WO2014128655A1

WO2014128655A1 - Substituted imidazo[4,5-c]quinoline derivatives as bromodomain inhibitors

Info

Publication number: WO2014128655A1
Application number: PCT/IB2014/059152
Authority: WO
Inventors: Sanjita SASMAL; Subramanya Hosahalli
Original assignee: Aurigene Discovery Technologies Ltd
Current assignee: Aurigene Oncology Ltd
Priority date: 2013-02-25
Filing date: 2014-02-21
Publication date: 2014-08-28
Anticipated expiration: 2015-08-25

Abstract

The present invention provides novel substituted imidazo[4,5-c]quinoline derivatives of formula (1), which may be therapeutically useful, more particularly as Bromodomain inhibitors; (1) in which Cy_i, Cy₂, R₁, R₂, R₃, R₄ and R₅ have the same meanings given in the specification, and pharmaceutically acceptable salts thereof that are useful in the treatment and prevention of diseases or disorder, in particular their use in diseases or disorder associated as bromodomain inhibitors. The present invention also provides preparation of the compounds and pharmaceutical formulations comprising at least one of the substituted imidazo[4,5-C]quinoline compounds of formula (1) together with a pharmaceutically acceptable carrier, diluent or excipient therefor.

Description

SUBSTITUTED IMIDAZO[4,5-c]QUINOLINE DERIVATIVES AS BROMODOMAIN

INHIBITORS

This application claims the benefit of Indian provisional application number 802/CHE/2013 filed on 25^th February 2013, which hereby incorporated by reference.

FIELD OF THE INVENTION

The present invention relates to compounds useful for the treatment and prevention of diseases or disorder, in particular their use in diseases or disorder associated where there is an advantage in inhibiting kinase enzyme activity, and more particularly bromodomain inhibitors. The invention also provides pharmaceutically acceptable compositions comprising compounds of the present invention and methods of using said compositions in the treatment of diseases or disorder associated with bromodomain.

BACKGROUND OF THE INVENTION

The acetylation of histone lysine is central to providing the dynamic regulation of chromatin-based gene transcription. The bromodomain (BRD), which is the conserved structural module in chromatin-associated proteins and histone acetyl tranferases, is the sole protein domain known to recognize acetyl-lysine residues on proteins.

The BET family of bromodomain containing proteins comprises 4 proteins (BRD2, BRD3, BRD4 and BRD-t) which contain tandem bromodomains capable of binding to two acetylated lysine residues in close proximity, increasing the specificity of the interaction. BRD2 and BRD3 are reported to associate with histones along actively transcribed genes and may be involved in facilitating transcriptional elongation (Leroy et al, Mol. Cell. 2008 30(1):51 -60), while BRD4 appears to be involved in the recruitment of the pTEF-[beta] complex to inducible genes, resulting in phosphorylation of RNA polymerase and increased transcriptional output (Hargreaves et al, Cell, 2009 138(1): 129-145). It has also been reported that BRD4 or BRD3 may fuse with NUT (nuclear protein in testis) forming novel fusion oncogenes, BRD4-NUT or BRD3- NUT, in a highly malignant form of epithelial neoplasia (French et al. Cancer Research, 2003, 63, 304-307 and French et al. Journal of Clinical Oncology, 2004, 22 (20), 4135-4139). Data suggests that BRD-NUT fusion proteins contribute to carcinogenesis (Oncogene, 2008, 27, 2237-2242). BRD-t is uniquely expressed in the testes and ovary. All family members have been reported to have some function in controlling or executing aspects of the cell cycle, and have been shown to remain in complex with chromosomes during cell division- suggesting a role in the maintenance of epigenetic memory. In addition some viruses make use of these proteins to tether their genomes to the host cell chromatin, as part of the process of viral replication (You et al Cell, 2004 117(3):349-60).

Japanese patent application JP2008-156311 disclosed a benzimidazole derivative which is said to be a BRD2 bromodomain binding agent has utility with respect to virus infection / proliferation.

International patent application WO2009084693A1 disclosed a series of thienotriazolodiazepiene derivatives that are said to inhibit the binding between an acetylated histone and a bromodomain containing protein which are said to be useful as anti-cancer agents.

International patent application WO2011054846A1 disclosed tricyclic compounds as bromodomain inhibitors.

However, there remains a need for potent bromodomain inhibitors with desirable pharmaceutical properties. Certain quinoline derivatives have been found in the context of this invention to have a class of compounds that inhibit the binding of BET family bromodomains to acetylated lysine residues for controlling the gene expressions in human health and disease. Such compounds will hereafter be referred to as "bromodomain inhibitors".

SUMMARY OF THE INVENTION

The present invention relates to substituted imidazo[4,5-c]quinoline derivatives of formula (1) which are useful as kinase inhibitors.

In one aspect, the present invention relates to the compound of formula (1)

or a pharmaceutically acceptable salt or a pharmaceutically acceptable stereoisomer thereof, wherein,

Cyi is an optionally substituted monocyclic ring having 1-3 heteroatoms independently selected from N and O; wherein the optional substituent is alkyl; Cy₂ is an optionally substituted monocyclic ring having 0-2 heteroatoms; wherein the heteroatom is N and the optional substituents are selected from alkyl, halogen and alkoxy;

Ri is selected from hydrogen, alkyl, hydroxyalkyl, alkoxyalkyl, arylalkyl, cycloalkylalkyl and heterocyclylalkyl;

R₂ and R₃ are independently selected from the halogen, hydroxy or alkyl; or R₂ and R₃ combined together to form an oxo group;

alternatively, R₂ and R₃ can be taken together with the carbon atom to which they are attached to form a 3-4 membered cycloalkyl ring;

R4 is selected from hydrogen, halogen and alkyl; and

R5 is selected from hydrogen, halogen, alkyl and alkoxy.

In another aspect of the present invention, it relates to the pharmaceutical composition comprising substituted imidazo[4,5-C]quinoline derivatives of formula ( 1) and process for preparing them.

In further another aspect of the present invention, it relates to the use of compounds of formula ( 1), its pharmaceutically acceptable salts or pharmaceutically acceptable stereoisomers thereof, including mixtures thereof in all suitable ratios wherever applicable as a medicament for the treatment and prevention of disorders or diseases for which a bromodomain inhibitor is indicated.

DETAILED DESCRIPTION OF THE INVENTION

Embodiments of the present invention provide substituted imidazo[4,5-c]quinoline derivatives of formula ( 1) which are useful as bromodomain inhibitors.

One of the e es to compounds of formula ( 1)

or a pharmaceutically acceptable salt or a pharmaceutically acceptable stereoisomer thereof, wherein, Cyi is an optionally substituted monocyclic ring having 1-3 heteroatoms independently selected from N and O; wherein the optional substituent is alkyl;

Cy₂ is an optionally substituted monocyclic ring having 0-2 heteroatoms; wherein the heteroatom is N and the optional substituents are selected from alkyl, halogen and alkoxy;

R4 is selected from hydrogen, halogen and alkyl; and

R5 is selected from hydrogen, halogen, alkyl and alkoxy.

The embodiments below are illustrative of the present invention and are not intended to limit the claims to the specific embodiments exemplified.

According to one embodiment, specifically provided are compounds of formula (1), wherein Cyi is 3,5-dimethylisoxazole.

According to another embodiment, specifically provided are compounds of formula (1), wherein, Cy₂ is selected from optionally substituted phenyl and optionally substituted pyridyl.

According to preceding embodiment, specifically provided are compounds of formula (1), wherein the optional substituents are selected from halogen, alkoxy and alkyl; in particular halogen is chloro and fluoro, alkoxy is methoxy, and alkyl is methyl.

According to yet another embodiment, specifically provided are compounds of formula (1), wherein Ri is selected from hydrogen, alkyl, hydroxyalkyl and alkoxyalkyl; in particular alkyl is methyl, hydroxyalkyl is -CH2CH2OH, and alkoxyalkyl is -CH₂CH₂OCH₃.

According to yet another embodiment, specifically provided are compounds of formula

(1), wherein Ri is selected from arylalkyl, cyaloalkylalkyl and heterocyclylalkyl.

According to preceding embodiment, specifically provided are compounds of formula (1),

wherein Ri

According to yet another embodiment, specifically provided are compounds of formula ( 1), wherein R₂ and R₃ are independently selected from halogen, hydroxy and alkyl; in particular halogen is fluoro, and alkyl is methyl and ethyl.

According to yet another embodiment, specifically provided are compounds of formula ( 1), wherein R₂ and R₃ taken together to form an oxo group.

According to yet another embodiment, specifically provided are compounds of formula ( 1), wherein R₂ and R₃ taken together with the carbon atom to which they are attached to form a 3-4 membered cycloalkyl ring; in particular cycloalkyl is cyclopropyl.

According to yet another embodiment, specifically provided are compounds of formula ( 1), wherein R₄ is hydrogen.

According to yet another embodiment, specifically provided are compounds of formula ( 1), wherein R₅ is alkoxy; in particular alkoxy is methoxy.

According to further yet another embodiment of the present invention, the compound of formula ( 1) is a compound of formula (la)

wherein, Ri and Cy₂ are same as defined in formula ( 1).

According to further yet another embodiment of the present invention, the compound of formula ( 1) is a compound of formula (lb)

wherein, Ri and Cy₂ are same as defined in formula (1).

According to further yet another embodiment of the present invention, the compound of formula (1) is a compound of formula (lc)

wherein, Ri and Cy₂ are same as defined in formula (1); and 'n' is an integer selected from 0 and 1.

According to yet another particular embodiment of the present invention, the compound of formula (1) is selected from the group consisting of

(7-(3,5-dimethylisoxazol-4-yl)-8-methoxy-l-((tetrahydro-2H-pyran-4-yl)methyl)- lH-imidazo[4,5-c]quinolin-2-yl)(pyridin-3-yl)methanone;

(l-benzyl-7-(3,5-dimethylisoxazol-4-yl)-8-methoxy-lH-imidazo[4,5-c]quinolin-2- yl)(pyridin-3-yl)methanone;

(7-(3,5-dimethylisoxazol-4-yl)-l-isopropyl-8-methoxy-lH-imidazo[4,5-c] quinolin-2-yl)(pyridin-3-yl)methanone;

(7-(3,5-dimethylisoxazol-4-yl)-8-methoxy-l-(2-methoxyethyl)-lH-imidazo[4,5-c] quinolin-2-yl)(pyridin-3-yl)methanone;

(l-benzyl-7-(3,5-dimethylisoxazol-4-yl)-8-methoxy-lH-imidazo[4,5-c]quinolin-2- yl)(6-methoxypyridin-3-yl)methanone;

(l-benzyl-7-(3,5-dimethylisoxazol-4-yl)-8-methoxy-lH-imidazo[4,5-c]quinolin-2- yl)(phenyl)methanone;

(l-benzyl-7-(3,5-dimethylisoxazol-4-yl)-8-methoxy-lH-imidazo[4,5-c]quinolin-2- yl)(4-fluorophenyl)methanone;

(7-(3,5-dimethylisoxazol-4-yl)-8-methoxy-l-((tetrahydro-2H-pyran-4-yl)methyl)- lH-imidazo[4,5-c]quinolin-2-yl)(5-fluoropyridin-2-yl)methanone;

(7-(3,5-dimethylisoxazol-4-yl)-8-methoxy-l-((tetrahydro-2H-pyran-4-yl)methyl)- lH-imidazo[4,5-c]quinolin-2-yl)(phenyl)methanone;

(7-(3,5-dimethylisoxazol-4-yl)-8-methoxy-l-((tetrahydro-2H-pyran-4-yl)methyl)- lH-imidazo[4,5-c]quinolin-2-yl)(4-fluorophenyl)methanone;

(7-(3,5-dimethylisoxazol-4-yl)-8-methoxy-l-((tetrahydro-2H-pyran-4-yl)methyl)- lH-imidazo[4,5-c]quinolin-2-yl)(pyridin-2-yl)methanone;

(l-benzyl-7-(3,5-dimethylisoxazol-4-yl)-8-methoxy-lH-imidazo[4,5-c]quinolin-2- yl)(4-methoxyphenyl)methanone;

(7-(3,5-dimethylisoxazol-4-yl)-8-methoxy-l-(thiazol-5-ylmethyl)-lH-imidazo[4,5- c]quinolin-2-yl)(pyridin-2-yl)methanone;

4-(2-(difluoro(pyridin-3-yl)methyl)-8-methoxy-lH-imidazo[4,5-c]quinolin-7-yl)- 3 , 5 -dimethylisoxazole ;

4-(2-(difluoro(pyridin-3-yl)methyl)-8-methoxy-l-methyl-lH-imidazo[4,5-c] quinolin-7-yl)-3,5-dimethylisoxazole; 4-(2-(difluoro(6-methylpyridin-3-yl)methyl)-8-methoxy-l-methyl-lH-imidazo [4,5-c]quinolin-7-yl)-3,5-dimethylisoxazole;

4-(2-(difluoro(pyridin-3-yl)methyl)-8-methoxy-l-((tetrahydro-2H-pyran-4-yl) methyl)- lH-imidazo[4,5-c]quinolin-7-yl)-3,5-dimethylisoxazole;

4-(l-benzyl-2-(difluoro(pyridin-3-yl)methyl)-8-methoxy-lH-imidazo[4,5-c] quinolin-7-yl)-3,5-dimethylisoxazole;

4-(2-(difluoro(pyridin-3-yl)methyl)-l-isopropyl-8-methoxy-lH-imidazo[4,5-c] quinolin-7-yl)-3,5-dimethylisoxazole;

4-(2-(difluoro(pyridin-3-yl)methyl)-8-methoxy-l-(2-methoxyethyl)-lH-imidazo [4,5-c]quinolin-7-yl)-3,5-dimethylisoxazole;

4-(2-(difluoro(5-fluoropyridin-2-yl)methyl)-8-methoxy-l-((tetrahydro-2H-pyran- 4-yl)methyl)-lH-imidazo[4,5-c]quinolin-7-yl)-3,5-dimethylisoxazole;

4-(l-benzyl-2-(difluoro(phenyl)methyl)-8-methoxy-lH-imidazo[4,5-c]quinolin-7- yl)-3 , 5-dimethylisoxazole ;

4-(2-(difluoro(pyridin-2-yl)methyl)-8-methoxy-l-((tetrahydro-2H-pyran-4-yl) methyl)- lH-imidazo[4,5-c]quinolin-7-yl)-3, 5-dimethylisoxazole;

4-(l-benzyl-2-(difluoro(4-fluorophenyl)methyl)-8-methoxy-lH-imidazo[4,5-c] quinolin-7-yl)-3, 5-dimethylisoxazole;

1- (7-(3,5-dimethylisoxazol-4-yl)-8-methoxy-l-methyl-lH-imidazo[4,5-c]quinolin-

2- yl)- l-(pyridin-3-yl)ethanol (Isomer- 1);

1- (7-(3,5-dimethylisoxazol-4-yl)-8-methoxy-l-methyl-lH-imidazo[4,5-c]quinolin-

2- yl)- l-(pyridin-3-yl)ethanol (Isomer-2);

l-(4-chlorophenyl)-l-(7-(3,5-dimethylisoxazol-4-yl)-8-methoxy-l-methyl-lH- imidazo [4, 5-c] quinolin-2-yl)propan- 1 -ol (Isomer- 1 ) ;

1- (7-(3,5-dimethylisoxazol-4-yl)-8-methoxy-l-methyl-lH-imidazo[4,5-c]quinolin-

2- yl)- 1 -(pyridin-3-yl)propan- 1 -ol (Isomer- 1 ) ;

1- (7-(3,5-dimethylisoxazol-4-yl)-8-methoxy-l-methyl-lH-imidazo[4,5-c]quinolin-

2- yl)-l-(pyridin-3-yl)propan-l-ol (Isomer-2); and 38. 4-(8-methoxy- l-methyl-2-( l-(pyridin-3-yl)cyclopropyl)-lH-imidazo[4,5-c] quinolin-7-yl)-3,5-dimethylisoxazole,

or a pharmaceutically acceptable salt or a pharmaceutically acceptable stereoisomer thereof.

In yet further another particular embodiment, the present invention provides process for preparation of compound of formula (1) and their pharmaceutical compositions.

In further yet another particular embodiment, the definition of "compounds of formula ( 1)" inherently includes all stereoisomers of the compound of formula ( 1) either as pure stereoisomer or as a mixture of two or more stereoisomers. The word stereoisomers include enantiomers, diasteroisomers, racemates, cis or trans isomers and mixture thereof.

The absolute configuration at an asymmetric atom is specified by either R or S. Resolved compounds whose absolute configuration is not known can be designated by (+) or (-) depending on the direction in which they rotate plane polarized light. When a specific stereoisomer is identified, this means that said stereoisomer is substantially free, i.e. associated with less than 50%, preferably less than 20%, more preferably less than 5%, in particularly less than 2% or 1 % of the other isomers. Thus when a compound of formula (1) is for instance specified as (R), this means that the compound is substantially free of (S) isomer; when the compound of formula ( 1) is for instance specified as E, this means that the compound is free of the Z isomer; when the compound of formula (1) is for instance specified as cis isomer, this means that the compound is free of the trans isomer.

Without limiting the scope of present invention, the following definitions are provided in order to aid those skilled in the art in understanding the detailed description of the present invention.

"Alkyl" refers to a hydrocarbon chain that may be a straight chain or branched chain, containing the indicated number of carbon atoms; in particular alkyl is Ci-Cio alkyl group which may have 1 to 10 (inclusive) carbon atoms in it; in more particular alkyl is Ci-C₆ alkyl group which may have 1 to 6 (inclusive) carbon atoms in it and in more preferred particular alkyl is Ci- C₄ alkyl group which may have 1 to 4 (inclusive) carbon atoms in it. Examples of alkyl groups include, but are not limited to, methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, isobutyl, sec- butyl, tert-butyl, isopentyl, neopentyl, and isohexyl. An alkyl group can be unsubstituted or substituted with one or more suitable groups. "Alkoxy" refers to the group alkyl-O- or -O-alkyl, where alkyl group is as defined above. Exemplary Ci-Cioalkyl group containing alkoxy groups include but are not limited to methoxy, ethoxy, n-propoxy, zso-propoxy, n-butoxy and i-butoxy. An alkoxy group can be unsubstituted or substituted with one or more suitable groups.

"Halogen" or "halo" includes fluorine, chlorine, bromine or iodine.

"Hydroxy" refers to -OH group.

"Oxo" refers to -C(O)-.

"Alkoxyalkyl" refers to an alkyl group substituted with one or more alkoxy groups; the alkyl group and alkoxy group are same as defined above, wherein one or more of the alkyl group's hydrogen atom has been replaced with alkoxy group. Representative examples of an alkoxyalkyl group include but are not limited to -CH₂OCH₃, -CH₂CH₂OCH₃, -CH₂OCH₂CH₃, -

CH₂CH₂OCH₂CH₃ and the like.

"Hydroxyalkyl" refers to an alkyl group substituted with one or more hydroxy groups; the alkyl group and hydroxy group are same as defined above, wherein one or more of the alkyl group's hydrogen atom has been replaced with hydroxy group. Representative examples of an hydroxyalkyl group includes but are not limited to -CH₂OH, -CH₂CH₂OH, -CH₂CH(OH)CH₃, -

CH₂CH(OH)CH₂CH₃ and the like.

"Aryl" refers to an optionally substituted monocylic, bicyclic or polycyclic aromatic hydrocarbon ring system of about 6 to 14 carbon atoms. Examples of a C₆-Ci4 aryl group include, but are not limited to phenyl, naphthyl, biphenyl, anthryl, tetrahydronaphthyl, fluorenyl, indanyl, biphenylenyl and acenaphthyl. Aryl group can be unsubstituted or substituted with one or more suitable groups;

"Arylalkyl" refers to an alkyl group, as defined above, wherein one or more of the alkyl group's hydrogen atom has been replaced with an aryl group as defined above. Examples of arylalkyl group include, but are not limited to benzyl, benzhydryl, 1-phenylethyl, 2-phenylethyl, 3-phenylpropyl, 2-phenylpropyl, 1-naphthylmethyl, 2-naphthylmethyl. An arylalkyl group can be unsubstituted or substituted with one or more suitable groups.

"Cycloalkyl" refers to a non-aromatic, saturated, monocyclic, bicyclic or polycyclic hydrocarbon ring system. Representative examples of a cycloalkyl include, but are not limited to cyclopropyl, cyclopentyl, cycloheptyl, cyclooctyl, decahydronaphthalen-l-yl, octahydro-lH- inden-2-yl and decahydro-lH-benzo[7] annulen-2-yl. A cycloalkyl can be unsubstituted or substituted with one or more suitable groups.

"Cyclyoalkylalkyl" refers to an alkyl group, as defined above, wherein one or more of the alkyl group's hydrogen atom has been replaced with cycloalkyl group as defined above. Representative examples of a cyclyoalkylalkyl group include, but are not limited to cyclopropylmethyl, cyclobutylmethyl, cyclohexylmethyl, cyclopentylmethyl, cyclohexylmethyl and the like. A cycloalkylalkyl group can be unsubstituted or substituted with one or more suitable groups.

The term "Heterocyclyl" includes the definitions of "heterocycloalkyl" and "heteroaryl". The term "Heterocycloalkyl" refers to a non-aromatic, saturated or partially saturated, monocyclic or polycyclic ring system of 3 to 10 member having at least one heteroatom or hetero group selected from O, N, S, S(O), S(0)₂, NH and C(O). Exemplary heterocycloalkyl groups include piperdinyl, piperazinyl, morpholinyl, thiomorpholinyl, 1,3-dioxolanyl, 1,4-dioxanyl and the like. A heterocycloalkyl group can be unsubstituted or substituted with one or more suitable groups.

"Heteroaryl" refers to an unsaturated, monocyclic, bicyclic, or polycyclic aromatic ring system containing at least one heteroatoms selected from oxygen, sulfur and nitrogen. Examples of C5-C10 heteroaryl groups include furan, thiophene, indole, azaindole, oxazole, thiazole, thiadiazole, isoxazole, isothiazole, imidazole, N-methylimidazole, pyridine, pyrimidine, pyrazine, pyrrole, N-methylpyrrole, pyrazole, N-methylpyrazole, 1,3,4-oxadiazole, 1,2,4-triazole, 1-methyl- 1,2,4-triazole, lH-tetrazole, 1-methyltetrazole, benzoxazole, benzothiazole, benzofuran, benzisoxazole, benzimidazole, N-methylbenzimidazole, azabenzimidazole, indazole, quinazoline, quinoline, and isoquinoline. Bicyclic heteroaryl groups include those where a phenyl, pyridine, pyrimidine or pyridazine ring is fused to a 5 or 6-membered monocyclic heterocyclyl ring having one or two nitrogen atoms in the ring, one nitrogen atom together with either one oxygen or one sulfur atom in the ring, or one O or S ring atom A heteroaryl group can be unsubstituted or substituted with one or more suitable groups.

"Heterocyclylalkyl" refers to an alkyl group, as defined above, wherein one or more of the alkyl group's hydrogen atom has been replaced with heterocyclyl group as defined above. Representative examples of a heterocyclylalkyl group include, but are not limited to tetrahydropyran-4yl-methyl-, thiazole-5yl-methyl-. 2-pyridinemethyl, 2-pyyrolidinemethyl and the like A heterocyclylalkyl group can be unsubstituted or substituted with one or more suitable groups.

"Hetero atom" refers to a sulfur, nitrogen or oxygen atom.

"Hetero group" refers to -C(O), -S(O), -NH and -S(0)₂.

"Monocyclic ring" refers to a saturated, partially saturated or unsaturated 3 to 7 membered ring, having 0-3 heteroatoms/heterogroups independently selected from N, O, S,-C(0), -S(O), - NH and -S(0)₂. Representative examples of a 3 to 7 membered ring include, but are not limited to cyclopropyl, cyclobutyl, cyclohexyl, azetidine, oxirane, phenyl, pyridyl, pyrazole, pyrimidine, piperizine, piperidine, morpholine, 1,2,3,6-tetrahydropyridine indazole and the like.

"Optionally substituted or substituted" as used herein means that at least one or two hydrogen atoms of the optionally substituted group has been substituted with suitable groups as exemplified but not limited to alkyl, alkenyl, alkoxy, alkynyl, aryl, amido, amino, carboxy, cyano, cycloalkyl, guanidine, halogen, imidamide, hydroxy, nitro, haloalkyl, haloalkoxy, heterocyclyl, oxo(=0), thio(=S), -P(0)₃H, -P(0)₂NH₂, -P(0)₂NH(alkyl), -P(0)₂NH(cycloalkyl),- P(0)₂NH(heterocyclyl), -P(0)₂NH(aryl), -C(0)(alkyl), -C(0)(aryl), -C(0)(cycloalkyl), - C(0)(heterocyclyl), or two substituents on the same carbon atom combined together to form an optionally substituted 3-8 member ring containing 0-3 heteroatoms independently selected form N, O and S in any stable combination.

In further yet another particular embodiment, the compounds and pharmaceutically compositions of the present invention are used in the treatment and/or prevention of diseases and/or disorders in which aberrant, abnormal or deregulated activity of bromodomain containing proteins contribute to the pathology and/or symptomology of such diseases and/or disorders. Such diseases and/or disorders mediated by one or more of these kinases are provided herein.

In further yet another particular embodiment, the compounds and pharmaceutically compositions of the present invention are used in the treatment and/or prevention of diseases and/or disorders in which aberrant, abnormal or deregulated activity of BET family of bromodomain containing proteins; in particular BRD2, BRD3, BRD4 and BRD-t proteins.

Bromodomain inhibitors are believed to be useful in the treatment of a variety of diseases or conditions related to systemic or tissue inflammation, inflammatory responses to infection or hypoxia, cellular activation and proliferation, lipid metabolism, fibrosis and in the prevention and treatment of viral infections. Bromodomain inhibitors may be useful in the treatment of a wide variety of chronic autoimmune and inflammatory conditions such as 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, myositis, eczema, dermatitis, alopecia, vitiligo, bullous skin diseases, nephritis, vasculitis, atherosclerosis, Alzheimer's disease, depression, retinitis, uveitis, scleritis, hepatitis, pancreatitis, primary biliary cirrhosis, sclerosing cholangitis, Addison's disease, hypophysitis, thyroiditis, type I diabetes and acute rejection of transplanted organs.

Bromodomain inhibitors may be useful in the treatment of a wide variety of acute inflammatory conditions such as acute gout, giant cell arteritis, nephritis including lupus nephritis, vasculitis with organ involvement such as glomerulonephritis, vasculitis including giant cell arteritis, Wegener's granulomatosis, Polyarteritisnodosa, Behcet's disease, Kawasaki disease, Takayasu's Arteritis, vasculitis with organ involvement and acute rejection of transplanted organs.

Bromodomain inhibitors may be useful in the prevention or treatment of diseases or conditions which involve inflammatory responses to infections with bacteria, viruses, fungi, parasites or their toxins, such as sepsis, sepsis syndrome, septic shock, endotoxaemia, systemic inflammatory response syndrome (SIRS), multi-organ dysfunction syndrome, toxic shock syndrome, acute lung injury, ARDS (adult respiratory distress syndrome), acute renal failure, fulminant hepatitis, burns, acute pancreatitis, post-surgical syndromes, sarcoidosis, Herxheimer reactions, encephalitis, myelitis, meningitis, malaria and SIRS associated with viral infections such as influenza, herpes zoster, herpes simplex and coronavirus.

Bromodomain inhibitors may be useful in the prevention or treatment of conditions associated with ischaemia-reperfusion injury such as myocardial infarction, cerebro- vascular 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.

Bromodomain inhibitors may be useful in the treatment of disorders of lipid metabolism via the regulation of APO-A1 such as hypercholesterolemia, atherosclerosis and Alzheimer's disease.

Bromodomain inhibitors may be useful in the treatment of fibrotic conditions such as idiopathic pulmonary fibrosis, renal fibrosis, post-operative stricture, keloid formation, scleroderma and cardiac fibrosis.

Bromodomain inhibitors may be useful in the prevention and treatment of viral infections such as herpes virus, human papilloma virus, adenovirus and poxvirus and other DNA viruses. Bromodomain inhibitors may be useful in the treatment of cancer, including hematological, epithelial including lung, breast and colon carcinomas, midline carcinomas, mesenchymal, hepatic, renal and neurological tumors.

In one embodiment the disease or condition for which a bromodomain inhibitor is indicated is selected from diseases associated with systemic inflammatory response syndrome, such as sepsis, burns, pancreatitis, major trauma, haemorrhage and ischaemia. In this embodiment the bromodomain inhibitor would be administered at the point of diagnosis to reduce the incidence of: SIRS, the onset of shock, multi-organ dysfunction syndrome, which includes the onset of acute lung injury, ARDS, acute renal, hepatic, cardiac and gastro-intestinal injury and mortality.

In another embodiment the bromodomain inhibitor would be administered prior to surgical or other procedures associated with a high risk of sepsis, haemorrhage, extensive tissue damage, SIRS or MODS (multiple organ dysfunction syndrome).

In a particular embodiment the disease or condition for which a bromodomain inhibitor is indicated is sepsis, sepsis syndrome, septic shock and endotoxaemia. In another embodiment, the bromodomain inhibitor is indicated for the treatment of acute or chronic pancreatitis. In another embodiment the bromodomain is indicated for the treatment of burns. In one embodiment the disease or condition for which a bromodomain inhibitor is indicated is selected from herpes simplex infections and reactivations, cold sores, herpes zoster infections and reactivations, chickenpox, shingles, human papilloma virus, cervical neoplasia, adenovirus infections, including acute respiratory disease, poxvirus infections such as cowpox and smallpox and African swine fever virus. In one particular embodiment a bromodomain inhibitor is indicated for the treatment of Human papilloma virus infections of skin or cervical epithelia.

The term "diseases or conditions for which a bromodomain inhibitor is indicated", is intended to include each of or all of the above disease states. While it is possible that for use in therapy, a compound of formula (1) as well as pharmaceutically acceptable salts thereof may be administered as the raw chemical, it is common to present the active ingredient as a pharmaceutical composition.

"Comprise" or "Comprising" is generally used in the sense of include, that is to say permitting the presence of one or more features or components.

"Pharmaceutically acceptable salt" or "pharmaceutically acceptable derivatives" is taken to mean an active ingredient, which comprises a compound of the formula ( 1 ) in the form of one of its salts, in particular if this salt form imparts improved pharmacokinetic properties on the active ingredient compared with the free form of the active ingredient or any other salt form of the active ingredient used earlier. The pharmaceutically acceptable salt form of the active ingredient can also provide this active ingredient for the first time with a desired pharmacokinetic property which it did not have earlier and can even have a positive influence on the pharmacodynamics of this active ingredient with respect to its therapeutic efficacy in the body.

The use of the term "including" as well as other forms, such as "include", "includes" and "included" is not limiting.

The term "therapeutically effective amount" means the amount of the subject compound that will elicit the biological or medical response of a tissue, system, animal or human that is being sought by the researcher, veterinarian, medical doctor or other clinician.

The compounds and pharmaceutically compositions of the present invention may be used in combination with other drugs that are used in the treatment/pre vention/suppression or amelioration of the diseases or conditions for which compounds of the present invention may be useful. Such other drugs may be administered, by a route and in an amount commonly used there for, contemporaneously or sequentially with a compound of the present invention. When a compound of the present invention is used contemporaneously with one or more other drugs, a pharmaceutical composition containing such other drugs in addition to the compound of the present invention may also be preferred. Accordingly, the pharmaceutical compositions of the present invention include those that also contain one or more other active ingredients, in addition to a compound of the present invention.

A pharmaceutical composition of the invention may be formulated as being compatible with its intended route of administration, which may preferably be an oral administration. For example the pharmaceutical compositions of the invention may be formulated for administration by inhalation, such as aerosols or dry powders; for oral administration, such in the form of tablets, capsules, gels, syrups, suspensions, emulsions, elixirs, solutions, powders or granules; for rectal or vaginal administration, such as suppositories; or for parenteral injection (including intravenous, subcutaneous, intramuscular, intravascular, or infusion) such as a sterile solution, suspension or emulsion.

The compounds of the present invention may also be entrapped in microcapsules prepared, for example, by coacervation techniques or by interfacial polymerization, for example, hydroxymethyl cellulose or gelatin-microcapsules and poly-(methylmethacylate) microcapsules, respectively, in colloidal drug delivery systems (for example, liposomes, albumin microspheres, microemulsions, nano -particles and nanocapsules) or in macroemulsions. Such techniques are disclosed in Remington's Pharmaceutical Sciences 16th edition, Osol, A. Ed. (1980).

The novel substituted imidazo[4,5-c]quinoline derivatives of formula (1) according to the present invention may be prepared from readily available starting materials using the following general methods and procedures. It will be appreciated that where typical or preferred experimental conditions (i.e. reaction temperatures, time, moles of reagents, solvents etc.) are given, other experimental conditions can also be used unless otherwise stated. Optimum reaction conditions may vary with the particular reactants or solvents used, but such conditions can be determined by the person skilled in the art, using routine optimization procedures. The specifics of the processes according to the present invention are detailed in the example section mentioned below.

In a further aspect, the compounds of the present invention can also contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute such compounds. For example, the present invention also embraces isotopically-labeled variants of the present invention which are identical to those recited herein, but for the fact that one or more atoms of the compound are replaced by an atom having the atomic mass or mass number different from the predominant atomic mass or mass number usually found in nature for the atom. All isotopes of any particular atom or element as specified are contemplated within the scope of the compounds of the invention, and their uses. Exemplary isotopes that can be incorporated in to compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, sulfur, fluorine, chlorine and iodine, such as ²H ("D"), ¾, ⁿC, ¹³C, ¹⁴C, ¹³N, ¹⁵N, ¹⁵0, ¹⁷0, ¹⁸0, ³²P, ³³P, ³⁵S, ¹⁸F, ³⁶C1, ¹²³I and ¹²⁵I. Isotopically labeled compounds of the present inventions can generally be prepared by following procedures analogous to those disclosed in the Schemes and/or in the examples herein below, by substituting an isotopically labeled reagent for a non-isotopically labeled reagent.

The abbreviations used in the entire specification may be summarized herein below with their particular meaning.

MeOH-Methanol; EtOH-Ethanol; DME-l,2-dimethoxyethane; DCM-Dichloromethane; DMF-N,N-Dimethylformamide; DMSO-Dimethylsulfoxide; CDCb-Deuterated chloroform; EtOAc-Ethyl acetate; THF-Tetrahydrofuran; TJuOH-tertiary butanol; AcOH-acetic acid; TEA- Triethylamine; TFA-trifluoroacetic acid; mL- milliliter; DAST-Diethylaminosulfurtrifluoride; EDC.HCl-l-Ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride; HOBt- 1 -Hydroxy benzotriazole; HATU-( l-[Bis(dimethylamino)methylene]-lH-l,2,3-triazolo[4,5-b]pyridinium3- oxid hexafluorophosphate; DIEA-diisopropylethylamine; TLC-Thin layer chromatography; KN03-Potassium nitrate; H2S04-Sulfuric acid; KOAc-Potassium acetate; NaOEt-Sodium ethoxide; Na2C03-Sodium carbonate; SnCl2.2H20-Stannous chloride dihydrate; POCI3- Phosphorousoxychloride; NaOH-Sodium hydroxide; HCl-Hydrochloric acid; Pd(pph3)4-Tetrakis (triphenylphosphine)palladium(O); Pd/C-Palladium on activated carbon; MnC -Manganese dioxide; fbO-Water; Fe-Iron powder; h-Hour; N-Normality; M-Molarity; s-Singlet; d-Doublet; dd-Doublet of a doublet; t-Triplet; m-Multiplet; 'HNMR-Proton nuclear magnetic resonance; MS- Mass spectroscopy; LC-Liquid chromatography; H-Proton; MHz-Mega hertz; Hz-Hertz; ppm- Parts per million; bs-Broad singlet; ES-Electro spray; Cone-Concentrated; g-Gram; mmol- Millimol.

Another embodiment of the present invention provides methods useful for making the compounds of formula (1) are set forth in the examples below and generalized in below scheme. One of skill in the art will recognize that the below scheme can be adapted to produce the compounds of formula ( 1) and pharmaceutically accepted salts of compounds of formula ( 1) according to the present invention. Wherein all symbols/variables are as defined earlier unless otherwise stated. The process is represented herein by below scheme.

GENERAL MODES OF PREPARATION

Compounds of this invention may be made by synthetic chemical processes, examples of which are shown herein. It is meant to be understood that the order of the steps in the processes may be varied, that reagents, solvents and reaction conditions may be substituted for those specifically mentioned, and that vulnerable moieties may be protected and deprotected, as necessary.

A general approach for the synthesis of compounds of general formula ( 1) is depicted in below scheme. As used herein the below scheme the terms 'Ri ', 'R₂', 'R3 ' , 'R4', 'R5' and 'n' represents all the possible substitutions as disclosed in formula (1) unless otherwise stated. Herein, the compounds of formula ( la), ( lb) and (lc) represent the compounds falling in the general formula (1). Any of the step disclosed herein may undergoes additional protection or deprotection steps as necessary.

As shown in the above scheme, the novel compounds of the present invention can be synthesized from formula ( 1.1). Formula ( 1.1) undergoes chlorination by using chlorinating agents such as POCI3, SOCb and the like in presence of suitable solvents such as DCM, DMF and the like at appropriate conditions, followed by N-alkylation by using suitable alkylamines in presence of suitable base such as TEA at suitable conditions to give formula (1.2). Formula ( 1.2) undergoes reduction in presence of catalyst such as 10% Pd-C/H₂ or SnCl₂.2H₂0/ Conc.HCl in presence of suitable solvents such as ethanol to give formula ( 1.3). Formula (1.3) undergoes amide coupling with appropriate acids in presence of suitable coupling reagents such as EDC.HCl/ HOBt or HATU/DIEA in presence of suitable base like TEA, in suitable solvents such as DCM, DMF and the like to give formula (1.4), which undergoes further cyclisation reaction in presence of acetic acid or potassium phosphate tribasic in presence of suitable solvents such as tet-butanol at appropriate conditions to give formula (1.5). Formula (1.5) undergoes oxidation in presence of Mn0₂ or Se0₂ in suitable solvents such as 1,4-dioxane at suitable conditions to give compounds of formula (la). Formula (la) further undergoes fluorination in presence of D AST ((Diethylamino)sulfurtrifluoride) at suitable solvents such as DCM and the like in suitable conditions to give compound of formula (lb). Alternatively, Formula (la) undergoes alkylation of carbonyl group in presence of appropriate Grignard reagent such as ethylmagnesiumbromide or organolithium reagent such as methyl lithium in presence of suitable solvents at suitable temperatures to give compound of formula (lc).

EXAMPLES

Although the invention has been illustrated by certain of the preceding examples, it is not to be construed as being limited thereby; but rather, the invention encompasses the generic area as hereinbefore disclosed. Various modifications and embodiments can be made without departing from the spirit and scope thereof.

The MS data provided in the examples described below were obtained as follows:

Mass spectrum: LC/MS Agilent 6120 Quadrapole LC/MS.

The NMR data provided in the examples described below were obtained as follows:

^!H NMR spectra were recorded on a Varian 400 MHz (Varian Mercury Plus) or 500 MHz

(Unity INOVA) spectrometers with DMSO-d₆ or CDCI3 as the solvents. Chemical shifts were reported in δ scale using tetramethylsilane (TMS, d 0.00) as internal standard and coupling constants (J) were reported in Hz.

The procedure for the compounds of formula (1) are detailed herein below stepwise including the general synthesis of various intermediates involved in process of manufacture of the compounds according to the present invention.

Intermediate-I: 7-(3. 5-dimethylisoxazol-4-yl)-6-methoxy-3-nitroquinolin-4-ol

Step-a: 4-bromo-5-fluoro-2-nitrobenzoic acid

To a stirred solution of 4-bromo-3-fluoro benzoic acid (2.0 g, 9.13 mmol) in sulphuric acid (15 mL), was added potassium nitrate (1.0 g, 10.04 mmol) in portions. The reaction mixture was stirred at 25-35°C for 16h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was poured slowly into the crushed ice and the solid formed was filtered off, washed with water and dried under vacuum to get the crude compound as pale yellow solid (2.0 g, 82%). ¾ NMR (400 MHz, DMSO-d₆) δ 8.51 (d, J=5.8 Hz, 1H), 7.90 (d, J=8.3 Hz, 1H); LC-MS: m/z264 (M+l)⁺.

Step-b: methyl 4-bromo-5-fluoro-2-nitrobenzoate

To a stirred solution of 4-bromo-5-fluoro-2-nitrobenzoic acid (2.0 g, 7.57 mmol) in methanol (20 mL) was added sulphuric acid (2 mL) at 0°C. The reaction mixture was heated to 80°C for 16h.The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was cooled to 25-35°C and methanol was concentrated under reduced pressure. The residue was diluted with ethyl acetate and washed with saturated sodium- bi-carbonate followed by brine. The organic layer was dried over sodium sulfate and evaporated under vacuum to get the desired crude product as pale yellow solid (1.8 g, 85%). ¾ NMR (400 MHz, CDCls) δ 8.20 (d, J=5.8 Hz, 1H), 7.47 (d, J=7.8 Hz, 1H), 3.94 (s, 3H); LC-MS: m/z 279 (M+l)⁺.

Step-c: methyl 4-bromo-5-methoxy-2-nitrobenzoate

To a stirred solution of methyl 4-bromo-5-fluoro-2-nitrobenzoate (1.2 g, 4.31 mmol) in methanol (12 mL) at 0°C was added sodium methoxide (0.7 g, 12.93 mmol) and then allowed to stir at 25-35°C for 16h. The progress of the reaction was monitored by TLC. After completion of the reaction, methanol was evaporated under vacuum. The residue was diluted with ethyl acetate and washed with water. Organic layer was dried over sodium sulfate and evaporated the solvent under vacuum to get the desired crude product as pale yellow solid. (0.9 g, 72%). ^!H NMR (400 MHz, CDCls) δ 8.26 (s, 1H), 7.06 (s, 1H), 4.02 (s, 3H), 3.94 (s, 3H); LC-MS: m/z 289 (M-l)\ Step-d: methyl 2-amino-4-bromo-5-methoxybenzoate.

To a stirred solution of methyl 4-bromo-5-methoxy-2-nitrobenzoate (4.0 g, 13.79 mmol) in ethanol (40 mL), was added water (20 mL), ammonium chloride (2.21 g, 41.37 mmol) and iron powder (3.85 g, 68.95 mmol) then heated to 110°C for 3h. The progress of the reaction was monitored by TLC. After completion of the reaction, the mixture was cooled to 25-35°C, then filtered through celite and washed with ethyl acetate. The filtrate was evaporated under vacuum. The residue was diluted with ethyl acetate and washed with water and dried over sodium sulfate and evaporated under vacuum to get the desired crude product as yellow solid (2.8 g, 78%). ^!H NMR (400 MHz, DMSO-d₆) δ 7.26 (s, 1H), 7.11 (s, 1H), 6.41 (s, 2H), 3.80 (s, 3H), 3.73 (s, 3H); LC-MS : m/z 260 (M+ 1 )⁺.

Step-e: 2-amino-4-bromo-5-methoxybenzoic acid

To a stirred solution of methyl 2-amino-4-bromo-5-methoxybenzoate (2.8 g, 10.76 mmol) in methanol (20 mL) was added 3N sodium hydroxide (20 mL). The reaction mixture was stirred at 25-35°C for 2h. The progress of the reaction was monitored by TLC. After the reaction was completed methanol was evaporated under vacuum. The residue was diluted with water and acidified with HC1 and the solid formed was filtered off, washed with water and dried under vacuum to get the crude compound as pale yellow solid (2.4 g, 90%). ¾ NMR (400 MHz, DMSO-de) δ 8.5 (bs, 2H), 7.27 (s, 1H), 7.07 (s, 1H), 3.72 (s, 3H); LC-MS: m/z 244 (M-2)\

Step-f: 4-bromo-5-methoxy-2-((2-nitrovinyl)amino)benzoic acid

Nitro methane (2.6 mL, 48.75 mmol) was added slowly to a solution of sodium hydroxide

(2.80 g, 70.2 mmol) in water (10 mL) drop wise. The solution slowly turned into reddish-brown color which was then heated to 50°C on water bath for 5 min. The solution poured into ice water (50 mL). Then concentrated HC1 (20 mL) and 2-amino-4-bromo-5-methoxybenzoic acid (2.4g, 9.75mmol) was added to the reaction mixture and it was stirred at 25-35°C for 16h. The solid was filtered off, washed with water and dried under vacuum to get the crude compound as yellow solid (2.1 g, 68%). Ή NMR (400 MHz, DMSO-d₆) δ 14.1 (bs, 1H), 12.88 (d, J=13.7Hz, 1H), 8.11 (s, 1H), 8.08-7.99 (m, 1H), 7.56 (s, 1H), 6.71 (d, J=6.4Hz, 1H), 3.89 (s, 3H); LC-MS: m/z 317 (M+l)⁺.

Step-g: 7-bromo-6-methoxy-3-nitroquinolin-4-ol

To a suspension of 4-bromo-5-methoxy-2-((2-nitrovinyl)amino)benzoic acid (2.1 g, 6.62 mmol) in acetic anhydride (20 mL) was added potassium acetate (0.78 g, 7.94 mmol) and heated to 140°C for 3h. The progress of the reaction was monitored by TLC. After reaction was completed, it was poured slowly into ice water and the solid was filtered off, washed with water, acetic acid (lOmL), and dried under vacuum to get the crude compound as dark brown solid (1.2 g, 60%). Ή NMR (400 MHz, DMSO-d₆) δ 12.94 (s, 1H), 9.17 (s, 1H), 7.98 (s, 1H), 7.71 (s, 1H), 3.98 (s, 3H); LC-MS: m/z 299 (M+l)⁺.

Step-h: 7-(3, 5-dimethylisoxazol-4-yl)-6-methoxy-3-nitroquinolin-4-ol

To a solution of 7-bromo-6-methoxy-3-nitroquinolin-4-ol (4.0 g, 13.37 mmol) in 1,2- dimethoxyethane (40 mL) and water (20 mL) was added sodium carbonate (4.25 g, 40.12 mmol) followed by 3,5-dimethylisoxazole-4-boronic acid (5.7 g, 40.12 mmol). The above mixture was degassed with nitrogen for 15 min then added Pd(PPh₃)₄ (1.55 g, 1.33 mmol) and heated to 100°C for 16h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was cooled to 25-35°C and water was added and extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate and evaporated under vacuum to get the desired crude product. Crude product was purified by column chromatography using 60-120 mesh silica gel and 5% methanol-DCM as eluent to get the pure product as brown solid (2.3 g, 54%). ¾ NMR (400 MHz, DMSO-d₆) δ 12.96 (bs, 1H), 9.18 (s, 1H), 7.78 (s, 1H), 7.61 (s, 1H), 3.92 (s, 3H), 2.32 (s, 3H), 2.12 (s, 3H); LC-MS: m/z 314 (M-l)\

Intermediate-II: 4-(8-methoxy-2-(pyridin-3-ylmethyl)-lH-imidazo[4,5-clquinolin-7-yl)-3,5-di methylisoxazole

Step-a: 4-(4-chloro-6-methoxy-3-nitroquinolin-7-yl)-3,5-dimethylisoxazole

POCI3 (5 mL) was added to 7-(3,5-dimethylisoxazol-4-yl)-6-methoxy-3-nitroquinolin-4-ol (0.18 g, 0.57 rnmol; intermediate-I) and heated to 90°C for 16h. The progress of the reaction was monitored by TLC. After reaction was completed, POCI3 was distilled off and the residue was quenched with saturated aqueous sodium bicarbonate and extracted with ethyl acetate. The organic layer dried over sodium sulfate and evaporated under vacuum to get the desired crude product which was purified by column chromatography using 60-120 mesh silica gel and 20% ethyl acetate-hexane as an eluent to get the product as yellow solid (0.14 g, 73%). ¾ NMR (400 MHz, DMSO-de) δ 9.28 (s, 1H), 8.15 (s, 1H), 7.74 (s, 1H), 4.05 (s, 3H), 2.36 (s, 3H), 2.15 (s, 3H); LC-MS: m/z 334 (M+l)⁺.

Alternatively this reaction can be performed by using other chlorinating agents such as thionyl chloride and the like.

Step-b: 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- dimethylisoxazole (0.5 g, 1.5 mmol,) in acetonitrile (5 mL), 4-methoxybenzylmine (0.22 mL, 1.65 mmol)was added. The reaction mixture was heated to 60°C for lh. The progress of the reaction was monitored by TLC. After completion of the reaction, it was cooled to 25-30°C and acetonitrile was removed. The residue was diluted with ethyl acetate and washed with water. The organic layer was washed with brine, dried over sodium sulfate and evaporated under vacuum to get the desired crude product which was purified by column chromatography using 100-200 mesh silica gel and 20% ethyl acetate-hexane as eluent to get pure product as yellow solid (0.4 g, 61%). Ή NMR (400 MHz, DMSO-d₆) δ 9.20 (m, 1H), 8.88 (s, 1H), 7.91 (s, 1H), 7.78 (s, 1H), 7.26 (d, J=8.3 Hz, 2H), 6.91 (d, J=8.8 Hz, 2H), 4.80 (d, J=5.9 Hz, 2H), 3.80 (s, 3H), 3.72 (s, 3H), 2.32 (s, 3H), 2.12 (s, 3H); LC-MS: m/z 435 (M+l)⁺.

Step-c: 7-(3, 5-dimethylisoxazol-4-yl)-6-methoxy-N⁴-(4-methoxybenzyl)quinoline-3,4-diamine

To a solution of 7-(3,5-dimethylisoxazol-4-yl)-6-methoxy-N-(4-methoxybenzyl)-3-nitro quinolin-4-amine (0.4 g, 0.92 mmol) in ethanol was added stannous chloride-dihydrate (0.83 g, 3.68 mmol) and concentrated HC1 (0.4 mL). The reaction mixture was heated to 60°C for lh. The progress of the reaction was monitored by TLC. After the reaction was completed, it was cooled to 25-30°C, quenched with aqueous sodium hydroxide and extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate and evaporated under vacuum to get the desired crude product as a brown solid (0.35g, 94%), which was used in the next step without further purification; LC-MS: m/z 405 (M+l)⁺.

Alternatively this reaction can be performed by hydro genation in presence of 10% Pd- C/H₂ and the like.

Step-d: N-(7-(3,5-dimethylisoxazol-4-yl)-6-methoxy-4-((4-methoxybenzyl)amino)quinolin-3-yl)- 2- (pyr idin-3 - yPacetamide

To a solution of 7-(3,5-dimethylisoxazol-4-yl)-6-methoxy-N⁴-(4-methoxybenzyl) quinoline-3,4-diamine (0.37 g, 0.92 mmol) in dichloromethane were added EDC.HC1 (0.57 g, 2.74 mmol), 1 -hydro xybenzotriazole (0.37 g, 2.74 mmol), triethylamine (0.44 mL, 3.2 mmol) and pyridine-3-acetic acid hydrochloride (0.24 g, 1.37 mmol). The reaction mixture stirred at 25-35°C for 16h. The progress of the reaction was monitored by TLC. After the reaction was completed, it was diluted with DCM and the organic layer was washed with water, dried over sodium sulfate and evaporated under vacuum to get the desired crude product as a brown solid (0.4 g, 83%), which was used in the next step without further purification. LC-MS: m/z 524 (M+l)⁺.

Step-e: 4-(8-methoxy-l-(4-methoxybenzyl)-2-(pyridin-3-ylmethyl)-lH-imidazo[4,5-clquinolin-7- yl)-3,5-dimethylisoxazole

A solution of N-(7-(3,5-dimethylisoxazol-4-yl)-6-methoxy-4-((4-methoxybenzyl)amino) quinolin-3-yl)-2-(pyridin-3-yl)acetamide (0.4 g, 0.76 mmol) in acetic acid (4 mL) was heated to 100°C for 16h. The progress of the reaction was monitored by TLC. After the reaction was completed, it was cooled to 25-35°C and the solvent was evaporated under vacuum to get the desired crude product which was purified by column chromatography using 100-200 mesh silica gel and 3% MeOH in DCM as eluent to get the pure product as off white solid (0.35 g, 90%). *H NMR (400 MHz, DMSO-de) δ 9.0 (s, 1H), 8.54 (d, J=1.9 Hz, 1H), 8.44-8.42 (m, 2H), 7.91 (s, 1H), 7.79 (s, 1H), 7.32-7.29 (m, 1H), 7.05 (d, J=8.8 Hz, 2H), 6.83 (d, J=8.3 Hz, 2H), 5.7 (s, 2H), 4.51 (s, 2H), 3.97 (s, 3H), 3.69 (s, 3H), 2.32 (s, 3H), 2.12 (s, 3H); LC-MS: m/z 506 (M+l)⁺.

Step-f: 4-(8-methoxy-2-(pyridin-3-ylmethyl)-lH-imidazo[4,5-clquinolin-7-yl)-3,5-dimethyl isoxazole

A solution of 4-(8-methoxy-l-(4-methoxybenzyl)-2-(pyridin-3-ylmethyl)-lH-imidazo[4,

5-c]quinolin-7-yl)-3,5-dimethylisoxazole (0.25 g, 0.49 mmol) in trifluoro acetic acid (2 mL) was heated to 100°C for lh. The progress of the reaction was monitored by TLC. After the reaction was completed, it was cooled to 25-35°C, neutralized with aqueous sodium bicarbonate and extracted the aqueous layer with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate and evaporated under vacuum to get the desired crude product which was purified by column chromatography using 100-200 mesh silica gel and 3% MeOH in DCM as eluent to get the pure product as off white solid (0.08 g, 39%). ¾ NMR (400 MHz, DMSO-d₆) δ 13.51 (s, 1H), 9.01 (s, 1H), 8.64( d, J=2 Hz, 1H), 8.5-8.48 (m, 1H), 7.91 (s, 1H), 7.82-7.76 (m, 2H), 7.40-7.37 (m, 1H), 4.41 (s, 2H), 3.96 (s, 3H), 2.32 (s, 3H), 2.12 (s, 3H); LC-MS: m/z 386 (M+l)⁺.

The below intermediates were prepared by procedure similar to the one described in intermediate-II till step-e, by using appropriate amines (reactant A), appropriate acids (reactant B) and suitable reagents under suitable reaction conditions. The physiochemical characteristics of the intermediates are summarized herein below table.

* Intermediate VII undergoes an additional reaction of protection of hydroxy group by teri-butyldimethylsilylchloride in presence of imidazole and dichloromethane solvent at appropriate conditions.

Example-A: Synthesis of (7-(3,5-dimethylisoxazol-4-yl)-8-methoxy-lH-imidazor4,5-clquinolin- 2-yl)(pyridin-3-yl)methanone (Compound- 1 )

To a solution of 4-(8-methoxy-2-(pyridin-3-ylmethyl)-lH-imidazo[4,5-c]quinolin-7-yl)- 3,5-dimethylisoxazole (0.06 g, 0.16 mmol) (intermediate-II) in 1,4-dioxane (6 mL) was added manganese dioxide (0.054 g, 0.62 mmol). The reaction mixture heated to 60°C for 4h. The progress of the reaction was monitored by TLC. After the reaction was completed, it was cooled to 25-35°C, then filtered through celite and washed with ethyl acetate. The filtrate was evaporated under vacuum to get the desired crude product which was purified by column chromatography using 60-120 mesh silica gel and 2% MeOH-DCM as eluent to get the pure product as pale yellow solid (0.01 g, 16%). Ή NMR (400 MHz, DMSO-d₆) δ 14.84 (bs, 1H), 9.69 (s, 1H), 9.28 (s, 1H), 8.91-8.87 (m, 2H), 8.63 (s, 1H), 8.01 (s, 1H), 7.72-7.69 (m, 1H), 4.0 (s, 3H), 2.35 (s, 3H), 2.15 (s, 3H); LC-MS: m/z 400 (M+l)⁺.

The below compounds were prepared by procedure similar to the one described in Example-A with appropriate variations in reactants, reagents under suitable reaction conditions. The physiochemical characteristics of the compounds are summarized herein below table.

δ 9.33 (d, J=2.0 Hz, IH), 9.27 (s, IH), 8.89

(dd, Ji=1.4 Hz & J₂=4.9 Hz, IH), 8.54 (dd, Ji=1.9 Hz & J₂=6.4 Hz, IH), 8.11 (s, IH), 7.81 (s, IH), 7.69-7.66 (m, IH), 5.19 (d, J=6.8 Hz,

8. IX

2H), 4.06 (s, 3H), 3.82-3.79 (m, 2H), 3.24 (t, J=11.3 Hz, 2H), 2.44-2.32 (m, IH), 2.37 (s, 3H), 2.17 (s, 3H), 1.54-1.42 (m, 4H); LC-MS: m/z 498.3 (M+l)⁺.

δ 9.42 (d, J=1.5 Hz, IH), 9.33 (s, IH), 8.90 (dd, Ji=1.5 Hz & J₂=4.9 Hz, IH), 8.63 (dd, Ji=2.0 Hz & J₂=3.9 Hz, IH), 8.03 (s, IH),

9. X 7.70-7.67 (m, IH), 7.47 (s, IH), 7.41-7.37 (m,

2H), 7.34-7.30 (m, 3H), 6.37 (s, 2H), 3.63 (s, 3H), 2.28 (s, 3H), 2.08 (s, 3H); LC-MS: m/z 490.2 (M+l)⁺.

δ 9.32 (d, J=1.9 Hz, IH), 9.22 (s, IH), 8.92 (dd, Ji=1.5 Hz & J₂=6.3 Hz, IH), 8.55-8.53 (m, IH), 8.11 (s, IH), 7.86 (s, IH), 7.69 (dd,

10. XI Ji=4.9 Hz & J₂=7.9 Hz, IH), 5.73-5.69 (m,

IH), 4.07 (s, 3H), 2.36 (s, 3H), 2.17 (s, 3H), 1.84 (d, J=6.8 Hz, 6H); LC-MS: m/z 442.2 (M+l)⁺.

δ 9.31 (d, J=1.5 Hz, IH), 9.25 (s, IH), 8.89- 8.88 (m, IH), 8.54-8.52 (m, IH), 8.08 (s, 2H), 7.69-7.66 (m, IH), 5.27 (t, J=5.3 Hz, 2H), 4.04

11. XII

(s, 3H), 4.02-4.01 (m, 2H), 3.22 (s, 3H), 2.36 (s, 3H), 2.17 (s, 3H); LC-MS: m/z 458.2 (M+l)⁺. δ 9.32 (s, 1H), 9.22 (s, 1H), 8.55 (dd, Ji=2.0

Hz & J₂=2.0 Hz, 1H), 8.02 (s, 1H), 7.45 (s, 1H), 7.40-7.36 (m, 2H), 7.33-7.27 (m, 3H),

12. XIII

7.06 (d, J=8.8 Hz, 1H), 6.33 (s, 2H), 4.02 (s, 3H), 3.60 (s, 3H), 2.28 (s, 3H), 2.08 (s, 3H); LC-MS: m/z 520.2 (M+l)⁺.

δ 9.31 (s, 1H), 8.30-8.28 (m, 2H), 8.02 (s, 1H), 7.78 (t, J=7.3 Hz, 1H), 7.65 (t, J=7.8 Hz, 2H),

13. XIV 7.46 (s, 1H), 7.40-7.37 (m, 1H), 7.33-7.26

(m,4H), 6.32 (s, 2H), 3.63 (s, 3H), 2.29 (s, 3H), 2.08 (s, 3H); LC-MS: m/z 489.2 (M+l)⁺. δ 9.31 (s, 1H), 8.42 (dd, Ji=5.9 Hz & J₂=8.8 Hz, 2H), 8.02 (s, 1H), 7.51-7.45 (m, 3H), 7.40-

14. XV 7.36 (m, 2H), 7.33-7.27 (m, 3H), 6.31 (s, 2H),

3.63 (s, 3H), 2.28 (s, 3H), 2.08 (s, 3H);

LC-MS: m/z 507.2 (M+l)⁺ .

δ 9.20 (s, 1H), 8.80 (d, J=2.4 Hz, 1H), 8.31 (dd, Ji=4.4 Hz & J₂=8.8 Hz, 1H), 8.10 (s, 1H), 8.07-8.04 (m, 1H), 7.79 (s, 1H), 5.08 (d, J=7.4

15. XVI Hz, 2H), 4.06 (s, 3H), 3.80-3.78 (m, 2H), 3.24

(t, J=10.8 Hz, 2H), 2.40-2.30 (m, 1H), 2.37 (s, 3H), 2.18 (s, 3H), 1.57-1.54 (m, 2H), 1.41-1.39 (m, 2H); LC-MS: m/z 516.2 (M+l)⁺.

δ 9.25 (s, 1H), 8.19 (d, J=7.3 Hz, 2H), 8.10 (s, 1H), 7.80-7.75 (m, 2H), 7.65-7.61 (m, 2H), 5.13 (d, J=7.3 Hz, 2H), 4.05 (s, 3H), 3.78-3.76

16. XVII

(m, 2H), 3.22 (t, J=10.6 Hz, 2H), 2.37 (s, 3H), 2.32 (m, 1H), 2.17 (s, 3H), 1.53-1.50 (m, 2H), 1.39-1.36 (m, 2H); LC-MS: m/z 497.3 (M+l)⁺. δ 9.25 (s, 1H), 8.33-8.30 (m, 2H), 8.10 (s, 1H),

7.80 (s, 1H), 7.47 (t, J=8.8 Hz, 2H), 5.13 (d, J=7.3 Hz, 2H), 4.05 (s, 3H), 3.79-3.73 (m, 2H),

17. XVIII

3.22 (t, J=10.7 Hz, 2H), 2.37 (s, 3H), 2.33-2.32 (m, 1H), 2.17 (s, 3H), 1.53-1.50 (m, 2H), 1.43- 1.36 (m, 2H); LC-MS: m/z 515.3 (M+l)⁺.

δ 9.19 (s, 1H), 8.78 (d, J=4.9 Hz, 1H), 8.16- 8.11 (m, 2H), 8.10 (s, 1H), 7.79 (s, 1H), 7.75- 7.72 (m, 1H), 5.07 (d, J=7.3 Hz, 2H), 4.06 (s,

18. XIX 3H), 3.83-3.78 (m, 2H), 3.24 (t, J=9.8 Hz, 2H),

2.37 (s, 3H), 2.34-2.30 (m, 1H), 2.18 (s, 3H), 1.58-1.55 (m, 2H), 1.44-1.38 (m, 2H); LC-MS: m/z 498.3 (M+l)⁺.

δ 9.30 (s, 1H), 8.33 (d, J=8.8 Hz, 2H), 8.02 (s, 1H), 7.44 (s, 1H), 7.36 (d, J=7.8 Hz, 2H), 7.32- 7.28 (m, 1H), 7.25 (d, J=6.8 Hz, 2H), 7.18 (d,

19. XX

J=8.8 Hz, 2H), 6.27 (s, 2H), 3.91 (s, 3H), 3.63 (s, 3H), 2.28 (s, 3H), 2.07 (s, 3H); LC-MS: m/z 519.2 (M+l)⁺.

δ 9.24 (s, 1H), 9.08 (s, 1H), 8.81 (d, J=4.4 Hz, 1H), 8.23-8.21 (m, 1H), 8.12 (m, 1H), 8.06 (s,

20. XXI 1H), 7.98 (s, 1H), 7.70 (m, 1H), 7.69 (s, 1H),

6.56 (s, 2H), 3.90 (s, 3H), 2.32 (s, 3H), 2.12 (s, 3H); LC-MS: m/z 497.1 (M+l)⁺.

* Compound 6 undergoes additional step of deprotection of teri-butyldimethylsilyl chloride in presence of 3N HCl in THF solvent to give compound 6.

Example-B: Synthesis of 4-(2-(difluoro(pyridin-3-yl)methyl)-8-methoxy-lH-imidazor4,5-cl quinolin-7-yl)-3,5-dimethylisoxazole (Compound-21)

Conditions: Diethylamino sulfur trifluoride (DAST), DCM, 0°C to 25-35°C, 16-48h.

To a solution of (7-(3,5-dimethylisoxazol-4-yl)-8-methoxy-lH-imidazo[4,5-c]quinolin-2- yl)(pyridin-3-yl)methanone (0.01 g, 0.025 mmol) in dichloromethane (2 mL) at 0°C was added diethylaminosulfurtrifluoride (0.01 mL, 0.075 mmol). The reaction mixture was stirred at 25-35°C for 16h. The progress of the reaction was monitored by TLC. After the reaction was completed, it was diluted with DCM and the organic layer was washed with saturated sodium bi carbonate, water; dried over sodium sulfate and evaporated under vacuum to get the desired crude product which was purified by column chromatography using 60-120 mesh silica gel and 2 % MeOH- DCM as eluent to get the pure product as yellow solid (0.003 g, 28%). ¾ NMR (400 MHz, DMSO-de) δ (14.6 (bs, 1H), 9.12 (s, 1H), 8.95 (s, 1H), 8.82 (s, 1H), 8.14 (m, 1H), 7.93 (m, 2H), 7.62 (m, 1H), 3.99 (s, 3H), 2.33 (s, 3H), 2.13 (s, 3H); LC-MS: m/z 422 (M+l)⁺.

The below compounds were prepared by procedure similar to the one described in Example-B with using appropriate starting compound, quantities of reagents and reaction conditions. The physiochemical characteristics of the compounds are summarized herein below table.

Example-C: Synthesis of l-(7-(3,5-dimethylisoxazol-4-yl)-8-methoxy-l-methyl-lH-imidazor4, 5-clquinolin-2-yl)-l-(pyridin-3-yl)ethanol (Compound-32 & Compound-33) mer-1

mer-2

Conditions: (i) Methyl lithium, THF, -78°C to 25-35°C, 2h.

To a solution of (7-(3,5-dimethylisoxazol-4-yl)-8-methoxy-l -methyl- lH-imidazo[4,5- c]quinolin-2-yl)(pyridin-3-yl)methanone (0.06 g, 0.145 mmol) in THF (3mL) at -78°C was added methyl lithium 1.6M in diethyl ether (0.11 mL, 0.17 mmol). The reaction mixture was stirred at 25-35°C for 2h. The progress of the reaction was monitored by TLC. After the reaction was completed, it was quenched with saturated ammonium chloride and extracted with ethyl acetate. The organic layer was dried over sodium sulfate and evaporated under vacuum to get the desired crude product which was purified by column chromatography using 60-120 mesh silica gel and 2 % MeOH-DCM as eluent to get the pure racemic compound as off white solid (0.03 g, 48%) which was further purified by chiral HPLC to get pure enantiomers as off white solid as isomer- 1 (0.008 g) and isomer-2 (0.01 g). Ή NMR (400 MHz, DMSO-d₆) δ 9.15 (s, 1H), 8.52-8.50 (m, 2H), 7.99 (s, 1H), 7.82 (s,lH), 7.66-7.64 (m, 1H), 7.40-7.37 (m, 1H), 6.92 (s, 1H), 4.11 (s, 3H), 3.95 (s, 3H), 2.32 (s, 3H), 2.12 (s, 3H), 2.07 (s, 3H); LC-MS: m/z 430 (M+l)⁺.

Compound-32 (Isomer-1): RT= 6.61 min, ee=99.93%,

Compound-33 (Isomer-2): RT= 11.07 min, ee=100%.

Example-D: Synthesis of l-(4-chlorophenyl)-l-(7-(3,5-dimethylisoxazol-4-yl)-8-methoxy-l- methyl- -imidazo[4,5-clquinolin-2-yl)propan-l-ol (Compound-34 & 35)

Conditions: Ethylmagnesiumbromide(lM in THF), THF, 0°C to 25-35°C, 16h. To a solution of (4-chlorophenyl)(7-(3,5-dimethylisoxazol-4-yl)-8-methoxy-l-methyl-lH- imidazo[4,5-c]quinolin-2-yl)methanone (0.1 g, 0.22 mmol) in THF (10 mL) at 0°C was added ethyl magnesium bromide (1.0 M in tetrahydrofuran) (1.1 mL, 1.11 mmol). The reaction mixture was stirred at 25-35°C for 16h. The progress of the reaction was monitored by TLC. After the reaction was completed, it was quenched with saturated ammonium chloride and extracted with ethyl acetate. The organic layer was dried over sodium sulfate and evaporated under vacuum to get the desired crude product which was purified by column chromatography using 100-200 mesh silica gel and 3 % MeOH-DCM as eluent to get the pure racemic compound as off white solid (0.05 g, 47%) which was further purified by chiral HPLC to get pure enantiomers as white solid Isomer- 1 (0.008 g) and Isomer-2 (0.008 g). Ή NMR (400 MHz, DMSO-de) δ 9.14 (s, 1H), 7.97 (s, 1H), 7.80 (s, 1H), 7.41 (d, J=8.8 Hz, 2H), 7.26 (d, J=8.8 Hz, 2H), 6.51 (s, 1H), 4.07 (s, 3H), 3.94 (s, 3H), 2.67-2.54 (m, 1H), 2.43-2.33 (m, 1H), 2.31 (s, 3H), 2.11 (s, 3H), 0.83 (t, J=7.40 Hz, 3H); LC-MS: m/z 477 (M+l)⁺.

Compound-34 (Isomer-1): RT= 11.31 min, ee=99.91%,

Compound-35 (Isomer-2): RT= 23.09 min, ee=99.66%.

The below compounds were prepared by procedure similar to the one described in

Example-D with appropriate starting compound, reagents under suitable reaction conditions. The physiochemical characteristics of the compounds are summarized herein below table.

Compound-36 (Isomer- 1):RT=10.66 min, ee=99.60%;

Compound-37 (Isomer-2): RT=16.87 min, ee=99.26%. In Examples C and D, the compounds were purified by chiral HPLC; the conditions for chiral preparative HPLC are as follows:

Column: Chiral pak AD; Column Dimension: (150-250 x 4.6 mm); 5μπι; Mobile phase A: n-hexane; B: EtOH (70:30 or 60:30 or 50:50); Flow Rate: 0.8 mL/min; Wavelength: 257 nm.

Example-E: Synthesis of 4-(8-methoxy-l-methyl-2-(l-(pyridin-3-yl)cyclopropyl)-lH-imidazor4, 5-clquinolin-7-yl)-3,5-dimethylisoxazole (Compound-38)

Conditions: (i) HATU, DIEA, DCM, 25-35°C, 16h; (ii) Acetic acid, 100°C, 4h;

Step-(i): N-(7-(3,5-dimethylisoxazol-4-yl)-6-methoxy-4-(methylamino)quinolin-3-yl)-l-(pyridin- 3-yl)cyclopropanecarboxamide

A process of this step was adopted from step-d of Intermediate-II to get the desired crude compound as brown oil (0.13 g); LC-MS: m/z 444.2 (M+l)⁺.

Step-(ii): 4-(8-methoxy-l-methyl-2-(l-(pyridin-3-yl)cyclopropyl)-lH-imidazor4,5-clquinolin-7- yl)-3,5-dimethylisoxazole

A process of this step was adopted from step-e of Intermediate-II to get the crude compound which was purified by preparative HPLC to get the pure product as white solid (0.02 g, 34%). Ή NMR (400 MHz, DMSO-de) δ 9.08 (s, 1H), 8.44 (dd, Ji=1.5 Hz & J₂=4.4 Hz, 1H), 8.30 (d, J=1.9 Hz, 1H), 7.98 (s, 1H), 7.85 (s, 1H), 7.50 (dd, Ji=6.4 Hz & J₂=8.8 Hz, 1H), 7.34 (dd, Ji=4.9 Hz & J₂=8.3 Hz, 1H), 4.18 (s, 3H), 3.98 (s, 3H), 2.33 (s, 3H), 2.13 (s, 3H), 1.73-1.70 (m, 4H); LC-MS: 426.2 (M+l)⁺.

PHARMACOLOGICAL DATA:

In-Vitro: Biochemical Data of Imidazo[4,5-C]quinoline derivatives in time-resolved fluorescence resonance energy transfer (TR-FRET) assay. The BET bromodomain TR-FRET assay has been used to identify compounds that bind to BET bromodomain and prevent its interaction with acetylated histone peptides.

In the assay, optimized concentration of in-house BET bromodomain protein and 300 nM of acetyl histone peptide substrate were diluted in assay buffer (50 mM HEPES, pH: 7.5, 50 mM NaCl, 500 μΜ CHAPS) and were added to the positive control and test control wells in a 384 well plate. Substrate control wells have 300 nM of acetyl histone peptide substrate diluted in assay buffer. Buffer blank wells were added with assay buffer. The reaction mixture was allowed for incubation at room temperature for 30mins. Stock solutions of test compounds at 20 mM DMSO are prepared. Compounds are serially diluted and added to the test wells in 384- well polypropylene plates. The reaction mixture was further incubated for 30mins at room temperature on a plate shaker. 2 nM of Europium labeled streptavidn and 10 nM of XL-665 labeled antibody diluted in detection buffer (50mM HEPES, P^H: 7.5, 50 mM NaCl, 500 μΜ CHAPS and 800 mM KF) were added to all the wells excluding the buffer blank wells. The reaction plate was incubated for additional 30mins at room temperature on plate shaker. The plate was read in Perkin Elmer WALLAC 1420 Multilabel Counter Victor 3 (Ex: 340 nm Em: 615& 665 nm). The amount of displacement of the peptide was measured as ratio of specific 665 nm energy transfer signal to 615 nm signals. The compound's IC50 was determined by fitting the dose response data to sigmoid curve fitting equation using Graph Pad Prism software V5.

The selected compounds were screened in the above mentioned assay and the results (IC50) are summarized in the below table. The IC50 values are set forth in the below table wherein Group 'A' refers to an IC50 value of less than 200 nM, Group 'B' refers to an IC50 value in range of 200 to 500 nM and Group 'C refers to an IC50 value of greater than 500 nM.

Claims

We Claim:

1. A compound of formula (1)

Cyi is an optionally substituted monocyclic ring having 1-3 heteroatoms independently selected from N and O; wherein the optional substituent is alkyl;

R₂ and R₃ are independently selected from halogen, hydroxy and alkyl; or R₂ and R₃ combined together to form an oxo group;

R4 is selected from hydrogen, halogen and alkyl; and

R5 is selected from hydrogen, halogen, alkyl and alkoxy.

2. The compound of claim 1 , wherein Cyi is 3,5-dimethylisoxazole.

3. The compound of claim 1 , wherein Cy₂ is selected from optionally substituted phenyl and optionally substituted pyridyl.

4. The compound of claim 3, wherein the optional substituents are selected form halogen, alkoxy and alkyl.

5. The compound of claiml, wherein Ri is selected from arylalkyl, cyaloalkylalkyl and heterocyclylalkyl.

6. The compound of claim 5, wherein Ri is

7. The compound of claim 1, wherein R4 is hydrogen.

8. The compound of claim 1, wherein R5 is alkoxy.

9. The compound of claim 8, wherein alkoxy is methoxy.

10. The compound of claim 1, wherein R₂ and R3 combined together to form an oxo group.

11. The compound of claim 1, wherein the compound of formula (1) is a compound of formula (la)

wherein, Ri and Cy₂ are same as defined in claim 1.

12. The compound of claim 1, wherein the compound of formula (1) is a compound of formula (lb)

wherein, Ri and Cy₂ are same as defined in claim 1.

13. The compound of claim 1, wherein the compound of formula (1) is a compound of formula (lc)

wherein, Ri and Cy₂ are same as defined in claim 1 ; and 'n' is an integer selected from 0 and 1.

14. A compound selected from the group consisting of

quinolin-2-yl)(pyridin-3-yl)methanone;

11. (7-(3,5-dimethylisoxazol-4-yl)-8-methoxy-l-(2-methoxyethyl)-lH-imidazo[4,5-c] quinolin-2-yl)(pyridin-3-yl)methanone;

12. (l-benzyl-7-(3,5-dimethylisoxazol-4-yl)-8-methoxy-lH-imidazo[4,5-c]quinolin-2- yl)(6-methoxypyridin-3-yl)methanone;

13. (l-benzyl-7-(3,5-dimethylisoxazol-4-yl)-8-methoxy-lH-imidazo[4,5-c]quinolin-2- yl)(phenyl)methanone;

14. (l-benzyl-7-(3,5-dimethylisoxazol-4-yl)-8-methoxy-lH-imidazo[4,5-c]quinolin-2- yl)(4-fluorophenyl)methanone;

15. (7-(3,5-dimethylisoxazol-4-yl)-8-methoxy-l-((tetrahydro-2H-pyran-4-yl)methyl)- lH-imidazo[4,5-c]quinolin-2-yl)(5-fluoropyridin-2-yl)methanone;

16. (7-(3,5-dimethylisoxazol-4-yl)-8-methoxy-l-((tetrahydro-2H-pyran-4-yl)methyl)- lH-imidazo[4,5-c]quinolin-2-yl)(phenyl)methanone;

17. (7-(3,5-dimethylisoxazol-4-yl)-8-methoxy-l-((tetrahydro-2H-pyran-4-yl)methyl)- lH-imidazo[4,5-c]quinolin-2-yl)(4-fluorophenyl)methanone;

18. (7-(3,5-dimethylisoxazol-4-yl)-8-methoxy-l-((tetrahydro-2H-pyran-4-yl)methyl)- lH-imidazo[4,5-c]quinolin-2-yl)(pyridin-2-yl)methanone;

19. (l-benzyl-7-(3,5-dimethylisoxazol-4-yl)-8-methoxy-lH-imidazo[4,5-c]quinolin-2- yl)(4-methoxyphenyl)methanone;

20. (7-(3,5-dimethylisoxazol-4-yl)-8-methoxy-l-(thiazol-5-ylmethyl)-lH-imidazo[4,5- c]quinolin-2-yl)(pyridin-2-yl)methanone;

21. 4-(2-(difluoro(pyridin-3-yl)methyl)-8-methoxy-lH-imidazo[4,5-c]quinolin-7-yl)- 3 , 5 -dimethylisoxazole ;

22. 4-(2-(difluoro(pyridin-3-yl)methyl)-8-methoxy-l-methyl-lH-imidazo[4,5-c]

quinolin-7-yl)-3,5-dimethylisoxazole;

23. 4-(2-(difluoro(6-methylpyridin-3-yl)methyl)-8-methoxy-l-methyl-lH-imidazo

[4,5-c]quinolin-7-yl)-3,5-dimethylisoxazole;

24. 4-(2-(difluoro(pyridin-3-yl)methyl)-8-methoxy-l-((tetrahydro-2H-pyran-4-yl) methyl)- lH-imidazo[4,5-c]quinolin-7-yl)-3,5-dimethylisoxazole;

25. 4-(l-benzyl-2-(difluoro(pyridin-3-yl)methyl)-8-methoxy-lH-imidazo[4,5-c] quinolin-7-yl)-3,5-dimethylisoxazole;

26. 4-(2-(difluoro(pyridin-3-yl)methyl)-l-isopropyl-8-methoxy-lH-imidazo[4,5-c] quinolin-7-yl)-3,5-dimethylisoxazole;

27. 4-(2-(difluoro(pyridin-3-yl)methyl)-8-methoxy-l-(2-methoxyethyl)-lH-imidazo

[4,5-c]quinolin-7-yl)-3,5-dimethylisoxazole;

28. 4-(2-(difluoro(5-fluoropyridin-2-yl)methyl)-8-methoxy-l-((tetrahydro-2H-pyran- 4-yl)methyl)-lH-imidazo[4,5-c]quinolin-7-yl)-3,5-dimethylisoxazole;

29. 4-(l-benzyl-2-(difluoro(phenyl)methyl)-8-methoxy-lH-imidazo[4,5-c]quinolin-7- yl)-3 , 5-dimethylisoxazole ;

30. 4-(2-(difluoro(pyridin-2-yl)methyl)-8-methoxy-l-((tetrahydro-2H-pyran-4-yl)

methyl)- lH-imidazo[4,5-c]quinolin-7-yl)-3, 5-dimethylisoxazole;

31. 4-(l-benzyl-2-(difluoro(4-fluorophenyl)methyl)-8-methoxy-lH-imidazo[4,5-c] quinolin-7-yl)-3, 5-dimethylisoxazole;

32. 1- (7-(3,5-dimethylisoxazol-4-yl)-8-methoxy-l-methyl-lH-imidazo[4,5-c]quinolin-

2- yl)- l-(pyridin-3-yl)ethanol (Isomer- 1);

33. 1- (7-(3,5-dimethylisoxazol-4-yl)-8-methoxy-l-methyl-lH-imidazo[4,5-c]quinolin-

2- yl)- l-(pyridin-3-yl)ethanol (Isomer-2);

34. l-(4-chlorophenyl)-l-(7-(3,5-dimethylisoxazol-4-yl)-8-methoxy-l-methyl-lH- imidazo [4, 5-c] quinolin-2-yl)propan- 1 -ol (Isomer- 1 ) ;

35. l-(4-chlorophenyl)-l-(7-(3,5-dimethylisoxazol-4-yl)-8-methoxy-l-methyl-lH- imidazo [4, 5-c] quinolin-2-yl)propan- 1 -ol (Isomer- 1 ) ;

36. 1- (7-(3,5-dimethylisoxazol-4-yl)-8-methoxy-l-methyl-lH-imidazo[4,5-c]quinolin-

2- yl)- 1 -(pyridin-3-yl)propan- 1 -ol (Isomer- 1 ) ;

37. 1- (7-(3,5-dimethylisoxazol-4-yl)-8-methoxy-l-methyl-lH-imidazo[4,5-c]quinolin-

2- yl)-l-(pyridin-3-yl)propan-l-ol (Isomer-2); and

38. 4-(8-methoxy-l-methyl-2-(l-(pyridin-3-yl)cyclopropyl)-lH-imidazo[4,5-c]

quinolin-7-yl)-3, 5-dimethylisoxazole,

15. A compound selected from the group consisting of

(l-benzyl-7-(3,5-dimethylisoxazol-4-yl)-8-methoxy-lH-imidazo[4,5-c]quinolin-2-yl)(6- methoxypyridin- 3 - yl)methanone ; (l-benzyl-7-(3,5-dimethylisoxazol-4-yl)-8-methoxy-lH-imidazo[4,5-c]quinolin-2- yl) (phenyl) methanone ;

(l-benzyl-7-(3,5-dimethylisoxazol-4-yl)-8-methoxy-lH-imidazo[4,5-c]quinolin-2-yl)(4- fluorophenyl)methanone; and

4-(2-(difluoro(5-fluoropyridin-2-yl)methyl)-8-methoxy-l-((tetrahydro-2H-pyran-4- yl)methyl)-lH-imidazo[4,5-c]quinolin-7-yl)-3,5-dimethylisoxazole,

16. A pharmaceutical composition comprising a therapeutically effective amount of at least one compound of formula (1) according to any of claims 1 to 15, their pharmaceutically acceptable salts and pharmaceutically acceptable stereoisomers, in admixture with atleast one pharmaceutically acceptable carrier or excipient including mixtures thereof in all ratios, for use as a medicament.

17. A method of treating diseases or disease condition for which a bromodomain inhibitor is indicated in a subject in need thereof which comprises administering an effective amount of a compound according to any of claims 1 to 15.

18. The method of claim 17, wherein the disease or disease condition for which a bromodomain inhibitor is indicated is autoimmune, inflammatory or cancer.

19. Use of a compound according to any of claims 1 to 15, in the manufacture of a medicament for use in the treatment of diseases associated with bromodomain in animals including humans.

20. The use of claim 19, wherein the bromodomain protein is BRD-2, BRD-3 or BRD-4 protein.