NZ732796B2 - Benzazepine dicarboxamide compounds - Google Patents

Benzazepine dicarboxamide compounds Download PDF

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NZ732796B2
NZ732796B2 NZ732796A NZ73279616A NZ732796B2 NZ 732796 B2 NZ732796 B2 NZ 732796B2 NZ 732796 A NZ732796 A NZ 732796A NZ 73279616 A NZ73279616 A NZ 73279616A NZ 732796 B2 NZ732796 B2 NZ 732796B2
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amino
dicarboxamide
c1alkyl
dipropyl
c1alkoxy
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NZ732796A
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NZ732796A (en
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Sabine Hoves
Lisha Wang
Hongying Yun
Weixing Zhang
Wei Zhu
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F Hoffmann La Roche Ag
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Priority claimed from PCT/EP2016/054487 external-priority patent/WO2016142250A1/en
Publication of NZ732796A publication Critical patent/NZ732796A/en
Publication of NZ732796B2 publication Critical patent/NZ732796B2/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • 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
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    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61P35/04—Antineoplastic agents specific for metastasis
    • A—HUMAN NECESSITIES
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    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61P37/00—Drugs for immunological or allergic disorders
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    • A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C229/00—Compounds containing amino and carboxyl groups bound to the same carbon skeleton
    • C07C229/02—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton
    • C07C229/34—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton containing six-membered aromatic rings
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    • C07D223/00—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom
    • C07D223/14—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
    • C07D223/16—Benzazepines; Hydrogenated benzazepines
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    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
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    • 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
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    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
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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
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
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    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
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    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Abstract

This invention relates to novel benzazepine dicarboxamide compounds of the formula (I), wherein R1 to R4 are as defined in the description and in the claims, as well as pharmaceutically acceptable salts thereof. These compounds are TLR agonists and may therefore be useful as medicaments for the treatment of diseases such as cancer, autoimmune diseases, inflammation, sepsis, allergy, asthma, graft rejection, graft- versus-host disease, immunodeficiencies, and infectious diseases.

Description

Benzazepine Dicarboxamide Compounds FIELD OF THE INVENTION The present invention s to novel epine dicarboxamide compounds having pharmaceutical activity, their manufacture, pharmaceutical compositions containing them and their ial use as medicaments.
In particular, the present invention relates to compounds of the formula wherein R1 to R4 are as described below, or to pharmaceutically acceptable salts thereof.
The compounds are TLR agonists. More particularly, the compounds are TLR8 ts and may be useful for the treatment and prevention (e.g. vaccination) of cancer, autoimmune diseases, inflammation, , allergy, asthma, graft rejection, versus-host e, immunodeficiencies, and infectious diseases.
Toll-like receptors (TLRs) are a family of membrane-spanning receptors that are expressed on cells of the immune system like dendritic cells, macrophages, monocytes, T cells, B cells, NK cells and mast cells but also on a variety of non-immune cells such as endothelial cells, epithelial cells and even tumor cells (Kawai et al., Immunity, 2011, 34, 637-650, Kawai et al., Nat.
Immunol., 2010, 11, 373-384). TLRs that recognize ial and fungal components are expressed on the cell e (i.e. TLR1, 2, 4, 5 and 6), while others that recognize viral or microbial nucleic acids like TLR3, 7, 8 and 9 are localized to the endolysosomal / phagosomal compartment (Henessy et al. Nat. Rev. Drug Discovery 2010, 9, 293-307) and predominantly found to be expressed by cells of the d lineage. TLR ligantion leads to activation of NF- κB and IRF-dependent pathways with the specific activation sequence and response with respect to the specific TLR and cell type. While TLR7 is mainly expressed in all dendritic cells subtypes (DC and here highly in pDC, plasmacytoid DC) and can be induced in B cells upon IFNα stimulation (Bekeredjian-Ding et al. J. Immunology 2005, 174:4043-4050), TLR8 expression is rather restricted to monocytes , macrophages and myeloid DC. TLR8 signaling via MyD88 can be activated by ial single stranded RNA, small le agonists and lately discovered microRNAs (Chen et al. RNA 2013, 19:737-739). The activation of TLR8 results in the production of various pro-inflammatory cytokines such as IL-6, IL-12 and TNF-α as well as ed expression of co-stimulatory molecules, such as CD80, CD86, and chemokine receptors (Cros et al. Immunity 2010, 33:375-386). In addition, TLR8 activation can induce type I interferon (IFNβ) in primary human monocytes (Pang et al. BMC Immunology 2011, 12:55).
Small molecule agonists for both the TLR7 and TLR8 receptor as well as analogs modified for use as vaccine adjuvants or conjugates have been identified in many patents (i.e.
WO1992015582, WO2007024612, WO2009111337, WO2010093436, WO2011017611, WO2011068233, WO2011139348, WO2012066336, WO2012167081, WO2013033345, WO2013166110, and US2013202629). Clinical ence has been obtained mainly for TLR7 agonists, but only very few clinical studies focused on using highly specific TLR8 agonists. To date, the only FDA (U.S. Food and Drug Administration)-approved small le drug is the TLR7 agonist imiquimod (ALDARA™) as a l agent for the treatment of genital warts, superficial basal cell oma and actinic keratosis. Systemic application however of the early TLR7 ts like imod has been abandoned due to intolerable cardiotoxicity observed upon global chemokine stimulation at therapeutic levels (Holldack, Drug Discovery Today, 2013, 1-4). Knowledge about TLR8 agonists is less advanced and mostly restricted to data with early mixed TLR7/8 agonists like resiquimod. For the resiquimod t, however, the stimulatory capacity of the TLR7 is or compared to the activation of the TLR8, so that most of the effects of resiquimod are dominated by the effect of TLR7 activity. More recently, TLR8 specific compounds like VTX-2337 have been described by VentiRX Pharmaceuticals (i.e. WO 2007024612), allowing for the first time to analyse the specific role of TLR8 without activation of TLR7 at the same time. At present there is still a need for small molecule TLR8 agonists, specifically those with improved potency or selectivity.
The present invention is directed to benzazepines with improved ar potency over known TLR8 ts of this type for use in the treatment of cancer, preferably solid tumors and mas, and for other uses including the treatment of certain skin conditions or diseases, such as atopic dermatitis, the treatment of infectious diseases, preferably viral diseases, and for use as adjuvants in vaccines formulated for use in cancer therapy or by desensitizing of the receptors by continuous stimulation in the treatment of autoimmune diseases.
Of note, these new compounds have ed cellular potency at TLR8 compared to known TLR8 ts such as VTX-2337. In addition these compounds are highly specific towards TLR8 and possess only low or even no activity towards TLR7. Thus, they are ed to possess advantageous properties compared to combined TLR7/8 agonists due to the more restricted expression pattern of TLR8 resulting in less servere side effects when administered ically; and/or to at least e the public with a useful choice.
SUMMARY OF THE INVENTION The present invention provides a compound of the formula N 4 R I N R2 R wherein R1 is C3alkyl, R2 is selected from the group consisting of C1alkyl, hydroxy-C1alkyl, C2alkenyl, C3 alkynyl, amino-C1alkoxy-C1alkyl, amino-C1alkoxy-C1alkoxy-C1alkyl, n- C1alkyl, C3cycloalkyl-C1alkyl and phenyl-C1alkyl, wherein phenyl is unsubstituted or substituted by amino-C1alkyl; R3 is hydrogen; R4 is selected from the group consisting of phenyl, said phenyl being unsubstituted or substituted by one or two groups selected from the group consisting of C1alkyl, halogen, halogen-C1alkyl, C1alkoxy, hydroxy-C1 alkyl, amino-C1alkyl, C1alkyl-amino-C1alkyl, di-C1alkyl-amino-C1alkyl, amino- lkenyl, C1alkyl-amino-C2alkenyl, di-C1alkyl-amino-C2alkenyl, amino-C2 l, C1alkyl-amino-C2alkynyl, 7-alkyl-amino-C2alkynyl, benzyloxycarbonylamino-C1alkyl, amino-C1alkoxy, amino-C1alkoxy-C1alkoxy, amino-C1alkoxy-C1alkyl, amino-C1alkoxy-C1alkoxy-C1alkyl, C1alkylsulfonyl, heterocyclylcarbonyl and phenyl-C1alkyl, wherein phenyl is unsubstituted or substituted by C1alkoxy or C1alkyl, or heteroaryl, said heteroaryl being a 5- or 6-membered aromatic ring containing one, two or three heteroatoms selected from N, O or S selected from the group consisting of imidazolyl, pyrazolyl, oxazolyl, thiazolyl, pyridyl, pyridazinyl and dinyl and being unsubstituted or tuted by one or two groups selected from the group consisting of C1alkyl, halogen, halogen-C1alkyl, C1alkoxy, hydroxy-C1alkyl, amino-C1alkyl, C1alkylamino-C1alkyl , 7-alkyl-amino-C1alkyl, amino-C2alkenyl, C1alkyl-amino-C2- 7-alkenyl, di-C1alkyl-amino-C2alkenyl, amino-C2alkynyl, C1alkyl-amino-C2 alkynyl, di-C1alkyl-amino-C2alkynyl, benzyloxycarbonylamino-C1alkyl, amino-C1- 7-alkoxy, amino-C1alkoxy-C1alkoxy, amino-C1alkoxy-C1alkyl, amino-C1 alkoxy-C1alkoxy-C1alkyl, C1alkylsulfonyl, heterocyclylcarbonyl and phenyl-C1 alkyl, wherein phenyl is unsubstituted or substituted by C1alkoxy or C1alkyl, or pharmaceutically acceptable salts thereof.
The present invention also provides a compound of a I of the present invention for use as medicament.
The present ion also provides a compound of formula I of the present invention for use as medicament for the treatment of diseases which can be mediated with TLR agonists, selected from the group consisting of cancer, autoimmune diseases, inflammation, sepsis, allergy, asthma, graft rejection, graft-versus-host disease, deficiencies, and infectious diseases.
The present invention also provides a pharmaceutical composition comprising a compound of formula I of the present invention and a pharmaceutically acceptable carrier and/or adjuvant.
The present invention also relates to the use of a compound of formula I of the present invention for the preparation of a medicament for the treatment of diseases which can be ed with TLR agonists.
The t invention also provides a process for the manufacture of a nd of formula I of the present invention, which process comprises a) ng a compound of the formula II PGHN N COOH N 2 R , wherein R1 and R2 are as defined above and PG is a protecting group, with a compound of the formula III HN III R , wherein R3 and R4 are as defined above, under basic conditions in the presence of a coupling agent and removing the protecting group PG under acidic conditions to obtain a compound of the formula I N 4 R I N R2 R , wherein R1 to R4 are as defined above, and, if desired, converting the compound obtained into a pharmaceutically able salt.
Described are epinecarboxamide compounds of the formula N 4 R I N R2 wherein R1 is C3alkyl or C3cycloalkyl, R2 is selected from the group consisting of lkyl, hydroxy-C1alkyl, C2alkenyl, C3 alkynyl, amino-C1alkoxy-C1alkyl, amino-C1alkoxy-C1alkoxy-C1alkyl, halogen- C1alkyl, C3cycloalkyl-C1alkyl and phenyl-C1alkyl, n phenyl is unsubstituted or substituted by amino-C1alkyl; R3 is hydrogen; R4 is selected from the group consisting of phenyl, said phenyl being unsubstituted or substituted by one or two groups selected from the group consisting of C1alkyl, halogen, halogen-C1alkyl, C1alkoxy, hydroxy-C1 alkyl, amino-C1alkyl, C1alkyl-amino-C1alkyl, di-C1alkyl-amino-C1alkyl, amino- C2alkenyl, C1alkyl-amino-C2alkenyl, di-C1alkyl-amino-C2alkenyl, C2 alkynyl, C1alkyl-amino-C2alkynyl, di-C1alkyl-amino-C2alkynyl, benzyloxycarbonylamino-C1alkyl, amino-C1alkoxy, amino-C1alkoxy-C1alkoxy, amino-C1alkoxy-C1alkyl, amino-C1alkoxy-C1alkoxy-C1alkyl, C1alkylsulfonyl heterocyclylcarbonyl and phenyl-C1alkyl, wherein phenyl is unsubstituted or substituted by C1alkoxy or amino-C1alkyl, or heteroaryl, said heteroaryl being a 5- or 6-membered aromatic ring containing one, two or three heteroatoms selected from N, O or S and being unsubstituted or tuted by one or two groups ed from the group consisting of C1alkyl, halogen, halogen-C1alkyl, C1alkoxy, hydroxy-C1alkyl, C1alkyl, C1alkyl-amino-C1alkyl, di-C1 alkyl-amino-C1alkyl, C2alkenyl, C1alkyl-amino-C2alkenyl, di-C1alkylamino-C2alkenyl , amino-C2alkynyl, C1alkyl-amino-C2alkynyl, di-C1alkylamino-C2alkynyl , oxycarbonylamino-C1alkyl, C1alkoxy, amino-C1 alkoxy-C1alkoxy, amino-C1alkoxy-C1alkyl, amino-C1alkoxy-C1alkoxy-C1 alkyl, C1alkylsulfonyl heterocyclylcarbonyl and phenyl-C1alkyl, wherein phenyl is unsubstituted or substituted by C1alkoxy or C1alkyl, or ceutically acceptable salts thereof.
Also described are processes for the manufacture of compounds of formula I.
Also described are pharmaceutical compositions comprising a compound of formula I as described above and a pharmaceutically acceptable carrier and/or adjuvant.
Also described is the use of compounds of formula I as therapeutic active substances for the treatment of diseases that can be ed with TLR agonists, in particular TLR8 agonists.
Also described is a method for the treatment of a disease that can be mediated with TLR agonists such as for example cancer and autoimmune or infectious es.
In the description in this specification reference may be made to subject matter which is not within the scope of the appended claims. That subject matter should be y identifiable by a person skilled in the art and may assist in putting into practice the ion as defined in the appended claims.
DETAILED DESCRIPTION OF THE INVENTION Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ry skill in the art to which this invention s. Furthermore, the ing definitions are set forth to illustrate and define the meaning and scope of the s terms used to describe the invention.
The nomenclature used in this application is based on IUPAC systematic nomenclature, unless indicated otherwise.
The term "compound(s) of this invention" and "compound(s) of the present invention" refers to compounds of formula I and solvates or salts thereof (e.g., pharmaceutically acceptable salts).
The term "substituent" denotes an atom or a group of atoms replacing a hydrogen atom on the parent molecule.
The term "halogen" refers to fluoro, chloro, bromo and iodo, with fluoro, chloro and bromo being of particular interest. More ularly, halogen refers to fluoro.
The term "alkyl", alone or in combination with other groups, refers to a branched or straight-chain monovalent saturated aliphatic hydrocarbon radical of one to twenty carbon atoms, particularly one to sixteen carbon atoms, more particularly one to ten carbon atoms. More particularly, the term "alkyl" also embraces lower alkyl groups as described below.
The term "lower alkyl" or "C1alkyl", alone or in combination, signifies a straight-chain or branched-chain alkyl group with 1 to 7 carbon atoms, in particular a straight or branchedchain alkyl group with 1 to 6 carbon atoms and more particularly a straight or branched-chain alkyl group with 1 to 4 carbon atoms. Examples of straight-chain and branched C1-7 alkyl groups are methyl, ethyl, propyl, isopropyl, butyl, isobutyl, utyl, the isomeric pentyls, the isomeric hexyls and the isomeric heptyls, in particular methyl and ethyl. The term "C2alkyl" refers to a straight-chain or branched-chain alkyl group with 2 to 7 carbon atoms as defined above, r the methyl or methylene group is excluded.
The term "lower l" or "C2alkenyl" signifies a straight-chain or branched chain hydrocarbon e comprising an olefinic bond and 2 to 7, ably 3 to 6, particularly preferred 3 to 4 carbon atoms. Examples of alkenyl groups are ethenyl, 1-propenyl, 2-propenyl, isopropenyl, 1-butenyl, nyl, 3-butenyl and isobutenyl, in particular 2-propenyl (allyl).
The term "lower alkynyl" or "C2alkynyl" signifies a straight-chain or branched chain hydrocarbon residue comprising a triple bond and 2 to 7 carbon atoms. Examples of lower alkynyl groups are ethinyl and 1-propinyl (-C≡C-CH3).
The term alkyl" or "C3cycloalkyl" denotes a saturated carbocyclic group containing from 3 to 7 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl, more particularly cyclopropyl.
The term "lower cycloalkylalkyl" or cycloalkyl-C1alkyl" refers to lower alkyl groups as defined above wherein at least one of the hydrogen atoms of the lower alkyl group is replaced by a cycloalkyl group. Among the lower cycloalkylalkyl groups of particular interest is cyclopropylmethyl.
The term "lower alkoxy" or "C1alkoxy" refers to the group R’-O-, wherein R’ is lower alkyl and the term "lower alkyl" has the usly given significance. Examples of lower alkoxy groups are methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec.-butoxy and tert-butoxy, in particular methoxy.
The term "lower alkoxyalkyl" or "C1alkoxy-C1alkyl" refers to lower alkyl groups as defined above wherein at least one of the hydrogen atoms of the lower alkyl group is replaced by a lower alkoxy group. Among the lower alkoxyalkyl groups of particular interest are methoxymethyl, 2-methoxyethyl and 2-ethoxyethyl, with 2-ethoxyethyl being of most particular interest.
The term hydroxy or hydroxyl means the group –OH.
The term "lower hydroxyalkyl" or xy-C1alkyl" refers to lower alkyl groups as defined above wherein at least one of the hydrogen atoms of the lower alkyl group is replaced by a hydroxy group. Among the particular interesting lower hydroxyalkyl groups are hydroxymethyl or hydroxyethyl.
The term "lower halogenalkyl" or en-C1alkyl" refers to lower alkyl groups as defined above wherein at least one of the hydrogen atoms of the lower alkyl group is replaced by a halogen atom, particularly fluoro or , most particularly fluoro. Among the lower halogenalkyl groups of particular interest are trifluoromethyl, romethyl, trifluoroethyl, 2,2- difluoroethyl, fluoromethyl and chloromethyl, with oromethyl being of more particular interest.
The term ocyclylcarbonyl" means the group -C(O)-Het, wherein Het is a heterocyclyl group as defined hereinafter. A heterocyclylcarbonyl group of particular interest is pyrrolidinylcarbonyl.
"Amino" refers to the group –NH2. The term "C1alkylamino" means a group –NHR, wherein R is lower alkyl and the term "lower alkyl" has the previously given significance. The term "di-C1alkylamino" means a group –NRR’, wherein R and R’ are lower alkyl groups as d above.
The term "lower aminoalkyl" or -C1alkyl" refers to lower alkyl groups as defined above wherein at least one of the hydrogen atoms of the lower alkyl group is replaced by an amino group. Among the particular interesting lower aminoalkyl groups are aminomethyl or 2- aminoethyl.
The term "lower alkylaminoalkyl" or "C1alkylamino-C1alkyl" refers to lower alkyl groups as defined above wherein at least one of the hydrogen atoms of the lower alkyl group is replaced by an C1alkylamino group. Among the particular interesting lower alkylaminoalkyl groups are ethylaminomethyl or 2-ethylaminoethyl.
The term "lower dialkylaminoalkyl" or alkylamino-C1alkyl" refers to lower alkyl groups as defined above wherein at least one of the en atoms of the lower alkyl group is replaced by an di-C1alkylamino group. Among the particular sting lower alkylaminoalkyl groups are dimethylaminomethyl or dimethylaminoethyl.
The term "lower lkenyl" or "amino-C3alkenyl" refers to lower alkenyl groups as defined above wherein at least one of the hydrogen atoms of the lower alkenyl group is replaced by an amino group. Among the particular interesting lower aminoalkenyl groups is 3-amino propenyl.
The term "lower aminoalkynyl" or "amino-C3alkynyl" refers to lower alkynyl groups as defined above n at least one of the hydrogen atoms of the lower alkynyl group is replaced by an amino group. A lower aminoalkynyl group of particular interest is 3-aminopropinyl.
The term "lower aminoalkoxy" or "amino-C1alkoxy" refers to lower alkoxy groups as defined above wherein at least one of the hydrogen atoms of the lower alkoxy group is replaced by an amino group. Among the particular interesting lower aminoalkoxy groups are aminomethoxy or aminoethoxy.
The term "lower aminoalkoxyalkyl" or "amino-C1alkoxy-C1alkyl" refers to lower alkoxyalkyl groups as defined above wherein at least one of the hydrogen atoms of the lower alkoxy group is ed by an amino group. Among the ular interesting lower aminoalkoxyalkyl groups are 2-aminoethoxymethyl or 2-aminoethoxyethyl.
The term "lower aminoalkoxyalkoxyalkyl" or "amino-C1alkoxy-C1alkoxy-C1alkyl" refers to lower alkoxyalkyl groups as defined above wherein at least one of the hydrogen atoms of the lower alkoxyalkyl group is replaced by a lower aminoalkoxy group. Among the particular interesting lower aminoalkoxyalkoxyalkyl groups are 2-aminoethoxy-ethoxymethyl or 2- aminoethoxy-ethoxyethyl.
The term "lower aminoalkoxyalkoxy" or "amino-C1alkoxy-C1alkoxy" refers to lower alkoxy groups as defined above wherein at least one of the hydrogen atoms of the lower alkoxy group is replaced by a lower aminoalkoxy group. Among the particular interesting lower aminoalkoxyalkoxy groups are 2-aminoethoxy-methoxy or 2-aminoethoxy-ethoxy.
The term "lower alkylamino-alkoxy-alkyl" or "C1alkylamino-C1alkoxy-C1alkyl" refers to lower alkoxyalkyl groups as defined above wherein at least one of the en atoms of the lower alkoxy group is replaced by an alkylamino group. Among the particular interesting lower alkylaminoalkoxyalkyl groups are 2-methylaminoethoxymethyl or ylaminoethoxyethyl.
The term "lower alkylsulfonyl" or "C1alkylsulfonyl" means the group -S(O)2-R, wherein R is a lower alkyl group as defined above. A lower alkylsulfonyl group of particular interest is methylsulfonyl.
The term "benzyloxycarbonylamino-C1alkyl" refers to an amino-C1alkyl group as defined herein , wherein one hydrogen atom of the amino group is substituted by a benzyloxycarbonyl or phenylmethyloxycarbonyl group.
The term "lower phenylalkyl" or "phenyl-C1alkyl" refers to lower alkyl groups as defined above wherein at least one of the hydrogen atoms of the lower alkyl group is replaced by a phenyl ring. Lower phenylalkyl groups of particular st are phenylmethyl and 2- phenylethyl, with ylethyl being of particular interest.
The term "heteroaryl" in general refers to an aromatic 5- or 6-membered ring which comprises one, two, three or four atoms selected from nitrogen, oxygen and/or sulfur, or to bicyclic aromatic groups comprising from 5 to 12 ring atoms, in which one or both rings can contain one, two or three atoms selected from nitrogen, oxygen or sulfur. Examples of heteroaryl groups are furanyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, thienyl, isoxazolyl, thiazolyl, isothiazolyl, azolyl, oxazolyl, imidazolyl, pyrazolyl, triazolyl, oxadiazolyl, oxatriazolyl, tetrazolyl, pentazolyl, or pyrrolyl, or bicyclic groups such as quinolinyl, isoquinolinyl, cinnolinyl, pyrazolo[1,5-a]pyridyl, imidazo[1,2-a]pyridyl, quinoxalinyl, benzothiazolyl, benzotriazolyl, indolyl, indazolyl, and 3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazinyl. aryl groups of particular interest are furanyl, pyridyl, pyrazinyl, dinyl, pyridazinyl, thienyl, olyl, thiazolyl, isothiazolyl, thiadiazolyl, oxazolyl, imidazolyl, pyrazolyl, triazolyl, zolyl, oxatriazolyl, tetrazolyl, olyl, or pyrrolyl. More particularly, heteroaryl groups are selected from the group consisting of imidazolyl, pyrazolyl, oxazolyl, thiazolyl, pyridyl, pyridazinyl and dinyl.
The term "heterocyclyl" refers to a saturated or partly unsaturated 3-, 4-, 5-, 6- or 7- membered ring which can comprise one, two or three heteroatoms selected from N, O and S.
Examples of heterocyclyl rings include piperidinyl, zinyl, azetidinyl, azepinyl, pyrrolidinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, oxazolidinyl, olidinyl, morpholinyl, thiazolidinyl, isothiazolidinyl, oxiranyl, azolylidinyl, oxetanyl, dioxolanyl, dihydrofuranyl, tetrahydrofuranyl, dihydropyranyl, tetrahydropyranyl, and thiomorpholinyl. Of particular st is the pyrrolidinyl group.
The term "pharmaceutically acceptable" denotes an attribute of a material which is useful in preparing a pharmaceutical composition that is generally safe, xic, and neither biologically nor otherwise undesirable and is acceptable for veterinary as well as human pharmaceutical use. nds of formula I can form pharmaceutically acceptable salts. The term "pharmaceutically acceptable salts" refers to those salts which retain the biological effectiveness and properties of the free bases or free acids, which are not biologically or otherwise undesirable.
Pharmaceutically acceptable salts include both acid and base on salts. The salts are for example acid addition salts of compounds of formula I with logically compatible mineral acids, such as hloric acid, hydrobromic acid, nitric acid, carbonic acid, sulfuric acid, sulfurous acid or phosphoric acid; or with organic acids, such as methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, formic acid, acetic acid, propionic acid, glycolic acid, pyruvic acid, oxylic acid, lactic acid, trifluoroacetic acid, citric acid, fumaric acid, maleic acid, malonic acid, tartaric acid, benzoic acid, cinnamic acid, mandelic acid, embonic acid, succinic acid or salicylic acid. In addition, pharmaceutically acceptable salts may be prepared from addition of an inorganic base or an organic base to the free acid. Salts derived from an inorganic base include, but are not limited to, the sodium, potassium, lithium, um, calcium, magnesium, zinc, copper, manganese and aluminium salts and the like. Salts derived from organic bases include, but are not limited to salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins, such as pylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline, betaine, ethylendiamine, glucosamine, glucamine, theobromine, zine, N- ethylpiperidine, piperidine and polyamine resins. The compound of formula I can also be t in the form of zwitterions. Pharmaceutically acceptable salts of nds of formula I of ular interest are the sodium salts or salts with tertiary amines.
The compounds of formula I can also be solvated, e.g., hydrated. The solvation can be effected in the course of the manufacturing process or can take place e.g. as a consequence of hygroscopic properties of an lly anhydrous compound of formula I tion). The term "pharmaceutically acceptable salts" also includes physiologically acceptable solvates.
The term "agonist" denotes a compound that enhances the ty of another compound or receptor site as defined e.g. in Goodman and Gilman's "The cological Basis of Therapeutics, 7th ed." in page 35, Macmillan Publ. Company, Canada, 1985. A "full agonist" effects a full se s a "partial agonist" effects less than full activation even when occupying the total receptor population. An "inverse agonist" produces an effect opposite to that of an agonist, yet binds to the same receptor g-site.
The term "half maximal effective concentration" (EC50) denotes the plasma tration of a particular compound required for obtaining 50% of the maximum of a particular effect in vivo.
The term "therapeutically effective amount" denotes an amount of a compound of the present invention that, when administered to a subject, (i) treats or prevents the particular disease, condition or disorder, (ii) attenuates, ameliorates or eliminates one or more symptoms of the particular disease, condition, or disorder, or (iii) prevents or delays the onset of one or more symptoms of the particular disease, condition or disorder described . The eutically effective amount will vary depending on the compound, disease state being treated, the severity or the disease treated, the age and relative health of the subject, the route and form of administration, the judgment of the ing medical or veterinary practitioner, and other factors.
The term "comprising" as used in this specification and claims means "consisting at least in part of". When interpreting statements in this ication and claims which include the term "comprising", other features besides the es prefaced by this term in each statement can also be present. Related terms such as "comprise" and "comprises" are to be interpreted in similar manner.
In detail, described are compounds of the formula N 4 R I N R2 wherein R1 is C3alkyl or C3cycloalkyl, R2 is selected from the group consisting of C1alkyl, hydroxy-C1alkyl, C2alkenyl, C3 alkynyl, amino-C1alkoxy-C1alkyl, amino-C1alkoxy-C1alkoxy-C1alkyl, halogen- C1alkyl, C3cycloalkyl-C1alkyl and phenyl-C1alkyl, wherein phenyl is unsubstituted or substituted by amino-C1alkyl; R3 is hydrogen; R4 is selected from the group consisting of phenyl, said phenyl being unsubstituted or substituted by one or two groups selected from the group consisting of C1alkyl, halogen, halogen-C1alkyl, C1alkoxy, hydroxy-C1 alkyl, amino-C1alkyl, C1alkyl-amino-C1alkyl, di-C1alkyl-amino-C1alkyl, amino- C2alkenyl, C1alkyl-amino-C2alkenyl, di-C1alkyl-amino-C2alkenyl, amino-C2 alkynyl, C1alkyl-amino-C2alkynyl, 7-alkyl-amino-C2alkynyl, benzyloxycarbonylamino-C1alkyl, amino-C1alkoxy, amino-C1alkoxy-C1alkoxy, C1alkoxy-C1alkyl, amino-C1alkoxy-C1alkoxy-C1alkyl, C1alkylsulfonyl heterocyclylcarbonyl and phenyl-C1alkyl, wherein phenyl is unsubstituted or substituted by lkoxy or amino-C1alkyl, or heteroaryl, said heteroaryl being a 5- or 6-membered aromatic ring containing one, two or three atoms selected from N, O or S and being unsubstituted or substituted by one or two groups selected from the group ting of C1alkyl, halogen, halogen-C1alkyl, lkoxy, hydroxy-C1alkyl, C1alkyl, C1alkyl-amino-C1alkyl, 7- alkyl-amino-C1alkyl, amino-C2alkenyl, C1alkyl-amino-C2alkenyl, 7-alkyl- amino-C2alkenyl, amino-C2alkynyl, C1alkyl-amino-C2alkynyl, di-C1alkylamino-C2alkynyl , benzyloxycarbonylamino-C1alkyl, amino-C1alkoxy, amino-C1 alkoxy-C1alkoxy, amino-C1alkoxy-C1alkyl, amino-C1alkoxy-C1alkoxy-C1 alkyl, lkylsulfonyl heterocyclylcarbonyl and phenyl-C1alkyl, wherein phenyl is unsubstituted or substituted by C1alkoxy or amino-C1alkyl, or pharmaceutically acceptable salts thereof.
Also described are compounds of formula I, wherein R1 is C1alkyl.
In particular, the invention is concerned with compounds of formula I, wherein R1 is propyl or butyl. More particularly, R1 is propyl.
In another aspect, the ion refers to compounds of formula I, wherein R2 is selected from the group consisting of C1alkyl, C2alkenyl, lkynyl, n-C1alkyl, C3 cycloalkyl-C1alkyl and hydroxy-C1alkyl. In r aspect, the invention refers to compounds of formula I, wherein R2 is selected from the group consisting of C1alkyl, C3 alkynyl, halogen-C1alkyl, C3cycloalkyl-C1alkyl and hydroxy-C1alkyl. In a further aspect, R2 is selected from the group consisting of C1alkyl, C3alkynyl and hydroxy-C1alkyl. In particular, R2 is C1alkyl or hydroxy-C1alkyl. More particularly, R2 is C1alkyl. More particularly, R2 is selected from the group consisting of propyl, 3-hydroxypropyl, cyclopropylmethyl and trifluoropropyl.
Also described are compounds of formula I, n R1 and R2 are C1alkyl, particularly propyl.
Also described are compounds of formula I, wherein R4 is a 5- or 6-membered heteroaryl ring containing one, two or three heteroatoms selected from N, O or S and being unsubstituted or substituted by one or two groups selected from the group consisting of C1alkyl, halogen, halogen-C1alkyl, C1alkoxy, hydroxy-C1alkyl, amino-C1alkyl, C1alkyl-amino-C1 alkyl, di-C1alkyl-amino-C1alkyl, C2alkenyl, C1alkyl-amino-C2alkenyl, di-C1 alkyl-amino-C2alkenyl, amino-C2alkynyl, C1alkyl-amino-C2alkynyl, di-C1alkylamino-C2alkynyl , benzyloxycarbonylamino-C1alkyl, C1alkoxy, amino-C1alkoxy- C1alkoxy, amino-C1alkoxy-C1alkyl, amino-C1alkoxy-C1alkoxy-C1alkyl, C1 alkylsulfonyl, heterocyclylcarbonyl and phenyl-C1alkyl, wherein phenyl is unsubstituted or substituted by C1alkoxy or amino-C1alkyl.
Also bed are compounds of a I, wherein R4 is a 5- or 6-membered heteroaryl ring containing one, two or three heteroatoms selected from N, O or S and being unsubstituted or tuted by one or two groups selected from the group consisting of C1alkyl, halogen, halogen-C1alkyl, C1alkoxy, hydroxy-C1alkyl, amino-C1alkyl, C2alkenyl, amino-C2alkynyl, C1alkoxy, amino-C1alkoxy-C1alkoxy, amino-C1alkoxy-C1 alkoxy-C1alkyl, C1alkylsulfonyl and heterocyclylcarbonyl.
Also described are compounds of formula I, wherein R4 is a 5- or 6-membered heteroaryl ring containing one, two or three heteroatoms selected from N, O or S and being substituted by one or two groups selected from the group consisting of C1alkyl, halogen, C1alkoxy, hydroxy-C1alkyl, amino-C1alkyl, di-C1alkyl-amino-C1alkyl, amino-C2alkenyl, amino- C2alkynyl, benzyloxycarbonylamino-C1alkyl, amino-C1alkoxy and -C1alkyl, n phenyl is tituted or substituted by C1alkoxy or amino-C1alkyl. In a further aspect, R4 is a 5- or 6-membered heteroaryl ring containing one, two or three heteroatoms selected from N, O or S and being substituted by one or two groups selected from the group consisting of C1alkyl, halogen, C1alkoxy, y-C1alkyl, C1alkyl, amino-C2 alkenyl, amino-C2alkynyl, amino-C1alkoxy, amino-C1alkoxy-C1alkoxy-C1alkyl and heterocyclylcarbonyl.
Also described are compounds of formula I, wherein R4 is a 5- or 6-membered heteroaryl ring containing one, two or three heteroatoms selected from N, O or S. More particularly, the invention relates to heteraryl as d herein before, wherein heteroaryl is ed from the group consisting of olyl, pyrazolyl, oxazolyl, thiazolyl, l, pyridazinyl and pyrimidinyl, said heteroaryl being unsubstituted or substituted by one or two groups selected from the group consisting of C1alkyl, halogen, halogen-C1alkyl, C1alkoxy, hydroxy-C1 alkyl, amino-C1alkyl, C1alkyl-amino-C1alkyl, di-C1alkyl-amino-C1alkyl, amino-C2 alkenyl, C1alkyl-amino-C2alkenyl, di-C1alkyl-amino-C2alkenyl, amino-C2alkynyl, C1- l-amino-C2alkynyl, di-C1alkyl-amino-C2alkynyl, benzyloxycarbonylamino-C1 alkyl, amino-C1alkoxy, amino-C1alkoxy-C1alkoxy, amino-C1alkoxy-C1alkyl, amino- C1alkoxy-C1alkoxy-C1alkyl, C1alkylsulfonyl, heterocyclylcarbonyl and phenyl-C1 alkyl, wherein phenyl is unsubstituted or substituted by C1alkoxy or amino-C1alkyl. In a particular aspect, the 5- or 6-membered heteroaryl ring is pyridyl.
In one aspect, the ion relates to nds of formula I, wherein R4 is unsubstituted heteroaryl selected from ed from the group consisting of imidazolyl, lyl, oxazolyl, lyl, pyridyl, pyridazinyl and pyrimidinyl.
In r aspect, the invention relates to compounds of formula I, wherein R4 is phenyl, said phenyl being unsubstituted or substituted by one or two groups selected from the group consisting of C1alkyl, halogen, halogen-C1alkyl, C1alkoxy, hydroxy-C1alkyl, amino-C1- 7-alkyl, C1alkyl-amino-C1alkyl, di-C1alkyl-amino-C1alkyl, amino-C2alkenyl, C1 alkyl-amino-C2alkenyl, di-C1alkyl-amino-C2alkenyl, amino-C2alkynyl, C1alkylamino-C2alkynyl , di-C1alkyl-amino-C2alkynyl, benzyloxycarbonylamino-C1alkyl, amino-C1alkoxy, amino-C1alkoxy-C1alkoxy, amino-C1alkoxy-C1alkyl, amino-C1 alkoxy-C1alkoxy-C1alkyl, C1alkylsulfonyl, heterocyclylcarbonyl and phenyl-C1alkyl, wherein phenyl is unsubstituted or substituted by C1alkoxy or amino-C1alkyl.
In one aspect, the invention s to compounds of formula I, wherein R4 is phenyl, said phenyl being unsubstituted or substituted by one or two groups selected from the group consisting of C1alkyl, halogen, halogen-C1alkyl, C1alkoxy, hydroxy-C1alkyl, amino-C1- 7-alkyl, amino-C2alkenyl, amino-C2alkynyl, amino-C1alkoxy, amino-C1alkoxy-C1 alkoxy, amino-C1alkoxy-C1alkoxy-C1alkyl, C1alkylsulfonyl and cyclylcarbonyl.
In particular, the invention relates to compounds of a I, wherein R4 is phenyl, said phenyl being unsubstituted or substituted by one or two groups selected from the group consisting of C1alkyl, halogen, halogen-C1alkyl, C1alkoxy, amino-C1alkyl, amino-C1 , amino-C1alkoxy-C1alkoxy, amino-C1alkoxy-C1alkyl, amino-C1alkoxy-C1 -C1alkyl, C1alkylsulfonyl and heterocyclylcarbonyl.
In one aspect, compounds of formula I of the invention are those, wherein R4 is phenyl substituted by one group selected from the group consisting of C1alkyl, halogen, halogen-C1 alkyl, C1alkoxy, amino-C1alkyl, amino-C1alkoxy, C1alkoxy-C1alkoxy, amino- C1alkoxy-C1alkyl, amino-C1alkoxy-C1alkoxy-C1alkyl, lkylsulfonyl and cyclylcarbonyl.
In a ular aspect, the invention relates to compounds of formula I, wherein R4 is , wherein one of R5 or R6 is selected from the group consisting of C1 alkyl, halogen, halogen-C1alkyl, C1alkoxy, amino-C1alkyl, amino-C1alkoxy, C1- 7-alkoxy-C1alkoxy, amino-C1alkoxy-C1alkyl, amino-C1alkoxy-C1alkoxy-C1alkyl, C1alkylsulfonyl and heterocyclylcarbonyl, and the other one of R5 and R6 is hydrogen.
In another aspect, the invention refers to compounds of formula I, wherein R4 is unsubstituted phenyl.
Also described are nds of formula I, wherein R1 is C3alkyl or C3cycloalkyl, R2 is selected from the group consisting of C1alkyl, C2alkenyl, C3alkynyl, hydroxy-C1- 7-alkyl, amino-C1alkoxy-C1alkoxy-C1alkyl, halogen-C1alkyl and C3cycloalkyl- C1alkyl; R3 is hydrogen; R4 is selected from the group consisting of phenyl, said phenyl being unsubstituted or tuted by one or two groups selected from the group consisting of C1alkyl, halogen, halogen-C1alkyl, C1alkoxy, hydroxy-C1 alkyl, amino-C1alkyl, amino-C2alkenyl, amino-C2alkynyl, amino-C1alkoxy, C1alkoxy-C1alkoxy, amino-C1alkoxy-C1alkoxy-C1alkyl, C1 alkylsulfonyl and heterocyclylcarbonyl, or heteroaryl, said heteroaryl being a 5- or 6-membered aromatic ring containing one, two or three heteroatoms selected from N, O or S and being unsubstituted or substituted by one or two groups selected from the group consisting of C1alkyl, halogen, n-C1alkyl, C1alkoxy, hydroxy-C1alkyl, amino-C1alkyl, amino-C2alkenyl, amino-C2alkynyl, amino-C1alkoxy, amino-C1alkoxy-C1alkoxy, amino-C1alkoxy-C1alkoxy-C1 alkyl, C1alkylsulfonyl and heterocyclylcarbonyl, or pharmaceutically acceptable salts thereof.
Particular compounds of formula I according to the invention are the following: 2-amino-N4,N4-dipropyl-N8-(3-pyridyl)-3Hbenzazepine-4,8-dicarboxamide, 2-amino-N4,N4-dipropyl-N8-pyrimidinyl-3Hbenzazepine-4,8-dicarboxamide, 2-amino-N4,N4-dipropyl-N8-(4-pyridyl)-3Hbenzazepine-4,8-dicarboxamide, 2-amino-N4,N4-dipropyl-N8-phenyl-3Hbenzazepine-4,8-dicarboxamide, 2-amino-N8-[6-(aminomethyl)pyridyl]-N4,N4-dipropyl-3Hbenzazepine-4,8-dicarboxamide, 2-amino-N8-[5-(hydroxymethyl)pyridyl]-N4,N4-dipropyl-3Hbenzazepine-4,8- oxamide, o-N8-[6-(hydroxymethyl)pyridyl]-N4,N4-dipropyl-3Hbenzazepine-4,8- dicarboxamide, 2-amino-N8-(3-methylsulfonylphenyl)-N4,N4-dipropyl-3Hbenzazepine-4,8-dicarboxamide, o-N4,N4-dipropyl-N8-thiazolyl-3Hbenzazepine-4,8-dicarboxamide, 2-amino-N8-(4-chlorophenyl)-N4,N4-dipropyl-3Hbenzazepine-4,8-dicarboxamide, 2-amino-N4,N4-dipropyl-N8-thiazolyl-3Hbenzazepine-4,8-dicarboxamide, 2-amino-N8-(3-methylimidazolyl)-N4,N4-dipropyl-3Hbenzazepine-4,8-dicarboxamide, 2-amino-N8-(4-fluorophenyl)-N4,N4-dipropyl-3Hbenzazepine-4,8-dicarboxamide, 2-amino-N8-(m-tolyl)-N4,N4-dipropyl-3Hbenzazepine-4,8-dicarboxamide, 2-amino-N4,N4-dipropyl-N8-[3-(pyrrolidinecarbonyl)phenyl]-3Hbenzazepine-4,8- dicarboxamide, o-N4,N4-dipropyl-N8-[5-(pyrrolidinecarbonyl)pyridyl]-3Hbenzazepine-4,8- dicarboxamide, 2-amino-N8-[3-(2-aminoethyl)phenyl]-N4,N4-dipropyl-3Hbenzazepine-4,8-dicarboxamide, 2-amino-N8-(5-methylpyridyl)-N4,N4-dipropyl-3Hbenzazepine-4,8-dicarboxamide, o-N8-(3-fluorophenyl)-N4,N4-dipropyl-3Hbenzazepine-4,8-dicarboxamide, 2-amino-N8-(5-fluoropyridyl)-N4,N4-dipropyl-3Hbenzazepine-4,8-dicarboxamide, 2-amino-N8-(2-methylpyridyl)-N4,N4-dipropyl-3Hbenzazepine-4,8-dicarboxamide, 2-amino-N8-(6-methylpyridyl)-N4,N4-dipropyl-3Hbenzazepine-4,8-dicarboxamide, 2-amino-N8-(3,5-dimethylphenyl)-N4,N4-dipropyl-3Hbenzazepine-4,8-dicarboxamide, 2-amino-N8-[4-(aminomethyl)phenyl]-N4,N4-dipropyl-3Hbenzazepine-4,8-dicarboxamide, 2-amino-N8-[4-(2-aminoethyl)phenyl]-N4,N4-dipropyl-3Hbenzazepine-4,8-dicarboxamide, 2-amino-N4-(3-hydroxypropyl)-N8-(m-tolyl)-N4-propyl-3Hbenzazepine-4,8-dicarboxamide, 2-amino-N8-(o-tolyl)-N4,N4-dipropyl-3Hbenzazepine-4,8-dicarboxamide, 2-amino-N4,N4-dipropyl-N8-(p-tolyl)-3Hbenzazepine-4,8-dicarboxamide, 2-amino-N8-(3-ethylphenyl)-N4,N4-dipropyl-3Hbenzazepine-4,8-dicarboxamide, 2-amino-N8-(3-methoxyphenyl)-N4,N4-dipropyl-3Hbenzazepine-4,8-dicarboxamide, 2-amino-N4,N4-dipropyl-N8-[3-(trifluoromethyl)phenyl]-3Hbenzazepine-4,8-dicarboxamide, 2-amino-N8-(3-chlorophenyl)-N4,N4-dipropyl-3Hbenzazepine-4,8-dicarboxamide, 2-amino-N8-[5-(aminomethyl)pyridyl]-N4,N4-dipropyl-3Hbenzazepine-4,8-dicarboxamide, 2-amino-N4,N4-dipropyl-N8-pyridazinyl-3Hbenzazepine-4,8-dicarboxamide, 2-amino-N8-(6-ethoxypyridyl)-N4,N4-dipropyl-3Hbenzazepine-4,8-dicarboxamide, 2-amino-N8-[3-(aminomethyl)phenyl]-N4,N4-dipropyl-3Hbenzazepine-4,8-dicarboxamide, 2-amino-N8-(1-methylpyrazolyl)-N4,N4-dipropyl-3Hbenzazepine-4,8-dicarboxamide, 2-amino-N8-oxazolyl-N4,N4-dipropyl-3Hbenzazepine-4,8-dicarboxamide, 2-amino-N4-(3-hydroxypropyl)-N4-propyl-N8-(3-pyridyl)-3Hbenzazepine-4,8-dicarboxamide, 2-amino-N8-(5-methoxypyridyl)-N4,N4-dipropyl-3Hbenzazepine-4,8-dicarboxamide, 2-amino-N8-(m-tolyl)-N4-propyl-N4-propynyl-3Hbenzazepine-4,8-dicarboxamide, 2-amino-N4,N4-dibutyl-N8-(m-tolyl)-3Hbenzazepine-4,8-dicarboxamide, 2-amino-N8-[3-(aminomethyl)methyl-phenyl]-N4,N4-dipropyl-3Hbenzazepine-4,8- dicarboxamide, 2-amino-N8-(5-ethoxypyridyl)-N4,N4-dipropyl-3Hbenzazepine-4,8-dicarboxamide, o-N8-[3-[2-(2-aminoethoxy)ethoxy]phenyl]-N4,N4-dipropyl-3Hbenzazepine-4,8- dicarboxamide, 2-amino-N8-[5-(5-aminopentoxy)pyridyl]-N4,N4-dipropyl-3Hbenzazepine-4,8- dicarboxamide, 2-amino-N8-[3-[2-(2-aminoethoxy)ethoxymethyl]phenyl]-N4,N4-dipropyl-3Hbenzazepine- 4,8-dicarboxamide, 2-amino-N8-[5-(3-aminopropynyl)pyridyl]-N4,N4-dipropyl-3Hbenzazepine-4,8- dicarboxamide, 2-amino-N4-[3-[2-(2-aminoethoxy)ethoxy]propyl]-N8-(m-tolyl)-N4-propyl-3Hbenzazepine- 4,8-dicarboxamide, 2-amino-N8-[5-(3-aminopropyl)pyridyl]-N4,N4-dipropyl-3Hbenzazepine-4,8- dicarboxamide, 2-amino-N8-(m-tolyl)-N4-propyl-N4-(3,3,3-trifluoropropyl)-3Hbenzazepine-4,8- dicarboxamide, 2-amino-N8-[5-[(E)aminopropenyl]pyridyl]-N4,N4-dipropyl-3Hbenzazepine-4,8- dicarboxamide, 2-amino-N4-(cyclopropylmethyl)-N8-(m-tolyl)-N4-propyl-3Hbenzazepine-4,8-dicarboxamide, and pharmaceutically acceptable salts thereof.
Further ular compounds of formula I according to the invention are the following: 2-amino-N8-[3-(2-aminoethyl)phenyl]-N4,N4-dipropyl-3Hbenzazepine-4,8-dicarboxamide, 2-amino-N4-isobutyl-N8-(m-tolyl)-N4-propyl-3Hbenzazepine-4,8-dicarboxamide, 2-amino-N4-[3-(3-aminopropoxy)propyl]-N8-(m-tolyl)-N4-propyl-3Hbenzazepine-4,8- dicarboxamide, o-N8-[3-(5-aminopentyl)phenyl]-N4,N4-dipropyl-3Hbenzazepine-4,8-dicarboxamide, 2-amino-N8-[4-(5-aminopentyl)phenyl]-N4,N4-dipropyl-3Hbenzazepine-4,8-dicarboxamide, 2-amino-N8-[3-(3-aminopropyl)phenyl]-N4,N4-dipropyl-3Hbenzazepine-4,8-dicarboxamide, 2-amino-N4-[[4-(aminomethyl)phenyl]methyl]-N8-(m-tolyl)-N4-propyl-3Hbenzazepine-4,8- dicarboxamide, o-N8-[4-(3-aminopropyl)phenyl]-N4,N4-dipropyl-3Hbenzazepine-4,8-dicarboxamide, 2-amino-N8-[4-(3-aminopropyl)phenyl]-N4,N4-dipropyl-3Hbenzazepine-4,8-dicarboxamide, 2-amino-N8-[3-(2-aminoethyl)fluoro-phenyl]-N4,N4-dipropyl-3Hbenzazepine-4,8- dicarboxamide, 2-amino-N8-[3-(2-aminoethyl)chloro-phenyl]-N4,N4-dipropyl-3Hbenzazepine-4,8- dicarboxamide, 2-amino-N4-butyl-N4-(2-hydroxyethyl)-N8-(m-tolyl)-3Hbenzazepine-4,8-dicarboxamide, 2-amino-N8-[5-(2-aminoethoxy)pyridyl]-N4,N4-dipropyl-3Hbenzazepine-4,8- dicarboxamide, benzyl-N-[[5-[[2-amino(dipropylcarbamoyl)-3Hbenzazepinecarbonyl]amino] pyridyl]methyl]carbamate, 2-amino-N8-[5-[(E)aminopropenyl]pyridyl]-N4,N4-dipropyl-3Hbenzazepine-4,8- dicarboxamide, 2-amino-N8-[5-(2-phenylethyl)pyridyl]-N4,N4-dipropyl-3Hbenzazepine-4,8- dicarboxamide, 2-amino-N8-[5-[2-(4-methoxyphenyl)ethyl]pyridyl]-N4,N4-dipropyl-3Hbenzazepine-4,8- dicarboxamide, 2-amino-N8-[5-[2-[4-(aminomethyl)phenyl]ethyl]pyridyl]-N4,N4-dipropyl-3H benzazepine-4,8-dicarboxamide, 2-amino-N8-[5-(5-aminopentyl)pyridyl]-N4,N4-dipropyl-3Hbenzazepine-4,8- dicarboxamide, o-N8-[5-[2-(3-methoxyphenyl)ethyl]pyridyl]-N4,N4-dipropyl-3Hbenzazepine-4,8- dicarboxamide, 2-amino-N8-[5-(6-aminohexyl)pyridyl]-N4,N4-dipropyl-3Hbenzazepine-4,8- dicarboxamide, 2-amino-N8-[6-(3-aminopropyl)pyridyl]-N4,N4-dipropyl-3Hbenzazepine-4,8- dicarboxamide, o-N8-[5-(4-aminobutyl)pyridyl]-N4,N4-dipropyl-3Hbenzazepine-4,8-dicarboxamide, 2-amino-N8-[6-(4-aminobutyl)pyridyl]-N4,N4-dipropyl-3Hbenzazepine-4,8-dicarboxamide, 2-amino-N8-[5-[(dimethylamino)methyl]pyridyl]-N4,N4-dipropyl-3Hbenzazepine-4,8- dicarboxamide, 2-amino-N4-(cyclopropylmethyl)-N8-(5-ethoxypyridyl)-N4-propyl-3Hbenzazepine-4,8- dicarboxamide, 2-amino-N8-[5-(2-aminoethyl)pyridyl]-N4,N4-dipropyl-3Hbenzazepine-4,8-dicarboxamide, and ceutically acceptable salts thereof.
More particularly, the invention relates to compounds of formula I that are the following: 2-amino-N4,N4-dipropyl-N8-(3-pyridyl)-3Hbenzazepine-4,8-dicarboxamide, 2-amino-N4,N4-dipropyl-N8-pyrimidinyl-3Hbenzazepine-4,8-dicarboxamide, 2-amino-N8-(4-chlorophenyl)-N4,N4-dipropyl-3Hbenzazepine-4,8-dicarboxamide, 2-amino-N8-(m-tolyl)-N4,N4-dipropyl-3Hbenzazepine-4,8-dicarboxamide, o-N4,N4-dipropyl-N8-[3-(pyrrolidinecarbonyl)phenyl]-3Hbenzazepine-4,8- dicarboxamide, 2-amino-N8-(6-methylpyridyl)-N4,N4-dipropyl-3Hbenzazepine-4,8-dicarboxamide, 2-amino-N8-(3,5-dimethylphenyl)-N4,N4-dipropyl-3Hbenzazepine-4,8-dicarboxamide, 2-amino-N4-(3-hydroxypropyl)-N8-(m-tolyl)-N4-propyl-3Hbenzazepine-4,8-dicarboxamide, 2-amino-N4,N4-dipropyl-N8-(p-tolyl)-3Hbenzazepine-4,8-dicarboxamide, 2-amino-N8-(3-ethylphenyl)-N4,N4-dipropyl-3Hbenzazepine-4,8-dicarboxamide, 2-amino-N8-(3-methoxyphenyl)-N4,N4-dipropyl-3Hbenzazepine-4,8-dicarboxamide, o-N8-(3-chlorophenyl)-N4,N4-dipropyl-3Hbenzazepine-4,8-dicarboxamide, 2-amino-N8-[5-(aminomethyl)pyridyl]-N4,N4-dipropyl-3Hbenzazepine-4,8-dicarboxamide, 2-amino-N4,N4-dipropyl-N8-pyridazinyl-3Hbenzazepine-4,8-dicarboxamide, 2-amino-N8-(6-ethoxypyridyl)-N4,N4-dipropyl-3Hbenzazepine-4,8-dicarboxamide, 2-amino-N8-(5-methoxypyridyl)-N4,N4-dipropyl-3Hbenzazepine-4,8-dicarboxamide, 2-amino-N8-(5-ethoxypyridyl)-N4,N4-dipropyl-3Hbenzazepine-4,8-dicarboxamide, 2-amino-N8-[3-[2-(2-aminoethoxy)ethoxymethyl]phenyl]-N4,N4-dipropyl-3Hbenzazepine- 4,8-dicarboxamide, 2-amino-N8-(m-tolyl)-N4-propyl-N4-(3,3,3-trifluoropropyl)-3Hbenzazepine-4,8- dicarboxamide, 2-amino-N4-(cyclopropylmethyl)-N8-(m-tolyl)-N4-propyl-3Hbenzazepine-4,8-dicarboxamide, and pharmaceutically acceptable salts thereof.
In a further particular aspect, the compound of formula I according to the invention is selected from the group consisting of 2-amino-N8-[3-(2-aminoethyl)phenyl]-N4,N4-dipropyl-3Hbenzazepine-4,8-dicarboxamide, 2-amino-N4-isobutyl-N8-(m-tolyl)-N4-propyl-3Hbenzazepine-4,8-dicarboxamide, 2-amino-N8-[3-(3-aminopropyl)phenyl]-N4,N4-dipropyl-3Hbenzazepine-4,8-dicarboxamide, benzyl-N-[[5-[[2-amino(dipropylcarbamoyl)-3Hbenzazepinecarbonyl]amino] pyridyl]methyl]carbamate, o-N8-[5-(2-phenylethyl)pyridyl]-N4,N4-dipropyl-3Hbenzazepine-4,8- dicarboxamide, 2-amino-N4-(cyclopropylmethyl)-N8-(5-ethoxypyridyl)-N4-propyl-3Hbenzazepine-4,8- dicarboxamide, and pharmaceutically acceptable salts f.
A r aspect of the present invention is the process for the manufacture of compounds of a I as defined above, which process comprises coupling a compound of the formula II PGHN N COOH N 2 R , wherein R1 and R2 are as defined herein before and PG is a protecting group, with an amine of the formula III HN III R , wherein R3 and R4 are as defined herein before, under basic conditions in the presence of a coupling agent and removing the protecting group PG under acidic conditions to obtain a nd of the a I N 4 R I N R2 R , wherein R1 to R4 are as defined herein before, and, if desired, converting the compound obtained into a pharmaceutically acceptable salt.
It will be appreciated, that the compounds of general formula I in this invention may be derivatised at functional groups to provide derivatives which are capable of conversion back to the parent compound in vivo. Physiologically acceptable and metabolically labile derivatives, which are capable of ing the parent compounds of general formula I in vivo are also within the scope of this invention.
In particular, a suitable protecting group PG is an amino-protecting group selected from Boc (tert-butoxycarbonyl), benzyl (Bz) and benzyloxycarbonyl (Cbz). In particular, the protecting group is Boc.
"Removing the protecting group PG under acidic ions" means treating the protected compound with acids in a suitable solvent, for instance trifluoroacetic acid (TFA) in a solvent such as dichloromethane (DCM) can be employed.
A suitable "coupling agent" for the on of compounds of formula II with amines of a III is selected from the group ting of N,N’-carbonyldiimidazole (CDI), N,N’- dicyclohexylcarbodiimide (DCC), 1-(3-dimethylaminopropyl)ethylcarbodiimide hydrochloride , 1-[bis(dimethylamino)-methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium oxide hexafluorophosphate (HATU), 1-hydroxy-1,2,3-benzotriazole (HOBT), O-benzotriazole- N,N,N’,N’-tetramethyl-uronium-hexafluoro-phosphate (HBTU) or O-benzotriazolyl- N,N,N’,N’-tetramethyluronium tetrafluoroborate (TBTU). In particular, the coupling agent is TBTU. Suitable bases include ylamine, N-methylmorpholine and, particularly, diisopropylethylamine.
"Under basic conditions" means the presence of a base, in particular a base ed from the group consisting of triethylamine, N-methylmorpholine and, ularly, diisopropylethylamine. Typically, the reaction is carried out in inert solvents such as dimethylformamide or dichloromethane at room temperature.
The invention further relates to compounds of formula I as d above able according to a process as defined above.
The compounds of the present invention can be prepared by any conventional means.
Suitable ses for synthesizing these compounds as well as their starting materials are provided in the schemes below and in the examples. All substituents, in ular, R1 to R4 are as defined above unless otherwise indicated. Furthermore, and unless explicitly otherwise stated, all reactions, reaction conditions, abbreviations and symbols have the meanings well known to a person of ordinary skill in organic chemistry.
A general synthetic route for preparing the compounds of formula I is shown in Scheme 1 below.
Compounds of formula I can be prepared according to Scheme 1. A coupling reaction between carboxylic acid A and a selected amine IV gives the amide of formula V, which is then protected with an amino protecting group such as Boc to obtain a compound of formula VI.
Hydrolysis of the compound of formula VI leads to a ylic acid of formula II. The carboxylic acid of formula II is then coupled with a ed amine III to obtain an amide of formula VII. Finally, the compound of formula I is obtained by deprotection of the amino protecting group (e.g. Boc). In some cases, the compound of formula VII may contain an additional acid labile protection group originated from amine IV or amine III, like Boc or TBS, which will be removed also in the final deprotection step.
A coupling reagent, like HBTU, is used to couple the carboxylic acid of formula A and a selected amine IV in the presence of a base, like DIPEA, in a solvent like DCM at ambient or elevated temperature to give a compound of formula V.
Then, the nd of formula V is protected with an amino ting group, in particular with Boc, to provide a compound of formula VI.
The compound of formula VI is yzed by a base, in particular LiOH, in a suitable solvent, for example a mixed solvent like THF/MeOH/H2O, at ambient or elevated temperature to obtain a ylic acid of formula II.
Scheme 1 R H2N H2N N CO2Me N 2 CO2Me R IV O N 2 1 R OH R H H Boc N Boc N N CO2H N CO2Me O O N 2 N 2 1 R 1 R R II R 4 III O O HN H2N N 3 3 R N R N N 4 4 R R O O N 2 R N 2 1 1 R R R VII I The carboxylic acid of formula II is then reacted with a selected amine III under the assistance of a suitable coupling t, in particular HBTU, in a solvent like DCM and in the presence of a base, in particular DIPEA, at ambient or elevated temperature to result in a compound of formula VII.
Finally, a compound of a I is ed by deprotecting the compound of formula VII with TFA in dichloromethane and subsequent purification by prep-HPLC. In some cases, besides the Boc protection group at amidine, a compound of formula VII may also contain an onal acid labile protection group, like Boc or TBS ated from amine IV or III, which will be also d in this step.
If one of the starting materials contains one or more functional groups which are not stable or are reactive under the reaction conditions of one or more reaction steps, appropriate protecting groups (PG) (as described e.g. in T.W. Greene et al., Protective Groups in Organic Chemistry, John Wiley and Sons Inc. New York 1999, 3rd edition) can be introduced before the al step applying methods well known in the art. Such protecting groups can be removed at a later stage of the synthesis using standard methods known in the art. In some cases, besides the Boc protection group at amidine, a compound of formula VII may also contain an additional acid labile protection group, like Boc or TBS originated from amine II or VI, which will be also removed in this step.
If one or more compounds of the a contain chiral centers, compounds of formula I can be obtained as es of diastereomers or enantiomers, which can be separated by s well known in the art, e.g. (chiral) HPLC or crystallization. Racemic compounds can e.g. be separated into their antipodes via diastereomeric salts by crystallization or by separation of the antipodes by specific chromatographic methods using either a chiral adsorbent or a chiral eluent.
As described herein before, the compounds of formula I of the present ion can be used as medicaments for the treatment of diseases which are mediated by TLR agonists, in particular for the treatment of diseases which are mediated by TLR8 agonists.
The nds defined in the present invention are agonists of TLR8 receptors in ar assays in vitro. Accordingly, the compounds of the present invention are expected to be potentially useful agents in the ent of diseases or medical conditions that may benefit from the tion of the immune system via TLR8 agonists. They are useful in the treatment or prevention of diseases such as cancer, autoimmune es, inflammation, sepsis, allergy, asthma, graft rejection, graft-versus-host disease, immunodeficiencies, and infectious diseases.
In more detail, the compounds of formula I of the present invention are useful in oncology, i.e. they may be used in the treatment of common cancers including bladder cancer, head and neck cancer, prostate cancer, colorectal cancer, kidney , breast cancer, lung cancer, ovarian cancer, cervical cancer, liver cancer, pancreatic cancer, bowel and colon cancer, stomach , thyroid cancer, melanoma, skin and brain tumors and malignancies affecting the bone marrow such as leukemias and lymphoproliferative systems, such as Hodgkin's and non- Hodgkin's lymphoma; including the prevention (e.g. vaccination) and treatment of metastatic cancer and tumor recurrences, and paraneoplastic syndromes.
The compounds of formula I of the present invention are also useful in the treatment of autoimmune diseases. An "autoimmune disease" is a e or disorder arising from and directed against an individual's own tissues or organs or a co-segregate or manifestation thereof or resulting ion therefrom. "Autoimmune disease" can be an organ-specific disease (i.e., the immune response is specifically directed against an organ system such as the endocrine system, the hematopoietic system, the skin, the cardiopulmonary system, the gastrointestinal and liver s, the renal system, the thyroid, the ears, the neuromuscular system, the central nervous system, etc.) or a systemic disease which can affect multiple organ s (for example, systemic lupus erythematosus (SLE), rheumatoid arthritis, polymyositis, etc.). In a ular aspect, the mune disease is associated with the skin, muscle , and/or connective tissue.
Particular autoimmune diseases include autoimmune rheumatologic disorders (such as, for example, rheumatoid tis, Sjogren's syndrome, scleroderma, lupus such as SLE and lupus tis, polymyositis/dermatomyositis, cryoglobulinemia, anti-phospholipid antibody syndrome, and tic arthritis), autoimmune gastrointestinal and liver disorders (such as, for example, inflammatory bowel diseases, ulcerative colitis and Crohn's disease), autoimmune gastritis and pernicious anemia, autoimmune hepatitis, primary biliary cirrhosis, primary sclerosing cholangitis, and celiac disease), itis (such as, for example, ANCA-negative vasculitis and ANCA-associated vasculitis, including Churg-Strauss vasculitis, r's granulomatosis, and microscopic giitis), autoimmune neurological disorders (such as, for example, multiple sclerosis, opsoclonus myoclonus syndrome, myasthenia gravis, neuromyelitis optica, Parkinson's disease, Alzheimer's e, and autoimmune polyneuropathies), renal disorders (such as, for e, glomerulonephritis, Goodpasture's syndrome, and Berger's disease), autoimmune dermatologic disorders (such as, for example, psoriasis, urticaria, hives, pemphigus vulgaris, bullous pemphigoid, and cutaneous lupus erythematosus), hematologic disorders (such as, for example, thrombocytopenic purpura, thrombotic thrombocytopenic purpura, post-transfusion purpura, and autoimmune hemolytic anemia), atherosclerosis, uveitis, autoimmune hearing diseases (such as, for e, inner ear disease and hearing loss), Behcet's disease, Raynaud's syndrome, organ transplant, and autoimmune endocrine ers (such as, for example, diabetic-related mune diseases such as insulin-dependent diabetes mellitus (IDDM), Addison's disease, and autoimmune thyroid disease (e.g., Graves' disease and thyroiditis)), allergic ions and responses, food allergies, drug allergies, insect ies, rare allergic ers such as ytosis, allergic reaction, eczema including allergic or atopic eczema, asthma such as bronchial asthma and auto-immune asthma, conditions involving infiltration of myeloid cells and T cells and chronic inflammatory responses: The compounds of formula I of the present invention are also useful in the treatment of infectious diseases. Thus, they may be useful in the treatment of viral diseases, in particular for es caused by infection with viruses selected from the group consisting of papilloma viruses, such as human papilloma virus (HPV) and those that cause genital warts, common warts and plantar warts, herpes simplex virus (HSV), molluscum contagiosum, hepatitis B virus (HBV), hepatitis C virus (HCV), Dengue virus, variola virus, human immunodeficiency virus (HIV), cytomegalovirus (CMV), varicella zoster virus (VZV), rhinovirus, enterovirus, irus, coronavirus (e.g. SARS), influenza, mumps and parainfluenza.
They may also be useful in the treatment of bacterial diseases, in particular for diseases caused by infection with bacteria selected from the group ting of mycobacterium such as mycobacterium tuberculosis, mycobacterium avium and mycobacterium . The compounds of formula I of the present invention may further be useful in the treatment of other infectious diseases, such as chlamydia, fungal diseases, in particular fungal diseases selected from the group consisting of iasis, illosis and cryptococcal meningitis, and tic diseases such as Pneumocystis carnii, pneumonia, cryptosporidiosis, histoplasmosis, toxoplasmosis, trypanosome infection and leishmaniasis.
Thus, the expression "diseases which are mediated by TLR agonists" means diseases which may be d by activation of the immune system with TLR8 agonists such as cancer, autoimmune diseases, inflammation, sepsis, allergy, asthma, graft rejection, graft-versus-host disease, immunodeficiencies, and infectious diseases. In particular, the expression "diseases which are mediated by TLR agonists" means cancer, autoimmune diseases, inflammation, sepsis, allergy, asthma, graft rejection, graft-versus-host disease, immunodeficiencies, and infectious diseases.
In a particular aspect, the expression "which are ed by TLR agonists" s to cancer selected from the group consisting of bladder cancer, head and neck cancer, liver cancer, prostate cancer, ctal cancer, kidney cancer, breast cancer, lung cancer, ovarian cancer, cervical cancer, pancreatic cancer, bowel and colon cancer, stomach cancer, thyroid cancer, melanoma, skin and brain tumors and malignancies affecting the bone marrow such as leukemias and lymphoproliferative systems, such as Hodgkin's and non-Hodgkin's lymphoma; including the prevention (e.g. vaccination) and treatment of metastatic cancer and tumor recurrences, and oplastic syndromes.
The invention also relates to pharmaceutical compositions comprising a compound of a I as defined above and a ceutically able carrier and/or nt. More specifically, the invention relates to pharmaceutical compositions useful for the treatment of diseases which are which are mediated by TLR agonists.
Further, the invention relates to compounds of a I as defined above for use as eutically active substances, particularly as eutically active substances for the treatment of diseases which are which are mediated by TLR agonists. In particular, the invention relates to compounds of formula I for use in the treatment of cancers or autoimmune diseases or infectious diseases selected from the group consisting of viral diseases, ial diseases, fungal diseases and parasitic diseases.
Also described is a method for the treatment a of es which are mediated by TLR agonists, which method comprises administering a therapeutically active amount of a compound of formula I to a human being or animal. In particular, bed is a method for the treatment of cancers and infectious diseases selected from the group consisting of viral diseases, bacterial es, fungal diseases and parasitic diseases.
Also described is the use of compounds of formula I as defined above for the treatment of es which are mediated by TLR agonists.
In addition, the invention s to the use of compounds of formula I as d above for the preparation of medicaments for the treatment of diseases which are mediated by TLR agonists. In particular, the invention relates to the use of compounds of formula I as defined above for the preparation of medicaments for the treatment of cancers or autoimmune diseases or infectious diseases selected from the group consisting of viral diseases, bacterial diseases, fungal diseases and parasitic diseases.
In a further aspect, compounds of a I can be in combination with one or more additional ent modalities in a regimen for the treatment of cancer.
Combination therapy encompasses, in addition to the administration of a compound of the invention, the adjunctive use of one or more modalities that are effective in the ent of . Such modalities include, but are not d to, chemotherapeutic , immunotherapeutics, anti-angiogenic agents, cytokines, hormones, antibodies, polynucleotides, radiation and photodynamic therapeutic agents. In a specific aspect, combination therapy can be used to prevent the recurrence of cancer, inhibit metastasis, or inhibit the growth and/or spread of cancer or metastasis. As used herein, "in ation with" means that the compound of formula I is administered as part of a treatment regimen that comprises one or more additional treatment modalities as mentioned above. Therefore, also described is a method for the treatment of cancer, which method comprises administering a therapeutically active amount of a compound of formula I in combination with one or more other pharmaceutically active compounds to a human being or animal.
Compounds of formula I can be used alone or in ation with one or more additional treatment modalities in treating autoimmune diseases.
Combination therapy asses, in addition to the stration of a compound of the invention, the adjunctive use of one or more modalities that aid in the prevention or treatment of autoimmune diseases. Such modalities include, but are not limited to, chemotherapeutic agents, immunotherapeutics, anti-angiogenic agents, cytokines, hormones, antibodies, polynucleotides, radiation and photodynamic therapeutic agents. As used herein, "in combination with" means that the compound of formula I is stered as part of a treatment n that comprises one or more onal treatment modalities as ned above. Therefore, also described is a method for the treatment of autoimmune diseases, which method comprises administering a therapeutically active amount of a compound of formula I in combination with one or more other pharmaceutically active nds to a human being or animal.
In a further aspect, compounds of formula I can be used alone or in ation with one or more additional treatment ties in treating infectious diseases.
Combination therapy encompasses, in addition to the stration of a compound of the invention, the adjunctive use of one or more modalities that aid in the prevention or treatment of infectious diseases. Such ties include, but are not limited to, antiviral agents, antibiotics, and anti-fungal agents. As used herein, "in combination with" means that the compound of formula I is administered as part of a treatment regimen that comprises one or more additional treatment modalities as mentioned above. Therefore, also described is a method for the treatment of ious diseases, which method comprises administering a therapeutically active amount of a compound of formula I in ation with one or more other pharmaceutically active compounds to a human being or animal.
In this specification where reference has been made to patent specifications, other external documents, or other s of information, this is generally for the purpose of providing a context for sing the features of the invention. Unless specifically stated otherwise, reference to such external documents is not to be construed as an admission that such documents, or such sources of information, in any jurisdiction, are prior art, or form part of the common l knowledge in the art.
PHARMACOLOGICAL TEST The following tests were carried out in order to determine the activity of the compounds of formula I: For TLR8 and TLR7 activity g, HEK-Blue human TLR8 or TLR7 cells (Invivogen, San Diego, CA, USA) are used, respectively. These cells are ed for studying the stimulation of human TLR8 or TLR7 by monitoring the activation of NF-κB. A SEAP (secreted embryonic alkaline phosphatase) reporter gene is placed under the control of the IFN-b minimal promoter fused to five NF-κB and APbinding sites. Therefore the reporter expression is regulated by the NF-κB promoter upon stimulation of human TLR8 or TLR7 for 20 hours. The cell culture supernatant SEAP reporter activity was determined using Quanti Blue kit (Invivogen, San Diego, Ca, USA) at a wavelength of 640 nm, a detection medium that turns purple/blue in the presence of alkaline atase. EC50 values were determined using Activity Base analysis (ID Business Solution, Limited).
The compounds according to formula I have an activity (EC50 value) in the above assay for human TLR8 in the range of 0.01 nM to 0.05 μM, more particularly of 0.001 nM to 0.03 μM, s the activity (EC50 value) in the above assay for human TLR7 is greater than 10 μM, in the range of 12 μM to > 100 μM, meaning the compounds show high selectivity towards human TLR8.
For example, the following compounds showed the ing EC50 values in the assay described above: human TLR8 EC50 human TLR7 EC50 Example [µM] [µM] 1 0.001 80.8 2 0.001 >100 3 0.013 70.1 4 0.007 >100 0.003 >100 6 0.008 >100 7 0.015 >100 8 0.01 44 9 0.003 >100 0.002 >100 11 0.029 >100 12 0.004 >100 13 0.007 >100 14 0.001 >100 0.002 >100 16 0.014 >100 17 0.006 >100 18 0.002 34 19 0.005 >100 0.003 46 21 0.021 >100 human TLR8 EC50 human TLR7 EC50 [µM] [µM] 22 0.003 >100 23 0.001 >100 24 0.009 >100 0.018 >100 26 0.002 >100 27 0.005 28 28 0.001 >100 29 0.001 >100 0.002 >100 31 0.005 >100 32 0.002 >100 33 0.002 >100 34 0.002 >100 0.001 >100 36 0.031 >100 37 0.023 38 38 0.029 45 39 0.029 >100 40 0.001 >100 41 0.006 >100 42 0.017 >100 43 0.015 61 44 0.001 12 45 0.026 >100 46 0.01 >100 47 0.006 >100 48 0.016 >100 49 0.031 >100 50 0.01 >100 51 0.002 22 52 0.006 >100 53 0.002 20 54 0.003 >100 55 0.002 >100 56 0.01 >100 human TLR8 EC50 human TLR7 EC50 Example [µM] [µM] 57 0.025 >100 58 0.015 >100 59 0.003 >100 60 0.027 >100 61 0.005 >100 62 0.007 >100 63 0.011 >100 64 0.029 >100 65 0.006 >100 66 0.031 >100 67 0.004 >100 68 0.008 >100 69 0.008 >100 70 0.012 >100 71 0.029 >100 72 0.025 >100 73 0.01 >100 74 0.027 >100 75 0.01 >100 76 0.024 >100 77 0.008 >100 78 0.012 >100 79 0.002 31 80 0.017 >100 PHARMACEUTICAL COMPOSITIONS The compounds of formula I and their pharmaceutically acceptable salts can be used as ments, e.g., in the form of pharmaceutical preparations for enteral, parenteral or topical administration. The compounds of formula I and their pharmaceutically acceptable salts may be administered by systemic (e.g., eral) or local (e.g., l or intralesional injection) administration. In some instances, the pharmaceutical formulation is topically, erally, orally, vaginally, intrauterine, intranasal, or by inhalation administered. As described herein, certain tissues may be preferred targets for the TLR agonist. Thus, administration of the TLR agonist to lymph nodes, spleen, bone marrow, blood, as well as tissue exposed to virus, are red sites of administration.
In one aspect, the pharmaceutical formulation comprising the compounds of formula I or its pharmaceutically acceptable salts is stered parenterally. eral routes of administration include, but are not limited to, ermal, ucosal, nasopharyngeal, pulmonary and direct injection. Parenteral administration by injection may be by any parenteral ion route, including, but not limited to, intravenous (IV), including bolus and infusion (e.g., fast or slow), intraperitoneal (IP), intramuscular (IM), subcutaneous (SC) and intradermal (ID) routes. Transdermal and ucosal administration may be accomplished by, for example, inclusion of a carrier (e.g., dimethylsulfoxide, DMSO), by application of electrical impulses (e.g., iontophoresis) or a combination thereof. A variety of devices are available for ermal administration which may be used. Formulations of the compounds of formula I suitable for parenteral administration are generally formulated in USP water or water for injection and may further comprise pH buffers, salts bulking agents, preservatives, and other ceutically acceptable excipients.
Transdermal administration is accomplished by ation of a cream, rinse, gel, etc. capable of allowing the TLR agonist to penetrate the skin and enter the blood stream.
Compositions suitable for transdermal administration include, but are not d to, pharmaceutically acceptable suspensions, oils, creams and ointments applied directly to the skin or incorporated into a protective carrier such as a transdermal device lled "patch"). es of suitable creams, ointments etc. can be found, for instance, in the Physician' s Desk Reference. Transdermal transmission may also be accomplished by iontophoresis, for example using commercially available patches which deliver their product continuously through unbroken skin for periods of several days or more. Use of this method allows for controlled transmission of pharmaceutical compositions in relatively great concentrations, permits infusion of ation drugs and allows for contemporaneous use of an absorption promoter. Administration via the transdermal and transmucosal routes may be continuous or pulsatile.
Pulmonary administration is accomplished by inhalation, and includes delivery routes such as intranasal, transbronchial and transalveolar routes. Formulations of compounds of formula I suitable for administration by inhalation ing, but not limited to, liquid suspensions for forming aerosols as well as powder forms for dry powder inhalation ry systems are provided. Devices suitable for administration by tion include, but are not d to, atomizers, vaporizers, nebulizers, and dry powder inhalation delivery devices. Other methods of delivering to respiratory mucosa include delivery of liquid ations, such as by nose drops.
Administration by inhalation is preferably accomplished in discrete doses (e.g., via a metered dose inhaler), although delivery similar to an infusion may be accomplished through use of a nebulizer.
The compounds of formula I and pharmaceutically acceptable salts thereof may also be administered orally, e.g., in the form of tablets, coated tablets, dragées, hard and soft gelatine capsules.
The production of the pharmaceutical preparations can be effected in a manner which will be familiar to any person skilled in the art by ng the described compounds of formula I and their pharmaceutically acceptable salts, ally in combination with other therapeutically valuable substances, into a galenical administration form together with suitable, non-toxic, inert, therapeutically compatible solid or liquid carrier materials and, if desired, usual pharmaceutical adjuvants.
Suitable carrier materials are not only inorganic carrier materials, but also organic carrier materials. Thus, for example, lactose, corn starch or derivatives f, talc, stearic acid or its salts can be used as carrier materials for tablets, coated tablets, dragées and hard gelatine capsules. le carrier materials for soft ne capsules are, for e, vegetable oils, waxes, fats and semi-solid and liquid polyols (depending on the nature of the active ingredient no carriers might, however, be required in the case of soft ne capsules). Suitable carrier materials for the production of solutions and syrups are, for example, water, polyols, sucrose, invert sugar and the like. Suitable r materials for injection solutions are, for example, water, alcohols, s, glycerol and vegetable oils. Suitable carrier als for suppositories are, for example, natural or hardened oils, waxes, fats and iquid or liquid polyols. Suitable r materials for topical preparations are glycerides, semi-synthetic and synthetic glycerides, hydrogenated oils, liquid waxes, liquid paraffins, liquid fatty alcohols, sterols, polyethylene glycols and cellulose derivatives.
Usual stabilizers, preservatives, wetting and fying agents, consistency-improving agents, flavour-improving agents, salts for varying the c pressure, buffer substances, lizers, colorants and g agents and antioxidants come into consideration as pharmaceutical adjuvants.
The dosage of the compounds of formula I can vary within wide limits depending on the disease to be controlled, the age and the individual condition of the patient and the mode of administration, and will, of course, be fitted to the individual ements in each particular case.
For adult patients a daily dosage of about 1 to 1000 mg, especially about 1 to 300 mg, comes into consideration. Depending on severity of the disease and the precise pharmacokinetic profile the compound could be administered with one or several daily dosage units, e.g., in 1 to 3 dosage units.
The ceutical preparations conveniently contain about 1-500 mg, preferably 1-100 mg, of a compound of formula I.
The ing examples C1 to C3 rate typical compositions of the present invention, but serve merely as representative thereof.
Example C1 Film coated tablets containing the following ingredients can be manufactured in a conventional manner: Ingredients Per tablet Kernel: Compound of formula I 10.0 mg 200.0 mg Microcrystalline cellulose 23.5 mg 43.5 mg Lactose s 60.0 mg 70.0 mg Povidone K30 12.5 mg 15.0 mg Sodium starch glycolate 12.5 mg 17.0 mg Magnesium stearate 1.5 mg 4.5 mg (Kernel Weight) 120.0 mg 350.0 mg Film Coat: Hydroxypropyl methyl cellulose 3.5 mg 7.0 mg Polyethylene glycol 6000 0.8 mg 1.6 mg Talc 1.3 mg 2.6 mg Iron oxide (yellow) 0.8 mg 1.6 mg Titanium dioxide 0.8 mg 1.6 mg The active ingredient is sieved and mixed with microcrystalline cellulose and the mixture is granulated with a solution of polyvinylpyrrolidone in water. The granulate is mixed with sodium starch glycolate and magnesiumstearate and compressed to yield kernels of 120 or 350 mg respectively. The s are lacquered with an aqueous solution / suspension of the above mentioned film coat.
Example C2 Capsules ning the following ingredients can be manufactured in a conventional manner: Ingredients Per capsule nd of a I 25.0 mg Lactose 150.0 mg Maize starch 20.0 mg Talc 5.0 mg The components are sieved and mixed and filled into capsules of size 2.
Example C3 Injection ons can have the following composition: Compound of formula I 3.0 mg Polyethylene glycol 400 150.0 mg Acetic acid q.s. ad pH 5.0 Water for injection solutions ad 1.0 ml The active ingredient is dissolved in a mixture of Polyethylene Glycol 400 and water for injection (part). The pH is ed to 5.0 by acetic acid. The volume is adjusted to 1.0 ml by addition of the residual amount of water. The solution is ed, filled into vials using an appropriate e and ized.
The following examples serve to illustrate the present invention in more detail. They are, however, not intended to limit its scope in any manner.
Examples Abbreviations used therein: Boc2O = di-tert-butyl dicarbonate, Boc = t-butyl carbamate, calc’d = calculated, CD3OD = deuterated methanol, d = day, DIPEA = N,N-diisopropylethylamine, DCM = dichloromethane, DMAP: 4-dimethylaminopyridine, DMF-DMA: N,N-dimethylformamide dimethyl acetal, EA = ethyl acetate or EtOAc, EC50 = half maximal effective concentration, EDCI = 1-(3- dimethylaminopropyl)ethylcarbodiimide hydrochloride, h or hr = hour, HOBT = N- hydroxybenzotriazole, HBTU= zotriazolyl)-N,N,N',N'-tetramethyluronium hexafluorophosphate, DMAP = 4-dimethylaminopyridine, TBAI = N,N,N-tributyl butanaminiuiodide , HPLC = high performance liquid chromatography, HPLC-UV = high performance liquid chromatography with ultraviolet detector, Hz = hertz, mg = milligram, MHz = megahertz, min = minute(s), mL = milliliter, mm = millimeter, mM = mmol/L, mmol = millimole, MS = mass spectrometry, MW = molecular weight, NMR = nuclear magnetic nce, PE = petroleum ether, prep-HPLC = preparative high performance liquid chromatography, rt = room temperature, sat. = sat., TBS = tert-butyldimethylsilyl, sxt = sextet, TEA = triethylamine, TFA = trifluoroacetic acid, THF = tetrahydrofuran, µM = micromole/L, µm = micrometer, UV = ultraviolet detector, OD = optical density, Pd(dppf)2Cl2 = [1,1′- Bis(diphenylphosphino)-ferrocene]dichloropalladium(II), TLR8 = toll-like receptor 8, TLR7 = toll-like receptor 7,NF-κB = nuclear factor kappa-light-chain-enhancer of activated B cells, SEAP = secreted nic ne phosphatase, IFN-β = interferon-beta.
Example A – Preparation of key intermediate A 2-Aminomethoxycarbonyl-3Hbenzazepinecarboxylic acid A detailed tic route is provided in Scheme 2.
Scheme 2 DMF-DMA NaIO 4 Fe, AcOH HCl/dioxane a) Preparation of nd B To a solution of methyl 4-methylnitrobenzoate (100 g, 0.51 mol) in DMF (1 L) was added DMF-DMA (73 g, 0.61 mol). The reaction mixture was heated to 105 °C for 18 hrs. Then the solvent was removed in vacuo to give methyl 4-(2-(dimethylamino)vinyl)nitrobenzoate (compound B, 127 g, crude) which was used in the next step without purification. MS: calc’d 251 (M+H)+, measured 251(M+H)+. b) Preparation of Compound C To a solution of NaIO4 (327 g, 1.53 mol) in a mixed solvent of THF (1.3 L) and water (2.0 L) was added a THF (0.7 L) solution of methyl 4-(2-(dimethylamino)vinyl)nitrobenzoate (compound A, 127 g, 0.51 mol) at 10 °C. After the reaction mixture was stirred at 25 °C for 18 hrs, the mixture was filtered and then ted with EA. The organic layer was washed with brine, dried over anhydrous Na2SO4, filtered and concentrated to give the crude product. The crude t was ed by silica gel column chromatography (PE:EA = 20:1-10:1) to give methyl 4-formylnitrobenzoate (compound C, 84 g, 79%) as a yellow solid. MS: calc’d 210 (M+H)+, measured 210 . c) Preparation of Compound D To a solution of tert-butyl 2-(triphenylphosphoranylidene)acetate (300 g, 0.797 mol) in EA (2 L) was added oacetonitrile (57 g, 0.479 mol) at 25 °C. The reaction was heated to reflux for 18 hrs. After it was cooled to ambient ature, the solid was filtered and the filtrate was concentrated. The residue was purified by triturating from EA and PE (200 mL, 2.5:1) to give the desired t tert-butyl 3-cyano(triphenylphosphoranylidene)propanoate (compound D, 125 g, 63%) as a white solid. MS: calc’d 416 (M+H)+, measured 416 (M+H)+. d) Preparation of Compound E To a solution of 4-formylnitrobenzoate (compound C, 50 g, 0.24 mol) in toluene (600 mL) was added tert-butyl 3-cyano(triphenylphosphoranylidene)propanoate (compound D, 109 g, 0.26 mol) at 25 °C. After the reaction mixture was stirred at 25 °C for 18 hrs, it was cooled in ice-bath for 1 hr. The precipitate was collected and dried to give the desired product as a white solid. The filtrate was concentrated and treated with EtOH (120 mL). The undissolved material was filtered and the te was concentrated to give an additional batch of the desired product.
These two batches were combined to give methyl 4-(3-(tert-butoxy)(cyanomethyl) oxopropenyl)nitrobenzoate (compound E, 60 g, 72%). MS: calc’d 347 , measured 347 (M+H)+. e) Preparation of nd F To a solution of methyl 4-(3-(tert-butoxy)(cyanomethyl)oxopropenyl) nitrobenzoate (compound E, 30 g, 87 mmol) in AcOH (450 mL) was added Fe powder (29.1 g, 520 mmol) at 60 °C. After the reaction mixture was heated at 85 °C for 3 hrs, it was filtered through celite and the precipitate was washed with acetic acid. The filtrate was concentrated in vacuo and the residue was carefully basified with aqueous sat. NaHCO3 solution (300 mL). Then EA (600 mL) was added. The mixture was filtered through celite and the itate was washed with EA (200 mL). The filtrate was then washed with water, dried over Na2SO4 and concentrated in vacuo to get -butyl 8-methyl 2-amino-3H-benzo[b]azepine-4,8-dicarboxylate und F, 25 g, 93%) as a light yellow solid. MS: calc’d 317 (M+H)+, measured 317 (M+H)+. f) Preparation of Compound A To a solution of 4-tert-butyl 8-methyl 2-amino-3H-benzo[b]azepine-4,8-dicarboxylate (compound F, 25 g, 80 mmol) in dioxane (400 mL) was added a 1 M solution of HCl in dioxane (600 mL) at 0 °C. After the reaction mixture was stirred at 25 °C for 18 hrs, it was concentrated in vacuo to give 2-amino(methoxycarbonyl)-3H-benzo[b]azepinecarboxylic acid hydrochloride (compound A, 25 g, crude) which was used in the next step without any purification. MS: calc’d 261 (M+H)+, ed 261 (M+H)+.
Example B – Preparation of key intermediate J 2-(tert-butoxycarbonylamino)(dipropylcarbamoyl)-3Hbenzazepinecarboxylic acid A detailed synthetic route is provided in Scheme 3. g) ation of Compound G To a mixture of 2-amino(methoxycarbonyl)-3H-benzo[b]azepinecarboxylic acid hydrochloride und A, 19 g, 64 mmol), HBTU (29 g, 77 mmol), DIPEA (33 g, 257 mmol) in DMF (400 mL) was added di-n-propylamine (13 g, 128 mmol) at 0 °C. After the reaction mixture was stirred for 2 hrs at 20 °C, it was quenched with sat. NH4Cl (500 mL), diluted with H2O (1 L), and extracted with EA (300 mL × 3). The combined organic layers were washed with brine (300 mL × 2), dried over Na2SO4 and concentrated to give the crude product. The crude t was purified by silica gel silica gel column chromatography (PE:EA = 1:1) to give methyl 2-amino(dipropylcarbamoyl)-3H-benzo[b]azepinecarboxylate (compound G, 18 g, 82%) as a yellow solid. MS: calc’d 344 (M+H)+, measured 344 (M+H)+.
Scheme 3 HBTU, DIPEA A TEA , Boc G aq. LiOH h) ation of Compound H To a e of methyl 2-amino(dipropylcarbamoyl)-3H-benzo[b]azepine carboxylate (compound G, 18 g, 53 mmol) and TEA (16 g, 157 mmol) in DCM (300 mL) was added Boc2O (17 g, 79 mmol) at 0 °C. After the mixture was stirred for 16 hrs at 20 °C, it was quenched with sat. NH4Cl (300 mL), diluted with H2O (500 mL), and ted with DCM (100 mL × 3). The combined organic layers were washed with brine (100 mL × 2), dried over Na2SO4 and concentrated to give the crude product. The crude product was purified by silica gel column chromatography (PE:EA = 3:1) to give methyl 2-((tert-butoxycarbonyl)amino) (dipropylcarbamoyl)-3H-benzo[b]azepinecarboxylate (compound H, 21 g, yield: 91%) as a yellow solid. MS: calc’d 444 (M+H)+, measured 444 (M+H)+. i) Preparation of Compound J To a solution of methyl 2-((tert-butoxycarbonyl)amino)(dipropylcarbamoyl)-3H- benzo[b]azepinecarboxylate (compound H, 5.0 g, 11.3 mmol) in THF/ H2O (1/1, 100 mL,) was added aq. LiOH solution (1 M , 17 mL, 17 mmol) at 0 oC. Then the mixture was warmed to oC and stirred for 6 hrs. The mixture was poured into ice-water (150 mL), acidified with aq. citric acid (5%) to pH = 5 and extracted with EtOAc (100 mL × 3). The combined organic layers were washed with brine (100 mL × 2), dried over Na2SO4 and concentrated in vacuo to give 2- (tert-butoxycarbonylamino)(dipropylcarbamoyl)-3Hbenzazepinecarboxylic acid (compound J, 4.0 g, 83.3 %) as a yellow solid. 1H NMR (400MHz, DMSO-d6) δ ppm = 7.78 - 7.72 (m, 1H), 7.64 (dd, J = 1.5, 8.0 Hz, 1H), 7.55 (d, J = 8.3 Hz, 1H), 6.93 - 6.89 (m, 1H), 3.14 (s, 6H), 1.54 (br. s., 4H), 1.44 (s, 9H), 0.80 (br. s., 6H). MS: calc’d 430 (M+H)+, measured 430 (M+H)+.
Example 1 2-Amino-N4,N4-dipropyl-N8-(3-pyridyl)-3Hbenzazepine-4,8-dicarboxamide Example 1 can be prepared according to general procedure in scheme 1. A ed synthetic route is provided in Scheme 4.
Scheme 4 J K Preparation of Example 1: To a solution of t-butoxycarbonylamino)(dipropylcarbamoyl)-3Hbenzazepine- 8-carboxylic acid (compound J, 80 mg, 0.186 mmol) in DCM (4 mL) was added EDCI (49 mg, 0.466 mmol), HOBT (19.6 mg, 0.220 mmol), DIPEA (96 mg, 0.744 mmol) and DMAP (6 mg, 0.046 mmol) at 10 °C. After the reaction was stirred for 30 minutes at 25 °C, pyridinamine (27 mg, 0.280 mmol) was added and the reaction mixture was stirred overnight. Water (2 mL) was added and the mixture was extracted with DCM (10 mL). The organic layer was washed successively with 5% citric acid, sat NaHCO3, and concentrated to give the crude product K (70 mg), which was dissolved in DCM (1.5 mL). To this DCM solution was added a solution of TFA (566 mg, 4.9 mmol) in DCM (0.5 mL) at 0 °C. After the reaction mixture was stirred at 20 °C for 4 hrs, it was concentrated and the residue was basified to pH 8 with sat.NaHCO3. The aqueous layer was extracted with DCM, dried over Na2SO4 and concentrated in vacuo to give the crude product that was purified by prep-HPLC to give 2-amino-N4,N4-dipropyl-N8-(3-pyridyl)-3H benzazepine-4,8-dicarboxamide (Example 1, 6.7 mg) as a white solid. 1H NMR (300 MHz, CDCl3) δ ppm = 8.64 (d, J = 2.3 Hz, 1H), 8.32 (d, J = 3.8 Hz, 1H), 8.29 - 8.14 (m, 2H), 7.62 (s, 1H), 7.56 (d, J = 7.9 Hz, 1H), 7.33 (d, J = 8.3 Hz, 1H), 7.26 (dd, J = 4.9, 8.3 Hz, 1H), 6.75 (s, 1H), 3.41 (d, J = 9.8 Hz, 4H), 2.74 (s, 2H), 1.63-1.56(m, 4H), 0.86 (t, J = 7.2 Hz, 6H). MS: calc’d 406 (M+H)+, measured 406 (M+H)+.
Example 2 o-N4,N4-dipropyl-N8-pyrimidinyl-3Hbenzazepine-4,8-dicarboxamide The title compound was ed in y to Example 1 by using pyrimidinamine d of pyridinamine. Example 2 was obtained as a white solid (5.1 mg). 1H NMR (400 MHz, CDCl3) δ ppm = 9.18 (s, 2H), 9.03 - 8.95 (m, 1H), 8.71 - 8.54 (m, 1H), 7.80 - 7.62 (m, 2H), 7.45 - 7.37 (m, 1H), 6.85 - 6.76 (m, 1H), 3.58 - 3.37 (m, 4H), 2.94 - 2.82 (m, 2H), 2.02 - 1.86 (m, 4H), 0.95 (br. s., 6H). MS: calc’d 407 (M+H)+, measured 407 (M+H)+.
Example 3 2-Amino-N4,N4-dipropyl-N8-(4-pyridyl)-3Hbenzazepine-4,8-dicarboxamide The title nd was prepared in analogy to Example 1 by using pyridinamine instead of pyridinamine. Example 3 was obtained as a yellow solid (15 mg). 1H NMR (400 MHz, DMSO-d6) δ ppm = 12.02 - 11.94 (m, 1H), 10.09 - 10.00 (m, 1H), 9.24 - 9.16 (m, 1H), 8.85 - 8.75 (m, 2H), 8.48 - 8.40 (m, 2H), 8.17 - 8.10 (m, 1H), 8.08 - 8.03 (m, 1H), 7.82 - 7.73 (m, 1H), 7.09 (s, 1H), 3.38 (br. s., 6H), 1.59 (d, J = 7.0 Hz, 4H), 1.03 - 0.67 (m, 6H). MS: calc’d 406 (M+H)+, measured 406 (M+H)+.
Example 4 o-N8-phenyl-N4,N4-dipropyl-3Hbenzazepine-4,8-dicarboxamide The title compound was prepared in analogy to Example 1 by using aniline instead of pyridinamine. Example 4 was obtained as a white solid (30 mg). 1H NMR (300 MHz, DMSO- d6) δ ppm = 10.49 - 10.40 (m, 1H), 9.96 - 9.87 (m, 1H), 9.09 - 8.97 (m, 1H), 8.03 - 7.91 (m, 2H), 7.82 - 7.67 (m, 3H), 7.43 - 7.32 (m, 2H), 7.20 - 7.09 (m, 1H), 7.09 - 7.02 (m, 1H), 3.31 - 3.14 (m, 6H), 1.69 - 1.45 (m, 4H), 1.04 - 0.69 (m, 6H). MS: calc’d 405 (M+H)+, measured 405 (M+H)+.
Example 5 2-Amino-N8-[6-(aminomethyl)pyridyl]-N4,N4-dipropyl-3Hbenzazepine-4,8- dicarboxamide The title compound was prepared in analogy to Example 1 by using tert-butyl ((5- yridinyl)methyl)carbamate instead of pyridinamine. e 5 was obtained as a gray gum (17 mg). 1H NMR (400 MHz, DMSO-d6) δ ppm = 10.05 (br. s., 1H), 9.22 (s, 1H), 9.07 (d, J = 2.01 Hz, 1H), 8.46 (br. s., 3H), 8.30 (dd, J = 2.26, 8.53 Hz, 1H), 8.07 (d, J = 8.16 Hz, 1H), 8.02 (s, 1H), 7.74 (d, J = 8.28 Hz, 1H), 7.56 (d, J = 8.66 Hz, 1H), 7.06 (s, 1H), 4.18 (d, J = 5.65 Hz, 2H), 3.29-3.39 (m, 6H), 1.52-1.65 (m, 4H), 0.74-0.98 (m, 6H) . MS: calc’d 435 (M+H)+, measured 435 .
Example 6 2-Amino-N8-[5-(hydroxymethyl)pyridyl]-N4,N4-dipropyl-3Hbenzazepine-4,8- dicarboxamide The title compound was prepared in analogy to Example 1 by using 5-(((tertbutyldimethylsilyl )oxy)methyl)pyridinamine (Compound 6A) instead of pyridinamine.
Example 6 was obtained as a yellow gum (9.6 mg). 1H NMR (400 MHz, CD3OD) δ ppm = 9.55 - 9.47 (m, 1H), 8.85 - 8.78 (m, 1H), 8.63 - 8.58 (m, 1H), 8.14 - 8.04 (m, 2H), 7.81 - 7.73 (m, 1H), 7.17 - 7.12 (m, 1H), 4.87 - 4.78 (m, 2H), 3.56 - 3.38 (m, 6H), 1.79 - 1.64 (m, 4H), 1.10 - 0.86 (m, 6H). MS: calc’d 436 (M+H)+, measured 436 (M+H)+. ation of ert-butyldimethylsilyl)oxy)methyl)pyridinamine und 6A): TBSCl, imidazole 6A To a mixture of (5-aminopyridinyl)methanol (100 mg, 0.8 mmol) and imidazole (160 mg, 2.4 mmol) in DMF (3 mL) was added TBSCl (145 mg, 1.0 mmol) at 0 °C. After the reaction mixture was d at 20 °C for 16 hrs, water (10 mL) was added and the mixture was extracted with EA (3 mL × 3). The combined organic layers were washed with sat. NH4Cl, brine, dried over Na2SO4 and concentrated to give 5-(((tert-butyldimethylsilyl)oxy)methyl)pyridinamine (compound 6A) (110 mg) which was used in the next step without any purification. MS: calc’d 239 (M+H)+, measured 239 (M+H)+.
Example 7 2-Amino-N8-[6-(hydroxymethyl)pyridyl]-N4,N4-dipropyl-3Hbenzazepine-4,8- dicarboxamide The title compound was prepared in analogy to Example 6 by using (5-aminopyridin yl)methanol instead of (5-aminopyridinyl)methanol. Example 7 was obtained as a yellow gum (17 mg). 1H NMR (400 MHz, CD3OD) δ ppm = 9.53 (s, 1H), 8.82 (d, J = 8.78 Hz, 1H), 8.13 (s, 1H), 8.09 (d, J = 8.16 Hz, 1H), 8.02 (d, J = 8.78 Hz, 1H), 7.76 (d, J = 8.16 Hz, 1H), 7.14 (s, 1H), .01 (s, 2H), 3.49 (br. s., 4H), 3.42 (s, 2H), 1.72 (sxt, J = 7.38 Hz, 4H), 0.97 (dd, J = 7.34, 14.87 Hz, 6H). MS: calc’d 436 (M+H)+, measured 436 (M+H)+.
Example 8 o-N8-(3-methylsulfonylphenyl)-N4,N4-dipropyl-3Hbenzazepine-4,8- dicarboxamide The title nd was prepared in y to Example 1 by using 3-(methylsulfonyl)- aniline instead of pyridinamine. Example 8 was obtained as a yellow solid (12.1 mg). 1H NMR (400 MHz, CD3OD) δ ppm = 8.52 - 8.44 (m, 1H), 8.10 - 8.04 (m, 1H), 8.04 - 7.98 (m, 2H), 7.81 - 7.63 (m, 3H), 7.14 (s, 1H), 3.49 (br. s., 4H), 3.42 - 3.37 (m, 2H), 3.18 (s, 3H), 1.72 (m, 4H), 0.99 (br. s., 6H). MS: calc’d 483 (M+H)+, measured 483 (M+H)+.
Example 9 2-Amino-N4,N4-dipropyl-N8-thiazolyl-3Hbenzazepine-4,8-dicarboxamide The title compound was prepared in analogy to Example 1 by using thiazolamine instead of pyridinamine. Example 9 was obtained as a yellow solid (17.4 mg). 1H NMR (300 MHz, DMSO-d6) δ ppm = 12.16 - 12.07 (m, 1H), 10.02 - 9.92 (m, 1H), 9.16 - 9.05 (m, 1H), 8.73 - 8.67 (m, 1H), 8.09 - 7.97 (m, 2H), 7.94 - 7.87 (m, 1H), 7.79 - 7.70 (m, 1H), 7.10 - 7.00 (m, 1H), 3.42 - 3.25 (m, 6H), 1.67 - 1.48 (m, 4H), 1.00 - 0.70 (m, 6H). MS: calc’d 412 (M+H)+, measured 412 (M+H)+.
Example 10 2-Amino-N8-(4-chlorophenyl)-N4,N4-dipropyl-3Hbenzazepine-4,8-dicarboxamide The title compound was prepared in analogy to Example 1 by using 4-chloroaniline d of namine. Example 10 was obtained as a yellow solid (14.8 mg). 1H NMR (400 MHz, CD3OD) δ ppm = 7.94-8.00 (m, 2H), 7.69-7.78 (m, 3H), 7.37-7.43 (m, 2H), 7.13 (s, 1H), 3.50 (br. s., 4H), 3.34 (s, 2H), 1.72 (sxt, J = 7.50 Hz, 4H), 0.98 (br. s., 6H). MS: calc’d 439 (M+H)+, measured 439 (M+H)+ Example 11 2-Amino-N4,N4-dipropyl-N8-thiazolyl-3Hbenzazepine-4,8-dicarboxamide The title compound was prepared in analogy to Example 1 by using thiazolamine instead of pyridinamine. Example 11 was obtained as a white solid (44 mg). 1H NMR (400 MHz, OL-d4) δ ppm = 7.91 (s, 1H), 7.87 (d, J = 8 Hz, 1H), 7.60 (d, J = 8 Hz, 1H), 7.50 (d, J = 4 Hz, 1H), 7.18 (d, J = 4 Hz, 1H), 7.01 (s, 1H), 4.94 (m, 2H), 3.44 (m, 4H), 1.71 - 1.65 (m, 4H), 0.96 - 0.89 (m, 6H). MS: calc’d 412 (M+H)+, measured 412 (M+H)+.
Example 12 o-N8-(3-methylimidazolyl)-N4,N4-dipropyl-3Hbenzazepine-4,8- dicarboxamide The title compound was prepared in analogy to Example 1 by using 1-methyl-1H- imidazolamine instead of pyridinamine. Example 12 was obtained as a yellow solid (12 mg). 1H NMR (300 MHz, CD3OD) δ ppm = 8.99 - 8.92 (m, 1H), 8.12 - 8.00 (m, 2H), 7.79 - 7.72 (m, 1H), 7.71 - 7.65 (m, 1H), 7.17 - 7.09 (m, 1H), 3.96 - 3.84 (m, 3H), 3.58 - 3.37 (m, 6H), 1.83 - 1.62 (m, 4H), 1.09 - 0.86 (m, 6H). MS: calc’d 409 (M+H)+, measured 409 (M+H)+.
Example 13 2-Amino-N8-(4-fluorophenyl)-N4,N4-dipropyl-3Hbenzazepine-4,8-dicarboxamide The title compound was prepared in analogy to Example 1 by using 4-fluoroaniline instead of namine. Example 13 was obtained as a yellow solid (22 mg). 1H NMR (400 MHz, CD3OD) δ ppm = 7.94-8.01 (m, 2H), 7.67-7.79 (m, 3H), 7.09-7.21 (m, 3H), 3.49 (br. s., 4H), 3.33-3.35 (m, 2H), 1.72 (sxt, J = 7.48 Hz, 4H), 0.97 (br. s., 6H). MS: calc’d 423 , measured 423 (M+H)+.
Example 14 2-Amino-N8-(m-tolyl)-N4,N4-dipropyl-3Hbenzazepine-4,8-dicarboxamide The title compound was prepared in analogy to Example 1 by using m-toluidine instead of pyridinamine. Example 14 was obtained as a white solid (38 mg). 1H NMR (400 MHz, CD3OD) δ ppm = 7.93-8.01 (m, 2H), 7.67-7.74 (m, 1H), 7.49-7.59 (m, 2H), 7.28 (t, J = 7.84 Hz, 1H), 7.12 (s, 1H), 7.03 (d, J = 7.65 Hz, 1H), 3.49 (br. s., 4H), 3.39 (s, 2H), 2.39 (s, 3H), 1.72 (sxt, J = 7.45 Hz, 4H), 0.98 (br. s., 6H). MS: calc’d 419 (M+H)+, ed 419 (M+H)+.
Example 15 2-Amino-N4,N4-dipropyl-N8-[3-(pyrrolidinecarbonyl)phenyl]-3Hbenzazepine-4,8- oxamide The title compound was prepared in analogy to Example 1 by using (3-aminophenyl)- (pyrrolidinyl)methanone (compound 15A) instead of pyridinamine. Example 15 was obtained as a yellow gum (15 mg). 1H NMR (400 MHz, CD3OD) δ ppm = 7.94-8.04 (m, 3H), 7.84 (d, J = 8.03 Hz, 1H), 7.72 (d, J = 8.28 Hz, 1H), 7.49 (t, J = 7.84 Hz, 1H), 7.35 (d, J = 7.53 Hz, 1H), 7.13 (s, 1H), 3.64 (t, J = 6.90 Hz, 2H), 3.43-3.58 (m, 6H), 3.40 (s, 2H), 1.91-2.08 (m, 4H), 1.66-1.78 (m, 4H), 0.87-1.07 (m, 6H). MS: calc’d 502 (M+H)+, measured 502 (M+H)+.
Preparation of (3-aminophenyl)(pyrrolidinyl)methanone (Compound 15A): O OH O N HN HBTU To a mixture of 3-aminobenzoic acid (500 mg, 3.6 mmol), HBTU (1.6 g, 4.3 mmol), DIPEA (930 mg, 7.2 mmol) in DMF (50 mL) was added pyrrolidine (380 mg, 5.4 mmol) at 0 °C. After the reaction mixture was stirred for 16 hrs at 20 °C, it was quenched with sat. NH4Cl (50 mL), d with H2O (200 mL), and extracted with EA (100 mL × 2). The combined organic layers were washed with brine (100 mL × 2), dried over Na2SO4 and concentrated to give the crude product that was purified by silica gel column chromatography (PE: EA = 1:1) to give (3- aminophenyl)(pyrrolidinyl)methanone (compound 15A, 400 mg, 60%) as yellow solid. MS: calc’d 191 (M+H)+, measured 191 (M+H)+. e 16 2-Amino-N4,N4-dipropyl-N8-[5-(pyrrolidinecarbonyl)pyridyl]-3Hbenzazepine-4,8- dicarboxamide The title compound was prepared in y to Example 1 by using (5-aminopyridin yl)(pyrrolidinyl)methanone (Compound 16A) instead of namine. Example 16 was obtained as a yellow gum (3.1 mg). 1H NMR (300 MHz, CD3OD) δ ppm = 9.39 - 9.32 (m, 1H), 8.83 - 8.66 (m, 2H), 8.13 - 8.02 (m, 2H), 7.80 - 7.72 (m, 1H), 7.18 - 7.11 (m, 1H), 3.72 - 3.56 (m, 4H), 3.55 - 3.43 (m, 4H), 3.42 - 3.38 (m, 2H), 2.14 - 1.93 (m, 4H), 1.81 - 1.63 (m, 4H), 1.08 - 0.81 (m, 6H). MS: calc’d 503 (M+H)+, measured 503 (M+H)+.
Preparation of (5-aminopyridinyl)(pyrrolidinyl)methanone (Compound 16A): A solution of 5-nitronicotinic acid (200 mg, 1.19 mmol) in DCM (4 mL) was added HBTU (544 mg, 1.43 mmol), DIPEA (307 mg, 2.38 mmol) and pyrrolidine (101 mg, 1.43 mmol) at 0 °C.
The reaction mixture was stirred at 25 °C for 18 hrs. Water (10 mL) was added, and the mixture was extracted with EA (10 mL). The organic layer was washed with brine, dried over anhydrous Na2SO4 and concentrated to give the crude product. The crude product was purified by silica gel column chromatography (PE:EA=1:1) to give the desired product (5-nitropyridin yl)(pyrrolidinyl)methanone (240 mg, 92%) as a yellow solid. MS: calc’d 222 (M+H)+, measured 222 (M+H)+.
To a solution of (5-nitropyridinyl)(pyrrolidinyl)methanone (240 mg, 1.13 mmol) in MeOH (5 mL) was added Pd/C(30 mg) at 25 °C. The reaction mixture was stirred at 25 °C under 1 atmosphere pressure of H2 for 18 hrs. The mixture was filtered and trated to give the d product (5-aminopyridinyl)(pyrrolidinyl)methanone (compound 16A, 180 mg, 87%) as a yellow solid. MS: calc’d 192 (M+H)+, measured 192 . e 17 2-Amino-N8-[3-(2-aminoethyl)phenyl]-N4,N4-dipropyl-3Hbenzazepine-4,8- dicarboxamide The title compound was prepared in analogy to Example 1 by using utyl N-[2-(3- aminophenyl)ethyl]carbamate instead of pyridinamine. Example 17 was obtained as a white solid (20 mg). 1H NMR (400 MHz, CD3OD) δ ppm = 7.70-7.99 (m, 3H), .68 (m, 2H), 7.39 (t, J = 7.9 Hz, 1H), 7.13 (d, J = 7.5 Hz, 1H), 6.90-7.07 (m, 1H), 3.47 (br. s., 4H), 3.33 (dt, J = 3.1, 1.6 Hz, 2H), 3.14-3.27 (m, 2H), 3.01 (t, J = 7.2 Hz, 2H), 1.54-1.81 (m, 4H), 0.70-1.14 (m, 6H). MS: calc’d 448(M+H)+, measured 448(M+H)+.
Example 18 2-Amino-N8-(5-methylpyridyl)-N4,N4-dipropyl-3Hbenzazepine-4,8-dicarboxamide The title nd was prepared in analogy to e 1 by using 5-methylpyridin amine instead of pyridinamine. Example 18 was obtained (12.5 mg) as a yellow solid. 1H NMR (300 MHz, DMSO-d6) δ ppm = 10.39 - 10.32 (m, 1H), 8.79 - 8.72 (m, 1H), 8.18 - 8.05 (m, 2H), 7.70 - 7.63 (m, 1H), 7.52 - 7.37 (m, 2H), 6.98 - 6.85 (m, 2H), 6.81 - 6.75 (m, 1H), 3.31 - 3.28 (m, 4H), 2.77 - 2.70 (m, 2H), 2.36 - 2.29 (m, 3H), 1.66 - 1.47 (m, 4H), 0.97 - 0.66 (m, 6H).
MS: calc’d 420 (M+H)+, measured 420 (M+H)+.
Example 19 2-Amino-N8-(3-fluorophenyl)-N4,N4-dipropyl-3Hbenzazepine-4,8-dicarboxamide The title compound was prepared in analogy to Example 1 by using 3-fluoroaniline instead of pyridinamine. Example 19 was obtained as a yellow solid (50 mg). 1H NMR (400 MHz, DMSO-d6) δ ppm = 10.6 (brs, 1H), 9.89 (brs, 1H), 8.98 (brs, 1H), 8.00 - 7.92 (m, 2H), 7.80 - 7.69 (m, 2H), 7.61 - 7.55 (m, 1H), 7.47 - 7.30 (m, 1H), 7.08 - 7.05 (m, 1H), 7.02 - 6.95 (m, 1H), 3.30 - 3.28 (m, 6H), 1.61 - 1.58 (m, 4H), 0.92 - 0.83 (m, 6H). MS: calc’d 423 (M+H)+, measured 423 (M+H)+.
Example 20 2-Amino-N8-(5-fluoropyridyl)-N4,N4-dipropyl-3Hbenzazepine-4,8-dicarboxamide The title compound was prepared in analogy to e 1 by using 5-fluoropyridin amine instead of pyridinamine. Example 20 was obtained as a yellow solid (8 mg). 1H NMR (400 MHz, CD3OD) δ ppm = 9.32 (br. s., 1H), 8.55-8.83 (m, 2H), .16 (m, 2H), 7.76 (d, J = 8.03 Hz, 1H), 7.10-7.18 (m, 1H), 3.49 (br. s., 4H), 3.42 (br. s., 2H), 1.72 (sxt, J = 7.28 Hz, 4H), 0.97 (d, J = 10.67 Hz, 6H). MS: calc’d 424 , measured 424 (M+H)+.
Example 21 2-Amino-N8-(2-methylpyridyl)-N4,N4-dipropyl-3Hbenzazepine-4,8-dicarboxamide The title compound was prepared in analogy to Example 1 by using 2-methylpyridin amine instead of pyridinamine. Example 21 was obtained as a yellow gum (60 mg). 1H NMR (400 MHz, DMSO-d6) δ ppm = 11.01 (br. s., 1H), 10.04 (br. s., 1H), 9.22 (br. s., 1H), 8.64-8.71 (m, 1H), 8.55 (br. s., 1H), 8.01-8.13 (m, 2H), 7.90 (br. s., 1H), 7.76 (d, J = 8.16 Hz, 1H), 7.08 (s, 1H), 3.37 (br. s., 6H), 2.66-2.75 (m, 3H), 1.53-1.65 (m, 4H), 0.75-0.98 (m, 6H). MS: calc’d 420(M+H)+, measured 420(M+H)+.
Example 22 2-Amino-N8-(6-methylpyridyl)-N4,N4-dipropyl-3Hbenzazepine-4,8-dicarboxamide The title compound was prepared in analogy to Example 1 by using ylpyridin amine instead of pyridinamine. Example 22 was obtained as a yellow solid (34.3 mg). 1H NMR (400 MHz, 6) δ ppm = 11.33 - 11.23 (m, 1H), 10.02 - 9.94 (m, 1H), 9.22 - 9.08 (m, 2H), 8.64 - 8.55 (m, 1H), 8.12 - 8.01 (m, 2H), 7.84 - 7.73 (m, 2H), 7.10 - 7.05 (m, 1H), 3.36 - 3.24 (m, 6H), 2.71 - 2.64 (m, 3H), 1.67 - 1.52 (m, 4H), 1.00 - 0.72 (m, 6H). MS: calc’d 420 (M+H)+, measured 420 (M+H)+.
Example 23 2-Amino-N8-(3,5-dimethylphenyl)-N4,N4-dipropyl-3Hbenzazepine-4,8-dicarboxamide The title compound was prepared in analogy to Example 1 by using 3,5-dimethylaniline instead of pyridinamine. Example 23 was obtained as a yellow solid (16 mg). 1H NMR (400 MHz, DMSO-d6) ppm =7.77 (d, J = 1.5 Hz, 1H), 7.70 (dd, J = 8.2, 1.6 Hz, 1H), 7.54 (d, J = 8.3 Hz, 1H), 7.34 (s, 2H), 6.99 (s, 1H), 6.85 (s, 1H), 3.35-3.61 (m, 4H), 3.21-3.23 (m, 2H), 2.35 (m, 6H), .86 (m, 4H), 0.59-1.20 ppm (m, 6H). MS: calc’d 433 (M+H)+, measured 433 (M+H)+.
Example 24 2-Amino-N8-[4-(aminomethyl)phenyl]-N4,N4-dipropyl-3Hbenzazepine-4,8- dicarboxamide The title compound was prepared in analogy to Example 1 by using tert-butyl N-[(4- aminophenyl)methyl]carbamate instead of pyridinamine. Example 24 was obtained as a yellow solid (4 mg). 1H NMR (400 MHz, DMSO-d6) δ ppm = 7.84 (d, J = 8.5 Hz, 2H), 7.76 (d, J = 1.5 Hz, 1H), 7.67 (dd, J = 8.0, 1.8 Hz, 1H), 7.38-7.57 (m, 3H), 6.88-7.03 (m, 1H), 4.04-4.21 (m, 2H), 3.37-3.54 (m, 4H), 3.31(m, 2H), 1.54-1.80 (m, 4H), 0.65-1.11 ppm (m, 6H). MS: calc’d 434 (M+H)+, measured 434 (M+H)+. e 25 o-N8-[4-(2-aminoethyl)phenyl]-N4,N4-dipropyl-3Hbenzazepine-4,8- dicarboxamide The title nd was prepared in analogy to Example 1 by using tert-butyl N-[2-(4- aminophenyl)ethyl]carbamate instead of pyridinamine. Example 25 was obtained as a yellow solid (4 mg). 1H NMR (400 MHz, DMSO-d6) δ ppm =7.86-8.00 (m, 2H), 7.57-7.80 (m, 3H), 7.34 (d, J = 8.5 Hz, 2H), 7.11 (s, 1H), 3.49 (m, 4H), 3.12-3.27 (m, 2H), .07 (m, 2H), 2.84 (m, 4H), 1.72 (m, 2H), 0.96 ppm (m, 6H). MS: calc’d 448 (M+H)+, measured 448 (M+H)+.
Example 26 2-Amino-N4-(3-hydroxypropyl)-N8-(m-tolyl)-N4-propyl-3Hbenzazepine-4,8- dicarboxamide A detailed synthetic route is provided in Scheme 5.
Preparation of Compound P: To a solution of 2-amino(methoxycarbonyl)-3H-benzo[b]azepinecarboxylic acid hydrochloride (compound A, 2.0 g, 6.7 mmol) in DMF (50 mL) was added HBTU (3.1 g, 8.1 mmol), DIPEA (3.4 g, 26.8 mmol) and 3-(propylamino)propanol (870 mg, 7.4 mmol) at 0 °C.
After the reaction mixture was stirred at 25 °C for 18 hrs, water (100 mL) was added and the mixture was ted with EA (50 mL). The organic layer was washed with brine, dried over anhydrous Na2SO4 and concentrated to give the crude product. The crude product was purified by silica gel column chromatography =1:1-0:1) to give the desired product methyl 2- amino((3-hydroxypropyl)(propyl)carbamoyl)-3H-benzo[b]azepinecarboxylate (compound P, 2 g) as a yellow oil. MS: calc’d 360 (M+H)+, measured 360 .
Preparation of Compound Q: To a solution of methyl 2-amino((3-hydroxypropyl)(propyl)carbamoyl)-3H- benzo[b]azepinecarboxylate (compound P, 2.0 g, 5.56 mmol) in DCM (50 mL) was added TEA (1.1 g, 11.12 mmol) and Boc2O (218 mg, 8.34 mmol) at 0 oC. After the reaction mixture was d at 25 °C for 24 hrs, water (10 mL) was added and the mixture was extracted with DCM (50 mL). The organic layer was washed with brine, dried over Na2SO4 and concentrated in vacuo. The residue was ed by silica gel column chromatography (PE:EA=1:1) to give the desired product methyl 2-((tert-butoxycarbonyl)amino)((3-hydroxypropyl)- (propyl)carbamoyl)-3H-benzo[b]azepinecarboxylate (compound Q, 1.3 g) as a yellow solid.
MS: calc’d 460 (M+H)+, measured 460 (M+H)+.
Scheme 5 T 26 Preparation of Compound R To a solution of methyl 2-((tert-butoxycarbonyl)amino)((3-hydroxypropyl)- (propyl)carbamoyl)-3H-benzo[b]azepinecarboxylate (compound Q, 100 mg, 0.22 mmol) in THF/H2O (1/1, 2 mL,) was added aq. LiOH(1 M , 0.3 mL, 0.30 mmol) at 0 °C. Then the mixture was warmed to 25 °C and stirred for 5 hrs. The mixture was poured into ice-water (10 mL) and acidified with aq. citric acid (5%) to pH 5. The mixture was extracted with EtOAc (30 mL × 3) and the combined organic layers were washed with brine (20 mL × 2), dried over Na2SO4 and concentrated in vacuo to give crude 2-((tert-butoxycarbonyl)amino)((3-hydroxypropyl)- (propyl)carbamoyl)-3H-benzo[b]azepinecarboxylic acid (compound R, 70 mg) as a yellow solid. MS: calc’d 450 (M+H)+, measured 450 (M+H)+.
Preparation of Compound T: To a solution of rt-butoxycarbonyl)amino)((3-hydroxypropyl)(propyl)carbamoyl)- 3H-benzo[b]azepinecarboxylic acid und R, 30 mg, 0.067 mmol) in DMF (1 mL) was added sively EDCI (32 mg, 0.167 mmol), HOBT (11 mg,0.084 mmol)，DIEA (35 mg, 0.268 mmol), DMAP (2 mg, 0.017 mmol) and idine (11 mg, 0.101 mmol). After the reaction was stirred at 25 °C for 18 hrs, it was poured into ice-water (10 mL) and extracted with EtOAc (20 mL × 2). The combined organic layers were washed with aq. citric acid (5%) and aq.
Na2CO3, dried over Na2SO4. After filtration, the filtrate was concentrated in vacuo to give tertbutyl (4-((3-hydroxypropyl)(propyl)carbamoyl)(m-tolylcarbamoyl)-3H-benzo[b]azepin yl)carbamate und T, 30 mg, crude) as a yellow solid. MS: calc’d 535 (M+H)+, measured 535 (M+H)+.
Preparation of Example 26 To a solution of tert-butyl (4-((3-hydroxypropyl)(propyl)carbamoyl)(m-tolylcarbamoyl )-3H-benzo[b]azepinyl)carbamate (compound T, 30 mg, 0.058 mmol) in DCM (0.8 mL) was added a on of TFA (128 mg, 0.123 mmol) in DCM (0.2 mL) at 0 °C. After the reaction was stirred at 25 °C for 4-5 hrs, the solvent was removed in vacuo and the residue was basified to pH 8 with sat. NaHCO3. The mixture was ted with DCM and dried over Na2SO4. Removal of solvent in vacuo gave the crude product which was purified by prep-HPLC to give 2-amino-N8-(5-methylpyridyl)-N4,N4-dipropyl-3Hbenzazepine-4,8-dicarboxamide (Example 26, 1.6 mg) as a yellow solid. 1H NMR (300 MHz, CD3OD) δ ppm = 8.03 - 7.87 (m, 2H), 7.77 - 7.67 (m, 1H), 7.58 - 7.44 (m, 2H), 7.33 - 7.22 (m, 1H), 7.17 - 7.11 (m, 1H), 7.07 - 6.99 (m, 1H), 3.80 - 3.43 (m, 6H), 3.42 - 3.36 (m, 2H), 2.49 - 2.28 (m, 3H), 1.97 - 1.84 (m, 2H), 1.80 - 1.64 (m, 2H), 1.09 - 0.86 (m, 3H). MS: calc’d 435 (M+H)+, measured 435 (M+H)+.
Example 27 2-Amino-N8-(o-tolyl)-N4,N4-dipropyl-3Hbenzazepine-4,8-dicarboxamide The title compound was prepared in analogy to Example 1 by using o-toluidine d of pyridinamine. Example 27 was obtained as a yellow gum (12 mg). 1H NMR (400 MHz, CDCl3) δ ppm = 7.99 (d, J = 7.91 Hz, 1H), 7.79 (s, 1H), 7.68 (s, 1H), 7.64 (d, J = 8.16 Hz, 1H), 7.42 (d, J = 8.16 Hz, 1H), 7.22-7.32 (m, 1H), 7.11-7.17 (m, 1H), 6.85 (s, 1H), 3.48 (br. s., 4H), 2.81 (s, 2H), 2.37 (s, 3H), 1.63-1.74 (m, 4H), 0.89-1.03 (m, 6H). MS: calc’d 419 (M+H)+, measured 419 (M+H)+ Example 28 2-Amino-N4,N4-dipropyl-N8-(p-tolyl)-3Hbenzazepine-4,8-dicarboxamide The title nd was prepared in analogy to Example 1 by using p-toluidine instead of pyridinamine. Example 28 was obtained as a yellow solid (43.7 mg). 1H NMR (400 MHz, DMSO-d6)： δ ppm = 10.42 (br, 1H), 10.01 (br, 1H), 9.21 (br, 1H), 7.92 - 8.01 (m, 2H), 7.62 - 7.74 (m, 3H), 7.11 - 7.23 (d, 2H), 7.04 (s, 1H), 3.25 - 3.37 (m, 6H), 2.28 (s, 3H), 1.48 - 1.66 (m, 4H), 0.66 - 1.06 (d, 6H). MS: calc’d 419 (M+H)+, measured 419 (M+H)+ Example 29 2-Amino-N8-(3-ethylphenyl)-N4,N4-dipropyl-3Hbenzazepine-4,8-dicarboxamide The title compound was prepared in analogy to e 1 by using 3-ethylaniline instead of namine. Example 29 was obtained as a white solid (35 mg). 1H NMR (400 MHz, CDCl3) δ ppm = 7.96 (s, 1H), 7.67 (d, J = 1.63 Hz, 1H), 7.63 (dd, J = 1.88, 8.03 Hz, 1H), 7.56 (s, 1H), 7.47 (d, J = 7.78 Hz, 1H), 7.41 (d, J = 8.16 Hz, 1H), 7.29-7.33 (m, 1H), 7.02 (d, J = 7.65 Hz, 1H), 6.85 (s, 1H), 3.48 (br. s., 4H), 2.81 (s, 2H), 2.69 (q, J = 7.61 Hz, 2H), 1.69 (qd, J = 7.47, 14.98 Hz, 4H), 1.28 (t, J = 7.59 Hz, 3H), 0.95 (t, J = 7.15 Hz, 6H). MS: calc’d 433 (M+H)+, measured 433 (M+H)+ Example 30 2-Amino-N8-(3-methoxyphenyl)-N4,N4-dipropyl-3Hbenzazepine-4,8-dicarboxamide The title compound was prepared in analogy to Example 1 by using 3-methoxyaniline instead of pyridinamine. Example 30 was obtained as a yellow solid (30.9 mg). 1H NMR (400 MHz, DMSO-d6) δ ppm = 10.47(br, 1H), 10.02(br, 1H), 9.2 (br, 1H), 7.93 - 8.02 (m, 2H), 7.67 - 7.74 (d, 1H), 7.46 - 7.52 (t, 1H), 7.36 - 7.44 (m, 1H), 7.23 - 7.31 (t, 1H), 7.04 (s, 1H), 6.67 - 6.75 (dd, 1H), 3.76 (s, 3H), 3.35 (m., 6H), 1.49 - 1.65 (m, 4H), 0.70 - 0.98 (d, 6H). MS: calc’d 435 (M+H)+, measured 435 (M+H)+ Example 31 2-Amino-N4,N4-dipropyl-N8-[3-(trifluoromethyl)phenyl]-3Hbenzazepine-4,8- dicarboxamide The title compound was prepared in y to e 1 by using fluoromethyl)- aniline instead of pyridinamine. Example 31 was obtained as a yellow gum (12 mg). 1H NMR (400 MHz, CDCl3) δ ppm = 8.20 (s, 1H), 8.03 (s, 1H), 7.86 (d, J = 8.16 Hz, 1H), 7.68 (d, J = 1.76 Hz, 1H), 7.62 (dd, J = 1.88, 8.16 Hz, 1H), 7.48-7.54 (m, 1H), 7.42 (d, J = 8.16 Hz, 2H), 6.84 (s, 1H), 3.36-3.57 (m, 4H), 2.81 (s, 2H), 1.69 (qd, J = 7.47, 14.98 Hz, 4H), 0.95 (t, J = 7.22 Hz, 6H). MS: calc’d 473 (M+H)+, measured 473 (M+H)+ Example 32 2-Amino-N8-(3-chlorophenyl)-N4,N4-dipropyl-3Hbenzazepine-4,8-dicarboxamide The title compound was prepared in analogy to Example 1 by using 3-chloroaniline instead of pyridinamine. Example 32 was obtained as a yellow solid (21.8 mg). 1H NMR (400 MHz, CDCl3) δ ppm = 8.05 (s, 1H), 7.85 (t, J = 2.01 Hz, 1H), 7.66 (d, J = 1.88 Hz, 1H), 7.61 (dd, J = 1.94, 8.09 Hz, 1H), 7.47-7.52 (m, 1H), 7.41 (d, J = 8.16 Hz, 1H), 7.29-7.34 (m, 1H), 7.14 (ddd, J = 0.94, 1.98, 8.00 Hz, 1H), 6.83 (s, 1H), 3.49 (d, J = 13.93 Hz, 4H), 2.80 (s, 2H), 1.69 (qd, J = 7.35, 14.98 Hz, 4H), 0.95 (t, J = 7.15 Hz, 6H). MS: calc’d 439 (M+H)+, measured 439 (M+H)+ Example 33 2-Amino-N8-[5-(aminomethyl)pyridyl]-N4,N4-dipropyl-3Hbenzazepine-4,8- dicarboxamide The title nd was prepared in y to Example 1 by using tert-butyl N-[(5- aminopyridyl)methyl]carbamate (compound 33A) instead of pyridinamine. Example 33 was obtained as a white solid (56.5 mg). 1H NMR (400 MHz, METHANOL-d4) δ ppm = 8.85 (s, 1H), 8.56 (s, 1H), 8.43 (s, 1H), 7.88 (s, 1H), 7.82 (d, J = 8 Hz, 1H), 7.62 (d, J = 8 Hz, 1H), 7.03 (s, 1H), 4.89 (m, 2H), 4.23 (s, 2H), 3.45 (m, 4H), 1.72 - 1.67 (m, 4H), 0.98 - 0.90 (m, 6H). MS: calc’d 435 (M+H)+, measured 435 (M+H)+. ation of tert-butyl N-[(5-aminopyridyl)methyl]carbamate (compound 33A): NiCl2 Boc2O NaBH4 Na2CO3 EtOH dioxane/H2O To a stirred solution of 5-aminopyridinecarbonitrile (238 mg, 2.0 mmol), anhydrous NiCl2 (259 mg, 2.0 mmol) in ethanol (8 mL) was added NaBH4 (303 mg, 8.0 mmol) nwise at 25 °C. After 8 hrs, the mixture was filtered through celite and the filtrate was concentrated to give the crude product, which was used directly in the following step. 5- (aminomethyl)pyridinamine (dark brown oil, 277 mg). MS: calc’d 124 (M+H)+, measured 124 (M+H)+.
To a solution of crude 5-(aminomethyl)pyridinamine (277 mg) in dioxane (8 mL) and H2O (8 mL) was added Na2CO3 (954 mg, 9.0 mmol). After the mixture was stirred at 25 °C for a while, Boc2O (1.47 g, 6.7 mmol) was added. After 3.5 hrs, the mixture was diluted with water and extracted with EA (25 mL × 3) and DCM (25 mL × 3). The combined organic layers were dried over Na2SO4 and concentrated in vacuo to give an orange oil. The oil was ed by silica gel column chromatography =1:0 to 1:1) to give the desired product tert-butyl N-[(5- aminopyridyl)methyl]carbamate (compound 33A, 92 mg, 21% yield over two steps) as an orange sticky solid. MS: calc’d 224 (M+H)+, measured 224 (M+H)+.
Example 34 2-Amino-N4,N4-dipropyl-N8-pyridazinyl-3Hbenzazepine-4,8-dicarboxamide The title compound was prepared in analogy to Example 1 by using zinamine instead of pyridinamine. Example 34 was obtained as a white solid (30.5 mg). 1H NMR (400 MHz, CD3OD) δ ppm = 9.50 (s, 1H), 9.05 (d, J = 8 Hz, 1H), 8.29 - 8.27 (m, 1H), 7.80 (s, 1H), 7.72 - 7.69 (m, 1H), 7.54 (d, J = 8 Hz, 1H), 6.69 (s, 1H), 4.87 (m, 2H), 3.44 (t, J = 8 Hz, 4H), 1.71 - 1.66 (m, 4H), 0.96 - 0.90 (m, 6H). MS: calc’d 407 (M+H)+, measured 407 (M+H)+.
Example 35 2-Amino-N8-(6-ethoxypyridyl)-N4,N4-dipropyl-3Hbenzazepine-4,8-dicarboxamide The title compound was prepared in analogy to Example 1 by using 6-ethoxypyridin amine instead of pyridinamine. Example 35 was obtained as a yellow solid (6 mg). 1H NMR (400 MHz, CD3OD) δppm = 8.76 (brs, 1H), 8.35 (d, J = 7.8 Hz, 1H), 8.05 - 7.99 (m, 2H), 7.74 (d, J = 8.3 Hz, 1H), 7.25 (d, J = 9.0 Hz, 1H), 7.14 (s, 1H), 4.46 (q, J = 6.9 Hz, 2H), 3.50 (brs, 4H), 3.40 (s, 2H), 1.80-1.65 (m, 4H), 1.49 (t, J = 7.0 Hz, 3H), 0.97 (brs, 6H). c’d 450 (M+H)+, measured 450 (M+H)+.
Example 36 o-N8-[3-(aminomethyl)phenyl]-N4,N4-dipropyl-3Hbenzazepine-4,8- dicarboxamide The title compound was prepared in analogy to Example 1 by using tert-butyl N-[(3- henyl)methyl]carbamate instead of pyridinamine. Example 36 was obtained as a yellow solid (6 mg). 1H NMR (400 MHz, CDCl3) δ ppm = 7.86-8.05 (m, 3H), 7.61-7.75 (m, 2H), 7.50 (t, J = 7.9 Hz, 1H), 7.30 (d, J = 7.5 Hz, 1H), 7.12 (s, 1H), 4.17 (s, 2H), 3.49 (br. s., 4H), 2.83 (s, 2H), 1.51-1.76 (m, 4H), 0.96 ppm (br. s., 6H). MS: calc’d 434 (M+H)+, measured 434 (M+H)+ Example 37 2-Amino-N8-(1-methylpyrazolyl)-N4,N4-dipropyl-3Hbenzazepine-4,8-dicarboxamide The title compound was prepared in analogy to Example 1 by using 1-methylpyrazol amine instead of pyridinamine. Example 37 was ed as a white solid (38.6 mg). 1H NMR (400 MHz, CD3OD) δ ppm = 7.90 - 7.88 (m, 2H), 7.67 - 7.64 (m, 1H), 7.53 (s, 1H), 7.08 (s, 1H), 6.63 (s, 1H), 4.87 (m, 2H), 3.85 (s, 3H), 3.46 (br.s., 4H), 1.75 - 1.65 (m, 4H), 0.96 - 0.93 (m, 6H).
MS: calc’d 409 (M+H)+, measured 409 (M+H)+.
Example 38 2-Amino-N8-oxazolyl-N4,N4-dipropyl-3Hbenzazepine-4,8-dicarboxamide The title compound was prepared in analogy to Example 1 by using oxazolamine instead of pyridinamine. e 38 was obtained as a white solid (15.3 mg). 1H NMR (400 MHz, CD3OD) δ ppm = 7.95 (s, 1H), 7.91 (d, J = 8 Hz, 1H), 7.71 (s, 1H), 7.63 (d, J = 8 Hz, 1H), 7.17 (s, 1H), 7.06 (s, 1H), 4.87 (m, 2H), 3.46 (br.s., 4H), 1.72 - 1.67 (m, 4H), 0.96 - 0.92 (m, 6H).
MS: calc’d 396 (M+H)+, measured 396 (M+H)+. e 39 2-Amino-N4-(3-hydroxypropyl)-N4-propyl-N8-(3-pyridyl)-3Hbenzazepine-4,8- dicarboxamide The title compound was prepared in analogy to e 26 by using pyridinamine instead of m-toluidine. Example 39 was obtained as a yellow solid (4.3 mg). 1H NMR (300 MHz, CD3OD) δ ppm = 9.63 (brs, 1H), 8.87 (d, J = 8.7 Hz, 1H), 8.66 (d, J = 5.5 Hz, 1H), .99 (m, 3H), 7.78 (d, J = 7.7 Hz, 1H), 7.17 (s, 1H), 3.62 (d, J = 7.0 Hz, 4H), 3.49-3.33(m, 4H), 1.91 (br s., 2H), 1.73 (d, J = 7.3 Hz, 2H), 0.97 (br s, 3H). MS: calc’d 422 (M+H)+, measured 422 (M+H)+.
Example 40 2-Amino-N8-(5-methoxypyridyl)-N4,N4-dipropyl-3Hbenzazepine-4,8-dicarboxamide The title compound was prepared in analogy to Example 1 by using 5-methoxypyridin amine instead of pyridinamine. Example 40 was obtained as a white solid (33.6 mg). 1H NMR (400 MHz, CD3OD) δ ppm = 8.49 (s, 1H), 8.04 (s, 1H), 7.98 (s, 1H), 7.80 (s, 1H), 7.73 (d, J = 8 Hz, 1H), 7.55 (d, J = 8 Hz, 1H), 6.98 (s, 1H), 4.87 (m, 2H), 3.92 (s, 3H), 3.44 (t, J = 8 Hz, 4H), 1.72 - 1.66 (m, 4H), 0.96 - 0.90 (m, 6H). MS: calc’d 436 (M+H)+, measured 436 (M+H)+.
Example 41 o-N8-(m-tolyl)-N4-propyl-N4-propynyl-3Hbenzazepine-4,8-dicarboxamide The title compound was prepared in analogy to Example 26 by using N-propylpropyn- 1-amine (compound 41A) instead of 3-(propylamino)propanol. Example 41 was obtained as a white solid (63 mg). 1H NMR (400 MHz, CD3OD) δppm= 7.99 - 7.90 (m, 2H), 7.73 - 7.65 (m, 1H), 7.57 - 7.45 (m, 2H), 7.26 (t, J = 7.8 Hz, 2H), 7.05 - 6.97 (m, 1H), 4.35 (brs, 2H), 3.58 (brs, 2H), 3.39 (s, 2H), 2.90 (brs, 1H), 2.37 (s, 3H), 1.76 (qd, J = 7.4, 14.9 Hz, 2H), 0.97 (t, J = 7.1 Hz, 3H). MS: calc’d 415 (M+H)+, measured 415 (M+H)+.
Preparation of Compound 41A: MsCl NH2 H OH OMs N Et3N,DCM K2CO3,CH3CN 41B 41A To the solution of propynol (1.0 g, 20.0 mmol) in DCM (30 mL) was added Et3N (3.02 g, 29.9 mmol). Then MsCl (2.3 g, 19.97 mmol) was added se at 0 °C. After the reaction mixture was d for 1 hr at 0 °C, it was poured into water (50 mL). The mixture was extracted with DCM (100 mL). The organic layer was washed with brine (100 mL), dried over Na2SO4, and concentrated in vacuo to give propynyl methanesulfonate (compound 41B, 2.2 g, 82%) as a yellow oil, which was dissolved in CH3CN (2 mL) and treated se with a solution of propylamine (1.94 g, 32.8 mmol) in CH3CN (30 mL) at 0 °C. After the mixture was stirred at 25 °C for 12 hrs, it was poured into water (50 mL) and extracted with DCM (100 mL × 2). The organic layers were washed with brine (100 mL), dried over Na2SO4, and trated in vacuo to give N-propylpropynamine (compound 41A, 0.5 g, 31.4%) as a yellow oil.
Example 42 2-Amino-N4,N4-dibutyl-N8-(m-tolyl)-3Hbenzazepine-4,8-dicarboxamide The title compound was prepared in analogy to Example 26 by using N-butylbutan amine instead of 3-(propylamino)propanol. Example 42 was obtained as a white solid (33.6 mg). 1H NMR (400 MHz, CD3OD) δ ppm =7.96 -7.94 (m, 2H), 7.73 - 7.65 (m, 1H), 7.57 - 7.46 (m, 2H), 7.30 - 7.22 (m, 1H), 7.12 (s, 1H), 7.02 (d, J = 7.4 Hz, 1H), 3.50 (br s, 4H), 3.37 (s, 2H), 2.37 (s, 3H), 1.66 (q, J = 7.6 Hz, 4H), 1.49 - 1.25 (m, 4H), 0.97 (br s, 6H). MS: calc’d 447 (M+H)+, measured 447 .
Example 43 2-Amino-N8-[3-(aminomethyl)methyl-phenyl]-N4,N4-dipropyl-3Hbenzazepine-4,8- dicarboxamide The title compound was prepared in analogy to Example 1 by using tert-butyl 3-amino methylbenzylcarbamate (compound 43A) instead of pyridinamine. Example 43 was obtained as a white solid (45 mg). 1H NMR (400 MHz, CD3OD) δ ppm = 8.03 (s, 1H), 8.00 (dd, J = 1.63, 8.16 Hz, 1H), 7.77 (s, 1H), 7.73 (d, J = 8.28 Hz, 1H), 7.57 (br. s., 1H), 7.14 (d, J = 3.89 Hz, 2H), 4.13 (s, 2H), 3.49 (br. s., 4H), 3.41 (s, 2H), 2.43 (s, 3H), 1.72 (sxt, J = 7.43 Hz, 4H), 0.87-1.08 (m, 6H). MS: calc’d 448(M+H)+, measured 448 (M+H)+.
Preparation of tert-butyl 3-aminomethylbenzylcarbamate (compound 43A): NaBH4, NiCl2 Ph NH H H N N Br CN Br Boc Ph N Boc 43B 43C H2N Boc a) Preparation of compound 43B To a on of 3-bromomethylbenzonitrile (1.0 g, 5.12 mmol) in MeOH (40 mL) was added NiCl2.6H2O (121 mg, 0.51 mmol), Boc2O (1.35 g, 6.20 mmol) and NaBH4 (780 mg, 20.5 mmol) at -20 °C. Then the mixture was stirred for 2 hrs at 0-10 °C. The on solution was quenched with sat. NH4Cl (120 mL), diluted with H2O (200 mL) and extracted with EA (100 mL × 3). The combined organic layers were washed by brine (50 mL × 2), dried over Na2SO4 and concentrated to give tert-butyl 3-bromomethylbenzylcarbamate (compound 43B, 1.3 g, 86.7%) as a white solid. MS: calc’d 300(M+H)+, measured 300 (M+H)+. b) Preparation of compound 43C To a on of tert-butyl 3-bromomethylbenzylcarbamate (compound 43B, 2.0 g, 6.7 mmol) and diphenylmethanimine (compound 43C, 1.44 g, 8.0 mmol) in toluene (50 mL) was added Cs2CO3 (4.3 g, 13.4 mmol), BINAP (833 mg, 1.34 mmol) and Pd(OAc)2 (150 mg, 0.67 mol) at 20 °C. After the reaction mixture was d at 90 °C for 16 hrs, it was quenched with sat.
NH4Cl (50 mL), diluted with H2O (100 mL) and ted with EA (50 mL × 3). The combined organic layers were washed with brine (30 mL × 2), dried over Na2SO4 and concentrated to give the crude product. The crude product was ed by silica gel column chromatography (PE:EA = 10:1) to give tert-butyl 3-((diphenylmethylene)amino)methylbenzylcarbamate (compound 43C, 1.2 g, 46.1%) as yellow oil. MS: calc’d 401 (M+H)+, measured 401(M+H)+. c) ation of compound 43A To a solution of utyl 3-((diphenylmethylene)amino)methylbenzylcarbamate (compound 43C, 1.2 g, 3.0 mmol) in MeOH (50 mL) was added NH2OH HCl (639 mg, 9.0 mmol), NaOAc (1.2 g, 15.0 mmol) at 0 °C. Then the mixture was stirred at 15 °C for 16 hrs. The reaction solution was quenched with sat. NH4Cl (80 mL), diluted with H2O (100 mL), and extracted with EA (50 mL × 3). The combined organic layers were washed with brine (30 mL × 2), dried over Na2SO4 and concentrated to give the crude product. The crude product was ed by silica gel column chromatography (PE:EA = 5:1) to give tert-butyl 3-amino methylbenzylcarbamate (compound 43A, 500 mg, 70%) as yellow oil. MS: calc’d 237(M+H)+, measured 237 (M+H)+.
Example 44 2-Amino-N8-(5-ethoxypyridyl)-N4,N4-dipropyl-3Hbenzazepine-4,8-dicarboxamide The title compound was prepared in analogy to Example 1 by using 5-ethoxypyridin amine instead of pyridinamine. e 44 was ed as a white solid (44.5 mg). 1H NMR (400 MHz, CD3OD) δ ppm = 8.48 (s, 1H), 8.02 (s, 1H), 7.95 (s, 1H), 7.80-7.79 (m, 1H), 7.73- 7.70 (m, 1H), 7.56-7.53 (s, 1H), 6.98-6.97 (m, 1H), 4.85 (m, 2H), 4.16 (q, J = 8 Hz, 2H), 3.44 (t, J = 8 Hz, 4H), 1.72 - 1.66 (m, 4H), 1.45 (t, J = 8 Hz, 3H), 0.96 - 0.91 (m, 6H). MS: calc’d 450 (M+H)+, measured 450 (M+H)+.
Example 45 2-Amino-N8-[3-[2-(2-aminoethoxy)ethoxy]phenyl]-N4,N4-dipropyl-3Hbenzazepine-4,8- dicarboxamide The title compound was ed in analogy to Example 1 by using tert-butyl N-[2-[2-(3- aminophenoxy)ethoxy]ethyl]carbamate (compound 45C) instead of pyridinamine. Example 45 was ed as a white solid (52 mg). 1H NMR (400 MHz, CD3OD) δ ppm = 7.80 (s, 1H), 7.74 (d, J = 8 Hz, 1H), 7.58 (t, J = 4 Hz, 1H), 7.55 (s, 1H), 7.28 (t, J = 8 Hz, 1H), 7.18 (d, J = 8 Hz, 1H), 6.99 (s, 1H), 6.77 (d, J = 8 Hz, 1H), 4.84 (m, 2H), 4.23-4.21 (m, 2H), 3.92-3.90 (m, 2H), 3.81-3.78 (m, 2H), 3.45 (t, J = 8 Hz, 4H), 3.18-3.15 (m, 2H), 1.74-1.65 (m, 4H), 0.93 (br, 6H).
MS: calc’d 508 (M+H)+, measured 508 (M+H)+.
Preparation of tert-butyl 2-(3-aminophenoxy)ethoxy]ethyl]carbamate (compound 45C): Boc2O DIAD TEA PPh3 acetone THF Pd(OH)2/C EtOH 45B 45C a) Preparation of compound 45A To a stirred solution of 2-(2-aminoethoxy)ethanol (1 g, 943 µL, 9.5 mmol), TEA (1.44 g, 1.99 mL, 14.3 mmol) in acetone (10 mL) was added (Boc)2O (3.11 g, 3.31 mL, 14.3 mmol) at ambient temperature. After the e was stirred for 14 hrs, it was concentrated to give a pale yellow oil, which was purified by silica gel column to give 1.6 g tert-butyl N-[2-(2- yethoxy)ethyl]carbamate (compound 45A) as pale yellow oil. MS: calc’d 206 (M+H)+, measured 206 (M+H)+. b) Preparation of compound 45B To a stirred solution of 3-nitrophenol (450 mg, 3.23 mmol), tert-butyl N-[2-(2- hydroxyethoxy)ethyl]carbamate (797 mg, 3.88 mmol) in THF (12 mL) was added nylphosphine (1.27 g, 4.85 mmol) and (E)-diisopropyl diazene-1,2-dicarboxylate (981 mg, 955 µL, 4.85 mmol) at r.t. After the reaction mixture was stirred at r.t. for 3 hrs, the solvent was removed in vacuo to give a yellow oil, which was purified by silica gel column to give tert-butyl N-[2-[2- (3-nitrophenoxy)ethoxy]ethyl]carbamate (compound 45B, 2 g) as pale yellow oil. MS: calc’d 327 (M+H)+, measured 327 (M+H)+. c) Preparation of compound 45C To a stirred solution of tert-butyl N-[2-[2-(3-nitrophenoxy)ethoxy]ethyl]carbamate (2 g, 6.13 mmol) in EtOH (15 mL) was added 20% Pd(OH)2 on carbon (0.5 g). After the reaction system was vacuumed and backfilled with en 3 times, the reaction mixture was stirred at room temperature with a hydrogen balloon for 6 hrs. The e was ed through celite and the filtrate was concentrated to give N-[2-[2-(3-aminophenoxy)ethoxy]ethyl]carbamate (compound 45C, 1.88 g) as a purple oil. MS: calc’d 297 (M+H)+, measured 297 (M+H)+.
Example 46 2-Amino-N8-[5-(5-aminopentoxy)pyridyl]-N4,N4-dipropyl-3Hbenzazepine-4,8- dicarboxamide The title compound was prepared in analogy to Example 1 by using tert-butyl N-[5-[(5- aminopyridyl)oxy]pentyl]carbamate (compound 46C) instead of namine. Example 46 was obtained as a white solid (22 mg). 1H NMR (400 MHz, CD3OD) δ ppm = 8.43 (s, 1H), 8.06 (s, 1H), 8.02 (s, 1H), 7.80 (s, 1H), 7.72 (s, 1H), 7.57-7.55 (m, 1H), 6.98 (s, 1H), 4.88 (m, 2H), 4.16-4.13 (m, 2H), 3.46-3.42 (m, 4H), 2.99-2.96 (m, 2H), 1.80-1.59 (m, 10H), 0.97-0.93 (br, 6H). MS: calc’d 507 (M+H)+, measured 507 (M+H)+.
Preparation of tert-butyl N-[5-[(5-aminopyridyl)oxy]pentyl]carbamate (compound 46C): The title compound was prepared in analogy to compound 45C by using opentan ol instead of 2-(2-aminoethoxy)ethanol and 5-nitropyridinol instead of 3-nitrophenol.
Example 47 2-Amino-N8-[3-[2-(2-aminoethoxy)ethoxymethyl]phenyl]-N4,N4-dipropyl-3H benzazepine-4,8-dicarboxamide The title compound was prepared in analogy to Example 1 by using tert-butyl ((3- aminobenzyl)oxy)ethoxy)ethyl)carbamate (compound 47A) instead of pyridinamine. e 47 was obtained as a white solid (78 mg). 1H NMR (400 MHz, CD3OD) δ ppm = 7.97 - 7.85 (m, 2H), 7.81 (s, 1H), 7.66 - 7.58 (m, 1H), 7.57 - 7.48 (m, 1H), 7.35 - 7.25 (m, 1H), 7.14 - 7.06 (m, 1H), 7.03 (s, 1H), 4.53 (s, 2H), 3.71 - 3.59 (m, 6H), 3.38 (br. s., 4H), 3.23 (td, J = 1.6, 3.3 Hz, 2H), 3.07 (t, J = 4.8 Hz, 2H), 1.62 (sxt, J = 7.4 Hz, 4H), 0.86 (br. s., 6H). MS: calc’d 522(M+H)+, measured H)+.
Preparation of tert-butyl (2-(2-((3-aminobenzyl)oxy)ethoxy)ethyl)carbamate (compound 47A): Zn, NH4Cl a) Preparation of compound 47B To the solution of 1-(bromomethyl)nitrobenzene (1.0 g, 4.63 mmol) and tert-butyl (2- (2-hydroxyethoxy)ethyl)carbamate (0.95 g, 4.63 mmol) in DMF (40 mL) was added KOH (518 mg, 9.25 mmol). After the solution was d at 50 °C for 15 hrs, it was poured into water (100 mL) and extracted with EtOAc (50 mL × 3). The combined c layers were washed with brine (50 mL × 3), dried over Na2SO4 and concentrated in vacuo. The residue was purified through silica gel column chromatography (DCM/MeOH = 200/1~80/1) to give tert-butyl (2-(2- ((3-nitrobenzyl)oxy)ethoxy)ethyl)carbamate (compound 47B, 400 mg, 25%) as a yellow oil. MS: calc’d 341(M+H)+, measured 341(M+H)+ . b) Preparation of nd 47A To the solution of tert-butyl(2-(2-((3-nitrobenzyl)oxy)ethoxy)ethyl)carbamate (compound 47B, 0.4 g, 1.2 mmol) in EtOH/H2O 5 mL) were added NH4Cl (377 mg, 7.1 mmol) and Zn powder (1.91 g, 29.4 mmol). After the solution was stirred at 80 °C for 3 hrs, it was filtered and the filtrate was concentrated in vacuo. The residue was dissolved in DCM (100 mL), washed with brine (50 mL × 2), dried over Na2SO4 and concentrated in vacuo to give tert-butyl (2-(2-((3- aminobenzyl)oxy)ethoxy)ethyl)carbamate (compound 47A, 365 mg, 100%) as a yellow oil, which was used directly for the next step. MS: calc’d H)+, measured 311(M+H)+.
Example 48 2-Amino-N8-[5-(3-aminopropynyl)pyridyl]-N4,N4-dipropyl-3Hbenzazepine-4,8- dicarboxamide The title compound was prepared in analogy to Example 1 by using tert-butyl 5- aminopyridyl)propynyl]carbamate (compound 48A) instead of pyridinamine. Example 48 was obtained as a white solid (0.3 mg). 1H NMR (400 MHz, CD3OD) δ ppm = 8.82 (s, 1H), 8.49 (s, 1H), 8.40 (s, 1H), 7.76 (s, 1H), 7.66 (d, J = 8 Hz, 1H), 7.52 (d, J = 8 Hz, 1H), 6.94 (s, 1H), 4.87 (m, 2H), 4.00 (s, 2H), 3.49-3.42 (m, 4H), 1.70 - 1.66 (m, 4H), 0.96 - 0.88 (m, 6H). MS: calc’d 459 , measured 459 (M+H)+.
Preparation of tert-butyl N-[3-(5-aminopyridyl)propynyl]carbamate (compound 48A): Pd(OAc)2 Cs2CO3 THF, reflux SnCl2 THF/EtOH a) Preparation of compound 48B To a solution of 3-bromonitropyridine (1 g, 4.93 mmol) in THF (30 mL) was added successively tert-butyl propynylcarbamate (1.15 g, 7.39 mmol), Pd(OAc)2 (55 mg, 246 µmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (285 mg, 493 µmol), and Cs2CO3 (4.82 g, 14.80 mmol). After the mixture was degassed and recharged with argon for five times, it was heated to reflux for 4.5 hrs. The reaction e was filtered through celite and the filtrate was concentrated to give a dark oil, which was purified by silica gel chromatography (eluting with EA/PE = 0~20% ~ 30%) to give a brown oil. The oil was triturated with PE to give tertbutyl N-[3-(5-nitropyridyl)propynyl]carbamate (compound 48B, 1 g) as brown solid. MS: calc’d 278 (M+H)+, measured 278 (M+H)+. b) Preparation of compound 48A To a on of tert-butyl (3-(5-nitropyridinyl)propynyl)carbamate (400 mg, 1.44 mmol) in THF (5 mL) and EtOH (0.5 mL) was added stannous chloride (1.3 g, 329 µL, 6.86 mmol) at room temperature. After the reaction mixture was stirred at room tempearture for 6 hrs, it was d with 20 mL of 25% aqueous KOH and 25 mL DCM. A precipitate was formed and then filtered. The filtrate was extracted with DCM (25 mL × 2). The ed organic layers were washed with brine (20 mL × 3), dried over Na2SO4 and concentrated to give a brown oil, which was purified by silica gel chromatography to give tert-butyl N-[3-(5-amino pyridyl)propynyl]carbamate (compound 48A, 28 mg) as a yellow oil. MS: calc’d 248 (M+H)+, measured 248 (M+H)+.
Example 49 2-Amino-N8-[5-(3-aminopropynyl)pyridyl]-N4,N4-dipropyl-3Hbenzazepine-4,8- dicarboxamide The title compound was prepared in analogy to Example 26 by using tert-butyl (2-(2-(3- (propylamino)propoxy)ethoxy)ethyl)carbamate (compound 49A) d of 3-(propylamino)- propanol. Example 49 was obtained as a yellow solid. (74.5 mg).1H NMR (400 MHz, CD3OD) δ = 8.02 - 7.94 (m, 2H), 7.77 - 7.69 (m, 1H), 7.60 - 7.49 (m, 2H), 7.28 (t, J = 7.8 Hz, 1H), 7.16 (s, 1H), 7.03 (d, J = 7.7 Hz, 1H), 3.81 - 3.45 (m, 12H), 3.41 (s, 2H), 3.23 - 2.98 (m, 2H), 2.39 (s, 3H), 2.04 - 1.93 (m, 2H), 1.73 (sxt, J = 7.4 Hz, 2H), 0.96 (br. s., 3H). MS: calc’d 522 (M+H)+, measured 522 (M+H)+.
Preparation of tert-butyl (2-(2-(3-(propylamino)propoxy)ethoxy)ethyl)carbamate und 49A): H Cbz HO NH2 + O HO N HO N 49B 49C Cbz N OH Cbz MsO N Boc O N O N Boc O 49D 49E H H N O N Boc O a) ation of Compound 49B: To the solution of 3-aminopropanol (1.0 g, 13.3 mmol) and propionaldehyde (0.77 g, 13.3 mmol) in MeOH (20 mL) was added MgSO4 (6.4 g, 53.3 mmol). After the reaction mixture was stirred at 25 °C for 12 hrs, the undissolved material was filtered and the filtrate was treated with NaBH4 (556 mg, 14.6 mmol) under ice-bath. Then the mixture was stirred at 25 °C for 1 h.
The reaction solution was concentrated in vacuo and the residue was dissolved in DCM (100 mL) and stirred for 5 min. The undissolved material was filtered and the filtrate was concentrated in vacuo to give 3-(propylamino)propanol (compound 49B, 1.0 g, 64.1%) as a yellow oil, which was used for the next step directly. b) Preparation of Compound 49C: To the solution of pylamino)propanol (compound 49B, 1.0 g, 8.53 mmol) in THF/H2O (20/10 mL) was added NaHCO3 (1.43 g, 17.06 mmol). Then Cbz-Cl (1.45 g, 8.53 mmol) was added dropwise under ice-bath. After the reaction mixture was stirred at 25 °C for 12 hrs, it was poured into water (50 mL) and ted with EtOAc (50 mL × 3). The combined organic layers were washed with brine (100 mL), dried over Na2SO4 and trated in vacuo.
The residue was purified through silica gel column tography (PE/EtOAc = 10/1 ~ 2/1) to give benzyl (3-hydroxypropyl)(propyl)carbamate (compound 49C, 0.7 g, 32.7%) as a colorless oil. MS: calc’d 252 (M+H)+, measured 252(M+H)+. c) Preparation of Compound 49D: To the solution of benzyl (3-hydroxypropyl)(propyl)carbamate (compound 49C, 0.7 g, 2.78 mmol) in DCM (20 mL) was added TEA (416 mg, 4.12 mmol). Then MsCl (319 mg, 2.78 mmol) was added under th. After the reaction mixture was stirred at 25 °C for 3 hrs, it was diluted with DCM (50 mL). The on was washed with aq. NaHCO3 (50 mL × 3) and brine (100 mL). The organic layer was dried over Na2SO4 and concentrated in vacuo to give 3- (((benzyloxy)carbonyl)(propyl)amino)propyl methanesulfonate (compound 49D, 0.9 g, 98.3%) as a yellow oil, which was used for the next step directly. d) Preparation of Compound 49E: To the solution of 3-(((benzyloxy)carbonyl)(propyl)amino)propyl methanesulfonate (compound 49D, 500 mg, 1.52 mmol) and tert-butyl hydroxyethoxy)ethyl)carbamate (311 mg, 1.52 mmol) in DCM (5 mL) was added TBAI (673 mg, 1.82 mmol). Then 30% of aq. NaOH (5 mL) was added. The mixture was stirred at 25 oC for 15 hrs. The reaction solution was then poured into 10% of citric acid (100 mL) and extracted with EtOAc (30 mL × 2). The combined c layers were washed with brine (100 mL), dried over Na2SO4, and trated in vacuo.
The residue was purified through silica gel column chromatography (DCM/MeOH = 200/1~ 80/1) to give benzyl (2,2-dimethyloxo-3,8,11-trioxaazatetradecanyl)(propyl)carbamate (compound 49E, 300 mg, 45%) as a yellow oil. MS: calc’d 439 (M+H)+, measured 439 (M+H)+ e) Preparation of Compound 49A: To the solution of benzyl (2,2-dimethyloxo-3,8,11-trioxaazatetradecan yl)(propyl)carbamate (compound 49E, 300 mg, 0.73 mmol) in MeOH (20 mL) was added Pd/C (300 mg, 10%, wet). Then the mixture was d under 50 psi H2 at 30 °C for 12 hrs. The reaction mixture was filtered and the filtrate was concentrated in vacuo to give tert-butyl (2-(2- opylamino)propoxy)ethoxy)ethyl)carbamate (compound 49A, 187 mg, 84%) as a yellow oil, which was used ly in the next step. MS: calc’d 305 (M+H)+, measured 305(M+H)+ Example 50 2-Amino-N8-[5-(3-aminopropyl)pyridyl]-N4,N4-dipropyl-3Hbenzazepine-4,8- dicarboxamide The title compound was prepared in analogy to Example 1 by using tert-butyl N-[3-(5- aminopyridyl)propyl]carbamate (compound 50A) instead of pyridinamine. Example 50 was obtained as a white solid (30.4 mg). 1H NMR (400 MHz, CD3OD) δ ppm = 8.67 (s, 1H), 8.30 (s, 1H), 8.22 (s, 1H), 7.74 (s, 1H), 7.63 (d, J = 8 Hz, 1H), 7.50 (d, J = 8 Hz, 1H), 6.93 (s, 1H), 4.88 (m, 2H), 3.45-3.42 (m, 4H), 3.00 (t, J = 8 Hz, 2H), 2.81 (t, J = 8 Hz, 2H), 2.07-1.99 (m, 2H), 1.71-1.66 (m, 4H), 0.97 - 0.88 (m, 6H). MS: calc’d 463 (M+H)+, measured 463 (M+H)+.
Preparation of tert-butyl 5-aminopyridyl)propyl]carbamate und 50A): Pd(OH)2/C N N H H N O N O O H2N EtOH O O 48B 50A To a flask was added tert-butyl (3-(5-nitropyridinyl)propynyl)carbamate (compound 48B) (100 mg, 0.361 mmol), ethanol (5 mL) and palladium hydroxide on carbon (15 mg, 0.107 mmol). After the mixture was degassed and recharged with hydrogen for five times, it was stirred at room temperature with a hydrogen balloon for 4 hrs. The reaction mixture was filtered through celite and the filtrate was concentrated to give crude utyl N-[3-(5-amino pyridyl)propyl]carbamate und 50A, 95 mg) as a brown sticky oil. MS: calc’d 252 (M+H)+, measured 252 .
Example 51 2-Amino-N8-(m-tolyl)-N4-propyl-N4-(3,3,3-trifluoropropyl)-3Hbenzazepine-4,8- dicarboxamide The title compound was prepared in analogy to Example 26 by using 3,3,3-trifluoro-N- propyl-propanamine instead of 3-(propylamino)propanol. Example 51 was ed as a white solid (3 mg). 1H NMR (400 MHz, CD3OD) δ ppm =7.85-7.82 (m, 2H), 7.61 (d, J = 8 Hz, 1H), 7.53 (s, 1H), 7.49 (d, J = 8 Hz, 1H), 7.26 (t, J = 8 Hz, 1H), 7.08 (s, 1H), 7.01 (d, J = 8 Hz, 1H), 4.87 (m, 2H), 3.75 (brs, 2H), 3.52-3.48 (m, 2H), 2.65-2.59 (m, 2H), 2.37 (s, 3H), 1.75-1.66 (m, 2H), 0.93 (brs, 3H), MS: calc’d 473 (M+H)+, measured 473 (M+H)+.
Example 52 2-Amino-N8-[5-[(Z)aminopropenyl]pyridyl]-N4,N4-dipropyl-3H benzazepine-4,8-dicarboxamide N NH2 The title compound was prepared in analogy to Example 1 by using tert-butyl N-[(Z)(5- aminopyridyl)allyl]carbamate (compound 52A) instead of pyridinamine. Example 52 was ed as a white solid (35 mg). 1H NMR (400 MHz, CD3OD) δ ppm = 8.75 (s, 1H), 8.35 (s, 1H), 8.27 (s, 1H), 7.80 (s, 1H), 7.70 (d, J = 8 Hz, 1H), 7.54 (d, J = 8 Hz, 1H), 6.97 (s, 1H), 6.88 (d, J = 12 Hz, 1H), 5.98-5.92 (m, 1H), 4.87 (m, 2H), 3.93 (d, J = 8 Hz, 2H), 3.46-3.42 (m, 4H), 1.72-1.66 (m, 4H), 0.97 - 0.90 (m, 6H). MS: calc’d 461 (M+H)+, measured 461 (M+H)+.
Preparation of tert-butyl N-[(Z)(5-aminopyridyl)allyl]carbamate (compound 52A): Lindlar Cat.
Toluene 48B 52A To a 25 mL flask was added tert-butyl nitropyridinyl)propynyl)carbamate (compound 48B) (400 mg, 1.44 mmol), Lindlar catalyst (200 mg, 968 µmol) and toluene (10 mL). After the e was degassed and recharged with hydrogen for five times, it was stirred at r.t. with a hydrogen balloon overnight. The mixture was filtered through celite and the filtrate was concentrated to give the crude tert-butyl N-[(Z)(5-aminopyridyl)allyl]carbamate (compound 52A) as sticky brown oil, which was used directly in the next step. MS: calc’d 250 (M+H)+, ed 250 (M+H)+. e 53 2-Amino-N4-(cyclopropylmethyl)-N8-(m-tolyl)-N4-propyl-3Hbenzazepine-4,8- oxamide The title compound was prepared in analogy to Example 26 by using N-(cyclopropyl methyl)propanamine instead of 3-(propylamino)propanol. Example 53 was obtained as a white solid (18.3 mg). 1H NMR (400 MHz, CD3OD) δ ppm =7.77 (s, 1H), 7.71 (d, J = 8 Hz, 1H), 7.55 - 7.53 (m, 2H), 7.49 (d, J = 8 Hz, 1H), 7.25 (t, J = 8 Hz, 1H), 7.00-7.69 (m, 2H), 4.87 (m, 2H), 3.55 (t, J = 8 Hz, 2H), 3.39 (d, J = 8 Hz, 2H), 2.37 (s, 3H), .70 (m, 2H), 1.09 (brs, 1H), 0.94 (br s, 3H), 0.62-0.57 (m, 2H), 0.28 (br s, 2H). MS: calc’d 431 (M+H)+, measured 431 (M+H)+.
Example 54 2-Amino-N8-[3-(2-aminoethyl)phenyl]-N4,N4-dipropyl-3Hbenzazepine-4,8- dicarboxamide The title compound was prepared in analogy to Example 1 by using tert-butyl 3- aminophenethylcarbamate instead of pyridinamine. Example 54 was obtained as a yellow solid (20 mg). 1H NMR (400 MHz, CD3OD) δ ppm = .95 (m, 3H), 7.50-7.67 (m, 2H), 7.39 (t, J = 7.9 Hz, 1H), 7.13 (d, J = 7.5 Hz, 1H), .07 (m, 1H), 3.47 (br. s., 4H), 3.10-3.29 (m, 4H), 2.79-3.07 (m, 2H), 1.47-1.82 (m, 4H), 0.66-1.17 ppm (m, 6H). MS: calc’d 448 (M+H)+, measured 448 (M+H)+.
Example 55 2-Amino-N4-isobutyl-N8-(m-tolyl)-N4-propyl-3Hbenzazepine-4,8-dicarboxamide The title compound was ed in analogy to Example 26 by using 2-methyl-N-propylpropanamine instead of 3-(propylamino)-propanol. Example 55 was obtained as a white solid (14.8 mg). 1H NMR (400MHz, CD3OD) δ ppm = 7.86-7.83 (m, 2H), 7.63 (d, J = 8 Hz, 1H), 7.53 (s, 1H), 7.50 (d, J = 8Hz, 1H), 7.26 (t, J = 8 Hz, 1H), 7.06 (s, 1H), 7.01 (d, J = 8 Hz, 1H), 3.48 (br, 4H), 3.31 (s, 2H), 2.37 (s, 3H), 1.69 (br, 3H), 0.99 - 0.91 (m, 9H). MS: calc’d 433 (M+H)+, measured 433 (M+H)+. e 56 2-Amino-N4-[3-(3-aminopropoxy)propyl]-N8-(m-tolyl)-N4-propyl-3Hbenzazepine-4,8- dicarboxamide The title compound was prepared in analogy to Example 26 by using tert-butyl N-[3-[3- (propylamino)propoxy]propyl]carbamate und 56B) instead of 3-(propylamino)-propan ol. Example 56 was obtained as a white solid (12.4 mg). 1H NMR (400MHz, CD3OD) δ ppm = 7.80-7.75 (m, 2H), 7.58-7.56 (m, 1H), 7.53 (s, 1H), 7.50 (d, J = 8Hz, 1H), 7.25 (t, J = 8 Hz, 1H), 7.03-6.99 (m, 2H), 3.60-3.56 (m, 4H), 3.48 (m, 4H), 3.31 (s, 2H), 3.30-3.08 (br, 2H), 2.37 (s, 3H), 1.95-1.92 (br, 3H), 1.73-1.67 (m, 3H), 0.97 - 0.90 (br, 3H). MS: calc’d 492 (M+H)+, measured 492 (M+H)+.
Preparation of compound 56B: Boc2O K2CO3 MeOH NaBH4 To a flask was added 3,3'-oxybis(propanamine) (1 g, 7.56 mmol) and DCM (1 mL). A yellow solution was formed, then a solution of Boc-anhydride (825 mg, 878 µl, 3.78 mmol) in DCM (4 mL) was added drop-wise via a dropping funnel at r.t. over 50 mins. When it was completed, the mixture was stirred for 3 hours. The e was concentrated to give a yellow slurry, then it was re-dissolved in water (30 mL) and filtered through celite. The residue was washed with another 20 mL water. The filtrate was extracted with DCM (25 mL x 6). The organic layer was washed with brine (30 mL x 2), dried over Na2SO4 and trated to give about 550 mg tert-butyl (3-(3-aminopropoxy)propyl)carbamate (Compound 56A) as yellow oil.
MS: calc’d 233 (M+H)+, measured 233 (M+H)+.
To a solution of tert-butyl (3-(3-aminopropoxy)propyl)carbamate (550 mg, 2.37 mmol) in methanol (9 mL) was added dropwisely propionaldehyde (137 mg, 172 µl, 2.37 mmol). A pale yellow solution was formed, then K2CO3 (327 mg, 2.37 mmol) was added. After the suspension was stirred overnight, the olved material was removed by filtration. The filtrate was cooled with ice bath, then NaBH4 (134 mg, 3.55 mmol) was added portion-wise. After the mixture was warmed to r.t. and stirred for 3 hours, it was treated with 30 mL water. The mixture was ted with DCM (25 mL x 6). The organic layer was washed with brine (30 mL), dried over Na2SO4 and concentrated to give the crude product. cation by lash (eluted with EA/PE=50% ~ 100%) gave about 440 mg tert-butyl-N-[3-[3-(propylamino)propoxy]- propyl]carbamate (Compound 56B) as yellow oil. MS: calc’d 275 (M+H)+, measured 275 (M+H)+. e 57 2-Amino-N8-[3-(5-aminopentyl)phenyl]-N4,N4-dipropyl-3Hbenzazepine-4,8- dicarboxamide N NH2 A detailed synthetic route is provided in Scheme 6.
Scheme 6 H O O Boc N H O N Boc N OH N N N 57C, HATU, DIEA N N N N 57E N NH2 MeNH2/EtOH N 57 Preparation of Compound 57C: Ph Br- NaOH O Ph P+ Br + O2N Br 57A O O Pd/C N N O2N H2N O O 57B 57C Preparation of Compound 57A: To a mixture of 3-nitrobenzaldehyde (1.0 g, 6.60 mmol) and (4-bromobutyl)triphenyl- phosphonium bromide (3.5 g, 7.26 mmol) in a mixed solvent of THF (20 mL) and water (3 drops) was added NaOH (331 mg, 8.25 mmol). After the mixture was heated to 70 °C for 18 hours, it was filtered and the filtrate was concentrated to give the crude product. The crude t was purified by column chromatography (PE : EA=20:1) to give romopentenyl) nitrobenzene (compound 57A, 400 mg, 22.5%) as a white solid. MS: calc’d 270 (M+H)+, measured 270 (M+H)+.
Preparation of Compound 57B: A solution of 1-(5-bromopentenyl)nitrobenzene (compound 57A, 300 mg, 1.11 mmol) and potassium 1,3-dioxoisoindolinide (210 mg, 1.11 mmol) in dimethylaniline (15 mL) was stirred under N2 at 110 °C for 18 hours. The on mixture was diluted with water (30 mL), then extracted with EtOAc (25 mL x 3). The ed organic phase was washed with brine (30 mL x 3), dried over anhydrous Na2SO4 and concentrated to give 2-(5-(3- nitrophenyl)pentenyl)-isoindoline-1,3-dione (compound 57B, 300 mg) as a yellow oil. MS: calc’d 337 , measured 337 (M+H)+. ation of Compound 57C: Pd/C (60 mg) was added into a solution of 2-(5-(3-nitrophenyl)pentenyl)- isoindoline-1,3-dione (compound 57B, 300 mg, 0.89 mmol) in MeOH (10 mL). After the mixture was degassed with hydrogen for 3 times with a hydrogen balloon, it was stirred under hydrogen (1103 hPA) at 16 °C for 18 hrs. The reaction mixture was filtered on celite, and the solid was washed with MeOH (5 mL x 2). The combined filtrates were concentrated to give 2-(5- (3-aminophenyl)pentyl)isoindoline-1,3-dione (compound 57C, 0.2 g, 72.7%) as a yellow solid.
MS: calc’d 309 (M+H)+, measured 309 (M+H)+.
Preparation of Compound 57D: To a solution of rt-butoxycarbonyl)amino)(dipropylcarbamoyl)-3H- benzo[b]azepinecarboxylic acid (compound J, 200 mg, 0.46 mmol) in DMF (5 mL) at 0 °C was added DIPEA (148 mg, 1.15 mmol), HATU (209.7 mg, 0.55 mmol) and 2-(5-(3- aminophenyl)pentyl)isoindoline-1,3-dione (compound 57C, 158 mg, 0.51 mmol). After the mixture was d at 25 °C for 16 hours, it was diluted with brine (20 mL) and then extracted with EtOAc (25 mL x 2). The combined organic phase was washed with saturated NH4Cl (20 mL), brine (30 mL x 3), dried over anhydrous Na2SO4 and concentrated to give utyl (8-((3- (5-(1,3-dioxoisoindolinyl)pentyl)phenyl)carbamoyl)(dipropylcarbamoyl)-3H- benzo[b]azepinyl)carbamate und 57D, 200 mg, 59.6%) as a yellow solid. MS: calc’d 720 (M+H)+, measured 720 .
Preparation of Compound 57E: TFA (561 mg) was added drop-wise to a solution of tert-butyl (8-((3-(5-(1,3- dioxoisoindolinyl)pentyl)phenyl)carbamoyl)(dipropylcarbamoyl)-3H-benzo[b]azepin yl)carbamate (compound 57D, 200 mg, 0.28 mmol) in DCM (5 mL) at 0 °C. After the e was stirred for 3 hours at 20 °C, it was trated to give the crude product. The crude product was added to aq.NaHCO3 (20 mL), extracted with DCM (5 mL). The organic layer was washed with brine, dried over anhydrous Na2SO4 and concentrated to give 2-amino-N8-(3-(5-(1,3- dioxoisoindolinyl)pentyl)phenyl)-N4,N4-dipropyl-3H-benzo[b]azepine-4,8-dicarboxamide (compound 57E, 150 mg, 87.2%) as a brown oil. MS: calc’d 620 (M+H)+, measured 620 (M+H)+.
Preparation of Example 57: A mixture of 2-amino-N8-(3-(5-(1,3-dioxoisoindolinyl)pentyl)phenyl)-N4,N4-dipropyl- 3H-benzo[b]azepine-4,8-dicarboxamide (compound 57E, 50 mg, 0.08 mmol) in ethanolic methylamine (1.0 mL) was d for 2 hours at 20 °C. The solvent was removed in vacuo at 16 °C. The residue was acidified with TFA (0.2 mL in 1 mL EtOH), and then concentrated to an oil. The oil was purified by Pre-HPLC (TFA-system) to give 2-amino-N8-[3-(5- aminopentyl)phenyl]-N4,N4-dipropyl-3Hbenzazepine-4,8-dicarboxamide example 57 (8.5 mg, 21.5%) as a white solid. 1H NMR (400MHz, METHANOL-d4) δ ppm = 7.99 - 7.93 (m, 2H), 7.71 (d, J = 8.8 Hz, 1H), 7.66 (s, 1H), 7.49 (d, J = 8.0 Hz, 1H), 7.32 (t, J = 7.8 Hz, 1H), 7.13 (s, 1H), 7.06 (d, J = 7.5 Hz, 1H), 3.49 (br. s., 4H), 3.38 (d, J = 8.8 Hz, 2H), 2.94 (t, J = 7.5 Hz, 2H), 2.71 (t, J = 7.5 Hz, 2H), 1.72 (qd, J = 7.1, 14.8 Hz, 8H), 1.55 - 1.42 (m, 2H), 0.98 (br. s., 6H).
MS: calc’d 490 (M+H)+, measured 490 (M+H)+. e 58 2-Amino-N8-[4-(5-aminopentyl)phenyl]-N4,N4-dipropyl-3Hbenzazepine-4,8- dicarboxamide The title compound was prepared in analogy to Example 57 by using 4-nitrobenzaldehyde instead of 3-nitrobenzaldehyde. e 58 was obtained as a white solid (13.5 mg). 1H NMR (400MHz, CD3OD) δ ppm = 7.94 (d, J = 1.63 Hz, 2H), 7.71-7.65 (m, 1H), 7.62 (d, J = 8.41 Hz, 2H), 7.26-7.19 (m, 2H), 7.12-7.08 (m, 1H), 3.53-3.40 (m, 4H), 3.38-3.35 (m, 1H), 3.35-3.33 (m, 1H), 2.95-2.88 (m, 2H), 2.70-2.62 (m, 2H), 1.75-1.65 (m, 8H), 1.50-1.39 (m, 2H), 1.07-0.81 (m, 6 H) MS: calc’d 490 (M+H)+, measured 490 (M+H)+.
Example 59 o-N8-[3-(3-aminopropyl)phenyl]-N4,N4-dipropyl-3Hbenzazepine-4,8- dicarboxamide N NH2 The title compound was prepared in y to Example 1 by using tert-butyl (3-(3- aminophenyl)propyl)carbamate instead of pyridinamine. Example 59 was obtained as a yellow solid (49 mg). 1H-NMR (400 MHz, CD3OD) δ ppm =7.82-7.97 (m, 2H), 7.60-7.76 (m, 2H), 7.51 (d, J = 8.3 Hz, 1H), 7.35 (t, J = 7.8 Hz, 1H), 6.98-7.14 (m, 2H), 3.48 (br. s., 4H), 2.90- 3.06 (m, 2H), 2.83 (s, 2H), 2.64-2.81 (m, 2H), 1.92-2.12 (m, 2H), 1.72 (sxt, J = 7.5 Hz, 4H), 0.96 ppm (d, J = 18.6 Hz, 6H). MS: calc’d 462(M+H)+, measured 462(M+H)+.
Example 60 2-Amino-N4-[[4-(aminomethyl)phenyl]methyl]-N8-(m-tolyl)-N4-propyl-3Hbenzazepine- 4,8-dicarboxamide The title compound was prepared in analogy to Example 26 by using utyl N-[[4- (propylaminomethyl)phenyl]methyl]carbamate (compound 60B) instead of 3-(propylamino)- propanol. Example 60 was obtained as a white solid (9.9 mg). 1H NMR (400MHz, CD3OD) δ ppm = 7.82-7.78 (m, 2H), .40 (m, 7H), 7.25 (t, J = 8 Hz, 1H), 7.09 (s, 1H), 7.00 (d, J = 8Hz, 1H), 4.80 (s, 2H), 4.13 (s, 2H), 3.49-3.45 (m, 2H), 3.31 (s, 2H), 2.37 (s, 3H), 1.71-1.66 (m, 2H), 0.90 (br, 3H). MS: calc’d 496 (M+H)+, measured 496 (M+H)+.
Preparation of compound 60B: Boc2O K2CO3 MeOH NaBH4 To a 50 mL flask was added 1,4-phenylenedimethanamine (1 g, 7.34 mmol), TEA (1.11 g, 1.54 mL, 11 mmol) and DCM (10 mL). Then a solution of Boc-anhydride (801 mg, 852 µL, 3.67 mmol) in DCM (10 mL) was added drop-wise at 0 °C. The mixture was warmed to r.t. and stirred for 2 hours. The e was then diluted with 20 mL DCM and 30 mL water. The suspension was separated and the water layer was extracted with 20 mL DCM. The organic layers were combined and washed with sat. NH4Cl, dried over Na2SO4 and concentrated to give a 0.5 g tert-butyl 4-(aminomethyl)benzylcarbamate (compound 60A) as a white solid. MS: calc’d 237 (M+H)+, measured 237 (M+H)+.
To a flask was added tert-butyl(aminomethyl)benzylcarbamate (0.5 g, 2.12 mmol,), propionaldehyde (184 mg, 230 µl, 3.17 mmol) and ol (15 mL) followed by K2CO3 (292 mg, 2.12 mmol) at r.t. After the mixture was stirred at r.t. ght, the precipitate was filtered through celite. The filtrate was cooled with ice bath and NaBH4 (120 mg, 3.17 mmol) was added portion-wise. The mixture was warmed to r.t. and stirred for about 2 hours. The mixture was concentrated to give a sticky solid which was purified via combiflash (eluted with EA/PE = 0~100%) to give about 123 mg of tert-butyl N-[[4-(propylaminomethyl)phenyl]-methyl]- carbamate (Compound 60B) as sticky oil. MS: calc’d 279 (M+H)+, measured 279 (M+H)+.
Example 61 2-Amino-N8-[4-(3-aminopropyl)phenyl]-N4,N4-dipropyl-3Hbenzazepine-4,8- dicarboxamide O NH2 The title compound was prepared in analogy to e 1 by using tert-butyl (3-(4- aminophenyl)propyl)carbamate instead of pyridinamine. Example 61 was obtained as a yellow solid (22 mg). 1H NMR (400 MHz, CD3OD) δ ppm =7.87-8.01 (m, 2H), 7.57-7.73 (m, 3H), 7.29 (d, J = 8.5 Hz, 2H), 7.05-7.13 (m, 1H), 3.48 (br. s., 4H), 3.20 (m, 2H), 2.91-3.02 (m, 2H), 2.65-2.82 (m, 2H), 2.00 (dt, J = 15.5, 7.7 Hz, 2H), 1.72 (dq, J = 15.1, 7.5 Hz, 4H), 0.97 ppm (br. s., 6H). MS: calc’d 462(M+H)+, measured 462(M+H)+.
Example 62 2-Amino-N8-[4-(3-aminopropyl)phenyl]-N4,N4-dipropyl-3Hbenzazepine-4,8- dicarboxamide The title compound was prepared in analogy to Example 1 by using tert-butyl (3-(4- aminophenyl)butyl)carbamate(compound 62F) instead of pyridinamine. Example 62 was obtained as a yellow solid (21 mg). 1H NMR z, CD3OD) δ ppm =7.98-7.93 (m, 2H), 7.72-7.63 (m, 2H), 7.55-7.50 (m, 1H), 7.35-7.29 (m, 1H), 7.12-7.09 (m, 1H), .04 (m, 1H), 3.55-3.41 (m, 4H), 3.38 (s, 2H), 3.00-2.92 (t, J = 6.8 Hz, 2H), 2.77-2.69 (t, J = 6.8 Hz, 2H), 1.82- 1.63 (m, 8H), 1.07-0.84 (m, 6 H). MS: calc’d 476 (M+H)+, measured 476 (M+H)+.
Preparation of compound 62F: 62A 62B 62C 62D Preparation of Compound 62A: A solution of 1,3-dibromopropane (16.4 g, 81.0 mmol) and potassium phthalimide (5.0 g, 27.0 mmol) in DMF (100 mL) was stirred under N2 at 18 °C for 20 hours. The reaction mixture was concentrated, and the residue was diluted with EtOAc (30 mL). The organic phase was washed with water (20 mL), brine (20 mL x 2), dried by anhydrous Na2SO4 and concentrated.
The residue was triturated with PE (30 mL), filtered to give 2-(3-bromopropyl)isoindoline-1,3- dione (compound 62A, 4.3 g, 59.7%) as a white solid. MS: calc’d 268 (M+H)+, ed 268 (M+H)+.
Preparation of Compound 62B: A solution of 2-(3-bromopropyl)isoindoline-1,3-dione (compound 62A, 1.0 g, 4.0 mmol), triphenylphosphine (1.0 g, 4.0 mmol) in toluene (50 mL) was stirred under N2 at 110 °C for 18 hours. The t was precipitated and collected by filtration to give [3-(1,3-dioxo-1,3-dihydroisoindolyl )-propyl]-triphenyl-phosphonium bromide (compound 62B, 280 mg, 13.2%) as a white solid.
Preparation of nd 62C: To a stirred solution of 3-nitrobenzaldehyde (80 mg, 0.53 mmol), 3-dioxo-1,3- dihydro-isoindolyl)-propyl]-triphenyl-phosphonium bromide (compound 62B, 280 mg, 0.53 mmol) in THF (5 mL) was added ium tert-butoxide (65 mg, 0.58 mmol) at 0 °C. Then the reaction mixture was d under N2 at 70 °C for 19 hours. The reaction mixture was filtered and the filtrate was concentrated to give a residue which was purified by silica gel tography (PE:EA = 20:1~10:1) to give (E)(4-(3-nitrophenyl)butenyl)isoindoline- 1,3-dione (compound 62C, 80 mg, 46.8%) as a white solid. MS: calc’d 323 (M+H)+, measured 323 (M+H)+.
Preparation of Compound 62D: To a stirred solution of (E)(4-(3-nitrophenyl)butenyl)isoindoline-1,3-dione (compound 62C, 80 mg, 0.25 mmol) in EtOH (4 mL) was added NH2NH2 x H2O (25 mg, 0.50 mmol) drop-wise at 0 °C. Then the mixture was stirred at 10 °C for 48 hrs. The reaction mixture was concentrated and the residue was d with DCM (30 mL) and stirred for 30 min. The undissolved material was filtered and the filtrate was concentrated to give a residue which was ed by Pre-TLC (DCM/MeOH=20:1 twice) to give (E)(3-nitrophenyl)butenamine und 62D, 23 mg, 47.9%) as a colorless oil. MS: calc’d 193 (M+H)+, measured 193 (M+H)+.
Preparation of Compound 62E: A solution of (E)(3-nitrophenyl)butenamine und 62D, 23 mg, 0.12 mmol), Et3N (24 mg, 0.24 mmol) and Boc2O (39 mg, 0.18 mmol) in DCM (1 mL) was stirred under N2 at 18 °C for 16 hrs. TLC (PE: EA=1:1) showed the (E)(3-nitrophenyl)butenamine was consumed completely. The reaction mixture was concentrated to give crude product. The crude product was purified by Pre-TLC (PE:EA=2:1) to give (E)-tert-butyl (4-(3-nitrophenyl)buten- 1-yl)carbamate (compound 62E, 28 mg, 80.0%) as colorless oil. MS: calc’d 315 (M+Na)+, measured 315 (M+Na)+.
Preparation of Compound 62F: Pd/C (3 mg) was added into a solution of (E)-tert-butyl (4-(3-nitrophenyl)buten yl)carbamate (compound 62E, 28 mg, 0.09 mmol) in MeOH (1.5 mL). The e was degassed with H2 for 3 times with a hydrogen balloon. Then the mixture was stirred under H2 (1103 hPa) at 18 °C for 4 hrs. The reaction mixture was filtered and the te was concentrated to give crude tert-butyl (4-(3-aminophenyl)butyl)carbamate (compound 62F, 30 mg) as a colorless oil. MS: calc’d 265 (M+H)+, measured 265 (M+H)+.
Example 63 2-Amino-N8-[3-(2-aminoethyl)fluoro-phenyl]-N4,N4-dipropyl-3Hbenzazepine-4,8- dicarboxamide The title compound was prepared in analogy to Example 1 by using tert-butyl 5-amino fluorophenethylcarbamate (compound 63E) instead of pyridinamine. Example 63 was obtained as a yellow solid (21 mg). 1H NMR z, CD3OD) δ ppm = .00 (m, 2H), 7.82 (br. s., 1H), 7.72 (d, J = 8.66 Hz, 1H), 7.57 (br. s., 1H), 7.20 (t, J = 9.35 Hz, 1H), 7.13 (s, 1H), 3.49 (d, J = 6.65 Hz, 4H), 3.39 (s, 2H), .27 (m, 2H), 3.04-3.11 (m, 2H), 1.66-1.78 (m, 4H), 0.97 (d, J = 5.52 Hz, 6H). MS: calc’d 466 (M+H)+, measured 466 (M+H)+.
Preparation of compound 63E: F F F NaCN BH3 Br CN O2N O2N O2N NH2 63A 63B 63C F F Pd/C, H2 Boc Boc O2N N H2N N H H 63D 63E Preparation of Compound 63B: To a solution of NaCN (0.63 g, 12.9 mmol) in H2O (6.0 mL) was added drop-wise 2- (bromomethyl)fluoronitrobenzene (compound 63A, 2.0 g, 8.6 mmol) in EtOH (30 mL) at °C. After the reaction mixture was stirred for 4 hrs, it was ed with 2 N NaOH (10 mL).
The mixture was diluted with H2O (100 mL) and extracted with EA (50 mL x 3). The combined organic layers were washed with brine (30 mL x 2), dried over Na2SO4, filtered and concentrated to give 2-(2-fluoronitrophenyl)acetonitrile (compound 63B, 1.6 g) as yellow oil without further purification. MS: calc’d 180 (M+H)+, measured 180 (M+H)+.
Preparation of Compound 63C: To a solution of 2-(2-fluoronitrophenyl)acetonitrile (compound 63B, 0.7 g, 3.9 mmol) in THF (20 mL) was added BH3/THF (1 M, 16 mL, 15.5 mmol) at 25 °C. After the reaction mixture was stirred for 2 hrs at 70 °C, it was quenched with MeOH (10 mL). The mixture was d with H2O (200 mL) and extracted with EA (50 mL x 3). The combined organic layers were washed with brine (30 mL x 2), dried over ous Na2SO4) and concentrated to give 2- (2-fluoronitrophenyl)ethanamine (compound 63C, 700 mg) as yellow oil without further purification. MS: calc’d 184 (M+H)+, measured 184 (M+H)+.
Preparation of Compound 63D: To a solution of 2-(2-fluoronitrophenyl)ethanamine (compound 63C, 700 mg, 3.9 mmol) and DIPEA (1.5 g, 11.7 mmol) in DCM (30 mL) was added Boc2O (932 mg, 4.3 mmol) at 0 oC.
Then the mixture was stirred for 1 h at 25 oC. The on on was quenched with saturated NH4Cl (20 mL), diluted with H2O (100 mL) and extracted with DCM (30 mL x 3). The combined organic layers were washed with brine (20 mL x 2), dried over anhydrous Na2SO4 and concentrated. The crude t was purified by silica gel column chromatography (PE: EA = 4:1) to give utyl 2-fluoronitrophenethylcarbamate (compound 63D, 600 mg, 54.5%) as yellow oil. MS: calc’d 284 (M+H)+, measured 284 (M+H)+.
Preparation of Compound 63E: To a solution of tert-butyl 2-fluoronitrophenethylcarbamate (compound 63D, 600 mg, 2.11 mmol) in MeOH (15 mL) was added Pd/C (100 mg). The reaction mixture was stirred for 18 hours at 25 °C under hydrogen atmosphere. The on was filtered and the filtrate was concentrated to give tert-butyl 5-aminofluorophenethylcarbamate (compound 63E, 500 mg) as green oil without further purification. MS: calc’d 254 (M+H)+, measured 254 (M+H)+.
Example 64 2-Amino-N8-[3-(2-aminoethyl)chloro-phenyl]-N4,N4-dipropyl-3Hbenzazepine-4,8- dicarboxamide The title compound was prepared in analogy to e 1 by using tert-butyl 3-amino chlorophenethylcarbamate (compound 64A) instead of pyridinamine. Example 64 was obtained as a yellow solid (20 mg). 1H NMR (400MHz, METHANOL-d4) δ ppm = 7.96-7.93 (m, 2H), 7.73-7.68 (m, 3H), 7.16 (s, 1H), 7.10 (s, 1H), 3.46 (br. s., 4H), 3.37 (s, 2H), 3.22-3.20 (m, 2H), 3.00-2.96 (m, 2H), 1.73-1.67 (m, 4H), 0.97 (br. s., 6H). MS: calc’d 482 (M+H)+, measured 482 (M+H)+, 482 (M+H)+.
Preparation of compound 64A: The title compound was prepared in analogy to e 63E by using momethyl)- 3-chloronitrobenzene instead of momethyl)fluoronitrobenzene.
Example 65 2-Amino-N4-butyl-N4-(2-hydroxyethyl)-N8-(m-tolyl)-3Hbenzazepine-4,8-dicarboxamide The title compound was prepared in analogy to Example 26 by using 2-(butylamino)- ethanol (compound 65A) d of 3-(propylamino)-propanol. Example 65 was obtained as a white solid (48 mg). 1H NMR (400 MHz, CD3OD) δ ppm = 7.94 - 7.92 (m, 2H), 7.69-7.67 (d, J = 8.0 Hz, 1H), 7.53 - 7.48 (m, 2H), 7.28 - 7.24 (m, 1H), 7.17 (s, 1H), 7.02 - 7.00 (d, J = 7.2, 1H), 3.70 - 3.53 (br, 6H), 3.34 (s, 2H), 2.37 (s, 3H), 1.71-1.63 (m, 2H), 1.40 (br, 2H), 0.98 (br, 3H).
MS: calc’d 435.2 (M+H)+, measured 435.2 (M+H)+.
Preparation of Compound 65A: NH2 OH HO N To a solution of butyraldehyde (1.0 g, 13.8 mmol) and 2-aminoethanol (847 mg, 13.8 mmol) in MeOH (20.0 mL) was added MgSO4 (6.65 g, 55.5 mmol). The mixture was stirred at 20 °C for 12 hrs. The reaction mixture was ed. To the filtrate was added NaBH4 (0.58 g, .3 mmol) under ice-bath. The on was stirred at 20 °C for 1 h. TLC (DCM/MeOH = 10/1) showed a new point was formed. The reaction solution was concentrated in vacuo. The residue was dissolved in water (50 mL) and extracted with DCM (100 mL × 3). The combined organic layers were dried over Na2SO4 and concentrated in vacuo to give crude 2-(butylamino)ethanol und 65A, 1.3 g, 80.2%) as colorless oil which was used for the next step ly.
Example 66 2-Amino-N8-[5-(2-aminoethoxy)pyridyl]-N4,N4-dipropyl-3Hbenzazepine-4,8- dicarboxamide The title compound was prepared in analogy to Example 1 by using tert-butyl (5- aminopyridyl)oxy]ethyl]carbamate (compound 66C ) instead of pyridinamine. Example 66 was obtained as a white solid (9.9 mg). 1H NMR (400MHz, CD3OD) δ ppm = 8.57 (s, 1H), 8.20- 8.17 (m, 2H), 8.00-7.97 (m, 2H), 7.72 (d, J = 8 Hz, 1H), 7.12 (s, 1H), 4.37 (t, J = 4 Hz, 2H), 3.45-3.43 (m, 6H), 3.38 (s, 2H), 1.75-1.66 (m, 4H), 0.97-0.93 (br, 6H). MS: calc’d 465 (M+H)+, measured 465 (M+H)+.
Preparation of compound 66C: The title compound was ed in analogy to compound 45C by using 2-aminoethanol instead of 2-(2-aminoethoxy)ethanol and 5-nitropyridinol instead of 3-nitrophenol. MS: calc’d 254 , measured 254 (M+H)+.
Example 67 Benzyl N-[[5-[[2-amino(dipropylcarbamoyl)-3Hbenzazepinecarbonyl]amino] pyridyl]methyl]carbamate H2N H N N O The title compound was prepared in analogy to Example 1 by using benzyl N-[(5-amino pyridyl)methyl]carbamate instead of pyridinamine. Example 67 was obtained as a white solid (17 mg). 1H NMR z, CD3OD) δ ppm = 9.12 (s, 1 H) 8.44 (d, J = 10.54 Hz, 2 H) 7.98 - 8.05 (m, 2 H) 7.75 (d, J = 8.03 Hz, 1 H) 7.22 - 7.42 (m, 5 H) 7.14 (s, 1 H) 5.14 (s, 2 H) 4.47 (s, 2 H) 3.50 (br. s., 4 H) 3.36 - 3.43 (m, 2 H) 1.67 - 1.79 (m, 4 H) 0.98 (d, J = 19.07 Hz, 6 H). MS: calc’d 569.3 (M+H)+, measured 569.3 (M+H)+.
Example 68 2-Amino-N8-[5-[(E)aminopropenyl]pyridyl]-N4,N4-dipropyl-3Hbenzazepine- 4,8-dicarboxamide The title compound was prepared in analogy to Example 1 by using tert-butyl N-[(E)(5- aminopyridyl)allyl]carbamate (compound 68C) instead of pyridinamine. e 68 was obtained as a white solid (23 mg). 1H NMR (400MHz, CD3OD) δ ppm = 8.73 (s, 1H), 8.56 (s, 1H), 8.39 (s, 1H), 7.82 (s, 1H), 7.75-7.74 (m, 1H), 7.57 (d, J = 8 Hz, 1H), 6.99 (s, 1H), 6.89 (d, J = 16 Hz, 1H), 6.49-6.45 (m, 1H), 3.78 (d, J = 4 Hz, 2H), 3.46-3.43 (m, 4H), 3.31 (s, 2H), 1.72- 1.67 (m, 4H), 0.98-0.89 (br, 6H). MS: calc’d 461 (M+H)+, measured 461 (M+H)+.
Preparation of compound 68C: ZrCp2HCl Pd(PPh3)4 K2CO3 SnCl2 DME EtOH/EA 68B 68C Preparation of Compound 68A: To a sealed tube was added utyl propynylcarbamate (1 g, 6.44 mmol), bis(cyclopentadienyl)zirconium chloride hydride (166 mg, 644 µmol), TEA (65.2 mg, 89.8 µl, 644 µmol) and 4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1.24 g, 1.4 ml, 9.67 mmol). The tube was sealed and heated to 65 °C (oil bath) for 18 hours. The mixture was diluted with 25 mL EA and ed with sat. NH4Cl. Then another 25 mL EA was added and the mixture was washed sequentially with sat. NH4Cl, sat. NaHCO3 and brine. The c layer was dried over Na2SO4 and concentrated to give 2.1 g pale yellow sticky oil. After purification via combiflash (eluted with EA/PE=0 ~ 40%), about 1.1 g (E)-tert-butyl (3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan yl)allyl)carbamate (Compound 68A) was obtained as pale yellow oil. MS: calc’d 284 , measured 284 (M+H)+.
Preparation of Compound 68B: To a 25 mL flask was added rt-butyl (3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan yl)allyl)carbamate (200 mg, 706 µmol), 3-bromonitropyridine (143 mg, 706 µmol), K2CO3 (293 mg, 2.12 mmol), dimethyl ether (4 mL), water (0.5 mL) and Pd(Ph3P)4 (81.6 mg, 70.6 µmol). Then the mixture was ed for five times and was heated to 85 °C (oil bath) for 23 hours. The e was diluted with EA and water, filtered through celite. The organic layer was separated and the aqueous layer was extracted with EA. The combined organic layers were washed with brine, dried over Na2SO4 and concentrated to give a brown oil. After purification via combifalsh (eluted with EA/PE=0 ~ 35%), about 160 mg rt-butyl (3-(5-nitropyridin yl)allyl)carbamate (Compound 68B) was obtained as yellow sticky solid. MS: calc’d 280 (M+H)+, ed 280 (M+H)+.
Preparation of Compound 68C: To a flask was added (E)-tert-butyl (3-(5-nitropyridinyl)allyl)carbamate (160 mg, 573 µmol), EtOAc (3 mL) and ethanol (2 mL). A pale yellow solution was formed and then heated to about 60 °C (oil bath). The stannous chloride (652 mg, 165 µl, 3.44 mmol) was added in small portions. The reaction was stirred at 60 °C for 3 hours. The mixture was cooled and diluted with mL EA. A 25 wt. % aqueous solution of KOH was added (pH > 7). The precipitate was ed through celite and the filtrate was extracted with EA (15 mL x 4). The combined organic layers were washed with brine, dried over Na2SO4 and concentrated to give about 90 mg tertbutyl N-[(E)(5-aminopyridyl)allyl] carbamate (Compound 68C) as yellow solid. MS: calc’d 250 (M+H)+, measured 250 (M+H)+.
Example 69 2-Amino-N8-[5-(2-phenylethyl)pyridyl]-N4,N4-dipropyl-3Hbenzazepine-4,8- dicarboxamide The title compound was prepared in analogy to Example 1 by using 5-(2- ethyl)pyridinamine (compound 69B) instead of pyridinamine. Example 69 was obtained as a white solid (45.7 mg). 1H NMR (400MHz, CD3OD) δ ppm = 8.74 (s, 1H), 8.11 (s, 2H), 7.96 (d, J = 4Hz, 2H), 7.70 (dd, J = 12 Hz, 4 Hz, 1H), 7.27-7.24 (m, 2H), .15 (m, 3H), 7.11 (s, 1H), 3.47 (br, 4H), 3.31 (s, 2H), 3.01-2.99 (m, 4H), 1.75-1.66 (m, 4H), 0.97-0.93 (br, 6H). MS: calc’d 510 (M+H)+, measured 510 (M+H)+. ation of compound 69B: Pd(OAc)2 Xantphos Cs2CO3 THF, reflux Pd(OH)2/C EtOH To a flask was added 3-bromonitropyridine (203 mg, 1 mmol), 1-chloro ethynylbenzene (164 mg, 1.2 mmol), )2 (11.2 mg, 50 µmol), 4,5- bis(diphenylphosphino)-9,9-dimethylxanthene (57.9 mg, 100 µmol), Cs2CO3 (652 mg, 2 mmol) and THF (4 mL). A pale brown suspension was formed. Then it was bubbled with N2 for 5 min and heated to reflux (70 oC oil bath) for about 16 hours. The mixture was filtered through celite and the filtrate was concentrated to give a dark oil. The oil was purified via combiflash ng with EA/PE = 0~20%~30%). About 200 mg 3-[2-(4-chlorophenyl)ethynyl]nitro-pyridine (Compound 69A) was obtained as yellow solid. MS: calc’d 259 (M+H)+, measured 259 (M+H)+.
To a flask was added 3-((4-chlorophenyl)ethynyl)nitropyridine (200 mg, 773 µmol) and EtOH (15 mL). A yellow suspension was formed. Then 2 on carbon (20 wt%, 50% H2O) (20 mg, 142 µmol) was added. After the mixture was sucked in vacuo and back-filled with H2 for 5 times, it was stirred with hydrogen balloon at r.t. for about 18 hours. The mixture was filtered through celite to remove the catalyst and the filtrate was concentrated to give about 170 mg 5-(2-phenylethyl)pyridinamine (Compound 69B) as yellow oil. MS: calc’d 199 (M+H)+, measured 199 (M+H)+.
Example 70 2-Amino-N8-[5-[2-(4-methoxyphenyl)ethyl]pyridyl]-N4,N4-dipropyl-3Hbenzazepine- 4,8-dicarboxamide The title compound was prepared in analogy to Example 1 by using 5-[2-(4- methoxyphenyl)ethyl]pyridinamine (compound 70B) instead of pyridinamine. Example 70 was obtained as a white solid (50 mg). 1H NMR (400MHz, CD3OD) δ ppm = 8.73 (s, 1H), 8.09 (s, 1H), 8.06 (s, 1H), 7.85 (s, 1H), 7.80 (d, J = 8 Hz, 1H), 7.60 (d, J = 8 Hz, 1H), 7.08 (d, J = 8 Hz, 2H), 7.02 (s, 1H), 6.81 (d, J = 8 Hz, 2H), 3.74 (s, 3H), 3.45 (br, 4H), 3.31 (s, 2H), 2.98-2.89 (m, 4H), 1.74-1.65 (m, 4H), 0.97-0.90 (br, 6H). MS: calc’d 540 (M+H)+, measured 540 (M+H)+.
Preparation of compound 70B: The title compound was prepared in analogy to compound 69B by using 1-ethynyl methoxy-benzene instead of roethynyl-benzene. MS: calc’d 229 (M+H)+, measured 229 Example 71 2-Amino-N8-[5-[2-[4-(aminomethyl)phenyl]ethyl]pyridyl]-N4,N4-dipropyl-3H epine-4,8-dicarboxamide The title compound was prepared in analogy to Example 1 by using tert-butyl N-[[4-[2-(5- aminopyridyl)ethyl]phenyl]methyl]carbamate (compound 71C) instead of pyridinamine.
Example 71 was obtained as a white solid (20.9 mg). 1H NMR (400MHz, CD3OD) δ ppm = 8.76 (br, 1H), 8.21 (s, 1H), 8.08 (br, 1H), 7.99-7.97 (m, 2H), 7.72 (d, J = 12 Hz, 1H), 7.36 (d, J = 8 Hz, 2H), 7.29 (d, J = 8 Hz, 2H), 7.12 (s, 1H), 4.07 (s, 2H), 3.48 (br, 4H), 3.38 (s, 2H), 3.04 (s, 4H), 1.75-1.66 (m, 4H), 1.00-0.94 (br, 6H). MS: calc’d 539 (M+H)+, ed 539 (M+H)+. ation of compound 71C: The 4-[2-(5-aminopyridyl)ethyl]benzonitrile (compound 71B) was prepared in analogy to compound 69B by using nylbenzonitrile instead of 1-chloroethynyl-benzene. MS: calc’d 224 , measured 224 (M+H)+. 1) BH3-THF BOMe3 2) Boc2O 71B 71C To a flask was added 4-(2-(5-aminopyridinyl)ethyl)benzonitrile (compound 71B, 223 mg, 1 mmol), trimethyl borate (935 mg, 1.01 ml, 9 mmol) and borane tetrahydrofuran complex (3 mL, 3 mmol) at r.t. After the reaction mixture was stirred at 25 °C for about 13.5 hours, it was quenched with 10 mL MeOH and stirred for 1 h. Then it was filtered through celite and the filtrate was trated to give a brown oil. To this brown oil was added DCM (8 mL) and TEA (121 mg, 167 µl, 1.2 mmol). After the mixture was cooled with ice bath, Boc-anhydride (218 mg, 232 µl, 1.0 mmol) was added. The reaction mixture was stirred for about 2 hours. The mixture was filtered through celite and the filtrate was concentrated to give a brown slurry. After purification via lash (eluted with EA/PE=0 ~ 50% ~ 100% and MeOH/EA=10%), about 110 mg tert-butyl N-[[4-[2-(5-aminopyridyl)ethyl]phenyl]methyl]carbamate (compound 71C) was obtained as yellow sticky oil. MS: calc’d 328 (M+H)+, measured 328 (M+H)+.
Example 72 2-Amino-N8-[5-(5-aminopentyl)pyridyl]-N4,N4-dipropyl-3Hbenzazepine-4,8- dicarboxamide The title compound was prepared in y to Example 1 by using tert-butyl N-[5-(5- aminopyridyl)pentyl]carbamate (compound 72B) instead of pyridinamine. Example 72 was ed as a white solid (23.9 mg). 1H NMR (400 MHz, CD3OD) δ ppm = 8.70 (s, 1H), 8.20 (s, 2H), 7.88 (s, 1H), 7.85-7.82 (m, 1H), 7.64-7.62 (m, 1H), 7.04 (s, 1H), 3.46 (br, 4H), 3.31 (s, 2H), 2.94 (t, J = 8 Hz, 2H), 2.75 (t, J = 8 Hz, 2H), 1.80-1.65 (m, 8H), 1.52-1.48 (m, 2H), 0.97 - 0.88 (m, 6H). MS: calc’d 491 (M+H)+, measured 491 (M+H)+.
Preparation of compound 72B: Pd(OAc)2 N Xantphos O Cs2CO3 O + N H N Br N O THF, reflux N O H O Pd(OH)2/C N O MeOH H2N To a flask was added 3-bromonitropyridine (60 mg, 296 µmol), THF (2 mL), tert-butyl pentynylcarbamate (59.6 mg, 325 µmol), Pd(OAc)2 (3.32 mg, 14.8 µmol), 4,5- bis(diphenylphosphino)-9,9-dimethylxanthene (17.1 mg, 29.6 µmol) and Cs2CO3 (193 mg, 591 µmol). Then the mixture was bubbled with N2 for 5 mins and heated to reflux (70 °C oil bath) for about 4.5 hours. The mixture was filtered through celite and the filtrate was trated to give a brown solid. After purification via combiflash (eluted with 0 ~ 20% ~ 40%), tert-butyl N-[5-(5-nitropyridyl)pentynyl]carbamate (Compound 72A) was obtained as pale brown oil.
Compound 72A was dissolved in ethanol (8 mL). Then 2 (20% on carbon with 50% H2O) (10 mg, 71.2 µmol) was added. The mixture was degassed in vacuo and backfilled with H2 for five times. Then it was stirred at r.t. with hydrogen balloon for about 14 h. The mixture was filtered through celite and the filtrate was concentrated directly to give about 55 mg tert-butyl N-[5-(5-aminopyridyl)pentyl]carbamate (compound 72B) as pale brown oil. MS: calc’d 280 (M+H)+, measured 280 (M+H)+.
Example 73 2-Amino-N8-[5-[2-(3-methoxyphenyl)ethyl]pyridyl]-N4,N4-dipropyl-3Hbenzazepine- 4,8-dicarboxamide The title compound was prepared in analogy to Example 1 by using 5-[2-(3- methoxyphenyl)ethyl]pyridinamine (compound 73B) instead of pyridinamine. Example 73 was ed as a white solid (29.4 mg). 1H NMR (400MHz, CD3OD) δ ppm = 8.74 (s, 1H), 8.10 (s, 2H), 7.91-7.88 (m, 2H), 7.65 (d, J = 8 Hz, 1H), 7.16 (t, J = 8 Hz, 1H), 7.07 (s, 1H), 6.77- 6.73 (m, 3H), 3.74 (s, 3H), 3.46 (br, 4H), 3.31 (s, 2H), 3.02-2.94 (m, 4H), 1.75-1.65 (m, 4H), 0.97-0.92 (br, 6H). MS: calc’d 540 (M+H)+, measured 540 (M+H)+.
Preparation of compound 73B: The title compound was ed in analogy to compound 69B by using 1-ethynyl methoxy-benzene d of 1-chloroethynyl-benzene. MS: calc’d 229 (M+H)+, ed 229 (M+H)+.
Example 74 2-Amino-N8-[5-(6-aminohexyl)pyridyl]-N4,N4-dipropyl-3Hbenzazepine-4,8- dicarboxamide The title nd was prepared in analogy to Example 1 by using tert-butyl N-[6-(5- aminopyridyl)hexyl]carbamate (compound 74B) instead of pyridinamine. Example 74 was obtained as a white solid (17.0 mg). 1H NMR (400 MHz, CD3OD) δ ppm = 8.68 (s, 1H), 8.20- 8.19 (m, 2H), 7.83 (s, 1H), 7.77 (d, J = 8 Hz, 1H), 7.58 (d, J = 8 Hz, 1H), 7.01 (s, 1H), 3.47-3.43 (br, 4H), 3.31 (s, 2H), 2.92 (t, J = 8 Hz, 2H), 2.73 (t, J = 8 Hz, 2H), 1.75-1.65 (m, 8H), 1.47-1.45 (m, 4H), 0.98 - 0.90 (m, 6H). MS: calc’d 505 (M+H)+, measured 505 (M+H)+.
Preparation of nd 74B: The title compound was prepared in analogy to compound 72B by using tert-butyl N-but- -ynylcarbamate instead of tert-butyl N-pentynylcarbamate. MS: calc’d 294 (M+H)+, measured 294 (M+H)+.
Example 75 2-Amino-N8-[6-(3-aminopropyl)pyridyl]-N4,N4-dipropyl-3Hbenzazepine-4,8- dicarboxamide The title compound was ed in analogy to Example 1 by using utyl N-[3-(5- aminopyridyl)propyl]carbamate (compound 75B) instead of pyridinamine. Example 75 was obtained as a white solid (33.6 mg). 1H NMR (400 MHz, CD3OD) δ ppm = 8.88 (s, 1H), 8.18 (dd, J = 8 Hz, 4 Hz, 1H), 7.92 (s, 1H), 7.88 (d, J = 12 Hz, 1H), 7.65 (d, J = 8 Hz, 1H), 7.38 (d, J = 8 Hz, 1H), 7.06 (s, 1H), 3.46 (br, 4H), 3.31 (s, 2H), 3.00 (t, J = 8 Hz, 2H), 2.91 (t, J = 8 Hz, 2H), 2.11-2.03 (m, 2H), 1.74-1.65 (m, 4H), 0.9 - 0.92 (br, 6H). MS: calc’d 463 (M+H)+, measured 463 (M+H)+.
Preparation of compound 75B: The title nd was prepared in analogy to compound 72B by using 2-bromonitropyridine instead of 3-bromonitro-pyridine and tert-butyl N-propynylcarbamate instead of tert-butyl N-pentynylcarbamate. MS: calc’d 252 (M+H)+, ed 252 (M+H)+. e 76 2-Amino-N8-[5-(4-aminobutyl)pyridyl]-N4,N4-dipropyl-3Hbenzazepine-4,8- dicarboxamide The title compound was prepared in analogy to Example 1 by using tert-butyl N-[4-(5- 3-pyridyl)butyl]carbamate (compound 76B) d of pyridinamine. Example 76 was obtained as a white solid (51.7 mg). 1H NMR (400 MHz, CD3OD) δ ppm = 8.91 (s, 1H), 8.35- 8.31 (m, 2H), 8.02 (s, 1H), 7.99 (d, J = 8 Hz, 1H), 7.72 (d, J = 8 Hz, 1H), 7.12 (s, 1H), 3.48 (br, 4H), 3.38 (s, 2H), 2.98 (t, J = 8 Hz, 2H), 2.82 (t, J = 8 Hz, 2H), 1.83-1.66 (m, 8H), 0.99 - 0.92 (br, 6H). MS: calc’d 477 (M+H)+, measured 477 (M+H)+. ation of compound 76B: The title compound was prepared in analogy to compound 72B by using tert-butyl N-but- 3-ynylcarbamate instead of tert-butyl N-pentynylcarbamate. MS: calc’d 266 (M+H)+, measured 266 (M+H)+.
Example 77 2-Amino-N8-[6-(4-aminobutyl)pyridyl]-N4,N4-dipropyl-3Hbenzazepine-4,8- dicarboxamide N NH2 The title compound was prepared in analogy to Example 1 by using utyl N-[4-(5- aminopyridyl)butyl]carbamate und 77B) instead of pyridinamine. Example 77 was obtained as a white solid (51.6 mg). 1H NMR (400 MHz, CD3OD) δ ppm = 9.10 (m, 1H), 8.38 (m, 1H), 8.02-7.98 (m, 2H), 7.72 (d, J = 8 Hz, 1H), 7.64-7.62 (m, 1H), 7.12 (s, 1H), 3.48 (br, 4H), 3.38 (s, 2H), 3.01-2.94 (m, 4H), 1.87-1.82 (m, 2H), 1.78-1.69 (m, 6H), 0.99 - 0.92 (br, 6H). MS: calc’d 477 (M+H)+, measured 477 (M+H)+.
Preparation of nd 77B: The title compound was prepared in analogy to compound 72B by using 2-bromonitropyridine instead of 3-bromonitro-pyridine and tert-butyl N-butynylcarbamate instead of tert-butyl N-pentynylcarbamate. MS: calc’d 266 (M+H)+, measured 266 (M+H)+.
Example 78 2-Amino-N8-[5-[(dimethylamino)methyl]pyridyl]-N4,N4-dipropyl-3Hbenzazepine- 4,8-dicarboxamide The title nd was prepared in analogy to Example 1 by using 5-[(dimethyl- amino)methyl]pyridinamine instead of pyridinamine. Example 78 was obtained as a white solid (16 mg). 1H NMR (400 MHz, CD3OD) δ ppm = 8.99 (br. s., 1H), 8.65 (br. s., 1H), 8.52 (br. s., 1H), 7.98-8.09 (m, 2H), 7.74 (d, J = 8.03 Hz, 1H), 7.14 (br. s., 1H), 4.48 (br. s., 2H), 3.49 (br. s., 4H), 3.40 (br. s., 2H), 2.96 (br. s., 6H), 1.72 (d, J = 6.40 Hz, 4H), 0.88-1.08 (m, 6H). MS: calc’d 463 (M+H)+, measured 463 (M+H)+.
Example 79 2-Amino-N4-(cyclopropylmethyl)-N8-(5-ethoxypyridyl)-N4-propyl-3Hbenzazepine- 4,8-dicarboxamide N O The title compound was prepared in analogy to Example 26 by using 5-ethoxypyridin amine instead of idine and N-(cyclopropylmethyl)propanamine instead of 3- lamino)propanol. Example 79 was obtained as a white solid (16.5 mg). 1H NMR (400 MHz, CD3OD) δ ppm =8.74 (br, 1H), 8.17-8.12 (m, 2H), 8.02-7.98 (m, 2H), 7.73 (d, J = 8 Hz, 1H), 7.14 (s, 1H), 4.25-4.20 (m, 2H), 3.58 (t, J = 8 Hz, 2H), 3.42 (d, J = 8Hz, 2H), 3.39 (s, 2H), 1.78-1.69 (m, 2H), 1.48 (t, J = 8 Hz, 3H), 1.11 (brs, 1H), 0.96 (br s, 3H), 0.63-0.61 (br, 2H), 0.31 (br s, 2H). MS: calc’d 462 (M+H)+, measured 462 (M+H)+.
Example 80 o-N8-[5-(2-aminoethyl)pyridyl]-N4,N4-dipropyl-3Hbenzazepine-4,8- dicarboxamide The title compound was prepared in analogy to Example 1 by using tert-butyl N-[2-(5- 3-pyridyl)ethyl]carbamate und 80E) instead of pyridinamine. Example 80 was obtained as a white solid (63 mg). 1H NMR (400 MHz, CD3OD) δ ppm = 9.02 (s, 1H), 8.49 (s, 1H), 8.40 (s, 1H), 8.04 (s, 1H), 8.01 - 7.98 (d, J = 10 Hz, 1H), 7.73 - 7.71 (d, J = 8.4 Hz, 1H), 7.11 (s, 1H), 3.47 (br. s., 4H), 3.37 (s, 2H), 3.31-3.28 (m, 2H), 3.14-3.10 (m, 2H), 1.73-1.67 (m, 4H), 0.96 (br. s., 6H). MS: calc’d 449.4 (M+H)+, measured 449.4 (M+H)+.
Preparation of nd 80E: 80A 80B 80C 80D 80E ation of compound 80B: To the on of 5-bromonicotinaldehyde (5.0 g, 27.0 mmol) in DCM (100 mL) was added Et3N (5.46 g, 54.1 mmol) and CH3NO2 (8.2 g, 135.1 mmol). The solution was stirred at °C for 15 hrs. The reaction solution was concentrated in vacuo to give a crude product (6.7 g) as yellow oil, which was dissolved in DCM (100 mL). Then DMAP (3.63 g, 29.7 mmol) and acetic anhydride (3.58 g, 35.1 mmol) was added at 0 °C. After the solution was stirred at 20 °C for 2 hours, it was poured into water (200 mL). The mixture was extracted with DCM (500 mL).
The organic layer was washed with brine (200 mL) and concentrated in vacuo. The residue was purified through column chromatography (PE/EtOAc=10/1) to give (E)bromo(2- nitrovinyl)pyridine (compound 80B, 4.1 g, 66.5% of yield for two steps) as a yellow solid. 1H NMR (400MHz, CDCl3) = 8.78 (s, 1H), 8.71 (s, 1H), 8.02 (s, 1H), 7.97 - 7.92 (d, J = 18.4 Hz, 1H), 7.63-7.59 (d, J = 18.4 Hz, 1H).
Preparation of compound 80C: To the solution of (E)bromo(2-nitrovinyl)pyridine (compound 80B, 2.0 g, 8.7 mmol) in THF (60 mL) was added LiAlH4 (1.33 g, 35.1 mmol) in portions at -30 °C. Then the mixture was warmed to -10 °C and stirred for 3 hours. The reaction was quenched by water and then Boc2O (2.3 g, 10.5 mmol) was added. After the solution was stirred at 20 °C for 3 hourrs, it was poured into water (50 mL) and then extracted with EtOAc (100 mL × 2). The combined organic layers were washed with brine (100 mL), dried over Na2SO4 and concentrated in vacuo. The residue (with another batch from 1.0 g of compound 80B) was purified through column chromatography (DCM/MeOH = 100/1 ~ 30/1) to give tert-butyl (2-(5-bromopyridin yl)ethyl)carbamate (compound 80C, 1.1 g, 28.0% of yield for two batches from 3.0 g of compound 80B) as yellow oil. MS: calc’d 301 (M+H)+, measured 301.1 ({79Br}M+H)+, 303.1 ({81Br}M+H)+.
Preparation of compound 80D: To the solution of utyl (2-(5-bromopyridinyl)ethyl)carbamate (compound 80C, 800 mg, 2.67 mmol) in dioxane (20 mL) was added diphenylmethanimine (482 mg, 2.67 mmol), Xant-phos (463 mg, 0.80 mmol) and Cs2CO3 (2.61 g, 8.01 mmol). The e was degassed for three times and then Pd2(dba)3 (244 mg, 0.267 mmol) was added. The mixture was further degassed for three times and stirred at 80 °C for 12 hrs. The reaction solution was diluted with EtOAc (50 mL) and then washed with brine (50 mL), dried over Na2SO4 and concentrated in vacuo to give crude tert-butyl (2-(5-((diphenylmethylene)amino)pyridinyl)ethyl)carbamate (compound 80D, 1.07 g) as a yellow oil, which was dissolved in MeOH (30 mL) followed by the addition of AcONa (1.09 g, 13.35 mmol) and NH2OH x HCl (278 mg, 4.0 mmol). After the mixture was d at 25 °C for 2 hours, it was concentrated in vacuo. The residue was diluted with water (50 mL) and then ted with DCM (50 mL × 3). The combined organic layers were dried over Na2SO4, concentrated in vacuo. The residue was purified (with another batch from 0.3 g compound 80C) through column chromatography (DCM/MeOH = 100/1 ~ 20/1) to give tert-butyl (2-(5-aminopyridinyl)ethyl)carbamate (compound 80E, 230 mg, 26.4% of yield from a total of 1.1 g compound 80C) as a yellow solid. MS: calc’d 238 , measured 238 (M+H)+.

Claims (24)

Claims
1. A compound of the formula N 4 R I N R2 wherein 5 R1 is C3alkyl, R2 is selected from the group consisting of C1alkyl, hydroxy-C1alkyl, C2alkenyl, C3 alkynyl, C1alkoxy-C1alkyl, amino-C1alkoxy-C1alkoxy-C1alkyl, halogen- C1alkyl, C3cycloalkyl-C1alkyl and phenyl-C1alkyl, n phenyl is unsubstituted or substituted by amino-C1alkyl; 10 R3 is hydrogen; R4 is selected from the group consisting of phenyl, said phenyl being unsubstituted or tuted by one or two groups selected from the group consisting of C1alkyl, halogen, halogen-C1alkyl, C1alkoxy, hydroxy-C1 alkyl, amino-C1alkyl, C1alkyl-amino-C1alkyl, 7-alkyl-amino-C1alkyl, amino- 15 C2alkenyl, C1alkyl-amino-C2alkenyl, di-C1alkyl-amino-C2alkenyl, amino-C2 alkynyl, C1alkyl-amino-C2alkynyl, di-C1alkyl-amino-C2alkynyl, benzyloxycarbonylamino-C1alkyl, amino-C1alkoxy, amino-C1alkoxy-C1alkoxy, amino-C1alkoxy-C1alkyl, C1alkoxy-C1alkoxy-C1alkyl, C1alkylsulfonyl, heterocyclylcarbonyl and phenyl-C1alkyl, wherein phenyl is unsubstituted or substituted 20 by C1alkoxy or amino-C1alkyl, or heteroaryl, said heteroaryl being a 5- or 6-membered ic ring containing one, two or three heteroatoms selected from N, O or S ed from the group consisting of imidazolyl, pyrazolyl, oxazolyl, thiazolyl, pyridyl, pyridazinyl and pyrimidinyl and being tituted or substituted by one or two groups selected from the group ting of C1alkyl, 25 halogen, halogen-C1alkyl, C1alkoxy, hydroxy-C1alkyl, amino-C1alkyl, C1alkylamino-C1alkyl , di-C1alkyl-amino-C1alkyl, amino-C2alkenyl, C1alkyl-amino-C2- 7-alkenyl, di-C1alkyl-amino-C2alkenyl, amino-C2alkynyl, C1alkyl-amino-C2 alkynyl, di-C1alkyl-amino-C2alkynyl, benzyloxycarbonylamino-C1alkyl, amino-C1- 7-alkoxy, amino-C1alkoxy-C1alkoxy, amino-C1alkoxy-C1alkyl, amino-C1 alkoxy-C1alkoxy-C1alkyl, C1alkylsulfonyl, heterocyclylcarbonyl and phenyl-C1 alkyl, wherein phenyl is unsubstituted or substituted by C1alkoxy or amino-C1alkyl, 5 or pharmaceutically acceptable salts thereof.
2. A compound of formula I according to claim 1, wherein R1 is propyl or butyl.
3. A compound of formula I according to claims 1 or 2, wherein R2 is selected from the group consisting of C1alkyl, C3alkynyl, halogen-C1alkyl, ycloalkyl-C1alkyl and hydroxy-C1alkyl. 10
4. A nd of formula I according to any one of claims 1 to 3, wherein R2 is C1alkyl.
5. A compound of formula I according to any one of claims 1 to 4, wherein R4 is a 5- or 6- membered heteroaryl ring containing one, two or three heteroatoms selected from N, O or S and being unsubstituted or substituted by one or two groups selected from the group consisting of C1- 7-alkyl, halogen, halogen-C1alkyl, C1alkoxy, hydroxy-C1alkyl, amino-C1alkyl, C1 15 alkyl-amino-C1alkyl, di-C1alkyl-amino-C1alkyl, C2alkenyl, C1alkyl-amino-C2- 7-alkenyl, di-C1alkyl-amino-C2alkenyl, amino-C2alkynyl, C1alkyl-amino-C2alkynyl, di-C1alkyl-amino-C2alkynyl, benzyloxycarbonylamino-C1alkyl, amino-C1alkoxy, amino-C1alkoxy-C1alkoxy, amino-C1alkoxy-C1alkyl, amino-C1alkoxy-C1alkoxy- C1alkyl, C1alkylsulfonyl, heterocyclylcarbonyl and phenyl-C1alkyl, n phenyl is 20 unsubstituted or substituted by C1alkoxy or amino-C1alkyl.
6. A compound of formula I according to any one of claim 1 to 5, wherein R4 is a 5- or 6- ed heteroaryl ring containing one, two or three heteroatoms selected from N, O or S and being substituted by one or two groups selected from the group consisting of lkyl, halogen, C1alkoxy, hydroxy-C1alkyl, amino-C1alkyl, di-C1alkyl-amino-C1alkyl, amino-C2 25 alkenyl, amino-C2alkynyl, benzyloxycarbonylamino-C1alkyl, amino-C1alkoxy and -C1alkyl, wherein phenyl is unsubstituted or substituted by C1alkoxy or amino-C1 alkyl.
7. A compound of formula I ing to any one of claims 1 to 6, wherein the 5- or 6- membered heteroaryl ring is pyridyl. 30
8. A compound of formula I according to any one of claims 1 to 4, n R4 is , said phenyl being unsubstituted or tuted by one or two groups selected from the group consisting of C1alkyl, halogen, halogen-C1alkyl, C1alkoxy, hydroxy-C1alkyl, amino-C1- l, C1alkyl-amino-C1alkyl, di-C1alkyl-amino-C1alkyl, amino-C2alkenyl, C1 alkyl-amino-C2alkenyl, di-C1alkyl-amino-C2alkenyl, amino-C2alkynyl, C1alkylamino-C2alkynyl , di-C1alkyl-amino-C2alkynyl, benzyloxycarbonylamino-C1alkyl, 5 C1alkoxy, amino-C1alkoxy-C1alkoxy, amino-C1alkoxy-C1alkyl, amino-C1 alkoxy-C1alkoxy-C1alkyl, C1alkylsulfonyl, heterocyclylcarbonyl and phenyl-C1alkyl, wherein phenyl is unsubstituted or tuted by C1alkoxy or amino-C1alkyl.
9. A compound of formula I according to any one of claims 1 to 4 or 8, wherein R4 is phenyl, said phenyl being unsubstituted or tuted by one or two groups selected from the 10 group consisting of C1alkyl, halogen, halogen-C1alkyl, C1alkoxy, C1alkyl, amino-C1alkoxy, amino-C1alkoxy-C1alkoxy, amino-C1alkoxy-C1alkyl, amino-C1 alkoxy-C1alkoxy-C1alkyl, C1alkylsulfonyl and heterocyclylcarbonyl.
10. A compound of formula I according to any one of claims 1 to 4 or 8 to 9, n R4 is phenyl substituted by one group ed from the group consisting of C1alkyl, halogen, 15 halogen-C1alkyl, C1alkoxy, amino-C1alkyl, amino-C1alkoxy, amino-C1alkoxy-C1 alkoxy, amino-C1alkoxy-C1alkyl, amino-C1alkoxy-C1alkoxy-C1alkyl, C1 alkylsulfonyl and heterocyclylcarbonyl.
11. A compound of formula I according to claim 1, selected from the group consisting of 2-amino-N4,N4-dipropyl-N8-(3-pyridyl)-3Hbenzazepine-4,8-dicarboxamide, 20 2-amino-N4,N4-dipropyl-N8-pyrimidinyl-3Hbenzazepine-4,8-dicarboxamide, 2-amino-N4,N4-dipropyl-N8-(4-pyridyl)-3Hbenzazepine-4,8-dicarboxamide, 2-amino-N4,N4-dipropyl-N8-phenyl-3Hbenzazepine-4,8-dicarboxamide, 2-amino-N8-[6-(aminomethyl)pyridyl]-N4,N4-dipropyl-3Hbenzazepine-4,8-dicarboxamide, 2-amino-N8-[5-(hydroxymethyl)pyridyl]-N4,N4-dipropyl-3Hbenzazepine-4,8- 25 dicarboxamide, 2-amino-N8-[6-(hydroxymethyl)pyridyl]-N4,N4-dipropyl-3Hbenzazepine-4,8- dicarboxamide, 2-amino-N8-(3-methylsulfonylphenyl)-N4,N4-dipropyl-3Hbenzazepine-4,8-dicarboxamide, 2-amino-N4,N4-dipropyl-N8-thiazolyl-3Hbenzazepine-4,8-dicarboxamide, 30 2-amino-N8-(4-chlorophenyl)-N4,N4-dipropyl-3Hbenzazepine-4,8-dicarboxamide, 2-amino-N4,N4-dipropyl-N8-thiazolyl-3Hbenzazepine-4,8-dicarboxamide, 2-amino-N8-(3-methylimidazolyl)-N4,N4-dipropyl-3Hbenzazepine-4,8-dicarboxamide, 2-amino-N8-(4-fluorophenyl)-N4,N4-dipropyl-3Hbenzazepine-4,8-dicarboxamide, o-N8-(m-tolyl)-N4,N4-dipropyl-3Hbenzazepine-4,8-dicarboxamide, 5 2-amino-N4,N4-dipropyl-N8-[3-(pyrrolidinecarbonyl)phenyl]-3Hbenzazepine-4,8- dicarboxamide, 2-amino-N4,N4-dipropyl-N8-[5-(pyrrolidinecarbonyl)pyridyl]-3Hbenzazepine-4,8- dicarboxamide, 2-amino-N8-[3-(2-aminoethyl)phenyl]-N4,N4-dipropyl-3Hbenzazepine-4,8-dicarboxamide, 10 2-amino-N8-(5-methylpyridyl)-N4,N4-dipropyl-3Hbenzazepine-4,8-dicarboxamide, 2-amino-N8-(3-fluorophenyl)-N4,N4-dipropyl-3Hbenzazepine-4,8-dicarboxamide, o-N8-(5-fluoropyridyl)-N4,N4-dipropyl-3Hbenzazepine-4,8-dicarboxamide, 2-amino-N8-(2-methylpyridyl)-N4,N4-dipropyl-3Hbenzazepine-4,8-dicarboxamide, 2-amino-N8-(6-methylpyridyl)-N4,N4-dipropyl-3Hbenzazepine-4,8-dicarboxamide, 15 2-amino-N8-(3,5-dimethylphenyl)-N4,N4-dipropyl-3Hbenzazepine-4,8-dicarboxamide, 2-amino-N8-[4-(aminomethyl)phenyl]-N4,N4-dipropyl-3Hbenzazepine-4,8-dicarboxamide, 2-amino-N8-[4-(2-aminoethyl)phenyl]-N4,N4-dipropyl-3Hbenzazepine-4,8-dicarboxamide, 2-amino-N4-(3-hydroxypropyl)-N8-(m-tolyl)-N4-propyl-3Hbenzazepine-4,8-dicarboxamide, 2-amino-N8-(o-tolyl)-N4,N4-dipropyl-3Hbenzazepine-4,8-dicarboxamide, 20 2-amino-N4,N4-dipropyl-N8-(p-tolyl)-3Hbenzazepine-4,8-dicarboxamide, 2-amino-N8-(3-ethylphenyl)-N4,N4-dipropyl-3Hbenzazepine-4,8-dicarboxamide, 2-amino-N8-(3-methoxyphenyl)-N4,N4-dipropyl-3Hbenzazepine-4,8-dicarboxamide, 2-amino-N4,N4-dipropyl-N8-[3-(trifluoromethyl)phenyl]-3Hbenzazepine-4,8-dicarboxamide, 2-amino-N8-(3-chlorophenyl)-N4,N4-dipropyl-3Hbenzazepine-4,8-dicarboxamide, 25 2-amino-N8-[5-(aminomethyl)pyridyl]-N4,N4-dipropyl-3Hbenzazepine-4,8-dicarboxamide, 2-amino-N4,N4-dipropyl-N8-pyridazinyl-3Hbenzazepine-4,8-dicarboxamide, 2-amino-N8-(6-ethoxypyridyl)-N4,N4-dipropyl-3Hbenzazepine-4,8-dicarboxamide, 2-amino-N8-[3-(aminomethyl)phenyl]-N4,N4-dipropyl-3Hbenzazepine-4,8-dicarboxamide, 2-amino-N8-(1-methylpyrazolyl)-N4,N4-dipropyl-3Hbenzazepine-4,8-dicarboxamide, 2-amino-N8-oxazolyl-N4,N4-dipropyl-3Hbenzazepine-4,8-dicarboxamide, 2-amino-N4-(3-hydroxypropyl)-N4-propyl-N8-(3-pyridyl)-3Hbenzazepine-4,8-dicarboxamide, 2-amino-N8-(5-methoxypyridyl)-N4,N4-dipropyl-3Hbenzazepine-4,8-dicarboxamide, o-N8-(m-tolyl)-N4-propyl-N4-propynyl-3Hbenzazepine-4,8-dicarboxamide, 5 2-amino-N4,N4-dibutyl-N8-(m-tolyl)-3Hbenzazepine-4,8-dicarboxamide, 2-amino-N8-[3-(aminomethyl)methyl-phenyl]-N4,N4-dipropyl-3Hbenzazepine-4,8- dicarboxamide, 2-amino-N8-(5-ethoxypyridyl)-N4,N4-dipropyl-3Hbenzazepine-4,8-dicarboxamide, 2-amino-N8-[3-[2-(2-aminoethoxy)ethoxy]phenyl]-N4,N4-dipropyl-3Hbenzazepine-4,8- 10 dicarboxamide, 2-amino-N8-[5-(5-aminopentoxy)pyridyl]-N4,N4-dipropyl-3Hbenzazepine-4,8- dicarboxamide, 2-amino-N8-[3-[2-(2-aminoethoxy)ethoxymethyl]phenyl]-N4,N4-dipropyl-3Hbenzazepine- 4,8-dicarboxamide, 15 2-amino-N8-[5-(3-aminopropynyl)pyridyl]-N4,N4-dipropyl-3Hbenzazepine-4,8- oxamide, 2-amino-N4-[3-[2-(2-aminoethoxy)ethoxy]propyl]-N8-(m-tolyl)-N4-propyl-3Hbenzazepine- 4,8-dicarboxamide, 2-amino-N8-[5-(3-aminopropyl)pyridyl]-N4,N4-dipropyl-3Hbenzazepine-4,8- 20 dicarboxamide, 2-amino-N8-(m-tolyl)-N4-propyl-N4-(3,3,3-trifluoropropyl)-3Hbenzazepine-4,8- dicarboxamide, 2-amino-N8-[5-[(E)aminopropenyl]pyridyl]-N4,N4-dipropyl-3Hbenzazepine-4,8- dicarboxamide, 25 2-amino-N4-(cyclopropylmethyl)-N8-(m-tolyl)-N4-propyl-3Hbenzazepine-4,8-dicarboxamide, and pharmaceutically able salts thereof.
12. A compound of formula I according to claim 1, selected from the group consisting of 2-amino-N8-[3-(2-aminoethyl)phenyl]-N4,N4-dipropyl-3Hbenzazepine-4,8-dicarboxamide, 2-amino-N4-isobutyl-N8-(m-tolyl)-N4-propyl-3Hbenzazepine-4,8-dicarboxamide, 30 2-amino-N4-[3-(3-aminopropoxy)propyl]-N8-(m-tolyl)-N4-propyl-3Hbenzazepine-4,8- dicarboxamide, 2-amino-N8-[3-(5-aminopentyl)phenyl]-N4,N4-dipropyl-3Hbenzazepine-4,8-dicarboxamide, 2-amino-N8-[4-(5-aminopentyl)phenyl]-N4,N4-dipropyl-3Hbenzazepine-4,8-dicarboxamide, o-N8-[3-(3-aminopropyl)phenyl]-N4,N4-dipropyl-3Hbenzazepine-4,8-dicarboxamide, 2-amino-N4-[[4-(aminomethyl)phenyl]methyl]-N8-(m-tolyl)-N4-propyl-3Hbenzazepine-4,8- 5 dicarboxamide, 2-amino-N8-[4-(3-aminopropyl)phenyl]-N4,N4-dipropyl-3Hbenzazepine-4,8-dicarboxamide, 2-amino-N8-[4-(3-aminopropyl)phenyl]-N4,N4-dipropyl-3Hbenzazepine-4,8-dicarboxamide, 2-amino-N8-[3-(2-aminoethyl)fluoro-phenyl]-N4,N4-dipropyl-3Hbenzazepine-4,8- oxamide, 10 2-amino-N8-[3-(2-aminoethyl)chloro-phenyl]-N4,N4-dipropyl-3Hbenzazepine-4,8- dicarboxamide, 2-amino-N4-butyl-N4-(2-hydroxyethyl)-N8-(m-tolyl)-3Hbenzazepine-4,8-dicarboxamide, 2-amino-N8-[5-(2-aminoethoxy)pyridyl]-N4,N4-dipropyl-3Hbenzazepine-4,8- dicarboxamide, 15 -N-[[5-[[2-amino(dipropylcarbamoyl)-3Hbenzazepinecarbonyl]amino] pyridyl]methyl]carbamate, 2-amino-N8-[5-[(E)aminopropenyl]pyridyl]-N4,N4-dipropyl-3Hbenzazepine-4,8- dicarboxamide, 2-amino-N8-[5-(2-phenylethyl)pyridyl]-N4,N4-dipropyl-3Hbenzazepine-4,8- 20 dicarboxamide, 2-amino-N8-[5-[2-(4-methoxyphenyl)ethyl]pyridyl]-N4,N4-dipropyl-3Hbenzazepine-4,8- dicarboxamide, 2-amino-N8-[5-[2-[4-(aminomethyl)phenyl]ethyl]pyridyl]-N4,N4-dipropyl-3H benzazepine-4,8-dicarboxamide, 25 2-amino-N8-[5-(5-aminopentyl)pyridyl]-N4,N4-dipropyl-3Hbenzazepine-4,8- dicarboxamide, 2-amino-N8-[5-[2-(3-methoxyphenyl)ethyl]pyridyl]-N4,N4-dipropyl-3Hbenzazepine-4,8- dicarboxamide, 2-amino-N8-[5-(6-aminohexyl)pyridyl]-N4,N4-dipropyl-3Hbenzazepine-4,8- 30 dicarboxamide, 2-amino-N8-[6-(3-aminopropyl)pyridyl]-N4,N4-dipropyl-3Hbenzazepine-4,8- dicarboxamide, 2-amino-N8-[5-(4-aminobutyl)pyridyl]-N4,N4-dipropyl-3Hbenzazepine-4,8-dicarboxamide, 2-amino-N8-[6-(4-aminobutyl)pyridyl]-N4,N4-dipropyl-3Hbenzazepine-4,8-dicarboxamide, 2-amino-N8-[5-[(dimethylamino)methyl]pyridyl]-N4,N4-dipropyl-3Hbenzazepine-4,8- dicarboxamide, 5 2-amino-N4-(cyclopropylmethyl)-N8-(5-ethoxypyridyl)-N4-propyl-3Hbenzazepine-4,8- oxamide, 2-amino-N8-[5-(2-aminoethyl)pyridyl]-N4,N4-dipropyl-3Hbenzazepine-4,8-dicarboxamide, and ceutically acceptable salts thereof.
13. A compound of formula I according to claim 1, selected from the group consisting of 10 2-amino-N4,N4-dipropyl-N8-(3-pyridyl)-3Hbenzazepine-4,8-dicarboxamide, 2-amino-N4,N4-dipropyl-N8-pyrimidinyl-3Hbenzazepine-4,8-dicarboxamide, 2-amino-N8-(4-chlorophenyl)-N4,N4-dipropyl-3Hbenzazepine-4,8-dicarboxamide, o-N8-(m-tolyl)-N4,N4-dipropyl-3Hbenzazepine-4,8-dicarboxamide, 2-amino-N4,N4-dipropyl-N8-[3-(pyrrolidinecarbonyl)phenyl]-3Hbenzazepine-4,8- 15 dicarboxamide, 2-amino-N8-(6-methylpyridyl)-N4,N4-dipropyl-3Hbenzazepine-4,8-dicarboxamide, 2-amino-N8-(3,5-dimethylphenyl)-N4,N4-dipropyl-3Hbenzazepine-4,8-dicarboxamide, 2-amino-N4-(3-hydroxypropyl)-N8-(m-tolyl)-N4-propyl-3Hbenzazepine-4,8-dicarboxamide, 2-amino-N4,N4-dipropyl-N8-(p-tolyl)-3Hbenzazepine-4,8-dicarboxamide, 20 2-amino-N8-(3-ethylphenyl)-N4,N4-dipropyl-3Hbenzazepine-4,8-dicarboxamide, 2-amino-N8-(3-methoxyphenyl)-N4,N4-dipropyl-3Hbenzazepine-4,8-dicarboxamide, 2-amino-N8-(3-chlorophenyl)-N4,N4-dipropyl-3Hbenzazepine-4,8-dicarboxamide, 2-amino-N8-[5-(aminomethyl)pyridyl]-N4,N4-dipropyl-3Hbenzazepine-4,8-dicarboxamide, 2-amino-N4,N4-dipropyl-N8-pyridazinyl-3Hbenzazepine-4,8-dicarboxamide, 25 2-amino-N8-(6-ethoxypyridyl)-N4,N4-dipropyl-3Hbenzazepine-4,8-dicarboxamide, 2-amino-N8-(5-methoxypyridyl)-N4,N4-dipropyl-3Hbenzazepine-4,8-dicarboxamide, 2-amino-N8-(5-ethoxypyridyl)-N4,N4-dipropyl-3Hbenzazepine-4,8-dicarboxamide, 2-amino-N8-[3-[2-(2-aminoethoxy)ethoxymethyl]phenyl]-N4,N4-dipropyl-3Hbenzazepine- 4,8-dicarboxamide, 2-amino-N8-(m-tolyl)-N4-propyl-N4-(3,3,3-trifluoropropyl)-3Hbenzazepine-4,8- dicarboxamide, 2-amino-N4-(cyclopropylmethyl)-N8-(m-tolyl)-N4-propyl-3Hbenzazepine-4,8-dicarboxamide, and pharmaceutically acceptable salts thereof. 5
14. A compound of formula I according to claim 1, selected from the group consisting of 2-amino-N8-[3-(2-aminoethyl)phenyl]-N4,N4-dipropyl-3Hbenzazepine-4,8-dicarboxamide, 2-amino-N4-isobutyl-N8-(m-tolyl)-N4-propyl-3Hbenzazepine-4,8-dicarboxamide, 2-amino-N8-[3-(3-aminopropyl)phenyl]-N4,N4-dipropyl-3Hbenzazepine-4,8-dicarboxamide, benzyl-N-[[5-[[2-amino(dipropylcarbamoyl)-3Hbenzazepinecarbonyl]amino] 10 l]methyl]carbamate, 2-amino-N8-[5-(2-phenylethyl)pyridyl]-N4,N4-dipropyl-3Hbenzazepine-4,8- dicarboxamide, 2.-amino-N4-(cyclopropylmethyl)-N8-(5-ethoxypyridyl)-N4-propyl-3Hbenzazepine-4,8- dicarboxamide, 15 and pharmaceutically acceptable salts thereof.
15. A compound of formula I according to any one of claims 1 to 14 for use as medicament.
16. A compound of formula I according to any one of claims 1 to 14 for use as medicament for the treatment of diseases which can be mediated with TLR agonists, ed from the group ting of cancer, mune diseases, inflammation, sepsis, allergy, asthma, graft rejection, 20 versus-host disease, immunodeficiencies, and infectious es.
17. A pharmaceutical composition comprising a compound of formula I according to any one of claims 1 to 14 and a pharmaceutically acceptable carrier and/or adjuvant.
18. The use of a compound of formula I according to any one of claims 1 to 14 for the preparation of a medicament for the treatment of diseases which can be mediated with TLR 25 agonists.
19. The use according to claim 18, wherein the disease is selected from the group consisting of , autoimmune diseases, inflammation, sepsis, allergy, asthma, graft rejection, graft versus host disease, immunodeficiencies, and infectious diseases.
20. A process for the manufacture of a compound of a I as defined in claim 1, which 5 process comprises a) coupling a compound of the formula II PGHN N COOH N 2 R , wherein R1 and R2 are as defined in claim 1 and PG is a protecting group, with a compound of the formula III HN III 10 R , wherein R3 and R4 are as defined in claim 1, under basic conditions in the presence of a coupling agent and removing the protecting group PG under acidic conditions to obtain a compound of the a I N 4 R I N R2 R , 15 wherein R1 to R4 are as d in claim 1, and, if d, converting the compound obtained into a pharmaceutically acceptable salt.
21. A compound of formula I according to any one of claims 1 to 16, substantially as herein described with reference to any example thereof.
22. A pharmaceutical composition according to claim 17, substantially as herein described with nce to any example thereof. 5
23. The use according to claims 18 or 19, substantially as herein described with reference to any example thereof.
24. A process according to claim 20, substantially as herein described with nce to any example thereof. 10 ***
NZ732796A 2015-03-06 2016-03-03 Benzazepine dicarboxamide compounds NZ732796B2 (en)

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CN2015096404 2015-12-04
PCT/EP2016/054487 WO2016142250A1 (en) 2015-03-06 2016-03-03 Benzazepine dicarboxamide compounds

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