WO2015049629A1 - Composés d'imidazoquinoline à utiliser en tant qu'inhibiteurs de bromodomaine - Google Patents

Composés d'imidazoquinoline à utiliser en tant qu'inhibiteurs de bromodomaine Download PDF

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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
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alkyl
imidazo
quinolin
dimethylisoxazol
methoxy
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PCT/IB2014/064949
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English (en)
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Rajiv Sharma
Sarang Kulkarni
Mahesh Kulkarni
Sumit Mukherjee
Rajesh Kumar YADAV
Madhavi AGARWAL
Sandeep BURUDKAR
Santosh SATHE
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Piramal Enterprises Limited
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—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

La présente invention concerne un composé de formule (I), ou une forme isotopique, un stéréoisomère, un tautomère, un sel pharmaceutiquement acceptable, un solvate, un polymorphe, un promédicament, N-oxyde ou S-oxyde de celui-ci ; et des procédés pour leur préparation. La présente invention concerne des compositions pharmaceutiques contenant lesdits composés et leur utilisation pour traiter des maladies ou des troubles dont la médiation est assurée par des protéines à bromodomaine, en particulier le cancer.
PCT/IB2014/064949 2013-10-01 2014-09-30 Composés d'imidazoquinoline à utiliser en tant qu'inhibiteurs de bromodomaine WO2015049629A1 (fr)

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