WO2015049629A1 - Imidazoquinoline compounds as bromodomain inhibitors - Google Patents

Imidazoquinoline compounds as bromodomain inhibitors Download PDF

Info

Publication number
WO2015049629A1
WO2015049629A1 PCT/IB2014/064949 IB2014064949W WO2015049629A1 WO 2015049629 A1 WO2015049629 A1 WO 2015049629A1 IB 2014064949 W IB2014064949 W IB 2014064949W WO 2015049629 A1 WO2015049629 A1 WO 2015049629A1
Authority
WO
WIPO (PCT)
Prior art keywords
alkyl
imidazo
quinolin
dimethylisoxazol
methoxy
Prior art date
Application number
PCT/IB2014/064949
Other languages
French (fr)
Inventor
Rajiv Sharma
Sarang Kulkarni
Mahesh Kulkarni
Sumit Mukherjee
Rajesh Kumar YADAV
Madhavi AGARWAL
Sandeep BURUDKAR
Santosh SATHE
Original Assignee
Piramal Enterprises Limited
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Piramal Enterprises Limited filed Critical Piramal Enterprises Limited
Publication of WO2015049629A1 publication Critical patent/WO2015049629A1/en

Links

Classifications

    • 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/4738—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/4745—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems condensed with ring systems having nitrogen as a ring hetero atom, e.g. phenantrolines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems

Definitions

  • the present invention relates to imidazoquinoline compounds (referred to herein as the compounds of formula (I)), processes for their preparation, pharmaceutical compositions containing them, their use as inhibitors of bromodomain containing proteins, and methods of using said compounds in the treatment of diseases or disorders mediated by bromodomain containing proteins.
  • Chromatin plays a critical role in regulating gene transcription within the cells of eukaryotic organisms.
  • Chromatin is constituted by compression via aggregation and folding of nucleosomes.
  • a nucleosome is constituted by an octomer of histone proteins such as H2A, H2B, H3 and H4, wrapped with strands of duplex DNA. The condensation of the chromatin varies during the cell cycle, being most compact during the process of cell division.
  • Gene transcription is a function of the extent of condensation of the chromatin in the cell, and the chromatin structure is controlled by a series of post translational modifications such as methylation, acetylation, phosphorylation, sumoylation or ubiquitination, of histone proteins, mainly histones H3 and H4, and most commonly within the histone tails which extend beyond the core nucleosome structure.
  • post translational modifications such as methylation, acetylation, phosphorylation, sumoylation or ubiquitination, of histone proteins, mainly histones H3 and H4, and most commonly within the histone tails which extend beyond the core nucleosome structure.
  • Histone acetylation is one of the processes associated with gene transcription, wherein specific proteins bind to acetylated lysine residues within histones to read the epigenetic code.
  • Bromodomains are small and distinct amino acid domains within proteins that bind to acetylated lysine resides.
  • the BET (extra-terminal) family of bromodomain containing proteins mainly comprises four proteins (BRD2, BRD3, BRD4 and BRDT) each containing two discrete bromodomain 'reader' modules which recognize the acetylated state of lysine residues on histone tails and other proteins, which are capable of binding to two acetylated lysine residues in close proximity, increasing the specificity of the interaction. While three members of this family (BRD2, BRD3 and BRD4) are ubiquitously expressed, the fourth member, BRDT, has to date only been found in ovary and testis (Bioorg. Med. Chem. Lett, 2012, 22, 2968-2972).
  • Dysregulation of chromatin modifiers is a recurrent event in oncogenesis. All the BET family members have been reported to have a role in controlling the cell cycle, and form a complex with chromosomes during cell division, which indicates that they play an important role in maintenance of epigenetic memory. In particular, the binding of bromodomain and extra-terminal (BET) proteins to chromatin regulates the transcription of oncogene proteins. Proteins that contain bromodomains have also been found to have a critical role in diverse, non-malignant phenotypes, directing transcription which controls adipogenesis, energy metabolism and inflammation.
  • BET bromodomain and extra-terminal
  • bromodomain inhibitors refer to a class of compounds, which inhibit the binding of bromodomains with its cognate acetylated proteins, more particularly which inhibit the binding of BET family bromodomains to acetylated lysine residues.
  • OTX-015 Mitsubishi Tanabe Pharma
  • (+)-JQ-1 Dana-Farber Cancer Institute
  • GSK-525762 GlaxoSmithKline
  • GSK-1210151A I-BET151
  • GlaxoSmithKline GlaxoSmithKline
  • GW-841819X GaxoSmithKline
  • RVX-2135 Resverlogix
  • bromodomains and extra- terminal (BET) proteins to chromatin
  • BET extra- terminal
  • PCT publication WO201 1/054846A1 discloses imidazo[4, 5-c]quinoline derivatives as bromodomain inhibitors used in the treatment of chronic autoimmune and inflammatory diseases or disorders, and cancer.
  • PCT publication WO2012/007926A1 discloses imidazo[4, 5-c]quinoline derivatives as kinase inhibitors used in the treatment of proliferative diseases, inflammatory diseases and angiogenesis related disorders.
  • the compounds of the present invention function as bromodomain inhibitors and thereby provide therapeutic benefit in the treatment of diseases or disorders mediated by bromodomain containing proteins.
  • the present invention relates to a compound of formula (I) (as described herein), or an isotopic form, a stereoisomer, a tautomer, a pharmaceutically acceptable salt, a solvate, a polymorph, a prodrug, S-oxide or N- oxide thereof.
  • the present invention relates to processes for the preparation of the compound of formula (I) or a pharmaceutically acceptable salt thereof.
  • the present invention relates to pharmaceutical composition
  • pharmaceutical composition comprising the compound of formula (I) or an isotopic form, a stereoisomer, a tautomer, a pharmaceutically acceptable salt or a solvate thereof; and at least one pharmaceutically acceptable carrier or excipient.
  • the present invention relates to a compound of formula (I) or a stereoisomer, a tautomer, a pharmaceutically acceptable salt, a solvate thereof, for use as inhibitor(s) of bromodomain containing proteins.
  • the present invention relates to a compound of formula (I) or a stereoisomer, a tautomer, a pharmaceutically acceptable salt, a solvate thereof; for use in the treatment of a disease or a disorder mediated by bromodomain containing proteins.
  • the present invention relates to a method for the treatment of a disease or disorder mediated by bromodomain containing proteins, comprising administering to a subject in need thereof a therapeutically effective amount of the compound of formula (I) or a stereoisomer, a tautomer, a pharmaceutically acceptable salt or a solvate thereof.
  • the present invention relates to use of a compound of formula (I) or a stereoisomer, a tautomer, a pharmaceutically acceptable salt or a solvate thereof, for the manufacture of a medicament for the treatment of diseases or disorders mediated by bromodomain containing proteins.
  • the present invention relates to use of a compound of formula (I) or a stereoisomer, a tautomer, a pharmaceutically acceptable salt or a solvate thereof; with one further therapeutically active agent.
  • the present invention relates to a compound of formula (I):
  • W is NR a or O;
  • Ri and R 4 are independently selected from the group consisting of hydrogen, halogen, cyano, nitro, (Ci-C 6 )-alkyl, (C 2 -C 8 )-alkenyl, (C 2 -C 8 )-alkynyl, halo(Ci-C 6 )-alkyl, (Ci-C 6 )- alkoxy, (C3-Ci2)-cycloalkyl, (C6-Ci 4 )-ar(Ci-C6)-alkyl-, (C6-Ci 4 )-aryl, heterocyclyl, heteroaryl, NR a R b , C(0)(C 1 -C 6 )-alkyl, C(O)NR a R b, COOH, C(0)0(C 1 -C 6 )-alkyl and S(0) m (Ci-C 6 )-alkyl;
  • R 2 , R3 and R 5 are independently selected from the group consisting of hydrogen, halogen, (Ci-C 6 )-alkyl, (C 2 -C 8 )-alkenyl, (C 2 -C 8 )-alkynyl, halo(Ci-C 6 )-alkyl and (Ci-C 6 )- alkoxy;
  • R 6 is hydrogen, (CrC 6 )-alkyl, amino(Ci-C 6 )-alkyl-, (Ci-C6)-alkoxy(Ci-C 6 )-alkyl-, (C 3 - Ci 2 )-cycloalkyl, (C6-Ci 4 )-aryl, (C6-Ci 4 )-ar(Ci-C6)-alkyl-, heterocyclyl, heteroaryl,
  • R 7 is hydrogen, cyano, nitro, (Ci-Ce)-alkyl or NR a R b ;
  • n is an integer from 0-2;
  • n is an integer from 0-3;
  • Y is (C3-Ci 2 )-cycloalkyl, (C6-Ci 4 )-ar(Ci-C6)-alkyl-, (C6-Ci 4 )-aryl, heterocyclyl, heteroaryl or NR a Rb;
  • each of the (CrC 6 )-alkyl and (Ci-C 6 )-alkoxy is unsubstituted or substituted with one to three groups independently selected from the group consisting of halogen, hydroxy, nitro, cyano, (Ci-C6)-alkoxy-(R c ) 0- 3, (C3-Ci 2 )-cycloalkyl-(R c ) 0- 3, (C3-Ci 2 )-cycloalkyloxy- (Rc)o-3, halo(Ci-C 6 )-alkoxy, (C 6 -Ci 4 )-aryl-(R c )o-3, (C 6 -Ci 4 )-aryloxy-(R c )o-3, (C 6 -Ci 4 )-ar(Ci- C 6 )-alkyloxy-(R c )o -3 , heterocyclyl-(R c ) 0-3 , heteroaryl-(
  • R a and R b are independently selected from the group consisting of hydrogen, (C-i-Ce)- alkyl, amino(Ci-C 6 )-alkyl, (Ci-C 6 )-alkoxy(Ci-C 6 )-alkyl, (C 3 -Ci 2 )-cycloalkyl, (C 6 -Ci 4 )-aryl, (C 6 -Ci 4 )-ar(Ci-C 6 )-alkyl, heterocyclyl, heteroaryl, C(0)(Ci-C 6 )-alkyl and S(0) m (Ci-C 6 )- alkyl; or
  • R a and R b together with the N to which they are attached can form a 3-8 membered heterocyclyl ring, optionally containing one to three additional heteroatoms independently selected from the group consisting of N, O and S, and the said heterocyclyl ring is unsubstituted or substituted with one to three groups as defined herein for the heterocyclyl group; and
  • R c is halogen, hydroxy, cyano, nitro, (Ci-C6)-alkyl-(R c ) 0- i, (Ci-C6)-alkoxy-(R c ) 0- i , (Ci- C 6 )-alkoxy(Ci-C6)-alkyl-(R c ) 0- i, (C 3 -Ci 2 )-cycloalkyl-(R c ) 0- i, (C 3 -Ci 2 )-cycloalkyloxy-(R c ) 0- , hydroxy(Ci-C 6 )-alkyl-(R c ) 0- i, halo(Ci-C 6 )-alkyl, halo(Ci-C 6 )-alkoxy, (C 6 -Ci 4 )-aryl- (Rc)o-i, (C 6 -Ci 4 )-aryloxy-(R c )
  • substitution means that one or more hydrogens of the specified moiety are replaced with a suitable substituent and includes the implicit proviso that such substitution is in accordance with permitted valence of the substituted atom and the substituent, and results in a stable compound.
  • (Ci -C6)-alkyl or “alkyl” whether used alone or as part of a substituent group, refers to the radical of saturated aliphatic groups, including straight or branched-chain alkyl groups.
  • a straight-chain or branched chain alkyl has six or fewer carbon atoms in its backbone, for instance, C1 -C6 for straight chain and C 3 -C 6 for branched chain.
  • alkyl groups containing from one to six carbon atoms include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, iso-butyl, sec-butyl, n-pentyl, isopentyl, 2-pentyl, 3-pentyl, neo-pentyl, n-hexyl, isohexyl, 2-hexyl and 3-hexyl.
  • alkyl groups may be unsubstituted or substituted with one or more substituents.
  • a substituted alkyl refers to a (Ci -Ce)-alkyl substituted with one or more groups, preferably one to three groups, independently selected from the group consisting of halogen, hydroxy, nitro, cyano, (Ci -C6)-alkoxy- (Rc)o-3, (C 3 -Ci2)-cycloalkyl-(R c ) 0- 3, (C 3 -Ci2)-cycloalkyloxy-(R c ) 0- 3, halo(Ci-C 6 )-alkoxy, (C 6 -C 14 )-aryl-(R c )o -3 , (C 6 -C 14 )-aryloxy-(R c )o -3 , (C 6 -C 14 )-ar(C 1 -C 6 )-alkyloxy-(R c )
  • substituted alkyls include, but are not limited to hydroxymethyl, hydroxyethyl and aminoethyl.
  • halogen refers to a fluorine, chlorine, bromine or iodine atom.
  • halo(Ci -C6)-alkyl When the alkyl group is substituted with one or more halogens, it is specifically referred to as "halo(Ci -C6)-alkyl" or "haloalkyl".
  • a monohalo(Ci -C6)-alkyl radical for example, may have one chlorine, bromine, iodine or fluorine atom.
  • Dihalo and polyhalo(Ci-C6)-alkyl radicals may have two or more of the same or different halogen atoms.
  • halo(Ci -C 6 )-alkyl examples include, but are not limited to, chloromethyl, dichloromethyl, trichloromethyl, dichloroethyl, dichloropropyl, fluoromethyl, difluoromethyl, trifluoromethyl, pentafluoroethyl, heptafluoropropyl, difluorochloromethyl, dichlorofluoromethyl, difluoroethyl and difluoropropyl.
  • (Ci -C6)-alkoxy refers to a (Ci -Ce)-alkyl having an oxygen radical attached thereto.
  • Representative alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, isobutoxy and t- butoxy.
  • halo(Ci-C6)-alkoxy refers to radicals wherein one or more of the hydrogen atoms of the alkoxy group are substituted with one or more halogens.
  • Representative examples of "haloalkoxy” or “halo(Ci -C 6 )- alkoxy” groups include, but are not limited to, difluoromethoxy (OCHF 2 ), trifluoromethoxy (OCF 3 ) and trifluoroethoxy (OCH 2 CF 3 ).
  • (C 3 -Ci2)-cycloalkyl or “cycloalkyl” whether used alone or as part of a substituent group, refers to a saturated or partially unsaturated cyclic hydrocarbon radical including 1 , 2 or 3 rings and including a total of 3 to 12 carbon atoms forming the rings.
  • the term cycloalkyi includes bridged, fused and spiro ring systems.
  • (C3-Ci2)-cycloalkyl refers to a cycloalkyi group having 3 to 12 (both inclusive) carbon atoms.
  • cycloalkyi examples include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, adamantyl, norbornyl, bicyclo[2.1 .0]pentane, bicyclo[2.2.1 ]heptyl, bicyclo[2.2.1 ]hept-2-ene, spiro[3.3]heptane and 1 ,2,3,3a-tetrahydropentalene.
  • the "cycloalkyi" group may be unsubstituted or substituted with one or more groups, preferably one to three groups independently selected from the group consisting of halogen, hydroxy, nitro, cyano, (C 1 -C 6 )-alkyl-(R c )o -3 , (C 1 -C 6 )-alkoxy-(R c )o -3 , (C 1 -C 6 )-alkoxy(C 1 -C 6 )-alkyl-(R c )o-3, (C 3 -Ci2)-cycloalkyl-(R c )o -3 , (C 3 -Ci2)-cycloalkyloxy-(R c )o -3 , halo(Ci-C 6 )-alkyl, halo(Ci-C 6 )- alkoxy, (C 6 -Ci 4 )-aryl-(R c )o -3 ,
  • (C 3 -Ci2)-cycloalkyloxy or cycloalkyloxy refers to a (C 3 -Ci2)-cycloalkyl having an oxygen radical attached thereto.
  • Representative cycloalkyloxy groups include, but are not limited to, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy and cyclohexyloxy.
  • the alkoxy and cycloalkyloxy may be unsubstituted or substituted with one or more groups independently selected from the group consisting of halogen, hydroxy, nitro, cyano, (Ci-C 6 )-alkyl-(R c )o -3 , (Ci-C 6 )-alkoxy-(R c )o -3 , (Ci-C 6 )- alkoxy(Ci-C 6 )-alkyl-(R c )o -3 , (C 3 -Ci 2 )-cycloalkyl-(R c ) 0-3 , (C 3 -Ci 2 )-cycloalkyloxy-(R c ) 0-3 , halo(Ci-C 6 )-alkyl, halo(Ci-C 6 )-alkoxy, (C 6 -Ci 4 )-aryl-(R c ) 0-3 , (C
  • substituted (Ci-Ce)-alkoxy examples include, but are not limited to, chloromethoxy, 2-cyanoethoxy, trifluoromethoxy and benzyloxy group.
  • (d- C6)-alkoxy-(Ci-C6)-alkyl” or “alkoxyalkyl” as used herein refers to a (Ci-Ce)-alkyl group, which is substituted with a (Ci-Ce)-alkoxy group.
  • (C6-Ci 4 )-aryl or "aryl” as used herein refers to monocyclic or bicyclic hydrocarbon groups having 6 to 14 ring carbon atoms, preferably 6 to 10 carbon atoms in which the carbocyclic ring(s) present have a conjugated pi electron system.
  • Examples of (C6-C-i 4 )-aryl residues are phenyl, naphthyl, fluorenyl or anthracenyl.
  • a preferred example of (C6-Ci 4 )-aryl residue is phenyl.
  • Aryl groups can be unsubstituted or substituted with one or more groups, for example 1 , 2, 3, 4 or 5 groups independently selected from the group consisting of halogen, hydroxy, nitro, cyano, (Ci-C 6 )-alkyl-(R c ) 0- 3, (Ci -C 6 )-alkoxy-(R c )o-3, (Ci -C 6 )-alkoxy(Ci -C 6 )-alkyl-(Rc)o-3, (C3-C12)- cycloalkyl-(R c )o-3, (C3-Ci2)-cycloalkyloxy-(R c ) 0- 3, halo(Ci-C6)-alkyl, halo(Ci-C6)-alkoxy, (C 6 -Ci 4 )-aryl-(R c ) 0- 3, (C 6 -Ci 4 )-aryloxy-(R c ) 0-
  • aryl is phenyl then in the monosubstituted phenyl, the substituent can be located in the 2-position, the 3-position or the 4- position. If the phenyl carries two substituents, they can be located in 2, 3-position, 2, 4-position, 2, 5-position, 2, 6-position, 3, 4-position or 3, 5-position.
  • monosubstituted phenyl groups include, but are not limited to, 3-trifluoromethylphenyl, 4-chlorophenyl and 4-cyanophenyl.
  • disubstituted phenyl groups include, but are not limited to, 3, 5-difluorophenyl, and 3, 4-dimethoxyphenyl.
  • (C6-Ci 4 )-aryloxy refers to an "(C6-C-i 4 )- aryl” group having an oxygen radical attached thereto.
  • the aryl of aryloxy group may be unsubstituted or substituted with groups as described in the definition of substituted (C6-Ci 4 )-aryl herein above. Examples of aryloxy groups include, but are not limited to, phenoxy, 4-chlorophenoxy, and 3, 4-dimethoxyphenoxy.
  • (C6-Ci 4 )-ar(Ci-C6)-alkyl-” or “aralkyi-” refers to (Ci- Ce)-alkyl group substituted with an (C6-Ci 4 )-aryl group, wherein the terms alkyl and aryl are as defined above, and wherein the aralkyi group attaches through alkyl radical.
  • exemplary aralkyi groups include -(CH 2 ) p- phenyl, wherein p is an integer from 1 to 6, such as benzyl (-CH 2 -phenyl).
  • the aryl of the (C6-Ci 4 )-aralkyl group may be unsubstituted or substituted with groups as described in the definition of aryl herein above.
  • (C6-Ci 4 )-ar(Ci-C6)-alkyloxy or "aralkyloxy” refers to an aralkyi group having an oxygen radical attached to the alkyl, and wherein the aralkyloxy group attaches through oxygen.
  • the aryl of aralkyloxy group may be unsubstituted or substituted with groups as described in the definition of substituted aryl herein above.
  • amino refers to the group “NH 2 " which may be unsubstituted or substituted with one or more substituents. Examples of substituents include, but are not limited to, (Ci-Ce)-alkyl and aryl.
  • amino(C-i-C 6 )-alkyl- refers to an amino substituted alkyl radical. This term is meant to include (Ci-Ce)-alkyl groups having an amino substituent at any position and wherein the aminoalkyl group attaches through alkyl radical.
  • the alkyl and/or amino portions of the amino(Ci-C6)- alkyl group may be substituted or unsubstituted.
  • Examples of aminoalkyl groups include, but are not limited to, -CH 2 -CH 2 -NH 2 , -CH 2 -CH 2 -NH(CH 3 ) and -CH 2 -CH 2 - N(CH 3 ) 2 .
  • (Ci-C6)-alkylamino- or “alkylamino-” refers to an alkyl substituted amino group. This term is meant to include an amino group having a (Ci- C 6 )-alkyl substituent and wherein the alkylamino group attaches through amino radical.
  • the alkyl and/or amino portions of the (Ci-C6)-alkylamino- group may be substituted or unsubstituted.
  • alkylamino groups include, but are not limited to -NH-CH 2 - CH 3 and -N(CH 3 )-CH 2 -CH 3 .
  • heteroatom as used herein, includes nitrogen (N), oxygen (0) and sulfur (S). Any heteroatom with unsatisfied valency is assumed to have a hydrogen atom to satisfy the valency.
  • heterocyclyl or “heterocyclic” whether used alone or as part of a substituent group, refers to a 3- to 12-membered saturated or partially unsaturated monocyclic or bicyclic ring system containing one to four heteroatoms independently selected from the group consisting of nitrogen (N), a sulphur (S) and an oxygen (O) atom.
  • Heterocyclyl includes saturated heterocyclic ring systems, which do not contain any double bond. Partially unsaturated heterocyclic ring systems containing at least one double bond, but do not form an aromatic system containing heteroatom.
  • Suitable saturated and partially unsaturated heterocyclic groups include, but are not limited to, aziridine, oxirane, oxiridine, thiirane, oxetane, azetidine, thietane, tetrahydrofuran, tetrahydrothiophene, pyrrolidine, dihydropyran, tetrahydropyran, thio- dihydropyran, thio-tetrahydropyran, piperidine, piperazine, morpholine, 1 ,3-oxazinane, 1 ,3-thiazinane, 4,5,6-tetrahydropyrimidine, 2,3-dihydrofuran, dihydrothiene, dihydropyridine, tetrahydropyridine, isoxazolidine, pyrazolidine, azepane, oxepane, thiepane and azocane.
  • heteroaryl refers to a 5- to 10-membered aromatic monocyclic or bicyclic ring system containing one to four heteroatoms independently selected from the group consisting of N, S and 0.
  • heteroaryl examples include, but are not limited to, pyrrole, pyrazole, imidazole, triazole, pyrazine, furan, thiophene, oxazole, thiazole, benzimidazole, benzoxazole, benzothiazole, benzofuran, indole, indazole, isoindole, isoquinoline, isooxazole, triazine, purine, pyridine, quinoline, oxadiazole, thiene, pyridazine, pyrimidine, isothiazole, quinoxaline (benzopyrine), tetrazole, azepine, oxepine, thiepine and azocine.
  • the oxidized form of the ring nitrogen atom of the heteroaryl to provide N- oxide is also encompassed.
  • heterocyclyl and heteroaryl group may be unsubstituted or substituted.
  • a substituted heterocyclyl or heteroaryl refers to a heterocyclyl or heteroaryl substituted with one to three groups independently selected from the group consisting of halogen, hydroxy, nitro, cyano, (Ci-C6)-alkyl-(R c )o-3, (C-i- C 6 )-alkoxy-(R c )o -3 , (Ci-C 6 )-alkoxy(Ci-C6)-alkyl-(R c )o-3, (C 3 -Ci2)-cycloalkyl-(R c )o -3 , (C 3 - Ci 2 )-cycloalkyloxy-(R c )o -3 , halo(C C 6 )-alkyl, halo(C C 6 )-alkoxy, (C 6 -Ci 4 )-aryl-(R
  • solvate refers to an aggregate of a molecule (in the present invention, a compound of formula (I) or a pharmaceutically acceptable salt thereof) with one or more solvent molecules.
  • solvents for the purpose of the invention may not interfere with the biological activity of the molecule.
  • the solvent used is a pharmaceutically acceptable solvent.
  • suitable pharmaceutically acceptable solvents include, without limitation, water, ethanol and acetic acid. Most preferably, the solvent used is water and the solvates obtained are referred to as hydrates. Examples for suitable solvates are the mono- or di-hydrates or alcoholates of the compounds according to the invention.
  • stereoisomer or “stereoisomeric form” is a general term used for all isomers of individual compounds (in the present invention, a compound of formula (I) or a pharmaceutically acceptable salt thereof) that differ only in the orientation of their atoms in space.
  • stereoisomer includes mirror image isomers (enantiomers), mixtures of mirror image isomers (racemates, racemic mixtures), geometric (cis/trans or E/Z) isomers, and isomers of compounds with more than one chiral center that are not mirror images of one another (diastereoisomers).
  • tautomer or “tautomeric form” refers to the coexistence of two (or more) compounds that differ from each other only in the position of one (or more) mobile atoms and in electron distribution, for example, keto-enol tautomers.
  • the term "pharmaceutically acceptable” means that the carrier, diluent, excipients, and/or salt must be compatible with the other ingredients of the formulation (composition), and not deleterious to the recipient thereof.
  • salts or “salt(s)” as used herein includes salts of the active compound i.e. the compound of formula (I), which retain the desired biological activity of the subject compound and exhibit minimal undesired toxicological effects; and are prepared with suitable acids or bases, depending on the particular substituents found on the compounds described herein.
  • polymorph or “pharmaceutically acceptable polymorph(s)” or “polymorphic form” refers to crystals of the same compound that differs only in the arrangement and/or conformation of the molecule (in the present invention, a compound of formula (I) or a pharmaceutically acceptable salt thereof) in the crystal lattice.
  • N-oxide refers to the oxide of the nitrogen atom of a nitrogen-containing heteroaryl or heterocycle.
  • N- oxide can be formed in the presence of an oxidizing agent such as m-chloro- perbenzoic acid or hydrogen peroxide.
  • N-oxide refers to an amine oxide, also known as amine-N-oxide, and is a chemical compound that contains N- 0 bond.
  • S-oxide refers to the oxide of the sulfur atom (S-oxide) or dioxide of the sulfur atom (S,S-dioxide) of a sulfur-containing heteroaryl or heterocycle.
  • S-oxide and S,S-dioxides can be formed in the presence of an oxidizing agent such as m-chloro-perbenzoic acid or oxone (potassium peroxymonosulfate).
  • a prodrug or “pharmaceutically acceptable prodrug(s)” refers to any compound (in the present invention, a compound of formula (I) or a pharmaceutically acceptable salt thereof), which are derivatives of the said compound.
  • prodrugs are those compounds that are converted intracellular ⁇ , more preferably, where the cellular converting location is the site of therapeutic action.
  • preferred prodrugs are pharmaceutically acceptable ester derivatives convertible by solvolysis under physiological conditions to the parent carboxylic acid.
  • esters examples include lower alkyl esters, cycloalkyl esters, lower alkenyl esters, benzyl esters, mono- or di-substituted lower alkyl esters such as the pivaloyloxymethyl ester and the like conventionally used in the art.
  • compound(s of the present invention) are used interchangeably and includes all the stereoisomeric and tautomeric forms and mixtures thereof in all ratios, and pharmaceutically acceptable salts, pharmaceutically acceptable solvates, pharmaceutically acceptable prodrugs, N-oxides, S-oxides and pharmaceutically acceptable polymorphs thereof.
  • the compound(s) of formula (I) can also be referred to herein as "the active compound” or "the active ingredient”.
  • bromodomain inhibitors' is used interchangeably with the term 'inhibitors of bromodomain containing proteins' and said term refer to a class of compounds, which inhibit the binding of one or more bromodomains with its cognate acetylated proteins, more particularly a class of compounds that inhibit the binding of one or more BET family bromodomains to acetylated lysine residues.
  • the bromodomain containing proteins that can be inhibited by the compounds and compositions of the present invention described herein include BET proteins such as BRD2, BRD3, BRD4 and BRDT, or an isoform or mutant thereof.
  • the term 'diseases or disorders mediated by bromodomain containing proteins means any disease or disorder in which one or more of the bromodomain-containing proteins, such as BET proteins, such as BRD2, BRD3, BRD4 and/ or BRDT, or a mutant thereof, are known to play a role, for example a disease or disorder characterised by abnormal binding of one or more of the bromodomain containing proteins such as BET proteins or mutants thereof, with its cognate acetylated proteins, more particularly by abnormal binding of one or more BET family bromodomains to acetylated lysine residues.
  • a few examples of the diseases or disorders mediated by bromodomain containing proteins include, but are not limited to, cancer, chronic autoimmune diseases, inflammatory disorders, cardiovascular diseases, metabolic disorders, disorders associated with fibrosis and viral infections.
  • therapeutically effective amount means an amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof or a composition comprising the compound of formula (I), effective in producing the desired therapeutic response in a particular patient suffering from a disease or disorder mediated by bromodomain containing proteins.
  • therapeutically effective amount includes the amount of a compound, when administered, that induces a positive modification in the disease or disorder to be treated or is sufficient to prevent development of, or alleviate to some extent, one or more of the symptoms of the disease or disorder being treated in a subject.
  • the amount of the compound used for the treatment of a subject is low enough to avoid undue or severe side effects, within the scope of sound medical judgment.
  • the therapeutically effective amount of the compound or composition will vary with the particular condition being treated, the age and physical condition of the end user, the severity of the condition being treated or prevented, the duration of the treatment, the nature of concurrent therapy, the specific compound or composition employed, the particular pharmaceutically acceptable carrier utilized and other factors.
  • the term "pharmaceutically acceptable carrier(s)” refers to a material that is non-toxic, inert, solid, semi-solid or liquid filler, diluent, encapsulating material or formulation auxiliary of any type which is compatible with a subject, preferably a mammal, more preferably a human, and is suitable for delivering an active agent to the target site without terminating the activity of the agent.
  • subject refers to an animal, preferably a mammal, and most preferably a human.
  • mammal refers to warm-blooded vertebrate animals of the class 'mammalia', including humans, characterized by a covering of hair on the skin and, in the female, milk-producing mammary glands for nourishing the young.
  • mammal includes animals such as cat, dog, rabbit, bear, fox, wolf, monkey, deer, mouse, pig and human.
  • subject may be used interchangeably with the term patient.
  • a subject in need thereof means a subject in need of the treatment for the disease or disorder that is mediated by bromodomain containing proteins.
  • a subject in need thereof means a subject (patient) diagnosed having a disease or disorder that is mediated by bromodomain containing proteins.
  • treatment refers to alleviate, slow the progression, attenuation or cure of existing diseases or condition (e.g. cancer). Treatment also includes treating, preventing development of, or alleviating to some extent, one or more of the symptoms of the diseases or condition.
  • the present invention relates to a compound of formula (I), wherein W is NR a ; and R a is as defined in the first aspect; or an isotopic form, a stereoisomer, a tautomer, a pharmaceutically acceptable salt, a solvate, a prodrug, a polymorph, N-oxide or S-oxide thereof.
  • the present invention relates to a compound of formula (I), wherein W is 0; or an isotopic form, a stereoisomer, a tautomer, a pharmaceutically acceptable salt, a solvate, a prodrug, a polymorph, N-oxide or S- oxide thereof.
  • the present invention relates to a compound of formula (I), wherein n is 0; or an isotopic form, a stereoisomer, a tautomer, a pharmaceutically acceptable salt, a solvate, a prodrug, a polymorph, N-oxide or S-oxide thereof.
  • the present invention relates to a compound of formula (I), wherein n is 1 ; or an isotopic form, a stereoisomer, a tautomer, a pharmaceutically acceptable salt, a solvate, a prodrug, a polymorph, N-oxide or S-oxide thereof.
  • the present invention relates to a compound of formula (I), wherein n is 2; or an isotopic form, a stereoisomer, a tautomer, a pharmaceutically acceptable salt, a solvate, a prodrug, a polymorph, N-oxide or S-oxide thereof.
  • the present invention relates to a compound of formula (I), wherein R 7 is cyano, W is NR a ; and R a is as defined in the first aspect; or an isotopic form, a stereoisomer, a tautomer, a pharmaceutically acceptable salt, a solvate, a prodrug, a polymorph, N-oxide or S-oxide thereof.
  • the present invention relates to a compound of formula (I), wherein R 7 is cyano, W is 0; or an isotopic form, a stereoisomer, a tautomer, a pharmaceutically acceptable salt, a solvate, a prodrug, a polymorph, N-oxide or S- oxide thereof.
  • the present invention relates to a compound of formula (I), wherein W is 0; R2 and R 3 are independently selected from the group consisting of (CrC 6 )-alkyl, halo(CrC 6 )-alkyl and (CrC 6 )-alkoxy; or an isotopic form, a stereoisomer, a tautomer, a pharmaceutically acceptable salt, a solvate, a prodrug, a polymorph, N-oxide or S-oxide thereof.
  • the present invention relates to a compound of formula (I), wherein Y is (C 6 -Ci 4 )-aryl, heterocyclyl or heteroaryl; or an isotopic form, a stereoisomer, a tautomer, a pharmaceutically acceptable salt, a solvate, a prodrug, a polymorph, N-oxide or S-oxide thereof.
  • the present invention relates to a compound of formula (I); wherein :
  • W is NR a or 0;
  • Ri and R 4 are independently selected from the group consisting of hydrogen, halogen, (Ci-C 6 )-alkyl, halo(Ci -C 6 )-alkyl, (Ci -C 6 )-alkoxy and (C 3 -Ci 2 )-cycloalkyl;
  • R 2 , R3 and R 5 are independently selected from the group consisting of hydrogen, halogen, (Ci -C6)-alkyl, halo(Ci -C6)-alkyl and (Ci -Ce)-alkoxy;
  • R 6 is hydrogen, (Ci-C 6 )-alkyl, (C 3 -Ci 2 )-cycloalkyl, alkyl, C(0)(Ci -C 6 )-alkyl or S(0) m (Ci- C 6 )-alkyl;
  • R 7 is hydrogen, (Ci -C6)-alkyl, cyano, nitro or NR a Rbi
  • n is an integer from 0-2;
  • n is an integer from 0-3;
  • R a is hydrogen, (Ci -C 6 )-alkyl, amino(Ci -C 6 )-alkyl- (Ci -C6)-alkoxy(Ci-C 6 )-alkyl, (C 3 - Ci2)-cycloalkyl, (C6-C-i 4 )-aryl, (C6-Ci 4 )-ar(Ci-C6)-alkyl-, heterocyclyl, heteroaryl, C(0)(Ci -C 6 )-alkyl or S(0) m (d-C 6 )-alkyl; and
  • Y is (C6-C-i 4 )-ar(Ci-C6)-alkyl- (C6-Ci 4 )-aryl, heterocyclyl or heteroaryl; or
  • the present invention relates to a compound of formula (I); Wherein:
  • W is NR a or 0;
  • R-i and R 4 are independently selected from the group consisting of hydrogen, halogen, (Ci-C 6 )-alkyl, halo(Ci-C 6 )-alkyl, (Ci-C 6 )-alkoxy and (C 3 -Ci 2 )-cycloalkyl;
  • R 2 , R3 and R 5 are independently selected from the group consisting of hydrogen, halogen, (Ci-C6)-alkyl, halo(Ci-C6)-alkyl and (Ci-Ce)-alkoxy;
  • R 6 is hydrogen, (Ci-C 6 )-alkyl, (C 3 -Ci 2 )-cycloalkyl, alkyl, C(0)(Ci-C 6 )-alkyl or S(0) m (Ci- C 6 )-alkyl;
  • R 7 is hydrogen, (Ci-C6)-alkyl, cyano, nitro or NR a R b ;
  • n is an integer from 0-2;
  • n is an integer from 0-3;
  • R a is hydrogen, (Ci-C 6 )-alkyl, amino(Ci-C 6 )-alkyl- (Ci-C6)-alkoxy(Ci-C 6 )-alkyl, (C 3 - Ci2)-cycloalkyl, (C6-C-i 4 )-aryl, (C6-Ci 4 )-ar(Ci-C6)-alkyl-, heterocyclyl, heteroaryl, C(0)(Ci-C 6 )-alkyl or S(0) m (Ci-C 6 )-alkyl; and
  • Y is (C6-Ci 4 )-aryl, heterocyclyl or heteroaryl
  • the present invention relates to a compound of formula (I), wherein
  • W is NR a or O
  • Ri and R 4 are independently selected from the group consisting of hydrogen, halogen, (Ci-C 6 )-alkyl, halo(Ci-C 6 )-alkyl, (Ci-C 6 )-alkoxy and (C 3 -Ci 2 )-cycloalkyl;
  • R 2 , R3 and R 5 are independently selected from the group consisting of hydrogen, halogen, (Ci-C 6 )-alkyl, halo(Ci-C 6 )-alkyl and (Ci-C 6 )-alkoxy;
  • R 6 is hydrogen, (Ci-C 6 )-alkyl, (C 3 -Ci 2 )-cycloalkyl, alkyl, C(0)(Ci-C 6 )-alkyl or S(0) m (Ci-
  • R 7 is cyano
  • n is an integer from 0-2;
  • n is an integer from 0-3;
  • R a is hydrogen, (Ci-C6)-alkyl, amino(C-i-C6)-alkyl- (Ci-C6)-alkoxy(Ci-C6)-alkyl, (C3- Ci 2 )-cycloalkyl, (C6-Ci 4 )-aryl, (C6-Ci 4 )-ar(Ci-C6)-alkyl-, heterocyclyl, heteroaryl, C(0)(C 1 -C 6 )-alkyl or S(0) m (C 1 -C 6 )-alkyl; and Y is (C6-C-i 4 )-ar(Ci-C6)-alkyl- (C6-C-i 4 )-aryl, heterocyclyl or heteroaryl; or an isotopic form, a stereoisomer, a tautomer, a pharmaceutically acceptable salt, a solvate, a prodrug, a polymorph, N-oxide or S-oxide thereof.
  • the present invention relates to a compound of formula (I), wherein
  • W is 0;
  • Ri and R 4 are independently selected from the group consisting of hydrogen, halogen, (Ci-C 6 )-alkyl, halo(Ci-C 6 )-alkyl, (Ci-C 6 )-alkoxy and (C 3 -Ci 2 )-cycloalkyl;
  • R 2 , R3 and R 5 are independently selected from the group consisting of hydrogen, halogen, (Ci-C 6 )-alkyl, halo(Ci-C 6 )-alkyl and (Ci-C 6 )-alkoxy;
  • R 6 is hydrogen, (Ci-Ce)-alkyl or (C3-Ci2)-cycloalkyl;
  • R 7 is cyano
  • n is an integer from 0-3;
  • Y is (C6-C-i 4 )-ar(Ci-C6)-alkyl- (C6-Ci 4 )-aryl, heterocyclyl or heteroaryl;
  • the present invention relates to a compound of formula (I), wherein
  • W is NR a ;
  • Ri and R 4 are independently selected from the group consisting of hydrogen, halogen,
  • R 2 , R3 and R 5 are independently selected from hydrogen and (Ci-Ce)-alkyl
  • R 6 is hydrogen, (Ci-Ce)-alkyl or (C3-Ci2)-cycloalkyl;
  • R 7 is cyano
  • n is an integer from 0-3;
  • R a is hydrogen or (Ci-C6)-alkyl
  • Y is (C6-C-i 4 )-ar(Ci-C6)-alkyl- (C6-Ci 4 )-aryl, heterocyclyl or heteroaryl;
  • the present invention relates to a compound of formula
  • W is O;
  • Ri and R 4 are independently selected from the group consisting of hydrogen, halogen, (Ci-C 6 )-alkyl, halo(Ci-C 6 )-alkyl, (Ci-C 6 )-alkoxy and (C 3 -Ci 2 )-cycloalkyl;
  • R 2 , R3 and R 5 are independently selected from hydrogen and (Ci-Ce)-alkyl
  • R 6 is hydrogen, (Ci-C 6 )-alkyl or (C 3 -Ci 2 )-cycloalkyl;
  • R 7 is cyano
  • n is an integer from 0-3;
  • Y is (C6-C-i 4 )-ar(Ci-C6)-alkyl- (C6-Ci 4 )-aryl, heterocyclyl or heteroaryl; or an isotopic form, a stereoisomer, a tautomer, a pharmaceutically acceptable salt, a solvate, a prodrug, a polymorph, N-oxide or S-oxide thereof.
  • the present invention relates to a compound of formula
  • W is NH or O
  • Ri is hydrogen, (C C 6 )-alkyl, (C 1 -C 6 )-alkoxy, NR a R b , C(0)(C C 6 )-alkyl, C(0)NR a R b, C(0)OH or C(0)0(Ci-C 6 )-alkyl;
  • R 2 and R 3 are independently selected from hydrogen and (Ci-Ce)-alkyl
  • R 4 is hydrogen
  • R 5 is hydrogen or (Ci-Ce)-alkyl
  • R 6 is hydrogen or (CrC 6 )-alkyl
  • R 7 is cyano
  • n is an integer from 0-3;
  • Y is (C6-C-i 4 )-ar(Ci-C6)-alkyl- (C6-Ci 4 )-aryl, heterocyclyl or heteroaryl;
  • the present invention relates to a compound of formula (I), wherein
  • W is O
  • Ri is hydrogen, (Ci-C 6 )-alkyl, (Ci-C 6 )-alkoxy, NR a R b , C(0)(Ci-C 6 )-alkyl, C(0)NR a R b , C(0)OH or C(0)0(C 1 -C 6 )-alkyl;
  • R 2 and R 3 are independently selected from hydrogen and (Ci-Ce)-alkyl
  • R 4 is hydrogen
  • R 5 is hydrogen or (Ci-Ce)-alkyl
  • R 6 is hydrogen or (Ci-Ce)-alkyl
  • R 7 is cyano; n is an integer from 0-3;
  • Y is (C6-C-i 4 )-ar(Ci-C6)-alkyl- (C6-Ci 4 )-aryl, heterocyclyl or heteroaryl;
  • the present invention relates to the compounds of formula (I), wherein
  • W is NH or O
  • Ri is (Ci -Ce)-alkoxy
  • R 2 and R 3 are (Ci -C 6 )-alkyl
  • R 4 is hydrogen
  • R 5 is (Ci -C 6 )-alkyl
  • R 6 is hydrogen
  • R 7 is cyano
  • n 1 or 2;
  • Y is (C6-Ci 4 )-aryl, heterocyclyl or heteroaryl
  • the present invention relates to the compounds of formula (I), wherein
  • W is O
  • Ri is (Ci -Ce)-alkoxy
  • R 2 and R 3 are (Ci -C 6 )-alkyl
  • R 4 is hydrogen
  • R 5 is (C 1 -C 6 )-alkyl
  • R 6 is hydrogen
  • R 7 is cyano
  • n 1 ;
  • Y is (C 6 -C 14 )-aryl
  • Representative compounds of the present invention include:
  • the compound of formula (I) can be prepared by various methods including using methods well known to the person skilled in the art. Examples of processes for the preparation of the compound of formula (I) are described below and illustrated in the scheme but are not limited thereto. It will be appreciated by persons skilled in the art that within certain of the processes described herein, the order of the synthetic steps employed may be varied and will depend inter alia on factors such as the nature of functional groups present in a particular substrate and the protecting group strategy (if any) to be adopted. Clearly, such factors will also influence the choice of reagent such as bases, solvents, coupling agents to be used in the reaction steps.
  • Scheme 1 depicts a process for the preparation of the compounds of formula (I), wherein R 7 is cyano; R-i , R 2 , R3, R 4 , R5, R6, n, W and Y are as defined in the first aspect of the present invention.
  • R 2 , R3 and W are as defined above; in the presence of a palladium catalyst selected from [1 , 1 '-bis(diphenylphosphino)ferrocene]dichloro palladium(ll) complex with dichloromethane, tetrakis(triphenylphosphine)palladium(0), bis(triphenylphosphine)palladium(ll) dichloride or [1 ,3-bis(2,6-diisopropylphenyl) imidazol-2-ylidene](3-chloropyridyl)palladium(ll) dichloride (PEPPSITM-IPr catalyst) and a base selected from sodium carbonate, potassium carbonate, sodium hydroxide or cesium carbonate in a solvent selected from ⁇ , ⁇ -dimethylformamide (DMF), 1 ,2-
  • step (i) The compound of formula 3 (as obtained in step (i)) is reacted with 2,2-dimethyl-1 ,3- dioxane-4,6-dione and reagent B having the following formula;
  • R 4 is as defined above;
  • step (ii) The compound of formula 4 (as obtained in step (ii)) is added to boiling diphenyl ether over a period of 10-30 minutes to obtain the compound of formula 5.
  • the compound of formula 5 (as obtained in step (iii)) is subjected to nitration using a nitrating agent such as a mixture of nitric acid and acetic acid or a mixture of nitric
  • step (iv) The compound of formula 6 (as obtained in step (iv)) is chlorinated by refluxing with phosphoryl chloride (POCI 3 ) for 1 -4 h to obtain the compound of formula 7.
  • the compound of formula 8 (as obtained in step (vi)) is reacted with a reducing agent such as stannous chloride and concentrated HCI or hydrogen in the presence of Pd/C or Fe/NH 4 CI in a solvent selected from an alcohol (methanol, ethanol or isopropanol), tetrahydrofuran, water or a mixture thereof, to obtain the compound of formula 9.
  • a reducing agent such as stannous chloride and concentrated HCI or hydrogen
  • Pd/C or Fe/NH 4 CI in a solvent selected from an alcohol (methanol, ethanol or isopropanol), tetrahydrofuran, water or a mixture thereof, to obtain the compound of formula 9.
  • step (vii) The compound of formula 9 (as obtained in step (vii)) is reacted with dimethylcyanocarbonimidodithioate in the presence of a base selected from sodium carbonate, potassium carbonate or cesium carbonate in a solvent selected from DMF, acetonitrile or an alcohol (methanol, ethanol or isopropanol), to obtain the compound of formula (I), wherein R 6 is hydrogen, R 7 is cyano; R-i , R 2 , R3, R 4 , R5, n, W and Y are as defined in the first aspect of the present invention.
  • a base selected from sodium carbonate, potassium carbonate or cesium carbonate
  • a solvent selected from DMF, acetonitrile or an alcohol (methanol, ethanol or isopropanol)
  • the compound of formula (I) (wherein R 6 is hydrogen) obtained in step (viii) can be converted to the compound of formula (I) wherein R 6 is (Ci-C6)-alkyl, (C3-C12)- cycloalkyl, (C 6 -Ci 4 )-aryl, (C6-Ci 4 )-ar(Ci-C 6 )-alkyl, heterocyclyl, heteroaryl, C(0)(CrC 6 )- alkyl or S(0) m (Ci-C6)-alkyl; by reacting it with an appropriate reagent by an appropriate method known to a person skill in the art for such a conversion.
  • the compound of formula (I) (wherein R 6 is hydrogen) obtained in step (viii) can be converted to the compound of formula (I) where R 6 is (Ci-C 6 )-alkyl by reacting the compound of formula (I) (wherein R 6 is hydrogen) with an appropriate alkyl halide in the presence of a base selected from triethylamine, sodium hydrogen carbonate, sodium carbonate, potassium carbonate or sodium hydride in a solvent selected from an alcohol (methanol, ethanol or isopropanol), DMF or THF.
  • a base selected from triethylamine, sodium hydrogen carbonate, sodium carbonate, potassium carbonate or sodium hydride
  • a solvent selected from an alcohol (methanol, ethanol or isopropanol), DMF or THF selected from an alcohol (methanol, ethanol or isopropanol), DMF or THF.
  • step (viii) or step (ix) can be converted into its pharmaceutically acceptable salt by process as described herein below.
  • Scheme 2 depicts an alternate process for preparation of the compounds of formula (I), wherein Ri is unsubstituted or substituted alkoxy designated as -OCH 2 T; wherein T is H, cyano, C(0)0(Ci-C 6 )alkyl, C(0)NR a R b or (Ci-C 6 )alkyl which is unsubstituted or substituted; and R 7 is cyano, n is 1 and R 2 , R3, R 4 , R5, R6, W and Y are as defined in the first aspect of the present invention.
  • T is H, cyano, C(0)0(C r C 6 )alkyl
  • alkoxy designated wherein is alkoxy as -OCH 2 T; designated as -OCH 2 T; f3 ⁇ 4 is H; R 7 is cyano R 6 is other than H; R 7 is cyano
  • the compound of formula 10 is reacted with bromine in presence of iron powder and in a solvent such as DCM at room temperature for 12-16 h to obtain the compound of formula 1 1 .
  • step (i) The compound of formula 1 1 , obtained from step (i) is reacted with the reagent D having the following formula,
  • T is H, cyano, C(0)0(Ci-C 6 )alkyl, C(0)NR a R b or (Ci-C 6 )alkyl which is unsubstituted or substituted; in the presence of a base selected from sodium carbonate, potassium carbonate or cesium carbonate by refluxing in a solvent such as acetone or DMF to obtain the compound of formula 12 (wherein T is as defined above).
  • a base selected from sodium carbonate, potassium carbonate or cesium carbonate by refluxing in a solvent such as acetone or DMF to obtain the compound of formula 12 (wherein T is as defined above).
  • step (ii) The compound of formula 12, obtained from step (ii), is reacted with iron powder in the presence of ammonium chloride under reflux condition in a mixture of solvent such as ethanol, THF and water to obtain the compound of formula 13 (wherein T is as defined above).
  • step (iii) The compound of formula 13, obtained from step (iii) is reacted with 2,2-dimethyl-1 ,3- dioxane-4,6-dione and reagent B (as described in step (ii) of scheme 1 ) with reflux for 1 -5 h, to obtain the compound of formula 14 (wherein T is as defined above).
  • step (iv) The compound of formula 14, as obtained in step (iv) is added into boiling diphenyl ether for 10-30 min to obtain the compound of formula 15 (wherein R 4 and T are as defined above).
  • step (v) The compound of formula 15, as obtained in step (v), is subjected to nitration using a nitrating agent such as a mixture of nitric acid and acetic acid or a mixture of nitric acid and propionic acid at a temperature range of 100-130 °C for 1 -5 h, to obtain compound of formula 16 (wherein R 4 and T are as defined above).
  • a nitrating agent such as a mixture of nitric acid and acetic acid or a mixture of nitric acid and propionic acid at a temperature range of 100-130 °C for 1 -5 h
  • step (vi) is halogenated by refluxing with phosphoryl chloride (POCI 3 ) or phosphorus tribromide (PBr 3 ) for 1 -4 h to obtain the compound of formula 17 (wherein R 4 and T are as defined above).
  • step (viii) The compound of formula 18, as obtained in step (viii), is reacted with a reducing agent such as stannous chloride and concentrated HCI or hydrogen in the presence of Pd/C or Fe/NH 4 CI in a solvent selected from an alcohol (methanol, ethanol or isopropanol), tetrahydrofuran, water or a mixture thereof, to obtain the compound of formula 19 (wherein R 4 , Y, R 5 , n and T are as defined above).
  • a reducing agent such as stannous chloride and concentrated HCI or hydrogen
  • Pd/C or Fe/NH 4 CI in a solvent selected from an alcohol (methanol, ethanol or isopropanol), tetrahydrofuran, water or a mixture thereof
  • step (ix) The compound of formula 19, as obtained in step (ix), is reacted with dimethyl cyanocarbonimidodithioate or diphenyl cyanocarbonimidate in the presence of a base selected from sodium carbonate, potassium carbonate or cesium carbonate in a solvent selected from DMF, acetonitrile or an alcohol (methanol, ethanol or isopropanol), to obtain the compound of formula 20 (wherein R 4 , Y, R 5 , n and T are as defined above).
  • step (ix) The compound of formula 19, as obtained in step (ix), is reacted with the reagent A (as described in step (i) of scheme 1 ) in the presence of a palladium catalyst selected from [1 ,1 '-bis(diphenylphosphino)ferrocene]dichloro palladium(ll) complex with dichloromethane, tetrakis(triphenylphosphine)palladium(0), bis(triphenyl- phosphine) palladium(ll) dichloride or [1 ,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidene](3- chloropyridyl)palladium(ll) dichloride (PEPPSITM-IPr catalyst) and a base selected from sodium carbonate, potassium carbonate, sodium hydroxide or cesium carbonate in a solvent selected from ⁇ , ⁇ -dimethylformamide (DMF), 1 ,2-dimethoxye
  • step (x) The compound of formula 20, as obtained in step (x) is reacted with the reagent A ((as described in step (i) of scheme 1 ) in the presence of a palladium catalyst selected from [1 ,1 '-bis(diphenylphosphino)ferrocene]dichloro palladium(ll) complex with dichloromethane, tetrakis(triphenylphosphine)palladium(0), bis(triphenyl-phosphine) palladium(ll) dichloride or [1 ,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidene](3- chloropyridyl)palladium(ll) dichloride (PEPPSITM-IPr catalyst) and a base selected from sodium carbonate, potassium carbonate, sodium hydroxide or cesium carbonate in a solvent selected from ⁇ , ⁇ -dimethylformamide (DMF), 1 ,2-dimethoxye
  • step (xa) The compound of formula 21 , as obtained in step (xa), is reacted with dimethyl cyanocarbonimidodithioate or diphenyl cyanocarbonimidate in the presence of a base selected from sodium carbonate, potassium carbonate or cesium carbonate in a solvent selected from DMF, acetonitrile or an alcohol (methanol, ethanol or isopropanol), to obtain the compound of formula (I) (wherein R 6 is H, R 7 is CN, Ri is alkoxy designated as -OCH 2 T; wherein T is as defined herein above; R 2 , R3, W, R 4 , R 5 , Y and n are as defined in the first aspect).
  • the compound of formula (I) (wherein R 6 is hydrogen) obtained in step (xi) or step (xia) can be converted to the compound of formula (I), wherein R 6 is (Ci-Ce)-alkyl, (C3- Ci 2 )-cycloalkyl, (C6-C-i 4 )-aryl, (C6-Ci 4 )-ar(Ci-C6)-alkyl-, heterocyclyl, heteroaryl, C(0)(Ci -C 6 )-alkyl or S(0) m (Ci -C 6 )-alkyl, by reacting it with an appropriate reagent by an appropriate method known to a person skill in the art for such a conversion.
  • the compound of formula (I) (wherein R 6 is hydrogen) obtained in step (xi) or step (xia) can be converted to the compound of formula (I) wherein R 6 is (Ci-Ce)-alkyl, by reacting the compound of formula (I) (wherein R 6 is hydrogen) with an appropriate alkyl halide in the presence of a base selected from triethylamine, sodium hydrogen carbonate, sodium carbonate, potassium carbonate or sodium hydride in a solvent selected from alcohol (methanol, ethanol or isopropanol), DMF or THF.
  • a base selected from triethylamine
  • sodium hydrogen carbonate sodium carbonate
  • potassium carbonate or sodium hydride in a solvent selected from alcohol (methanol, ethanol or isopropanol), DMF or THF.
  • step(s) (xi), (xia) or (xii) can be converted into its pharmaceutically acceptable salt by a process as described below.
  • the process of preparation of pharmaceutically acceptable salt of the compound of formula (I) involves contacting the compound of formula (I) with a sufficient amount of an appropriate base or an appropriate acid, either neat or in a suitable inert solvent.
  • a hydrochloride salt of a compound of formula (I) containing a basic group can be prepared by contacting the compound of formula (I) with hydrochloric acid either neat or in a suitable solvent, such as an alcohol.
  • a sodium salt of a compound of formula (I) containing an acidic group can be prepared by contacting the compound of formula (I) with sodium hydroxide in a suitable solvent, such as tetrahydrofuran.
  • pharmaceutically acceptable salts refers to organic and inorganic salts of a compound of the invention, depending on the particular group (acidic or basic group) present in the compounds of formula (I) described herein.
  • base addition salts can be obtained by contacting the compounds of formula (I) with a sufficient amount of an appropriate base, either neat or in a suitable inert solvent.
  • pharmaceutically acceptable base addition salts include sodium, potassium, calcium, magnesium, ammonium or an organic base salt.
  • organic base addition salts examples include those derived from organic bases such as lysine, arginine, guanidine, diethanolamine, choline, tromethamine and the like or other organic bases known to a person skilled in the art.
  • acid addition salts can be obtained by contacting the compounds of formula (I) with a sufficient amount of an appropriate acid, either neat or in a suitable inert solvent.
  • suitable inert solvent examples include those derived from inorganic acids like hydrochloric, hydrobromic, nitric, carbonic, monohydrogencarbonic, phosphoric, sulfuric, monohydrogenphosphoric, dihydrogenphosphoric, mono-hydrogensulfuric or hydriodic acids and the like, as well as the salts derived from organic acids like acetic, propionic, isobutyric, oxalic, maleic, malonic, benzoic, succinic, suberic, fumaric, mandelic, phthalic, benzenesulfonic, p- tolylsulfonic, citric, tartaric, methanesulfonic, glucuronic or galacturonic acids and the like.
  • Certain specific compounds of the present invention contain both basic and acidic functional
  • the compounds of formula (I) can be regenerated from their corresponding salts by contacting the salt with an appropriate base or acid depending on the type of salt and isolating the parent compound in the conventional manner.
  • the compound differs from the various salt forms in certain physical properties.
  • One such physical property that would make the salt form of a compound of formula (I) differ from the corresponding compound is solubility in polar solvents.
  • Certain compounds of the present invention can exist in unsolvated forms as well as solvated forms, including hydrated forms. Certain compounds of the present invention may exist in multiple crystalline or amorphous forms. In general, all physical forms are suitable for the uses contemplated by the present invention and are intended to be within the scope of the present invention.
  • polymorphs of compounds of formula (I) can be prepared by crystallization of the compounds under different conditions.
  • the different conditions are, for example, using different solvents or their mixtures for crystallization; crystallization at different temperatures; various modes of cooling, ranging from very fast to very slow cooling during crystallizations.
  • Polymorphs can also be obtained by heating or melting the compound followed by gradual or fast cooling.
  • the presence of polymorphs can be determined by IR (infra-red) spectroscopy, solid probe NMR (nuclear magnetic resonance) spectroscopy, differential scanning calorimetry, powder X-ray diffraction or such other techniques.
  • the present invention includes all possible stereoisomers and geometric isomers of formula (I) and includes not only racemic compounds but also the optically active isomers as well.
  • a compound of formula (I) When a compound of formula (I) is desired as a single enantiomer, it may be obtained either by resolution of the final product or by stereospecific synthesis from either isomerically pure starting material or an appropriate intermediate. Resolution of the final product, an intermediate or a starting material may be effected by any suitable method known in the art, for example, Chiral reagents for asymmetric synthesis by Leo A. Paquette; John Wiley & Sons Ltd (2003).
  • the present invention is intended to include all tautomeric forms of the compounds.
  • prodrugs of the compound of formula (I) are those compounds that are converted intracellular ⁇ , more preferably, where the cellular converting location is the site of therapeutic action.
  • preferred produgs are pharmaceutically acceptable ester derivatives convertible by solvolysis under physiological conditions to the parent carboxylic acid.
  • pharmaceutically acceptable esters include lower alkyl esters, cycloalkyl esters, lower alkenyl esters, benzyl esters, mono- or di- substituted lower alkyl esters such as the pivaloyloxymethyl ester and the like conventionally used in the art (An introduction to Medicinal Chemistry, Graham. L.
  • the present invention relates to pharmaceutical composition(s) containing a therapeutically effective amount of at least one compound of formula (I) or a isomer, a tautomer, pharmaceutically acceptable salt or a solvate thereof; and a conventional pharmaceutically acceptable carrier.
  • the present invention also relates to a process for production of the pharmaceutical composition, which includes bringing at least one compound of formula (I), into a suitable administration form using a pharmaceutically acceptable and physiologically tolerable excipient and, if appropriate, further suitable additives or auxiliaries can be added.
  • compositions can be administered orally, for example in the form of pills, tablets, coated tablets, capsules, granules or elixirs. Administration, however, can also be carried out rectally, for example in the form of suppositories, or parenterally, for example intravenously, intramuscularly or subcutaneously, in the form of injectable sterile solutions or suspensions, or topically, for example in the form of ointments or creams or transdermally, in the form of patches, or in other ways, for example in the form of aerosols or nasal sprays.
  • Carriers for soft gelatin capsules and suppositories are, for example, fats, waxes, natural or hardened oils, etc.
  • Suitable carriers for the production of solutions, for example injection solutions, or of emulsions or syrups are, for example, water, physiological sodium chloride solution or alcohols, for example, ethanol, propanol or glycerol, sugar solutions, such as glucose solutions or mannitol solutions, or a mixture of the various solvents which have been mentioned.
  • the pharmaceutical composition(s) normally contain about 1 % to 99 %, for example, from about 5 % to about 70 %, or from about 10 % to about 30 % by weight of the compound of formula (I) or its pharmaceutically acceptable salt.
  • the amount of the compound of formula (I) or its pharmaceutically acceptable salt in the pharmaceutical composition(s) can range from about 1 mg to about 1000 mg or from about 2.5 mg to about 500 mg or from about 5 mg to about 250 mg or in any range falling within the broader range of 1 mg to 1000 mg or higher or lower than the specified range.
  • the dosage range which is suitable in a specific case depends on the type of disease or disorder to be treated and on the state of the respective condition or disorder.
  • the selected dosage level can be readily determined by a skilled medical practitioner in the light of the relevant circumstances, including the disease or disorder to be treated, the chosen route of administration including other factors such as age, weight and physical health and response of the individual patient (subject), pharmacokinetics, severity of the disease and other like factors known in the medical art.
  • Actual dosage levels of the active ingredients i.e. the compounds of formula (I) in the pharmaceutical composition of this present invention can be varied so as to obtain an amount of the active ingredient, which is effective to achieve the desired therapeutic response for a particular patient (subject in need of the treatment), composition, and mode of administration without being toxic to the patient.
  • the dose of the compounds of formula (I) or pharmaceutically acceptable salts thereof, which is to be administered can cover a wide range.
  • the dose to be administered daily is to be selected to suit the desired therapeutic effect.
  • a suitable dosage is about 0.01 mg/kg/day to about 200 mg/kg/day of the compound of formula (I) or its pharmaceutically acceptable salt, for example, about 0.1 mg/kg/day to about 100 mg/kg/day of a compound of formula (I) or its pharmaceutically acceptable salt. If required, higher or lower daily doses can also be administered.
  • the pharmaceutical compositions can contain additives such as, for example, fillers, antioxidants, dispersants, emulsifiers, defoamers, flavors, preservatives, solubilizers or colorants. They can also contain two or more compounds of formula (I) or pharmaceutically acceptable salts thereof.
  • the present invention relates to a compound of formula (I) or a stereoisomer, a tautomer, a pharmaceutically acceptable salt or a solvate thereof; for use as inhibitors of bromodomain containing proteins.
  • the present invention relates to a compound of formula (I) or a stereoisomer, a tautomer, a pharmaceutically acceptable salt or a solvate thereof; for use as inhibitors of bromodomain containing protein 4 (BRD4).
  • BBD4 bromodomain containing protein 4
  • the present invention relates to a method for the treatment of a disease or a disorder mediated by bromodomain containing proteins, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula (I) or a stereoisomer, a tautomer, a pharmaceutically acceptable salt or a solvate thereof.
  • the present invention provides use of a compound of formula (I) or a stereoisomer, a tautomer, a pharmaceutically acceptable salt or a solvate thereof; for the treatment of a disease or a disorder mediated by bromodomain containing proteins.
  • the present invention provides use of a compound of formula (I) or a stereoisomer, a tautomer, a pharmaceutically acceptable salt or a solvate thereof; for the manufacture of a medicament for the treatment of a disease or a disorder mediated by bromodomain containing proteins.
  • the disease or disorder is mediated by bromodomain containing protein 4 (BRD4).
  • BBD4 bromodomain containing protein 4
  • the disease or disorder mediated by bromodomain containing proteins are selected from: proliferative disorders, chronic autoimmune diseases or disorders, inflammatory disorders, conditions associated with ischaemia-reperfusion injury, metabolic disorders, cardiovascular diseases, disorders associated with fibrosis and viral infections.
  • the proliferative disorders are selected from: cancers, tumors, polyps or cysts.
  • the chronic autoimmune and inflammatory diseases are selected from: rheumatoid arthritis, osteoarthritis, acute gout, psoriasis, systemic lupus erythematosus, multiple sclerosis, inflammatory bowel disease (Crohn's disease and Ulcerative colitis), asthma, chronic obstructive airways disease, pneumonitis, myocarditis, pericarditis, eczema, dermatitis, alopecia, nephritis, vasculitis, Alzheimer's disease, retinitis, hepatitis, pancreatitis, primary biliary cirrhosis, sclerosing cholangitis or thyroiditis.
  • the conditions associated with ischaemia-reperfusion injury are selected from: myocardial infarction, cerebrovascular ischaemia (stroke), acute coronary syndromes, renal reperfusion injury, organ transplantation, coronary artery bypass grafting, cardio-pulmonary bypass procedures, pulmonary, renal, hepatic, gastro-intestinal or peripheral limb embolism.
  • stroke cerebrovascular ischaemia
  • renal reperfusion injury organ transplantation
  • coronary artery bypass grafting coronary artery bypass grafting
  • cardio-pulmonary bypass procedures pulmonary, renal, hepatic, gastro-intestinal or peripheral limb embolism.
  • the metabolic disorders are selected from: metabolic syndrome, dyslipidemia, Type 2 diabetes or obesity.
  • the cardiovascular diseases are selected from: hypercholesterolemia, atherosclerosis, myocardial infarction, congestive heart failure or cardiac reperfusion injury.
  • the disorders associated with fibrosis are selected from: idiopathic pulmonary fibrosis, renal fibrosis, post-operative stricture, keloid formation, scleroderma and cardiac fibrosis.
  • the disorders associated with viral infections are selected from disorders caused by herpes virus, human papilloma virus, adenovirus, poxvirus and other DNA viruses.
  • the disease or disorder mediated by bromodomain containing proteins is cancer.
  • the present invention relates to a method for the treatment of cancer, comprising administering to a subject in need thereof a therapeutically effective amount of the compound of formula (I) or a stereoisomer, a tautomer, a pharmaceutically acceptable salt or a solvate thereof. Further, the present invention relates to use of a compound of formula (I) or a pharmaceutically acceptable salt thereof for the treatment of cancer.
  • the present invention provides use of a compound of formula (I) or a stereoisomer, a tautomer, a pharmaceutically acceptable salt or a solvate thereof, for the manufacture of a medicament for the treatment of cancer.
  • cancers that can be treated by the compounds of formula (I) or a stereoisomer, a tautomer, a pharmaceutically acceptable salt or a solvate thereof; or pharmaceutical compositions containing the said compounds; include, but are not limited to thyroid carcinoma, cardiac sarcoma, lung carcinoma, gastrointestinal carcinoma, genitourinary tract carcinoma, liver carcinoma, mantle cell lymphoma, bone sarcoma, sarcoma of the nervous system, gynaecological carcinoma, haematological cancer, adrenal gland neuroblastoma, skin cancer, astrocytic cancer, breast cancer, colorectal cancer, NUT midline carcinoma (NMC, a form of epithelial cancer caused by a mutation of the nuclear protein in testis), endometrial cancer, head and neck cancer or oral cancer.
  • thyroid carcinoma cardiac sarcoma
  • lung carcinoma gastrointestinal carcinoma
  • genitourinary tract carcinoma liver carcinoma
  • mantle cell lymphoma mantle cell lymphoma
  • the cancer is cardiac sarcoma selected from angiosarcoma, fibrosarcoma, rhabdomyosarcoma, liposarcoma, rhabdomyoma, fibroma, lipoma or teratoma.
  • the cancer is lung carcinoma selected from squamous cell carcinoma, undifferentiated small or large cell carcinoma, adenocarcinoma, bronchiolar carcinoma, bronchial adenoma, bronchial sarcoma, bronchial lymphoma.
  • the cancer is gastrointestinal carcinoma selected from stomach carcinoma, stomach lymphoma, pancreatic (ductal adenocarcinoma, insulinoma, glucagonoma, gastrinoma), small bowel carcinoma (adenocarcinoma, lymphoma, Karposi's sarcoma, hemangioma, lipoma, neurofibroma, fibroma) or large bowel carcinoma (adenocarcinoma, tubular adenoma).
  • pancreatic ductal adenocarcinoma, insulinoma, glucagonoma, gastrinoma
  • small bowel carcinoma adenocarcinoma, lymphoma, Karposi's sarcoma, hemangioma, lipoma, neurofibroma, fibroma
  • large bowel carcinoma adenocarcinoma, tubular adenoma
  • the cancer is genitourinary tract carcinoma selected from carcinoma of kidney (adenocarcinoma, nephroblastoma, lymphoma, leukemia), carcinoma of bladder and urethra (squamous cell carcinoma, adenocarcinoma), carcinoma of prostate (adenocarcinoma, sarcoma), or carcinoma of testis (seminoma, teratoma, embryonal carcinoma, teratocarcinoma, sarcoma, interstitial cell carcinoma, fibroma, fibroadenoma, lipoma).
  • the cancer is liver carcinoma selected from hepatoma (hepatocellular carcinoma), hepatoblastoma, angiosarcoma or hepatocellular adenoma.
  • the cancer is bone sarcoma selected from osteogenic sarcoma (osteosarcoma), fibrosarcoma, Ewing's sarcoma, malignant lymphoma (reticulum cell sarcoma), multiple myeloma, benign chondroma, chondroblastoma, chondromyxofibroma, osteoid osteoma or giant cell tumors.
  • osteogenic sarcoma osteosarcoma
  • fibrosarcoma fibrosarcoma
  • Ewing's sarcoma malignant lymphoma (reticulum cell sarcoma)
  • multiple myeloma benign chondroma
  • chondroblastoma chondromyxofibroma
  • osteoid osteoma giant cell tumors.
  • the cancer is sarcoma of the nervous system selected from sarcoma of skull (osteoma, granuloma, xanthoma), meninges (meningioma, meningiosarcoma, gliomatosis), sarcoma of brain (astrocytoma, medulloblastoma, glioma, glioblastoma multiform, oligodendroglioma, retinoblastoma, congenital tumors) or sarcoma of spinal cord (neurofibroma, meningioma, glioma, sarcoma).
  • skull osteoma, granuloma, xanthoma
  • meninges meningioma, meningiosarcoma, gliomatosis
  • sarcoma of brain astrocytoma, medulloblastoma, glioma, glioblastom
  • the cancer is carcinoma of gynaecological organs selected from carcinoma of uterus (endometrial carcinoma), carcinoma of cervix (cervical carcinoma, ovary carcinoma), carcinoma of vulva (squamous cell carcinoma, intraepithelial carcinoma, adenocarcinoma, fibrosarcoma, melanoma), carcinoma of vagina (clear cell carcinoma, squamous cell carcinoma, embryonal rhabdomyosarcoma) or carcinoma of fallopian tubes.
  • carcinoma of gynaecological organs selected from carcinoma of uterus (endometrial carcinoma), carcinoma of cervix (cervical carcinoma, ovary carcinoma), carcinoma of vulva (squamous cell carcinoma, intraepithelial carcinoma, adenocarcinoma, fibrosarcoma, melanoma), carcinoma of vagina (clear cell carcinoma, squamous cell carcinoma, embryonal rhabdomyosarcoma) or carcinoma of fallopian tubes
  • the cancer is haematological cancer selected from blood cancer (acute myeloid leukemia (AML), chronic myeloid leukemia (CML), acute lymphoblastic leukemia, chronic lymphocytic leukemia, myeloproliferative diseases, multiple myeloma, myelodysplastic syndrome), Hodgkin's disease, non-Hodgkin's lymphoma (malignant lymphoma) or mantle cell lymphoma.
  • blood cancer acute myeloid leukemia (AML), chronic myeloid leukemia (CML), acute lymphoblastic leukemia, chronic lymphocytic leukemia, myeloproliferative diseases, multiple myeloma, myelodysplastic syndrome
  • Hodgkin's disease non-Hodgkin's lymphoma (malignant lymphoma) or mantle cell lymphoma.
  • the disease or disorder mediated by bromodomain containing proteins is a skin cancer selected from malignant melanoma, basal cell carcinoma, squamous cell carcinoma, Kaposi's sarcoma, angioma or dermatofibroma.
  • the present invention also encompasses within its scope use of a compound of formula (I) or a stereoisomer, a tautomer or a pharmaceutically acceptable salt thereof; administered in combination, either simultaneously or sequentially with other therapeutically active agents.
  • the compounds of the present invention can be used in combination with known anti-cancer agents. Combinations of the compounds of the present invention with other anti-cancer or chemotherapeutic agents are within the scope of the invention.
  • the therapeutically active agents used in combination with one or more compounds of formula (I) or a stereoisomer, a tautomer, or pharmaceutically acceptable salt thereof can be selected from anti-cancer or chemotherapeutic agents such as anti-microtubule agents (diterpenoids (paclitaxel, docetaxel) and vinca alkaloids (vinblastine, vincristine, vinorelbine); platinum coordination complexes (cisplatin, carboplatin), alkylating agents (nitrogen mustards (oxazaphosphorines, cyclophosphamide, melphalan, chlorambucil)); alkyl sulfonates (busulfan); nitrosoureas (carmustine); triazenes (dacarbazine); topoisomerase I inhibitors (camptothecins (irinotecan, topotecan)); topoisomerase II inhibitors (epipodophyllotoxins (etoposide, teniposide));
  • a pharmaceutical composition containing a compound of formula (I) or its pharmaceutically acceptable salt can be administered to a subject, in particular a human, with any other therapeutically active compounds, in mixtures with one another or in the form of pharmaceutical preparations.
  • Nitric acid (21 .5 mL, 481 mmol) was added to a stirred solution of the compound of example 3 (26.0 g, 96.0 mmol) in acetic acid (300 mL).
  • the resulting reaction mixture was heated to 120 °C for 2 h and then cooled to 25-30 °C. Solid thus obtained was collected by filtration and the solid was washed with cold water.
  • the crude product obtained was further purified by trituration in ethyl acetate and petroleum ether to afford the title compound.
  • Phenylmethanamine (0.389 g, 3.63 mmol) was added to a stirred solution of the compound of example 5 (1 .1 g, 3.30 mmol) in acetonitrile (10 mL) and the reaction mixture was heated to reflux for 2 h. The reaction mixture was cooled to room temperature and the solvent was evaporated. Water (25mL) was added to the resulting residue and extracted with ethyl acetate (2x25 mL). The combined organic layers were washed with water (25 mL) and brine (25 mL) and further dried over anhydrous Na 2 S0 4 . The solvent was evaporated to obtain a crude product, which was further purified by column chromatography (silica gel, 7:3 petroleum ether: ethyl acetate) to obtain the title compound.
  • Diphenyl cyanocarbonimidate (0.356 g, 1 .493 mmol) was added to a stirred solution of the compound of example 29 (0.50 g, 1 .357 mmol) in acetonitrile (10 mL) and the resulting reaction mixture was heated to reflux for 16 h. The reaction mixture was filtered and washed with a mixture of ethyl acetate and petroleum ether to obtain the title compound.
  • PdCl2(dppf)-CH 2 Cl2 adduct (8.70 mg, 10.66 pmol) was added to a stirred solution of the compound of example 86 (0.15 g, 0.355 mmol) and 2-(3-methyl-4-(4, 4,5,5- tetramethyl-1 ,3,2-dioxaborolan-2-yl)isoxazol-5-yl)ethyl acetate (0.210 g, 0.710 mmol) in DMF (2 mL). To the reaction mixture, sodium carbonate (0.075 g, 0.710 mmol) solution in water (0.4 mL) was added and heated at 120 °C for 1 h. The reaction mixture was then cooled to room temperature and concentrated.
  • Triethyl orthoformate (67.1 mL, 403 mmol) and 2,2-dimethyl-1 ,3-dioxane-4,6-dione (20.14 g, 140 mmol) was mixed together and heated to reflux for 1.5 h.
  • 3-bromo-4-methylaniline 25 g, 134 mmol was added in portions for 5 minutes and heated to reflux for 2 h.
  • the reaction mixture was cooled to room temperature and the solid obtained was filtered, washed with diethyl ether (50 mL) to obtain the title compound.
  • Nitric Acid (1 1 .26 mL, 252 mmol) was added to a stirred solution of 7-bromo-6- methylquinolin-4-ol (example 90, 20 g, 84 mmol) in acetic acid (150 mL) and the resulting reaction mixture was heated to 120 °C for 2 h and then cooled to room temperature. The solid obtained was filtered, washed with cold water and triturated in ethyl acetate and petroleum ether to obtain the title compound.
  • PBr 3 (9.33 mL, 99 mmol) was added dropwise to a stirred solution of the compound of example 91 (14 g, 49.5 mmol) in DMF (70 mL) and the resulting solution was stirred at 25-30°C for 3 h.
  • the reaction mixture was quenched in water (500 mL), the solid obtained was filtered and washed with water and petroleum ether to obtain the title compound.
  • reaction mixture was stirred for 1 h at room temperature, quenched in ice cold water (20 mL) and extracted with ethyl acetate (3 x 20 mL). The combined organic layers were washed with brine (20 mL), dried over anhydrous Na 2 S0 4 and the solvent was evaporated to yield a crude product, which was purified by column chromatography (silica gel, 9: 1 CHC : MeOH) to obtain the title compound.
  • Nitric acid (10.63 ml_, 166 mmol) was added to a stirred solution of the compound of example 103 (16 g, 66.6 mmol) in acetic acid (300 ml_).
  • the resulting reaction mixture was heated to 120 °C for 2 h and cooled to room temperature.
  • the solid obtained was filtered and washed with cold water followed by diethyl ether. The solid was dried under high vacuum to obtain the title compound.
  • Potassium permanganate (77 g, 486 mmol) was added to a stirred solution of water (400 mL) and pyridine (300 mL) and the reaction mixture was heated to reflux for 2 h. The reaction mixture was filtered through celite, pyridine was removed and adjusted the pH to 1 -2 with dilute HCI. The solid obtained was filtered, washed with water and petroleum ether to obtain the title compound.
  • Trimethyl orthoformate 25.8 mL, 234 mmol
  • 2,2-dimethyl-1 ,3-dioxane-4,6-dione (1 1 .67 g, 81 mmol) was mixed together and heated to reflux for 1 .5 h.
  • the compound of example 1 1 1 (19 g, 78 mmol) was added in portions and continued heating for 2 h.
  • the reaction mixture was cooled, the solid obtained was filtered and washed with diethyl ether to obtain the title compound.
  • Nitric Acid (5.63 mL, 88 mmol) was added to a stirred solution of the compound of example 1 13 (12.8 g, 29.4 mmol) in acetic acid (40 mL) and heated to 120 °C for 2 h. The reaction mixture was cooled to room temperature and stirred for 12 h. The solid obtained was filtered, washed with acetic acid and petroleum ether and dried to obtain the title compound.
  • PdCI 2 (dppf)-CH 2 CI 2 adduct (0.063 g, 0.078 mmol) was added to a stirred solution of the compound of example 1 18 (1 .2 g, 2.58 mmol) and (3,5-dimethyl isoxazol-4- yl)boronic acid (0.474 g, 3.36 mmol) in DMF (20 mL) followed by sodium carbonate (0.548 g, 5.17 mmol) solution in water (4 mL) and the resulting reaction mixture was heated to 120 °C for 5 h. The reaction mixture was then cooled to room temperature, concentrated, added water (50 mL) and extracted with CHCI 3 (3 x 50 mL).
  • HATU (55.5 mg, 0.146 mmol) and N,N-diisopropylethylamine (0.106 ml_, 0.608 mmol) was added to a stirred solution of the compound of example 120 (55 mg, 0.122 mmol) in THF (2 ml_) and stirred at room temperature for 1 h.
  • ethanamine 5.48 mg, 0.122 mmol was added and stirred at room temperature for 12 h.
  • the solid obtained was filtered and purified by preparative TLC to afford the title compound.
  • Nitric acid (6.74 mL, 106 mmol) was added to a stirred solution of the compound of example 129 (1 1 .4 g, 35.2 mmol) in acetic acid (60 mL). The reaction mixture was heated to 120 °C for 2 h and cooled to room temperature. The solid obtained was filtered, washed with petroleum ether and triturated in ethyl acetate and petroleum ether to obtain the title compound.
  • Iron (0.638 g, 1 1 .43 mmol) and ammonium chloride (0.612 g, 1 1 .43 mmol) were added to a stirred solution of the compound of example 132 (1 .8 g, 3.81 mmol) in mixture of ethanol (10 ml_): THF (10.00 ml_): water (5.00 ml_) and heated to reflux for 2 h.
  • the reaction mixture was filtered through celite, the filtrate was concentrated, diluted with 10% NaHCO 3 solution (50 ml_) and extracted with ethyl acetate (3 x 50 ml_).
  • reaction mixture was then cooled to room temperature, concentrated, added water (25 mL) and extracted with CHC (3 x 25 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na 2 S0 4 and the solvent was evaporated to yield a crude product, which was purified by column chromatography (silica gel, ethyl acetate: petroleum ether 1 : 1 )) to obtain the title compound.
  • Lithium hydroxide (297 mg, 7.08 mmol) was added to a stirred solution of the compound of example 135 (600 mg, 1 .180 mmol) in mixture of MeOH (2 mL): THF (2. mL):water (2mL) and stirred at room temperature for 2 h.
  • the reaction mixture was concentrated to remove the solvent and adjusted pH to 5 with dilute HCI.
  • the solid obtained was filtered and triturated in 5 % ethyl acetate: petroleum ether to obtain the title compound.
  • Ethanamine (0.1 14 mL, 0.229 mmol) was added to a stirred solution of the compound of example 136 (100 mg, 0.208 mmol), 2-(3H-[1 ,2,3]triazolo[4,5-b]pyridin-3-yl)-1 , 1 ,3,3- tetramethylisouronium,hexafluoro phosphate (V) salt (95 mg, 0.250 mmol) and N-ethyl- N-isopropylpropan-2 -amine (0.109 mL, 0.624 mmol) in THF (2 mL) and stirred at room temperature for 12 h under argon atomosphere.
  • V tetramethylisouronium,hexafluoro phosphate

Abstract

The present invention provides compound of formula (I), or an isotopic form, a stereoisomer, a tautomer, a pharmaceutically acceptable salt, a solvate, a polymorph, a prodrug, N-oxide or S-oxide thereof; and processes for their preparation. The invention further relates to pharmaceutical compositions containing said compounds and their use in the treatment of diseases or disorders mediated by bromodomain containing proteins, particularly cancer.

Description

IMIDAZOQUINOLINE COMPOUNDS AS BROMODOMAIN INHIBITORS
FIELD OF THE INVENTION
The present invention relates to imidazoquinoline compounds (referred to herein as the compounds of formula (I)), processes for their preparation, pharmaceutical compositions containing them, their use as inhibitors of bromodomain containing proteins, and methods of using said compounds in the treatment of diseases or disorders mediated by bromodomain containing proteins. BACKGROUND OF THE INVENTION
Chromatin plays a critical role in regulating gene transcription within the cells of eukaryotic organisms. Chromatin is constituted by compression via aggregation and folding of nucleosomes. A nucleosome is constituted by an octomer of histone proteins such as H2A, H2B, H3 and H4, wrapped with strands of duplex DNA. The condensation of the chromatin varies during the cell cycle, being most compact during the process of cell division. Gene transcription is a function of the extent of condensation of the chromatin in the cell, and the chromatin structure is controlled by a series of post translational modifications such as methylation, acetylation, phosphorylation, sumoylation or ubiquitination, of histone proteins, mainly histones H3 and H4, and most commonly within the histone tails which extend beyond the core nucleosome structure. These modifications are carried out by specific enzymes leading to formation of an epigenetic code, which is interpreted by the cell, leading to gene specific regulation of the chromatin structure and thereby gene transcription.
Histone acetylation is one of the processes associated with gene transcription, wherein specific proteins bind to acetylated lysine residues within histones to read the epigenetic code. Bromodomains are small and distinct amino acid domains within proteins that bind to acetylated lysine resides. There are 61 bromodomains in proteins that have a variety of functions including functioning as histone acetyl transferases such as CBP (cyclic AMP response element-binding protein, binding protein), methyl transferases, transcriptional regulators such as BRD4 (bromodomain-containing protein 4) and chromatin remodelling complexes (Med. Chem. Commun., 2013, 4, 140-144). The BET (extra-terminal) family of bromodomain containing proteins mainly comprises four proteins (BRD2, BRD3, BRD4 and BRDT) each containing two discrete bromodomain 'reader' modules which recognize the acetylated state of lysine residues on histone tails and other proteins, which are capable of binding to two acetylated lysine residues in close proximity, increasing the specificity of the interaction. While three members of this family (BRD2, BRD3 and BRD4) are ubiquitously expressed, the fourth member, BRDT, has to date only been found in ovary and testis (Bioorg. Med. Chem. Lett, 2012, 22, 2968-2972).
Dysregulation of chromatin modifiers is a recurrent event in oncogenesis. All the BET family members have been reported to have a role in controlling the cell cycle, and form a complex with chromosomes during cell division, which indicates that they play an important role in maintenance of epigenetic memory. In particular, the binding of bromodomain and extra-terminal (BET) proteins to chromatin regulates the transcription of oncogene proteins. Proteins that contain bromodomains have also been found to have a critical role in diverse, non-malignant phenotypes, directing transcription which controls adipogenesis, energy metabolism and inflammation.
Considering that bromodomains (BRDs) play an important role in targeting chromatin-modifying enzymes to specific sites and often it has been found that they act with other protein-interaction modules to guarantee a high level of targeting specificity for these essential enzymes, therapeutic strategies that selectively alter the recruitment and/or catalytic activity of these enzymes at chromatin hold great promise as targeted therapies. Bromodomain inhibitors refer to a class of compounds, which inhibit the binding of bromodomains with its cognate acetylated proteins, more particularly which inhibit the binding of BET family bromodomains to acetylated lysine residues. A few examples of investigational drugs that function as bromodomain inhibitors are OTX-015 (Mitsubishi Tanabe Pharma), (+)-JQ-1 (Dana-Farber Cancer Institute), GSK-525762 (GlaxoSmithKline), GSK-1210151A (I-BET151 , GlaxoSmithKline), GW-841819X (GlaxoSmithKline) and RVX-2135 (Resverlogix).
The main advantage of targeting the binding of bromodomains and extra- terminal (BET) proteins to chromatin is that this enables the regulation of gene expression, particularly the transcription of key oncogenes such as MYC (myelocytomatosis viral oncogene), which can lead to arresting of cell-cycle progression and apoptosis (programmed cell death), i.e. the cancer cells are selectively killed. Expert Reviews in Molecular Medicine, 201 1 , 13, 1 -21 , reports bromodomains as therapeutic targets for the treatment of cancer, inflammation and neurological disorders.
PCT publication WO201 1/054846A1 discloses imidazo[4, 5-c]quinoline derivatives as bromodomain inhibitors used in the treatment of chronic autoimmune and inflammatory diseases or disorders, and cancer.
PCT publication WO2012/007926A1 discloses imidazo[4, 5-c]quinoline derivatives as kinase inhibitors used in the treatment of proliferative diseases, inflammatory diseases and angiogenesis related disorders.
There is a need for selective therapeutic agents directed against this emerging class of gene regulatory proteins which promise new approaches to the treatment of diseases such as cancer, metabolic disorders, cardiovascular diseases, inflammation or auto-immune diseases. The compounds of the present invention function as bromodomain inhibitors and thereby provide therapeutic benefit in the treatment of diseases or disorders mediated by bromodomain containing proteins.
SUMMARY OF THE INVENTION
According to one aspect, the present invention relates to a compound of formula (I) (as described herein), or an isotopic form, a stereoisomer, a tautomer, a pharmaceutically acceptable salt, a solvate, a polymorph, a prodrug, S-oxide or N- oxide thereof.
According to another aspect, the present invention relates to processes for the preparation of the compound of formula (I) or a pharmaceutically acceptable salt thereof.
According to a further aspect, the present invention relates to pharmaceutical composition comprising the compound of formula (I) or an isotopic form, a stereoisomer, a tautomer, a pharmaceutically acceptable salt or a solvate thereof; and at least one pharmaceutically acceptable carrier or excipient.
According to another aspect, the present invention relates to a compound of formula (I) or a stereoisomer, a tautomer, a pharmaceutically acceptable salt, a solvate thereof, for use as inhibitor(s) of bromodomain containing proteins.
According to yet another aspect, the present invention relates to a compound of formula (I) or a stereoisomer, a tautomer, a pharmaceutically acceptable salt, a solvate thereof; for use in the treatment of a disease or a disorder mediated by bromodomain containing proteins.
According to a further aspect, the present invention relates to a method for the treatment of a disease or disorder mediated by bromodomain containing proteins, comprising administering to a subject in need thereof a therapeutically effective amount of the compound of formula (I) or a stereoisomer, a tautomer, a pharmaceutically acceptable salt or a solvate thereof.
According to yet another aspect, the present invention relates to use of a compound of formula (I) or a stereoisomer, a tautomer, a pharmaceutically acceptable salt or a solvate thereof, for the manufacture of a medicament for the treatment of diseases or disorders mediated by bromodomain containing proteins.
According to a further aspect, the present invention relates to use of a compound of formula (I) or a stereoisomer, a tautomer, a pharmaceutically acceptable salt or a solvate thereof; with one further therapeutically active agent.
One or more further aspects of the present inventions are discussed in detail herein below. These and other objectives and advantages of the present invention will be apparent to those skilled in the art from the following description.
DETAILED DESCRIPTION OF THE INVENTION
According to a first aspect, the present invention relates to a compound of formula (I):
Figure imgf000005_0001
Formula (I)
or an isotopic form, a stereoisomer, a tautomer, a pharmaceutically acceptable salt, a solvate, a polymorph, a prodrug, N-oxide or S-oxide thereof,
wherein,
W is NRa or O; Ri and R4 are independently selected from the group consisting of hydrogen, halogen, cyano, nitro, (Ci-C6)-alkyl, (C2-C8)-alkenyl, (C2-C8)-alkynyl, halo(Ci-C6)-alkyl, (Ci-C6)- alkoxy, (C3-Ci2)-cycloalkyl, (C6-Ci4)-ar(Ci-C6)-alkyl-, (C6-Ci4)-aryl, heterocyclyl, heteroaryl, NRaRb, C(0)(C1-C6)-alkyl, C(O)NRaRb, COOH, C(0)0(C1-C6)-alkyl and S(0)m(Ci-C6)-alkyl;
R2, R3 and R5 are independently selected from the group consisting of hydrogen, halogen, (Ci-C6)-alkyl, (C2-C8)-alkenyl, (C2-C8)-alkynyl, halo(Ci-C6)-alkyl and (Ci-C6)- alkoxy;
R6 is hydrogen, (CrC6)-alkyl, amino(Ci-C6)-alkyl-, (Ci-C6)-alkoxy(Ci-C6)-alkyl-, (C3- Ci2)-cycloalkyl, (C6-Ci4)-aryl, (C6-Ci4)-ar(Ci-C6)-alkyl-, heterocyclyl, heteroaryl,
C(0)(Ci-C6)-alkyl or S(0)m(Ci-C6)-alkyl;
R7 is hydrogen, cyano, nitro, (Ci-Ce)-alkyl or NRaRb;
m is an integer from 0-2;
n is an integer from 0-3;
Y is (C3-Ci2)-cycloalkyl, (C6-Ci4)-ar(Ci-C6)-alkyl-, (C6-Ci4)-aryl, heterocyclyl, heteroaryl or NRaRb;
wherein:
each of the (CrC6)-alkyl and (Ci-C6)-alkoxy is unsubstituted or substituted with one to three groups independently selected from the group consisting of halogen, hydroxy, nitro, cyano, (Ci-C6)-alkoxy-(Rc)0-3, (C3-Ci2)-cycloalkyl-(Rc)0-3, (C3-Ci2)-cycloalkyloxy- (Rc)o-3, halo(Ci-C6)-alkoxy, (C6-Ci4)-aryl-(Rc)o-3, (C6-Ci4)-aryloxy-(Rc)o-3, (C6-Ci4)-ar(Ci- C6)-alkyloxy-(Rc)o-3, heterocyclyl-(Rc)0-3, heteroaryl-(Rc)0-3, C(0)(Ci-C6)-alkyl,, COOH, C(O)O(Ci-C6)-alkyl, OC(O)(d-C6)-alkyl, C(O)NRaRb, NRaRb and S(O)m(Ci-C6)-alkyl; each of the (C3-Ci2)-cycloalkyl, (C3-Ci2)-cycloalkyloxy, (C6-Ci4)-aryl, (C6-Ci4)-aryloxy, (C6-Ci4)-ar(Ci-C6)-alkyl- and (C6-Ci4)-ar(Ci-C6)-alkyloxy is unsubstituted or substituted with one to three groups independently selected from the group consisting of halogen, hydroxy, nitro, cyano, (Ci-C6)-alkyl-(Rc)0-3, (Ci-C6)-alkoxy-(Rc)0-3, (Ci-C6)- alkoxy(Ci-C6)-alkyl-(Rc)o-3, (C3-Ci2)-cycloalkyl-(Rc)o-3, (C3-Ci2)-cycloalkyloxy-(Rc)o-3, halo(Ci-C6)-alkyl, halo(Ci-C6)-alkoxy, (C6-Ci4)-aryl-(Rc)o-3, (C6-Ci4)-aryloxy-(Rc)o-3, (C6- Ci4)-ar(Ci-C6)-alkyl-(Rc)o-3, (C6-Ci4)-ar(Ci-C6)-alkyloxy-(Rc)o-3, heterocyclyl-(Rc)0-3, heteroaryl-(Rc)o-3, C(O)(Ci-C6)-alkyl, COOH, C(O)O(Ci-C6)-alkyl, C(O)NRaRb, NRaR and S(O)m(Ci-C6)-alkyl; the heterocyclyl is a 3- to 12-membered saturated or partially unsaturated monocyclic or bicyclic ring system containing one to four heteroatoms independently selected from the group consisting of a nitrogen (N), a sulphur (S) and an oxygen (0) atom, the heteroaryl is a 5- to 10-membered aromatic monocyclic or bicyclic ring system containing one to four heteroatoms independently selected from the group consisting of N, S and O; each of the heterocyclyl and heteroaryl is unsubstituted or substituted with one to three groups independently selected from the group consisting of halogen, hydroxy, nitro, cyano, (Ci-C6)-alkyl-(Rc)o-3, (Ci-C6)-alkoxy-(Rc)o-3, (Ci-C6)-alkoxy(Ci-C6)-alkyl- (Rc)o-3, (C3-Ci2)-cycloalkyl-(Rc)o-3, (C3-Ci2)-cycloalkyloxy-(Rc)o-3, halo(d-C6)-alkyl, halo(Ci-C6)-alkoxy, (C6-Ci4)-aryl-(Rc)o-3, (C6-Ci4)-aryloxy-(Rc)0-3, (C6-Ci4)-ar(Ci-C6)- alkyl-(Rc)0-3, (C6-Ci4)-ar(Ci-C6)-alkyloxy-(Rc)o-3, heterocyclyl-(Rc)0-3, heteroaryl-(Rc)0-3, C(0)(Ci-C6)-alkyl, COOH, C(0)0(Ci-C6)-alkyl, C(0)NRaRb, NRaRb and S(0)m(Ci-C6)- alkyl;
Ra and Rb are independently selected from the group consisting of hydrogen, (C-i-Ce)- alkyl, amino(Ci-C6)-alkyl, (Ci-C6)-alkoxy(Ci-C6)-alkyl, (C3-Ci2)-cycloalkyl, (C6-Ci4)-aryl, (C6-Ci4)-ar(Ci-C6)-alkyl, heterocyclyl, heteroaryl, C(0)(Ci-C6)-alkyl and S(0)m(Ci-C6)- alkyl; or
Ra and Rb together with the N to which they are attached can form a 3-8 membered heterocyclyl ring, optionally containing one to three additional heteroatoms independently selected from the group consisting of N, O and S, and the said heterocyclyl ring is unsubstituted or substituted with one to three groups as defined herein for the heterocyclyl group; and
Rc is halogen, hydroxy, cyano, nitro, (Ci-C6)-alkyl-(Rc)0-i, (Ci-C6)-alkoxy-(Rc)0-i , (Ci- C6)-alkoxy(Ci-C6)-alkyl-(Rc)0-i, (C3-Ci2)-cycloalkyl-(Rc)0-i, (C3-Ci2)-cycloalkyloxy-(Rc)0- , hydroxy(Ci-C6)-alkyl-(Rc)0-i, halo(Ci-C6)-alkyl, halo(Ci-C6)-alkoxy, (C6-Ci4)-aryl- (Rc)o-i, (C6-Ci4)-aryloxy-(Rc)0-i , (C6-Ci4)-ar(Ci-C6)-alkyl-(Rc)0-i , (C6-Ci4)-ar(Ci-C6)- alkyloxy-(Rc)o-i , heterocyclyl-(Rc)0-i, heteroaryl-(Rc)0-i, C(0)(Ci-C6)-alkyl, COOH, C(O)O(C C6)-alkyl, C(O)NRaRb, NRaRb or S(O)m(Ci-C6)-alkyl. DEFINITIONS
Unless otherwise indicated, the following definitions are set forth to illustrate and define the meaning and scope of the various terms used to describe the invention herein and the appended claims. These definitions should not be interpreted in the literal sense as they are not general definitions and are relevant only for this application.
It will be understood that "substitution", "substituted" or "substituted with" means that one or more hydrogens of the specified moiety are replaced with a suitable substituent and includes the implicit proviso that such substitution is in accordance with permitted valence of the substituted atom and the substituent, and results in a stable compound.
The terms "a", "an" and "the" refers to "one or more" when used in the subject specification, including the claims. Thus, for example, reference to "a compound" may include a plurality of such compounds, or reference to "a disease" or "a disorder" includes a plurality of diseases or disorders.
It should also be noted that the term "or" is generally employed in its sense including "and/or" unless the content clearly dictates otherwise.
The term "independently" when used in the context of selection of substituents for a variable, it means that where more than one substituent is selected from a number of possible substituents, those substituents may be the same or different.
Also, use of "(s)" as part of a term, includes reference to the term singly or in plurality, e.g. the term compound(s) may indicate a single compound or more compounds.
As used herein, the term "(Ci -C6)-alkyl" or "alkyl" whether used alone or as part of a substituent group, refers to the radical of saturated aliphatic groups, including straight or branched-chain alkyl groups. A straight-chain or branched chain alkyl has six or fewer carbon atoms in its backbone, for instance, C1 -C6 for straight chain and C3-C6 for branched chain. Examples of alkyl groups containing from one to six carbon atoms, include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, iso-butyl, sec-butyl, n-pentyl, isopentyl, 2-pentyl, 3-pentyl, neo-pentyl, n-hexyl, isohexyl, 2-hexyl and 3-hexyl.
Furthermore, unless stated otherwise, the alkyl groups may be unsubstituted or substituted with one or more substituents. A substituted alkyl refers to a (Ci -Ce)-alkyl substituted with one or more groups, preferably one to three groups, independently selected from the group consisting of halogen, hydroxy, nitro, cyano, (Ci -C6)-alkoxy- (Rc)o-3, (C3-Ci2)-cycloalkyl-(Rc)0-3, (C3-Ci2)-cycloalkyloxy-(Rc)0-3, halo(Ci-C6)-alkoxy, (C6-C14)-aryl-(Rc)o-3, (C6-C14)-aryloxy-(Rc)o-3, (C6-C14)-ar(C1 -C6)-alkyloxy-(Rc)o-3, heterocyclyl-(Rc)o-3, heteroaryl-(Rc)0-3, C(0)(Ci -C6)-alkyl, COOH, C(0)0(Ci-C6)-alkyl, OC(0)(Ci-C6)-alkyl, C(0)NRaRb, NRaRb and S(0)m(Ci-C6)-alkyl; wherein m is an integer from 0-2; Ra and Rb are independently selected from the group consisting of hydrogen, (C C6)-alkyl, amino^ -Ce^alkyl-, (C1 -C6)-alkoxy(C1-C6)-alkyl-, (C3-C12)- cycloalkyl, (C6-Ci4)-aryl, (C6-Ci4)-ar(Ci -C6)-alkyl-, heterocyclyl, heteroaryl, C(0)(Ci - Ce)-alkyl and S(0)m(Ci-C6)-alkyl; or Ra and Rb together with the N to which they are attached can form a 3-8 membered heterocyclyl ring, optionally containing 1 -3 additional heteroatoms independently selected from the group consisting of N, 0 and S, and the said heterocyclyl ring is unsubstituted or substituted with one or more groups as defined herein for the heterocyclyl group.
Examples of substituted alkyls include, but are not limited to hydroxymethyl, hydroxyethyl and aminoethyl.
The term "halogen" refers to a fluorine, chlorine, bromine or iodine atom.
When the alkyl group is substituted with one or more halogens, it is specifically referred to as "halo(Ci -C6)-alkyl" or "haloalkyl". A monohalo(Ci -C6)-alkyl radical, for example, may have one chlorine, bromine, iodine or fluorine atom. Dihalo and polyhalo(Ci-C6)-alkyl radicals may have two or more of the same or different halogen atoms. Examples of halo(Ci -C6)-alkyl include, but are not limited to, chloromethyl, dichloromethyl, trichloromethyl, dichloroethyl, dichloropropyl, fluoromethyl, difluoromethyl, trifluoromethyl, pentafluoroethyl, heptafluoropropyl, difluorochloromethyl, dichlorofluoromethyl, difluoroethyl and difluoropropyl.
As used herein, the term "(Ci -C6)-alkoxy" or "alkoxy" refers to a (Ci -Ce)-alkyl having an oxygen radical attached thereto. Representative alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, isobutoxy and t- butoxy.
As used herein, the term "halo(Ci-C6)-alkoxy" or "haloalkoxy" refers to radicals wherein one or more of the hydrogen atoms of the alkoxy group are substituted with one or more halogens. Representative examples of "haloalkoxy" or "halo(Ci -C6)- alkoxy" groups include, but are not limited to, difluoromethoxy (OCHF2), trifluoromethoxy (OCF3) and trifluoroethoxy (OCH2CF3).
As used herein, the term "(C3-Ci2)-cycloalkyl" or "cycloalkyl" whether used alone or as part of a substituent group, refers to a saturated or partially unsaturated cyclic hydrocarbon radical including 1 , 2 or 3 rings and including a total of 3 to 12 carbon atoms forming the rings. The term cycloalkyi includes bridged, fused and spiro ring systems. For example, (C3-Ci2)-cycloalkyl refers to a cycloalkyi group having 3 to 12 (both inclusive) carbon atoms. Examples of cycloalkyi include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, adamantyl, norbornyl, bicyclo[2.1 .0]pentane, bicyclo[2.2.1 ]heptyl, bicyclo[2.2.1 ]hept-2-ene, spiro[3.3]heptane and 1 ,2,3,3a-tetrahydropentalene. Unless stated otherwise, the "cycloalkyi" group may be unsubstituted or substituted with one or more groups, preferably one to three groups independently selected from the group consisting of halogen, hydroxy, nitro, cyano, (C1-C6)-alkyl-(Rc)o-3, (C1-C6)-alkoxy-(Rc)o-3, (C1-C6)-alkoxy(C1-C6)-alkyl-(Rc)o-3, (C3-Ci2)-cycloalkyl-(Rc)o-3, (C3-Ci2)-cycloalkyloxy-(Rc)o-3, halo(Ci-C6)-alkyl, halo(Ci-C6)- alkoxy, (C6-Ci4)-aryl-(Rc)o-3, (C6-Ci4)-aryloxy-(Rc)0-3, (C6-Ci4)-ar(Ci-C6)-alkyl-(Rc)o-3, (C6-Ci4)-ar(Ci-C6)-alkyloxy-(Rc)o-3, heterocyclyl-(Rc)0-3, heteroaryl-(Rc)0-3, C(0)(Ci-C6)- alkyl, COOH, C(0)0(C1-C6)-alkyl, C(0)NRaRb, NRaRb and S(0)m(C1-C6)-alkyl; wherein Ra, Rt>, Rc and m are as defined above.
The term, (C3-Ci2)-cycloalkyloxy or cycloalkyloxy refers to a (C3-Ci2)-cycloalkyl having an oxygen radical attached thereto. Representative cycloalkyloxy groups include, but are not limited to, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy and cyclohexyloxy.
Unless stated otherwise, the alkoxy and cycloalkyloxy may be unsubstituted or substituted with one or more groups independently selected from the group consisting of halogen, hydroxy, nitro, cyano, (Ci-C6)-alkyl-(Rc)o-3, (Ci-C6)-alkoxy-(Rc)o-3, (Ci-C6)- alkoxy(Ci-C6)-alkyl-(Rc)o-3, (C3-Ci2)-cycloalkyl-(Rc)0-3, (C3-Ci2)-cycloalkyloxy-(Rc)0-3, halo(Ci-C6)-alkyl, halo(Ci-C6)-alkoxy, (C6-Ci4)-aryl-(Rc)0-3, (C6-Ci4)-aryloxy-(Rc)0-3, (C6- Ci4)-ar(Ci-C6)-alkyl-(Rc)0-3, (C6-Ci4)-ar(Ci-C6)-alkyloxy-(Rc)o-3, heterocyclyl-(Rc)0-3, heteroaryl-(Rc)o-3, C(0)(Ci-C6)-alkyl, COOH, C(O)O(d-C6)-alkyl, C(O)NRaRb, NRaRb and S(O)m(Ci-C6)-alkyl; wherein Ra, R , Rc and m are as defined herein above.
Examples of substituted (Ci-Ce)-alkoxy include, but are not limited to, chloromethoxy, 2-cyanoethoxy, trifluoromethoxy and benzyloxy group. The term "(d- C6)-alkoxy-(Ci-C6)-alkyl" or "alkoxyalkyl" as used herein refers to a (Ci-Ce)-alkyl group, which is substituted with a (Ci-Ce)-alkoxy group.
The term "(C6-Ci4)-aryl" or "aryl" as used herein refers to monocyclic or bicyclic hydrocarbon groups having 6 to 14 ring carbon atoms, preferably 6 to 10 carbon atoms in which the carbocyclic ring(s) present have a conjugated pi electron system. Examples of (C6-C-i4)-aryl residues are phenyl, naphthyl, fluorenyl or anthracenyl. A preferred example of (C6-Ci4)-aryl residue is phenyl. Aryl groups can be unsubstituted or substituted with one or more groups, for example 1 , 2, 3, 4 or 5 groups independently selected from the group consisting of halogen, hydroxy, nitro, cyano, (Ci-C6)-alkyl-(Rc)0-3, (Ci -C6)-alkoxy-(Rc)o-3, (Ci -C6)-alkoxy(Ci -C6)-alkyl-(Rc)o-3, (C3-C12)- cycloalkyl-(Rc)o-3, (C3-Ci2)-cycloalkyloxy-(Rc)0-3, halo(Ci-C6)-alkyl, halo(Ci-C6)-alkoxy, (C6-Ci4)-aryl-(Rc)0-3, (C6-Ci4)-aryloxy-(Rc)0-3, (C6-Ci 4)-ar(Ci -C6)-alkyl-(Rc)o-3, (C6-Ci 4)- ar(Ci-C6)-alkyloxy-(Rc)o-3, heterocyclyl-(Rc)0-3, heteroaryl-(Rc)0-3, C(0)(Ci-C6)-alkyl, COOH, C(0)0(C C6)-alkyl, C(0)N RaRb, N RaRb and S(0)m(C C6)-alkyl; wherein Ra, Rb, Rc and m are as defined above. When aryl is phenyl then in the monosubstituted phenyl, the substituent can be located in the 2-position, the 3-position or the 4- position. If the phenyl carries two substituents, they can be located in 2, 3-position, 2, 4-position, 2, 5-position, 2, 6-position, 3, 4-position or 3, 5-position. Examples of monosubstituted phenyl groups include, but are not limited to, 3-trifluoromethylphenyl, 4-chlorophenyl and 4-cyanophenyl. Examples of disubstituted phenyl groups include, but are not limited to, 3, 5-difluorophenyl, and 3, 4-dimethoxyphenyl.
As used herein, the term "(C6-Ci4)-aryloxy" or "aryloxy" refers to an "(C6-C-i4)- aryl" group having an oxygen radical attached thereto. The aryl of aryloxy group may be unsubstituted or substituted with groups as described in the definition of substituted (C6-Ci4)-aryl herein above. Examples of aryloxy groups include, but are not limited to, phenoxy, 4-chlorophenoxy, and 3, 4-dimethoxyphenoxy.
As used herein, the term "(C6-Ci4)-ar(Ci-C6)-alkyl-" or "aralkyi-" refers to (Ci- Ce)-alkyl group substituted with an (C6-Ci4)-aryl group, wherein the terms alkyl and aryl are as defined above, and wherein the aralkyi group attaches through alkyl radical. Exemplary aralkyi groups include -(CH2)p-phenyl, wherein p is an integer from 1 to 6, such as benzyl (-CH2-phenyl). The aryl of the (C6-Ci4)-aralkyl group may be unsubstituted or substituted with groups as described in the definition of aryl herein above.
As used herein, the term "(C6-Ci4)-ar(Ci-C6)-alkyloxy" or "aralkyloxy" refers to an aralkyi group having an oxygen radical attached to the alkyl, and wherein the aralkyloxy group attaches through oxygen. The aryl of aralkyloxy group may be unsubstituted or substituted with groups as described in the definition of substituted aryl herein above. As used herein, the term "amino" refers to the group "NH2" which may be unsubstituted or substituted with one or more substituents. Examples of substituents include, but are not limited to, (Ci-Ce)-alkyl and aryl.
As used herein, the term "amino(C-i-C6)-alkyl-" or "aminoalkyl-" refers to an amino substituted alkyl radical. This term is meant to include (Ci-Ce)-alkyl groups having an amino substituent at any position and wherein the aminoalkyl group attaches through alkyl radical. The alkyl and/or amino portions of the amino(Ci-C6)- alkyl group may be substituted or unsubstituted. Examples of aminoalkyl groups include, but are not limited to, -CH2-CH2-NH2, -CH2-CH2-NH(CH3) and -CH2-CH2- N(CH3)2.
As used herein, the term "(Ci-C6)-alkylamino-" or "alkylamino-" refers to an alkyl substituted amino group. This term is meant to include an amino group having a (Ci- C6)-alkyl substituent and wherein the alkylamino group attaches through amino radical. The alkyl and/or amino portions of the (Ci-C6)-alkylamino- group may be substituted or unsubstituted. Examples of alkylamino groups include, but are not limited to -NH-CH2- CH3 and -N(CH3)-CH2-CH3.
The term "heteroatom" as used herein, includes nitrogen (N), oxygen (0) and sulfur (S). Any heteroatom with unsatisfied valency is assumed to have a hydrogen atom to satisfy the valency.
As used herein, the term "heterocyclyl" or "heterocyclic" whether used alone or as part of a substituent group, refers to a 3- to 12-membered saturated or partially unsaturated monocyclic or bicyclic ring system containing one to four heteroatoms independently selected from the group consisting of nitrogen (N), a sulphur (S) and an oxygen (O) atom. Heterocyclyl includes saturated heterocyclic ring systems, which do not contain any double bond. Partially unsaturated heterocyclic ring systems containing at least one double bond, but do not form an aromatic system containing heteroatom. Suitable saturated and partially unsaturated heterocyclic groups include, but are not limited to, aziridine, oxirane, oxiridine, thiirane, oxetane, azetidine, thietane, tetrahydrofuran, tetrahydrothiophene, pyrrolidine, dihydropyran, tetrahydropyran, thio- dihydropyran, thio-tetrahydropyran, piperidine, piperazine, morpholine, 1 ,3-oxazinane, 1 ,3-thiazinane, 4,5,6-tetrahydropyrimidine, 2,3-dihydrofuran, dihydrothiene, dihydropyridine, tetrahydropyridine, isoxazolidine, pyrazolidine, azepane, oxepane, thiepane and azocane. Heterocyclyl having an aromatic ring containing heteroatom(s) are herein referred to by the customary term "heteroaryl". Within the context of the present invention and as used herein, the term "heteroaryl" refers to a 5- to 10-membered aromatic monocyclic or bicyclic ring system containing one to four heteroatoms independently selected from the group consisting of N, S and 0. Examples of heteroaryl include, but are not limited to, pyrrole, pyrazole, imidazole, triazole, pyrazine, furan, thiophene, oxazole, thiazole, benzimidazole, benzoxazole, benzothiazole, benzofuran, indole, indazole, isoindole, isoquinoline, isooxazole, triazine, purine, pyridine, quinoline, oxadiazole, thiene, pyridazine, pyrimidine, isothiazole, quinoxaline (benzopyrine), tetrazole, azepine, oxepine, thiepine and azocine. The oxidized form of the ring nitrogen atom of the heteroaryl to provide N- oxide is also encompassed.
Unless stated otherwise, heterocyclyl and heteroaryl group may be unsubstituted or substituted. A substituted heterocyclyl or heteroaryl refers to a heterocyclyl or heteroaryl substituted with one to three groups independently selected from the group consisting of halogen, hydroxy, nitro, cyano, (Ci-C6)-alkyl-(Rc)o-3, (C-i- C6)-alkoxy-(Rc)o-3, (Ci-C6)-alkoxy(Ci-C6)-alkyl-(Rc)o-3, (C3-Ci2)-cycloalkyl-(Rc)o-3, (C3- Ci2)-cycloalkyloxy-(Rc)o-3, halo(C C6)-alkyl, halo(C C6)-alkoxy, (C6-Ci4)-aryl-(Rc)o-3, (C6-Ci4)-aryloxy-(Rc)o-3, (C6-Ci4)-ar(Ci-C6)-alkyl-(Rc)o-3, (C6-Ci4)-ar(Ci-C6)-alkyloxy- (Rc)o-3, heterocyclyl-(Rc)o-3, heteroaryl-(Rc)o-3, C(0)(d-C6)-alkyl, COOH, C(0)0(Ci-C6)- alkyl, C(0)NRaRb, NRaRb and S(0)m(Ci-C6)-alkyl; wherein Ra, Rb, Rc and m are as defined above. The substituents may be present on either the ring carbon or the ring nitrogen atom(s). The substituents can be present at one or more positions provided that a stable molecule results.
The term "pharmaceutically acceptable solvate" or "solvates" as used herein refers to an aggregate of a molecule (in the present invention, a compound of formula (I) or a pharmaceutically acceptable salt thereof) with one or more solvent molecules. Such solvents for the purpose of the invention may not interfere with the biological activity of the molecule. Preferably, the solvent used is a pharmaceutically acceptable solvent. Examples of suitable pharmaceutically acceptable solvents include, without limitation, water, ethanol and acetic acid. Most preferably, the solvent used is water and the solvates obtained are referred to as hydrates. Examples for suitable solvates are the mono- or di-hydrates or alcoholates of the compounds according to the invention.
Within the context of the present invention and as used herein, the term "stereoisomer" or "stereoisomeric form" is a general term used for all isomers of individual compounds (in the present invention, a compound of formula (I) or a pharmaceutically acceptable salt thereof) that differ only in the orientation of their atoms in space. The term stereoisomer includes mirror image isomers (enantiomers), mixtures of mirror image isomers (racemates, racemic mixtures), geometric (cis/trans or E/Z) isomers, and isomers of compounds with more than one chiral center that are not mirror images of one another (diastereoisomers).
The term "tautomer" or "tautomeric form" refers to the coexistence of two (or more) compounds that differ from each other only in the position of one (or more) mobile atoms and in electron distribution, for example, keto-enol tautomers.
As used herein, the term "pharmaceutically acceptable" means that the carrier, diluent, excipients, and/or salt must be compatible with the other ingredients of the formulation (composition), and not deleterious to the recipient thereof.
The term "pharmaceutically acceptable salts" or "salt(s)" as used herein includes salts of the active compound i.e. the compound of formula (I), which retain the desired biological activity of the subject compound and exhibit minimal undesired toxicological effects; and are prepared with suitable acids or bases, depending on the particular substituents found on the compounds described herein.
Within the context of the present invention and as used herein the term "polymorph" or "pharmaceutically acceptable polymorph(s)" or "polymorphic form" refers to crystals of the same compound that differs only in the arrangement and/or conformation of the molecule (in the present invention, a compound of formula (I) or a pharmaceutically acceptable salt thereof) in the crystal lattice.
Within the context of the present invention and as used herein, "N-oxide" refers to the oxide of the nitrogen atom of a nitrogen-containing heteroaryl or heterocycle. N- oxide can be formed in the presence of an oxidizing agent such as m-chloro- perbenzoic acid or hydrogen peroxide. N-oxide refers to an amine oxide, also known as amine-N-oxide, and is a chemical compound that contains N- 0 bond.
Within the context of the present invention and as used herein "S-oxide" refers to the oxide of the sulfur atom (S-oxide) or dioxide of the sulfur atom (S,S-dioxide) of a sulfur-containing heteroaryl or heterocycle. S-oxide and S,S-dioxides can be formed in the presence of an oxidizing agent such as m-chloro-perbenzoic acid or oxone (potassium peroxymonosulfate).
Within the context of the present invention and as used herein, the term "a prodrug" or "pharmaceutically acceptable prodrug(s)" refers to any compound (in the present invention, a compound of formula (I) or a pharmaceutically acceptable salt thereof), which are derivatives of the said compound. Preferably prodrugs are those compounds that are converted intracellular^, more preferably, where the cellular converting location is the site of therapeutic action. For instance, preferred prodrugs are pharmaceutically acceptable ester derivatives convertible by solvolysis under physiological conditions to the parent carboxylic acid. Examples of pharmaceutically acceptable esters include lower alkyl esters, cycloalkyl esters, lower alkenyl esters, benzyl esters, mono- or di-substituted lower alkyl esters such as the pivaloyloxymethyl ester and the like conventionally used in the art.
In the context of the present invention, the term "compound(s) of formula (I)" or
"compounds of the present invention" are used interchangeably and includes all the stereoisomeric and tautomeric forms and mixtures thereof in all ratios, and pharmaceutically acceptable salts, pharmaceutically acceptable solvates, pharmaceutically acceptable prodrugs, N-oxides, S-oxides and pharmaceutically acceptable polymorphs thereof. The compound(s) of formula (I) can also be referred to herein as "the active compound" or "the active ingredient".
The term 'bromodomain inhibitors' is used interchangeably with the term 'inhibitors of bromodomain containing proteins' and said term refer to a class of compounds, which inhibit the binding of one or more bromodomains with its cognate acetylated proteins, more particularly a class of compounds that inhibit the binding of one or more BET family bromodomains to acetylated lysine residues. The bromodomain containing proteins that can be inhibited by the compounds and compositions of the present invention described herein include BET proteins such as BRD2, BRD3, BRD4 and BRDT, or an isoform or mutant thereof.
As used herein, the term 'diseases or disorders mediated by bromodomain containing proteins' means any disease or disorder in which one or more of the bromodomain-containing proteins, such as BET proteins, such as BRD2, BRD3, BRD4 and/ or BRDT, or a mutant thereof, are known to play a role, for example a disease or disorder characterised by abnormal binding of one or more of the bromodomain containing proteins such as BET proteins or mutants thereof, with its cognate acetylated proteins, more particularly by abnormal binding of one or more BET family bromodomains to acetylated lysine residues. A few examples of the diseases or disorders mediated by bromodomain containing proteins include, but are not limited to, cancer, chronic autoimmune diseases, inflammatory disorders, cardiovascular diseases, metabolic disorders, disorders associated with fibrosis and viral infections.
The term, "therapeutically effective amount" as used herein means an amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof or a composition comprising the compound of formula (I), effective in producing the desired therapeutic response in a particular patient suffering from a disease or disorder mediated by bromodomain containing proteins. Particularly, the term "therapeutically effective amount" includes the amount of a compound, when administered, that induces a positive modification in the disease or disorder to be treated or is sufficient to prevent development of, or alleviate to some extent, one or more of the symptoms of the disease or disorder being treated in a subject. In respect of the therapeutic amount of the compound, consideration is also given that the amount of the compound used for the treatment of a subject is low enough to avoid undue or severe side effects, within the scope of sound medical judgment. The therapeutically effective amount of the compound or composition will vary with the particular condition being treated, the age and physical condition of the end user, the severity of the condition being treated or prevented, the duration of the treatment, the nature of concurrent therapy, the specific compound or composition employed, the particular pharmaceutically acceptable carrier utilized and other factors.
As used herein, the term "pharmaceutically acceptable carrier(s)" refers to a material that is non-toxic, inert, solid, semi-solid or liquid filler, diluent, encapsulating material or formulation auxiliary of any type which is compatible with a subject, preferably a mammal, more preferably a human, and is suitable for delivering an active agent to the target site without terminating the activity of the agent.
The term "subject" as used herein refers to an animal, preferably a mammal, and most preferably a human. The term "mammal" used herein refers to warm-blooded vertebrate animals of the class 'mammalia', including humans, characterized by a covering of hair on the skin and, in the female, milk-producing mammary glands for nourishing the young. The term mammal includes animals such as cat, dog, rabbit, bear, fox, wolf, monkey, deer, mouse, pig and human. The term "subject" may be used interchangeably with the term patient. In the context of the present invention the phrase "a subject in need thereof" means a subject in need of the treatment for the disease or disorder that is mediated by bromodomain containing proteins. Alternatively, the phrase "a subject in need thereof" means a subject (patient) diagnosed having a disease or disorder that is mediated by bromodomain containing proteins.
As used herein, the terms "treatment", "treat" and "therapy" refer to alleviate, slow the progression, attenuation or cure of existing diseases or condition (e.g. cancer). Treatment also includes treating, preventing development of, or alleviating to some extent, one or more of the symptoms of the diseases or condition.
EMBODIMENTS
In one embodiment, the present invention relates to a compound of formula (I), wherein W is NRa; and Ra is as defined in the first aspect; or an isotopic form, a stereoisomer, a tautomer, a pharmaceutically acceptable salt, a solvate, a prodrug, a polymorph, N-oxide or S-oxide thereof.
In another embodiment, the present invention relates to a compound of formula (I), wherein W is 0; or an isotopic form, a stereoisomer, a tautomer, a pharmaceutically acceptable salt, a solvate, a prodrug, a polymorph, N-oxide or S- oxide thereof.
In another embodiment, the present invention relates to a compound of formula (I), wherein n is 0; or an isotopic form, a stereoisomer, a tautomer, a pharmaceutically acceptable salt, a solvate, a prodrug, a polymorph, N-oxide or S-oxide thereof.
In another embodiment, the present invention relates to a compound of formula (I), wherein n is 1 ; or an isotopic form, a stereoisomer, a tautomer, a pharmaceutically acceptable salt, a solvate, a prodrug, a polymorph, N-oxide or S-oxide thereof.
In another embodiment, the present invention relates to a compound of formula (I), wherein n is 2; or an isotopic form, a stereoisomer, a tautomer, a pharmaceutically acceptable salt, a solvate, a prodrug, a polymorph, N-oxide or S-oxide thereof.
In another embodiment, the present invention relates to a compound of formula (I), wherein R7 is cyano, W is NRa; and Ra is as defined in the first aspect; or an isotopic form, a stereoisomer, a tautomer, a pharmaceutically acceptable salt, a solvate, a prodrug, a polymorph, N-oxide or S-oxide thereof.
In another embodiment, the present invention relates to a compound of formula (I), wherein R7 is cyano, W is 0; or an isotopic form, a stereoisomer, a tautomer, a pharmaceutically acceptable salt, a solvate, a prodrug, a polymorph, N-oxide or S- oxide thereof.
In another embodiment, the present invention relates to a compound of formula (I), wherein W is 0; R2 and R3 are independently selected from the group consisting of (CrC6)-alkyl, halo(CrC6)-alkyl and (CrC6)-alkoxy; or an isotopic form, a stereoisomer, a tautomer, a pharmaceutically acceptable salt, a solvate, a prodrug, a polymorph, N-oxide or S-oxide thereof.
In one embodiment, the present invention relates to a compound of formula (I), wherein Y is (C6-Ci4)-aryl, heterocyclyl or heteroaryl; or an isotopic form, a stereoisomer, a tautomer, a pharmaceutically acceptable salt, a solvate, a prodrug, a polymorph, N-oxide or S-oxide thereof.
In one embodiment, the present invention relates to a compound of formula (I); wherein :
W is NRa or 0;
Ri and R4 are independently selected from the group consisting of hydrogen, halogen, (Ci-C6)-alkyl, halo(Ci -C6)-alkyl, (Ci -C6)-alkoxy and (C3-Ci2)-cycloalkyl;
R2, R3 and R5 are independently selected from the group consisting of hydrogen, halogen, (Ci -C6)-alkyl, halo(Ci -C6)-alkyl and (Ci -Ce)-alkoxy;
R6 is hydrogen, (Ci-C6)-alkyl, (C3-Ci2)-cycloalkyl, alkyl, C(0)(Ci -C6)-alkyl or S(0)m(Ci- C6)-alkyl;
R7 is hydrogen, (Ci -C6)-alkyl, cyano, nitro or NRaRbi
m is an integer from 0-2;
n is an integer from 0-3;
Ra is hydrogen, (Ci -C6)-alkyl, amino(Ci -C6)-alkyl- (Ci -C6)-alkoxy(Ci-C6)-alkyl, (C3- Ci2)-cycloalkyl, (C6-C-i4)-aryl, (C6-Ci4)-ar(Ci-C6)-alkyl-, heterocyclyl, heteroaryl, C(0)(Ci -C6)-alkyl or S(0)m(d-C6)-alkyl; and
Y is (C6-C-i4)-ar(Ci-C6)-alkyl- (C6-Ci4)-aryl, heterocyclyl or heteroaryl; or
an isotopic form, a stereoisomer, a tautomer, a pharmaceutically acceptable salt, a solvate, a prodrug, a polymorph, N-oxide or S-oxide thereof. In one embodiment, the present invention relates to a compound of formula (I); Wherein:
W is NRa or 0;
R-i and R4 are independently selected from the group consisting of hydrogen, halogen, (Ci-C6)-alkyl, halo(Ci-C6)-alkyl, (Ci-C6)-alkoxy and (C3-Ci2)-cycloalkyl;
R2, R3 and R5 are independently selected from the group consisting of hydrogen, halogen, (Ci-C6)-alkyl, halo(Ci-C6)-alkyl and (Ci-Ce)-alkoxy;
R6 is hydrogen, (Ci-C6)-alkyl, (C3-Ci2)-cycloalkyl, alkyl, C(0)(Ci-C6)-alkyl or S(0)m(Ci- C6)-alkyl;
R7 is hydrogen, (Ci-C6)-alkyl, cyano, nitro or NRaRb;
m is an integer from 0-2;
n is an integer from 0-3;
Ra is hydrogen, (Ci-C6)-alkyl, amino(Ci-C6)-alkyl- (Ci-C6)-alkoxy(Ci-C6)-alkyl, (C3- Ci2)-cycloalkyl, (C6-C-i4)-aryl, (C6-Ci4)-ar(Ci-C6)-alkyl-, heterocyclyl, heteroaryl, C(0)(Ci-C6)-alkyl or S(0)m(Ci-C6)-alkyl; and
Y is (C6-Ci4)-aryl, heterocyclyl or heteroaryl;
or an isotopic form, a stereoisomer, a tautomer, a pharmaceutically acceptable salt, a solvate, a prodrug, a polymorph, N-oxide or S-oxide thereof.
In another embodiment, the present invention relates to a compound of formula (I), wherein
W is NRa or O;
Ri and R4 are independently selected from the group consisting of hydrogen, halogen, (Ci-C6)-alkyl, halo(Ci-C6)-alkyl, (Ci-C6)-alkoxy and (C3-Ci2)-cycloalkyl;
R2, R3 and R5 are independently selected from the group consisting of hydrogen, halogen, (Ci-C6)-alkyl, halo(Ci-C6)-alkyl and (Ci-C6)-alkoxy;
R6 is hydrogen, (Ci-C6)-alkyl, (C3-Ci2)-cycloalkyl, alkyl, C(0)(Ci-C6)-alkyl or S(0)m(Ci-
C6)-alkyl;
R7 is cyano;
m is an integer from 0-2;
n is an integer from 0-3;
Ra is hydrogen, (Ci-C6)-alkyl, amino(C-i-C6)-alkyl- (Ci-C6)-alkoxy(Ci-C6)-alkyl, (C3- Ci2)-cycloalkyl, (C6-Ci4)-aryl, (C6-Ci4)-ar(Ci-C6)-alkyl-, heterocyclyl, heteroaryl, C(0)(C1-C6)-alkyl or S(0)m(C1-C6)-alkyl; and Y is (C6-C-i4)-ar(Ci-C6)-alkyl- (C6-C-i4)-aryl, heterocyclyl or heteroaryl; or an isotopic form, a stereoisomer, a tautomer, a pharmaceutically acceptable salt, a solvate, a prodrug, a polymorph, N-oxide or S-oxide thereof.
In another embodiment, the present invention relates to a compound of formula (I), wherein
W is 0;
Ri and R4 are independently selected from the group consisting of hydrogen, halogen, (Ci-C6)-alkyl, halo(Ci-C6)-alkyl, (Ci-C6)-alkoxy and (C3-Ci2)-cycloalkyl;
R2, R3 and R5 are independently selected from the group consisting of hydrogen, halogen, (Ci-C6)-alkyl, halo(Ci-C6)-alkyl and (Ci-C6)-alkoxy;
R6 is hydrogen, (Ci-Ce)-alkyl or (C3-Ci2)-cycloalkyl;
R7 is cyano;
n is an integer from 0-3; and
Y is (C6-C-i4)-ar(Ci-C6)-alkyl- (C6-Ci4)-aryl, heterocyclyl or heteroaryl;
or an isotopic form, a stereoisomer, a tautomer, a pharmaceutically acceptable salt, a solvate, a prodrug, a polymorph, N-oxide or S-oxide thereof.
In another embodiment, the present invention relates to a compound of formula (I), wherein
W is NRa;
Ri and R4 are independently selected from the group consisting of hydrogen, halogen,
(Ci-C6)-alkyl, halo(Ci-C6)-alkyl, (Ci-C6)-alkoxy and (C3-Ci2)-cycloalkyl;
R2, R3 and R5 are independently selected from hydrogen and (Ci-Ce)-alkyl;
R6 is hydrogen, (Ci-Ce)-alkyl or (C3-Ci2)-cycloalkyl;
R7 is cyano;
n is an integer from 0-3;
Ra is hydrogen or (Ci-C6)-alkyl, and
Y is (C6-C-i4)-ar(Ci-C6)-alkyl- (C6-Ci4)-aryl, heterocyclyl or heteroaryl;
or an isotopic form, a stereoisomer, a tautomer, a pharmaceutically acceptable salt, a solvate, a prodrug, a polymorph, N-oxide or S-oxide thereof.
In another embodiment, the present invention relates to a compound of formula
(I), wherein
W is O; Ri and R4 are independently selected from the group consisting of hydrogen, halogen, (Ci-C6)-alkyl, halo(Ci-C6)-alkyl, (Ci-C6)-alkoxy and (C3-Ci2)-cycloalkyl;
R2, R3 and R5 are independently selected from hydrogen and (Ci-Ce)-alkyl;
R6 is hydrogen, (Ci-C6)-alkyl or (C3-Ci2)-cycloalkyl;
R7 is cyano;
n is an integer from 0-3; and
Y is (C6-C-i4)-ar(Ci-C6)-alkyl- (C6-Ci4)-aryl, heterocyclyl or heteroaryl; or an isotopic form, a stereoisomer, a tautomer, a pharmaceutically acceptable salt, a solvate, a prodrug, a polymorph, N-oxide or S-oxide thereof.
In another embodiment, the present invention relates to a compound of formula
(I), wherein
W is NH or O;
Ri is hydrogen, (C C6)-alkyl, (C1-C6)-alkoxy, NRaRb, C(0)(C C6)-alkyl, C(0)NRaRb, C(0)OH or C(0)0(Ci-C6)-alkyl;
R2 and R3 are independently selected from hydrogen and (Ci-Ce)-alkyl;
R4 is hydrogen;
R5 is hydrogen or (Ci-Ce)-alkyl;
R6 is hydrogen or (CrC6)-alkyl;
R7 is cyano;
n is an integer from 0-3;
Y is (C6-C-i4)-ar(Ci-C6)-alkyl- (C6-Ci4)-aryl, heterocyclyl or heteroaryl;
or an isotopic form, a stereoisomer, a tautomer, a pharmaceutically acceptable salt, a solvate, a prodrug, a polymorph, N-oxide or S-oxide thereof.
In another embodiment, the present invention relates to a compound of formula (I), wherein
W is O;
Ri is hydrogen, (Ci-C6)-alkyl, (Ci-C6)-alkoxy, NRaRb, C(0)(Ci-C6)-alkyl, C(0)NRaRb, C(0)OH or C(0)0(C1-C6)-alkyl;
R2 and R3 are independently selected from hydrogen and (Ci-Ce)-alkyl;
R4 is hydrogen;
R5 is hydrogen or (Ci-Ce)-alkyl;
R6 is hydrogen or (Ci-Ce)-alkyl;
R7 is cyano; n is an integer from 0-3;
Y is (C6-C-i4)-ar(Ci-C6)-alkyl- (C6-Ci4)-aryl, heterocyclyl or heteroaryl;
or an isotopic form, a stereoisomer, a tautomer, a pharmaceutically acceptable salt, a solvate, a prodrug, a polymorph, N-oxide or S-oxide thereof.
In another embodiment, the present invention relates to the compounds of formula (I), wherein
W is NH or O;
Ri is (Ci -Ce)-alkoxy;
R2 and R3 are (Ci -C6)-alkyl;
R4 is hydrogen;
R5 is (Ci -C6)-alkyl;
R6 is hydrogen;
R7 is cyano;
n is 1 or 2;
Y is (C6-Ci4)-aryl, heterocyclyl or heteroaryl;
or an isotopic form, a stereoisomer, a tautomer, a pharmaceutically acceptable salt, a solvate, a prodrug, a polymorph, N-oxide or S-oxide thereof.
In another embodiment, the present invention relates to the compounds of formula (I), wherein
W is O;
Ri is (Ci -Ce)-alkoxy;
R2 and R3 are (Ci -C6)-alkyl;
R4 is hydrogen;
R5 is (C1 -C6)-alkyl;
R6 is hydrogen;
R7 is cyano;
n is 1 ;
Y is (C6-C14)-aryl;
or an isotopic form, a stereoisomer, a tautomer, a pharmaceutically acceptable salt, a solvate, a prodrug, a polymorph, N-oxide or S-oxide thereof.
It is to be understood that all the embodiments of the compound of formula (I) encompasses within their scope the said compounds in their isotopic form, stereoisomer, tautomer, pharmaceutically acceptable salt, solvate, polymorph, prodrug, N-oxide or S-oxide thereof.
Representative compounds of the present invention include:
(E)-N-(7-(3,5-Dimethylisoxazol-4-yl)-8-methoxy-1 -((R)-1 -(pyridin-2-yl)ethyl)-1 H- imidazo[4,5-c]quinolin-2(3H)-ylidene)cyanamide;
(E)-N-(7-(3,5-Dimethylisoxazol-4-yl)-8-methoxy-3-methyl-1 -((R)-1 -(pyridin-2-yl)ethyl)- 1 H-imidazo[4,5-c]quinolin-2(3H)-ylidene)cyanamide;
(E)-N-(7-(3,5-dimethylisoxazol-4-yl)-8-methoxy-1 H-imidazo[4,5-c]quinolin-2(3H)- ylidene)cyanamide;
(E)-N-(1 -Benzyl-7-(3,5-dimethylisoxazol-4-yl)-8-methoxy-1 H-imidazo[4,5-c]quinolin- 2(3H)-ylidene)cyanamide;
(E)-N-(7-(3,5-Dimethylisoxazol-4-yl)-8-methoxy-1 -((tetrahydrofuran-2-yl)methyl)-1 H- imidazo[4,5-c]quinolin-2(3H)-ylidene)cyanamide;
(E)-N-(7-(3,5-Dimethylisoxazol-4-yl)-8-methoxy-1 -phenethyl-1 H-imidazo[4,5-c]quinolin- 2(3H)-ylidene)cyanamide;
(E)-N-(7-(3,5-Dimethylisoxazol-4-yl)-8-methoxy-3-methyl-1 -phenethyl-1 H-imidazo[4,5- c]quinolin-2(3H)-ylidene)cyanamide;
(E)-N-(7-(3,5-Dimethylisoxazol-4-yl)-8-methoxy-1 -(((S)-tetrahydrofuran-2-yl)methyl)- 1 H-imidazo[4,5-c]quinolin-2(3H)-ylidene)cyanamide;
(E)-N-(7-(3,5-Dimethylisoxazol-4-yl)-8-methoxy-3-methyl-1 -(((S)-tetrahydrofuran-2- yl)methyl)-1 H-imidazo[4,5-c]quinolin-2(3H)-ylidene)cyanamide;
(E)-N-(7-(3,5-Dimethylisoxazol-4-yl)-8-methoxy-1 -(((R)-tetrahydrofuran-2-yl)methyl)- 1 H-imidazo[4,5-c]quinolin-2(3H)-ylidene)cyanamide;
(E)-N-(7-(3,5-dimethylisoxazol-4-yl)-8-methoxy-1 -(((R)-tetrahydrofuran-2-yl)methyl)- 1 H-imidazo[4,5-c]quinolin-2(3H)-ylidene)cyanamide;
(E)-N-(7-(3,5-Dimethylisoxazol-4-yl)-8-methoxy-1 -((S)-1 -phenylethyl)-1 H-imidazo[4,5- c]quinolin-2(3H)-ylidene)cyanamide;
(E)-N-(7-(3,5-Dimethylisoxazol-4-yl)-8-methoxy-1 -(2-(pyridin-2-yl)ethyl)-1 H- imidazo[4,5-c]quinolin-2(3H)-ylidene)cyanamide;
(E)-N-(7-(3,5-Dimethylisoxazol-4-yl)-8-methoxy-3-methyl-1 -(2-(pyridin-2-yl)ethyl)-1 H- imidazo[4,5-c]quinolin-2(3H)-ylidene)cyanamide;
(E)-N-(7-(3,5-Dimethylisoxazol-4-yl)-1 -(3,5-dimethylphenyl)-8-methoxy-1 H- imidazo[4,5-c]quinolin-2(3H)-ylidene)cyanamide; (E)-N-(7-(3,5-Dimethylisoxazol-4-yl)-1 -(3,5-dimethylphenyl)-8-methoxy-3-methyl-1 H imidazo[4,5-c]quinolin-2(3H)-ylidene)cyanamide;
(E)-N-(7-(3,5-Dimethylisoxazol-4-yl)-8-methoxy-1 -phenyl-1 H-imidazo[4,5-c]quinolin 2(3H)-ylidene)cyanamide;
(E)-N-(7-(3,5-Dimethylisoxazol-4-yl)-8-methoxy-3-methyl-1 -phenyl-1 H-imidazo [4,5- c]quinolin-2(3H)-ylidene)cyanamide;
(E)-N-(7-(3,5-Dimethylisoxazol-4-yl)-8-methoxy-1 -(o-tolyl)-1 H-imidazo[4,5-c]quinoli 2(3H)-ylidene)cyanamide;
(E)-N-(7-(3,5-Dimethylisoxazol-4-yl)-1 -(2-fluorophenyl)-8-methoxy-1 H-imidazo[4,5- c]quinolin-2(3H)-ylidene)cyanamide;
(E)-N-(7-(3,5-Dimethylisoxazol-4-yl)-8-methoxy-1 -(p-tolyl)-1 H-imidazo[4,5-c]quinolin 2(3H)-ylidene)cyanamide;
(Z)-N-(7-(3,5-Dimethylisoxazol-4-yl)-8-methoxy-1 -(m-tolyl)-1 H-imidazo[4,5-c]quinolin- 2(3H)-ylidene)cyanamide;
(E)-N-(7-(3,5-Dimethylisoxazol-4-yl)-8-methoxy-3-methyl-1 -(p-tolyl)-l H-imidazo[4,5- c]quinolin-2(3H)-ylidene)cyanamide;
(E)-N-(1 -(2-(tert-Butyl)phenyl)-7-(3,5-dimethylisoxazol-4-yl)-8-methoxy-1 H-imidazo[4 c]quinolin-2(3H)-ylidene)cyanamide;
(E)-N-(1 -(2-(tert-Butyl)phenyl)-7-(3,5-dimethylisoxazol-4-yl)-8-methoxy-3-methyl-1 H imidazo[4,5-c]quinolin-2(3H)-ylidene)cyanamide;
7-(3,5-Dimethylisoxazol-4-yl)-8-methoxy-1 -(2-phenylpropan-2-yl)-1 H-imidazo[4,5- c]quinolin-2(3H)-ylidene)cyanamide;
7-(3,5-Dimethylisoxazol-4-yl)-8-methoxy-1 -(tetrahydro-2H-pyran-4-yl)-1 H-imidazo[4,5- c]quinolin-2(3H)-ylidene)cyanamide;
(E)-N-(7-(3,5-Dimethylisoxazol-4-yl)-1 -(3-(1 , 1 , 1 ,3,3,3-hexafluoro-2-hydroxypropan-2- yl)phenyl)-8-methoxy-1 H-imidazo[4,5-c]quinolin-2(3H)-ylidene) cyanamide;
(E)-N-(7-(3,5-Dimethylisoxazol-4-yl)-1 -(3-(1 , 1 , 1 ,3,3,3-hexafluoro-2-methoxy propan-2 - yl)phenyl)-8-methoxy-3-methyl-1 H-imidazo[4,5-c]quinolin-2(3H)-ylidene)cyanamide;
(E)-N-(7-(3,5-Dimethylisoxazol-4-yl)-1 -(3-(1 , 1 , 1 ,3,3,3-hexafluoro-2-methoxypropan-2- yl)phenyl)-8-methoxy-1 H-imidazo[4,5-c]quinolin-2(3H)-ylidene)cyanamide;
(E)-N-(7-(3,5-Dimethylisoxazol-4-yl)-1 -(4-(1 , 1 , 1 ,3,3,3-hexafluoro-2-hydroxy propan-2- yl)benzyl)-8-methoxy-1 H-imidazo[4,5-c]quinolin-2(3H)-ylidene) cyanamide; (E)-N-(7-(3,5-Dimethylisoxazol-4-yl)-1 -(4-(1 , 1 , 1 ,3,3,3-hexafluoro-2-methoxy propan-2- yl)benzyl)-8-methoxy-3-methyl-1 H-imidazo[4,5-c]quinolin-2(3H)-ylidene)cyanamide; (E)-N-(7-(3,5-Dimethylisoxazol-4-yl)-8-methoxy-1 -(4-methoxybenzyl)-1 H-imidazo[4,5- c]quinolin-2(3H)-ylidene)cyanamide;
(E)-N-(1 -(4-Chlorobenzyl)-7-(3,5-dimethylisoxazol-4-yl)-8-methoxy-1 H-imidazo [4,5- c]quinolin-2(3H)-ylidene)cyanamide;
(E)-N-(1 -(4-Chlorobenzyl)-7-(3,5-dimethylisoxazol-4-yl)-8-methoxy-3-methyl-1 H- imidazo[4,5-c]quinolin-2(3H)-ylidene)cyanamide;
2-(4-((E)-2-(Cyanoimino)-8-methoxy-1 -((R)-1 -phenylethyl)-2,3-dihydro-1 H-imidazo[4,5- c]quinolin-7-yl)-3-methylisoxazol-5-yl)ethyl acetate;
(E)-N-(7-(3,5-Dimethyl-1 H-pyrazol-4-yl)-8-methoxy-1 -((R)-1 -phenylethyl)-1 H- imidazo[4,5-c]quinolin-2(3H)-ylidene)cyanamide;
(E)-N-(7-(3,5-Dimethylisoxazol-4-yl)-8-methyl-1 -((R)-1 -phenylethyl)-1 H-imidazo[4,5- c]quinolin-2(3H)-ylidene)cyanamide;
(E)-N-(7-(3,5-Dimethylisoxazol-4-yl)-3,8-dimethyl-1 -((R)-1 -phenylethyl)-1 H- imidazo[4,5-c]quinolin-2(3H)-ylidene)cyanamide;
(E)-N-(7-(3,5-Ddimethyl-1 H-pyrazol-4-yl)-8-methyl-1 -((R)-1 -phenylethyl)-1 H- imidazo[4,5-c]quinolin-2(3H)-ylidene)cyanamide;
Ethyl 2-(4-((E)-2-(cyanoimino)-8-methyl-1 -((R)-1 -phenylethyl)-2,3-dihydro-1 H- imidazo[4,5-c]quinolin-7-yl)-3-methylisoxazol-5-yl)acetate;
(E)-N-(7-(5-(2-Hydroxyethyl)-3-methylisoxazol-4-yl)-8-methyl-1 -((R)-1 -phenylethyl)-1 H- imidazo[4,5-c]quinolin-2(3H)-ylidene)cyanamide;
(R, E)-N-(7-(3,5-Dimethylisoxazol-4-yl)-1 -(1 -phenylethyl)-1 H-imidazo[4,5-c] quinolin- 2(3H)-ylidene)cyanamide;
(E)-Ethyl 2-(cyanoimino)-7-(3,5-dimethylisoxazol-4-yl)-1 -((R)-1 -phenyl ethyl)- 2,3- dihydro-1 H-imidazo[4,5-c]quinoline-8-carboxylate;
(E)-2-(Cyanoimino)-7-(3,5-dimethylisoxazol-4-yl)-1 -((R)-1 -phenylethyl)-2,3-dihydro-1 H- imidazo[4,5-c]quinoline-8-carboxylic acid;
(E)-2-(cyanoimino)-7-(3,5-dimethylisoxazol-4-yl)-N-ethyl-1 -((R)-1 -phenyl ethyl)-2,3- dihydro-1 H-imidazo[4,5-c]quinoline-8-carboxamide;
(E)-2-(Cyanoimino)-N-cyclopropyl-7-(3,5-dimethylisoxazol-4-yl)-1 -((R)-1 -phenyl ethyl)- 2,3-dihydro-1 H-imidazo[4,5-c]quinoline-8-carboxamide; (E)-2-(Cyanoimino)-7-(3,5-dimethylisoxazol-4-yl)-N-(4-hydroxyphenyl)-1 -((R)-1 - phenylethyl)-2,3-dihydro-1 H-imidazo[4,5-c]quinoline-8-carboxamide;
Ethyl 3-((E)-2-(cyanoimino)-7-(3,5-dimethylisoxazol-4-yl)-1 -((R)-1 -phenyl ethyl)-2,3- dihydro-1 H-imidazo[4,5-c]quinolin-8-yl)propanoate;
3-((E)-2-(Cyanoimino)-7-(3,5-dimethylisoxazol-4-yl)-1 -((R)-1 -phenylethyl)-2,3-dihydro- 1 H-imidazo[4,5-c]quinolin-8-yl)propanoic acid;
3-((E)-2-(Cyanoimino)-7-(3,5-dimethylisoxazol-4-yl)-1 -((R)-1 -phenylethyl)-2,3-dihydro- 1 H-imidazo[4,5-c]quinolin-8-yl)-N-ethylpropanamide;
3-((E)-2-(Cyanoimino)-7-(3,5-dimethylisoxazol-4-yl)-1 -((R)-1 -phenylethyl)-2,3-dihydro- 1 H-imidazo[4,5-c]quinolin-8-yl)-N-(4-hydroxyphenyl) propanamide;
3-((E)-2-(Cyanoimino)-7-(3,5-dimethylisoxazol-4-yl)-1 -((R)-1 -phenylethyl)-2,3-dihydro- 1 H-imidazo[4,5-c]quinolin-8-yl)-N-((R)-1 -phenylethyl) propanamide;
3-((E)-2-(Cyanoimino)-7-(3,5-dimethylisoxazol-4-yl)-3-methyl-1 -((R)-1 -phenyl ethyl)- 2,3-dihydro-1 H-imidazo[4,5-c]quinolin-8-yl)-N-((R)-1 -phenylethyl) propanamide;
(E)-N-(8-(3-Cyanopropyl)-7-(3,5-dimethylisoxazol-4-yl)-1 -((R)-1 -phenylethyl)-1 H- imidazo[4,5-c]quinolin-2(3H)-ylidene)cyanamide;
Methyl 2-((E)-2-(cyanoimino)-7-(3,5-dimethylisoxazol-4-yl)-1 -((R)-1 -phenyl ethyl)-2,3- dihydro-1 H-imidazo[4,5-c]quinolin-8-yl)acetate;
Ethyl 2-(4-((E)-2-(cyanoimino)-8-methoxy-1 -((R)-1 -phenylethyl)-2,3-dihydro-1 H- imidazo[4,5-c]quinolin-7-yl)-3-methylisoxazol-5-yl)acetate;
2-(4-((E)-2-(Cyanoimino)-8-methoxy-1 -((R)-1 -phenylethyl)-2,3-dihydro-1 H-imidazo[4,5- c]quinolin-7-yl)-3-methylisoxazol-5-yl)acetic acid;
Ethyl 3-(4-((E)-2-(cyanoimino)-8-methoxy-1 -((R)-1 -phenylethyl)-2,3-dihydro-1 H- imidazo[4,5-c]quinolin-7-yl)-5-methylisoxazol-3-yl)propanoate;
3-(4-((E)-2-(Cyanoimino)-8-methoxy-1 -((R)-1 -phenylethyl)-2,3-dihydro-1 H-imidazo[4,5- c]quinolin-7-yl)-5-methylisoxazol-3-yl)propanoic acid;
Methyl 2-((2-(cyanoimino)-7-(3,5-dimethylisoxazol-4-yl)-1 -((R)-1 -phenylethyl) -2,3- dihydro-1 H-imidazo[4,5-c]quinolin-8-yl)oxy)acetate;
2-((-2-(Cyanoimino)-7-(3,5-dimethylisoxazol-4-yl)-1 -((R)-1 -phenylethyl)-2,3-dihydro- 1 H-imidazo[4,5-c]quinolin-8-yl)oxy)acetic acid;
2-((-2-(Cyanoimino)-7-(3,5-dimethylisoxazol-4-yl)-1 -((R)-1 -phenylethyl)-2,3-dihydro- 1 H-imidazo[4,5-c]quinolin-8-yl)oxy)-N-ethylacetamide; N-(8-(3-Cyanopropoxy)-7-(3,5-dimethylisoxazol-4-yl)-1 -((R)-1 -phenyl ethyl)-1 H- imidazo[4,5-c]quinolin-2(3H)-ylidene)cyanamide;
(E)-N-(8-(Cyanomethoxy)-7-(3,5-dimethyl-4,5-dihydroisoxazol-4-yl)-1 -((R)-1 - phenylethyl)-1 H-imidazo[4,5-c]quinolin-2(3H)-ylidene)cyanamide;
(E)-N-(7-(3,5-Dimethylisoxazol-4-yl)-8-(2-methoxyethoxy)-1 -((R)-1 -phenylethyl)-1 H- imidazo[4,5-c]quinolin-2(3H)-ylidene)cyanamide; and
(E)-tert-Butyl (3-(2-(cyanoimino)-7-(3,5-dimethylisoxazol-4-yl)-8-methoxy-2,3-dihydro- 1 H-imidazo[4,5-c]quinolin-1 -yl)propyl)carbamate;
or a stereoisomer, a tautomer, a pharmaceutically acceptable salt, a solvate, a polymorph or N-oxide thereof.
According to another aspect of the present invention, there are provided processes for the preparation of the compound of formula (I).
Thus, the compound of formula (I) can be prepared by various methods including using methods well known to the person skilled in the art. Examples of processes for the preparation of the compound of formula (I) are described below and illustrated in the scheme but are not limited thereto. It will be appreciated by persons skilled in the art that within certain of the processes described herein, the order of the synthetic steps employed may be varied and will depend inter alia on factors such as the nature of functional groups present in a particular substrate and the protecting group strategy (if any) to be adopted. Clearly, such factors will also influence the choice of reagent such as bases, solvents, coupling agents to be used in the reaction steps.
The reagents, reactants and intermediates used in the following processes are either commercially available or can be prepared according to standard procedures known in the art, for instance those reported in the literature references. In the following schemes and the description of the processes for the synthesis of the compounds of formula (I), the starting compounds and the intermediates used for the synthesis of compounds of the present invention, are designated as compounds 2-9 for ease of reference. Unless stated otherwise, throughout the description of the process, the corresponding substituent groups in the various formulae representing starting compounds and intermediates have the same meanings as that for the compound(s) of formula (I) as described in one or more of the embodiments. The processes used in the scheme are referred to by using general symbols namely (i), (ii), (iii), (iv), (v), (vi), (vii), (viii) and (ix).
Scheme 1 depicts a process for the preparation of the compounds of formula (I), wherein R7 is cyano; R-i , R2, R3, R4, R5, R6, n, W and Y are as defined in the first aspect of the present invention.
Scheme 1
Figure imgf000028_0001
Step (i): Preparation of the compound of formula 3:
The compound of formula 2, wherein X is halogen; R-i , R2, R3 and W are as defined above; is reacted with reagent A having the following formula;
Figure imgf000029_0001
reagent A
wherein R2, R3 and W are as defined above; in the presence of a palladium catalyst selected from [1 , 1 '-bis(diphenylphosphino)ferrocene]dichloro palladium(ll) complex with dichloromethane, tetrakis(triphenylphosphine)palladium(0), bis(triphenylphosphine)palladium(ll) dichloride or [1 ,3-bis(2,6-diisopropylphenyl) imidazol-2-ylidene](3-chloropyridyl)palladium(ll) dichloride (PEPPSI™-IPr catalyst) and a base selected from sodium carbonate, potassium carbonate, sodium hydroxide or cesium carbonate in a solvent selected from Ν,Ν-dimethylformamide (DMF), 1 ,2-
0
dimethoxyethane or dioxane at a temperature range of 100-130 C for 1 -20 h to obtain the compound of formula 3.
Step (ii): Preparation of the compound of formula 4:
The compound of formula 3 (as obtained in step (i)) is reacted with 2,2-dimethyl-1 ,3- dioxane-4,6-dione and reagent B having the following formula;
Figure imgf000029_0002
reagent B
wherein R4 is as defined above;
with reflux for 2-5 h, to obtain the compound of formula 4 (wherein R-i , R2, R3 and R4 are as defined above). Step (iii): Preparation of the compound of formula 5:
The compound of formula 4 (as obtained in step (ii)) is added to boiling diphenyl ether over a period of 10-30 minutes to obtain the compound of formula 5. Step (iv): Preparation of compound of formula 6:
The compound of formula 5 (as obtained in step (iii)) is subjected to nitration using a nitrating agent such as a mixture of nitric acid and acetic acid or a mixture of nitric
0
acid and propionic acid at a temperature range of 100-130 C for 1 -5 h, to obtain compound of formula 6.
Step (v): Preparation of the compound of formula 7:
The compound of formula 6 (as obtained in step (iv)) is chlorinated by refluxing with phosphoryl chloride (POCI3) for 1 -4 h to obtain the compound of formula 7.
Step (vi): Preparation of the compound of formula 8:
The compound of formula 7 (as obtained in step (v)) is reacted with reagent C having the following formula;
Figure imgf000030_0001
reagent C
wherein Y, R5 and n are as defined above; by refluxing in a solvent selected from acetonitrile or DMF for 2-5 h to obtain the compound of formula 8. Step (vii): Preparation of compound of formula 9:
The compound of formula 8 (as obtained in step (vi)) is reacted with a reducing agent such as stannous chloride and concentrated HCI or hydrogen in the presence of Pd/C or Fe/NH4CI in a solvent selected from an alcohol (methanol, ethanol or isopropanol), tetrahydrofuran, water or a mixture thereof, to obtain the compound of formula 9.
Step (viii): Preparation of compound of formula (I) (wherein R6 is hydrogen and R7 is cyano):
The compound of formula 9 (as obtained in step (vii)) is reacted with dimethylcyanocarbonimidodithioate in the presence of a base selected from sodium carbonate, potassium carbonate or cesium carbonate in a solvent selected from DMF, acetonitrile or an alcohol (methanol, ethanol or isopropanol), to obtain the compound of formula (I), wherein R6 is hydrogen, R7 is cyano; R-i , R2, R3, R4, R5, n, W and Y are as defined in the first aspect of the present invention.
Step (ix): Preparation of compound of formula (I) (wherein R6 is (Ci-C6)-alkyl, (C3-C12)- cycloalkyl, (C6-Ci4)-aryl, (C6-Ci4)-ar(Ci-C6)-alkyl-, heterocyclyl, heteroaryl, C(0)(Ci- C6)-alkyl or S(0)m(Ci-C6)-alkyl; wherein m is 0-2):
The compound of formula (I) (wherein R6 is hydrogen) obtained in step (viii) can be converted to the compound of formula (I) wherein R6 is (Ci-C6)-alkyl, (C3-C12)- cycloalkyl, (C6-Ci4)-aryl, (C6-Ci4)-ar(Ci-C6)-alkyl, heterocyclyl, heteroaryl, C(0)(CrC6)- alkyl or S(0)m(Ci-C6)-alkyl; by reacting it with an appropriate reagent by an appropriate method known to a person skill in the art for such a conversion. For example, the compound of formula (I) (wherein R6 is hydrogen) obtained in step (viii) can be converted to the compound of formula (I) where R6 is (Ci-C6)-alkyl by reacting the compound of formula (I) (wherein R6 is hydrogen) with an appropriate alkyl halide in the presence of a base selected from triethylamine, sodium hydrogen carbonate, sodium carbonate, potassium carbonate or sodium hydride in a solvent selected from an alcohol (methanol, ethanol or isopropanol), DMF or THF.
Step (x): Preparation of pharmaceutically acceptable salt of the compound of formula (I):
The compound of formula (I) obtained in step (viii) or step (ix) can be converted into its pharmaceutically acceptable salt by process as described herein below.
Scheme 2 depicts an alternate process for preparation of the compounds of formula (I), wherein Ri is unsubstituted or substituted alkoxy designated as -OCH2T; wherein T is H, cyano, C(0)0(Ci-C6)alkyl, C(0)NRaRb or (Ci-C6)alkyl which is unsubstituted or substituted; and R7 is cyano, n is 1 and R2, R3, R4, R5, R6, W and Y are as defined in the first aspect of the present invention.
Figure imgf000032_0001
T is H, cyano, C(0)0(CrC6)alkyl,
C(0)NRaRb or (CrC6)alkyl which
is unsubstituted or substituted
Figure imgf000032_0002
wherein is alkoxy designated wherein is alkoxy as -OCH2T; designated as -OCH2T; f¾ is H; R7 is cyano R6 is other than H; R7 is cyano
Step (i): Preparation of compound of formula 1 1 :
The compound of formula 10 is reacted with bromine in presence of iron powder and in a solvent such as DCM at room temperature for 12-16 h to obtain the compound of formula 1 1 .
Step (ii): Preparation of compound of formula 12:
The compound of formula 1 1 , obtained from step (i) is reacted with the reagent D having the following formula,
Β ^Τ
reagent D
wherein T is H, cyano, C(0)0(Ci-C6)alkyl, C(0)NRaRb or (Ci-C6)alkyl which is unsubstituted or substituted; in the presence of a base selected from sodium carbonate, potassium carbonate or cesium carbonate by refluxing in a solvent such as acetone or DMF to obtain the compound of formula 12 (wherein T is as defined above). Step (iii): Preparation of compound of formula 13:
The compound of formula 12, obtained from step (ii), is reacted with iron powder in the presence of ammonium chloride under reflux condition in a mixture of solvent such as ethanol, THF and water to obtain the compound of formula 13 (wherein T is as defined above).
Step (iv): Preparation of compound of formula 14:
The compound of formula 13, obtained from step (iii) is reacted with 2,2-dimethyl-1 ,3- dioxane-4,6-dione and reagent B (as described in step (ii) of scheme 1 ) with reflux for 1 -5 h, to obtain the compound of formula 14 (wherein T is as defined above).
Step (v): Preparation of compound of formula 15:
The compound of formula 14, as obtained in step (iv) is added into boiling diphenyl ether for 10-30 min to obtain the compound of formula 15 (wherein R4 and T are as defined above).
Step (vi): Preparation of compound of formula 16:
The compound of formula 15, as obtained in step (v), is subjected to nitration using a nitrating agent such as a mixture of nitric acid and acetic acid or a mixture of nitric acid and propionic acid at a temperature range of 100-130 °C for 1 -5 h, to obtain compound of formula 16 (wherein R4 and T are as defined above).
Step (vii): Preparation of compound of formula 17:
The compound of formula 16, as obtained in step (vi), is halogenated by refluxing with phosphoryl chloride (POCI3) or phosphorus tribromide (PBr3) for 1 -4 h to obtain the compound of formula 17 (wherein R4 and T are as defined above).
Step (viii): Preparation of compound of formula 18: The compound of formula 17, as obtained in step (vii), is reacted with reagent C (as described in step (vi) of scheme 1 ) by refluxing in a solvent selected from acetonitrile or DMF for 2-5 h to obtain the compound of formula 18 (wherein R4, Y, R5, n and T are as defined above).
Step (ix): Preparation of compound of formula 19:
The compound of formula 18, as obtained in step (viii), is reacted with a reducing agent such as stannous chloride and concentrated HCI or hydrogen in the presence of Pd/C or Fe/NH4CI in a solvent selected from an alcohol (methanol, ethanol or isopropanol), tetrahydrofuran, water or a mixture thereof, to obtain the compound of formula 19 (wherein R4, Y, R5, n and T are as defined above).
Step (x): Preparation of compound of formula 20:
The compound of formula 19, as obtained in step (ix), is reacted with dimethyl cyanocarbonimidodithioate or diphenyl cyanocarbonimidate in the presence of a base selected from sodium carbonate, potassium carbonate or cesium carbonate in a solvent selected from DMF, acetonitrile or an alcohol (methanol, ethanol or isopropanol), to obtain the compound of formula 20 (wherein R4, Y, R5, n and T are as defined above).
Step (xa): Preparation of compound of formula 21 :
The compound of formula 19, as obtained in step (ix), is reacted with the reagent A (as described in step (i) of scheme 1 ) in the presence of a palladium catalyst selected from [1 ,1 '-bis(diphenylphosphino)ferrocene]dichloro palladium(ll) complex with dichloromethane, tetrakis(triphenylphosphine)palladium(0), bis(triphenyl- phosphine) palladium(ll) dichloride or [1 ,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidene](3- chloropyridyl)palladium(ll) dichloride (PEPPSI™-IPr catalyst) and a base selected from sodium carbonate, potassium carbonate, sodium hydroxide or cesium carbonate in a solvent selected from Ν,Ν-dimethylformamide (DMF), 1 ,2-dimethoxyethane or dioxane at a temperature range of 100-130 °C for 1 -20 h to obtain the compound of formula 21 (wherein Ri is alkoxy designated as -OCH2T; T is as defined above; R2, R3, W, R4, R5, Y and n are as defined in the first aspect). Step (xi): Preparation of compound of formula (I):
The compound of formula 20, as obtained in step (x) is reacted with the reagent A ((as described in step (i) of scheme 1 ) in the presence of a palladium catalyst selected from [1 ,1 '-bis(diphenylphosphino)ferrocene]dichloro palladium(ll) complex with dichloromethane, tetrakis(triphenylphosphine)palladium(0), bis(triphenyl-phosphine) palladium(ll) dichloride or [1 ,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidene](3- chloropyridyl)palladium(ll) dichloride (PEPPSI™-IPr catalyst) and a base selected from sodium carbonate, potassium carbonate, sodium hydroxide or cesium carbonate in a solvent selected from Ν,Ν-dimethylformamide (DMF), 1 ,2-dimethoxyethane or dioxane at a temperature range of 100-130 °C for 1 -20 h to obtain the compound of formula (I) (wherein R6 is H , R7 is CN, R-i is alkoxy designated as -OCH2T; wherein T is as defined above; R2, R3, W, R4, R5, Y and n are as defined in the first aspect).
Step (xia): Preparation of compound of formula (I):
The compound of formula 21 , as obtained in step (xa), is reacted with dimethyl cyanocarbonimidodithioate or diphenyl cyanocarbonimidate in the presence of a base selected from sodium carbonate, potassium carbonate or cesium carbonate in a solvent selected from DMF, acetonitrile or an alcohol (methanol, ethanol or isopropanol), to obtain the compound of formula (I) (wherein R6 is H, R7 is CN, Ri is alkoxy designated as -OCH2T; wherein T is as defined herein above; R2, R3, W, R4, R5, Y and n are as defined in the first aspect).
Step (xii): Preparation of compound of formula (I) (wherein R6 is (Ci-Ce)-alkyl, (C3-Ci2)- cycloalkyl, (C6-Ci4)-aryl, (C6-Ci4)-ar(Ci -C6)-alkyl, heterocyclyl, heteroaryl, C(0)(Ci-Ce)- alkyl or S(0)m(C1 -C6)-alkyl):
The compound of formula (I) (wherein R6 is hydrogen) obtained in step (xi) or step (xia) can be converted to the compound of formula (I), wherein R6 is (Ci-Ce)-alkyl, (C3- Ci2)-cycloalkyl, (C6-C-i4)-aryl, (C6-Ci4)-ar(Ci-C6)-alkyl-, heterocyclyl, heteroaryl, C(0)(Ci -C6)-alkyl or S(0)m(Ci -C6)-alkyl, by reacting it with an appropriate reagent by an appropriate method known to a person skill in the art for such a conversion. For example, the compound of formula (I) (wherein R6 is hydrogen) obtained in step (xi) or step (xia) can be converted to the compound of formula (I) wherein R6 is (Ci-Ce)-alkyl, by reacting the compound of formula (I) (wherein R6 is hydrogen) with an appropriate alkyl halide in the presence of a base selected from triethylamine, sodium hydrogen carbonate, sodium carbonate, potassium carbonate or sodium hydride in a solvent selected from alcohol (methanol, ethanol or isopropanol), DMF or THF. Step (xiii): Preparation of pharmaceutically acceptable salt of a compound of formula (I):
The compound of formula (I) obtained in step(s) (xi), (xia) or (xii) can be converted into its pharmaceutically acceptable salt by a process as described below.
The process of preparation of pharmaceutically acceptable salt of the compound of formula (I) involves contacting the compound of formula (I) with a sufficient amount of an appropriate base or an appropriate acid, either neat or in a suitable inert solvent. For example, a hydrochloride salt of a compound of formula (I) containing a basic group can be prepared by contacting the compound of formula (I) with hydrochloric acid either neat or in a suitable solvent, such as an alcohol. Similarly, a sodium salt of a compound of formula (I) containing an acidic group can be prepared by contacting the compound of formula (I) with sodium hydroxide in a suitable solvent, such as tetrahydrofuran.
The term "pharmaceutically acceptable salts" as used herein refers to organic and inorganic salts of a compound of the invention, depending on the particular group (acidic or basic group) present in the compounds of formula (I) described herein. When the compounds of the present invention contain relatively acidic groups, base addition salts can be obtained by contacting the compounds of formula (I) with a sufficient amount of an appropriate base, either neat or in a suitable inert solvent. Examples of pharmaceutically acceptable base addition salts include sodium, potassium, calcium, magnesium, ammonium or an organic base salt. Examples of pharmaceutically acceptable organic base addition salts include those derived from organic bases such as lysine, arginine, guanidine, diethanolamine, choline, tromethamine and the like or other organic bases known to a person skilled in the art.
When compounds of the present invention contain relatively basic groups, acid addition salts can be obtained by contacting the compounds of formula (I) with a sufficient amount of an appropriate acid, either neat or in a suitable inert solvent. Examples of pharmaceutically acceptable acid addition salts include those derived from inorganic acids like hydrochloric, hydrobromic, nitric, carbonic, monohydrogencarbonic, phosphoric, sulfuric, monohydrogenphosphoric, dihydrogenphosphoric, mono-hydrogensulfuric or hydriodic acids and the like, as well as the salts derived from organic acids like acetic, propionic, isobutyric, oxalic, maleic, malonic, benzoic, succinic, suberic, fumaric, mandelic, phthalic, benzenesulfonic, p- tolylsulfonic, citric, tartaric, methanesulfonic, glucuronic or galacturonic acids and the like. Certain specific compounds of the present invention contain both basic and acidic functionalities that allow the compounds to be converted into either base or acid addition salts.
The compounds of formula (I) can be regenerated from their corresponding salts by contacting the salt with an appropriate base or acid depending on the type of salt and isolating the parent compound in the conventional manner. The compound differs from the various salt forms in certain physical properties. One such physical property that would make the salt form of a compound of formula (I) differ from the corresponding compound is solubility in polar solvents.
Certain compounds of the present invention can exist in unsolvated forms as well as solvated forms, including hydrated forms. Certain compounds of the present invention may exist in multiple crystalline or amorphous forms. In general, all physical forms are suitable for the uses contemplated by the present invention and are intended to be within the scope of the present invention.
Various polymorphs of compounds of formula (I) can be prepared by crystallization of the compounds under different conditions. The different conditions are, for example, using different solvents or their mixtures for crystallization; crystallization at different temperatures; various modes of cooling, ranging from very fast to very slow cooling during crystallizations. Polymorphs can also be obtained by heating or melting the compound followed by gradual or fast cooling. The presence of polymorphs can be determined by IR (infra-red) spectroscopy, solid probe NMR (nuclear magnetic resonance) spectroscopy, differential scanning calorimetry, powder X-ray diffraction or such other techniques.
Those skilled in the art will recognize that stereocentres exist in the compounds of formula (I). Accordingly, the present invention includes all possible stereoisomers and geometric isomers of formula (I) and includes not only racemic compounds but also the optically active isomers as well. When a compound of formula (I) is desired as a single enantiomer, it may be obtained either by resolution of the final product or by stereospecific synthesis from either isomerically pure starting material or an appropriate intermediate. Resolution of the final product, an intermediate or a starting material may be effected by any suitable method known in the art, for example, Chiral reagents for asymmetric synthesis by Leo A. Paquette; John Wiley & Sons Ltd (2003).
Additionally, in situations wherein tautomers of the compounds of formula (I) are possible, the present invention is intended to include all tautomeric forms of the compounds.
The present invention also encompasses within its scope prodrugs of the compound of formula (I). Preferably prodrugs are those compounds that are converted intracellular^, more preferably, where the cellular converting location is the site of therapeutic action. For instance, preferred produgs are pharmaceutically acceptable ester derivatives convertible by solvolysis under physiological conditions to the parent carboxylic acid. Examples of pharmaceutically acceptable esters include lower alkyl esters, cycloalkyl esters, lower alkenyl esters, benzyl esters, mono- or di- substituted lower alkyl esters such as the pivaloyloxymethyl ester and the like conventionally used in the art (An introduction to Medicinal Chemistry, Graham. L. Patrick, Second Edition, Oxford University Press, pg 239-248; Prodrugs: Challenges and Rewards, Part 1 and Part 2, AAPS Press, Edited by Valentino J. Stella, Renald T. Borchardt, Michael J. Hagemon, Reza Oliyai, Hans Maag, Jefferson W. Tilley).
In another further aspect, the present invention relates to pharmaceutical composition(s) containing a therapeutically effective amount of at least one compound of formula (I) or a isomer, a tautomer, pharmaceutically acceptable salt or a solvate thereof; and a conventional pharmaceutically acceptable carrier. The present invention also relates to a process for production of the pharmaceutical composition, which includes bringing at least one compound of formula (I), into a suitable administration form using a pharmaceutically acceptable and physiologically tolerable excipient and, if appropriate, further suitable additives or auxiliaries can be added.
The compositions can be administered orally, for example in the form of pills, tablets, coated tablets, capsules, granules or elixirs. Administration, however, can also be carried out rectally, for example in the form of suppositories, or parenterally, for example intravenously, intramuscularly or subcutaneously, in the form of injectable sterile solutions or suspensions, or topically, for example in the form of ointments or creams or transdermally, in the form of patches, or in other ways, for example in the form of aerosols or nasal sprays.
For the production of pills, tablets, coated tablets and hard gelatin capsules, it is possible to use, for example, lactose, corn starch or derivatives thereof, gum arabica, magnesia or glucose, etc. Carriers for soft gelatin capsules and suppositories are, for example, fats, waxes, natural or hardened oils, etc. Suitable carriers for the production of solutions, for example injection solutions, or of emulsions or syrups are, for example, water, physiological sodium chloride solution or alcohols, for example, ethanol, propanol or glycerol, sugar solutions, such as glucose solutions or mannitol solutions, or a mixture of the various solvents which have been mentioned.
The pharmaceutical composition(s) normally contain about 1 % to 99 %, for example, from about 5 % to about 70 %, or from about 10 % to about 30 % by weight of the compound of formula (I) or its pharmaceutically acceptable salt. The amount of the compound of formula (I) or its pharmaceutically acceptable salt in the pharmaceutical composition(s) can range from about 1 mg to about 1000 mg or from about 2.5 mg to about 500 mg or from about 5 mg to about 250 mg or in any range falling within the broader range of 1 mg to 1000 mg or higher or lower than the specified range.
As is customary, the dosage range which is suitable in a specific case depends on the type of disease or disorder to be treated and on the state of the respective condition or disorder. The selected dosage level can be readily determined by a skilled medical practitioner in the light of the relevant circumstances, including the disease or disorder to be treated, the chosen route of administration including other factors such as age, weight and physical health and response of the individual patient (subject), pharmacokinetics, severity of the disease and other like factors known in the medical art. Actual dosage levels of the active ingredients i.e. the compounds of formula (I) in the pharmaceutical composition of this present invention can be varied so as to obtain an amount of the active ingredient, which is effective to achieve the desired therapeutic response for a particular patient (subject in need of the treatment), composition, and mode of administration without being toxic to the patient. Typically, the dose of the compounds of formula (I) or pharmaceutically acceptable salts thereof, which is to be administered, can cover a wide range. The dose to be administered daily is to be selected to suit the desired therapeutic effect. A suitable dosage is about 0.01 mg/kg/day to about 200 mg/kg/day of the compound of formula (I) or its pharmaceutically acceptable salt, for example, about 0.1 mg/kg/day to about 100 mg/kg/day of a compound of formula (I) or its pharmaceutically acceptable salt. If required, higher or lower daily doses can also be administered.
In addition to the compound of the formula (I) or its pharmaceutically acceptable salt and carrier substances, the pharmaceutical compositions can contain additives such as, for example, fillers, antioxidants, dispersants, emulsifiers, defoamers, flavors, preservatives, solubilizers or colorants. They can also contain two or more compounds of formula (I) or pharmaceutically acceptable salts thereof.
In one aspect, the present invention relates to a compound of formula (I) or a stereoisomer, a tautomer, a pharmaceutically acceptable salt or a solvate thereof; for use as inhibitors of bromodomain containing proteins.
In an embodiment, the present invention relates to a compound of formula (I) or a stereoisomer, a tautomer, a pharmaceutically acceptable salt or a solvate thereof; for use as inhibitors of bromodomain containing protein 4 (BRD4).
In one aspect, the present invention relates to a method for the treatment of a disease or a disorder mediated by bromodomain containing proteins, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula (I) or a stereoisomer, a tautomer, a pharmaceutically acceptable salt or a solvate thereof.
In another aspect, the present invention provides use of a compound of formula (I) or a stereoisomer, a tautomer, a pharmaceutically acceptable salt or a solvate thereof; for the treatment of a disease or a disorder mediated by bromodomain containing proteins.
In one aspect, the present invention provides use of a compound of formula (I) or a stereoisomer, a tautomer, a pharmaceutically acceptable salt or a solvate thereof; for the manufacture of a medicament for the treatment of a disease or a disorder mediated by bromodomain containing proteins.
In an embodiment, the disease or disorder is mediated by bromodomain containing protein 4 (BRD4).
In an embodiment of the present invention, the disease or disorder mediated by bromodomain containing proteins are selected from: proliferative disorders, chronic autoimmune diseases or disorders, inflammatory disorders, conditions associated with ischaemia-reperfusion injury, metabolic disorders, cardiovascular diseases, disorders associated with fibrosis and viral infections.
In an embodiment, the proliferative disorders are selected from: cancers, tumors, polyps or cysts.
In an embodiment, the chronic autoimmune and inflammatory diseases are selected from: rheumatoid arthritis, osteoarthritis, acute gout, psoriasis, systemic lupus erythematosus, multiple sclerosis, inflammatory bowel disease (Crohn's disease and Ulcerative colitis), asthma, chronic obstructive airways disease, pneumonitis, myocarditis, pericarditis, eczema, dermatitis, alopecia, nephritis, vasculitis, Alzheimer's disease, retinitis, hepatitis, pancreatitis, primary biliary cirrhosis, sclerosing cholangitis or thyroiditis.
In an embodiment, the conditions associated with ischaemia-reperfusion injury are selected from: myocardial infarction, cerebrovascular ischaemia (stroke), acute coronary syndromes, renal reperfusion injury, organ transplantation, coronary artery bypass grafting, cardio-pulmonary bypass procedures, pulmonary, renal, hepatic, gastro-intestinal or peripheral limb embolism.
In an embodiment, the metabolic disorders are selected from: metabolic syndrome, dyslipidemia, Type 2 diabetes or obesity.
In an embodiment, the cardiovascular diseases are selected from: hypercholesterolemia, atherosclerosis, myocardial infarction, congestive heart failure or cardiac reperfusion injury.
In an embodiment, the disorders associated with fibrosis are selected from: idiopathic pulmonary fibrosis, renal fibrosis, post-operative stricture, keloid formation, scleroderma and cardiac fibrosis.
In an embodiment, the disorders associated with viral infections are selected from disorders caused by herpes virus, human papilloma virus, adenovirus, poxvirus and other DNA viruses.
In an embodiment, the disease or disorder mediated by bromodomain containing proteins is cancer.
Accordingly, the present invention relates to a method for the treatment of cancer, comprising administering to a subject in need thereof a therapeutically effective amount of the compound of formula (I) or a stereoisomer, a tautomer, a pharmaceutically acceptable salt or a solvate thereof. Further, the present invention relates to use of a compound of formula (I) or a pharmaceutically acceptable salt thereof for the treatment of cancer.
In one aspect, the present invention provides use of a compound of formula (I) or a stereoisomer, a tautomer, a pharmaceutically acceptable salt or a solvate thereof, for the manufacture of a medicament for the treatment of cancer.
In an embodiment, cancers that can be treated by the compounds of formula (I) or a stereoisomer, a tautomer, a pharmaceutically acceptable salt or a solvate thereof; or pharmaceutical compositions containing the said compounds; include, but are not limited to thyroid carcinoma, cardiac sarcoma, lung carcinoma, gastrointestinal carcinoma, genitourinary tract carcinoma, liver carcinoma, mantle cell lymphoma, bone sarcoma, sarcoma of the nervous system, gynaecological carcinoma, haematological cancer, adrenal gland neuroblastoma, skin cancer, astrocytic cancer, breast cancer, colorectal cancer, NUT midline carcinoma (NMC, a form of epithelial cancer caused by a mutation of the nuclear protein in testis), endometrial cancer, head and neck cancer or oral cancer.
According to an embodiment of the present invention, the cancer is cardiac sarcoma selected from angiosarcoma, fibrosarcoma, rhabdomyosarcoma, liposarcoma, rhabdomyoma, fibroma, lipoma or teratoma.
According to another embodiment of the present invention, the cancer is lung carcinoma selected from squamous cell carcinoma, undifferentiated small or large cell carcinoma, adenocarcinoma, bronchiolar carcinoma, bronchial adenoma, bronchial sarcoma, bronchial lymphoma.
According to yet another embodiment of the present invention, the cancer is gastrointestinal carcinoma selected from stomach carcinoma, stomach lymphoma, pancreatic (ductal adenocarcinoma, insulinoma, glucagonoma, gastrinoma), small bowel carcinoma (adenocarcinoma, lymphoma, Karposi's sarcoma, hemangioma, lipoma, neurofibroma, fibroma) or large bowel carcinoma (adenocarcinoma, tubular adenoma).
According to another embodiment of the present invention, the cancer is genitourinary tract carcinoma selected from carcinoma of kidney (adenocarcinoma, nephroblastoma, lymphoma, leukemia), carcinoma of bladder and urethra (squamous cell carcinoma, adenocarcinoma), carcinoma of prostate (adenocarcinoma, sarcoma), or carcinoma of testis (seminoma, teratoma, embryonal carcinoma, teratocarcinoma, sarcoma, interstitial cell carcinoma, fibroma, fibroadenoma, lipoma).
According to yet another embodiment of the present invention, the cancer is liver carcinoma selected from hepatoma (hepatocellular carcinoma), hepatoblastoma, angiosarcoma or hepatocellular adenoma.
According to yet another embodiment of the present invention, the cancer is bone sarcoma selected from osteogenic sarcoma (osteosarcoma), fibrosarcoma, Ewing's sarcoma, malignant lymphoma (reticulum cell sarcoma), multiple myeloma, benign chondroma, chondroblastoma, chondromyxofibroma, osteoid osteoma or giant cell tumors.
According to another embodiment of the present invention, the cancer is sarcoma of the nervous system selected from sarcoma of skull (osteoma, granuloma, xanthoma), meninges (meningioma, meningiosarcoma, gliomatosis), sarcoma of brain (astrocytoma, medulloblastoma, glioma, glioblastoma multiform, oligodendroglioma, retinoblastoma, congenital tumors) or sarcoma of spinal cord (neurofibroma, meningioma, glioma, sarcoma).
According to yet another further embodiment of the present invention, the cancer is carcinoma of gynaecological organs selected from carcinoma of uterus (endometrial carcinoma), carcinoma of cervix (cervical carcinoma, ovary carcinoma), carcinoma of vulva (squamous cell carcinoma, intraepithelial carcinoma, adenocarcinoma, fibrosarcoma, melanoma), carcinoma of vagina (clear cell carcinoma, squamous cell carcinoma, embryonal rhabdomyosarcoma) or carcinoma of fallopian tubes.
According to another embodiment of the present invention, the cancer is haematological cancer selected from blood cancer (acute myeloid leukemia (AML), chronic myeloid leukemia (CML), acute lymphoblastic leukemia, chronic lymphocytic leukemia, myeloproliferative diseases, multiple myeloma, myelodysplastic syndrome), Hodgkin's disease, non-Hodgkin's lymphoma (malignant lymphoma) or mantle cell lymphoma.
According to another embodiment of the present invention, the disease or disorder mediated by bromodomain containing proteins is a skin cancer selected from malignant melanoma, basal cell carcinoma, squamous cell carcinoma, Kaposi's sarcoma, angioma or dermatofibroma. The present invention also encompasses within its scope use of a compound of formula (I) or a stereoisomer, a tautomer or a pharmaceutically acceptable salt thereof; administered in combination, either simultaneously or sequentially with other therapeutically active agents. For example, the compounds of the present invention can be used in combination with known anti-cancer agents. Combinations of the compounds of the present invention with other anti-cancer or chemotherapeutic agents are within the scope of the invention. Examples of such agents can be found in Cancer Principles and Practice of Oncology by V.T. Devita and S. Hellman (editors), 6th edition (February 15, 2001 ), Lippincott Williams & Wilkins Publishers. A person of ordinary skill in the art would be able to discern which combinations of therapeutic agents would be useful based on the particular characteristics of the therapeutic agent and the cancer involved.
The therapeutically active agents used in combination with one or more compounds of formula (I) or a stereoisomer, a tautomer, or pharmaceutically acceptable salt thereof; can be selected from anti-cancer or chemotherapeutic agents such as anti-microtubule agents (diterpenoids (paclitaxel, docetaxel) and vinca alkaloids (vinblastine, vincristine, vinorelbine); platinum coordination complexes (cisplatin, carboplatin), alkylating agents (nitrogen mustards (oxazaphosphorines, cyclophosphamide, melphalan, chlorambucil)); alkyl sulfonates (busulfan); nitrosoureas (carmustine); triazenes (dacarbazine); topoisomerase I inhibitors (camptothecins (irinotecan, topotecan)); topoisomerase II inhibitors (epipodophyllotoxins (etoposide, teniposide)); antimetabolite neoplastic agents (fluorouracil, methotrexate, cytarabine, mecaptopurine, thioguanine, gemcitabine); hormones and hormonal analogues (retinoids, histone deacetylase inhibitors); DNA methy transferase inhibitors (azacitidine, decitabine); non-receptor tyrosine kinase angiogenesis inhibitors (endostatin, angiostatin); antibiotics (daunorubicin, doxorubicin, bleomycin); inhibitors of growth factor receptors ((VEGFR inhibitors (pazopanib, ZD6474 (vandetanib, AstraZeneca), AZD2171 (cediranib, Astrazeneca), vatalanib, sunitinib and sorafenib), trastuzumab, cetuximab, bevacizumab, lapatinib, erlotinib, imatinib mesylate), cell cycle signaling inhibitors (CDK inhibitors (ABT-751 (Eisai), veliparib)) or bromodomain inhibitors (OTX-015 (Mitsubishi Tanabe Pharma), (+)-JQ-1 (Dana-Farber Cancer Institute), GSK-525762 (GlaxoSmithKline), GSK-1210151A (I- ΒΕΤΊ 51 , GlaxoSmithKline), GW-841819X (GlaxoSmithKline), RVX-2135 (Resverlogix)).
For instance, a pharmaceutical composition containing a compound of formula (I) or its pharmaceutically acceptable salt can be administered to a subject, in particular a human, with any other therapeutically active compounds, in mixtures with one another or in the form of pharmaceutical preparations.
It is understood that modifications that do not substantially affect the activity of the various aspects of this invention are included. Accordingly, the following examples are intended to illustrate but not to limit the present invention.
The following abbreviations or terms are used herein:
eV Electronvolt
CDCIs Cholorform
CD2C I2 Dichloromethane
DCM Dichloromethane
DMF N, N-dimethylformamide
DMSO Dimethylsulfoxide
DMSO-de Deuterated dimethylsulfoxide
EtOH Ethanol
EtOAc Ethyl acetate
g Gram
h Hour
HCI Hydrochloric acid
HATU 1 -[Bis(dimethylamino)methylene]-1 H-1 ,2,3-triazolo[4,5- b]pyridinium 3-oxid hexafluorophosphate
LiOH Lithium hydroxide
mg Milligram
mm Minute(s)
mL Millilitre
ML Microlitre
M Micromolar
Microsecond
mmol Millimolar
mol Mole MeOH Methanol
NaOH Sodium hydroxide
NaHC03 Sodium bicarbonate
Na2S04 Sodium sulphate
NMP N-Methylpyrrolidone
nm Nanometer
°C Degree Centigrade
POCI3 Phosphoryl chloride
Pd(Ph3P)4 Tetrakis(triphenylphosphine)palladium(0)
PBr3 Phosphorus tribromide
PdCI2(dppf)-CH2CI2 1 , 1 '-Bis(diphenylphosphino)ferrocene-palladium(ll)
dichloride dichloromethane
SnCI2 Stannous chloride
RT Room temperature (20-35 °C)
THF Tetrahydrofuran
TEA Triethylamine
EXAMPLES
Example 1 :
3-(3,5-Dimethylisoxazol-4-yl)-4-methoxyaniline
[1 ,1 '-Bis(diphenylphosphino)ferrocene]dichloro palladium(ll) complex with dichloro methane (6.56 g, 8.03 mmol) was added to a stirred solution of 3-iodo-4- methoxyaniline (20.0 g, 80.0 mmol) and (3,5-dimethylisoxazol-4-yl)boronic acid (13.6 g, 96.0 mmol) in DMF (100 ml_) followed by sodium carbonate (17.0 g, 161 mmol) solution in water (20 ml_) and the resulting reaction mixture was heated to 120 °C for 1 h. The reaction mixture was then cooled to RT and concentrated. Water (200 ml) was added to the resulting residue and extracted with CHCI3 (3x100 ml_).The combined organic layers were washed with brine (150 ml_), dried over anhydrous Na2S04 and solvent was evaporated to obtain the crude product which was further purified by column chromatography (silica gel, 1 : 1 ethyl acetate in petroleum ether) to obtain the title compound.
Yield: 15.0 g (86.0 %) ; 1H NMR (300 MHz, DMSO-d6): δ 2.05 (s, 3H, CH3), 2.22 (s, 3H, CH3), 3.63 (s, 3H, OCH3), 4.70 (br s, 2H, NH2, exchangeable with D20), 6.40 - 6.41 (d, 1 H, J = 2.7 Hz, Ar), 6.55-6.59 (dd, 1 H, J = 8.7 Hz , J = 3.0Hz Ar), 6.79 - 7.82 (d, 1 H, J = 8.7 Hz , Ar); MS (El, 70 eV): m/z 219.1 (M+H+); HPLC purity: 96.89 % .
Example 2:
(E)-5-(((3-(3,5-Dimethylisoxazol-4-yl)-4-methoxyphenyl)imino)methyl)-2,2- dimethyl-1 ,3-dioxane-4,6-dione
2,2-Dimethyl-1 ,3-dioxane-4,6-dione (18.5 g, 128 mmol) and 1 , 1 ,1 -trimethoxymethane (13.6 g, 128 mmol) was mixed together and heated to reflux for 1 h. The compound of example 1 (28.0 g, 128 mmol) was added in portions and heated for 2.5 h. The reaction mixture was cooled to 25-30 °C and the solid obtained was filtered and washed with diethyl ether (25 mL) to obtain the crude product which was further purified by column chromatography (silica gel, 1 : 1 ethyl acetate in petroleum ether) to obtain the title compound.
Yield: 39.5 g (83.0 %); 1 H NMR (300 MHz, DMSO-d6): δ 1 .60 (s, 6H, 2xCH3 ), 2.08 (s, 3H, CH3), 2.27 (s, 3H, CH3), 3.78 (s, 3H, OCH3), 7.14 - 7.17 (d, 1 H, J = 9.0 Hz, Ar), 7.49- 7.50 (d, 1 H, J = 1 .5 Hz, Ar), 7.57- 7.61 (dd, 1 H, J = 9.0 Hz, J = 2.7 Hz, Ar), 8.49 (d, 1 H, J = 14.7 Hz, CH), 1 1 .27 (d, 1 H, J = 14.7 Hz, NH, exchangeable with D20); MS (El, 70 eV): m/z 373 (M+H+); HPLC purity: 95 % . Example 3:
7-(3,5-Dimethylisoxazol-4-yl)-6-methoxyquinolin-4-ol
The compound of example 2 (0.400 g, 1 .10 mmol) was added to boiling diphenyl ether (10 mL) and stirred for 10 min. The reaction mixture was then cooled to 25 - 30 °C and diluted with petroleum ether (100 mL). The precipitated solid was collected by filtration and washed with petroleum ether to obtain the crude product, which was further purified by flash column chromatography (silica gel, 5:95 MeOH in CHCI3) to obtain the title compound.
Yield: 0.130 g (43.9 %); 1 H NMR (300 MHz, DMSO-d6): δ 2.10 (s, 3H, CH3), 2.30 (s, 3H, CH3), 3.85 (s, 3H, OCH3), 6.03 (d, 1 H, J = 7.2 Hz, Ar), 7.41 (s, 1 H, Ar), 7.60 (s, 1 H, Ar), 7.88 (t, 1 H, J = 6.6 Hz, Ar), 1 1 .72 (d, 1 H, J = 4.8 Hz, OH, exchangeable with D2O); MS (El, 70 eV): m/z 271 .2 (M+H+); HPLC purity: 98.15 % . Example 4:
7-(3,5-Dimethylisoxazol-4-yl)-6-methoxy-3-nitroquinolin-4-ol
Nitric acid (21 .5 mL, 481 mmol) was added to a stirred solution of the compound of example 3 (26.0 g, 96.0 mmol) in acetic acid (300 mL). The resulting reaction mixture was heated to 120 °C for 2 h and then cooled to 25-30 °C. Solid thus obtained was collected by filtration and the solid was washed with cold water. The crude product obtained was further purified by trituration in ethyl acetate and petroleum ether to afford the title compound.
Yield: 20.0 g (65.9 %); 1 H NMR (300 MHz, DMSO-d6): δ 2.10 (s, 3H, CH3), 2.31 (s, 3H, CH3), 3.90 (s, 3H, OCH3), 7.59 (s, 1 H, Ar), 7.75 (s, 1 H, Ar), 9.17 (s, 1 H, Ar); MS (El, 70 eV): m/z 316 (M+H+); HPLC purity: 82.00 % .
Example 5:
4-(4-Chloro-6-methoxy-3-nitroquinolin-7-yl)-3,5-dimethylisoxazole
POCI3 (4.29 mL, 46.0 mmol) was added to the compound of example 4 (14.5 g, 46.0 mmol) and heated to reflux for 2 h. After 2 h, POCI3 was removed and the resulting residue was quenched with aqueous saturated bicarbonate solution (25 mL). The aqueous layer was extracted with CH2CI2 (2x50 mL) and the combined organic layer was washed with brine (50 mL), dried over anhydrous Na2S04 and concentrated. The crude product obtained was further purified by trituration in dichloromethane in petroleum ether to obtain the title compound.
Yield: 14.0 g (91 .00 %); 1H NMR (300 MHz, DMSO-d6): δ 2.24 (s, 3H, CH3), 2.40 (s, 3H, CH3), 4.06 (s, 3H, OCH3), 7.69 (s, 1 H, Ar), 7.99 (s, 1 H, Ar), 9.16 (s, 1 H, Ar); MS (El, 70 eV): m/z 334.1 (M+H+); HPLC purity: 97.9 % .
Example 6:
7-(3,5-Dimethylisoxazol-4-yl)-6-methoxy-3-nitro-N-((R)-1-(pyridin-2-yl)ethyl) quinolin-4-amine
(fl)-1 -(Pyridin-2-yl) ethanamine (600 mg, 4.91 mmol) was added to a stirred solution of compound of example 5 (1 .00 g, 3.00 mmol) in acetonitrile (20 mL) and heated to reflux for 3 h. The solvent was evaporated and the residue obtained was purified by column chromatography (silica gel, 1 : 1 ethyl acetate in petroleum ether) to obtain the title compound. Yield: 1.10 g (88 %); 1 H NMR (300 MHz, DMSO-d6): δ 1 .23 (d, 3H, J = 6.6 Hz, CH3), 2.12 (s, 3H, CH3), 2.32 (s, 3H, CH3), 3.81 (s, 3H, OCH3), 5.55 (m, 1 H, CH), 7.31 - 7.35 (m, 1 H, Ar), 7.612 (d, 1 H, J = 7.8 Hz, Ar), 7.73 (s, 1 H, Ar), 7.80 (s, 1 H, Ar), 7.83 (dd, 1 H, J = 7.8 Hz, 1 .5 Hz, Ar), 8.58 (d, 1 H, J = 4.5 Hz, Ar), 9.04 (s, 1 H, Ar), 9.58 (d, 1 H, J = 7.8 Hz, Ar); MS (El, 70 eV): m/z 420.2 (M+H+); HPLC purity: 98.47 % .
Example 7:
7-(3,5-Dimethylisoxazol-4-yl)-6-methoxy-N4-((R)-1-(pyridin-2-yl)ethyl)quinoline- 3,4-diamine
Stannous chloride (3.27 g, 15.7 mmol) was added to a stirred solution of the compound of example 6 (1 .10 g, 2.62 mmol) in ethanol (10 mL) followed by concentrated HCI (3 mL) and the resulting reaction mixture was stirred at 25-30 °C for 12 h. After 12 h, aqueous sodium hydroxide (2N, 50 mL) was added and extracted with dichloromethane (3 x 50 mL). The combined organic layers were washed with brine (50 mL) and dried over anhydrous Na2S04. The solvent was evaporated and the residue obtained was purified by column chromatography (silica gel, 5:95 MeOH in CHCI3,) to obtain the title compound.
Yield: 0.52 g (50.90 %); 1 H NMR (300 MHz, DMSO-d6): δ 1 .54 (d, 3H, J = 6.6 Hz, CH3), 2.12 (s, 3H, CH3), 2.31 (s, 3H, CH3), 3.81 (s, 3H, OCH3), 4.64 - 4.66 (m, 1 H, CH), 5.19 (s, 1 H, NH, exchangeable with D20), 5.22 (s, 2H, NH2, exchangeable with D20) , 7.21 - 7.26 (m, 1 H, Ar), 7.32 (s, 1 H, Ar), 7.49 - 7.51 (m, 2H, Ar), 7.69 - 7.72 (m, 1 H, Ar), 8.28 (s, 1 H, Ar), 7.53 (d, 1 H, J = 3.9 Hz, Ar); MS (El, 70 eV), m/z 390.2 (M+H+); HPLC purity: 88.6 % . Example 8:
(E)-N-(7-(3,5-Dimethylisoxazol-4-yl)-8-methoxy-1 -((R)-1 -(pyridin-2-yl)ethyl)-1 H- imidazo[4,5-c]quinolin-2(3H)-ylidene)cyanamide
To a stirred solution of the compound of example 7 (0.500 g, 1 .28 mmol) in DMF (10 mL) was added cesium carbonate (1 .67 g, 5.14 mmol) and dimethyl cyanocarbonimidodithioate (0.375 g, 2.57 mmol) and heated at 80 °C for 12 h. The solvent was evaporated and water (25 mL) was added to the resulting residue. The reaction mixture was extracted with ethyl acetate (3x25 mL). Combined organic layers were washed with brine (50 mL) and dried over anhydrous Na2S04. The solvent was evaporated to obtain the crude product, which was further purified by column chromatography (silica gel, 1 :9 MeOH in CHCI3 and a few drops of triethyl amine) to obtain the title compound.
Yield: 0.126 g (22.33 %); 1H NMR (300 MHz, DMSO-d6): δ 2.04 - 2.05 (d, 3H, J = 6.6Hz, CH3), 2.26 (s, 3H, CH3), 2.50 (s, 3H, CH3), 3.45 (s, 3H, OCH3), 6.41 - 6.46 (q, 1 H, CH), 6.65 (s, 1 H, Ar), 7.38 (t, 1 H, Ar), 7.52 (d, 1 H, J= 7.8Hz, Ar), 7.78 (t, 1 H, Ar), 7.91 (s, 1 H, Ar), 8.60 (d, 1 H, J = 4.5 Hz, Ar), 8.84 (s, 1 H, Ar); MS (El, 70 eV): m/z 440.2 (M+H+); HPLC purity: 98.96 % .
Example 9:
(E)-N-(7-(3,5-Dimethylisoxazol-4-yl)-8-methoxy-3-methyl-1-((R)-1-(pyridin-2-yl) ethyl)-1 H-imidazo[4,5-c]quinolin-2(3H)-ylidene)cyanamide
Sodium hydride (36.4 mg, 0.910 mmol) was added to a stirred solution of the compound of example 8 (200 mg, 0.455 mmol) in DMF (5 mL) at 0-5 °C. The reaction mixture was stirred at the same temperature for 10 min and iodomethane (194 mg, 1 .365 mmol) was added. The reaction mixture was allowed to reach the temperature of 25-30 °C and stirred at the same temperature for 1 h. The resulting reaction mixture was quenched on ice cold water (25 mL), extracted with ethyl acetate (2x25 mL) and the combined organic layers were washed with water (25 mL), brine (25 mL) and dried over anhydrous Na2S04. Solvent was removed to obtain a crude product, which was further purified by column chromatography (silica gel, 9: 1 :0.05 CHCI3: MeOH: triethylamine) to obtain the title compound.
Yield: 0.058 g (28.1 %); 1H NMR (300 MHz, DMSO-d6): δ 2.04 (s, 3H, CH3), 2.07 (d, 3H, J = 7.0 Hz, CH3), 2.26 (s, 3H, CH3), 3.44 (s, 3H, OCH3), 4.15 (s, 3H, NCH3), 6.57 - 6.59 (q, 1 H, J = 7.0 Hz, CH), 7.39 (t, 1 H, Ar), 7.52 (d, 1 H, J = 4.5 Hz, Ar), 7.81 (t, 1 H, Ar), 7.92 (s, 1 H, Ar), 8.62 (d, 1 H, J = 2.1 Hz, Ar), 9.08 (s, 1 H, Ar); MS (El, 70 eV): m/z 454.2 (M+H+); HPLC purity: 99.32 % .
Example 10:
7-(3,5-Dimethylisoxazol-4-yl)-6-methoxy-3-nitro-N-((R)-1-phenylethyl)quinolin-4- amine
(R)-I -Phenylethanamine (1 .089 g, 8.99 mmol) was added to a stirred solution of the compound of example 5 (1 .5 g, 4.49 mmol) in acetonitrile (10 mL) and the reaction mixture was heated to reflux for 2 h. After 2 h, the mixture was cooled to room temperature and the solvent was evaporated. Water (25 mL) was added to resulting residue and extracted with ethyl acetate (2x25 mL), the combined organic layers were washed with water (25 mL), brine (25 mL) and dried over anhydrous Na2S04. The solvent was evaporated to obtain a crude product, which was further purified by column chromatography (silica gel, 3:7 ethyl acetate: petroleum ether) to obtain the title compound.
Yield: 1 .85 g (98 %); 1 H NMR (300 MHz, DMSO-d6): δ 1 .70 (d, 3H, J = 6.3Hz, CH3), 2.08 (s, 3H, CH3), 2.28 (s, 3H, CH3), 3.50 (s, 3H, OCH3), 5.42 (m, 1 H, CH), 7.26 - 7.31 (m, 1 H, Ar), 7.38 (t, 2H, Ar), 7.45 (d, 2H, J = 7.5 Hz, Ar), 7.58 (s, 1 H, Ar), 7.78 (s, 1 H, Ar), 9.01 (s, 1 H, Ar), 9.18 (d, 1 H, J = 7.5Hz, Ar); MS (El, 70 eV): m/z 419.1 (M+H+); HPLC purity: 99.59 % .
Example 11 A:
7-(3,5-Dimethylisoxazol-4-yl)-6-methoxy-N4-((R)-1 -phenylethyl)quinoline-3,4- diamine
SnC (2.68 g, 12.90 mmol) was added to a stirred solution of the compound of example 10 (1 .8 g, 4.30 mmol) in a mixture of ethanol (15 mL) and THF (5 mL) and the resulting reaction mixture was heated to reflux for 1 h. After 1 h, reaction mixture was cooled to 25-30 °C and solvent was removed. Water (25 mL) was added to the resulting residue and was extracted with dichloromethane (3x25 mL). The combined organic layers were washed with water (25 mL), brine (25 mL) and dried over anhydrous Na2S04. The solvent was evaporated to obtain a crude product, which was further purified by column chromatography in (silica gel, 1 :9 MeOH in CHCI3) to obtain the title compound. (Compound of example 1 1 B was also obtained).
Yield: 0.6 g (36 %); 1H NMR (300 MHz, DMSO-d6): δ 1 .70 (d, 3H, J = 6.5Hz, CH3), 2.19 (s, 3H, CH3), 2.34 (s, 3H, CH3), 3.73 (s, 3H, OCH3), 4.1 1 - 4.16 (q, 1 H, CH), 5.42 (m, 1 H, CH), 6.88 (s, 1 H, Ar), 7.28- 7.40 (m, 5H, Ar), 7.69 (s, 1 H, Ar), 8.38 (s, 1 H, Ar); MS (El, 70 eV): m/z 389.2 (M+H+); HPLC purity: 98.49 % .
Example 11 B:
7-(3,5-Dimethylisoxazol-4-yl)-6-methoxyquinoline-3,4-diamine SnCI2 (2.68 g, 12.90 mmol) was added to a stirred solution of the compound of example 10 (1 .8 g, 4.30 mmol) in a mixture of ethanol (15 mL) and THF (5 mL) and the resulting reaction mixture was heated to reflux for 1 h. After 1 h, the reaction mixture was cooled to 25-30 °C and solvent was removed. Water (25 mL) was added to the resulting residue and was extracted with dichloromethane (3x25 mL). The combined organic layers were washed with water (25 mL), brine (25 mL) and dried over anhydrous Na2S04. The solvent was evaporated to obtain a crude product, which was further purified by column chromatography in (silica gel, 1 :9 MeOH in CHC ) to afford the title compound
Yield: (0.7 g, 57.2 %); 1 H NMR (300 MHz, DMSO-d6): δ 2.09 (s, 3H, CH3 ), 2.28 (s, 3H, CH3), 3.81 (s, 3H, OCH3), 4.78 (s, 2H, NH2, Exchangeable with D2O), 5.79 (s, 2H, NH2, Exchangeable with D2O), 7.42 (s, 1 H, CH), 7.46 (s, 1 H, Ar), 8.10 (s, 1 H, Ar); MS (El, 70 eV): m/z 285.1 (M+H+); HPLC purity: 98.94 % Example 12:
(E)-N-(7-(3,5-dimethylisoxazol-4-yl)-8-methoxy-1 -((R)-1 -phenylethyl)-1 H-imidazo
[4,5-c]quinolin-2(3H)-ylidene)cyanamide
To a stirred solution of the compound of example 1 1A in DMF (10 mL) was added cesium carbonate (0.629 g, 1 .931 mmol) and dimethyl cyanocarbonimidodithioate (0.282 g, 1 .931 mmol) and heated at 80°C for 12 h. The solvent was evaporated and water (25 mL) was added to the resulting residue. The reaction mixture was extracted with ethyl acetate (3x25 mL) and the combined organic layers were washed with brine (50 mL) and dried (Na2SO4). The solvent was evaporated to obtain a crude solid, which was purified using column chromatography (silica gel, 1 :9:0.01 MeOH: CHCI3: triethylamine) to obtain the title compound.
Yield: 0.05g (17.72 %); 1H NMR (300 MHz, DMSO-d6): δ 1 .97 - 2.01 (d, 3H, J = 6.9Hz, CH3), 2.02 (s, 3H, CH3), 2.24 (s, 3H, CH3 ), 3.30 (s, 3H, OCH3 ), 6.41 - 6.46 (q, 1 H, CH), 6.64 (s, 1 H, Ar), 7.41 (m, 5H, Ar), 7.89 (s, 1 H, Ar), 8.83 (s, 1 H, Ar); MS (El, 70 eV), m/z 439.4 (M+H+); HPLC purity: 99.40% .
Example 13:
(E)-N-(7-(3,5-dimethylisoxazol-4-yl)-8-methoxy-1 H-imidazo[4,5-c]quinolin-2(3H)- ylidene)cyanamide The compound of example 12 (0.25 g, 0.879 mmol) and dimethyl cyanocarbonimidodithioate (0.257 g, 1 .759 mmol) were mixed together and heated to 120 °C for 30 min. The resulting reaction mixture was cooled to room temperature. Water (25 mL) was added to the resulting residue and extracted with dichloromethane (3x25 mL). The combined organic layers were washed with brine (25 mL), and dried over anhydrous Na2S04. The solvent was evaporated to obtain a crude product, which was purified by column chromatography (silica gel, 9:1 CHC : MeOH) to obtain the title compound
Yield: 0.16 g (54.48 .00 %); 1H NMR (300 MHz, DMSO-d6): δ 2.12 (s, 3H, CH3); 2.32 (s, 3H, CH3) 3.94 (s, 3H, OCH3), 7.84-7.95 (m, 2H, Ar), 8.62 (s, 1 H, Ar), MS (El, 70 eV): m/z 335.1 (M+H+); HPLC purity: 98.94 %.
Example 14:
N-Benzyl-7-(3,5-dimethylisoxazol-4-yl)-6-methoxy-3-nitroquinolin-4-amine
Phenylmethanamine (0.389 g, 3.63 mmol) was added to a stirred solution of the compound of example 5 (1 .1 g, 3.30 mmol) in acetonitrile (10 mL) and the reaction mixture was heated to reflux for 2 h. The reaction mixture was cooled to room temperature and the solvent was evaporated. Water (25mL) was added to the resulting residue and extracted with ethyl acetate (2x25 mL). The combined organic layers were washed with water (25 mL) and brine (25 mL) and further dried over anhydrous Na2S04. The solvent was evaporated to obtain a crude product, which was further purified by column chromatography (silica gel, 7:3 petroleum ether: ethyl acetate) to obtain the title compound.
Yield: 1 .33 g (96 .0 %); 1H NMR (300 MHz, DMSO-d6): δ 2.1 1 (s, 3H, CH3), 2.48 (s, 3H, CH3), 3.73 (s, 3H, OCH3), 4.88 (d, 1 H, J= 6.3Hz, CH2), 7.32 -7.75 (m, 5H, Ar), 7.77 (s, 1 H, Ar), 7.90 (s, 1 H, Ar), 9.01 (s, 1 H, Ar); MS (El, 70 eV): m/z 405.1 (M+H+); HPLC purity: 99.59 % .
Example 15:
N4-Benzyl-7-(3,5-dimethylisoxazol-4-yl)-6-methoxyquinoline-3,4-diamine
SnCI2 (2.67 g, 12.86 mmol) was added to a stirred solution of the compound of example 14 (1 .3 g, 3.21 mmol) in a mixture of ethanol (15 mL) and THF (5 mL) and the resulting reaction mixture was heated to reflux for 1 h. After 1 h, reaction mixture was cooled to 25-30 °C and solvent was removed. Water (25 mL) was added to the resulting residue and was extracted with dichloromethane (3x25 mL). The combined organic layers were washed with water (25 mL), brine (25 mL) and dried over anhydrous Na2S04. The solvent was evaporated to obtain a crude title compound, which was used for the next step, without purification.
Example 16:
(E)-N-(1-Benzyl-7-(3,5-dimethylisoxazol-4-yl)-8-methoxy-1 H-imidazo[4,5- c]quinolin-2(3H)-ylidene)cyanamide
To a stirred solution of the compound of example 15 (0.3 g, 0.801 mmol) in DMF (5 mL) was added cesium carbonate (0.783 g, 2.404 mmol) and dimethyl cyanocarbonimidodithioate (0.234 g, 1 .602 mmol) and heated at 80 °C for 24 h. The solvent was evaporated and water (25 mL) was added to the resulting residue. The reaction residue was extracted with ethyl acetate (3 x 25 mL). Combined organic layers were washed with brine (50 mL) and dried over anhydrous Na2S04. The solvent was evaporated to obtain the crude product which was further purified by column chromatography (silica gel, 1 :9 MeOH: CHC ) to obtain the title compound.
Yield: 0.064 g (18.25 %); 1 H NMR (300 MHz, DMSO-d6): δ 2.03 (s, 3H, CH3), 2.24 (s, 3H, CH3), 3.60 (s, 3H, OCH3), 5.17 (s, 2H, CH2), 7.23 (s, 1 H, Ar), 7.29 - 7.38 (m, 5H, Ar), 7.87 (s, 1 H, Ar), 8.76 (s, 1 H, Ar), 9.27 (s, 1 H, NH), Exchangeable with D20); MS (El, 70 eV): m/z 425.1 (M+H+); HPLC purity: 96.99 %.
Example 17:
7-(3,5-Dimethylisoxazol-4-yl)-6-methoxy-3-nitro-N-((tetrahydrofuran-2-yl)methyl) quinolin-4-amine
(Tetrahydrofuran-2-yl)methanamine (0.364 g, 3.60 mmol) was added to a stirred solution of the compound of example 5 (0.6 g, 1 .79 mmol) in acetonitrile (10 mL) and heated to reflux for 2 h. After 2 h, the reaction mixture was cooled to room temperature and the solvent was evaporated. Water (25 mL) was added to the resulting residue and the residue was extracted with ethyl acetate (2x25 mL). The combined organic layers were washed with water (25 mL), brine (25 mL) and dried over anhydrous Na2S04. The solvent was evaporated to obtain a crude product, which was further purified by column chromatography (silica gel, 7:3 petroleum ether: ethyl acetate) to obtain the title compound.
Yield: 0.65 g (91 %); 1 H NMR (300 MHz, DMSO-d6): δ 1 .56 - 1 .62 (m, 1 H, CH), 1 .83 - 1 .99 (m, 4H, CH), 2.14 (s, 3H, CH3), 2.33 (s, 3H, CH3), 3.66 - 3.73 (m, 1 H, CH), 3.78 - 3.85 (m, 2H, CH2), 3.97 (s, 3H, OCH3), 4.1 1 - 4.13 (m, 1 H, CH), 7.79 (s, 1 H, Ar), 7.88 (s, 1 H, Ar), 9.00 (s, 1 H, Ar), 9.17 (br s, 1 H, NH, exchangeable with D20); MS (El, 70 eV): m/z 399.1 (M+H+); HPLC purity: 96.90 % .
Example 18:
7-(3,5-Dimethylisoxazol-4-yl)-6-methoxy-N4-((tetrahydrofuran-2-yl)methyl) quinoline-3,4-diamine
SnCI2 (0.625 g, 3.01 mmol) was added to a stirred solution of the compound of example 17 (0.6 g, 1 .50 mmol) in ethanol (20 mL) followed by concentrated HCI (3.0 mL) and the resulting reaction mixture was stirred at room temperature for 3 h. Water (50 mL) was added to the resulting reaction mixture and pH was adjusted to 9-10 with sodium hydroxide solution (2 N). The reaction mixture was extracted with dichloromethane (3x25 mL) and the combined organic layers were washed with water (25 mL), brine (25 mL) and dried over anhydrous Na2S04. The solvent was evaporated to obtain a crude product, which was further purified by column chromatography (silica gel, 95:5 CHCI3: MeOH) to obtain the title compound.
Yield: 0.52 g, (94 %); 1H NMR (300 MHz, DMSO-d6): δ 1 .56 -1 .62 (m, 1 H, CH), 1 .83 - 1 .99 (m, 4H, CH), 2.14 (s, 3H, CH3), 2.33 (s, 3H, CH3), 3.66 - 3.73 (m, 1 H, CH), 3.78 - 3.85 (m, 2H, CH2), 3.97 (s, 3H, OCH3), 4.1 1 - 4.13 (m, 1 H, CH), 4.88 (br s, 1 H, NH, exchangeable with D20), 5.18 (br s, 2H, NH2, exchangeable with D20) 7.39 (s, 1 H, Ar), 7.54 (s, 1 H, Ar), 8.26 (s, 1 H, Ar); MS (El, 70 eV), m/z 369.2 (M+H+); HPLC purity: 94.24 %.
Example 19:
(E)-N-(7-(3,5-Dimethylisoxazol-4-yl)-8-methoxy-1-((tetrahydrofuran-2-yl)methyl)- 1 H-imidazo[4,5-c]quinolin-2(3H)-ylidene)cyanamide
Cesium carbonate (1 .327 g, 4.07 mmol) and dimethyl cyanocarbonimidodithioate (0.298 g, 2.036 mmol) was added to a stirred solution of the compound of example 18 (0.5 g, 1 .357 mmol) in DMF (10 mL) and the resulting reaction mixture was heated to 80 °C for 12-16 h. The reaction mixture was cooled to room temperature, the solvent was evaporated and the resulting residue was quenched in water (25 mL). The solid obtained was filtered and the filtrate was extracted with ethyl acetate (3x25 mL). The combined organic layers were washed with brine (25 mL), dried over anhydrous Na2S04 and the solvent was evaporated to obtain a crude product, which was further purified by column chromatography (silica gel, 9: 1 :0.05 CHC : MeOH: triethylamine) to obtain the title compound.
Yield: 0.120 g (21 .13 %); 1H NMR (300 MHz, DMSO-d6): δ 1 .14 - 1 .18 (m, 1 H, CH),
1 .80 - 2.06 (m, 3H, CH), 2.32 (s, 3H, CH3), 2.48 (s, 3H, CH3), 3.56 - 3.63 (m, 1 H, CH), 3.76 - 3.83 (m, 1 H, CH), 3.96 (s, 3H, OCH3), 4.30 (s, 1 H, CH), 4.50-4.54 (m, 1 H, CH2),
7.81 (s, 1 H, Ar), 7.94 (s, 1 H, Ar), 8.72 (s, 1 H, Ar), 13.51 (br s, 1 H, NH, exchangeable with D20); MS (El, 70 eV): m/z 419.3 (M+H+); HPLC purity: 98.74 % .
Example 20:
7-(3,5-Dimethylisoxazol-4-yl)-6-methoxy-3-nitro-N-phenethylquinolin-4-amine
2-Phenylethanamine (0.508 g, 4.20 mmol) was added to a stirred solution of the compound of example 5 (0.7 g, 2.098 mmol) in acetonitrile (10 mL) and heated to reflux for 3 h. The reaction mixture was cooled to room temperature. The solvent was evaporated and the crude product obtained was purified by column chromatography (silica gel, 2:8 ethyl acetate: pet ether) to obtain the title compound.
Yield: 0.8 g (91 .00 %); 1H NMR (300 MHz, DMSO-d6): δ 2.12 (s, 3H, CH3), 2.32 (s, 3H, CH3), 3.30 (t, 2H, CH2), 3.75 (t, 2H, CH2), 3.95 (s, 3H, OCH3), 7.18 - 7.20 (m, 1 H, Ar), 7.25 - 7.27 (m, 4H, Ar), 7.75 (s, 1 H, Ar), 7.86 (s, 1 H, Ar), 8.61 (s, 1 H, NH, Exchangeable with D20), 8.88 (s, 1 H, Ar); MS (El, 70 eV): m/z 419.2 (M+H+); HPLC purity: 99.69 % .
Example 21 :
7-(3,5-Dimethylisoxazol-4-yl)-6-methoxy-N4-phenethylquinoline-3,4-diamine
Stannous chloride (347 mg, 1 .673 mmol) was added to a stirred solution of the compound of example 20 (0.7 g, 1 .673 mmol) in ethanol (20 mL) followed by addition of hydrogen chloride (0.61 .0 g, 1 .673 mmol). The resulting reaction mixture was stirred at 25-30 °C for 12-16 h and sodium hydroxide (2N) solution (50 mL) was added and extracted with dichloromethane (3x50 mL). The combined organic layers were washed with brine (50 mL) and dried over anhydrous Na2S04. The solvent was evaporated to obtain a crude product, which was further purified by column chromatography (silica gel, 9.5:0.5 CHCI3: MeOH) to obtain the title compound.
Yield: 0.6 g (92.00 %); 1 H NMR (300 MHz, DMSO-d6): δ 2.09 (s, 3H, CH3), 2.28 (s, 3H, CH3), 2.84 (t, 2H, CH2), 3.78 (s, 3H, OCH3), 4.87 (t, 2H, CH2), 5.00 (s, 2H, NH2, Exchangeable with D20), 7.19 (t, 1 H, Ar), 7.24 - 7.28 (m, 5H, Ar), 7.54 (s, 1 H, Ar), 8.27 (s, 1 H, Ar); MS (El, 70 eV): m/z 389.1 (M+H+); HPLC purity: 97.01 %
Example 22:
(E)-N-(7-(3,5-Dimethylisoxazol-4-yl)-8-methoxy-1 -phenethyl-1 H-imidazo[4,5-c] quinolin-2(3H)-ylidene)cyanamide
Cesium carbonate (1 .510 g, 4.63 mmol) was added to a stirred solution of compound of example 21 (600 mg, 1 .545 mmol) and dimethyl cyanocarbonimidodithioate (452 mg, 3.09 mmol) in DMF (10 mL). The resulting reaction mixture is heated to 80 °C for 12-16 h and cooled to room temperature. The solvent was evaporated and water (25 mL) was added to the resulting residue. The reaction mixture was extracted with ethyl acetate (3x25 mL), the combined organic layers were washed with brine (50 mL) and dried over anhydrous Na2S04. The solvent was evaporated to obtain a crude product, which was further purified by column chromatography (silica gel, 1 :9:0.1 MeOH: CHCI3: triethylamine) to obtain the title compound.
Yield: 0.208 g (30.7 %); 1H NMR (300 MHz, DMSO-d6): δ 2.10 (s, 3H, CH3), 2.33 (s, 3H, CH3), 3.17 (t, 2H, CH2), 3.98 (s, 3H, OCH3), 4.71 (t, 2H, CH2), 7.20 (t, 1 H, Ar), 7.24 - 7.29 (m, 4H, Ar), 7.55 (s, 1 H, Ar), 7.96 (s, 1 H, Ar), 8.74 (s, 1 H, Ar), 13.44 (s, 1 H, NH, exchangeable with D2O); MS (El, 70 eV): m/z 439 (M+H+); HPLC purity: 99.72 %.
Example 23:
(E)-N-(7-(3,5-Dimethylisoxazol-4-yl)-8-methoxy-3-methyl-1 -phenethyl-1 H-imidazo
[4,5-c]quinolin-2(3H)-ylidene)cyanamide
Sodium hydride (0.036 g, 0.912 mmol) was added to a stirred solution of the compound of example 22 (0.2 g, 0.456 mmol) in DMF (2 mL) at 0-5 °C. The reaction mixture is stirred at the same temperature for 10 min. lodomethane (0.194 g, 1 .368 mmol) was added and the reaction mixture was allowed to attain a temperature of 25- 30 °C and stirred at the same temperature for 1 h. After 1 h, the reaction mixture was quenched with ice cold water (25 mL) and the residue was extracted with ethyl acetate (2x25 mL). The combined organic layers were washed with water (25 mL), brine (25 mL) and dried over anhydrous Na2S04. The solvent was evaporated to obtain a crude product, which was further purified by column chromatography (silica gel, 9: 1 :0.05 CHC : MeOH: triethylamine) to obtain the title compound.
Yield: 0.02 g (9.69 %); 1H NMR (300 MHz, DMSO-d6): δ 2.14 (s, 3H, CH3), 2.34 (s, 3H, CH3), 3.24 (t, 2H, CH2), 3.96 (s, 3H, NCH3), 3.97 (s, 3H, OCH3), 4.88 (t, 2H, CH2), 7.22 (t, 1 H, Ar), 7.28 - 7.35 (m, 4H, Ar), 7.55 (s, 1 H, Ar), 8.00 (s, 1 H, Ar), 9.027 (s, 1 H, Ar); MS (El, 70 eV): m/z 453.3 (M+H+); HPLC purity: 98.61 % .
Example 24:
7-(3,5-Dimethylisoxazol-4-yl)-6-methoxy-3-nitro-N-(((S)-tetrahydrofuran-2-yl) methyl)quinolin-4-amine
(S)-(Tetrahydrofuran-2-yl)methanamine (0.303 g, 3.00 mmol) was added to a stirred solution of 4-(4-chloro-6-methoxy-3-nitroquinolin-7-yl)-3,5-dimethylisoxazole (1.0 g, 3.00 mmol) in acetonitrile (10 mL) and heated to reflux for 2 hours. The reaction mixture was cooled to room temperature and the solvent was evaporated. Water (25 mL) was added to the resulting residue and the residue was extracted with ethyl acetate (2 x 25 mL). The combined organic layers were washed with water (25 mL), brine (25 mL) and dried over anhydrous Na2S04. The solvent was evaporated to obtain a crude product, which was further purified by column chromatography (silica gel, 7:3 petroleum ether: ethyl acetate) to obtain the title compound.
Yield: 1 .05 g (87 %); 1 H NMR (300 MHz, DMSO-d6): δ 1 .56 - 1 .62 (m, 1 H, CH), 1 .84 - 1 .87 (m, 2H, CH), 1 .89 - 1 .99 (m, 1 H, CH), 2.14 (s, 3H, CH3), 2.34 (s, 3H, CH3), 3.70 - 3.71 (m, 1 H, CH), 3.80 - 3.82 (m, 2H, CH2), 3.97 (s, 3H, OCH3), 4.12 - 4.13 (m,1 H, CH), 7.80 (s, 1 H, Ar), 7.89 (s, 1 H, Ar), 9.01 (s, 1 H, Ar), 9.17 (s, 1 H, NH, exchangable with D20); MS (El, 70 eV): m/z 399.4 (M+H+); HPLC purity: 98.58% .
Example 25:
7-(3,5-Dimethylisoxazol-4-yl)-6-methoxy-N4-(((S)-tetrahydrofuran-2-yl)methyl) quinoline-3,4-diamine
SnCI2 (1 .251 g, 6.02 mmol) was added to a stirred solution of the compound of example 24 (0.8 g, 2.008 mmol) in ethanol (10 mL) followed by concentrated HCI (1 mL, 32.9 mmol) and the resulting reaction mixture was stirred at room temperature for 12 hours. Aqueous sodium hydroxide (2 N, 5 OmL) was added to the reaction mixture and extracted with ethyl acetate (3 x 50 mL). The combined organic layers were washed with brine (50 mL), dried (anhydrous Na2S04) and the solvent was evaporated to obtain a crude product. The crude product obtained was further purified by column chromatography (silica gel, 95:5 CHC : MeOH) to obtain the title compound.
Yield: 0.55 g, (72.0 %); 1 H NMR (300 MHz, DMSO-d6): δ 1.59 - 1 .62 (m, 1 H, CH), 1.81 - 1 .91 (m, 3H, CH), 2.10 (s, 3H, CH3), 2.29 (s, 3H, CH3), 3.15 - 3.22 (m, 2H, CH2), 3.67
- 3.68 (m, 1 H, CH), 3.81 - 3.82 (m, 1 H, CH), 3.89 (s, 3H, OCH3), 3.91 - 3.92 (m, 1 H, CH), 4.81 (t, 1 H, J = 4.2 Hz, NH, exchangeable with D20), 5.18 (s, 1 H, NH2, exchangeable with D20), 7.50 (s, 1 H, Ar), 7.55 (s, 1 H, Ar), 8.27 (s, 1 H, Ar); MS (El, 70 eV): m/z 369.5 (M+H+); HPLC purity: 97.25 %.
Example 26:
(E)-N-(7-(3,5-Dimethylisoxazol-4-yl)-8-methoxy-1 -(((S)-tetrahydrofuran-2-yl) methyl)-1 H-imidazo[4,5-c]quinolin-2(3H)-ylidene)cyanamide
Cesium carbonate (1 .326 g, 4.07 mmol) and dimethyl cyanocarbonimidodithioate (0.794 g, 5.43 mmol) was added to a stirred solution of the compound of example 25 (0.5 g, 1 .357 mmol) in DMF (10 mL) and the resulting reaction mixture was heated to 120 °C for 12-16 h. The reaction mixture was cooled to room temperature, the solvent was evaporated and the resulting residue was quenched in water (25 mL). The solid obtained was filtered and the filtrate was extracted with ethyl acetate (3 x 25 mL). The combined organic layers were washed with brine (25 mL), dried over anhydrous Na2S04 and the solvent was evaporated to obtain a crude product, which was further purified by column chromatography (silica gel, 9: 1 :0.05 CHCI3: MeOH: triethylamine) to obtain the title compound.
Yield: 0.35 g (61 .4 %); 1 H NMR (300 MHz, DMSO-d6): δ 1.81 - 1.92 (m, 3H, CH), 2.10 - 2.1 1 (m, 1 H, CH), 2.13 (s, 3H, CH3), 2.33 (s, 3H, CH3), 3.59 - 3.63 (m, 1 H, CH), 3.79
- 3.82 (m, 1 H, CH), 3.98 (s, 3H, OCH3), 4.31 (s, 1 H, CH), 4.49-4.59 (m, 2H, CH2), 7.82 (s, 1 H, Ar), 7.95 (s, 1 H, Ar), 8.74 (s, 1 H, Ar), 13.53 (br s, 1 H, NH, Exchangeable with
D2O); MS (El, 70 eV): m/z 419.3 (M+H+); HPLC purity: 99.62 % . Example 27:
(E)-N-(7-(3,5-Dimethylisoxazol-4-yl)-8-methoxy-3-methyl-1-(((S)-tetrahydrofuran- 2-yl)methyl)-1 H-imidazo[4,5-c]quinolin-2(3H)-ylidene)cyanamide
Sodium hydride (0.023 g, 0.956 mmol) was added to a solution of the compound of example 26 (0.2 g, 0.478 mmol) in DMF (5 mL) at 0-5 °C followed by iodomethane (0.067 mL, 1 .075 mmol). The resulting reaction mixture was stirred at the same temperature for 0.5 h. and then allowed to warm to room temperature and stirred for 2 h. Water (25 mL) was added to the resulting reaction mixture and extracted with DCM (2 x 25 mL). The combined organic layers were washed with brine (25 mL), dried over anhydrous Na2S04 and the solvent was evaporated to obtain crude product which was purified by using column chromatography (silica gel, 9: 1 :0.05 CHC : MeOH: TEA) to obtain the title compound.
Yield: 0.045 g (21.5 %); 1H NMR (300 MHz, DMSO-d6): δ 1 .84 - 1 .98 (m, 4H, CH), 2.13 (s, 3H, CH3 ), 2.33 (s, 3H, CH3 ), 3.60 - 3.62 (m, 1 H, CH), 3.80 - 3.82 (m, 1 H, CH), 3.97 (s, 6H, 2 x CH3), 4.30 - 4.33 (m, 1 H, CH), 4.40 - 4.69 (m, 2H, CH2), 7.82 (s, 1 H, Ar), 7.97(s, 1 H, Ar), 8.99 (s, 1 H, Ar); MS (El, 70eV): m/z 433.4 (M+H+); HPLC purity: 98.98 % .
Example 28:
7-(3,5-Dimethylisoxazol-4-yl)-6-methoxy-3-nitro-N-(((R)-tetrahydrofuran-2-yl) methyl)quinolin-4-amine
(R)-(Tetrahydrofuran-2-yl)methanamine (0.455 g, 4.49 mmol) was added to a stirred solution of 4-(4-chloro-6-methoxy-3-nitroquinolin-7-yl)-3,5-dimethylisoxazole (1.0 g, 3.00 mmol) in acetonitrile (10 mL) and heated to reflux for 2 h. After 2 h, the reaction mixture was cooled to room temperature and the solvent was evaporated. Water (25 mL) was added to the resulting residue and the residue was extracted with ethyl acetate (2x25 mL). The combined organic layers were washed with water (25 mL), brine (25 mL) and dried over anhydrous Na2S04. The solvent was evaporated to obtain a crude product, which was further purified by column chromatography (silica gel, 7:3 petroleum ether: ethyl acetate) to obtain the title compound.
Yield: 1 .1 g (91 %); 1 H NMR (300 MHz, DMSO-d6): δ 1.58 - 1.62 (m, 1 H, CH), 1 .84 - 1 .87 (m, 2H, CH2), 1 .94 - 1 .98 (m, 1 H, CH), 2.14 (s, 3H, CH3), 2.33 (s, 3H, CH3), 3.70 -
3.72(m, 1 H, CH), 3.80 - 3.84 (m, 2H, CH2), 3.96 (s, 1 H, CH ), 3.97 (s, 3H, OCH3), 4.12 - 4.14 (m, 1 H, CH), 7.80 (s, 1 H, Ar), 7.89 (s, 1 H, Ar), 9.01 (s, 1 H, Ar), 9.17 (s, 1 H, NH, exchangable with D20); MS (El, 70 eV): m/z 399.4 (M+H+); HPLC purity: 98.28% .
Example 29:
7-(3,5-Dimethylisoxazol-4-yl)-6-methoxy-N4-(((R)-tetrahydrofuran-2-yl)methyl) quinoline-3,4-diamine
SnCI2 (1 .042 g, 5.02 mmol) was added to a stirred solution of the compound of example 28 (1 .0 g, 2.510 mmol) in ethanol (10 mL) followed by concentrated HCI (1 mL, 32.9 mmol) and the resulting reaction mixture was stirred at room temperature for 12 h. After this time, aqueous sodium hydroxide (2 N, 50 mL) was added and extracted with ethyl acetate (3 x 50 mL). The combined organic layers were washed with brine (50 mL) and dried over anhydrous Na2S04. The solvent was evaporated to obtain a crude product, which was further purified by column chromatography (silica gel, 95:5 CHCI3: MeOH) to obtain the title compound.
Yield: 0.8 g (84 %); 1 H NMR (300 MHz, DMSO-d6): δ 1.59 - 1.62 (m, 1 H, CH), 1 .81 - 1 .91 (m, 3H, CH and CH2), 2.10 (s, 3H, CH3), 2.29 (s, 3H, CH3), 3.16 - 3.32 (m, 3H,
CH and CH2), 3.67 - 3.68 (m, 1 H, CH), 3.81 - 3.82 (m, 1 H, CH), 3.89 (s, 3H, OCH3), 3.90 - 3.92 (m, 1 H, CH), 4.60 - 4.71 (m, 1 H, NH, exchangeable with D20), 5.18 (s, 1 H, NH, exchangeable with D20), 7.50 (s, 1 H, Ar), 7.55 (s, 1 H, Ar), 8.27 (s, 1 H, Ar); MS (El, 70 eV): m/z 369.5 (M+H+); HPLC purity: 97.67 %.
Example 30:
(E)-N-(7-(3,5-Dimethylisoxazol-4-yl)-8-methoxy-1-(((R)-tetrahydrofuran-2-yl) methyl)-1 H-imidazo[4,5-c]quinolin-2(3H)-ylidene)cyanamide
Diphenyl cyanocarbonimidate (0.356 g, 1 .493 mmol) was added to a stirred solution of the compound of example 29 (0.50 g, 1 .357 mmol) in acetonitrile (10 mL) and the resulting reaction mixture was heated to reflux for 16 h. The reaction mixture was filtered and washed with a mixture of ethyl acetate and petroleum ether to obtain the title compound.
Yield: 0.45 g (79.0 %); 1 H NMR (300 MHz, DMSO-d6): δ 1.83 - 1.93 (m, 3H, CH), 2.07 - 2.1 1 (m, 1 H, CH), 2.14 (s, 3H, CH3), 2.33 (s, 3H, CH3), 3.60 - 3.63 (m, 1 H, CH), 3.79 - 3.83 (m, 1 H, CH), 3.98 (s, 3H, OCH3 ), 4.30 - 4.32 (m, 1 H, CH), 4.48 - 4.57 (m, 2H, CH2), 7.82 (s, 1 H, Ar), 7.95 (s, 1 H, Ar), 8.74 (s, 1 H, Ar), 13.49 (s, 1 H, NH, exchangeable with D20); MS (El, 70 eV): m/z 419.3 (M+H+); HPLC purity: 99.23 %.
Example 31 :
(E)-N-(7-(3,5-Dimethylisoxazol-4-yl)-8-methoxy-1-(((R)-tetrahydrofuran-2-yl) methyl)-1 H-imidazo[4,5-c]quinolin-2(3H)-ylidene)cyanamide
Sodium hydride (0.029 g, 0.717 mmol) was added to a solution of the compound of example 30 (0.15 g, 0.358 mmol) in DMF (2 mL) at 0-5 °C followed by iodomethane (0.067 mL, 1.075 mmol). The reaction mixture was stirred at the same temperature for 0.5 h. and then allowed to warm at room temperature and stirred for 2 h. Water (25 mL) was added to the reaction mixture and extracted with DCM (2x25 mL). The combined organic layer were washed with brine (25 mL) and dried over anhydrous Na2S04. The solvent was evaporated to obtain a crude product, which was purified by column chromatography (silica gel, 9: 1 :0.05 CHC : MeOH: TEA) to obtain the title compound.
Yield: 0.04 g (24.5 %); 1H NMR (300 MHz, DMSO-d6): δ 1 .83 - 1.90 (m, 2H, CH2), 1 .96 - 1 .99 (m, 1 H, CH), 2.14 (s, 3H, CH3), 2.34 (s, 3H, CH3), 3.61 - 3.63 (m, 1 H, CH), 3.85 - 3.86 (m, 1 H, CH), 3.98 (s, 6H, NCH3 and OCH3), 4.30-4.32 (m, 1 H, CH), 4.69 - 4.73 (m, 2H, CH2), 7.83 (s, 1 H, Ar), 7.98 (s, 1 H, Ar), 9.00 (s, 1 H, Ar); MS (El, 70 eV): m/z 433.4 (M+H+); HPLC purity: 99.90%.
Example 32:
7-(3,5-Dimethylisoxazol-4-yl)-6-methoxy-3-nitro-N-((S)-1-phenylethyl)quinolin-4- amine
To a stirrred solution of 4-(4-chloro-6-methoxy-3-nitroquinolin-7-yl)-3,5-dimethyl isoxazole (1.0 g, 3.00 mmol) in acetonitrile (10 mL) was added (S)-1 -phenyl ethanamine (0.726 g, 5.99 mmol) and refluxed for 2 h. On completion of the reaction, the reaction mixture was concentrated and purified by column chromatography (silica gel, 1 : 1 ethyl acetate: petroleum ether) to obtain the title compound.
Yield: 0.5 g, 39.9 %; 1 H NMR (300 MHz, DMSO-d6): δ 1 .70 (d, 3H, J = 6.6 Hz, CH3), 2.08 (s, 3H, CH3), 2.28 (s, 3H, CH3 ), 3.50 (s, 3H, OCH3 ), 5.43 (m, 1 H, CH), 7.29 (t, 1 H, J = 7.2 Hz, Ar), 7.37 (t, 2H, J = 7.5 Hz, Ar), 7.50 (d, J = 7.2 Hz, 2H, Ar), 7.58 (s, 1 H, Ar), 7.78 (s, 1 H, Ar), 9.01 (s, 1 H, Ar), 9.17 (d, 1 H, J = 7.2 Hz, NH); MS (El, 70 eV): m/z 464.2 (M+H+); HPLC purity: 97.75 %.
Example 33:
7-(3,5-Dimethylisoxazol-4-yl)-6-methoxy-N4-((S)-1-phenylethyl)quinoline-3,4- diamine
To a stirred solution of the compound of example 32 (450 mg, 1.075 mmol) in ethanol (20 mL) and hydrochloric acid, 37 % (4.0 mL) was added stannous chloride (670 mg, 3.23 mmol) and stirred for 12 h. After completion of the reaction, 1 N NaOH solution was added and extracted with ethyl acetate and purified by column chromatography (silica gel, 9: 1 CHC : MeOH) to obtain the title compound.
Yield: 0.35 g (84 %) ; 1H NMR (300 MHz, DMSO-d6): δ 1 .53 (d, 3H, J = 6.6 Hz, CH3), 2.06 (s, 3H, CH3), 2.26 (s, 3H, CH3 ), 3.72 (s, 3H, OCH3 ), 4.57 (m, 1 H, Ar), 5.14 (brs, 2H, NH2, exchangeable with D20), 7.13 (m, 1 H, Ar), 7.26 (m, 3H, Ar), 7.47 (m, 3H,Ar), 8.26 (s, 1 H, Ar); MS (El, 70 eV), m/z 464.2 (M+H+); HPLC purity: 97.75 %.
Example 34
(E)-N-(7-(3,5-Dimethylisoxazol-4-yl)-8-methoxy-1 -((S)-1 -phenylethyl)-1 H-imidazo
[4,5-c]quinolin-2(3H)-ylidene)cyanamide
To a stirred solution of the compound of example 33 (300 mg, 0.772 mmol) in DMF (10 mL) was added cesium carbonate (1258 mg, 3.86 mmol) and dimethyl cyanocarbonimidodithioate (339 mg, 2.317 mmol) and heated at 80 °C for 12 h. The solvent was evaporated and water was added to the resulting residue. The mixture was extracted with ethyl acetate (3 x 25 mL). The combined organic layer was washed with brine (25 mL) and dried over anhydrous Na2S04. The solvent was evaporated and the product was purified by column chromatography (silica gel, 9: 1 CHCI3: MeOH) to afford the title compound.
Yield: 120 mg (35.4 %); 1 H NMR (300 MHz, DMSO-d6): δ 1 .67 (d, 3H, J = 6.6 Hz, CH3), 2.07 (s, 3H, CH3), 2.28 (s, 3H, CH3 ), 3.60 (s, 3H, OCH3 ), 5.52 (m, 1 H, CH), 7.26 (t, 1 H, J = 7.2 Hz, Ar), 7.36 (t, 2H, J = 7.5 Hz, Ar), 7.43 (s, 1 H, Ar), 7.51 (d, 2H, J = 7.2 Hz, Ar), 7.65 (s, 1 H, Ar), 8.25 (s, 1 H, Ar), 14.29 (bs, 1 H, NH, exchangeable with D2O); MS (El, 70 eV): m/z 439.3 (M+H+); HPLC purity: 97.26 %. Example 35:
7-(3,5-Dimethylisoxazol-4-yl)-6-methoxy-3-nitro-N-(2-(pyridin-2-yl)ethyl) quinolin- 4-amine
2-(Pyridin-2-yl)ethanamine (0.732 g, 5.99 mmol) was added to a stirred solution of 4- (4-chloro-6-methoxy-3-nitroquinolin-7-yl)-3,5-dimethylisoxazole (1 .0 g, 3.00 mmol) in acetonitrile (5 mL) and heated to reflux for 2 h. After 2 h, the reaction mixture was cooled to room temperature and the solvent was evaporated. Water (25 mL) was added to the resulting residue and the residue was extracted with ethyl acetate (2x25 mL). The combined organic layers were washed with water (25 mL), brine (25 mL) and dried over anhydrous Na2S04. The solvent was evaporated to obtain a crude product, which was further purified by column chromatography (silica gel, 5:5 petroleum ether: ethyl acetate) to obtain the title compound.
Yield: 1 .1 g (86 %); 1H NMR (300 MHz, DMSO-d6): δ 2.12 (s, 3H, CH3), 2.32 (s, 3H, CH3), 3.18 - 3.20 (m, 2H, CH2), 3.93 -3.95 (m, 2H, CH2), 3.96 (s, 3H, CH3), 7.19 -7.32 (m, 2H, Ar), 7.62 - 7.66 (m, 2H, Ar), 7.84 (s, 1 H, Ar), 8.47 (m, 1 H, Ar), 8.90 (m, 2H, Ar); MS (El, 70 eV): m/z 420.2 (M+H+); HPLC purity: 97.94 % .
Example 36:
7-(3,5-Dimethylisoxazol-4-yl)-6-methoxy-N4-(2-(pyridin-2-yl)ethyl)quinoline-3,4- diamine
Stannous chloride (0.520 g, 2.503 mmol) was added to a stirred solution of the compound of example 35 (1 .05 g, 2.503 mmol) in ethanol (20 mL) followed by addition of concentrated HCI (0.076 mL, 2.503 mmol) and the resulting reaction mixture was stirred at room temperature for 12 h. Aqueous sodium hydroxide (2 N, 50 mL) was added and the reaction mixture was extracted with ethyl acetate (3 x 50 mL). The combined organic layers were washed with brine (50 mL) and dried over anhydrous Na2S04. The solvent was evaporated to obtain a crude product, which was further purified by column chromatography (silica gel, 95:5 CHCI3: MeOH) to obtain the title compound.
Yield: 0.8 g (79.0 %); 1H NMR (300 MHz, DMSO-d6): δ 2.09 (s, 3H, CH3), 2.28 (s, 3H, CH3), 3.00 (m, 2H, CH2), 3.32 -3.33 (m, 2H, CH2), 3.82 (s, 3H, CH3), 4.94 (s, 1 H, NH, exchangeable with D20), 5.20 (s, 2H, NH2, exchangeable with D20), 7.21 -7.25 (m, 2H, Ar), 7.28 (s, 1 H, Ar), 7.54 - 7.69 (m, 2H, Ar), 7.27 (m, 1 H, Ar), 8.50 (s, 1 H, Ar); MS (El, 70 eV): m/z 390.5 (M+H+); HPLC purity: 96.32 %.
Example 37:
(E)-N-(7-(3,5-Dimethylisoxazol-4-yl)-8-methoxy-1 -(2-(pyridin-2-yl)ethyl)-1 H- imidazo[4,5-c]quinolin-2(3H)-ylidene)cyanamide
Cesium carbonate (1 .958 g, 6.01 mmol) and dimethyl cyanocarbonimidodithioate (0.879 g, 6.01 mmol) was added to a stirred solution of the compound of example 36 (0.780 g, 2.003 mmol) in DMF (20 ml_) and the resulting reaction mixture was heated to 80 °C for 12-16 h. The reaction mixture was cooled to room temperature, the solvent was evaporated and the resulting residue was quenched in water (25 ml_). The solid obtained was filtered and the filtrate was extracted with ethyl acetate (3x25 ml_). The combined organic layers were washed with brine (25 ml_), dried over anhydrous Na2S04 and the solvent was evaporated to obtain a crude product, which was further purified by column chromatography (silica gel, 9: 1 :0.05 CHC : MeOH: triethylamine) to obtain the title compound.
Yield: 0.51 g (57.2 %); 1 H NMR (300 MHz, DMSO-d6): δ 2.13 (s, 3H, CH3), 2.33 (s, 3H, CH3), 3.29 (m, 2H, CH2), 4.04 (s, 3H, CH3), 4.75-4.78 (m, 2H, CH2), 7.24 -7.28 (m, 1 H, Ar), 7.39 (d, 1 H, J = 7.8 Hz, Ar), 7.74 (t, 1 H, J = 7.8 Hz Ar), 7.85 (s, 1 H, Ar), 7.96 (s, 1 H, Ar), 8.48 (d, 1 H, J = 4.2 Hz, Ar), 8.74 (s, 1 H, Ar), 13.49 (s, 1 H, NH, exchangeable with D20); MS (El, 70 eV): m/z 440.2 (M+H+); HPLC purity: 98.67 % .
Example 38:
(E)-N-(7-(3,5-Dimethylisoxazol-4-yl)-8-methoxy-3-methyl-1-(2-(pyridin-2-yl)ethyl)- 1 H-imidazo[4,5-c]quinolin-2(3H)-ylidene)cyanamide
Sodium hydride (0.027 g, 1 .138 mmol) was added to a solution of the compound of example 37 (0.25 g, 0.569 mmol) in DMF (5 ml_) at 0-5 °C followed by iodomethane (0.161 g, 1 .138 mmol). The reaction mixture was stirred at the same temperature for 0.5 h, allowed to warm at room temperature and stirred for 2 h. Water (25 ml_) was added to the reaction mixture and extracted with DCM (2 x 25 ml_). The combined organic layers were washed with brine (25 ml_), dried over anhydrous Na2S04 and the solvent was evaporated to obtain the crude product, which was further purified by column chromatography (silica gel, 9: 1 :0.05 CHCI3: MeOH: TEA) to obtain the title compound.
Yield: 0.18 g (69.8 %); 1 H NMR (300 MHz, DMSO-d6): δ 2.13 (s, 3H, CH3), 2.33 (s, 3H, CH3), 3.31 -3.37 (m, 2H, CH2), 3.96 (s, 3H, NCH3), 4.01 (s, 3H, OCH3), 4.91 -4.93 (m, 2H, CH2), 7.28 (t, 1 H, J = 6.6 Hz, Ar), 7.43(d, 1 H, J = 7.8 Hz, Ar), 7.64 (t, 1 H, J = 7.5 Hz Ar), 7.89 (s, 1 H, Ar), 8.00 (s, 1 H, Ar), 8.30 (d, 1 H, J = 4.5 Hz, Ar), 9.01 (s, 1 H, Ar); MS (El, 70 eV): m/z 454.3 (M+H+); HPLC purity: 93.22 % .
Example 39:
7-(3,5-Dimethylisoxazol-4-yl)-N-(3,5-dimethylphenyl)-6-methoxy-3-nitroquinolin- 4-amine
3,5-Dimethylaniline (0.363 g, 3.00 mmol) was added to a stirred solution of 4-(4-chloro-
6- methoxy-3-nitroquinolin-7-yl)-3,5-dimethylisoxazole (1.0 g, 3.00 mmol) in acetonitrile (10 ml_) and heated to reflux for 2 h. After 2 h, the reaction mixture was cooled to room temperature and the solvent was evaporated. Water (25 ml_) was added to the resulting residue and the residue was extracted with ethyl acetate (2x25 ml_). The combined organic layers were washed with water (25 ml_), brine (25 ml_) and dried over anhydrous Na2S04. The solvent was evaporated to obtain a crude product, which was further purified by column chromatography (silica gel, 5:5 petroleum ether: ethyl acetate) to obtain the title compound.
Yield: 1 .25 g (97.0 %); 1 H NMR (300 MHz, DMSO-d6): 5 2.14 (s, 3H, CH3), 2.24 (s, 3H, CH3), 2.29 (s, 3H, CH3), 2.35 (s, 3H, CH3), 3.92 (s, 3H, CH3), 6.41 (s, 2H, Ar), 7.94 (s, 1 H, Ar), 7.04 (s, 1 H, NH, exchangable with D20), 7.97 (s, 1 H, Ar), 8.21 (s, 1 H, Ar), 9.15 (s, 1 H, Ar); MS (El, 70 eV): m/z 419.3 (M+H+); HPLC purity: 97.5 %.
Example 40:
7- (3,5-Dimethylisoxazol-4-yl)-N4-(3,5-dimethylphenyl)-6-methoxyquinoline-3,4- diamine
Stannous chloride (1.191 g, 5.74 mmol) was added in portion to a stirred solution of the compound of example 39 (1 .2 g, 2.87 mmol) and concentrated hydrochloric acid (1.434 ml_, 14.34 mmol) in ethanol (20 ml_). The resulting reaction mixture was stirred at room temperature for 16 h. The reaction mixture was quenched in NaOH solution (1 N, 100 ml_) and the resulting solution was extracted with ethyl acetate (3 x 50 ml_). The combined organic layers were washed with water (50 mL), brine (50 mL), dried over anhydrous Na2S04 and the solvent was removed by evaporation to obtain a crude product, which was purified by column chromatography (silica gel, 5:5 petroleum ether: ethyl acetate) to obtain the title compound.
Yield: 0.78 g (69.4 %); 1 H NMR (300 MHz, DMSO-d6): δ 2.09 (s, 3H, CH3), 2.13 (s, 6H, 2 x CH3), 2.29 (s, 3H, CH3), 3.73 (s, 3H, OCH3), 5.14(s, 2H, NH2, exchangable with D20), 6.21 (s, 2H, Ar), 6.35 (s, 1 H, Ar), 7.18 (s, 1 H, Ar), 7.64 (s, 1 H, Ar), 7.66 (s, 1 H, NH, exchangable with D20), 8.44 (s, 1 H, Ar); MS (El, 70 eV): m/z 389.5 (M+H+); HPLC purity: 99.1 1 %.
Example 41 :
(E)-N-(7-(3,5-Dimethylisoxazol-4-yl)-1-(3,5-dimethylphenyl)-8-methoxy-1 H- imidazo[4,5-c]quinolin-2(3H)-ylidene)cyanamide
Cesium carbonate (1837 mg, 5.64 mmol) and dimethyl cyanocarbonimidodithioate (824 mg, 5.64 mmol) was added to a stirred solution of the compound of example 40 (730 mg, 1 .879 mmol) in DMF (20 mL) and the resulting reaction mixture was heated to 80 °C for 12-16 h. The reaction mixture was cooled to room temperature, the solvent was evaporated and the resulting residue was quenched in water (25 mL) and extracted with ethyl acetate (3 x 25 mL). The combined organic layers were washed with brine (25 mL), dried over anhydrous Na2S04 and the solvent was evaporated to obtain a crude product, which was further purified by column chromatography (silica gel, 9: 1 :0.05 CHCI3: MeOH: triethylamine) to obtain the title compound.
Yield: 0.53 g (63.3 %); 1 H NMR (300 MHz, DMSO-d6): δ 2.05 (s, 3H, CH3), 2.25 (s, 3H, CH3), 2.39 (s, 3H, CH3), 2.49 (s, 3H, CH3), 3.34 (s, 3H, OCH3), 6.32 (s, 1 H, Ar), 7.31 - 7.34 (m, 3H, Ar), 7.90 (s, 1 H, Ar), 8.80 (s, 1 H, Ar); MS (El, 70 eV): m/z 439.5 (M+H+); HPLC purity: 97.46 %.
Example 42:
(E)-N-(7-(3,5-Dimethylisoxazol-4-yl)-1-(3,5-dimethylphenyl)-8-methoxy-3-methyl- 1 H-imidazo[4,5-c]quinolin-2(3H)-ylidene)cyanamide
Sodium hydride (0.033 g, 1 .368 mmol) was added to a stirred solution of the compound of example 41 (0.20 g, 0.456 mmol) in DMF (2 mL) at 0-5 °C followed by addition of iodomethane (0.086 mL, 1 .368 mmol) and resulting reaction mixture was stirred at the same temperature for 0.5 h. The reaction mixture was stirred at room temperature for 2 h. Water (25 mL) was added to the reaction mixture and extracted with DCM (2 x 25 mL). The combined organic layers were washed with brine (25 mL), dried over anhydrous Na2S04 and the solvent was removed by evaporation to obtain a crude product, which was further purified by column chromatography (silica gel, 9: 1 :0.05 CHCI3: MeOH: triethylamine) to obtain the title compound.
Yield: 0.12 g (58.0 %); 1 H NMR (300 MHz, DMSO-d6): δ 2.04 (s, 3H, CH3), 2.25 (s, 3H, CH3), 2.39 (s, 6H, 2 x CH3), 3.31 (s, 3H, OCH3), 3.85 (s, 3H, NCH3), 6.23 (s, 1 H, Ar), 7.38-7.42 (m, 3H, Ar), 7.93 (s, 1 H, Ar), 9.07 (s, 1 H, Ar); MS (El, 70 eV): m/z 453.4 (M+H+); HPLC purity: 99.79 %
Example 43:
7-(3,5-Dimethylisoxazol-4-yl)-6-methoxy-3-nitro-N-phenylquinolin-4-amine
Aniline (0.558 g, 5.99 mmol) was added to a stirred solution of 4-(4-chloro-6-methoxy- 3-nitroquinolin-7-yl)-3,5-dimethylisoxazole 1 .0 g, 3.00 mmole) in acetonitrile (10 mL) and heated to reflux for 3 h. The solvent was evaporated and the residue was purified by column chromatography (silica gel, 7:3 ethyl acetate: petroleum ether) to obtain the title compound.
Yield: 1 .05 g, 90 %; 1 H NMR (300 MHz, CDCI3): 5 2.18 (s, 3H, CH3), 2.36 (s, 3H, CH3), 3.26 (s, 3H, OCH3), 7.06 (s, 1 H, Ar), 7.44 (d, 2H, J = 4.2 Hz, Ar), 7.52 (t, 1 H, 4.5 Hz, Ar), 7.62 (d, 2H, J = 4.5 Hz, Ar), 9.54 (s, 1 H, Ar), 1 1 .5 (br, 1 H, NH, exchangeable) MS (El, 70 eV): m/z 391.3 (M+H+).
Example 44:
7-(3,5-Dimethylisoxazol-4-yl)-6-methoxy-N4-phenylquinoline-3,4-diamine
Stannous chloride (0.532 g, 2.56 mmol) was added to a stirred solution of the compound of example 43 (1 g, 2.56 mmol) in ethanol (10 mL) followed by concentrated HCI (2 mL) and the resulting reaction mixture was stirred at room temperature for 12 h. The aqueous sodium hydroxide (2N, 50 mL) was added to the reaction mixture and extracted with DCM (3 x 50 mL). The combined organic layers were washed with brine (50 mL) and dried over anhydrous sodium sulphate. The solvent was evaporated and the residue was purified by column chromatography (silica gel, 5:95 MeOH:CHCI3) to obtain the title compound. Yield: 0.85 g (92 %); 1H NMR (300 MHz, DMSO-d6): δ 2.09 (s, 3H, CH3 ), 2.29 (s, 3H, CH3), 3.69 (s, 3H, OCH3), 5.25 (s, 2H, NH2, exchangeable with D20), 6.59 (d, 2H, J = 4.5 Hz, Ar), 6.70 (t, 1 H, J = 4.2 Hz, Ar), 7.13 (m, 3H, Ar + NH), 7.65 (s, 1 H, Ar), 7.77 (s, 1 H, Ar), 8.45 (s, 1 H, Ar); MS (El, 70 eV): m/z 361 .4 (M+H+).
Example 45:
(E)-N-(7-(3,5-Dimethylisoxazol-4-yl)-8-methoxy-1-phenyl-1 H-imidazo[4,5-c] quinolin-2(3H)-ylidene)cyanamide
To a stirred solution of the compound of example 44 (650 mg, 1 .804 mmol) in DMF (10 ml_) was added cesium carbonate (1763 mg, 5.41 mmol) and then after 15 minutes, dimethyl cyanocarbonimidodithioate (791 mg, 5.41 mmol) was added and heated at 80 °C for 16 h. After completion of the reaction, the solvent was evaporated. The residue was extracted with ethyl acetate and dried over sodium sulphate and purified by preparative HPLC to obtain the title compound.
Yield: 0.2 g (26.9 %); 1 H NMR (300 MHz, DMSO-d6): δ 2.05 (s, 3H, CH3 ), 2.26 (s, 3H, CH3 ), 3.29 (s, 3H, OCH3 ), 6.25 (s, 1 H, Ar), 7.73 (bs, 5H, Ar), 7.93 (s, 1 H, Ar), 8.81 (s, 1 H, Ar), 13.59 (brs, 1 H, NH); MS (El, 70 eV): m/z 41 1.2 (M+H+); HPLC purity: 99.46 %.
Example 46:
(E)-N-(7-(3,5-Dimethylisoxazol-4-yl)-8-methoxy-3-methyl-1 -phenyl-1 H-imidazo
[4,5-c]quinolin-2(3H)-ylidene)cyanamide
To a stirred solution of the compound of example 45 (125 mg, 0.305 mmol) in DMF (5 ml_) was added sodium hydride (24.36 mg, 0.609 mmol) at 0 °C. After 10 minutes, iodomethane (0.038 ml_, 0.609 mmol) was added and stirred for 2 h at room temperature. After completion of the reaction, water was added to quench the reaction mixture. The solvent was evaporated and extracted with ethyl acetate and purified by column chromatography (silica gel, 1 : 1 EtOAc: petroleum ether) to obtain the title compound.
Yield: 0.035 g (27.13 %); 1 H NMR (300 MHz, DMSO-d6): δ 2.03 (s, 3H, CH3), 2.25 (s, 3H, CH3 ), 3.26 (s, 3H, OCH3 ), 3.86 (s, 3H, NCH3 ), 6.13 (s, 1 H, Ar), 7.74 (m, 3H, Ar), 7.81 (s, 2H, Ar), 7.94 (s, 1 H, Ar), 9.08 (s, 1 H, Ar); MS (El, 70 eV): m/z 425.6 (M+H+); HPLC purity: 98.14 % . Example 47:
7-(3,5-Dimethylisoxazol-4-yl)-6-methoxy-3-nitro-N-(o-tolyl)quinolin-4-amine
To a stirred solution of 4-(4-chloro-6-methoxy-3-nitroquinolin-7-yl)-3,5-dimethyl isoxazole (1 .0 g, 3.00 mmol) in acetonitrile (20 ml_) was added o-toluidine (0.642 ml_, 5.99 mmol) and refluxed for 2 h. The solvent was evaporated and the residue was treated with water, extracted with ethyl acetate and dried over anhydrous sodium sulphate. The product obtained was purified by column chromatography (silica gel, 7:3 ethyl acetate: petroleum ether) to obtain the title compound. Yield: 0.68 g (56.1 %). Example 48:
7-(3,5-Dimethylisoxazol-4-yl)-6-methoxy-N4-(o-tolyl)quinoline-3,4-diamine
To a stirred solution of the compound of example 47 (700 mg, 1.731 mmol) in ethanol (10 ml_) and hydrochloric acid, 37 % (2.0 ml_) was added stannous chloride (719 mg, 3.46 mmol). After completion of the reaction, 2 N NaOH solution was added, the reaction mixture was extracted with chloroform (3 x 100 ml_), dried over anhydrous Na2S04 and purified by column chromatography (silica gel, 2:8 methanol: chloroform) to obtain the title compound.
Yield: 0.3 g (46.3 %). Example 49:
(E)-N-(7-(3,5-Dimethylisoxazol-4-yl)-8-methoxy-1-(o-tolyl)-1 H-imidazo[4,5-c] quinolin-2(3H)-ylidene)cyanamide
To a stirred solution of the compound of example 48 (250 mg, 0.668 mmol) in DMF (10 ml_) was added cesium carbonate (653 mg, 2.003 mmol) and then after 15 minutes, dimethyl cyanocarbonimidodithioate (293 mg, 2.003 mmol) was added and heated at 80 °C for 16 h. After completion of the reaction, the solvent was evaporated, the residue was extracted with ethyl acetate, dried over sodium sulphate and purified by column chromatography (silica gel, 9: 1 CHCI3: MeOH) to obtain the title compound. Yield: 0.075 g (26.5 %); 1 H NMR (300 MHz, DMSO-d6): δ 2.04 (s, 3H, CH3), 2.09 (s, 3H, CH3 ), 2.26 (s, 3H, CH3 ), 3.26 (s, 3H, OCH3 ), 6.14 (s, 1 H, Ar), 7.57 (m, 5H, Ar), 7.93 (s, 1 H, Ar), 8.82 (s, 1 H, Ar); MS (El, 70 eV): m/z 425.5 (M+H+); HPLC purity: 93.78 %. Example 50:
7-(3,5-Dimethylisoxazol-4-yl)-N-(2-fluorophenyl)-6-methoxy-3-nitroquinolin-4- amine
To a stirred solution of 4-(4-chloro-6-methoxy-3-nitroquinolin-7-yl)-3,5-dimethyl isoxazole (1 .0 g, 3.00 mmol) in acetonitrile (20 mL) was added 2-fluoroaniline (0.579 mL, 5.99 mmol) and the reaction mixture was refluxed for 2 h. The solvent was evaporated, the residue was treated with water, extracted with ethyl acetate and dried over anhydrous sodium sulphate. The product obtained was purified by column chromatography (silica gel, 7:3 ethyl acetate: petroleum ether) to obtain the title compound.
Yield: 0.71 g (58 %); 1H NMR (300 MHz, DMSO-d6): δ 2.13 (s, 3H, CH3), 2.33 (s, 3H, CH3), 3.85 (s, 3H, OCH3 ), 7.21-7.30 (m, 3H, Ar), 7.90 (s, 1 H, Ar), 7.94 (s, 1 H, Ar), 8.94 (s, 1 H, Ar), 9.82 (s, 1 H, NH, exchangeable with D20); MS (El, 70 eV): m/z 409.2 (M+H+); HPLC purity: 89.02 %.
Example 51 :
7-(3,5-Dimethylisoxazol-4-yl)-N4-(2-fluorophenyl)-6-methoxyquinoline-3,4- diamine
To a stirred solution of the compound of example 50 (700 mg, 1.714 mmol) in ethanol (20 mL) and hydrochloric acid, 37 % (4.00 mL) was added stannous chloride (712 mg, 3.43 mmol) portion wise. After completion of the reaction, 2 N NaOH solution was added, the reaction mixture was extracted with chloroform (3 x 100 mL), dried over anhydrous Na2S04 and purified by column chromatography (silica gel, 2:8 methanol: chloroform) to obtain the title compound.
Yield: 0.4 g (61 .7 %); 1H NMR (300 MHz, DMSO-d6): δ 2.08 (s, 3H, CH3), 2.28 (s, 3H, CH3 ), 3.67 (s, 3H, OCH3 ), 5.40 (s, 2H, NH2, exchangeable with D20), 6.16 (t, 1 H, J = 8.1 Hz, Ar), 6.71 (m, 1 H, Ar), 6.87 (t, 1 H, J = 7.5 Hz, Ar), 7.07 (s, 1 H, Ar), 7.14-7.21 (m, 1 H, Ar), 7.56 (s, 1 H, NH, exchangeable with D20), 7.65 (s, 1 H, Ar), 8.46 (s, 1 H, Ar); MS (El, 70 eV): m/z 379.2 (M+H+); HPLC purity: 77.65 %.
Example 52:
(E)-N-(7-(3,5-Dimethylisoxazol-4-yl)-1-(2-fluorophenyl)-8-methoxy-1 H-imidazo
[4,5-c]quinolin-2(3H)-ylidene)cyanamide To a stirred solution of the compound of example 51 (375 mg, 0.991 mmol) in DMF (10 ml_) was added cesium carbonate (969 mg, 2.97 mmol) and then after 15 minutes, dimethyl cyanocarbonimidodithioate (435 mg, 2.97 mmol) was added and heated at 80 °C for 16 h. After completion of the reaction, the solvent was evaporated, the residue obtained was extracted with ethyl acetate, dried over anhydrous sodium sulphate and purified by preparative HPLC to obtain the title compound.
Yield: 0.060 g (14.13 %); 1 H NMR (300 MHz, DMSO-d6): δ 2.05 (s, 3H, CH3), 2.26 (s, 3H, CH3 ), 3.33 (s, 3H, OCH3 ), 6.31 (s, 1 H, Ar), 7.56 (m, 1 H, Ar), 7.66 (t, 1 H, J = 8.7 Hz, Ar), 7.78 (m, 1 H, Ar), 7.89 (m, 1 H, Ar), 7.95 (s, 1 H, Ar), 8.85 (s, 1 H, Ar), 13.72 (s, 1 H, NH, exchangeable with D20); MS (El, 70 eV): m/z 429.2 (M+H+); HPLC purity: 98.55 %.
Example 53:
(3,5-Dimethylisoxazol-4-yl)-6-methoxy-3-nitro-N-(p-tolyl)quinolin-4-amine
To a stirred solution of 4-(4-chloro-6-methoxy-3-nitroquinolin-7-yl)-3,5-dimethyl isoxazole (1 .0 g, 3.00 mmol) in acetonitrile (20 ml_) was added p-toluidine (0.642 g, 5.99 mmol) and the reaction mixture was refluxed for 2 h. The solvent was evaporated and the residue was treated with water, extracted with ethyl acetate and dried over anhydrous sodium sulphate. The product obtained was purified by column chromatography (silica gel, 7:3 ethyl acetate: petroleum ether) to obtain the title compound.
Example 54:
7-(3,5-Dimethylisoxazol-4-yl)-6-methoxy-N4-(p-tolyl)quinoline-3,4-diamine
To a stirred solution of the compound of example 53 (600 mg, 1.484 mmol) in ethanol (20 ml_) and hydrochloric acid (37 %, 4.00 ml_) was added stannous chloride (616 mg, 2.97 mmol) portion wise. After completion of the reaction, 2 N NaOH solution was added, extracted with chloroform (3 x 100 ml_), dried over anhydrous Na2SO4 and purified by column chromatography (silica gel, 2:8 methanol: chloroform) to obtain the title compound. Example 55:
(E)-N-(7-(3,5-Dimethylisoxazol-4-yl)-8-methoxy-1-(p-tolyl)-1 H-imidazo[4,5- c]quinolin-2(3H)-ylidene)cyanamide
To a stirred solution of the compound of example 54 (275 mg, 0.734 mmol) in DMF (10 ml_) was added cesium carbonate (718 mg, 2.203 mmol) and then after 15 minutes, dimethyl cyanocarbonimidodithioate (322 mg, 2.203 mmol) was added and heated at 80 °C for 16 h. After completion of the reaction, the solvent was evaporated, extracted with ethyl acetate and dried over anhydrous sodium sulphate. The product obtained was purified by preparative HPLC to obtain the title compound.
Yield: 0.045 g (14.44 %); 1 H NMR (300 MHz, DMSO-d6): δ 2.06 (s, 3H, CH3), 2.27 (s, 3H, CH3), 2.47 (s, 3H, CH3), 3.30 (s, 3H, OCH3), 6.28 (s, 1 H, Ar), 7.55-7.66 (m, 4H, Ar), 7.93 (s, 1 H, Ar), 8.81 (s, 1 H, Ar), 13.71 (s, 1 H, NH, exchangeable with D20); MS (El, 70 eV): m/z 425.1 (M+H+); HPLC purity: 87.03 %. Example 56:
7-(3,5-Dimethylisoxazol-4-yl)-6-methoxy-3-nitro-N-(m-tolyl)quinolin-4-amine
To a stirred solution of 4-(4-chloro-6-methoxy-3-nitroquinolin-7-yl)-3,5-dimethyl isoxazole (1 .0 g, 3.00 mmol) in acetonitrile (20 ml_) was added m-toluidine (0.643 ml_, 5.99 mmol) and was refluxed for 2 h. The solvent was evaporated and the residue obtained was treated with water, extracted with ethyl acetate and dried over anhydrous sodium sulphate. The product obtained was purified by column chromatography (silica gel, 7:3 ethyl acetate: petroleum ether) to obtain the title compound.
Yield: 0.4 g (33.0 %). Example 57:
7-(3,5-Dimethylisoxazol-4-yl)-6-methoxy-N4-(m-tolyl)quinoline-3,4-diamine
To a stirred solution of the compound of example 56 (350 mg, 0.865 mmol) in ethanol (20 ml_) and 37 % hydrochloric acid (4.00 ml_) was added portion wise. After completion of the reaction, 2N NaOH solution was added, extracted with chloroform (3 x 100 ml_), dried over anhydrous Na2S04 and purified by column chromatography (silica gel, 2:8 methanol:chloroform) to obtain the title compound.
Yield: 0.25 g (77 %). Example 58:
(Z)-N-(7-(3,5-Dimethylisoxazol-4-yl)-8-methoxy-1-(m-tolyl)-1 H-imidazo[4,5- c]quinolin-2(3H)-ylidene)cyanamide
To a stirred solution of the compound of example 57 (250 mg, 0.668 mmol) in DMF (10 mL) was added cesium carbonate (653 mg, 2.003 mmol) and dimethyl cyanocarbonimidodithioate (293 mg, 2.003 mmol) and heated at 80 °C for 12 h. The solvent was evaporated and water was added to the resulting residue. The mixture was extracted with ethyl acetate (3 x 25 mL). The combined organic layer was washed with brine (25 mL) and dried over anhydrous Na2S04. The solvent was evaporated and purified by column chromatography (silica gel, 1 :1 EtOAc: petroleum ether) to obtain the title compound.
Yield: 0.04 g (14.1 %); 1 H NMR (300 MHz, DMSO-d6): δ 2.04 (s, 3H, CH3), 2.25 (s, 3H, CH3), 2.43 (s, 3H, CH3), 3.30 (s, 3H, OCH3), 6.28 (s, 1 H, Ar), 7.50 - 7.60 (m, 4H, Ar), 7.92 (s, 1 H, Ar), 7.80 (s, 1 H, Ar); MS (El, 70 eV): m/z 425.4 (M+H+); HPLC purity: 98.51 %.
Example 59:
(E)-N-(7-(3,5-Dimethylisoxazol-4-yl)-8-methoxy-3-methyl-1-(p-tolyl)-1 H- imidazo[4,5-c]quinolin-2(3H)-ylidene)cyanamide
To a stirred solution of the compound of example 58 (150 mg, 0.353 mmol) in DMF (5 mL) was added sodium hydride (28.3 mg, 0.707 mmol) at 0 °C. After 10 minutes, iodomethane (0.044 mL, 0.707 mmol) was added and stirred for 2 h at room temperature. After completion of the reaction, water was added to quench the reaction. The solvent was evaporated and the residue was extracted with ethyl acetate and purified by column chromatography (silica gel, 1 :1 EtOAc: petroleum ether) to obtain the title compound.
Yield: 0.05 g (28.1 %); 1 H NMR (300 MHz, DMSO-d6): δ 2.04 (s, 3H, CH3), 2.25 (s, 3H, CH3), 2.46 (s, 3H, CH3), 3.29 (s, 3H, OCH3), 3.83 (s, 3H, NCH3), 6.12 (s, 1 H, Ar), 7.53 (d, 2H, J = 8.1 Hz, Ar), 7.69 (d, 2H, J = 8.1 Hz, Ar), 7.93 (s, 1 H, Ar), 9.07 (s, 1 H, Ar); MS (El, 70 eV): m/z 439.5 (M+H+); HPLC purity: 98.32 %. Example 60:
N-(2-(tert-Butyl)phenyl)-7-(3,5-dimethylisoxazol-4-yl)-6-methoxy-3-nitroquinolin- 4-amine
To a stirred solution of 4-(4-chloro-6-methoxy-3-nitroquinolin-7-yl)-3,5-dimethyl isoxazole (1 .0 g, 3.00 mmol) in acetonitrile (10 ml_) was added 2-(tert-butyl)aniline (0.935 ml_, 5.99 mmol) and the reaction mixture was refluxed for 2 h. The solvent was evaporated and the residue was treated with water, extracted with ethyl acetate, dried over anhydrous sodium sulphate and purified by column chromatography (silica gel, 7:3 ethyl acetate: petroleum ether) to obtain the title compound.
Yield: 0.75 g (56.1 %); 1H NMR (300 MHz, DMSO-d6): δ 1 .93 (s, 9H, f-Bu), 2.06 (s, 3H, CH3), 2.28 (s, 3H, CH3), 3.18 (s, 3H, OCH3), 6.83 (s, 1 H, Ar), 7.27 (t, 1 H, J = 7.2 Hz, Ar), 7.37 (d, 1 H, J = 7.2 Hz, Ar), 7.64 (d, 1 H, J = 6.9 Hz, Ar), 7.82 (s, 1 H, Ar), 9.22 (s, 1 H, Ar); 10.77 (s, 1 H, NH, exchangeable with D20), MS (El, 70 eV): m/z 447.4 (M+H+); HPLC purity: 97.94 %.
Example 61 :
N4-(2-(tert-Butyl)phenyl)-7-(3,5-dimethylisoxazol-4-yl)-6-methoxyquinoline-3,4- diamine
To a stirred solution of the compound of example 60 (650 mg, 1.456 mmol) in ethanol (10 ml_) and 37 % hydrochloric acid (2.0 ml_) was added stannous chloride (605 mg, 2.91 mmol) and stirred for 16 h. After completion of the reaction, 1 N NaOH solution was added and extracted with ethyl acetate and purified by column chromatography (silica gel, 7: 3 ethyl acetate: petroleum ether) to obtain the title compound.
Yield: 0.5 g (82 %); 1H NMR (300 MHz, DMSO-d6): δ 1 .57 (s, 9H, f-Bu) 2.06 (s, 3H, CH3), 2.27 (s, 3H, CH3), 3.51 (s, 3H, OCH3), 5.32 (s, 2H, NH2, exchangeable with D2O), 6.21 (d, 1 H, J = 7.8 Hz, Ar), 6.28 (br, 1 H, NH), 6.77 (t, 1 H, J = 7.2 Hz, Ar), 6.93 (t, 1 H, J = 6.9 Hz, Ar), 7.33 (d, 1 H, J = 7.2 Hz, Ar), 7.64 (s, 1 H, Ar), 8.46 (s, 1 H, Ar); MS (El, 70 eV): m/z 417.6 (M+H+); HPLC purity: 95.30 %. Example 62:
(E)-N-(1-(2-(tert-Butyl)phenyl)-7-(3,5-dimethylisoxazol-4-yl)-8-methoxy-1 H- imidazo[4,5-c]quinolin-2(3H)-ylidene)cyanamide To a stirred solution of the compound of example 61 (400 mg, 0.960 mmol) in DMF (10 ml_) was added cesium carbonate (1564 mg, 4.80 mmol) and dimethyl cyanocarbonimidodithioate (421 mg, 2.88 mmol) and the reaction mixture was heated at 80 °C for 12 h. The solvent was evaporated and water was added to the resulting residue. The mixture was extracted with ethyl acetate (3 x 25 ml_). The combined organic layer was washed with brine (25 ml_) and dried over anhydrous Na2S04. The solvent was evaporated and purified by column chromatography (silica gel, 1 : 1 ethyl acetate: petroleum ether) to obtain the title compound.
Yield: 0.15 g (33.5 %); 1H NMR (300 MHz, DMSO-d6): 5 1 .18 (s, 9H, f-Bu), 2.04 (s, 3H, CH3), 2.26 (s, 3H, CH3 ), 3.24 (s, 3H, OCH3), 6.05 (s, 1 H, Ar), 7.49 (m, 2H, Ar), 7.66 (t, 2H, J = 8.4 Hz, Ar), 7.88 (d, 1 H, J = 8.1 Hz, Ar), 7.93 (s, 1 H, Ar), 8.82 (s, 1 H, Ar); MS (El, 70 eV): m/z 467.6 (M+H+); HPLC purity: 98.49 %.
Example 63:
(E)-N-(1 -(2-(tert-Butyl)phenyl)-7-(3,5-dimethylisoxazol-4-yl)-8-methoxy-3-methyl- 1 H-imidazo[4,5-c]quinolin-2(3H)-ylidene)cyanamide
To a stirred solution of the compound of example 62 (150 mg, 0.322 mmol) in DMF (5 ml_) was added sodium hydride (25.7 mg, 0.643 mmol) at 0 °C. After 10 minutes, iodomethane (0.040 ml_, 0.643 mmol) was added and stirred for 2 h at room temperature. After completion of the reaction, water was added to quench the reaction. The solvent was evaporated and the residue was extracted with ethyl acetate and purified by column chromatography (silica gel, 1 :1 EtOAc: petroleum ether) to obtain the title compound.
Yield: 0.05 g (31 .2 %); 1H NMR (300 MHz, DMSO-d6): δ 1 .20 (s, 9H, f-Bu) 2.04 (s, 3H, CH3), 2.26 (s, 3H, CH3), 3.25 (s, 3H, OCH3), 3.83 (s, 3H, NCH3 ), 6.00 (s, 1 H, Ar), 7.48 (t, 1 H, J = 8.1 Hz, Ar), 7.51 (d, 1 H, J = 7.2 Hz, Ar), 7.70 (t, 1 H, J = 7.2 Hz, Ar), 7.88 (d, 1 H, J = 8.4 Hz, Ar), 7.95 (s, 1 H, Ar), 9.10 (s, 1 H, Ar); MS (El, 70 eV): m/z 481 .2 (M+H+); HPLC purity: 96.79 %. Example 64:
7-(3,5-dimethylisoxazol-4-yl)-6-methoxy-3-nitro-N-(2-phenylpropan-2-yl)quinolin- 4-amine To a stirred solution of 4-(4-chloro-6-methoxy-3-nitroquinolin-7-yl)-3,5- dimethylisoxazole (2.0 g, 5.99 mmol) in acetonitrile (20 mL) was added 2- phenylpropan-2-amine (4.29 mL, 30.0 mmol) and the reaction mixture was refluxed for 2 h. The solvent was evaporated and the residue was treated with water, extracted with ethyl acetate, dried over anhydrous sodium sulphate and purified by column chromatography (silica gel, 7:3 ethyl acetate: petroleum ether) to obtain the title compound.
Yield: 0.95 g (36.7 %); 1H NMR (300 MHz, DMSO-d6): δ 1 .80 (s, 6H, 2 x CH3), 2.03 (s, 3H, CH3), 2.25 (s, 3H, CH3), 2.87 (s, 3H, OCH3), 7.14 (s, 1 H, Ar), 7.33 (t, 2H, J = 8.1 Hz, Ar), 7.46 (t, 2H, J = 7.8 Hz, Ar), 7.77 (brs, 2H, J = 5.1 Hz, Ar), 9.18 (s, 1 H, Ar), 9.69 (s, 1 H, NH, exchangeable with D20); MS (El, 70 eV): m/z 433.1 (M+H+); HPLC purity: 95.64%.
Example 65:
7-(3,5-dimethylisoxazol-4-yl)-6-methoxy-N4-(2-phenylpropan-2-yl)quinoline-3,4- diamine
To a stirred solution of the compound of example 64 (1500 mg, 3.47 mmol) in ethanol (10 mL), THF (10.00 mL) and water (5 mL) was added iron (387 mg, 6.94 mmol) and ammonium chloride (371 mg, 6.94 mmol) and heated at 80 °C for 2 h. The reaction mixture was filtered through celite and the filtrate was concentrated. To the concentrate, ethyl acetate was added and the reaction mixture was washed with saturated sodium bicarbonate. The ethyl acetate layer was concentrated and purified by column chromatography (silica gel, 9: 1 CHCI3: MeOH) to obtain the title compound. Yield: 0.8 g (57.3 %); 1H NMR (300 MHz, DMSO-d6): δ 1 .50 (s, 6H, CH3), 2.04 (s, 3H, CH3), 2.24 (s, 3H, CH3), 3.35 (s, 3H, OCH3), 4.74 (s, 1 H, NH, exchangeable with D20), 5.06 (s, 2H, NH2, exchangeble with D20), 7.04 (s, 1 H, Ar), 7.25 (t, 1 H, J = 7.2 Hz, Ar), 7.38 (t, 1 H, J = 7.8 Hz, Ar), 7.50 (s, 1 H, Ar), 7.74 (d, 3H, J = 7.8 Hz, Ar), 8.30 (s, 1 H, Ar); MS (El, 70 eV): m/z 403.1 (M+H+); HPLC purity: 97.09 %. Example 66:
7-(3,5-Dimethylisoxazol-4-yl)-8-methoxy-1-(2-phenylpropan-2-yl)-1 H-imidazo[4,5- c]quinolin-2(3H)-ylidene)cyanamide To a stirred solution of the compound of example 65 (700 mg, 1 .739 mmol) in DMF (20 mL) was added cesium carbonate (2833 mg, 8.70 mmol) and dimethyl cyanocarbonimidodithioate (763 mg, 5.22 mmol) and heated at 80 °C for 12 h. The solvent was evaporated and water was added to the resulting residue. The mixture was extracted with ethyl acetate (3 x 25 mL). The combined organic layer was washed with brine (25 mL) and dried over anhydrous Na2S04. The solvent was evaporated and the residue was purified by column chromatography (silica gel, 9: 1 CHCI3: MeOH) to obtain the title compound.
Yield: 0.085 g (10.80 %); 1 H NMR (300 MHz, DMSO-d6): δ 2.00 (s, 3H, CH3), 2.20 (s, 3H, CH3), 2.22 (s, 6H, CH3), 3.23 (s, 3H, OCH3), 6.53 (s, 1 H, Ar), 7.30 (m, 1 H, Ar), 7.36 (t, 2H, J = 7.8 Hz, Ar), 7.49 (m, 2H, Ar), 7.83 (s, 1 H, Ar), 8.80 (s, 1 H, Ar), 13.37 (brs, 1 H, NH, exchangeable with D20); MS (El, 70 eV): m/z 452.9 (M+H+); HPLC purity: 93.62 %. Example 67:
7-(3,5-Dimethylisoxazol-4-yl)-6-methoxy-3-nitro-N-(tetrahydro-2H-pyran-4- yl)quinolin-4-amine
To a stirred solution of 4-(4-chloro-6-methoxy-3-nitroquinolin-7-yl)-3,5-dimethyl isoxazole (1 g, 3.00 mmol) in acetonitrile (20 mL) was added tetrahydro-2H-pyran-4- amine (0.620 mL, 5.99 mmol) and refluxed for 2 h. After completion of reaction, the reaction mixture was concentrated and purified by column chromatography (silica gel, 1 : 1 EtOAc: petroleum ether) to obtain the title compound.
Yield: 0.32 g (26.8 %) Example 68:
7-(3,5-Dimethylisoxazol-4-yl)-6-methoxy-N4-(tetrahydro-2H-pyran-4-yl)quinoline- 3,4-diamine
To a stirred solution of the compound of example 67 (300 mg, 0.753 mmol) in ethanol (5 mL), THF (5.0 mL) and water (2.5 mL) was added iron (84 mg, 1 .506 mmol) and ammonium chloride (81 mg, 1 .506 mmol) and heated at 80 °C for 2 h. The reaction mixture was filtered through celite and the filtrate was concentrated. To the concentrate was added ethyl acetate and washed with saturated sodium bicarbonate. The ethyl acetate layer was concentrated and purified by column chromatography (silica gel, 1 : 1 CHCI3: MeOH) to obtain the title compound.
Yield: 0.2 g (72.1 %) Example 69:
7-(3,5-Dimethylisoxazol-4-yl)-8-methoxy-1-(tetrahydro-2H-pyran-4-yl)-1 H-imidazo
[4,5-c]quinolin-2(3H)-ylidene)cyanamide
To a stirred solution of the compound of example 68 (75 mg, 0.204 mmol) in DMF (2 ml_) was added cesium carbonate (332 mg, 1 .018 mmol) and stirred for 15 minutes. To the reaction mixture, dimethyl cyanocarbonimidodithioate (89 mg, 0.61 1 mmol) was added and heated at 80 °C for 16 h. After completion of the reaction, the solvent was evaporated, the residue was extracted with ethyl acetate, dried over anhydrous sodium sulphate and purified using column chromatography (silica gel, 9: 1 CHCI3: MeOH) to obtain the title compound.
Yield: 0.005 g (5.87 %); 1 H NMR (300 MHz, DMSO-d6): δ 1.92 (m, 2H CH2), 2.13 (s, 3H, CH3), 2.32 (s, 3H, CH3), 2.7 (brs, 2H, CH2), 3.56 (t, 2H, J = 1 1 .4 Hz, CH2), 4.0 (s, 3H, CH3), 4.1 (m, 2H, CH2), 5.20 (brs, 1 H, CH), 7.72 (brs, 1 H, Ar), 7.98 (s, 1 H, Ar), 8.74 (s, 1 H, Ar); MS (El, 70 eV): m/z 419.2 (M+H+); HPLC purity: 96.92 %. Example 70:
2-(3-((7-(3,5-dimethylisoxazol-4-yl)-6-methoxy-3-nitroquinolin-4-yl)amino)phenyl)- 1 ,1 ,1 ,3,3,3-hexafluoropropan-2-ol
2-(3-Aminophenyl)-1 , 1 , 1 ,3,3,3-hexafluoropropan-2-ol (2.330 g, 8.99 mmol) was added to a stirred solution of 4-(4-chloro-6-methoxy-3-nitroquinolin-7-yl)-3,5-dimethyl isoxazole (2.0 g, 5.99 mmol) in acetonitrile (10 ml_) and heated to reflux for 3 h. The reaction mixture was cooled to room temperature and the solvent was evaporated. Water (25 ml_) was added to the resulting residue and the residue was extracted with ethyl acetate (2 x 25 ml_). The combined organic layers were washed with water (25 ml_), brine (25 ml_) and dried over anhydrous Na2SO4. The solvent was evaporated to obtain a crude product, which was further purified by column chromatography (silica gel, 5:5 petroleum ether: ethyl acetate) to obtain the title compound.
Yield: 3.23 g (85 %); 1H NMR (300 MHz, DMSO-d6): δ 2.13 (s, 3H, CH3), 2.34 (s, 3H, CH3), 3.82 (s, 3H, OCH3), 7.35 -7.37 (m, 1 H, Ar), 7.50 (s, 2H, Ar), 7.94-7.96 (m, 2H, Ar), 8.83 (s, 1 H, Ar), 9.18 (s, 1 H, Ar), 10.67 (s, 1 H, NH, exchangeable with D20); MS (El, 70 eV): m/z 557.3 (M+H+); HPLC purity: 88.13 %.
Example 71 :
2-(3-((3-amino-7-(3,5-dimethylisoxazol-4-yl)-6-methoxyquinolin-4-yl)amino) phenyl)-1 ,1 ,1 ,3,3,3-hexafluoropropan-2-ol
Stannous chloride (3.81 g, 18.33 mmol) was added to a stirred solution of the compound of example 70 (3.4 g, 6.1 1 mmol) in ethanol (20 mL) followed by concentrated HCI (1.1 14 g, 30.6 mmol) and the resulting reaction mixture was stirred at 50 °C for 1 h. To the reaction mixture was added aqueous sodium hydroxide (2 N, 50 mL) and extracted with DCM (3 x 50 mL). The combined organic layers were washed with brine (50 mL) and dried over anhydrous Na2S04. The solvent was evaporated and the residue was purified by column chromatography (silica gel, 5:95 MeOH: CHCI3) to obtain the title compound.
Yield: 2.4 g (71 .4 %); 1H NMR (300 MHz, DMSO-d6): δ 2.07 (s, 3H, CH3), 2.27 (s, 3H, CH3), 3.61 (s, 3H, OCH3), 5.37(s, 2H, NH2, exchangable with D20 ), 6.69 (d, 1 H, J = 8.1 Hz, Ar), 6.96 (s, 1 H, Ar), 6.99 (s, 1 H, Ar), 7.26 (t, 1 H, J = 4.8 Hz, Ar), 7.64 (s, 1 H, Ar), 7.99 (s, 1 H, Ar), 8.46 (s, 1 H, Ar), 8.46 (s, 1 H, NH, exchangeable with D20); MS (El, 70 eV): m/z 527.4 (M+H+); HPLC purity: 95.66 %.
Example 72:
(E)-N-(7-(3,5-Dimethylisoxazol-4-yl)-1-(3-(1 ,1 ,1 ,3,3,3-hexafluoro-2-hydroxypropan -2-yl)phenyl)-8-methoxy-1 H-imidazo[4,5-c]quinolin-2(3H)-ylidene) cyanamide
Cesium carbonate (5.94 g, 18.24 mmol) and dimethyl cyanocarbonimidodithioate (2 g, 13.68 mmol) was added to a stirred solution of the compound of example 71 (2.4 g, 4.56 mmol) in DMF (20 mL) and the resulting reaction mixture was heated to 120 °C for 12 h. The reaction mixture was cooled to room temperature, the solvent was evaporated and the resulting residue was quenched in water (100 mL) and extracted with ethyl acetate (3 x 100 mL). The combined organic layers were washed with brine (100 mL), dried over anhydrous Na2S04 and the solvent was evaporated to obtain a crude product, which was further purified by column chromatography (silica gel, 9: 1 :0.05 CHCI3: MeOH: triethylamine) to obtain the title compound. Yield: 0.7 g (23.45 %); 1 H NMR (300 MHz, DMSO-d6): δ 2.03 (s, 3H, CH3), 2. 25 (s, 3H, CH3), 3.23 (s, 3H, OCH3), 6.21 (s, 1 H, Ar), 7.88-8.06 (m, 5H, Ar), 8.81 (s, 1 H, Ar), 9.10 (s, 1 H, Ar), 13.68 (s, 1 H, NH, exchangable with D20); MS (El, 70 eV): m/z 577.1 (M+H+); HPLC purity: 88.05 %.
Example 73:
(E)-N-(7-(3,5-Dimethylisoxazol-4-yl)-1 -(3-(1 ,1 ,1 ,3,3,3-hexafluoro-2-methoxy propan-2-yl)phenyl)-8-methoxy-3-methyl-1 H-imidazo[4,5-c]quinolin-2(3H)- ylidene)cyanamide
Sodium hydride (0.104 g, 2.60 mmol) was added to a stirred solution of the compound of example 72 (0.5 g, 0.867 mmol) in DMF (5 mL) at 0-5 °C and iodomethane (0.163 mL, 2.60 mmol) was added. The reaction mixture was stirred for 1 h at room temperature. The reaction mixture was quenched in cold water (50 mL) and extracted with ethyl acetate (3 x 50 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na2S04, evaporated the solvent to get crude product, which was purified by column chromatography (silica gel, 9: 1 CHCI3: MeOH) to obtain the title compound.
Yield: 0.05 g (8.87 %); 1 H NMR (300 MHz, DMSO-d6): δ 2.05 (s, 3H, CH3), 2.26 (s, 3H, CH3), 3.24 (s, 3H, OCH3), 3.53 (s, 3H, OCH3), 3.83 (s, 3H, NCH3), 6.08 (s, 1 H, Ar), 7.97 - 7.98 (m, 3H, Ar), 8.12 - 8.13 (m, 1 H, Ar), 8.21 (s, 1 H, Ar), 9.12 (s, 1 H, Ar); MS (El, 70 eV): m/z 605.7 (M+H+); HPLC purity: 92.99 %.
Example 74:
(E)-N-(7-(3,5-Dimethylisoxazol-4-yl)-1 -(3-(1 ,1 ,1 ,3,3,3-hexafluoro-2-methoxy propan-2-yl)phenyl)-8-methoxy-1 H-imidazo[4,5-c]quinolin-2(3H)-ylidene) cyanamide
This compound was isolated together with the compound of example 73 under the same condition.
Yield: 0.06 g (10.84 %); 1 H NMR (300 MHz, DMSO-d6): δ 2.05 (s, 3H, CH3), 2.26 (s, 3H, CH3), 3.25 (s, 3H, OCH3), 3.52 (s, 3H, OCH3), 6.15 (s, 1 H, Ar), 7.95 - 7.98 (m, 5H, Ar), 8.87 (s, 1 H, Ar), 13.63 (s, 1 H, NH, exchangeable with D20); MS (El, 70 eV): m/z 591 .6 (M+H+); HPLC purity: 92.56 %. Example 75:
2-(4-(((7-(3,5-Dimethylisoxazol-4-yl)-6-methoxy-3-nitroquinolin-4-yl)amino) methyl)phenyl)-1 ,1 ,1 ,3,3,3-hexafluoropropan-2-ol
2-(4-(Aminomethyl)phenyl)-1 , 1 , 1 ,3,3,3-hexafluoropropan-2-ol (1 .637 g, 5.99 mmol) was added to a stirred solution of 4-(4-chloro-6-methoxy-3-nitroquinolin-7-yl)-3,5- dimethylisoxazole (2.0 g, 5.99 mmol) in acetonitrile (20 mL) and heated to reflux for 3 h. The reaction mixture was cooled to room temperature and the solvent was evaporated. Water (25 mL) was added to the resulting residue and the residue was extracted with ethyl acetate (2 x 25 mL). The combined organic layers were washed with water (25 mL), brine (25 mL) and dried over anhydrous Na2S04. The solvent was evaporated to obtain a crude product, which was further purified by column chromatography (silica gel, 1 : 1 petroleum ether: ethyl acetate) to obtain the title compound.
Yield: 1 .85 g (53.0 %); 1 H NMR (300 MHz, DMSO-d6): 5 2.1 1 (s, 3H, CH3), 2.32 (s, 3H, CH3), 3.66 (s, 3H, OCH3), 4.97(s, 2H, CH2), 7.56 (d, 2H, J = 8.4 Hz, Ar), 7.69 (d, 2H, J = 8.4 Hz, Ar), 7.85 (s, 1 H, Ar), 8.19 (s, 1 H, OH, exchangable with D2O), 8.76 (s, 1 H, Ar), 9.29 (s, 1 H, Ar), 10.03 (s, 1 H, NH, exchangable with D2O); MS (El, 70 eV): m/z 571 .4 (M+H+); HPLC purity: 97.86 %. Example 76:
2-(4-(((3-Amino-7-(3,5-dimethylisoxazol-4-yl)-6-methoxyquinolin-4-yl)amino) methyl)phenyl)-1 ,1 ,1 ,3,3,3-hexafluoropropan-2-ol
Stannous chloride (1 .966 g, 9.47 mmol) was added to a stirred solution of the compound of example 75 (1 .8 g, 3.16 mmol) in ethanol (20 mL) followed by concentrated HCI (0.288 mL, 9.47 mmol) and the resulting reaction mixture was stirred at 50 °C for 1 h. To the reaction mixture, aqueous sodium hydroxide (2 N, 50 mL) was added and extracted with DCM (3 x 50 mL). The combined organic layers were washed with brine (50 mL) and dried over anhydrous Na2SO4. The solvent was evaporated and the residue was purified by column chromatography (silica gel, 5:95 MeOH: CHCI3) to obtain the title compound.
Yield: 1.1 g (63.0 %); 1H NMR (300 MHz, DMSO-d6): δ 2.05 (s, 3H, CH3), 2.30 (s, 3H, CH3), 3.63 (s, 3H, OCH3), 4.37 (d, 2H, J = 7.2 Hz, CH2), 5.19 (s, 2H, NH2, exchangable with D2O), 5.44 (s, 1 H, NH, exchangeable with D2O), 7.26 (s, 1 H, Ar), 7.60 (s, 4H, Ar), 8.28 (s, 1 H, Ar), 8.64 (s, 1 H, Ar), 9.29 (s, 1 H, Ar); MS (El, 70 eV): m/z 541 .3 (M+H+); HPLC purity: 97.73 %.
Example 77:
(E)-N-(7-(3,5-Dimethylisoxazol-4-yl)-1 -(4-(1 ,1 ,1 ,3,3,3-hexafluoro-2-hydroxy propan-2-yl)benzyl)-8-methoxy-1 H-imidazo[4,5-c]quinolin-2(3H)-ylidene) cyanamide
Cesium carbonate (2.41 1 g, 7.40 mmol) and dimethyl cyanocarbonimidodithioate (0.812 g, 5.55 mmol) was added to a stirred solution of the compound of example 76 (1.0 g, 1 .850 mmol) in DMF (20 mL) and the resulting reaction mixture was heated to 120 °C for 12 h. The reaction mixture was cooled to room temperature, the solvent was evaporated and the resulting residue was quenched in water (100 mL) and extracted with ethyl acetate (3x100 mL). The combined organic layers were washed with brine (100 mL), dried over anhydrous Na2S04 and the solvent was evaporated to obtain a crude product, which was further purified by column chromatography (silica gel, 9: 1 :0.05 CHC : MeOH: triethylamine) to obtain the title compound.
Yield: 0.17 g (16.0 %); 1 H NMR (300 MHz, DMSO-d6): δ 2.02 (s, 3H, CH3), 2.25 (s, 3H, CH3), 3.48 (s, 3H, OCH3), 5.81 (s, 2H, CH2),7.07 (s, 1 H, Ar), 7.49 (d, 2H, J = 8.1 Hz, Ar), 7.67 (d, 2H, J = 8.1 Hz, Ar), 7.92 (s, 1 H, Ar), 8.74 (s, 1 H, OH, exchangeable with D2O), 8.83 (s, 1 H, Ar); MS (El, 70 eV): m/z 591 .2 (M+H+); HPLC purity: 99.03 %.
Example 78:
(E)-N-(7-(3,5-Dimethylisoxazol-4-yl)-1 -(4-(1 ,1 ,1 ,3,3,3-hexafluoro-2-methoxy propan-2-yl)benzyl)-8-methoxy-3-methyl-1 H-imidazo[4,5-c]quinolin-2(3H)- ylidene)cyanamide
Sodium hydride (0.030 g, 1 .270 mmol) was added to a stirred solution of the compound of example 77 (0.25 g, 0.423 mmol) in DMF (5 mL) at 0-5 °C. To the reaction mixture iodomethane (0.079 mL, 1.270 mmol) was added and the reaction mixture was stirred at same temperature for 30 minutes and slowly raised temperature to 25-30 °C and stirred for 1 h. The reaction was quenched with ice cold water (20 mL), extracted with ethyl acetate (3x20 mL), the combined organic layer was washed with brine (20 mL) and dried over anhydrous Na2SO4. The solvent was evaporated to yield a crude product, which was purified by column chromatography (silica gel, 9: 1 CHCI3: MeOH) to obtain the title compound.
Yield: 0.14 g (53.5 %); 1 H NMR (300 MHz, DMSO-d6): δ 2.02 (s, 3H, CH3), 2.25 (s, 3H, CH3), 3.32 (s, 3H, OCH3), 3.47 (s, 3H, OCH3), 4.10 (s, 3H, NCH3), 5.95(s, 2H, CH2), 707 (s, 1 H, Ar), 7.59 (s, 4H, Ar), 7.94 (s, 1 H, Ar), 9.08 (s, 1 H, Ar); MS (El, 70 eV): m/z 619.2 (M+H+); HPLC purity: 98.46 %.
Example 79:
7-(3,5-dimethylisoxazol-4-yl)-6-methoxy-N-(4-methoxybenzyl)-3-nitroquinolin-4- amine
To a stirred solution of 4-(4-chloro-6-methoxy-3-nitroquinolin-7-yl)-3,5-dimethyl isoxazole (1 .2 g, 3.60 mmol) in acetonitrile (10 mL) was added (4-methoxyphenyl) methanamine (0.940 mL, 7.19 mmol) and refluxed for 2 h. After completion of the reaction, the reaction mixture was concentrated and purified by column chromatography (silica gel, 1 : 1 EtOAc: petroleum ether) to obtain the title compound. Yield: 1 .2 g (77 %); 1H NMR (300 MHz, DMSO-d6): δ 2.13 (s, 3H, CH3), 2.33 (s, 3H, CH3), 3.73 (s, 3H, OCH3), 3.81 (s, 3H, OCH3), 4.80 (d, 2H, J = 3.0 Hz, CH2), 6.91 (d, 2H, J = 5.1 Hz, Ar), 7.26 (d, 2H, J = 4.8 Hz, Ar), 7.79 (s, 1 H, Ar), 7.91 (s, 1 H, Ar), 8.88 (s, 1 H, Ar), 9.21 (bs, 1 H, NH, exchangeable with D20); MS (El, 70 eV): m/z 435.4 (M+H+); HPLC purity: 95.03 %.
Example 80:
7-(3,5-dimethylisoxazol-4-yl)-6-methoxy-N4-(4-methoxybenzyl)quinoline-3,4- diamine
To a stirred solution of the compound of example 79 (1.1 g, 2.53 mmol) in EtOH (20 mL) and hydrochloric acid (37 %, 4.0 mL) was added stannous chloride (1 .051 g, 5.06 mmol) portion wise. After completion of the reaction, 1 N NaOH solution was added, extracted with DCM (3 x 100 mL), dried over anhydrous Na2SO4 and purified by column chromatography (silica gel, 5:95 MeOH: CHCI3 ) to obtain the title compound. Yield: 0.45 g (43.9 %); 1 H NMR (300 MHz, DMSO-d6): δ 2.07 (s, 3H, CH3), 2.27 (s, 3H, CH3), 3.71 (s, 3H, OCH3), 3.86 (s, 3H, OCH3), 4.40 (d, 2H, J = 5.7 Hz, CH2), 5.29 (m, 1 H, NH, exchangaeble with D2O), 6.01 (bs, 2H, NH2, exchangeable with D2O), 6.87 (d, 2H, J = 8.4 Hz, Ar), 7.31 (d, 2H, J = 8.4 Hz, Ar), 7.43 (d, 2H, J = 3.9 Hz, Ar), 8.04 (s, 1 H, Ar); MS (El, 70eV), m/z 405.5 (M+H+); HPLC purity: 96.98 %.
Example 81 :
(E)-N-(7-(3,5-Dimethylisoxazol-4-yl)-8-methoxy-1 -(4-methoxybenzyl)-1 H-imidazo
[4,5-c]quinolin-2(3H)-ylidene)cyanamide
To a stirred solution of the compound of example 80 (400 mg, 0.989 mmol) in DMF (10 mL) was added cesium carbonate (967 mg, 2.97 mmol) and stirred for 15 minutes. To the reaction mixture, dimethyl cyanocarbonimidodithioate (434 mg, 2.97 mmol) was added and heated at 80 °C for 12 h. After completion of the reaction, the solvent was evaporated, extracted with ethyl acetate, dried over anhydrous sodium sulphate and purified by preparative HPLC to obtain the title compound.
Yield: 0.02 g (40 %); 1H NMR (300 MHz, DMSO-d6): δ 2.12 (s, 3H, CH3), 2.32 (s, 3H, CH3), 3.70 (s, 3H, OCH3), 3.98 (s, 3H, OCH3), 5.25 (s, 2H, CH2), 6.90 (d, 2H, J = 7.8 Hz, Ar), 7.33 (d, 2H, J = 7.8 Hz, Ar), 7.88 (s, 1 H, Ar), 7.94 (s, 1 H, Ar), 8.89 (s, 1 H, Ar); MS (El, 70 eV): m/z 455.4 (M+H+); HPLC purity: 97.88 %.
Example 82:
N-(4-chlorobenzyl)-7-(3,5-dimethylisoxazol-4-yl)-6-methoxy-3-nitroquinolin-4- amine
To a stirred solution of 4-(4-chloro-6-methoxy-3-nitroquinolin-7-yl)-3,5-dimethyl isoxazole (2.0 g, 5.99 mmol) in acetonitrile (20 mL) was added (4-chlorophenyl) methanamine (1 .458 mL, 1 1 .99 mmol) and refluxed for 2 h. After completion of the reaction, the reaction mass was concentrated and purified by column chromatography (silica gel, 1 : 1 ethyl acetate: petroleum ether) to obtain the title compound.
Yield: 2.5 g (95 %); 1H NMR (300 MHz, DMSO-d6): δ 2.1 1 (s, 3H, CH3), 2.31 (s, 3H, CH3 ), 3.76 (s, 3H, OCH3 ), 4.82 (d, 2H, J = 5.7 Hz, CH2), 7.36 (d, 2H, J = 8.4 Hz, Ar), 7.41 (d, 2H, J = 8.7 Hz, Ar), 7.79 (s, 1 H, Ar), 7.83 (s, 1 H, Ar), 8.86 (s, 1 H, Ar), 9.19 (bs, 1 H, NH, exchangeable with D20); MS (El, 70 eV): m/z 439.8 (M+H+); HPLC purity: 98.09 %. Example 83:
N4-(4-chlorobenzyl)-7-(3,5-dimethylisoxazol-4-yl)-6-methoxyquinoline-3,4- diamine
To a stirred solution of the compound of example 82 (2.4 g, 5.47 mmol) in ethanol (20 mL) and hydrochloric acid (37 %, 4.00 mL) was added stannous chloride (2.271 g, 10.94 mmol) portionwise. After completion of the reaction, 1 N NaOH solution was added and the reaction mixture was extracted with chloroform (3 x 100 mL), dried over anhydrous sodium sulphate, concentrated and purified by column chromatography (silica gel, 5:95 MeOH: CHCI3) to obtain the title compound.
Yield: 1.5 g (67.1 %); 1H NMR (300 MHz, DMSO-d6): δ 2.06 (s, 3H, CH3), 2.26 (s, 3H, CH3), 3.74 (s, 3H, OCH3), 4.32 (d, 2H, J = 7.2 Hz, CH2), 5.14 (s, 2H, NH2, exchangeable with D20), 5.45 (t, 1 H, J = 7.5 Hz, NH, exchangaeble with D20), 7.33 (d, 3H, J = 9.0 Hz, Ar), 7.44 (d, 2H, J = 8.1 Hz, Ar), 7.51 (s, 1 H, Ar), 8.26 (s, 1 H, Ar); MS (El, 70eV): m/z 409.8 (M+H+); HPLC purity: 99.84 %.
Example 84:
(E)-N-(1-(4-Chlorobenzyl)-7-(3,5-dimethylisoxazol-4-yl)-8-methoxy-1 H-imidazo
[4,5-c]quinolin-2(3H)-ylidene)cyanamide
To a stirred solution of the compound of example 83 (1 .4 g, 3.42 mmol) in DMF (25 mL) was added cesium carbonate (4.46 g, 13.70 mmol) and stirred for 15 minutes. To the reaction mixture, dimethyl cyanocarbonimidodithioate (1 .502 g, 10.27 mmol) was added and the reaction mixture was heated at 80 °C for 12 h. After completion of the reaction, the solvent was evaporated, extracted with ethyl acetate, dried over anhydrous sodium sulphate and purified by preparative HPLC to obtain the title compound.
Yield: 0.25 g (15.91 %); 1 H NMR (300 MHz, DMSO-d6): δ 2.07 (s, 3H, CH3), 2.28 (s, 3H, CH3), 3.68 (s, 3H, OCH3), 5.76 (s, 2H, CH2), 7.23 (s, 1 H, Ar), 7.39 (d, 2H, J = 5.1 Hz, Ar), 7.46 (d, 2H, J = 5.1 Hz, Ar), 7.95 (s, 1 H, Ar), 8.83 (s, 1 H, Ar); MS (El, 70eV): m/z 460.0 (M+H+); HPLC purity: 98.52 %.
Example 85:
(E)-N-(1-(4-Chlorobenzyl)-7-(3,5-dimethylisoxazol-4-yl)-8-methoxy-3-methyl-1 H- imidazo[4,5-c]quinolin-2(3H)-ylidene)cyanamide To a stirred solution of the compound of example 84 (100 mg, 0.218 mmol) in DMF was added sodium hydride (17.43 mg, 0.436 mmol) at 0 °C and stirred for 10 minutes. To the reaction mixture, iodomethane (27.3 μΙ_, 0.436 mmol) was added and stirred for 2 h at room temperature. After completion of the reaction, water was added to the reaction mixture, solvent was evaporated, extracted with ethyl acetate and purified by column chromatography (silica gel, 5:95 MeOH: CHC ) to obtain the title compound. Yield: 0.02 g (19.41 %); 1 H NMR (300 MHz, DMSO-d6): δ 2.12 (s, 3H, CH3), 2.32 (s, 3H, CH3), 3.84 (s, 3H, OCH3), 4.00 (s, 3H, NCH3), 4.46 (bs, 2H, CH2), 7.67 (d, 2H, J = 8.1 Hz, Ar), 7.90 (s, 1 H, Ar), 7.94 (s, 1 H, Ar), 8.21 (d, 1 H, J = 7.8 Hz, Ar), 9.03 (s, 1 H, Ar); MS (El, 70eV): m/z 486.9 (M+H+); HPLC purity: 90.44 %.
Example 86:
(R,E)-N-(7-bromo-8-methoxy-1 -(1 -phenylethyl)-1 H-imidazo[4,5-c]quinolin-2(3H)- ylidene)cyanamide
Cesium carbonate (3.15 g, 9.67 mmol) and dimethyl cyanocarbonimidodithioate (0.389 g, 2.66 mmol) was added to a stirred solution of (R)-7-bromo-6-methoxy-N4-(1 - phenylethyl)quinoline-3,4-diamine (9 g, 2.418 mmol) in DMF (20 ml_) and the reaction mixture was heated at 120 °C for 12 h. The solvent was evaporated, water (25 ml_) was added and extracted with ethyl acetate (3 x 25 ml_). The combined organic layers were washed with brine (50 ml_) and dried over anhydrous Na2S04. The solvent was evaporated to yield a crude product, which was purified by column chromatography (silica gel, 1 :9: few drops MeOH: CHCI3: triethyl amine) to obtain the title compound. Yield: 0.34 g (31.7 %); 1 H NMR (300 MHz, DMSO-d6): δ 1 .96 (d, 3H, J = 6.9 Hz, CH3), 3.35 (s, 3H, OCH3), 6.38 (d, 1 H, J = 7.2 Hz, Ar), 6.59 (t, 1 H, CH), 7.38 (bs, 5H, Ar), 8.27 (s, 1 H, Ar), 8.20 (s, 1 H, Ar), 13.72 (s, 1 H, NH, exchangeable with D2O); MS (El, 70 eV): m/z 423.3 (M+H+); HPLC purity: 95.14 %.
Example 87:
2-(4-((E)-2-(Cyanoimino)-8-methoxy-1 -((R)-1 -phenylethyl)-2,3-dihydro-1 H- imidazo[4,5-c]quinolin-7-yl)-3-methylisoxazol-5-yl)ethyl acetate
PdCl2(dppf)-CH2Cl2 adduct (8.70 mg, 10.66 pmol) was added to a stirred solution of the compound of example 86 (0.15 g, 0.355 mmol) and 2-(3-methyl-4-(4, 4,5,5- tetramethyl-1 ,3,2-dioxaborolan-2-yl)isoxazol-5-yl)ethyl acetate (0.210 g, 0.710 mmol) in DMF (2 mL). To the reaction mixture, sodium carbonate (0.075 g, 0.710 mmol) solution in water (0.4 mL) was added and heated at 120 °C for 1 h. The reaction mixture was then cooled to room temperature and concentrated. Water (10 mL) was added to the residue and extracted with CHCI3 (3x10 mL). The combined organic layers were washed with brine (15 mL), dried over anhydrous Na2S04 and the solvent was evaporated to yield a crude product, which was purified by column chromatography (silica gel, 1 : 1 ethyl acetate: petroleum ether) to obtain the title compound.
Yield: 0.09 g (47.4 %); 1 H NMR (300 MHz, DMSO-d6): δ 1 .81 (s, 3H, CH3), 1 .96 (d, 3H, CH3), 2.02 (s, 3H, CH3), 2.94 (t, 2H, CH2), 3.30 (s, 3H, OCH3), 4.15 (t, 2H, CH2), 6.40 (d, 1 H, Ar), 6.59 (s, 1 H, CH), 7.37 (s, 5H, Ar), 7.84 (s, 1 H, Ar), 8.77 (s, 1 H, Ar), 13.74(s, 1 H, NH, exchangable with D20); MS (El, 70 eV): m/z 51 1 .3 (M+H+); HPLC purity: 95.42 %. Example 88:
(E)-N-(7-(3,5-Dimethyl-1 H-pyrazol-4-yl)-8-methoxy-1 -((R)-1 -phenylethyl)-1 H- imidazo[4,5-c]quinolin-2(3H)-ylidene)cyanamide
In a sealed tube, Pd(Ph3P)4 (0.137 g, 0.474 mmol) was added to a stirred solution of the compound of example 86 (0.2 g, 0.474 mmol) and 3,5-dimethyl-4-(4,4,5,5- tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1 H-pyrazole (0.210 g, 0.947 mmol) in DMF (2 mL) followed by sodium carbonate (0.100 g, 0.947 mmol) solution in water (0.4 mL) and the reaction mixture was heated at 120 °C for 12-18 h. The reaction mixture was then cooled to room temperature and concentrated. Water (10 mL) was added to the resulting residue and extracted with CHCI3 (3 x 10 mL). The combined organic layers were washed with brine (15 mL), dried over anhydrous Na2S04 and the solvent evaporated to obtain the crude product which was purified by column chromatography (silica gel, 1 : 1 ethyl acetate: petroleum ether) to obtain the title compound.
Yield: 0.64 g (29.5 %); 1 H NMR (300 MHz, DMSO-d6): δ 1 .96 (s, 3H, CH3), 2.00 (s, 6H, CH3), 3.26 (s, 3H, OCH3), 6.42 (m, 1 H, CH, 6.59 (s, 1 H, Ar), 7.38 (s, 5H, Ar), 7.69 (s, 1 H, Ar), 8.76 (s, 1 H, Ar), 12.35 (s, 1 H, NH, exchangable with D20); MS (El, 70 eV): m/z 439.3 (M+H+); HPLC purity: 95.37 % . Example 89:
(Z)-5-(((3-Bromo-4-methylphenyl)imino)methyl)-2,2-dimethyl-1 ,3-dioxane-4,6- dione
Triethyl orthoformate (67.1 mL, 403 mmol) and 2,2-dimethyl-1 ,3-dioxane-4,6-dione (20.14 g, 140 mmol) was mixed together and heated to reflux for 1.5 h. To the reaction mixture, 3-bromo-4-methylaniline (25 g, 134 mmol) was added in portions for 5 minutes and heated to reflux for 2 h. The reaction mixture was cooled to room temperature and the solid obtained was filtered, washed with diethyl ether (50 mL) to obtain the title compound.
Yield: 31.0 g (63.3 %); 1 H NMR (300 MHz, CDCI3): δ 1 .77(s, 6H, CH3), 2.42 (s, 3H, CH3), 7.1 1 (dd, 1 H, J = 8.1 Hz, 2.1 Hz, Ar), 7.29 (d, 1 H, J = 8.1 Hz, Ar), 7.48 (d, 1 H, J = 2.1 Hz Ar), 8.59( d, 1 H, J = 14.1 Hz, CH), 1 1 .18( d, 1 H, J = 13.9 Hz, NH, exchangeable with D20); MS (El, 70 eV): m/z 341 .9 (M+H+); HPLC purity: 93.37 %. Example 90:
7-Bromo-6-methylquinolin-4-ol
The compound of example 89 (31 g, 91 mmol) was added in portions to boiling diphenyl ether (120 mL) and maintained reaction at 260 °C for 10 minutes. The reaction mixture was cooled to 100 °C and quenched in pre-cooled petroleum ether (500 mL). The solid precipitated was filtered and washed with hot petroleum ether (2x150 mL) to obtain the title compound.
Yield: 19.5 g (58.2 %); MS (El, 70 eV): m/z 237.9 (M+H+).
Example 91 :
7-Bromo-6-methyl-3-nitroquinolin-4-ol
Nitric Acid (1 1 .26 mL, 252 mmol) was added to a stirred solution of 7-bromo-6- methylquinolin-4-ol (example 90, 20 g, 84 mmol) in acetic acid (150 mL) and the resulting reaction mixture was heated to 120 °C for 2 h and then cooled to room temperature. The solid obtained was filtered, washed with cold water and triturated in ethyl acetate and petroleum ether to obtain the title compound.
Yield: 14.0 g (58.9 %); MS (El, 70 eV): m/z 284.9 (M+H+). Example 92:
4,7-Dibromo-6-methyl-3-nitroquinoline
PBr3 (9.33 mL, 99 mmol) was added dropwise to a stirred solution of the compound of example 91 (14 g, 49.5 mmol) in DMF (70 mL) and the resulting solution was stirred at 25-30°C for 3 h. The reaction mixture was quenched in water (500 mL), the solid obtained was filtered and washed with water and petroleum ether to obtain the title compound.
Yield: 14.0 g (82.0 %); MS (El, 70 eV): m/z 346.9 (M+H+). Example 93:
(R)-7-Bromo-6-methyl-3-nitro-N-(1-phenylethyl)quinolin-4-amine
(R)-I -Phenylethanamine (4.90 g, 40.5 mmol) was added to a stirred solution of the compound of example 92 (7.0 g, 20.23 mmol) in acetonitrile (50 mL) and heated to reflux for 3 h. The solvent was evaporated and the residue was purified by column chromatography (silica gel, chloroform: methanol (9: 1 )) to obtain the title compound. Yield: 7.5 g (96.0 %); 1H NMR (300 MHz, DMSO-d6): δ 1 .67 (d, 3H, J = 6.3 Hz, CH3), 2.30 (s, 3H, CH3), 5.28-5.33 (m, 1 H, CH), 7.22 - 7.40 (m, 5H, Ar), 8.08 (s, 1 H, Ar), 8.32 (s, 1 H, Ar), 8.99 (s, 1 H, Ar), 9.23(d, 1 H, NH, exchangeable with D20); MS (El, 70 eV): m/z 388.1 (M+H+); HPLC purity: 99.75 %.
Example 94:
(R)-7-Bromo-6-methyl-N4-(1-phenylethyl)quinoline-3,4-diamine
Iron (2.169 g, 38.8 mmol) and ammonium chloride (2.077 g, 38.8 mmol) was added to a stirred solution of the compound of example 93 (7.5 g, 19.42 mmol) in the mixture of ethanol (50 mL): THF (50 mL): water (25 mL) and the reaction mixture was heated to reflux for 1 h. The reaction mixture was filtered through celite and washed with ethanol and ethyl acetate. The filtrate was concentrated, diluted with 10 % NaHC03 solution (50 mL) and extracted with ethyl acetate (2x50 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na2S04 and the solvent was evaporated to obtain the title compound.
Yield: 2.62 g (37.8 %); m/z 357.25 (M+H+). Example 95:
(R,E)-N-(7-Bromo-8-methyl-1 -(1 -phenylethyl)-1 H-imidazo[4,5-c]quinolin-2(3H)- ylidene)cyanamide
Diphenyl cyanocarbonimidate (1 .739 g, 7.30 mmol) was added to a solution of the compound of example 94 (2.6 g, 7.30 mmol) in acetonitrile (25 mL) and heated to reflux for 5 h. The solid obtained was filtered and washed with 5% ethyl acetate in petroleum ether to obtain the title compound.
Yield: 2.3 g (77.0 %); 1H NMR (300 MHz, DMSO-d6): δ 1 .94 (d, 3H, J = 6.9 Hz, CH3), 2.21 (s, 3H, CH3), 6.42(q, 1 H, CH), 7.33-7.38 (m, 6H, Ar), 8.25 (s, 1 H, Ar), 8.87 (s, 1 H, Ar), 13.70 (s, 1 H, NH, exchangable with D20); MS (El, 70 eV): m/z 408.1 (M+H+); HPLC purity: 99.79 % .
Example 96:
(E)-N-(7-(3,5-Dimethylisoxazol-4-yl)-8-methyl-1-((R)-1-phenylethyl)-1 H-imidazo
[4,5-c]quinolin-2(3H)-ylidene)cyanamide
[1 ,1 '-Bis(diphenylphosphino)ferrocene]dichloro palladium(ll) complex with dichloromethane (40.2 mg, 0.049 mmol) was added to a stirred solution of the compound of example 95 (400 mg, 0.985 mmol) and (3,5-dimethylisoxazol-4- yl)boronic acid (208 mg, 1 .477 mmol) in DMF (10 mL). To the reaction mixture sodium carbonate (209 mg, 1.969 mmol) solution in water (2.0 mL) was added and heated at 120 °C for 2 h. The reaction mixture was then cooled to room temperature and concentrated. Water (20 mL) was added and extracted with CHCI3 (3x20 mL). The combined organic layers were washed with brine (25 mL), dried over anhydrous Na2S04 and the solvent was evaporated to obtain crude product which was purified by column chromatography (silica gel, 9: 1 CHCI3: Methanol) to obtain the title compound. Yield: 0.34 g (82.0 %); 1 H NMR (300 MHz, DMSO-d6): δ 1 .96 -2.00 (m, 9H, CH3), 2.18 (d, 3H, J = 8.7 Hz, CH3), 6.45 (d, 1 H, J = 6.9 Hz, CH), 7.34 - 7.42 (m, 6H, Ar), 7.84 (s, 1 H, Ar), 8.89 (s, 1 H, Ar), 13.67 (s, 1 H, NH, exchangeable with D20); MS (El, 70 eV): m/z 423.1 (M+H+); HPLC purity: 99.84 %.
Example 97:
(E)-N-(7-(3,5-Dimethylisoxazol-4-yl)-3,8-dimethyl-1 -((R)-1 -phenylethyl)-1 H- imidazo[4,5-c]quinolin-2(3H)-ylidene)cyanamide Sodium hydride (0.038 g, 0.947 mmol) was added to a stirred solution of the compound of example 96 (0.2 g, 0.473 mmol) in DMF (2 mL) at 0-5 °C. To the reaction mixture, iodomethane (0.059 mL, 0.947 mmol) was added and stirred at 0-5 °C for 30 minutes. The reaction mixture was stirred for 1 h at room temperature, quenched in ice cold water (20 mL) and extracted with ethyl acetate (3 x 20 mL). The combined organic layers were washed with brine (20 mL), dried over anhydrous Na2S04 and the solvent was evaporated to yield a crude product, which was purified by column chromatography (silica gel, 9: 1 CHC : MeOH) to obtain the title compound. Yield: 0.13 g (62.4 %); 1 H NMR (300 MHz, DMSO-d6): δ 2.00 -2.1 1 (m, 9H, CH3), 2.24 (d, 3H, J = 10.5 Hz, CH3), 4.28 (s, 3H, CH3), 6.71-6.73 (m, 1 H, CH), 7.34 - 7.41 (m, 6H, Ar), 7.88 (s, 1 H, Ar), 8.88 (s, 1 H, Ar); MS (El, 70 eV): m/z 437.2 (M+H+); HPLC purity: 98.40 %.
Example 98:
(E)-N-(7-(3,5-Dimethyl-1 H-pyrazol-4-yl)-8-methyl-1 -((R)-1 -phenylethyl)-1 H-imidazo
[4,5-c]quinolin-2(3H)-ylidene)cyanamide
In a sealed tube, Pd(Ph3P)4 (28.4 mg, 0.098 mmol) was added to a stirred solution of the compound of example 95 (400 mg, 0.985 mmol) and (3,5-dimethyl-1 H-pyrazol-4- yl)boronic acid (207 mg, 1 .477 mmol) in DMF (10 mL). To the reaction mixture, sodium carbonate (209 mg, 1.969 mmol) solution in water (2.0 mL) was added and heated to 120°C for 1 h. The reaction mixture was then cooled to room temperature, concentrated, water (20 mL) was added and extracted with CHCI3 (3x10 mL). The combined organic layers were washed with brine (25 mL), dried over anhydrous Na2S04 and the solvent was evaporated to obtain crude product which was purified by column chromatography (silica gel, 9: 1 CHCI3: MeOH) to obtain the title compound.
Yield: 0.18 g (42.0 %); 1H NMR (300 MHz, DMSO-d6): δ 1 .93 - 1.98 (m, 9H, CH3), 2.50 (s, 3H, CH3), 6.46 (m, 1 H, CH), 7.34-7.41 (m, 6H, Ar), 7.70 (s, 1 H, Ar), 8.87 (s, 1 H, Ar), 12.35 (s, 1 H, NH, exchangable with D2O), 13.71 (s, 1 H, NH, exchangeable with D2O); MS (El, 70 eV): m/z 422.2 (M+H+); HPLC purity: 96.91 %.
Example 99:
Ethyl 2-(4-((E)-2-(cyanoimino)-8-methyl-1 -((R)-1 -phenylethyl)-2,3-dihydro-1 H- imidazo[4,5-c]quinolin-7-yl)-3-methylisoxazol-5-yl)acetate PdCI2(dppf)-CH2Cl2 adduct (0.012 g, 0.015 mmol) was added to a stirred solution of the compound of example 95, 0.2 g, 0.492 mmol) and ethyl 2-(3-methyl-4-(4, 4,5,5- tetramethyl-1 ,3,2-dioxaborolan-2-yl)isoxazol-5-yl)acetate (0.203 g, 0.689 mmol) in DMF (5 mL). To the reaction mixture, sodium carbonate (0.104 g, 0.985 mmol) solution in water (1.0 mL) was added and heated to 120 °C for 4 h. The reaction mixture was then cooled to room temperature, concentrated, water (20 mL) was added and extracted with CHC (3 x 20 mL). The combined organic layers were washed with brine (25 mL), dried over anhydrous Na2S04 and the solvent was evaporated to yield a crude product, which was purified by column chromatography (silica gel, 9: 1 CHCI3: MeOH) to obtain the title compound.
Yield: 0.14 g (53.6 %); 1H NMR (300 MHz, DMSO-d6): δ 0.96 - 1.05 (m, 3H, CH3), 1 .96 (s, 3H, CH3), 1 .98 (s, 3H, CH3), 2.02 (s, 3H, CH3), 3.73 - 3.78 (m, 2H, CH2), 3.83- 3.98 (m, 2H, CH2), 6.43 - 6.45(m, 1 H, J = 7.2 Hz, CH), 7.33 - 7.41 (m, 6H, Ar), 7.83 (s, 1 H, Ar), 8.89 (s, 1 H, Ar), 13.70 (s, 1 H, NH, exchangeable with D20); MS (El, 70 eV): m/z 495.2 (M+H+); HPLC purity: 93.23 %.
Example 100:
(E)-N-(7-(5-(2-Hydroxyethyl)-3-methylisoxazol-4-yl)-8-methyl-1-((R)-1-phenyl ethyl)-1 H-imidazo[4,5-c]quinolin-2(3H)-ylidene)cyanamide
Sodium methoxide (0.032 g, 0.588 mmol) was added to a stirred solution of the compound of example 99 (0.1 g, 0.196 mmol) in methanol (1 mL) and stirred at room temperature for 2 h. Methanol was evaporated and residue was diluted with water (10 mL), extracted with ethyl acetate (2 x 10 mL). The combined organic layers were washed with brine (10 mL), dried over anhydrous Na2S04 and evaporated the solvent to yield a crude product, which was purified by column chromatography (silica gel, 9: 1 CHCI3 MeOH) to obtain the title compound.
Yield: 0.062 g (64.9 %); 1 H NMR (300 MHz, CDCI3): δ 2.08 (s, 3H, CH3), 2.1 1 (s, 3H, CH3), 2.92 (t, 2H, J = 6.0 Hz, CH2), 3.30 (s, 3H, CH3), 3.93 (t, 2H, J = 6.0 Hz, CH2), 6.60 - 6.62 (m, CH), 6.70 (s, 1 H, Ar), 7.35-7.42 (m, 5H, Ar), 7.96 (s, 1 H, Ar), 8.94 (s, 1 H, Ar), 13.70 (s, 1 H, NH, exchangable with D2O); MS (El, 70 eV): m/z 469.2 (M+H+); HPLC purity: 96.02 %. Example 101 :
3-(3,5-dimethylisoxazol-4-yl)aniline
[1 ,1 '-Bis(diphenylphosphino)ferrocene]dichloro palladium(ll) complex with dichloromethane (1 1 .87 g, 14.53 mmol) was added to a stirred solution of 3- bromoaniline (50 g, 291 mmol) and (3,5-dimethylisoxazol-4-yl)boronic acid (53.3 g, 378 mmol) in DMF (150 mL). To the reaction mixture sodium carbonate (61 .6 g, 581 mmol) solution in water (40 mL) was added and was heated to 120 °C for 1 h. The reaction mixture was then cooled to room temperature, concentrated, water (200 mL) was added and extracted with CHCI3 (3x100 mL). The combined organic layers were washed with brine (150 mL), dried over anhydrous Na2S04 and the solvent was evaporated to give a crude product, which was purified by column chromatography (silica gel, 1 : 1 ethyl acetate: pet ether) to obtain the title compound.
Yield: 32 g (58 %); 1 H NMR (300 MHz, DMSO-d6): δ 2.19 (s, 3H, CH3), 2.37 (s, 3H, CH3), 6.47 (d, 1 H, J= 4.5 Hz, Ar), 6.53 (s, 1 H, Ar), 6.56 (d, 1 H, J = 5.1 Hz, Ar), 7.09( t, 1 H, J= 4.5 Hz, Ar); MS (El, 70 eV): m/z 189.0 (M+H+); HPLC purity: 99.76 %.
Example 102:
5-(((3-(3,5-Dimethylisoxazol-4-yl)phenyl)amino)methylene)-2,2-dimethyl-1 ,3- dioxane-4,6-dione
2,2-Dimethyl-1 ,3-dioxane-4,6-dione (24.50 g, 170 mmol) and 1 , 1 , 1 -trimethoxyethane (200 mL) was mixed together and heated to reflux for 1 h. To the reaction mixture, 3- (3,5-dimethylisoxazol-4-yl)aniline (32 g, 170 mmol) was added in portions and heated to 1 10 °C for 2.5 h. The reaction mixture was cooled to room temperature, the solid obtained was filtered and washed with diethyl ether (200 mL) to obtain the title compound.
Yield: 51 g (88 %).
Example 103:
7-(3,5-Dimethylisoxazol-4-yl)quinolin-4-ol
The compound of example 102 (51 g, 149 mmol) was added to boiling diphenyl ether (450 mL) and stirred for 10 minutes. The reaction mixture was then cooled to 100 °C and diluted with petroleum ether (60 mL). The solid obtained was filtered and washed with hot petroleum ether to obtain the title compound. Yield: 27 g (76%); MS (El, 70 eV): m/z 241.4 (M+H+); HPLC purity: 60.00 %. Example 104:
7-(3,5-dimethylisoxazol-4-yl)-3-nitroquinolin-4-ol
Nitric acid (10.63 ml_, 166 mmol) was added to a stirred solution of the compound of example 103 (16 g, 66.6 mmol) in acetic acid (300 ml_). The resulting reaction mixture was heated to 120 °C for 2 h and cooled to room temperature. The solid obtained was filtered and washed with cold water followed by diethyl ether. The solid was dried under high vacuum to obtain the title compound.
Yield: 8 g (42 %); MS (El, 70 eV): m/z 286.4 (M+H+).
Example 105:
4-(4-chloro-3-nitroquinolin-7-yl)-3,5-dimethylisoxazole
POC (30 ml_) was added to the compound of example 104 (7.8 g, 27.3 mmol) and heated to reflux for 2 h. The excess POCI3 was removed and the resulting residue was quenched with aqueous saturated bicarbonate solution (25 ml_). The aqueous layer was extracted with CH2CI2 (2 x 50 ml_). The combined organic layer was washed with brine (50 ml_), dried over anhydrous Na2S04, concentrated and purified by trituration in DCM and petroleum ether to obtain the title compound.
Yield: 2.0 g (27.0 %); 1H NMR (300 MHz, DMSO-d6): δ 2.08 (s, 3H, CH3), 2.48 (s, 6H, CH3), 7.57 (d, 1 H, J= 8.4 Hz, Ar), 7.82 (s, 1 H, Ar), 8.31 (d, 1 H, J = 8.1 Hz, Ar), 9.23 (s, 1 H, Ar); MS (El, 70 eV): m/z 304.7 (M+H+); HPLC purity: 95.36 %.
Example 106:
(R)-7-(3,5-dimethylisoxazol-4-yl)-3-nitro-N-(1-phenylethyl)quinolin-4-amine
(R)-I -Phenylethanamine (0.798 g, 6.59 mmol) was added to a stirred solution of the compound of example 105 (1 g, 3.29 mmol) in acetonitrile (10 ml_) and heated to reflux for 2 h. The reaction mixture was cooled to room temperature and the solvent was evaporated. Water (25 ml_) was added to the resulting residue and the residue was extracted with ethyl acetate (2 x 25 ml_). The combined organic layers were washed with water (25 ml_), brine (25 ml_) and dried over anhydrous Na2S04. The solvent was evaporated to obtain a crude product, which was further purified by column chromatography (silica gel, 7:3 petroleum ether: ethyl acetate) to obtain the title compound.
Yield: 800 mg (72 %); 1 H NMR (300 MHz, DMSO-d6): δ 1.70 (d, 3H, J = 1.2 Hz, CH3), 2.92 (s, 6H, CH3), 5.34 (t, 1 H, J = 6.9 Hz, CH), 7.15- 7.18 (m, 1 H, Ar), 7.21 -7.26 (m, 2H, Ar), 7.31 -7.35 (m, 3H, Ar), 7.44 (d, J=7.2 Hz, 2H, Ar), 7.65(s, 1 H, Ar), 8.04 (d, J= 7.2 Hz 1 H, Ar), 8.38 (s, 1 H, Ar) 9.18 (bs, 1 H, NH, exchangeable with D20); MS (El, 70 eV): m/z 389.1 (M+H+); HPLC purity: 92.82 %.
Example 107:
(R)-7-(3,5-dimethylisoxazol-4-yl)-N4-(1 -phenylethyl)quinoline-3,4-diamine
Stannous Chloride (1084 mg, 4.80 mmol) was added to a stirred solution of the compound of example 106 (933 mg, 2.402 mmol) in ethanol (10 mL) followed by concentrated HCI (2 mL) and the resulting reaction mixture was stirred at room temperature for 12 h. To the reaction mixture, aqueous sodium hydroxide (2N, 50 mL) was added and extracted with DCM (3 x 50 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na2S04, the solvent was evaporated and the residue was purified by column chromatography (silica gel, 5:95 MeOH: CHCI3) to obtain the title compound.
Yield: 252 mg (29 %); 1H NMR (300 MHz, DMSO-d6): δ 1.51 (d, 3H, J =1.2 Hz, CH3), 2.25 (s, 3H, CH3), 2.42 (s, 3H, CH3), 4.17 (bs, 1 H, NH, exchangeable with D20), 5.15 (s, 2H, NH2, exchangeable with D20), 5.21 (bs, 1 H, CH), 7.15 - 7. 17 (m, 1 H, Ar), 7.22 -7.27 (m, 2H, Ar), 7.31 -7.34 (m, 1 H, Ar), 7.44 (d, J= 1.2 Hz, 2H, Ar), 7.65(s, 1 H, Ar), 8.04 (d, J=7.2 Hz, 1 H, Ar), 8.38 (s, 1 H, Ar); MS (El, 70 eV): m/z 359.2 (M+H+); HPLC purity: 96.22% .
Example 108:
(R,E)-N-(7-(3,5-Dimethylisoxazol-4-yl)-1 -(1 -phenylethyl)-1 H-imidazo[4,5-c] quinolin-2(3H)-ylidene)cyanamide
Dimethyl cyanocarbonimidodithioate (310 mg, 2.1 18 mmol and cesium carbonate (690 mg, 2.1 18 mmol) were added to a stirred solution of the compound of example 107 (253 mg, 0.706 mmol) in DMF (3 mL) and the reaction mixture was heated to 85 °C for 12 h. The reaction mixture was cooled to room temperature, the solvent was evaporated and the residue was quenched in water (10 mL). The solid obtained was filtered and the filtrate was extracted with ethyl acetate (3x10 mL). The combined organic layers were washed with brine (15 mL), dried over anhydrous Na2S04 and the solvent was evaporated to obtain a crude product, which was further purified by preparative thin layer chromatography (silica gel, 9: 1 :0.05 CHCI3: MeOH: triethylamine) to obtain the title compound.
Yield: 50 mg (17 %); 1 H NMR (300 MHz, DMSO-d6): δ 1 .98 (d, 3H, J = 7.2Hz, CH3), 2.23 (s, 3H, CH3), 2.41 (s, 3H, CH3), 6.43 (m, 1 H, CH), 7.31 - 7. 35 (m, 5H, Ar), 7.36 (s, 1 H, Ar), 8.33 (s, 1 H, Ar), 8.93 (s, 1 H, Ar), 13.82 (s, 1 H, NH, exchangeable with D20); MS (El, 70 eV): m/z 409.5 (M+H+); HPLC purity: 91 .30 %.
Example 109:
2-Bromo-4-nitrobenzoic acid
Potassium permanganate (77 g, 486 mmol) was added to a stirred solution of water (400 mL) and pyridine (300 mL) and the reaction mixture was heated to reflux for 2 h. The reaction mixture was filtered through celite, pyridine was removed and adjusted the pH to 1 -2 with dilute HCI. The solid obtained was filtered, washed with water and petroleum ether to obtain the title compound.
Yield: 23.5 g (59.0 %); 1H NMR (300 MHz, DMSO-d6): δ 7.95 (d, 1 H, J = 8.7 Hz, Ar), 8.28 (dd, 1 H, J = 8.4 Hz, 2.1 Hz, Ar), 8.48 (d, 1 H, J = 2.1 Hz Ar), 14.10 (s, 1 H, COOH, exchangeable with D20); MS (El, 70 eV): m/z 245.7 (M-H+).
Example 110:
Ethyl 2-bromo-4-nitrobenzoate
H2S04 (2.438 mL, 45.7 mmol) was added to a stirred solution of the compound of example 109 (22.5 g, 91 mmol) in ethanol (100 mL) and heated the reaction mixture to reflux for 3 h. The reaction mixture was cooled to room temperature and diluted with water. The solid obtained was filtered and washed with water to obtain the title compound.
Yield: 23.00 g (92.0 %); 1 H NMR (300 MHz, DMSO-d6): δ 1 .45 (t, 3H, J = 7.2 Hz, CH3), 4.48 (q, 3H, J = 7.2 Hz, CH2), 7.92 (d, 1 H, J = 8.7 Hz, Ar), 8.23 (dd, 1 H, J = 8.4 Hz, 2.1 Hz, Ar), 8.53 (d, 1 H, J = 2.1 Hz Ar); MS (El, 70 eV): m/z 275.9 (M+H+). Example 111 :
Ethyl 4-amino-2-bromobenzoate
Iron (8.97 g, 161 mmol) and ammonium chloride (8.59 g, 161 mmol) was added to a stirred solution of the compound of example 1 10 (22 g, 80 mmol) in mixture of ethanol (100 mL): THF (100 mL): water (50 mL) and the reaction mixture was heated to reflux for 1 h. The reaction mixture was filtered through celite and washed with ethanol and ethyl acetate. The filtrate was concentrated and diluted with 10% NaHC03 solution (250 mL), extracted with ethyl acetate (2 x 250 mL). The combined organic layers were washed with brine (250 mL), dried over anhydrous Na2S04, evaporated the solvent to yield a crude product, which was purified by column chromatography (silica gel, petroleum ether: EtOAc (6:4)) to obtain the title compound.
Yield: 19.0 g (91 .0 %); 1H NMR (300 MHz, DMSO-d6): δ 1 .38 (t, 3H, J = 6.9 Hz, CH3), 4.06 (s, 2H, NH2, exchangable with D20), 4.33 (q, 3H, J = 6.9 Hz, CH2), 6.59 (dd, 1 H, J = 8.4 Hz, 2.1 Hz, Ar), 7.95 (d, 1 H, J = 2.4 Hz, Ar), 7.79 (d, 1 H, J = 8.4 Hz, Ar); MS (El, 70 eV): m/z 245.9 (M+H+).
Example 112:
Ethyl 2-bromo-4-(((5,5-dimethyl-4,6-dioxo-1 ,3-dioxan-2-ylidene)methyl)amino) benzoate
Trimethyl orthoformate (25.8 mL, 234 mmol) and 2,2-dimethyl-1 ,3-dioxane-4,6-dione (1 1 .67 g, 81 mmol) was mixed together and heated to reflux for 1 .5 h. The compound of example 1 1 1 (19 g, 78 mmol) was added in portions and continued heating for 2 h. The reaction mixture was cooled, the solid obtained was filtered and washed with diethyl ether to obtain the title compound.
Yield: 19.5 g (58.2 %); 1 H NMR (300 MHz, CDCI3): δ 1 .40 (t, 3H, J = 7.2 Hz, CH3), 1 .78 (s, 6H, 2 x CH3), 4.43 (q, 3H, J = 7.2 Hz, CH2), 7.25 (dd, 1 H, J = 8.7 Hz, 2.4 Hz, Ar), 7.59 (d, 1 H, J = 2.4 Hz, Ar), 7.95 (d, 1 H, J = 8.1 Hz, Ar), 8.66 ( d, 1 H, J = 14.1 Hz, CH), 1 1.25 (d, 1 H, J = 13.9 Hz, NH, exchangeable with D20); MS (El, 70 eV): m/z 399.9 (M+H+); HPLC purity: 92.58.
Example 113:
Ethyl 7-bromo-4-hydroxyquinoline-6-carboxylate The compound of example 1 12 (19 g, 47.7 mmol) was added in portions to boiling diphenyl ether (90 mL) and heated at 80°C for 10 minutes. To the reaction mixture, petroleum ether (300 mL) was added, the solid obtained was filtered and washed with hot petroleum ether followed by trituration in methanol to obtain the title compound. Yield: 12.9 g (91 .0 %); 1H NMR (300 MHz, DMSO-d6): δ 0.97 (t, 3H, J = 6.9 Hz, CH3), 4.95 (q, 3H, J = 6.9 Hz, CH2), 6.06 -6.18 (m, 1 H, Ar), 7.22 -7.75 (m, 1 H, Ar), 7.55 (s, 1 H, Ar), 1 1 .96 (s, 1 H, OH, exchangeable with D2O); MS (El, 70 eV): m/z 297.2 (M+H+).
Example 114:
Ethyl 7-bromo-4-hydroxy-3-nitroquinoline-6-carboxylate
Nitric Acid (5.63 mL, 88 mmol) was added to a stirred solution of the compound of example 1 13 (12.8 g, 29.4 mmol) in acetic acid (40 mL) and heated to 120 °C for 2 h. The reaction mixture was cooled to room temperature and stirred for 12 h. The solid obtained was filtered, washed with acetic acid and petroleum ether and dried to obtain the title compound.
Yield: 7.5 g (74.8 %); 1H NMR (300 MHz, DMSO-d6): δ 1 .33 (t, 3H, J = 6.9 Hz, CH3), 4.37 (q, 3H, J = 6.9 Hz, CH2), 8.05 (s, 1 H, Ar), 8.57 (s, 1 H, Ar), 9.31 (s, 1 H, Ar), 13.1 1 (s, 1 H, J = 13.9 Hz, OH, exchangeable with D2O); MS (El, 70 eV): m/z 342.2 (M+H+). Example 115:
Ethyl 7-bromo-4-chloro-3-nitroquinoline-6-carboxylate
The compound of example 1 14 (7.5 g, 21 .99 mmol) was mixed with POC (2.049 mL, 21.99 mmol) and heated to reflux for 1 h. Excess POCI3 was removed by distillation and the residue was quenched in saturated NaHCO3 solution (100 mL) and extracted with DCM (3 x 100 mL). The combined organic layers were washed with brine (150 mL), dried over anhydrous Na2SO4, evaporated the solvent to afford the title compound. Yield: 7.2 g (91 .0 %); LCMS: m/z 360.71 (M+H+).
Example 116:
(R)-Ethyl 7-bromo-3-nitro-4-((1 -phenylethyl)amino)quinoline-6-carboxylate
(R)-I -Phenylethanamine (4.79 g, 39.5 mmol) was added to a stirred solution of the compound of example 1 15 (7.1 g, 19.75 mmol) in acetonitrile (35 mL) and heated to reflux for 3 h. The solvent was evaporated and residue was purified by column chromatography (silica gel, 1 : 1 ethyl acetate: petroleum ether) to obtain the title compound.
Yield: 6.1 g (70.7 %); 1H NMR (300 MHz, CDCI3): δ 1 .33 (t, 3H, J = 1.2 Hz, CH3), 1 .81 (d, 3H, J = 6.6 Hz, CH3), 4.28 - 4.38 (m, 2H, CH2), 5.37 - 5.47 (m, 1 H, CH), 7.28 (s, 1 H, Ar), 7.35 - 7.44 (m, 4H, Ar), 8.26(s, 1 H, Ar), 8.64 (s, 1 H, Ar), 9.45 (s, 1 H, Ar), 10.20 (s, 1 H, J = 7.2 Hz, OH, exchangeable with D2O) ; MS (El, 70 eV): m/z 444.0 (M+H+); HPLC purity: 98.81 %.
Example 117:
(R)-Ethyl 3-amino-7-bromo-4-((1-phenylethyl)amino)quinoline-6-carboxylate
Iron (1 .508 g, 27.0 mmol) and ammonium chloride (1 .445 g, 27.0 mmol) were added to a stirred solution of the compound of example 1 16 (6 g, 13.51 mmol) in a mixture of ethanol (30 mL): THF (30 mL):water (15 mL) and heated to reflux for 1 h. The reaction mixture was filtered through celite and washed with ethanol and ethyl acetate. The filtrate was concentrated, diluted with 10 % NaHCO3 solution (100 mL) and extracted with ethyl acetate (2x100 mL). The combined organic layers were washed with brine (100 mL), dried over anhydrous Na2SO4 and evaporated the solvent to yield a crude product, which was purified by column chromatography (silica gel, 6:4 petroleum ether: EtOAc) to obtain the title compound.
Yield: 2.3 g (41.8 %); 1H NMR (300 MHz, CDCI3): δ 1 .28 (t, 3H, J = 7.2 Hz, CH3), 1 .67 (d, 3H, J = 6.6 Hz, CH3), 3.70 (s, 2H, NH2, exchangeable with D2O), 4.01 (d, 1 H, J = 9.6 Hz, NH, exchangeable with D2O), 4.45 (q, 2H, J = 7.2 Hz, CH2), 4.67-4.72 (m, 1 H, CH), 7.22 -7.32 (m, 5H, Ar), 8.15 (s, 1 H, Ar), 8 .22 (s, 1 H, Ar); MS (El, 70 eV): m/z 415.1 (M+H+); HPLC purity: 99.64 %.
Example 118:
(R,E)-Ethyl 7-bromo-2-(cyanoimino)-1-(1-phenylethyl)-2,3-dihydro-1 H-imidazo
[4,5-c]q u i n ol i ne-8-car boxy I ate
Diphenyl cyanocarbonimidate and the compound of example 1 17 (2.0 g, 4.83 mmol) (1.610 g, 6.76 mmol) were mixed together in acetonitrile (20 mL) and heated to reflux for 12 h. The solid obtained was filtered, washed with hot petroleum ether and air dried to afford the title compound. Yield: 1 .6 g (71.1 %); 1H NMR (300 MHz, CDCI3): δ 1 .31 (t, 3H, J = 6.9 Hz, CH3), 1 .96 (d, 3H, J = 7.2 Hz, CH3), 4.24 (q, 2H, J = 6.9 Hz, CH2), 6.40 (q, 1 H, J = 7.2 Hz, CH), 7.34 (m, 5H, Ar), 7.87 (s, 1 H, Ar), 8.37 (s, 1 H, Ar), 9.01 (s, 1 H), 13.90 (s, 1 H, NH, exchangable with D20); MS (El, 70 eV): m/z 466.0 (M+H+); HPLC purity: 99.59 % .
Example 119:
(E)-Ethyl 2-(cyanoimino)-7-(3,5-dimethylisoxazol-4-yl)-1-((R)-1-phenylethyl)-2,3- dihydro-1 H-imidazo[4,5-c]quinoline-8-carboxylate
PdCI2(dppf)-CH2CI2 adduct (0.063 g, 0.078 mmol) was added to a stirred solution of the compound of example 1 18 (1 .2 g, 2.58 mmol) and (3,5-dimethyl isoxazol-4- yl)boronic acid (0.474 g, 3.36 mmol) in DMF (20 mL) followed by sodium carbonate (0.548 g, 5.17 mmol) solution in water (4 mL) and the resulting reaction mixture was heated to 120 °C for 5 h. The reaction mixture was then cooled to room temperature, concentrated, added water (50 mL) and extracted with CHCI3 (3 x 50 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na2S04 and the solvent was evaporated to give crude product which was purified by column chromatography (silica gel, 9: 1 CHCI3: MeOH) to obtain the title compound. Yield: 1 .1 g (86.0 %); 1H NMR (300 MHz, CDCI3): δ 1 .17 (t, 3H, J = 6.9 Hz, CH3), 1 .94 (s, 3H, CH3), 2.91 (d, 3H, J = 6.9 Hz, CH3), 2.18 (s, 3H, CH3), 4.09 - 4.14 (m, 2H, CH2), 6.43 (m, 1 H, CH), 7.32 - 7.39 (m, 5H, Ar), 7.98 (s, 1 H, Ar), 8.15 (s, 1 H, Ar), 9.04 (s, 1 H, Ar), 13.91 (s, 1 H, NH, exchangeable with D20); MS (El, 70 eV): m/z 481 .1 (M+H+); HPLC purity: 97.65 %.
Example 120:
(E)-2-(Cyanoimino)-7-(3,5-dimethylisoxazol-4-yl)-1-((R)-1-phenylethyl)-2,3- dihydro-1 H-imidazo[4,5-c]quinoline-8-carboxylic acid
LiOH (400 mg, 9.99 mmol) was added to a stirred solution of the compound of example 1 19 (800 mg, 1 .665 mmol) in mixture of THF (1 mL): water (1 .000 mL): MeOH (1 mL) and stirred for 1 h. The reaction mixture was diluted with water (25 mL) and pH was adjusted to ~4-5 with dilute HCI. The solid obtained was filtered and dried to afford the title compound.
Yield: 0.3 g (39.0 %); 1H NMR (300 MHz, DMSO-d6): δ 1 .91 -2.00 (m, 6H, 2 x CH3), 2.20 (s, 3H, CH3), 6.38 - 6.45 (m, 1 H, CH), 7.18 - 7.36 (m, 5H, Ar), 7.92 (s, 1 H, Ar), 8.21 (s, 1 H, Ar), 9.01 (s, 1 H), 12.97(s, 1 H, COOH, exchangable with D20), 13.84(s, 1 H, NH, exchangeable with D20); MS (El, 70 eV): m/z 453.1 (M+H+); HPLC purity: 98.01 %. Example 121 :
(E)-2-(Cyanoimino)-7-(3,5-dimethylisoxazol-4-yl)-N-ethyl-1-((R)-1-phenylethyl)- 2,3-dihydro-1 H-imidazo[4,5-c]quinoline-8-carboxamide
HATU (55.5 mg, 0.146 mmol) and N,N-diisopropylethylamine (0.106 ml_, 0.608 mmol) was added to a stirred solution of the compound of example 120 (55 mg, 0.122 mmol) in THF (2 ml_) and stirred at room temperature for 1 h. To the reaction mixture, ethanamine (5.48 mg, 0.122 mmol) was added and stirred at room temperature for 12 h. The solid obtained was filtered and purified by preparative TLC to afford the title compound.
Yield: 0.06 g (9.66 %); 1H NMR (300 MHz, DMSO-d6): δ 1.00 (t, 3H, J = 7.2Hz, CH3), 1 .24 (d, 3H, J = 6.9 Hz, 3H, CH3), 2.02 (s, 3H, CH3), 2.21 (s, 3H, CH3), 3.08 - 3.10 (m, 2H, CH2), 6.38 - 6.45 (m, 1 H, CH), 7.32-7.36 (m, 4H, Ar), 7.64 (s, 1 H, Ar), 7.92 (s, 1 H, Ar), 8.10 (s, 1 H, Ar), 8.97 (s, 1 H), 13.81 (s, 1 H, NH, exchangeable with D20); MS (El, 70 eV): m/z 480.1 (M+H+); HPLC purity: 93.82 %. Example 122:
(E)-2-(Cyanoimino)-N-cyclopropyl-7-(3,5-dimethylisoxazol-4-yl)-1-((R)-1-phenyl ethyl)-2,3-dihydro-1 H-imidazo[4,5-c]quinoline-8-carboxamide
HATU (46.2 mg, 0.122 mmol) and N-ethyl-N-isopropylpropan-2-amine (15.71 mg, 0.122 mmol) were added to a stirred solution of the compound of example 120 (55 mg, 0.122 mmol) in THF (2 mL) and stirred at room temperature for 1 h. To the reaction mixture, cyclopropylamine (15.71 mg, 0.122 mmol) was added and stirred at room temperature for 12 h. The solid obtained was filtered and purified by preparative TLC to afford the title compound.
Yield: 0.01 g (16.27 %); 1H NMR (300 MHz, DMSO-d6): δ 0.67 (d, 2H, J = 6.6 Hz, CH2), 0.84 (d, 2H, J = 6.6 Hz, CH2), 2.00 (m, 3H, CH3), 2.03 (s, 3H, CH3), 2.21 (s, 3H, CH3), 2.52( m, 1 H, CH), 6.38 - 6.45 (m, 1 H, CH), 7.35 (s, 4H, Ar), 7.50 (s, 1 H, Ar), 7.92 (s, 1 H, Ar), 8.26 (s, 1 H, Ar), 8.97 (s, 1 H), 13.81 (s, 1 H, NH, exchangeable with D20); MS (El, 70 eV): m/z 492.2 (M+H+); HPLC purity: 97.20 %. Example 123:
(E)-2-(Cyanoimino)-7-(3,5-dimethylisoxazol-4-yl)-N-(4-hydroxyphenyl)-1-((R)-1- phenylethyl)-2,3-dihydro-1 H-imidazo[4,5-c]quinoline-8-carboxamide
2-(3H-[1 ,2,3]Triazolo[4,5-b]pyridin-3-yl)-1 ,1 ,3,3-tetramethylisouronium, hexafluoro phosphate (V) salt (0.050 g, 0.133 mmol) and N-ethyl-N-isopropylpropan-2-amine (0.043 g, 0.332 mmol) were added to a stirred solution of the compound of example 120 (0.05 g, 0.1 1 1 mmol) in THF (1 mL) and stirred at room temperature for 1 h. To the reaction mixture, 4-aminophenol (0.013 g, 0.122 mmol) was added and stirred at room temperature for 12 h. The solid obtained was filtered and purified by preparative TLC to afford the title compound.
Yield: 0.005 g (8.19 %); 1H NMR (300 MHz, DMSO-d6): δ 2.03 -2.05 (m, 6H, CH3), 2.24 (s, 3H, CH3), 6.43 - 6.45 (m, 1 H, CH), 6.75 (d, 2H, J = 8.7 Hz, Ar), 7 '.22-7 '.27 (m, 5H, Ar), 7.36 (d, 2H, J = 7.2 Hz, Ar), 7.98 (s, 1 H, Ar), 8.99 (s, 1 H, Ar), 9.31 (s, 1 H), 9.92 (s, 1 H, OH, exchangeable with D2O), 13.86 (s, 1 H, NH, exchangeable with D2O); MS (El, 70 eV): m/z 544.1 (M+H+); HPLC purity: 98.39 %.
Example 124:
2-Bromo-1 -iodo-4-nitrobenzene
Ice-cold solution of sodium nitrite (57.2 g, 829 mmol) and potassium iodide (138 g, 829 mmol) in water (25 mL) was added drop wise simultaneously to a stirred suspension of 2-bromo-4-nitroaniline (60 g, 276 mmol) in acetonitrile (250 mL) at 0-5 °C and stirred for 30 minutes. The reaction mixture was then poured on to ice-cold water (1000 mL). The solid obtained was filtered, washed with water and dried to afford the title compound.
Yield: 70.0 g (77 %); 1H NMR (300 MHz, CDCI3): δ 7.86 (dd, 1 H, J = 8.7, 2.4 Hz, Ar), 8.10(d, 1 H, J = 8.7 Hz, Ar), 8.45 (d, 1 H, J = 2.4 Hz, Ar); MS (El, 70 eV): m/z 328.3 (M+H). Example 125:
(E)-Ethyl 3-(2-bromo-4-nitrophenyl)acrylate
Palladium acetate (0.147 g, 0.656 mmol) and triethylamine (7.31 mL, 52.5 mmol) were added to a stirred solution of the compound of example 124 (4.3 g, 13.1 1 mmol) and ethyl acrylate (6.98 mL, 65.6 mmol) in NMP (20 mL) and heated to 90 °C for 2 h. The reaction mixture was cooled, diluted with 1 M HCI (200 mL) and extracted with ethyl acetate (2x50 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na2S04 and evaporated the solvent to afford the title compound. Yield: 3.6 g (89.0 %); 1H NMR (300 MHz, CDCI3): δ 1 .38 (t, 3H, J = 6.9 Hz, CH3), 4.33 (q, 2H, J = 6.9 Hz, CH2), 6.55 (d, 1 H, J = 15.5 Hz, CH), 7.73 (d, 1 H, J = 7.5 Hz, Ar), 8.03 (d, 1 H, J = 15.9 Hz, CH), 8.21 (d, 1 H, J = 8.4 Hz, Ar), 8.51 (d, 1 H, J = 1 .8 Hz, Ar); MS (El, 70 eV): m/z 300.1 (M+H).
Example 126:
Ethyl 3-(2-bromo-4-nitrophenyl)propanoate
Sodium acetate (164 g, 1999 mmol) and 4-methylbenzenesulfonohydrazide (372 g, 1999 mmol) were added to a stirred solution of the compound of example 125 (40 g, 133 mmol) in o-xylene (25 mL) and stirred at reflux for 12 h. The reaction mixture was cooled, filtered and the filtrate was concentrated to yield a crude product, which was purified by column chromatography (silica gel, 7:3 petroleum ether: ethyl acetate) to afford the title compound.
Yield: 31 .0 g (77.0 %); 1 H NMR (300 MHz, CDCI3): δ 1 .26 (t, 3H, J = 7.2 Hz, CH3), 2.70 (t, 2H, J = 7.5 Hz, CH2), 3.18 (t, 2H, J = 7.5 Hz, CH2), 4.16 (q, 2H, J = 7.2 Hz, CH2), 7.48 (d, 1 H, J = 8.4 Hz, Ar), 8.12 (dd, 1 H, J = 8.4 Hz, 2.4 Hz, Ar), 8.44 (d, 1 H, J = 2.1 Hz, Ar); MS (El, 70 eV): m/z 303.9 (M+H+).
Example 127:
Ethyl 3-(4-amino-2-bromophenyl) propanoate
Iron (17.19 g, 308 mmol) and ammonium chloride (16.47 g, 308 mmol) was added to a stirred solution of the compound of example 128 (31 g, 103 mmol) in mixture of ethanol (150 mL): THF (150 mL): water (75 mL) and heated to reflux for 1 h. The reaction mixture was filtered through celite bed and washed with ethanol and ethyl acetate. The filtrate was concentrated, diluted with 10 % NaHC03 solution (250 mL) and extracted with ethyl acetate (2 x 250 mL). The combined organic layers were washed with brine (250 mL), dried over anhydrous Na2S04 and evaporated the solvent to yield a crude product, which was purified by column chromatography (silica gel, 6:4 petroleum ether: ethyl acetate) to obtain the title compound. Yield: 27.1 g (97.0 %); 1 H NMR (300 MHz, CDCI3): δ 1 .26 (t, 3H, J = 7.2 Hz, CH3), 2.59 (t, 2H, J = 7.5 Hz, CH2), 2.96 (t, 2H, J = 7.5 Hz, CH2), 4.15 (q, 2H, J = 7.2 Hz, CH2), 6.57 (dd, 1 H, J = 8.1 Hz, 2.4 Hz, Ar), 6.91 (d, 1 H, J = 2.1 Hz, Ar), 7.03(d, 1 H, J = 8.1 Hz, Ar); MS (El, 70 eV): m/z 273.9 (M+H).
Example 128:
Ethyl 3-(2-bromo-4-(((2,2-dimethyl-4,6-dioxo-1 ,3-dioxan-5-ylidene)methyl) amino)phenyl) propanoate
2,2-Dimethyl-1 ,3-dioxane-4,6-dione (14.87 g, 103 mmol) and trimethyl orthoformate (10.97 mL, 99 mmol) were mixed together and heated to reflux for 1 h. To the reaction mixture, the compound of example 127 (27 g, 99 mmol) was added in portions and heated to 1 10 °C for 2.5 h. The reaction mixture was cooled to room temperature, the solid obtained was filtered and washed with diethyl ether (25 mL) to obtain the title compound.
Yield: 30.0 g (70.9 %); 1 H NMR (300 MHz, CDCI3): δ 1 .26 (t, 3H, J = 7.2 Hz, CH3), 1 .77 (s, 6H, CH3), 2.66 (t, 2H, J = 7.5 Hz, CH2), 3.08 (t, 2H, J = 7.8 Hz, CH2), 4.15 (q, 2H, J = 7.2 Hz, CH2), 7.15 (dd, 1 H, J = 8.4 Hz, 2.4 Hz, Ar), 7.35(d, 1 H, J = 8.1 Hz, Ar), 7.49(d, 1 H, J = 2.1 Hz, Ar), 8.58 (d, 1 H, J = 14.4 Hz, CH), 1 1 .19 (d, 1 H, J = 13.8 Hz, NH, exchangeable with D20); MS (El, 70 eV): m/z 423.9 (M-H).
Example 129:
Ethyl 3-(7-bromo-4-hydroxyquinolin-6-yl)propanoate
The compound of example 130 (30 g, 70.4 mmol) was added in portions to boiling diphenyl ether (140 mL) and continued heating for 10 minutes. The reaction mixture was cooled to 80 °C and poured into ice cold petroleum ether (500 mL). The solid obtained was filtered, washed petroleum ether and triturated in methanol to obtain the title compound.
Yield: 15.0 g (63.8 %); 1 H NMR (300 MHz, CDCI3): δ 1.15 (q, 3H, J = 6.0 Hz, CH3), 2.66 (t, 2H, J = 7.2 Hz, CH2), 3.03 (t, 2H, J = 7.2 Hz, CH2), 4.04 (q, 2H, J = 6.9 Hz, CH2), 6.02 (d, 1 H, J = 7.2 Hz, Ar), 7.79 (s, 1 H, Ar), 7.90 (t, 1 H, J = 6.0 Hz, Ar), 7.98 (s, 1 H, Ar), 1 1 .71 (d, 1 H, J = 13.8 Hz, OH, exchangeable with D2O); MS (El, 70 eV): m/z 326.0 (M+2H+). Example 130:
Ethyl 3-(7-bromo-4-hydroxy-3-nitroquinolin-6-yl) propanoate
Nitric acid (6.74 mL, 106 mmol) was added to a stirred solution of the compound of example 129 (1 1 .4 g, 35.2 mmol) in acetic acid (60 mL). The reaction mixture was heated to 120 °C for 2 h and cooled to room temperature. The solid obtained was filtered, washed with petroleum ether and triturated in ethyl acetate and petroleum ether to obtain the title compound.
Yield: 9.0 g (69.3 %); 1H NMR (300 MHz, CDCI3): δ 1 .16 (t, 3H, J = 6.9 Hz, CH3), 2.58 - 2.71 (m, 2H, CH2), 3.02 - 3.15 (m, 2H, CH2), 4.05 (q, 2H, J = 6.9 Hz, CH2), 7.95 (s, 1 H, Ar), 8.15 (s, 1 H, Ar), 9.22 (s, 1 H, Ar), 12.94 (s, 1 H, OH, exchangeable with D2O); MS (El, 70 eV): m/z 369.0 (M+H).
Example 131 :
Ethyl 3-(7-bromo-4-chloro-3-nitroquinolin-6-yl) propanoate
The compound of example 130 (8 g, 21 .67 mmol) was mixed with phosphorus oxychloride (10.10 mL, 108 mmol) and heated to reflux for 1 h. Excess POC was distilled out, the residue was quenched in saturated NaHCO3 solution (50 mL) and extracted with DCM (3 x 50 mL). The combined organic layers were washed with brine (100 mL), dried over anhydrous Na2SO4 and removed the solvent to obtain the title compound.
Yield: 8.4 g (100 %); LCMS: 388.27 (M+H).
Example 132:
(R)-Ethyl 3-(7-bromo-3-nitro-4-((1-phenylethyl)amino)quinolin-6-yl)propanoate The compound of example 131 (4.5 g, 1 1 .61 mmol) and (S)-l -phenylethanamine (2.81 g, 23.22 mmol) were mixed together in acetonitrile (25 mL) and heated to reflux for 2 h. The reaction mixture was concentrated to remove solvent, diluted with water (50 mL) and extracted with ethyl acetate (2 x 50 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na2SO4 and evaporated the solvent to yield a crude product, which was purified by column chromatography to obtain the title compound.
Yield: 1 .85 g (33.4 %); 1H NMR (300 MHz, CDCI3): δ 1 .16 -1 .20 (m, 3H, CH3), 2.20 - 2.34 (m, 3H, CH3), 2.36-2.54 (m, 2H, CH2), 2.89 - 3.03 (m, 2H, CH2), 4.10 - 4.17 (m, 2H, CH2), 5.43 - 5.48 (m, 1 H, CH), 7.28 -7.50 (m, 5H, Ar), 8.05 (s, 1 H, Ar), 8.17 (s, 1 H, Ar), 9.36 (s, 1 H, Ar), 10.09 (d, 1 H, J = 7.5 Hz OH, exchangeable with D2O); MS (El, 70 eV): m/z 474.0 (M+2H). Example 133:
(R)-Ethyl 3-(3-amino-7-bromo-4-((1-phenylethyl)amino)quinolin-6-yl)propanoate
Iron (0.638 g, 1 1 .43 mmol) and ammonium chloride (0.612 g, 1 1 .43 mmol) were added to a stirred solution of the compound of example 132 (1 .8 g, 3.81 mmol) in mixture of ethanol (10 ml_): THF (10.00 ml_): water (5.00 ml_) and heated to reflux for 2 h. The reaction mixture was filtered through celite, the filtrate was concentrated, diluted with 10% NaHCO3 solution (50 ml_) and extracted with ethyl acetate (3 x 50 ml_). The combined organic layers were washed with brine (50 ml_), dried over anhydrous Na2SO4 and the solvent was evaporated to give crude product, which was purified by column chromatography (silica gel, 1 : 1 ethyl acetate: petroleum ether) to obtain the title compound.
Yield: 1 .48 g (86.0 %); 1 H NMR (300 MHz, CDCI3): δ 1 .27 (t, 3H, J = 7.2 Hz, CH3), 1 .66 (d, 3H, J = 6.6 Hz, CH3), 2.58-2.71 (m, 3H, CH2), 3.15 (t, 3H, J = 7.5 Hz, CH2), 3.66 (s, 2H, NH2 exchangeable with D2O), 4.16 (q, 2H, J = 7.2 Hz, CH2), 4.62 (s, 1 H, NH, exchangeable with D2O), 7.25 -7.35 (m, 5H, Ar), 7.49 (s, 1 H, Ar), 8.15 (s, 1 H, Ar), 8.41 (s, 1 H, Ar); MS (El, 70 eV): m/z 444.4 (M+H); HPLC purity: 97.43%.
Example 134:
(R,E)-Ethyl 3-(7-bromo-2-(cyanoimino)-1 -(1 -phenylethyl)-2,3-dihydro-1 H-imidazo
[4,5-c]quinolin-8-yl)propanoate
The compound of example 135 (1 .4 g, 3.16 mmol) and diphenyl cyanocarbonimidate (1.131 g, 4.75 mmol) were mixed together in acetonitrile (10 ml_) and heated to reflux for 5 h. The solid obtained was filtered and washed with acetonitrile and diethyl ether to obtain the title compound.
Yield: 0.95 g (60.3 %); 1H NMR (300 MHz, DMSO-d6): δ 1.19 (t, 3H, J = 6.9 Hz, CH3), 1 .94 (d, 3H, J = 7.5 Hz, CH3), 2.20 -2.26 (m, 2H, CH2), 2.76 - 2.83 (m, 2H, CH2), 4.07 (q, 2H, J = 7.2 Hz, CH2), 6.40 (q, 1 H, J = 7.5 Hz, CH), 7.35 (m, 6H, Ar), 8.28 (s, 1 H, Ar), 8.29 (s, 1 H, Ar), 13.75 (s, 1 H, NH, exchangable with D2O); MS (El, 70 eV): m/z 493.4 (M+H+); HPLC purity: 98.90 %. Example 135:
Ethyl 3-((E)-2-(Cyanoimino)-7-(3,5-dimethylisoxazol-4-yl)-1-((R)-1-phenylethyl)- 2,3-dihydro-1 H-imidazo[4,5-c]quinolin-8-yl)propanoate
[1 ,1 '-Bis(diphenylphosphino)ferrocene]dichloro palladium(ll) complex with dichloromethane (44.8 mg, 0.055 mmol) was added to a stirred solution of the compound of example 134 (900 mg, 1 .828 mmol) and (3,5-dimethylisoxazol-4- yl)boronic acid (335 mg, 2.376 mmol) in DMF (10 mL) followed by sodium carbonate (387 mg, 3.66 mmol) solution in water (2 mL) and the resulting reaction mixture was heated to 120 °C for 1 h. The reaction mixture was then cooled to room temperature, concentrated, added water (25 mL) and extracted with CHC (3 x 25 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na2S04 and the solvent was evaporated to yield a crude product, which was purified by column chromatography (silica gel, ethyl acetate: petroleum ether 1 : 1 )) to obtain the title compound.
Yield: 0.85 g (90.0 %); 1 H NMR (300 MHz, CDCI3): δ 1 .24 (t, 3H, J = 6.9 Hz, CH3), 2.01 - 2.03 (m, 2H, CH2), 2.04 - 2.12 (m, 6H, CH3), 2.24 (s, 3H, CH3), 2.58 - 2.67 (m, 2H, CH2), 4.09 (q, 2H, J = 7.2 Hz, CH2), 6.32 (q, 1 H, J = 7.5 Hz, CH), 7.40 -7.43 (m, 6H, Ar), 7.90 (s, 1 H, Ar), 9.06 (s, 1 H, Ar); MS (El, 70 eV): m/z 509.2 (M+H+); HPLC purity: 98.24 %.
Example 136:
3-((E)-2-(Cyanoimino)-7-(3,5-dimethylisoxazol-4-yl)-1-((R)-1-phenylethyl)-2,3- dihydro-1 H-imidazo[4,5-c]quinolin-8-yl)propanoic acid
Lithium hydroxide (297 mg, 7.08 mmol) was added to a stirred solution of the compound of example 135 (600 mg, 1 .180 mmol) in mixture of MeOH (2 mL): THF (2. mL):water (2mL) and stirred at room temperature for 2 h. The reaction mixture was concentrated to remove the solvent and adjusted pH to 5 with dilute HCI. The solid obtained was filtered and triturated in 5 % ethyl acetate: petroleum ether to obtain the title compound.
Yield: 0.55 g (90 %); 1H NMR (300 MHz, DMSO- d6): δ 1 .96 - 2.00 (m, 6H, CH3), 2.19 (d, 3H, J = 16.2 Hz, CH3), 3.33 (s, 4H, CH2), 6.43 (q, 1 H, J = 7.5 Hz, CH), 7.37 -7.41 (m, 6H, Ar), 7.83 (s, 1 H, Ar), 8.91 (s, 1 H, Ar), 12.16 (s, 1 H, COOH, exchangable with D20), 13.67 (s, 1 H, NH, exchangeable with D20); MS (El, 70 eV): m/z 481 .1 (M+H+); HPLC purity: 92.71 %.
Example 137:
3-((E)-2-(Cyanoimino)-7-(3,5-dimethylisoxazol-4-yl)-1 -((R)-1 -phenylethyl)-2,3- dihydro-1 H-imidazo[4,5-c]quinolin-8-yl)-N-ethylpropanamide
Ethanamine (0.1 14 mL, 0.229 mmol) was added to a stirred solution of the compound of example 136 (100 mg, 0.208 mmol), 2-(3H-[1 ,2,3]triazolo[4,5-b]pyridin-3-yl)-1 , 1 ,3,3- tetramethylisouronium,hexafluoro phosphate (V) salt (95 mg, 0.250 mmol) and N-ethyl- N-isopropylpropan-2 -amine (0.109 mL, 0.624 mmol) in THF (2 mL) and stirred at room temperature for 12 h under argon atomosphere. The solvent was concentrated, diluted with water (20 mL) and extracted with ethyl acetate (2 x 20 mL). The combined organic layers were washed with brine, dried over anhydrous Na2S04 and the solvent was evaporated to yield a crude product, which was purified by column chromatography (silica gel, 9: 1 CHCI3 MeOH) to obtain the title compound.
Yield: 0.03 g (27.9 %); 1 H NMR (300 MHz, CDCI3): δ 1 .1 1 (t, 3H, J = 4.8 Hz, CH3), 1 .48 - 1 .54 (d, 3H, CH3), 2.09 (s, 3H, CH3), 2.12 (s, 3H, CH3), 3.10-3.40 (m, 4H, CH2), 3.72 - 3.76 (m, 2H, CH2), 6.61 (q, 1 H, J = 7.5 Hz, CH), 7.39 -7.45 (m, 6H, Ar), 7.9 (s, 1 H, Ar), 9.05 (s, 1 H, Ar); MS (El, 70 eV): m/z 508.2 (M+H+); HPLC purity: 97.43 %.
Example 138:
3-((E)-2-(Cyanoimino)-7-(3,5-dimethylisoxazol-4-yl)-1-((R)-1-phenylethyl)-2,3- dihydro-1 H-imidazo[4,5-c]quinolin-8-yl)-N-(4-hydroxyphenyl)propanamide
2-(3H-[1 ,2,3]Triazolo[4,5-b]pyridin-3-yl)-1 ,1 ,3,3-tetramethylisouronium, hexafluoro phosphate(V) salt (95 mg, 0.250 mmol) and N-ethyl-N-isopropylpropan-2-amine (81 mg, 0.624 mmol) was added to a stirred solution of the compound of example 136 (100 mg, 0.208 mmol) in THF (2 mL) and stirred at room temperature for 1 h. To the reaction mixture, 4-aminophenol (24.98 mg, 0.229 mmol) was added and stirred at room temperature for 12 h. The solid obtained was filtered and purified by column chromatography (silica gel, 9:1 CHCI3: MeOH) to afford the title compound.
Yield: 0.04 g (32 %); 1H NMR (300 MHz, CDCI3): δ 1 .86 (d, 3H, J = 7.2 Hz, CH3), 1 .99 (d, 3H, J = 17.7 Hz, CH3), 2.19 (d, 3H, J = 15.0 Hz, CH3), 2.94 (s, 4H, CH2), 6.40 (q, 1 H, J = 7.5 Hz, CH), 6.67 (d, 2H, J = 8.7 Hz, Ar), 7.26 -7.35 (m, 7H, Ar), 7.62 (s, 1 H, Ar), ), 8.75 (s, 1 H, Ar), 9.14 (s, 1 H, OH, exchangable with D2O), 9.50 (s, 1 H, Ar); MS (El, 70 eV): m/z 572.1 (M+H+); HPLC purity: 95.1 1 %.
Example 139:
3-(7-Bromo-3-nitro-4-(((R)-1-phenylethyl)amino)quinolin-6-yl)-N-((R)-1- phenylethyl)propanamide
Ethyl 3-(7-bromo-4-chloro-3-nitroquinolin-6-yl)propanoate (4.5 g, 1 1 .61 mmol) and (S)- 1 -phenylethanamine (2.81 g, 23.22 mmol) was mixed together in acetonitrile (25 ml) and heated to reflux for 2 h. Concentrated the reaction mixture, diluted with water (50 mL) and extracted with ethyl acetate (2 x 50 ml). The combined organic layers were washed with brine (50 mL), dried over anhydrous sodium sulphate and evaporated solvent to get crude which was purified by column chromatography (ethyl acetate: pet ether, 1 : 1 ) to obtain the title compound.
Yield: 1 .64 g (25.8 %); 1 H NMR (300 MHz, DMSO-d6): δ 1 .24 (d, 3H, J = 6.9 Hz, CH3), 1 .52 (d, 3H, J = 6.3 Hz, CH3), 2.82 - 2.98 (m, 2H, CH2), 4.91 - 5.10( m, 2H, CH2), 6.95 (s, 5H, Ar), 7.23 -7.24 (m, 4H, Ar), 7.48 (d, 2H, J = 7.2 Hz, Ar), 8.08 (t, 1 H, J = 4.2 Hz, Ar), 8.33 (d, 1 H, J = 8.1 Hz, Ar), 9.1 1 (d, 1 H, J = 2.4 Hz, Ar), 9.58 (d, 1 H, J = 5.7 Hz, Ar); MS (El, 70 eV): m/z 547.1 (M+H+); HPLC purity: 97.47 %. Example 140:
3-(3-Amino-7-bromo-4-(((R)-1-phenylethyl)amino)quinolin-6-yl)-N-((R)-1-phenyl ethyl)propanamide
Iron (0.326 g, 5.85 mmol) and ammonium chloride (0.313 g, 5.85 mmol) were added to a stirred solution of the compound of example 139 (1 .6 g, 2.92 mmol) in a mixture of ethanol (10 mL): THF (10 mL): water (5 mL) and heated to reflux for 2 h. The reaction mixture was filtered through celite bed, filtrate was concentrated, diluted with 10 % NaHCO3 solution (50 mL) and extracted with ethyl acetate (3 x 50 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na2SO4 and the solvent was evaporated to yield a crude product, which was purified by column chromatography (silica gel, 1 : 1 ethyl acetate: petroleum ether) to obtain the title compound.
Yield: 1 .64 g (25.8 %); 1 H NMR (300 MHz, DMSO-d6): δ 1 .39 (d, 3H, J = 6.9 Hz, CH3), 1 .60 (d, 3H, J = 6.3 Hz CH3), 2.42 - 2.56(m, 2H, CH2), 3.18 (t, 2H, CH2), 3.67 (s, 2H, NH2, exchangeable with D20), 3.84 (s, 1 H, NH, exchangeable with D20), 4.59 (s, 1 H, NH, exchangeable with D20), 5.10 (q, 1 H, J = 7.5 Hz, CH), 5.58 (d, 1 H, J = 8.1 Hz, CH), 7.13 - 7.15 (m, 2H, Ar), 7.20 -7.22 (m, 3H, Ar), 7.28 -7.41 (m, 5H, Ar), 7.51 (s, 1 H, Ar), 8.14 (s, 1 H, Ar), 8.40 (s, 1 H, Ar); MS (El, 70 eV): m/z 517.1 (M+H); HPLC purity: 92.27 %.
Example 141
3-((E)-7-Bromo-2-(cyanoimino)-1 -((R)-1 -phenylethyl)-2,3-dihydro-1 H-imidazo [4,5- c]quinolin-8-yl)-N-((R)-1-phenylethyl)propanamide
The compound of example 140 (890 mg, 1 .720 mmol) and diphenyl cyanocarbonimidate (615 mg, 2.58 mmol) were mixed together in acetonitrile (10 mL) and heated to reflux for 4 h. The solid precipitated was filtered and washed with acetonitrile and diethyl ether to obtain the title compound.
Yield: 0.44 g (44.2 %); 1H NMR (300 MHz, DMSO-d6): δ 1 .25 (t, 3H, J = 6.9 Hz, CH3), 1 .91 (t, 3H, J = 6.9 Hz, CH3), 2.08-2.27 (m, 2H, CH2), 2.75 - 2.78 (m, 2H, CH2), 4.89 - 4.94 (m, 1 H, CH), 6.31-6.33 (m, 1 H, CH), 7.27-7.37 (m, 10H, Ar), 8.23 (s, 1 H, Ar), 8.27(s, 1 H, Ar), 8.88 (s, 1 H, Ar), 13.72 (s, 1 H, NH, exchangeable with D20); MS (El, 70 eV): m/z 569.1 (M+2H+); HPLC purity: 98.04 %. Example 142:
3-((E)-2-(Cyanoimino)-7-(3,5-dimethylisoxazol-4-yl)-1-((R)-1-phenylethyl)-2,3- dihydro-1 H-imidazo[4,5-c]quinolin-8-yl)-N-((R)-1-phenylethyl)propanamide
[1 ,1 '-Bis(diphenylphosphino)ferrocene]dichloro palladium(ll) complex with dichloro methane (27.0 mg, 0.033 mmol) was added to a stirred solution of the compound of example 141 (375 mg, 0.661 mmol) and (3,5-dimethylisoxazol-4-yl)boronic acid (1 12 mg, 0.793 mmol) in DMF (10 mL) followed by sodium carbonate (140 mg, 1 .322 mmol) solution in water (2 mL) and the reaction mixture was heated to 120 °C for 3 h. The reaction mixture was then cooled to room temperature, concentrated, water (25 mL) was added and extracted with CHC (3 x 25 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na2S04 and the solvent was evaporated to yield a crude product, which was purified by column chromatography (silica gel, 9: 1 CHCI3: MeOH) to obtain the title compound. Yield: 0.37 g (95.0 %); 1 H NMR (300 MHz, CDCI3): δ 1 .23 (t, 3H, J = 6.9 Hz, CH3), 1 .65-1 .67 (m, 2H, CH2), 2.05 (d, 3H, J = 7.2 Hz, CH3), 2.10 (d, 3H, J = 3.6 Hz, CH3), 2.26 (d, 3H, J = 3.3 Hz, CH3), 2.27 (m, 2H, CH2), 5.06-5.07 (m, 1 H, CH), 5.26-5.30 (m, 1 H, CH), 6.55 (q, 1 H, J = 1 1 .7 Hz, CH), 7.17-7.34 (m, 1 1 H, Ar), 7.90 (s, 1 H, Ar), 9.04(s, 1 H, Ar); MS (El, 70 eV): m/z 584.2 (M+H+); HPLC purity: 97.51 %.
Example 143:
3-((E)-2-(Cyanoimino)-7-(3,5-dimethylisoxazol-4-yl)-3-methyl-1-((R)-1-phenyl ethyl)-2,3-dihydro-1 H-imidazo[4,5-c]quinolin-8-yl)-N-((R)-1-phenylethyl)
propanamide
Sodium hydride (0.019 g, 0.771 mmol) was added to a stirred solution of the compound of example 142 (0.15 g, 0.257 mmol) in DMF (1 mL) at 0-5°C and stirred for 10 minutes followed by addition of iodomethane (0.032 mL, 0.514 mmol) and stirred for 2 h. The reaction mixture was quenched by addition of methanol. The solvent was removed and the residue obtained was purified by column chromatography (silica gel, 9:1 CHCI3:MeOH) to obtain the title compound.
Yield: 0.04 g (25.4 %); 1 H NMR (300 MHz, CDCI3): δ 1 .40 - 1 .44 (m, 3H, CH3), 1 .67- 1 .69 (m, 1 H), 2.01 (d, 3H, J = 7.2 Hz, CH3), 2.09 (d, 3H, J = 6.0 Hz, CH3), 2.25 (d, 3H, J = 6.9 Hz, CH3), 2.56 -2.79 (m, 2H, CH2), 4.28 (s, 3H, CH3), 5.03 - 5.05 (m, 1 H, CH), 5.24 - 5.26 (m, 1 H, CH), 6.68 (q, 1 H, J = 1 1 .7 Hz, CH), 7.15 (s, 1 H, Ar), 7.28 -7.42 (m, 10H, Ar), 7.88 (s, 1 H, Ar), 8.90 (s, 1 H, Ar); MS (El, 70 eV): m/z 598.3 (M+H+); HPLC purity: 97.40 %.
Example 144:
4-(2-Bromo-4-nitrophenyl) butanenitrile
Diethyl 2-(2-bromo-4-nitrophenyl)-2-(2-cyanoethyl)malonate (12 g, 29.0 mmol) was taken in a sealed tube, dimethylacetamide and magnesium chloride (5.53 g, 58.1 mmol) was added and heated to 155 °C for 12 h. The reaction mixture was cooled to room temperature, water (200 mL) was added and was extracted with ethyl acetate (2x100 mL). The combined organic layers were washed with water (200 mL), brine (200 mL) and dried over anhydrous Na2S04. The solvent was evaporated to yield a crude product, which was further purified by column chromatography (silica gel, 7:3 petroleum ether: ethyl acetate) to obtain the title compound.
Ill Yield: 4 g (51 %); 1 H NMR (300 MHz, CDCI3): δ 2.0-2.07 (m, 2H, CH2), 2.46 (t, 2H, J= 6.9 Hz, CH2), 3.03 (t, 2H, J= 7.5 Hz, CH2), 7.45 (d, 1 H, J= 8.4 Hz, Ar), 8.16 (dd, 1 H, J= 8.4 Hz, 2.1 Hz, Ar), 8.45 (d, 1 H, J= 2A Hz, Ar). Example 145:
4-(4-Amino-2-bromophenyl) butanenitrile
Iron (4.41 g, 79 mmol) and ammonium chloride (4.22 g, 79 mmol) were added to a stirred solution of the compound of example 144 (8.5 g, 31 .6 mmol) in THF: ethanol: water (50:50:25 mL) and the resulting reaction mixture was stirred at 85 °C for 1 h. The reaction mixture was filtered through a celite bed. The filtrate was added to a solution of saturated sodium bicarbonate (100 mL) and extracted with ethyl acetate (3 x 100 mL). The combined organic layers were washed with brine (100 mL) and dried over anhydrous Na2S04. The solvent was evaporated to yield a crude product, which was further purified by column chromatography (silica gel, 95:5 CHC : MeOH) to obtain the title compound.
Yield: 4 g (53%); 1 H NMR (300 MHz, CDCI3): δ 2.0-2.07 (m, 2H, CH2), 2.56 (t, 2H, J= 6.9 Hz, CH2), 3.13 (t, 2H, J= 7.5 Hz, CH2), 7.55 (d, 1 H, J= 8.4 Hz, Ar), 8.19 (dd, 1 H, J = 8.4Hz, 2.1 Hz, Ar), 8.45 (d, 1 H, J= 2.1 Hz, Ar); MS (El, 70 eV): m/z 240.2 (M+H+). Example 146:
4-(2-Bromo-4-(((2,2-dimethyl-4,6-dioxo-1 ,3-dioxan-5-ylidene)methyl)amino) phenyl)butanenitrile
2,2-Dimethyl-1 ,3-dioxane-4,6-dione (1 .989 g, 13.80 mmol) and 1 ,1 , 1 -trimethoxyethane (20 mL) were mixed together and heated to reflux for 1 h. The compound of example 145 (3.0 g, 12.55 mmol) was added in portions and heated for 2.5 h. The reaction mixture was cooled to room temperature and the solid obtained was filtered and washed with diethyl ether (80 mL) to obtain the title compound.
Yield: 2.0 g (41 %); 1 H NMR (300 MHz, DMSO-d6): δ 1 .67 (s, 6H, CH3), 1 .79-1 .89 (m, 2H, CH2), 2.56 (t, 2H, J= 6.9Hz, CH2), 2.78 (t, 2H, J= 7.5Hz, CH2), 7.40 (d, 1 H, J= 8.1 Hz, Ar), 7.93 (s, 1 H, Ar), 8.57 (d, 1 H, J= 8.2 Hz, Ar); MS (El, 70 eV): m/z 394.2 (M+H+). Example 147:
4-(7-Bromo-4-hydroxyquinolin-6-yl) butanenitrile
The compound of example 146 (1 .0 g, 2.54 mmol) was added to boiling diphenyl ether (10 mL) and stirred for 10 minutes. The reaction mixture was then cooled to 100 °C and diluted with petroleum ether (100 mL). The solid precipitated was filtered and washed with hot petroleum ether to yield the crude product.
Yield: 600 mg (65 %); MS (El, 70 eV): m/z 292.2 (M+H+); HPLC purity: 64 %.
Example 148:
4-(7-Bromo-4-hydroxy-3-nitroquinolin-6-yl) butanenitrile
Nitric acid (0.288 mL, 4.48 mmol) was added to a stirred solution of the compound of example 147 (435 mg, 1 .494 mmol) in acetic acid (3 mL) and heated to 120 °C for 2 h. The reaction mixture was cooled to room temperature. The solid obtained was filtered, washed with cold water and diethyl ether and dried to obtain the title compound.
Yield: 145 mg (30 %); MS (El, 70 eV): m/z 337.2 (M+H+).
Example 149:
4-(7-Bromo-4-chloro-3-nitroquinolin-6-yl) butanenitrile
Phosphorus oxychloride (776 μΙ, 8.33 mmol) was added to the compound of example 148 (140 mg, 0.416 mmol) and heated to reflux for 2 h. Excess POC was removed, the residue was quenched with aqueous saturated bicarbonate solution (15 mL) and the aqueous layer was extracted with CH2CI2 (2x25 mL). The combined organic layer was washed with brine (15 mL), dried over anhydrous Na2S04 and concentrated. The residue obtained was triturated in DCM: petroleum ether to obtain the title compound. Yield: 96 mg (65 %); MS (El, 70 eV): m/z 355.2 (M+H+); HPLC purity: 54 %.
Example 150:
(R)-4-(7-Bromo-3-nitro-4-((1-phenylethyl)amino)quinolin-6-yl)butanenitrile
(R)-I -Phenylethanamine (0.101 mL, 0.790 mmol) was added to a stirred solution of the compound of example 149 (140 mg, 0.395 mmol) in acetonitrile (5 mL) and heated to reflux for 2 h. The reaction mixture was cooled to room temperature, the solvent was evaporated, water (10 mL) was added and extracted with ethyl acetate (2x10 mL). The combined organic layers were washed with water (10 mL), brine (10 mL) and dried over anhydrous Na2S04. The solvent was evaporated to yield a crude product, which was further purified by column chromatography (silica gel, 7:3 petroleum ether: ethyl acetate) to obtain the title compound.
Yield: 30 mg (17 %); 1 H NMR (300 MHz, DMSO-d6): δ 1 .63-1 .65 (m, 2H, CH2), 1 .71 (d, J = 6.3Hz, CH3), 2.50-2.54 (m, 2H, CH2), 2.76-2.82 (m, 2H, CH2), 5.41 (m, 1 H, CH), 7.45-7.25 (m, 5H, Ar), 8.1 1 (s, 1 H, Ar), 8.21 (s, 1 H, Ar), 9.45 (s, 1 H, Ar), 9.47 (s, 1 H, exchangeable with D20); MS (El, 70 eV): m/z 440.2 (M+H+).
Example 151 :
(R)-4-(3-Amino-7-bromo-4-((1 -phenylethyl)amino)quinolin-6-yl)butanenitrile
Iron (109 mg, 1 .960 mmol) and ammonium chloride (105 mg, 1.960 mmol) were added to a stirred solution of the compound of example 150 (287 mg, 0.653 mmol) in THF: ethanol: water (30:30: 15m L) and the resulting reaction mixture was stirred at 85°C for 1 h. The reaction mixture was filtered through celite. The filtrate was added to a solution of saturated sodium bicarbonate (20 mL) and extracted with ethyl acetate (3 x 20 mL). The combined organic layers were washed with brine (20 mL) and dried over anhydrous Na2S04. The solvent was evaporated to obtain a crude product, which was further purified by column chromatography (silica gel, 95:5 CHCI3: MeOH) to obtain the title compound.
Yield: 165 mg (62 %); MS (El, 70 eV): m/z 410.2 (M+H+); HPLC purity: 64 % Example 152:
4-(3-Amino-7-(3,5-dimethylisoxazol-4-yl)-4-(((R)-1-phenylethyl)amino)quinolin-6- yl)butanenitrile
1 , 1 '-Bis(diphenylphosphino)ferrocene]dichloro palladium(ll) complex with dichloro methane (64.2 mg, 0.079 mmol) was added to a stirred solution of the compound of example 151 (161 mg, 0.393 mmol) and (3,5-dimethylisoxazol-4-yl)boronic acid (1 1 1 mg, 0.787 mmol) in DMF (5 mL) followed by potassium carbonate (163 mg, 1 .180 mmol) solution in water (1 mL) and heated to 120 °C for 1 h. The reaction mixture was then cooled to room temperature, concentrated, water (10 mL) was added and extracted with CHC (3x10 mL).The combined organic layers were washed with brine (10 mL), dried over anhydrous Na2S04 and solvent was evaporated to yield the crude product, which was further purified by column chromatography (silica gel, 9: 1 CHCI3: MeOH) to obtain the title compound.
Yield: 65 mg (39 %); 1 H NMR (300 MHz, DMSO-d6): δ 1 .51 (d, J= 6.3Hz, CH3) , 1 .67- 1 .62 (m, 2H, CH2), 2.0 (s, 1 H, CH3), 2.22 (s, 1 H, CH3), 2.39-2.41 (m, 2H, CH2), 2.41 - 2.50 (m, 2H, CH2), 4.17 (bs, 1 H, NH, exchangeable with D20), 4.68 (m, 1 H, CH), 5.15 (s, 2H, NH2, exchangeable with D20), 7.45-7.25 (m, 5H, Ar), 7.83 (s, 1 H, Ar), 8.25 (s, 1 H, Ar), 8.34 (s, 1 H, Ar); MS (El, 70 eV): m/z 426.2 (M+H+).
Example 153:
(E)-N-(8-(3-Cyanopropyl)-7-(3,5-dimethylisoxazol-4-yl)-1-((R)-1-phenylethyl)-1 H- imidazo[4,5-c]quinolin-2(3H)-ylidene)cyanamide
Diphenyl cyanocarbonimidate (43.7 mg, 0.183 mmol) was added to a stirred solution of the compound of example 152 (52 mg, 0.122 mmol) in acetonitrile (1 ml_) and the resulting reaction mixture was heated to 85 °C for 12-16 h. The reaction mixture was cooled to room temperature, the solvent was evaporated and the resulting residue was quenched in water (5 ml_). The solid obtained was filtered and the filtrate was extracted with ethyl acetate (3x5 ml_). The combined organic layers were washed with brine (1 ) ml_), dried over anhydrous Na2S04 and the solvent was evaporated to yield a crude product, which was further purified by preparative thin layer chromatography (silica gel, 9: 1 :0.05 CHCI3: MeOH: triethylamine) to obtain the title compound.
Yield: 12 mg (20 %); 1 H NMR (300 MHz, DMSO-d6): δ 1 .51 (d, J= 6.3Hz, CH3) , 1 .67- 1 .62 (m, 2H, CH2), 2.0 (s, 3H, CH3), 2.22 (s, 3H, CH3), 2.41 -2.39 (m, 2H, CH2), 2.50- 2.41 (m, 2H, CH2), 6.42 (m, 1 H, CH), 7.43-7.34 (m, 5H, Ar), 7.84 (s, 1 H, Ar), 8.25 (s, 1 H, Ar), 8.92 (s, 1 H, Ar), 13.7 (s, 1 H, NH, exchangeable with D2O); MS (El, 70 eV): m/z 476.2 (M+H+). HPLC purity: 94 %.
Example 154:
Methyl 2-(4-amino-2-bromophenyl) acetate
Iron (20.01 g, 374 mmol) and ammonium chloride (20.89 g, 374 mmol) were added to a stirred solution of methyl 2-(2-bromo-4-nitrophenyl)acetate (41 g, 150 mmol) in THF: ethanol: water (100: 100:50 ml_) and the resulting reaction mixture was stirred at 85 °C or 1 h. The reaction mixture was filtered through celite. The filtrate was added to a solution of saturated sodium bicarbonate (100 ml_) and extracted with ethyl acetate (3 x 100 ml_). The combined organic layers were washed with brine (100 ml_), and dried over anhydrous. Na2S04. The solvent was evaporated to obtain a crude product, which was further purified by column chromatography (silica gel, 95:5 CHC : MeOH) to obtain the title compound.
Yield: 31 g (85 %); 1H NMR (300 MHz, CDCI3): 3.64 (s, 3H, -OCH3), 4.03 (s, 2H, CH2), 7.45 (d, 1 H, J= 8.4 Hz, Ar), 8.29 (dd, 1 H, J = 8.4 Hz, 2.1 Hz, Ar), 8.46 (d, 1 H, J= 2.1 Hz, Ar); MS (El, 70 eV): m/z 245.2 (M+H+).
Example 155:
Methyl 2-(2-bromo-4-(((2,2-dimethyl-4,6-dioxo-1 ,3-dioxan-5-ylidene)methyl) amino)phenyl)acetate
2,2-Dimethyl-1 ,3-dioxane-4,6-dione (20.14 g, 140 mmol) and 1 , 1 , 1 -trimethoxyethane (150 ml_) were mixed together and heated to reflux for 1 h. The compound of example 154 (31 g, 127 mmol) was added in portions and heated for 2.5 h. The reaction mixture was cooled to room temperature and the solid obtained was filtered and washed with diethyl ether (200 ml_) to obtain the title compound.
Yield: 40 g (79 %).
Example 156:
Methyl 2-(7-bromo-4-hydroxyquinolin-6-yl)acetate
The compound of example 155 (45 g, 1 13 mmol) was added to boiling diphenyl ether (300 ml_) and stirred for 10 minutes. The reaction mixture was then cooled to 100 °C and diluted with petroleum ether (1000 ml_). The solid obtained was filtered and washed with hot petroleum ether to yield the crude title compound.
Yield: 24.0 g (71 %); MS (El, 70 eV): m/z 297.5 (M+H+).
Example 157:
Methyl 2-(7-bromo-4-hydroxy-3-nitroquinolin-6-yl) acetate
Nitric acid (9.24 ml_, 203 mmol) was added to a stirred solution of the compound of example 156 (24 g, 81 mmol) in acetic acid (23 ml_). The resulting reaction mixture was heated to 120 °C for 2 h. and then cooled to room temperature. The solid obtained was filtered, washed with cold water and diethyl ether and dried to obtain the title compound. Yield: 15.0 g (54 %); MS (El, 70 eV): m/z 342.5 (M+H+); Example 158:
Methyl 2-(4,7-dibromo-3-nitroquinolin-6-yl)acetate
To a solution of the compound of example 157 (6.6 g, 19.35 mmol) in DMF was added PBr3 (2.76 mL, 23.22 mmol) dropwise. The solid obtained was filtered and washed with water. The compound obtained was dried to obtain the title compound.
Yield: 6.0 g (77 %); 1H NMR (300 MHz, DMSO-d6): δ 3.63 (s, 3H, OCH3), 4.03 (s, 2H, CH2), 7.98 (s, 1 H, Ar), 8.27 (s, 1 H, Ar), 9.23 (s, 1 H, Ar); MS (El, 70 eV): m/z 405.4 (M+H+).
Example 159:
(R)-Methyl 2-(7-bromo-3-nitro-4-((1-phenylethyl)amino)quinolin-6-yl)acetate
(R)-I -Phenylethanamine (4.20 g, 34.7 mmol) was added to a stirred solution of the compound of example 158 (7 g, 17.33 mmol) in acetonitrile (50 mL) and heated to reflux for 2 h. The reaction mixture was cooled to room temperature, the solvent was evaporated, water (100 mL) was added and extracted with ethyl acetate (2 x 50 mL). The combined organic layers were washed with water (100 mL), brine (100 mL) and dried over anhydrous Na2S04. The solvent was evaporated to yield a crude product, which was further purified by column chromatography (silica gel, 7:3 petroleum ether: ethyl acetate) to obtain the title compound.
Yield: 3.0 g (39 %); 1H NMR (300 MHz, DMSO-d6): δ 1 .69 (d, 3H, J=7.1 Hz, CH3), 3.33 (s, 3H, -OCH3), 3.64 (s , 2H, CH2), 5.38 (m, 1 H, CH), 7.37-7.23 (m, 5H, Ar), 8.12 (s, 1 H, Ar), 8.45 (s, 1 H, Ar), 9.05 (s, 1 H, Ar), 9.28 (s, 1 H, NH, exchangeable with D20); MS (El, 70 eV): m/z 44.4 (M+H+); HPLC purity: 98.00 %.
Example 160:
(R)-Methyl 2-(3-amino-7-bromo-4-((1-phenylethyl)amino)quinolin-6-yl)acetate
Iron (1 .508 g, 27.0 mmol) and ammonium chloride (1 .445 g, 27.0 mmol) were added to a stirred solution of the compound of example 159 (3 g, 6.75 mmol) in THF: ethanol: water (30:30: 15 mL) and the resulting reaction mixture was stirred at 85 °C for 1 h. The reaction mixture was filtered through celite. The filtrate was added to a solution of saturated sodium bicarbonate (20 mL) and extracted with ethyl acetate (3 x 20 mL). The combined organic layers were washed with brine (20 mL) and dried over anhydrous Na2S04. The solvent was evaporated to obtain a crude product, which was further purified by column chromatography (silica gel, 95:5 CHCI3: MeOH) to obtain the title compound.
Yield: 1 .5 g (54 %); MS (El, 70 eV): m/z 415.2 (M+H+).
Example 161 :
(R,E)-Methyl 2-(7-bromo-2-(cyanoimino)-1 -(1 -phenylethyl)-2,3-dihydro-1 H- i midazo[4,5-c]q ui nol i n-8-yl)acetate
Diphenyl cyanocarbonimidate (569 mg mg, 2.390 mmol) was added to a stirred solution of the compound of example 160 (900 mg, 2.172 mmol) in acetonitrile (2 mL) and the resulting reaction mixture was heated to 85 °C for 12-16 h. The reaction mixture was cooled to room temperature, the solvent was evaporated and the resulting residue was quenched in water (10 mL). The solid obtained was filtered and the filtrate was extracted with ethyl acetate (3x10 mL). The combined organic layers were washed with brine (15 mL), dried over anhydrous Na2S04 and the solvent was evaporated to obtain a crude product, which was further purified by preparative thin layer chromatography (silica gel, 9: 1 :0.05 CHCI3: MeOH: triethylamine) to obtain the title compound.
Yield: 400 mg (40 %); 1 H NMR (300 MHz, DMSO-d6): δ 1.96 (d, 3H, J = 6.9 Hz, CH3), 3.39 (s, 3H, OCH3), 3.74 (s, 2H, CH2), 6.43 (m, 1 H, CH), 7.31 (s, 1 H, Ar), 7.36-7.35 (m, 5H, Ar), 8.30 (s, 1 H, Ar), 8.91 (s, 1 H, Ar), 13.76 (s, 1 H, NH, exchangeable with D2O); MS (El, 70 eV): m/z 465.4 (M+H+).
Example 162:
Methyl 2-((E)-2-(cyanoimino)-7-(3,5-dimethylisoxazol-4-yl)-1-((R)-1-phenylethyl)- 2,3-dihydro-1 H-imidazo[4,5-c]quinolin-8-yl)acetate
1 , 1 '-Bis(diphenylphosphino)ferrocene]dichloro palladium(ll) complex with dichloromethane (70.4 mg, 0.086 mmol) was added to a stirred solution of the compound of example 161 (400 mg, 0.861 mmol) and (3,5-dimethylisoxazol-4- yl)boronic acid (219 mg, 1 .551 mmol) in DMF (5 mL) followed by sodium carbonate (274 mg, 2.54 mmol) solution in water (1 mL) and the resulting reaction mixture was heated to 120 °C for 1 h. The reaction mixture was then cooled to room temperature and concentrated. Water (10 mL) was added to the resulting residue and extracted with CHCl3 (3 x 10 ml_). The combined organic layers were washed with brine (15 ml_), dried over anhydrous Na2S04 and the solvent was evaporated to yield the crude product, which was further purified by column chromatography (silica gel, 9: 1 CHC : MeOH) to obtain the title compound.
Yield: 200 mg (48 %); 1 H NMR (300 MHz, DMSO-d6): δ 1 .94 (s, 3H, CH3), 1.96 (s, 3H, CH3), 2.15 (d, 3H, J=10.2 Hz, CH3), 3.45 (s, 3H, -OCH3), 3.37 (s , 2H, CH2), 6.44 (m, 1 H, CH), 7.34 (s, 1 H, Ar), 7.37-7.39 (m, 5H, Ar), 7.88 (s, 1 H, Ar), 8.93 (s, 1 H, Ar), 13.79 (s, 1 H, NH, exchangeable with D20); MS (El, 70 eV): m/z 481 .5 (M+H+); HPLC purity: 97 %.
Example 163:
Methyl 2-(4-iodo-3-methylisoxazol-5-yl) acetate
To a stirred solution of ethyl methyl 2-(3-methylisoxazol-5-yl) acetate (5.2 g, 33.5 mmol) in trifluoroacetic acid (60 ml_) was added N-lodosuccinimide (7.54 g, 33.5 mmol) and the resulting mixture was heated to 65 °C for 3 h. The reaction mixture was quenched with sodium bicarbonate solution and extracted with ethyl acetate. The separated organic layer was washed with water and brine. The organic layer was dried over anhydrous sodium sulphate, concentrated and dried to obtain the title compound. Yield: 7.2 g (76 %); 1H NMR (300 MHz, CDCI3): δ 2.31 (s, 3H, CH3), 3.86 (s, 2H, CH2), 3.77 (s, 3H, COOCH3), MS: m/z 282 (M + H)+; HPLC purity: 97.1 1 %.
Example 164:
Ethyl2-(3-methyl-4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)isoxazol-5- yl)acetate
Dichlorobis (acetonitrile) palladium (II) (0.046 g, 0.178 mmol) and dicyclohexyl (2',6'- dimethoxy-[1 , 1 '-biphenyl]-2-yl) phosphine (0.292 g, 0.712 mmol) were added under an atmosphere of nitrogen. The compound of example 163 (2.500 g, 8.90 mmol) in 1 ,4- dioxane (6.00 ml_) and TEA (3.72 ml_, 26.7 mmol) with 4,4,5,5-tetramethyl-1 ,3,2- dioxaborolane (1 .936 ml_, 13.34 mmol) were sequentially added. The flask was sequentially evacuated and purged under argon gas. The reaction mixture was heated to 1 10 °C under argon gas and stirred for 4 h. The reaction mixture was diluted with ethyl acetate, filtered and concentrated to obtain the title compound.
Yield: 5.5 g (100 %). Example 165:
4,7-dibromo-6-methoxy-3-nitroquinoline
To a stirred solution of 7-Bromo-6-methoxy-3-nitroquinolin-4-ol (30 g, 100 mmol) in DMF (500.0 ml_) was added PBr3 (10.41 ml_, 1 10 mmol) slowly and stirred for 1 h at room temperature. To the reaction mixture ice water (400 ml_) was added, stirred, filtered and washed with water to obtain the title compound.
Yield: 35.1 g (97 %); 1H N MR (300 MHz, DMSO d6): 5 4.10 (s, 3H, OCH3), 7.62 (s, 1 H, Ar), 8.52 (s, 1 H, Ar), 9.15 (s, 1 H, Ar); MS: m/z 363 (M + 2H)+.
Example 166:
(R)-7-Bromo-6-methoxy-3-nitro-N-(1-phenylethyl) quinolin-4-amine
(R)-I -Phenylethanamine (12.72 g, 105 mmol) was added to a stirred solution of the compound of example 165 (19.00 g, 52.5 mmol) in acetonitrile (600 ml_) and the mixture was refluxed for 12 h. The mixture was cooled to room temperature and the reaction mass was concentrated to yield a crude product. This was purified by column chromatography (silica gel, 0 - 15 % ethyl acetate: petroleum ether) to obtain the title compound.
Yield: 16.5 g (78 %); 1H NMR (300 MHz, 300 MHz, CDCI3): δ 1 .76 (d, J = 6.6 Hz, 3H, CH3), 3.28 (s, 3H, OCH3), 5.32 (m, 1 H, Ar), 7.23 (s, 1 H, Ar), 7.53-7.33 (m, 5H, Ar), 8.18 (s, 1 H, Ar), 9.29 (s, 1 H, Ar), 9.60 (d, 1 H, J = 7.2 Hz, NH); MS: m/z 404.1 (M + 2H)+.
Example 167:
(R)-7-bromo-6-methoxy-N4-(1 -phenylethyl) quinoline-3,4-diamine
To a stirred solution of the compound of example 166 (6.00 g, 14.92 mmol), ammonium chloride (3.19 g, 59.7 mmol) and iron (3.33 g, 59.7 mmol) in water (12.50 ml_), ethanol (25.0 ml_) and THF (25.0 ml_) mixture were added subsequently and heated at 85 °C for 2 h. The reaction mixture was allowed to cool to room temperature and the reaction mass was filtered through celite bed. The filtrate was concentrated, triturated with ethyl acetate and petroleum ether to obtain the title compound.
Yield: 3.0 g (54 %); 1H NMR (300 MHz, CDCI3): δ 1 .69 (d, J = 6.6 Hz, 3H, CH3), 3.57 (s, 1 H, N-H, exchangeable), 3.70 (s, 2H, NH), 3.79 (s, 3H, 0-CH3), 4.52 (m, 1 H, CH), 6.77 (s, 1 H, Ar), 7.32-7.28 (m, 5H, Ar), 8.14 (s, 1 H, Ar), 8.34 (s, 1 H, Ar); MS: m/z: 372.1 (M + H)+; HPLC purity: 99.05 %.
Example 168:
Ethyl 2-(4-((E)-2-(cyanoimino)-8-methoxy-1-((R)-1-phenylethyl)-2,3-dihydro-1 H- imidazo[4,5-c]quinolin-7-yl)-3-methylisoxazol-5-yl)acetate
Palladium catalyst PdCI2(dppf)-CH2CI2 adduct (0.058 g, 0.071 mmol) was added to a stirred solution of the compound of example 86 (1 .00 g, 2.368 mmol) and ethyl 2-(3- methyl-4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)isoxazol-5-yl)acetate (1.398 g, 4.74 mmol) in N,N-dimethylformamide (20.0 mL). To the reaction mixture was added a solution of sodium carbonate (0.502 g, 4.74 mmol) in water (4.00 mL) and stirred at 120 °C for 1 h. The reaction mixture was allowed to cool to room temperature, the solvent was removed and diluted with water. The resulting mixture was extracted with ethyl acetate, washed with water and brine, dried over anhydrous Na2S04 and concentrated to yield a crude product. The crude product obtained was purified by column chromatography (silica gel, 0 - 15 % methanol in chloroform) to obtain the title compound.
Yield: 0.694 g (56.8 %); 1H NMR (300 MHz, CDCI3) δ 1 .28 (t, J = 6.9 Hz, 3H, CH3), 2.09 (d, J = 7.2 Hz, 3H, CH3), 2.20 (s, 3H, CH3), 3.29 (s, 3H, 0-CH3), 3.70 (s, 2H, CH2), 4.1 1 (q, J = 6.9 Hz, 2H, CH2), 6.62 (m, 1 H, CH), 6.69 (s, 1 H, Ar), 7.34-7.43 (m, 5H, Ar), ), 6.98 (s, 1 H, Ar), 8.98 (s, 1 H, Ar); MS: m/z 51 1 .3 (M + H)+; HPLC purity: 98.87 %.
Example 169:
2-(4-((E)-2-(Cyanoimino)-8-methoxy-1-((R)-1-phenylethyl)-2,3-dihydro-1 H-imidazo
[4,5-c]quinolin-7-yl)-3-methylisoxazol-5-yl)acetic acid
To a solution of the compound of example 168 (300 mg, 0.588 mmol) in THF: MeOH (4: 1 ) was added lithium hydroxide hydrate (148 mg, 3.53 mmol) and stirred at room temperature for 14 h. The solvent was evaporated, washed with 5 % ethyl acetate in petroleum ether, quenched with addition of saturated NH4CI and extracted with ethyl acetate. The organic layer was dried and concentrated to yield a crude product. The crude product was purified by column chromatography (silica gel, 0 - 15 % methanol in chloroform) to obtain the title compound. Yield: 0.265 g (93 %); 1H NMR (300 MHz, DMSO-d6) δ 1 .88 (d, J = 7.2 Hz, 3H, CH), 2.04 (s, 3H, CH3), 3.20-3.27 (br, 1 H, COOH, exchangeable with D20), 3.24 (s, 3H, 0- CH3), 3.53 (s, 2H, CH2), 6.41 (m, 1 H, CH), 6.55 (s, 1 H, Ar-H), 7.27-7.39 (m, 6H, Ar), 7.75 (s, 1 H, Ar), 8.65 (s, 1 H, Ar); MS: m/z 483.1 (M + H)+; HPLC purity: 99.52 %.
Example 170:
Ethyl 3-(4-iodo-5-methylisoxazol-3-yl) propanoate
To a stirred solution of ethyl 3-(5-methylisoxazol-3-yl) propanoate (1.1 g, 6.00 mmol) in TFA (13 mL) was added N-iodosuccinimide (2.70 g, 12.01 mmol) and the resulting mixture was heated to 65 °C for 3 h. The reaction mixture was quenched with sodium bicarbonate solution, extracted with ethyl acetate, washed with water and brine and dried over sodium sulphate. The organic layer was concentrated and dried to obtain the title compound.
Yield: 3.5 g (71 .7 %); 1H NMR (300 MHz, CDCI3): δ 1 .28 (t, J = 7.2 Hz, 2H, CH2), 2.46 (s, 3H, CH3), 2.78 (m, 2H, CH2), 2.92 (m, 2H, CH2), 4.18 (q, J = 7.2 Hz, 2H, CH2), MS: m/z 310 (M + H)+; HPLC purity: 92.30 %.
Example 171 :
Ethyl 3-(5-methyl-4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)isoxazol-3-yl) propanoate
Dichlorobis (acetonitrile)palladium(ll) (0.022 g, 0.084 mmol) was reacted with dicyclohexyl(2',6'-dimethoxy-[1 ,1 '-biphenyl]-2-yl)phosphine (0.138 g, 0.336 mmol) under an atmosphere of nitrogen. To the reaction mixture was sequentially added a solution of the compound of example 170 (1.300 g, 4.21 mmol) in 1 ,4-dioxane (20.00 mL), TEA (1 .759 mL, 12.62 mmol) and 4,4,5,5-tetramethyl-1 ,3,2-dioxaborolane (0.915 mL, 6.31 mmol) under argon gas atmosphere. The reaction mixture was heated to 1 10 °C under argon gas and stirred for 4.0 h. The reaction mixture was diluted with ethyl acetate, filtered and concentrated to obtain the title compound.
Yield: 1.3 g (100 %).
Example 172:
Ethyl 3-(4-((E)-2-(cyanoimino)-8-methoxy-1-((R)-1-phenylethyl)-2,3-dihydro-1 H- imidazo[4,5-c]quinolin-7-yl)-5-methylisoxazol-3-yl)propanoate Palladium catalyst PdCI2(dppf)-CH2CI2 adduct (0.013 g, 0.016 mmol) was added to a stirred solution of the compound of example 86 (0.230 g, 0.545 mmol) and the compound of example 175 (0.337 g, 1 .089 mmol) in N,N-dimethylformamide (7.0 ml_). To the reaction mixture, was added a solution of sodium carbonate (0.1 15 g, 1.089 mmol) in water (4.00 ml_) and stirred at 120 °C for 1 h. The reaction mixture was allowed to cool to room temperature, the solvent was removed and diluted with water. The resulting mixture was extracted with ethyl acetate, washed with water and brine, dried over anhydrous sodium sulphate and concentrated to yield a crude product. The crude product was purified by column chromatography (silica gel, 0 - 15 % methanol in chloroform) to obtain the title compound.
Yield: 0.155 g (54.2 %); 1H NMR (300 MHz, DMSO-d6): δ 1 .08 (t, J = 7.2 Hz, 3H, CH3), 2.00 (d, J = 6.9 Hz, 3H, CH3), 2.24 (s, 3H, CH3), 3.34 (s, 3H, 0-CH3), 2.44-2.55 (m, 4H, CH2), 3.94 (q, J = 7.2 Hz, 2H, CH2), 6.42 (m, 1 H, CH), 6.65 (s, 1 H, Ar), 7.42 (m, 5H, Ar), ), 7.90 (s, 1 H, Ar), 8.82 (s, 1 H, Ar), 13.66 (s, 1 H, NH); MS: m/z 525.2 (M + H)+; HPLC purity: 88.93 %.
Example 173:
3-(4-((E)-2-(Cyanoimino)-8-methoxy-1-((R)-1^henylethyl)-2,3-dihydro-1 H-imidazo
[4,5-c]quinolin-7-yl)-5-methylisoxazol-3-yl)propanoic acid
To a stirred solution of the compound of example 172 (200 mg, 0.381 mmol) in THF: MeOH (4: 1 ) was added lithium hydroxide hydrate (96 mg, 2.288 mmol) and stirred at room temperature for 14 h. The solvent was evaporated, washed with 5 % ethyl acetate in petroleum ether, quenched with saturated NH4CI and extracted with ethyl acetate. The organic layer was dried and concentrated to give crude product. The crude product obtained was purified by column chromatography (silica gel, 0 - 15 % methanol in chloroform) to obtain the title compound.
Yield: 0.132 g (69.7 %); 1H NMR (300 MHz, DMSO-d6): δ 1 .88 (d, J = 6.9 Hz, 3H, CH3), 2.20 (s, 3H, CH3), 2.39-2.46 (m, 2H, CH2), 2.57-2.62 (m, 2H, CH2), 3.25 (s, 3H,
0- CH3), 6.40 (m, 1 H, CH), 6.56 (s, 1 H, Ar), 7.28-7.42 (m, 5H, Ar), 7.67 (s, 1 H, Ar), 8.66 (s, 1 H, Ar); MS: m/z 497 (M + H)+; HPLC purity: 92.52 %.
Example 174:
1- (Benzyloxy)-2-bromo-4-nitrobenzene Benzyl bromide (83 mL, 0.702 mmol) was added drop-wise to a solution of 2-bromo-4- nitrophenol (170 g, 0.780 mmol) and potassium carbonate (323 g, 2.34 mmol) in acetone (1 L) and refluxed at 60 °C for 12 h. The reaction mixture was filtered through celite and washed with 200 mL ethyl acetate. The solvent was removed, triturated with hexane (400 mL) at 60 °C to obtain the title compound.
Yield: 190 g (79 %); 1 H NMR (300 MHz, DMSO-d6): δ 5.37 (s, 2H, CH2), 7.33-7.50 (m, 6H, Ar), 8.27 (dd, J = 2.4 Hz, 9.1 Hz, 1 H, Ar), 8.45 (d, J = 2.4 Hz, 1 H, Ar).
Example 175:
4-(2-(Benzyloxy)-5-nitrophenyl)-3,5-dimethylisoxazole
Tetrakis(triphenylphosphine)palladium(0) (23.9 g, 28.6 mmol) was added to a solution of the compound of example 174 (1 10 g, 357 mmol) and (3,5-dimethylisoxazol-4- yl)boronic acid (65.4 g, 464 mmol) in 1 ,4 dioxane (1 L), followed by added a solution of sodium carbonate (95 g, 892 mmol) in water (333 mL) and the resulting mixture was heated to 1 10 °C for 5 h. The reaction mixture was cooled to room temperature and concentrated. Water (700 mL) was added to the residue and extracted with CHC (3 x 400 mL).The combined organic extracts were washed with brine (500 mL), dried over anhydrous Na2S04 and concentrated to yield the crude product, which was purified by column chromatography (silica gel, 1 :1 ethyl acetate : petroleum ether) to obtain the title compound.
Yield: 90 g (78 %); 1H NMR (300 MHz, DMSO-d6): δ 2.06 (s, 3H, CH), 2.26 (s, 3H, CH), 5.30 (s, 2H, CH2), 7.33 - 7.41 (m, 5H, Ar), 7.48 (d, J = 9.3 Hz, 1 H, Ar), 8.12 (d, J = 3 Hz, 1 H, Ar), 8.33 (dd, J = 3.0 Hz, 9.3 Hz, 1 H, Ar); MS: m/z 325.2 (M + H)+. Example 176:
2-(3,5-Dimethylisoxazol-4-yl)-4-nitrophenol
A 1 M solution of boron tribromide in DCM (393 mL, 393 mmol) was added to a solution of the compound of example 175 (85 g, 262 mmol) in DCM (600 mL) at 0 °C and stirred at room temperature for 2 h. The reaction was quenched with ice water and extracted with DCM (3 x 200 mL). The combined extracts were washed with water (2 x 150 mL), brine (100 mL), dried over anhydrous sodium sulphate and concentrated to afford the title compound. Yield: 56 g (91 %); 1 H NMR (300 MHz, DMSO-d6): δ 2.1 1 (s, 3H, CH), 2.90 (s, 3H, CH), 7.14 (d, J = 9 Hz, 1 H, Ar), 8.04 (d, J = 2.7 Hz, 1 H, Ar), 8.17 (dd, J = 2.7 Hz, 9 Hz, 1 H, Ar), 1 1 .45 (s, 1 H, exchangeable in D20, OH); MS: m/z 235.1 (M + H)+. Example 177:
Methyl 2-(2-(3,5-dimethylisoxazol-4-yl)-4-nitrophenoxy)acetate
To a solution of the compound of example 176 (55 g, 235 mmol) and potassium carbonate (64.9 g, 470 mmol) in DMF (300 mL) was added methyl 2-bromoacetate (26.8 mL, 282 mmol) and heated at 65 °C for 2 h. To the reaction mixture, ice water was added and extracted with ethyl acetate. The organic layer was separated and washed with water and brine, dried over anhydrous sodium sulphate and concentrated to yield the crude product, which was purified by column chromatography (silica gel, 1 : 1 ethyl acetate : petroleum ether) to obtain the title compound.
Yield: 51 g (71 %); 1 H NMR (300 MHz, DMSO-d6): δ 1 .99 (s, 3H, CH), 2.14 (s, 3H, CH), 3.71 (s, 3H, -OCH3), 5.06 (s, 2H, -OCH2), 7.28 (d, J = 9.3 Hz, 1 H, Ar), 8.13 (brs, 1 H, Ar), 8.27 (d, J = 9.3 Hz, 1 H, Ar).
Example 178:
Methyl 2-(4-amino-2-(3,5-dimethylisoxazol-4-yl)phenoxy)acetate
To a solution of the compound of example 177 (50 g, 163 mmol) and ammonium chloride (21.83 g, 408 mmol) in ethanol:THF:water (300 mL : 300 mL : 150 mL) was added iron powder (22.79 g, 408 mmol) in portions and the mixture was refluxed at 85 °C for 12 h. The reaction mixture was filtered through celite, filtrate was concentrated and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulphate and concentrated to yield a crude solid. The solid obtained was washed with petroleum ether to obtain the title compound.
Yield: 40 g, 89 %; 1H NMR (500 MHz, DMSO-d6): δ 2.1 1 (s, 3H, CH), 2.28 (s, 3H, CH), 3.66 (s, 3H, -OCH3), 4.60 (s, 2H, -OCH2), 4.79 (brs, 2H, exchangeable in D2O, - NH2), 6.44 (brs, 1 H, Ar), 6.55 (d, J = 8 Hz, 1 H, Ar), 6.72 (d, J = 8.5 Hz, 1 H, Ar).
Example 179:
Methyl 2-(4-(((2,2-dimethyl-4,6-dioxo-1 ,3-dioxan-5-ylidene)methyl)amino)-2-(3,5- dimethylisoxazol-4-yl)phenoxy)acetate A mixture of 2,2-dimethyl-1 ,3-dioxane-4,6-dione (20.87 g, 145 mmol) and trimethoxy methane (15.84 ml_, 145 mmol) were heated at 1 10 °C for 1 h. To the reaction mixture, the compound of example 178 (40 g, 145 mmol) was added portionwise and stirred at reflux for 1 h. The reaction mixture was cooled to room temperature, diethyl ether (100 ml_) was added and stirred for 12 h. The precipitate obtained was filtered and dried to obtain the title compound.
Yield: 60 g (66 %).
Example 180:
Methyl 2-((7-(3,5-dimethylisoxazol-4-yl)-4-hydroxyquinolin-6-yl)oxy)acetate
The compound of example 179 (60 g, 139 mmol) was added to boiling diphenyl ether (360 ml_) and stirred for 10 minutes. The reaction mixture was then cooled to room temperature and diluted with petroleum ether (1000 ml_). The precipitated solid was collected by filtration and washed with petroleum ether to obtain the title compound. Yield: 40 g (55 %)
Example 181 :
Methyl 2-((7-(3,5-dimethylisoxazol-4-yl)-4-hydroxy-3-nitroquinolin-6-yl)oxy) acetate
Nitric acid (16.23 ml_, 363 mmol) was added to a solution of the compound of example 180 (40 g, 121 mmol) in acetic acid (350 ml_). The resulting reaction mixture was heated at 120 °C for 2 h and then cooled to room temperature. The solid obtained was filtered, washed with cold water and dried to afford the title compound.
Yield: 21 g (75 %); MS m/z: 374.1 (M + H)+.
Example 182:
Methyl 2-((4-bromo-7-(3,5-dimethylisoxazol-4-yl)-3-nitroquinolin-6-yl)oxy) acetate
Phosphorous tribromide (3.79 ml_, 40.2 mmol) was added drop-wise to a solution of the compound of example 181 (10 g, 26.8 mmol) in DMF (200 ml_) at 0 °C over 30 minutes. The reaction mixture was stirred for 2 h at room temperature. The reaction mixture was quenched with ice cold water to afford a solid which was filtered, washed with cold water and dried to afford the title compound. Yield: 5.5 g; 1H NMR (300 MHz, DMSO-d6): δ 2.21 (s, 3H, CH), 2.39 (s, 3H, CH), 3.75 (s, 3H, -OCH3), 5.18 (s, 2H, -OCH2), 7.61 (s, 1 H, Ar), 8.19 (s, 1 H, Ar), 9.20 (s, 1 H, Ar).
Example 183:
Methyl 2-((7-(3,5-dimethylisoxazol-4-yl)-3-nitro-4-(((R)-1 -phenylethyl)amino) q u i no I i n-6-y I )oxy)acetate
To a solution of the compound of example 182 (3.0 g, 6.88 mmol) in acetonitrile (50 mL) was added (R)-l -phenylethanamine (1 .064 mL, 8.25 mmol) and heated at 85 °C for 2 h. The solvent was evaporated and water (50 mL) was added to the residue. The mixture was extracted with ethyl acetate (3x25 mL). The combined organic layers were washed with brine (50 mL) and dried over anhydrous Na2S04. The solvent was evaporated to yield the crude product, which was purified by column chromatography (silica gel, 2 % MeOH in CHCI3) to obtain the title compound.
Yield: 2.0 g (61 %); 1H NMR (300 MHz, DMSO-d6): δ 1 .69 (d, J = 6.6 Hz, 1 H, -CH3), 2.16 (s, 3H, CH), 2.34 (s, 3H, CH), 3.68 (s, 3H, -OCH3), 4.61 (d, J = 16.2 Hz, 1 H, -CH), 4.82 (d, J = 16.5 Hz, 1 H, -CH), 5.24 (m, 1 H, -CH), 7.28 - 7.43 (m, 5H, Ar), 7.61 (s, 1 H, Ar), 7.83 (s, 1 H, Ar), 8.88 (d, J = 7.2 Hz, 1 H, exchangeable in D20, -NH), 8.97 (s, 1 H, Ar); MS: m/z 477.2 (M + H)+. Example 184:
Methyl 2-((3-amino-7-(3,5-dimethylisoxazol-4-yl)-4-(((R)-1-phenylethyl)amino) q u i no I i n-6-y l)oxy)acetate
To a solution of the compound of example 183 (250 mg, 0.525 mmol) and ammonium chloride (70.2 mg, 1 .312 mmol) in ethanol:THF:water (7 mL : 7 mL : 3 mL) was added iron powder (73.3 mg, 1 .312 mmol) in portions and the mixture was refluxed at 85 °C for 2 h. The reaction mass was filtered through celite bed, filtrate was concentrated and extracted with ethyl acetate. The organic extracts were washed with brine, dried over sodium sulphate and concentrated under vacuum to yield a crude solid. The solid obtained was washed with petroleum ether to obtain the title compound.
Yield: 0.18 g (77 %); 1 H NMR (300 MHz, DMSO-d6): δ 1 .48 (d, J = 6.9 Hz, 1 H, -CH3), 2.15 (s, 3H, isoxazole-H), 2.31 (s, 3H, isoxazole-H), 3.67 (s, 3H, -OCH3), 4.58 (m, 1 H, -CH), 4.85 (s, 2H, -OCH2), 5.08 (s, 1 H, exchangeable in D20, -NH), 5.14 (s, 2H, exchangeable in D20, -NH2), 7.18-7.30 (m, 5H, Ar-H), 7.44 (s, 1 H, Ar-H), 7.54 (s, 1 H, Ar-H), 8.27 (s, 1 H, Ar-H); MS: m/z 447.2 (M + H)+.
Example 185:
Methyl 2-((2-(cyanoimino)-7-(3,5-dimethylisoxazol-4-yl)-1-((R)-1-phenylethyl) -2,3- dihydro-1 H-imidazo[4,5-c]quinolin-8-yl)oxy)acetate
To a solution of the compound of example 184 (180 mg, 0.403 mmol) in acetonitrile (7 ml_) was added diphenyl cyanocarbonimidate (96 mg, 0.403 mmol) and heated at 85 °C for 12 h. Water (20 ml_) was added to the reaction mixture and extracted with ethyl acetate (2 x 20 ml_). The extracts were washed with water (20 ml_), brine (20 ml_) and dried over anhydrous sodium sulphate. The organic layer was concentrated to yield the crude product which was purified by flash chromatography (silica gel, 2% methanol in chloroform) to obtain the title compound.
Yield: 20 mg (10 %); 1 H NMR (300 MHz, DMSO-d6): δ 1 .89 (d, J = 6.9 Hz, 1 H, -CH3), 2.10 (s, 3H, CH), 2.29 (s, 3H, CH), 3.77 (s, 3H, -OCH3), 3.87 (s, 1 H, -OCH), 4.40 (m, 1 H, -CH), 6.37 (s, 1 H, -OCH), 6.40 (s, 1 H, Ar), 7.37 - 7.40 (m, 5H, Ar), 7.94 (s, 1 H, Ar), 8.84 (s, 1 H, Ar), 13.74 (s, 1 H, exchangeable in D2O, NH); MS: m/z 497.2 (M + H)+.
Example 186:
2-((-2-(Cyanoimino)-7-(3,5-dimethylisoxazol-4-yl)-1 -((R)-1 -phenylethyl)-2,3- dihydro-1 H-imidazo[4,5-c]quinolin-8-yl)oxy)acetic acid
To a solution of the compound of example 185 (230 mg, 0.463 mmol) in 15 mL of THF: methanol: water (1 : 1 : 1 ) was added LiOH. H2O (1 1 1 mg, 2.78 mmol) and the mixture was stirred at room temperature for 3 h. The solvent was removed to give a sticky solid. To the solid obtained was added water and acidified with 1 N HCI (pH = 2). The resulting mixture was extracted with ethyl acetate, washed with water and brine, dried over anhydrous Na2SO4 and concentrated. The crude material was purified by column chromatography (silica gel, 80 - 90 % ethyl acetate in petroleum ether) to obtain the title compound.
Yield: 90 mg (40 %); 1 H NMR (300 MHz, DMSO-d6): δ 1 .65 (d, J = 7.2 Hz, 3H, -CH3), 2.10 (s, 3H, CH), 2.29 (s, 3H, CH), 3.87 (brs, 1 H, CH), 4.29 (m, 1 H, -CH), 6.39 (m, 1 H, CH), 6.53 (m, 1 H, Ar), 7.37 - 7.40 (m, 5H, Ar), 7.94 (s, 1 H, Ar), 8.85 (s, 1 H, Ar), 1 1 .71 (bs, 1 H, exchangeable in D20, -NH ), 13.51 (bs, 1 H, exchangeable in D20, -OH); MS: m/z 483.1 (M + H)+.
Example 187:
2-((7-(3,5-dimethylisoxazol-4-yl)-3-nitro-4-(((R)-1-phenylethyl)amino)quinolin-6-yl) oxy)-N-ethylacetamide
To a solution of methyl 2-((7-(3,5-dimethylisoxazol-4-yl)-3-nitro-4-(((R)-1 - phenylethyl)amino)quinolin-6-yl)oxy)acetate (0.8 g, 1 .679 mmol) in toluene (5 ml_) were added ethanamine (1 .259 ml_, 2.52 mmol) and lanthanum (III) trifluoromethanesulfonate (0.049 g, 0.084 mmol) at room temperature and the mixture was stirred for 5 h. The solvent was evaporated, added water and extracted with ethyl acetate. The organic layer was washed with water and brine, dried over sodium sulphate and concentrated to obtain the crude product, which was purified by column chromatography (silica gel, 1 : 1 ethyl acetate in petroleum ether) to obtain the title compound.
Yield: 0.31 g (37 %); 1 H NMR (300 MHz, DMSO-d6) δ 1 .03 (t, J = 7.2 Hz, 3H, CH3), 1 .70 (d, J = 6.6 Hz, 3H, CH3), 2.15 (s, 3H, CH), 2.34 (s, 3H, CH), 3.08-3.17 (m, 2H, CH2), 4.35 - 4.52 (m, 2H, -OCH2), 5.29 (q, J = 6.6 Hz, 1 H, -CH), 7.26-7.40 (m, 5H, Ar), 7.70 (s, 1 H, Ar), 7.81 (s, 1 H, Ar), 7.86 (t, J = 7.2 Hz, 1 H, exchangeable in D2O, - NH), 8.93 (s, 1 H, exchangeable in D2O, NH), 8.97 (s, 1 H, Ar); MS: m/z 490.2 (M+H)+.
Example 188:
2-((3-amino-7-(3,5-dimethylisoxazol-4-yl)-4-(((R)-1-phenylethyl)amino)quinolin-6- yl)oxy)-N-ethylacetamide
To a solution of the compound of example 187 (300 mg, 0.613 mmol)) and ammonium chloride (82 mg, 1 .532 mmol) in ethanol:THF:water (7 ml_ : 7 ml_ : 3 ml_) was added iron powder (86 mg, 1.532 mmol) in portions and the mixture was refluxed at 85 °C for 2 h. The reaction mixture was filtered through celite bed, concentrated the filtrate, and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulphate and concentrated to yield a crude solid. The solid was washed with petroleum ether to obtain the title compound.
Yield: 1 10 mg (39 %); 1H NMR (300 MHz, DMSO-d6): δ 1 .03 (t, J = 7.2 Hz, 3H, CH3), 1 .50 (d, J = 6.9 Hz, 3H, CH3), 2.15 (s, 3H, CH), 2.33 (s, 3H, CH), 3.1 1-3.15 (m, 2H, - CH2), 4.50-4.57 (m, 2H, -OCH2), 4.62 (q, J = 6.9 Hz, 1 H, -CH), 5.01 (t, J = 7.2 Hz, 1 H, exchangeable in D20, -NH), 5.15 (s, 2H, exchangeable in D20, NH2), 7.15 - 7.29 (m, 5H, Ar), 7.41 (s, 1 H, Ar), 7.44 (s, 1 H, exchangeable in D20, -NH), 7.83 (bs, 1 H, Ar), 8.24 (s, 1 H, Ar); MS: m/z 460.2 (M + H)+.
Example 189:
2-((-2-(Cyanoimino)-7-(3,5-dimethylisoxazol-4-yl)-1-((R)-1-phenylethyl)-2,3- dihydro-1 H-imidazo[4,5-c]quinolin-8-yl)oxy)-N-ethylacetamide
To a solution of the compound of example 188 (100 mg, 0.218 mmol) in acetonitrile (7 ml_) was added diphenyl cyanocarbonimidate (51 .8 mg, 0.218 mmol) and heated at 85 °C for 12 h. Water (20 ml_) was added to the reaction mixture and extracted with ethyl acetate (2 x 20 ml_). The extracts were washed with water (20 ml_) and brine (20 ml_) and dried over anhydrous sodium sulphate. The organic layer was concentrated to yield the crude product, which was purified by column chromatography (silica gel, 2 % methanol in chloroform) to obtain the title compound.
Yield: 20 mg (18 %); 1H NMR (300 MHz, DMSO-d6): δ 1 .08 (t, J = 7.2 Hz, 3H, CH3), 1 .93 (d, J = 6.9 Hz, 3H, -CH3), 2.10 (s, 3H, CH), 2.29 (s, 3H, CH), 3.12 - 3.16 (m, 2H, CH2), 3.90-4.27 (m, 2H, -OCH2), 6.40 (t, J = 6.9 Hz, 1 H, exchangeable in D20, -NH), 6.59 (m, 1 H, -CH), 7.33-7.41 (m, 5H, Ar), 7.91 (bs, 2H, Ar), 8.83 (bs, 1 H, Ar), 13.69 (s, 1 H, exchangeable in D20, -NH); MS: m/z 510.2 (M + H)+.
Example 190:
4-(2-bromo-4-nitrophenoxy)butanenitrile
To a solution of 2-bromo-4-nitrophenol (100 g, 0.46 mol) and potassium carbonate (190 g, 1 .37 mol) in DMF (1 .20 L) was added 4-chlorobutanenitrile (52.1 ml_, 550 mmol) and heated at 65 °C for 2 h. Ice water was added and the mixture was extracted with ethyl acetate. The organic layer was separated and washed with water and brine, dried over anhydrous sodium sulphate, concentrated and purified by column chromatography (silica gel, 1 : 1 ethyl acetate in petroleum ether) to obtain the title compound. Yield: 101 g (77 %); 1 H NMR (300 MHz, DMSO-d6): δ 2.06 - 2.17 (m, 2H, -CH2), 2.69 (t, J = 6.0 Hz, 2H, CH2), 4.28 (t, J = 6.0 Hz, 2H, -OCH2), 7.35 (d, J = 9.3 Hz, 1 H, Ar), 8.26 (dd, J = 2.7 Hz, 9.3 Hz, 1 H, Ar), 8.43 (d, J = 2.7 Hz, 1 H, Ar); MS: m/z 285.0 (M)+. Example 191 :
4-(4-Amino-2-bromophenoxy)butanenitrile
To a solution of the compound of example 190 (100 g, 351 mmol) and ammonium chloride (46.9 g, 877 mmol) in ethanol:THF:water (400 ml_ : 400 ml_ : 200 ml_) was added iron powder (49.0 g, 877 mmol) in portions and the mixture was refluxed at 85 °C for 12 h. The reaction mixture was filtered through celite bed, concentrated the filtrate and extracted with ethyl acetate. The organics were washed with brine, dried over anhydrous Na2S04 and concentrated to yield a crude solid. The solid was washed with petroleum ether to obtain the title compound.
Yield: 77 g (86 %); 1 H NMR (300 MHz, DMSO-d6): δ 1 .93 - 2.01 (m, 2H, -CH2), 2.66 (t, J = 6.0 Hz, 2H, -CH2), 3.93 (t, J = 6.0 Hz, 2H, -OCH2), 4.94 (s, 2H, exchangeable in D20, -NH2), 6.52 (dd, J = 2.7 Hz, 8.7 Hz, 1 H, Ar), 6.80 (d, J = 2.7 Hz, 1 H, Ar), 6.84 (s, 1 H, Ar); MS: m/z 256.9 (M + H)+.
Example 192:
4-(2-Bromo-4-(((2,2-dimethyl-4,6-dioxo-1 ,3-dioxan-5-ylidene)methyl)amino) phenoxy)butanenitrile
A mixture of 2,2-dimethyl-1 ,3-dioxane-4,6-dione (42.9 g, 298 mmol) and trimethoxymethane (32.6 ml_, 298 mmol) was heated at 1 10 °C for 1 h and the compound of example 191 (76 g, 298 mmol) was added portion-wise. The reaction mixture was stirred at reflux for 1 h and cooled to room temperature. Diethyl ether (1000 ml_) was added and the reaction mixture was stirred at room temperature for 12 h. The resulting precipitate was filtered and dried to afford the title compound.
Yield: 75 g (61 %); 1H NMR (300 MHz, DMSO-d6): δ 1 .66 (s, 6H, CH3), 2.02-2.1 1 (m, 2H, CH2), 2.69 (t, J = 7.2 Hz, 2H, -CH2), 4.13 (t, J = 5.7 Hz, 2H, -OCH2), 7.19 (d, J = 9.0 Hz, 1 H, Ar), 7.57 (dd, J = 2.7 Hz, 9.0 Hz, 1 H, Ar), 7.93 (d, J = 2.7 Hz, 1 H, Ar), 8.45 (d, J = 14.7 Hz, 1 H, CH), 1 1 .20 (d, J = 14.7 Hz, 1 H, exchangeable in D20, -NH); MS: m/z 408.8 (M - H)+. Example 193:
4-((7-Bromo-4-hydroxyquinolin-6-yl)oxy)butanenitrile
The compound of example 192 (74 g, 181 mmol) was added to boiling diphenyl ether (250 mL) and stirred for 10 minutes. The reaction mixture was then cooled to room temperature and diluted with petroleum ether (1000 mL). The solid obtained was filtered and washed with petroleum ether to obtain the title compound.
Yield: 40 g (72 %); 1 H NMR (300 MHz, DMSO-d6): δ 2.07 - 2.15 (m, 2H, CH2), 2.74 (t, J = 8.4 Hz, 2H, CH2), 4.19 (t, J = 5.7 Hz, 2H, -OCH2), 6.02 (d, J = 7.2 Hz, 1 H, Ar), 7.57 (s, 1 H, Ar), 7.84 (s, 1 H, Ar), 7.90 (d, J = 7.2 Hz, 1 H, Ar), 1 1 .74 (bs, 1 H, exchangeable in D20, -OH); MS: m/z 307 (M)+.
Example 194:
4-((7-Bromo-4-hydroxy-3-nitroquinolin-6-yl)oxy)butanenitrile
Nitric acid (24.94 mL, 391 mmol) was added to a solution of the compound of example 193 (40 g, 130 mmol) in acetic acid (300 mL) and the resulting reaction mixture was heated at 120 °C for 2 h. The reaction mixture was cooled to room temperature. The solid obtained was filtered, washed with cold water and dried to afford the title compound.
Yield: 20 g (43 %); 1 H NMR (300 MHz, DMSO-d6): δ 2.1 1 - 2.15 (m, 2H, -CH2), 2.72 (t, J = 7.2 Hz, 2H, -CH2CN), 4.26 (t, J = 6.0 Hz, 2H, -OCH2), 7.72 (s, 1 H, Ar), 7.92 (s, 1 H, Ar), 9.20 (s, 1 H, Ar), 12.99 (bs, 1 H, exchangeable in D2O, -OH); MS: m/z 352 (M)+.
Example 195:
4-((4,7-Dibromo-3-nitroquinolin-6-yl)oxy)butanenitrile
To a solution of the compound of example 194 (17 g, 48.3 mmol) in DMF (200 mL) was added phosphorus tribromide (5.01 mL, 53.1 mmol) drop-wise at room temperature. The reaction mixture was stirred for 2 h at room temperature and quenched with ice cold water. The solid obtained was filtered, washed with cold water and dried to afford the title compound.
Yield: 15 g (75 %); 1 H NMR (300 MHz, DMSO-d6): δ 2.1 1 - 2.20 (m, 2H, -CH2), 2.72 (t, J = 6.0 Hz, 2H, -CH2), 4.25 (t, J = 5.7 Hz, 2H, -OCH2), 7.72 (s, 1 H, Ar), 7.92 (s, 1 H, Ar), 9.25 (s, 1 H, Ar); MS: m/z 415.9. Example 196:
(R)-4-((7-Bromo-3-nitro-4-((1^henylethyl)amino)quinolin-6-yl)oxy)butanenitrile
To a mixture of the compound of example 195 (15 g, 36.1 mmol) in acetonitrile (150 mL) was added (R)-l -phenylethanamine (5.59 mL, 43.4 mmol) and heated at 85 °C for 2 h. The solvent was evaporated and water (100 mL) was added to the resulting residue. The reaction mixture was extracted with ethyl acetate (3 x 50 mL). The combined organic layers were washed with brine (100 mL) and dried over anhydrous Na2S04. The solvent was evaporated to yield the crude product, which was further purified by column chromatography (silica gel, 2 % MeOH in CHCI3) to obtain the title compound.
Yield: 7.0 g (42 %); 1H NMR (300 MHz, DMSO-d6): δ 1 .48 (d, J = 6.6 Hz, 3H, -CH3), 1 .98 - 2.02 (m, 2H, -CH2), 2.64 (t, J = 7.2 Hz, 2H, -CH2), 3.61 (m, 1 H, -CH), 5.30 (t, 2H, -OCH2), 7.28 - 7.46 (m, 5H, Ar), 7.60 (s, 1 H, Ar), 8.17 (s, 1 H, Ar), 8.98 (s, 1 H, Ar), 9.06 (d, J = 7.2 Hz, 1 H, exchangeable in D20, -NH); MS: m/z 455.3 (M)+.
Example 197:
(R)-4-((3-Amino-7-bromo-4-((1-phenylethyl)amino)quinolin-6-yl)oxy)
butanenitrile
To a solution of the compound of example 196 (5.0 g, 10.98 mmol) and ammonium chloride (1.469 g, 27.5 mmol) in ethanol:THF:water (40 mL : 40 mL : 20 mL) was added iron powder (1 .533 g, 27.5 mmol) in portions and the mixture was refluxed at 85 °C for 2 h. The reaction mixture was filtered through a celite bed, concentrated the filtrate and extracted with ethyl acetate. The organic layers were washed with brine, dried over anhydrous Na2S04 and concentrated to yield a crude solid. The solid obtained was washed with petroleum ether to obtain the title compound.
Yield: 3.2 g (6 %); 1 H NMR (300 MHz, DMSO-d6): δ 1 .54 (d, J = 6.6 Hz, 3H, -CH3), 2.04-2.13 (m, 2H, -CH2), 2.70 (t, J = 6.9 Hz, 2H, -CH2), 4.06 (t, 2H, -OCH2), 4.55 (m, 1 H, -CH), 5.16 - 5.22 (m, 3H, exchangeable in D20, -NH2 and -NH ), 7.10 - 7.27 (m, 5H, Ar), 7.40 (s, 1 H, Ar), 7.86 (s, 1 H, Ar), 8.25 (s, 1 H, Ar); MS: m/z 425 (M)+.
Example 198:
(R)-N-(7-Bromo-8-(3-cyanopropoxy)-1-(1-phenylethyl)-1 H-imidazo[4,5-c]quinolin -2(3H)-ylidene)cyanamide To a solution of the compound of example 197 (200 mg, 0.470 mmol) in acetonitrile (7 mL) was added diphenyl cyanocarbonimidate (1 12 mg, 0.470 mmol) and heated at 85 °C for 12 h. Water (20 mL) was added to the reaction mixture and extracted with ethyl acetate (2 X 20 mL). The organic layers were washed with water (20 mL), brine solution (20 mL) and dried over anhydrous sodium sulphate. The organic layer was concentrated to give the crude product, which was purified by column chromatography (silica gel, 2 % methanol in chloroform) to afford the title compound.
Yield: 85 mg (38 %); 1 H NMR (300 MHz, DMSO-d6): δ 1 .95 (d, J = 7.2 Hz, 3H, -CH3), 2.00 - 2.07 (m, 2H, -CH2), 2.65 (t, J = 6.9 Hz, 2H, -CH2), 3.05 (bs, 1 H, -CH), 3.77- 3.84 (m, 1 H, -OCH), 6.34 - 6.41 (m, 1 H, -OCH), 6.59 (s, 1 H, Ar), 7.34 - 7.45 (m, 5H, Ar), 8.29 (s, 1 H, Ar), 8.81 (s, 1 H, Ar), 13.72 (bs, 1 H, exchangeable in -NH); MS: m/z 477 (M + H)+.
Example 199:
N-(8-(3-Cyanopropoxy)-7-(3,5-dimethylisoxazol-4-yl)-1 -((R)-1 -phenylethyl)-1 H- imidazo[4,5-c]quinolin-2(3H)-ylidene)cyanamide
[1 , 1 '-Bis(diphenylphosphino) ferrocene]dichloropalladium(ll), complex with dichloro methane (4.12 mg, 5.05 pmol) was added to a solution of the compound of example 198 (80 mg, 0.168 mmol) and (3,5-dimethylisoxazol-4-yl)boronic acid (30.8 mg, 0.219 mmol) in DMF (10 mL), followed by a solution of sodium carbonate (35.7 g, 0.337 mmol) in water (1 mL) and the resulting reaction mixture was heated at 1 10 °C for 5 h. The reaction mixture was then cooled to room temperature and concentrated. Water (10 mL) was added to the resulting residue and extracted with CHCI3 (3 x 20 mL).The combined organic layers were washed with brine (20 mL), dried over anhydrous Na2S04 and concentrated to obtain the crude product, which was further purified by column chromatography (silica gel, 1 : 1 ethyl acetate in petroleum ether) to obtain the title compound.
Yield: 15 mg (18 %); 1 H NMR (300 MHz, DMSO-d6) δ 1 .87 - 1 .91 (m, 2H, -CH2), 1 .98 (d, J = 7.2 Hz, 3H, -CH3), 2.04 (s, 3H, CH), 2.25 (s, 3H, CH), 2.45 (m, 2H, -CH2), 3.73 (bs, 1 H, -CH), 3.77 - 3.84 (m, 1 H, -OCH), 6.36 - 6.43 (m, 1 H, -OCH), 6.66 (s, 1 H, Ar), 7.34 - 7.43 (m, 5H, Ar), 7.90 (s, 1 H, Ar), 8.83 (s, 1 H, Ar), 13.77 (bs, 1 H, exchangeable in -NH ); MS: m/z 492.2 (M + H)+. Example 200:
2-(2-Bromo-4-nitrophenoxy)acetonitrile
To a solution of 2-bromo-4-nitrophenol (40.7 g, 187 mmol), bromoacetonitrile (14.30 ml_, 205 mmol) in acetonitrile (600 ml_) was added potassium carbonate (31 .0 g, 224 mmol) and the resulting mixture was heated to 50 °C for 5 h. The reaction mixture was concentrated, dissolved in EtOAc (30 ml_) and washed with H20 (30 ml_), 1 N NaOH, and brine. The organic layer was concentrated and the residue was purified by column chromatography (silica gel, 2:8 ethyl acetate: petroleum ether) to obtain the title compound.
Yield: 44.02 g (92 %); 1 H NMR (300 MHz, DMSO-d6): δ 4.98 (s, 2H, CH2), 7.13 (d, 1 H, J = 9.3 Hz, Ar), 8.29 (dd, 1 H, J1 = 9.3 Hz, J2 = 2.4 Hz, Ar), 8.54 (d, 1 H, J = 2.4 Hz, Ar); MS (El, 70 eV): m/z 252.1 (M+H+).
Example 201 :
2-(4-Amino-2-bromophenoxy)acetonitrile
To a stirred solution of the compound of example 200 (42.50 g, 165 mmol) in THF (90 ml_), water (90.0 ml_) and EtOH (45.0 ml_) were added ammonium chloride (17.69 g, 331 mmol) and iron (18.47 g, 331 mmol). The reaction mixture was heated to 80 °C for 3 h. The reaction mixture was cooled to room temperature, filtered through a celite bed and washed with ethanol. The combined filtrate was concentrated, diluted with saturated aqueous NaHC03 and extracted with ethyl acetate (3 x 300 ml_). The combined organic layers were washed with brine, dried over anhydrous Na2S04 and evaporated to obtain the title compound.
Yield: 30.8 g, (82 %); 1 H NMR (300 MHz, DMSO-d6): δ 4.74 (s, 2H, CH2), 6.62 (dd, 1 H, J1 = 8.7 Hz, J2 = 2.7 Hz, Ar), 6.92 (d, 1 H, J = 2.7 Hz, Ar), 6.99 (d, 1 H, J = 8.7 Hz, Ar); MS (El, 70 eV): m/z 252.1 (M+H+).
Example 202:
2-(2-Bromo-4-(((2,2-dimethyl-4,6-dioxo-1 ,3-dioxan-5-ylidene)methyl)amino) phenoxy)acetonitrile
To a solution of the compound of example 201 (30.8 g, 136 mmol) in trimethyl orthoformate (150 ml_, 1356 mmol) was added 2,2-dimethyl-1 ,3-dioxane-4,6-dione (23.46 g, 163 mmol) and the resulting mixture was heated to 100 °C for 1 h. The reaction mixture was then cooled to room temperature and added diethyl ether (1000 mL). The solid obtained was filtered, washed with diethyl ether and dried to obtain the title compound.
Yield: 42.42 g (82 %).
Example 203:
2-((7-Bromo-4-hydroxyquinolin-6-yl)oxy)acetonitrile
To a stirred solution of diphenyl ether (500 mL) at 260 °C was added the compound of example 202 (42 g, 1 10 mmol) and stirred for 10 minutes. The reaction mixture was cooled to 100 °C and carefully poured into stirred petroleum ether. The black oil obtained was dissolved in methanol and diethyl ether was added. The solid obtained was filtered to obtain the title compound.
Example 204:
2-((7-Bromo-4-hydroxy-3-nitroquinolin-6-yl)oxy)acetonitrile
A stirred solution of the compound of example 203 (25.00 g, 90 mmol) in acetic acid (125 mL) was heated to 120 °C and nitric acid (12.58 mL, 197 mmol) was added drop wise over period of 30 minutes. The reaction mixture was further heated at 1 10 °C for 2 h. The reaction mixture was cooled to room temperature and poured into a beaker containing ethanol (1 L). The solid obtained was filtered and dried to obtain the title compound.
Yield: 16.03 g (55.2 %). Example 205:
2-((4,7-Dibromo-3-nitroquinolin-6-yl)oxy)acetonitrile
To a stirred solution of the compound of example 204 (15.80 g, 48.8 mmol) in DMF (150 mL) was added PBr3 (9.20 mL, 98 mmol) and the resulting solution was stirred at room temperature for 3 h. The reaction mixture was quenched by addition of ice water and stirred for 1 h. The solid obtained was filtered and dried to obtain the title compound.
Yield: 16.05 g (85 %); 1 H NMR (300 MHz, DMSO-d6): δ 5.63 (s, 2H, CH2), 7.84 (s, 1 H, Ar), 8.62 (s, 1 H, Ar), 9.23 (s, 1 H, Ar); MS (El, 70 eV): m/z 387.9 (M+H+). Example 206:
(R)-2-((7-Bromo-3-nitro-4-((1-phenylethyl)amino)quinolin-6-yl)oxy)acetonitrile
To a stirred solution of the compound of example 205 (15 g, 38.8 mmol) in acetonitrile (150 ml_) was added (R)-l -phenylethanamine (9.87 ml_, 78 mmol) and refluxed for 2 h. The reaction mixture was concentrated and purified by column chromatography (silica gel, 1 : 1 ethyl acetate: petroleum ether) to obtain the title compound.
Yield: 10.2 g (60.9 %); 1 H NMR (300 MHz, DMSO-d6): δ 1 .70 (d, 3H, J = 6.6 Hz, CH3), 5.14-5.33 (m, 3H, CH and CH2), 7.25-7.37 (m, 5H, Ar), 7.89 (s, 1 H, Ar), 8.23 (s, 1 H, Ar), 8.77 (d, 1 H, J = 7.5 Hz, exchangeable with D20, NH), 8.94 (s, 1 H, Ar); MS (El, 70 eV): m/z 427 (M+H+); HPLC purity: 98.84 %.
Example 207:
(R)-2-((3-Amino-7-bromo-4-((1-phenylethyl)amino)quinolin-6-yl)oxy)acetonitrile
To a stirred solution of the compound of example 206 (4.0 g, 9.36 mmol) in ethanol (20 ml_), THF (20.00 ml_) and water (10.00 ml_) was added iron (1 .046 g, 18.72 mmol) and ammonium chloride (1 .002 g, 18.72 mmol) and heated at 80 °C for 2 h. The reaction mixture was filtered through celite and the organic layer was concentrated. The organic layer was diluted with ethyl acetate and washed with saturated sodium bicarbonate. The ethyl acetate layer was concentrated and purified by column chromatography (silica gel, 9:1 CHC : MeOH) to obtain the title compound.
Yield: 2.4 g (64.4 %); 1H NMR (300 MHz, DMSO-d6): δ 1 .53 (d, 3H, J = 6.6 Hz, CH3), 4.73 (m, 1 H, CH), 5.24 (m, 3H, NH and NH2, exchangeable with D20), 5.32 (s, 2H, CH2), 7.13 (t, 1 H, J = 7.2 Hz, Ar), 7.21 (t, 2H, J = 7.5 Hz, Ar), 7.40 (d, 2H, J = 7.2 Hz, Ar), 7.58 (s, 1 H, Ar), 7.93 (s, 1 H, Ar), 8.26 (s, 1 H, Ar); MS (El, 70 eV): m/z 397.1 (M+H+); HPLC purity: 99.76 %.
Example 208:
(R,E)-N-(7-Bromo-8-(cyanomethoxy)-1 -(1 -phenylethyl)-1 H-imidazo[4,5-c] quinolin-2(3H)-ylidene)cyanamide
To a stirred solution of the compound of example 207 (2.4 g, 6.04 mmol), diphenyl cyanocarbonimidate (1 .468 g, 6.16 mmol) in acetonitrile (24 ml_) was added and the reaction mixture was heated to 80 °C for 5 h. The solvent was evaporated and purified by column chromatography (silica gel, 9: 1 CHCI3: MeOH) to obtain the title compound. Yield: 1.5 g (54.9 %); 1H NMR (300 MHz, DMSO-d6): δ 1 .99 (d, 3H, J = 7.2 Hz, CH3), 4.31 (m, 1 H, CH2), 4.84 (m, 1 H, CH2), 6.41 (q, 1 H, CH, J = 7.2 Hz, ), 6.70 (s, 1 H, Ar), 7.40 (m, 5H, Ar), 8.35 (s, 1 H, Ar), 8.86 (s, 1 H, Ar); MS (El, 70 eV): m/z 449.1 (M+H+); HPLC purity: 98.96 %.
Example 209:
(E)-N-(8-(Cyanomethoxy)-7-(3,5-dimethyl-4,5-dihydroisoxazol-4-yl)-1-((R)-1- phenylethyl)-1 H-imidazo[4,5-c]quinolin-2(3H)-ylidene)cyanamide
The compound of example 208 (300 mg, 0.671 mmol), 3,5-dimethyl-4-(4, 4,5,5- tetramethyl-1 ,3,2-dioxaborolan-2-yl)isoxazole (180 mg, 0.805 mmol) and sodium carbonate (142 mg, 1 .341 mmol) were mixed with DMF (10 ml_) and water (1 ml_). The reaction mixture was degassed with nitrogen for 10 minutes. PdCl2(dppf)-CH2Cl2 adduct (27.4 mg, 0.034 mmol) catalyst was added and the reaction mixture was heated to 120 °C for 2 h. The reaction mixture was cooled and diluted with ethyl acetate and the resulting suspension was filtered through celite bed, and the filtrate was washed with water. The organic layer was dried over anhydrous sodium sulphate and the solvent was removed to yield the crude product, which was purified by column chromatography (silica gel, 9:1 CHCI3: MeOH) to obtain the title compound.
Yield: 240 mg (77 %); 1 H NMR (300 MHz, DMSO-d6): δ 2.02 (d, 3H, J = 7.2 Hz, CH3), 2.07 (s, 3H, CH3), 2.27 (s, 3H, CH3), 4.15 (s, 1 H, CH), 4.83 (s, 1 H, CH), 6.43 (q, 1 H, J = 7.2 Hz, Ar), 6.70 (s, 1 H, Ar), 7.41 (m, 5H, Ar), 8.00 (s, 1 H, Ar), 8.88 (s, 1 H, Ar), 13.78 (s, 1 H, NH, exchangeable with D20); MS (El, 70 eV): m/z 464.2 (M+H+): HPLC purity: 97.75 %. Example 210:
5-(((3-Bromo-4-hydroxyphenyl)amino)methylene)-2,2-dimethyl-1 ,3-dioxane-4,6- dione
2,2-Dimethyl-1 ,3-dioxane-4,6-dione (31 .2 g, 216 mmol) and 1 , 1 , 1 -trimethoxyethane (150 ml_) were mixed together and heated to reflux for 1 h. 4-Amino-2-bromophenol (37 g, 197 mmol) was added in portions and heated at 1 10 °C for 2.5 h. The reaction mixture was cooled to room temperature and the solid obtained was filtered and washed with diethyl ether (200 ml_) to obtain the title compound. Yield: 55 g (82 %); 1 H NMR (300 MHz, DMSO-d6): δ 1 .75 (s, 6H, CH3), 6.96 (d, 1 H, J= 8.7 Hz, CH), 7.40 (d, 1 H, J= 8.7 Hz, Ar), 7.84 (s, 1 H, Ar), 8.41 (d, 1 H, J= 14.4 Hz, CH), 10.46 (s, 1 H, OH, exchangeable with D2O), 1 1.17 (d, 1 H, J= 14.7Hz, NH, exchangeable with D2O); MS (El, 70 eV): m/z 341 .0 (M-H+); HPLC purity: 98.92 %.
Example 211 :
5-(((3-Bromo-4-(2-methoxyethoxy)phenyl)amino)methylene)-2,2-dimethyl-1 ,3- dioxane-4,6-dione
To a solution of the compound of example 210 (4.03 g, 1 1 .78 mmol) in DMF (30 ml_) was added dried cesium carbonate (1 1 .51 g, 35.3 mmol) and stirred for 30 minutes. To the reaction mixture, 2-methoxy 4-methylbenzensulfonate (4.07 g, 17.67 mmol) was added and stirred at 1 10 °C for 12 h. The reaction mass was quenched in water and extracted with ethyl acetate. The ethyl acetate layers were combined and washed with water. The ethyl acetate layer was combined and purified by column chromatography (silica gel, 0-10 % MeOH in DCM) to obtain the title compound.
Yield: 4.0 g (85 %); 1 H NMR (300 MHz, DMSO-d6): δ 1H NMR (300 MHz, DMSO-d6): δ 1 .99 (s, 6H, CH3), 3.43 (m, 2H, CH2), 4.18 (m, 2H, CH2) 7.15 (d, 1 H, J = 8.7 Hz, CH), 7.54 (d, 1 H, J = 8.7 Hz, Ar), 7.95 (s, 1 H, Ar), 8.46 (s, 1 H, CH), 1 1 .20 (s, 1 H, NH, exchangeable with D2O); MS (El, 70 eV): m/z 401 .2 (M+H+); HPLC purity: 96 %.
Example 212:
7-Bromo-6-(2-methoxyethoxy)quinolin-4-ol
The compound of example 21 1 (1 .0 g, 2.499 mmol) was added to boiling diphenyl ether (10 ml_) and stirred for 10 minutes. The reaction mixture was then cooled to 100 °C and diluted with petroleum ether (60 ml_). The solid obtained was filtered and washed with hot petroleum ether to obtain the title compound.
Yield: 660 mg (89 %); 1 H NMR (300 MHz, DMSO-d6): δ 3.69 (s, 3H, OCH3), 3.74 (bs, 2H, CH2), 3.98 (m, 2H, CH2), 7.52 (s, 1 H, Ar), 7.57 (s, 1 H, Ar), 7.88 (m, 2H, Ar), 1 1.72 (s, 1 H, OH, exchangeable with D2O); MS (El, 70 eV): m/z 299.2 (M+H+); HPLC purity: 48 %.
Example 213:
7-Bromo-6-(2-methoxyethoxy)-3-nitroquinolin-4-ol Nitric acid (0.707 mL, 1 1.07 mmol) was added to a stirred solution of the compound of example 212 (1 .1 g, 3.69 mmol) in acetic acid (7 mL). The reaction mixture was heated to 120 °C for 2 h and cooled the reaction mixture to room temperature. The solid obtained was filtered and washed with cold water, diethyl ether and dried to obtain the title compound.
Yield: 500 mg (40 %); 1 H NMR (300 MHz, DMSO-d6): δ 3.36 (s, 3H, OCH3), 3.75 (bs, 2H, CH2), 4.30 (m, 2H, CH2), 7.73 (s, 1 H, Ar), 8.00 (s, 1 H, Ar), 9.18 (bs, 1 H, Ar), 12.94 (s, 1 H, OH, exchangeable with D2O); HPLC purity: 77.90 %. Example 214:
7-Bromo-4-chloro-6-(2-methoxyethoxy)-3-nitroquinoline
POC (4.75 mL, 51 .0 mmol) was added to the compound of example 213 (2.5 g, 7.29 mmol) and heated to reflux for 2 h. Excess POCI3 was removed and the residue was quenched with aqueous saturated bicarbonate solution (25 mL). The aqueous layer was extracted with CH2CI2 (2 x 50 mL) and the combined organic layer was washed with brine (50 mL), dried over anhydrous Na2SO4 and concentrated. The residue was triturated in DCM: petroleum ether to obtain the title compound.
Yield: 2.1 g (75 %); MS (El, 70 eV): m/z 362.2 (M+H+). Example 215:
(R)-7-Bromo-6-(2-methoxyethoxy)-3-nitro-N-(1-phenylethyl)quinolin-4-amine
(R)-I -Phenylethanamine (387 μΙ, 3.04 mmol) was added to a stirred solution of the compound of example 214 (550 mg, 1 .521 mmol) in acetonitrile (10 mL) and heated to reflux for 2 h. The reaction mixture was cooled to room temperature and the solvent was evaporated. Water (25 mL) was added to the residue and extracted with ethyl acetate (2 x 25 mL). The combined organic layers were washed with water (25 mL), brine (25 mL) and dried over anhydrous Na2SO4. The solvent was evaporated to obtain a crude product, which was further purified by column chromatography (silica gel, 7:3 petroleum ether: ethyl acetate) to obtain the title compound.
Yield: 500 mg (74 %); 1 H NMR (300 MHz, DMSO-d6): δ 1.68 (d, 3H, J = 6.0 Hz, CH3), 3.61 -3.64 (m, 2H, CH2), 3.71 (s, 3H, -OCH3), 4.02-4.05 (m, 2H, CH2) 5.29 (m, 1 H, CH), 7.20-7.13 (m, 5H, Ar), 7.58 (s, 1 H, Ar) 8.15 (s, 1 H, Ar), 9.06 (s, 1 H, Ar), 9.08 (bs, 1 H, NH, exchangeable with D20); MS (El, 70 eV): m/z 447.2 (M+H+); HPLC purity: 99.50 %.
Example 216:
(R)-7-Bromo-6-(2-methoxyethoxy)-N4-(1 -phenylethyl) quinoline-3,4-diamine
Iron (1 .126 g, 20.17 mmol) and ammonium chloride (1 .079 g, 20.17 mmol) were added to a stirred solution of the compound of example 215 (3.0 g, 6.72 mmol) in THF: ethanol: water (30:30: 15 mL) and the resulting reaction mixture was stirred at 85 °C for 1 h. The reaction mixture was filtered through a celite bed. The filtrate was added to a solution of saturated sodium bicarbonate (20 mL) and extracted with ethyl acetate (3 x 20 mL). The combined organic layers were washed with brine (20 mL) and dried over anhydrous Na2S04. The solvent was evaporated to obtain a crude product, which was further purified by column chromatography (silica gel, 95:5 CHCI3: MeOH) to obtain the title compound.
Yield: 2.1 g (75 %); 1 H NMR (300 MHz, DMSO-d6): δ 1 .54 (d, 3H, J = 6.0 Hz, CH3), 3.61 (bs, 2H, CH2), 3.71 (s, 3H, -OCH3), 4.1 1 (m, 2H, CH2), 4.17 (bs, 1 H, NH, exchangeable with D20), 5.15 (s, 2H, NH2, exchangeable with D20) 5.19 (m, 1 H, CH), 7.20-7.13 (m, 5H, Ar), 7.25 (s, 1 H, Ar), 7.86(s, 1 H, Ar), 8.24 (s, 1 H, Ar); MS (El, 70 eV): m/z 433.2 (M+H+); HPLC purity: 99 %.
Example 217:
7-(3,5-Dimethylisoxazol-4-yl)-6-(2-methoxyethoxy)-N4-((R)-1-phenylethyl) quinoline-3,4-diamine
1 , 1 '-Bis(diphenylphosphino)ferrocene]dichloro palladium(ll) complex with dichloromethane (157 mg, 0.192 mmol) was added to a stirred solution of the compound of example 216 (800mg, 1 .922 mmol) and (3,5-dimethylisoxazol-4- yl)boronic acid (542 mg, 3.84 mmol) in DMF (10 mL) followed by sodium carbonate (61 1 mg, 5.76 mmol) solution in water (3 mL) and the reaction mixture was heated to 120 °C for 1 h. The reaction mixture was then cooled to room temperature and concentrated. Water (20 mL) was added to the resulting residue and extracted with CHCI3 (3 x 10 mL). The combined organic layers were washed with brine (15 mL), dried over anhydrous Na2S04 and the solvent was evaporated to yield the crude product which was further purified by column chromatography (silica gel, 9: 1 CHCI3: MeOH) to obtain the title compound.
Yield: 400 mg (48 %); 1 H NMR (300 MHz, DMSO-d6): δ 1.54 (d, 3H, J = 6.0 Hz, CH3), 2.10 (s, 3H, CH3), 2.28 (s, 3H, CH3), 3.26 (s, 3H, -OCH3), 3.61 (bs, 2H, CH2), 4.05-4.13 (m, 2H, CH2), 4.17 (bs, 1 H, NH, exchangeable with D20), 5.12 (m, 1 H, CH), 5.15 (s, 2H, NH2, exchangeable with D20), 7.26 (s, 1 H, Ar), 7.46 -7.50 (m, 5H, Ar), 7.56 (s, 1 H, Ar), 8.31 (s, 1 H, Ar); MS (El, 70 eV): m/z 433.2 (M+H+); HPLC purity: 92 %.
Example 218:
(E)-N-(7-(3,5-Dimethylisoxazol-4-yl)-8-(2-methoxyethoxy)-1-((R)-1-phenylethyl)- 1 H-imidazo[4,5-c]quinolin-2(3H)-ylidene)cyanamide
Diphenyl cyanocarbonimidate (49.6 mg, 0.208 mmol) was added to a stirred solution of the compound of example 217 (60 mg, 0.139 mmol) in acetonitrile (2 mL) and the resulting reaction mixture was heated to 85 °C for 12-16 h. The reaction mixture was cooled to room temperature, the solvent was evaporated and the resulting residue was quenched in water (10 mL). The solid obtained was filtered and the filtrate was extracted with ethyl acetate (3x10 mL). The combined organic layers were washed with brine (15 mL), dried over anhydrous Na2S04 and the solvent was evaporated to obtain a crude product, which was further purified by preparative thin layer chromatography (silica gel, 9: 1 :0.05 CHCI3: MeOH: triethylamine) to obtain the title compound.
Yield: 14 mg (21 %); 1 H NMR (300 MHz, DMSO-d6): δ 1 .98 (d, 3H, J = 7.2Hz, CH3), 2.08 (s, 3H, CH3), 2.27 (s, 3H, CH3), 3.22 (s, 3H, -OCH3), 3.51 (m , 2H, CH2), 3.73 (m, 2H, CH2) 6.41 (bq, 1 H, CH), 7.36 (bs, 1 H, Ar), 7.43-7.42 (m, 5H, Ar), 7.89 (s, 1 H, Ar), 8.82 (s, 1 H, Ar), 13.75 (s, 1 H, NH, exchangeable with D2O); MS (El, 70 eV): m/z 483.2 (M+H+); HPLC purity: 91 %.
Example 219:
tert-Butyl (3-((7-(3,5-dimethylisoxazol-4-yl)-6-methoxy-3-nitroquinolin-4-yl) amino)propyl)carbamate
(3-Aminopropyl)carbamate (1 .044 g, 5.99 mmol) was added to a stirred solution of 4- (4-chloro-6-methoxy-3-nitroquinolin-7-yl)-3,5-dimethylisoxazole (1 .0 g, 3.00 mmol) in acetonitrile (10 mL) and heated to reflux for 2 h. The reaction mixture was cooled to room temperature and the solvent was evaporated. Water (25 mL) was added to the resulting residue and the residue was extracted with ethyl acetate (2x25 mL). The combined organic layers were washed with water (25 mL), brine (25 mL) and dried over anhydrous Na2S04. The solvent was evaporated to obtain crude product, which was further purified by column chromatography (silica gel, 7:3 petroleum ether: ethyl acetate) to obtain the title compound. Yield: 1 .2 g (85 %); MS: m/z 472.3 (M+H+).
Example 220:
tert-Butyl (3-((3-amino-7-(3,5-dimethylisoxazol-4-yl)-6-methoxyquinolin-4-yl) amino)propyl)carbamate
Palladium over carbon (0.271 g, 2.55 mmol) was added to a stirred solution of the compound of example 219 (1 .2 g, 2.55 mmol) in ethanol (20 mL) and the resulting reaction mixture was stirred under hydrogen atmosphere for 16 h. The reaction mixture was filtered through celite bed and the filtrate was concentrated to obtain crude product which was purified by column chromatography (silica gel, CHC : MeOH (95:5)) to obtain the title compound. Yield: 0.7 g; MS (El, 70 eV): m/z 442.3 (M+H+).
Example 221 :
(E)-tert-Butyl (3-(2-(cyanoimino)-7-(3,5-dimethylisoxazol-4-yl)-8-methoxy-2,3- dihydro-1 H-imidazo[4,5-c]quinolin-1-yl)propyl)carbamate
Cesium carbonate (0.443 g, 1 .359 mmol) and dimethyl cyanocarbonimidodithioate (0.199 g, 1.359 mmol) was added to a stirred solution of the compound of example 220 in DMF (20 mL) and the resulting reaction mixture was heated to 120 °C for 12-16 h. The reaction mixture was cooled to room temperature, the solvent was evaporated and the resulting residue was quenched in water (25 mL). The solid obtained was filtered and the filtrate was extracted with ethyl acetate (3x25 mL). The combined organic layers were washed with brine (25 mL), dried over anhydrous Na2S04 and the solvent was evaporated to obtain crude product, which was further purified by column chromatography (silica gel, 9: 1 :0.05 CHCI3: MeOH: triethylamine) to obtain the title compound.
Yield: 0.32 g (47.4 %); 1H NMR (300 MHz, DMSO-d6): δ 1 .34 (s, 9H, t-Butyl), 1 .96 (s, 2H, CH2), 2.12 (s, 3H, CH3), 2.32 (s, 3H, CH3), 3.1 1 (m, 2H, CH2), 4.02 (s, 3H, CH3), 4.43 (m, 2H, CH2), 6.56 (s, 1 H, NH), 7.52 (s, 1 H, Ar), 7.96 (s, 1 H, Ar), 8.72 (s, 1 H, Ar), 13.43 (br s, 1 H, NH, exchangeable with D20); MS (El, 70 eV): m/z 492.4 (M+H+); HPLC purity: 99.63 %.
BIOLOGICAL ASSAYS
Representative compounds of formula (I) of the present invention (referred to as test compounds) are tested for their inhibitory activity of bromodomain containing proteins using the assays and the methods described below:
Example 222:
BRD-4 Inhibition Assay:
The BRD4 (bromodomain containing protein 4) assay was conducted as per the protocol given in the BRD4 assay kit (Cayman). 5 μί of 4x test compound was added to the black low volume 384 well plate provided in the kit. +(-)JQ-1 (bromodomain inhibitor, Dana-Farber Cancer Institute) was used as a positive control. Final DMSO concentration was kept at 0.5 %. 10 μί of diluted BRD4 bromodomain-1 europium chelate was added to the test compounds and incubated for 15 min at room temperature. Further, 5 μί of diluted BRD4 bromodomain-1 ligand/APC (Allophycocyanin) acceptor was added to the plate and incubated at room temperature for 1 h. The plate was read in time resolved format by exciting the sample at 340 nm and reading the emissions at 620 nm and 665 nm using a delay of 100 s and 500 s read window. Data analysis was performed using the TR-FRET (time resolved fluorescence resonance energy transfer) ratio (665 nm emission/620 nm emission). Results for the two tandem bromodomains BD1 and BD2 of BRD4 (bromodomain containing protein 4) are provided in Table 1 .
Table 1 :
Figure imgf000146_0001
In the above Tablel :
"+" denotes IC50 in the range of 10 nM to 300 nM (inclusive of 300 nM)
"++" denotes IC50 in the range of 301 nM to 3000 nM
"-" denotes not tested.
Example 223:
Cell viability assay
The cancer cell lines were obtained from ATCC (American Type Culture Collection) and cultured as per ATCC's recommended culture mediums primarily in RPMI (Roswell Park Memorial Institute medium) supplemented with 15 % FBS (fetal bovine serum), 100 unit ml_"1 penicillin and 100 g ml_"1 streptomycin. Cytotoxic activity of the test compounds was quantitatively determined by a colorimetric assay utilizing CCK8 (Cell counting kit-8 measures cell viability by utilizing Dojindo's highly water-soluble tetrazolium salt. (WST-8) or [2-(2-methoxy-4-nitrophenyl)-3-(4-nitrophenyl)-5-(2,4- disulfophenyl)-2H-tetrazolium, monosodium salt] produced a water-soluble formazan dye upon reduction in the presence of an electron mediator). Cells were seeded at 3000 cells well-1 in 96-well plates and maintained in culture for 24 h at 37 °C in RPMI supplemented with 15 % FBS. The test compounds were added in varying concentrations (0.01 -30 μΜ) and incubated for 3 days, following which 10 μί of CCK8 was added per well. Plates were further incubated in the same incubation conditions for 2-4 h, followed by spectrophotometric absorbance at 450 nm on a plate reader. Background readings (blank) were obtained from cell-free wells containing media and CCK8. IC50 of the compounds was calculated using the SoftMax® Pro software. The IC50 values of the test compounds are provided in table 2. Table 2:
Figure imgf000147_0001
In the above Table 2:
"+" denotes IC5o in the range of 0.01 μΜ to 10 μΜ (inclusive of 10 μΜ)
"++" denotes IC5o in the range of 10.1 μΜ to 50 μΜ
MM.1 S denotes multiple myeloma cell line
MOLM-13 denotes lukemia cell line
All publications and patent applications in this specification are indicative of the level of ordinary skill in the art to which this invention pertains.
The invention has been described with reference to various specific and preferred embodiments and techniques. However, it should be understood that many variations and modifications may be made while remaining within the spirit and scope of the invention.

Claims

We Claim:
1 . A compound of formula
Figure imgf000148_0001
Formula (I)
wherein,
W is NRa or O;
Ri and R4 are independently selected from the group consisting of hydrogen, halogen, cyano, nitro, (C C6)-alkyl, (C2-C8)-alkenyl, (C2-C8)-alkynyl, halo(d-C6)-alkyl, (C C6)- alkoxy, (C3-Ci2)-cycloalkyl, (C6-Ci4)-ar(Ci-C6)-alkyl-, (C6-Ci4)-aryl, heterocyclyl, heteroaryl, NRaRb, C(O)(C1-C6)-alkyl, C(O)NRaRb, COOH, 0(0)0(0! -C6)-alkyl and S(0)m(Ci-C6)-alkyl;
R2, R3 and R5 are independently selected from the group consisting of hydrogen, halogen, (C C6)-alkyl, (C2-C8)-alkenyl, (C2-C8)-alkynyl, halo(C C6)-alkyl and (C C6)- alkoxy;
R6 is hydrogen, (CrC6)-alkyl, amino(Ci-C6)-alkyl-, (Ci-C6)-alkoxy(Ci-C6)-alkyl-, (C3- C 2)-cycloalkyl, (C6-C 4)-aryl, (C6-C 4)-ar(C -C6)-alkyl-, heterocyclyl, heteroaryl, C(O)(CrC6)-alkyl or S(O)m(CrC6)-alkyl;
R7 is hydrogen, cyano, nitro, (CrC6)-alkyl or N RaRb;
m is an integer from 0-2;
n is an integer from 0-3;
Y is (C3-Ci2)-cycloalkyl, (C6-Ci4)-ar(Ci-C6)-alkyl-, (C6-Ci4)-aryl, heterocyclyl, heteroaryl or NRaRb;
wherein:
each of the (CrC6)-alkyl and (CrC6)-alkoxy is unsubstituted or substituted with one to three groups independently selected from the group consisting of halogen, hydroxy, nitro, cyano, (Ci-C6)-alkoxy-(Rc)o-3, (C3-Ci2)-cycloalkyl-(Rc)o-3, (C3-Ci2)-cycloalkyloxy- (Rc)o-3, halo(CrC6)-alkoxy, (C6-Ci4)-aryl-(Rc)0-3, (C6-Ci4)-aryloxy-(Rc)o-3, (C6-Ci4)-ar(Ci- C6)-alkyloxy-(Rc)o-3, heterocyclyl-(Rc)o-3, heteroaryl-(Rc)0-3, C(0)(Ci-C6)-alkyl, COOH, C(O)O(CrC6)-alkyl, OC(0)(Ci-C6)-alkyl, C(O)NRaRb, NRaRb and S(O)m(C C6)-alkyl; each of the (C3-Ci2)-cycloalkyl, (C3-Ci2)-cycloalkyloxy, (C6-Ci4)-aryl, (C6-Ci4)-aryloxy, (C6-C 4)-ar(C-i-C6)-alkyl- and (C6-C 4)-ar(C-i-C6)-alkyloxy is unsubstituted or substituted with one to three groups independently selected from the group consisting of halogen, hydroxy, nitro, cyano, (Ci-C6)-alkyl-(Rc)o-3, (Ci-C6)-alkoxy-(Rc)o-3. (Ci-C6)-alkoxy(C C6)-alkyl-(Rc)o-3, (C3-Ci2)-cycloalkyl-(Rc)0-3, (C3-Ci2)-cycloalkyloxy-(Rc)o-3, halo(C C6)- alkyl, halo(C C6)-alkoxy, (C6-Ci4)-aryl-(Rc)0-3, (C6-Ci4)-aryloxy-(Rc)o-3, (C6-Ci4)-ar(C C6)-alkyl-(Rc)o-3, (C6-C14)-ar(C1-C6)-alkyloxy-(Rc)o-3, heterocyclyl-(Rc)0-3, heteroaryl- (Rc)o-3, C(O)(Ci-C6)-alkyl, COOH, C(O)O(C C6)-alkyl, C(O)NRaRb, NRaRb and S(0)m(Ci-C6)-alkyl;
the heterocyclyl is a 3- to 12-membered saturated or partially unsaturated monocyclic or bicyclic ring system containing one to four heteroatoms independently selected from the group consisting of a nitrogen (N), a sulphur (S) and an oxygen (O) atom, the heteroaryl is a 5- to 10-membered aromatic monocyclic or bicyclic ring system containing one to four heteroatoms independently selected from the group consisting of N, S and O; each of the heterocyclyl and heteroaryl is unsubstituted or substituted with one to three groups independently selected from the group consisting of halogen, hydroxy, nitro, cyano, (Ci-C6)-alkyl-(Rc)o-3, (CrC6)-alkoxy-(Rc)o-3, (Ci-C6)-alkoxy(Ci-C6)-alkyl-(Rc)0-3, (C3-Ci2)-cycloalkyl-(Rc)o-3, (C3-Ci2)-cycloalkyloxy-(Rc)o-3, halo(C C6)-alkyl, halo(C C6)- alkoxy, (C6-Ci4)-aryl-(Rc)0-3, (C6-Ci4)-aryloxy-(Rc)o-3, (C6-Ci4)-ar(Ci-C6)-alkyl-(Rc)o-3, (C6-Ci4)-ar(Ci-C6)-alkyloxy-(Rc)o-3, heterocyclyl-(Rc)o-3, heteroaryl-(Rc)o-3, C(O)(C C6)- alkyl, COOH, C(O)O(CrC6)-alkyl, C(O)NRaR , NRaR and S(O)m(CrC6)-alkyl;
Ra and R are independently selected from the group consisting of hydrogen, (C C6)- alkyl, amino(Ci-C6)-alkyl-, (Ci-C6)-alkoxy(Ci-C6)-alkyl-, (C3-Ci2)-cycloalkyl, (C6-Ci4)- aryl, (C6-Ci4)-ar(Ci-C6)-alkyl-, heterocyclyl, heteroaryl, C(O)(CrC6)-alkyl and S(O)m(CrC6)-alkyl; or
Ra and R together with the N to which they are attached can form a 3-8 membered heterocyclyl ring, optionally containing one to three additional heteroatoms independently selected from the group consisting of N, O and S, wherein the said heterocyclyl ring is unsubstituted or substituted with one to three groups as defined above; and Rc is halogen, hydroxy, cyano, nitro, (Ci-C6)-alkyl-(Rc)o-i, (Ci-C6)-alkoxy-(Rc)o-i, (Cr C6)-alkoxy(Ci-C6)-alkyl-(Rc)o-i, (C3-Ci2)-cycloalkyl-(Rc)0-i, (C3-Ci2)-cycloalkyloxy-(Rc)o- 1, hydroxy (Ci-C6)-alkyl-(Rc)o-i, halo(CrC6)-alkyl, halo(C C6)-alkoxy, (C6-Ci4)-aryl- (Rc)o-i, (C6-C14)-aryloxy-(Rc)o-i, (C6-C14)-ar(C1-C6)-alkyl-(Rc)0-i, (C6-C14)-ar(C C6)- alkyloxy-(Rc)o-i, heterocyclyl-(Rc)o-i, heteroaryl-(Rc)0-i, C(O)(Ci-C6)-alkyl, COOH, C(O)O(CrC6)-alkyl, C(O)NRaRb, NRaRb or S(O)m(CrC6)-alkyl;
or an isotopic form, a stereoisomer, a tautomer, a pharmaceutically acceptable salt, a solvate, a polymorph, a prodrug, N-oxide or S-oxide thereof.
2. The compound according to claim 1 ;
wherein:
W is NRa Or O;
R-i and R4 are independently selected from the group consisting of hydrogen, halogen, (CrC6)-alkyl, halo(d-C6)-alkyl, (CrC6)-alkoxy and (C3-Ci2)-cycloalkyl;
R2, R3 and R5 are independently selected from the group consisting of hydrogen, halogen, (CrC6)-alkyl, halo(CrC6)-alkyl and (CrC6)-alkoxy;
R6 is hydrogen, (C C6)-alkyl, (C3-Ci2)-cycloalkyl, alkyl, C(O)(Ci-C6)-alkyl or S(O)m(C C6)-alkyl;
R7 is hydrogen, (CrC6)-alkyl, cyano, nitro or NRaRb;
m is an integer from 0-2;
n is an integer from 0-3;
Ra is hydrogen, (CrC6)-alkyl, amino(Ci-C6)-alkyl-, (Ci-C6)-alkoxy(Ci-C6)-alkyl-, (C3- Ci2)-cycloalkyl, (C6-Ci4)-aryl, (C6-Ci4)-ar(Ci-C6)-alkyl-, heterocyclyl, heteroaryl, C(O)(C1-C6)-alkyl or S Ud-C^-alkyl; and
Y is (C6-Ci4)-ar(Ci-C6)-alkyl-, (C6-Ci4)-aryl, heterocyclyl or heteroaryl.
3. The compound according to claim 1 or claim 2;
wherein:
W is O; and
R7 is cyano.
4. The compound according to claim 1 or claim 2;
wherein: W is NRa; wherein Ra is as defined in claim 1 or 2; and
R7 is cyano.
5. The compound according to claim 1 or claim 2;
wherein:
W is O;
R2, R3 and R5 are independently selected from hydrogen and (d-C6)-alkyl;
R6 is hydrogen, (CrC6)-alkyl or (C3-Ci2)-cycloalkyl;
R7 is cyano; and
Y is (C6-Ci4)-ar(Ci-C6)-alkyl-, (C6-Ci4)-aryl, heterocyclyl or heteroaryl.
6. The compound according to claim 1 or claim 2;
wherein:
W is NRa;
R2, R3 and R5 are independently selected from hydrogen and (CrC6)-alkyl;
R6 is hydrogen, (CrC6)-alkyl or (C3-Ci2)-cycloalkyl;
R7 is cyano;
Ra is hydrogen or (C-i-C6)-alkyl, and
Y is (C6-Ci4)-ar(Ci-C6)-alkyl, (C6-Ci4)-aryl, heterocyclyl or heteroaryl.
7. The compound according to claim 1 or claim 2;
wherein:
W is O; and
R2 and R3 are independently selected from (C-i-C6)-alkyl, halo(CrC6)-alkyl and (C-i-C6)- alkoxy.
8. The compound according to claim 1 or claim 2;
wherein:
Y is selected from (C6-Ci4)-aryl, heterocyclyl or heteroaryl.
9. The compound according to claim 1 or claim 2;
wherein:
W is NH or O; Ri is hydrogen, (C C6)-alkyl, (CrC6)-alkoxy, NRaRb, C(O) (CrC6)-alkyl, C(O)NRaRb, C(O)OH and C(O)O(CrC6)-alkyl;
R2 and R3 are independently selected from hydrogen and (C C6)-alkyl;
R4 is hydrogen;
R5 is hydrogen or (CrC6)-alkyl;
R6 is hydrogen or (CrC6)-alkyl;
R7 is cyano;
n is an integer from 0-3; and
Y is (C6-C14)-ar(CrC6)-alkyl-, (C6-C14)-aryl, heterocyclyl or heteroaryl.
10. The compound according to any one of the claims 1 , 2 and 9; wherein: W is O.
1 1 . The compound according to any one of the claims 1 , 2 and 9;
wherein:
W is NH or O;
Ri is (CrC6)-alkoxy;
R2 and R3 are (CrC6)-alkyl;
R4 is hydrogen;
R5 is (CrC6)-alkyl;
R6 is hydrogen;
R7 is cyano;
n is 1 or 2; and
Y is (C6-Ci 4)-aryl, heterocyclyl or heteroaryl.
12. The compound according to any one of the claims 1 , 2, 9 amd 1 1 ;
wherein:
W is O;
R-i is (C-i -C6)-alkoxy;
R2 and R3 are (C C6)-alkyl;
R4 is hydrogen;
R5 is (CrC6)-alkyl;
R6 is hydrogen;
R7 is cyano; n is 1 ; and
Figure imgf000153_0001
13. The compound according toany one of claims 1 to 12 selected from the group consisting of:
(E)-N-(7-(3,5-Dimethylisoxazol-4-yl)-8-methoxy-1 -((R)-1 -(pyridin-2-yl)ethyl)-1 H- imidazo[4,5-c]quinolin-2(3H)-ylidene)cyanamide;
(E)-N-(7-(3,5-Dimethylisoxazol-4-yl)-8-methoxy-3-methyl-1 -((R)-1 -(pyridin-2-yl)ethyl)- 1 H-imidazo[4,5-c]quinolin-2(3H)-ylidene)cyanamide;
(E)-N-(7-(3,5-dimethylisoxazol-4-yl)-8-methoxy-1 H-imidazo[4,5-c]quinolin-2(3H)- ylidene)cyanamide;
(E)-N-(1 -Benzyl-7-(3,5-dimethylisoxazol-4-yl)-8-methoxy-1 H-imidazo[4,5-c]quinolin- 2(3H)-ylidene)cyanamide;
(E)-N-(7-(3,5-Dimethylisoxazol-4-yl)-8-methoxy-1 -((tetrahydrofuran-2-yl)methyl)-1 H- imidazo[4,5-c]quinolin-2(3H)-ylidene)cyanamide;
(E)-N-(7-(3,5-Dimethylisoxazol-4-yl)-8-methoxy-1 -phenethyl-1 H-imidazo[4,5-c]quinolin- 2(3H)-ylidene)cyanamide;
(E)-N-(7-(3,5-Dimethylisoxazol-4-yl)-8-methoxy-3-methyl-1 -phenethyl-1 H-imidazo[4,5- c]quinolin-2(3H)-ylidene)cyanamide;
(E)-N-(7-(3,5-Dimethylisoxazol-4-yl)-8-methoxy-1 -(((S)-tetrahydrofuran-2-yl)methyl)- 1 H-imidazo[4,5-c]quinolin-2(3H)-ylidene)cyanamide;
(E)-N-(7-(3,5-Dimethylisoxazol-4-yl)-8-methoxy-3-methyl-1 -(((S)-tetrahydrofuran-2- yl)methyl)-1 H-imidazo[4,5-c]quinolin-2(3H)-ylidene)cyanamide;
(E)-N-(7-(3,5-Dimethylisoxazol-4-yl)-8-methoxy-1 -(((R)-tetrahydrofuran-2-yl)methyl)- 1 H-imidazo[4,5-c]quinolin-2(3H)-ylidene)cyanamide;
(E)-N-(7-(3,5-dimethylisoxazol-4-yl)-8-methoxy-1 -(((R)-tetrahydrofuran-2-yl)methyl)- 1 H-imidazo[4,5-c]quinolin-2(3H)-ylidene)cyanamide;
(E)-N-(7-(3,5-Dimethylisoxazol-4-yl)-8-methoxy-1 -((S)-1 -phenylethyl)-1 H-imidazo[4,5- c]quinolin-2(3H)-ylidene)cyanamide;
(E)-N-(7-(3,5-Dimethylisoxazol-4-yl)-8-methoxy-1 -(2-(pyridin-2-yl)ethyl)-1 H- imidazo[4,5-c]quinolin-2(3H)-ylidene)cyanamide;
(E)-N-(7-(3,5-Dimethylisoxazol-4-yl)-8-methoxy-3-methyl-1 -(2-(pyridin-2-yl)ethyl)-1 H- imidazo[4,5-c]quinolin-2(3H)-ylidene)cyanamide; (E)-N-(7-(3,5-Dimethylisoxazol-4-yl)-1 -(3,5-dimethylphenyl)-8-methoxy-1 H- imidazo[4,5-c]quinolin-2(3H)-ylidene)cyanamide;
(E)-N-(7-(3,5-Dimethylisoxazol-4-yl)-1 -(3,5-dimethylphenyl)-8-methoxy-3-methyl-1 H- imidazo[4,5-c]quinolin-2(3H)-ylidene)cyanamide;
(E)-N-(7-(3,5-Dimethylisoxazol-4-yl)-8-methoxy-1 -phenyl-1 H-imidazo[4,5-c]quinolin- 2(3H)-ylidene)cyanamide;
(E)-N-(7-(3,5-Dimethylisoxazol-4-yl)-8-methoxy-3-methyl-1 -phenyl-1 H-imidazo [4,5- c]quinolin-2(3H)-ylidene)cyanamide;
(E)-N-(7-(3,5-Dimethylisoxazol-4-yl)-8-methoxy-1 -(o-tolyl)-1 H-imidazo[4,5-c]quinolin- 2(3H)-ylidene)cyanamide;
(E)-N-(7-(3,5-Dimethylisoxazol-4-yl)-1 -(2-fluorophenyl)-8-methoxy-1 H-imidazo[4,5- c]quinolin-2(3H)-ylidene)cyanamide;
(E)-N-(7-(3,5-Dimethylisoxazol-4-yl)-8-methoxy-1 -(p-tolyl)-1 H-imidazo[4,5-c]quinolin- 2(3H)-ylidene)cyanamide;
(Z)-N-(7-(3,5-Dimethylisoxazol-4-yl)-8-methoxy-1 -(m-tolyl)-l H-imidazo[4,5-c]quinolin- 2(3H)-ylidene)cyanamide;
(E)-N-(7-(3,5-Dimethylisoxazol-4-yl)-8-methoxy-3-methyl-1 -(p-tolyl)-1 H-imidazo[4,5- c]quinolin-2(3H)-ylidene)cyanamide;
(E)-N-(1 -(2-(tert-Butyl)phenyl)-7-(3,5-dimethylisoxazol-4-yl)-8-methoxy-1 H-imidazo[4,5- c]quinolin-2(3H)-ylidene)cyanamide;
(E)-N-(1 -(2-(tert-Butyl)phenyl)-7-(3,5-dimethylisoxazol-4-yl)-8-methoxy-3-methyl-1 H- imidazo[4,5-c]quinolin-2(3H)-ylidene)cyanamide;
7-(3,5-Dimethylisoxazol-4-yl)-8-methoxy-1 -(2-phenylpropan-2-yl)-1 H-imidazo[4,5- c]quinolin-2(3H)-ylidene)cyanamide;
7-(3,5-Dimethylisoxazol-4-yl)-8-methoxy-1 -(tetrahydro-2H-pyran-4-yl)-1 H-imidazo[4,5- c]quinolin-2(3H)-ylidene)cyanamide;
(E)-N-(7-(3,5-Dimethylisoxazol-4-yl)-1 -(3-(1 ,1 ,1 ,3,3,3-hexafluoro-2-hydroxypropan-2- yl)phenyl)-8-methoxy-1 H-imidazo[4,5-c]quinolin-2(3H)-ylidene) cyanamide;
(E)-N-(7-(3,5-Dimethylisoxazol-4-yl)-1 -(3-(1 ,1 ,1 ,3,3,3-hexafluoro-2-methoxy propan-2- yl)phenyl)-8-methoxy-3-methyl-1 H-imidazo[4,5-c]quinolin-2(3H)-ylidene)cyanamide; (E)-N-(7-(3,5-Dimethylisoxazol-4-yl)-1 -(3-(1 ,1 ,1 ,3,3,3-hexafluoro-2-methoxypropan-2- yl)phenyl)-8-methoxy-1 H-imidazo[4,5-c]quinolin-2(3H)-ylidene)cyanamide; (E)-N-(7-(3,5-Dimethylisoxazol-4-yl)-1 -(4-(1 ,1 ,1 ,3,3,3-hexafluoro-2-hydroxy propan-2- yl)benzyl)-8-methoxy-1 H-imidazo[4,5-c]quinolin-2(3H)-ylidene) cyanamide;
(E)-N-(7-(3,5-Dimethylisoxazol-4-yl)-1 -(4-(1 ,1 ,1 ,3,3,3-hexafluoro-2-methoxy propan-2- yl)benzyl)-8-methoxy-3-methyl-1 H-imidazo[4,5-c]quinolin-2(3H)-ylidene)cyanamide; (E)-N-(7-(3,5-Dimethylisoxazol-4-yl)-8-methoxy-1 -(4-methoxybenzyl)-1 H-imidazo[4,5- c]quinolin-2(3H)-ylidene)cyanamide;
(E)-N-(1 -(4-Chlorobenzyl)-7-(3,5-dimethylisoxazol-4-yl)-8-methoxy-1 H-imidazo [4,5- c]quinolin-2(3H)-ylidene)cyanamide;
(E)-N-(1 -(4-Chlorobenzyl)-7-(3,5-dimethylisoxazol-4-yl)-8-methoxy-3-methyl-1 H- imidazo[4,5-c]quinolin-2(3H)-ylidene)cyanamide;
2-(4-((E)-2-(Cyanoimino)-8-methoxy-1 -((R)-1 -phenylethyl)-2,3-dihydro-1 H-imidazo[4,5- c]quinolin-7-yl)-3-methylisoxazol-5-yl)ethyl acetate;
(E)-N-(7-(3,5-Dimethyl-1 H-pyrazol-4-yl)-8-methoxy-1 -((R)-1 -phenylethyl)-1 H- imidazo[4,5-c]quinolin-2(3H)-ylidene)cyanamide;
(E)-N-(7-(3,5-Dimethylisoxazol-4-yl)-8-methyl-1 -((R)-1 -phenylethyl)-1 H-imidazo[4,5- c]quinolin-2(3H)-ylidene)cyanamide;
(E)-N-(7-(3,5-Dimethylisoxazol-4-yl)-3,8-dimethyl-1 -((R)-1 -phenylethyl)-1 H- imidazo[4,5-c]quinolin-2(3H)-ylidene)cyanamide;
(E)-N-(7-(3,5-Ddimethyl-1 H-pyrazol-4-yl)-8-methyl-1 -((R)-1 -phenylethyl)-1 H- imidazo[4,5-c]quinolin-2(3H)-ylidene)cyanamide;
Ethyl 2-(4-((E)-2-(cyanoimino)-8-methyl-1 -((R)-1 -phenylethyl)-2,3-dihydro-1 H- imidazo[4,5-c]quinolin-7-yl)-3-methylisoxazol-5-yl)acetate;
(E)-N-(7-(5-(2-Hydroxyethyl)-3-methylisoxazol-4-yl)-8-methyl-1 -((R)-1 -phenylethyl)-1 H- imidazo[4,5-c]quinolin-2(3H)-ylidene)cyanamide;
(R, E)-N-(7-(3,5-Dimethylisoxazol-4-yl)-1 -(1 -phenylethyl)-1 H-imidazo[4,5-c] quinolin- 2(3H)-ylidene)cyanamide;
(E)-Ethyl 2-(cyanoimino)-7-(3,5-dimethylisoxazol-4-yl)-1 -((R)-1 -phenyl ethyl)- 2,3- dihydro-1 H-imidazo[4,5-c]quinoline-8-carboxylate;
(E)-2-(Cyanoimino)-7-(3,5-dimethylisoxazol-4-yl)-1 -((R)-1 -phenylethyl)-2,3-dihydro-1 H- imidazo[4,5-c]quinoline-8-carboxylic acid;
(E)-2-(cyanoimino)-7-(3,5-dimethylisoxazol-4-yl)-N-ethyl-1 -((R)-1 -phenyl ethyl)-2,3- dihydro-1 H-imidazo[4,5-c]quinoline-8-carboxamide; (E)-2-(Cyanoimino)-N-cyclopropyl-7-(3,5-dimethylisoxazol-4-yl)-1 -((R)-1 -phenyl ethyl)- 2,3-dihydro-1 H-imidazo[4,5-c]quinoline-8-carboxamide;
(E)-2-(Cyanoimino)-7-(3,5-dimethylisoxazol-4-yl)-N-(4-hydroxyphenyl)-1 -((R)-1 - phenylethyl)-2,3-dihydro-1 H-imidazo[4,5-c]quinoline-8-carboxamide;
Ethyl 3-((E)-2-(cyanoimino)-7-(3,5-dimethylisoxazol-4-yl)-1 -((R)-1 -phenyl ethyl)-2,3- dihydro-1 H-imidazo[4,5-c]quinolin-8-yl)propanoate;
3-((E)-2-(Cyanoimino)-7-(3,5-dimethylisoxazol-4-yl)-1 -((R)-1 -phenylethyl)-2,3-dihydro- 1 H-imidazo[4,5-c]quinolin-8-yl)propanoic acid;
3-((E)-2-(Cyanoimino)-7-(3,5-dimethylisoxazol-4-yl)-1 -((R)-1 -phenylethyl)-2,3-dihydro- 1 H-imidazo[4,5-c]quinolin-8-yl)-N-ethylpropanamide;
3-((E)-2-(Cyanoimino)-7-(3,5-dimethylisoxazol-4-yl)-1 -((R)-1 -phenylethyl)-2,3-dihydro-
1 H-imidazo[4,5-c]quinolin-8-yl)-N-(4-hydroxyphenyl) propanamide;
3-((E)-2-(Cyanoimino)-7-(3,5-dimethylisoxazol-4-yl)-1 -((R)-1 -phenylethyl)-2,3-dihydro-
1 H-imidazo[4,5-c]quinolin-8-yl)-N-((R)-1 -phenylethyl) propanamide;
3-((E)-2-(Cyanoimino)-7-(3,5-dimethylisoxazol-4-yl)-3-methyl-1 -((R)-1 -phenyl ethyl)-
2,3-dihydro-1 H-imidazo[4,5-c]quinolin-8-yl)-N-((R)-1 -phenylethyl) propanamide;
(E)-N-(8-(3-Cyanopropyl)-7-(3,5-dimethylisoxazol-4-yl)-1 -((R)-1 -phenylethyl)-1 H- imidazo[4,5-c]quinolin-2(3H)-ylidene)cyanamide;
Methyl 2-((E)-2-(cyanoimino)-7-(3,5-dimethylisoxazol-4-yl)-1 -((R)-1 -phenyl ethyl)-2,3- dihydro-1 H-imidazo[4,5-c]quinolin-8-yl)acetate;
Ethyl 2-(4-((E)-2-(cyanoimino)-8-methoxy-1 -((R)-1 -phenylethyl)-2,3-dihydro-1 H- imidazo[4,5-c]quinolin-7-yl)-3-methylisoxazol-5-yl)acetate;
2- (4-((E)-2-(Cyanoimino)-8-methoxy-1 -((R)-1 -phenylethyl)-2,3-dihydro-1 H-imidazo[4,5- c]quinolin-7-yl)-3-methylisoxazol-5-yl)acetic acid;
Ethyl 3-(4-((E)-2-(cyanoimino)-8-methoxy-1 -((R)-1 -phenylethyl)-2,3-dihydro-1 H- imidazo[4,5-c]quinolin-7-yl)-5-methylisoxazol-3-yl)propanoate;
3- (4-((E)-2-(Cyanoimino)-8-methoxy-1 -((R)-1 -phenylethyl)-2,3-dihydro-1 H-imidazo[4,5- c]quinolin-7-yl)-5-methylisoxazol-3-yl)propanoic acid;
Methyl 2-((2-(cyanoimino)-7-(3,5-dimethylisoxazol-4-yl)-1 -((R)-1 -phenylethyl) -2,3- dihydro-1 H-imidazo[4,5-c]quinolin-8-yl)oxy)acetate;
2-((-2-(Cyanoimino)-7-(3,5-dimethylisoxazol-4-yl)-1 -((R)-1 -phenylethyl)-2,3-dihydro- 1 H-imidazo[4,5-c]quinolin-8-yl)oxy)acetic acid; 2-((-2-(Cyanoimino)-7-(3,5-dimethylisoxazol-4-yl)-1 -((R)-1 -phenylethyl)-2,3-di
1 H-imidazo[4,5-c]quinolin-8-yl)oxy)-N-ethylacetamide;
N-(8-(3-Cyanopropoxy)-7-(3,5-dimethylisoxazol-4-yl)-1 -((R)-1 -phenyl ethyl)- 1 H- imidazo[4,5-c]quinolin-2(3H)-ylidene)cyanamide;
(E)-N-(8-(Cyanomethoxy)-7-(3,5-dimethyl-4,5-dihydroisoxazol-4-yl)-1 -((R)-1 - phenylethyl)-1 H-imidazo[4,5-c]quinolin-2(3H)-ylidene)cyanamide;
(E)-N-(7-(3,5-Dimethylisoxazol-4-yl)-8-(2-methoxyethoxy)-1 -((R)-1 -phenylethyl)-1 H- imidazo[4,5-c]quinolin-2(3H)-ylidene)cyanamide; and
(E)-tert-Butyl (3-(2-(cyanoimino)-7-(3,5-dimethylisoxazol-4-yl)-8-methoxy-2,3-dihydro- 1 H-imidazo[4,5-c]quinolin-1 -yl)propyl)carbamate;
or a stereoisomer, a tautomer, a pharmaceutically acceptable salt, a solvate, a polymorph or N-oxide thereof.
14. A pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (I) according to any one of the claims 1 to 13, or a stereoisomer, a tautomer, a pharmaceutically acceptable salt or a solvate thereof and at least one pharmaceutically acceptable excipient.
15. The compound according to any one of the claims 1 to 13, for use as inhibitors of bromodomain containing proteins.
16. A method for the treatment of a disease or a disorder mediated by bromodomain containing proteins, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula (I) according to any one of the claims 1 to 13, or a stereoisomer, a tautomer, a pharmaceutically acceptable salt or a solvate thereof.
17. A method for the treatment of a disease or a disorder mediated by bromodomain containing proteins, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula (I) according to any one of the claims 1 to 13, or a stereoisomer, a tautomer, a pharmaceutically acceptable salt or a solvate thereof, along with one further therapeutically active agent.
18. The method according to claim 16 or claim 17, wherein the disease or disorder mediated by bromodomain containing proteins is selected from proliferative disorders, chronic autoimmune and inflammatory disorders, conditions associated with ischaemia-reperfusion injury, metabolic disorders, cardiovascular diseases, disorders associated with fibrosis or viral infections.
19. The method according to claim 16 or claim 17, wherein the disease or disorder mediated by bromodomain containing proteins is cancer.
20. The method according to claim 16 or claim 17, wherein the disease or disorder mediated by bromodomain containing proteins is a chronic autoimmune or inflammatory disease.
PCT/IB2014/064949 2013-10-01 2014-09-30 Imidazoquinoline compounds as bromodomain inhibitors WO2015049629A1 (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US201361885100P 2013-10-01 2013-10-01
US61/885,100 2013-10-01

Publications (1)

Publication Number Publication Date
WO2015049629A1 true WO2015049629A1 (en) 2015-04-09

Family

ID=52778316

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/IB2014/064949 WO2015049629A1 (en) 2013-10-01 2014-09-30 Imidazoquinoline compounds as bromodomain inhibitors

Country Status (1)

Country Link
WO (1) WO2015049629A1 (en)

Cited By (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2016186453A1 (en) * 2015-05-20 2016-11-24 Kainos Medicine, Inc. Quinoline derivatives as bromodomain inhibitors
US9957233B1 (en) 2016-08-05 2018-05-01 Calitor Sciences, Llc Process for preparing substituted quinolin-4-ol compounds
US10501438B2 (en) 2015-08-11 2019-12-10 Neomed Institute Aryl-substituted dihydroquinolinones, their preparation and their use as pharmaceuticals
US10501459B2 (en) 2015-10-21 2019-12-10 Neomed Institute Substituted imidazo[1,2-a]pyridines as bromodomain inhibitors
US10519151B2 (en) 2016-01-28 2019-12-31 Neomed Institute Substituted [1,2,4]triazolo[4,3-A]pyridines, their preparation and their use as pharmaceuticals
US10703740B2 (en) 2015-08-12 2020-07-07 Neomed Institute Substituted benzimidazoles, their preparation and their use as pharmaceuticals
US10836742B2 (en) 2015-08-11 2020-11-17 Neomed Institute N-substituted bicyclic lactams, their preparation and their use as pharmaceuticals
CN115304546A (en) * 2022-02-18 2022-11-08 宁波申泰生物科技有限公司 3-substituted quinoline derivative and preparation method thereof
WO2024008113A1 (en) * 2022-07-07 2024-01-11 深圳微芯生物科技股份有限公司 Formamide-substituted heterotricyclic derivative, method for preparing same, and use thereof

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2011054846A1 (en) * 2009-11-05 2011-05-12 Glaxosmithkline Llc Imidazo [4, 5-c] quinoline derivates as bromodomain inhibitors
WO2012007926A1 (en) * 2010-07-16 2012-01-19 Piramal Life Sciences Limited Substituted imidazoquinoline derivatives as kinase inhibitors
WO2012143416A2 (en) * 2011-04-21 2012-10-26 Glaxosmithkline Llc Novel compounds
WO2013024104A1 (en) * 2011-08-17 2013-02-21 Glaxosmithkline Llc 4-(8-methoxy-1-((1-methoxypropan-2-yl)-2-(tetrahydro-2h-pyran-4-yl)-1 h-imidazo[4,5-c]quinolin-7-yl)-3,5-dimethylisoxazole and its use as bromodomain inhibitor

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2011054846A1 (en) * 2009-11-05 2011-05-12 Glaxosmithkline Llc Imidazo [4, 5-c] quinoline derivates as bromodomain inhibitors
WO2012007926A1 (en) * 2010-07-16 2012-01-19 Piramal Life Sciences Limited Substituted imidazoquinoline derivatives as kinase inhibitors
WO2012143416A2 (en) * 2011-04-21 2012-10-26 Glaxosmithkline Llc Novel compounds
WO2013024104A1 (en) * 2011-08-17 2013-02-21 Glaxosmithkline Llc 4-(8-methoxy-1-((1-methoxypropan-2-yl)-2-(tetrahydro-2h-pyran-4-yl)-1 h-imidazo[4,5-c]quinolin-7-yl)-3,5-dimethylisoxazole and its use as bromodomain inhibitor

Cited By (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2016186453A1 (en) * 2015-05-20 2016-11-24 Kainos Medicine, Inc. Quinoline derivatives as bromodomain inhibitors
US10501438B2 (en) 2015-08-11 2019-12-10 Neomed Institute Aryl-substituted dihydroquinolinones, their preparation and their use as pharmaceuticals
US10836742B2 (en) 2015-08-11 2020-11-17 Neomed Institute N-substituted bicyclic lactams, their preparation and their use as pharmaceuticals
US10703740B2 (en) 2015-08-12 2020-07-07 Neomed Institute Substituted benzimidazoles, their preparation and their use as pharmaceuticals
US11365186B2 (en) 2015-08-12 2022-06-21 Epigenetix, Inc. Substituted benzimidazoles, their preparation and their use as pharmaceuticals
US10501459B2 (en) 2015-10-21 2019-12-10 Neomed Institute Substituted imidazo[1,2-a]pyridines as bromodomain inhibitors
US10519151B2 (en) 2016-01-28 2019-12-31 Neomed Institute Substituted [1,2,4]triazolo[4,3-A]pyridines, their preparation and their use as pharmaceuticals
US9957233B1 (en) 2016-08-05 2018-05-01 Calitor Sciences, Llc Process for preparing substituted quinolin-4-ol compounds
CN115304546A (en) * 2022-02-18 2022-11-08 宁波申泰生物科技有限公司 3-substituted quinoline derivative and preparation method thereof
WO2024008113A1 (en) * 2022-07-07 2024-01-11 深圳微芯生物科技股份有限公司 Formamide-substituted heterotricyclic derivative, method for preparing same, and use thereof

Similar Documents

Publication Publication Date Title
WO2015049629A1 (en) Imidazoquinoline compounds as bromodomain inhibitors
TWI551595B (en) 2,4-disubstituted benzene-1,5-diamine derivatives and their use, Its preparation of pharmaceutical compositions and pharmaceutical compositions
CN108137588B (en) Tricyclic fused pyridin-2-one derivatives and their use as BRD4 inhibitors
CA3210332A1 (en) Tricyclic-amido-bicyclic prmt5 inhibitors
AU2017203986A1 (en) Novel furanone derivative
JP2023522863A (en) Tricyclic compounds as EGFR inhibitors
WO2016140501A1 (en) Pyridine n-oxide for enhancer of zeste homolog 2 inhibitors
AU2018373464B2 (en) 6,7-dihydropyrazolo[1,5-a] pyrazinone derivative and medical use thereof
KR102588109B1 (en) Tricyclic fused derivatives of 1-(cyclo)alkyl pyridin-2-one useful in cancer treatment
CN115991706A (en) PIM kinase inhibitors
WO2015092118A1 (en) Spiro[cyclobutane-1,3'-indolin]-2'-one derivatives as bromodomain inhibitors
AU2019230859B2 (en) Oxazino-quinazoline and oxazino-quinazoline type compound, preparation method therefor, and uses thereof
EP2307401A2 (en) Antineoplastic derivatives of 4-oxo-1,4-dihydro-quinoline, preparation thereof, and therapeutic use thereof
ES2960408T3 (en) Heterocyclic compound and its use as a positive allosteric modulator of the muscarinic cholinergic M1 receptor
JP2023539275A (en) Methods for preparing novel RHO-related protein kinase inhibitors and intermediates in the preparation methods
AU2018289939B2 (en) Heterocyclic compound
JP2020196709A (en) Pharmaceutical containing 6,7-dihydropyrazolo [1,5-a]pyrazinone derivative or salt thereof
JP2022551180A (en) isocitrate dehydrogenase (IDH) inhibitors
JP2018154562A (en) Novel bicyclic heterocyclic compound and pharmaceutical use thereof
TW202218661A (en) Tricyclic compounds as egfr inhibitors
WO2022171126A1 (en) Fused ring compound used as wee-1 inhibitor
CN116113416A (en) Tetracyclic derivative, preparation method and medical application thereof
US20240124442A1 (en) Tricyclic-amido-bicyclic prmt5 inhibitors
JP2024508769A (en) Pyrimidine compounds as Wee-1 inhibitors
TW202304910A (en) Modulators of bcl-2 or bcl-2/bcl-xl and uses thereof

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 14851106

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 14851106

Country of ref document: EP

Kind code of ref document: A1