This application is a § 371 of International Application No. PCT/EP2018/076938, filed 4 Oct. 2018, which claims the priority of GB 1716392.4, filed 6 Oct. 2017.

FIELD OF THE INVENTION

The present invention is directed to certain compounds which are bromodomain inhibitors, processes for their preparation, pharmaceutical compositions comprising the compounds and the use of the compounds or the compositions in the treatment of various diseases or conditions, for example acute or chronic autoimmune and/or inflammatory conditions, viral infections and cancer.

BACKGROUND TO THE INVENTION

The genomes of eukaryotic organisms are highly organised within the nucleus of the cell. The long strands of duplex DNA are wrapped around an octomer of histone proteins (most usually comprising two copies of histones H2A, H2B, H3 and H4) to form a nucleosome. This basic unit is then further compressed by the aggregation and folding of nucleosomes to form a highly condensed chromatin structure. A range of different states of condensation are possible, and the tightness of this structure varies during the cell cycle, being most compact during the process of cell division. Chromatin structure plays a critical role in regulating gene transcription, which cannot occur efficiently from highly condensed chromatin. The chromatin structure is controlled by a series of post translational modifications to histone proteins, notably histones H3 and H4, and most commonly within the histone tails which extend beyond the core nucleosome structure. These modifications include acetylation, methylation, phosphorylation, ubiquitinylation, SUMOylation. These epigenetic marks are written and erased by specific enzymes, which place the tags on specific residues within the histone tail, thereby forming an epigenetic code, which is then interpreted by the cell to allow gene specific regulation of chromatin structure and thereby transcription.

Histone acetylation is most usually associated with the activation of gene transcription, as the modification loosens the interaction of the DNA and the histone octomer by changing the electrostatics. In addition to this physical change, specific proteins recognise and bind to acetylated lysine residues within histones to read the epigenetic code. Bromodomains are small (˜110 amino acid) distinct domains within proteins that bind to acetylated lysine residues commonly but not exclusively in the context of histones. There is a family of around 50 proteins known to contain bromodomains, and they have a range of functions within the cell.

The BET family of bromodomain containing proteins comprises 4 proteins (BRD2, BRD3, BRD4 and BRDT) which contain tandem bromodomains capable of binding to two acetylated lysine residues in close proximity, increasing the specificity of the interaction. Numbering from the N-terminal end of each BET protein the tandem bromodomains are typically labelled Binding Domain 1 (BD1) and Binding Domain 2 (BD2) (Chung et al, J Med. Chem., 2011, 54, 3827-3838).

Chan et al. report that BET bromodomain inhibition suppresses transcriptional responses to cytokine-Jak-STAT signalling in a gene-specific manner in human monocytes, which suggests that BET inhibition reduces inflammation partially through suppression of cytokine activity. (Chan et al.,Eur. J. Immunol.,2015, 45: 287-297).

Klein et al. report that the bromodomain protein inhibitor I-BET151 suppresses expression of inflammatory genes and matrix degrading enzymes in rheumatoid arthritis synovial fibroblasts, which suggests a therapeutic potential in the targeting of epigenetic reader proteins in rheumatoid arthritis. (Klein et al.,Ann. Rheum. Dis.,2014, 0:1-8).

Park-Min et al. report that I-BET151 that targets bromo and extra-terminal (BET) proteins that ‘read’ chromatin states by binding to acetylated histones, strongly suppresses osteoclastogenesis. (Park-Min et al.Nature Communications,2014, 5, 5418).

PCT patent application PCT/EP2017/058049 discloses a series dibenzofuran derivatives as BET family bromodomain inhibitors.

SUMMARY OF THE INVENTION

The invention is directed to compounds of formula (I)


or a salt thereof
wherein:

R1is —C1-3alkyl or cyclopropyl;

R2is —C0-3alkyl-cycloalkyl, wherein the cycloalkyl group is optionally substituted with one, two or three R5groups which may be the same or different; or

R2is —C0-4alkyl-heterocyclyl or —(CH2)pO-heterocyclyl wherein each heterocyclyl is optionally substituted by one or two R9groups which may be the same or different; or

R2is H, —CH3, —C2-6alkyl optionally substituted by up to five fluoro, —C2-6alkylOR13, —C2-6alkylNR11R12, —(CH2)mSO2C1-3alkyl, —(CH2)mSO2NR11R12, —(CH2)mC(O)NR11R12, —(CH2)mCN, —(CH2)mCO2R13, —(CH2)mNHCO2C1-4alkyl —(CH2)mNHC(O)C1-4alkyl or —(CH2)nheteroaryl, wherein heteroaryl is optionally substituted by one or two R14groups which may be the same or different;

R3is phenyl optionally substituted with one, two or three R′ groups which may be the same or different;

R4is —CH2OR6or —C1-3alkyl optionally substituted by up to three fluoro;

each R5is independently halo, —C0-6alkyl-R8, —O—C2-6alkyl-R8, —CN or —SO2C1-3alkyl;

R6is —H or —C1-3alkyl;

each R′ is independently -halo, —C1-4alkyl, —C0-3alkyl-OR10, —C0-3alkyl-NR15R16, —C0-3alkyl-CONR15R16, —CN or —SO2R17;

R8is —H, —OR10a, —NR18R19or heteroaryl;

each R9is independently halo, C1-4alkyl, cyclopropyl, cyclobutyl, —CH2CF3, —CH2CHF2, —CH2CH2F, —OCH2CH2OR13, —C0-3alkylOR13, —C0-3alkylNR11R12, —NHCH2CH2OR13, —NHCO2R13, oxo, —C(O)R13, —C(O)OR13or —C(O)NR11R12;

R10ais —H, —C1-3alkyl, —C2-3alkylNR11R12or —C2-3alkylOH;

R10is —H, —C1-3alkyl, —C2-3alkylNR15R16or —C2-3alkylOH;

R11and R12are each independently selected from —H and —C1-3alkyl; or R11and R12may join together with the nitrogen to which they are attached, to form a 4 to 7-membered heterocyclyl group optionally substituted by one or two substituents independently selected from —C1-3alkyl, —OH and F;

R13is —H or —C1-4alkyl;

each R14is independently halo, C1-4alkyl, cyclopropyl, cyclobutyl or —OR13;

R15and R16are each independently selected from —H and —C1-3alkyl; or R15and R16may join together with the nitrogen to which they are attached, to form a 4 to 7-membered heterocyclyl group optionally substituted by one or two substituents independently selected from —C1-3alkyl, —OH and F;

R17is —C1-3alkyl or —NR15R16;

R18and R19are each independently selected from —H, —C(O)OC(CH3)3, —C1-6alkyl, cycloalkyl, heterocyclyl, —C2-3alkylNR13COC1-3alkyl, —C2-3alkylNR15R16and —C2-3alkyl-O—C1-3alkyl wherein the —C1-6alkyl and cycloalkyl may be optionally substituted by one, two or three fluoro; or R18and R19may join together with the nitrogen to which they are attached, to form a 4 to 7-membered heterocyclyl group optionally substituted by one or two substituents independently selected from —C1-3alkyl, —OH and F;

m is an integer selected from 2, 3 and 4;

p is an integer selected from 2, 3 and 4; and

n is an integer selected from 0, 1, 2, 3 and 4.

Compounds of the invention have been shown to be bromodomain inhibitors, in particular BD2 selective and may be useful in the treatment of various diseases or conditions, for example acute or chronic auto-immune and/or inflammatory conditions, for example rheumatoid arthritis and cancer. Accordingly, the invention is further directed to pharmaceutical compositions comprising a compound of formula (I), or a pharmaceutically acceptable salt thereof. The invention is still further directed to methods of treatment of diseases or conditions associated therewith using a compound of formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof. The invention is yet further directed towards processes for the preparation of the compounds of the invention.

