solid (yield was 95%), MS obsd. (ESI+) +] 430. [4-(Benzyloxy)(1-oxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinazolin yl]methanol and [4-(Benzyloxy)(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)- yl)quinazolinyl]methanol OH O OH O N N N N S O O O To a solution of [4-(benzyloxy)(2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinazolin yl]methanol (1.0 g, 2.33 mmol) in romethane (20 mL) was added 3-chloroperoxybenzoic acid (536 mg, 2.33 mmol, 75% purity) at 0 oC. After being stirred at 0 oC for 15 minutes, the mixture was warmed to room temperature, diluted with water, extracted with dichloromethane (20 mL × 3). The combined organic layers were washed with a saturated s 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)(1-oxido-2,3-dihydro- 1,4-benzothiazepin-4(5H)-yl)quinazolinyl]methanol and [4-(benzyloxy)(1,1-dioxido-2,3- dihydro-1,4-benzothiazepin-4(5H)-yl)quinazolinyl]methanol as a yellow solid. [4-({[3-(Aminomethyl)oxetanyl]methyl}amino)(1-oxido-2,3-dihydro-1,4- benzothiazepin-4(5H)-yl)quinazolinyl]methanol and [4-({[3-(Aminomethyl)oxetan yl]methyl}amino)(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinazolin yl]methanol OH NH NH2 OH NH NH2 N O N O N N N N S S O O A mixture of [4-(benzyloxy)(1-oxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinazolin yl]methanol and [4-(benzyloxy)(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)- yl)quinazolinyl]methanol (700 mg, about 1.57 mmol) and oxetane-3,3-diyldimethanamine (700 mg, 6.03 mmol) was heated at 160 oC for 30 minutes. After being cooled to room temperature, the on mixture was d with water (10 mL), extracted with dichloromethane (20 mL × 3). The organic layers were washed with brine (40 mL), dried over anhydrous sodium e and concentrated in vacuo. The residue was purified by preparative HPLC to afford [4-({[3-(aminomethyl)oxetanyl]methyl}amino)(1-oxido-2,3-dihydro-1,4- benzothiazepin-4(5H)-yl)quinazolinyl]methanol, MS obsd. (ESI+) [(M+H)+] 454, 1H NMR (400 MHz, DMSO-d6) 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)oxetanyl]methyl}amino)(1,1- dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinazolinyl]methanol, MS obsd. (ESI+) [(M+H)+] 470, 1H NMR (400 MHz, DMSO-d6) 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 N-[(3-Aminooxetanyl)methyl](5,5-difluoro-1,3,4,5-tetrahydro-2Hbenzazepinyl)- ylquinolinamine O NH N N 2-(4-Chloromethylquinolinyl)-5,5-difluoro-2,3,4,5-tetrahydro-1H-benzo[c]azepine N N A solution of 2,4-dichloromethylquinoline (500 mg, 2.358 mmol) and 5,5-difluoro-2,3,4,5- tetrahydro-1H-benzazepine (432 mg, 2.358 mmol) in n-butanol (10 mL) was heated at 160 oC for hours under microwave irradiation. The resulting reaction mixture was poured into water (10 mL) and extracted with ethyl acetate (20 mL × 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 %).
N-[(3-Aminooxetanyl)methyl](5,5-difluoro-1,3,4,5-tetrahydro-2Hbenzazepinyl)- 6-methylquinolinamine O NH N N F A solution of hloromethylquinolinyl)-5,5-difluoro-2,3,4,5-tetrahydro-1H- benzazepine (250 mg, 0.697 mmol), nomethyl)oxetanamine (119 mg, 0.697 mmol, purity: 60 %), 1,1'-bis(diphenylphosphino)ferrocene (39 mg, 0.0697 mmol), 1,1'- 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 oC for 1.5 hours under microwave irradiation. The resulting reaction mixture was poured into water (10 mL) and extracted with dichloromethane (20 mL × 3), the combined c layers were dried over sodium sulfate and concentrated in vacuo. The residue was purified by flash column chromatography (eluting with 0 - 10% methanol in romethane) 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, CD 3OD) 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 N-[2-(2-Aminoethoxy)ethyl](5,5-difluoro-1,3,4,5-tetrahydro-2Hbenzazepinyl) methylquinolinamine NH NH N N The title compound was prepared in analogy to Example 110-1 in Scheme 56 by using 2-(4- chloromethylquinolinyl)-5,5-difluoro-2,3,4,5-tetrahydro-1H-benzazepine and 2-(2- aminoethoxy)ethanamine. 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 Example 110-3 N-[2-(5,5-Difluoro-1,3,4,5-tetrahydro-2Hbenzazepinyl)methylquinolinyl]-N'- methylethane-1,2-diamine N N The title compound was prepared in analogy to Example 110-1 in Scheme 56 by using 2-(4- chloromethylquinolinyl)-5,5-difluoro-2,3,4,5-tetrahydro-1H-benzazepine and (2- thyl)(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 1-Amino{[2-(5,5-difluoro-1,3,4,5-tetrahydro-2Hbenzazepinyl)methylquinolin yl]amino}propanol NH NH N N The title compound was ed in analogy to Example 110-1 in Scheme 56 by using 2-(4- chloromethylquinolinyl)-5,5-difluoro-2,3,4,5-tetrahydro-1H-benzazepine and 1,3- diaminopropanol. 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,1 H), 2.45 - 2.35 (m, 2 H), 2.32 (s, 3 H).
Example 110-5 3-{[2-(5,5-Difluoro-1,3,4,5-tetrahydro-2Hbenzazepinyl)methylquinolin yl]amino}propane-1,2-diol NH OH N N The title compound was prepared in analogy to Example 110-1 in Scheme 56 by using 2-(4- chloromethylquinolinyl)-5,5-difluoro-2,3,4,5-tetrahydro-1H-benzazepine and 3- aminopropane-1,2-diol. MS obsd. (ESI+) [(M+H)+] 414, 1H NMR (400 MHz, CDCl3) 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-1,3,4,5-tetrahydro-2Hbenzazepinyl)methylquinolin yl]amino}propanol NH OH N N The title compound was ed in analogy to Example 110-1 in Scheme 56 by using 2-(46-methylquinolinyl)-5,5-difluoro-2,3,4,5-tetrahydro-1H-benzazepine and 3- aminopropaneol. MS obsd. (ESI+) [(M+H)+] 398, 1H NMR (400 MHz, CD3Cl) 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). e 110-7 2-(5,5-Difluoro-1,3,4,5-tetrahydro-2Hbenzazepinyl)methyl-N-[2-(piperazin yl)ethyl]quinolinamine N N The title compound was prepared in analogy to Example 110-1 in Scheme 56 by using 2-(4- chloromethylquinolinyl)-5,5-difluoro-2,3,4,5-tetrahydro-1H-benzazepine and 2-(piperazin- 1-yl)ethanamine. MS obsd. (ESI+) [(M+H)+] 452, 1H NMR (400 MHz, CD3Cl) 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 2-(5,5-Difluoro-1,3,4,5-tetrahydro-2Hbenzazepinyl)methylquinolin yl]propane-1,2-diamine NH 2 N N The title compound was prepared in analogy to Example 110-1 in Scheme 56 by using 2-(4- chloromethylquinolinyl)-5,5-difluoro-2,3,4,5-tetrahydro-1H-benzazepine and propane-1,2- diamine. MS obsd. (ESI+) [(M+H)+] 397, 1H NMR (400 MHz, CD3Cl) 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-N-[2-(5,5-Difluoro-1,3,4,5-tetrahydro-2Hbenzazepinyl)methylquinolin yl]cyclohexane-1,4-diamine N N The title compound was prepared in analogy to Example 110-1 in Scheme 56 by using 2-(4- chloromethylquinolinyl)-5,5-difluoro-2,3,4,5-tetrahydro-1H-benzazepine and ciscyclohexane-1 ,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]annulenyl)methyl-N-(pyrrolidin yl)quinolinamine N N The title compound was ed in analogy to Example 110-1 in Scheme 56 by using 2-(4- methylquinolinyl)-5,5-difluoro-2,3,4,5-tetrahydro-1H-benzazepine and pyrrolidin 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-2Hbenzazepinyl)methylquinolin yl]imino}diethanol OH OH N N The title compound was prepared in analogy to Example 110-1 in Scheme 56 by using 2-(4- chloromethylquinolinyl)-5,5-difluoro-2,3,4,5-tetrahydro-1H-benzazepine and 2,2'- iethanol. 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 N~1~-[2-(5,5-Difluoro-1,3,4,5-tetrahydro-2Hbenzazepinyl)methylquinolinyl] methylpropane-1,2-diamine NH 2 N N The title compound was prepared in analogy to Example 110-1 in Scheme 56 by using 2-(4- methylquinolinyl)-5,5-difluoro-2,3,4,5-tetrahydro-1H-benzazepine and 2- methylpropane-1,2-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 = 5.6 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[6-methyl(4-methylpiperazinyl)quinolinyl]-2,3,4,5-tetrahydro-1H benzazepine N N The title compound was prepared in analogy to Example 110-1 in Scheme 56 by using 2-(4- chloromethylquinolinyl)-5,5-difluoro-2,3,4,5-tetrahydro-1H-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). e 110-14 1-[2-(9,9-Difluoro-6,7,8,9-tetrahydro-5H-benzo[7]annulenyl)methylquinolinyl] ethylurea NH N N N The title nd was prepared in analogy to Example 110-1 in Scheme 56 by using 2-(4- chloromethylquinolinyl)-5,5-difluoro-2,3,4,5-tetrahydro-1H-benzazepine and ethylurea.
MS obsd. (ESI+) [(M+H)+] 411, 1H NMR (400 MHz, CDCl3) 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 N-{[3-(Aminomethyl)oxetanyl]methyl}(5,5-difluoro-1,3,4,5-tetrahydro-2H benzazepinyl)methylquinolinamine NH NH N N The title compound was prepared in analogy to Example 110-1 in Scheme 56 by using 2-(4- chloromethylquinolinyl)-5,5-difluoro-2,3,4,5-tetrahydro-1H-benzazepine and oxetane-3,3- diyldimethanamine. MS obsd. (ESI+) [(M+H)+] 439, 1H NMR (400 MHz, CDCl3) 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-Difluoro[6-methyl(piperazinyl)quinolinyl]-2,3,4,5-tetrahydro-1H benzazepine N N F A mixture of 2-(4-chloromethylquinolinyl)-5,5-difluoro-2,3,4,5-tetrahydro-1H- benzazepine (100 mg, 0.279 mmol) and piperazine (300 mg, 3.488 mmol) was heated at 150 oC for 2 hours under microwave irradiation. The ing 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 d 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). e 111-2 2-[4-(1,4-Diazepanyl)methylquinolinyl]-5,5-difluoro-2,3,4,5-tetrahydro-1H benzazepine N N The title nd was prepared in analogy to Example 111-1 in Scheme 56 by using 2-(4- chloromethylquinolinyl)-5,5-difluoro-2,3,4,5-tetrahydro-1H-benzazepine and [1,4]diazepane. MS obsd. (ESI+) [(M+H)+] 423, 1H NMR (400 MHz, CD3Cl) 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 N-[2-(5,5-Difluoro-1,3,4,5-tetrahydro-2Hbenzazepinyl)methylquinolinyl]-N- methylethane-1,2-diamine N N The title compound was prepared in analogy to Example 111-1 in Scheme 56 by using 2-(4- chloromethylquinolinyl)-5,5-difluoro-2,3,4,5-tetrahydro-1H-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). e 111-4 1-[2-(5,5-Difluoro-1,3,4,5-tetrahydro-2Hbenzazepinyl)methylquinolin yl]pyrrolidinamine N N The title compound was prepared in analogy to Example 111-1 in Scheme 56 by using 2-(4- chloromethylquinolinyl)-5,5-difluoro-2,3,4,5-tetrahydro-1H-benzazepine and idin amine. MS obsd. (ESI+) +] 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 Example 111-5 2-{[2-(5,5-Difluoro-1,3,4,5-tetrahydro-2Hbenzazepinyl)methylquinolin yl]amino}ethanol N N The title compound was prepared in analogy to Example 111-1 in Scheme 56 by using 2-(4- chloromethylquinolinyl)-5,5-difluoro-2,3,4,5-tetrahydro-1H-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 N-[2-(5,5-Difluoro-1,3,4,5-tetrahydro-2Hbenzazepinyl)methylquinolinyl]ethane- 1,2-diamine N N The title compound was prepared in analogy to e 111-1 in Scheme 56 by using 2-(4- chloromethylquinolinyl)-5,5-difluoro-2,3,4,5-tetrahydro-1H-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), .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 N-[2-(5,5-Difluoro-1,3,4,5-tetrahydro-2Hbenzazepinyl)methylquinolin yl]cyclohexane-1,3-diamine N N The title compound was prepared in analogy to Example 111-1 in Scheme 56 by using 2-(4- chloromethylquinolinyl)-5,5-difluoro-2,3,4,5-tetrahydro-1H-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), .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 (5,5-Difluoro-1,3,4,5-tetrahydro-2Hbenzazepinyl)methylquinolinyl]-N,N- dimethylethane-1,2-diamine N N The title compound was prepared in analogy to Example 111-1 in Scheme 56 by using 2-(4- chloromethylquinolinyl)-5,5-difluoro-2,3,4,5-tetrahydro-1H-benzazepine and N,N- dimethylethane-1,2-diamine. MS obsd. (ESI+) [(M+H)+] 411, 1H NMR (400 MHz, CDCl3) 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 N-[2-(5,5-Difluoro-1,3,4,5-tetrahydro-2Hbenzazepinyl)methylquinolin yl]propane-1,3-diamine N N The title compound was prepared in analogy to e 111-1 in Scheme 56 by using 2-(4- chloromethylquinolinyl)-5,5-difluoro-2,3,4,5-tetrahydro-1H-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 ,5-Difluoro-1,3,4,5-tetrahydro-2Hbenzazepinyl)methylquinolinyl]butane- 1,4-diamine N N The title compound was prepared in analogy to Example 111-1 in Scheme 56 by using 2-(4- chloromethylquinolinyl)-5,5-difluoro-2,3,4,5-tetrahydro-1H-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 transAmino[2-(5,5-difluoro-1,3,4,5-tetrahydro-2Hbenzazepinyl) methylquinolinyl]pyrrolidinol OH NH2 N N The title compound was prepared in analogy to Example 111-1 in Scheme 56 by using 2-(4- chloromethylquinolinyl)-5,5-difluoro-2,3,4,5-tetrahydro-1H-benzazepine and utyl [(3S,4S)hydroxypyrrolidinyl]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 - , 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 N-{[3-(Aminomethyl)-1,1-dioxidothietanyl]methyl}(5,5-difluoro-1,3,4,5-tetrahydro- 2Hbenzazepinyl)methylquinolinamine O NH N N A mixture solution of 2-(4-chloromethyl-quinolinyl)-5,5-difluoro-2,3,4,5-tetrahydro-1H- benzazepine (218 mg, 0.609 mmol), (1,1-dioxidothietane-3,3-diyl)dimethanamine (110 mg, 0.670 mmol), (tris(dibenzylideneacetone) adium(0) (56 mg, 0.061 mmol), 2,2’- bis(diphenylphosphino)-1,1′-binaphthalene (38 mg, 0.061 mmol) and sodium tert-butoxide (117 mg, 1.218 mmol) in toluene (5 mL) was heated at 110 oC overnight. The resulting reaction mixture was poured into water (10 mL) and extracted with dichloromethane (20 mL × 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+) +] 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 N-[(3-Aminooxetanyl)methyl][(5E)(methoxyimino)-1,3,4,5-tetrahydro-2H benzazepinyl]methylquinolinamine O NH N N (5E)(4-Chloromethylquinolinyl)-N-methoxy-1,2,3,4-tetrahydro-5Hbenzazepin imine N N The title compound was prepared in analogy to 2-(4-chloromethylquinolinyl)-5,5-difluoro- 2,3,4,5-tetrahydro-1H-benzazepine in Example 110-1 in Scheme 56 by using 2,4-dichoro methylquinoline and N-methoxy-1,2,3,4-tetrahydro-5Hbenzazepinimine.
N-[(3-Aminooxetanyl)methyl][(5E)(methoxyimino)-1,3,4,5-tetrahydro-2H benzazepinyl]methylquinolinamine O NH N N The title compound was ed in analogy to Example 112-1 in Scheme 56 by using (5E)(4- chloromethylquinolinyl)-N-methoxy-1,2,3,4-tetrahydro-5Hbenzazepinimine and 3- (aminomethyl)oxetanamine. 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 (2-Aminoethyl)sulfonyl]ethyl}(5,5-difluoro-1,3,4,5-tetrahydro-2Hbenzazepin yl)methylquinolinamine O O S NH NH 2 N N N-{2-[(2-Aminoethyl)sulfanyl]ethyl}(5,5-difluoro-1,3,4,5-tetrahydro-2Hbenzazepin yl)methylquinolinamine S NH NH 2 N N A mixture of hloromethylquinolinyl)-5,5-difluoro-2,3,4,5-tetrahydro-1H- benzazepine (160 mg, 0.447 mmol) and 2-[(2-aminoethyl)sulfanyl]ethanamine (1.5 mL) was heated at 150 oC 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 e 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.
N-{2-[(2-Aminoethyl)sulfonyl]ethyl}(5,5-difluoro-1,3,4,5-tetrahydro-2Hbenzazepin yl)methylquinolinamine O O S NH NH 2 N N To a solution of N-{2-[(2-aminoethyl)sulfanyl]ethyl}(5,5-difluoro-1,3,4,5-tetrahydro-2H benzazepinyl)methylquinolinamine (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 minutes, the resulting mixture was concentrated in vacuo. The residue was ed by preparative HPLC to afford 5 mg of the desired t 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-Aminooxetanyl)methyl]amino}methylquinazolinyl)-1,2,3,4-tetrahydro- 5Hbenzazepinone O NH N N 2-(4-Hydroxymethylquinazolinyl)-1,2,3,4-tetrahydro-5Hbenzazepinone N N O To a stirred solution of ro-4(3H)-quinazolinone (580 mg, 3.0 mmol ) and 1,2,3,4- tetrahydro-5Hbenzazepinone (591 mg, 3.0 mmol ) in toluene (20 mL) was added triethylamine (626 µL, 4.5 mmol ). After being refluxed 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 d product as a white solid (yield was 81%). 2-(4-{[(3-Aminooxetanyl)methyl]amino}methylquinazolinyl)-1,2,3,4-tetrahydro- 5Hbenzazepinone O NH N N The title compound was prepared in analogy to Example 62-1 in Scheme 23 by using 2-(4- ymethylquinazolinyl)-1,2,3,4-tetrahydro-5Hbenzazepinone and 3- (aminomethyl)oxetanamine. 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 N-{[3-(Aminomethyl)thietanyl]methyl}(5,5-difluoro-1,3,4,5-tetrahydro-2H benzazepinyl)methylquinazolinamine N N The title compound was prepared in analogy to Example 114-1 in Scheme 23 by using 2-chloro- 4(3H)-quinazolinone, 5,5-difluoro-2,3,4,5-tetrahydro-1H-benzazepine and thietane-3,3- methanamine. 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 N-{[3-(Aminomethyl)oxetanyl]methyl}(5,5-difluoro-1,3,4,5-tetrahydro-2H epinyl)methylquinazolinamine N N F The title compound was prepared in analogy to Example 114-1 in Scheme 23 by using 2-chloro- 4(3H)-quinazolinone, 5,5-difluoro-2,3,4,5-tetrahydro-1H-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-(5,5-difluoro-1,3,4,5-tetrahydro-2Hbenzazepinyl) methylquinazolinyl]amino}methyl)propane-1,3-diol OH NH N N 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-Aminooxetanyl)methyl]amino}methylquinazolinyl)methyl-2,3,4,5- tetrahydro-1Hbenzazepinol O NH N N 2-(5-Hydroxymethyl-1,3,4,5-tetrahydro-benzoazepinyl)methyl-3H-quinazolin N N To a suspension of 2-(4-hydroxymethylquinazolinyl)-1,2,3,4-tetrahydro-5Hbenzazepin- -one (500 mg, 1.57 mmol) in tetrahydrofuran (15 mL), a solution of methyl magnesium bromide in ydrofuran (3 M, 0.57 ml, 1.72 mmol) was added at 0 oC. The reaction mixture was heated at 50 oC for 4 hours, and then poured into a saturated aqueous on of ammonium chloride (10 mL) and stirred for 10 minutes. The resulting e was extracted with dichloromethane (15 mL × 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-Aminooxetanyl)methyl]amino}methylquinazolinyl)methyl-2,3,4,5- tetrahydro-1Hbenzazepinol O NH N N The title compound was prepared in analogy to Example 114-1 in Scheme 57 by using 2-(5- hydroxymethyl-1,3,4,5-tetrahydro-benzoazepinyl)methyl-3H-quinazolinone and 3- (aminomethyl)oxetanamine. MS obsd. (ESI+) [(M+H)+] 420, 1H NMR (400 MHz, CD 3OD) 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). e 116-1 Aminooxetanyl)methyl](5,5-difluoro-1,3,4,5-tetrahydro-2Hbenzazepinyl)- 6-methylquinazolinamine O NH2 N N 2-Chloro-N-{[3-(dibenzylamino)oxetanyl]methyl}ethylquinazolinamine O N N Cl A solution of 2,4-dichloromethylquinazoline (1.0 g, 4.69 mmol) in methanol (10 mL) was added 3-(aminomethyl)-N,N-dibenzyloxetanamine (1.4 g, 5.16 mmol, 60% purity) and triethylamine (0.1 g, 1 mmol). After being d 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 t as a white solid (yield was 76%).
N-{[3-(Dibenzylamino)oxetanyl]methyl}(5,5-difluoro-1,3,4,5-tetrahydro-2H benzazepinyl)methylquinazolinamine O N N N F To a solution of 2-chloro-N-{[3-(dibenzylamino)oxetanyl]methyl}methylquinazolin amine (200 mg, 0.436 mmol) in N,N-dimethylformamide (3 mL) was added 5,5-difluoro-1,3,4,5- tetrahydro-2Hbenzazepine (80 mg, 0.436 mmol) and ylamine (89 mg, 0.872 mmol). The mixture was heated at 120 oC for 30 minutes under microwave irradiation. The reaction was poured into water (10 mL) and extracted with romethane (15 mL × 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%).
N-[(3-Aminooxetanyl)methyl](5,5-difluoro-1,3,4,5-tetrahydro-2Hbenzazepinyl)- 6-methylquinazolinamine O NH N N A solution of (dibenzylamino)oxetanyl]methyl}(5,5-difluoro-1,3,4,5-tetrahydro-2H- 2-benzazepinyl)methylquinazolinamine (190 mg, 0.314 mmol) and trifluororacetic acid (1 drop) in ol was d 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 N-[(3-Amino-1,1-dioxidothietanyl)methyl](5,5-difluoro-1,3,4,5-tetrahydro-2H benzazepinyl)methylquinazolinamine O NH N N F The title compound was prepared in analogy to Example 116-1 in Scheme 57 by using 2,4- dichloromethylquinazoline, 3-(aminomethyl)-N,N-dibenzyl(1,1-dioxido)thietanamine and ,5-difluoro-1,3,4,5-tetrahydro-2Hbenzazepine. 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 N-[2-(5,5-Difluoro-1,3,4,5-tetrahydro-2Hbenzazepinyl)methylquinazolinyl]-2,2- difluoropropane-1,3-diamine F F N N hloromethylquinazolinyl)-2,2-difluoropropane-1,3-diamine F F N Cl To a solution of fluoropropane-1,3-diamine (1.1 g,10 mmol) and triethylamine (1.4 mL, 10 mol) in dichloromethane (15 mL) was added a solution of 2,4-dichloromethylquinazoline (500 mg, 2.36 mmol) in dichloromethane (5 mL) dropwise. After being stirred at room temperature ght, the resulting mixture was poured into water (50 mL) and extracted with dichloromethane (50 mL × 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% ol in dichloromethane) to afford 41.8 mg of the desired product as a white solid (yield was 62%). MS obsd. (ESI+) [(M+H)+] 287.
N-[2-(5,5-Difluoro-1,3,4,5-tetrahydro-2Hbenzazepinyl)methylquinazolinyl]-2,2- difluoropropane-1,3-diamine F F N N A solution of N-(2-chloromethylquinazolinyl)-2,2-difluoropropane-1,3-diamine (97 mg, 0.34 mmol) and 5,5-difluoro-2,3,4,5-tetrahydro-1H-benzazepine (310 mg, 1.70 mmol) in nbutanol (1 mL) was heated at 160 oC 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). e 118-1 7-Bromo-1,3,4,5-tetrahydro-2Hbenzazepinyl)chloroquinolinyl]ethane-1,2- diamine N N o-1,2,4,5-tetrahydro-3Hbenzazepinone To a cooled solution of 6-bromo-3,4-dihydro-1H-naphthalenone (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 dichloromethane (1000 mL × 3). The organic layers were combined and dried over sodium sulfate, and then trated 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+) +] 240. 7-Bromo-2,3,4,5-tetrahydro-1Hbenzazepine To a solution of 7-bromo-1,2,4,5-tetrahydro-3Hbenzazepinone (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 d for further 2 hours. The resulting mixture was trated 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, CDCl3) 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(4,6-dichloroquinolinyl)-2,3,4,5-tetrahydro-1Hbenzazepine N N The mixture of 2,4,6-trichloroquinoline (300 mg, 1.29 mmol), 7-bromo-2,3,4,5-tetrahydro-1H 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 ºC 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.
N-[2-(7-Bromo-1,3,4,5-tetrahydro-2Hbenzazepinyl)chloroquinolinyl]ethane-1,2- diamine N N The mixture of 7-bromo(4,6-dichloroquinolinyl)-2,3,4,5-tetrahydro-1Hbenzazepine (200 mg, 0.47 mmol) and ethane-1,2-diamine (0.5 mL) was heated with ng in a 5 mL microwave process vial for 2 hours at 160 ºC under microwave ation. The solvent was removed under reduced pressure, and the residue was ed 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]quinolinyl}-2,3,4,5-tetrahydro-1Hbenzazepinol N N The title compound was prepared in analogy to Example 118-1 in Scheme 59 by using 2,3,4,5- tetrahydro-1Hbenzazepineol (commercial available) and 2,4-dichloroquinoline (commercial ble) instead of o-2,3,4,5-tetrahydro-1Hbenzazepine 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 N-[6-Methyl(1,3,4,5-tetrahydro-2Hbenzazepinyl)quinolinyl]ethane-1,2 diamine N N The title compound was prepared in analogy to e 118-1 in Scheme 59 by using 2,3,4,5- tetrahydro-1Hbenzazepine (commercial available) and 2,4-dichloromethylquinoline (commercial available) instead of 7-bromo-2,3,4,5-tetrahydro-1Hbenzazepine and 2,4,6- trichloroquinoline respectively. MS obsd. (ESI+) [(M+H)+] 347. 1H NMR (400 MHz, DMSO-d6) 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 N-[2-(8-Fluoro-1,3,4,5-tetrahydro-2Hbenzazepinyl)methylquinolinyl]ethane-1,2- diamine N N The title compound was prepared in analogy to Example 118-1 in Scheme 59 by using 8-fluoro- 2,3,4,5-tetrahydro-1Hbenzazepine (commercial available) and 2,4-dichloromethylquinoline (commercial available) instead of 7-bromo-2,3,4,5-tetrahydro-1Hbenzazepine and 2,4,6- oroquinoline 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 N-[6-Chloro(1,3,4,5-tetrahydro-2Hbenzazepinyl)quinolinyl]ethane-1,2-diamine N N The title compound was prepared in analogy to Example 118-1 in Scheme 59 by using 2,3,4,5- tetrahydro-1Hbenzazepine (commercial available) d 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 Example 118-6 hloro(9-fluoro-1,3,4,5-tetrahydro-2Hbenzazepinyl)quinolinyl]ethane-1,2- diamine Cl F N N The title compound was prepared in analogy to Example 118-1 in Scheme 59 by using 9-fluoro- 2,3,4,5-tetrahydro-1Hbenzazepine (commercial available) instead of o-2,3,4,5- ydro-1Hbenzazepine. 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 N-[2-(8-Fluoro-1,3,4,5-tetrahydro-2Hbenzazepinyl)quinolinyl]ethane-1,2-diamine N N The title compound was prepared in analogy to e 118-1 in Scheme 59 by using 8-fluoro- 2,3,4,5-tetrahydro-1Hbenzazepine (commercial available) and 2,4-dichloroquinoline (commercial available) instead of 7-bromo-2,3,4,5-tetrahydro-1Hbenzazepine 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 1-Amino{[2-(1,3,4,5-tetrahydro-2Hbenzazepinyl)quinolinyl]amino}propanol trifluoroacetate (salt) NH F N N The title compound was prepared in analogy to Example 118-1 in Scheme 59 by using 2,3,4,5- tetrahydro-1Hbenzazepine (commercial available), chloroquinoline (commercial available) and 1,3-diamino-propanol (commercial available) instead of 7-bromo-2,3,4,5- tetrahydro-1Hbenzazepine, 2,4,6-trichloroquinoline and ethane-1,2-diamine respectively. MS obsd. (ESI+) +] 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). e 118-9 N-[2-(1,3,4,5-Tetrahydro-2Hbenzazepinyl)quinolinyl]ethane-1,2-diamine N N The title compound was prepared in analogy to Example 118-1 in Scheme 59 by using 2,3,4,5- tetrahydro-1Hbenzazepine (commercial available) and chloroquinoline (commercial available) instead of 7-bromo-2,3,4,5-tetrahydro-1Hbenzazepine and 2,4,6-trichloroquinoline 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 N-[6-Bromo(1,3,4,5-tetrahydro-2Hbenzazepinyl)quinolinyl]ethane-1,2-diamine N N The title compound was prepared in analogy to Example 118-1 in Scheme 59 by using 2,3,4,5- tetrahydro-1Hbenzazepine (commercial available) and 6-bromo-2,4-dichloroquinoline (commercial available) instead of 7-bromo-2,3,4,5-tetrahydro-1Hbenzazepine and 2,4,6- trichloroquinoline tively. MS obsd. (ESI+) +] 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 N-[6-Methoxy(1,3,4,5-tetrahydro-2Hbenzazepinyl)quinolinyl]ethane-1,2- diamine N N The title compound was prepared in analogy to Example 118-1 in Scheme 59 by using 2,3,4,5- tetrahydro-1Hbenzazepine (commercial available) and 2,4-dichloromethoxyquinoline (commercial available) instead of 7-bromo-2,3,4,5-tetrahydro-1Hbenzazepine and 2,4,6- oroquinoline 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 N-[2-(6-Chloro-1,3,4,5-tetrahydro-2Hbenzazepinyl)quinolinyl]ethane-1,2-diamine N N The title compound was prepared in analogy to Example 118-1 in Scheme 59 by using 5-chloro- 3,4-dihydro-1H-naphthalenone (commercial available) and 2,4-dichloroquinoline rcial available) d of 6-bromo-3,4-dihydro-1H-naphthalenone 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 N-[2-(7-Fluoro-1,3,4,5-tetrahydro-2Hbenzazepinyl)methylquinolinyl]ethane-1,2- diamine N N The title compound was prepared in analogy to Example 118-1 in Scheme 59 by using ro- 3,4-dihydro-1H-naphthalenone (commercial available) and 2,4-dichloromethylquinoline (commercial available) instead of 6-bromo-3,4-dihydro-1H-naphthalenone 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 N-Methyl-N'-[2-(1,3,4,5-tetrahydro-2Hbenzazepinyl)quinolinyl]ethane-1,2-diamine N N The title compound was prepared in analogy to Example 118-1 in Scheme 59 by using 2,3,4,5- tetrahydro-1Hbenzazepine (commercial available), chloroquinoline (commercial available) and N-methyl-ethane-1,2-diamine (commercial available) instead of 7-bromo-2,3,4,5- tetrahydro-1Hbenzazepine, 2,4,6-trichloroquinoline and ethane-1,2-diamine tively. MS obsd. (ESI+) [(M+H)+] 347. 1H NMR (400 MHz, DMSO-d6) 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 7-Methoxy-1,3,4,5-tetrahydro-2Hbenzazepinyl)quinolinyl]ethane-1,2- diamine N N The title compound was prepared in analogy to Example 118-1 in Scheme 59 by using 7- methoxy-2,3,4,5-tetrahydro-1Hbenzazepine (commercial available) and 2,4-dichloroquinoline (commercial available) instead of 7-bromo-2,3,4,5-tetrahydro-1Hbenzazepine and 2,4,6- oroquinoline 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 N-[2-(7-Fluoro-1,3,4,5-tetrahydro-2Hbenzazepinyl)quinolinyl]ethane-1,2-diamine N N The title compound was ed in analogy to Example 118-1 in Scheme 59 by using 6-fluoro- hydro-1H-naphthalenone (commercial available) and 2,4-dichloroquinoline (commercial available) instead of 6-bromo-3,4-dihydro-1H-naphthalenone 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 8-Methoxy-1,3,4,5-tetrahydro-2Hbenzazepinyl)quinolinyl]ethane-1,2- diamine N N The title compound was prepared in analogy to Example 118-1 in Scheme 59 1 by using 8- methoxy-2,3,4,5-tetrahydro-1Hbenzazepine (commercial available) and 2,4-dichloroquinoline (commercial available) instead of 7-bromo-2,3,4,5-tetrahydro-1Hbenzazepine 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 N-[6-(Difluoromethoxy)(1,3,4,5-tetrahydro-2Hbenzazepinyl)quinolinyl]ethane- 1,2-diamine F F N N The title compound was prepared in analogy to Example 118-1 in Scheme 59 by using 2,3,4,5- tetrahydro-1Hbenzazepine (commercial ble) and 2,4-dichloro difluoromethoxyquinoline (commercial available) instead of 7-bromo-2,3,4,5-tetrahydro-1H 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, HCF2O- ), 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 N-[2-(1,3,4,5-Tetrahydro-2Hbenzazepinyl)(trifluoromethyl)quinolinyl]ethane- 1,2-diamine F NH N N The title compound was prepared in analogy to Example 118-1 in Scheme 59 by using 2,3,4,5- tetrahydro-1Hbenzazepine rcial ble) and 2,4-dichloro trifluoromethylquinoline (commercial available) instead of 7-bromo-2,3,4,5-tetrahydro-1H benzazepine and 2,4,6-trichloroquinoline respectively. MS obsd. (ESI+) [(M+H)+] 401. 1H NMR (400 MHz, 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 N-[8-Chloro(1,3,4,5-tetrahydro-2Hbenzazepinyl)quinolinyl]ethane-1,2-diamine N N The title nd was prepared in analogy to Example 118-1 in Scheme 59 by using 2,3,4,5- tetrahydro-1Hbenzazepine (commercial available) and 2,4,8-trichloroquinoline (commercial available) instead of 7-bromo-2,3,4,5-tetrahydro-1Hbenzazepine and 2,4,6-trichloroquinoline 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 N-[6-Fluoro(1,3,4,5-tetrahydro-2Hbenzazepinyl)quinolinyl]ethane-1,2-diamine N N The title compound was ed in analogy to Example 118-1 in Scheme 59 by using 2,3,4,5- tetrahydro-1Hbenzazepine rcial available) and 2,4-dichlorofluoroquinoline (commercial available) instead of 7-bromo-2,3,4,5-tetrahydro-1Hbenzazepine 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 N,N-Dimethyl-N'-[2-(1,3,4,5-tetrahydro-2Hbenzazepinyl)quinolinyl]ethane-1,2- diamine N N The title compound was prepared in analogy to Example 118-1 in Scheme 59 by using 2,3,4,5- tetrahydro-1Hbenzazepine (commercial available), 2,4-dichloroquinoline rcial available) and N,N-dimethyl-ethane-1,2-diamine (commercial available) instead of 7-bromo- 5-tetrahydro-1Hbenzazepine, 2,4,6-trichloroquinoline and ethane-1,2-diamine respectively. MS obsd. (ESI+) [(M+H)+] 361. 1H NMR (400 MHz, DMSO-d6) 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 N-[2-(1,3,4,5-Tetrahydro-2Hbenzazepinyl)(trifluoromethoxy)quinolinyl]ethane- 1,2-diamine N N The title compound was prepared in y to Example 118-1 in Scheme 59 by using 2,3,4,5- ydro-1Hbenzazepine (commercial available) and 2,4-dichloro trifluoromethoxyquinoline (commercial available) instead of 7-bromo-2,3,4,5-tetrahydro-1H 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 N-[6-(Methylsulfonyl)(1,3,4,5-tetrahydro-2Hbenzazepinyl)quinolinyl]ethane-1,2- diamine O NH N N The title compound was prepared in analogy to Example 118-1 in Scheme 59 by using 2,3,4,5- tetrahydro-1Hbenzazepine (commercial available) and 2,4-dichloro methanesulfonylquinoline (commercial ble) instead of 7-bromo-2,3,4,5-tetrahydro-1H benzazepine and 2,4,6-trichloroquinoline respectively. MS obsd. (ESI+) [(M+H)+] 411. 1H NMR (400 MHz, DMSO-d6) 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-Aminoethyl)amino]quinolinyl}-2,3,4,5-tetrahydro-1Hbenzazepine carboxylic acid N N The title nd was prepared in analogy to Example 118-1 in Scheme 59 by using 2,3,4,5- tetrahydro-1Hbenzazepinecarboxylic acid (commercial available) and 2,4- dichloroquinoline (commercial available) instead of 7-bromo-2,3,4,5-tetrahydro-1H 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-Chloroquinolinyl)-2,3,4,5-tetrahydro-1Hbenzazepine N N The title compound was prepared in Scheme 1 by using 2,3,4,5-tetrahydro-1Hbenzazepine rcial available) and chloroquinoline (commercial available) instead of 7-bromo- 2,3,4,5-tetrahydro-1Hbenzazepine and 2,4,6-trichloroquinoline respectively. MS obsd. (ESI+) [(M+H)+] 309. 1H NMR (400 MHz, CDCl3) 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 N-[5-Chloro(1,3,4,5-tetrahydro-2Hbenzazepinyl)quinolinyl]ethane-1,2-diamine Cl NH N N 1-(1,3,4,5-Tetrahydro-2Hbenzazepinyl)ethanone A suspension of 2,3,4,5-tetrahydro-1Hbenzazepine hydrochloride (10 g, 54.4 mmol) in dry dichloromethane (450 mL) was stirred at 0 ºC. 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 e 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 t as colorless oil (yield was 97%). It was used in next step without further purification. MS obsd. (ESI+) [(M+H)+] 190. 2-Chloro{[1-(1,3,4,5-tetrahydro-2Hbenzazepinyl)ethylidene]amino}benzonitrile Cl N N N Phosphorus oxychloride (2.93 mL, 32.0 mmol) was added to a stirred solution of 1-(1,3,4,5- tetrahydro-2Hbenzazepinyl)ethanone (5.5 g, 29.0 mmol) in dry dichloromethane (100 mL) at 10 ºC. After that, the mixture was stirred for 20 minutes at room temperature. Then a solution of 2-aminochloro-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 onate 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 t as a brown powder (yield was 63.7%). It was used in the next step without further purification. MS obsd. (ESI+) [(M+H)+] 324. ro(1,3,4,5-tetrahydro-2Hbenzazepinyl)quinolinamine Cl NH2 N N The mixture of 2-chloro{[1-(1,3,4,5-tetrahydro-2Hbenzazepin ylidene]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 ºC for 3 hours under argon. After the reaction was allowed to cool to about 40 ºC, sodium hydroxide (2 N, 20 mL) was added and then d 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-Dichloroquinolinyl)-2,3,4,5-tetrahydro-1Hbenzazepine Cl Cl N N To the suspension of 5-chloro(1,3,4,5-tetrahydro-2Hbenzazepinyl)quinolinamine (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 ºC. After the addition, the reaction mixture was stirred for further 30 minutes, and then sodium chloride (2 g) was added. The resulting e was stirred at room temperature overnight and neutralized with saturated sodium bicarbonate, extracted with dichloromethane (50 mL × 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.
N-[5-Chloro(1,3,4,5-tetrahydro-2Hbenzazepinyl)quinolinyl]ethane-1,2-diamine Cl NH N N The mixture of 2-(4,5-dichloroquinolinyl)-2,3,4,5-tetrahydro-1Hbenzazepine 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 ºC under microwave irradiation. The reaction mixture was diluted with ethyl acetate (20 mL), and then washed with water (20 mL). The c fraction was dried over sodium sulfate, and concentrated under reduced pressure to give a e which was purified by preparative HPLC to give 20 mg of t as a white . MS obsd. (ESI+) [(M+H)+] 367. 1H NMR (400 MHz, CD 3OD) 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). e 120-1 N-{2-[7-(Methylsulfonyl)-1,3,4,5-tetrahydro-2Hbenzazepinyl]quinolinyl}ethane- 1,2-diamine N N 7-(Methylsulfonyl)-2,3,4,5-tetrahydro-1Hbenzazepine The mixture of 7-bromo-2,3,4,5-tetrahydro-1Hbenzazepine (226 mg, 1.0 mmol), sodium methanesulfinate (120 mg, 1.2 mmol), copper(I) iodide (19 mg, 0.1 mmol), L-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 ºC. The resulting mixture was diluted with water, and extracted with ethyl acetate (30 mL × 3). The organic layers were combined and washed with brine (40 mL × 3), and then dried over sodium sulfate. The solvent was removed under d pressure and the residue was purified by column chromatography on silica gel (methanol/dichloromethane, 1:20) to give 144 mg of t as a light-brown viscous oil (yield was 63.9%). MS obsd. (ESI+) [(M+H)+] 226. 2-(4-Chloroquinolinyl)(methylsulfonyl)-2,3,4,5-tetrahydro-1Hbenzazepine N N The mixture of 2,4-dichloroquinoline (126 mg, 0.637 mmol), 7-(methylsulfonyl)-2,3,4,5- ydro-1Hbenzazepine (144 mg, 0.637 mmol), triethylamine (0.106 mL, 0.765 mmol) and N-methylpyrrolidone (2 mL) was heated with stirring in a sealed tube for 4 hours at 100 ºC.
The resulting mixture was diluted with water and extracted with ethyl acetate (15 mL × 3). The organic layers were combined and washed with brine (15 mL × 3), and then dried over sodium sulfate. The solvent was d 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.
N-{2-[7-(Methylsulfonyl)-1,3,4,5-tetrahydro-2Hbenzazepinyl]quinolinyl}ethane- 1,2-diamine N N The mixture of 2-(4-chloroquinolinyl)(methylsulfonyl)-2,3,4,5-tetrahydro-1H epine (55.6 mg, 0.144 mmol) and ethane-1,2-diamine (1 mL) was heated with stirring in a mL microwave s vial for 2 hours at 150 ºC 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 N-{2-[7-(Ethylsulfonyl)-1,3,4,5-tetrahydro-2Hbenzazepinyl]quinolinyl}ethane-1,2- diamine N N The title compound was prepared in analogy to Example 120-1 by using sodium ethanesulfinate (commercial available) d of sodium methanesulfinate. 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-2Hbenzazepinyl)quinolinyl]ethane-1,2-diamine N N O 2-(4-Chloroquinolinyl)ethoxy-2,3,4,5-tetrahydro-1Hbenzazepine N N O To a solution of 2-(4-chloroquinolinyl)-2,3,4,5-tetrahydro-1Hbenzazepinol (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 d at room temperature for r 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 ed by column chromatography on silica gel to give 28 mg of product. MS obsd. (ESI+) [(M+H)+] 353.
N-[2-(8-Ethoxy-1,3,4,5-tetrahydro-2Hbenzazepinyl)quinolinyl]ethane-1,2-diamine N N O The mixture of 2-(4-chloroquinolinyl)ethoxy-2,3,4,5-tetrahydro-1Hbenzazepine (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 ºC under ave 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 N-[6-(Pyridinyloxy)(1,3,4,5-tetrahydro-2Hbenzazepinyl)quinolinyl]ethane- 1,2-diamine N N 4-Chloro(1,3,4,5-tetrahydro-2Hbenzazepinyl)quinolinol N N To a solution of 2-(4-chloromethoxy-quinolinyl)-2,3,4,5-tetrahydro-1Hbenzazepine (800 mg, 2.37 mmol) in 15 mL of romethane was added slowly a on 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 ºC 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 × 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 e/hexane, 1:5) to give 500 mg of t (yield was 65%). 2-[4-Chloro(pyridinyloxy)quinolinyl]-2,3,4,5-tetrahydro-1Hbenzazepine N N The mixture of 4-chloro(1,3,4,5-tetrahydro-2Hbenzazepinyl)quinolinol (200 mg, 0.617 mmol), 2-fluoro-pyridine (180 mg, 1.85 mmol), ium carbonate (73 mg, 0.53 mmol) and dry dimethylsulfoxide was heated with stirring in a sealed tube for 40 minutes at 130 ºC under microwave irradiation. The resulting mixture was cooled to room temperature, then diluted with water (10 mL) and extracted with ethyl acetate (10 mL × 2). The combined organic layer was washed with brine (10 mL × 3), and then dried over sodium sulfate. The solvent was removed in vacuo and the e 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%).
Pyridinyloxy)(1,3,4,5-tetrahydro-2Hbenzazepinyl)quinolinyl]ethane- 1,2-diamine N N The mixture of 2-[4-chloro(pyridinyloxy)quinolinyl]-2,3,4,5-tetrahydro-1H 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 ºC under microwave irradiation. The solvent was removed under reduced re 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]chloroquinolinyl}-N,N-dimethyl-2,3,4,5-tetrahydro-1H benzazepinecarboxamide N N Methyl 2-(4,6-dichloroquinolinyl)-2,3,4,5-tetrahydro-1Hbenzazepinecarboxylate N N o(4,6-dichloroquinolinyl)-2,3,4,5-tetrahydro-1H-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 e 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 e and trated 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-Dichloroquinolinyl)-2,3,4,5-tetrahydro-1Hbenzazepinecarboxylic acid N N Methyl 2-(4,6-dichloroquinolinyl)-2,3,4,5-tetrahydro-1Hbenzazepinecarboxylate (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+) +] 387. 2-(4,6-Dichloroquinolinyl)-N,N-dimethyl-2,3,4,5-tetrahydro-1Hbenzazepine carboxamide N N The mixture of 2-(4,6-dichloroquinolinyl)-2,3,4,5-tetrahydro-1Hbenzazepinecarboxylic acid (135 mg, 0.35 mmol), dimethylamine hydrochloride (34.2 mg, 0.42 mmol), triethylamine (105 mg, 1.05 mmol), O-(7-azabenzotriazolyl)-N,N,N',N'-tetramethyluronium uorophosphate (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-Aminoethyl)amino]chloroquinolinyl}-N,N-dimethyl-2,3,4,5-tetrahydro-1H benzazepinecarboxamide N N The mixture of -dichloroquinolinyl)-N,N-dimethyl-2,3,4,5-tetrahydro-1H benzazepinecarboxamide (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 ºC under microwave irradiation. The solvent was removed under reduced pressure and the residue was purified by ative 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]quinolinyl}bromo-1,2,4,5-tetrahydro-3Hbenzazepin N N 7-Bromo(4-chloroquinolinyl)-1,2,4,5-tetrahydro-3Hbenzazepinone N N To a solution of chloroquinoline (196 mg, 1.0 mmol) in dioxane (4 mL) was added 7- bromo-1,2,4,5-tetrahydro-3Hbenzazepinone (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 ic (212 mg, 1.0 mmol). The resultant mixture was refilled with nitrogen and heated at 130 ºC overnight.
After cooled to room temperature, the mixture was d 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]quinolinyl}bromo-1,2,4,5-tetrahydro-3Hbenzazepin one N N To a on of 7-bromo(4-chloroquinolinyl)-1,2,4,5-tetrahydro-3Hbenzazepinone (40 mg, 0.1 mmol) was added ethane-1,2-diamine (0.5 mL) in a microwave vessel, which was degassed and ed with nitrogen. The resultant mixture was heated at 170 ºC under microwave irradiation for 30 minutes. After cooled to room temperature, the mixture was diluted with methanol (10 mL) and 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 1-(2-{[2-(1,3,4,5-Tetrahydro-2Hbenzazepinyl)quinolinyl]amino}ethyl)guanidine oroacetate NH NH NH F N N To a solution of N-[2-(1,3,4,5-tetrahydro-2Hbenzazepinyl)quinolinyl]ethane-1,2- diamine (200 mg, 0.6 mmol) and methyl-1H-pyrazolecarboximidamide nitrate (122 mg, 0.6 mmol) in ethanol (15 mL) was ed 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 × 2). The dichloromethane fractions were combined and dried over sodium sulfate, and then concentrated under d 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 N-[(2-Amino-4,5-dihydro-1,3-oxazolyl)methyl](1,3,4,5-tetrahydro-2Hbenzazepin yl)quinolinamine trifluoroacetate NH F N N The mixture of 1-amino{[2-(1,3,4,5-tetrahydro-2Hbenzazepinyl)quinolin no}propanol (690 mg, 1.9 mmol) and potassium acetate (490 mg, 5 mmol) in methanol (7 mL) and water (1.75 mL) was d at 0 ºC. 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 on was dried over sodium sulfate, and concentrated under d 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 N-[(2-Amino-4,5-dihydro-1,3-oxazolyl)methyl]chloro(1,3,4,5-tetrahydro-2H benzazepinyl)quinolinamine N N The title compound was prepared in y to Example 9-1 by using 1-amino{6-chloro-[2- (1,3,4,5-tetrahydro-2Hbenzazepinyl)quinolinyl]amino}propanol [It was prepared in Scheme 1 by using 2,3,4,5-tetrahydro-1Hbenzazepine (commercial available) and 1,3- diamino-propanol (commercial available) instead of 7-bromo-2,3,4,5-tetrahydro-1H benzazepine and ethane-1,2-diamine respectively.] instead of 1-amino{[2-(1,3,4,5-tetrahydro- 2Hbenzazepinyl)quinolinyl]amino}propanol. 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 1,3,4,5-Tetrahydro-2Hbenzazepinyl)quinolinyl]glycinamide NH O N N 2-Chloro-N-[2-(1,3,4,5-tetrahydro-2Hbenzazepinyl)quinolinyl]acetamide NH O N N To the solution of 2-(1,3,4,5-tetrahydro-2Hbenzazepinyl)quinolinamine (500 mg, 1.73 mmol) was added 1,8-diazabicyclo[5.4.0]undecene (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 ºC for 2 hours under nitrogen. After cooled to room temperature, the reaction was diluted with ethyl e (50 mL), and then washed with water (50 mL × 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 . MS obsd. (ESI+) [(M+H)+] 366. 2-Azido-N-[2-(1,3,4,5-tetrahydro-2Hbenzazepinyl)quinolinyl]acetamide NH O N N To a solution of 2-chloro-N-[2-(1,3,4,5-tetrahydro-2Hbenzazepinyl)quinolin yl]acetamide (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.
N-[2-(1,3,4,5-Tetrahydro-2Hbenzazepinyl)quinolinyl]glycinamide NH O N N To a solution of 2-azido-N-[2-(1,3,4,5-tetrahydro-2Hbenzazepinyl)quinolinyl]acetamide (65 mg, 0.17 mmol) in methanol was added palladium (10% on carbon, 7 mg). After being d at room temperature overnight under a hydrogen atmosphere, the resulting mixture was ed. The te 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-d6) 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). e 128 3-[2-(1,3,4,5-Tetrahydro-2Hbenzazepinyl)quinolinyl]propanamine N N Methyl -[2-(1,3,4,5-tetrahydro-2Hbenzazepinyl)quinolinyl]propenoate O O N N The mixture of 2-(4-chloroquinolinyl)-2,3,4,5-tetrahydro-1Hbenzazepine (1.5 g, 4.86 mmol), acrylic acid methyl ester (0.88 ml, 9.7 mmol), ylamine (6 mL) and N,N- dimethylformamide (6 mL), i-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 ºC under argon.
The reaction mixture was poured into water (30 mL) and extracted with ethyl acetate (20 mL × 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-(1,3,4,5-tetrahydro-2Hbenzazepinyl)quinolinyl]propanoate O O N N To a solution of methyl (2E)[2-(1,3,4,5-tetrahydro-2Hbenzazepinyl)quinolinyl]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 t as a white solid (yield was 98%).
MS obsd. (ESI+) [(M+H)+] 361. 3-[2-(1,3,4,5-Tetrahydro-2Hbenzazepinyl)quinolinyl]propanoic acid O OH N N To a solution of methyl 3-[2-(1,3,4,5-tetrahydro-2Hbenzazepinyl)quinolinyl]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 ied to pH 4 with 5 N hydrochloric acid, and then extracted with ethyl acetate (10 mL × 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-(1,3,4,5-Tetrahydro-2Hbenzazepinyl)quinolinyl]propanamide O NH N N To a solution of 3-[2-(1,3,4,5-tetrahydro-2Hbenzazepinyl)quinolinyl]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 ºC. The resulting mixture was warmed to room ature and stirred for further 2 hours. The solvent was removed under reduced re and the residue was dissolved in dichloromethane (5 mL), to which a tetrahydrofuran on of ammonia (4 N, 5 mL) was added at 0 ºC, 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 t as a white solid. It was used in next step without further purification.
MS obsd. (ESI+) [(M+H)+] 346. 3-[2-(1,3,4,5-Tetrahydro-2Hbenzazepinyl)quinolinyl]propanamine N N To the mixture of 3-[2-(1,3,4,5-tetrahydro-2Hbenzazepinyl)quinolinyl]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 ºC, followed by stirring at 70 ºC for 4 hours. After being ed with methanol (5 mL) at 0 ºC, 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-d6) 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 3,4,5-Tetrahydro-2Hbenzazepinyl)quinolinyl]methanol N N Methyl 2-(1,3,4,5-tetrahydro-2Hbenzazepinyl)quinolinecarboxylate O O N N The mixture of 2-chloroquinolinecarboxylic acid methyl ester (3 g, 13.5 mmol), 5- tetrahydro-1Hbenzazepine hydrochloride (3 g, 16.3 mmol), potassium carbonate (4.5 g, 32.6 mmol), tetrabutylammonium iodide (300 mg) and e (60 mL) was heated with stirring at 110 ºC 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-(1,3,4,5-Tetrahydro-2Hbenzazepinyl)quinolinyl]methanol N N To the mixture of methyl 2-(1,3,4,5-tetrahydro-2Hbenzazepinyl)quinolinecarboxylate (30 mg, 0.087 mmol ) in tetrahydrofuran (2 mL) was added a tetrahydrofuran solution of borane (1.5 mL, 1.5 mmol) at 0 ºC. After being d at 70 ºC for 4 hours, the mixture was quenched with methanol (5 mL) at 0 ºC. The solvent was removed in vacuo to give a e 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-d6) 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-Chloroquinolinyl)-2,3,4,5-tetrahydro-1Hbenzazepine N N 2-[6-Chloro(propenyl)quinolinyl]-2,3,4,5-tetrahydro-1Hbenzazepine N N The mixture of 2-(4,6-dichloroquinolinyl)-2,3,4,5-tetrahydro-1Hbenzazepine (200 mg, 0.58 mmol), 2-allyl-4,4,5,5-tetramethyl-[1,3,2]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 ºC 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 e, and then concentrated under reduced pressure to give a residue which was separated by column tography on silica gel (ethyl acetate/petroleum ether, 0.1:5) to afford 2-[6-chloro(propenyl)quinolinyl]-2,3,4,5- tetrahydro-1Hbenzazepine (20 mg) and 2-(6-chloroquinolinyl)-2,3,4,5-tetrahydro-1H benzazepine (50 mg). hloro(propenyl)quinolinyl]-2,3,4,5-tetrahydro-1Hbenzazepine MS obsd. (ESI+) [(M+H)+] 349. 2-(6-chloroquinolinyl)-2,3,4,5-tetrahydro-1Hbenzazepine MS obsd. (ESI+) [(M+H)+] 309. 1H NMR (400 MHz, DMSO-d6) 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(1,3,4,5-tetrahydro-2Hbenzazepinyl)quinolinyl]propane-1,2-diol N N To a solution of 2-[6-chloro(propenyl)quinolinyl]-2,3,4,5-tetrahydro-1H 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) ed by osmium tetroxide (0.14 mg, 0.0005 mmol). The resulting mixture was stirred at room temperature overnight. The t 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 Example 131 (4S){2-[2-(1,3,4,5-Tetrahydro-2Hbenzazepinyl)quinolinyl]ethyl}-4,5-dihydro- 1,3-oxazolamine N N tert-Butyl (4S)-2,2-dimethyl{(E)[2-(1,3,4,5-tetrahydro-2Hbenzazepinyl)quinolin- 4-yl]ethenyl}-1,3-oxazolidinecarboxylate N N The mixture of 2-(4-chloroquinolinyl)-2,3,4,5-tetrahydro-1Hbenzazepine (310 mg, 1.0 mmol), (S)-2,2-dimethylvinyl-oxazolidinecarboxylic 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 ºC under microwave irradiation. The reaction mixture was diluted with ethyl acetate and washed with brine. The c layer was dried over sodium sulfate, and then concentrated under d 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{2-[2-(1,3,4,5-tetrahydro-2Hbenzazepinyl)quinolin yl]ethyl}-1,3-oxazolidinecarboxylate N N The mixture of tert-butyl (4S)-2,2-dimethyl{(E)[2-(1,3,4,5-tetrahydro-2Hbenzazepin yl)quinolinyl]ethenyl}-1,3-oxazolidinecarboxylate (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 trated in vacuo to give 340 mg of product as a white solid (yield was 89%). MS obsd.
(ESI+) [(M+H)+] 502. (2S)Amino[2-(1,3,4,5-tetrahydro-2Hbenzazepinyl)quinolinyl]butanol N N To the solution of tert-butyl (4S)-2,2-dimethyl{2-[2-(1,3,4,5-tetrahydro-2Hbenzazepin nolinyl]ethyl}-1,3-oxazolidinecarboxylate (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 lized 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. (4S){2-[2-(1,3,4,5-Tetrahydro-2Hbenzazepinyl)quinolinyl]ethyl}-4,5-dihydro- azolamine N N To the stirred mixture of (2S)amino[2-(1,3,4,5-tetrahydro-2Hbenzazepinyl)quinolin- 4-yl]butanol (110 mg, 0.3 mmol), ium 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 ºC. 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 . MS obsd. (ESI+) [(M+H)+] 387. 1H NMR (400 MHz, DMSO-d6) 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 N-(2-Aminoethyl)(1,3,4,5-tetrahydro-2Hbenzazepinyl)quinolinesulfonamide trifluoroacetate O N S NH F O 2 F N N 2-(1,3,4,5-Tetrahydro-2Hbenzazepinyl)quinolinethiol N N A mixture of 2-(4-chloroquinolinyl)-2,3,4,5-tetrahydro-1Hbenzazepine (2 g, 6.47 mmol) and sodium thiomethoxide (2.4 g, 34 mmol) in dry N,N-dimethylformamide (20 mL) was heated with stirring ght under reflux. The reaction mixture was cooled to 50 ºC and the volatile ents were evaporated under reduced re 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 ant solution was extracted with chilled dichloromethane (30 mL × 3). The dichloromethane fractions were combined and washed with chilled brine (30 mL × 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-(1,3,4,5-Tetrahydro-2Hbenzazepinyl)quinolinesulfonyl chloride O S O N N Gaseous chlorine was passed through a well stirred solution of 2-(1,3,4,5-tetrahydro-2H benzazepinyl)quinolinethiol (2 g, 6.5 mmol) in concentrated hloric acid (17 mL) at - ºC at such a rate that ature was maintained between -5 and -10 ºC. The passage of chlorine was discontinued after 30 s. 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 × 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.
N-(2-Aminoethyl)(1,3,4,5-tetrahydro-2Hbenzazepinyl)quinolinesulfonamide trifluoroacetate O N S NH F O 2 F N N 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 ter bath, followed by the addition of the solution of 2- (1,3,4,5-tetrahydro-2Hbenzazepinyl)quinolinesulfonyl chloride (400 mg, 0.9 mmol) in dichloromethane (20 mL) prepared above slowly. After being d overnight, the solvent was removed under d 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]methylquinolinyl}-1,3,4,5-tetrahydro-2H-1,4- benzodiazepinone N N O H 4-(4-Chloromethylquinolinyl)-1,3,4,5-tetrahydro-2H-1,4-benzodiazepinone N N O H The mixture of 2,4-dichloromethyl-quinoline (422 mg, 2 mmol), 1,3,4,5-tetrahydro-2H-1,4- benzodiazepinone (298 mg, 2 mmol) and l alcohol (15 mL) was heated with stirring in a 20 mL microwave process vial for 3 hours at 160 ºC under microwave irradiation. After cooling, the solvent was d 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]methylquinolinyl}-1,3,4,5-tetrahydro-2H-1,4- benzodiazepinone N N O H The mixture of 4-(4-chloromethylquinolinyl)-1,3,4,5-tetrahydro-2H-1,4-benzodiazepin one (60 mg, 1 mmol), [1,1'-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 s vial for 1 hour at 120 ºC 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 e 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, 1 H), 7.44 - 7.40 (m, 2 H), 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). e 133-2 N-[6-Methyl(1,2,3,5-tetrahydro-4H-1,4-benzodiazepinyl)quinolinyl]ethane-1,2- diamine N N The title compound was prepared in analogy to Example 16-1 by using 2,3,4,5-tetrahydro-1H- 1,4-benzodiazepine (commercial available) instead of 1,3,4,5-tetrahydro-2H-1,4-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 Example 134 N-[2-(2,3-Dihydro-1,4-benzoxazepin-4(5H)-yl)quinolinyl]ethane-1,2-diamine N N Methyl (2-cyanophenoxy)acetate O CO Me To the mixture of 2-hydroxybenzonitrile (40 g, 0.34 mol) and potassium ate (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 d at room ature 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 e which was recrystallized in methanol to give 40 g of product as a white solid. 4,5-Dihydro-1,4-benzoxazepin-3(2H)-one 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 d at room temperature overnight under hydrogen atmosphere. Raney Ni was d by filtration, and the filtrated was concentrated under reduced pressure to give a residue which was purified by column chromatography on silica gel (methanol/dichloromethane, 1:50) to give 23 g of product.
MS obsd. (ESI+) [(M+H)+] 164. 2,3,4,5-Tetrahydro-1,4-benzoxazepine O To the suspension of lithium aluminium hydride (15.2 g, 0.4 mol) in 600 mL of ether was added a on of 4,5-dihydro-1,4-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 dropwise to quench the reaction at 0 ºC, The ing 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 e then ether, and then dried in vacuo to give 13.5 g of product. MS obsd. (ESI+) [(M+H)+] 150. 4-(4-Chloroquinolinyl)-2,3,4,5-tetrahydro-1,4-benzoxazepine N N O The mixture of 2,4-dichloroquinoline (198 mg, 0.1 mmol), 2,3,4,5-tetrahydro-1,4-benzoxazepine hydrochloride (186 mg, 0.1 mmol), diisopropylethylamine (0.4 mL) and 5 mL of N-methyl pyrrolidone was heated with stirring at 100 ºC overnight. The mixture was cooled to room temperature, diluted with brine, and extracted with ethyl acetate (30 mL × 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 ed by column chromatography on silica gel to give 119 mg of t as a white solid. MS obsd. (ESI+) [(M+H)+] 311.
N-[2-(2,3-Dihydro-1,4-benzoxazepin-4(5H)-yl)quinolinyl]ethane-1,2-diamine N N The mixture of 4-(4-chloroquinolinyl)-2,3,4,5-tetrahydro-1,4-benzoxazepine (100 mg, 0.32 mmol) and 1.6 mL of ethane-1,2-diamine was heated with stirring in a 5 mL ave process vial for 3 hours at 150 ºC under microwave irradiation. The mixture was concentrate in vacuo to give a e 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-[(1-Aminocyclopropyl)methyl](1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)- 6-methylquinazolinamine N N O tert-Butyl (1-{[(2-chloromethylquinazolinyl)amino]methyl}cyclopropyl)carbamate N O N Cl To a solution of tert-butyl [1-(aminomethyl)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 ature. 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 t as a white . tert-Butyl [({2-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl) quinazolinyl]amino}methyl)cyclopropyl]carbamate N O N N A mixture of tert-butyl (1-{[(2-chloromethylquinazolinyl)amino]methyl}cyclopropyl) carbamate (1.5 g, 4.1 mmol), 2,3,4,5-tetrahydro-1,4-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 oC 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 ed with 1 N of sodium hydroxide. The organic phase was separated and used for the next step directly. (1-Amino-cyclopropylmethyl)-[2-(5,5-dioxo-5,6,7,9-tetrahydro-5lambda*6*-thiaaza- benzocycloheptenyl)methyl-quinazolinyl]-amine N N 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 on 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 ed white solid was ted by filtration and dried in vacuo to afford 400 mg of the t 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-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)methyl-N-(pyrrolidin yl)quinazolinamine N N O The title compound was prepared in analogy to Example 135-1 in Scheme 70 by using 2,4- dichloromethylquinazoline, tert-butyl 3-aminopyrrolidinecarboxylate, 2,3,4,5-tetrahydro- 1,4-benzothiazepine 1,1-dioxide and trifluoroacetic acid instead of 2,4-dichloro methylquinazoline, tert-butyl [1-(aminomethyl)cyclopropyl]carbamate, 2,3,4,5-tetrahydro-1,4- benzothiazepine oxide and trifluoroacetic acid. MS obsd. (ESI+) [(M+H)+] 424, 1H NMR (400 MHz, DMSO-d6) 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 6x103 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 µL 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% ive concentration (EC50).
The compounds of the t 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 µM to about 10 µM. ular compound of formula (I) were found to have EC50 of about 0.0001 µM to about 1 µM. r particular compound of formula (I) were found to have EC50 of about 0.0001 µM to about 0.1 µM.
Results of CPE assays are given in Table 1.
Table 1: Example EC50 (µM, Example EC50 (µM, Example EC50 (µM, 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 2-7 0.234 15-3 2.697 69-2 0.007 2-8 0.055 15-4 0.257 70 0.071 2-9 0.007 15-5 0.740 71 0.005 2-10 0.005 16-1 2.567 72 0.002 2-11 0.008 16-2 9.642 73 6.978 3-1 0.006 17-1 5.538 74 1.936 3-2 3.051 17-2 0.616 75 0.002 3-3 3.552 17-3 2.17 76 0.006 3-4 0.006 17-4 0.071 77 8.78 3-5 0.002 17-5 1.504 78-1 0.016 3-6 0.058 17-6 0.086 78-2 0.25 3-7 0.009 17-7 0.642 79 2.791 3-8 0.002 17-8 0.021 80 5.479 3-9 0.248 18-1 0.003 81 0.353 3-10 0.053 18-2 0.024 82 0.014 3-11 0.054 18-3 0.014 83 0.662 3-12 1.654 18-4 0.061 84 2.965 3-13 0.099 18-5 0.057 85 0.008 3-14 0.017 18-6 0.061 86 2.222 3-15 0.482 18-7 0.023 87-1 0.096 3-16 0.075 18-8 0.0007 87-2 9.31 3-17 5.053 18-9 0.005 88 0.007 3-18 0.024 18-10 0.011 89 0.007 3-19 0.009 18-11 0.619 90 0.005 3-20 0.507 19-1 0.043 91 0.004 3-21 0.006 19-2 0.011 92-1 0.009 3-22 0.032 19-3 0.006 92-2 0.019 3-23 0.002 19-4 0.02 93-1 0.005 3-24 0.021 19-5 3.073 93-2 0.009 3-25 0.022 19-6 0.054 94 6.527 3-26 0.876 19-7 6.856 95 3.039 3-27 1.394 19-8 2.749 96 2.833 3-28 0.149 20-1 0.073 97 0.177 3-29 0.022 20-2 0.31 98-1 0.778 3-30 7.81 20-3 0.093 98-2 3.163 3-31 0.014 21-1 0.023 99 2.999 3-32 0.037 21-2 0.161 100 9.191 3-33 0.426 21-3 0.015 101 8.579 3-34 0.085 21-4 0.004 102 9.76 3-35 0.013 21-5 0.007 103 0.202 3-36 0.092 22 0.036 104 0.89 3-37 0.017 23 5.185 105 1.084 3-38 0.0439 24 0.016 106 0.002 3-39 0.030 25 0.002 107 0.001 3-40 0.022 26-1 0.005 108-1 0.488 3-41 0.071 26-2 0.179 108-2 2.474 3-42 0.007 27 2.393 109-1 8 3-43 2.394 28-1 0.007 109-2 0.0015 3-44 0.012 28-2 0.007 110-1 0.017 3-45 5.229 28-3 0.001 110-2 2.607 3-46 0.053 28-4 0.001 110-3 0.161 3-47 0.101 28-5 0.003 110-4 0.06 3-48 0.023 29 0.042 110-5 1.655 3-49 0.099 30-1 0.317 110-6 4.278 3-50 0.0004 30-2 0.218 110-7 1.178 3-51 0.004 31 0.702 110-8 0.081 3-52 0.005 32-1 0.019 110-9 1.367 3-53 0.261 32-2 2.454 110-10 0.099 3-54 0.114 32-3 1.991 110-11 6.753 3-55 0.027 32-4 0.272 110-12 0.072 3-56 0.716 32-5 2.58 110-13 3.679 3-57 7.534 33-1 0.044 110-14 0.648 3-58 0.184 33-2 0.627 110-15 0.004 3-59 1.083 34 2.086 111-1 2.007 3-60 0.617 35 2.791 111-2 1.345 3-61 0.118 36-1 0.073 111-3 0.0768 3-62 0.589 36-2 1.474 111-4 0.066 3-63 9.899 36-3 2.153 111-5 1.64 3-64 0.874 36-4 0.138 111-6 0.062 3-65 0.002 36-5 0.026 111-7 0.873 4-1 0.269 36-6 0.264 111-8 0.283 4-2 0.098 37-1 0.005 111-9 0.047 4-3 0.026 37-2 0.043 111-10 0.107 4-4 0.208 38-1 0.01 111-11 0.588 4-5 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 6-1 0.025 44-1 0.084 118-3 0.063 6-2 0.908 44-2 1.547 118-4 0.104 7 1.418 45-1 0.021 118-5 0.178 8-1 5.513 45-2 0.253 118-6 0.173 8-2 0.817 45-3 0.031 118-7 0.166 8-3 0.9 46 0.682 118-8 0.223 8-4 0.064 47-1 7.881 118-9 0.202 8-5 0.074 47-2 5.822 118-10 0.289 8-6 3.767 47-3 5.692 118-11 0.323 8-7 0.322 47-4 0.993 118-12 0.448 9-1 2.35 47-5 0.835 118-13 0.463 9-2 4.77 47-6 2.312 118-14 0.616 9-3 0.001 47-7 3.4107 118-15 0.626 9-4 8.874 47-8 0.432 118-16 0.695 9-5 0.179 47-9 0.192 118-17 0.806 9-6 0.275 48 0.009 118-18 0.973 9-7 0.002 49 0.721 118-19 1.236 9-8 3.478 50-1 0.931 118-20 1.129 9-9 0.157 50-2 2.423 118-21 1.382 9-10 0.037 51 0.056 118-22 2.227 9-11 0.953 52 0.419 118-23 2.641 9-12 2.663 53 0.094 118-24 6.451 9-13 0.701 54 4.798 118-25 7.623 9-14 0.025 55-1 0.007 118-26 7.754 9-15 0.012 55-2 0.202 119 6.656 9-16 0.005 55-3 0.006 120-1 2.193 9-17 0.025 56-1 0.002 120-2 1.785 9-18 0.01 56-2 0.023 121 1.103 9-19 0.0007 56-3 0.004 122 3.125 9-20 0.760 56-4 0.027 123 3.144 9-21 0.021 56-5 0.022 124 6.102 9-22 0.872 56-6 0.002 125 2.521 9-23 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 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 s of the following composition: Per tablet Active ingredient 200 mg Microcrystalline cellulose 155 mg Corn starch 25 mg Talc 25 mg Hydroxypropylmethylcellulose 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 Talc 4.5 mg ium stearate 0.5 mg 220.0 mg

Claims (5)

Claims 1. A compound of formula (I) R3 Q A Y R4 R6 R2 N N R7 R10 X R8 R9 (I) 5 Wherein R1 is hydrogen, halogen, or C1-6alkyl; R2 is hydrogen, halogen, or kyl; R3 is hydrogen, halogen, or C1-6alkyl; R4 is en, or kyl; 10 R5 is hydrogen, or halogen; R6 is hydrogen, halogen, hydroxy, C1-6alkoxy, carboxy, morpholinyl, or 4-C0- 6alkylpiperazinyl; R7 is hydrogen, halogen, C1-6alkyl, C1-6alkoxy, C1-6alkylaminocarbonyl, diC1-6 alkylaminocarbonyl, C1-6alkylsulfonyl, y, or hydroxy(CH2)2O-; 15 R8 is hydrogen, halogen, or C1-6alkoxy; R9 is hydrogen, C1-6alkyl, or =O; R10 is hydrogen, or =O, provided that R9 and R10 are not =O simultaneously; A is nitrogen, or -C-R11, wherein R11 is hydrogen, halogen, C1-6alkyl, cycloalkyl, C1- 6alkoxy, trifluoromethyl, trifluoromethoxy, pyridinyloxy, C1-6alkoxy(CH2)1O-, 20 difluoromethoxy, cyano, nitro, amino, vinyl, acetylenyl, aminocarbonyl, hydroxy(CH2)2O-, C1- 6alkylsulfinyl, C1-6alkylsulfonyl, hydroxy(CH2)1-6, deuteratedC1-6alkyl, carboxyl, C1- 6alkoxycarbonyl, hydroxy, difluoromethyl, -CH(hydroxy) kyl, or C1-6alkylsulfanyl; X is -CH2-, -O-, -NH-, -CF2-, -C(C1-6alkyl)(OH)-, -S-, -C(=O)-, C0-6alkyl)-, - S(=O)-, -S(O2)- or -S(=O)(NH)-; Y is -CH-, or nitrogen; Q is hydrogen; halogen; C1-6alkyl, unsubstituted or once or twice substituted by amino or 5 hydroxy, provided that di-substitution is not on the same carbon; amino(CH2)2- 6aminosulfonyl; 2-amino-4,5-dihydro-1,3-oxazolyl(CH 2)1-6; carboxy(CH2)1-6; phenylsulfonyl; piperidinyl-carbonyl; 1H-pyrazolyl; pyrrolidinyloxy; piperidin yloxy; amino(CH2)2O-; or NR 12 R13 , wherein one of R12 and R13 is hydrogen, C 1-6alkyl, or hydroxy(CH2)2-6, and the 10 other one is {1-[amino(CH2)0-6]-3,3-difluorocyclobutyl}(CH 2)1-6; ino(CH2)2-6; (S-C1- 6alkylsulfonimidoyl)(CH 2)2-6; 2-oxaaza-spiro[3.4]octyl; {3-[amino(CH2)0- ahydrofuranyl}(CH 2)1-6; 3-aminomethyl-1,1-dioxidothietanylmethyl; o- 1,1-dioxidothietanylmethyl; 3-(aminomethyl)thietanylmethyl; (1,1- dioxidothiomorpholinyl)ethyl; C0-6alkyl(oxetanyl)N(CH 2)2-6; 4,5-dihydro-1H-imidazol- 15 2-yl; amino(CH2)2O-(CH 2)2-6; amino(CH2)2-10 ; amino(CH2)1-6difluoromethyl(CH 2)1-6; CH 2)1-6difluoromethyldifluoromethyl(CH 2)1-6; amino(CH2)1-6fluoromethyl(CH 2)1-6; amino(CH 2)1-6oxetanyl(CH 2)0-6; amino(CH2)0-6oxetanyl(CH 2)1-6; CH2)2- nyl(CH 2)2-6; amino(CH2)2-6sulfonyl(CH 2)2-6; amino(CH2)0-6carbonyl(CH 2)0- 6; aminocycloalkyl(CH2)0-6; 2-aminodihydrooxazolyl(CH2)1-6; 2-aminodihydrooxazol 20 yl(CH 2)1-6; (2-aminomethyl-4,5-dihydro-1,3-oxazolyl)methyl; aminophenyl; 4- aminotetrahydropyranyl(CH 2)1-6; azetidinyl(CH2)1-6; azetidinyl(CH2)0-6; azetidinylcarbonyl; C1-6alkoxy(CH 2)2-6; C1-6alkoxy(CH 2)2-6amino(CH 2)2-6; C1-6alkyl; C1- 6alkylamino(CH 2)2-6; kylaminocarbonyl(CH 2)0-6; C1-6alkylaminooxetanyl(CH 2)1-6; C1- 6alkylcarbonyl; C1-6alkylcarbonylamino(CH 2)2-6; C1-6alkylcarbonylamino(CH 2)1- 25 6oxetanyl(CH 2)0-6; C1-6alkylsulfinyl(CH 2)2-6; C1-6alkylsulfonyl; carboxy(CH2)1-6; cyano(CH 2)1-6; diC1-6alkylamino(CH 2)2-6; diC1-6alkylaminocarbonyl; difluoromethyl(CH2)1- 6amino(CH 2)2-6; hydrogen; hydroxy(CH2)2-10 ; hydroxy(CH2)2-6amino(CH 2)2-6; y(CH 2)1-6carbonyl; hydroxy(CH2)0-6oxetanyl(CH 2)1-6; hydroxy(CH2)1- 6oxetanyl(CH 2)0-6; hydroxycycloalkyl; isoxazolyl; linyl(CH2)1-6; lin 30 yl(CH 2)2-6; yl(CH2)0-6; N-oxetanylpyrrolidinyl; oxo-pyrrolidinylcarbonyl; phenylaminocarbonyl; phenyl(CH2)0-6aminooxetanyl(CH 2)1-6; phenylcarbonyl; piperazinyl(CH 2)2-6; piperidinyl(CH2)2-6; piperidinyl(CH2)1-6; piperidinyl(CH2)0-6; piperidinyl(CH 2)0-6; piperidinylcarbonyl; pyrazinylcarbonyl; pyrazolyl; pyridazinylcarbonyl; pyridinyl(CH2)0-6carbonyl; pyridinylamino(CH2)2-6; pyrrolidinyl, 35 unsubstituted or 4-substituted by halogen; pyrrolidinyl, unsubstituted or 3-substituted by hydroxy or C1-6alkoxy; pyrrolidinyl(CH2)1-6; pyrrolidinylcarbonyl; tetrahydrofuranyl; tetrahydropyranyl; tetrazolyl(CH2)2-6; trifluoromethylcarbonylamino(CH2)1-6oxetanyl; -(CH2)1-6 C R15 trifluoromethylsulfonyl; R16 , wherein R14 is hydrogen, kyl or hydroxy(CH2)1-6; R15 is hydroxy, C1-6alkyl, hydroxy(CH2)1-6 or amino; and R16 is C1-6alkyl, trifluoromethyl, hydroxy(CH2)1-6, amino(CH2)1-6, aminocarboxy or carboxy(CH2)1-6; C R18 5 R19 , wherein R17 is hydrogen, C 18 is hydroxy(CH 1-6alkyl or y(CH2)1-6; R 2)1-6 or C1-6alkyl; R19 is hydroxy(CH2)1-6, CH2)1-6, carboxy or aminocarboxy(CH2)0-6; C R21 or R22 , wherein R20 is hydrogen or C1-6alkyl; R21 is C1-6alkyl; R22 is C1-6alkoxy or amino; R12 and R13, with the nitrogen atom to which they are attached, may form a pyrrolidinyl, 10 piperazinyl, piperidinyl, morpholinyl, azetidinyl, diazepanyl or oxopyrrolidinyl ring; which may be unsubstituted, once or twice substituted by a group selected from halogen, C1- 6alkyl, koxy, gemdimethyl, amino, aminocarbonyl, y, oxetanylamino, C1- 6alkylpiperazinyl, and amino(CH2)1-6; R12 and R13, with the en atom to which they are attached may form a bridge ring or a 15 spiral ring selected from 2-oxaaza-spiro[3.4]octanyl, 2-oxa-5,7-diazaspiro[3.4]octan- 6-oneyl, (4aS,7aR)-hexahydropyrrolo[3,4-b][1,4]oxazin-6(2H)-yl, 4,5,6,6a-tetrahydro- 3aH-pyrrolo[3,4-d][1,3]oxazolyl, 2-aza-bicyclo[2.1.1]hexanyl, and 3-azabicyclo [3.1.0]hexanyl; which may be unsubstituted or r substituted by amino; and pharmaceutically acceptable salt and stereoisomers f. 20 2. A compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R1 is hydrogen, halogen or C1-6alkyl; R2 is hydrogen, halogen or C1-6alkyl; R3 is hydrogen, halogen or C1-6alkyl; R4 is hydrogen or C1-6alkyl; 25 R5 is hydrogen; R6 is hydrogen, halogen, hydroxy, koxy, morpholinyl or 4-C0-6alkylpiperazinyl; R7 is hydrogen, halogen, C1-6alkyl, C1-6alkoxy, phenoxy or hydroxy(CH2)2O-; R8 is hydrogen, halogen or C1-6alkoxy; R9 is hydrogen or C1-6alkyl; R10 is hydrogen; A is nitrogen or -C-R11 , n R11 is hydrogen, halogen, C1-6 alkyl, cycloalkyl, C1- 5 6alkoxy, trifluoromethyl, trifluoromethoxy, pyridinyloxy, C1-6alkoxy(CH 2)1O-, difluoromethoxy, cyano, nitro, amino, vinyl, acetylenyl, aminocarbonyl, hydroxy(CH2)2O-, C1- 6alkylsulfinyl, hydroxy(CH2)1-6, deuteratedC1-6alkyl, yl, alkoxycarbonyl, hydroxy, difluoromethyl, -CH(hydroxy)C1-6alkyl or C1-6alkylsulfanyl; X is S, S=O, SO2 or S(O)NH; 10 Y is -CH- or nitrogen; Q is C1-6alkyl, unsubstituted or once substituted by amino; amino(CH 2)2-6aminosulfonyl; 2-amino-4,5-dihydro-1,3-oxazolylethyl; carboxy(CH2)1-6; phenylsulfonyl; piperidinylcarbonyl ; 1H-pyrazolyl; idinyloxy; dinyloxy; amino(CH2)2O-; or NR 12 R13 , wherein one of R12 and R13 is hydrogen, C 1-6alkyl or hydroxy(CH2)2-6, and the other 15 one is {1-[amino(CH2)0-6]-3,3-difluorocyclobutyl}(CH 2)1-6; (S-C1- 6alkylsulfonimidoyl)(CH 2)2-6; {3-[amino(CH2)0-6]tetrahydrofuranyl}(CH 2)1-6; (2-amino methyl-4,5-dihydro-1,3-oxazolyl)methyl; 3-aminomethyl-1,1-dioxidothietanylmethyl; 3- methyl)thietanylmethyl; (1,1-dioxidothiomorpholinyl)ethyl; C0- 6alkyl(oxetanyl)N(CH 2)2-6; hydro-1H-imidazolyl; amino(CH2)2O-(CH 2)2-6; 20 amino(CH 2)2-10 ; amino(CH2)0-6carbonyl(CH 2)0-6; amino(CH2)1-6difluoromethyl(CH 2)1-6; amino(CH 2)1-6difluoromethyldifluoromethyl(CH 2)1-6; amino(CH2)1-6fluoromethyl(CH 2)1-6; amino(CH 2)1-6oxetanyl(CH 2)0-6; CH2)0-6oxetanyl(CH 2)1-6; amino(CH2)2-6sulfanyl(CH 2)2-6; amino(CH 2)2-6sulfonyl(CH 2)2-6; 1-aminocyclobutylmethyl; 2-aminocyclohexyl; 3- aminocyclohexyl; 4-aminocyclohexyl; 1-aminocyclohexylmethyl; 2-aminocyclopentyl; 1- 25 aminocyclopropylethyl; 1-aminocyclopropylmethyl; (2-amino-4,5-dihydro-oxazolyl)(CH 2)1-6; (2-amino-4,5-dihydro-oxazolyl)(CH 2)1-6; aminophenyl; 4-aminotetrahydropyranyl(CH2)1-6; azetidinyl(CH 2)1-6; azetidinyl(CH2)0-6; azetidinylcarbonyl; C1-6alkoxy(CH 2)2-6; C1- 6alkoxy(CH 2)2-6amino(CH 2)2-6; C1-6alkyl; C1-6alkylamino(CH 2)2-6; C1- 6alkylaminooxetanyl(CH 2)1-6; kylcarbonyl; C1-6alkylaminocarbonyl(CH 2)0-6; C1- 30 6alkylcarbonylamino(CH 2)2-6; C1-6alkylcarbonylamino(CH 2)1-6oxetanyl(CH 2)0-6; C1- 6alkylsulfinyl(CH 2)2-6; C1-6alkylsulfonyl; carboxy(CH2)1-6; CH2)1-6; diC1- 6alkylamino(CH 2)2-6; diC1-6alkylaminocarbonyl; difluoromethyl(CH2)1-6amino(CH 2)2-6; hydrogen; y(CH2)2-10 ; hydroxy(CH2)2-6amino(CH 2)2-6; hydroxy(CH2)1-6carbonyl; hydroxy(CH2)1-6oxetanyl(CH2)0-6; hydroxy(CH2)0-6oxetanyl(CH2)1-6; 4-hydroxycyclohexyl; isoxazolyl; morpholinyl(CH2)1-6; morpholinyl(CH2)2-6; 2-oxaaza-spiro[3.4]octyl; oxetanyl(CH2)0-6; N-oxetanylpyrrolidinyl; oxo-pyrrolidinylcarbonyl; phenylaminocarbonyl; phenyl(CH2)0-6aminooxetanyl(CH2)1-6; phenylcarbonyl; piperazinyl(CH2)2-6; din 5 yl(CH2)2-6; dinyl(CH2)1-6; piperidinyl(CH2)0-6; piperidinyl(CH2)0-6; piperidinylcarbonyl; nylcarbonyl; pyrazolyl; pyridazinylcarbonyl; nyl(CH2)0- 6carbonyl; pyridinylamino(CH2)2-6; pyrrolidinyl, unsubstituted or 4-substituted by n; pyrrolidinyl, unsubstituted or 3-substituted by hydroxy or C1-6alkoxy; pyrrolidinyl(CH2)1-6; pyrrolidinylcarbonyl; tetrahydrofuranyl; ydropyranyl; olyl(CH2)2-6; -(CH2)1-6 C R15 10 oromethylcarbonylamino(CH2)1-6oxetanyl; trifluoromethylsulfonyl; R16 , wherein R14 is hydrogen or C1-6alkyl; R15 is hydroxy, C1-6alkyl or amino; and R16 is C1-6alkyl, C R18 trifluoromethyl, hydroxy(CH2)1-6, amino(CH2)1-6, aminocarbonyl or carboxy(CH2)1-6; R19 , wherein R17 is hydrogen, C1-6alkyl or hydroxy(CH2)1-6; R18 is y(CH2)1-6 or C1-6alkyl; R19 C R21 is hydroxy(CH2)1-6, amino(CH2)1-6, carboxy or aminocarbonyl(CH2)0-6; or R22 , wherein 15 R20 is hydrogen or C1-6alkyl; R21 is C1-6alkyl; R22 is C1-6alkoxy or amino; R12 and R13, with the nitrogen atom to which they are attached, may form a pyrrolidinyl, piperazinyl, piperidinyl, morpholinyl, azetidinyl, anyl or oxopyrrolidinyl ring; which may be unsubstituted, once or twice substituted by a group selected from halogen, C1-6alkyl, C1- 6alkoxy, gemdimethyl, amino, aminocarbonyl, hydroxy, oxetanylamino, C1-6alkylpiperazinyl, 20 and CH2)1-6; R12 and R13, with the nitrogen atom to which they are may form a bridge ring or a spiral ring selected from 2-oxaaza-spiro[3.4]octanyl, 2-oxa-5,7-diazaspiro[3.4]octanoneyl, (4aS,7aR)-hexahydropyrrolo[3,4-b][1,4]oxazin-6(2H)-yl, 4,5,6,6a-tetrahydro-3aH-pyrrolo[3,4- d][1,3]oxazolyl, 2-aza-bicyclo[2.1.1]hexanyl and 3-aza-bicyclo[3.1.0]hexanyl; which 25 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-(propanyl)piperazinyl; R7 is hydrogen, fluoro, chloro, , methoxy, ethoxy, hydroxyethoxy or phenoxy; R8 is hydrogen, fluoro or methoxy; 5 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, arbonyl, hydroxyethoxy, 10 methylsulfanyl, sulfinyl, hydroxymethyl, deuteratedmethyl, yl, methoxycarbonyl, hydroxy, difluoromethyl, methylCH(hydroxy)- or methylsulfonyl; X is S, S=O, SO2 or S(O)NH; Y is -CH- or nitrogen; Q is 2-amino-4,5-dihydro-1,3-oxazolylethyl; aminoethoxy; thylaminosulfonyl; 15 aminopropyl; yethyl; ; phenylsulfonyl; piperidinyl-carbonyl; piperidin yloxy; 1H-pyrazolyl; pyrrolidinyloxy; or NR 12 R13 , wherein one of R12 and R13 is hydrogen, methyl or hydroxyethyl, and the other one is aminobutyl; aminocarbonylethyl; aminocarbonylmethyl; 1-aminocyclobutylmethyl; 2-aminocyclohexyl; 3-aminocyclohexyl; 4-aminocyclohexyl; 1-aminocyclohexylmethyl; 2- 20 aminocyclopentyl; 1-aminocyclopropylethyl; 1-aminocyclopropylmethyl; aminodecyl; (2- amino-4,5-dihydro-oxazolyl)methyl; (2-amino-4,5-dihydro-oxazolyl)methyl; aminoethoxyethyl; aminoethyl; aminoethylcarbonyl; aminoethylfluoromethylmethyl; aminoethylsulfanylethyl; aminoethylsulfonylethyl; aminoheptyl; aminohexyl; aminomethylcarbonyl; (1-aminomethyl-3,3-difluorocyclobutyl)methyl; 25 ethyldifluoromethyldifluoromethylmethyl; ethyldifluoromethylmethyl; (2- aminomethyl-4,5-dihydro-1,3-oxazolyl)methyl; 3-aminomethyl-1,1-dioxidothietan ylmethyl; aminomethylfluoromethylethyl; aminomethylfluoromethylmethyl; aminomethyloxetanyl; aminomethyloxetanylmethyl; 3-(aminomethyl)thietanylmethyl; aminononyl; aminooctyl; aminooxetanylethyl; aminooxetanylmethyl; aminopentyl; 30 aminophenyl; aminopropyl; otetrahydropyranylmethyl; 3-aminotetrahydrofuran- 3-ylmethyl; azetidinyl; azetidinylcarbonyl; azetidinylmethyl; azetidinylmethyl; carboxyethyl; carboxymethyl; cyanoethyl; romethylmethylaminoethyl; 4,5-dihydro- 1H-imidazolyl; dimethylaminocarbonyl; dimethylaminoethyl; (1,1- dioxidothiomorpholinyl)ethyl; ethyl; ethylaminocarbonyl; ethylaminoethyl; ethylaminooxetanylmethyl; ethyl (oxetanyl)aminoethyl; hydrogen; 4-hydroxycyclohexyl; 5 hydroxyethyl; hydroxyethylaminoethyl; hydroxyethyloxetanyl; hydroxymethylcarbonyl; hydroxymethyloxetanylmethyl; hydroxynonyl; hydroxypropyl; olyl; methoxyethyl; methoxyethylaminoethyl; methyl; methylaminocarbonylmethyl; methylaminoethyl; carbonyl; methylcarbonylaminoethyl; methylcarbonylaminomethyloxetanylmethyl; methylcarbonylaminopropyl; 10 methylsulfinylethyl; 2-(S-methylsulfonimidoyl)ethyl; methylsulfonyl; morpholinylethyl; morpholinylmethyl; 6-aza-spiro[3.4]octyl; oxetanyl; ylaminoethyl; oxetanylaminopropyl; oxetanylmethyl; N-oxetanylpyrrolidinyl; oxo-pyrrolidin ylcarbonyl; phenylaminocarbonyl; phenylcarbonyl; phenylmethylaminooxetanylmethyl; piperazinylethyl; dinylcarbonyl; piperidinylcarbonyl; dinylcarbonyl; 15 piperidinyl; piperidinyl; piperidinylethyl; piperidinylmethyl; pyrazin ylcarbonyl; pyrazolyl; pyridazinylcarbonyl; pyridineylmethylcarbonyl; pyridine ylaminoethyl; pyridineylcarbonyl; pyridineylcarbonyl; pyrrolidinyl, unsubstituted or 4-substituted by fluoro; pyrrolidinyl, unsubstituted or 3-substituted by hydroxy or y; pyrrolidinylmethyl; pyrrolidinylcarbonyl; tetrahydrofuranyl; 20 tetrahydropyranyl; tetrazolylethyl; trifluoromethylsulfonyl; -(CH2)1-6 C R15 trifluoromethylcarbonylaminomethyloxetanyl; R16 , n R14 is en or methyl; R15 is hydroxy, methyl or amino; and R16 is methyl, trifluoromethyl, C R18 hydroxymethyl, hydroxyethyl, aminomethyl, aminocarbonyl or carboxymethyl; R19 , wherein R17 is hydrogen, methyl or hydroxymethyl; R18 is hydroxymethyl or methyl; R19 is 25 hydroxymethyl, aminomethyl, carboxy, aminocarbonyl or aminocarbonylmethyl; C R21 or R22 , n 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 30 may be unsubstituted, once or twice substituted by a group selected from fluoro, methyl, methoxy, gemdimethyl, amino, aminocarbonyl, hydroxy, oxetanylamino, piperazinyl and aminomethyl; R12 and R13 , with the nitrogen atom to which they are ed may form a bridge ring or a spiral ring selected from 2-oxaaza-spiro[3.4]octanyl, 2-oxa-5,7-diazaspiro[3.4]octan- 6-oneyl, (4aS ,7aR )-hexahydropyrrolo[3,4-b][1,4]oxazin-6(2 H)-yl, 6a-tetrahydro- 3a H-pyrrolo[3,4-d][1,3]oxazolyl, 2-aza-bicyclo[2.1.1]hexanyl or 3-aza- 5 bicyclo[3.1.0]hexanyl; which may be tituted 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 C1-6alkyl; 10 X is S; Y is -CH- or nitrogen; Q is NR12 R13 , wherein one of R12 and R13 is hydrogen, and the other one is amino(CH 2)2-6; amino(CH2)1-6difluoromethyl(CH 2)1-6; amino(CH2)0-6oxetanyl(CH 2)1-6 or hydrogen; 15 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 en; A is -C-R11 , wherein R11 is hydrogen, chloro or methyl; 20 Q is NR12 R13 , wherein one of R12 and R13 is hydrogen, and the other one is aminoethyl; aminomethyldifluoromethylmethyl; ethyloxetanylmethyl; aminooxetanylmethyl or hydrogen; R12 and R13 , with the en atom to which they are attached, may form a pyrrolidinyl ring, which may be once substituted by amino. 25 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 en; A is -C-R11 , wherein R11 is hydrogen, halogen, C1-6alkyl, hydroxy(CH2)1-6, deuteratedmethyl or carboxyl; X is S=O; Y is -CH- or nitrogen; Q is NR12R13, wherein one of R12 and R13 is hydrogen; and the other one is amino(CH2)2-6; amino(CH2)1-6difluoromethyl(CH2)1-6; amino(CH2)1-6fluoromethyl(CH2)1-6; 5 amino(CH2)1-6oxetanyl; amino(CH2)1-6oxetanyl(CH2)1-6; aminooxetanyl(CH2)1-6; hydroxy(CH2)2- 10; phenyl(CH2)1-6aminooxetanyl(CH2)1-6; idinyl, 4-substituted by halogen; -(CH2)1-6 C R15 or R16 , wherein R14 is hydrogen, R15 is y, and R16 is hydroxy(CH2)1-6; 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. 10 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, hydroxymethyl, atedmethyl or carboxyl; Q is NR12R13, wherein one of R12 and R13 is hydrogen, and the other one is aminoethyl; 15 aminomethyldifluoromethylmethyl; ethylfluoromethylmethyl; aminomethyloxetanyl; aminomethyloxetanylmethyl; aminooxetanylmethyl; aminopropyl; hydroxyethyl; -(CH2)1-6 C R15 phenylmethylaminooxetanylmethyl; pyrrolidinyl, 4-substituted by fluoro; or R16 , wherein R14 is en, R15 is y, and R16 is hydroxymethyl; R12 and R13, with the en atom to which they are attached, may form a pyrrolidinyl ring, 20 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 C1-6alkyl; R4 is hydrogen or C1-6alkyl; 25 R5 is hydrogen; R6 is hydrogen, halogen, hydroxy, C1-6alkoxy, morpholinyl or 4-(propanyl)piperazin- 1-yl; R7 is hydrogen, halogen, C1-6alkyl, koxy, hydroxy(CH2)2O-, or phenoxy; R8 is en, halogen or koxy; R9 is en or C1-6alkyl; R10 is hydrogen; 5 A is nitrogen or -C-R11 , n R11 is hydrogen, halogen, C1-6alkyl, C1-6alkoxy, trifluoromethyl, trifluoromethoxy, pyridinyloxy, C1-6alkoxy(CH 2)1O-, difluoromethoxy, nitro, cycloalkyl, cyano, amino, vinyl, acetylenyl, arbonyl, hydroxy(CH2)2O-, C1- 6alkylsulfanyl, kylsulfinyl, hydroxy(CH2)1-6, deuteratedmethyl, carboxyl, C1- 6alkoxycarbonyl, hydroxy, difluoromethyl or CH(hydroxy)-; 10 X is SO2; Y is -CH- or nitrogen; Q is 2-amino-4,5-dihydro-1,3-oxazolylethyl; amino(CH 2)2O-; amino(CH2)2- 6aminosulfonyl; C1-6alkyl, unsubstituted or once substituted by amino; carboxy(CH 2)1-6; phenylsulfonyl; piperidinyl-carbonyl; piperidinyloxy; 1H-pyrazolyl; pyrrolidinyloxy; 15 or NR 12 R13 , wherein one of R12 and R13 is hydrogen, C 1-6alkyl or hydroxy(CH2)2-6; and the other one is {1-[amino(CH2)0-6]-3,3-difluorocyclobutyl}(CH 2)1-6; (S-C1- 6alkylsulfonimidoyl)(CH 2)2-6; 3-aminotetrahydrofuranyl(CH2)1-6; (2-aminomethyl-4,5- dihydro-1,3-oxazolyl)methyl; 3-aminomethyl-1,1-dioxidothietanylmethyl; 3- 20 (aminomethyl)thietanylmethyl; (1,1-dioxidothiomorpholinyl)ethyl; C0- 6alkyl(oxetanyl)N(CH 2)2-6; 4,5-dihydro-1H-imidazolyl; amino(CH2)2O-(CH 2)2-6; amino(CH 2)2-10 ; amino(CH2)1-6carbonyl; aminocarbonyl(CH2)1-6; amino(CH2)1- 6difluoromethyl(CH 2)1-6; amino(CH2)1-6difluoromethyldifluoromethyl(CH 2)1-6; amino(CH2)1- 6fluoromethyl(CH 2)1-6; amino(CH2)1-6oxetanyl(CH 2)0-6; amino(CH2)0-6oxetanyl(CH 2)1-6; 25 CH 2)2-6sulfanyl(CH 2)2-6; amino(CH2)2-6sulfonyl(CH 2)2-6; 1-aminocyclobutylmethyl; 2- aminocyclohexyl; 3-aminocyclohexyl; 4-aminocyclohexyl; 1-aminocyclohexylmethyl; 2- aminocyclopentyl; 1-aminocyclopropylethyl; 1-aminocyclopropylmethyl; (2-amino-4,5-dihydrooxazolyl )(CH 2)1-6; (2-amino-4,5-dihydro-oxazolyl) (CH2)1-6; aminophenyl; 4- etrahydropyranyl(CH 2)1-6; azetidinyl(CH2)1-6; azetidinyl(CH2)0-6; azetidin 30 ylcarbonyl; C1-6alkoxy(CH 2)2-6; C1-6alkoxy(CH 2)2-6amino(CH 2)2-6; C1-6alkyl; C1- 6alkylamino(CH 2)2-6; C1-6alkylaminooxetanyl(CH 2)1-6; C1-6alkylcarbonyl; C1- 6alkylcarbonylamino(CH 2)2-6; C1-6alkylcarbonylamino(CH 2)1-6oxetanyl(CH 2)0-6; C1- sulfinyl(CH2)2-6; C1-6alkylsulfonyl; carboxy(CH2)1-6; cyano(CH2)1-6; C1- 6alkylaminocarbonyl(CH2)0-6; diC1-6alkylamino(CH2)2-6; diC1-6alkylaminocarbonyl; difluoromethyl(CH2)1-6amino(CH2)2-6; hydrogen; hydroxy(CH2)2-10; hydroxy(CH2)2- 6amino(CH2)2-6; hydroxy(CH2)1-6carbonyl; hydroxy(CH2)1-6oxetanyl(CH2)0-6; 4- 5 hydroxycyclohexyl; isoxazolyl; morpholinyl(CH2)1-6; morpholinyl(CH2)2-6; 2-oxa aza-spiro[3.4]octyl; oxetanyl(CH2)0-6; N-oxetanylpyrrolidinyl; oxo-pyrrolidin ylcarbonyl; phenylaminocarbonyl; phenyl(CH2)1-6aminooxetanyl(CH2)1-6; phenylcarbonyl; piperazinyl(CH2)2-6; piperidinyl(CH2)2-6; piperidinyl(CH2)1-6; piperidinyl(CH2)0-6; piperidinyl(CH2)0-6; dinylcarbonyl; piperidinylcarbonyl; piperidinylcarbonyl; 10 pyrazinylcarbonyl; pyrazolyl; pyridazinylcarbonyl; neyl(CH2)0-6carbonyl; pyridineyl(CH2)0-6carbonyl; pyridineylamino(CH2)2-6; pyrrolidinyl, unsubstituted or 4- substituted by halogen; pyrrolidinyl, unsubstituted or 3-substituted by hydroxy or C1-6alkoxy; pyrrolidinyl(CH2)1-6; pyrrolidinylcarbonyl; ydrofuranyl; tetrahydropyranyl; tetrazolyl(CH2)2-6; trifluoromethylcarbonylamino(CH2)1-6oxetanyl; trifluoromethylsulfonyl; -(CH2)1-6 C R15 15 R16 , wherein R14 is hydrogen or C1-6alkyl; R15 is hydroxy, C1-6alkyl or amino; and R16 is C1-6alkyl, trifluoromethyl, hydroxy(CH2)1-6, amino(CH2)1-6, aminocarbonyl or carboxy(CH2)1- C R18 R19 , n R17 is hydrogen, C 18 is hydroxy(CH 6; 1-6alkyl or hydroxy(CH2)1-6; R 2)1-6 or C1-6alkyl; R19 is hydroxy(CH2)1-6, amino(CH2)1-6, carboxy or arbonyl(CH2)0-6; C R21 or R22 , wherein R20 is hydrogen or C1-6alkyl; R21 is C1-6alkyl; R22 is C1-6alkoxy or amino; 20 R12 and R13, with the nitrogen atom to which they are attached, may form a pyrrolidinyl, zinyl, piperidinyl, morpholinyl, inyl, diazepanyl or oxopyrrolidinyl ring; which may be unsubstituted, once or twice tuted by a group selected from halogen, C1-6alkyl, C1- 6alkoxy, gemdimethyl, amino, aminocarbonyl, hydroxy, oxetanylamino, C1-6alkylpiperazinyl and amino(CH2)1-6; 25 R12 and R13, with the nitrogen atom to which they are attached may form a bridge ring or a spiral ring selected from 2-oxaaza-spiro[3.4]octanyl, 5,7-diazaspiro[3.4]octanoneyl, (4aS,7aR)-hexahydropyrrolo[3,4-b][1,4]oxazin-6(2H)-yl, 4,5,6,6a-tetrahydro-3aH-pyrrolo[3,4- d][1,3]oxazolyl, 2-aza-bicyclo[2.1.1]hexanyl or 3-aza-bicyclo[3.1.0]hexanyl; which may be tituted or r substituted by amino. 30 9. A compound according to claim 8 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-(propanyl)piperazinyl; R7 is hydrogen, fluoro, chloro, methyl, y, hydroxyethoxy, or phenoxy; 5 R8 is hydrogen, fluoro or methoxy; R9 is hydrogen or methyl; R10 is hydrogen; A is nitrogen or -C-R11 , wherein R11 is en, fluoro, chloro, bromo, methyl, ethyl, methoxy, trifluoromethyl, trifluoromethoxy, pyridinyloxy, methoxyethoxy, difluoromethoxy, 10 nitro, ropyl, cyano, amino, vinyl, acetylenyl, aminocarbonyl, hydroxyethoxy, methylsulfanyl, methylsulfinyl, hydroxymethyl, deuteratedmethyl, carboxyl, methoxycarbonyl, y, difluoromethyl or methylCH(hydroxy)-; Y is -CH- or nitrogen; Q is o-4,5-dihydro-1,3-oxazolylethyl; aminoethoxy; aminoethylaminosulfonyl; 15 aminopropyl; carboxyethyl; methyl; phenylsulfonyl; piperidinyl-carbonyl; din yloxy; 1H-pyrazolyl; pyrrolidinyloxy; or NR12 R13 , n one of R12 and R13 is en, methyl or hydroxyethyl, and the other one is aminobutyl; aminocarbonylethyl; aminocarbonylmethyl; 1-aminocyclobutylmethyl; 2-aminocyclohexyl; 3-aminocyclohexyl; 4-aminocyclohexyl; 1-aminocyclohexylmethyl; 2-aminocyclopentyl; 1- 20 aminocyclopropylethyl; 1-aminocyclopropylmethyl; aminodecyl; (2-amino-4,5-dihydrooxazolyl )methyl; (2-amino-4,5-dihydro-oxazolyl)methyl; aminoethoxyethyl; aminoethyl; aminoethylcarbonyl; aminoethylfluoromethylmethyl; aminoethylsulfanylethyl; aminoethylsulfonylethyl; aminoheptyl; aminohexyl; aminomethylcarbonyl; (1- aminomethyl-3,3-difluorocyclobutyl)methyl; 25 aminomethyldifluoromethyldifluoromethylmethyl; aminomethyldifluoromethylmethyl; (2- aminomethyl-4,5-dihydro-1,3-oxazolyl)methyl; 3-aminomethyl-1,1-dioxidothietan ylmethyl; aminomethylfluoromethylethyl; aminomethylfluoromethylmethyl; aminomethyloxetanyl; aminomethyloxetanylmethyl; 3-(aminomethyl)thietanylmethyl; aminononyl; aminooctyl; aminooxetanylethyl; aminooxetanylmethyl; entyl; 30 aminophenyl; aminopropyl; 4-aminotetrahydropyranylmethyl; 3-aminotetrahydrofuran- 3-ylmethyl; azetidinyl; azetidinylcarbonyl; azetidinylmethyl; azetidinylmethyl; carboxyethyl; carboxymethyl; thyl; difluoromethylmethylaminoethyl; 4,5-dihydro- 1H-imidazolyl; dimethylaminocarbonyl; dimethylaminoethyl; (1,1- dioxidothiomorpholinyl)ethyl; ethyl; ethylaminocarbonyl; ethylaminoethyl; ethylaminooxetanylmethyl; ethyl (oxetanyl)aminoethyl; en; oxycyclohexyl; hydroxyethyl; hydroxyethylaminoethyl; hydroxyethyloxetanyl; hydroxymethylcarbonyl; 5 hydroxymethyloxetanylmethyl; ynonyl; hydroxypropyl; isoxazolyl; methoxyethyl; methoxyethylaminoethyl; methyl; methylaminocarbonylmethyl; methylaminoethyl; methylcarbonyl; methylcarbonylaminoethyl; methylcarbonylaminomethyloxetanylmethyl; methylcarbonylaminopropyl; methylsulfinylethyl; 2-(S-methylsulfonimidoyl)ethyl; methylsulfonyl; morpholinylethyl; 10 morpholinylmethyl; 2-oxaaza-spiro[3.4]octyl; oxetanyl; oxetanylaminoethyl; oxetanylaminopropyl; oxetanylmethyl; N-oxetanylpyrrolidinyl; oxo-pyrrolidin ylcarbonyl; aminocarbonyl; phenylcarbonyl; phenylmethylaminooxetanylmethyl; piperazinylethyl; piperidinylcarbonyl; piperidinylcarbonyl; piperidin ylcarbonyl; piperidineyl; piperidineyl; piperidinylethyl; piperidinylmethyl; 15 pyrazinylcarbonyl; pyrazolyl; pyridazinylcarbonyl; pyridineylmethylcarbonyl; pyridineylaminoethyl; pyridineylcarbonyl; pyridineylcarbonyl; pyrrolidinyl, unsubstituted or 4-substituted by fluoro; pyrrolidinyl, unsubstituted or 3-substituted by hydroxy or methoxy; idinylmethyl; pyrrolidinylcarbonyl; tetrahydrofuranyl; tetrahydropyranyl; tetrazolylethyl; trifluoromethylsulfonyl; -(CH2)1-6 C R15 20 trifluoromethylcarbonylaminomethyloxetanyl; R16 , wherein R14 is hydrogen or methyl; R15 is hydroxy, methyl or amino; and R16 is methyl, trifluoromethyl, C R18 hydroxymethyl, hydroxyethyl, aminomethyl, arbonyl or carboxymethyl; R19 , wherein R17 is hydrogen, methyl or hydroxymethyl; R18 is hydroxymethyl or ; R19 is hydroxymethyl, aminomethyl, carboxy, aminocarbonyl or aminocarbonylmethyl; C R21 25 or R22 , wherein R20 is en 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, zinyl, piperidinyl, morpholinyl, azetidinyl, diazepanyl or oxopyrrolidinyl ring; which may be unsubstituted, once or twice substituted by a group selected from fluoro, methyl, 30 methoxy, ethyl, amino, aminocarbonyl, hydroxy, ylamino, 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-oxaaza-spiro[3.4]octanyl, 2-oxa-5,7-diazaspiro[3.4]octan- 6-oneyl, (4aS ,7aR )-hexahydropyrrolo[3,4-b][1,4]oxazin-6(2 H)-yl, 4,5,6,6a-tetrahydro- 3a olo[3,4-d][1,3]oxazolyl, 2-aza-bicyclo[2.1.1]hexanyl or 3-aza- 5 bicyclo[3.1.0]hexanyl; which may be unsubstituted or r substituted by amino. 10. A nd 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; A is -C-R11 , wherein R11 is C1-6alkyl; 10 X is ; Y is -CH-; Q is NR12 R13 , n one of R12 and R13 is hydrogen; and the other one is amino(CH 2)2-6; R12 and R13 , with the nitrogen atom to which they are attached, may form a pyrrolidinyl 15 ring, which may be twice substituted by a group selected from amino and hydroxyl. 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 , n R11 is methyl; Q is NR12 R13 , wherein one of R12 and R13 is hydrogen; and the other one is aminoethyl; 20 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 hydroxyl. 12. A compound according to any one of claims 1 to 11 or a pharmaceutically acceptable salt thereof, selected from N-[(3-aminooxetanyl)methyl](8-methoxy-1,1-dioxido-2,3-dihydro-1,4-benzothiazepin- 25 4(5 H)-yl)methylquinolinamine; N-[(3-aminooxetanyl)methyl](8-fluoro-1,1-dioxido- 2,3-dihydro-1,4-benzothiazepin-4(5 H)-yl)methylquinolinamine; N-[(3-aminooxetan yl)methyl](7-fluoro-1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5 H)-yl)methylquinolin- 4-amine; aminooxetanyl)methyl](9-fluoro-1,1-dioxido-2,3-dihydro-1,4- benzothiazepin-4(5 H)-yl)methylquinolinamine; N-[(3-aminooxetanyl)methyl](7- methoxy-1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5 H)-yl)methylquinolinamine; N- [(3-aminooxetanyl)methyl](8-chloro-1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5 H)- methylquinolinamine; N-[(3-aminooxetanyl)methyl](7-methoxy-1,1-dioxido-2,3- dihydro-1,4-benzothiazepin-4(5 H)-yl)quinolinamine; N-[(3-aminotetrahydrofuran 5 yl)methyl](1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)methylquinolinamine; N-[(3-aminooxetanyl)methyl](1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5 H)-yl) methylquinolinamine; aminotetrahydro-2H-pyranyl)methyl](1,1-dioxido-2,3- dihydro-1,4-benzothiazepin-4(5 H)-yl)methylquinolinamine; aminooxetan yl)methyl](8-methyl-1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5 H)-yl)quinolinamine; 10 N-[(3-aminooxetanyl)methyl]methyl(8-methyl-1,1-dioxido-2,3-dihydro-1,4- benzothiazepin-4(5 H)-yl)quinolinamine; -dioxido-2,3-dihydro-1,4-benzothiazepin- 4(5 H)-yl)methyl-N-(2-oxaazaspiro[3.4]octyl)quinolinamine; N-[2-(3-aminooxetan yl)ethyl](1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5 H)-yl)methylquinolinamine; N-[(3-aminooxetanyl)methyl]methyl(5-methyl-1,1-dioxido-2,3-dihydro-1,4- 15 benzothiazepin-4(5 H)-yl)quinolinamine; N-[(3-aminooxetanyl)methyl](8-methoxy-1,1- dioxido-2,3-dihydro-1,4-benzothiazepin-4(5 H)-yl)quinolinamine; N-[(3-aminooxetan yl)methyl](1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5 H)-yl)-1,6-naphthyridinamine; N-[(1-aminocyclohexyl)methyl](1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5 H)-yl) methylquinolinamine; N-{[3-(aminomethyl)oxetanyl]methyl}(8-fluoro-1,1-dioxido-2,3- 20 dihydro-1,4-benzothiazepin-4(5 H)-yl)methylquinolinamine; N-{[3-(benzylamino)oxetan yl]methyl}chloro(7-fluoro-1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5 quinolin- 4-amine; N-[(3-aminooxetanyl)methyl]chloro(7-fluoro-1,1-dioxido-2,3-dihydro-1,4- benzothiazepin-4(5 H)-yl)quinolinamine; N-{[3-(aminomethyl)oxetanyl]methyl}(7- methoxy-1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5 H)-yl)quinolinamine; N-{[3- 25 (aminomethyl)oxetanyl]methyl}(7-methoxy-1,1-dioxido-2,3-dihydro-1,4-benzothiazepin- 4(5 H)-yl)methylquinolinamine; N-{[3-({[2-(7-methoxy-1,1-dioxido-2,3-dihydro-1,4- benzothiazepin-4(5 methylquinolinyl]amino}methyl)oxetanyl]methyl}acetamide; N-{[3-(aminomethyl)oxetanyl]methyl}(8-methyl-1,1-dioxido-2,3-dihydro-1,4- benzothiazepin-4(5 H)-yl)quinolinamine; N-{[3-(aminomethyl)oxetanyl]methyl}methyl- 30 2-(8-methyl-1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5 quinolinamine; [3-({[2- (1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5 H)-yl)methylquinolin yl]amino}methyl)oxetanyl]methanol; (2S ){[2-(1,1-dioxido-2,3-dihydro-1,4- benzothiazepin-4(5 H)-yl)methylquinolinyl]amino}propane-1,2-diol; (2R ){[2-(1,1- dioxido-2,3-dihydro-1,4-benzothiazepin-4(5 H)-yl)methylquinolinyl]amino}propane-1,2- 35 diol; N-{[1-(aminomethyl)-3,3-difluorocyclobutyl]methyl}(1,1-dioxido-2,3-dihydro-1,4- benzothiazepin-4(5 H)-yl)methylquinolinamine; N-[(3-aminooxetanyl)methyl]chloro- 2-(8-methoxy-1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5 H)-yl)quinolinamine; N-{[3- (aminomethyl)oxetanyl]methyl}chloro(8-methoxy-1,1-dioxido-2,3-dihydro-1,4- benzothiazepin-4(5 H)-yl)quinolinamine; trans-N-[2-(1,1-dioxido-2,3-dihydro-1,4- benzothiazepin-4(5 H)-yl)methylquinolinyl]cyclohexane-1,2-diamine; N-[2-(1,1-dioxido- 2,3-dihydro-1,4-benzothiazepin-4(5 H)-yl)methylquinolinyl]cyclohexane-1,3-diamine; (3R )[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5 H)-yl)methylquinolinyl]-4,4- 5 dimethylpyrrolidinol; cis-N-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl) methylquinolinyl]cyclohexane-1,4-diamine; N-[2-(1,1-dioxido-2,3-dihydro-1,4- benzothiazepin-4(5 H)-yl)methylquinolinyl]-2,2-difluoropropane-1,3-diamine; hloro- 2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5 H)-yl)quinolinyl]-2,2-difluoropropane-1,3- diamine; N-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)methylquinolinyl] 10 propane-1,3-diamine; N-[(3-aminooxetanyl)methyl]chloro(1,1-dioxido-2,3- dihydro-1,4-benzothiazepin-4(5 H)-yl)quinolinamine; [4-{[(3-aminooxetan yl)methyl]amino}(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5 H)-yl)quinolin yl]methanol; N-[(3-aminooxetanyl)methyl](1,1-dioxido-2,3-dihydro-1,4-benzothiazepin- 4(5 H)-yl)fluoromethylquinolinamine; N-[(3-aminooxetanyl)methyl](1,1-dioxido- 15 2,3-dihydro-1,4-benzothiazepin-4(5 fluoromethylquinolinamine; N~1~-[6-chloro- -dioxido-2,3-dihydro-1,4-benzothiazepin-4(5 H)-yl)quinolinyl]methylpropane-1,2- diamine; 2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5 H)-yl)methyl-N-(tetrahydro-2H- pyranyl)quinolinamine; 2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5 H)-yl) methyl-N-[2-(piperazinyl)ethyl]quinolinamine; 2-(1,1-dioxido-2,3-dihydro-1,4- 20 benzothiazepin-4(5 H)-yl)methyl-N-(piperidinylmethyl)quinolinamine; N-[2-(1,1- dioxido-2,3-dihydro-1,4-benzothiazepin-4(5 H)-yl)methylquinolinyl]heptane-1,7-diamine; N-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)methylquinolinyl]-N'- ethane-1,2-diamine; N'-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5 H)-yl) methylquinolinyl]-N,N-dimethylethane-1,2-diamine; 2-(1,1-dioxido-2,3-dihydro-1,4- 25 benzothiazepin-4(5 H)-yl)-N,6-dimethylquinolinamine trifluoroacetate; (3S ,4S )[2-(1,1- dioxido-2,3-dihydro-1,4-benzothiazepin-4(5 methylquinolinyl]pyrrolidine-3,4-diol; 2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5 H)-yl)methyl-N-(pyrrolidin ylmethyl)quinolinamine; 4-[4-(1,4-diazepanyl)methylquinolinyl]-2,3,4,5-tetrahydro- nzothiazepine oxide; N-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl) 30 methylquinolinyl]-N'-ethylethane-1,2-diamine; 2-{[2-(1,1-dioxido-2,3-dihydro-1,4- benzothiazepin-4(5 H)-yl)methylquinolinyl]amino}ethanol; 2-(1,1-dioxido-2,3-dihydro-1,4- benzothiazepin-4(5 H)-yl)methyl-N-(piperidinyl)quinolinamine; 2-(1,1-dioxido-2,3- dihydro-1,4-benzothiazepin-4(5 H)-yl)methyl-N-(piperidinyl)quinolinamine; 2-(1,1- dioxido-2,3-dihydro-1,4-benzothiazepin-4(5 H)-yl)methyl-N-(piperidinylmethyl)quinolin- 35 4-amine; 2-[(2-{[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5 H)-yl)methylquinolin yl]amino}ethyl)amino]ethanol; N-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl) methylquinolinyl]-2,2,3,3-tetrafluorobutane-1,4-diamine; N-[2-(1,1-dioxido-2,3-dihydro-1,4- benzothiazepin-4(5 H)-yl)methylquinolinyl]-N'-(2-methoxyethyl)ethane-1,2-diamine; 1-[2- (1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5 H)-yl)methylquinolinyl] methylpyrrolidinol; N-[6-chloro(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5 H)- nolinyl]ethane-1,2-diamine; 2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5 H)-yl)- 6-methyl-N-(oxetanyl)quinolinamine; N-[(3-aminooxetanyl)methyl](1,1-dioxido-2,3- 5 dihydro-1,4-benzothiazepin-4(5 H)-yl)quinolinamine; 2-(1,1-dioxido-2,3-dihydro-1,4- benzothiazepin-4(5 H)-yl)methyl-N-[( 3R )-tetrahydrofuranyl]quinolinamine; N-{[3- (aminomethyl)oxetanyl]methyl}(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5 H)-yl) methylquinolinamine; N-{[3-(aminomethyl)oxetanyl]methyl}chloro(1,1-dioxido-2,3- dihydro-1,4-benzothiazepin-4(5 H)-yl)quinolinamine; N-{[3-(aminomethyl)oxetan 10 yl]methyl}(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5 H)-yl)quinolinamine; 2-(1,1- dioxido-2,3-dihydro-1,4-benzothiazepin-4(5 H)-yl)methyl-N-(oxetanylmethyl)quinolin amine; N-[(1-aminocyclobutyl)methyl](1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5 H)- yl)methylquinolinamine; 1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl) methylquinolinyl]pentane-1,5-diamine; N-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin- 15 4(5 H)-yl)methylquinolinyl]hexane-1,6-diamine; 1,1-dioxido-2,3-dihydro-1,4- benzothiazepin-4(5 H)-yl)methylquinolinyl]-1,1,1-trifluoromethanesulfonamide hydrochloride; N-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)methylquinolin yl]pyridazinecarboxamide; 1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl) methylquinolinyl]benzamide; 1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl) 20 methylquinolinyl]acetamide; N-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl) methylquinolinyl]piperidinecarboxamide; N-[2-(1,1-dioxido-2,3-dihydro-1,4- hiazepin-4(5 H)-yl)methylquinolinyl]piperidinecarboxamide; 3-[2-(1,1-dioxido- 2,3-dihydro-1,4-benzothiazepin-4(5 H)-yl)methylquinolinyl]-1,1-dimethylurea; 2-(1,1- dioxido-2,3-dihydro-1,4-benzothiazepin-4(5 H)-yl)methyl-N-(1,2-oxazolyl)quinolin 25 amine; N-{[3-(aminomethyl)oxetanyl]methyl}(1,1-dioxido-2,3-dihydro-1,4- benzothiazepin-4(5 H)-yl)(~2~ H_3_)methylquinolinamine; N-[(3-aminooxetan yl)methyl]chloro(2,3-dihydro-1,4-benzothiazepin-4(5 H)-yl)quinolinamine; N-[6-chloro- 2-(2,3-dihydro-1,4-benzothiazepin-4(5 H)-yl)quinolinyl]ethane-1,2-diamine; N-[(3- aminooxetanyl)methyl](2,3-dihydro-1,4-benzothiazepin-4(5 H)-yl)methylquinolin 30 amine; 2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)methylquinolinyl]pyrrolidin amine; N-[2-(2,3-dihydro-1,4-benzothiazepin-4(5 H)-yl)methylquinazolinyl]-2,2- difluoropropane-1,3-diamine; 2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5 H)-yl)-N-[2- (1,1-dioxidothiomorpholinyl)ethyl]methylquinolinamine; N-[2-(2-aminoethoxy)ethyl]- 2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5 H)-yl)methylquinolinamine; N~1~-[2- 35 (1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5 H)-yl)methylquinolinyl] methylpropane-1,2-diamine; N~1~-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5 H)- yl)quinolinyl]methylpropane-1,2-diamine; N~1~-[2-(1,1-dioxido-2,3-dihydro-1,4- benzothiazepin-4(5 H)-yl)methylquinolinyl]propane-1,2-diamine; 4-[6-methyl(4- methylpiperazinyl)quinolinyl]-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide; 1-{[2- (1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5 H)-yl)methylquinolinyl]amino}propan ol; (2S )-N~1~-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5 H)-yl)methylquinolin yl]propane-1,2-diamine; (2R )-N~1~-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5 H)-yl)- 5 6-methylquinolinyl]propane-1,2-diamine; N-[(3-aminooxetanyl)methyl](1,1-dioxido- 2,3-dihydro-1,4-benzothiazepin-4(5 H)-yl)-7,8-difluoromethylquinolinamine; N-(2,2- difluoroethyl)-N'-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5 H)-yl)methylquinolin yl]ethane-1,2-diamine; 3-{[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5 H)-yl) methylquinolinyl]amino}oxetanethanol; N-{[3-(aminomethyl)thietanyl]methyl}(1,1- 10 dioxido-2,3-dihydro-1,4-benzothiazepin-4(5 H)-yl)methylquinolinamine; N-{[3- (aminomethyl)-1,1-dioxidothietanyl]methyl}(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin- 4(5 methylquinolinamine; N-(4,5-dihydro-1H-imidazolyl)(1,1-dioxido-2,3- dihydro-1,4-benzothiazepin-4(5 H)-yl)methylquinolinamine; trans -(1,1-dioxido-2,3- dihydro-1,4-benzothiazepin-4(5 H)-yl)methylquinolinyl]amino}cyclohexanol; (2S ){[2- 15 (1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5 H)-yl)methylquinolinyl]amino}propan ol; trans [2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5 methylquinolinyl] ypyrrolidinamine; 2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin+D154-4(5 H)-yl)-N- [trans methoxypyrrolidinyl]methylquinolinamine; 4-{4-[(4aS ,7aR )- dropyrrolo[3,4-b][1,4]oxazin-6(2 H)-yl]methylquinolinyl}-2,3,4,5-tetrahydro-1,4- 20 benzothiazepine 1,1-dioxide; (3R ,4R -(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5 H)- yl)methylquinolinyl](4-methylpiperazinyl)pyrrolidinol; (2- aminoethyl)sulfanyl]ethyl}(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5 H)-yl) methylquinolinamine; 1-{1-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5 H)-yl) methylquinolinyl]piperidinyl}methanamine; 2-{[2-(8-methoxy-1,1-dioxido-2,3-dihydro- 25 1,4-benzothiazepin-4(5 H)-yl)quinolinyl]amino}ethanol; N-[2-(1,1-dioxido-2,3-dihydro-1,4- benzothiazepin-4(5 H)-yl)methylquinolinyl]propane-1,3-diamine; 4-[6-methyl (morpholinyl)quinolinyl]-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide; 3-{[2-(1,1- dioxido-2,3-dihydro-1,4-benzothiazepin-4(5 methylquinolinyl]amino}propanol; 2- (1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5 H)-yl)methyl-N-[2-(piperidin 30 yl)ethyl]quinolinamine; 1-amino{[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5 H)- methylquinolinyl]amino}propanol; N-[2-(1,1-dioxido-2,3-dihydro-1,4- benzothiazepin-4(5 H)-yl)methylquinolinyl]glycine; N-[2-(1,1-dioxido-2,3-dihydro-1,4- benzothiazepin-4(5 H)-yl)fluoroquinolinyl]ethane-1,2-diamine; N-[2-(1,1-dioxido-2,3- dihydro-1,4-benzothiazepin-4(5 H)-yl)ethylquinolinyl]ethane-1,2-diamine; N-[7-chloro 35 (1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5 H)-yl)quinolinyl]propane-1,3-diamine; N-[8- chloro(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5 H)-yl)quinolinyl]propane-1,3- diamine; N-[5-chloro(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5 H)-yl)quinolin yl]propane-1,3-diamine; N-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl) methylquinolinyl]-2,2-dimethylpropane-1,3-diamine; N-[2-(1,1-dioxido-2,3-dihydro-1,4- benzothiazepin-4(5 H)-yl)quinolinyl]ethane-1,2-diamine; N-[2-(1,1-dioxido-2,3-dihydro-1,4- benzothiazepin-4(5 H)-yl)methylquinolinyl]ethane-1,2-diamine; N~2~-[2-(1,1-dioxido-2,3- dihydro-1,4-benzothiazepin-4(5 H)-yl)methylquinolinyl]methylpropane-1,2-diamine; 5 N~2~-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5 H)-yl)methylquinolin yl]propane-1,2-diamine; N-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl) methylquinolinyl]butane-1,4-diamine; N-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin- 4(5 H)-yl)nitroquinolinyl]ethane-1,2-diamine; N-[2-(1,1-dioxido-2,3-dihydro-1,4- benzothiazepin-4(5 H)-yl)fluoromethylquinolinyl]ethane-1,2-diamine; 2-{[2-(1,1- 10 o-2,3-dihydro-1,4-benzothiazepin-4(5 H)-yl)fluoromethylquinolin yl]amino}ethanol; 2-{[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5 H)-yl)fluoro methylquinolinyl]amino}ethanol; N-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)- yl)fluoromethylquinolinyl]ethane-1,2-diamine; N-[2-(1,1-dioxido-2,3-dihydro-1,4- benzothiazepin-4(5 H)-yl)-7,8-difluoromethylquinolinyl]ethane-1,2-diamine; - 15 o-2,3-dihydro-1,4-benzothiazepin-4(5 H)-yl)-N-(2-methoxyethyl)methylquinolin amine; 1-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5 H)-yl)methylquinolin yl]piperidinamine; 1-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5 H)-yl)-1,6- naphthyridinyl]pyrrolidinamine; N-[6-(difluoromethyl)(1,1-dioxido-2,3-dihydro-1,4- benzothiazepin-4(5 H)-yl)quinolinyl]propane-1,3-diamine; ro(1,1-dioxido-2,3- 20 dihydro-1,4-benzothiazepin-4(5 -N-ethylquinolinamine; chloro(1,1-dioxido- 2,3-dihydro-1,4-benzothiazepin-4(5 H)-yl)quinolinyl]amino}ethanol; N-[6-chloro(1,1- dioxido-2,3-dihydro-1,4-benzothiazepin-4(5 H)-yl)quinolinyl]-N'-methylethane-1,2-diamine; N-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)(methylsulfanyl)quinolin yl]propane-1,3-diamine; N-[6-bromo(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5 H)- 25 yl)quinolinyl]propane-1,3-diamine; {4-[(2-aminoethyl)amino](1,1-dioxido-2,3-dihydro- 1,4-benzothiazepin-4(5 quinolinyl}methanol; 2-{[2-(1,1-dioxido-2,3-dihydro-1,4- benzothiazepin-4(5 H)-yl)methylquinolinyl]amino}propane-1,3-diol; 2,2'-{[2-(1,1-dioxido- hydro-1,4-benzothiazepin-4(5 H)-yl)methylquinolinyl]imino}diethanol; 4-{[2-(1,1- dioxido-2,3-dihydro-1,4-benzothiazepin-4(5 H)-yl)methylquinolinyl]amino} 30 hydroxybutanoic acid; 1-amino{[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5 H)-yl) methylquinolinyl]amino}methylpropanol; 2-(1,1-dioxido-2,3-dihydro-1,4- benzothiazepin-4(5 H)-yl)methyl-N-[2-(morpholinyl)ethyl]quinolinamine; 2-{[2-(1,1- dioxido-2,3-dihydro-1,4-benzothiazepin-4(5 H)-yl)-1,6-naphthyridinyl]amino}ethanol; N-[2- (1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5 H)-yl)methylquinolinyl]nonane-1,9- 35 diamine; N-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)methylquinolin yl]decane-1,10-diamine; N-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl) methylquinolinyl]octane-1,8-diamine; 9-{[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin- 4(5 H)-yl)methylquinolinyl]amino}nonanol; N-[2-(1,1-dioxido-2,3-dihydro-1,4- benzothiazepin-4(5 H)-yl)methylquinolinyl]octane-1,8-diamine; cis amino[2-(1,1- dioxido-2,3-dihydro-1,4-benzothiazepin-4(5 H)-yl)methylquinolinyl]pyrrolidinol; N-[2- (1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5 methylquinolinyl]-L-alanine; N-[2- (1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5 H)-yl)methylquinolinyl]-beta-alanine; N- 5 [2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5 H)-yl)methylquinolinyl]benzene-1,3- diamine; N-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)methylquinolin yl]benzene-1,4-diamine; (3S )[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5 H)-yl) methylquinolinyl]pyrrolidinol; (3R )[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin- 4(5 H)-yl)methylquinolinyl]pyrrolidinol; trans -N-[2-(1,1-dioxido-2,3-dihydro-1,4- 10 benzothiazepin-4(5 H)-yl)methylquinolinyl]cyclopentane-1,2-diamine; 1-[2-(1,1-dioxido- 2,3-dihydro-1,4-benzothiazepin-4(5 H)-yl)methylquinolinyl]piperidinamine; - dioxido-2,3-dihydro-1,4-benzothiazepin-4(5 H)-yl)-N,N,6-trimethylquinolinamine; N-[2-(1,1- dioxido-2,3-dihydro-1,4-benzothiazepin-4(5 H)-yl)(trifluoromethoxy)quinolinyl]propane- 1,3-diamine; N-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl) 15 (trifluoromethyl)quinolinyl]propane-1,3-diamine; N-[6-(difluoromethoxy)(1,1-dioxido-2,3- dihydro-1,4-benzothiazepin-4(5H)-yl)quinolinyl]propane-1,3-diamine; N-[2-(1,1-dioxido-2,3- o-1,4-benzothiazepin-4(5 H)-yl)methoxyquinolinyl]propane-1,3-diamine; N-[2-(1,1- dioxido-2,3-dihydro-1,4-benzothiazepin-4(5 H)-yl)methylquinolinyl]propane-1,3-diamine; N-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)methylquinolinyl]propane- 20 1,3-diamine; N-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)methylquinolin yl]propane-1,3-diamine; N-{[3-(aminomethyl)oxetanyl]methyl}(1,1-dioxido-2,3-dihydro- 1,4-benzothiazepin-4(5 H)-yl)fluoroquinolinamine; N-[(3-aminooxetanyl)methyl] methyl(1-oxido-2,3-dihydro-1,4-benzothiazepin-4(5 H)-yl)quinolinamine; (+)-N-[(3- aminooxetanyl)methyl]methyl[1-oxido-2,3-dihydro-1,4-benzothiazepin-4(5 H)- 25 nolinamine; [(3-aminooxetanyl)methyl]methyl[1-oxido-2,3-dihydro-1,4- benzothiazepin-4(5 H)-yl]quinolinamine; N-[(3-aminooxetanyl)methyl]chloro(1- oxido-2,3-dihydro-1,4-benzothiazepin-4(5 H)-yl)quinolinamine; 2,2-difluoro-N-[6-methyl (1-oxido-2,3-dihydro-1,4-benzothiazepin-4(5 H)-yl)quinolinyl]propane-1,3-diamine; N-[6- chloro(1-oxido-2,3-dihydro-1,4-benzothiazepin-4(5 H)-yl)quinolinyl]-2,2-difluoropropane- 30 1,3-diamine; N-[6-chloro(1-oxido-2,3-dihydro-1,4-benzothiazepin-4(5 H)-yl)quinolin yl]ethane-1,2-diamine; N-{[3-(aminomethyl)oxetanyl]methyl}methyl(1-oxido-2,3- o-1,4-benzothiazepin-4(5 H)-yl)quinolinamine; N-{[3-(aminomethyl)oxetan yl]methyl}chloro(1-oxido-2,3-dihydro-1,4-benzothiazepin-4(5 H)-yl)quinolinamine; N- [6-methyl(1-oxido-2,3-dihydro-1,4-benzothiazepin-4(5 quinolinyl]ethane-1,2- 35 diamine; 2-{[6-methyl(1-oxido-2,3-dihydro-1,4-benzothiazepin-4(5 H)-yl)quinolin yl]amino}ethanol; trans amino[6-methyl(1-oxido-2,3-dihydro-1,4-benzothiazepin- 4(5 quinolinyl]pyrrolidinol; (1R ,5S ,6S )[2-(1,1-dioxido-2,3-dihydro-1,4- benzothiazepin-4(5 H)-yl)methylquinolinyl]azabicyclo[3.1.0]hexanamine; trans amino[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5 H)-yl)methylquinolin yl]pyrrolidinol; 1-[6-methyl(1-oxido-2,3-dihydro-1,4-benzothiazepin-4(5 H)-yl)quinolin rolidinamine; trans [6-chloro(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5 H)- yl)quinolinyl]fluoropyrrolidinamine; trans amino[6-chloro(1,1-dioxido-2,3- 5 dihydro-1,4-benzothiazepin-4(5 H)-yl)quinolinyl]pyrrolidinol; trans [6-chloro(1- oxido-2,3-dihydro-1,4-benzothiazepin-4(5 H)-yl)quinolinyl]fluoropyrrolidinamine; 2-[2- (1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5 H)-yl)methylquinolinyl] yclo[2.1.1]hexanamine; 2-(8-methoxy-1,1-dioxido-2,3-dihydro-1,4-benzothiazepin- 4(5 H)-yl)methylquinolinamine; 2-(7-methoxy-1,1-dioxido-2,3-dihydro-1,4- 10 benzothiazepin-4(5 H)-yl)methylquinolinamine; N-[2-(1-aminocyclopropyl)ethyl](1,1- dioxido-2,3-dihydro-1,4-benzothiazepin-4(5 H)-yl)methylquinolinamine; 2-(1,1-dioxido- 2,3-dihydro-1,4-benzothiazepin-4(5 H)-yl)methyl-N-(morpholinylmethyl)quinolinamine; N-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)methylquinolinyl]-N- methylethane-1,2-diamine; N-(azetidinylmethyl)(1,1-dioxido-2,3-dihydro-1,4- 15 benzothiazepin-4(5 H)-yl)methylquinolinamine; 2-(1,1-dioxido-2,3-dihydro-1,4- benzothiazepin-4(5H)-yl)methyl-N-(pyrrolidinyl)quinolinamine; N-[(1- aminocyclopropyl)methyl](1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5 H)-yl) methylquinolinamine; tidinyl)chloro(1,1-dioxido-2,3-dihydro-1,4- benzothiazepin-4(5 H)-yl)quinolinamine; 6-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin- 20 4(5 methylquinolinyl]oxaazaspiro[3.4]octanamine; trans amino[2-(1,1- dioxido-2,3-dihydro-1,4-benzothiazepin-4(5 H)-yl)-1,6-naphthyridinyl]pyrrolidinol; 1-[2- (1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5 H)-yl)methylquinolinyl]pyrrolidin amine; N-(azetidinyl)(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5 H)-yl) methylquinolinamine; 1-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5 H)-yl) 25 quinolinyl]azetidinamine; N-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)- yl)methylquinolinyl]prolinamide; 2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5 H)- (trans fluoropyrrolidinyl)methylquinolinamine; trans {[2-(1,1-dioxido-2,3- dihydro-1,4-benzothiazepin-4(5 H)-yl)quinolinyl]amino}pyrrolidinol; trans {[2-(1,1- dioxido-2,3-dihydro-1,4-benzothiazepin-4(5 methylquinolinyl]amino}pyrrolidinol; 30 cis {[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5 H)-yl)methylquinolin yl]amino}pyrrolidinol; N-[trans fluoropyrrolidinyl]methyl(1-oxido-2,3-dihydro- 1,4-benzothiazepin-4(5 H)-yl)quinolinamine; 4-[(3-aminopropyl)amino](1,1-dioxido-2,3- dihydro-1,4-benzothiazepin-4(5 H)-yl)quinolinol; 2-({4-[(3-aminopropyl)amino](1,1- dioxido-2,3-dihydro-1,4-benzothiazepin-4(5 H)-yl)quinolinyl}oxy)ethanol; N-[2-(1,1-dioxido- 35 2,3-dihydro-1,4-benzothiazepin-4(5 H)-yl)(2-methoxyethoxy)quinolinyl]propane-1,3- diamine; N-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)(pyridin yloxy)quinolinyl]propane-1,3-diamine; 3-{[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin- 4(5 H)-yl)methylquinolinyl]amino}propane-1,2-diol; 3-{[6-chloro(1,1-dioxido-2,3- dihydro-1,4-benzothiazepin-4(5 H)-yl)quinolinyl]amino}propane-1,2-diol; 3-{[2-(8-chloro- 1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5 H)-yl)methylquinolinyl]amino}propane- 1,2-diol; 3-{[6-methyl(1-oxido-2,3-dihydro-1,4-benzothiazepin-4(5 H)-yl)quinolin yl]amino}propane-1,2-diol; 3-{[6-methyl(5-methyl-1,1-dioxido-2,3-dihydro-1,4- 5 benzothiazepin-4(5 H)-yl)quinolinyl]amino}propane-1,2-diol; N-[(3-aminooxetan yl)methyl]methyl[7-(morpholinyl)-1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5 H)- yl]quinolinamine; N-[(3-aminooxetanyl)methyl]{1,1-dioxido[4-(propan yl)piperazinyl]-2,3-dihydro-1,4-benzothiazepin-4(5 H)-yl}methylquinolinamine; 3-{[4- (4-aminoquinolinyl)-1,1-dioxido-2,3,4,5-tetrahydro-1,4-benzothiazepinyl]oxy}propan 10 ol; N-[(3-aminooxetanyl)methyl](1,1-dioxidophenoxy-2,3-dihydro-1,4-benzothiazepin- 4(5 H)-yl)methylquinolinamine; N~3~-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin- 4(5 H)-yl)methylquinolinyl]-beta-alaninamide; 3-{[2-(1,1-dioxido-2,3-dihydro-1,4- benzothiazepin-4(5 H)-yl)methylquinolinyl]amino}butanamide; (1,1-dioxido-2,3- dihydro-1,4-benzothiazepin-4(5 H)-yl)methylquinolinyl]amino}methylpropanamide; 15 N~2~-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5 H)-yl)methylquinolinyl]-L- amide; N~2~-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5 H)-yl)methylquinolin- 4-yl]glycinamide; N~2~-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5 H)-yl) methylquinolinyl]-N-methylglycinamide; (2S )amino{[2-(1,1-dioxido-2,3-dihydro-1,4- benzothiazepin-4(5 H)-yl)methylquinolinyl]amino}propanol; (2R )amino{[2-(1,1- 20 dioxido-2,3-dihydro-1,4-benzothiazepin-4(5 H)-yl)methylquinolinyl]amino}propanol; N-[(2-amino-4,5-dihydro-1,3-oxazolyl)methyl](1,1-dioxido-2,3-dihydro-1,4- benzothiazepin-4(5 H)-yl)methylquinolinamine; N-[(2-aminomethyl-4,5-dihydro-1,3- oxazolyl)methyl](1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5 H)-yl)methylquinolin- 4-amine; N-{[(4R )amino-4,5-dihydro-1,3-oxazolyl]methyl}(1,1-dioxido-2,3-dihydro- 25 1,4-benzothiazepin-4(5 H)-yl)methylquinolinamine; N-{[( 4S )amino-4,5-dihydro-1,3- oxazolyl]methyl}(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5 H)-yl) methylquinolinamine; cis [2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5 quinolinyl]-4,5,6,6a-tetrahydro-3a H-pyrrolo[3,4-d][1,3]oxazolamine; 2-(1,1- dioxido-2,3-dihydro-1,4-benzothiazepin-4(5 H)-yl)methylquinolinamine; N-[2-(1,1- 30 o-2,3-dihydro-1,4-benzothiazepin-4(5 H)-yl)methylquinolinyl]glycinamide; N-[2- ioxido-2,3-dihydro-1,4-benzothiazepin-4(5 H)-yl)methylquinolinyl] methylalaninamide; N-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl) methylquinolinyl]alaninamide; 2-amino-N-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin- 4(5 methylquinolinyl]butanamide; N-[2-(1,1-dioxido-2,3-dihydro-1,4- 35 benzothiazepin-4(5 H)-yl)methylquinolinyl]methoxymethylpropanamide; N~1~-[2- (1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5 H)-yl)methylquinolinyl]-4,4,4- trifluorobutane-1,3-diamine; N-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl) methylquinolinyl]-beta-alaninamide; 2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5 H)- {[3-(ethylamino)oxetanyl]methyl}methylquinolinamine; 2-(1,1-dioxido-2,3- dihydro-1,4-benzothiazepin-4(5 H)-yl)methyl-N-[1-(oxetanyl)pyrrolidinyl]quinolin amine; N'-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5 H)-yl)methylquinolinyl]-N- ethyl-N-(oxetanyl)ethane-1,2-diamine; N-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin- 5 4(5 H)-yl)methylquinolinyl]-N'-(oxetanyl)propane-1,3-diamine; 1-[2-(1,1-dioxido-2,3- dihydro-1,4-benzothiazepin-4(5 H)-yl)methylquinolinyl]-N-(oxetanyl)pyrrolidin amine; N-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)methylquinolinyl]-N'- (oxetanyl)ethane-1,2-diamine; N-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)- 6-methylquinolinyl]-N'-(pyridinyl)ethane-1,2-diamine; (4R )[2-(1,1-dioxido-2,3-dihydro- 10 1,4-benzothiazepin-4(5 H)-yl)methylquinolinyl]hydroxypyrrolidinone; N-[2-(1,1- dioxido-2,3-dihydro-1,4-benzothiazepin-4(5 H)-yl)methylquinolinyl]oxopyrrolidine carboxamide; 2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5 H)-yl)methyl-N-(1 H- pyrazolyl)quinolinamine; 1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl) methylquinolinyl]pyridinecarboxamide; N-[2-(1,1-dioxido-2,3-dihydro-1,4- 15 benzothiazepin-4(5 methylquinolinyl]piperidinecarboxamide; N-[2-(1,1-dioxido- 2,3-dihydro-1,4-benzothiazepin-4(5 H)-yl)methylquinolinyl](pyridinyl)acetamide; N- [2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5 H)-yl)methylquinolin yl]methanesulfonamide trifluoroacetate; N-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin- 4(5 H)-yl)methylquinolinyl]pyrazinecarboxamide; N-[2-(1,1-dioxido-2,3-dihydro-1,4- 20 benzothiazepin-4(5 methylquinolinyl]hydroxyacetamide; 1,1-dioxido-2,3- dihydro-1,4-benzothiazepin-4(5 H)-yl)methylquinolinyl]pyridinecarboxamide; N-[2- (1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5 H)-yl)methylquinolinyl]azetidine carboxamide; 1-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5 H)-yl)methylquinolin yl]phenylurea; 1-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5 H)-yl) 25 methylquinolinyl]ethylurea; N-[6-cyclopropyl(1,1-dioxido-2,3-dihydro-1,4- benzothiazepin-4(5 H)-yl)quinolinyl]propane-1,3-diamine; 4-[(3-aminopropyl)amino](1,1- dioxido-2,3-dihydro-1,4-benzothiazepin-4(5 H)-yl)quinolinecarbonitrile; N-[2-(1,1-dioxido- 2,3-dihydro-1,4-benzothiazepin-4(5 H)-yl)ethenylquinolinyl]propane-1,3-diamine; N-[2- (1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5 H)-yl)ethynylquinolinyl]propane-1,3- 30 diamine; N-[(3-aminooxetanyl)methyl]methyl(1-oxido-2,3-dihydro-1,4-benzothiazepin- 4(5 H)-yl)quinazolinamine; N-{[3-(benzylamino)oxetanyl]methyl}methyl(1-oxido- 2,3-dihydro-1,4-benzothiazepin-4(5 quinazolinamine; 2-fluoro-N-[6-methyl(1-oxido- hydro-1,4-benzothiazepin-4(5 H)-yl)quinazolinyl]propane-1,3-diamine; N-{[3- (aminomethyl)oxetanyl]methyl}(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5 H)-yl) 35 methylquinazolinamine; 2,2-difluoro-N-[6-methyl(1-oxido-2,3-dihydro-1,4- benzothiazepin-4(5 quinazolinyl]propane-1,3-diamine; N-{[3-(aminomethyl)oxetan yl]methyl}chloro(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5 H)-yl)quinazolin amine; N-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)methylquinazolinyl]- 2,2-difluoropropane-1,3-diamine; N-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)- 6-methylquinazolinyl]fluoropropane-1,3-diamine; N-[6-methyl(1-oxido-2,3-dihydro- 1,4-benzothiazepin-4(5 H)-yl)quinazolinyl]propane-1,3-diamine; N-[(3-aminooxetan yl)methyl](2,3-dihydro-1,4-benzothiazepin-4(5 H)-yl)quinazolinamine; N-[(3-aminooxetan- 5 3-yl)methyl](1-oxido-2,3-dihydro-1,4-benzothiazepin-4(5 H)-yl)quinazolinamine; N-[(3- aminooxetanyl)methyl](1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5 H)-yl)quinazolin- 4-amine; N-[(3-aminooxetanyl)methyl]chloro(2,3-dihydro-1,4-benzothiazepin-4(5 H)- yl)quinazolinamine; N-[(3-aminooxetanyl)methyl]chloro(1-oxido-2,3-dihydro-1,4- benzothiazepin-4(5 H)-yl)quinazolinamine; aminooxetanyl)methyl]chloro(1,1- 10 dioxido-2,3-dihydro-1,4-benzothiazepin-4(5 quinazolinamine; 2-{[2-(1,1-dioxido-2,3- dihydro-1,4-benzothiazepin-4(5 H)-yl)methylquinazolinyl]amino}ethanol; 2-(2,3-dihydro- 1,4-benzothiazepin-4(5 H)-yl)methylquinazolinamine; 2-(1,1-dioxido-2,3-dihydro-1,4- benzothiazepin-4(5 H)-yl)methylquinazolinamine; N~1~-[2-(1,1-dioxido-2,3-dihydro-1,4- benzothiazepin-4(5 methylquinazolinyl]methylpropane-1,2-diamine; N-[(3- 15 aminooxetanyl)methyl](1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5 H)-yl) quinazolinamine; N-[(1-aminocyclobutyl)methyl](1,1-dioxido-2,3-dihydro-1,4- benzothiazepin-4(5 H)-yl)methylquinazolinamine; N-{[3-(aminomethyl)oxetan yl]methyl}methyl(1-oxido-2,3-dihydro-1,4-benzothiazepin-4(5 H)-yl)quinazolinamine; (-)-N-{[3-(aminomethyl)oxetanyl]methyl}methyl[1-oxido-2,3-dihydro-1,4- 20 benzothiazepin-4(5 H)-yl]quinazolinamine; (+)-N-{[3-(aminomethyl)oxetanyl]methyl} methyl[1-oxido-2,3-dihydro-1,4-benzothiazepin-4(5 H)-yl]quinazolinamine; N~4~-[2-(1,1- dioxido-2,3-dihydro-1,4-benzothiazepin-4(5 methylquinazolinyl]fluorobutane-1,4- diamine; N~1~-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5 H)-yl)methylquinazolin yl]fluorobutane-1,4-diamine; N-{[3-(aminomethyl)oxetanyl]methyl}(2,3-dihydro-1,4- 25 benzothiazepin-4(5 H)-yl)methylquinazolinamine; trans fluoro[6-methyl(1-oxido- hydro-1,4-benzothiazepin-4(5 H)-yl)quinazolinyl]pyrrolidinamine; N-(Azetidinyl)- 6-methyl(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5 H)-yl) quinazolinamine; N-(2- {[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)methylquinolin yl]amino}ethyl)acetamide; N-{[3-({[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5 H)-yl) 30 quinolinyl]amino}methyl)oxetanyl]methyl}acetamide; N-(3-{[2-(1,1-dioxido-2,3- dihydro-1,4-benzothiazepin-4(5 H)-yl)methylquinolinyl]amino}propyl)acetamide; N-[2- (1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5 H)-yl)methylquinazolinyl]acetamide; 1- [2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5 H)-yl)methylquinolinyl] methylpyrrolidinamine; N-[(3-aminooxetanyl)methyl](9-methoxy-1,1-dioxido-2,3- 35 o-1,4-benzothiazepin-4(5 H)-yl)methylquinolinamine; 4-(4-{[(3-aminooxetan yl)methyl]amino}methylquinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepinol 1,1- dioxide; 3-{[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5 H)-yl)methylquinolin yl]amino}methylpropane-1,2-diol; 4-{[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5 H)- yl)methylquinolinyl]amino}butane-1,3-diol; N-[6-methyl(2-methyl-1,1-dioxido-2,3- dihydro-1,4-benzothiazepin-4(5 H)-yl)quinolinyl]ethane-1,2-diamine; N-[(3-aminooxetan yl)methyl]methyl(2-methyl-1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5 H)- yl)quinolinamine; N-[(3-{[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5 H)-yl) 5 methylquinolinyl]amino}oxetanyl)methyl]-2,2,2-trifluoroacetamide; N-[3- (aminomethyl)oxetanyl](1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5 H)-yl) methylquinolinamine; 2-(aminomethyl){[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin- 4(5 H)-yl)methylquinolinyl]amino}propane-1,3-diol; 4-amino[2-(1,1-dioxido-2,3- dihydro-1,4-benzothiazepin-4(5 H)-yl)methylquinolinyl]pyrrolidinone; 2-(1,1-dioxido- 10 2,3-dihydro-1,4-benzothiazepin-4(5 H)-yl)methyl-N-[2-(methylsulfinyl)ethyl]quinolin amine; N-{2-[(2-aminoethyl)sulfonyl]ethyl}(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin- 4(5 H)-yl)methylquinolinamine; N-[2-(1-iminooxido-1,2,3,5-tetrahydro-4H- 1lambda ~4~,4-benzothiazepinyl)methylquinolinyl]ethane-1,2-diamine; 2-(1,1-dioxido- 2,3-dihydro-1,4-benzothiazepin-4(5 H)-yl)methyl-N-[2-(S- 15 methylsulfonimidoyl)ethyl]quinolinamine; trans no[2-(1-iminooxido-1,2,3,5- ydro-4H-1lambda ~4~,4-benzothiazepinyl)methylquinolinyl]pyrrolidinol; trans -
1-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5 H)-yl)methylquinolinyl] fluoropyrrolidinamine; 1-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5 H)-yl) methylquinolinyl]pyrrolidinecarboxamide; N-[2-(1,1-dioxido-2,3-dihydro-1,4- 20 benzothiazepin-4(5 H)-yl)(methylsulfinyl)quinolinyl]propane-1,3-diamine; 4-[(3- aminopropyl)amino](1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5 H)-yl)quinoline carboxamide; (3-aminopropyl)amino](1,1-dioxido-2,3-dihydro-1,4-benzothiazepin- 4(5 H)-yl)quinolinyl}ethanol; 3-{[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5 H)-yl) methylquinolinyl]amino}propanenitrile; 2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin- 25 4(5 H)-yl)methyl-N-[2-(1 H-tetrazolyl)ethyl]quinolinamine; N~4~-(2-aminoethyl)(1,1- dioxido-2,3-dihydro-1,4-benzothiazepin-4(5 H)-yl)quinoline-4,6-diamine; 1,1-dioxido-2,3- dihydro-1,4-benzothiazepin-4(5 H)-yl)methylquinolinyl]oxa-5,7-diazaspiro[3.4]octan one; 3-{[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5 H)-yl)methylquinazolin no}propane-1,2-diol; 3-{[6-chloro(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5 H)- 30 yl)quinazolinyl]amino}propane-1,2-diol; 2,3-dihydro-1,4-benzothiazepin-4(5 H)-yl) methylquinazolinyl]ethane-1,2-diamine; N-[6-methyl(1-oxido-2,3-dihydro-1,4- hiazepin-4(5 H)-yl)quinazolinyl]ethane-1,2-diamine; N-[2-(1,1-dioxido-2,3-dihydro- 1,4-benzothiazepin-4(5 H)-yl)methylquinazolinyl]ethane-1,2-diamine; N-[3- (aminomethyl)oxetanyl]methyl(1-oxido-2,3-dihydro-1,4-benzothiazepin-4(5 H)- 35 yl)quinazolinamine; N-(trans fluoropyrrolidinyl)methyl(1-oxido-2,3-dihydro-1,4- benzothiazepin-4(5 H)-yl)quinazolinamine; N-(trans fluoropyrrolidinyl)methyl(1,1- dioxido-2,3-dihydro-1,4-benzothiazepin-4(5 H)-yl)quinazolinamine; 1-[6-methyl(1-oxido- hydro-1,4-benzothiazepin-4(5 H)-yl)quinazolinyl]pyrrolidinamine; N-(azetidinyl)- 6-methyl(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5 H)-yl)quinazolinamine; (4R ) {2-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5 H)-yl)methylquinolinyl]ethyl}-4,5- dihydro-1,3-oxazolamine; 3-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5 ethylquinolinyl]propanoic acid; 3-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5 H)-yl)- 5 6-methylquinolinyl]propanamine; 2-{[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin- 4(5 H)-yl)methylquinolinyl]oxy}ethanamine; 4-[6-methyl(pyrrolidinyloxy)quinolin- 2-yl]-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide; 4-[6-methyl(piperidin quinolinyl]-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide; 4-(4,6- ylquinolinyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide; [2-(1,1-dioxido-2,3- 10 o-1,4-benzothiazepin-4(5 H)-yl)methylquinolinyl](piperidinyl)methanone; 4-[6- methyl(1 H-pyrazolyl)quinolinyl]-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide; 4- [6-methyl(phenylsulfonyl)quinolinyl]-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide; N-(2-aminoethyl)(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5 H)-yl)methylquinoline- 4-sulfonamide; methyl 4-({[3-(aminomethyl)oxetanyl]methyl}amino)(1,1-dioxido-2,3- 15 dihydro-1,4-benzothiazepin-4(5 H)-yl)quinolinecarboxylate; 4-({[3-(aminomethyl)oxetan yl]methyl}amino)(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5 H)-yl)quinoline ylic acid; 3-(aminomethyl)oxetanyl]methyl}amino)(1,1-dioxido-2,3-dihydro- 1,4-benzothiazepin-4(5 H)-yl)quinolinyl]methanol; N-{[3-(aminomethyl)oxetanyl]methyl}- 6-(~2~ H_3_)methyl(1-oxido-2,3-dihydro-1,4-benzothiazepin-4(5 H)-yl)quinazolinamine; 20 4-({[3-(aminomethyl)oxetanyl]methyl}amino)(1,1-dioxido-2,3-dihydro-1,4- hiazepin-4(5 H)-yl)quinazolinecarboxylic acid; -(aminomethyl)oxetan yl]methyl}amino)(1-oxido-2,3-dihydro-1,4-benzothiazepin-4(5 H)-yl)quinazoline carboxylic acid; [4-({[3-(aminomethyl)oxetanyl]methyl}amino)(1-oxido-2,3-dihydro-1,4- benzothiazepin-4(5 H)-yl)quinazolinyl]methanol; [4-({[3-(aminomethyl)oxetan 25 yl]methyl}amino)(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5 H)-yl)quinazolin yl]methanol; N-[(1-aminocyclopropyl)methyl](1,1-dioxido-2,3-dihydro-1,4-benzothiazepin- 4(5 H)-yl)methylquinazolinamine; and 2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin- 4(5 H)-yl)methyl-N-(pyrrolidinyl)quinazolinamine. 13. A compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein 30 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, C1-6alkoxy or carboxy; R7 is hydrogen, halogen, C1-6alkoxy, C1-6alkylaminocarbonyl, diC1-6 alkylaminocarbonyl or C1-6alkylsulfonyl; R8 is hydrogen or halogen; R9 is hydrogen or =O; 5 R10 is hydrogen or =O, provided that R9 and R10 are not =O simultaneously; A is -C-R11, wherein R11 is hydrogen, n, C1-6alkyl, C1-6alkoxy, trifluoromethyl, trifluoromethoxy, pyridinyloxy, difluoromethoxy or C 1-6alkylsulfonyl; X is -CH2-, -O-, –NH-, -CF2, -C(CH3)(OH)-, C=O, or -C(=N-C1-6alkoxy)-; Y is -CH- or nitrogen; 10 Q is hydrogen; halogen; C1-6alkyl, 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-1,3-oxazolylethyl; or NR12R13, wherein one of R12 and R13 is hydrogen, C1-6alkyl or hydroxy(CH2)2-, and the other one is ino(CH2)2-6; 3- aminomethyl-1,1-dioxidothietanylmethyl; 3-amino-1,1-dioxidothietanylmethyl; 3- 15 (aminomethyl)thietanylmethyl; amino(CH2)2O-(CH2)2-6; amino(CH2)2-10; amino(CH2)1-6carbonyl; amino(CH2)1-6difluoromethyl(CH2)1-6; amino(CH2)1- 6oxetanyl(CH2)1-6; amino(CH2)2-6sulfonyl(CH2)2-6; 3-aminocyclohexyl; 4- aminocyclohexyl; 2-amino-4,5-dihydro-oxazolyl(CH2)1-6; aminooxetanyl(CH2)1-6; C1- 6alkylamino(CH2)2-6; C1-6alkylaminocarbonyl; diC1-6alkylamino(CH2)2-6; hydroxy(CH2)2-6; -C1-6alkyl C R15 20 zinyl(CH2)2-6; pyrrolidinyl; or R16 , wherein R14 is en, C1-6alkyl or hydroxy(CH2)1-6; R15 is y, hydroxy(CH2)1-6 or amino; and R16 is C1-6alkyl, hydroxy(CH2)1-6 or amino(CH2)1-6; R12 and R13, with the nitrogen atom to which they are attached, may form a pyrrolidinyl, piperazinyl or diazepanyl ring; which may be tituted, once or twice tuted by a 25 group selected from C1-6alkyl, amino or hydroxy. 14. A compound according to claim 13 or a pharmaceutically acceptable salt f, n 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; 5 R8 is hydrogen or chloro. A is CR11, wherein R11 is hydrogen, fluoro, , bromo, methyl, methoxy, trifluoromethyl, trifluoromethoxy, pyridinyloxy, difluoromethoxy or methylsulfonyl; Q is hydrogen; chloro; hydroxymethyl; hydroxymethyl(hydroxy)ethyl; aminoethylaminosulfonyl; 2-amino-4,5-dihydro-1,3-oxazolylethyl; or NR12R13, 10 wherein one of R12 and R13 is hydrogen, methyl or hydroxyethyl;and the other one is aminobutyl; 3-aminocyclohexyl; ocyclohexyl; 2-amino-4,5-dihydro-oxazol ylmethyl; 3-amino-1,1-dioxidothietanylmethyl; aminoethoxyethyl; aminoethyl; aminoethylsulfonylethyl; aminomethylcarbonyl; aminomethyldifluoromethylmethyl; 3- aminomethyl-1,1-dioxidothietanylmethyl; 3-(aminomethyl)thietanylmethyl; 15 aminomethyloxetanylmethyl; aminooxetanylmethyl; ropyl; dimethylaminoethyl; ethylaminocarbonyl; guanidinoethyl; hydroxyethyl; hydroxypropyl; methylaminoethyl; piperazinylethyl; pyrrolidinyl; -C1-6alkyl C R15 or R16 , wherein R14 is en, methyl or hydroxymethyl; R15 is hydroxy, hydroxymethyl or amino; and R16 is methyl, hydroxymethyl or aminomethyl;R12 and R13, 20 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 25 N-[(3-aminooxetanyl)methyl](5,5-difluoro-1,3,4,5-tetrahydro-2Hbenzazepinyl) methylquinolinamine; N-[2-(2-aminoethoxy)ethyl](5,5-difluoro-1,3,4,5-tetrahydro-2H benzazepinyl)methylquinolinamine; N-[2-(5,5-difluoro-1,3,4,5-tetrahydro-2H epinyl)methylquinolinyl]-N'-methylethane-1,2-diamine; 1-amino{[2-(5,5- ro-1,3,4,5-tetrahydro-2Hbenzazepinyl)methylquinolinyl]amino}propanol; 3- 30 {[2-(5,5-difluoro-1,3,4,5-tetrahydro-2Hbenzazepinyl)methylquinolin no}propane-1,2-diol; 3-{[2-(5,5-difluoro-1,3,4,5-tetrahydro-2Hbenzazepinyl) methylquinolinyl]amino}propanol; 2-(5,5-difluoro-1,3,4,5-tetrahydro-2Hbenzazepin yl)methyl-N-[2-(piperazinyl)ethyl]quinolinamine; N~1~-[2-(5,5-difluoro-1,3,4,5- tetrahydro-2Hbenzazepinyl)methylquinolinyl]propane-1,2-diamine; cis (5,5- difluoro-1,3,4,5-tetrahydro-2Hbenzazepinyl)methylquinolinyl]cyclohexane-1,4- 5 diamine; 2-(9,9-difluoro-6,7,8,9-tetrahydro-5H-benzo[7]annulenyl)methyl-N-(pyrrolidin yl)quinolinamine; 2,2'-{[2-(5,5-difluoro-1,3,4,5-tetrahydro-2Hbenzazepinyl) methylquinolinyl]imino}diethanol; N~1~-[2-(5,5-difluoro-1,3,4,5-tetrahydro-2H benzazepinyl)methylquinolinyl]methylpropane-1,2-diamine; 5,5-difluoro[6- methyl(4-methylpiperazinyl)quinolinyl]-2,3,4,5-tetrahydro-1Hbenzazepine; 1-[2- 10 (9,9-difluoro-6,7,8,9-tetrahydro-5H-benzo[7]annulenyl)methylquinolinyl]ethylurea; N-{[3-(aminomethyl)oxetanyl]methyl}(5,5-difluoro-1,3,4,5-tetrahydro-2Hbenzazepin- 2-yl)methylquinolinamine; fluoro[6-methyl(piperazinyl)quinolinyl]- 2,3,4,5-tetrahydro-1Hbenzazepine; 2-[4-(1,4-diazepanyl)methylquinolinyl]-5,5- difluoro-2,3,4,5-tetrahydro-1Hbenzazepine; N-[2-(5,5-difluoro-1,3,4,5-tetrahydro-2H 15 benzazepinyl)methylquinolinyl]-N-methylethane-1,2-diamine; 1-[2-(5,5-difluoro- 1,3,4,5-tetrahydro-2Hbenzazepinyl)methylquinolinyl]pyrrolidinamine; 2-{[2-(5,5- difluoro-1,3,4,5-tetrahydro-2Hbenzazepinyl)methylquinolinyl]amino}ethanol; N-[2- (5,5-difluoro-1,3,4,5-tetrahydro-2Hbenzazepinyl)methylquinolinyl]ethane-1,2- e; N-[2-(5,5-difluoro-1,3,4,5-tetrahydro-2Hbenzazepinyl)methylquinolin 20 yl]cyclohexane-1,3-diamine; (5,5-difluoro-1,3,4,5-tetrahydro-2Hbenzazepinyl) methylquinolinyl]-N,N-dimethylethane-1,2-diamine; N-[2-(5,5-difluoro-1,3,4,5-tetrahydro- 2Hbenzazepinyl)methylquinolinyl]propane-1,3-diamine; N-[2-(5,5-difluoro-1,3,4,5- tetrahydro-2Hbenzazepinyl)methylquinolinyl]butane-1,4-diamine; trans amino [2-(5,5-difluoro-1,3,4,5-tetrahydro-2Hbenzazepinyl)methylquinolinyl]pyrrolidinol; 25 N-{[3-(aminomethyl)-1,1-dioxidothietanyl]methyl}(5,5-difluoro-1,3,4,5-tetrahydro-2H epinyl)methylquinolinamine; N-{2-[(2-aminoethyl)sulfonyl]ethyl}(5,5- difluoro-1,3,4,5-tetrahydro-2Hbenzazepinyl)methylquinolinamine; N-{[3- methyl)thietanyl]methyl}(5,5-difluoro-1,3,4,5-tetrahydro-2Hbenzazepinyl) methylquinazolinamine; N-{[3-(aminomethyl)oxetanyl]methyl}(5,5-difluoro-1,3,4,5- 30 tetrahydro-2Hbenzazepinyl)methylquinazolinamine; 2-(aminomethyl)({[2-(5,5- difluoro-1,3,4,5-tetrahydro-2Hbenzazepinyl)methylquinazolin yl]amino}methyl)propane-1,3-diol; 2-(4-{[(3-aminooxetanyl)methyl]amino} methylquinazolinyl)methyl-2,3,4,5-tetrahydro-1Hbenzazepinol; N-[(3-aminooxetan- 3-yl)methyl](5,5-difluoro-1,3,4,5-tetrahydro-2Hbenzazepinyl)methylquinazolin 35 amine; N-[(3-amino-1,1-dioxidothietanyl)methyl](5,5-difluoro-1,3,4,5-tetrahydro-2H benzazepinyl)methylquinazolinamine; N-[2-(5,5-difluoro-1,3,4,5-tetrahydro-2H benzazepinyl)methylquinazolinyl]-2,2-difluoropropane-1,3-diamine; N-[2-(7-bromo- 1,3,4,5-tetrahydro-2Hbenzazepinyl)chloroquinolinyl]ethane-1,2-diamine; 2-{4-[(2- aminoethyl)amino]quinolinyl}-2,3,4,5-tetrahydro-1Hbenzazepinol; N-[6-methyl (1,3,4,5-tetrahydro-2Hbenzazepinyl)quinolinyl]ethane-1,2-diamine; N-[2-(8-fluoro- 1,3,4,5-tetrahydro-2Hbenzazepinyl)methylquinolinyl]ethane-1,2-diamine; N-[6- chloro(1,3,4,5-tetrahydro-2Hbenzazepinyl)quinolinyl]ethane-1,2-diamine; N-[6- 5 chloro(9-fluoro-1,3,4,5-tetrahydro-2Hbenzazepinyl)quinolinyl]ethane-1,2-diamine; N-[2-(8-fluoro-1,3,4,5-tetrahydro-2Hbenzazepinyl)quinolinyl]ethane-1,2-diamine; 1- amino{[2-(1,3,4,5-tetrahydro-2Hbenzazepinyl)quinolinyl]amino}propanol trifluoroacetate; N-[2-(1,3,4,5-tetrahydro-2Hbenzazepinyl)quinolinyl]ethane-1,2- diamine; N-[6-bromo(1,3,4,5-tetrahydro-2Hbenzazepinyl)quinolinyl]ethane-1,2- 10 diamine; N-[6-methoxy(1,3,4,5-tetrahydro-2Hbenzazepinyl)quinolinyl]ethane-1,2- diamine; N-[2-(6-chloro-1,3,4,5-tetrahydro-2Hbenzazepinyl)quinolinyl]ethane-1,2- diamine; N-[2-(7-fluoro-1,3,4,5-tetrahydro-2Hbenzazepinyl)methylquinolin yl]ethane-1,2-diamine; N-methyl-N'-[2-(1,3,4,5-tetrahydro-2Hbenzazepinyl)quinolin ane-1,2-diamine; N-[2-(7-methoxy-1,3,4,5-tetrahydro-2Hbenzazepinyl)quinolin 15 yl]ethane-1,2-diamine; N-[2-(7-fluoro-1,3,4,5-tetrahydro-2Hbenzazepinyl)quinolin yl]ethane-1,2-diamine; N-[2-(8-methoxy-1,3,4,5-tetrahydro-2Hbenzazepinyl)quinolin yl]ethane-1,2-diamine; N-[6-(difluoromethoxy)(1,3,4,5-tetrahydro-2Hbenzazepin yl)quinolinyl]ethane-1,2-diamine; N-[2-(1,3,4,5-tetrahydro-2Hbenzazepinyl) (trifluoromethyl)quinolinyl]ethane-1,2-diamine; N-[8-chloro(1,3,4,5-tetrahydro-2H 20 benzazepinyl)quinolinyl]ethane-1,2-diamine; N-[6-fluoro(1,3,4,5-tetrahydro-2H epinyl)quinolinyl]ethane-1,2-diamine; N,N-dimethyl-N'-[2-(1,3,4,5-tetrahydro-2H- 2-benzazepinyl)quinolinyl]ethane-1,2-diamine; N-[2-(1,3,4,5-tetrahydro-2Hbenzazepin- 2-yl)(trifluoromethoxy)quinolinyl]ethane-1,2-diamine; N-[6-(methylsulfonyl)(1,3,4,5- tetrahydro-2Hbenzazepinyl)quinolinyl]ethane-1,2-diamine; 2-{4-[(2- 25 thyl)amino]quinolinyl}-2,3,4,5-tetrahydro-1Hbenzazepinecarboxylic acid; 2-(4- chloroquinolinyl)-2,3,4,5-tetrahydro-1Hbenzazepine; N-[5-chloro(1,3,4,5-tetrahydro- 2Hbenzazepinyl)quinolinyl]ethane-1,2-diamine; 7-(methylsulfonyl)-1,3,4,5- tetrahydro-2Hbenzazepinyl]quinolinyl}ethane-1,2-diamine; N-{2-[7-(ethylsulfonyl)- 1,3,4,5-tetrahydro-2Hbenzazepinyl]quinolinyl}ethane-1,2-diamine; N-[2-(8-ethoxy- 30 1,3,4,5-tetrahydro-2Hbenzazepinyl)quinolinyl]ethane-1,2-diamine; pyridin yloxy)(1,3,4,5-tetrahydro-2Hbenzazepinyl)quinolinyl]ethane-1,2-diamine; 2-{4-[(2- aminoethyl)amino]chloroquinolinyl}-N,N-dimethyl-2,3,4,5-tetrahydro-1Hbenzazepine- oxamide; 2-{4-[(2-aminoethyl)amino]quinolinyl}bromo-1,2,4,5-tetrahydro-3H benzazepinone; 1-(2-{[2-(1,3,4,5-tetrahydro-2Hbenzazepinyl)quinolin 35 yl]amino}ethyl)guanidine trifluoroacetate; N-[(2-amino-4,5-dihydro-1,3-oxazolyl)methyl] (1,3,4,5-tetrahydro-2Hbenzazepinyl)quinolinamine trifluoroacetate; N-[(2-amino-4,5- dihydro-1,3-oxazolyl)methyl]chloro(1,3,4,5-tetrahydro-2Hbenzazepinyl)quinolin- 4-amine; N-[2-(1,3,4,5-tetrahydro-2Hbenzazepinyl)quinolinyl]glycinamide; 3-[2- (1,3,4,5-tetrahydro-2Hbenzazepinyl)quinolinyl]propanamine; [2-(1,3,4,5-tetrahydro- 2Hbenzazepinyl)quinolinyl]methanol; 2-(6-chloroquinolinyl)-2,3,4,5-tetrahydro-1H-
2-benzazepine;
3-[6-chloro(1,3,4,5-tetrahydro-2Hbenzazepinyl)quinolinyl]propane- 1,2-diol; (4S ){2-[2-(1,3,4,5-tetrahydro-2Hbenzazepinyl)quinolinyl]ethyl}-4,5- 5 dihydro-1,3-oxazolamine; N-(2-aminoethyl)(1,3,4,5-tetrahydro-2Hbenzazepin yl)quinolinesulfonamide trifluoroacetate; (2-aminoethyl)amino]methylquinolin yl}-1,3,4,5-tetrahydro-2H-1,
4-benzodiazepinone; N-[6-methyl(1,2,3,
5-tetrahydro-4H-1,4- benzodiazepinyl)quinolinyl]ethane-1,2-diamine; N-[2-(2,3-dihydro-1,4-benzoxazepin- 4(5 H)-yl)quinolinyl]ethane-1,2-diamine; N-[(3-aminooxetanyl)methyl][(5 E) 10 xyimino)-1,3,4,5-tetrahydro-2Hbenzazepinyl]methylquinolinamine and 2-(4- {[(3-aminooxetanyl)methyl]amino}methylquinazolinyl)-1,2,3,4-tetrahydro-5H benzazepinone. 16. A compound according to any one of claims 1 to 15 for use as a therapeutically active substance. 15 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 ing to any one of claims 1 to 15 for the preparation of a medicament for the treatment or laxis of respiratory syncytial virus infection. 19. A compound according to any one of claims 1 to 15 for the treatment or prophylaxis of 20 atory syncytial virus infection. 20. A pharmaceutical composition according to claim 17 substantially as herein described with reference to any example thereof. 21. A use according to claim 18 substantially as herein described with reference to any e thereof.
NZ620079A 2011-08-11 2012-08-08 Compounds for the treatment and prophylaxis of respiratory syncytial virus disease NZ620079B2 (en)

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CNPCT/CN2011/078258 2011-08-11
CN2011078258 2011-08-11
CN2012078439 2012-07-10
CNPCT/CN2012/078439 2012-07-10
PCT/EP2012/065499 WO2013020993A1 (en) 2011-08-11 2012-08-08 Compounds for the treatment and prophylaxis of respiratory syncytial virus disease

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