WO2022038116A1

WO2022038116A1 - N-hydroxycarboxamide derivatives useful as inhibitors of mammalian histone deacetylase activity

Info

Publication number: WO2022038116A1
Application number: PCT/EP2021/072793
Authority: WO
Inventors: Kristin Hammer
Original assignee: Kancera Ab
Priority date: 2020-08-19
Filing date: 2021-08-17
Publication date: 2022-02-24

Abstract

A compound of formula (I) or a pharmaceutically acceptable salt thereof. The compound is useful for the treatment of a disorder selected from autoimmune disorders, mental disorders, neurodegenerative disorders, pain, respiratory diseases, and hyperproliferative disorders, in particular cancers.

Description

N-HYDROXYCARBOXAMIDE DERIVATIVES USEFUL AS INHIBITORS OF MAMMALIAN HISTONE

DEACETYLASE ACTIVITY

FIELD OF THE INVENTION

The present invention relates to novel bicyclic N-hydroxy carboxamide derivatives. More particularly, the invention relates to novel bicyclic N-hydroxycarboxamide derivatives useful as inhibitors of a histone deacetylase, and to their use in therapy.

BACKGROUND OF THE INVENTION

Histone deacetylases (HDACs) are a class of enzymes that catalyzes the removal of an acetyl group from an a-N-acetyl lysine amino acid residue from other proteins, mainly histones. The histones are an essential part of how the genome is stored in the cell nucleus and DNA expression is regulated by histone acetylation and de-acetyl ati on. Lysine acetylation is a key post-translational modification of many proteins, and which underlie many aspects of gene transcription, cellular signaling, cellular transport and metabolic changes (Kouzarides et al. 2007, Choudhary et al. 2009, Zhao et al. 2010). HDACs have pivotal roles in the regulation of gene expression, forming complexes with DNA binding proteins and thereby affecting histone acetylation and chromatin accessibility at promoter regions. These enzymes also have nonhistone substrates, such as transcription factors and structural proteins whose biological activity is partly regulated by acetylation.

The common classification of human deacetylases is based on molecular phylogenetic analysis of primary structure, subsequently grouped based on homology to yeast enzymes (Gregoretti et al. 2004). This approach yields four distinct classes that vary in size and function. Class I (HDAC1, HDAC2, HDAC3 and HDAC8), class Ila (HDAC4, HDAC5, HDAC7 and HDAC9), class lib (HDAC6 and HDAC10) and class IV (HDAC11). The HDACs require a divalent ion for catalysis. The class III proteins form a structurally and mechanistically distinct class of hydrolases dependent on nicotinamide adenine dinucleotide (NAD⁺) (sirtuins, Sirtl— Sirt7) (Smith et al. 2008). The class I HDACs are found primarily in the nucleus, while the class Ila and class lib HDACs are able to translocate in and out of the nucleus, depending on different signals.

There are numerous diseases that are related to dysregulated HD AC enzymatic function, including cancer, autoimmune and neurodegenerative disorders (Karberg 2009). For example, overexpression of specific HDACs has been identified in a range of human cancers, including HDAC1 in gastric and prostate cancer, HDAC1 and HDAC6 in breast cancer, and HDAC2 and HDAC3 in colorectal cancer (Ververis et al. 2013). Extensive cell-based assays and clinical studies with HD AC inhibitors have been shown to reduce proliferation, induce cell death and apoptosis, cause cell-cycle arrest, and prevent differentiation and migration selectively in malignant and transformed cells with little effect in normal cells (Ververis et al. 2013). Thus, HD AC inhibitors have the potential to be used as monotherapies in oncology. In addition to their intrinsic cytotoxic properties when tested as a single treatment, HD AC inhibitors have been shown to induce additive cytotoxic effects when used in combination with conventional anticancer therapies, such as chemotherapy (anthracyclines and retinoic acid) and radiotherapy (Suraweera et al. 2018). Furthermore, studies with HD AC inhibitors in combination with ultraviolet radiation and potent iodinated DNA minor groove-binding ligands have been shown to augment photosensitization and cytotoxicity in tumor (Ververis et al. 2013). Currently, there are four HD AC inhibitors that have received approval from the US FDA for the treatment of various cancers: vorinostat (suberoylanilide hydroxamic acid, Zolinza), depsipeptide (romidepsin, Istodax), belinostat (PXD101, Beleodaq), and panobinostat (LBH-539, Farydak). In addition, chidamide (tucidinostat, Epidaza) is approved in China (Suraweera et al. 2018). Many clinical trials assessing the effects of various HDAC inhibitors on hematological and solid cancers are being conducted (Ververis et al. 2013, Suraweera et al. 2018). The approved inhibitors are active against several members of the HDAC family of enzymes leading to acute toxicities such as gastrointestinal symptoms and myelosuppression as well as severe fatigue (Prince et al. 2009). Also, the risk of significant negative impact on cardiac function is considered to be large (Brana & Tabernero 2010, Suraweera et al. 2018). Several reports show that there are intrinsic toxic side effects associated with inhibition of the HDAC class I isoforms and that this prevents the application of broad spectrum and class I selective inhibitors to areas outside of oncology because of a small therapeutic window. Early clinical trials with the selective HDAC6 inhibitor ACY-1215 appear to largely circumvent undesirable side-effects classically reported with broad-acting or class I-selective inhibitors (Raje et al, 2013). Although it remains to be demonstrated in the clinic, compounds that target specific HDACs with greater selectivity may be beneficial in certain cancers (Balasubramanian et al. 2009). For example, the selective HDAC8 inhibitor PCI-3405, was shown to selectively inhibit HDAC8 and induce apoptosis specifically in T- cell lymphomas and not other tumor or normal cells, showing that HDC8 plays an important role in the pathophysiology of this disease and suggesting that therapy with an HDAC8 specific inhibitor may lead to less side effects (Balasubramanian et al. 2008).

The class lib enzymes, HDAC6 and HD AC 10, differ from the other HDACs in that they primarily localize to the cytoplasm and differ structurally by containing two catalytic sites. HDAC6 is a microtubule-associated enzyme and deacetylases primarily non-histone proteins such as a-tubulin, cortactin, and Hsp90 (Aldana-Masangkay & Sakamoto 2011). a-tubulin is involved in cytoskeletal structural integrity and cellular motility, cortactin plays a role in cell motility, while Hsp90 (heat shock protein) is a molecular chaperone helping client proteins to fold properly and maintain function. Therapeutic areas susceptible to alterations in HDAC6 activity include cancer, autoimmune disorders, neurodegenerative diseases, pain and respiratory diseases. In contrast to other HDACs and especially class I isoforms, the loss of function of HDAC6 does not produce toxicity or major developmental defects in rodents (Govindarajan et al. 2013; Morris et al. 2010; Zhang et al. 2008). Inhibition of HDAC6 does not appear to be associated with the same level of toxicity observed with inhibition of the class I isoforms. The lower level of toxicity associated with HDAC6 inhibition compared to inhibition of the HD AC class I isoforms suggest that selective inhibition may provide a way to circumvent toxicity issues and thereby allow a superior side-effect profile and/or a higher dose with an accompanying superior effect on target. This may permit treatment of a wider range of cancer diseases and also treatment of non-oncology diseases requiring a wider therapeutic window (Best & Carey 2010, Zhang et al. 2008).

Cancer

Oncogenes, such as Ras, deregulate fundamental cellular functions, which can lead to the development of tumors and metastases. The Ras/MAPK signaling pathway is known to be required for tumorigenesis and HDAC6 is required for Ras-induced oncogenic transformation by providing anchorage-independent proliferation (Aldana-Masangkay & Sakamoto 2011). This allows the cancer cell to divide freely without being part of a tissue and is a hallmark of malignant transformation. Further, it has been shown that HDAC6 is required for oncogenes to be able to change the spatial organization of the vimentin fibers of the intracellular cytoskeleton which will induce cell stiffness and promote the invasive capacity of cells (Rathje et al. 2014). Thus, HDAC6 activity contributes to cell changes that lead to both tumor formation and invasion of tumor cells into healthy tissue (metastases). The antitumor effect observed via HDAC6 inhibition is probably the result of multiple mechanisms involving cell motility/migration, invasion, angiogenesis, induction of apoptosis, and inhibition of DNA repair (Kalin & Bergman 2013). HDAC6 knockout mice demonstrated reduced phosphorylation of AKT and ERK1/2 (signaling pathways involved in tumor growth) and lower levels of activated Ras than those derived from wild-type mice (Lee et al. 2008). HDAC6 knock-down cells from SCID mice subcutaneously injected with HDAC6 specific shRNA showed retarded growth. By reconstitution with wild type HDAC6, but not with catalytically inactive mutant HDAC6, these knock-down cells regained its phenotype indicating that HDAC6 is specifically required for tumorigenic growth (Lee et al. 2008). Another method to combat cancer cells is to target the two major pathways for protein turnover in eukaryotic cells - the Ubiquitin-Proteasome-System (UPS) and the HDAC6- dependent lysosomal pathway. HDAC6 directly interacts with misfolded or poly-ubiquinated proteins to target them for lysosome-mediated protein degradation via aggresome formation and autophagy (Aldana-Masangkay & Sakamoto 2011). If UPS activity is insufficient, this HDAC6 dependent pathway is able to compensate for intracellular protein degradation.

Cancer cells accumulate more misfolded proteins compared to nonmalignant cells and depend on efficient disposal of these misfolded proteins for cell survival. Thus, simultaneous inhibition of proteasome and HDAC6 activities has been proposed as a strategy to synergistically induce cancer cell death. Successful examples of this approach have used the proteasome inhibitor bortezomib together with different specific HDAC6 inhibitors such as tubacin on multiple myeloma cells (Hideshima et al. 2005), NK84 on ovarian cancer cells (Bazzaro et al. 2008), and ACY-1215 on cells and animal models of multiple myeloma (Santo et al., 2012). In all cases the two inhibitors showed synergistic effects and high selectivity for cancer cells compared to normal cells.

Autoimmune disorders

There is strong evidence supporting HDAC6 as a target for the treatment of numerous autoimmune disorders (Greer et al. 2012). In murine models, pan-HDAC inhibitors, such as vorinostat and TSA, were able to alleviate the symptoms and reverse the progression of established colitis (de Zoeten et al. 2011). HDAC6 selective inhibitors such as tubacin and tubastatin A but not class I selective HD AC inhibitors such as entinostat were able to confer protection in these in vivo models. In murine models of allograft rejection tubacin and tubastatin A in combination with low-dose rapamycin, a clinically used immunosuppressant, were able to significantly increase the lifespan of mice from approximately 15 days to more than 60 days in comparison to mice treated with rapamycin alone (de Zoeten et al. 2011). This combination therapy was only administered for 14 days but was able to confer long term protection against allograft rejection.

Mental disorders

In the mammalian brain, HDAC6 is mainly found in neurons (Southwood et al., 2007) and with the highest levels at the dorsal and median raphe nuclei, parts of the brain that are involved in emotional behaviors. HDAC6-deficient mice exhibit antidepressant-like behavior in behavioral tests, and this was mimicked by administration of NCT-14b, a HDAC6-specific inhibitor, to wild type mice (Fukada et al., 2012). Further, selective knockout of the highly abundant HDAC6 in serotonin neurons reduced acute anxiety caused by administration of the steroid hormone corticosterone, and blocked the expression of social deficits in mice exposed to inescapable traumatic stress (Espallergues et al., 2012). Administration of the selective HDAC6 inhibitors ACY-738 and ACY-775 has been shown to induce dramatic increases in a-tubulin acetylation in brain and stimulate mouse exploratory behaviors in novel, but not familiar environments (Jochems et al. 2014). The two compounds share the antidepressantlike properties of pan-HDAC inhibitors, such as SAHA and MS-275, in the tail suspension test and social defeat paradigm without any detectable effect on histone acetylation. These effects of ACY-738 and ACY-775 are directly attributable to the inhibition of HDAC6 expressed centrally, as they are fully abrogated in mice with a neural-specific loss of function ofHDAC6.

Taken together, these findings suggest that HDAC6-mediated reversible acetylation contribute to maintain proper neuronal activity in serotonergic neurons, and also provide a new therapeutic target for depression. In addition, acute stress, via glucocorticoid receptors (GRs), enhances glutamatergic signalling in the prefrontal cortex, a region responsible for high-order cognitive functions. It has been shown (Lee et al. 2012) that inhibition or knockdown of HDAC6 blocks the enhancement of glutamatergic signalling by acute stress and that inhibition or knockdown of the GR chaperone protein Hsp90 (a HDAC6 substrate) produces a similar blockade of the acute stress-induced enhancement of glutamatergic signalling. This suggests that HDAC6 is a key controller of neuronal adaptations to acute stress and that inhibition of HDAC6 may provide neuroprotective effects against stress- induced mental illness. Neurodegenerative disorders

There are numerous reports suggesting that HDAC6 inhibition exert neuroprotection which may benefit patients afflicted with neurodegenerative disorders such as Alzheimer's, Parkinson's and Huntington's diseases as well as patients afflicted by traumatic brain injury (TBI) and inherited neurological disorders such as Charcot-Mari e-Tooth disease (CMT) and Rett syndrome (Kalin & Bergman 2013, Simoes-Pires et al. 2013). On the other hand, an induction of HDAC6 would theoretically contribute to the degradation of protein aggregates which characterize various neurodegenerative disorders (Simoes-Pires et al. 2013). HDAC6 has been identified as a potential therapeutic target to modulate Alzheimer's disease (AD) pathogenesis. Specific HDAC6 inhibitors exert neuroprotection by increasing the acetylation levels of a-tubulin with subsequent improvement of the axonal transport, which is usually impaired in neurodegenerative disorders such as AD (Simoes-Pires et al. 2013). The loss of proper axonal transport leads to synaptic degradation through impaired mitochondrial and neurotransmitter trafficking (Kalin & Bergman 2013). It has been demonstrated that treatment of neurons with amyloid beta (AP) oligomers significantly attenuated mitochondrial elongation and transport, which was subsequently alleviated by treatment with the HDAC6 inhibitor tubastatin A (Kim et al. 2012). In another report, it was shown that reducing endogenous HDAC6 levels in an AD mouse model restored learning and memory (Govindarajan et al. 2013). These results suggest that HDAC6 inhibition may slow or reverse the neuronal damage associated with Ap and thus represents a viable drug target for the treatment of AD. Further, HDAC6 together with Hsp90 and the ubiquitin ligase CHIP form a network of chaperone complexes that modulates levels of tau - the microtubule-associated protein that is hyperphosphorylated and forms the pathological hallmark of neurofibrillary tangles in AD (Cook & Petrucelli 2013). It has been demonstrated that HDAC6 levels positively correlate with tau burden, while a decrease in HDAC6 activity or expression promotes tau clearance (Cook et al., 2012). Inhibition or depletion of HDAC6 causes Hsp90 hyperacetylation and the concomitant decreased affinity of Hsp90 for client proteins such as tau, leads to client protein degradation (Kalin & Bergman 2013). In addition, loss of HDAC6 activity augments the efficacy of an Hsp90 inhibitor, opening the possibility to synergistically promoting the degradation of Hsp90 client proteins by co-treatments with both HDAC6 and Hsp90 inhibitors, as has been shown for leukemia cells (Cook et al. 2012; Rao et al. 2008; George et al. 2005). The neuroprotective effect of HDAC6 inhibition may be beneficial for patients suffering from traumatic brain injuries. For example, it has been reported that HDAC6 inhibition results in the hyperacetylation of peroxiredoxin- 1 and -2 leading to increased resistance against oxidative stress such as that observed during ischemic stroke (Parmigiani et al. 2008). HDAC6 inhibition may also be beneficial for patients afflicted by inherited neurological disorders such as Charcot-Mari e-Tooth disease (CMT) and Rett syndrome. For example, symptomatic improvement was observed in a transgenic mouse model of CMT after the treatment with specific HDAC6 inhibitors, together with the increase in tubulin acetylation (D'Ydewalle et al. 2011). HDAC6 inhibition by tubastatin A has been shown to restore brain- derived neurotropic factor (BDNF) neurological function in Mecp2 knockout hippocampal neurons showing that HDAC6 is a potential target for Rett syndrome (Xu et al. 2014).

Pain

Pharmacological inhibition of HDAC6 in a mouse model has been shown to completely reverse all the hallmarks of established cisplatin-induced peripheral neuropathy by normalization of mitochondrial function in dorsal root ganglia and nerve, and restoration of intraepidermal innervation. The HDAC6 selective compound ACY-1083 was shown to both prevent cisplatin-induced mechanical allodynia, and also reverse already existing cisplatin- induced mechanical allodynia, spontaneous pain, and numbness (Krukowski et al. 2017). Further, HDAC6-inhibition has been shown to protect also against vincristine-induced sensory neurotoxicity in mice without interfering with the anti-cancer efficacy of vincristine (Van Helleputte et al. 2018).

Respiratory diseases

HDAC6 has been shown to be significantly upregulated in lungs, distal pulmonary arteries, and isolated pulmonary artery smooth muscle cells from pulmonary arterial hypertension (PAH) patients and animal models. Pharmacological inhibition of HDAC6 in in-vivo models improved established PAH and can be safely given in combination with currently approved PAH therapies. Moreover, mice lacking the HDAC6 gene were partially protected against chronic hypoxia induced pulmonary hypertension (Boucherat et al. 2017)

The above described data serve to illustrate the validity of modulating HDAC6 activity for treatment of disorders and diseases that include not only hyperproliferative indications, such as cancer, but also other therapeutic areas such as neurodegenerative disorders, autoimmune disorders, mental disorders, pain and respiratory diseases.

SUMMARY OF THE INVENTION

A first aspect is a compound of formula (I)

or a pharmaceutically acceptable salt thereof, wherein two of X, Y, Z and W are N, and two of X, Y, Z and W are C;

L is a direct bond or L₁-L₂; L₁ is O, NRL, or a direct bond; L₂ is C1-C4 alkylene;

RL is H or C1-C3 alkyl; R₁ is H, halogen, or C1-C3 alkyl; R₂ is H, halogen, or C1-C3 alkyl; R₃ is H, R₄R₅N, or a cyclic moiety Q₁ selected from 3-to 10-membered, monocyclic or bicyclic carbocyclyl, and 5- to 10-membered, monocyclic or bicyclic heterocyclyl, said cyclic moiety being attached to L by a bond to a carbon atom of the cyclic moiety and said cyclic moiety optionally being substituted by one or more moieties R₆; R₄ and R₅ are independently selected from H and C1-C6 alkyl; or R₄ and R₅ together with the nitrogen atom to which they are both attached form a 5- or 6-membered heterocyclic ring, which ring optionally contains one or more further heteroatoms and which ring is optionally sustituted by one or more moieties Re; each R₆ is independently selected from C1-C6 alkyl, halogen, R₇O(CH₂)_n, R₆S(O)₂(CH₂)_o, R₉R₁₀N(CH₂)_P, and R₁₁(CH₂)_q;

R₇ is selected from H, C1-C6 alkyl, R_7aR_7bN(CH₂)_r, R_7cR₇dNC(O)(CH₂)_s, and R_7e(CH₂)_t;

R_7a and R_7b are independently selected from H and C1-C6 alkyl; or R_7a and R_7b together with the nitrogen atom to which they are both attached form a 5- or 6-membered heterocyclic ring, which ring optionally contains one or more further heteroatoms and optionally is substituted by one or more C1-C6 alkyl; R_7c and R_7d are independently selected from H and C1-C6 alkyl; or R_7c and R_7d together with the nitrogen atom to which they are both attached form a 5- or 6-membered heterocyclic ring, which ring optionally contains one more further heteroatoms and optionally is substituted by one or more C1-C6 alkyl; R_7e is a cyclic moiety Q₂ selected from 5- or 6-membered carbocyclyl and 5- or 6-membered heterocyclyl, said cyclic moiety being attached to (CH₂)_t by a bond to a carbon atom of the cyclic moiety and said cyclic moiety optionally being substituted by one or more C1-C6 alkyl; R₈ is H or C1-C6 alkyl; R₉ and R₁₀ are independently selected from H and C1-C6 alkyl; or R₉ and R₁₀ together with the nitrogen atom to which they are both attached form a 4- to 6-membered heterocyclic ring, said ring optionally containing one more heteroatoms and said ring optionally being substituted by one or more moieties R₁₂; R₁₁ is a cyclic moiety Q3 selected from 3- to 6-membered carbocyclyl and 4- to 6-membered heterocyclyl, said cyclic moiety being attached to (CH₂)_q by a bond to a carbon atom of the cyclic moiety and said cyclic moiety optionally being substituted by one or more moieties R₁₂; each R₁₂ is independently selected from halogen, C1-C6 alkyl, R₁₃R₁₄N(CH₂)_u, and R₁₅OC(O)(CH₂)v; each R₁₃, R₁₄ and R₁₅ is independently selected from H and C1-C6 alkyl; n, o, p, q, s, t, u, and v are integers of from 0 to 3; r is an integer of from 1 to 4; and any alkyl is optionally substituted by one or more F, provided that the compound is not 4-(dimethylamino)-N-hydroxyquinazoline-7-carboxamide, or N-hydroxyquinoxaline-6-carboxamide.

The compounds of formula (I) are useful in therapy. Therefore, one aspect is a compound of formula (I) or a pharmaceutically acceptable salt thereof for use in therapy.

The compounds of formula (I) are histone deacetylase (HD AC) inhibitors. Therefore, one aspect is a compound of formula (I) or a pharmaceutically acceptable salt thereof for use as an HD AC inhibitor.

The compounds of formula (I) have a selectivity for, in particular, HDAC6. Therefore, one aspect is a compound of formula (I) or a pharmaceutically acceptable salt thereof for use as a selective HDAC6 inhibitor.

Disorders associated with or mediated by HD AC may be treated by use of the compounds of the invention. One aspect therefore is a method of treatment of a mammal suffering from a disorder associated with or mediated by HD AC, in particular HDAC6, by administering to said mammal a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof.

Another aspect is a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof and optionally a pharmaceutically acceptable excipient.

Another aspect is a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof and optionally a pharmaceutically acceptable excipient for use in the treatment of a disorder associated with or mediated by HD AC, in particular HDAC6.

Another aspect is a compound of formula (I) or a pharmaceutically acceptable salt thereof for use in the treatment of a disorder associated with or mediated by HD AC, in particular HDAC6. A further aspect is the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment of a disorder associated with or mediated by HD AC, in particular HDAC6.

Another aspect is a compound of formula (I) or a pharmaceutically acceptable salt thereof for use in the treatment of a disorder selected from autoimmune disorders, mental disorders, neurodegenerative disorders, pain, such as neuropathic pain, respiratory diseases, and hyperproliferative disorders, in particular cancers.

A further aspect is the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment of a disorder selected from autoimmune disorders, mental disorders, neurodegenerative disorders, pain, such as neuropathic pain, respiratory diseases, and hyperproliferative disorders, in particular cancers.

A further aspect is a method of treatment of a mammal suffering from a disorder selected from autoimmune disorders, mental disorders, neurodegenerative disorders, pain, such as neuropathic pain, respiratory diseases, and hyperproliferative disorders, in particular cancers by administering to said mammal a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof.

DETAILED DESCRIPTION

Definitions

Unless defined otherwise or clearly indicated by context, all technical and scientific terms and abbreviations used herein have the same meaning as commonly understood by one of ordinary skill in the field of art to which this disclosure belongs. However, definitions of some of the terms used herein will be given herein below.

The term “alkyl” either alone or as part of a radical, includes straight or branched chain alkyl of the general formula CnHin+i.

The term “C1-C6 alkyl” refers to an alkyl as defined herein above, of the general formula CH₃, C2H5, C3H7, C4H9, C5H11 or CeHi3. Thus, an alkyl moiety according to the invention having from 1-6 C (i.e. a C1-C6 alkyl) may be branched or linear, e.g. selected from methyl, ethyl, //-propyl, isopropyl, //-butyl, isobutyl, .scc-butyl, tert-butyl, //-pentyl, 2-methylbutyl, 2,2-dimethylpropyl, w-hexyl, 2-methylpentyl, 3 -methylpentyl, 2,2-dimethylbutyl, and 2,3- dimethylbutyl etc.

Unless otherwise specified or apparent from the context, any C1-C6 alkyl herein more specifically may be selected from C1-C5 alkyl, or from C1-C4 alkyl, or from C1-C3 alkyl, or from C1-C2 alkyl, e.g. methyl.

The term “halogen” refers to F, Cl, Br or I. Unless otherwise specified or apparent from the context, any halogen herein preferably is selected from F and Cl.

The term “carbocyclyl” refers to a saturated or unsaturated ring, wherein the ring is formed by carbon atoms, and which ring, when unsaturated, may be aromatic or non-aromatic. A saturated monocyclic carbocyclyl may also be referred to as a cycloalkyl, a monounsaturated carbocyclic ring may also be referred to as a cycloalkenyl etc.

The term “aryl” refers to an aromatic carbocyclyl, such as phenyl.

The term “heterocyclyl” refers to a saturated or unsaturated and aromatic or non-aromatic cyclic moiety containing at least one heteroatom in the ring and also containing at least one carbon atom in the ring.

Unless otherwise specified or apparent from the context, any heterocyclyl referred to herein contains 1, 2 or 3 heteroatoms in the ring, selected from N, O and S; preferably 1 or 2 heteroatoms, selected from N, O and S, and more preferabley 1 or 2 heteroatoms, selected from N and O.

The term “m- to n-membered” when referring to a cyclic moiety, indicates the number of atoms in the ring(s) of the cyclic moiety. For example, cyclohexyl, phenyl and pyridyl are 6- membered, whereas e.g. naphthyl is 10-membered.

As used herein with respect to any carbocyclyl or heterocyclyl, the term bicyclic refers to a cyclic moiety containing two rings, fused to each other. It should be noted though, that the term “ring” as used herein could refer to a monocyclic or bicyclic system. Any ring or cyclyl containing 5, 6, 7 or 8 atoms in the ring is monocyclic. Unless otherwise specified or apparent from the context, a ring or cyclyl containing 9 or 10 atoms in the ring is bicyclic.

The term “aromatic”, as used herein, refers to an unsaturated cyclic (carbocyclic or heterocyclic) moiety that has an aromatic character, while the term “non-aromatic”, as used herein, refers to a cyclic moiety, that may be unsaturated, but that does not have an aromatic character.

A bicyclic cyclyl, as referred to herein, contains two rings, fused to each other, which may be both saturated or both unsaturated, e.g. both (hetero)aromatic. The rings may also be of different degrees of saturation, and one ring may be (hetero)aromatic whereas the other is non-aromatic. If at least one of the rings is (hetero)aromatic, the cyclyl is defined herein as (hetero)aromatic. The rings may comprise different numbers of atoms, e.g. one ring being 5- membered and the other one being 6-membered, forming together a 9-membered bicyclic ring.

In a bicyclic heterocyclyl as referred to herein, one or both of the rings may contain one or several, e.g. 1, 2, 3 or 4 heteroatoms, independently selected from N, O and S.

Examples of bicyclic heteroaryl containing one aromatic and one non-aromatic ring, include e.g. indolinyl, chromanyl, thiochromanyl, dihydrobenzofuryl, 1,2,3,4-tetrahydroisoquinolyl, etc.

Further examples of heteroaryl according to the invention are pyrrolyl, pyrazolyl, imidazolyl, furyl, thienyl, oxadiazolyl, thiadiazolyl, thiazolyl, oxazolyl, triazolyl, tetrazolyl, isoxazolyl, isothiazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, benzothiazolyl, benzoxadiazolyl, benzimidazolyl, indazolyl, benzothiadizolyl, benzofuryl, benzoxazolyl, benzothienyl, isoquinolinyl, naphthyridinyl, quinolinyl, phthalazinyl, quinazolinyl, quinolinyl, quinoxalinyl, cinnolinyl, pteridinyl, etc.

As used herein, and unless otherwise specified, “non-aromatic heterocyclyl” refers to a non- aromatic cyclyl containing one or more heteroatom(s) selected from N, O and S, such as a dihydropyrrolyl, dioxolanyl, dithiolanyl, imidazolidinyl, imidazolinyl, pyrrolidinyl, pyrazolidinyl, tetrahydrofuryl, thiolanyl, dihydropyranyl, dihydropyridyl, dioxanyl, dithianyl, morpholinyl, piperidyl, piperazinyl, pyranyl, tetrahydropyranyl, tetrahydropyridyl, tetrahydro- 2H-thiopyranyl, and trithianyl etc.

The term “alkylene” refers to a branched or linear, saturated diradical of formula C_nH_2n. For example, a C2 alkylene is a diradical selected from -CH₂CH₂- and -C(CH₃)-, i.e.:

A term of the type RO refers to a moiety of formula

The term “hydroxy” refers to a moiety of the type RO, i.e. wherein R is H.

A term of the type “R(CH₂)n”, refers to a moiety of the formula

wherein n is an integer of at least 0. In the particular case where n is 0, the moiety has the formula

Thus, e.g. the moiety OH(CH₂)_n is hydroxy in case n is 0 and is hydroxymethyl in case n is 1.

The term “heteroatom” refers to an atom selected from N, O and S, preferably from N and O.

A term of the type RR'N refers to a moiety of formula

A term of the type RS(O)₂- refers to a moiety of formula

A term of the type RR'NC(O) refers to a moiety of the formula

The term phenyl refers to the moiety

The term benzyl refers to the moiety

A term of the type “ROC(O)” refers to a moiety of formula

An “alkyl substituted by one or more F” is an alkyl wherein one or more hydrogens have been replaced by the corresponding number of fluorines, such as in CH₂F, CHF₂ or CF₃. The alkyl may be part of a functional group, such as in trifluoromethoxy (CF₃O).

By “selective HDAC6 inhibitor” is meant a compound capable of inhibiting the activity of HDAC6 and having an IC₅₀ towards HDAC6 which is at least twice as high as that for at least one other HD AC, preferably at least 5 times, at least 10 times, at least 20 times, at least 50 times, or at least 100 times as high as the IC₅₀ for at least one other HD AC when measured under similar conditions.

The term “IC₅₀” refers to the half maximal inhibitory concentration and in the context of the present invention indicates how much (i.e. what concentration) of a particular compound is needed to inhibit the activity of a HD AC (at a given concentration) by half.

"Optional" or "optionally" means that the subsequently described event or circumstance may but need not occur, and that the description includes instances where the event or circumstance occurs and instances in which it does not.

"Pharmaceutically acceptable" means that which is useful in preparing a pharmaceutical composition that is generally safe, non-toxic, and neither biologically nor otherwise undesirable and includes that which is acceptable for veterinary as well as human pharmaceutical use. The term “excipient” refers to a pharmaceutically acceptable chemical, such as known to those of ordinary skill in the art of pharmacy to aid in the administration of the medicinal agent. It is a compound that is useful in preparing a pharmaceutical composition, generally safe, non-toxic and neither biologically nor otherwise undesirable, and includes excipients that are acceptable for veterinary use as well as human pharmaceutical use. Exemplary excipients include binders, surfactants, diluents, disintegrants, anti adherents, and lubricants.

"Therapeutically effective amount" means an amount of a compound that, when administered to a subject for treating a disease state, is sufficient to effect such treatment for the disease state. The "therapeutically effective amount" will vary depending on the compound, the disease state being treated, the severity of the disease treated, the age and relative health of the subject, the route and form of administration, the judgment of the attending medical or veterinary practitioner, etc.

As used herein the terms "treatment" or “treating” is an approach for obtaining beneficial or desired results including clinical results. Beneficial or desired clinical results can include, but are not limited to, alleviation or amelioration of one or more symptoms or conditions, diminishment of extent of disease, stabilized (i.e., not worsening) state of disease, preventing spread of disease, delay or slowing of disease progression, amelioration or palliation of the disease state, and remission (whether partial or total) whether detectable or undetectable. The term can also mean prolonging survival as compared to expected survival without the treatment.

The term “mammal” refers to a human or any mammalian animal, e.g. a primate, a farm animal, a pet animal, or a laboratory animal. Examples of such animals are monkeys, cows, sheep, horses, pigs, dogs, cats, rabbits, mice, rats etc. Preferably, the mammal is a human.

The term “hyperproliferative disorder” refers to a disorder involving undesired and uncontrolled cell proliferation. The hyperproliferative disorder may be benign or malignant (cancer). The term “cancer” thus refers to any malignant growth or tumor caused by abnormal and uncontrolled cell division; it may spread to other parts of the body through the lymphatic system or the blood stream and includes both solid tumors and blood-borne tumors.

Exemplary cancers include adrenocortical carcinoma, AIDS-related cancers, AIDS-related lymphoma, anal cancer, anorectal cancer, appendix cancer, childhood cerebellar astrocytoma, childhood cerebral astrocytoma, basal cell carcinoma, biliary cancer, extrahepatic bile duct cancer, intrahepatic bile duct cancer, urinary bladder cancer, bone and joint cancer, osteosarcoma and malignant fibrous histiocytoma, brain tumor, brain stem glioma, cerebellar astrocytoma, cerebral astrocytoma/malignant glioma, ependymoma, medulloblastoma, visual pathway and hypothalamic glioma, breast cancer, bronchial adenomas/carcinoids, nervous system cancer, nervous system lymphoma, central nervous system cancer, central nervous system lymphoma, cervical cancer, childhood cancers, chronic lymphocytic leukemia, chronic myelogenous leukemia, chronic myeloproliferative disorders, colon cancer, colorectal cancer, cutaneous T-cell lymphoma, lymphoid neoplasm, mycosis fungoides, Sezary syndrome, endometrial cancer, esophageal cancer, extracranial germ cell tumor, extragonadal germ cell tumor, eye cancer, retinoblastoma, gallbladder cancer, gastric (stomach) cancer, gastrointestinal carcinoid tumor, gastrointestinal stromal tumor (GIST), germ cell tumor, ovarian germ cell tumor, gestational trophoblastic tumor glioma, head and neck cancer, hepatocellular (liver) cancer, Hodgkin’s lymphoma, hypopharyngeal cancer, ocular cancer, Kaposi’s sarcoma, renal cancer, laryngeal cancer, acute lymphoblastic leukemia, acute myeloid leukemia, hairy cell leukemia, lip and oral cavity cancer, lung cancer, non-small cell lung cancer, small cell lung cancer, non-Hodgkin’s lymphoma, primary central nervous system lymphoma, Waldenstrom’s macroglobulinemia, intraocular (eye) melanoma, Merkel cell carcinoma, malignant mesothelioma, metastatic squamous neck cancer, cancer of the tongue, multiple endocrine neoplasia syndrome, myelodysplastic syndromes, myelodysplastic/myeloproliferative diseases, nasopharyngeal cancer, neuroblastoma, oral cancer, oral cavity cancer, oropharyngeal cancer, ovarian cancer, ovarian epithelial cancer, ovarian low malignant potential tumor, pancreatic cancer, islet cell pancreatic cancer, paranasal sinus and nasal cavity cancer, parathyroid cancer, penile cancer, pheochromocytoma, pineoblastoma and supratentorial primitive neuroectodermal tumors, pituitary tumor, plasma cell neoplasm/multiple myeloma, pleuropulmonary blastoma, prostate cancer, rhabdomyosarcoma, salivary gland cancer, Ewing’s sarcoma family of tumors, soft tissue sarcoma, uterine cancer, uterine sarcoma, skin cancer (non-melanoma), skin cancer (melanoma), small intestine cancer, squamous cell carcinoma, testicular cancer, throat cancer, thymoma, thymoma and thymic carcinoma, thyroid cancer, transitional cell cancer of the renal pelvis and ureter and other urinary organs, gestational trophoblastic tumor, urethral cancer, vaginal cancer, vulvar cancer, and Wilm's tumor. The term “benign hyperproliferative disorder” refers to disorders such as benign tumors, e.g. hemangiomas, hepatocellular adenoma, cavernous haemangioma, focal nodular hyperplasia, acoustic neuromas, neurofibroma, bile duct adenoma, bile duct cystanoma, fibroma, lipomas, leiomyomas, mesotheliomas, teratomas, myxomas, nodular regenerative hyperplasia, trachomas and pyogenic granulomas. Other types of non-malignant hyperproliferative disorders are abnormal cell proliferation due to insults to body tissue during surgery, proliferative responses associated with organ transplantation, abnormal angiogenesis, e.g. abnormal angiogenesis accompanying rheumatoid arthritis, ischemic-reperfusion related brain edema and injury, cortical ischemia, ovarian hyperplasia and hypervascularity, (polycystic ovary syndrome), endometriosis, psoriasis, diabetic retinopaphy, and other ocular angiogenic diseases such as retinopathy of prematurity (retrolental fibroplastic), macular degeneration, corneal graft rejection, neuroscular glaucoma and Oster Webber syndrome, etc.

The term “autoimmune disorder” (or autoimmune disease) refers to any disorder arising from an inappropriate immune response of the body against substances and tissues normally present in the body (autoimmunity). Such response may be restricted to certain organs or involve a particular tissue in different places. Exemplary autoimmune disorders are acute disseminated encephalomyelitis (ADEM), Addison's disease, agammaglobulinemia, alopecia areata, amyotrophic lateral sclerosis, ankylosing spondylitis, antiphospholipid syndrome, anti synthetase syndrome, atopic allergy, atopic dermatitis, autoimmune aplastic anemia, autoimmune cardiomyopathy, autoimmune enteropathy, autoimmune hemolytic anemia, autoimmune hepatitis, autoimmune inner ear disease, autoimmune lymphoproliferative syndrome, autoimmune peripheral neuropathy, autoimmune pancreatitis, autoimmune poly endocrine syndrome, autoimmune progesterone dermatitis, autoimmune thrombocytopenic purpura, autoimmune urticarial, autoimmune uveitis, Balo disease/Balo concentric sclerosis, Behcet's disease, Berger's disease, Bickerstaffs encephalitis, Blau syndrome, bullous pemphigoid, Castleman's disease, celiac disease, Chagas disease, chronic inflammatory demyelinating polyneuropathy, chronic recurrent multifocal osteomyelitis, chronic obstructive pulmonary disease, Churg-Strauss syndrome, cicatricial pemphigoid, Cogan syndrome, cold agglutinin disease, complement component 2 deficiency, contact dermatitis, cranial arteritis, CREST syndrome, Crohn's disease (one of two types of idiopathic inflammatory bowel disease "IBD"), Cushing's Syndrome, cutaneous leukocytoclastic angiitis, Dego's disease, Dercum's disease, dermatitis herpetiformis, dermatomyositis, diabetes mellitus type 1, diffuse cutaneous systemic sclerosis, Dressier's syndrome, drug- induced lupus, discoid lupus erythematosus, eczema, endometriosis, enthesitis-related arthritis, eosinophilic fasciitis, eosinophilic gastroenteritis, epidermolysis bullosa acquisita, erythema nodosum, erythroblastosis fetalis, essential mixed cryoglobulinemia, Evan's syndrome, fibrodysplasia ossificans progressive, fibrosing alveolitis (or Idiopathic pulmonary fibrosis), gastritis, gastrointestinal pemphigoid, glomerulonephritis, Goodpasture's syndrome, Graves' disease, Guillain-Barre syndrome (GBS), Hashimoto's encephalopathy, Hashimoto's thyroiditis, Henoch-Schonlein purpura, herpes gestationis (aka gestational pemphigoid), Hidradenitis suppurativa, Hughes-Stovin syndrome, hypogammaglobulinemia, idiopathic inflammatory demyelinating diseases, idiopathic pulmonary fibrosis, idiopathic thrombocytopenic purpura , IgA nephropathy, inclusion body myositis, chronic inflammatory demyelinating polyneuropathy, interstitial cystitis juvenile idiopathic arthritis (aka juvenile rheumatoid arthritis), Kawasaki's disease, Lambert-Eaton myasthenic syndrome, leukocytoclastic vasculitis, lichen planus, lichen sclerosus, linear IgA disease (LAD), lupoid hepatitis (aka autoimmune hepatitis), lupus erythematosus, Majeed syndrome, Meniere's disease, microscopic polyangiitis, mixed connective tissue disease, morphea, Mucha- Habermann disease (aka pityriasis lichenoides et varioliformis acuta), multiple sclerosis, myasthenia gravis, myositis, narcolepsy, neuromyelitis optica (also Devic's disease), neuromyotonia, occular cicatricial pemphigoid, opsoclonus myoclonus syndrome, Ord's thyroiditis, palindromic rheumatism, PANDAS (pediatric autoimmune neuropsychiatric disorders associated with streptococcus), paraneoplastic cerebellar degeneration, paroxysmal nocturnal hemoglobinuria (PNH), Parry Romberg syndrome, Parsonage-Turner syndrome, pars planitis, pemphigus vulgaris, pernicious anaemia, perivenous encephalomyelitis, POEMS syndrome, polyarteritis nodosa, polymyalgia rheumatic, polymyositis, primary biliary cirrhosis, primary sclerosing cholangitis, progressive inflammatory neuropathy, psoriasis, psoriatic arthritis, pyoderma gangrenosum, pure red cell aplasia, Rasmussen's encephalitis, Raynaud phenomenon, relapsing polychondritis, Reiter's syndrome, restless leg syndrome, retroperitoneal fibrosis, rheumatoid arthritis, rheumatic fever, sarcoidosis, schizophrenia, Schmidt syndrome another form of APS, Schnitzler syndrome, Scleritis, Scleroderma, Serum Sickness, Sjogren's syndrome, spondyloarthropathy, stiff person syndrome, subacute bacterial endocarditis (SBE), Susac's syndrome, Sweet's syndrome, sympathetic ophthalmia, systemic lupus erythematosis, Takayasu's arteritis, temporal arteritis (also known as "giant cell arteritis"), thrombocytopenia, Tolosa-Hunt syndrome, transverse myelitis, ulcerative colitis (one of two types of idiopathic inflammatory bowel disease "IBD"), undifferentiated connective tissue disease different from mixed connective tissue disease, undifferentiated spondyloarthropathy, urticarial vasculitis, vasculitis, vitiligo, and Wegener's granulomatosis.

The term “neurogenerative disorder” (or neurogenerative disease) refers to disorders associated with a progressive loss of structure or function of neurons affecting the structure or function of the brain, spinal cord or peripheral nervous system. Exemplary neurodegenerative disorders include mitochondrial encephalomyopathies and gut dysmotility syndromes, ataxia syndromes including Friedreich's ataxia and spinocerebellar ataxia (SCA), spinal cord injury, familial and sporadic amyotrophic lateral sclerosis (FALS and ALS, respectively), familial and sporadic Parkinson's disease, familial and sporadic Alzheimer's disease, Huntington's disease, olivopontocerebellar atrophy, multiple system atrophy, progressive supranuclear palsy, diffuse lewy body disease and synucleinopathies, Down Syndrome, corticodentatonigral degeneration, progressive familial myoclonic epilepsy, strionigral degeneration, torsion dystonia, familial tremor, Gilles de la Tourette syndrome, and Hallervorden-Spatz disease.

The term “mental disorder” refers to a disorder as e.g. referred to in the Diagnostic and Statistical Manual of Mental Disorders (DSM) published by American Psychiatric Publishing Inc. (Arlington, Va.). Examples of mental disorders are psychotic disorders and schizophrenia spectrum disorders such as schizotypal (personality) disorder, delusional disorder, brief psychotic disorder, schizophreniform disorder, schizophrenia, schizoaffective disorder, substance/medication-induced psychotic disorder, and psychotic disorder due to another medical condition; bipolar disorders such as bipolar I disorder, bipolar II disorder, cyclothymic disorder, substance/medication-induced bipolar and related disorder, depressive disorders, such as disruptive mood dysregulation disorder, major depressive disorder, single and recurrent episodes, persistent depressive disorder (dysthymia), premenstrual dysphoric disorder, substance/medication-induced depressive disorder, and depressive disorder due to another medical condition; anxiety disorders, such as separation anxiety disorder, selective mutism, specific phobia, social anxiety disorder (social phobia), panic disorder, agoraphobia, generalized anxiety disorder etc.

The term “pain” refers in particular to neuropathic pain, i.e. pain as a result of an injury or malfunction in the peripheral or central nervous system. Examples of neuropathic pain include post herpetic (or post-shingles) neuralgia, reflex sympathetic dystrophy, components of cancer pain, phantom limb pain, entrapment neuropathy (e.g., carpal tunnel syndrome), and peripheral neuropathy.

The term “respiratory disease” refers generally to a disease that affects the respiratory system, including conditions of the upper respiratory tract, trachea, bronchi, bronchioles, alveoli, pleura and pleural cavity. Examples of respiratory diseases include asthma, obstructive pulmonary disease, such as chronic obstructive pulmonary disease, respiratory disease in connection with cystic fibrosis, pulmonary arterial hypertension, respiratory allergic diseases such as allergic rhinitis, hypersensitivity lung diseases, hypersensitivity pneumonitis, eosinophilic pneumonias, Loeffler's syndrome, chronic eosinophilic pneumonia, interstitial lung diseases (ILD), such as idiopathic pulmonary fibrosis, bronchiolitis etc.

The compound

In a compound of formula (I)

the moiety R₁ is H, halogen, or C1-C3 alkyl. In some embodiments, R₁ is H or halogen. In some other embodiments, R₁ is H or C1-C3 alkyl. When R₁ is halogen, said halogen e.g. is F or Cl, in particular F. Thus, in some embodiments, R₁ is H or F. In some embodiments, R₁ is F. When R₁ is C1-C3 alkyl, said alkyl more particularly is C1-C2 alkyl, in particular methyl. In some embodiments, R₁ is H, F or methyl. In some other embodiments, R₁ is H or methyl. Preferably, R₁ is H.

The moiety R₂ is H, halogen, or C1-C3 alkyl. In some embodiments, R₂ is H or halogen. In some other embodiments, R₂ is H or C1-C3 alkyl. When R₂ is halogen, said halogen e.g. is F or Cl, in particular F. Thus, in some embodiments, R₂ is H or F. When R₂ is C1-C3 alkyl, said alkyl more particularly is C1-C2 alkyl, in particular methyl. In some embodiments, R₂ is H, F or methyl. Preferably, R₂ is H.

In a compound of formula (I), two of X, Y, Z and W are N, and two of X, Y, Z and W are C, whereby the two moieties that are C are attached to R₂ and R₃-L-, respectively. In some embodiments, W is N, i.e. the compound may be represented by formula (la)

wherein X, Y, Z, R₁, R₂, R₃, and L are as defined herein.

In some embodiments of a compound of formula (I), Z is C. For example, in some embodiments of a compound of formula (I), W is N and Z is C; i.e. the compound may be represented by formula (lb)

wherein X, Y, Z, R₁, R₂, R₃, and L are as defined herein.

In some embodiments of a compound of formula (I), e.g. in some embodiments of formula (lb), X is N, i.e. the compound may be represented by formula (Ic)

wherein R₁, R₂, R₃, and L are as defined herein.

In some embodiments of a compound of formula (I), e.g. in some embodiments of formula (lb), Y is N.

In a compound of formula (I), the moiety R₃-L may be attached to any one of X, Y, Z and W, in particular to any one of X, Y and Z. In some embodiments, R₃-L is attached to Y or Z. In some embodiments, R₃-L is attached to Y. For example, in some embodiments, the compound of formula (I) more particularly is a compound of formula (Id)

wherein X, Z, R₁, R₂, R₃, and L are as defined herein. In some embodiments of a compound of formula (Id), X is N. In some other embodiments of a compound of formula (d), Z is N.

In some other embodiments, R₃-L is attached to Z. For example, in some embodiments, the compound of formula (I) more particularly is a compound of formula (le)

wherein X, Y, R₁, R₂, R₃, and L are as defined herein. In some embodiments of a compound of formula (le), X is N. In some other embodiments of a compound of formula (Ie),Y is N.

In a compound of formula (I), L is a direct bond or L₁-L₂, wherein L₁ is O, NR_L, or a direct bond; and L₂ is C1-C4 alkylene. In some embodiments, L is a direct bond, i.e. the compound may be represented by formula (If)

wherein X, Y, Z, W, R₁, R₂, and R₃, are as defined herein.

In some other embodiments, L is L₁-L₂. For the avoidance of doubt, it is pointed out that when L is L₁-L₂, R₃ is attached to L₂ and the ring containing X, Y, Z and W is attached to L₁. Thus, when L is L₁-L₂ the compound may be represented by formula (Ig)

wherein X, Y, Z, W, L₁, L₂, R₁, R₂, and R₃, are as defined herein. The moiety L₁ is selected from O, NR_L and a direct bond. In some embodiments, L₁ is O or NR_L. In some embodiments, L₁ is O or a direct bond. In some embodiments, L₁ is O. In some other embodiments, L1 is NRL or a direct bond. In some embodiments, L1 is NRL. In some embodiments, L₁ is a direct bond. The moiety L₂ is C1-C4 alkylene. In some embodiments, L₂ is C1-C3 alkylene, e.g. C1-C2 alkylene, in particular C1 alkylene, i.e. methylene (CH₂). In some embodiments, L₂ is a moiety selected from CH₂CH₂, CH₂CH(CH₃), CH(CH₃)CH(CH₃), CH(CH₂CH₃)CH₂, CH₂, CH(CH₃), and C(CH₃)₂; or from CH₂CH₂, CH₂CH(CH₃), CH₂, CH(CH₃), and C(CH₃)₂; or from CH₂, CH(CH₃), and C(CH₃)₂; e.g from CH₂ and CH(CH₃). When L₁ is NRL, the moiety RL is selected from H and C1-C3 alkyl. In some embodiments, RL is selected from H and C1-C2 alkyl. In some embodiments, RL is H or methyl. In some embodiments, RL is H. In some further embodiments, RL is selected from C1-C3 alkyl, e.g. from C1-C2 alkyl. In some embodiments, R_L is methyl. In some particular embodiments, L is selected from a direct bond, OCH₂, NR_LCH₂, NR_LCH(CH₃), O(CH₂)₂, and O(CH₂)₄. In some further, particular embodiments, L is selected from a direct bond, OCH₂, NHCH₂, NHCH(CH₃), N(CH₃)CH(CH₃), O(CH₂)₂, and O(CH₂)4. In some further particular embodiments, L is selected from a direct bond, OCH₂, NHCH₂, NHCH(CH₃), N(CH₃)CH(CH₃), and O(CH₂)₂. In still other embodiments, L is selected from a direct bond, OCH₂, and O(CH₂)₂; e.g. from a direct bond and OCH_2. In some further particular embodiments, L is selected from a direct bond, OCH₂, NHCH₂, and NHCH(CH₃). In some further particular embodiments, L is selected from a direct bond, NHCH₂, NHCH(CH₃), and N(CH₃)CH(CH₃). In a compound of formula (I), R₃ is H, R₄R₅N, or a cyclic moiety Q1 selected from 3-to 10- membered, monocyclic or bicyclic carbocyclyl and 5- to 10-membered, monocyclic or bicyclic heterocyclyl, said cyclic moiety being attached to L by a bond to a carbon atom of the cyclic moiety and said cyclic moiety optionally being substituted by one or more moieties R6. In some embodiments, R₃ is H; e.g. L is a direct bond and R₃ is H. In some further embodiments, R₃ is H, and L is a direct bond, or L is L₁-L₂ and L1 is a direct bond, i.e. the moiety R₃-L₂-L₁ is H or C1-C4 alkyl. In some of these embodiments, R₃-L₂-L₁ is C1-C4 alkyl. In some further embodiments, R₃ is H only when L is a direct bond or L is L₁-L₂ andL₁ is O.

In some embodiments, R₃ is H only when L is a direct bond.

In some embodiments, R₃ is H only when L is L₁-L₂. In some further embodiments, R₃ is H only when L is L₁-L₂ and L₁ is O or NRL. In some further embodiments, R₃ is H only when L is L₁-L₂ and L₁ is O. In some further embodiments, R₃ is H only when L is L₁-L₂, L₁ is O and L₂ is C2-C4 alkylene, e.g. L₂ is C3-C4 alkylene.

In some embodiments, R₃ is R₄R₅N or a cyclic moiety Q₁ selected from 3-to 10-membered, monocyclic or bicyclic carbocyclyl and 5- to 10-membered, monocyclic or bicyclic heterocyclyl, said cyclic moiety being attached to L by a bond to a carbon atom of the cyclic moiety and said cyclic moiety optionally being substituted by one or more moieties R₆.

In some embodiments, R₃ is H or a cyclic moiety Q₁ selected from 3-to 10-membered, monocyclic or bicyclic carbocyclyl, and 5- to 10-membered, monocyclic or bicyclic heterocyclyl, said cyclic moiety being attached to L by a bond to a carbon atom of the cyclic moiety and said cyclic moiety optionally being substituted by one or more moieties R₆.

In some embodiments, R₃ is a cyclic moiety Q₁ selected from 3-to 10-membered, monocyclic or bicyclic carbocyclyl, and 5- to 10-membered, monocyclic or bicyclic heterocyclyl, said cyclic moiety being attached to L by a bond to a carbon atom of the cyclic moiety and said cyclic moiety optionally being substituted by one or more moieties R₆.

In some of these embodiments, when R₃ is a cyclic moiety Q₁ as defined herein above, optionally substituted by R₆, R₃ more particularly may be represented by formula (II)

wherein the cyclic moiety Q₁ (also referred to herein below as “ring Q₁” or “ Q₁”) and R₆ are as defined herein and i is an integer of from 0 to 3; e.g.

In some embodiments, i is 0, 1 or 2. In some embodiments, i is 1, 2 or 3, in particular 1 or 2.

In some other embodiments, i is 0 or 1. In some embodiments, i is 1. Thus, in some embodiments, the compound of formula (I) more particularly may be represented by formula (Ih)

wherein X, Y, Z, W, L, ring Q₁, R₁, R₂, each R₆, and i are as defined herein.

In some embodiments, ring Q₁ is selected from 3- to 8-membered, monocyclic carbocyclyl and 5- to 10-membered, monocyclic or bicyclic heterocyclyl; e.g. from 3- to 8-membered, monocyclic carbocyclyl, 5- to 8-membered monocyclic heterocyclyl, and 9- or 10-membered bicyclic heterocyclyl; or from 5- to 7-membered monocyclic carbocyclyl, 5- to 7-membered monocyclic heterocyclyl, and 9- or 10-membered bicyclic heterocyclyl; or from 6- or 7- membered monocyclic carbocyclyl, 5- or 6-membered monocyclic heterocyclyl, and 9- or 10- membered bicyclic heterocyclyl; or from 6-membered monocyclic carbocyclyl, 6-membered monocyclic heterocyclyl, and 9-membered bicyclic heterocyclyl.

In some embodiments, Q₁ is selected from phenyl, 5-or 6-membered monocyclic heteroaryl, and 9- or 10-membered bicyclic heteroaryl. In some of these embodiments, Q₁ is selected from phenyl, 6-membered monocyclic heteroaryl, and 9-membered bicyclic heteroaryl.

In some embodiments, Q₁ is selected from phenyl, and 5-or 6-membered heteroaryl. In some of these embodiments, Q₁ is selected from phenyl, and 6-membered heteroaryl.

In some embodiments, Q₁ is selected from 3-to 10-membered, monocyclic or bicyclic carbocyclyl.

When Q₁ is selected from 3-to 10-membered, monocyclic or bicyclic carbocyclyl, Q₁ more particularly is 3- to 8-membered, monocyclic carbocyclyl; or 5- to 7-membered monocyclic carbocyclyl; or 6- or 7-membered monocyclic carbocyclyl; or Q₁ is 6-membered monocyclic carbocyclyl. In some particular embodiments, when Q₁ is selected from 3-to 10-membered, monocyclic or bicyclic carbocyclyl, Q₁ is phenyl, i.e. R₃ may be represented by formula (Ila)

wherein R₆ and i are as defined herein. Thus, in some embodiments, the compound of formula (I) more particularly is a compound of formula (li)

wherein X, Y, Z, W, L, R₁, R₂, each R₆, and i are as defined herein.

When Q₁ is 5- to 10-membered, monocyclic or bicyclic heterocyclyl, the heterocyclyl contains one or more (e.g. 1-4) heteroatoms independently selected from N, O and S. In some embodiments, the number of heteroatoms in the heterocyclyl is 1, 2 or 3. In some embodiments, the number of heteroatoms in the heterocyclyl is 1 or 2. In some embodiments, the heterocyclyl contains one heteroatom. In some embodiments, the one or more heteroatoms are independently selected from N and O. In some embodiments, the one or more heteroatoms are N.

When Q₁ is 5- to 10-membered, monocyclic or bicyclic heterocyclyl, Q₁ more particularly may be selected from 5- to 6-membered heteroaryl and 9-or 10-membered bicyclic heteroaryl, said heteroaryl containing 1-4 heteroatoms, or 1-3 heteroatoms, or 1-2 heteroatoms, or 1 heteroatom, selected from N, O and S, or from N and O, in particular N. In some embodiments, when Q₁ is 5- to 10-membered, monocyclic or bicyclic heterocyclyl, Q₁ more particularly is 5- to 6-membered heteroaryl, e.g. Q₁ is 5- or 6-membered heteroaryl containing 1-4 heteroatoms, or 1-3 heteroatoms, or 1-2 heteroatoms, or 1 heteroatom, selected from N, O and S, or from N and O, in particular N. In some embodiments, when Q₁ is 5- to 10- membered, monocyclic or bicyclic heterocyclyl, Q₁ more particularly is 6-membered heteroaryl containing 1-4 heteroatoms, or 1-3 heteroatoms, or 1-2 heteroatoms, or 1 heteroatom, and each heteroatom is N; e.g. Q₁ is pyridinyl, in particular pyridin-4-yl or pyridin-3-yl. In some embodiments, when Q₁ is pyridinyl, said pyridinyl is pyridin-4-yl. In some other embodiments, when Q₁ is pyridinyl, said pyridinyl is pyridin-3-yl. In some embodiments, Q₁ is 5- to 10-membered, monocyclic or bicyclic heterocyclyl.

In some other embodiments, Q₁ is selected from phenyl, heptyl, pyridinyl (in particular 4- pyridyl or 3-pyridyl), and benzofuryl, e.g. benzofuran-2-yl; e.g. from phenyl, pyridinyl (in particular 4-pyridyl or 3-pyridyl), and benzofuryl, e.g. benzofuran-2-yl.

In some embodiments, when R₃ is a cyclic moiety of formula (II), said moiety more particularly is as represented by formula (lib)

wherein

G₁ is selected from CH and CR₆, and G₂ is selected from CH and N; or

G₁ is selected from CH and N; and G₂ is selected from CH and CR₆; j is an integer of from 0 to 3 when neither G₁ nor G₂ is CR₂; and j is an integer of from 0 to 2 when either G₁ or G₂ is CR₂.

In some of these embodiments, one of G₁ and G₂ is selected from CH and CR₆, and the other one is CH; j is an integer of from 0 to 3 when neither G₁ nor G₂ is CR₂; and j is an integer of from 0 to 2 when either G₁ or G₂ is CR₂. In some further of these embodiments, one of G₁ and G₂ is selected from CH and CR₆, and the other one is CH; j is an integer of from 0 to 3 when neither G₁ nor G₂ is CR₂; and j is an integer of from 0 to 2 when either G₁ or G₂ is CR₂. In some further of these embodiments, one of G₁ and G₂ is selected from CH and CR₆, and the other one is CH; j is an integer of from 0 to 2 when neither G₁ nor G₂ is CR₂; and j is an integer of from 0 to 1 when either G₁ or G₂ is CR₂. In some further of these embodiments, one of G₁ and G₂ is selected from CH and CR₆, and the other one is CH; j is 0 or 1 when neither

G₁ nor G₂ is CR₂; and j is an integer of from 0 when either G₁ or G₂ is CR₂.

In still other of these embodiments, one of G₁ and G₂ is selected from CH and CR₆, and the other one is CH; j is an integer of from 1 to 3 when neither G₁ nor G₂ is CR₂; and j is an integer of from 0 to 2 when either G₁ or G₂ is CR₂. In some of these embodiments, one of G₁ and G₂ is selected from CH and CR₆, and the other one is CH; j is 1 or 2 when neither G₁ nor G₂ is CR₂; and j is 0 or 1 when either G₁ or G₂ is CR₂. In some of these embodiments, one of G₁ and G₂ is selected from CH and CR₆, and the other one is CH; j is 1 when neither G₁ nor G₂ is CR₂; and j is 0 when either G₁ or G₂ is CR₂.

In still other embodiments, G₁ is CR₆, G₂ is CH; and j is an integer of from 0 to 2, e.g. j is 0 or 1, or j is 0. In still other embodiments, G₁ is H, G₂ is CR₆; and j is an integer of from 0 to 2, e.g. j is 0 or 1, or j is 0.

In still other embodiments, G₁ is CR₆, and G₂ is selected from CH and N; or G₁ is selected from CH and N; and G₂ is CR₆; and j is an integer of from 0 to 2, e.g. j is 0 or 1, or j is 0. In still other embodiments, G₁ is CR₆; G₂ is selected from CH and N; and j is an integer of from 0 to 2, e.g. j is 0 or 1, or j is 0. In still other embodiments, G₁ is selected from CH and N; and G₂ is CR₆; and j is an integer of from 0 to 2, e.g. j is 0 or 1, or j is 0.

Thus, in some embodiments, the compound of formula (I) more particularly is represented by formula (Ij)

wherein X, Y, Z, W, L, G₁, G₂, R₁, R₂, each R₆, and j are as defined herein.

In some embodiments of a compound of formula (Ij), j is 0 or 1. In some particular embodiments of a compound of formula (Ij), j is 0.

In some particular embodiments of a compound of formula (I), i is not 0 when Q₁ is phenyl and L is a direct bond. In some further particular embodiments of a compound of formula (I), i is not 0 when Q₁ is phenyl. In still further particular embodiments of a compound of formula (I), i is not 0 when L is a direct bond.

In some embodiments, R₃ is R₄R₅N, i.e. the compound of formula (I) may be represented by formula (Ik)

wherein X, Y, Z, W, R₁, R₂, R₄ and R₅, are as defined herein.

The moi eties R₄ and R₅ are independently selected from H and C1-C6 alkyl; or R₄ and R₅ together with the nitrogen atom to which they are both attached form a 5- or 6-membered heterocyclic ring, which ring optionally contains one or more further heteroatoms and which ring is optionally substituted by one or more moieties R₆. In some embodiments, the moieties R₄ and R₅ are independently selected from H and C1-C6 alkyl.

When R₄ and R₅ are independently selected from H and C1-C6 alkyl, R₄ and R₅ more particularly may be selected from H and C1-C4 alkyl, or from H and C1-C3 alkyl, e.g. from H, methyl and ethyl. In some embodiments, when R₄ and R₅ are independently selected from H and C1-C6 alkyl, R₄ and R₅ more particularly are selected from C1-C6 alkyl, or from C1- C4 alkyl, or from C1-C3 alkyl, e.g. from methyl and ethyl. In some embodiments, R₄ and R₅ more particularly are selected from C2-C6 alkyl, or from C2-C4 alkyl, or from C2-C3 alkyl, e.g. both R₄ and R₅ are ethyl.

In some other embodiments, R₄ and R₅ together with the nitrogen atom to which they are both attached form a 5- or 6-membered heterocyclic ring, which ring optionally contains one or more further heteroatoms and which ring is optionally substituted by one or more moieties R₆.

When R₄ and R₅ together with the nitrogen atom to which they are both attached form a 5- or 6-membered heterocyclic ring, said ring may be saturated or unsaturated, e.g. contain one double bond. In some embodiments, the ring is saturated. The ring may contain one or more further heteroatoms, e.g. 1 or 2 further heteroatoms selected from N and O, in particular 1 or 2 further N. In some embodiments, the ring contains at most one further heteroatom selected from N and O. In some embodiments, the ring is selected from pyrrolidinyl, piperazinyl and morpholinyl, in particular from pyrrolidinyl and piperazinyl.

In some embodiments, when R₄ and R₅ together with the nitrogen atom to which they are both attached form a 5- or 6-membered heterocyclic ring, said ring is piperazinyl. When R₄ and R₅ together with the nitrogen atom to which they are both attached form a 5- or 6-membered heterocyclic ring, said ring may optionally be substituted by one or more moieties R₆.

In some embodiments, when R₄ and R₅ together with the nitrogen atom to which they are both attached form a 5- or 6-membered heterocyclic ring optionally substituted by R₆, the number of moeties R₆ attached to said ring are 0, 1, 2 or 3, in particular 0, 1 or 2, e.g. 0 or 1. Thus, in some embodiments, R₄ and R₅ are independently selected from H and C1-C6 alkyl; or R₄ and R₆ together with the nitrogen atom to which they are both attached form a moiety represented by formula (III)

wherein the ring A is a 5- or 6-membered ring optionally containing 1 or 2 further heteroatoms in the ring, R₆ is as defined herein, and k is an integer of from 0 to 3, e.g. k is 0, 1 or 2, or k is 0 or 1, or k is 1.

Thus, in some embodiments, the compound of formula (I) more particularly may be represented by formula (Im)

wherein X, Y, Z, W, ring A, R₁, R₂, R₆ and k are as defined herein.

In some embodiments, ring A is 6-membered, saturated, and contains one further nitrogen atom in the ring. In some particular embodiments, R₃ may be represented by formula (Illa)

wherein each R₆ is as defined herein, and k is 1, 2, or 3, e.g. k is 1 or 2, in particular k is 1. In some other embodiments of the moiety (III), ring A contains no further heteroatom. In some embodiments, ring A is pyrrolidinyl or piperidinyl, in particular pyrrolidinyl.

In some embodiments of a compound of formula (Ik) or (Im), L is a direct bond, L₁-L₂, and L₁ is selected from O and a direct bond, e.g. O. In some embodiments of a compound of formula (Im), L is a direct bond.

In some embodiments, R₃ is R₄R₅N, wherein R₄ and R₅ together with the nitrogen atom to which they are both attached form a 5- or 6-membered heterocyclic ring, which ring optionally contains one or more further heteroatoms and which ring is optionally substituted by one or more moieties R₆; or a cyclic moiety Q₁ selected from 3-to 10-membered, monocyclic or bicyclic carbocyclyl, and 5- to 10-membered, monocyclic or bicyclic heterocyclyl, said cyclic moiety being attached to L by a bond to a carbon atom of the cyclic moiety and said cyclic moiety optionally being substituted by one or more moieties R₆.

In some embodiments of a compound of formula (I): R₃ is H, R₄R₅N, or a moiety of formula (II)

as defined herein; and R₄ and R₅ are independently selected from H and C1-C6 alkyl; or R₄ and R₅ together with the nitrogen atom to which they are both attached form a moiety of formula (III),

as defined herein.

In some particular embodiments of a compound of formula (I), R₃ is H or a moiety of formula (II) as defined herein, e.g. R₃ is H or a moiety of formula (Ila) as defined herein, or R₃ is H or a moiety of formula (lib) as defined herein. In some other particular embodiments of a compound of formula (I), R₃ is R₄R₅N or a moiety of formula (II) as defined herein, e.g. R₃ is R₄R₅N or a moiety of formula (Ila) as defined herein, or R₃ is R₄R₅N or a moiety of formula (IIb) as defined herein.

In some other particular embodiments of a compound of formula (I), R₃ is a moiety of formula (II) or a moiety of formula (III) as defined herein.

In a compound of formula (I), each R₆ is independently selected from C1-C6 alkyl, halogen, R₇O(CH₂)n, R₈S(O)₂(CH₂)_o, R₉R₁₀N(CH₂)_P, and R₁₁(CH₂)_q. In some embodiments, each R₆ is independently selected from halogen, R₇O(CH₂)_n, R₈S(O)₂(CH₂)_o, R₉R₁₀N(CH₂)_P, and R₁₁(CH₂)q. In some embodiments, each R₆ is independently selected from C1-C6 alkyl, R₇O(CH₂)n, R₈S(O)₂(CH₂)_o, R₉R₁₀N(CH₂)_P, and R₁₁(CH₂)_q. In some embodiments, each R₆ is independently selected from C1-C6 alkyl, halogen, R₇O(CH₂)_n, R₉R₁₀N(CH₂)_P, and R₁₁(CH₂)_q. In some embodiments, each R₆ is independently selected from C1-C6 alkyl, halogen, R₇O(CH₂)_n, R₈S(O)₂(CH₂)_o, and R₁₁(CH₂)_q. In some embodiments, each R₆ is independently selected from C1-C6 alkyl, halogen, R₇O(CH₂)_n, R₈S(O)₂(CH₂)_o, and R₉R₁₀N(CH₂)_P.

In some further embodiments, each R₆ is independently selected from halogen, R₇O(CH₂)_n, R₉R₁₀N(CH₂)_P, and R₁₁(CH₂)_q. In still further embodiments, each R₆ is independently selected from C1-C6 alkyl, R₇O(CH₂)_n, R₉R₁₀N(CH₂)_P, and R₁₁(CH₂)_q. In still further embodiments, each R₆ is independently selected from C1-C6 alkyl, halogen, R₇O(CH₂)_n, and R₁₁(CH₂)_q. In still further embodiments, each R₆ is independently selected from C1-C6 alkyl, halogen, R₇O(CH₂)_n, and R₉RIQN(CH₂)_P. In still further embodiments, each R₆ is independently selected from C1-C6 alkyl, halogen, and R₇O(CH₂)_n.

In some embodiments, when the compound of formula (I) comprises more than one R₆, at least one R₆ is selected from C1-C6 alkyl and halogen, e.g. from C-C3 alkyl and halogen, e.g. methyl and F. In some further embodiments, when the compound of formula (I) comprises more than one R₆, one R₆ is selected from R₇O(CH₂)_n, R₈S(O)₂(CH₂)_o, R₉R₁₀N(CH₂)_P, and R₁₁(CH₂)_q; and any further R₆ is selected from C1-C6 alkyl and halogen. For example, in some embodiments of a compound of formula (Ij), one R₆ in para or meta position is selected from C1-C6 alkyl, halogen, R₇O(CH₂)_n, R₈S(O)₂(CH₂)_o, R₉R₁₀N(CH₂)_P, and R₁₁(CH₂)_q, and any further R₆ is selected from C1-C6 alkyl and halogen, e.g. methyl and F. In some embodiments of a compound of formula (Ij), one R₆ is in para position and is selected from C1-C6 alkyl, halogen, R₇O(CH₂)_n, R₈S(O)₂(CH₂)_o, R₉R₁₀N(CH₂)_P, and R₁₁(CH₂)_q, and any further R₆ is selected from C1-C6 alkyl and halogen.

When R₆ is C1-C6 alkyl, said alkyl optionally is substituted by one or more F. In some embodiments, said alkyl more particularly is selected from C1-C4 alkyl, or from C1-C3 alkyl, e.g. from methyl and isopropyl, optionally substituted by one or more F. In some embodiments, when R₆ is C1-C6 alkyl optionally substituted by one or more F, R₆ more particularly is selected from trifluoromethyl and isopropyl, e.g. R₆ is isopropyl.

In some embodiments, the compound of formula (I) comprises a moiety R₆ selected from Cl- C6 alkyl. In some embodiments, the compound of formula (I) comprises a moiety R₆ in para position selected from C1-C6 alkyl, e.g. from C2-C6 alkyl, or from C2-C4 alkyl, e.g. isopropyl.

In some embodiments, the compound of formula (I) comprises a moiety R₆ that is halogen. When R₆ is halogen, said halogen in particular may be selected from F and Cl. In some embodiments, when R₆ is halogen, said halogen is F.

In some embodiments, the compound of formula (I) comprises a moiety R₆ that is R₇O(CH₂)_n. In R₇O(CH₂)_n the moiety R₇ is selected from H, C1-C6 alkyl, R_7aR_7bN(CH₂)_r, R_7cR₇dNC(O)(CH₂)_s, and R_7e(CH₂)_t. In some embodiments, R₇ is selected from H, C1-C6 alkyl, R_7aR_7bN(CH₂)_r, and R_7e(CH₂)_t. In some embodiments, R₇ is selected from H, C1-C6 alkyl, and R_7e(CH₂)_t. In some embodiments, R₇ is selected from H and C1-C6 alkyl. In some embodiments, R₇ is selected from R_7aR_7bN(CH₂)_r and R_7e(CH₂)_t. In still other embodiments, R₇ is H.

When R₇ is C1-C6 alkyl, said alkyl optionally is substituted by one or more F. In some embodiments, said alkyl more particularly is selected from C1-C4 alkyl, or from C1-C3 alkyl, e.g. R₇ is methyl, and is optionally substituted by one or more F. In some embodiments, said alkyl is methyl or trifluoromethyl.

In some embodiments, R₇ is R_7aR_7bN(CH₂)_r. In the moiety R_7aR_7bN(CH₂)_r, R_7a and R_7b are independently selected from H and C1-C6 alkyl; or R_7a and R_7b together with the nitrogen atom to which they are both attached form a 5- or 6-membered heterocyclic ring, which ring optionally contains one or more (e.g. 1 or 2, in particular 1) further heteroatoms and optionally is substituted by one or more C1-C6 alkyl.

In some embodiments, R_7a and R_7b are independently selected from H and C1-C6 alkyl, e.g. both R_7a and R_7b are selected from C1-C6 alkyl.

When any one of R_7a and R_7b is C1-C6 alkyl, said alkyl optionally is substituted by one or more F. In some embodiments, said alkyl more particularly is selected from C1-C4 alkyl, or from C1-C3 alkyl, e.g. from methyl, ethyl and isopropyl.

In some embodiments, R_7a and R_7b together with the nitrogen atom to which they are both attached form a 5- or 6-membered heterocyclic ring, which ring optionally contains one or more further heteroatoms, e.g one or more (e.g. 1 or 2, or 1) heteroatoms selected from N and O, and optionally is substituted by one or more (e.g. 1, 2 or 3, or 1 or 2, or 1) C1-C6 alkyl, e.g. one or more C1-C3 alkyl, or one or more methyl. In some embodiments, when R_7a and R_7b together with the nitrogen atom to which they are both attached form a 5- or 6-membered heterocyclic ring, said ring is 6-membered, e.g. said ring is morpholinyl.

In some embodiments, in the moiety R_7aR_7bN(CH₂)_r, R_7aR_7bN is selected from dimethylamino, diethylamino, diisopropylamino, and morpholinyl.

In the moiety R_7aR_7bN(CH₂)_r, r is an integer of from 1 to 4. In some embodiments, r is an integer of from 1 to 3. In some further embodiments, r is an integer of from 2 to 4, e.g. r is 2 or 3. In some embodiments, r is 2. In some other embodiments, r is 3.

In some embodiments, the moiety R_7aR_7bN(CH₂)_r is selected from (dimethylamino)ethyl, 3- (diethylamino)propyl, (diisopropylamino)ethyl, and morpholin-4-ylethyl.

In some embodiments, R₇ is R_7cR₇dNC(O)(CH₂)_s. In the moiety R_7cR₇dNC(O)(CH₂)_s, R_7c and R₇d are independently selected from H and C1-C6 alkyl; or R_7c and R₇d together with the nitrogen atom to which they are both attached form a 5- or 6-membered heterocyclic ring, which ring optionally contains one or more further heteroatoms and optionally is substituted by one or more C1-C6 alkyl. In some embodiments, R_7c and R₇d are independently selected from H and C1-C6 alkyl, e.g. both R_7c and R₇d are selected from C1-C6 alkyl.

When any one of R_7c and R₇d is C1-C6 alkyl, said alkyl optionally is substituted by one or more F. In some embodiments, said alkyl more particularly is selected from C1-C4 alkyl, or from C1-C3 alkyl, e.g. from methyl, ethyl and isopropyl, in particular ethyl.

In some embodiments, R_7c and R₇d together with the nitrogen atom to which they are both attached form a 5- or 6-membered heterocyclic ring, which ring optionally contains one or more further heteroatoms, e.g one or more (e.g. 1 or 2, or 1) heteroatoms selected from N and O, and optionally is substituted by one or more (e.g. 1, 2 or 3, or 1 or 2, or 1) C1-C6 alkyl, e.g. one or more C1-C3 alkyl, or one or more methyl. In some embodiments, when R_7c and R₇d together with the nitrogen atom to which they are both attached form a 5- or 6-membered heterocyclic ring, said ring is 6-membered, e.g. said ring is morpholinyl.

In the moiety R₇cR₇dNC(O)(CH₂)_s, s is an integer of from 0 to 3. In some embodiments, s is an integer of from 1 to 3, e.g. s is 1 or 2, or s is 1. In some further embodiments, s is an integer of from 0 to 2, e.g. s is 0 or 1.

In some embodiments, R₇ is R_7e(CH₂)_t. In the moiety R_7e(CH₂)_t, R₇e is a cyclic moiety Q₂ selected from 5- or 6-membered carbocyclyl and 5- or 6-membered heterocyclyl, said cyclic moiety being attached to (CH₂)_t by a bond to a carbon atom of the cyclic moiety and said cyclic moiety optionally being substituted by one or more (e.g. 1, 2 or 3; or 1 or 2) C1-C6 alkyl.

In some embodiments, the cyclic moiety Q₂ (also referred to herein as “ring Q₂” or “Q₂”) is selected from phenyl and 5- or 6-membered heterocyclyl. In some embodiments, Q₂ is selected from phenyl and 5- or 6-membered heteroaryl. In some embodiments, Q₂ is selected from phenyl and 6-membered heteroaryl. In some other embodiments, Q₂ is selected from 5- or 6-membered heteroaryl. When Q₂ is substituted by one or more C1-C6 alkyl, said alkyl more particularly may be selected from C1-C3 alkyl, e.g. methyl. When Q₂ is 5- or 6- membered heterocyclyl, e.g. 5- or 6-membered heteroaryl, the heteroatoms may be selected from N, O and S, e.g. from N and O, and Q₂ may contain from 1 to 4 such heteroatoms, e.g. from 1 to 3 such heteroatoms, e.g. 1 or 2 such heteroatoms, or 1 such heteroatom. In some embodiments, Q₂ is selected from phenyl, pyridinyl, oxazolyl, piperidinyl, and tetrahydropyridinyl; e.g. from phenyl, pyridinyl, oxazolyl, and piperidinyl; or from phenyl, pyridinyl, and oxazolyl.

In the moiety R_7e(CH₂)_t, t is an integer of from 0 to 3. In some embodiments, t is an integer of from 0 to 2. In some embodiments, t is 0 or 1. In some embodiments, t is 0. In some other embodiments, t is 1.

In some embodiments, R₇ selected from H, methyl, trifluoromethyl, 2-(diethylamino)ethyl, 2- (diisopropylamino)ethyl, 3-(dimethylamino)propyl, 2-morpholin-4-ylethyl, 4-(2- (diethylamino)-2-oxoethyl, 1-methylpiperi din-3 -yl, benzyl, pyridin-4-ylmethyl, pyri din-3 -yl, (3,5-dimethylisoxazol-4-yl)methyl, and (3,5-dimethylisoxazol-4-yl)methyl.

For example, in some embodiments, the compound of formula (I) comprises a moiety R₇O(CH₂)n selected from hydroxy, methoxy, trifluoromethoxy, hydroxymethyl, 2- (diethylamino)ethoxy, 2-(diisopropylamino)ethoxy, 3-(dimethylamino)propoxy, 2-morpholin- 4-ylethoxy, 4-(2-(diethylamino)-2-oxoethoxy, (1-methylpiperi din-3 -yl)oxy, benzyloxy, pyridin-4-ylmethoxy, pyri din-3 -yloxy, (3,5-dimethylisoxazol-4-yl)methoxy, and (3,5- dimethylisoxazol-4-yl)methoxy.

In some embodiments, the compound of formula (I) comprises a moiety R₆ that is R8S(O)₂(CH₂)_O. In the moiety R₆S(O)₂(CH₂)_o, R₆ is selected from H and C1-C6 alkyl, e.g. from H and C1-C4 alkyl, or from H and C1-C3 alkyl, or H and methyl. In some embodiments R₆ is selected from C1-C6 alkyl, e.g. from C1-C4 alkyl, or from C1-C3 alkyl. In some embodiments R₆ is methyl. In the moiety R₆S(O)₂(CH₂)_o, o is an integer of from 0 to 3, e.g. from 0 to 2. In some embodiments, o is 0 or 1. In some embodiments, o is 0, i.e. the moiety is RSS(O)₂. In some embodiments, R₆S(O)₂(CH₂)_o is methyl sulfonyl.

In some embodiments, the compound of formula (I) comprises a moiety R₆ that is R₉R₁₀N(CH₂)_P. In the moiety R₉R₁₀N(CH₂)_P, R₉ and R₁₀ are independently selected from H and C1-C6 alkyl; or R₉ and R₁₀ together with the nitrogen atom to which they are both attached form a 4- to 6-membered heterocyclic ring, said ring optionally containing one more heteroatoms and said ring optionally being substituted by one or more moieties R₁₂. In some embodiments, when R₉ and R₁₀ are independently selected from H and C1-C6 alkyl, R₉ and R₁₀ more particularly are selected from H and C1-C4 alkyl, or from H and C1-C3 alkyl, e.g. from H and methyl, e.g both are H.

In some embodiments, R₉ and R₁₀ together with the nitrogen atom to which they are both attached form a 4- to 6-membered heterocyclic ring (e.g. a 5- or 6-membered heterocyclic ring), which ring optionally contains one or more further heteroatoms, e.g one or more (e.g. 1 or 2; or 1) heteroatoms selected from N and O, and optionally is substituted by one or more (e.g. 1, 2 or 3; or 1 or 2; or 1) R₁₂. In some embodiments, when R₉ and R₁₀ together with the nitrogen atom to which they are both attached form a 4- to 6-membered heterocyclic ring, said ring is saturated, e.g. said ring is 6-membered, and saturated and optionally contains one further heteroatom selected from N and O. In some embodiments, R₉R10N is selected from piperidinyl, piperazinyl and morpholinyl.

In the moiety R₉ R₁₀N(CH₂)_P, p is an integer of from 0 to 3. In some embodiments, p is an integer of from 0 to 2. In some further embodiments, p is 0 or 1. In some embodiments, p is 0. In some further embodiments, p is 1.

In some embodiments, any moiety R₉R₁₀N(CH₂)_P is selected from aminomethyl, 4- ethylpiperazin-l-yl)methyl, 4-(diethylamino)piperidin-l-yl, piperidin-l-ylmethyl, (4- ethylpiperazin-l-yl)methyl, 2,6-dimethylmorpholin-4-yl]methyl, and (4-(tert- butoxy carbonyl)piperazin- 1 -yl)methyl .

In some embodiments, the compound of formula (I) comprises a moiety R₅ that is R₁₁(CH₂)_q. In the moiety R₁₁(CH₂)_q, R11 is a cyclic moiety Q₃ selected from 3- to 6-membered carbocyclyl and 4- to 6-membered heterocyclyl, said cyclic moiety being attached to (CH₂)_q by a bond to a carbon atom of the cyclic moiety and said cyclic moiety optionally being substituted by one or more moieties R₁₂.

In some embodiments, R₁₁ is a cyclic moiety Q₃ selected from 5- or 6-membered carbocyclyl and 5- or 6-membered heterocyclyl, said cyclic moiety being attached to (CH₂)_q by a bond to a carbon atom of the cyclic moiety and said cyclic moiety optionally being substituted by one or more moieties R₁₂. In some embodiments, the cyclic moiety Q₃ (also referred to as “ring Q₃” or “Q₃”) is selected from 6-membered carbocyclyl and 6-membered heterocyclyl. In some further embodiments, Q₃ is selected from phenyl and 5- or 6-membered heterocyclyl, wherein the heterocyclyl is saturated or unsaturated and aromatic or non-aromatic. In still further embodiments, Q₃ is selected from phenyl and 5- or 6-membered heteroaryl. In some particular embodiments, In some other embodiments, Q₃ is selected from phenyl and non-aromatic 5- or 6-membered heterocyclyl. In some particular embodiments, Q₃ is phenyl. In some other embodiments, 5- or 6-membered heterocyclyl, e.g. Q₃ is 6-membered heterocyclyl. When Q₃ is 5- or 6- membered heterocyclyl, e.g. 6-membered heterocyclyl, the heteroatoms may be selected from N, O and S, e.g. from N and O, and Q₃ may contain from 1 to 4 such heteroatoms, e.g. from 1 to 3 such heteroatoms, e.g. 1 or 2 such heteroatoms, or 1 such heteroatom. In some embodiments, Q₃ is selected from phenyl, pyridinyl, oxazolyl, piperidinyl, and tetrahydropyridinyl, e.g. from phenyl and tetrahydropyridinyl.

In some further embodiments, when Q₃ is 3- to 6-membered carbocyclyl, Q₃ is selected from C3-C6 cycloalkyl and phenyl.

In the moiety R₁₁(CH₂)_q, q is an integer of from 0 to 3. In some embodiments, q is an integer of from 0 to 2. In some further embodiments, q is 0 or 1. In some embodiments, q is 0.

In some embodiments, any moiety R₁₁(CH₂)_qis selected from phenyl, 4- (dimethylamino)methyl)phenyl, l,2,3,6-tetrahydropyridin-4-yl, and 4-fluorophenyl.

In some embodiments, the compound of formula (I) comprises one or more moieties R₁₂, e.g. 1, 2 or 3 moieties R₁₂, in particular 1 or 2 moieties R₁₂, such as 1 moiety R₁₂, each R₁₂ being independently selected from halogen, C1-C6 alkyl, R₁₃R₁₄N(CH₂)_u, and R₁₅OC(O)(CH₂)v.

In some embodiments, each R₁₂ is independently selected from halogen, C1-C6 alkyl, and R₁₃R₁₄N(CH₂)u. In some further embodiments, each R₁₂ is independently selected from halogen and C1-C6 alkyl. In still further embodiments, each R₁₂ is independently selected from C1-C6 alkyl.

When any R₁₂ is selected from halogen, said halogen e.g. may be F or Cl, in particular F. When any R₁₁ is C1-C6 alkyl said C1-C6 alkyl e.g. may be selected from C1-C4 alkyl, or from C1-C3 alkyl, e.g. from methyl and ethyl.

In the moiety R₁₃R₁₄N(CH₂)_u, RD and Ru are independently selected from H and C1-C6 alkyl, or from H and C1-C4 alkyl, or from H and C1-C3 alkyl; or from C1-C6 alkyl, or from C1-C4 alkyl, or from C1-C3 alkyl, e.g. from methyl and ethyl; and u is an integer of from 0 to 3, e.g. from 0 to 2; e.g. u is 0 or 1.

In the moiety R₁₅OC(O)(CH₂)_v, R₁₅ is selected from H and C1-C6 alkyl, e.g. from H and Cl- C4 alkyl; and v is an integer is an integer of from 0 to 3, e.g. from 0 to 2; e.g. v is 0 or 1. In some embodiments, R₁₅ is selected from C1-C6 alkyl, e.g. from C1-C4 alkyl. In some embodiments, when R₁₂ is attached to a heterocyclic ring and v is 0, R₁₅OC(O) is attached to a nitrogen atom present in the heterocyclic ring.

In some particular embodiments, the compound of formula (I) comprises a moiety R₁₅OC(O) attached to a nitrogen atom of a heterocyclic ring Q₃ or a heterocyclic ring formed by R₉ and R₁₀.

In some embodiments, any R₁₂ is selected from fluoro, methyl, ethyl, diethylamino, and (dimethylamino)methyl.

From the above, it should be understood that the compound of formula (I) may vary with respect to various features, such as the ring containing W, X, Y and Z, as e.g. represented by formulas (la), (lb), (Ic), (Id), and (le); the linking moiety L, as e.g. represented by formulas (If), and (Ig); and the moiety R₃, as e.g. represented by formulas (Ih), (li), (Ij), (Ik) and (Im). It should be realized that unless mutually exclusive and unless otherwise specified, any combination of the various embodiments lies within the scope of the invention as defined by formula (I). Thus, in some embodiments, a compound of formula (la), or (lb), or (Ic), or (Id), also is a compound of formula (If).

In some particular embodiments, a compound of formula (le) also is a compound of formula (If), and thus may be represented by formula (In)

wherein X, Y, R₁, R₂ and R₃ are as defined herein.

In some other embodiments, a compound of formula (la), or (lb), or (Ic), or (Id), in particular (le) also is a compound of formula (Ig).

In still further embodiments, a compound of formula (la), (lb), (Ic), (Id), (le), and (If) or (Ig), also is a compound of formula (Ih), (li), (Ij), (Ik) or (Im). Thus, in some particular embodiments, a compound of formula (If) also is a compound of formula (Ih), and may be represented by formula (Io)

wherein X, Y, Z, W, ring Q₁, R₁, R₂, each R₆, and i are as defined herein.

In some further embodiments, a compound of formula (If) also is a compound of formula (li), i.e. a compound that may be represented by formula (Ip)

wherein X, Y, Z, W, R₁, R₂, each R₆, and i are as defined herein.

In still some further embodiments, a compound of formula (If) also is a compound of formula (Ij), i.e. a compound that may be represented by formula (Iq)

wherein X, Y, Z, G₁, G₂, R₁, R₂, each R₆, and j are as defined herein. In some further particular embodiments of a compound of formula (I), Q₁ is a phenyl ring optionally substituted by one R₆ and said R₆ is in para position, i.e. the compound may be represented by formula (Ir)

wherein X, Y, Z, W, R₁, R₂, R₆, and L are as defined herein, and i is 0 or 1.

In some particular embodiments of a compound of formula (Id), (le), (If), (Ig), (Ih), (li), (Ij), (Ik), (Ik), (Im), (In), (Io), (Ip), (Iq) or (Ir), (Io), (Ip), (Iq), or (Ir), X is N.

In some particular embodiments of a compound of formula (If), (Ig), (Ih), (li), (Ij), (Ik), (Ik), (Im), (Io), (Ip), (Iq) or (Ir), (Io), (Ip), (Iq), or (Ir), X and W are N.

In some particular embodiments of a compound of formula (If), (Ig), (Ih), (li), (Ij), (Ik), (Ik), (Im), (Io), (Ip), (Iq) or (Ir), (Io), (Ip), (Iq), or (Ir), X and W are N, R₂ is attached to Y, and R₃- L is attached to Z.

In some other particular embodiments of a compound of formula (If), (Ig), (Ih), (li), (Ij), (Ik), (Ik), (Im), (Io), (Ip), (Iq) or (Ir), (Io), (Ip), (Iq), or (Ir), X and W are N, R₂ is attached to Z, and R₃-L is attached to Y.

In some embodiments of a compound of formula (I), e.g. of formula (Ih), (li), (Ij), (Io), (Ip), (Iq), or (Ir), R₆ is selected from C1-C6 alkyl, R₇O(CH₂)n and R₁₁(CH₂)_q.

In some embodiments of a compound of formula (I), e.g. of formula (Ih), (li), (Ij), (Io), (Ip), (Iq), or (Ir), R₆ is selected from C1-C6 alkyl, R₇O(CH₂)n and R₁₁(CH₂)_q;

R11 is phenyl optionally substituted by 1 or 2 moi eties R₁₂, e.g. 1 moeity R₁₂; and

R₇ is R_7aR_7bN(CH₂)_r, or R₇e(CH₂)_t. In some embodiments of a compound of formula (I), e.g. of formula (Ih), (li), (Ij), (Io), (Ip), (Iq), or (Ir), R₆ is selected from C1-C6 alkyl, R₇O(CH₂)n and R₁₁(CH₂)_q; R₁₁ is phenyl optionally substituted by 1 or 2 moi eties R₁₂, e.g. 1 moiety R₁₂; and R₇ is R_7aR_7bN(CH₂)_r, or R₇e(CH₂)_t; and R₇c is phenyl or 5- or 6-membered heteroaryl; optionally substituted by one or more C1-C6 alkyl, e.g. one or more C1-C3 alkyl, such as one or more methyl.

In some embodiments of a compound of formula (I), e.g. of formula (Ih), (li), (Ij), (Io), (Ip), (Iq), or (Ir), R₆ is selected from C1-C6 alkyl, R₇O(CH₂)_n and R₁₁(CH₂)_q; R₁₁ is phenyl optionally substituted by one moiety R₁₂;

R₇ is R_7aR_7bN(CH₂)_r, or R₇e(CH₂)_t; R_7a and R_7b are independently selected from C1-C6 alkyl, e.g. from C1-C3 alkyl; R_7c is phenyl or 5- or 6-membered heteroaryl; optionally substituted by one or more C1-C6 alkyl, e.g. one or more C1-C3 alkyl, such as one or more methyl; R₁₂ is R₁₃R₁₄N(CH₂)u; and R₁₃ and R14 are independently selected from C1-C6 alkyl, e.g. from C1-C3 alkyl.

In some of these embodiments, n is 0; q is 0; r is 2 or 3; t is 1; and u is 1 or 2; e.g. n and q are 0, r is 2, and t and u are 1.

In some embodiments of a compound of formula (I), e.g. of formula (Ih), (li), (Ij), (Io), (Ip), (Iq), or (Ir), R₅ is R₁₁(CH₂)_q and R₁₁ is phenyl optionally substituted by one moiety R₁₂.

In some of the above embodiments, R₁₁ is phenyl optionally substituted by one moiety R₁₂, which moiety is in para position on the phenyl ring.

In some of further of the above embodiments, R₁₁ is phenyl substituted by R₁₃R₁₄N(CH₂)_u; and R₁₃ and R14 are independently selected from C1-C6 alkyl, e.g. from C1-C3 alkyl.

In some of the above embodiments, q is 0; and u is 1 or 2, e.g. q is 0 and u is 1. In some embodiments of a compound of formula (I), e.g. of formula (Ih), (li), (Ij), (Io), (Ip), (Iq), or (Ir), R₆ is C1-C6 alkyl.

In some embodiments of a compound of formula (I), e.g. of formula (Ih), (li), (Ij), (Io), (Ip), (Iq), or (Ir), R₆ is R₇O(CH₂)_n;

R₇ is R_7aR_7bN(CH₂)_r, or R_7e(CH₂)_t;

R_7a and R_7b are independently selected from C1-C6 alkyl, e.g from C1-C3 alkyl; and

R_7e is phenyl or 5- or 6-membered heteroaryl; optionally substituted by one or more C1-C6 alkyl, e.g. one or more C1-C3 alkyl, such as one or more methyl.

In some of the above embodiments, n is 0; r is 2 or 3; and t is 1 or 2; e.g. n is 0, r is 2 and t is 1.

R₇ is R_7e(CH₂)_t;

In some of the above embodiments, n is 0; and t is 1 or 2; e.g. n is 0, and t is 1.

In some embodiments of a compound of formula (I), e.g. of formula (Ih), (li), (Ij), (Io), (Ip), (Iq), or (Ir), R₆ is selected from R₇O(CH₂)_n and R₁₁(CH₂)_q;

R₇ is R_7e(CH₂)_t;

R_7e is phenyl or 5- or 6-membered heteroaryl; optionally substituted by one or more C1-C6 alkyl, e.g. one or more C1-C3 alkyl, such as one or more methyl; and R₁₁ is phenyl optionally substituted by one or more moi eties RI₂; e.g. R₁₁ is phenyl optionally substituted by 1 or 2 moieties RI₂, or phenyl optionally substituted by one moiety RI₂.

In some of the above embodiments, n is 0; q is 0; and t is lor 2; e.g. n and q are 0 and t is 1. In some of these embodiments, R₁₁ is phenyl optionally substituted by one moiety R₁₂, e.g. one moiety R₁₂ in para position; e.g a moiety R₁₃R₁₄N(CH₂)_u in para position.

In some particular embodiments, the compound may be represented by formula (Is)

wherein X, Y, Z, W, R₁, R₂, R₁₂, and L are as defined herein, and x is an integer of from 0 to 3, e.g. x is an integer of from 0 to 2, or x is 0 or 1, e.g. x is 1; e.g. x is 1 and R₁₂ is in para position. In some embodiments of a compound of formula (Is), L is a direct bond. In some embodiments of a compound of formula (Is), L is a direct bond, x is 1 and R₁₂ is as defined herein, e.g. R₁₂ is R₁₃R₁₄N(CH₂)_u. In some embodiments, a compound of formula (Is) also is a compound of formula (la), or (lb), or (Ic), or (Id), or (le). In some embodiments, the compound of formula (Is) also is a compound of formula (le) wherein X is N.

In some embodiments of a compound of formula (I), e.g. of formula (Ih), (li), (Ij), (Io), (Ip), or (Iq), at least one R₆ is halogen; e.g. 1 or 2 R₆ are halogen.

In some further embodiments of a compound of formula (I) R₃ is H, R₄R₅N, or a cyclic moiety Q₁ selected from phenyl, C6-C8 cycloalkyl, and 5- to 9- membered heteroaryl, said cyclic moiety being attached to L by a bond to a carbon atom of the cyclic moiety and said cyclic moiety optionally being substituted by 1 or 2 moi eties R₆; R₄ and R₅ are independently selected from H and C1-C6 alkyl; or R₄ and R₅ together with the nitrogen atom to which they are both attached form a 5- or 6-membered heterocyclic ring, which ring optionally contains one further heteroatom selected from N and O, and which ring optionally is substituted by 1 or 2 moieties R₆; each R₆ is independently selected from C1-C6 alkyl, halogen, R₇O(CH₂)_n, R₆S(O)₂(CH₂)_o, R₉R₁₀N(CH₂)_P, and R₁₁(CH₂)_q;

R_7a and R_7b are independently selected from H and C1-C6 alkyl; or R_7a and R_7b together with the nitrogen atom to which they are both attached form a 5- or 6-membered heterocyclic ring, which ring optionally contains one further heteroatom selected from N and O, and which ring optionally is substituted by 1 or 2 C1-C6 alkyl; R_7c and R_7a are independently selected from H and C1-C6 alkyl;

R_7e is a cyclic moiety Q₂ selected from phenyl and 5- or 6-membered heteroaryl, said cyclic moiety being attached to (CH₂)_t by a bond to a carbon atom of the cyclic moiety and said cyclic moiety optionally being substituted by 1 or 2 C1-C6 alkyl; R₆ is C1-C6 alkyl; R₉ and R₁₀ are independently selected from H and C1-C6 alkyl; or R₉ and R₁₀ together with the nitrogen atom to which they are both attached form a 5- or 6-membered heterocyclic ring, which ring optionally contains one further heteroatom selected from N and O, and which ring optionally is substituted by 1 or 2 moieties R₁₂;

R11 is a cyclic moiety Q₃ selected from phenyl and 5- or 6-membered heterocyclyl containing 1 or 2 heteroatoms selected from N and O, said cyclic moiety being attached to (CH₂)_q by a bond to a carbon atom of the cyclic moiety and said cyclic moiety optionally being substituted by 1 or 2 moieties R₁₂; each R₁₂ is independently selected from halogen, C1-C6 alkyl, R₁₃R₁₄N(CH₂)_u, and RI₅OC(O)(CH₂)_V; each R₁₃, R₁₄ and R₁₅ is independently selected from C1-C6 alkyl; n, o, p, q, s, t, u, and v are independently selected from 0 and 1; r is 2 or 3; and any alkyl is optionally substituted by one or more F.

In some embodiments of a compound of formula (I), each one of Q₁, Q₂ and Q₃ is phenyl or 5- or 6-membered heteroaryl.

In some particular embodiments of a compound of formula (I) R₃ is a cyclic moiety selected from phenyl and 5- or 6-membered heteroaryl, said cyclic moiety being attached to L by a bond to a carbon atom of the cyclic moiety and said cyclic moiety optionally being substituted by 1 or 2 moieties R₆; each R₆ is independently selected from C1-C6 alkyl, halogen, R₇O(CH₂)_n, R₆S(O)₂(CH₂)_o, R₉R₁₀N(CH₂)_P, and R₁₁(CH₂)_q;

R_7a and R_7b are independently selected from H and C1-C6 alkyl; or R_7a and R_7b together with the nitrogen atom to which they are both attached form a 5- or 6-membered heterocyclic ring, which ring optionally contains one further heteroatom selected from N and O, and which ring optionally is substituted by 1 or 2 C1-C6 alkyl; R_7c and R₇d are independently selected from H and C1-C6 alkyl;

R11 is a cyclic moiety Q₃ selected from phenyl and 5- or 6-membered heteroaryl containing 1 or 2 heteroatoms selected from N and O, said cyclic moiety being attached to (CH₂)_q by a bond to a carbon atom of the cyclic moiety and said cyclic moiety optionally being substituted by 1 or 2 moieties R₁₂; each R₁₂ is independently selected from halogen, C1-C6 alkyl, R₁₃R₁₄N(CH₂)_u, and R₁₅OC(O)(CH₂)_V; each R₁₃, R₁₄ and R₁₅ is independently selected from C1-C6 alkyl; n, o, p, q, s, t, u, and v are independently selected from 0 and 1; r is 2 or 3; and any alkyl is optionally substituted by one or more F.

In some embodiments, each one of Q₂ and Q₃ is phenyl.

R_7a and R_7b are independently selected from H and C1-C6 alkyl; or R_7a and R_7b together with the nitrogen atom to which they are both attached form a 5- or 6-membered heterocyclic ring, which ring optionally contains one further heteroatom selected from N and O, and which ring optionally is substituted by 1 or 2 C1-C6 alkyl;

R_7C and R₇d are independently selected from H and C1-C6 alkyl; R_7e is phenyl, optionally substituted by 1 or 2 C1-C6 alkyl; R₆ is C1-C6 alkyl; R₉ and R₁₀ are independently selected from H and C1-C6 alkyl; or R₉ and R₁₀ together with the nitrogen atom to which they are both attached form a 5- or 6-membered heterocyclic ring, which ring optionally contains one further heteroatom selected from N and O, and which ring optionally is substituted by 1 or 2 moieties R₁₂;

R₁₁ is phenyl, optionally substituted by 1 or 2 moieties R₁₂; each R₁₂ is independently selected from halogen, C1-C6 alkyl, R₁₃R₁₄N(CH₂)_u, and R₁₅OC(O)(CH₂)_V; each R₁₃, R₁₄ and R₁₅ is independently selected from C1-C6 alkyl; n, o, p, q, s, t, u, and v are independently selected from 0 and 1; r is 2 or 3; and any alkyl is optionally substituted by one or more F.

In some embodiments, each one of QI, Q₂ and Q₃ is phenyl.

In some particular embodiments of a compound of formula (I) R₃ is phenyl, optionally substituted by 1 or 2 moieties R₆; each R₆ is independently selected from C1-C6 alkyl, halogen, R₇O(CH₂)_n, R₆S(O)₂(CH₂)_o, R₉R₁₀N(CH₂)_P, and R₁₁(CH₂)_q;

R_7c and R_7d are independently selected from H and C1-C6 alkyl;

R_7e is phenyl, optionally substituted by 1 or 2 C1-C6 alkyl; R₆ is C1-C6 alkyl; R₉ and R₁₀ are independently selected from H and C1-C6 alkyl; or R₉ and R₁₀ together with the nitrogen atom to which they are both attached form a 5- or 6-membered heterocyclic ring, which ring optionally contains one further heteroatom selected from N and O, and which ring optionally is substituted by 1 or 2 moieties R₁₂;

R11 is phenyl, optionally substituted by 1 or 2 moieties R₁₂; each R₁₁ is independently selected from halogen, C1-C6 alkyl, R₁₃R₁₄N(CH₂)_u, and RI₅OC(O)(CH₂)_V; each R₁₃, R₁₄ and R₁₅ is independently selected from C1-C6 alkyl; n, o, p, q, s, t, u, and v are independently selected from 0 and 1; r is 2 or 3; and any alkyl is optionally substituted by one or more F.

In some embodiments, when R₃ is phenyl, said phenyl is substituted by 1, 2 or 3 moi eties R₆, e.g. by 1 or 2 moieties R₆, in particular by one moiety R₆.

In some particular embodiments of a compound of formula (I) R₃ is phenyl, optionally substituted by 1 or 2 moieties R₆; each R₆ is independently selected from C1-C6 alkyl, halogen, R₇O(CH₂)n, R₉R₁₀N(CH₂)_P, and R₁₁(CH₂)_q; R₇ is selected from H, C1-C6 alkyl, R_7aR_7bN(CH₂)_r, and R₇e(CH₂)_t; R_7a and R_7b are independently selected from H and C1-C6 alkyl; or R_7a and R_7b together with the nitrogen atom to which they are both attached form a 5- or 6-membered heterocyclic ring, which ring optionally contains one further heteroatom selected from N and O, and which ring optionally is substituted by 1 or 2 C1-C6 alkyl; R_7c is phenyl, optionally substituted by 1 or 2 C1-C6 alkyl; R₉ and R₁₀ are independently selected from H and C1-C6 alkyl; or R₉ and R₁₀ together with the nitrogen atom to which they are both attached form a 5- or 6-membered heterocyclic ring, which ring optionally contains one further heteroatom selected from N and O, and which ring optionally is substituted by 1 or 2 moieties R₁₂; R₁₁ is phenyl, optionally substituted by 1 or 2 moieties R₁₂; each R₁₂ is independently selected from halogen, C1-C6 alkyl, R₁₃R₁₄N(CH₂)_u, and RI₅OC(O)(CH₂)_V; each R₁₃, R14 and R₁₅ is independently selected from C1-C6 alkyl; n, p, q, t, u, and v are independently selected from 0 and 1; r is 2 or 3; and any alkyl is optionally substituted by one or more F.

In some of the above embodiments, when the cyclic moiety Q₁ is substituted by more than one R₆, one R₆ is as indicated herein above, and any further R₆ is selected from C1-C6 alkyl and halogen, e.g. from C1-C3 alkyl and halogen, in particular from methyl, F and Cl; or from F and Cl, e.g. any further R₆ is F.

In a compound of formula (I), n, o, p, q, s, t, u, and v are independently selected from 0, 1, 2 and 3; and r is 1, 2, 3 or 4. In some embodiments, n, o, p, q, s, t, u, and v are independently selected from 0, 1, and 2 and 3; and r is 1, 2, or 3. In some embodiments, n, o, p, q, s, t, u, and v are independently selected from 0, 1, and 2; and r is 2 or 3. In some embodiments, n, o, p, q, s, t, u, and v are independently selected from 0 and 1; and r is 2 or 3. In some embodiments, n, p, t and u are 0 or 1; o, q and v are 0; r is 2 or 3; and s is 1.

Unless otherwise specified or apparent from the context, any reference made herein to a compound of formula (I) also should be construed as a reference to a compound of any of the formulas (la), (lb), (Ic), (Id), (le), (If), (Ig), (Ih), (li), (Ij), (Ik), (Im), (In), (Io), (Ip), (Iq), (Ir), or (Is).

Stereoisomers

Whenever a chiral carbon is present in the compound of formula (I), it is intended that all stereoisomers associated with that chiral carbon are encompassed formula (I), unless otherwise specified. Using the Cahn-Ingold-Prelog RS notational system, any asymmetric carbon atom may be present in the (R)- or (S)-configuration, and the compound may be present as a mixture of its stereoisomers, e.g. a racemic (equal) or unequal mixture, or one stereoisomer only. Stereoisomers include enantiomers and diastereomers.

Pharmaceutially acceptable salts

A pharmaceutically acceptable salt of the compound of formula (I) may be an acid addition salt or a base addition salt.

In the preparation of acid or base addition salts, such acids or bases are used which form suitable pharmaceutically acceptable salts. Examples of such acids are inorganic acids such as hydrohalogen acids, sulfuric acid, phosphoric acid, nitric acid; organic aliphatic, alicyclic, aromatic or heterocyclic carboxylic or sulfonic acids, such as formic acid, acetic acid, propionic acid, succinic acid, glycolic acid, lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, maleic acid, hydroxymaleic acid, pyruvic acid, p-hydroxybenzoic acid, embonic acid, methanesulfonic acid, ethanesulfonic acid, hydroxyethanesulfonic acid, halogenbenzenesulfonic acid, toluenesulfonic acid or naphthalenesulfonic acid. Base addition salts include those derived from inorganic bases, such as ammonium or alkali or alkaline earth metal hydroxides, carbonates, bicarbonates, and the like, and organic bases such as alkoxides, alkyl amides, alkyl and aryl amines, and the like. Examples of bases useful in preparing salts of the present invention include sodium hydroxide, potassium hydroxide, ammonium hydroxide, potassium carbonate, and the like.

Pharmaceutical formulations

A pharmaceutical composition according to the invention may be for topical (local) or systemic administration, e.g. for enteral administration, such as rectal or oral administration, or for parenteral administration to a mammal (especially a human), and comprises a therapeutically effective amount of a compound according to the invention or a pharmaceutically acceptable salt thereof, as active ingredient, in association with a pharmaceutically acceptable excipient, e.g. a pharmaceutically acceptable carrier. The therapeutically effective amount of the active ingredient is as defined herein above and depends e.g. on the species of mammal, the body weight, the age, the individual condition, individual pharmacokinetic data, the disease to be treated and the mode of administration.

For enteral, e.g. oral, administration, the compounds of the invention may be formulated in a wide variety of dosage forms. The pharmaceutical compositions and dosage forms may comprise a compound or compounds of the present invention or pharmaceutically acceptable salt(s) thereof as the active component. The pharmaceutically acceptable carriers may be either solid or liquid. Solid form preparations include powders, tablets, pills, lozenges, capsules, cachets, suppositories, and dispersible granules. A solid carrier may be one or more substances which may also act as diluents, flavouring agents, solubilizers, lubricants, suspending agents, binders, preservatives, tablet disintegrating agents, or an encapsulating material. In powders, the carrier generally is a finely divided solid which is a mixture with the finely divided active component. In tablets, the active component generally is mixed with the carrier having the necessary binding capacity in suitable proportions and compacted in the shape and size desired. Suitable carriers include but are not limited to magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatine, tragacanth, methylcellulose, sodium carboxymethylcellulose, a low melting wax, cocoa butter, and the like. The formulation of the active compound may comprise an encapsulating material as carrier, providing a capsule in which the active component, with or without carriers, is surrounded by a carrier, which is in association with it.

Other forms suitable for oral administration include liquid form preparations including emulsions, syrups, elixirs, aqueous solutions, aqueous suspensions, or solid form preparations which are intended to be converted shortly before use to liquid form preparations. Emulsions may be prepared in solutions, for example, in aqueous propylene glycol solutions or may contain emulsifying agents, for example, such as lecithin, sorbitan monooleate, or acacia. Aqueous solutions can be prepared by dissolving the active component in water and adding suitable colorants, flavors, stabilizers, and thickening agents. Aqueous suspensions can be prepared by dispersing the finely divided active component in water with viscous material, such as natural or synthetic gums, resins, methylcellulose, sodium carboxymethylcellulose, and other well known suspending agents. Solid form preparations include solutions, suspensions, and emulsions, and may contain, in addition to the active component, colorants, flavors, stabilizers, buffers, artificial and natural sweeteners, dispersants, thickeners, solubilizing agents, and the like.

Exemplary compositions for rectal administration include suppositories which can contain, for example, a suitable non-irritating excipient, such as cocoa butter, synthetic glyceride esters or polyethylene glycols, which are solid at ordinary temperatures, but liquefy and/or dissolve in the rectal cavity to release the drug.

The compounds of the invention also may be administered parenterally, e.g. by inhalation, injection or infusion, e.g. by intravenous, intraarterial, intraosseous, intramuscular, intracerebral, intracerebroventricular, intrasynovial, intrastemal, intrathecal, intralesional, intracranial, intratumoral, intracutaneous and subcutaneous injection or infusion.

Thus, for parenteral administration, the pharmaceutical compositions of the invention may be in the form of a sterile injectable or infusible preparation, for example, as a sterile aqueous or oleaginous suspension. This suspension may be formulated according to techniques known in the art using suitable dispersing or wetting agents (e.g. Tween 80), and suspending agents. The sterile injectable or infusible preparation may also be a sterile injectable or infusible solution or suspension in a non-toxic parenterally acceptable diluent or solvent. For example, the pharmaceutical composition may be a solution in 1,3 -butanediol. Other examples of acceptable vehicles and solvents that may be employed in the compositions of the present invention include, but are not limited to, mannitol, water, Ringer's solution and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose, any bland fixed oil may be employed including synthetic mono- or di glycerides. Fatty acids, such as oleic acid and its glyceride derivatives are useful in the preparation of injectables, as are natural pharmaceutically acceptable oils, such as olive oil or castor oil, especially in their polyoxyethylated versions. These oil solutions or suspensions may also contain a long-chain alcohol diluent or dispersant.

Solutions for parenteral use also may contain suitable stabilizing agents, and if necessary, buffer substances. Suitable stabilizing agents include antioxidizing agents, such as sodium bisulfate, sodium sulfite or ascorbic acid, either alone or combined, citric acid and its salts and sodium EDTA. Parenteral solutions may also contain preservatives, such as benzalkonium chloride, methyl- or propyl-paraben, and chlorobutanol.

For inhalation or nasal administration, suitable pharmaceutical formulations are as particles, aerosols, powders, mists or droplets, e.g. with an average size of about 10 pm in diameter or less. For example, compositions for inhalation may be prepared as solutions in saline, employing benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, fluorocarbons, and/or other solubilizing or dispersing agents known in the art.

The pharmaceutical compositions of the invention also may be administered topically, to the skin or to a mucous membrane. For topical application, the pharmaceutical composition may be e.g. a lotion, a gel, a paste, a tincture, a transdermal patch, a gel for transmucosal delivery. The composition may be formulated with a suitable ointment containing the active components suspended or dissolved in a carrier. Carriers for topical administration of the compounds of this invention include, but are not limited to, mineral oil, liquid petroleum, white petroleum, propylene glycol, polyoxyethylene polyoxypropylene compound, emulsifying wax and water. Alternatively, the pharmaceutical composition may be formulated as a suitable lotion or cream containing the active compound suspended or dissolved in a carrier. Suitable carriers include, but are not limited to, mineral oil, sorbitan monostearate, polysorbate 60, cetyl esters wax, cetaryl alcohol, 2-octyldodecanol, benzyl alcohol and water. The pharmaceutical compositions of this invention may also be topically applied to the lower intestinal tract by rectal suppository formulation or in a suitable enema formulation. Suitable pharmaceutical excipients, e.g. carriers, and methods of preparing pharmaceutical dosage forms are described in Remington's Pharmaceutical Sciences, Mack Publishing Company, a standard reference text in art of drug formulation.

The pharmaceutical compositions may comprise from approximately 1 % to approximately 95%, preferably from approximately 20% to approximately 90% of a compound of formula (I), together with at least one pharmaceutically acceptable excipient. In general, the compounds of the invention will be administered in a therapeutically effective amount by any of the accepted modes of administration for agents that serve similar utilities. Suitable daily dosages typically ranges from 1 to 1000 mg, e.g. 1-500 mg daily, or 1-50 mg daily, depending upon numerous factors such as the severity of the disease to be treated, the age and relative health of the patient, the potency of the compound used, the route and form of administration, and the indication towards which the administration is directed, etc. One of ordinary skill in the art of treating such diseases will be able, without undue experimentation and in reliance upon personal knowledge and the disclosure of this application, to ascertain a therapeutically effective amount of the compounds of the present invention for a given disease. Compounds of the invention may be administered as pharmaceutical formulations including those suitable for enteral or parenteral administration. The preferred manner of administration is generally oral using a convenient daily dosage regimen which can be adjusted according to the degree of affliction.

The compounds of the present invention may also be used or administered in combination with one or more additional therapeutically active agents, e.g. drugs useful in the treatment of a disorder selected from autoimmune disorders, mental disorders, neurodegenerative disorders and cancers. The components may be in the same formulation or in separate formulations for administration simultaneously or sequentially.

In some embodiments, the compounds is used or administered in combination with dexamethasone.

Accordingly, in a further aspect of the invention, there is provided a combination product comprising:

(A) a compound of the invention, as defined herein; and (B) another therapeutic agent, e.g. one that is useful in the treatment of a disorder selected from autoimmune disorders, mental disorders, neurodegenerative disorders and cancers; whereby (A) and (B) is formulated in admixture with a pharmaceutically acceptable excipient.

In some embodiments, the combination product contains dexamethasone as the other therapeutic agent.

Such combination products provide for the administration of a compound of the invention in conjunction with the other therapeutic agent, and may thus be presented either as separate formulations, wherein at least one of those formulations comprises a compound of the invention, and at least one comprises the other therapeutic agent, or may be presented (i.e. formulated) as a combined preparation (i.e. presented as a single formulation including a compound of the invention and the other therapeutic agent).

Thus, there is further provided:

(1) a pharmaceutical formulation including a compound of the invention, as hereinbefore defined, another therapeutic agent, and a pharmaceutically acceptable excipient, e.g. an adjuvant, diluent or carrier; and

(2) a kit of parts comprising, as components:

(a) a pharmaceutical formulation including a compound of the invention, as defined herein, in admixture with a pharmaceutically acceptable excipient, e.g. an adjuvant, diluent or carrier; and

(b) a pharmaceutical formulation including another therapeutic agent in admixture with a pharmaceutically acceptable excipient, e.g. an adjuvant, diluent or carrier, which components (a) and (b) are each provided in a form that is suitable for administration in conjunction with the other.

The compounds of the present invention may also be used or administered in combination with other treatment such as irradiation for the treatment of cancer.

Methods of treatment

According to one aspect, the present invention relates to a method of treatment of a disease that responds to inhibition of histone deacetylase 6, e.g. a disorder selected from autoimmune disorders, neurodegenerative disorders, pain, and hyperproliferative disorders, such as cancers, which method comprises administering a therapeutically effective amount of a compound of formula (I), or pharmaceutically acceptable salt thereof, to a warm-blooded animal, e.g. a mammal, such as a human, in need of such treatment.

While the compounds of the invention may be administered to a subject in need of treatment e.g. by use of a pharmaceutical formulation and administration route as generally outlined herein above, it should be realized that precise treatment regime, e.g. dosage, will normally be determined by the treating physician.

In some embodiments, the disorder to be treated is an autoimmune disorder, such as any of the autoimmune disorders mentioned herein above, e.g. colitis, or allograft rejection.

In some embodiments, the disorder is a neurodegenerative disorder, such as any of the neurodegenerative disorders mentioned herein above, for example Alzheimer's disease, Parkinson's disease or Huntington's disease.

In some embodiments, the disorder is a mental disorder, such as any of the mental disorders referred to herein above, e.g. a depressive disorder or a stress-induced mental disorder.

In some embodiments, the disorder is a hyperproliferative disorder, such as any of the hyperproliferative disorders mentioned herein above, e.g, a malignant hyperproliferative disorder (cancer). For example, in some embodiments, the cancer is selected from pancreatic cancer, multiple myeloma, and plasmacytoma. In some particular embodiments, the cancer is pancreatic cancer. In som other particular embodiments, the cancer is multiple myeloma.

Methods of preparation

The compounds of formula (I) may be prepared by the person of ordinary skill in the art, using conventional methods of chemical synthesis. The preparation of some intermediates and compounds according to the present invention may in particular be illustrated by the following Schemes.

Compounds of formula (I) may for example be prepared according to the route shown in Scheme 1. A phenacyl bromide and methyl 3,4-diaminobenzoate in DMF are heated at 180 °C. Treatment of the ester with hydroxylamine potassium salt in methanol gives the hydoxamic acids (1) and (2) which can be separated by chromatography.

Compounds of formula (I) may for example be prepared according to the route shown in Scheme 2. Methyl 3,4-diaminobenzoate and ethyl glycoxalate are condensed to give a mixture of methyl 3-oxo-3,4-dihydroquinoxaline and methyl 2-oxo-3,4-dihydroquinoxaline. The mixture is converted to methyl 3-chloro-3,4-dihydroquinoxaline (3) and methyl 2-chloro3,4- dihydroquinoxaline (4). The chlorides are isolated by flash chromatography and used in substitution reaction using for example amines or alcohol as nucleophiles followed by conversion of the esters to hydroxamic acids using aqueous hydroxylamine in methanolic potassium hydroxide which gives hydroxamic acids (6) or (8). The chlorides (3) and (4) are also substrates for Suzuki couplings and the resulting esters are converted to hydroxamic acids (5) of (7) using aqueous hydroxylamine in methanolic potassium hydroxide.

Compounds of formula (I) may for example be prepared according to the route shown in Scheme 3. Compound (3) is selective synthesized starting from methyl 4-fluoro-3- nitrobenzoate and glycine ethyl ester hydrochloride. The intermediate (9) was reduced using palladium on charcoal as catalyst under an atmosphere of hydrogen. After oxidation using iodine the intermediate is converted to the chloride (3), which is used as a substrate in Suzuki couplings and substitution reaction followed by conversion of ester to hydroxamic acids (5) and (6).

The necessary starting materials for preparation of the compounds of formula (I) are either commercially available, or may be prepared by methods known in the art.

The reactions described below in the experimental section may be carried out to give a compound of the invention in the form of a free base or as an acid or base addition salt. The term pharmaceutically acceptable salt of a compound refers to a salt that is pharmaceutically acceptable, as defined herein, and that possesses the desired pharmacological activity of the parent compound. A pharmaceutically acceptable acid addition salt may be obtained by dissolving the free base in a suitable organic solvent and treating the solution with an acid, in accordance with conventional procedures for preparation of acid addition salts from free bases.

The compounds of formula (I) may possess one or more chiral carbon atoms, and may therefore be obtained in the form of optical isomers, e.g. as a pure enantiomer, or as a mixture of enantiomers (racemate) or as a mixture of diastereomers. The separation of mixtures of optical isomers to obtain pure enantiomers is well known in the art and may, for example, be achieved by fractional crystallization of salts with optically active (chiral) acids or by chromatographic separation on chiral columns.

The chemicals used in the synthetic routes described herein may include, for example, solvents, reagents, catalysts, and protecting group and deprotecting group reagents. Examples of protecting groups are t-butoxycarbonyl (Boc), benzyl, trityl (triphenylmethyl) and trimethylsilyl. The methods described above may also additionally include steps, either before or after the steps described specifically herein, to add or to remove suitable protecting groups in order to ultimately allow synthesis of the compounds. In addition, various synthetic steps may be performed in an alternate sequence or order to give the desired compounds. Synthetic chemistry transformations and protecting group methodologies are known in the art and include, for example, those described in R. C. Larock, Comprehensive Organic Transformations, VCH Publishers (1989); L. Fieser and M. Fieser, Fieser and Fieser’s Reagents for Organic Synthesis, John Wiley and Sons (1994); L. A. Paquette, ed., Encyclopedia of Reagents for Organic Synthesis, John Wiley and Sons (1995); T. H. Greene and P. G. M. Wuts, Protective Groups in Organic Synthesis, 3rd Ed., John Wiley and Sons (1999); and P. J. Kocieński, Protecting Groups, Georg Thieme Verlag, (2000) and subsequent editions thereof. All references cited herein, whether in print, electronic, computer readable storage media or other form, are expressly incorporated by reference in their entirety, including but not limited to abstracts, articles, journals, publications, texts, treatises, technical data sheets, internet web sites, databases, patents, patent applications, and patent publications. The invention will now be further illustrated by the following non-limiting examples. The specific examples below are to be construed as merely illustrative, and not limitative of the remainder of the disclosure in any way whatsoever. Without further elaboration, it is believed that one skilled in the art can, based on the description herein, utilize the present invention to its fullest extent. EXAMPLES The following abbreviations have been used: AcOH Acetic acid DCE 1,2-Dichloroethane DCM Dichloromethane DEAD Diethyl azodicarboxylate DIPEA N,N-diisopropylethylamine DMF N,N-Dimethylformamide DMSO Dimethyl sulfoxide dppf 1,1′-Bis(diphenylphosphino)ferrocene ESI Electrospray ionization Et3N Triethylamine EtOAc Ethyl acetate HPLC High Performance Liquid Chromatography MIDA Methyliminodiacetic acid MeCN Acetonitrile MeOH Methanol MS Mass Spectrometry MTBE Methyl tert-butyl ether NMR Nuclear Magnetic Resonance PEPPSI-iPr 1,3-Bis(2,6-Diisopropylphenyl)imidazol-2-ylidene](3-chloropyridyl)- palladium(II) dichloride rt Room temperature THF Tetrahydrofuran TFA Trifluoroacetic acid Preparative HPLC was performed on a Gilson 306 HPLC system using an ACE C8 (5 µm, 21x50 mm) or Kinetex C18 (5 µm, 21x100 mm) column with 0.1% TFA in MilliQ H2O / CH3CN as mobile phase (Acidic systems) (flow 25 ml/min, gradient over 6 or 12 min), or Gemini-NX C18 (5 µm, 21x50 mm) with 50 mM NH₄HCO₃ in MilliQ H₂O / CH₃CN as mobile phase (basic system) (flow 25 ml/min, gradient over 12 min). Fractions were collected based on the UV-signal at 254 nm. Preparative flash chromatography was performed on Merck silica gel 60 (230-400 mesh) or YMC gel 120Å S-150 µm. The compounds were named using the software ACD Labs 10.0 Name module. Hydroxylamine potassium salt solution in MeOH (ca 1.7 M) was prepared according to the procedure reported by C. Blackburn et.al. (U.S. Pat. Appl. Publ.20120015943). Hydroxylamine hydrochloride (2.0 g, 29 mmol) in methanol (10 mL) was heated at 90 oC for 15 min. Everything dissolved. KOH (2.85 g, 50.8 mmol) was dissolved in MeOH (6 mL) and added to the solution of hydroxylamine hydrochloride (white precipitate upon addition). The mixture was heated at 90 oC for 30 min. Cooled to room temperature and centrifuged. The clear solution was taken out by a syringe. INTERMEDIATE 1 Methyl 3-chloroquinoxaline-6-carboxylate Methyl 4-fluoro-3-nitrobenzoate (3.50 g, 17.6 mmol), glycine methyl ester hydrochloride (2.21 g, 17.6 mmol) and DIPEA (7.66 ml, 44 mmol) in MeCN (100 mL) were stirred at rt for 3 d. EtOAc and 0.1 M HCl were added and the aqueous layer was extracted with EtOAc and DCM. The combined organic layers were dried (MgSO4) and evaporated. Yield: 6.72 g; yellow solid. The residue from above was suspended in MeOH (200 mL) and 10% Pd on charcoal (300 mg) was added. The mixture was stirred at 50 oC under H₂ overnight. Potassium carbonate (4.86 g, 32.5 mmol) and iodine (6.70 g, 26.4 mmol) were added and the mixture was stirred at 50 oC for 3 h. Silica was added to the mixture and solvents were evaporated. The dry mixture was applied on a flash column which was eluted with 20-100% EtOAc in hexanes and 10% MeOH in EtOAc. Yield: 4.9 g; dark brown solid. POCl (7 mL) was o 3 added to the material from above and the mixture was heated at 80 C overnight. Silica was added and solvents were evaporated. The dry silica was applied on a flash column which was eluted with 10-20% EtOAc in hexanes as eluent. Yield: 2.49 g (63%, four steps); beige solid. MS(ESI+) m/z 223 [M+H]+. HPLC purity: 100%.1H NMR (600 MHz, DMSO-d₆) δ ppm 9.14 (s, 1 H) 8.55 (d, J=1.8 Hz, 1 H) 8.34 (dd, J=8.7, 2.0 Hz, 1 H) 8.24 - 8.30 (m, 1 H) 3.96 (s, 3 H) . INTERMEDIATE 2 Methyl 3-(4-chlorophenyl)quinoxaline-6-carboxylate PEPPSI-iPr (20 mg) was added to a mixture of INTERMEDIATE 1 (409 mg, 1.83 mmol), 4- chlorophenylboronic acid (314 mg, 2.01 mmol) and potassium carbonate (379 mg, 2.75 mmol) in toluene (5 mL) and MeOH (5 mL). The mixture was stirred at 60 oC for 1 h in a microwave reactor. CHCl3 and water were added. The aqueous layer was extracted with CHCl3 and combined organic layers were evaporated. The residue was purified by flash chromatography using 5% EtOAc in toluene as eluent. Yield: 466 mg (85%); yellow solid MS(ESI+) m/z 299 [M+H]+. HPLC purity: 95%. INTERMEDIATE 3 Methyl 3-(4-{[(methylsulfonyl)oxy]methyl}phenyl)quinoxaline-6-carboxylate PEPPSI-iPr (10 mg) was added to a mixture of INTERMEDIATE 1 (195 mg, 0.878 mmol), 4- (hydroxymethyl)phenylboronic acid (173 mg, 1.14 mmol) and potassium carbonate (207 mg, 1.50 mmol) in toluene (2.5 mL) and MeOH (2.5 mL). The mixture was heated at 100 °C for 30 min in a microwave reactor. Water and EtOAc were added. The aqueous layer was extracted with EtOAc and combined organic layers were dried (MgSO4) and evaporated. Yield: 365 mg; yellow solid.

Methane sulfonyl chloride (132 pl, 196 mg, 1.71 mmol) was added dropwise to a solution of the material from above (335 mg, 1.14 mmol) and DIEPA (400 pl, 2.28 mmol) in THF (20 mL). The mixture was stirred at rt overnight. Silica was added and solvents were evaporated. The dry silica was applied on a flash column which was eluted with 10% EtOAc in toluene. Yield: 101 mg (24%); white solid.

INTERMEDIATE 4

Methyl 3-(6-fluoropyridin-3-yl)quinoxaline-6-carboxylate

PEPPSI-iPr (ca 5 mg) was added to a mixture of INTERMEDIATE 1 (60.2 mg, 0.270 mmol), 2-fluoro-5-pyridylboronic acid (45 mg, 0.324 mmol) and potassium carbonate (56 mg, 0.405 mmol) in toluene (2 mL) and MeOH (2 mL). The mixture was heated at 60 °C for 30 min. Water and EtOAc were added and the aqueous layer was extracted with EtOAc. The combined organic layers were evaporated. Yield: 91 mg (119%); white solid. The material was used without further purifications.

INTERMDIATE 5

Methyl 3-(4-hydroxyphenyl)quinoxaline-6-carboxylate

PEPPSI-iPr (5 mg) was added to a mixture of INTERMEDIATE 1 (205 mg, 0.921 mmol), 4- hydroxphenylboronic acid (152 mg, 1.10 mmol) and potassium carbonate (166 mg, 1.20 mmol) in toluene (2.5 mL) and MeOH (2.5 mL). The mixture was heated at 80 °C for 30 min in a microwave reactor. Water and EtOAc were added. The organic layer was separated and evaporated. Yield: 291 mg; yellow solid. The material was used without further purifications.

INTERMEDIATE 6

Methyl 3-(2-fluoro-4-formylphenyl)quinoxaline-6-carboxylate

PEPPSI-iPr (ca 10 mg) was added to a mixture of INTERMEDIATE 1 (222 mg, 1.00 mmol), 2-fluoro-4-formylphenylboronic acid (167 mg, 1.00 mmol) and potassium carbonate (160 mg, 1.15 mmol) in toluene (2 mL) and MeOH (2 mL). The mixture was heated at 80 °C for 30 min in a microwave reactor. Water and EtOAc were added. The aqueous layer was extracted with EtOAc and combined organic layers filtered and evaporated. The residue was purified by flash chromatography using 10-20% EtOAc in toluene. Yield: 161 mg (52%); white solid.1H NMR (600 MHz, CDCl3) δ 10.12 (d, J=1.5 Hz, 1 H) 9.47 (d, J=2.7 Hz, 1 H) 8.93 (d, J=1.8 Hz, 1 H) 8.37 - 8.47 (m, 2 H) 8.24 (d, J=8.5 Hz, 1 H) 7.92 (dd, J=7.9, 1.5 Hz, 1 H) 7.80 (dd, J=10.5, 1.4 Hz, 1 H) 4.05 (s, 3 H). INTERMEDIATE 7 Methyl 3-(3-hydroxyphenyl)quinoxaline-6-carboxylate PEPPSI-iPr (ca 10 mg) was added to a mixture of INTERMEDIATE 1 (328 mg, 1.47 mmol), 3-hydroxyphenylboronic acid (243 mg, 1.76 mmol) and potassium carbonate (304 mg, 2.20 mmol) in toluene (5 mL) and MeOH (5 mL). The mixture was heated at 80 oC for 45 min in microwave reactor. EtOAc and water were added. The aqueous layer was extracted with EtOAc and combined organic layers were filtered and evaporated. Yield: 336 mg (81%); beige solid. MS(ESI+) m/z 281 [M+H]+. HPLC purity: 95%. The product was used without further purifications. EXAMPLES 1 AND 2 N-Hydroxy-2-phenylquinoxaline-6-carboxamide and N-hydroxy-3-phenylquinoxaline-6- carboxamide Methyl 3,4-diaminobenzoate (121 mg, 0.728 mmol) and 2-bromoacetophenone (145 mg, 0.728 mmol) were dissolved in DMF (2 mL). The mixture was stirred at rt for 5 min before heated at 180 oC for 10 min in a microwave reactor. The solvent was evaporated and the residue purified by flash chromatography using hexanes/EtOAc 2:1 as eluent. Yield: 87 mg (45%); yellow solid. MS(ESI+) m/z 265 [M+H]+. Freshly prepared hydroxylamine potassium salt solution (ca 1.7 M in MeOH, 1.5 mL) was added to the product from above (17.0 mg, 0.064 mmol) and the mixture was heated at 60 oC for 1 h before quenched with AcOH (0.5 mL). The title compounds were isolated by reversed phase chromatography (Kinetex C18, 5 µm, 21.2 x 100 mm, flow 25 ml/min, gradient 0.1% TFA in water / acetonitrile over 15 minutes). N-hydroxy-2-phenylquinoxaline-6-carboxamide (main product). Yield: 6.9 mg (41%); white solid and N-hydroxy-3-phenylquinoxaline-6-carboxamide (minor product). Yield: 2.6 mg (15%); white solid. EXAMPLES 3 AND 4 N-Hydroxy-2-[4-(1-methylethyl)phenyl]quinoxaline-6-carboxamide and N-hydroxy-3-[4- (1-methylethyl)phenyl]quinoxaline-6-carboxamide Ethyl glycoxalate (50% in toluene, 950 µl, 4.02 mmol) was added dropwise to a solution of methyl 3,4 diaminobenzoate (668 mg, 4.02 mmol) in EtOH (20 mL) at 70 oC. The mixture was stirred at 70 oC for 3 d. White solid precipitates. Dioxane was added until everything dissolved. Silica was added and solvents evaporated. The dry silica was applied on a column which was eluted with EtOAc/heptane 1:1, 2:1 and 1:0 Methyl 3-oxo-3,4-dihydroquinoxaline- 6-carboxylate: Yield: 190 mg (23%); white solid. NMR: 3:1 mixture of isomers. The material from above (190 mg, 0.931 mmol) in POCl (5 mL) was heat o 3 ed at 110 C for 1 h. The mixture was poured on ice and extracted with EtOAc. The combined organic layers were dried (MgSO4) and evaporated. The residue was purified by flash chromatography using heptane/EtOAc 4:1 as eluent. Yield: 92 mg (44%); white solid. PEPPSI-iPr (ca 5 mg) was added to a nitrogen flushed mixture of the material from above (22.8 mg,0.102 mmol), 4-isopropylphenylboronic acid (25.2 mg, 0.153 mmol) and potassium carbonate (28.2 mg, 0.204 mmol) in toluene (1 mL) and MeOH (1 mL). The mixture was heated at 100 oC for 20 min in a microwave reactor. EtOAc and water were added. Organic layer was concentrated and 10% KOH in MeOH (1 mL) and 50% hydroxylamine in water (0.5 mL) were added. The mixture was heated at 60 oC for 30 min before quenched with AcOH (0.5 mL). The two title compounds were isolated by reversed phase chromatography (Kinetex C18, 5 µm, 21.2 x 100 mm, flow 25 ml/min, gradient 0.1% TFA in water / acetonitrile over 15 minutes). N-hydroxy-3-[4-(1-methylethyl)phenyl]quinoxaline-6-carboxamide: Yield: 16.7 mg (53%); white solid. N-hydroxy-2-[4-(1-methylethyl)phenyl]quinoxaline-6-carboxamide. Yield: 1.5 mg. EXAMPLE 5 2-[4-(4-Fluorophenyl)piperazin-1-yl]-N-hydroxyquinoxaline-6-carboxamide trifluoroacetate Ethyl glycoxalate (50% in toluene, 950 µl, 4.02 mmol) was added dropwise to a solution of methyl 3,4 diaminobenzoate (668 mg, 4.02 mmol) in EtOH (20 mL) at 70 oC. The mixture was stirred at 70 oC for 3 d. White solid precipitates. Dioxane was added until everything was dissolved. Silica was added and the solvents were evaporated. The dry silica was applied on a column which was eluted with EtOAc/heptane 1:1 and 2:1 and 1:0 Methyl 2-oxo-3,4- dihydroquinoxaline-6-carboxylate: Yield: 149 mg (18%); white solid. NMR: contains 8% of other isomer. The material from above (149 mg, 0.730 mmol) in POCl3 (5 mL) and the solution was heated at 110 oC for 6 h. The mixture was poured on ice and extracted with EtOAc. Silica was added to the combined organic layers and solvents were evaporated. The dry silica was applied on a flash column which was eluted with heptane/EtOAc 4:1. Yield: 119.4 mg (73%); white solid. ¹H NMR (600 MHz, DMSO-d6) δ 9.12 (s, 1 H) 8.65 - 8.67 (m, 1 H) 8.36 (dd, J=8.9, 1.8 Hz, 1 H) 8.17 (d, J=8.9 Hz, 1 H) 3.96 (s, 3 H). The material from above (13.9 mg, 0.062 mmol), 1-(4-fluorophenyl)piperazine (16.9 mg, 0.0936 mmol) and DIPEA (16.4 µl, 0.0936 mmol) in MeCN (1 mL) was heated in a microwave reactor at 120 oC for 20 min. The solvent was evaporated, and 10% KOH in MeOH (1 mL) and 50% hydroxylamine in water (0.5 mL) were added to the residue. The mixture was heated at 60 oC for 2 h before quenched with AcOH (0.5 mL). The title compound was isolated by reversed phase chromatography (Kinetex C18, 5 µm, 21.2 x 100 mm, flow 25 ml/min, gradient 0.1% TFA in water / acetonitrile over 15 minutes). Yield: 11.6 mg (39%); yellow solid. EXAMPLE 6 2-(Benzyloxy)-N-hydroxyquinoxaline-6-carboxamide Ethyl glycoxalate (50% in toluene, 950 µl, 4.02 mmol) was added dropwise to a solution of methyl 3,4 diaminobenzoate (668 mg, 4.02 mmol) in EtOH (20 mL) at 70 oC. The mixture was stirred at 70 oC for 3 d. White solid precipitates. Dioxane was added until everything dissolved. Silica was added and solvents evaporated. The dry silica was applied on a column which was eluted with EtOAc/heptane 1:1 and 2:1 and 1:0 Methyl 2-oxo-3,4- dihydroquinoxaline-6-carboxylate: Yield: 149 mg (18%); white solid. NMR: contains 8% of other isomer. The material from above (149 mg, 0.730 mmol) in POCl₃ (5 mL) and the solution was heated at 110 oC for 6 h. The mixture was poured on ice and extracted with EtOAc. The organic layers were evaporated on silica and the dry silica applied on a flash column which was eluted with heptane/EtOAc 4:1. Yield: 119.4 mg (73%); white solid. The material from above (13.9 mg, 0.062 mmol), benzyl alcohol (20 µl) and potassium carbonate (17 mg, 0.123 mmol) in dioxane (1 mL) and MeCN (1 mL) were heated at 150 oC for 10 min in a microwave reactor. Solvents were evaporated and hydroxylamine potassium salt in MeOH (ca 1.7 M, 1.5 mL) was added. The mixture was stirred at rt for 16 h before quenched with AcOH (0.5 mL). The title compound was isolated by reversed phase chromatography (Kinetex C18, 5 µm, 21.2 x 100 mm, flow 25 ml/min, gradient 0.1% TFA in water / acetonitrile over 15 minutes). Yield: 3.7 mg (20%); white solid. EXAMPLE 7 N-Hydroxy-3-pyridin-3-ylquinoxaline-6-carboxamide trifluoroacetate GENERAL PROCEDURE A PEPPSI-iPr (ca 5 mg) was added to a nitrogen flushed mixture of INTERMEDIATE 1 (15 mg, 0.067 mmol), pyridine-3-boronic acid (12.5 mg, 0.102 mmol) and potassium carbonate (17.3 mg, 0.135 mmol) in MeOH (1 mL) and toluene (1 mL). The mixture was heated at 100 oC for 30 min in a microwave reactor. Water and EtOAc were added. The organic phase was separated and solvents evaporated. Hydroxylamine potassium salt in MeOH (ca 1.7 M, 1.5 mL) was added to the residue and the mixture was heated at 60 oC for 30 min before quenched with AcOH (0.5 mL). The title compound was isolated by reversed phase chromatography (Kinetex C18, 5 µm, 21.2 x 100 mm, flow 25 ml/min, gradient 0.1% TFA in water / acetonitrile over 15 minutes). Yield: 11.0 mg (43%, two steps); white solid. EXAMPLE 13 3-(4-Fluorophenyl)-N-hydroxyquinoxaline-6-carboxamide GENERAL PROCEDURE B PEPPSI-iPr (ca 5 mg) was added to a nitrogen flushed mixture of INTERMEDIATE 1 (18 mg, 0.067 mmol), 4-fluorobenzeneboronic acid (14.0 mg, 0.100 mmol) and potassium carbonate (20.7 mg, 0.150 mmol) in MeOH (1 mL) and toluene (1 mL). The mixture was heated at 100 oC for 30 min in a microwave reactor. Water and EtOAc were added. The organic phase was separated and solvents evaporated. Hydroxylamine potassium salt in MeOH (ca 1.7 M, 1.5 mL) was added to the residue and the mixture was heated at 60 oC for 45 min before quenched with AcOH (0.5 mL). The title compound was isolated by reversed phase chromatography (Kinetex C18, 5 µm, 21.2 x 100 mm, flow 25 ml/min, gradient 0.1% TFA in water / acetonitrile over 15 minutes). Yield: 14.4 mg (59%, two steps); white solid. EXAMPLE 27 3-(Cycloheptylamino)-N-hydroxyquinoxaline-6-carboxamide A mixture of INTERMEDIATE 1 (16.0 mg, 0.072 mmol), cycloheptylamine (11.3 mg, 0.100 mmol) and DIPEA (17.4 µl, 0.100 mmol) in MeCN (2 mL) was heated at 120 oC for 20 min in a microwave reactor and at 150 oC for 30 min. Potassium carbonate (20 mg, 0.150 mmol) was added and the mixture was heated at 150 oC for 2.5 h. The solvent was evaporated and hydroxylamine potassium salt (ca 1.7 M in MeOH, 1 mL) was added. The mixture was heated at 60 oC for 45 min before quenched with AcOH (0.5 mL). The title compound was isolated by reversed phase chromatography (Kinetex C18, 5 µm, 21.2 x 100 mm, flow 25 ml/min, gradient 0.1% TFA in water / acetonitrile over 15 minutes). Yield: 8.3 mg (38%, two steps); brown solid. EXAMPLE 28 N-Hydroxy-3-pyrrolidin-1-ylquinoxaline-6-carboxamide A mixture of INTERMEDIATE 1 (16.0 mg, 0.072 mmol), pyrrolidine (7.1 mg, 0.100 mmol) and DIPEA (17.4 µl, 0.100 mmol) in MeCN (2 mL) was heated at 120 oC for 20 min in a microwave reactor. The solvent was evaporated and hydroxylamine potassium salt (ca 1.7 M in MeOH, 1 mL) was added. The mixture was heated at 60 oC for 45 min before quenched with AcOH (0.5 mL). The title compound was isolated by reversed phase chromatography (Kinetex C18, 5 µm, 21.2 x 100 mm, flow 25 ml/min, gradient 0.1% TFA in water / acetonitrile over 15 minutes). Yield: 19.9 mg (100%); yellow solid. EXAMPLE 29 3-(Benzylamino)-N-hydroxyquinoxaline-6-carboxamide A mixture of INTERMEDIATE 1 (16.0 mg, 0.072 mmol), benzylamine (10.7 mg, 0.100 mmol) and DIPEA (17.4 µl, 0.100 mmol) in MeCN (2 mL) was heated at 120 oC for 20 min and at 150 oC for 30 min in a microwave reactor. Potassium carbonate (20 mg, 0.150 mmol) was added and the mixture was heated at 150 oC for 2.5 h in a microwave reactor. The solvent was evaporated and hydroxylamine potassium salt (ca 1.7 M in MeOH, 1 mL) was added. The mixture was heated at 60 oC for 45 min before quenched with AcOH (0.5 mL). The title compound was isolated by reversed phase chromatography (Kinetex C18, 5 µm, 21.2 x 100 mm, flow 25 ml/min, gradient 0.1% TFA in water / acetonitrile over 15 minutes). Yield: 6.0 mg (28%, two steps); yellow solid. EXAMPLE 30 N-Hydroxy-3-{[(1S)-1-phenylethyl]amino}quinoxaline-6-carboxamide A mixture of INTERMEDIATE 1 (16.0 mg, 0.072 mmol), 1S-methylbenzylamine (12.1 mg, 0.100 mmol) and DIPEA (17.4 µl, 0.100 mmol) in MeCN (2 mL) was heated at 120 oC for 20 min and at 150 oC for 30 min in a microwave reactor. Potassium carbonate (20 mg, 0.150 mmol) was added and the mixture was heated at 150 oC for 4.5 h in a microwave reactor. The solvent was evaporated and hydroxylamine potassium salt (ca 1.7 M in MeOH, 1 mL) was added. The mixture was heated at 60 oC for 45 min before quenched with AcOH (0.5 mL). The title compound was isolated by reversed phase chromatography (Kinetex C18, 5 µm, 21.2 x 100 mm, flow 25 ml/min, gradient 0.1% TFA in water / acetonitrile over 15 minutes). Yield: 3.9 mg (18%, two steps); brown oil. EXAMPLE 31 3-[Benzyl(methyl)amino]-N-hydroxyquinoxaline-6-carboxamide A mixture of INTERMEDIATE 1 (16.0 mg, 0.072 mmol), N-benzyl-N-methylamine (12.1 mg, 0.100 mmol) and DIPEA (17.4 µl, 0.100 mmol) in MeCN (2 mL) was heated at 120 oC for 20 min and at 150 oC for 30 min in a microwave reactor. The solvent was evaporated and hydroxylamine potassium salt (ca 1.7 M in MeOH, 1 mL) was added. The mixture was heated at 60 oC for 45 min before quenched with AcOH (0.5 mL). The title compound was isolated by reversed phase chromatography (Kinetex C18, 5 µm, 21.2 x 100 mm, flow 25 ml/min, gradient 0.1% TFA in water / acetonitrile over 15 minutes). Yield: 9.8 mg (44%, two steps); brown oil. EXAMPLE 32 3-[4-(4-Fluorophenyl)piperazin-1-yl]-N-hydroxyquinoxaline-6-carboxamide A mixture of INTERMEDIATE 1 (16.0 mg, 0.072 mmol), 1-(4-fluorophenyl)piperazine (18.0 mg, 0.100 mmol) and DIPEA (17.4 µl, 0.100 mmol) in MeCN (2 mL) was heated at 120 oC for 20 min and at 150 oC for 30 min in a microwave reactor. The solvent was evaporated and hydroxylamine potassium salt (ca 1.7 M in MeOH, 1 mL) was added. The mixture was heated at 60 oC for 45 min before quenched with AcOH (0.5 mL). The title compound was isolated by reversed phase chromatography (Kinetex C18, 5 µm, 21.2 x 100 mm, flow 25 ml/min, gradient 0.1% TFA in water / acetonitrile over 15 minutes). Yield: 22.5 mg (85%, two steps); yellow solid. EXAMPLE 33 3-{4'-[(Dimethylamino)methyl]biphenyl-4-yl}-N-hydroxyquinoxaline-6-carboxamide trifluoroacetate PEPPSI-iPr (ca 2 mg) was added to a mixture of INTERMEDIATE 2 (21 mg, 0.070 mmol), 4-(N,N’-dimethylbenzylamine)phenylboronic acid pinacol ester hydrochloride (31.4 mg, 0.105 mmol) and potassium carbonate (29.0 mg 0.210 mmol) in toluene (1 mL) and MeOH (1 mL). The mixture was heated at 100 oC for 30 min in a microwave reactor. Water and EtOAc were added. The organic layer was separated, filtered and evaporated. KOH in MeOH (10 mg/ml, 1 mL) and 50% hydroxylamine in water (0.5 mL) were added to the residue from above. The mixture was stirred at rt overnight before quenched with AcOH (0.5 mL). The title compound was isolated by reversed phase chromatography (Kinetex C18, 5 µm, 21.2 x 100 mm, flow 25 ml/min, gradient 0.1% TFA in water / acetonitrile over 15 minutes). Yield: 18.0 mg (50%, two steps); white solid. EXAMPLE 34 N-Hydroxy-3-[2-(hydroxymethyl)phenyl]quinoxaline-6-carboxamide GENERAL PROCEDURE C PEPPSI-iPr (ca 5 mg) was added to a mixture of INTERMEDIATE 1 (22.2 mg, 0.100 mmol), 2-hydroxymethylphenylboronic acid (18.2 mg, 0.120 mmol) and potassium carbonate (21 mg, 0.150 mmol) in toluene (1 mL) and MeOH (1 mL). The mixture was heated at 100 oC for 30 min in a microwave reactor. Water and EtOAc were added. The aqueous layer was extracted with EtOAc and the combined organic layers were evaporated. KOH in MeOH (10 mg/ml, 1 mL) and 50% hydroxylamine in water (0.5 mL) were added to the residue and the mixture was stirred at rt overnight before AcOH (0.5 mL) was added. The title compound was isolated by reversed phase chromatography (Kinetex C18, 5 µm, 21.2 x 100 mm, flow 25 ml/min, gradient 0.1% TFA in water / acetonitrile over 15 minutes). Yield: 9.2 mg (31%); yellow solid. EXAMPLE 39 3-(4-Chloro-2-fluorophenyl)-N-hydroxyquinoxaline-6-carboxamide PEPPSI-iPr (4 mg) was added to a mixture of INTERMEDIATE 1 (30.6 mg, 0.137 mmol), 4- chloro-2-fluorophenylboronic acid (24 mg, 0.137 mmol) and potassium carbonate (21 mg, 0.150 mmol) in toluene (1 mL) and MeOH (1 mL). The mixture was heated at 80 oC for 20 min in a microwave reactor. Water and EtOAc were added. The organic layer was separated and evaporated. To the residue were added 50% hydroxylamine (0.5 mL) in water and KOH in MeOH (10 mg/ml, 1 mL) and the mixture was stirred at rt overnight before quenched with AcOH (0.5 mL). The title compound was isolated by reversed phase chromatography (Kinetex C18, 5 µm, 21.2 x 100 mm, flow 25 ml/min, gradient 0.1% TFA in water / acetonitrile over 15 minutes). Yield: 6.6 mg (15%, two steps); white solid. EXAMPLE 40 3-(2,4-Dichlorophenyl)-N-hydroxyquinoxaline-6-carboxamide PEPPSI-iPr (2.5 mg) was added to a mixture of INTERMEDIATE 1 (31 mg, 0.139 mmol), 2,4-dichlorobenzeneboronic acid (26.5 mg, 0.139 mmol) and potassium carbonate (21 mg, 0.150 mmol) in toluene (1 mL) and MeOH (1 mL). The mixture was heated at 60 oC for 1.25 h. Water and EtOAc were added, the aqueous layer was extracted with EtOAc and the combined organic layers were evaporated. Hydroxylamine (50% in water, 0.5 mL) and KOH in MeOH (1 mL) were added to the residue and the mixture was stirred at 50 oC for 2 h before quenched with AcOH (0.5 mL). The title compound was isolated by reversed phase chromatography (Kinetex C18, 5 µm, 21.2 x 100 mm, flow 25 ml/min, gradient 0.1% TFA in water / acetonitrile over 15 minutes). Yield: 4.9 mg (11%, two steps); white solid. EXAMPLE 41 3-(Benzyloxy)-N-hydroxyquinoxaline-6-carboxamide GENERAL PROCEDURE D A mixture of INTERMEDIATE 1 (15.9 mg, 0.071 mmol), benzylalcohol (20 µl) and potassium carbonate (20 mg, 0.142 mmol) in dioxane (1 mL) and MeCN (1 mL) was heated at 150 oC for 1 h in a microwave reactor. The solvents were evaporated and hydroxylamine (50% in water, 0.5 mL) and KOH in MeOH (10 mg/ml, 1 mL) were added. The mixture was stirred at rt overnight before quenched with AcOH (0.5 mL). The title compound was isolated by reversed phase chromatography (Kinetex C18, 5 µm, 21.2 x 100 mm, flow 25 ml/min, gradient 0.1% TFA in water / acetonitrile over 15 minutes). Yield: 7.6 mg (36%, two steps); white solid. EXAMPLE 48 N-Hydroxy-3-{4-[(pyridin-3-yloxy)methyl]phenyl}quinoxaline-6-carboxamide trifluoroacetate A mixture of INTERMEDIATE 3 (33 mg, 0.090 mmol), 3-hydroxypyridine (10 mg, 0.108 mmol) and potassium carbonate (21 mg, 0.150 mmol) in MeCN (2 mL) and dioxane (2 mL) was heated at 100 oC for 1 h 20 min in a microwave reactor. The solvents were evaporated and 50 % hydroxylamine in water (0.5 mL) and KOH in MeOH (10 mg/ml, 1 mL) were added. The mixture was stirred at rt overnight before quenched with AcOH (0.5 mL). The title compound was isolated by reversed phase chromatography (Kinetex C18, 5 µm, 21.2 x 100 mm, flow 25 ml/min, gradient 0.1% TFA in water / acetonitrile over 15 minutes). Yield: 17.3 mg (40%); white solid. EXAMPLE 49 N-Hydroxy-3-[4-(piperidin-1-ylmethyl)phenyl]quinoxaline-6-carboxamide trifluoroacetate A mixture of INTERMEDIATE 3 (33 mg, 0.090 mmol) and piperidine (30 µl, 0.300 mmol) in MeCN (2 mL) and dioxane (2 mL). The mixture was heated at 100 oC for 1 h and 20 min in a microwave reactor. The solvents were evaporated and 50 % hydroxylamine in water (0.5 mL) and KOH in MeOH (10 mg/ml, 1 mL) were added. The mixture was stirred at rt overnight before quenched with AcOH (0.5 mL). The title compound was isolated by reversed phase chromatography (Kinetex C18, 5 µm, 21.2 x 100 mm, flow 25 ml/min, gradient 0.1% TFA in water / acetonitrile over 15 minutes). Yield: 40.1 mg (95%); yellow solid. EXAMPLE 50 3-{4-[(4-Ethylpiperazin-1-yl)methyl]phenyl}-N-hydroxyquinoxaline-6-carboxamide bis(trifluoroacetate) INTERMEDIATE 3 (33 mg, 0.090 mmol) and N-ethylpiperazine (38 µl, 0.300 mmol) in MeCN (2 mL) and dioxane (2 mL) were heated at 100 oC for 1 h in a microwave reactor. The solvent was evaporated and 50 % hydroxylamine in water (0.5 mL) and KOH in MeOH (10 mg/ml, 1 mL) were added. The mixture was stirred at rt overnight before quenched with AcOH (0.5 mL). The title compound was isolate by reversed phase chromatography (Kinetex C18, 5 µm, 21.2 x 100 mm, flow 25 ml/min, gradient 0.1% TFA in water / acetonitrile over 15 minutes). Yield: 41.0 mg (74%); yellow solid. EXAMPLE 51 3-{6-[4-(Diethylamino)piperidin-1-yl]pyridin-3-yl}-N-hydroxyquinoxaline-6- carboxamide trifluoroacetate A mixture of INTERMEDIATE 4 (25.5 mg, 0.090 mmol) and 4-diethylaminopiperidine (47 mg.0.300 mmol) in MeCN (1 mL) and dioxane (1 mL) was heated at 100 oC for 20 min and at 120 oC for 30 min in a microwave reactor. The solvents were evaporated and 50% hydroxylamine in water (0.5 mL) and KOH in MeOH (10 mg/ml, 1 mL) were added. The mixture was stirred at rt for 2 h before quenched with AcOH (0.5 mL). The title compound was isolated by reversed phase chromatography (Kinetex C18, 5 µm, 21.2 x 100 mm, flow 25 ml/min, gradient 0.1% TFA in water / acetonitrile over 15 minutes). Yield: 33.3 mg (88%); bright yellow solid. EXAMPLE 52 3-{4-[2-(Diethylamino)ethoxy]phenyl}-N-hydroxyquinoxaline-6-carboxamide trifluoroacetate GENERAL PROCEDURE E A mixture of INTERMEDIATE 5 (25.2 mg, 0.090 mmol), 2-bromo-N,N-diethylethylamine hydrobromide (39.2 mg, 0.150 mmol) and potassium carbonate (55 mg, 0.400 mmol) in DMF (1.5 mL) was stirred at rt overnight. The solvent was evaporated and 50% hydroxylamine in water (0.5 mL) and KOH in MeOH (10 mg/ml, 10 mL) were added. The mixture was stirred at rt for 2 h before quenched with AcOH (0.5 mL). The title compound was isolated by reversed phase chromatography (Kinetex C18, 5 µm, 21.2 x 100 mm, flow 25 ml/min, gradient 0.1% TFA in water / acetonitrile over 15 minutes). Yield: 21.1 mg (47%, two steps); yellow solid. EXAMPLE 57 3-[2-Fluoro-4-(piperidin-1-ylmethyl)phenyl]-N-hydroxyquinoxaline-6-carboxamide trifluoroacetate GENERAL PROCEDURE F Sodium triacetoxyborohydride (32 mg, 0.150 mmol) was added to a solution of INTERMEDIATE 6 (31 mg, 0.100 mmol) and piperidine (12.7 mg, 0.150 mmol) in DCE (2 mL) and the mixture was stirred at rt for 18 h. The solvent was evaporated and hydroxylamine (50% in water, 0.5 mL) and KOH in MeOH (10 mg/ml, 1.5 mL) were added. The mixture was heated at 50 oC for 24 h before quenched with AcOH (0.5 mL) . The title compound was isolated by reversed phase chromatography (Kinetex C18, 5 µm, 21.2 x 100 mm, flow 25 ml/min, gradient 0.1% TFA in water / acetonitrile over 15 minutes). Yield: 34.8 mg (70%, two steps); white solid. EXAMPLE 61 3-{3-[3-(Dimethylamino)propoxy]phenyl}-N-hydroxyquinoxaline-6-carboxamide trifluoroacetate GENERAL PROCEDURE G DEAD (21 µl, 0.133 mmol) was added to a mixture of INTERMEDIATE 7 (31 mg, 0.110 mmol), 3-dimethylamine-1-propanol (13.7 mg, 0.133 mmol) and triphenylphosphine (34.9 mg, 0.133 mmol) in THF (1.5 mL). The mixture was stirred at rt overnight before solvent was evaporated. Hydroxylamine (50% in water, 0.4 mL) and KOH in MeOH (10 mg/ml, 0.8 mL) were added to the residue and the mixture was stirred at rt for 2 h before quenched with AcOH (0.4 mL). The title compound was isolated by reversed phase chromatography (Kinetex C18, 5 µm, 21.2 x 100 mm, flow 25 ml/min, gradient 0.1% TFA in water / acetonitrile over 15 minutes). Yield: 24.6 mg (47%); yellow gum. EXAMPLE 66 N-Hydroxy-3-[4-(1,2,3,6-tetrahydropyridin-4-yl)phenyl]quinoxaline-6-carboxamide trifluoroacetate PEPPSI-iPr (ca 10 mg) was added to a mixture of INTERMEDIATE 2 (87.6 mg, 0.293 mmol), 3,6-dihydro-2H-pyridine-1-N-BOC-4-boronic acid pinacol ester (118 mg, 0.381 mmol) and potassium carbonate (61 mg, 0.440 mmol) in toluene (2 mL) and MeOH (2 mL). The mixture was heated at 80 oC for 1 h in a sealed tube. EtOAc and water were added. Aqueous layer was extracted with EtOAc in combined organic layers were filtered and evaporated. The residue was dissolved in DCM (3 mL) and TFA (3 mL) and the mixture was stirred at rt overnight and solvents evaporated. Yield: 386 mg; orange solid. Part of the material from above (40 mg) was added hydroxylamine (50% in water, 0.4 mL) and KOH in MeOH (10 mg/mL) and the mixture was stirred at rt overnight before quenched with AcOH (0.4 mL). The title compound was isolated by reversed phase chromatography (Kinetex C18, 5 µm, 21.2 x 100 mm, flow 25 ml/min, gradient 0.1% TFA in water / acetonitrile over 15 minutes). Yield: 6.7 mg; white solid EXAMPLES 67 AND 68 8-Fluoro-N-hydroxy-3-[4-(1-methylethyl)phenyl]quinoxaline-6-carboxamide and 8-fluoro-N-hydroxy-2-[4-(1-methylethyl)phenyl]quinoxaline-6-carboxamide 3,4,5-Trifluorobenzonitrile (4.85 g, 30.9 mmol), tert-butylamine (10 ml, 92.8 mmol) and potassium carbonate (6.4 g, 46.3 mmol) in DMF (30 mL) was heated at 50 oC in a sealed tube for 2 d. Water and EtOAc were added. The aqueous layer was extracted with EtOAc and the combined organic layers were dried (MgSO4) and solvents evaporated. Yield: 6.91 g (106%); pink oil which solidifies. The material from above was dissolved in MeOH (60 mL) and conc. H2SO4 (15 mL) was added. The mixture was heated at 100 oC for 3 h. Water and EtOAc were added. The organic layer was washed with sat. NaHCO₃, dried (MgSO₄) and evaporated. The residue was purified by flash chromatography using 10% EtOAc in hexanes as eluent. Methyl 4-amino-3,5-difluorobenzoate: Yield: 2.26 g (39%, two steps); white solid. MS(ESI+) m/z 188 [M+H]+. HPLC purity: 95%.1H NMR (600 MHz, DMSO-d₆) δ 7.43 (dd, J=7.3, 2.4 Hz, 2 H) 6.21 (s, 2 H) 3.78 (s, 3 H). A mixture of the material from above (755 mg, 3.48 mmol), 4-methoxybenzylamine (477 mg, 3.48 mmol) and Et₃N (723 µl, 5.22 mmol) in MeCN (30 mL) was stirred at rt overnight. EtOAc and sat. NaHCO3 were added. The aqueous layer was extracted with EtOAc and combined organic layers were dried (MgSO₄) and evaporated. The residue from above was dissolved in MeOH (25 mL) and 10% palladium on charcoal (ca 50 mg) was added. The mixture was stirred at rt under H2 for 3 d. The mixture was filtered, and solvents evaporated. The residue was purified by flash chromatography using hexanes/EtOAc 2:1 as eluent. Methyl 3,4-diamino-5-fluorobenzoate: Yield: 352 mg (55%); yellow solid. MS(ESI+) m/z 185 [M+H]+. HPLC purity: 100%.1H NMR (600 MHz, DMSO- d₆) δ 7.03 (d, J=1.2 Hz, 1 H) 6.91 (dd, J=11.3, 1.8 Hz, 1 H) 5.24 (s, 2 H) 5.06 (s, 2 H) 3.73 (s, 3 H). The material from above (187 mg.1.02 mmol) and ethyl glyoxalate (50% in toluene, 202 µl, 104 mg, 1.02 mmol) in EtOH (10 mL) was heated at 70 oC for 3 d and the solvent evaporated. The residue was suspended in MeCN (15 mL). POCl3 (300 µl) was added and the mixture was heated at 80 oC overnight. Silica was added and solvents evaporated. The dry silica was applied on a flash column which was eluted with 10-20% EtOAc in hexanes. Two spots on tlc, but no separation on column. Yield: 187 mg (76%); white solid. PEPPSI-iPr (10 mg) was added to a mixture of the material from above (185 mg, 0.769 mmol), 4-isopropylphenylboronic acid (151 mg, 0.922 mmol) and potassium carbonate (159 mg, 1.15 mmol) in toluene (2.5 mL) and MeOH (2.5 mL). The mixture was heated at 80 oC for 45 min in a microwave reactor. Silica was added and solvents evaporated. The dry silica was applied on a flash column which was eluted with 5% EtOAc in toluene. The first fractions (47 mg) were added hydroxylamine (50% in water, 0.5 mL) and KOH in MeOH (10 mg/ml, 1 mL). The mixture was stirred at rt for 30 min and at 50 oC for 1 h. AcOH (0.5 mL) and 8-fluoro-N-hydroxy-3-[4-(1-methylethyl)phenyl]quinoxaline-6- carboxamide was isolated by reversed phase chromatography (Kinetex C18, 5 µm, 21.2 x 100 mm, flow 25 ml/min, gradient 0.1% TFA in water / acetonitrile over 15 minutes).Yield: 14.5 mg; white solid. The last eluted fractions (82 mg) were to added hydroxylamine (50% in water, 0.5 mL) and KOH in MeOH (10 mg/ml, 1 mL). The mixture was stirred at rt for 30 min and at 50 oC for 1 h. AcOH (0.5 mL) and 8-fluoro-N-hydroxy-2-[4-(1-methylethyl)phenyl]quinoxaline-6- carboxamide was isolated by reversed phase chromatography (Kinetex C18, 5 µm, 21.2 x 100 mm, flow 25 ml/min, gradient 0.1% TFA in water / acetonitrile over 15 minutes).Yield: 7.6 mg; white solid. EXAMPLE 69 N-Hydroxy-2-phenylquinazoline-7-carboxamide 4-Methyl-3-nitrobenzoic acid (4.71 g, 26.0 mmol) in MeOH (20 mL) and conc. H₂SO₄ (5 mL) was heated at reflux overnight. Water and EtOAc were added and the organic layer was washed with water and sat. NaHCO3, dried (MgSO4) and evaporated. Methyl 4-methyl-3- nitrobenzoate. Yield: 4.69 g (92%); white solid. The ester from above (2.62 g, 13.4 mmol) and N,N-dimethylformamide dimethyl acetal (2.31 ml, 17.4 mmol) in DMF (12 mL) was heated at 140 oC for 3 h in a closed tube and the solvents evaporated. The residue was dissolved in THF (40 mL) and water (40 mL) and sodium periodate (8.60 g, 40.2 mmol) was added portion-wise. The mixture was stirred at rt for 1 h before the mixture was filtered and the solid material washed with EtOAc. The filtrate was washed with NaHCO3, dried and concentrated. The residue was purified by flash chromatography using 2.5 % EtOAc in toluene as eluent. Methyl 3-formyl-4-nitrobenzoate: Yield: 2.40 g (86%); white solid.1H NMR (600 MHz, DMSO-d6) δ 10.31 (s, 1 H), 8.54 (d, J=1.5 Hz, 1 H) 8.42 (dd, J=7.9, 1.5 Hz, 1 H) 8.03 (d, J=7.9 Hz, 1 H) 3.95 (s, 3 H). A mixture of the aldehyde from above (310 mg, 1.48 mmol) and O-methylhydroxylamine hydrochloride (149 mg, 1.77 mmol) in EtOH (10 mL) was heated at 65 oC overnight. The solvent was evaporated and water and DCM was added. The organic layer washed with water and dried (MgSO4). Yield: 348 mg In a tube was added benzyl alcohol (308 µl, 2.96 mmol), dppf (82 mg, 0.148 mmol), Pd(OAc)₂ (16,6 mg, 0.074 mmol) and the material from above (348 mg) dissolved in anisole (2 mL). The tube was flushed with N₂ before the mixture was heated at 160 oC for 3 d. Solvent was evaporated and the residue purified by flash chromatography using 10-20% EtOAc in hexanes as eluent. Yield: 115 mg (ca 400 µmol, ca 25-30% yield). Part of the material from above (25 mg, ca 100 µmol) was added KOH (10 mg/ml, 1 mL) and 50% hydroxylamine in water (0.5 mL). The mixture was stirred at rt for 1 h before quenched AcOH (0.5 mL). The title compound was isolated by reversed phase chromatography (Kinetex C18, 5 µm, 21.2 x 100 mm, flow 25 ml/min, gradient 0.1% TFA in water / acetonitrile over 15 minutes). Yield: 12.2 mg (46%); white solid. EXAMPLE 70 N-Hydroxy-3-(o-tolyl)quinoxaline-6-carboxamide To a solution of INTERMEDIATE 1 (0.3 g, 1.35 mmol) and o-tolylboronic acid (0.238 g, 1.75 mmol) in DMF (10 mL) was added K₂CO₃ (0.56 g, 4.05 mmol). The resulting solution was degassed with argon for 15 min before the addition of Pd(dppf)Cl2.DCM (0.1 g, 0.13 mmol). The resulting solution was heated at 100 ºC for 3 h. The reaction mixture was filtered through Celite, diluted with MTBE and washed with water (20 mL) and brine (20 mL). The organic layer was dried over Na₂SO₄ and concentrated to get a crude product which was purified by flash chromatography (silica gel; 0-30 % ethyl acetate/hexane) yielding methyl 3- (o-tolyl)quinoxaline-6-carboxylate as white solid. Yield: 0.13 g (34 %). To a suspension of the material from above (0.13 g, 0.467 mmol) in MeOH (5 mL) and DCM (5 mL) were added aqueous NH2OH (5 mL, 50% solution) and saturated NaOH solution in MeOH (0.75 mL) dropwise at 0 oC. The reaction mixture was stirred for 5 h, cooled to 0 oC and neutralized with a solution of 1 M NaHSO₄ and the resulting suspension was filtered through sintered funnel and the filtrate was concentrated. The resulting crude material was purified by combi flash column chromatography (silica gel; 0-10% MeOH/DCM) to yield the title compound as brown solid. Yield: 0.06 g (46 %). EXAMPLE 71 3-(4-(Azetidin-1-yl)phenyl)-N-hydroxyquinoxaline-6-carboxamide To a solution of INTERMEDIATE 1 (0.2 g, 0.9 mmol) and 2-(azetidin-1-yl)-5-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)benzene (0.303 g, 1.17 mmol) in dioxane (15 mL) was added Cs₂CO₃ (0.585 g, 1.8 mmol) and the resulting solution was degassed with argon for 15 min before the addition of Pd(dppf)Cl₂.DCM (0.065 g, 0.061 mmol). The resulting solution was heated at 100 ºC for 16 h. Reaction mixture was filtered through Celite and concentrated to get a crude material which was purified by flash chromatography (silica gel; 0-50 % ethyl acetate/hexane). Yield: 0.25 g (86 %); off-white solid. To a suspension of the material from above (0.15 g, 0.47 mmol) in MeOH (6 mL) and DCM (6 mL) were added aqueous NH₂OH (6 mL, 50% solution) and saturated NaOH solution in MeOH (0.9 mL) dropwise at 0 oC and the reaction mixture was stirred for 2 h. Reaction mixture was cooled to 00 C and neutralized with 1 M NaHSO4 and the resulting suspension was filtered through sintered funnel and the filtrate was concentrated. The residue was purified by flash column chromatography (silica gel; 0-10 % MeOH/DCM) and the material obtained was washed with acetonitrile and hexane to yield the title compound. Yield: 0.11 g (46%); yellowish solid. EXAMPLE 72 N-Hydroxy-3-(4-morpholinophenyl)quinoxaline-6-carboxamide To a solution of INTERMEDIATE 1 (0.1 g, 0.45 mmol) and 4-(4-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)phenyl)morpholine (0.143 g, 0.49 mmol) in dioxane (2 mL) was added Cs2CO3 (0.293 g, 0.9 mmol) and the resulting solution was purged with argon for 15 min before the addition of Pd(dppf)Cl₂*DCM (0.033 g, 0.045 mmol). The resulting mixture was stirred in a sealed tube at 100 ºC for 16 h. The reaction mixture was filtered through Celite and concentrated to get crude material which was purified by flash chromatography (silica gel; 0-10 % methanol/DCM) yielding methyl 3-(4- morpholinophenyl)quinoxaline-6-carboxylate. Yield: 0.120 g (66 %); off-white solid. To a suspension of the material from above (0.24 g, 0.68 mmol) in MeOH (10 mL) and DCM (10 mL) were added aqueous NH₂OH (10 mL, 50% solution) and saturated NaOH solution in MeOH (1.5 mL) dropwise at 0 oC. The reaction mixture was stirred for 2 h, cooled to 0 oC and neutralized with a solution of 1 M NaHSO4. The reaction mixture was extracted with THF- ethyl acetate, dried over sodium sulfate and evaporated. The crude material was washed with acetonitrile and ether to yield N-hydroxy-3-(4-morpholinophenyl)quinoxaline-6-carboxamide as an orange solid. Yield: 0.11 g (46 %) EXAMPLE 73 3-(6-Cyclopropylpyridin-3-yl)-N-hydroxyquinoxaline-6-carboxamide To a solution of INTERMEDIATE 1 (0.15 g, 0.6 mmol) and (6-cyclopropylpyridin-3- yl)boronic acid (0.135 g, 0.61 mmol) in dioxane (8 mL) was added Cs₂CO₃ (0.397 g, 1.2 mmol) and the resulting solution was degassed with argon for 15 min before the addition of Pd(dppf)Cl2.DCM (0.044 g, 0.061 mmol). The resulting solution was heated at 100 ºC for 16 h. The reaction mixture was filtered through Celite and concentrated and the residue was purified by flash chromatography (silica gel; 0-50 % ethyl acetate/hexane) yielding methyl 3- (6-cyclopropylpyridin-3-yl)quinoxaline-6-carboxylate as off white solid. Yield: 0.17 g (92 %). To a suspension of the ester from above (0.16 g, 0.52 mmol) in MeOH (7 mL) and DCM (7 mL) were added aqueous NH2OH (7 mL, 50% solution) and saturated NaOH solution in MeOH (1 mL) drop-wise at 0 oC and stirred for 3 h. Reaction mixture was cooled to 0 oC and neutralized with a solution of 1 M NaHSO4 and extracted with THF, the organic layer was dried over sodium sulfate and evaporated. The crude material was purified by flash column chromatography (silica gel; 0-10% MeOH/DCM) and the material obtained was washed with acetonitrile and hexane to yield 3-(6-cyclopropylpyridin-3-yl)-N-hydroxyquinoxaline-6- carboxamide as off white solid. Yield: 0.11 g (46 %). EXAMPLE 74 3-(4-(2-(Dimethylamino)ethoxy)phenyl)-N-hydroxyquinoxaline-6-carboxamide A solution of 4-bromophenol (2.0 g, 11.63 mmol), 2-chloro-N,N-dimethylethan-1-amine hydrochloride (2.5 g, 17.45 mmol), K2CO3 (3.21 g, 23.26 mmol), KI (0.193 g, 1.16 mmol) in acetone (50 mL) was heated at 80 ºC for 16 h. The reaction mixture was cooled, filtered and concentrated to get crude product which was by purified by flash column chromatography (silica gel; 0-70 % EtOAc/hexane) to yield 2-(4-bromophenoxy)-N,N-dimethylethan-1-amine as gummy material. Yield: 0.75 g (26 %). A solution of 2-(4-bromophenoxy)-N,N-dimethylethan-1-amine (0.7 g, 2.88 mmol), bis(pinacolato)diboron (0.878 g, 3.4 mmol) and KOAc (0.85 g, 8.64 mmol) in dioxane (20 mL) was purged with argon for 15 min followed by the addition of Pd(dppf)Cl₂*DCM (0.105 g, 0.14 mmol). The resulting mixture was stirred for 5 h at 10 ºC. The reaction mixture was filtered through celite bed, washed with ethyl acetate and concentrated. The residue was taken in ethyl acetate and washed with brine, water, dried over sodium sulfate and concentrated to yield N,N-dimethyl-2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)ethan-1- amine (0.8 g, crude) which was used in next step without further purification. To a solution of INTERMEDIATE 1 (0.25 g, 1.1 mmol) and N,N-dimethyl-2-(4-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)ethan-1-amine (0.48 g, 1.65 mmol) in dioxane (15 mL) was added Cs₂CO₃ (0.717 g, 2.2 mmol) and the resulting solution was purged with argon for 15 min before the addition of Pd(dppf)Cl₂*DCM (0.08 g, 0.11 mmol) in a sealed tube. The resulting solution was heated at 100 ºC for 16 h. The reaction mixture was filtered through Celite and concentrated to get crude product which was purified by flash chromatography (silica gel; 0-10 % methanol/DCM) yielding methyl 3-(4-(2- (dimethylamino)ethoxy)phenyl)quinoxaline-6-carboxylate as an off-white solid. Yield: 0.255 g (66 %). To a suspension of methyl 3-(4-(2-(dimethylamino)ethoxy)phenyl)quinoxaline-6-carboxylate (0.25 g, 0.71 mmol) in MeOH (5 mL) were added aqueous NH2OH (5 mL, 50% solution) and saturated NaOH solution in MeOH (0.75 mL) dropwise at 0 oC and the resulting mixture was stirred for 2 h before the reaction mixture was cooled to 0 oC and neutralized with 1 M NaHSO₄. The solvent was evaporated, and the residue was taken in 10 % MeOH-DCM and filtered. The filtrate was concentrated and the crude product was purified by column chromatography (amine silica gel (Chromatorex(R) NH DM1020 (mesh 100-200)); 0-10 % MeOH/DCM) to yield 3-(4-(2-(dimethylamino)ethoxy)phenyl)-N-hydroxyquinoxaline-6- carboxamide as an off-white solid. Yield: 0.075 g (30 %). EXAMPLE 75 N-Hydroxy-3-(4-(4-methylpiperazin-1-yl)phenyl)quinoxaline-6-carboxamide To a solution of INTERMEDIATE 1 (0.2 g, 0.9 mmol) and 1-methyl-4-(4-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperazine (0.27 g, 0.9 mmol) in dioxane (12 mL) was added Cs2CO3 (0.587 g, 1.8 mmol) and the resulting solution was purged with argon for 15 min before the addition of Pd(dppf)Cl2*DCM (0.663 g, 0.09 mmol). The resulting mixture was heated in a seal tube at 100 ºC for 16 h. The reaction mixture was filtered through celite bed and concentrated to get crude product which was purified by flash chromatography (silica gel; 0-10 % methanol/DCM) yielding methyl 3-(4-(4- methylpiperazin-1-yl)phenyl)quinoxaline-6-carboxylate as an off-white solid. Yield: 0.15 g (46 %). To a suspension of methyl 3-(4-(4-methylpiperazin-1-yl)phenyl)quinoxaline-6-carboxylate (0.15 g, 0.41 mmol) in MeOH (6 mL) were added aqueous NH₂OH (6 mL, 50 % solution) and saturated NaOH solution in MeOH (0.9 mL) dropwise at 0 oC. The reaction mixture was stirred for 4 h, cooled to 0 oC and neutralized with cold 1 M HCl solution. A precipitate was formed which was filtered off and washed with acetonitrile and ether to yield N-hydroxy-3- (4-(4-methylpiperazin-1-yl)phenyl)quinoxaline-6-carboxamide as a yellow solid. Yield: 0.055 g (37 %). EXAMPLE 76 3-{6-[2-(Dimethylamino)ethoxy]pyridin-3-yl}-N-hydroxyquinoxaline-6-carboxamide To a solution of 5-bromo-2-fluoropyridine (1.5 g, 16.84 mmol) in DMF (20 mL) was added NaH (60 % in oil, 0.674 g, 16.84 mmol) at 0 ºC and the resulting mixture was stirred for 30 min followed by the addition of 2-(dimethylamino)ethan-1-ol (2.36 g, 13.47 mmol). The resulting mixture was stirred at rt for 16 h. The reaction mixture was quenched by careful addition of water and extracted with ethyl acetate (3 x 30 mL). The organic layer dried was over sodium sulfate and concentrated. The residue was purified by Combiflash (0-10 % MeOH in DCM) to yield 2-((5-bromopyridin-2-yl)oxy)-N,N-dimethylethan-1-amine as gummy material. Yield: 1.5 g (36 %). 2-((5-Bromopyridin-2-yl)oxy)-N,N-dimethylethan-1-amine (1.0 g, 4.09 mmol) was taken in THF (4 mL) and triisopropyl borate (0.95 mL, 4.09 mmol) was added. The reaction mixture was cooled to -78 ºC followed by the addition of BuLi (1.8 M in hexane, 2.27 mL) and stirred at -78 ºC for 1 h. Tjhe mixture was warmed to rt and stirred for 2 h followed by the addition of DMSO (8 mL) and MIDA (1.02 g, 4.09 mmol). The resulting mixture was heated at 115 ºC for 2 h. The solvent was evaporated and the solid which was obtained was washed with ether to yield (6-(2-(dimethylamino)ethoxy)pyridin-3-yl)boronic acid MIDA ester which was used in next step without further purification. (6-(2-(Dimethylamino)ethoxy)pyridin-3-yl)boronic acid MIDA ester (0.434 g, 1.35 mmol), INTERMEDIATE 1 (0.25 g, 1.12 mmol) and Cs₂CO₃ (0.734 g, 2.25 mmol) were taken in dioxane (25 mL) and degassed for 15 min before the addition of PdCl2(dppf)*DCM (0.082 g, 0.112 mmol). The resulting mixture was heated in a sealed tube at 100 ºC for 16 h. The reaction mixture was cooled, filtered through Celite and evaporated. The residue was purified by flash column chromatography (silica gel; 0-10 % MeOH in DCM) to yield methyl 3-(6-(2- (dimethylamino)ethoxy)pyridin-3-yl)quinoxaline-6-carboxylate as an off-white solid. Yield (crude): 0.35 g (73 %). To a suspension of methyl 3-(6-(2-(dimethylamino)ethoxy)pyridin-3-yl)quinoxaline-6- carboxylate (0.3 g, 0.85 mmol) in MeOH (12 mL) were added aqueous NH₂OH (12 mL, 50 % solution) and saturated NaOH solution in MeOH (1.2 mL) dropwise at 0 oC. The reaction mixture was stirred for 4 h, then cooled to 0 oC and neutralized with cold 1 M NaHSO4 solution. Reaction mixture was concentrated under reduced pressure and purified by flash chromatography (silica gel; 0-10 % MeOH-DCM) to yield 3-{6-[2- (dimethylamino)ethoxy]pyridin-3-yl}-N-hydroxyquinoxaline-6-carboxamide as light yellow solid. Yield: 0.13 g (43 %). EXAMPLE 77 8-Fluoro-3-phenyl-quinoxaline-6-carboxylic acid hydroxyamide A mixture of 4-bromo-2-fluoro-6-nitrophenylamine (2.0 g, 8.54 mmol), ethyl 2-bromoacetate (9.4 ml, 85.4 mmol) and K₂CO₃ (1.89 g, 13.6 mmol) was heated at 140 oC for 48 h. The reaction mixture was quenched with 1 N NaOH at 0 oC, stirred for 10 min and extracted with MTBE (500 mL). The organic layer dried over sodium sulfate and concentrated under reduced pressure to get a crude product which was purified by column chromatography (silica gel; 10% EtOAc/hexane) to yield 2-(4-bromo-2-fluoro-6-nitrophenylamino)acetic acid ethyl ester. Yield: 900 mg (32%). To a solution of 2-(4-bromo-2-fluoro-6-nitrophenylamino)acetic acid ethyl ester (150 mg, 0.46 mmol) in ethanol (15 mL) were added iron powder (158 mg, 2.81 mmol) and NH4Cl (151 mg, 2.81 mmol) at rt. The reaction mixture was heated at reflux for 3 h before filtered through celite and the filter cake was washed with DCM (200 mL). Combined filtrate was washed with water (50 mL). Organic layer was dried over sodium sulfate and concentrated under reduced pressure to yield 7-bromo-5-fluoro-3,4-dihydro-1H-quinoxalin-2-one. Yield: 75 mg (65%). A mixture of 7-bromo-5-fluoro-3,4-dihydro-1H-quinoxalin-2-one (2.25 g, 9.22 mmol) and triethylamine (12.9 ml, 92.2 mmol) in a mixture of MeOH:DMSO (100 ml, 1:1) was degassed with argon for 30 min followed by addition of Pd(OAc)2 (414 mg, 1.84 mmol) and 1,3- bis(diphenylphosphino)propane (761 mg, 1.84 mmol) at rt. The reaction mixture was heated at 80 oC under 1 atm CO (g) pressure in Amar Autoclave instrument for 16 h. The reaction mixture was filtered through Celite and filter cake was washed with water (150 mL). The combined filtrates were extracted with ethyl acetate (300 mL). The organic layer was dried over sodium sulfate and concentrated under reduced pressure to give a crude product which was purified by column chromatography (silica gel; 50% ethyl acetate/hexane) to yield 8- fluoro-3-oxo-1,2,3,4-tetrahydro-quinoxaline-6-carboxylic acid methyl ester. Yield: 800 mg (38%) as an off-white solid. To a solution of methyl 8-fluoro-3-oxo-1,2,3,4-tetrahydroquinoxaline-6-carboxylate (800 mg, 3.57 mmol) in THF (50 mL) was added MnO2 (1.55 g, 17.85 mmol) at rt. The reaction mixture was filtered through celite and filter cake was washed with THF (100 mL). The filtrate was concentrated under reduced pressure to get crude methyl 8-fluoro-3-oxo-3,4- dihydroquinoxaline-6-carboxylate (1.5 g) as brown solid which was used in the next step without further purification. A solution of methyl 8-fluoro-3-oxo-3,4-dihydroquinoxaline-6-carboxylate (1.5 g, 6.76 mmol, crude) in POCl3 (30 mL) was heated at 90 oC for 2 h. The volume of the reaction mixture was reduced to ~3-4 ml under reduced pressure and the resulting mixture was diluted with ethyl acetate (250 mL), washed with water (100 mL), sat. aq. NaHCO₃ solution (100 mL) and brine (100 mL). The organic layer was dried over sodium sulfate and concentrated under reduced pressure to get a crude product which was purified by column chromatography (silica gel, 4% ethyl acetate/hexane) to yield 3-chloro-8-fluoroquinoxaline-6-carboxylic acid methyl ester. Yield: 400 mg (46%, over two steps); brown solid. A mixture of 3-chloro-8-fluoroquinoxaline-6-carboxylic acid methyl ester (125 mg, 0.52 mmol), phenylboronic acid (95 mg, 0.78 mmol,) and Cs2CO3 (338 mg, 1.04 mmol) in dioxane (20 mL) was degassed with argon for 30 min followed by addition of Pd(dppf)Cl2 (38 mg, 0.052 mmol) at rt. The reaction mixture was heated at 100 oC for 4 h, filtered through celite and filter cake was washed with ethyl acetate (100 mL). The combined filtrates were concentrated, diluted with ethyl acetate (100 mL), washed with water (50 mL) and brine (50 mL). The organic layer was dried over sodium sulfate and concentrated under reduced pressure to get crude product which was purified by column chromatography (silica gel; 4% acetone/hexane) to yield 8-fluoro-3-phenylquinoxaline-6-carboxylic acid methyl ester. Yield: 140 mg (80%); light yellow solid. To a suspension of 8-fluoro-3-phenylquinoxaline-6-carboxylic acid methyl ester (140 mg, 0.49 mmol) in MeOH (11 mL) were added 50 wt% aq. NH2OH (6 mL) and sat. NaOH solution in MeOH (0.9 mL) dropwise at 0 oC followed by addition of DCM (11 mL). The reaction mixture was stirred at rt for 1 h before the mixture was acidified with sat. NaHSO₄ solution (precipitation observed). The precipitate was separated by filtration and dried under reduced pressure to yield 8-fluoro-3-phenylquinoxaline-6-carboxylic acid hydroxyamide (85 mg, 0.3 mmol, 61%) as an off-white solid. EXAMPLE 78 3-(5-((2-(Dimethylamino)ethyl)amino)pyridin-2-yl)-N-hydroxyquinoxaline-6- carboxamide To a solution of 6-bromopyridin-3-ol (4.0 g, 22.98 mmol) in DMF (50 mL) were added Cs₂CO₃ (14.9 g, 45.97 mmol), NaI (0.345 g, 2.29 mmol) and 2-chloro-N,N-dimethylethan-1- amine hydrochloride (4.96 g, 34.48 mmol). The resulting mixture was heated at 100 ºC for 16 h. The reaction mixture was diluted with water, extracted with ethyl acetate (3 x 30 mL), dried over sodium sulfate and evaporated. The residue was purified by flash chromatography (0-15 % MeOH in DCM) to yield 2-((6-bromopyridin-3-yl)oxy)-N,N-dimethylethan-1-amine. Yield: 2.0 g (35 %); brown liquid. 2-((6-bromopyridin-3-yl)oxy)-N,N-dimethylethan-1-amine (1.0 g, 4.09 mmol) was taken in THF (4 mL) and triisopropyl borate (0.95 mL, 4.09 mmol) was added. Reaction mixture was cooled to -78 ºC followed by the addition of BuLi (1.8 M in hexane, 2.27 mL) and stirred at - 78 ºC for 1 h. The reaction mixture was warmed to rt and stirred for 2 h followed by the addition of DMSO (8 mL) and MIDA (1.02 g, 4.09 mmol). The resulting mixture was heated at 115 ºC for 2 h before the solvent was evaporated and the residue which obtained was washed with ether to yield (5-(2-(dimethylamino)ethoxy)pyridin-2-yl)boronic acid MIDA ester which was used in next step without further purification. The ((5-(2-Dimethylamino)ethoxy)pyridin-2-yl)boronic acid MIDA ester from above (0.347 g, 1.08 mmol), INTERMEDIATE 1 (0.20 g, 0.9 mmol) and Cs₂CO₃ (0.587 g, 1.8 mmol) were taken in dioxane (20 mL) and degassed for 15 min before the addition of PdCl₂(dppf)*DCM (0.066 g, 0.09 mmol). The resulting mixture was heated in a sealed tube at 100 ºC for 16 h. After cooling the mixture was filtered through Celite and the filtrate was evaporated. The residue was purified by flash column chromatography (silica; 0-15 % MeOH-DCM) to yield methyl 3-(5-(2-(dimethylamino)ethoxy)pyridin-2-yl)quinoxaline-6-carboxylate. Yield (crude): 0.30 g (78 %). To a suspension of methyl 3-(6-(2-(dimethylamino)ethoxy)pyridin-3-yl)quinoxaline-6- carboxylate (0.13 g, 0.36 mmol) in MeOH (5 mL) and DCM (5 mL) were added aqueous NH2OH (5 mL, 50 % solution) and saturated NaOH solution in MeOH (0.78 mL) dropwise at 0 oC. The reaction mixture was stirred for 4 h at rt, then cooled to 00 C and neutralized with cold 1 M NaHSO4 solution. The reaction mixture was concentrated and the residue was purified by flash chromatography (amine silica gel (Chromatorex(R) NH DM1020 (mesh 100-200)); 0-10 % MeOH-DCM) to yield 3-(5-((2-(dimethylamino)ethyl)amino)pyridin-2- yl)-N-hydroxyquinoxaline-6-carboxamide as brown solid. Yield: 0.03 g (23 %). EXAMPLE 79 8-Fluoro-N-hydroxy-3-(4-methyl-6-morpholinopyridin-3-yl)quinoxaline-6-carboxamid To a solution of 3-chloro-8-fluoroquinoxaline-6-carboxylate, see EXAMPLE 77 (0.225 g, 0.937 mmol) and 4-(4-methyl-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridin-2- yl)morpholine (0.57g, 1.87 mmol) in dioxane (25 mL) was added CS2CO3 (0.611 g, 1.87 mmol). The resulting solution was purged with argon for 15 min followed by the addition of Pd(dppf)C12*DCM (0.069 g, 0.093 mmol). The resulting mixture was heated in a seal tube at 100 °C for 16 h. The reaction mixture was filtered through Celite and concentrated to get a crude material which was purified by flash chromatography (silica gel; 0-10 % methanol/DCM) yielding methyl 8-fluoro-3-(4-methyl-6-morpholinopyri din-3 - yl)quinoxaline-6-carboxylate as a yellowish solid. Yield: 0.2 g (56 %).

To a suspension of methyl 8-fluoro-3-(4-methyl-6-morpholinopyri din-3 -yl)quinoxaline-6- carboxylate (0.2 g, 0.523 mmol) in MeOH (8 mL) and DCM (8 mL) were added aqueous NH2OH (8 mL, 50 % solution) and saturated NaOH solution in MeOH (1.2 mL) dropwise at 0 °C. The reaction mixture was stirred for 4 h, cooled to 0 °C, neutralized with cold 1 M HC1 solution and concentrated. The residue was purified by flash chromatography (amine silica gel (Chromatorex(R) NH DM1020 (mesh 100-200)); 0-10 % MeOH-DCM) to yield 8-fluoro- N-hydroxy-3-(4-methyl-6-morpholinopyridin-3-yl)quinoxaline-6-carboxamide. Yield: 0.07 g (7.8 %); yellow solid.

EXAMPLE 80

N-Hydroxy-3-[4-methyl-6-(morpholin-4-yl)pyridin-3-yl]quinoxaline-6-carboxamide

To a stirred solution of 5-bromo-2-fluoro-4-methylpyridine (2.5 g, 13.23 mmol) in MeCN (6 mL) at rt was added morpholine (5.0 mL, 57.97 mmol) and the resulting mixture was heated at 150 °C in a sealed tube for 16 h. The reaction mixture was cooled, diluted with ethyl acetate (50 mL) and filtered through Celite. The filtrate was concentrated to get crude product which was purified by flash chromatography (silica; 0-50 % ethyl acetate in hexane) to yield 4-(5- bromo-4-methylpyridin-2-yl)morpholine. Yield: 2.2 g (64%); off-white solid.

To a stirred solution of 4-(5-bromo-4-methylpyridin-2-yl)morpholine (2.2 g, 8.55 mmol) in dry dioxane (50 mL) were added bis pinacolato diboron (4.3 g, 17.11 mmol) and anhydrous KOAc (2.51 g, 25.66 mmol) at rt and the reaction mixture was purged with argon for 15 min followed by the addition of PdC12(dppf)*DCM (0.35 g, 0.427 mmol) at rt. The reaction mixture was heated at 100 °C for 16 h, then cooled down to rt, diluted with ethyl acetate (40 mL) and filtered through Celite. The filtrate was concentrated to get a crude product which was purified by flash chromatography (silica; 0-40 % ethyl acetate in hexane) to yield 4-[4- methyl-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridin-2-yl]morpholine as pale yellow liquid. Yield: quantitative.

A solution of INTERMEDIATE 1 (0.20 g,0.90 mmmol) and 4-[4-methyl-5-(4,4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)pyridin-2-yl]morpholine (0.549 g, 1.80 mmol) in 1,4 dioxane (10 mL) was purged with argon for 10 min followed by the addition of CS2CO3 (0.585 g, 1.80 mmol) and PdC12(dppf) (0.06 6 g, 0.09 mmol). The resulting mixture was heated at 100°C for 16 h. The reaction mixture was cooled and filtered though Celite. The filtrate was concentrated and the residue was purified by flash chromatography (silica ; 0-50% ethyl acetate in hexane) to yield methyl 3-[4-methyl-6-(morpholin-4-yl)pyridin-3- yl]quinoxaline-6-carboxylate as off white solid. Yield: 0.1 g (30 %)

To a suspension of methyl 3-[4-methyl-6-(morpholin-4-yl)pyridin-3-yl]quinoxaline-6- carboxylate (0.075 g, 0.206 mmol) in MeOH (3 mL) were added aqueous NH2OH (3 mL, 50% solution) and sat. NaOH solution in MeOH (0.5 mL) dropwise at 0 °C followed by addition of DCM (3 mL). The resulting mixture was stirred at rt for 4 h, then neutralized with sat. NaHSO4 solution at 0 °C and extracted with ethyl acetate-THF (1 : 1) (50 mL). The organic layer was washed with brine (20 mL), dried over Na2SO4 and concentrated under reduced pressure to get crude product which was purified by column chromatography (amine silica gel (Chromatorex(R) NH DM1020 (mesh 100-200); 5-15 % methanol in DCM) to yield N- hydroxy-3-[4-methyl-6-(morpholin-4-yl)pyridin-3-yl]quinoxaline-6-carboxamide as yellow solid. Yield: 0.051 g (39%); yellow solid.

EXAMPLE 81

N-Hydroxy-2-methyl-3-[4-(l-methylethyl)phenyl]quinoxaline-6-carboxamide

To a solution of methyl 3-fluoro-4-nitrobenzoate (5.0 g, 25.11 mmol) in acetonitrile (125 mL) were added K2CO3 (6.93 g, 50.22 mmol) and methyl glycinate hydrochloride (4.72 g, 37.66 mmol). The resulting mixture was heated at 70 °C for 16 h. The reaction mixture was filtered and concentrated. The residue was purified by flash chromatography (silica gel; 0-10 % ethyl acetate in hexane) to yield methyl 3-((2-methoxy-2-oxoethyl)amino)-4-nitrobenzoate as yellow solid. Yield: 5.0 g (74 %). A solution of methyl 3-((2-methoxy-2-oxoethyl)amino)-4-nitrobenzoate (5.0 g, 18.65 mmol) in MeOH (120 mL) and ethyl acetate (60 mL) was purged with argon prior to the addition of Pd-C (10 %, 50 % wet, 1.25 g). The resulting mixture was stirred under hydrogen atmosphere (balloon pressure) for 16 h at rt. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to yield methyl 2-oxo-l,2,3,4-tetrahydroquinoxaline-6- carboxylate as an off-white solid. Yield: 3.2 g (83 %).

To a solution of methyl 2-oxo-l,2,3,4-tetrahydroquinoxaline-6-carboxylate (3.2 g, 15.51 mmol) in THF (200 mL) was added MnCL (5.4 g, 62.21 mmol). The resulting solution was stirred at rt for 16 h. Reaction mixture was filtered through Celite, concentrated and the residue was purified by flash chromatography (silica gel; 0-40 % ethyl acetate in hexane) to yield methyl 2-oxo-l,2-dihydroquinoxaline-6-carboxylate as an off-white solid. Yield: 2.0 g (63 %).

Methyl 2-oxo-l,2-dihydroquinoxaline-6-carboxylate (1.2 g, 5.88 mmol) was dissolved in DMSO (100 mL) and the solution was purged with argon before the addition of MeSChH (0.45 mL, 7.05 mmol), tBuONO (1.04 mmol, 8.82 mmol) and 4-isopropylaniline (3.17 g, 23.52 mmol). The resulting mixture was stirred at rt for 2 h, then poured onto water and extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate and concentrated. The residue was purified by flash chromatography (silica; 0-50 % ethyl acetate in hexane) to yield methyl 3-(4-isopropylphenyl)-2-oxo-l,2-dihydroquinoxaline- 6-carboxylate as an off-white solid. Yield: 0.5 g (26 %).

To a solution of methyl 2-hydroxy-3-(4-isopropylphenyl)quinoxaline-6-carboxylate (0.3 g, 0.931 mmol) in SOCL (5 mL) was added DMF (1 mL). The resulting solution was heated at 90 °C for 1 h. Reaction mixture was cooled and evaporated to dryness. The residue was taken in ethyl acetate, washed with cold sodium bicarbonate solution, and dried over sodium sulfate. The resulting solution was concentrated under reduced pressure and the residue was washed with hexanes to yield 2-chloro-3-(4-isopropylphenyl)quinoxaline-6-carboxylate as a yellowish solid. Yield: 0.25 g (78 %).

To a solution of methyl 2-chloro-3-(4-isopropylphenyl)quinoxaline-6-carboxylate (0.25 g, 0.763 mmol) in THF (30 mL) at 0 °C was added MeMgBr (3M in THF, 0.73 mL, 2.28 mmol) and iron(III) acetylacetonate (75 mg, 0.23 mmol). The resulting mixture was stirred at 0 °C for 2 h, then quenched by the addition of water and extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by column chromatography (silica gel; 0-20 % ethyl acetate in hexane) to yield methyl 3-(4-isopropylphenyl)-2-methylquinoxaline-6- carboxylate as an off-white solid. Yield: 0.13 g (52 %).

To a suspension of methyl 3-(4-isopropylphenyl)-2-methylquinoxaline-6-carboxylate (0.12 g, 0.37 mmol) in MeOH (5 mL) and DCM (5 mL) were added aqueous NH2OH (5 mL, 50 % solution) and saturated NaOH solution in MeOH (0.75 mL) dropwise at 0 °C. The reaction mixture was stirred for 3 h at rt, then cooled to 0 °C and neutralized with cold NaHSO4 solution and concentrated under reduced pressure. The residue was purified by flash chromatography (amine silica gel (Chromatorex(R) NH DM1020 (mesh 100-200); 0-10 % MeOH-DCM) to yield N-Hydroxy-2-methyl-3-[4-(l-methylethyl)phenyl]quinoxaline-6- carboxamide as a white solid. Yield: 0.06 g (18 %).

EXAMPLE 82

N-Hydroxy-3-[6-(morpholin-4-yl)pyridin-3-yl]quinoxaline-6-carboxamide

A solution of INTERMEDIATE 1 (0.20 g, 0.890 mmmol) and 4-[5-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)pyridin-2-yl]morpholine (0.391 g, 1.34 mmol) in 1,4 dioxane (10 mL) was purged with argon for 10 min followed by the addition of CS2CO3 (0.585 g, 1.79 mmol) and PdC12(dppf) (0.066 g, 0.09 mmol). The resulting mixture was heated at 100 °C for 16 h. The reaction mixture was cooled and filtered through Celite. The filtrate was concentrated under reduced pressure and the residue was purified by flash chromatography (silica gel; 0-60 % ethyl acetate in hexane) to yield methyl 3-[6-(morpholin-4-yl)pyridin-3-yl]quinoxaline-6- carboxylate as an off-white solid. Yield: 0.26 g (83%).

To a suspension of methyl 3-[6-(morpholin-4-yl)pyridin-3-yl]quinoxaline-6-carboxylate (0.15 g, 0.428 mmol) in MeOH (6 mL) were added aqueous NH2OH (6 mL, 50% solution) and sat. NaOH solution in MeOH (0.9 mL) dropwise at 0 °C followed by addition of DCM (6 mL). The reaction mixture was stirred at rt for 3 h, then neutralized with sat. aq. NaHSO4 solution at 0 °C and extracted ethyl acetate-THF (1 : 1) (100 mL). The organic layer was washed with brine (20 mL), dried over Na2SO4 and concentrated and under reduced pressure to get crude material which was purified by flash chromatography (amine silica gel (Chromatorex(R) NH DM1020 (mesh 100-200); 5-15 % methanol in DCM) to yield N-hydroxy-3-[6-(morpholin-4- yl)pyridin-3-yl]quinoxaline-6-carboxamide as an orange solid. Yield: 0.056 g (37%).

EXAMPLE 83

N-Hydroxy-3-[(l-methyl-l-pyridin-2-ylethyl)amino]quinoxaline-6-carboxamide

To a solution of INTERMEDIATE 1 (250 mg, 1.12 mmol) in DMSO (20 mL) were added DIPEA (0.58 ml, 3.36 mmol) and l-methyl-l-pyridin-2-yl-ethylamine (228 mg, 1.68 mmol) at rt. The reaction mixture was heated at 120 °C for 16 h, then diluted with ethyl acetate (200 mL), washed with water (100 mL) and cold brine (100 mL). The organic layer was dried over sodium sulfate and concentrated under reduced pressure to get crude product which was purified by column chromatography (silica gel; 2% MeOH/DCM) to yield 3 -(1 -methyl- 1- pyri din-2 -yl-ethylamino)-quinoxaline-6-carboxylic acid methyl ester (210 mg, impure) as brown solid.

To a suspension of methyl 3 -(1 -methyl- 1-pyri din-2 -yl-ethylamino)-quinoxaline-6-carboxylate (210 g, 0.65 mmol) in MeOH (8 mL) were added 50% aqueous hydroxylamine (4 mL) and sat. NaOH solution in MeOH (0.6 mL) dropwise at 0 °C followed by addition of DCM (8 mL). The reaction mixture was stirred at rt for 2 h, then neutralized with sat. aq. NaHSO4 at 0 °C, extracted with ethyl acetate (200 mL) and washed with brine (50 mL). The organic layer was dried over sodium sulfate and concentrated under reduced pressure to get a crude product which was purified by column chromatography (silica gel; 4% MeOH/DCM) followed by triturating using DCM in pentane to yield N-hydroxy-3-[(l-methyl-l-pyridin-2- ylethyl)amino]quinoxaline-6-carboxamide (115 mg, 0.35 mmol, 54%) as light brown solid. Yield: 115 mg (32%, two steps).

EXAMPLE 84

N-Hydroxy-3-[(l-methyl-l-phenylethyl)amino]quinoxaline-6-carboxamide

To a solution of INTERMEDIATE 1 (250 mg, 1.12 mmol) in DMSO (20 mL) were added DIPEA (0.58 ml, 3.36 mmol) and 1 -methyl- 1-phenyl-ethylamine (227 mg, 1.68 mmol) at rt and the reaction mixture was heated at 120 °C for 16 h. Reaction mixture was diluted with ethyl acetate (200 mL), washed with water (100 mL) and cold brine (100 mL). Organic layer was dried over sodium sulfate and concentrated under reduced pressure to get crude product which was purified by column chromatography (silica gel; 2% MeOH/DCM) to yield methyl 3-(l-methyl-l-phenyl-ethylamino)-quinoxaline-6-carboxylate. Yield: 250 mg; brown solid. To a suspension of methyl 3 -[(1 -methyl- l-phenylethyl)amino]quinoxaline-6-carboxylate (250 mg, 0.77 mmol) in MeOH (10 mL) were added 50% aqueous hydroxylamine (5 mL) and sat. NaOH solution in MeOH (0.75 mL) dropwise at 0 °C followed by addition of DCM (10 mL). The reaction mixture was stirred at rt for 30 min, then neutralized with sat. aq. NaHSO4 at 0 °C, extracted with ethyl acetate (200 mL) and washed with brine (100 mL). The organic layer was dried over sodium sulfate and concentrated under reduced pressure to get crude product which was purified by prep. HPLC to yield N-Hydroxy-3-[(l-methyl-l- phenylethyl)amino]quinoxaline-6-carboxamide. Yield: 30 mg as light brown solid.

Preparative HPLC was done on Waters auto purification instrument. Hydrosphere Cl 8 (250 x 20 mm, 5p) operating at ambient temperature and flow rate of 16 ml/min. Mobile phase: A = 10 mM ammonium acetate in water, B=Acetonitrile; Gradient Profile: Mobile phase initial composition of 80% A and 20% B, then to 40% A and 60% B in 22 min, then to 100% B in 23 min., held this composition up to 25 min. for column washing, then returned to initial composition in 26 min. and held till 28 min.

EXAMPLE 85

\-IIydroxy-3- |(3.3.3-trinuoro-l ,l-dimethylpropyl)amino]quinoxaline-6-carboxamide

To a solution of INTERMEDIATE 1 (400 mg, 1.8 mmol) in DMSO (24 mL) were added DIPEA (0.94 ml, 5.4 mmol) and 3,3,3-trifluoro-l,l-dimethyl-propylamine hydrochloride salt (478 mg, 2.7 mmol) at rt. The reaction mixture was heated at 120 °C for 16 h, then diluted with ethyl acetate (200 mL), washed with water (100 mL) and cold brine (100 mL). The organic layer was dried over sodium sulfate and concentrated under reduced pressure to get crude product which was purified by column chromatography (silica gel; 20% acetone/hexane) to yield methyl 3-(3,3,3-trifluoro-l,l-dimethyl-propylamino)-quinoxaline-6- carboxylate (50 mg, 0.15 mmol, 8.3%) as an off-white solid.

To a suspension of the ester from above (50 mg, 0.15 mmol) in MeOH (2 mL) were added 50% aqueous hydroxylamine (2 mL) and sat. NaOH solution in MeOH (0.3 mL) dropwise at 0 °C followed by addition of DCM (2 mL). The reaction mixture was stirred at rt for 3 h, then neutralized with sat. aq. NaHSO4 at 0 °C, extracted with ethyl acetate (100 mL) and washed with brine (30 mL). The organic layer was dried over sodium sulfate and concentrated under reduced pressure to get crude product which was purified by column chromatography (silica gel, 7% MeOH/DCM) followed by prep. HPLC to yield the title compound. Yield: 10 mg (20%); light brown solid.

Preparative HPLC was done on Waters auto purification instrument. Column name: Gemini Cl 8 (250 x 21.2 mm, 5p) operating at ambient temperature and flow rate of 16 ml/min. Mobile phase: A = 20 mM Ammonium Bicarbonate in water, B=Acetonitrile; Gradient Profile: Mobile phase initial composition of 80% A and 20% B, then 80% A and 20% B in 3 min, then to 50% A and 50% B in 22 min., then to 5% A and 95% B in 23 min., held this composition up to 25 min. for column washing, then returned to initial composition in 26 min. and held till 28 min.

Examples of the present invention are listed in Table 1, with analytical data and synthetic details listed in Table 2. Table 1

Table 2

BIOLOGICAL TESTS

Method for measurement of enzymatic activity of HDACs

Materials & Methods All Examples were tested in HDAC1,2,3,6 and 8 in vitro enzymatic assays. The assay principle is well known (Hauser et al. 2009, Bradner et al. 2010) and all necessary reagents like enzymes, substrates, developer and reference compounds are commercially available (see e.g. BPS Biosciences http://www.bpsbioscience.com/). Stock solutions (10 mM in DMSO) of compounds were serially diluted 1 :3 in 11 concentrations with a top concentration of 200 pM for HD AC 1,2, 3 and 2 pM for HDAC6 and HDAC8. The enzymatic reactions were conducted in a mixture containing assay buffer, bovine serum albumin, HD AC substrate, and a test compound. After enzymatic reaction, developer was added and after an additional incubation time, fluorescence intensity was measured at an excitation wavelength of 360 nm and an emission wavelength of 460 nm. All experiments were performed in duplicate.

Results IC₅₀ values for HDAC6 inhibition of some compounds of the invention are shown in Table 3.

Table 3

The selectivity of compounds of the invention for HDAC6 over other isoenzymes in the HD AC family is exemplified in Table 4. Table 4

Method for measurement of cell viability

The CellTiter-Blue® Cell Viability Assay (Promega) provides a homogeneous, fluorometric method for estimating the number of viable cells present in multi-well plates. The assay uses the indicator dye resazurin to measure the metabolic capacity of cells. Viable cells retain the ability to reduce resazurin into resorufin, which is highly fluorescent. Non-viable cells rapidly lose metabolic capacity and do not reduce the indicator dye, and thus do not generate a fluorescent signal. Materials & Methods

Stock solutions (10 mM in DMSO) of compounds were serially diluted 1 :2 in 11 concentrations. 50 nL/well (10 mM compound stock in DMSO) was acoustically dispensed in 384-well assay plates with an acoustic dispenser (EDC Biosystems ATS-100AV). Final starting concentration in the assay was 20 pM (0.2% DMSO) for test compounds. The following cell-lines (and origin) have been primarily used: PaCa2 (pancreatic), U266 (multiple myeloma), AMO-1 (plasmacytoma). PBMCs (peripheral blood mononuclear cells) from healthy donors were used as control cells. Cells were seeded in assay plates (384-well black/clear, Greiner #781091) pre-dispensed with compounds, 25pL/well, and cultured for 72 hours. After 72 hours, Celltiter Blue reagent (Promega #G8081) was diluted 1 : 10 with PBS and then added to wells (5 pL/well). The plates were incubated for 2 hours following addition of reagent. The plates were read in an EnVision fluorescence reader (PerkinElmer) with Ex544 nm/Em590 nm. Results were calculated as % cell viability compared to background (cells treated with 0.2% DMSO).

Results

Table 5 shows cell viability IC₅₀ values for a number of compounds of the invention based on cell viability of a selection of tumor cell lines and healty PBMCs after 72 hours of treatment with the compounds.

Table 5

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Claims

CLAIMS 1. A compound of formula (I)

or a pharmaceutically acceptable salt thereof, wherein two of X, Y, Z and W are N, and two of X, Y, Z and W are C; L is a direct bond or L₁-L₂; L1 is O, NRL, or a direct bond; L2 is C1-C4 alkylene; R_L is H or C1-C3 alkyl; R1 is H, halogen, or C1-C3 alkyl; R₂ is H, halogen, or C1-C3 alkyl; R₃ is H, R₄R₅N, or a cyclic moiety Q₁ selected from 3-to 10-membered, monocyclic or bicyclic carbocyclyl, and 5- to 10-membered, monocyclic or bicyclic heterocyclyl, said cyclic moiety being attached to L by a bond to a carbon atom of the cyclic moiety and said cyclic moiety optionally being substituted by one or more moieties R6; R₄ and R₅ are independently selected from H and C1-C6 alkyl; or R₄ and R₅ together with the nitrogen atom to which they are both attached form a 5- or 6-membered heterocyclic ring, which ring optionally contains one or more further heteroatoms and which ring is optionally substituted by one or more moieties R₆; each R₆ is independently selected from C1-C6 alkyl, halogen, R₇O(CH₂)_n, R₈S(O)₂(CH₂)_o, R₉R₁₀N(CH₂)_p, and R₁₁(CH₂)_q; R₇ is selected from H, C1-C6 alkyl, R_7aR_7bN(CH₂)_r, R_7cR_7dNC(O)(CH₂)_s, and R_7e(CH₂)_t; R7a and R7b are independently selected from H and C1-C6 alkyl; or R7a and R7b together with the nitrogen atom to which they are both attached form a 5- or 6-membered heterocyclic ring, which ring optionally contains one or more further heteroatoms and optionally is substituted by one or more C1-C6 alkyl; R_7c and R_7d are independently selected from H and C1-C6 alkyl; or R_7c and R_7d together with the nitrogen atom to which they are both attached form a 5- or 6-membered heterocyclic ring, which ring optionally contains one more further heteroatoms and optionally is substituted by one or more C1-C6 alkyl; R_7e is a cyclic moiety Q2 selected from 5- or 6-membered carbocyclyl and 5- or 6-membered heterocyclyl, said cyclic moiety being attached to (CH₂)_t by a bond to a carbon atom of the cyclic moiety and said cyclic moiety optionally being substituted by one or more C1-C6 alkyl; R₈ is H or C1-C6 alkyl; R₉ and R₁₀ are independently selected from H and C1-C6 alkyl; or R₉ and R₁₀ together with the nitrogen atom to which they are both attached form a 4- to 6-membered heterocyclic ring, said ring optionally containing one more heteroatoms and said ring optionally being substituted by one or more moieties R₁₂; R₁₁ is a cyclic moiety Q3 selected from 3- to 6-membered carbocyclyl and 4- to 6-membered heterocyclyl, said cyclic moiety being attached to (CH₂)_q by a bond to a carbon atom of the cyclic moiety and said cyclic moiety optionally being substituted by one or more moieties R₁₂; each R₁₂ is independently selected from halogen, C1-C6 alkyl, R13R14N(CH2)u, and R15OC(O)(CH2)v; each R₁₃, R₁₄ and R₁₅ is independently selected from H and C1-C6 alkyl; n, o, p, q, s, t, u, and v are integers of from 0 to 3; r is an integer of from 1 to 4; and any alkyl is optionally substituted by one or more F; provided that the compound is not

4-(dimethylamino)-N-hydroxyquinazoline-7-carboxamide, or N-hydroxyquinoxaline-6-carboxamide.

2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein W is N and Z is C.

3. The compound of claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein X is N and Y is C.

4. The compound of any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, wherein R₃-L is attached to Z.

5. The compound of any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, wherein L is L₁-L₂.

6. The compound of any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof, wherein L₁ is O or NRL.

7. The compound of any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof, wherein L₂ is C1-C2 alkylene.

8. The compound of any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, wherein L is a direct bond.

9. The compound of any one of claims 1 to 8, or a pharmaceutically acceptable salt thereof, wherein R₃ is H or a cyclic moiety Q₁ selected phenyl and 5- or 6-membered heteroaryl, said cyclic moiety optionally being substituted by one or more moieties Re.

10. The compound of claim 9, or a pharmaceutically acceptable salt thereof, wherein R₃ is a cyclic moiety Q₁ selected phenyl and 5- or 6-membered heteroaryl, said cyclic moiety optionally being substituted by one or more moieties R₆.

11. The compound of any one of claims 1 to 10, or a pharmaceutically acceptable salt thereof, wherein the cyclic moiety Q₁ is phenyl.

12. A compound according to claim 1, selected from

N-hydroxy-2-phenylquinoxaline-6-carboxamide,

N-hydroxy-3-phenylquinoxaline-6-carboxamide,

N-hydroxy-2-[4-(l-methylethyl)phenyl]quinoxaline-6-carboxamide,

N-hydroxy-3 -[4-(l-methylethyl)phenyl]quinoxaline-6-carboxamide, 2-[4-(4-fluorophenyl)piperazin-l-yl]-N-hydroxyquinoxaline-6-carboxamide,

2-(benzyloxy)-N-hydroxyquinoxaline-6-carboxamide,

N-hydroxy-3 -pyri din-3 -ylquinoxaline-6-carboxamide,

3-[3-(benzyloxy)phenyl]-N-hydroxyquinoxaline-6-carboxamide, N-hydroxy-3-[4-(methylsulfonyl)phenyl]quinoxaline-6-carboxamide, 3-(2-fluoro-3-methoxyphenyl)-N-hydroxyquinoxaline-6-carboxamide, 3-biphenyl-4-yl-N-hydroxyquinoxaline-6-carboxamide, N-hydroxy-3-[3-(methylsulfonyl)phenyl]quinoxaline-6-carboxamide, 3-(4-fluorophenyl)-N-hydroxyquinoxaline-6-carboxamide, 3-(2,5-difluorophenyl)-N-hydroxyquinoxaline-6-carboxamide, N-hydroxy-3 -(2 -methoxyphenyl)quinoxaline-6-carboxamide, 3-(3-fluoro-4-hydroxyphenyl)-N-hydroxyquinoxaline-6-carboxamide, N-hydroxy-3 -(3 -hydroxyphenyl)quinoxaline-6-carboxamide, 3-(l-benzofuran-2-yl)-N-hydroxyquinoxaline-6-carboxamide, N-hydroxy-3 -pyri din-4-ylquinoxaline-6-carboxamide, N-hydroxy-3-(2-hydroxyphenyl)quinoxaline-6-carboxamide,

N-hydroxy-3 -(6-methoxypyri din-3 -yl)quinoxaline-6-carboxamide,

N-hydroxy-3 -[4-(trifluoromethyl)phenyl]quinoxaline-6-carboxamide, 3-(3-fluoro-4-methoxyphenyl)-N-hydroxyquinoxaline-6-carboxamide, 3-(3-fluoro-2-hydroxyphenyl)-N-hydroxyquinoxaline-6-carboxamide, 3-(2-fluorophenyl)-N-hydroxyquinoxaline-6-carboxamide, N-hydroxy-3-[4-(trifluoromethoxy)phenyl]quinoxaline-6-carboxamide, 3-(cycloheptylamino)-N-hydroxyquinoxaline-6-carboxamide,

N-hydroxy-3-pyrrolidin-l-ylquinoxaline-6-carboxamide, 3-(benzylamino)-N-hydroxyquinoxaline-6-carboxamide, N-hydroxy-3-{[(lS)-l-phenylethyl]amino}quinoxaline-6-carboxamide, 3-[benzyl(methyl)amino]-N-hydroxyquinoxaline-6-carboxamide, 3-[4-(4-fluorophenyl)piperazin-l-yl]-N-hydroxyquinoxaline-6-carboxamide,

3-{4'-[(dimethylamino)methyl]biphenyl-4-yl}-N-hydroxyquinoxaline-6-carboxamide, N-hydroxy-3-[2-(hydroxymethyl)phenyl]quinoxaline-6-carboxamide, 3-(5-fluoro-2-hydroxyphenyl)-N-hydroxyquinoxaline-6-carboxamide, N-hydroxy-3-(4-hydroxyphenyl)quinoxaline-6-carboxamide,

N-hydroxy-3-[4-(hydroxymethyl)phenyl]quinoxaline-6-carboxamide, 3-[4-(aminomethyl)phenyl]-N-hydroxyquinoxaline-6-carboxamide, 3-(4-chl oro-2 -fluorophenyl)-N-hydroxyquinoxaline-6-carboxamide, 3-(2,4-dichlorophenyl)-N-hydroxyquinoxaline-6-carboxamide, 3-(benzyloxy)-N-hydroxyquinoxaline-6-carboxamide,

3-[(4-fluorobenzyl)oxy]-N-hydroxyquinoxaline-6-carboxamide,

N-hydroxy-3 -(pyri din-3 -ylmethoxy)quinoxaline-6-carboxamide, 3-butoxy-N-hydroxyquinoxaline-6-carboxamide, 3-{[3-(benzyloxy)benzyl]oxy}-N-hydroxyquinoxaline-6-carboxamide, 3-[2-(diethylamino)ethoxy]-N-hydroxyquinoxaline-6-carboxamide, N-hydroxy-3-(2-pyridin-4-ylethoxy)quinoxaline-6-carboxamide,

N-hydroxy-3-{4-[(pyridin-3-yloxy)methyl]phenyl}quinoxaline-6-carboxamide, N-hydroxy-3-[4-(piperidin-l-ylmethyl)phenyl]quinoxaline-6-carboxamide, 3-{4-[(4-ethylpiperazin-l-yl)methyl]phenyl}-N-hydroxyquinoxaline-6-carboxamide, 3-{6-[4-(diethylamino)piperidin-l-yl]pyridin-3-yl}-N-hydroxyquinoxaline-6-carboxamide, 3-{4-[2-(diethylamino)ethoxy]phenyl}-N-hydroxyquinoxaline-6-carboxamide, 3-{4-[(3,5-dimethylisoxazol-4-yl)methoxy]phenyl}-N-hydroxyquinoxaline-6-carboxamide,

N-hydroxy-3 -[4-(pyridin-4-ylmethoxy)phenyl]quinoxaline-6-carboxamide, 3-{4-[2-(diethylamino)-2-oxoethoxy]phenyl}-N-hydroxyquinoxaline-6-carboxamide, N-hydroxy-3 -[4-(2-morpholin-4-ylethoxy)phenyl]quinoxaline-6-carboxamide, 3-[2-fluoro-4-(piperidin-l-ylmethyl)phenyl]-N-hydroxyquinoxaline-6-carboxamide, 3-{4-[(4-ethylpiperazin-l-yl)methyl]-2-fluorophenyl}-N-hydroxyquinoxaline-6-carboxamide, 3-(4-{[(cis)-2,6-dimethylmorpholin-4-yl]methyl}-2-fluorophenyl)-N-hydroxyquinoxaline-6- carboxamide, tert-butyl 4-{3-fluoro-4-[7-(hydroxycarbamoyl)quinoxalin-2-yl]benzyl}piperazine-l- carboxylate,

3-{3-[3-(dimethylamino)propoxy]phenyl}-N-hydroxyquinoxaline-6-carboxamide, 3-(3-{2-[bis(l-methylethyl)amino]ethoxy}phenyl)-N-hydroxyquinoxaline-6-carboxamide, 3-{3-[2-(diethylamino)ethoxy]phenyl}-N-hydroxyquinoxaline-6-carboxamide, N-hydroxy-3-{3-[(l-methylpiperidin-3-yl)oxy]phenyl}quinoxaline-6-carboxamide,

3-{3-[(3,5-dimethylisoxazol-4-yl)methoxy]phenyl}-N-hydroxyquinoxaline-6-carboxamide, N-hydroxy-3-[4-(l,2,3,6-tetrahydropyridin-4-yl)phenyl]quinoxaline-6-carboxamide, 8-fluoro-N-hydroxy-3-[4-(l-methylethyl)phenyl]quinoxaline-6-carboxamide, 8-fluoro-N-hydroxy-2-[4-(l-methylethyl)phenyl]quinoxaline-6-carboxamide,

N-hydroxy-2-phenylquinazoline-7-carboxamide, and

N-hydroxy-3-(2-methylphenyl)quinoxaline-6-carboxamide

3-[4-(azetidin-l-yl)phenyl]-N-hydroxyquinoxaline-6-carboxamide

N-hydroxy-3-(4-morpholin-4-ylphenyl)quinoxaline-6-carboxamide 3-(6-cyclopropylpyridin-3-yl)-N-hydroxyquinoxaline-6-carboxamide 3-[4-[2-(dimethylamino)ethoxy]phenyl]-N-hydroxyquinoxaline-6-carboxamide N-hydroxy-3-[4-(4-methylpiperazin-l-yl)phenyl]quinoxaline-6-carboxamide

3-{6-[2-(dimethylamino)ethoxy]pyridin-3-yl}-N-hydroxyquinoxaline-6-carboxamide 8-fluoro-N-hydroxy-3-phenylquinoxaline-6-carboxamide

3-[5-[2-(dimethylamino)ethoxy]pyridin-2-yl]-N-hydroxyquinoxaline-6-carboxamide 8-fluoro-N-hydroxy-3-(4-methyl-6-morpholin-4-ylpyridin-3-yl)quinoxaline-6-carboxamide N-hydroxy-3-(4-methyl-6-morpholin-4-ylpyridin-3-yl)quinoxaline-6-carboxamide N-Hydroxy-2-methyl-3-[4-(l-methylethyl)phenyl]quinoxaline-6-carboxamide

N-hydroxy-3-(6-morpholin-4-ylpyridin-3-yl)quinoxaline-6-carboxamide

N-Hydroxy-3-[(l -methyl-1 -pyri din-2 -ylethyl)amino]quinoxaline-6-carboxamide

N-hydroxy-3-[(l-methyl-l-phenylethyl)amino]quinoxaline-6-carboxamide and N-hydroxy-3-[(3,3,3-trifluoro-l,l-dimethylpropyl)amino]quinoxaline-6-carboxamide, or a pharmaceutically acceptable salt thereof.

13. A compound according to any one of the claims 1 to 12, or pharmaceutically acceptable salt thereof, for use in therapy.

14. A pharmaceutical composition comprising a compound according to any one of the claims 1 to 12, or a pharmaceutically acceptable salt thereof, and optionally a pharmaceutically acceptable excipient.

15. A compound according to any one of the claims 1 to 12, or a pharmaceutically acceptable salt thereof, for use in the treatment of an autoimmune disorder, a mental disorder, a neurodegenerative disorder, pain, a respiratory disease, or a hyperproliferative disorder.

16. The use of a compound according to any one of the claims 1 to 12, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of an autoimmune disorder, a mental disorder, a neurodegenerative disorder, pain, a respiratory disease, or a hyperproliferative disorder.

17. A method for the treatment of a mammal suffering from a disorder selected from an autoimmune disorder, a mental disorder, a neurodegenerative disorder, pain, a respiratory disease, or a hyperproliferative disorder, by administering to said mammal a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof.