FIELD

The present disclosure relates to novel compounds. The present disclosure also relates to said compounds for use as a medicine, more in particular for the prevention or treatment of diseases mediated by activity of YAP/TAZ-TEAD transcription, such as for the prevention or treatment of cancer or fibrosis. Methods for the prevention or treatment of said diseases comprising the use of the novel compounds are also disclosed herein.

The present disclosure furthermore relates to pharmaceutical compositions or combination preparations of the novel compounds as well as to said compositions or preparations for use as a medicine, more preferably for the prevention or treatment of diseases mediated by activity of YAP/TAZ-TEAD transcription, such as for the prevention or treatment of cancer or fibrosis. Processes for the preparation of said compounds are also disclosed herein.

BACKGROUND

Hippo signaling is critical to restrict organ size through inactivation of the YAP/TAZ-TEAD transcriptional complex. In several aggressive solid cancers, Hippo signaling is inactivated through loss-of-function mutations or deletions in the genes encoding the upstream regulators (e.g. NF2, MST1/2 or LATS1/2), unleashing constitutive YAP/TAZ-TEAD transcriptional activity leading to unbridled tumor growth and metastasis. Knock-out, knockdown or pharmacologic inactivation of YAP/TAZ-TEAD is sufficient to impair YAP/TAZ-dependent tumorigenesis. The YAP/TAZ-TEAD complex can be pharmacologically inactivated through targeted disruption of the YAP/TAZ-TEAD protein-protein interaction interface, or through an allosteric autopalmitoylation pocket in TEAD.

The main physiologic function of the Hippo pathway is to restrict tissue growth in adult tissue and modulate cell proliferation, differentiation and migration in developing organs. The core of the Hippo pathway consists of a kinase cascade, transcription coactivators and DNA-binding partners. In mammals, the Ste20-like kinases, MST1/2 (homologs of Drosophila Hippo) phosphorylate and activate Large Tumor Suppressor 1/2 (LATS1/2). NF2 is a scaffold for the core Hippo kinases, promoting LATS1/2 activation by tethering MST1/2 to LATS1/2 (Lallemand et al., 2003, Genes Dev 17, 1090-1100; Yin et al., 2013, Dev Cell 19, 27-38). The LATS kinases will in turn phosphorylate and inactivate two highly homologous transcriptional co-activators: Yes- associated Protein (YAP) and Transcriptional co-activator with PDZ-binding motif (TAZ) by cytoplasmic sequestration via 14-3-3 and by ubiquitin-mediated degradation induced by p-TRCP E3 ligase. When the Hippo pathway is inactive, YAP and TAZ translocate in the nucleus to bind to the TEAD transcription factor family to induce expression of a specific signature promoting matrix remodeling, cell proliferation, survival and migration. TEAD1-4 can also bind to VGLL4 in the nucleus and act as a transcriptional repressor. VGLL4 is not structurally related to YAP/TAZ, but competes with YAP/TAZ based on a partially overlapping binding site on TEAD (Johnson and Halder, 2014, Nat Rev Drug Discov 13, 63-79). TEADs are evolutionarily conserved proteins required for cardiogenesis, myogenesis, and for the development of the neural crest, notochord, and trophoectoderm. In mammals, there are four genes encoding four homologous members of the TEAD family named TEAD1–4. Each TEAD gene has a distinct but not mutually exclusive expression pattern. All TEAD family members are controlled by YAP/TAZ. In fruit flies, loss of function of Hippo or Warts kinases (MST1/2 or LATS1/2 in mammals), or overexpression of Yorkie (the Drosophila homolog of YAP and TAZ), results in a dramatic overgrowth of the cuticle, as a result of dysregulated cell proliferation and resistance to apoptosis, leading to increased organ size. In mice, YAP overexpression, loss of MST1/2 or LATS1/2 kinase activities, or loss of NF2 leads to TEAD target gene up-regulation and progenitor cell expansion, resulting in liver and cardiac overgrowth and ultimately cancer formation in the liver, the small intestine and in skin. In contrast, a serine to alanine mutation at position 94 in YAP, that is unable to bind to TEAD, is not oncogenic (Zhao et al., 2008, Genes Dev 22, 1962-1971). Likewise, a dominant-negative TEAD mutant that is unable to bind DNA, overcomes YAP-driven liver tumorigenesis. In addition, NF2 mutant liver carcinoma was greatly suppressed by heterozogous loss of Yap (Zhang et al., 2010, Dev Cell 19, 27-38). Finally, verteporfin, a small molecule that inhibits YAP-TEAD association significantly suppressed the oncogenic activity of YAP in these models (Liu-Chittenden et al., 2012, Genes Dev 26, 1300-1305). Gene amplification of YAP1 (encoding for YAP) and WWTR1 (encoding for TAZ) as well as constitutive nuclear localization of YAP/TAZ have been reported in many human solid malignancies, including liver, lung, breast, skin, colon and ovarian cancer and YAP/TAZ promote the acquisition of several important cancer cell phenotypes, such as proliferation, resistance to apoptosis, invasion, and immune-suppression (e.g. by attracting myeloid derived suppressor cells (Wang et al., 2016, Cancer Discov 6, 80-95)). In addition, gene fusions with YAP1 have been identified in several cancer types including ependymomas, vascular cancers, cervical carcinomas and porocarcinomas, which results in constitutive activation of YAP-TEAD, and are oncogenic in mice (Szulzewsky et al., 2020, Genes Dev 34: 1-14). In addition, several germline or somatic mutations in components of the Hippo pathway associated with various cancer types have been discovered in targeted and whole-genome sequencing studies. The best studied example is the NF2 locus, mutated with a high frequency in neurofibromatosis. Loss of NF2 and LATS2 are also frequently observed in schwannomas. Another tumor type that is commonly (in about 70% of all cases) associated with constitutive YAP-TEAD activation through genetic inactivation of NF2, LATS1/2, MST1/2 or SAV1, is malignant mesothelioma (Bueno et al., 2016, Nat Genet 48, 407- 416.). Recent studies have shown that several mesothelioma cell lines with NF2 loss-of-function mutations exhibit a decrease in YAP phosphorylation and an increase in YAP-TEAD reporter activity. The YAP-TEAD transcription and viability of NF2 mutant mesothelioma cell lines (but not WT mesothelioma) are sensitive to YAP siRNA (an effect which can be rescued by overexpression of siRNA resistant YAP) and to treatment with verteporfin, a YAP antagonist (Zhang et al., 2017, J Cell Mol Med 21: 2663-2676). Nuclear YAP has also emerged as a critical mediator of WNT dependent colorectal tumorigenesis. YAP-TEAD mediated transcription of genes involved in proliferation and stem cell renewal cooperate with WNT driven beta-catenin, and YAP is required for formation of adenomas following APC (adenomatous polyposis coli) inactivation (Azzolin et al., 2014 Cell 158, 157-170; Gregorieff et al., 2015 Nature 526, 715-718.). Recently, TIAM1, was identified as a suppressor of aggressive, metastatic colorectal cancer (CRC) by antagonizing YAP-TEAD transcription, again highlighting the role of YAP-TEAD in CRC (Diamantopoulou et al., 2017 Cancer Cell 31, 621-634). In summary, YAP/TAZ activation has been shown to drive tumorigenesis and YAP/TAZ is hyperactivated in many different types of cancer in humans (often through loss-of-function mutations in upstream negative regulators). Genetic deletion or pharmacologic inhibition of YAP/TAZ has been shown to suppress tumor development and progression in different types of cancer. Therefore, it is believed that deregulation of the Hippo tumor suppressor pathway is a major event in the development of a wide range of cancer types and malignancies. Hence, pharmacological targeting of the Hippo cascade through inhibition of YAP, TAZ, TEAD, and/or the YAP/TAZ-TEAD protein-protein interaction would be a valuable approach for the treatment of cancers that harbor functional alterations of this pathway. YAP/TAZ-TEAD activation has also been shown to play an important role in other diseases than cancer, namely such as in fibrosis and certain congenital disorders. A hallmark of fibrosis is the excessive deposition of extracellular matrix (ECM), including cross- linked collagen fibres, which results in the stiffening of tissues and eventually in dysfunctioning of affected organs. ECM stiffening promotes the nuclear activity of YAP/TAZ in cancer- associated fibroblasts, and fibroblasts of the liver, kidney, lung and skin (Mannaerts et al., 2015, J. Hepatol. 63, 679-688; Piersma et al., 2015, Am. J. Pathol.185, 3326-3337) . Nuclear YAP/TAZ promotes fibrotic cellular phenotypes, such as myofibroblast differentiation and increased matrix remodeling. Several genes that encode key secreted factors implicated in fibrosis are direct YAP/TAZ-TEAD targets. These genes include well-characterized pro-fibrotic factors, such as connective tissue growth factor (CTGF), plasminogen activator inhibitor 1 (PAI-1) and the lysyl oxidase (LOX) family of collagen cross- linking enzymes. Several lines of evidence support YAP/TAZ as contributors to fibrotic disease in vivo. These include reports of elevated YAP/TAZ levels and transcriptional activity in fibroblasts as well as in alveolar and respiratory epithelium of patients with idiopathic pulmonary fibrosis (Gokey et al., 2018 JCI Insight 3: e98738). Increased nuclear YAP has also been observed in patients with primary sclerosing cholangitis and primary biliary cirrhosis, which are chronic fibrotic disorders of liver injury. Expression of YAP or TAZ in the duct cells of the liver drives fibrosis progression that parallels fibrosis in nonalcoholic fatty liver disease (Machado et al., 2015, J. Hepatol 63, 962-970). Collectively, these studies suggest that targeting aberrant YAP/TAZ activity in fibrotic diseases may hold promise for therapy. Neurofibromatosis type 2 is characterized by nervous system tumors including schwannomas, meningiomas, and ependymomas. Neurofibromatosis type 2 is an inheritable disorder caused by the inactivation of NF2 (Striedinger et al., 2008, Neoplasia 10, 1204-1210). Loss of NF2 leads to constitutive activation of YAP/TAZ-TEAD. The Sturge–Weber syndrome is a congenital eurocutaneous disorder characterized by a port-wine stain affecting the skin in the distribution of the ophthalmic branch of the trigeminal nerve, abnormal capillary venous vessels in the leptomeninges of the brain and choroid, glaucoma, seizures, stroke, and intellectual disability. The Sturge–Weber syndrome and port-wine stains are caused by a somatic activating mutation in GNAQ which leads to activation of YAP/TAZ-TEAD transcription (Shirley et al., 2013, NEJM, 368, 1971-1979). Therefore, several congenital disorders, characterized by constitutive YAP/TAZ-TEAD activation could be treated with inhibitors of YAP/TAZ-TEAD. A few publications describe inhibitors of the YAP-TEAD transcriptional activation. Inventiva highlighted YAP-TEAD protein-protein interaction inhibitors in WO2020/070181, WO2018/185266, and WO2017/064277. The General Hospital Corporation, Boston described autopalmitoylation inhibitors in WO2017/053706. Vivace Therapeutics, Inc. disclosed non-fused tricyclic (WO2018/204532), benzosulfonyl (WO2019/040380), benzocarbonyl (WO2019/113236), oxadiazole (WO2019/222431), and bicyclic (WO2020/097389) compounds that modulate the interaction between YAP/TAZ and TEAD. The Regents of the University of California and Vivace Therapeutics, Inc. described tricyclic compounds that inhibit the Hippo-YAP signaling pathway in WO2013/188138 and WO2017/058716, respectively. Kyowa Hakko Kirin Co., Ltd. revealed alpha,beta-unsaturated amide compounds that display anti-cancer activity in WO2018/235926 and US2019/0010136. Genentech, Inc. disclosed carboxamide and sulfonamide derivatives useful as inhibitors of the YAP-TEAD protein-protein interaction in WO2019/232216 and WO2020/051099. Dana-Farber Cancer Institute, Inc. highlighted inhibitors of TEAD transcription factors in WO2020/081572. The Trustees of Indiana University described small-molecules that bind within the hydrophobic palmitate-binding pocket of TEADs in WO2020/087063. Wenchao Lu, et al. published vinylsulfonamides as covalent TEAD autopalmitoylation inhibitors (2019, European Journal of Medicinal Chemistry, 184, p.111767). Korean Research Institute of Chemical Technology disclosed benzo[cd]indol-2(1H)-one derivatives that inhibit YAP-TEAD binding. However, there is still a great need for novel, alternative or better therapeutics for the prevention or treatment of diseases mediated by the YAP/TAZ-TEAD activation, such as cancer and fibrosis among potentially other indications. Therapeutics with better potency, less side- effects, a higher activity, a lower toxicity or better pharmacokinetic or –dynamic properties or combinations thereof would be very welcome. The present disclosure provides a class of novel compounds which can be used as inhibitors of the YAP/TAZ-TEAD activation mediated diseases. SUMMARY OF THE DISCLOSURE The present disclosure is based on the finding that at least one of the above-mentioned problems can be solved by the below described class of compounds. The present disclosure provides new compounds, especially a compound of formula (Ia), a stereo-isomeric form, a tautomer, a salt (in particular a pharmaceutically acceptable salt), solvate, polymorph and/or prodrug thereof, wherein: -E is selected from (5-membered) heterocycle which can be unsubstituted or substituted with one or more substituents selected from C _1-6 alkyl, C _3-9 cycloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, hydroxyl, =O, halogen, -SH, =S, trifluoromethyl, -O-C _1-6 alkyl, -OCF ₃ , cyano, nitro, -C(O)OH, - C(O)OC _1-6 alkyl, -C(O)C _1-6 alkyl, -CONH ₂ , -CONHC _1-6 alkyl, -CON(C _1-6 alkyl) ₂ , -SO ₂ C _1-6 alkyl, - SO ₂ NH ₂ , -SO ₂ NHC _1-6 alkyl, -SO ₂ N(C _1-6 alkyl) ₂ , -S(O)(NH)C1-6alkyl, -S(O)(NC1-6alkyl)C1-6alkyl, - S(NH)(NH)C1-6alkyl,-NH ₂ , -NHC _1-6 alkyl, and -N(C _1-6 alkyl) ₂ ; and -(CR ^10a R ^10b ) _n -NR ¹ R ² ; - n is selected from 0; 1; and 2; - m is selected from 0; and 1; - each represents an optional double bond, whereby maximally 3 are a double bond at the same time; - R ¹ is selected from C _1-6 alkyl; C _3-9 cycloalkyl; C _2-6 alkenyl; C _5-9 cycloalkenyl; C _2-6 alkynyl; C _{5- 9} cycloalkynyl; C _1-6 heteroalkyl; C _2-6 heteroalkenyl; C _2-6 heteroalkynyl; -C(O)H; -C(O)R ³ ; -C(O)OR ⁴ ; - C(O)NR ⁵ R ⁶ ; -S(O) ₂ R ^3a ; -S(O)R ^4a ; -S(O)2NR ^5a R ^6a ; -S(O)(NR ^5a )R ^4a ; -S(NR ^5a )(NR ^6a )R ^3a ; and - P(O)R ^5b R ^6b ; wherein said C _1-6 alkyl, C _3-9 cycloalkyl, C _2-6 alkenyl, C _5-9 cycloalkenyl, C _2-6 alkynyl, C _{5- 9} cycloalkynyl, C _1-6 heteroalkyl, C _2-6 heteroalkenyl and C _2-6 heteroalkynyl can be unsubstituted or substituted with one or more substituents selected from C _1-6 alkyl, C _3-9 cycloalkyl, C _2-6 alkenyl, C _{2- 6} alkynyl, hydroxyl, =O, halogen, -SH, =S, trifluoromethyl, -O-C _1-6 alkyl, -OCF ₃ , cyano, nitro, - C(O)OH, -C(O)OC _1-6 alkyl, -C(O)C _1-6 alkyl, -CONH ₂ , -CONHC _1-6 alkyl, -CON(C _1-6 alkyl) ₂ , -SO ₂ C _{1- 6} alkyl, -SO ₂ NH ₂ , -SO ₂ NHC _1-6 alkyl, -SO ₂ N(C _1-6 alkyl) ₂ , -S(O)(NH)C _1-6 alkyl, -S(O)(NC _1-6 alkyl)C _{1- 6} alkyl, -S(NH)(NH)C _1-6 alkyl, -S(O)(NH)C1-6alkyl, -S(O)(NC1-6alkyl)C1-6alkyl, -S(O) ₂ OH, - S(NH)(NH)C1-6alkyl, -NH ₂ , -NHC _1-6 alkyl, -N(C _1-6 alkyl) ₂ ; - R ² is selected from hydrogen; C _1-6 alkyl; C _3-9 cycloalkyl; and C _1-6 heteroalkyl; - R ¹ and R ² can be taken together to form a (4-; 5-; 6- or 7-membered) heterocycle which can be unsubstituted or substituted with one or more substituents selected from C _1-6 alkyl, C _{3- 9} cycloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, hydroxyl, =O, halogen, -SH, =S, trifluoromethyl, -O-C _1-6 alkyl, -OCF ₃ , cyano, nitro, -C(O)OH, -C(O)OC _1-6 alkyl, -C(O)C _1-6 alkyl, -CONH ₂ , -CONHC _1-6 alkyl, - CON(C _1-6 alkyl) ₂ , -SO ₂ C _1-6 alkyl, -SO ₂ NH ₂ , -SO ₂ NHC _1-6 alkyl, -SO ₂ N(C _1-6 alkyl) ₂ , -S(O)(NH)C1- 6alkyl, -S(O)(NC1-6alkyl)C1-6alkyl, -S(NH)(NH)C1-6alkyl,-NH ₂ , -NHC _1-6 alkyl, -N(C _1-6 alkyl) ₂ ; - each R ³ and R ^3a is independently selected from hydroxyl; C _1-6 alkyl; C _3-9 cycloalkyl; C _{2- 6} alkenyl; C _5-9 cycloalkenyl; C _2-6 alkynyl; C _5-9 cycloalkynyl; C _1-6 heteroalkyl; C _2-6 heteroalkenyl; and C _{2- 6} heteroalkynyl; wherein said C _1-6 alkyl, C _3-9 cycloalkyl, C _2-6 alkenyl, C _5-9 cycloalkenyl, C _2-6 alkynyl, C _{5- 9} cycloalkynyl, C _1-6 heteroalkyl, C _2-6 heteroalkenyl and C _2-6 heteroalkynyl can be unsubstituted or substituted with one or more substituents selected from alkyl, cycloalkyl, alkenyl, alkynyl, hydroxyl, =O, halogen, -SH, =S, -CF ₃ , -O-alkyl, -OCF3, -CHF ₂ , -OCHF ₂ , cyano, nitro, -C(O)OH; NH ₂ ; - NHalkyl, and -N(alkyl) ₂ ; - each R ⁴ and R ^4a is independently selected from C _1-6 alkyl; C _3-9 cycloalkyl; C _2-6 alkenyl; C _{5- 9} cycloalkenyl; C _2-6 alkynyl; C _5-9 cycloalkynyl; C _1-6 heteroalkyl; C _2-6 heteroalkenyl; and C _{2- 6} heteroalkynyl; wherein said C _1-6 alkyl, C _3-9 cycloalkyl, C _2-6 alkenyl, C _5-9 cycloalkenyl, C _2-6 alkynyl, C _{5- 9} cycloalkynyl, C _1-6 heteroalkyl, C _2-6 heteroalkenyl and C _2-6 heteroalkynyl can be unsubstituted or substituted with one or more substituents selected from alkyl, cycloalkyl, alkenyl, alkynyl, hydroxyl, =O, halogen, -SH, =S, -CF ₃ , -O-alkyl, -OCF3, -CHF ₂ , -OCHF ₂ , cyano, nitro, -C(O)OH; NH ₂ ; - NHalkyl, and -N(alkyl) ₂ ; - each R ⁵ , R ^5a , R ^5b , R ⁶ , R ^6a and R ^6b is independently selected from hydrogen; C _1-6 alkyl; C _{3- 9} cycloalkyl; C _2-6 alkenyl; C _5-9 cycloalkenyl; C _2-6 alkynyl; C _5-9 cycloalkynyl; C _1-6 heteroalkyl; C _{2- 6} heteroalkenyl; and C _2-6 heteroalkynyl; wherein said C _1-6 alkyl, C _3-9 cycloalkyl, C _2-6 alkenyl, C _5-9 cycloalkenyl, C _2-6 alkynyl, C _{5- 9} cycloalkynyl, C _1-6 heteroalkyl, C _2-6 heteroalkenyl and C _2-6 heteroalkynyl can be unsubstituted or substituted with one or more substituents selected from alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, hydroxyl, =O, halogen, -SH, =S, -CF ₃ , -O-alkyl, -OCF3, -CHF ₂ , -OCHF ₂ , cyano, nitro, -C(O)OH; NH ₂ ; -NHalkyl, and -N(alkyl) ₂ ; and wherein each R ⁵ and R ⁶ or R ^5a and R ^6a can be taken together in order to form a (4-, 5- , 6-, or 7-membered) heterocycle which can be unsubstituted or substituted with one or more substituents selected from alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, hydroxyl, =O, halogen, -SH, =S, -CF ₃ , -O-alkyl, -OCF3, -CHF ₂ , -OCHF ₂ , cyano, nitro, -C(O)OH; NH ₂ ; - NHalkyl, and -N(alkyl) ₂ ; - cycle A is selected from aryl; heteroaryl; C _3-9 cycloalkyl; and heterocycle; wherein said aryl, heteroaryl, C _3-9 cycloalkyl and heterocycle is substituted with one or more R ⁷ ; - each R ⁷ is independently selected from halogen; hydroxyl; sulfhydryl; =O; =S; -OZ1; - SZ1; -SCF3; -SF5; -CF ₃ ; -OCF ₃ ; -CHF ₂ ; -OCHF ₂ ; -NZ3Z4; -NZ3C(O)Z1; cyano; -C(O)Z2; -- C(O)OZ ¹ ; -C(O)NZ ³ Z ⁴ ; C _1-6 alkyl; C _3-9 cycloakyl; C _2-6 alkenyl; C _2-6 alkynyl; C _1-6 heteroalkyl; C _{2- 6} heteroalkenyl; C _2-6 heteroalkynyl; aryl; heteroaryl; heterocycle; arylC _1-6 alkyl; arylC _2-6 alkenyl; arylalkynyl; arylC _1-6 heteroalkyl; arylC _2-6 heteroalkenyl; arylC _2-6 heteroalkynyl; heteroarylC _1-6 alkyl; heteroarylC _2-6 alkenyl; heteroarylC _2-6 alkynyl; heteroarylC _1-6 heteroalkyl; heteroarylC _{2- 6} heteroalkenyl; heteroarylC _2-6 heteroalkynyl; heterocycle-C _1-6 alkyl; heterocycle-C _2-6 alkenyl; heterocycle-C _2-6 alkynyl; heterocycle-C _1-6 heteroalkyl; heterocycle-C _2-6 heteroalkenyl; and heterocycle-C _2-6 heteroalkynyl; wherein said C _1-6 alkyl, C _3-9 cycloakyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 heteroalkyl, C _{2- 6} heteroalkenyl, C _2-6 heteroalkynyl, aryl, heteroaryl, heterocycle, arylC _1-6 alkyl, arylC _2-6 alkenyl, arylalkynyl, arylC _1-6 heteroalkyl, arylC _2-6 heteroalkenyl, arylC _2-6 heteroalkynyl, heteroarylC _1-6 alkyl, heteroarylC _2-6 alkenyl, heteroarylC _2-6 alkynyl, heteroarylC _1-6 heteroalkyl, heteroarylC _{2- 6} heteroalkenyl, heteroarylC _2-6 heteroalkynyl, heterocycle-C _1-6 alkyl, heterocycle-C _2-6 alkenyl, heterocycle-C _2-6 alkynyl, heterocycle-C _1-6 heteroalkyl, heterocycle-C _2-6 heteroalkenyl and heterocycle-C _2-6 heteroalkynyl can be unsubstituted or substituted with one or more substituents selected from C _1-6 alkyl, C _3-9 cycloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, hydroxyl, =O, halogen, -SH, =S, - CF ₃ , -O-C _1-6 alkyl, -OCF ₃ , -CHF ₂ ; -OCHF ₂ , cyano, nitro, -C(O)OH, -NH ₂ , -NHC _1-6 alkyl, and -N(C _{1- 6} alkyl) ₂ ; - X ¹ is selected from CR ⁸ ; N; and NR ^8a ; whereby X ¹ can only be NR ^8a when X ² and/or X ⁴ are C=O or C=S; - X ² is selected from CR ⁹ ; N; and NR ^9a ; whereby X ² can only be NR ^9a when X ¹ and/or X ³ are C=O or C-SH; - X ³ is selected from CH; and N; - X ⁴ is selected from CH; and N; - X ⁵ is selected from -S(=O) ₂ -; -C(=O)-; and -CH ₂ -; -each R ^10a is independently selected from hydrogen; and C _1-4 alkyl ; -each R ^10b is independently selected from hydrogen; and C _1-4 alkyl wherein said alkyl can be unsubstituted or substituted with one or more substituents selected from C _1-6 alkyl, C _3-9 cycloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, hydroxyl, =O, halogen, -SH, =S, - CF ₃ , -O-C _1-6 alkyl, -OCF ₃ , -CHF ₂ ; -OCHF ₂ , cyano, nitro, -C(O)OH, -NH ₂ , -NHC _1-6 alkyl, and -N(C _{1- 6} alkyl) ₂ ; whereby maximally 2 of X ¹ , X ² , X ³ and X ⁴ can be a N (selected from N and NR ^8a for X ¹ , from N and NR ^9a for X ² , from N for X ³ , and from Nfor X ⁴ respectively) at the same time; - provided that at least one of R ⁸ and R ⁹ is not hydrogen, each R ⁸ and R ⁹ are independently selected from hydrogen; halogen; hydroxyl; sulfhydryl; =O; =S; -OZ1a; -SZ1a; -SCF3; -SF5; - S(O)Z1a; -S(O)(NZ3a)Z1a; -S(NZ3a)(NZ3a)Z1a; -S(O)2Z2a; -S(O)2NZ3aZ4a; -CF ₃ ; -OCF ₃ ; - CHF ₂ ; -OCHF ₂ ; nitro; -NZ3aZ4a; -NZ3aS(O)2Z1a; -NZ3aC(O)Z1a; -NZ3aC(O)NZ3aZ4a; cyano; - C(O)Z2a; -C(O)OZ1a; -C(O)NZ3aZ4a; -C(O)H; -P(O)Z ^3a Z ^4a ; C _1-6 alkyl; C _3-9 cycloakyl; C _2-6 alkenyl; C _2-6 alkynyl; C _1-6 heteroalkyl; C _2-6 heteroalkenyl; C _2-6 heteroalkynyl; aryl; heteroaryl; heterocycle; arylC _1-6 alkyl; arylC _2-6 alkenyl; arylC _2-6 alkynyl; arylC _1-6 heteroalkyl; arylC _2-6 heteroalkenyl; arylC _{2- 6} heteroalkynyl; heteroarylC _1-6 alkyl; heteroarylC _2-6 alkenyl; heteroarylC _2-6 alkynyl; heteroarylC _{1- 6} heteroalkyl; heteroarylC _2-6 heteroalkenyl; heteroarylC _2-6 heteroalkynyl; heterocycle-C _1-6 alkyl; heterocycle-C _2-6 alkenyl; heterocycle-C _2-6 alkynyl; heterocycle-C _1-6 heteroalkyl; heterocycle- C _{2- 6} heteroalkenyl; and heterocycle- C _2-6 heteroalkynyl; wherein said C _1-6 alkyl, C _3-9 cycloakyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 heteroalkyl, C _{2- 6} heteroalkenyl, C _2-6 heteroalkynyl, aryl, heteroaryl, heterocycle, arylC _1-6 alkyl, arylC _2-6 alkenyl, arylalkynyl, arylC _1-6 heteroalkyl, arylC _2-6 heteroalkenyl, arylC _2-6 heteroalkynyl, heteroarylC _1-6 alkyl, heteroarylC _2-6 alkenyl, heteroarylC _2-6 alkynyl, heteroarylC _1-6 heteroalkyl, heteroarylC _{2- 6} heteroalkenyl, heteroarylC _2-6 heteroalkynyl, heterocycle-C _1-6 alkyl, heterocycle-C _2-6 alkenyl, heterocycle-C _2-6 alkynyl, heterocycle-C _1-6 heteroalkyl, heterocycle-C _2-6 heteroalkenyl and heterocycle-C _2-6 heteroalkynyl can be unsubstituted or substituted with one or more substituents selected from C _1-6 alkyl, C _3-9 cycloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, hydroxyl, =O, halogen, -SH, =S, - CF ₃ , -O-C _1-6 alkyl, -OCF ₃ , -CHF ₂ ; -OCHF ₂ , cyano, nitro, -C(O)OH, -NH ₂ , -NHC _1-6 alkyl, and -N(C _{1- 6} alkyl) ₂ ; - each R ^8a and R ^9a are independently selected from hydrogen; hydroxyl; sulfhydryl; -OZ1a; -SZ1a; -SCF3; -SF5; -S(O)Z1a; -S(O)(NZ3a)Z1a; -S(NZ3a)(NZ3a)Z1a; -S(O)2Z2a; - S(O)2NZ3aZ4a; -CF ₃ ; -OCF ₃ ; -CHF ₂ ; -OCHF ₂ ; nitro; -NZ3aZ4a; -NZ3aS(O)2Z2a; -NZ3aC(O)Z1a; -NZ3aC(O)NZ3aZ4a; cyano; -C(O)Z2a; -C(O)OZ1a; -C(O)NZ3aZ4a; -C(O)H; -P(O)Z ^3a Z ^4a ; C _{1- 6} alkyl; C _3-9 cycloakyl; C _2-6 alkenyl; C _2-6 alkynyl; C _1-6 heteroalkyl; C _2-6 heteroalkenyl; C _2-6 heteroalkynyl; aryl; heteroaryl; heterocycle; arylC _1-6 alkyl; arylC _2-6 alkenyl; arylC _2-6 alkynyl; arylC _1-6 heteroalkyl; arylC _2-6 heteroalkenyl; arylC _2-6 heteroalkynyl; heteroarylC _1-6 alkyl; heteroarylC _2-6 alkenyl; heteroarylC _2-6 alkynyl; heteroarylC _1-6 heteroalkyl; heteroarylC _2-6 heteroalkenyl; heteroarylC _{2- 6} heteroalkynyl; heterocycle-C _1-6 alkyl; heterocycle-C _2-6 alkenyl; heterocycle-C _2-6 alkynyl; heterocycle-C _1-6 heteroalkyl; heterocycle- C _2-6 heteroalkenyl; and heterocycle- C _2-6 heteroalkynyl; wherein said C _1-6 alkyl, C _3-9 cycloakyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 heteroalkyl, C _{2- 6} heteroalkenyl, C _2-6 heteroalkynyl, aryl, heteroaryl, heterocycle, arylC _1-6 alkyl, arylC _2-6 alkenyl, arylalkynyl, arylC _1-6 heteroalkyl, arylC _2-6 heteroalkenyl, arylC _2-6 heteroalkynyl, heteroarylC _1-6 alkyl, heteroarylC _2-6 alkenyl, heteroarylC _2-6 alkynyl, heteroarylC _1-6 heteroalkyl, heteroarylC _{2- 6} heteroalkenyl, heteroarylC _2-6 heteroalkynyl, heterocycle-C _1-6 alkyl, heterocycle-C _2-6 alkenyl, heterocycle-C _2-6 alkynyl, heterocycle-C _1-6 heteroalkyl, heterocycle-C _2-6 heteroalkenyl and heterocycle-C _2-6 heteroalkynyl can be unsubstituted or substituted with one or more substituents selected from C _1-6 alkyl, C _3-9 cycloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, hydroxyl, =O, halogen, -SH, =S, - CF ₃ , -O-C _1-6 alkyl, -OCF ₃ , -CHF ₂ ; -OCHF ₂ , cyano, nitro, -C(O)OH, -NH ₂ , -NHC _1-6 alkyl, and -N(C _{1- 6} alkyl) ₂ ; - each Z ¹ and Z ^1a is independently selected from C _1-6 alkyl; C _3-9 cycloakyl; C _2-6 alkenyl; C _{5- 9} cycloalkenyl; C _2-6 alkynyl; C _5-9 cycloalkynyl; C _1-6 heteroalkyl; C _2-6 heteroalkenyl; C _2-6 heteroalkynyl; aryl; heteroaryl; heterocycle; arylC _1-6 alkyl; arylC _2-6 alkenyl; arylC _2-6 alkynyl; arylC _1-6 heteroalkyl; arylC _2-6 heteroalkenyl; arylC _2-6 heteroalkynyl; heteroarylC _1-6 alkyl; heteroarylC _2-6 alkenyl; heteroarylC _2-6 alkynyl; heteroarylC _1-6 heteroalkyl; heteroarylC _2-6 heteroalkenyl; heteroarylC _{2- 6} heteroalkynyl; heterocycle-C _1-6 alkyl; heterocycle-C _2-6 alkenyl; heterocycle-C _2-6 alkynyl; heterocycle-C _1-6 heteroalkyl; heterocycle- C _2-6 heteroalkenyl; and heterocycle- C _2-6 heteroalkynyl; wherein said C _1-6 alkyl, C _3-9 cycloakyl, C _2-6 alkenyl, C _5- 9cycloalkenyl, C _2-6 alkynyl, C _{5- 9} cycloalkynyl, C _1-6 heteroalkyl, C _2-6 heteroalkenyl, C _2-6 heteroalkynyl, aryl, heteroaryl, heterocycle, arylC _1-6 alkyl, arylC _2-6 alkenyl, arylC _2-6 alkynyl, arylC _1-6 heteroalkyl, arylC _2-6 heteroalkenyl, arylC _{2- 6} heteroalkynyl, heteroarylC _1-6 alkyl, heteroarylC _2-6 alkenyl, heteroarylC _2-6 alkynyl, heteroarylC _{1- 6} heteroalkyl, heteroarylC _2-6 heteroalkenyl, heteroarylC _2-6 heteroalkynyl, heterocycle-C _1-6 alkyl, heterocycle-C _2-6 alkenyl, heterocycle-C _2-6 alkynyl, heterocycle-C _1-6 heteroalkyl, heterocycle- C _{2- 6} heteroalkenyl, and heterocycle- C _2-6 heteroalkynyl can be unsubstituted or substituted with one or more substituents selected from C _1-6 alkyl, C _3-9 cycloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, hydroxyl, =O, halogen, -SH, =S, -CF ₃ , -O-C _1-6 alkyl, -OCF ₃ , -CHF ₂ ; -OCHF ₂ , cyano, nitro, -C(O)OH, -NH ₂ , -NHC _{1- 6} alkyl, and -N(C _1-6 alkyl) ₂ ; - each Z ² and Z ^2a is independently selected from hydroxyl; C _1-6 alkyl; C _3-9 cycloakyl; C _{2- 6} alkenyl; C _5- 9cycloalkenyl; C _2-6 alkynyl; C _5-9 cycloalkynyl; C _1-6 heteroalkyl; C _2-6 heteroalkenyl; C _{2- 6} heteroalkynyl; aryl; heteroaryl; heterocycle; arylC _1-6 alkyl; arylC _2-6 alkenyl; arylC _2-6 alkynyl; arylC _{1- 6} heteroalkyl; arylC _2-6 heteroalkenyl; arylC _2-6 heteroalkynyl; heteroarylC _1-6 alkyl; heteroarylC _{2- 6} alkenyl; heteroarylC _2-6 alkynyl; heteroarylC _1-6 heteroalkyl; heteroarylC _2-6 heteroalkenyl; heteroarylC _2-6 heteroalkynyl; heterocycle-C _1-6 alkyl; heterocycle-C _2-6 alkenyl; heterocycle-C _{2- 6} alkynyl; heterocycle-C _1-6 heteroalkyl; heterocycle- C _2-6 heteroalkenyl; and heterocycle- C _{2- 6} heteroalkynyl; wherein said C _1-6 alkyl, C _3-9 cycloakyl, C _2-6 alkenyl, C _5- 9cycloalkenyl, C _2-6 alkynyl, C _{5- 9} cycloalkynyl, C _1-6 heteroalkyl, C _2-6 heteroalkenyl, C _2-6 heteroalkynyl, aryl, heteroaryl, heterocycle, arylC _1-6 alkyl, arylC _2-6 alkenyl, arylC _2-6 alkynyl, arylC _1-6 heteroalkyl, arylC _2-6 heteroalkenyl, arylC _{2- 6} heteroalkynyl, heteroarylC _1-6 alkyl, heteroarylC _2-6 alkenyl, heteroarylC _2-6 alkynyl, heteroarylC _{1- 6} heteroalkyl, heteroarylC _2-6 heteroalkenyl, heteroarylC _2-6 heteroalkynyl, heterocycle-C _1-6 alkyl, heterocycle-C _2-6 alkenyl, heterocycle-C _2-6 alkynyl, heterocycle-C _1-6 heteroalkyl, heterocycle- C _{2- 6} heteroalkenyl, and heterocycle- C _2-6 heteroalkynyl can be unsubstituted or substituted with one or more substituents selected from C _1-6 alkyl, C _3-9 cycloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, hydroxyl, =O, halogen, -SH, =S, -CF ₃ , -O-C _1-6 alkyl, -OCF3, -CHF ₂ , -OCHF ₂ , cyano, nitro, -C(O)OH; NH ₂ ; -NHC _{1- 6} alkyl, and -N(C _1-6 alkyl) ₂ ; - each Z ³ , Z ^3a , Z ⁴ , and Z ^4a is independently selected from hydrogen; C _1-6 alkyl; C _3-9 cycloakyl; C _2-6 alkenyl; C _5-9 cycloalkenyl; C _2-6 alkynyl; C _5-9 cycloalkynyl; C _1-6 heteroalkyl; C _2-6 heteroalkenyl; C _{2- 6} heteroalkynyl; aryl; heteroaryl; heterocycle; arylC _1-6 alkyl; arylC _2-6 alkenyl; arylC _2-6 alkynyl; arylC _{1- 6} heteroalkyl; arylC _2-6 heteroalkenyl; arylC _2-6 heteroalkynyl; heteroarylC _1-6 alkyl; heteroarylC _{2- 6} alkenyl; heteroarylC _2-6 alkynyl; heteroarylC _1-6 heteroalkyl; heteroarylC _2-6 heteroalkenyl; heteroarylC _2-6 heteroalkynyl; heterocycle-C _1-6 alkyl; heterocycle-C _2-6 alkenyl; heterocycle-C _{2- 6} alkynyl; heterocycle-C _1-6 heteroalkyl; heterocycle- C _2-6 heteroalkenyl; and heterocycle- C _{2- 6} heteroalkynyl; wherein said C _1-6 alkyl, C _3-9 cycloakyl, C _2-6 alkenyl, C _5-9 cycloalkenyl, C _2-6 alkynyl, C _{5- 9} cycloalkynyl, C _1-6 heteroalkyl, C _2-6 heteroalkenyl, C _2-6 heteroalkynyl, aryl, heteroaryl, heterocycle, arylC _1-6 alkyl, arylC _2-6 alkenyl, arylC _2-6 alkynyl, arylC _1-6 heteroalkyl, arylC _2-6 heteroalkenyl, arylC _{2- 6} heteroalkynyl, heteroarylC _1-6 alkyl, heteroarylC _2-6 alkenyl, heteroarylC _2-6 alkynyl, heteroarylC _{1- 6} heteroalkyl, heteroarylC _2-6 heteroalkenyl, heteroarylC _2-6 heteroalkynyl, heterocycle-C _1-6 alkyl, heterocycle-C _2-6 alkenyl, heterocycle-C _2-6 alkynyl, heterocycle-C _1-6 heteroalkyl, heterocycle- C _{2- 6} heteroalkenyl, and heterocycle- C _2-6 heteroalkynyl can be unsubstituted or substituted with one or more substituents selected from C _1-6 alkyl, C _3-9 cycloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, hydroxyl, =O, halogen, -SH, =S, -CF ₃ , -O-C _1-6 alkyl, -OCF3, -CHF ₂ , -OCHF ₂ , cyano, nitro, -C(O)OH; NH ₂ ; -NHC _{1- 6} alkyl, and -N(C _1-6 alkyl) ₂ ; and wherein each Z ³ and Z ⁴ or Z ^3a and Z ^4a can be taken together in order to form a (4-, 5- , 6-, or 7-membered) heterocycle which can be unsubstituted or substituted with one or more substituents selected from C _1-6 alkyl, C _3-9 cycloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, hydroxyl, =O, halogen, -SH, =S, -CF ₃ , -O-C _1-6 alkyl, -OCF3, -CHF ₂ , -OCHF ₂ , cyano, nitro, -C(O)OH; NH ₂ ; -NHC _1-6 alkyl, and -N(C _1-6 alkyl) ₂ . The present disclosure also provides new compounds, especially a compound of formula (I), a stereo-isomeric form, a tautomer, a salt (in particular a pharmaceutically acceptable salt), solvate, polymorph and/or prodrug thereof, wherein: - n is selected from 0; 1; and 2; - each represents an optional double bond, whereby maximally 3 are a double bond at the same time; - R ¹ is selected from alkyl; cycloalkyl; alkenyl; cycloalkenyl; alkynyl; cycloalkynyl; heteroalkyl; heteroalkenyl; heteroalkynyl; -C(O)H; -C(O)R ³ ; -C(O)OR ⁴ ; -C(O)NR ⁵ R ⁶ ; -S(O) ₂ R ^3a ; -S(O)R ^4a ; - ^S(O) ₂ ^{NR5aR6a; -S(O)(NR5a)R4a; -S(NR5a)(NR6a)R3a; and -P(O)R5bR6b;} wherein said alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, heteroalkyl, heteroalkenyl and heteroalkynyl can be unsubstituted or substituted with one or more substituents selected from alkyl, cycloalkyl, alkenyl, alkynyl, hydroxyl, =O, halogen, -SH, =S, trifluoromethyl, -O-alkyl, -OCF ₃ , cyano, nitro, -C(O)OH, -C(O)Oalkyl, -C(O)alkyl, - CONH ₂ , -CONHalkyl, -CON(alkyl) ₂ , -SO ₂ alkyl, -SO ₂ NH ₂ , -SO ₂ NHalkyl, -SO ₂ N(alkyl) ₂ , - S(O)(NH)alkyl, -S(O)(Nalkyl)alkyl, -S(NH)(NH)alkyl, -NH ₂ , -NHalkyl, -N(alkyl) ₂ ; - R ² is selected from hydrogen; alkyl; cycloalkyl; and heteroalkyl; - R ¹ and R ² can be taken together to form a (4-; 5-; 6- or 7-membered) heterocycle which can be unsubstituted or substituted with one or more substituents selected from alkyl, cycloalkyl, alkenyl, alkynyl, hydroxyl, =O, halogen, -SH, =S, trifluoromethyl, -O-alkyl, -OCF ₃ , cyano, nitro, -C(O)OH, -C(O)Oalkyl, -C(O)alkyl, -CONH ₂ , -CONHalkyl, -CON(alkyl) ₂ , - SO ₂ alkyl, -SO ₂ NH ₂ , -SO ₂ NHalkyl, -SO ₂ N(alkyl) ₂ , -S(O)(NH)alkyl, -S(O)(Nalkyl)alkyl, - S(NH)(NH)alkyl, -NH ₂ , -NHalkyl, -N(alkyl) ₂ ; - each R ³ and R ^3a is independently selected from hydroxyl; alkyl; cycloalkyl; alkenyl; cycloalkenyl; alkynyl; cycloalkynyl; heteroalkyl; heteroalkenyl; and heteroalkynyl; wherein said alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, heteroalkyl, heteroalkenyl and heteroalkynyl can be unsubstituted or substituted with one or more substituents selected from alkyl, cycloalkyl, alkenyl, alkynyl, hydroxyl, =O, halogen, -SH, = ^{S, -CF} ₃ ^{, -O-alkyl, -OCF} ₃ ^{, -CHF} ₂ ^{, -OCHF} ₂ ^{, cyano, nitro, -C(O)OH; NH} _2; ^{-NHalkyl, and -} N(alkyl) ₂ ; - each R ⁴ and R ^4a is independently selected from alkyl; alkenyl; cycloalkenyl; alkynyl; cycloalkyl; cycloalkynyl; heteroalkyl; heteroalkenyl; and heteroalkynyl; wherein said alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, heteroalkyl, heteroalkenyl and heteroalkynyl can be unsubstituted or substituted with one or more substituents selected from alkyl, cycloalkyl, alkenyl, alkynyl, hydroxyl, =O, halogen, - S ^{H, =S, -CF} ₃ ^{, -O-alkyl, -OCF} ₃ ^{, -CHF} ₂ ^{, -OCHF} ₂ ^{, cyano, nitro, -C(O)OH; NH} _2; ^-NHalkyl, and -N(alkyl) ₂ ; - each R ⁵ , R ^5a , R ^5b , R ⁶ , R ^6a and R ^6b is independently selected from hydrogen; alkyl; cycloalkyl; alkenyl; cycloalkenyl; alkynyl; cycloalkynyl; heteroalkyl; heteroalkenyl; and heteroalkynyl; wherein said alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, heteroalkyl, heteroalkenyl and heteroalkynyl can be unsubstituted or substituted with one or more substituents selected from alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, hydroxyl, =O, halogen, -SH, =S, - C ^F ₃ ^{, -O-alkyl, -OCF} ₃ ^{, -CHF} ₂ ^{, -OCHF} ₂ ^{, cyano, nitro, -C(O)OH; NH} _2; ^-NHalkyl, and -N(alkyl) ₂ ; and wherein each R ⁵ and R ⁶ or R ^5a and R ^6a can be taken together in order to form a (4-, 5-, 6-, or 7-membered) heterocycle which can be unsubstituted or substituted with one or more substituents selected from alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, hydroxyl, =O, halogen, -SH, =S, - C ^F ₃ ^{, -O-alkyl, -OCF} ₃ ^{, -CHF} ₂ ^{, -OCHF} ₂ ^{, cyano, nitro, -C(O)OH; NH} _2; ^-NHalkyl, and -N(alkyl) ₂ . - cycle A is selected from aryl; heteroaryl; cycloalkyl; and heterocycle; wherein said aryl, heteroaryl, cycloalkyl and heterocycle can be unsubstituted or substituted with one or more R ⁷ ; _{- each R} ⁷ _{is independently selected from halogen; hydroxyl; sulfhydryl; =O; =S; -OZ} ¹ _{; -SZ} ¹ _{; - SCF3; -SF5; -CF3; -OCF} 3 _{; -CHF2; -OCHF2; -NZ} ³ _Z ⁴ _{; -NZ} ³ _C(O)Z ¹ _{; cyano; -C(O)Z} ² _{; -C(O)OZ} ¹ _; -C(O)NZ ³ Z ⁴ ; alkyl; cycloakyl; alkenyl; alkynyl; heteroalkyl; heteroalkenyl; heteroalkynyl; aryl; heteroaryl; heterocycle; arylalkyl; arylalkenyl; arylalkynyl; arylheteroalkyl; arylheteroalkenyl; arylheteroalkynyl; heteroarylalkyl; heteroarylalkenyl; heteroarylalkynyl; heteroarylheteroalkyl; heteroarylheteroalkenyl; heteroarylheteroalkynyl; heterocycle-alkyl; heterocycle-alkenyl; heterocycle-alkynyl; heterocycle-heteroalkyl; heterocycle-heteroalkenyl; and heterocycle- heteroalkynyl; wherein said alkyl, cycloakyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, aryl, heteroaryl, heterocycle, arylalkyl, arylalkenyl, arylalkynyl, arylheteroalkyl, arylheteroalkenyl, arylheteroalkynyl, heteroarylalkyl, heteroarylalkenyl, heteroarylalkynyl, heteroarylheteroalkyl, heteroarylheteroalkenyl, heteroarylheteroalkynyl, heterocycle-alkyl, heterocycle-alkenyl, heterocycle-alkynyl, heterocycle-heteroalkyl, heterocycle-heteroalkenyl, or heterocycle-heteroalkynyl can be unsubstituted or substituted with one or more substituents selected from alkyl, cycloalkyl, alkenyl, alkynyl, hydroxyl, =O, halogen, -SH, =S, -CF ₃ , -O-alkyl, -OCF ₃ , - CHF ₂ ; -OCHF ₂ , cyano, nitro, -C(O)OH, -NH ₂ , -NHalkyl, and -N(alkyl) ₂ ; - X ¹ is selected from CR ⁸ ; N; and NR ^8a ; whereby X ¹ can only be NR ^8a when X ² and/or X ⁴ are C=O or C=S; - X ² is selected from CR ⁹ ; N; and NR ^9a ; whereby X ² can only be NR ^9a when X ¹ and/or X ³ are C=O or C-SH; - X ³ is selected from CH; and N; - X ⁴ is selected from CH; and N; whereby maximally 2 of X ¹ , X ² , X ³ and X ⁴ can be a N (selected from N and NR ^8a for X ¹ , from N and NR ^9a for X ² , from N for X ³ , and from Nfor X ⁴ respectively) at the same time; - each R ⁸ and R ⁹ are independently selected from hydrogen; halogen; hydroxyl; sulfhydryl; =O; _{=S; -OZ} ^1a _{; -SZ} ^1a _{; -SCF3; -SF5; -S(O)Z} ^1a _{; -S(O)(NZ} ^3a _)Z ^1a _{; -S(NZ} ^3a _)(NZ ^3a _)Z ^1a _{; -S(O)2Z} ^2a _{; -S(O)2NZ} ^3a _Z ^4a _{; -CF3; -OCF3; -CHF2; -OCHF2; nitro; -NZ} ^3a _Z ^4a _{; -NZ} ^3a _S(O)2Z ^1a _{; - NZ} ^3a _C(O)Z ^1a _{; -NZ} ^3a _C(O)NZ ^3a _Z ^4a _{; cyano; -C(O)Z} ^2a _{; -C(O)OZ} ^1a _{; -C(O)NZ} ^3a _Z ^4a _{; -C(O)H;} -P(O)Z ^3a Z ^4a ; alkyl; cycloakyl; alkenyl; alkynyl; heteroalkyl; heteroalkenyl; heteroalkynyl; aryl; heteroaryl; heterocycle; arylalkyl; arylalkenyl; arylalkynyl; arylheteroalkyl; arylheteroalkenyl; arylheteroalkynyl; heteroarylalkyl; heteroarylalkenyl; heteroarylalkynyl; heteroarylheteroalkyl; heteroarylheteroalkenyl; heteroarylheteroalkynyl; heterocycle-alkyl; heterocycle-alkenyl; heterocycle-alkynyl; heterocycle-heteroalkyl; heterocycle-heteroalkenyl; and heterocycle- heteroalkynyl; wherein said alkyl, cycloakyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, aryl, heteroaryl, heterocycle, arylalkyl, arylalkenyl, arylalkynyl, arylheteroalkyl, arylheteroalkenyl, arylheteroalkynyl, heteroarylalkyl, heteroarylalkenyl, heteroarylalkynyl, heteroarylheteroalkyl, heteroarylheteroalkenyl, heteroarylheteroalkynyl, heterocycle-alkyl, heterocycle-alkenyl, heterocycle-alkynyl, heterocycle-heteroalkyl, heterocycle-heteroalkenyl, or heterocycle-heteroalkynyl can be unsubstituted or substituted with one or more substituents selected from alkyl, cycloalkyl, alkenyl, alkynyl, hydroxyl, =O, halogen, -SH, =S, -CF ₃ , -O-alkyl, -OCF ₃ , -CHF ₂ ; -OCHF2, cyano, nitro, -C(O)OH, -NH ₂ , -NHalkyl, and -N(alkyl) ₂ ; _{- each R} ^8a _{and R} ^9a _{are independently selected from hydrogen; hydroxyl; sulfhydryl; -OZ} ^1a _{; - SZ} ^1a _{; -SCF3; -SF5; -S(O)Z} ^1a _{; -S(O)(NZ} ^3a _)Z ^1a _{; -S(NZ} ^3a _)(NZ ^3a _)Z ^1a _{; -S(O)2Z} ^2a _{; - S(O)2NZ} ^3a _Z ^4a _{; -CF3; -OCF3; -CHF2; -OCHF2; nitro; -NZ} ^3a _Z ^4a _{; -NZ} ^3a _S(O)2Z ^2a _{; - NZ} ^3a _C(O)Z ^1a _{; -NZ} ^3a _C(O)NZ ^3a _Z ^4a _{; cyano; -C(O)Z} ^2a _{; -C(O)OZ} ^1a _{; -C(O)NZ} ^3a _Z ^4a _{; -C(O)H;} -P(O)Z ^3a Z ^4a ; alkyl; cycloakyl; alkenyl; alkynyl; heteroalkyl; heteroalkenyl; heteroalkynyl; aryl; heteroaryl; heterocycle; arylalkyl; arylalkenyl; arylalkynyl; arylheteroalkyl; arylheteroalkenyl; arylheteroalkynyl; heteroarylalkyl; heteroarylalkenyl; heteroarylalkynyl; heteroarylheteroalkyl; heteroarylheteroalkenyl; heteroarylheteroalkynyl; heterocycle-alkyl; heterocycle-alkenyl; heterocycle-alkynyl; heterocycle-heteroalkyl; heterocycle-heteroalkenyl; and heterocycle- heteroalkynyl; wherein said alkyl, cycloakyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, aryl, heteroaryl, heterocycle, arylalkyl, arylalkenyl, arylalkynyl, arylheteroalkyl, arylheteroalkenyl, arylheteroalkynyl, heteroarylalkyl, heteroarylalkenyl, heteroarylalkynyl, heteroarylheteroalkyl, heteroarylheteroalkenyl, heteroarylheteroalkynyl, heterocycle-alkyl, heterocycle-alkenyl, heterocycle-alkynyl, heterocycle-heteroalkyl, heterocycle-heteroalkenyl, or heterocycle-heteroalkynyl can be unsubstituted or substituted with one or more substituents selected from alkyl, cycloalkyl, alkenyl, alkynyl, hydroxyl, =O, halogen, -SH, =S, -CF ₃ , -O-alkyl, -OCF ₃ , -CHF ₂ ; -OCHF2, cyano, nitro, -C(O)OH, -NH ₂ , -NHalkyl, and -N(alkyl) ₂ ; - each Z ¹ and Z ^1a is independently selected from alkyl; alkenyl; alkynyl; cycloalkynyl; heteroalkyl; heteroalkenyl; heteroalkynyl; aryl; heteroaryl; heterocycle; arylalkyl; arylalkenyl; arylalkynyl; arylheteroalkyl; arylheteroalkenyl; arylheteroalkynyl; heteroarylalkyl; heteroarylalkenyl; heteroarylalkynyl; heteroarylheteroalkyl; heteroarylheteroalkenyl; heteroarylheteroalkynyl; heterocycle-alkyl; heterocycle-alkenyl; heterocycle-alkynyl; heterocycle-heteroalkyl; heterocycle-heteroalkenyl; or heterocycle-heteroalkynyl; wherein said alkyl, cycloalkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, aryl, heteroaryl, heterocycle, arylalkyl, arylalkenyl, arylalkynyl, arylheteroalkyl, arylheteroalkenyl, arylheteroalkynyl, heteroarylalkyl, heteroarylalkenyl, heteroarylalkynyl, heteroarylheteroalkyl, heteroarylheteroalkenyl, heteroarylheteroalkynyl, heterocycle-alkyl, heterocycle-alkenyl, heterocycle-alkynyl, heterocycle-heteroalkyl, heterocycle-heteroalkenyl, or heterocycle-heteroalkynyl can be unsubstituted or substituted with one or more substituents selected from alkyl, c ^{ycloalkyl, alkenyl, alkynyl, hydroxyl, =O, halogen, -SH, =S, -CF} ₃ ^{, -O-alkyl, -OCF} ₃ ^{, - CHF} ₂ ^{, -OCHF} ₂ ^{, cyano, nitro, -C(O)OH; NH} _2; ^{-NHalkyl, and -N(alkyl)} ₂ ^; - each Z ² and Z ^2a is independently selected from hydroxyl; alkyl; cycloalkyl; alkenyl; alkynyl; heteroalkyl; heteroalkenyl; heteroalkynyl; aryl; heteroaryl; heterocycle; arylalkyl; arylalkenyl; arylalkynyl; arylheteroalkyl; arylheteroalkenyl; arylheteroalkynyl; heteroarylalkyl; heteroarylalkenyl; heteroarylalkynyl; heteroarylheteroalkyl; heteroarylheteroalkenyl; heteroarylheteroalkynyl; heterocycle-alkyl; heterocycle-alkenyl; heterocycle-alkynyl; heterocycle-heteroalkyl; heterocycle-heteroalkenyl; or heterocycle- heteroalkynyl; wherein said alkyl, cycloalkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, aryl, heteroaryl, heterocycle, arylalkyl, arylalkenyl, arylalkynyl, arylheteroalkyl, arylheteroalkenyl, arylheteroalkynyl, heteroarylalkyl, heteroarylalkenyl, heteroarylalkynyl, heteroarylheteroalkyl, heteroarylheteroalkenyl, heteroarylheteroalkynyl, heterocycle- alkyl, heterocycle-alkenyl, heterocycle- alkynyl, heterocycle-heteroalkyl, heterocycle- heteroalkenyl, or heterocycle-heteroalkynyl can be unsubstituted or substituted with one or more substituents selected from alkyl, cycloalkyl, alkenyl, alkynyl, hydroxyl, =O, h ^{alogen, -SH, =S, -CF} ₃ ^{, -O-alkyl, -OCF} ₃ ^{, -CHF} ₂ ^{, -OCHF} ₂ ^{, cyano, nitro, -C(O)OH; NH} _2; - NHalkyl, and -N(alkyl) ₂ ; - _{each Z} ³ _{, Z} ^3a _{, Z} ⁴ _{, and Z} ^4a _{is independently selected from hydrogen; alkyl; cycloalkyl;} alkenyl; alkynyl; heteroalkyl; heteroalkenyl; heteroalkynyl; aryl; heteroaryl; heterocycle; arylalkyl; arylalkenyl; arylalkynyl; arylheteroalkyl; arylheteroalkenyl; arylheteroalkynyl; heteroarylalkyl; heteroarylalkenyl; heteroarylalkynyl; heteroarylheteroalkyl; heteroarylheteroalkenyl; heteroarylheteroalkynyl; heterocycle-alkyl; heterocycle- alkenyl; heterocycle-alkynyl; heterocycle-heteroalkyl; heterocycle-heteroalkenyl; or heterocycle-heteroalkynyl; wherein said alkyl, cycloalkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, aryl, heteroaryl, heterocycle, cycloalkyl, arylalkyl, arylalkenyl, arylalkynyl, arylheteroalkyl, arylheteroalkenyl, arylheteroalkynyl, heteroarylalkyl, heteroarylalkenyl, heteroarylalkynyl, heteroarylheteroalkyl, heteroarylheteroalkenyl, heteroarylheteroalkynyl, heterocycle-alkyl, heterocycle-alkenyl, heterocycle-alkynyl, heterocycle-heteroalkyl, heterocycle- heteroalkenyl, or heterocycle-heteroalkynyl can be unsubstituted or substituted with one or more substituents selected from alkyl, cycloalkyl, alkenyl, alkynyl, h ^{ydroxyl, =O, halogen, -SH, =S, -CF} ₃ ^{, -O-alkyl, -OCF} ₃ ^{, -CHF} ₂ ^{, -OCHF} ₂ ^{, cyano, nitro, -C(O)OH; NH} _2; ^{-NHalkyl, and -N(alkyl)} ₂ ^; and wherein each Z ³ and Z ⁴ or Z ^3a and Z ^4a can be taken together in order to form a (4-, 5-, 6-, or 7-membered) heterocycle which can be unsubstituted or substituted with one or more substituents selected from alkyl, cycloalkyl, alkenylalkynyl, hydroxyl, =O, halogen, -SH, =S, -CF ₃ , -O-alkyl, -OCF ₃ , -CHF ₂ , - ^OCHF ₂ ^{, cyano, nitro, -C(O)OH; NH} _2; ^{-NHalkyl, and -N(alkyl)} ₂ ^. The present disclosure provides new compounds which have been shown to possess inhibitory activity on the YAP/TAZ-TEAD transcription. The present disclosure furthermore demonstrates that these compounds efficiently inhibit the activity of YAP/TAZ-TEAD transcription. Therefore, these compounds constitute a useful class of new potent compounds that can be used in the treatment and/or prevention of Hippo mediated disorders in animals, mammals and humans, more specifically for the treatment and/or prevention of (i) cancer, more specifically lung cancer, breast cancer, head and neck cancer, oesophageal cancer, kidney cancer, bladder cancer, colon cancer, ovarian cancer, cervical cancer, endometrial cancer, liver cancer (including but not limited to cholangiocarcinoma), skin cancer, pancreatic cancer, gastric cancer, brain cancer and prostate cancer, mesotheliomas, and/or sarcomas (ii) fibrosis, and (iii) YAP/TAZ-TEAD activation related congenital disorders, among others. In some aspects, the compounds described herein can be used in the treatment and/or prevention of Hippo mediated disorders in animals, mammals and humans, more specifically for the treatment and/or prevention of acoustic neuroma, acute leukemia, acute lymphocytic leukemia, acute myelocytic leukemia (monocytic, myeloblastic, adenocarcinoma, angiosarcoma, astrocytoma, myelomonocytic and promyelocytic), acute T-cell leukemia, basal cell carcinoma, bile duct carcinoma, bronchogenic carcinoma, chondrosarcoma, chordoma, choriocarcinoma, chronic leukemia, chronic lymphocytic leukemia, chronic myelocytic (granulocytic) leukemia, chronic myelogenous leukemia, colorectal cancer, craniopharyngioma, cystadenocarcinoma, diffuse large B-cell lymphoma, dysproliferative changes (dysplasias and metaplasias), embryonal carcinoma, endometrial cancer, endotheliosarcoma, ependymoma, epithelial carcinoma, erythroleukemia, esophageal cancer, estrogen-receptor positive breast cancer, essential thrombocythemia, Ewing’s tumor, fibrosarcoma, follicular lymphoma, germ cell testicular cancer, glioma, glioblastoma, gliosarcoma, heavy chain disease, hemangioblastoma, hepatoma, hepatocellular cancer, hormone insensitive prostate cancer, leiomyosarcoma, leukemia, liposarcoma, lymphagioendotheliosarcoma, lymphangiosarcoma, lymphoblastic leukemia, lymphoma (Hodgkin’s and non-Hodgkin’s), malignancies and hyperproliferative disorders of the bladder, breast, colon, lung, ovaries, pancreas, prostate, skin and uterus, lymphoid malignancies of T-cell or B-cell origin, medullary carcinoma, medulloblastoma, melanoma, meningioma, mesothelioma, multiple myeloma, myelogenous leukemia, myeloma, myxosarcoma, neuroblastoma, NUT midline carcinoma (NMC), non-small cell lung cancer, oligodendroglioma, oral cancer, osteogenic sarcoma, papillary adenocarcinomas, papillary carcinoma, pinealoma, polycythemia vera, rectal cancer, renal cell carcinoma, retinoblastoma, rhabdomyosarcoma, sarcoma, sebaceous gland carcinoma, seminoma, small cell lung carcinoma, solid tumors (carcinomas and sarcomas), small cell lung cancer, stomach cancer, squamous cell carcinoma, synovioma, sweat gland carcinoma, thyroid cancer, Waldenstrom’s macroglobulinemia, testicular tumors, uterine cancer and Wilms’ tumor. The present disclosure furthermore relates to the compounds of the invention for use as a medicine, to the use of such compounds as medicines and to their use for the manufacture of medicaments, more in particular for treating and/or preventing YAP/TAZ-TEAD activation mediated diseases, in particular (i) cancer, more specifically lung cancer, breast cancer, head and neck cancer, oesophageal cancer, kidney cancer, bladder cancer, colon cancer, ovarian cancer, cervical cancer, endometrial cancer, liver cancer (including but not limited to cholangiocarcinoma), skin cancer, pancreatic cancer, gastric cancer, brain cancer and prostate cancer, mesotheliomas, and/or sarcomas and (ii) fibrosis in animals or mammals, more in particular in humans. The invention also relates to methods for the preparation of all such compounds and to pharmaceutical compositions comprising them in an effective amount. In some embodiments, the disclosure relates to the compounds of the invention for use as a medicine, to the use of such compounds as medicines and to their use for the manufacture of medicaments, more in particular for treating and/or preventing YAP/TAZ-TEAD activation mediated diseasesmore specifically for the treatment and/or prevention of acoustic neuroma, acute leukemia, acute lymphocytic leukemia, acute myelocytic leukemia (monocytic, myeloblastic, adenocarcinoma, angiosarcoma, astrocytoma, myelomonocytic and promyelocytic), acute T-cell leukemia, basal cell carcinoma, bile duct carcinoma, bronchogenic carcinoma, chondrosarcoma, chordoma, choriocarcinoma, chronic leukemia, chronic lymphocytic leukemia, chronic myelocytic (granulocytic) leukemia, chronic myelogenous leukemia, colorectal cancer, craniopharyngioma, cystadenocarcinoma, diffuse large B-cell lymphoma, dysproliferative changes (dysplasias and metaplasias), embryonal carcinoma, endometrial cancer, endotheliosarcoma, ependymoma, epithelial carcinoma, erythroleukemia, esophageal cancer, estrogen-receptor positive breast cancer, essential thrombocythemia, Ewing’s tumor, fibrosarcoma, follicular lymphoma, germ cell testicular cancer, glioma, glioblastoma, gliosarcoma, heavy chain disease, hemangioblastoma, hepatoma, hepatocellular cancer, hormone insensitive prostate cancer, leiomyosarcoma, leukemia, liposarcoma, lymphagioendotheliosarcoma, lymphangiosarcoma, lymphoblastic leukemia, lymphoma (Hodgkin’s and non-Hodgkin’s), malignancies and hyperproliferative disorders of the bladder, breast, colon, lung, ovaries, pancreas, prostate, skin and uterus, lymphoid malignancies of T-cell or B-cell origin, medullary carcinoma, medulloblastoma, melanoma, meningioma, mesothelioma, multiple myeloma, myelogenous leukemia, myeloma, myxosarcoma, neuroblastoma, NUT midline carcinoma (NMC), non-small cell lung cancer, oligodendroglioma, oral cancer, osteogenic sarcoma, papillary adenocarcinomas, papillary carcinoma, pinealoma, polycythemia vera, rectal cancer, renal cell carcinoma, retinoblastoma, rhabdomyosarcoma, sarcoma, sebaceous gland carcinoma, seminoma, small cell lung carcinoma, solid tumors (carcinomas and sarcomas), small cell lung cancer, stomach cancer, squamous cell carcinoma, synovioma, sweat gland carcinoma, thyroid cancer, Waldenstrom’s macroglobulinemia, testicular tumors, uterine cancer and Wilms’ tumor. The present disclosure also relates to a method of treatment or prevention of TEAD activation mediated disorders in humans by the administration of one or more such compounds, optionally in combination with one or more other medicines, to a patient in need thereof. The present disclosure also relates to methods of preparing the compounds disclosed herein comprising the steps for synthesis of the compounds described herein. FIGURES Figure 1: In vivo tumor growth inhibition with Cpd. No.002 and Cpd. No.086. Antitumor activity of Cpd. No. 002 and Cpd. No.086 in the treatment of a mesothelioma NCI-H226 subcutaneous human lung cancer xenograft Model in Female Balb/c Nude Mice performed in accordance with example 86. DETAILED DESCRIPTION The present invention will be further described and in some instances with respect to particular embodiments, but the invention is not limited thereto. Definitions The term “YAP/TAZ-TEAD activation mediated diseases” refers to diseases in which hippo signaling is inactivated and whereby YAP/TAZ-TEAD activation is contributing, driving, sustaining, enabling or the like such disease. This might be through loss-of-function mutations or deletions in the genes encoding the upstream regulators of YAP/TAZ-TEAD (e.g. NF2, MST1/2,LATS1/2, FAT1 or SAV1), unleashing constitutive YAP-TEAD transcriptional activity leading to unbridled tumor growth and metastasis of some cancers. This might also be through YAP1 or WWTR1 (TAZ) gene amplifications, gene fusions or activating mutations, or YAP/TAZ overexpression or hyperactivity, among others. YAP/TAZ-TEAD activation mediated diseases therefore refers to cancer, but also includes fibrosis and certain congential disorders. Cancers that are included in YAP/TAZ-TEAD mediated diseases are, without being limited thereto, lung cancer, breast cancer, head and neck cancer, oesophageal cancer, kidney cancer, bladder cancer, colon cancer, ovarian cancer, cervical cancer, endometrial cancer, liver cancer (including but not limited to cholangiocarcinoma), skin cancer, pancreatic cancer, gastric cancer, brain cancer and prostate cancer, mesotheliomas, and/or sarcomas. Also inlcdued are (i) squamous cell carcinomas of the lung, cervix, ovaries, head and neck, oesophagus, and/or skin, or (ii) cancers that originate from neuroectoderm-derived tissues, such as ependymomas, meningiomas, schwannomas, peripheral nerve-sheet tumors and/or neuroblastomas, or (iii) vascular cancers, such as epithelioid haemangioendotheliomas. Fibrotic diseases or fibrosis that is included in YAP/TAZ-TEAD mediated diseases are, without being limited thereto, liver fibrosis, lung fibrosis and heart fibrosis. Congenital disorders that are included in YAP/TAZ-TEAD mediated diseases are, without being limited thereto, Sturge-Weber syndrome and Neurofibromatosis type 2. YAP/TAZ-TEAD mediated diseases also includes cancers that have developed resistance to prior treatments such has EGFR inhibitors, MEK inhibitors, AXL inhibitors, B-RAF inhibitors, RAS inhibitors and others. The term “treat” or “treating” as used herein is intended to refer to administration of a compound or composition to a subject for the purpose of effecting a therapeutic benefit or prophylactic benefit through inhibition of the YAP/TAZ-TEAD transcription. Treating includes reversing, ameliorating, alleviating, inhibiting the progress of, lessening the severity of, or preventing a disease, disorder, or condition, or one or more symptoms of such disease, disorder or condition mediated through YAP/TAZ-TEAD transcription. By "therapeutic benefit" is meant eradication, amelioration, reversing, alleviating, inhibiting the progress of or lessening the severity of the underlying disorder being treated. Also, a therapeutic benefit is achieved with the eradication or amelioration of one or more of the physiological symptoms associated with the underlying disorder such that an improvement is observed in the patient, notwithstanding that the patient is afflicted with the underlying disorder in some embodiments. For prophylactic benefit, in some embodiments, the compositions are administered to a patient at risk of developing a particular disease, or to a patient reporting one or more of the physiological symptoms of a disease, even though a diagnosis of this disease has not been made. The term “subject” as used herein, refers to an animal, for example a mammal, such as a human, a patient, who has been the object of treatment, observation or experiment or who is in need of such treatment. The term “therapeutically effective amount” as used herein, means that amount of active compound or pharmaceutical agent that elicits the biological or medicinal response in a tissue system, animal or human that is being sought by a researcher, veterinarian, medical doctor or other clinician, which includes alleviation or partial alleviation of the symptoms of the disease or disorder being treated. The term “composition” as used herein is intended to encompass a product comprising the specified ingredients in the therapeutically effective amounts, as well as any product which results, directly or indirectly, from combinations of the specified ingredients in the specified amounts. The term “antagonist” or “inhibitor” as used herein in reference to inhibitors of the YAP/TAZ-TEAD activation, refers to a compound capable of producing, depending on the circumstance, a functional antagonism of YAP/TAZ-TEAD activation. It is to be noticed that the term "comprising", used in the claims, should not be interpreted as being restricted to the means listed thereafter; it does not exclude other elements or steps. Reference throughout this specification to "one embodiment" or "an embodiment" means that a particular feature, structure or characteristic described in connection with the embodiment is included in at least one embodiment of the disclosure. Furthermore, the particular features, structures or characteristics may be combined in any suitable manner, as would be apparent to one of ordinary skill in the art from this disclosure, in one or more embodiments. Where an indefinite or definite article is used when referring to a singular noun e.g. "a" or "an", "the", this includes a plural of that noun unless something else is specifically stated. Similarly it should be appreciated that in the description of exemplary embodiments of the disclosure, various features of the disclosure are sometimes grouped together in a single embodiment, figure, or description thereof for the purpose of streamlining the disclosure and aiding in the understanding of one or more of the various inventive aspects. In each of the following definitions, the number of carbon atoms represents the maximum number of carbon atoms generally optimally present in the substituent or linker; it is understood that where otherwise indicated in the present application, the number of carbon atoms represents the optimal maximum number of carbon atoms for that particular substituent or linker. The term “leaving group” or “LG” as used herein means a chemical group which is susceptible to be displaced by a nucleophile or cleaved off or hydrolyzed in basic or acidic conditions. In a particular embodiment, a leaving group is selected from a halogen atom (e.g., Cl, Br, I) or a sulfonate (e.g., mesylate, tosylate, triflate). The term “protecting group” refers to a moiety of a compound that masks or alters the properties of a functional group or the properties of the compound as a whole. The chemical substructure of a protecting group varies widely. One function of a protecting group is to serve as intermediates in the synthesis of the parental drug substance. Chemical protecting groups and strategies for protection/deprotection are well known in the art. See: “Protective Groups in Organic Chemistry”, Theodora W. Greene (John Wiley & Sons, Inc., New York, 1991. Protecting groups are often utilized to mask the reactivity of certain functional groups, to assist in the efficiency of desired chemical reactions, e.g. making and breaking chemical bonds in an ordered and planned fashion. Protection of functional groups of a compound alters other physical properties besides the reactivity of the protected functional group, such as the polarity, lipophilicity (hydrophobicity), and other properties which can be measured by common analytical tools. Chemically protected intermediates may themselves be biologically active or inactive. Protected compounds may also exhibit altered, and in some cases, optimized properties in vitro and in vivo, such as passage through cellular membranes and resistance to enzymatic degradation or sequestration. In this role, protected compounds with intended therapeutic effects may be referred to as prodrugs. Another function of a protecting group is to convert the parental drug into a prodrug, whereby the parental drug is released upon conversion of the prodrug in vivo. Because active prodrugs may be absorbed more effectively than the parental drug, prodrugs may possess greater potency in vivo than the parental drug. Protecting groups are removed either in vitro, in the instance of chemical intermediates, or in vivo, in the case of prodrugs. With chemical intermediates, it is not particularly important that the resulting products after deprotection, e.g. alcohols, be physiologically acceptable, although in general it is more desirable if the products are pharmacologically innocuous. The term “alkyl” or “C _1-18 alkyl” as used herein means C ₁ -C ₁₈ normal, secondary, or tertiary, linear, branched or straight hydrocarbon with no site of unsaturation. Examples are methyl, ethyl, 1-propyl (n-propyl), 2-propyl (iPr), 1-butyl, 2-methyl-1-propyl(i-Bu), 2-butyl (s-Bu), 2-dimethyl-2- propyl (t-Bu), 1-pentyl (n-pentyl), 2-pentyl, 3-pentyl, 2-methyl-2-butyl, 3-methyl-2-butyl, 3-methyl- 1-butyl, 2-methyl-1-butyl, 1-hexyl, 2-hexyl, 3-hexyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4- methyl-2-pentyl, 3-methyl-3-pentyl, 2-methyl-3-pentyl, 2,3-dimethyl-2-butyl, 3,3-dimethyl-2-butyl, n-heptyl, n-octyl, n-nonyl, n-decyl, n-undecyl, n-dodecyl, n-tridecyl, n-tetradecyl, n-pentadecyl, n- hexadecyl, n-heptadecyl, n-octadecyl, n-nonadecyl, and n-icosyl. In particular embodiments, the term alkyl refers to C _1-12 alkyl (C _1-12 hydrocarbons), yet more in particular to C _1-9 alkyl (C _1-9 hydrocarbons), yet more in particular to C _1-6 alkyl (C _1-6 hydrocarbons) as further defined herein above. The term "haloalkyl" as a group or part of a group, refers to an alkyl group having the meaning as defined above wherein one, two, or three hydrogen atoms are each replaced with a halogen as defined herein. Non-limiting examples of such haloalkyl groups include chloromethyl, 1-bromoethyl, fluoromethyl, difluoromethyl, trifluoromethyl, 1,1,1-trifluoroethyl and the like. The term “alkoxy" or “alkyloxy”, as a group or part of a group, refers to a group having the formula –OR ^b wherein R ^b is C _1-6 alkyl as defined herein above. Non-limiting examples of suitable C _1-6 alkoxy include methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert- butoxy, pentyloxy and hexyloxy. The term “haloalkoxy”, as a group or part of a group, refers to a group of formula -O-R ^c , wherein R ^c is haloalkyl as defined herein. Non-limiting examples of suitable haloalkoxy include fluoromethoxy, difluoromethoxy, trifluoromethoxy, 2,2,2-trifluoroethoxy, 1,1,2,2-tetrafluoroethoxy, 2-fluoroethoxy, 2-chloroethoxy, 2,2-difluoroethoxy, 2,2,2-trichloroethoxy, trichloromethoxy, 2- bromoethoxy, pentafluoroethyl, 3,3,3-trichloropropoxy, 4,4,4-trichlorobutoxy. The term “cycloalkyl” or “C _3-18 cycloalkyl” as used herein and unless otherwise stated means a saturated hydrocarbon monovalent group having from 3 to 18 carbon atoms consisting of or comprising a C _3-10 monocyclic or C _7-18 polycyclic saturated hydrocarbon, such as for instance cyclopropyl, cyclobutyl, cyclopentyl, cyclopropylethylene, methylcyclopropylene, cyclohexyl, cycloheptyl, cyclooctyl, cyclooctylmethylene, norbornyl, fenchyl, trimethyltricycloheptyl, decalinyl, adamantyl and the like. In particular embodiments, the term cycloalkyl refers to C _3-12 cycloalkyl (saturated cyclic C _3-12 hydrocarbons), yet more in particular to C _3-9 cycloalkyl (saturated cyclic C _{3- 9} hydrocarbons), still more in particular to C _3-6 cycloalkyl (saturated cyclic C _3-6 hydrocarbons) as further defined herein above. For the avoidance of doubt, fused systems of a cycloalkyl ring with a heterocyclic ring are considered as heterocycle irrespective of the ring that is bound to the core structure. Fused systems of a cycloalkyl ring with an aryl ring are considered as aryl irrespective of the ring that is bound to the core structure. Fused systems of a cycloalkyl ring with a heteroaryl ring are considered as heteroaryl irrespective of the ring that is bound to the core structure. The term “alkenyl” or “C _2-18 alkenyl” as used herein is C ₂ -C ₁₈ normal, secondary or tertiary, linear, branched or straight hydrocarbon with at least one site (usually 1 to 3, preferably 1) of unsaturation, namely a carbon-carbon, sp2 double bond. Examples include, but are not limited to: ethylene or vinyl (-CH=CH ₂ ), allyl (-CH ₂ CH=CH ₂ ), and 5-hexenyl (-CH ₂ CH ₂ CH ₂ CH ₂ CH=CH ₂ ). The double bond may be in the cis or trans configuration. In particular embodiments, the term alkenyl refers to C _2-12 alkenyl (C _2-12 hydrocarbons), yet more in particular to C _2-9 alkenyl (C _2-9 hydrocarbons), still more in particular to C _2-6 alkenyl (C _2-6 hydrocarbons) as further defined herein above with at least one site (usually 1 to 3, preferably 1) of unsaturation, namely a carbon-carbon, sp2 double bond. The term “alkenyloxy”, as a group or part of a group, refers to a group having the formula –OR ^d wherein R ^d is alkenyl as defined herein above. The term “cycloalkenyl” as used herein refers to a non-aromatic hydrocarbon group having from 5 to 18 carbon atoms with at least one site (usually 1 to 3, preferably 1) of unsaturation, namely a carbon-carbon, sp2 double bond and consisting of or comprising a C _5-10 monocyclic or C _7-18 polycyclic hydrocarbon. Examples include, but are not limited to: cyclopentenyl (-C ₅ H ₇ ), cyclopentenylpropylene, methylcyclohexenylene and cyclohexenyl (-C ₆ H ₉ ). The double bond may be in the cis or trans configuration. In particular embodiments, the term cycloalkenyl refers to C _{5- 12} cycloalkenyl (cyclic C _5-12 hydrocarbons), yet more in particular to C _5-9 cycloalkenyl (cyclic C _5-9 hydrocarbons), still more in particular to C _5-6 cycloalkenyl (cyclic C _5-6 hydrocarbons) as further defined herein above with at least one site of unsaturation, namely a carbon-carbon, sp2 double bond. For the avoidance of doubt, fused systems of a cycloalkenyl ring with a heterocyclic ring are considered as heterocycle irrespective of the ring that is bound to the core structure. Fused systems of a cycloalkenyl ring with an aryl ring are considered as aryl irrespective of the ring that is bound to the core structure. Fused systems of a cycloalkenyl ring with a heteroaryl ring are considered as heteroaryl irrespective of the ring that is bound to the core structure. The term “alkynyl” or “C _2-18 alkynyl” as used herein refers to C ₂ -C ₁₈ normal, secondary, tertiary, linear, branched or straight hydrocarbon with at least one site (usually 1 to 3, preferably 1) of unsaturation, namely a carbon-carbon, sp triple bond. Examples include, but are not limited to: ethynyl (-C≡CH), 3-ethyl-cyclohept-1-ynylene, and 1-propynyl (propargyl, -CH ₂ C≡CH). In particular embodiments, the term alkynyl refers to C _2-12 alkynyl (C _2-12 hydrocarbons), yet more in particular to C _2-9 alkynyl (C _2-9 hydrocarbons) yet more in particular to C _2-6 alkynyl (C _2-6 hydrocarbons) as further defined herein above with at least one site (usually 1 to 3, preferably 1) of unsaturation, namely a carbon-carbon, sp triple bond. The term “alkynyloxy”, as a group or part of a group, refers to a group having the formula –OR ^e wherein R ^e is alkynyl as defined herein above. The term “cycloalkynyl” as used herein refers to a non-aromatic hydrocarbon group having from 5 to 18 carbon atoms with at least one site (usually 1 to 3, preferably 1) of unsaturation, namely a carbon-carbon, sp triple bond and consisting of or comprising a C _5-10 monocyclic or C _{7- 18} polycyclic hydrocarbon. Examples include, but are not limited to: cyclohept-1-yne, 3-ethyl- cyclohept-1-ynylene, 4-cyclohept-1-yn-methylene and ethylene-cyclohept-1-yne. In particular embodiments, the term cycloalkynyl refers to C _5-10 cycloalkynyl (cyclic C _5-10 hydrocarbons), yet more in particular to C _5-9 cycloalkynyl (cyclic C _5-9 hydrocarbons), still more in particular to C _5-6 cycloalkynyl (cyclic C _5-6 hydrocarbons) as further defined herein above with at least one site (usually 1 to 3, preferably 1) of unsaturation, namely a carbon-carbon, sp triple bond. For the avoidance of doubt, fused systems of a cycloalkynyl ring with a heterocyclic ring are considered as heterocycle irrespective of the ring that is bound to the core structure. Fused systems of a cycloalkynyl ring with an aryl ring are considered as aryl irrespective of the ring that is bound to the core structure. Fused systems of a cycloalkynyl ring with a heteroaryl ring are considered as heteroaryl irrespective of the ring that is bound to the core structure. The term “alkylene” as used herein each refer to a saturated, branched or straight chain hydrocarbon group of 1-18 carbon atoms (more in particular C _1-12 , C _1-9 or C _1-6 carbon atoms), and having two monovalent group centers derived by the removal of two hydrogen atoms from the same or two different carbon atoms of a parent alkane. Typical alkylene include, but are not limited to: methylene (-CH ₂ -), 1,2-ethyl (-CH ₂ CH ₂ -), 1,3-propyl (-CH ₂ CH ₂ CH ₂ -), 1,4-butyl (- CH ₂ CH ₂ CH ₂ CH ₂ -), and the like. The term “alkenylene” as used herein each refer to a branched or straight chain hydrocarbon of 2-18 carbon atoms (more in particular C _2-12 , C _2-9 or C _2-6 carbon atoms) with at least one site (usually 1 to 3, preferably 1) of unsaturation, namely a carbon-carbon, sp2 double bond, and having two monovalent centers derived by the removal of two hydrogen atoms from the same or two different carbon atoms of a parent alkene. The term “alkynylene” as used herein each refer to a branched or straight chain hydrocarbon of 2-18 carbon atoms (more in particular C _2-12 , C _2-9 or C _2-6 carbon atoms) with at least one site (usually 1 to 3, preferably 1) of unsaturation, namely a carbon-carbon, sp triple bond, and having two monovalent centers derived by the removal of two hydrogen atoms from the same or two different carbon atoms of a parent alkyne. The term “heteroalkyl” as used herein refers to an alkyl wherein one or more carbon atoms are replaced by one or more atoms selected from the group comprising oxygen, nitrogen or sulphur atom. The term heteroalkyl thus comprises –O-R ^b , -NR ^o -R ^b , -R ^a -O-R ^b , and –S-R ^b , wherein R ^a is alkylene, R ^b is alkyl, and R ^o is hydrogen or alky as defined herein. In particular embodiments, the term refers to C _1-12 heteroalkyl, C _1-9 heteroalkyl or C _1-6 heteroalkyl. In some embodiments heteroalkyl is selected from the group comprising alkyloxy, alkyl-oxy-alkyl, (mono or di)alkylamino, (mono or di-)alkyl-amino-alkyl, alkylthio, and alkyl-thio-alkyl. The term “heteroalkenyl” as used herein refers to an acyclic alkenyl wherein one or more carbon atoms are replaced by one or more atoms selected from oxygen, nitrogen or sulphur atom. The term heteroalkenyl thus comprises –O-R ^d , -NH-(R ^d ), -N(R ^d )) ₂ , -N(R ^b )(R ^d ), and –S-R ^d wherein R ^b is alkyl and R ^d is alkenyl as defined herein. In particular embodiments, the term refers to C _{2- 12} heteroalkenyl, C _2-9 heteroalkenyl or C _2-6 heteroalkenyl. In some embodiments heteroalkenyl is selected from the group comprising alkenyloxy, alkenyl-oxy-alkenyl, (mono or di-)alkenylamino, (mono or di-)alkenyl-amino-alkenyl, alkenylthio, and alkenyl-thio-alkenyl, The term “heteroalkynyl” as used herein refers to an acyclic alkynyl wherein one or more carbon atoms are replaced by an oxygen, nitrogen or sulphur atom. The term heteroalkynyl thus comprises but is not limited to -O-R ^d , -N(R ^d ) ₂ , NHR ^d , -N(R ^b )(R ^e ), -N(R ^d )(R ^e ), and -S-R ^d wherein R ^b is alkyl, R ^e is alkynyl and R ^d is alkenyl as defined herein. In particular embodiments, the term refers to C _2-12 heteroalkynyl, C _2-9 heteroalkynyl or C _2-6 heteroalkynyl. In some embodiments the term heteroalkynyl is selected from the group comprising alkynyloxy, alkynyl-oxy-alkynyl, (mono or di- )alkynylamino, (mono or di-)alkynyl-amino-alkynyl, alkynylthio, alkynyl-thio-alkynyl, The term “heteroalkylene” as used herein refers to an alkylene wherein one or more carbon atoms are replaced by one or more oxygen, nitrogen or sulphur atoms. The term “heteroalkenylene” as used herein refers to an alkenylene wherein one or more carbon atoms are replaced by one or more oxygen, nitrogen or sulphur atoms. The term “heteroalkynylene” as used herein refers to an alkynylene wherein one or more carbon atoms are replaced by one or more oxygen, nitrogen or sulphur atom. The term “aryl” as used herein means an aromatic hydrocarbon of 6-20 carbon atoms derived by the removal of hydrogen from a carbon atom of a parent aromatic ring system. Typical aryl groups include, but are not limited to 1 ring, or 2 or 3 rings fused together, derived from benzene, naphthalene, anthracene, biphenyl, and the like. In particular embodiments, the term aryl refers to a 6-14 carbon atoms membered aromatic cycle, yet more in particular refers to a 6- 10 carbon atoms membered aromatic cycle. Fused systems of an aryl ring with a cycloalkyl ring, or a cycloalkenyl ring, or a cycloalkynyl ring, are considered as aryl irrespective of the ring that is bound to the core structure. Fused systems of an aryl ring with a heterocycle are considered as heterocycle irrespective of the ring that is bound to the core structure. Thus, indoline, dihydrobenzofurane, dihydrobenzothiophene and the like are considered as heterocycle according to the invention. Fused systems of an aryl ring with a heteroaryl ring are considered as heteroaryl irrespective of the ring that is bound to the core structure. The term “aryloxy”, as a group or part of a group, refers to a group having the formula – OR ^g wherein R ^g is aryl as defined herein above. The term “arylalkyl” or “arylalkyl-“ as used herein refers to an alkyl in which one of the hydrogen atoms bonded to a carbon atom, typically a terminal or sp3 carbon atom, is replaced with an aryl. Typical arylalkyl groups include, but are not limited to, benzyl, 2-phenylethan-1-yl, 2- phenylethen-1-yl, naphthylmethyl, 2-naphthylethyl, and the like. The arylalkyl group comprises 6 to 20 carbon atoms, e.g. the alkyl moiety of the arylalkyl group is 1 to 6 carbon atoms and the aryl moiety is 6 to 14 carbon atoms. The term “arylalkyloxy”, as a group or part of a group, refers to a group having the formula -O-R ^a -R ^g wherein R ^g is aryl, and R ^a is alkylene as defined herein above. The term “arylalkenyl” or “arylalkenyl-“ as used herein refers to an alkenyl in which one of the hydrogen atoms bonded to a carbon atom, is replaced with an aryl. The arylalkenyl group comprises 6 to 20 carbon atoms, e.g. the alkenyl moiety of the arylalkenyl group is 1 to 6 carbon atoms and the aryl moiety is 6 to 14 carbon atoms. The term “arylalkynyl” or “arylalkynyl-“ as used herein refers to an alkynyl in which one of the hydrogen atoms bonded to a carbon atom, is replaced with an aryl. The arylalkynyl group comprises 6 to 20 carbon atoms, e.g. the alkynyl moiety of the arylalkynyl group is 1 to 6 carbon atoms and the aryl moiety is 6 to 14 carbon atoms. The term “arylheteroalkyl” or “arylheteroalkyl-“ as used herein refers to a heteroalkyl in which one of the hydrogen atoms bonded to a carbon atom, typically a terminal or sp3 carbon atom, is replaced with an aryl. The arylheteroalkyl group comprises 6 to 20 carbon atoms, e.g. the heteroalkyl moiety of the arylheteroalkyl group is 1 to 6 carbon atoms and the aryl moiety is 6 to 14 carbon atoms. In some embodiments arylheteroalkyl is selected from the group comprising aryl-O-alkyl, arylalkyl-O-alkyl, aryl-NH-alkyl, aryl-N(alkyl) ₂ , arylalkyl-NH-alkyl, arylalkyl-N-(alkyl) ₂ , aryl–S-alkyl, and arylalkyl-S-alkyl. The term “arylheteroalkenyl” or “arylheteroalkenyl-“ as used herein refers to a heteroalkenyl in which one of the hydrogen atoms bonded to a carbon atom, is replaced with an aryl. The arylheteroalkenyl group comprises 6 to 20 carbon atoms, e.g. the heteroalkenyl moiety of the arylheteroalkenyl group is 1 to 6 carbon atoms and the aryl moiety is 6 to 14 carbon atoms. In some embodiments arylheteroalkenyl is selected from the group comprising aryl-O-alkenyl, arylalkenyl-O-alkenyl, aryl-NH-alkenyl, aryl-N(alkenyl) ₂ , arylalkenyl-NH-alkenyl, arylalkenyl-N- (alkenyl) ₂ , aryl–S-alkenyl, and arylalkenyl-S-alkenyl. The term “arylheteroalkynyl” or “arylheteroalkynyl-“ as used herein refers to a heteroalkynyl in which one of the hydrogen atoms bonded to a carbon atom, is replaced with an aryl. The arylheteroalkynyl group comprises 6 to 20 carbon atoms, e.g. the heteroalkynyl moiety of the arylheteroalkynyl group is 1 to 6 carbon atoms and the aryl moiety is 6 to 14 carbon atoms. In some embodiments arylheteroalkynyl is selected from the group comprising aryl-O-alkynyl, arylalkynyl-O-alkynyl, aryl-NH-alkynyl, aryl-N(alkynyl) ₂ , arylalkynyl-NH-alkynyl, arylalkynyl-N- (alkynyl) ₂ , aryl–S-alkynyl, and arylalkynyl-S-alkynyl. The term “heterocycle” or “heterocyclyl” as used herein refer to non-aromatic, fully saturated or partially unsaturated ring system of 3 to 18 atoms including at least one N, O, S, or P (for example, 3 to 7 member monocyclic, 7 to 11 member bicyclic, or comprising a total of 3 to 10 ring atoms). Each ring of the heterocycle or heterocyclyl may have 1, 2, 3 or 4 heteroatoms selected from N, O and/or S, where the N and S heteroatoms may optionally be oxidized and the N heteroatoms may optionally be quaternized; and wherein at least one carbon atom of heterocyclyl can be oxidized to form at least one C=O. The heterocycle may be attached at any heteroatom or carbon atom of the ring or ring system, where valence allows. The rings of multi- ring heterocyclyls or heterocycles may be fused, bridged and/or joined through one or more spiro atoms. Fused systems of a heterocycle or heterocyclyl with an aryl ring are considered as heterocycle or heterocyclyl irrespective of the ring that is bound to the core structure. Fused systems of a heterocycle or heterocyclyl with a heteroaryl ring are considered as heteroaryl irrespective of the ring that is bound to the core structure. Non limiting exemplary heterocycles or heterocyclic groups include piperidinyl, piperazinyl, homopiperazinyl, morpholinyl, tetrahydropyranyl, tetrahydrofuranyl, pyrrolidinyl, aziridinyl, oxiranyl, thiiranyl, azetidinyl, oxetanyl, thietanyl, 2-imidazolinyl, pyrazolidinyl imidazolidinyl, isoxazolinyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl, isothiazolidinyl, succinimidyl, 3H-indolyl, indolinyl, isoindolinyl, chromanyl (also known as 3,4-dihydrobenzo[b]pyranyl), 2H-pyrrolyl, 1- pyrrolinyl, 2-pyrrolinyl, 3-pyrrolinyl, 4H-quinolizinyl, 2-oxopiperazinyl, 2-pyrazolinyl, 3-pyrazolinyl, tetrahydro-2H-pyranyl, 2H-pyranyl, 4H-pyranyl, 3,4-dihydro-2H-pyranyl, 3-dioxolanyl, 1,4- dioxanyl, 2,5-dioximidazolidinyl, 2-oxopiperidinyl, 2-oxopyrrolodinyl, indolinyl, tetrahydrothiophenyl, tetrahydroquinolinyl, tetrahydroisoquinolin-1-yl, tetrahydroisoquinolin-2-yl, tetrahydroisoquinolin-3-yl, tetrahydroisoquinolin-4-yl, thiomorpholin-4-yl, thiomorpholin-4- ylsulfoxide, thiomorpholin-4-ylsulfone, 1,3-dioxolanyl, 1,4-oxathianyl, 1,4-dithianyl, 1,3,5-trioxanyl, 1H-pyrrolizinyl, tetrahydro-1,1-dioxothiophenyl, N- formylpiperazinyl, and morpholin-4-yl. The term “aziridinyl” as used herein includes aziridin-1-yl and aziridin-2-yl. The term “oxyranyl” as used herein includes oxyranyl-2-yl. The term “thiiranyl” as used herein includes thiiran-2-yl. The term “azetidinyl” as used herein includes azetidin-1-yl, azetidin-2-yl and azetidin-3-yl. The term “oxetanyl” as used herein includes oxetan-2-yl and oxetan-3-yl. The term “thietanyl” as used herein includes thietan-2-yl and thietan-3-yl. The term “pyrrolidinyl” as used herein includes pyrrolidin-1-yl, pyrrolidin-2-yl and pyrrolidin-3-yl. The term “tetrahydrofuranyl” as used herein includes tetrahydrofuran-2-yl and tetrahydrofuran-3-yl. The term “tetrahydrothiophenyl” as used herein includes tetrahydrothiophen-2-yl and tetrahydrothiophen-3-yl. The term “succinimidyl” as used herein includes succinimid-1-yl and succininmid-3-yl. The term “dihydropyrrolyl” as used herein includes 2,3-dihydropyrrol-1-yl, 2,3-dihydro-1H-pyrrol-2-yl, 2,3-dihydro-1H-pyrrol-3-yl, 2,5- dihydropyrrol-1-yl, 2,5-dihydro-1H-pyrrol-3-yl and 2,5-dihydropyrrol-5-yl. The term “2H-pyrrolyl” as used herein includes 2H-pyrrol-2-yl, 2H-pyrrol-3-yl, 2H-pyrrol-4-yl and 2H-pyrrol-5-yl. The term “3H-pyrrolyl” as used herein includes 3H-pyrrol-2-yl, 3H-pyrrol-3-yl, 3H-pyrrol-4-yl and 3H-pyrrol- 5-yl. The term “dihydrofuranyl” as used herein includes 2,3-dihydrofuran-2-yl, 2,3-dihydrofuran-3- yl, 2,3-dihydrofuran-4-yl, 2,3-dihydrofuran-5-yl, 2,5-dihydrofuran-2-yl, 2,5-dihydrofuran-3-yl, 2,5- dihydrofuran-4-yl and 2,5-dihydrofuran-5-yl. The term “dihydrothiophenyl” as used herein includes 2,3-dihydrothiophen-2-yl, 2,3-dihydrothiophen-3-yl, 2,3-dihydrothiophen-4-yl, 2,3- dihydrothiophen-5-yl, 2,5-dihydrothiophen-2-yl, 2,5-dihydrothiophen-3-yl, 2,5-dihydrothiophen-4- yl and 2,5-dihydrothiophen-5-yl. The term “imidazolidinyl” as used herein includes imidazolidin-1- yl, imidazolidin-2-yl and imidazolidin-4-yl. The term “pyrazolidinyl” as used herein includes pyrazolidin-1-yl, pyrazolidin-3-yl and pyrazolidin-4-yl. The term “imidazolinyl” as used herein includes imidazolin-1-yl, imidazolin-2-yl, imidazolin-4-yl and imidazolin-5-yl. The term “pyrazolinyl” as used herein includes 1-pyrazolin-3-yl, 1-pyrazolin-4-yl, 2-pyrazolin-1-yl, 2-pyrazolin-3-yl, 2- pyrazolin-4-yl, 2-pyrazolin-5-yl, 3-pyrazolin-1-yl, 3-pyrazolin-2-yl, 3-pyrazolin-3-yl, 3-pyrazolin-4-yl and 3-pyrazolin-5-yl. The term “dioxolanyl” also known as “1,3-dioxolanyl” as used herein includes dioxolan-2-yl, dioxolan-4-yl and dioxolan-5-yl. The term “dioxolyl” also known as “1,3-dioxolyl” as used herein includes dioxol-2-yl, dioxol-4-yl and dioxol-5-yl. The term “oxazolidinyl” as used herein includes oxazolidin-2-yl, oxazolidin-3-yl, oxazolidin-4-yl and oxazolidin-5-yl. The term “isoxazolidinyl” as used herein includes isoxazolidin-2-yl, isoxazolidin-3-yl, isoxazolidin-4-yl and isoxazolidin-5-yl. The term “oxazolinyl” as used herein includes 2-oxazolinyl-2-yl, 2-oxazolinyl-4- yl, 2-oxazolinyl-5-yl, 3-oxazolinyl-2-yl, 3-oxazolinyl-4-yl, 3-oxazolinyl-5-yl, 4-oxazolinyl-2-yl, 4- oxazolinyl-3-yl, 4-oxazolinyl-4-yl and 4-oxazolinyl-5-yl. The term “isoxazolinyl” as used herein includes 2-isoxazolinyl-3-yl, 2-isoxazolinyl-4-yl, 2-isoxazolinyl-5-yl, 3-isoxazolinyl-3-yl, 3- isoxazolinyl-4-yl, 3-isoxazolinyl-5-yl, 4-isoxazolinyl-2-yl, 4-isoxazolinyl-3-yl, 4-isoxazolinyl-4-yl and 4-isoxazolinyl-5-yl. The term “thiazolidinyl” as used herein includes thiazolidin-2-yl, thiazolidin- 3-yl, thiazolidin-4-yl and thiazolidin-5-yl. The term “isothiazolidinyl” as used herein includes isothiazolidin-2-yl, isothiazolidin-3-yl, isothiazolidin-4-yl and isothiazolidin-5-yl. The term “thiazolinyl” as used herein includes 2-thiazolinyl-2-yl, 2-thiazolinyl-4-yl, 2-thiazolinyl-5-yl, 3- thiazolinyl-2-yl, 3-thiazolinyl-4-yl, 3-thiazolinyl-5-yl, 4-thiazolinyl-2-yl, 4-thiazolinyl-3-yl, 4- thiazolinyl-4-yl and 4-thiazolinyl-5-yl. The term “isothiazolinyl” as used herein includes 2- isothiazolinyl-3-yl, 2-isothiazolinyl-4-yl, 2-isothiazolinyl-5-yl, 3-isothiazolinyl-3-yl, 3-isothiazolinyl- 4-yl, 3-isothiazolinyl-5-yl, 4-isothiazolinyl-2-yl, 4-isothiazolinyl-3-yl, 4-isothiazolinyl-4-yl and 4- isothiazolinyl-5-yl. The term “piperidyl” also known as “piperidinyl” as used herein includes piperid- 1-yl, piperid-2-yl, piperid-3-yl and piperid-4-yl. The term “dihydropyridinyl” as used herein includes 1,2-dihydropyridin-1-yl, 1,2-dihydropyridin-2-yl, 1,2-dihydropyridin-3-yl, 1,2-dihydropyridin-4-yl, 1,2-dihydropyridin-5-yl, 1,2-dihydropyridin-6-yl, 1,4-dihydropyridin-1-yl, 1,4-dihydropyridin-2-yl, 1,4-dihydropyridin-3-yl, 1,4-dihydropyridin-4-yl, 2,3-dihydropyridin-2-yl, 2,3-dihydropyridin-3-yl, 2,3-dihydropyridin-4-yl, 2,3-dihydropyridin-5-yl, 2,3-dihydropyridin-6-yl, 2,5-dihydropyridin-2-yl, 2,5-dihydropyridin-3-yl, 2,5-dihydropyridin-4-yl, 2,5-dihydropyridin-5-yl, 2,5-dihydropyridin-6-yl, 3,4-dihydropyridin-2-yl, 3,4-dihydropyridin-3-yl, 3,4-dihydropyridin-4-yl, 3,4-dihydropyridin-5-yl and 3,4-dihydropyridin-6-yl. The term “tetrahydropyridinyl” as used herein includes 1,2,3,4- tetrahydropyridin-1-yl, 1,2,3,4-tetrahydropyridin-2-yl, 1,2,3,4-tetrahydropyridin-3-yl, 1,2,3,4- tetrahydropyridin-4-yl, 1,2,3,4-tetrahydropyridin-5-yl, 1,2,3,4-tetrahydropyridin-6-yl, 1,2,3,6- tetrahydropyridin-1-yl, 1,2,3,6-tetrahydropyridin-2-yl, 1,2,3,6-tetrahydropyridin-3-yl, 1,2,3,6- tetrahydropyridin-4-yl, 1,2,3,6-tetrahydropyridin-5-yl, 1,2,3,6-tetrahydropyridin-6-yl, 2,3,4,5- tetrahydropyridin-2-yl, 2,3,4,5-tetrahydropyridin-3-yl, 2,3,4,5-tetrahydropyridin-3-yl, 2,3,4,5- tetrahydropyridin-4-yl, 2,3,4,5-tetrahydropyridin-5-yl and 2,3,4,5-tetrahydropyridin-6-yl. The term “tetrahydropyranyl” also known as “oxanyl” or “tetrahydro-2H-pyranyl”, as used herein includes tetrahydropyran-2-yl, tetrahydropyran-3-yl and tetrahydropyran-4-yl. The term “2H-pyranyl” as used herein includes 2H-pyran-2-yl, 2H-pyran-3-yl, 2H-pyran-4-yl, 2H-pyran-5-yl and 2H-pyran-6- yl. The term “4H-pyranyl” as used herein includes 4H-pyran-2-yl, 4H-pyran-3-yl and 4H-pyran-4- yl. The term “3,4-dihydro-2H-pyranyl” as used herein includes 3,4-dihydro-2H-pyran-2-yl, 3,4- dihydro-2H-pyran-3-yl, 3,4-dihydro-2H-pyran-4-yl, 3,4-dihydro-2H-pyran-5-yl and 3,4-dihydro-2H- pyran-6-yl. The term “3,6-dihydro-2H-pyranyl” as used herein includes 3,6-dihydro-2H-pyran-2-yl, 3,6-dihydro-2H-pyran-3-yl, 3,6-dihydro-2H-pyran-4-yl, 3,6-dihydro-2H-pyran-5-yl and 3,6-dihydro- 2H-pyran-6-yl. The term “tetrahydrothiophenyl”, as used herein includes tetrahydrothiophen-2-yl, tetrahydrothiophenyl -3-yl and tetrahydrothiophenyl -4-yl. The term “2H-thiopyranyl” as used herein includes 2H-thiopyran-2-yl, 2H-thiopyran-3-yl, 2H-thiopyran-4-yl, 2H-thiopyran-5-yl and 2H-thiopyran-6-yl. The term “4H-thiopyranyl” as used herein includes 4H-thiopyran-2-yl, 4H- thiopyran-3-yl and 4H-thiopyran-4-yl. The term “3,4-dihydro-2H-thiopyranyl” as used herein includes 3,4-dihydro-2H-thiopyran-2-yl, 3,4-dihydro-2H-thiopyran-3-yl, 3,4-dihydro-2H-thiopyran- 4-yl, 3,4-dihydro-2H-thiopyran-5-yl and 3,4-dihydro-2H-thiopyran-6-yl. The term “3,6-dihydro-2H- thiopyranyl” as used herein includes 3,6-dihydro-2H-thiopyran-2-yl, 3,6-dihydro-2H-thiopyran-3- yl, 3,6-dihydro-2H-thiopyran-4-yl, 3,6-dihydro-2H-thiopyran-5-yl and 3,6-dihydro-2H-thiopyran-6- yl. The term “piperazinyl” also known as “piperazidinyl” as used herein includes piperazin-1-yl and piperazin-2-yl. The term “morpholinyl” as used herein includes morpholin-2-yl, morpholin-3-yl and morpholin-4-yl. The term “thiomorpholinyl” as used herein includes thiomorpholin-2-yl, thiomorpholin-3-yl and thiomorpholin-4-yl. The term “dioxanyl” as used herein includes 1,2-dioxan- 3-yl, 1,2-dioxan-4-yl, 1,3-dioxan-2-yl, 1,3-dioxan-4-yl, 1,3-dioxan-5-yl and 1,4-dioxan-2-yl. The term “dithianyl” as used herein includes 1,2-dithian-3-yl, 1,2-dithian-4-yl, 1,3-dithian-2-yl, 1,3- dithian-4-yl, 1,3-dithian-5-yl and 1,4-dithian-2-yl. The term “oxathianyl” as used herein includes oxathian-2-yl and oxathian-3-yl. The term “trioxanyl” as used herein includes 1,2,3-trioxan-4-yl, 1,2,3-trioxan-5-yl, 1,2,4-trioxan-3-yl, 1,2,4-trioxan-5-yl, 1,2,4-trioxan-6-yl and 1,3,4-trioxan-2-yl. The term “azepanyl” as used herein includes azepan-1-yl, azepan-2-yl, azepan-3-yl and azepan- 4-yl. The term “homopiperazinyl” as used herein includes homopiperazin-1-yl, homopiperazin-2- yl, homopiperazin-3-yl and homopiperazin-4-yl. The term “indolinyl” as used herein includes indolin-1-yl, indolin-2-yl, indolin-3-yl, indolin-4-yl, indolin-5-yl, indolin-6-yl, and indolin-7-yl. The term “quinolizinyl” as used herein includes quinolizidin-1-yl, quinolizidin-2-yl, quinolizidin-3-yl and quinolizidin-4-yl. The term “isoindolinyl” as used herein includes isoindolin-1-yl, isoindolin-2-yl, isoindolin-3-yl, isoindolin-4-yl, isoindolin-5-yl, isoindolin-6-yl, and isoindolin-7-yl. The term “3H- indolyl” as used herein includes 3H-indol-2-yl, 3H-indol-3-yl, 3H-indol-4-yl, 3H-indol-5-yl, 3H-indol- 6-yl, and 3H-indol-7-yl. The term “quinolizinyl” as used herein includes quinolizidin-1-yl, quinolizidin-2-yl, quinolizidin-3-yl and quinolizidin-4-yl. The term “quinolizinyl” as used herein includes quinolizidin-1-yl, quinolizidin-2-yl, quinolizidin-3-yl and quinolizidin-4-yl. The term “tetrahydroquinolinyl” as used herein includes tetrahydroquinolin-1-yl, tetrahydroquinolin-2-yl, tetrahydroquinolin-3-yl, tetrahydroquinolin-4-yl, tetrahydroquinolin-5-yl, tetrahydroquinolin-6-yl, tetrahydroquinolin-7-yl and tetrahydroquinolin-8-yl. The term “tetrahydroisoquinolinyl” as used herein includes tetrahydroisoquinolin-1-yl, tetrahydroisoquinolin-2-yl, tetrahydroisoquinolin-3-yl, tetrahydroisoquinolin-4-yl, tetrahydroisoquinolin-5-yl, tetrahydroisoquinolin-6-yl, tetrahydroisoquinolin-7-yl and tetrahydroisoquinolin-8-yl. The term “chromanyl” as used herein includes chroman-2-yl, chroman-3-yl, chroman-4-yl, chroman-5-yl, chroman-6-yl, chroman-7-yl and chroman-8-yl. The term “1H-pyrrolizine” as used herein includes 1H-pyrrolizin-1-yl, 1H- pyrrolizin-2-yl, 1H-pyrrolizin-3-yl, 1H-pyrrolizin-5-yl, 1H-pyrrolizin-6-yl and 1H-pyrrolizin-7-yl. The term “3H-pyrrolizine” as used herein includes 3H-pyrrolizin-1-yl, 3H-pyrrolizin-2-yl, 3H-pyrrolizin- 3-yl, 3H-pyrrolizin-5-yl, 3H-pyrrolizin-6-yl and 3H-pyrrolizin-7-yl. The term “heteroaryl” refers to an aromatic ring system of 5 to 18 atoms including at least one N, O, S, or P, containing 1 or 2 rings which can be fused together or linked covalently, each ring typically containing 5 to 6 atoms; at least one of said rings is aromatic, where the N and S heteroatoms may optionally be oxidized and the N heteroatoms may optionally be quaternized, and wherein at least one carbon atom of said heteroaryl can be oxidized to form at least one C=O. Fused systems of a heteroaryl ring with a cycloalkyl ring, or a cycloalkenyl ring, or a cycloalkynyl ring, are considered as heteroaryl irrespective of the ring that is bound to the core structure. Fused systems of a heteroaryl ring with a heterocycle are considered as heteroaryl irrespective of the ring that is bound to the core structure. Fused systems of a hetero aryl ring with an aryl ring are considered as heteroaryl irrespective of the ring that is bound to the core structure. Non-limiting examples of such heteroaryl, include: triazol-2-yl, pyridinyl, 1H-pyrazol-5-yl, pyrrolyl, furanyl, thiophenyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, oxatriazolyl, thiatriazolyl, pyrimidyl, pyrazinyl, pyridazinyl, oxazinyl, dioxinyl, thiazinyl, triazinyl, imidazo[2,1-b][1,3]thiazolyl, thieno[3,2-b]furanyl, thieno[3,2- b]thiophenyl, thieno[2,3-d][1,3]thiazolyl, thieno[2,3-d]imidazolyl, tetrazolo[1,5-a]pyridinyl, indolyl, indolizinyl, isoindolyl, benzofuranyl, isobenzofuranyl, benzothiophenyl, isobenzothiophenyl, indazolyl, benzimidazolyl, 1,3-benzoxazolyl, 1,2-benzisoxazolyl, 2,1-benzisoxazolyl, 1,3- benzothiazolyl, 1,2-benzoisothiazolyl, 2,1-benzoisothiazolyl, benzotriazolyl, 1,2,3- benzoxadiazolyl, 2,1,3-benzoxadiazolyl, 1,2,3-benzothiadiazolyl, 2,1,3-benzothiadiazolyl, benzo[d]oxazol-2(3H)-one, 2,3-dihydro-benzofuranyl, thienopyridinyl, purinyl, imidazo[1,2- a]pyridinyl, 6-oxo-pyridazin-1(6H)-yl, 2-oxopyridin-1(2H)-yl, 6-oxo-pyridazin-1(6H)-yl, 2- oxopyridin-1(2H)-yl, 1,3-benzodioxolyl, quinolinyl, isoquinolinyl, cinnolinyl, quinazolinyl, quinoxalinyl; preferably said heteroaryl group is selected from the group comprising pyridyl, pyrazinyl, pyrimidinyl, pyrazolyl, pyrrolyl, isoxazolyl, thiophenyl, imidazolyl, indolyl, benzimidazolyl, s-triazinyl, oxazolyl, isothiazolyl, furyl, thienyl, triazolyl and thiazolyl ; more preferably, said heteroaryl group is selected from from the group comprising pyridyl, pyrazinyl, pyrimidinyl, indolyl and benzimidazolyl. The term “pyrrolyl” (also called azolyl) as used herein includes pyrrol-1-yl, pyrrol-2-yl and pyrrol- 3-yl. The term “furanyl” (also called "furyl") as used herein includes furan-2-yl and furan-3-yl (also called furan-2-yl and furan-3-yl). The term “thiophenyl” (also called "thienyl") as used herein includes thiophen-2-yl and thiophen-3-yl (also called thien-2-yl and thien-3-yl). The term “pyrazolyl” (also called 1H-pyrazolyl and 1,2-diazolyl) as used herein includes pyrazol-1-yl, pyrazol-3-yl or 1H-pyrazol-5-yl, pyrazol-4-yl and pyrazol-5-yl. The term “imidazolyl” as used herein includes imidazol-1-yl, imidazol-2-yl, imidazol-4-yl and imidazol-5-yl. The term “oxazolyl” (also called 1,3-oxazolyl) as used herein includes oxazol-2-yl, oxazol-4-yl and oxazol-5-yl. The term “isoxazolyl” (also called 1,2-oxazolyl), as used herein includes isoxazol-3-yl, isoxazol-4-yl, and isoxazol-5-yl. The term “thiazolyl” (also called 1,3-thiazolyl),as used herein includes thiazol-2-yl, thiazol-4-yl and thiazol-5-yl (also called 2-thiazolyl, 4-thiazolyl and 5-thiazolyl). The term “isothiazolyl” (also called 1,2-thiazolyl) as used herein includes isothiazol-3-yl, isothiazol-4-yl, and isothiazol-5-yl. The term “triazolyl” as used herein includes triazol-2-yl, 1H-triazolyl and 4H-1,2,4- triazolyl, “1H-triazolyl” includes 1H-1,2,3-triazol-1-yl, 1H-1,2,3-triazol-4-yl, 1H-1,2,3-triazol-5-yl, 1H-1,2,4-triazol-1-yl, 1H-1,2,4-triazol-3-yl and 1H-1,2,4-triazol-5-yl. “4H-1,2,4-triazolyl” includes 4H-1,2,4-triazol-4-yl, and 4H-1,2,4-triazol-3-yl. The term “oxadiazolyl” as used herein includes 1,2,3-oxadiazol-4-yl, 1,2,3-oxadiazol-5-yl, 1,2,4-oxadiazol-3-yl, 1,2,4-oxadiazol-5-yl, 1,2,5- oxadiazol-3-yl and 1,3,4-oxadiazol-2-yl. The term “thiadiazolyl” as used herein includes 1,2,3- thiadiazol-4-yl, 1,2,3-thiadiazol-5-yl, 1,2,4-thiadiazol-3-yl, 1,2,4-thiadiazol-5-yl, 1,2,5-thiadiazol-3- yl (also called furazan-3-yl) and 1,3,4-thiadiazol-2-yl. The term “tetrazolyl” as used herein includes 1H-tetrazol-1-yl, 1H-tetrazol-5-yl, 2H-tetrazol-2-yl, and 2H-tetrazol-5-yl. The term “oxatriazolyl” as used herein includes 1,2,3,4-oxatriazol-5-yl and 1,2,3,5-oxatriazol-4-yl. The term “thiatriazolyl” as used herein includes 1,2,3,4-thiatriazol-5-yl and 1,2,3,5-thiatriazol-4-yl. The term “pyridinyl” (also called "pyridyl") as used herein includes pyridin-2-yl, pyridin-3-yl and pyridin-4-yl (also called 2- pyridyl, 3-pyridyl and 4-pyridyl). The term “pyrimidyl” as used herein includes pyrimid-2-yl, pyrimid- 4-yl, pyrimid-5-yl and pyrimid-6-yl. The term “pyrazinyl” as used herein includes pyrazin-2-yl and pyrazin-3-yl. The term “pyridazinyl as used herein includes pyridazin-3-yl and pyridazin-4-yl. The term “oxazinyl” (also called "1,4-oxazinyl") as used herein includes 1,4-oxazin-4-yl and 1,4-oxazin- 5-yl. The term “dioxinyl” (also called "1,4-dioxinyl”) as used herein includes 1,4-dioxin-2-yl and 1,4-dioxin-3-yl. The term “thiazinyl” (also called "1,4-thiazinyl”) as used herein includes 1,4-thiazin- 2-yl, 1,4-thiazin-3-yl, 1,4-thiazin-4-yl, 1,4-thiazin-5-yl and 1,4-thiazin-6-yl. The term “triazinyl” as used herein includes 1,3,5-triazin-2-yl, 1,2,4-triazin-3-yl, 1,2,4-triazin-5-yl, 1,2,4-triazin-6-yl, 1,2,3- triazin-4-yl and 1,2,3-triazin-5-yl. The term “imidazo[2,1-b][1,3]thiazolyl” as used herein includes imidazo[2,1-b][1,3]thiazoi-2-yl, imidazo[2,1-b][1,3]thiazol-3-yl, imidazo[2,1-b][1,3]thiazol-5-yl and imidazo[2,1-b][1,3]thiazol-6-yl. The term “thieno[3,2-b]furanyl” as used herein includes thieno[3,2- b]furan-2-yl, thieno[3,2-b]furan-3-yl, thieno[3,2-b]furan-4-yl, and thieno[3,2-b]furan-5-yl. The term “thieno[3,2-b]thiophenyl” as used herein includes thieno[3,2-b]thien-2-yl, thieno[3,2-b]thien-3-yl, thieno[3,2-b]thien-5-yl and thieno[3,2-b]thien-6-yl. The term “thieno[2,3-d][1,3]thiazolyl” as used herein includes thieno[2,3-d][1,3]thiazol-2-yl, thieno[2,3-d][1,3]thiazol-5-yl and thieno[2,3- d][1,3]thiazol-6-yl. The term “thieno[2,3-d]imidazolyl” as used herein includes thieno[2,3- d]imidazol-2-yl, thieno[2,3-d]imidazol-4-yl and thieno[2,3-d]imidazol-5-yl. The term “tetrazolo[1,5- a]pyridinyl” as used herein includes tetrazolo[1,5-a]pyridine-5-yl, tetrazolo[1,5-a]pyridine-6-yl, tetrazolo[1,5-a]pyridine-7-yl, and tetrazolo[1,5-a]pyridine-8-yl. The term “indolyl” as used herein includes indol-1-yl, indol-2-yl, indol-3-yl,-indol-4-yl, indol-5-yl, indol-6-yl and indol-7-yl. The term “indolizinyl” as used herein includes indolizin-1-yl, indolizin-2-yl, indolizin-3-yl, indolizin-5-yl, indolizin-6-yl, indolizin-7-yl, and indolizin-8-yl. The term “isoindolyl” as used herein includes isoindol-1-yl, isoindol-2-yl, isoindol-3-yl, isoindol-4-yl, isoindol-5-yl, isoindol-6-yl and isoindol-7-yl. The term “benzofuranyl” (also called benzo[b]furanyl) as used herein includes benzofuran-2-yl, benzofuran-3-yl, benzofuran-4-yl, benzofuran-5-yl, benzofuran-6-yl and benzofuran-7-yl. The term “isobenzofuranyl” (also called benzo[c]furanyl) as used herein includes isobenzofuran-1-yl, isobenzofuran-3-yl, isobenzofuran-4-yl, isobenzofuran-5-yl, isobenzofuran-6-yl and isobenzofuran-7-yl. The term “benzothiophenyl” (also called benzo[b]thienyl) as used herein includes 2-benzo[b]thiophenyl, 3-benzo[b]thiophenyl, 4-benzo[b]thiophenyl, 5- benzo[b]thiophenyl, 6-benzo[b]thiophenyl and -7-benzo[b]thiophenyl (also called benzothien-2-yl, benzothien-3-yl, benzothien-4-yl, benzothien-5-yl, benzothien-6-yl and benzothien-7-yl). The term “isobenzothiophenyl” (also called benzo[c]thienyl) as used herein includes isobenzothien-1-yl, isobenzothien-3-yl, isobenzothien-4-yl, isobenzothien-5-yl, isobenzothien-6-yl and isobenzothien- 7-yl. The term “indazolyl” (also called 1H-indazolyl or 2-azaindolyl) as used herein includes 1H- indazol-1-yl, 1H-indazol-3-yl, 1H-indazol-4-yl, 1H-indazol-5-yl, 1H-indazol-6-yl, 1H-indazol-7-yl, 2H-indazol-2-yl, 2H-indazol-3-yl, 2H-indazol-4-yl, 2H-indazol-5-yl, 2H-indazol-6-yl, and 2H- indazol-7-yl. The term “benzimidazolyl” as used herein includes benzimidazol-1-yl, benzimidazol- 2-yl, benzimidazol-4-yl, benzimidazol-5-yl, benzimidazol-6-yl and benzimidazol-7-yl. The term “1,3-benzoxazolyl” as used herein includes 1,3-benzoxazol-2-yl, 1,3-benzoxazol-4-yl, 1,3- benzoxazol-5-yl, 1,3-benzoxazol-6-yl and 1,3-benzoxazol-7-yl. The term “1,2-benzisoxazolyl” as used herein includes 1,2-benzisoxazol-3-yl, 1,2-benzisoxazol-4-yl, 1,2-benzisoxazol-5-yl, 1,2- benzisoxazol-6-yl and 1,2-benzisoxazol-7-yl. The term “2,1-benzisoxazolyl” as used herein includes 2,1-benzisoxazol-3-yl, 2,1-benzisoxazol-4-yl, 2,1-benzisoxazol-5-yl, 2,1-benzisoxazol-6- yl and 2,1-benzisoxazol-7-yl. The term “1,3-benzothiazolyl” as used herein includes 1,3- benzothiazol-2-yl, 1,3-benzothiazol-4-yl, 1,3-benzothiazol-5-yl, 1,3-benzothiazol-6-yl and 1,3- benzothiazol-7-yl. The term “1,2-benzoisothiazolyl” as used herein includes 1,2-benzisothiazol-3- yl, 1,2-benzisothiazol-4-yl, 1,2-benzisothiazol-5-yl, 1,2-benzisothiazol-6-yl and 1,2- benzisothiazol-7-yl. The term “2,1-benzoisothiazolyl” as used herein includes 2,1-benzisothiazol- 3-yl, 2,1-benzisothiazol-4-yl, 2,1-benzisothiazol-5-yl, 2,1-benzisothiazol-6-yl and 2,1- benzisothiazol-7-yl. The term “benzotriazolyl” as used herein includes benzotriazol-1-yl, benzotriazol-4-yl, benzotriazol-5-yl, benzotriazol-6-yl and benzotriazol-7-yl. The term “1,2,3- benzoxadiazolyl” as used herein includes 1,2,3-benzoxadiazol-4-yl, 1,2,3-benzoxadiazol-5-yl, 1,2,3-benzoxadiazol-6-yl and 1,2,3-benzoxadiazol-7-yl. The term “2,1,3-benzoxadiazolyl” as used herein includes 2,1,3-benzoxadiazol-4-yl, 2,1,3-benzoxadiazol-5-yl, 2,1,3-benzoxadiazol-6-yl and 2,1,3-benzoxadiazol-7-yl. The term “1,2,3-benzothiadiazolyl” as used herein includes 1,2,3- benzothiadiazol-4-yl, 1,2,3-benzothiadiazol-5-yl, 1,2,3-benzothiadiazol-6-yl and 1,2,3- benzothiadiazol-7-yl. The term “2,1,3-benzothiadiazolyl” as used herein includes 2,1,3- benzothiadiazol-4-yl, 2,1,3-benzothiadiazol-5-yl, 2,1,3-benzothiadiazol-6-yl and 2,1,3- benzothiadiazol-7-yl. The term “thienopyridinyl” as used herein includes thieno[2,3-b]pyridinyl, thieno[2,3-c]pyridinyl, thieno[3,2-c]pyridinyl and thieno[3,2-b]pyridinyl. The term “purinyl” as used herein includes purin-2-yl, purin-6-yl, purin-7-yl and purin-8-yl. The term “imidazo[1,2-a]pyridinyl”, as used herein includes imidazo[1,2-a]pyridin-2-yl, imidazo[1,2-a]pyridin-3-yl, imidazo[1,2- a]pyridin-4-yl, imidazo[1,2-a]pyridin-5-yl, imidazo[1,2-a]pyridin-6-yl and imidazo[1,2-a]pyridin-7-yl. The term “1,3-benzodioxolyl”, as used herein includes 1,3-benzodioxol-4-yl, 1,3-benzodioxol-5-yl, 1,3-benzodioxol-6-yl, and 1,3-benzodioxol-7-yl. The term “quinolinyl” as used herein includes quinolin-2-yl, quinolin-3-yl, quinolin-4-yl, quinolin-5-yl, quinolin-6-yl, quinolin-7-yl and quinolin-8- yl. The term “isoquinolinyl” as used herein includes isoquinolin-1-yl, isoquinolin-3-yl, isoquinolin- 4-yl, isoquinolin-5-yl, isoquinolin-6-yl, isoquinolin-7-yl and isoquinolin-8-yl. The term “cinnolinyl” as used herein includes cinnolin-3-yl, cinnolin-4-yl, cinnolin-5-yl, cinnolin-6-yl, cinnolin-7-yl and cinnolin-8-yl. The term “quinazolinyl” as used herein includes quinazolin-2-yl, quinazolin-4-yl, quinazolin-5-yl, quinazolin-6-yl, quinazolin-7-yl and quinazolin-8-yl. The term “quinoxalinyl” as used herein includes quinoxalin-2-yl, quinoxalin-5-yl, and quinoxalin-6-yl. Heteroaryl and heterocycle or heterocyclyl as used herein includes by way of example and not limitation these groups described in Paquette, Leo A. “Principles of Modern Heterocyclic Chemistry” (W.A. Benjamin, New York, 1968), particularly Chapters 1, 3, 4, 6, 7, and 9; “The Chemistry of Heterocyclic Compounds, A series of Monographs” (John Wiley & Sons, New York, 1950 to present), in particular Volumes 13, 14, 16, 19, and 28; Katritzky, Alan R., Rees, C.W. and Scriven, E. “Comprehensive Heterocyclic Chemistry” (Pergamon Press, 1996); and J. Am. Chem. Soc. (1960) 82:5566. The term “heterocyclyloxy” or “heterocycleoxy”, as a group or part of a group, refers to a group having the formula -O-R ⁱ wherein R ⁱ is heterocyclyl as defined herein above. The term “heterocyclylalkyloxy” or “heterocycleoxy”, as a group or part of a group, refers to a group having the formula -O-R ^a -R ⁱ wherein R ⁱ is heterocyclyl, and R ^a is alkyl as defined herein above. The term “heteroaryloxy”, as a group or part of a group, refers to a group having the formula -O-R ^k wherein R ^k is heteroaryl as defined herein above. The term “heteroarylalkyloxy”, as a group or part of a group, refers to a group having the formula -O-R ^a -R ⁱ wherein R ⁱ is heteroaryl, and R ^a is alkyl as defined herein above. The term “heterocyclyl-alkyl” or “heterocycle-alkyl” as a group or part of a group, refers to an alkyl in which one of the hydrogen atoms bonded to a carbon atom, typically a terminal or sp3 carbon atom, is replaced with a heterocyclyl. A non-limiting example of a heterocyclyl-alkyl or heterocycle-alkyl group is 2-piperidinyl-methylene. The heterocyclyl-alkyl or heterocycle-alkyl group can comprise 6 to 20 atoms, e.g. the alkyl moiety is 1 to 6 carbon atoms and the heterocyclyl moiety is 3 to 14 atoms. The term “heterocyclyl-alkenyl” or “heterocycle-alkenyl” as a group or part of a group refers to an alkenyl in which one of the hydrogen atoms bonded to a carbon atom, is replaced with an heterocyclyl. The heterocyclyl-alkenyl or heterocycle-alkenyl group can comprise 6 to 20 atoms, e.g. the alkenyl moiety is 2 to 6 carbon atoms and the heterocyclyl moiety is 3 to 14 atoms. The term “heterocyclyl-alkynyl” or “heterocycle-alkynyl” as a group or part of a group refers to an alkynyl in which one of the hydrogen atoms bonded to a carbon atom, is replaced with a heterocyclyl. The heterocyclyl-alkynyl or heterocycle-alkynyl group can comprise 6 to 20 atoms, e.g. the alkynyl moiety can comprise 2 to 6 carbon atoms and the heterocyclyl moiety can comprise 3 to 14 atoms. The term “heterocyclyl-heteroalkyl” or “heterocycle-heteroalkyl” as a group or part of a group refers to a heteroalkyl in which one of the hydrogen atoms bonded to a carbon atom, typically a terminal or sp3 carbon atom, is replaced with a heterocyclyl. The heterocyclyl- heteroalkyl or heterocycle-heteroalkyl group can comprise 6 to 20 atoms, e.g. the heteroalkyl moiety can comprise 1 to 6 carbon atoms and the heterocyclyl moiety can comprise 3 to 14 atoms. In some embodiments heterocyclyl-heteroalkyl or heterocycle-heteroalkyl is selected from the group comprising heterocyclyl-O-alkyl, heterocyclylalkyl-O-alkyl, heterocyclyl-NH-alkyl, heterocyclyl-N(alkyl) ₂ , heterocyclylalkyl-NH-alkyl, heterocyclylalkyl-N-(alkyl) ₂ , heterocyclyl–S- alkyl, and heterocyclylalkyl-S-alkyl. The term “heterocyclyl-heteroalkenyl” or “heterocycle-heteroalkenyl” as a group or part of a group refers to a heteroalkenyl in which one of the hydrogen atoms bonded to a carbon atom, is replaced with a heterocyclyl. The heterocyclyl-heteroalkenyl or heterocycle-heteroalkenyl group can comprise 6 to 20 atoms, e.g. the heteroalkenyl moiety can comprise 2 to 6 carbon atoms and the heterocyclyl moiety can comprise 3 to 14 atoms. In some embodiments heterocyclyl- heteroalkenyl or heterocycle-heteroalkenyl is selected from the group comprising heterocyclyl-O- alkenyl, heterocyclylalkyl-O-alkenyl, heterocyclyl-NH-alkenyl, heterocyclyl-N(alkenyl) ₂ , heterocyclylalkyl-NH-alkenyl, heterocyclylalkyl-N-(alkenyl) ₂ , heterocyclyl–S-alkenyl, and heterocyclylalkenyl-S-alkenyl. The term “heterocyclyl-heteroalkynyl” or “heterocycle-heteroalkynyl” as a group or part of a group refers to a heteroalkynyl in which one of the hydrogen atoms bonded to a carbon atom, is replaced with a heterocyclyl. The heterocyclyl-heteroalkynyl or heterocycle-heteroalkynyl group can comprise 6 to 20 atoms, e.g. the heteroalkynyl moiety can comprise 2 to 6 carbon atoms and the heterocyclyl moiety can comprise 3 to 14 atoms. In some embodiments heterocyclyl- heteroalkynyl is selected from the group comprising heterocyclyl-O-alkynyl, heterocyclylalkynyl- O-alkynyl, heterocyclyl-NH-alkynyl, heterocyclyl-N(alkynyl) ₂ , heterocyclylalkynyl-NH-alkynyl, heterocyclylalkynyl-N-(alkynyl) ₂ , heterocyclyl–S-alkynyl, and heterocyclylalkynyl-S-alkynyl. The term “heteroaryl-alkyl” as a group or part of a group refers to an alkyl in which one of the hydrogen atoms bonded to a carbon atom, typically a terminal or sp3 carbon atom, is replaced with a heteroaryl. An example of a heteroaryl-alkyl group is 2-pyridyl-methylene. The heteroaryl- alkyl group can comprise 6 to 20 atoms, e.g. the alkyl moiety of the heteroaryl-alkyl group can comprise 1 to 6 carbon atoms and the heteroaryl moiety can comprise 5 to 14 atoms. The term “heteroaryl-alkenyl” as a group or part of a group refers to an alkenyl in which one of the hydrogen atoms bonded to a carbon atom, is replaced with an heteroaryl. The heteroaryl-alkenyl group can comprise 6 to 20 atoms, e.g. the alkenyl moiety of the heteroaryl- alkenyl group can comprise 2 to 6 carbon atoms and the heteroaryl moiety can comprise 5 to 14 atoms. The term “heteroaryl-alkynyl” as a group or part of a group as used herein refers to an alkynyl in which one of the hydrogen atoms bonded to a carbon atom, is replaced with a heteroaryl. The heteroaryl-alkynyl group comprises 6 to 20 atoms, e.g. the alkynyl moiety of the heteroaryl- alkynyl group is 2 to 6 carbon atoms and the heteroaryl moiety is 5 to 14 atoms. The term “heteroaryl-heteroalkyl” as a group or part of a group as used herein refers to a heteroalkyl in which one of the hydrogen atoms bonded to a carbon atom, typically a terminal or sp3 carbon atom, is replaced with a heteroaryl. The heteroaryl-heteroalkyl group comprises 7 to 20 atoms, e.g. the heteroalkyl moiety of the heteroaryl-heteroalkyl group is 2 to 6 carbon atoms and the heteroaryl moiety is 5 to 14 atoms. In some embodiments heteroaryl-heteroalkyl is selected from the group comprising heteroaryl-O-alkyl, heteroarylalkyl-O-alkyl, heteroaryl-NH- alkyl, heteroaryl-N(alkyl) ₂ , heteroarylalkyl-NH-alkyl, heteroarylalkyl-N-(alkyl) ₂ , heteroaryl–S-alkyl, and heteroarylalkyl-S-alkyl. The term “heteroaryl-heteroalkenyl” as a group or part of a group as used herein refers to a heteroalkenyl in which one of the hydrogen atoms bonded to a carbon atom, is replaced with an heteroaryl. The heteroaryl-heteroalkenyl group comprises 8 to 20 atoms, e.g. the heteroalkenyl moiety of the heteroaryl-heteroalkenyl group is 3 to 6 carbon atoms and the heteroaryl moiety is 5 to 14 atoms. In some embodiments heteroaryl-heteroalkenyl is selected from the group comprising heteroaryl-O-alkenyl, heteroarylalkenyl-O-alkenyl, heteroaryl-NH-alkenyl, heteroaryl- N(alkenyl) ₂ , heteroarylalkenyl-NH-alkenyl, heteroarylalkenyl-N-(alkenyl) ₂ , heteroaryl–S-alkenyl, and heteroarylalkenyl-S-alkenyl. The term “heteroaryl-heteroalkynyl” as a group or part of a group as used herein refers to a heteroalkynyl in which one of the hydrogen atoms bonded to a carbon atom, is replaced with a heteroaryl. The heteroaryl-heteroalkynyl group comprises 8 to 20 atoms, e.g. the heteroalkynyl moiety of the heteroaryl-heteroalkynyl group is 2 to 6 carbon atoms and the heteroaryl moiety is 5 to 14 atoms. In some embodiments heteroaryl-heteroalkynyl is selected from the group comprising heteroaryl-O-alkynyl, heteroarylalkynyl-O-alkynyl, heteroaryl-NH-alkynyl, heteroaryl- N(alkynyl) ₂ , heteroarylalkynyl-NH-alkynyl, heteroarylalkynyl-N-(alkynyl) ₂ , heteroaryl–S-alkynyl, and heteroarylalkynyl-S-alkynyl. By way of example, carbon bonded heteroaryl or heterocyclic rings (or heterocycles) can be bonded at position 2, 3, 4, 5, or 6 of a pyridine, position 3, 4, 5, or 6 of a pyridazine, position 2, 4, 5, or 6 of a pyrimidine, position 2, 3, 5, or 6 of a pyrazine, position 2, 3, 4, or 5 of a furan, tetrahydrofuran, thiophene, pyrrole or tetrahydropyrrole, position 2, 4, or 5 of an oxazole, imidazole or thiazole, position 3, 4, or 5 of an isoxazole, pyrazole, or isothiazole, position 2 or 3 of an aziridine, position 2, 3, or 4 of an azetidine, position 2, 3, 4, 5, 6, 7, or 8 of a quinoline or position 1, 3, 4, 5, 6, 7, or 8 of an isoquinoline. Still more typically, carbon bonded heteroaryls and heterocyclyls include 2-pyridyl, 3-pyridyl, 4-pyridyl, 5-pyridyl, 6-pyridyl, 3-pyridazinyl, 4- pyridazinyl, 5-pyridazinyl, 6-pyridazinyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, 6-pyrimidinyl, 2-pyrazinyl, 3-pyrazinyl, 5-pyrazinyl, 6-pyrazinyl, 2-thiazolyl, 4-thiazolyl, or 5-thiazolyl. By way of example, nitrogen bonded heterocyclic rings are bonded at position 1 of an aziridine, azetidine, pyrrole, pyrrolidine, 2-pyrroline, 3-pyrroline, imidazole, imidazolidine, 2-imidazoline, 3-imidazoline, pyrazole, pyrazoline, 2-pyrazoline, 3-pyrazoline, piperidine, piperazine, indole, indoline, 1H- indazole, position 2 of a isoindole, or isoindoline, position 4 of a morpholine, and position 9 of a carbazole, or ß-carboline. Still more typically, nitrogen bonded heteroaryls or heterocyclyls include 1-aziridyl, 1-azetedyl, 1-pyrrolyl, 1-imidazolyl, 1-pyrazolyl, and 1-piperidinyl. As used herein and unless otherwise stated, the terms “alkoxy”, “cyclo-alkoxy”, “aryloxy”, “arylalkyloxy”, “heteroaryloxy” “heterocyclyloxy”, “alkylthio”, “cycloalkylthio”, “arylthio”, “arylalkylthio”, “heteroarylthio” and “heterocyclylthio” refer to substituents wherein an alkyl group, respectively a cycloalkyl, aryl, arylalkyl heteroaryl, or heterocyclyl (each of them such as defined herein), are attached to an oxygen atom or a sulfur atom through a single bond, such as but not limited to methoxy, ethoxy, propoxy, butoxy, thioethyl, thiomethyl, phenyloxy, benzyloxy, mercaptobenzyl and the like. The same definitions will apply for alkenyl and alkynyl instead of alkyl. The term “alkylthio", as a group or part of a group, refers to a group having the formula – S-R ^b wherein R ^b is alkyl as defined herein above. Non-limiting examples of alkylthio groups include methylthio (-SCH ₃ ), ethylthio (-SCH ₂ CH ₃ ), n-propylthio, isopropylthio, n-butylthio, isobutylthio, sec-butylthio, tert-butylthio and the like. The term “alkenylthio", as a group or part of a group, refers to a group having the formula –S-R ^d wherein R ^d is alkenyl as defined herein above. The term “alkynylthio", as a group or part of a group, refers to a group having the formula –S-R ^e wherein R ^e is alkynyl as defined herein above. The term “arylthio", as a group or part of a group, refers to a group having the formula –S- R ^g wherein R ^g is aryl as defined herein above. The term “arylalkylthio", as a group or part of a group, refers to a group having the formula -S-R ^a -R ^g wherein R ^a is alkylene and R ^g is aryl as defined herein above. The term “heterocyclylthio", as a group or part of a group, refers to a group having the formula –S-R ⁱ wherein R ⁱ is heterocyclyl as defined herein above. The term “heteroarylthio", as a group or part of a group, refers to a group having the formula –S-R ^k wherein R ^k is heteroaryl as defined herein above. The term “heterocyclylalkylthio", as a group or part of a group, refers to a group having the formula -S-R ^a -R ⁱ wherein R ^a is alkylene and R ⁱ is heterocyclyl as defined herein above. The term “heteroarylalkylthio", as a group or part of a group, refers to a group having the formula -S-R ^a -R ^k wherein R ^a is alkylene and R ^k is heteroaryl as defined herein above. The term “mono- or di-alkylamino”, as a group or part of a group, refers to a group of formula -N(R ^o )(R ^b ) wherein R ^o is hydrogen, or alkyl, R ^b is alkyl. Thus, alkylamino include mono- alkyl amino group (e.g. mono-alkylamino group such as methylamino and ethylamino), and di- alkylamino group (e.g. di-alkylamino group such as dimethylamino and diethylamino). Non-limiting examples of suitable mono- or di-alkylamino groups include n-propylamino, isopropylamino, n- butylamino, i-butylamino, sec-butylamino, t-butylamino, pentylamino, n-hexylamino, di-n- propylamino, di-i-propylamino, ethylmethylamino, methyl-n-propylamino, methyl-i-propylamino, n- butylmethylamino, i-butylmethylamino, t-butylmethylamino, ethyl-n-propylamino, ethyl-i- propylamino, n-butylethylamino, i-butylethylamino, t-butylethylamino, di-n-butylamino, di-i- butylamino, methylpentylamino, methylhexylamino, ethylpentylamino, ethylhexylamino, propylpentylamino, propylhexylamino, and the like. The term “mono- or di-arylamino”, as a group or part of a group, refers to a group of formula -N(R ^q )(R ^r ) wherein R ^q and R ^r are each independently selected from hydrogen, aryl, or alkyl, wherein at least one of R ^q or R ^r is aryl. The term “mono- or di-heteroarylamino”, as a group or part of a group, refers to a group of formula -N(R ^u )(R ^v ) wherein R ^u and R ^v are each independently selected from hydrogen, heteroaryl, or alkyl, wherein at least one of R ^u or R ^v is heteroaryl as defined herein. The term “mono- or di-heterocyclylamino”, as a group or part of a group, refers to a group of formula -N(R ^w )(R ^x ) wherein R ^w and R ^x are each independently selected from hydrogen, heterocyclyl, or alkyl, wherein at least one of R ^w or R ^x is heterocyclyl as defined herein. As used herein and unless otherwise stated, the term halogen means any atom selected from the group consisting of fluorine (F), chlorine (Cl), bromine (Br) and iodine (I). The terminology regarding a chemical group “which optionally includes one or more heteroatoms, said heteroatoms being selected from the atoms consisting of O, S, and N” as used herein, refers to a group where one or more carbon atoms are replaced by an oxygen, nitrogen or sulphur atom and thus includes, depending on the group to which is referred, heteroalkyl, heteroalkenyl, heteroalkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloheteroalkyl, cycloheteroalkenyl, cycloheteroalkynyl, heteroaryl, arylheteroalkyl, heteroarylalkyl, heteroarylheteroalkyl, arylheteroalkenyl, heteroarylalkenyl, heteroarylheteroalkenyl, heteroarylheteroalkenyl, arylheteroalkynyl, heteroarylalkynyl, heteroarylheteroalkynyl, among others. This term therefore comprises, depending on the group to which is referred, as an example alkoxy, alkenyloxy, alkynyloxy, alkyl-O-alkylene, alkenyl-O-alkylene, arylalkoxy, benzyloxy, heteroaryl-heteroalkyl, heterocyclyl-heteroalkyl, heteroaryl-alkoxy, heterocyclyl-alkoxy, among others. As an example, the terminology “alkyl which optionally includes one or more heteroatoms, said heteroatoms being selected from the atoms consisting of O, S, and N” therefore refers to heteroalkyl, meaning an alkyl which comprises one or more heteroatoms in the hydrocarbon chain, whereas the heteroatoms may be positioned at the beginning of the hydrocarbon chain, in the hydrocarbon chain or at the end of the hydrocarbon chain. Examples of heteroalkyl include methoxy, methylthio, ethoxy, propoxy, CH ₃ -O-CH ₂ -, CH ₃ -S-CH ₂ -, CH ₃ -CH ₂ -O-CH ₂ -, CH ₃ -NH-, (CH ₃ ) ₂ -N-, (CH ₃ ) ₂ -CH ₂ -NH-CH ₂ -CH ₂ -, among many other examples. As an example, the terminology “arylalkylene which optionally includes one or more heteroatoms in the alkylene chain, said heteroatoms being selected from the atoms consisting of O, S, and N” therefore refers to arylheteroalkylene, meaning an arylalkylene which comprises one or more heteroatoms in the hydrocarbon chain, whereas the heteroatoms may be positioned at the beginning of the hydrocarbon chain, in the hydrocarbon chain or at the end of the hydrocarbon chain. “Arylheteroalkylene” thus includes aryloxy, arylalkoxy, aryl-alkyl-NH- and the like and examples are phenyloxy, benzyloxy, aryl-CH ₂ -S-CH ₂ -, aryl-CH ₂ -O-CH ₂ -, aryl-NH-CH ₂ - among many other examples. The same counts for “heteroalkenylene”, “heteroalkynylene”, and other terms used herein when referred to “which optionally includes one or more heteroatoms, said heteroatoms being selected from the atoms consisting of O, S, and N”. The terminology regarding a chemical group “wherein optionally two or more hydrogen atoms on a carbon atom or heteroatom of said group can be taken together to form a =O or =S” as used herein, refers to a group where two or more hydrogen atoms on a carbon atom or heteroatom of said group are taken together to form =O or =S. As an example, the terminology refers to “an alkyl wherein optionally two or more hydrogen atoms on a carbon atom or heteroatom of said alkyl can be taken together to form a =O or =S”, includes among other examples CH ₃ - C(O)-CH ₂ -, CH ₃ -C(O)-, CH ₃ -C(S)-CH ₂ -, CH ₃ -S(O) ₂ -CH ₂ - and (CH ₃ ) ₂ -CH ₂ -C(O)-CH ₂ -CH ₂ -. The combination for a group “which optionally includes one or more heteroatoms, said heteroatoms being selected from the atoms consisting of O, S, and N” and “wherein optionally two or more hydrogen atoms on a carbon atom or heteroatom of said group can be taken together to form a =O or =S” can combine the two aspects described herein above and includes, if the group referred to is alkyl, among other examples CH ₃ -C(O)O-, CH ₃ -C(O)O-CH ₂ -, CH ₃ -NH-C(O)-, CH ₃ - C(O)-NH- CH ₃ -NH-C(O)-CH ₂ -, CH ₃ -NH-C(S)-CH ₂ -, CH ₃ -NH-C(S)-NH-CH ₂ -, CH ₃ -NH-S(O) ₂ - and CH ₃ -NH-S(O) ₂ -NH-CH ₂ -. The term “single bond” as used herein for a linking group i.e. in a way that a certain linking group is selected from a single bond, etc. in the formulas herein, refers to a molecule wherein the linking group is not present and therefore refers to compounds with a direct linkage via a single bond between the two moieties being linked by the linking group. As used herein with respect to a substituting group, and unless otherwise stated, the terms “substituted” such as in “substituted alkyl”, “substituted alkenyl”, substituted alkynyl”, “substituted aryl”, “substituted heteroaryl”, “substituted heterocyclyl”, “substituted arylalkyl”, “substituted heteroaryl-alkyl”, “substituted heterocyclyl-alkyl” and the like refer to the chemical structures defined herein, and wherein the said alkyl, alkenyl, alkynyl, group and/or the said aryl, heteroaryl, or heterocyclyl may be optionally substituted with one or more substituents (preferable 1, 2, 3, 4, 5 or 6), meaning that one or more hydrogen atoms are each independently replaced with at least one substituent. Typical substituents include, but are not limited to and in a particular embodiment said substituents are being independently selected from the group consisting of halogen, amino, hydroxyl, sulfhydryl, alkyl, alkoxy, alkenyl, alkenyloxy, alkynyl, alkynyloxy, cycloalkyl, cycloalkenyl, cycloalkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, aryl, heteroaryl, heterocyclyl, arylalkyl, arylalkenyl, arylalkynyl, cycloalkyl-alkyl, cycloalkylalkenyl, cycloalkylalkynyl, heteroaryl-alkyl, heterocyclyl-alkyl, heteroaryl-alkenyl, heterocyclyl-alkenyl and heteroaryl-alkynyl, heterocyclyl- alkynyl, -X, -Z, -O-, -OZ, =O, -SZ, -S-, =S, -NZ ₂ , -N ⁺ Z ₃ , =NZ, =N-OZ, -CX ₃ (e.g. trifluoromethyl), - CN, -OCN, -SCN, -N=C=O, -N=C=S, -NO, -NO ₂ , =N ₂ , -N ₃ , -NZC(O)Z, -NZC(S)Z, -NZC(O)O-, - NZC(O)OZ, -NZC(S)OZ, -NZC(O)NZZ, NZC(NZ)Z, NZC(NZ)NZZ, -C(O)NZZ, -C(NZ)Z, -S(O) ₂ O-, -S(O) ₂ OZ, -S(O) ₂ Z, -OS(O) ₂ OZ, -OS(O) ₂ Z, -OS(O) ₂ O-, -S(O) ₂ NZZ, -S(O)(NZ)Z, -S(O)Z, - OP(O)(OZ) ₂ , -P(O)(OZ) ₂ , -P(O)(O-) ₂ , -P(O)(OZ)(O-), -P(O)(OH) ₂ , -C(O)Z, -C(O)X, -C(S)Z, - C(O)OZ, -C(O)O-, -C(S)OZ, -C(O)SZ, -C(S)SZ, -C(O)NZZ, -C(S)NZZ, -C(NZ)NZZ, -OC(O)Z, - OC(S)Z, -OC(O)O-, -OC(O)OZ, -OC(S)OZ, wherein each X is independently a halogen selected from F, Cl, Br, or I; and each Z is independently –H, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, aryl, heteroaryl, heterocyclyl, cycloalkyl, protecting group or prodrug moiety, while two Z bonded to a nitrogen atom can be taken together with the nitrogen atom to which they are bonded to form a heteroaryl, or heterocyclyl. Alkyl(ene), alkenyl(ene), and alkynyl(ene) groups may also be similarly substituted. Any substituent designation that is found in more than one site in a compound of this invention shall be independently selected. Substituents optionally are designated with or without bonds. Regardless of bond indications, if a substituent is polyvalent (based on its position in the structure referred to), then any and all possible orientations of the substituent are intended. As used herein and unless otherwise stated, the term “solvate” includes any combination which may be formed by a derivative of this invention with a suitable inorganic solvent (e.g. hydrates) or organic solvent, such as but not limited to alcohols, ketones, esters, ethers, nitriles and the like. The term “heteroatom(s)” as used herein means an atom selected from nitrogen, which can be quaternized; oxygen; and sulfur, including sulfoxide and sulfone. The term “hydroxy” as used herein means -OH. The term “carbonyl” as used herein means carbon atom bonded to oxygen with a double bond, i.e., C═O. The term “amino” as used herein means the -NH ₂ group. The present disclosure provides novel compounds which have been shown to possess YAP/TAZ-TEAD transcription inhibitory activity. The present invention furthermore demonstrates that these compounds efficiently inhibit TEAD activation and thereby inhibit YAP/TAZ-TEAD transcription activation. Therefore, these compounds constitute a useful class of new potent compounds that can be used in the treatment and/or prevention of YAP/TAZ-TEAD activation mediated diseases in subjects, more specifically for the treatment and/or prevention of cancer and fibrosis, among other diseases. The present disclosure furthermore relates to the compounds for use as medicines and to their use for the manufacture of medicaments for treating and/or preventing cancer or fibrosis. The present disclosure relates to the compounds for use as medicines for treating and/or preventing YAP/TAZ-TEAD activation mediated diseases such as cancer or fibrosis in animals, mammals, more in particular in humans. The disclosure also relates to methods for the preparation of all such compounds and to pharmaceutical compositions comprising them in an effective amount. The present disclosure also relates to a method of treatment or prevention of cancer or fibrosis in humans by the administration of one or more such compounds, optionally in combination with one or more other medicines, to a patient in need thereof. The present disclosure also relates to the compounds for veterinary use and to their use as medicines for the prevention or treatment of diseases in a non-human mammal, such as cancer and fibrosis in non-human mammals. More particularly, the compounds of the disclosure are compounds of formula (Ia) and any subgroup thereof as described herein, a stereo-isomeric form, a tautomer, a salt (in particular a pharmaceutically acceptable salt), solvate, polymorph and/or prodrug thereof, wherein: -E is selected from (5-membered) heterocycle which can be unsubstituted or substituted with one or more substituents selected from C _1-6 alkyl, C _3-9 cycloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, hydroxyl, =O, halogen, -SH, =S, trifluoromethyl, -O-C _1-6 alkyl, -OCF ₃ , cyano, nitro, -C(O)OH, -C(O)OC _1-6 alkyl, - C(O)C _1-6 alkyl, -CONH ₂ , -CONHC _1-6 alkyl, -CON(C _1-6 alkyl) ₂ , -SO ₂ C _1-6 alkyl, -SO ₂ NH ₂ , -SO ₂ NHC _{1- 6} alkyl, -SO ₂ N(C _1-6 alkyl) ₂ , -S(O)(NH)C1-6alkyl, -S(O)(NC1-6alkyl)C1-6alkyl, -S(NH)(NH)C1- 6alkyl,-NH ₂ , -NHC _1-6 alkyl, and -N(C _1-6 alkyl) ₂ ; and -(CR ^10a R ^10b ) _n -NR ¹ R ² ; - n is selected from 0; 1; and 2; - m is selected from 0; and 1; - each represents an optional double bond, whereby maximally 3 are a double bond at the same time; - R ¹ is selected from C _1-6 alkyl; C _3-9 cycloalkyl; C _2-6 alkenyl; C _5-9 cycloalkenyl; C _2-6 alkynyl; C _{5- 9} cycloalkynyl; C _1-6 heteroalkyl; C _2-6 heteroalkenyl; C _2-6 heteroalkynyl; -C(O)H; -C(O)R ³ ; -C(O)OR ⁴ ; -C(O)NR ⁵ R ⁶ ; -S(O) ₂ R ^3a ; -S(O)R ^4a ; -S(O) ₂ NR ^5a R ^6a ; -S(O)(NR ^5a )R ^4a ; -S(NR ^5a )(NR ^6a )R ^3a ; and - P(O)R ^5b R ^6b ; wherein said C _1-6 alkyl, C _3-9 cycloalkyl, C _2-6 alkenyl, C _5-9 cycloalkenyl, C _2-6 alkynyl, C _{5- 9} cycloalkynyl, C _1-6 heteroalkyl, C _2-6 heteroalkenyl and C _2-6 heteroalkynyl can be unsubstituted or substituted with one or more substituents selected from C _1-6 alkyl, C _{3- 9} cycloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, hydroxyl, =O, halogen, -SH, =S, trifluoromethyl, -O- C _1-6 alkyl, -OCF ₃ , cyano, nitro, -C(O)OH, -C(O)OC _1-6 alkyl, -C(O)C _1-6 alkyl, -CONH ₂ , - CONHC _1-6 alkyl, -CON(C _1-6 alkyl) ₂ , -SO ₂ C _1-6 alkyl, -SO ₂ NH ₂ , -SO ₂ NHC _1-6 alkyl, -SO ₂ N(C _{1- 6} alkyl) ₂ , -S(O)(NH)C _1-6 alkyl, -S(O)(NC _1-6 alkyl)C _1-6 alkyl, -S(NH)(NH)C _1-6 alkyl, - S(O)(NH)C1-6alkyl, -S(O)(NC1-6alkyl)C1-6alkyl, -S(O) ₂ OH, -S(NH)(NH)C1-6alkyl, -NH ₂ , -NHC _1-6 alkyl, -N(C _1-6 alkyl) ₂ ; - R ² is selected from hydrogen; C _1-6 alkyl; C _3-9 cycloalkyl; and C _1-6 heteroalkyl; - R ¹ and R ² can be taken together to form a (4-; 5-; 6- or 7-membered) heterocycle which can be unsubstituted or substituted with one or more substituents selected from C _1-6 alkyl, C _3-9 cycloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, hydroxyl, =O, halogen, -SH, =S, trifluoromethyl, -O- C _1-6 alkyl, -OCF ₃ , cyano, nitro, -C(O)OH, -C(O)OC _1-6 alkyl, -C(O)C _1-6 alkyl, -CONH ₂ , - CONHC _1-6 alkyl, -CON(C _1-6 alkyl) ₂ , -SO ₂ C _1-6 alkyl, -SO ₂ NH ₂ , -SO ₂ NHC _1-6 alkyl, -SO ₂ N(C _{1- 6} alkyl) ₂ , -S(O)(NH)C1-6alkyl, -S(O)(NC1-6alkyl)C1-6alkyl, -S(NH)(NH)C1-6alkyl,-NH ₂ , - NHC _1-6 alkyl, -N(C _1-6 alkyl) ₂ ; - each R ³ and R ^3a is independently selected from hydroxyl; C _1-6 alkyl; C _3-9 cycloalkyl; C _{2- 6} alkenyl; C _5-9 cycloalkenyl; C _2-6 alkynyl; C _5-9 cycloalkynyl; C _1-6 heteroalkyl; C _2-6 heteroalkenyl; and C _2-6 heteroalkynyl; wherein said C _1-6 alkyl, C _3-9 cycloalkyl, C _2-6 alkenyl, C _5-9 cycloalkenyl, C _2-6 alkynyl, C _{5- 9} cycloalkynyl, C _1-6 heteroalkyl, C _2-6 heteroalkenyl and C _2-6 heteroalkynyl can be unsubstituted or substituted with one or more substituents selected from alkyl, cycloalkyl, a ^{lkenyl, alkynyl, hydroxyl, =O, halogen, -SH, =S, -CF} ₃ ^{, -O-alkyl, -OCF} ₃ ^{, -CHF} ₂ ^{, -OCHF} ₂ ^{, cyano, nitro, -C(O)OH; NH} _2; ^{-NHalkyl, and -N(alkyl)} ₂ ^; - each R ⁴ and R ^4a is independently selected from C _1-6 alkyl; C _3-9 cycloalkyl; C _2-6 alkenyl; C _{5- 9} cycloalkenyl; C _2-6 alkynyl; C _5-9 cycloalkynyl; C _1-6 heteroalkyl; C _2-6 heteroalkenyl; and C _{2- 6} heteroalkynyl; wherein said C _1-6 alkyl, C _3-9 cycloalkyl, C _2-6 alkenyl, C _5-9 cycloalkenyl, C _2-6 alkynyl, C _{5- 9} cycloalkynyl, C _1-6 heteroalkyl, C _2-6 heteroalkenyl and C _2-6 heteroalkynyl can be unsubstituted or substituted with one or more substituents selected from alkyl, c ^{ycloalkyl, alkenyl, alkynyl, hydroxyl, =O, halogen, -SH, =S, -CF} ₃ ^{, -O-alkyl, -OCF} ₃ ^{, - CHF} ₂ ^{, -OCHF} ₂ ^{, cyano, nitro, -C(O)OH; NH} _2; ^{-NHalkyl, and -N(alkyl)} ₂ ^; - each R ⁵ , R ^5a , R ^5b , R ⁶ , R ^6a and R ^6b is independently selected from hydrogen; C _1-6 alkyl; C _{3- 9} cycloalkyl; C _2-6 alkenyl; C _5-9 cycloalkenyl; C _2-6 alkynyl; C _5-9 cycloalkynyl; C _1-6 heteroalkyl; C _{2- 6} heteroalkenyl; and C _2-6 heteroalkynyl; wherein said C _1-6 alkyl, C _3-9 cycloalkyl, C _2-6 alkenyl, C _5-9 cycloalkenyl, C _2-6 alkynyl, C _5-9 cycloalkynyl, C _1-6 heteroalkyl, C _2-6 heteroalkenyl and C _2-6 heteroalkynyl can be unsubstituted or substituted with one or more substituents selected from alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, hydroxyl, =O, halogen, - ^{SH, =S, -CF} ₃ ^{, -O-alkyl, -OCF} ₃ ^{, -CHF} ₂ ^{, -OCHF} ₂ ^{, cyano, nitro, -C(O)OH; NH} _2; - NHalkyl, and -N(alkyl) ₂ ; and wherein each R ⁵ and R ⁶ or R ^5a and R ^6a can be taken together in order to form a (4-, 5-, 6-, or 7-membered) heterocycle which can be unsubstituted or substituted with one or more substituents selected from alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, hydroxyl, =O, halogen, -SH, =S, -CF ₃ , -O- a ^{lkyl, -OCF} ₃ ^{, -CHF} ₂ ^{, -OCHF} ₂ ^{, cyano, nitro, -C(O)OH; NH} _2; ^{-NHalkyl, and -} N(alkyl) ₂ ; - cycle A is selected from aryl; heteroaryl; C _3-9 cycloalkyl; and heterocycle; wherein said aryl, heteroaryl, C _3-9 cycloalkyl and heterocycle is substituted with one or more R ⁷ ; _{- each R} ⁷ _{is independently selected from halogen; hydroxyl; sulfhydryl; =O; =S; -OZ} ¹ _{; -SZ} ¹ _{; - SCF3; -SF5; -CF3; -OCF3; -CHF2; -OCHF2; -NZ} ³ _Z ⁴ _{; -NZ} ³ _C(O)Z ¹ _{; cyano; -C(O)Z} ² _{; --C(O)OZ} ¹ _; -C(O)NZ ³ Z ⁴ ; C _1-6 alkyl; C _3-9 cycloakyl; C _2-6 alkenyl; C _2-6 alkynyl; C _1-6 heteroalkyl; C _2-6 heteroalkenyl; C _2-6 heteroalkynyl; aryl; heteroaryl; heterocycle; arylC _1-6 alkyl; arylC _2-6 alkenyl; arylalkynyl; arylC _{1- 6} heteroalkyl; arylC _2-6 heteroalkenyl; arylC _2-6 heteroalkynyl; heteroarylC _1-6 alkyl; heteroarylC _{2- 6} alkenyl; heteroarylC _2-6 alkynyl; heteroarylC _1-6 heteroalkyl; heteroarylC _2-6 heteroalkenyl; heteroarylC _2-6 heteroalkynyl; heterocycle-C _1-6 alkyl; heterocycle-C _2-6 alkenyl; heterocycle-C _{2- 6} alkynyl; heterocycle-C _1-6 heteroalkyl; heterocycle-C _2-6 heteroalkenyl; and heterocycle-C _{2- 6} heteroalkynyl; wherein said C _1-6 alkyl, C _3-9 cycloakyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 heteroalkyl, C _{2- 6} heteroalkenyl, C _2-6 heteroalkynyl, aryl, heteroaryl, heterocycle, arylC _1-6 alkyl, arylC _{2- 6} alkenyl, arylalkynyl, arylC _1-6 heteroalkyl, arylC _2-6 heteroalkenyl, arylC _2-6 heteroalkynyl, heteroarylC _1-6 alkyl, heteroarylC _2-6 alkenyl, heteroarylC _2-6 alkynyl, heteroarylC _{1- 6} heteroalkyl, heteroarylC _2-6 heteroalkenyl, heteroarylC _2-6 heteroalkynyl, heterocycle- C _1-6 alkyl, heterocycle-C _2-6 alkenyl, heterocycle-C _2-6 alkynyl, heterocycle-C _{1- 6} heteroalkyl, heterocycle-C _2-6 heteroalkenyl and heterocycle-C _2-6 heteroalkynyl can be unsubstituted or substituted with one or more substituents selected from C _1-6 alkyl, C _3-9 cycloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, hydroxyl, =O, halogen, -SH, =S, -CF ₃ , -O-C _{1- 6} alkyl, -OCF ₃ , -CHF ₂ ; -OCHF ₂ , cyano, nitro, -C(O)OH, -NH ₂ , -NHC _1-6 alkyl, and -N(C _{1- 6} alkyl) ₂ ; - X ¹ is selected from CR ⁸ ; N; and NR ^8a ; whereby X ¹ can only be NR ^8a when X ² and/or X ⁴ are C=O or C=S; - X ² is selected from CR ⁹ ; N; and NR ^9a ; whereby X ² can only be NR ^9a when X ¹ and/or X ³ are C=O or C-SH; - X ³ is selected from CH; and N; - X ⁴ is selected from CH; and N; - X ⁵ is selected from -S(=O) ₂ -; -C(=O)-; and -CH ₂ -; -each R ^10a is independently selected from hydrogen; and C _1-4 alkyl ; -each R ^10b is independently selected from hydrogen; and C _1-4 alkyl wherein said alkyl can be unsubstituted or substituted with one or more substituents selected from C _1-6 alkyl, C _3-9 cycloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, hydroxyl, =O, halogen, -SH, =S, -CF ₃ , -O-C _1-6 alkyl, -OCF ₃ , -CHF ₂ ; -OCHF ₂ , cyano, nitro, -C(O)OH, -NH ₂ , -NHC _1-6 alkyl, and -N(C _1-6 alkyl) ₂ ; whereby maximally 2 of X ¹ , X ² , X ³ and X ⁴ can be a N (selected from N and NR ^8a for X ¹ , from N and NR ^9a for X ² , from N for X ³ , and from Nfor X ⁴ respectively) at the same time; - provided that at least one of R ⁸ and R ⁹ is not hydrogen, each R ⁸ and R ⁹ are independently _{selected from hydrogen; halogen; hydroxyl; sulfhydryl; =O; =S; -OZ} ^1a _{; -SZ} ^1a _{; -SCF3; -SF5; - S(O)Z} ^1a _{; -S(O)(NZ} ^3a _)Z ^1a _{; -S(NZ} ^3a _)(NZ ^3a _)Z ^1a _{; -S(O)2Z} ^2a _{; -S(O)2NZ} ^3a _Z ^4a _{; -CF3; -OCF3; - CHF2; -OCHF2; nitro; -NZ} ^3a _Z ^4a _{; -NZ} ^3a _S(O)2Z ^1a _{; -NZ} ^3a _C(O)Z ^1a _{; -NZ} ^3a _C(O)NZ ^3a _Z ^4a _{; cyano; -C(O)Z} ^2a _{; -C(O)OZ} ^1a _{; -C(O)NZ} ^3a _Z ^4a _{; -C(O)H; -P(O)Z} ^3a _Z ^4a _{; C1-6alkyl; C3-9cycloakyl;} C _2-6 alkenyl; C _2-6 alkynyl; C _1-6 heteroalkyl; C _2-6 heteroalkenyl; C _2-6 heteroalkynyl; aryl; heteroaryl; heterocycle; arylC _1-6 alkyl; arylC _2-6 alkenyl; arylC _2-6 alkynyl; arylC _1-6 heteroalkyl; arylC _{2- 6} heteroalkenyl; arylC _2-6 heteroalkynyl; heteroarylC _1-6 alkyl; heteroarylC _2-6 alkenyl; heteroarylC _{2- 6} alkynyl; heteroarylC _1-6 heteroalkyl; heteroarylC _2-6 heteroalkenyl; heteroarylC _2-6 heteroalkynyl; heterocycle-C _1-6 alkyl; heterocycle-C _2-6 alkenyl; heterocycle-C _2-6 alkynyl; heterocycle-C _{1- 6} heteroalkyl; heterocycle- C _2-6 heteroalkenyl; and heterocycle- C _2-6 heteroalkynyl; wherein said C _1-6 alkyl, C _3-9 cycloakyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 heteroalkyl, C _{2- 6} heteroalkenyl, C _2-6 heteroalkynyl, aryl, heteroaryl, heterocycle, arylC _1-6 alkyl, arylC _{2- 6} alkenyl, arylalkynyl, arylC _1-6 heteroalkyl, arylC _2-6 heteroalkenyl, arylC _2-6 heteroalkynyl, heteroarylC _1-6 alkyl, heteroarylC _2-6 alkenyl, heteroarylC _2-6 alkynyl, heteroarylC _{1- 6} heteroalkyl, heteroarylC _2-6 heteroalkenyl, heteroarylC _2-6 heteroalkynyl, heterocycle-C _{1- 6} alkyl, heterocycle-C _2-6 alkenyl, heterocycle-C _2-6 alkynyl, heterocycle-C _1-6 heteroalkyl, heterocycle-C _2-6 heteroalkenyl and heterocycle-C _2-6 heteroalkynyl can be unsubstituted or substituted with one or more substituents selected from C _1-6 alkyl, C _3-9 cycloalkyl, C _{2- 6} alkenyl, C _2-6 alkynyl, hydroxyl, =O, halogen, -SH, =S, -CF ₃ , -O-C _1-6 alkyl, -OCF ₃ , -CHF ₂ ; - OCHF ₂ , cyano, nitro, -C(O)OH, -NH ₂ , -NHC _1-6 alkyl, and -N(C _1-6 alkyl) ₂ ; _{- each R} ^8a _{and R} ^9a _{are independently selected from hydrogen; hydroxyl; sulfhydryl; -OZ} ^1a _{; - SZ} ^1a _{; -SCF3; -SF5; -S(O)Z} ^1a _{; -S(O)(NZ} ^3a _)Z ^1a _{; -S(NZ} ^3a _)(NZ ^3a _)Z ^1a _{; -S(O)2Z} ^2a _{; - S(O)2NZ} ^3a _Z ^4a _{; -CF3; -OCF3; -CHF2; -OCHF2; nitro; -NZ} ^3a _Z ^4a _{; -NZ} ^3a _S(O)2Z ^2a _{; - NZ} ^3a _C(O)Z ^1a _{; -NZ} ^3a _C(O)NZ ^3a _Z ^4a _{; cyano; -C(O)Z} ^2a _{; -C(O)OZ} ^1a _{; -C(O)NZ} ^3a _Z ^4a _{; -C(O)H;} -P(O)Z ^3a Z ^4a ; C _1-6 alkyl; C _3-9 cycloakyl; C _2-6 alkenyl; C _2-6 alkynyl; C _1-6 heteroalkyl; C _2-6 heteroalkenyl; C _2-6 heteroalkynyl; aryl; heteroaryl; heterocycle; arylC _1-6 alkyl; arylC _2-6 alkenyl; arylC _2-6 alkynyl; arylC _1-6 heteroalkyl; arylC _2-6 heteroalkenyl; arylC _2-6 heteroalkynyl; heteroarylC _1-6 alkyl; heteroarylC _2-6 alkenyl; heteroarylC _2-6 alkynyl; heteroarylC _1-6 heteroalkyl; heteroarylC _{2- 6} heteroalkenyl; heteroarylC _2-6 heteroalkynyl; heterocycle-C _1-6 alkyl; heterocycle-C _2-6 alkenyl; heterocycle-C _2-6 alkynyl; heterocycle-C _1-6 heteroalkyl; heterocycle- C _2-6 heteroalkenyl; and heterocycle- C _2-6 heteroalkynyl; wherein said C _1-6 alkyl, C _3-9 cycloakyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 heteroalkyl, C _{2- 6} heteroalkenyl, C _2-6 heteroalkynyl, aryl, heteroaryl, heterocycle, arylC _1-6 alkyl, arylC _{2- 6} alkenyl, arylalkynyl, arylC _1-6 heteroalkyl, arylC _2-6 heteroalkenyl, arylC _2-6 heteroalkynyl, heteroarylC _1-6 alkyl, heteroarylC _2-6 alkenyl, heteroarylC _2-6 alkynyl, heteroarylC _{1- 6} heteroalkyl, heteroarylC _2-6 heteroalkenyl, heteroarylC _2-6 heteroalkynyl, heterocycle-C _{1- 6} alkyl, heterocycle-C _2-6 alkenyl, heterocycle-C _2-6 alkynyl, heterocycle-C _1-6 heteroalkyl, heterocycle-C _2-6 heteroalkenyl and heterocycle-C _2-6 heteroalkynyl can be unsubstituted or substituted with one or more substituents selected from C _1-6 alkyl, C _3-9 cycloalkyl, C _{2- 6} alkenyl, C _2-6 alkynyl, hydroxyl, =O, halogen, -SH, =S, -CF ₃ , -O-C _1-6 alkyl, -OCF ₃ , -CHF ₂ ; - OCHF ₂ , cyano, nitro, -C(O)OH, -NH ₂ , -NHC _1-6 alkyl, and -N(C _1-6 alkyl) ₂ ; - each Z ¹ and Z ^1a is independently selected from C _1-6 alkyl; C _3-9 cycloakyl; C _2-6 alkenyl; C _{5- 9} cycloalkenyl; C _2-6 alkynyl; C _5-9 cycloalkynyl; C _1-6 heteroalkyl; C _2-6 heteroalkenyl; C _2-6 heteroalkynyl; aryl; heteroaryl; heterocycle; arylC _1-6 alkyl; arylC _2-6 alkenyl; arylC _2-6 alkynyl; arylC _1-6 heteroalkyl; arylC _2-6 heteroalkenyl; arylC _2-6 heteroalkynyl; heteroarylC _1-6 alkyl; heteroarylC _2-6 alkenyl; heteroarylC _2-6 alkynyl; heteroarylC _1-6 heteroalkyl; heteroarylC _2-6 heteroalkenyl; heteroarylC _{2- 6} heteroalkynyl; heterocycle-C _1-6 alkyl; heterocycle-C _2-6 alkenyl; heterocycle-C _2-6 alkynyl; heterocycle-C _1-6 heteroalkyl; heterocycle- C _2-6 heteroalkenyl; and heterocycle- C _2-6 heteroalkynyl; wherein said C _1-6 alkyl, C _3-9 cycloakyl, C _2-6 alkenyl, C _5- 9cycloalkenyl, C _2-6 alkynyl, C _{5- 9} cycloalkynyl, C _1-6 heteroalkyl, C _2-6 heteroalkenyl, C _2-6 heteroalkynyl, aryl, heteroaryl, heterocycle, arylC _1-6 alkyl, arylC _2-6 alkenyl, arylC _2-6 alkynyl, arylC _1-6 heteroalkyl, arylC _{2- 6} heteroalkenyl, arylC _2-6 heteroalkynyl, heteroarylC _1-6 alkyl, heteroarylC _2-6 alkenyl, heteroarylC _2-6 alkynyl, heteroarylC _1-6 heteroalkyl, heteroarylC _2-6 heteroalkenyl, heteroarylC _2-6 heteroalkynyl, heterocycle-C _1-6 alkyl, heterocycle-C _2-6 alkenyl, heterocycle-C _2-6 alkynyl, heterocycle-C _1-6 heteroalkyl, heterocycle- C _2-6 heteroalkenyl, and heterocycle- C _2-6 heteroalkynyl can be unsubstituted or substituted with one or more substituents selected from C _1-6 alkyl, C _3-9 cycloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, hydroxyl, =O, halogen, -SH, =S, -CF ₃ , -O-C _1-6 alkyl, -OCF ₃ , -CHF ₂ ; -OCHF ₂ , cyano, nitro, - C(O)OH, -NH ₂ , -NHC _1-6 alkyl, and -N(C _1-6 alkyl) ₂ ; - each Z ² and Z ^2a is independently selected from hydroxyl; C _1-6 alkyl; C _3-9 cycloakyl; C _2-6 alkenyl; C _5- 9cycloalkenyl; C _2-6 alkynyl; C _5-9 cycloalkynyl; C _1-6 heteroalkyl; C _2-6 heteroalkenyl; C _{2- 6} heteroalkynyl; aryl; heteroaryl; heterocycle; arylC _1-6 alkyl; arylC _2-6 alkenyl; arylC _2-6 alkynyl; arylC _1-6 heteroalkyl; arylC _2-6 heteroalkenyl; arylC _2-6 heteroalkynyl; heteroarylC _1-6 alkyl; heteroarylC _2-6 alkenyl; heteroarylC _2-6 alkynyl; heteroarylC _1-6 heteroalkyl; heteroarylC _{2- 6} heteroalkenyl; heteroarylC _2-6 heteroalkynyl; heterocycle-C _1-6 alkyl; heterocycle-C _2-6 alkenyl; heterocycle-C _2-6 alkynyl; heterocycle-C _1-6 heteroalkyl; heterocycle- C _2-6 heteroalkenyl; and heterocycle- C _2-6 heteroalkynyl; wherein said C _1-6 alkyl, C _3-9 cycloakyl, C _2-6 alkenyl, C _5- 9cycloalkenyl, C _2-6 alkynyl, C _{5- 9} cycloalkynyl, C _1-6 heteroalkyl, C _2-6 heteroalkenyl, C _2-6 heteroalkynyl, aryl, heteroaryl, heterocycle, arylC _1-6 alkyl, arylC _2-6 alkenyl, arylC _2-6 alkynyl, arylC _1-6 heteroalkyl, arylC _{2- 6} heteroalkenyl, arylC _2-6 heteroalkynyl, heteroarylC _1-6 alkyl, heteroarylC _2-6 alkenyl, heteroarylC _2-6 alkynyl, heteroarylC _1-6 heteroalkyl, heteroarylC _2-6 heteroalkenyl, heteroarylC _2-6 heteroalkynyl, heterocycle-C _1-6 alkyl, heterocycle-C _2-6 alkenyl, heterocycle- C _2-6 alkynyl, heterocycle-C _1-6 heteroalkyl, heterocycle- C _2-6 heteroalkenyl, and heterocycle- C _2-6 heteroalkynyl can be unsubstituted or substituted with one or more substituents selected from C _1-6 alkyl, C _3-9 cycloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, hydroxyl, =O, halogen, - S ^{H, =S, -CF} ₃ ^{, -O-C} _1-6 ^{alkyl, -OCF} ₃ ^{, -CHF} ₂ ^{, -OCHF} ₂ ^{, cyano, nitro, -C(O)OH; NH} _2; ^-NHC _{1- 6} alkyl, and -N(C _1-6 alkyl) ₂ ; - _{each Z} ³ _{, Z} ^3a _{, Z} ⁴ _{, and Z} ^4a _{is independently selected from hydrogen; C1-6alkyl; C3- 9} cycloakyl; C _2-6 alkenyl; C _5-9 cycloalkenyl; C _2-6 alkynyl; C _5-9 cycloalkynyl; C _1-6 heteroalkyl; C _2-6 heteroalkenyl; C _2-6 heteroalkynyl; aryl; heteroaryl; heterocycle; arylC _1-6 alkyl; arylC _{2- 6} alkenyl; arylC _2-6 alkynyl; arylC _1-6 heteroalkyl; arylC _2-6 heteroalkenyl; arylC _{2- 6} heteroalkynyl; heteroarylC _1-6 alkyl; heteroarylC _2-6 alkenyl; heteroarylC _2-6 alkynyl; heteroarylC _1-6 heteroalkyl; heteroarylC _2-6 heteroalkenyl; heteroarylC _2-6 heteroalkynyl; heterocycle-C _1-6 alkyl; heterocycle-C _2-6 alkenyl; heterocycle-C _2-6 alkynyl; heterocycle- C _1-6 heteroalkyl; heterocycle- C _2-6 heteroalkenyl; and heterocycle- C _2-6 heteroalkynyl; wherein said C _1-6 alkyl, C _3-9 cycloakyl, C _2-6 alkenyl, C _5-9 cycloalkenyl, C _2-6 alkynyl, C _5-9 cycloalkynyl, C _1-6 heteroalkyl, C _2-6 heteroalkenyl, C _2-6 heteroalkynyl, aryl, heteroaryl, heterocycle, arylC _1-6 alkyl, arylC _2-6 alkenyl, arylC _2-6 alkynyl, arylC _{1- 6} heteroalkyl, arylC _2-6 heteroalkenyl, arylC _2-6 heteroalkynyl, heteroarylC _1-6 alkyl, heteroarylC _2-6 alkenyl, heteroarylC _2-6 alkynyl, heteroarylC _1-6 heteroalkyl, heteroarylC _2-6 heteroalkenyl, heteroarylC _2-6 heteroalkynyl, heterocycle-C _1-6 alkyl, heterocycle-C _2-6 alkenyl, heterocycle-C _2-6 alkynyl, heterocycle-C _1-6 heteroalkyl, heterocycle- C _2-6 heteroalkenyl, and heterocycle- C _2-6 heteroalkynyl can be unsubstituted or substituted with one or more substituents selected from C _{1- 6} alkyl, C _3-9 cycloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, hydroxyl, =O, halogen, -SH, =S, - C ^F ₃ ^{, -O-C} _1-6 ^{alkyl, -OCF} ₃ ^{, -CHF} ₂ ^{, -OCHF} ₂ ^{, cyano, nitro, -C(O)OH; NH} _2; ^-NHC _{1- 6} alkyl, and -N(C _1-6 alkyl) ₂ ; and wherein each Z ³ and Z ⁴ or Z ^3a and Z ^4a can be taken together in order to form a (4-, 5-, 6-, or 7-membered) heterocycle which can be unsubstituted or substituted with one or more substituents selected from C _1-6 alkyl, C _3-9 cycloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, hydroxyl, =O, halogen, -SH, =S, - ^CF ₃ ^{, -O-C} _1-6 ^{alkyl, -OCF} ₃ ^{, -CHF} ₂ ^{, -OCHF} ₂ ^{, cyano, nitro, -C(O)OH; NH} _2; ^-NHC _1-6 ^{alkyl, and -N(C} _{1- 6} alkyl) ₂ . The compounds of the disclosure also are compounds of formula (I) and any subgroup thereof as described herein, a stereo-isomeric form, a tautomer, a salt (in particular a pharmaceutically acceptable salt), solvate, polymorph and/or prodrug thereof, wherein: - n is selected from 0; 1; and 2; - each represents an optional double bond, whereby maximally 3 are a double bond at the same time; - R ¹ is selected from alkyl; cycloalkyl; alkenyl; cycloalkenyl; alkynyl; cycloalkynyl; heteroalkyl; heteroalkenyl; heteroalkynyl; -C(O)H; -C(O)R ³ ; -C(O)OR ⁴ ; -C(O)NR ⁵ R ⁶ ; -S(O) ₂ R ^3a ; -S(O)R ^4a ; - ^S(O) ₂ ^{NR5aR6a; -S(O)(NR5a)R4a; -S(NR5a)(NR6a)R3a; and -P(O)R5bR6b;} wherein said alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, heteroalkyl, heteroalkenyl and heteroalkynyl can be unsubstituted or substituted with one or more substituents selected from alkyl, cycloalkyl, alkenyl, alkynyl, hydroxyl, =O, halogen, -SH, =S, trifluoromethyl, -O-alkyl, -OCF ₃ , cyano, nitro, -C(O)OH, -C(O)Oalkyl, -C(O)alkyl, - CONH ₂ , -CONHalkyl, -CON(alkyl) ₂ , -SO ₂ alkyl, -SO ₂ NH ₂ , -SO ₂ NHalkyl, -SO ₂ N(alkyl) ₂ , - S(O)(NH)alkyl, -S(O)(Nalkyl)alkyl, -S(NH)(NH)alkyl, -NH ₂ , -NHalkyl, -N(alkyl) ₂ ; - R ² is selected from hydrogen; alkyl; cycloalkyl; and heteroalkyl; - R ¹ and R ² can be taken together to form a (4-; 5-; 6- or 7-membered) heterocycle which can be unsubstituted or substituted with one or more substituents selected from alkyl, cycloalkyl, alkenyl, alkynyl, hydroxyl, =O, halogen, -SH, =S, trifluoromethyl, -O-alkyl, -OCF ₃ , cyano, nitro, -C(O)OH, -C(O)Oalkyl, -C(O)alkyl, -CONH ₂ , -CONHalkyl, -CON(alkyl) ₂ , - SO ₂ alkyl, -SO ₂ NH ₂ , -SO ₂ NHalkyl, -SO ₂ N(alkyl) ₂ , -S(O)(NH)alkyl, -S(O)(Nalkyl)alkyl, - S(NH)(NH)alkyl, -NH ₂ , -NHalkyl, -N(alkyl) ₂ ; - each R ³ and R ^3a is independently selected from hydroxyl; alkyl; cycloalkyl; alkenyl; cycloalkenyl; alkynyl; cycloalkynyl; heteroalkyl; heteroalkenyl; and heteroalkynyl; wherein said alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, heteroalkyl, heteroalkenyl and heteroalkynyl can be unsubstituted or substituted with one or more substituents selected from alkyl, cycloalkyl, alkenyl, alkynyl, hydroxyl, =O, halogen, -SH, = ^{S, -CF} ₃ ^{, -O-alkyl, -OCF} ₃ ^{, -CHF} ₂ ^{, -OCHF} ₂ ^{, cyano, nitro, -C(O)OH; NH} _2; ^{-NHalkyl, and -} N(alkyl) ₂ ; - each R ⁴ and R ^4a is independently selected from alkyl; alkenyl; cycloalkenyl; alkynyl; cycloalkyl; cycloalkynyl; heteroalkyl; heteroalkenyl; and heteroalkynyl; wherein said alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, heteroalkyl, heteroalkenyl and heteroalkynyl can be unsubstituted or substituted with one or more substituents selected from alkyl, cycloalkyl, alkenyl, alkynyl, hydroxyl, =O, halogen, - S ^{H, =S, -CF} ₃ ^{, -O-alkyl, -OCF} ₃ ^{, -CHF} ₂ ^{, -OCHF} ₂ ^{, cyano, nitro, -C(O)OH; NH} _2; ^-NHalkyl, and -N(alkyl) ₂ ; - each R ⁵ , R ^5a , R ^5b , R ⁶ , R ^6a and R ^6b is independently selected from hydrogen; alkyl; cycloalkyl; alkenyl; cycloalkenyl; alkynyl; cycloalkynyl; heteroalkyl; heteroalkenyl; and heteroalkynyl; wherein said alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, heteroalkyl, heteroalkenyl and heteroalkynyl can be unsubstituted or substituted with one or more substituents selected from alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, hydroxyl, =O, halogen, -SH, =S, - C ^F ₃ ^{, -O-alkyl, -OCF} ₃ ^{, -CHF} ₂ ^{, -OCHF} ₂ ^{, cyano, nitro, -C(O)OH; NH} _2; ^-NHalkyl, and -N(alkyl) ₂ ; and wherein each R ⁵ and R ⁶ or R ^5a and R ^6a can be taken together in order to form a (4-, 5-, 6-, or 7-membered) heterocycle which can be unsubstituted or substituted with one or more substituents selected from alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, hydroxyl, =O, halogen, -SH, =S, - C ^F ₃ ^{, -O-alkyl, -OCF} ₃ ^{, -CHF} ₂ ^{, -OCHF} ₂ ^{, cyano, nitro, -C(O)OH; NH} _2; ^-NHalkyl, and -N(alkyl) ₂ . - cycle A is selected from aryl; heteroaryl; cycloalkyl; and heterocycle; wherein said aryl, heteroaryl, cycloalkyl and heterocycle can be unsubstituted or substituted with one or more R ⁷ ; - _{each R} ⁷ _{is independently selected from halogen; hydroxyl; sulfhydryl; =O; =S; -OZ} ¹ _{; -SZ} ¹ _{; - SCF3; -SF5; -CF3; -OCF3; -CHF2; -OCHF2; -NZ} ³ _Z ⁴ _{; -NZ} ³ _C(O)Z ¹ _{; cyano; -C(O)Z} ² _{; -C(O)OZ} ¹ _; -C(O)NZ ³ Z ⁴ ; alkyl; cycloakyl; alkenyl; alkynyl; heteroalkyl; heteroalkenyl; heteroalkynyl; aryl; 35 heteroaryl; heterocycle; arylalkyl; arylalkenyl; arylalkynyl; arylheteroalkyl; arylheteroalkenyl; arylheteroalkynyl; heteroarylalkyl; heteroarylalkenyl; heteroarylalkynyl; heteroarylheteroalkyl; heteroarylheteroalkenyl; heteroarylheteroalkynyl; heterocycle-alkyl; heterocycle-alkenyl; heterocycle-alkynyl; heterocycle-heteroalkyl; heterocycle-heteroalkenyl; and heterocycle- heteroalkynyl; wherein said alkyl, cycloakyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, aryl, heteroaryl, heterocycle, arylalkyl, arylalkenyl, arylalkynyl, arylheteroalkyl, arylheteroalkenyl, arylheteroalkynyl, heteroarylalkyl, heteroarylalkenyl, heteroarylalkynyl, heteroarylheteroalkyl, heteroarylheteroalkenyl, heteroarylheteroalkynyl, heterocycle-alkyl, heterocycle-alkenyl, heterocycle-alkynyl, heterocycle-heteroalkyl, heterocycle-heteroalkenyl, or heterocycle-heteroalkynyl can be unsubstituted or substituted with one or more substituents selected from alkyl, cycloalkyl, alkenyl, alkynyl, hydroxyl, =O, halogen, -SH, =S, -CF ₃ , -O-alkyl, -OCF ₃ , - CHF ₂ ; -OCHF ₂ , cyano, nitro, -C(O)OH, -NH ₂ , -NHalkyl, and -N(alkyl) ₂ ; - X ¹ is selected from CR ⁸ ; N; and NR ^8a ; whereby X ¹ can only be NR ^8a when X ² and/or X ⁴ are C=O or C=S; - X ² is selected from CR ⁹ ; N; and NR ^9a ; whereby X ² can only be NR ^9a when X ¹ and/or X ³ are C=O or C-SH; - X ³ is selected from CH; and N; - X ⁴ is selected from C ^H ; and N; whereby maximally 2 of X ¹ , X ² , X ³ and X ⁴ can be a N (selected from N and NR ^8a for X ¹ , from N and NR ^9a for X ² , from N for X ³ , and from Nfor X ⁴ respectively) at the same time; - each R ⁸ and R ⁹ are independently selected from hydrogen; halogen; hydroxyl; sulfhydryl; =O; = _{S; -OZ} ^1a _{; -SZ} ^1a _{; -SCF3; -SF5; -S(O)Z} ^1a _{; -S(O)(NZ} ^3a _)Z ^1a _{; -S(NZ} ^3a _)(NZ ^3a _)Z ^1a _{; -S(O)2Z} ^2a _{; -S(O)2NZ} ^3a _Z ^4a _{; -CF3; -OCF3; -CHF2; -OCHF2; nitro; -NZ} ^3a _Z ^4a _{; -NZ} ^3a _S(O)2Z ^1a _{; - NZ} ^3a _C(O)Z ^1a _{; -NZ} ^3a _C(O)NZ ^3a _Z ^4a _{; cyano; -C(O)Z} ^2a _{; -C(O)OZ} ^1a _{; -C(O)NZ} ^3a _Z ^4a _{; -C(O)H;} -P(O)Z ^3a Z ^4a ; alkyl; cycloakyl; alkenyl; alkynyl; heteroalkyl; heteroalkenyl; heteroalkynyl; aryl; heteroaryl; heterocycle; arylalkyl; arylalkenyl; arylalkynyl; arylheteroalkyl; arylheteroalkenyl; arylheteroalkynyl; heteroarylalkyl; heteroarylalkenyl; heteroarylalkynyl; heteroarylheteroalkyl; heteroarylheteroalkenyl; heteroarylheteroalkynyl; heterocycle-alkyl; heterocycle-alkenyl; heterocycle-alkynyl; heterocycle-heteroalkyl; heterocycle-heteroalkenyl; and heterocycle- heteroalkynyl; wherein said alkyl, cycloakyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, aryl, heteroaryl, heterocycle, arylalkyl, arylalkenyl, arylalkynyl, arylheteroalkyl, arylheteroalkenyl, arylheteroalkynyl, heteroarylalkyl, heteroarylalkenyl, 35 heteroarylalkynyl, heteroarylheteroalkyl, heteroarylheteroalkenyl, heteroarylheteroalkynyl, heterocycle-alkyl, heterocycle-alkenyl, heterocycle-alkynyl, heterocycle-heteroalkyl, heterocycle-heteroalkenyl, or heterocycle-heteroalkynyl can be unsubstituted or substituted with one or more substituents selected from alkyl, cycloalkyl, alkenyl, alkynyl, hydroxyl, =O, halogen, -SH, =S, -CF ₃ , -O-alkyl, -OCF ₃ , -CHF ₂ ; -OCHF2, cyano, nitro, -C(O)OH, -NH ₂ , -NHalkyl, and -N(alkyl) ₂ ; _{- each R} ^8a _{and R} ^9a _{are independently selected from hydrogen; hydroxyl; sulfhydryl; -OZ} ^1a _{; - SZ} ^1a _{; -SCF3; -SF5; -S(O)Z} ^1a _{; -S(O)(NZ} ^3a _)Z ^1a _{; -S(NZ} ^3a _)(NZ ^3a _)Z ^1a _{; -S(O)2Z} ^2a _{; - S(O)2NZ} ^3a _Z ^4a _{; -CF3; -OCF3; -CHF2; -OCHF2; nitro; -NZ} ^3a _Z ^4a _{; -NZ} ^3a _S(O)2Z ^2a _{; - NZ} ^3a _C(O)Z ^1a _{; -NZ} ^3a _C(O)NZ ^3a _Z ^4a _{; cyano; -C(O)Z} ^2a _{; -C(O)OZ} ^1a _{; -C(O)NZ} ^3a _Z ^4a _{; -C(O)H;} -P(O)Z ^3a Z ^4a ; alkyl; cycloakyl; alkenyl; alkynyl; heteroalkyl; heteroalkenyl; heteroalkynyl; aryl; heteroaryl; heterocycle; arylalkyl; arylalkenyl; arylalkynyl; arylheteroalkyl; arylheteroalkenyl; arylheteroalkynyl; heteroarylalkyl; heteroarylalkenyl; heteroarylalkynyl; heteroarylheteroalkyl; heteroarylheteroalkenyl; heteroarylheteroalkynyl; heterocycle-alkyl; heterocycle-alkenyl; heterocycle-alkynyl; heterocycle-heteroalkyl; heterocycle-heteroalkenyl; and heterocycle- heteroalkynyl; wherein said alkyl, cycloakyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, aryl, heteroaryl, heterocycle, arylalkyl, arylalkenyl, arylalkynyl, arylheteroalkyl, arylheteroalkenyl, arylheteroalkynyl, heteroarylalkyl, heteroarylalkenyl, heteroarylalkynyl, heteroarylheteroalkyl, heteroarylheteroalkenyl, heteroarylheteroalkynyl, heterocycle-alkyl, heterocycle-alkenyl, heterocycle-alkynyl, heterocycle-heteroalkyl, heterocycle-heteroalkenyl, or heterocycle-heteroalkynyl can be unsubstituted or substituted with one or more substituents selected from alkyl, cycloalkyl, alkenyl, alkynyl, hydroxyl, =O, halogen, -SH, =S, -CF ₃ , -O-alkyl, -OCF ₃ , -CHF ₂ ; -OCHF2, cyano, nitro, -C(O)OH, -NH ₂ , -NHalkyl, and -N(alkyl) ₂ ; - each Z ¹ and Z ^1a is independently selected from alkyl; alkenyl; alkynyl; cycloalkynyl; heteroalkyl; heteroalkenyl; heteroalkynyl; aryl; heteroaryl; heterocycle; arylalkyl; arylalkenyl; arylalkynyl; arylheteroalkyl; arylheteroalkenyl; arylheteroalkynyl; heteroarylalkyl; heteroarylalkenyl; heteroarylalkynyl; heteroarylheteroalkyl; heteroarylheteroalkenyl; heteroarylheteroalkynyl; heterocycle-alkyl; heterocycle-alkenyl; heterocycle-alkynyl; heterocycle-heteroalkyl; heterocycle-heteroalkenyl; or heterocycle-heteroalkynyl; wherein said alkyl, cycloalkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, aryl, heteroaryl, heterocycle, arylalkyl, arylalkenyl, arylalkynyl, arylheteroalkyl, arylheteroalkenyl, arylheteroalkynyl, heteroarylalkyl, heteroarylalkenyl, heteroarylalkynyl, heteroarylheteroalkyl, heteroarylheteroalkenyl, heteroarylheteroalkynyl, heterocycle-alkyl, heterocycle-alkenyl, heterocycle-alkynyl, heterocycle-heteroalkyl, heterocycle-heteroalkenyl, or heterocycle-heteroalkynyl can be unsubstituted or substituted with one or more substituents selected from alkyl, c ^{ycloalkyl, alkenyl, alkynyl, hydroxyl, =O, halogen, -SH, =S, -CF} ₃ ^{, -O-alkyl, -OCF} ₃ ^{, - CHF} ₂ ^{, -OCHF} ₂ ^{, cyano, nitro, -C(O)OH; NH} _2; ^{-NHalkyl, and -N(alkyl)} ₂ ^; - each Z ² and Z ^2a is independently selected from hydroxyl; alkyl; cycloalkyl; alkenyl; alkynyl; heteroalkyl; heteroalkenyl; heteroalkynyl; aryl; heteroaryl; heterocycle; arylalkyl; arylalkenyl; arylalkynyl; arylheteroalkyl; arylheteroalkenyl; arylheteroalkynyl; heteroarylalkyl; heteroarylalkenyl; heteroarylalkynyl; heteroarylheteroalkyl; heteroarylheteroalkenyl; heteroarylheteroalkynyl; heterocycle-alkyl; heterocycle-alkenyl; heterocycle-alkynyl; heterocycle-heteroalkyl; heterocycle-heteroalkenyl; or heterocycle- heteroalkynyl; wherein said alkyl, cycloalkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, aryl, heteroaryl, heterocycle, arylalkyl, arylalkenyl, arylalkynyl, arylheteroalkyl, arylheteroalkenyl, arylheteroalkynyl, heteroarylalkyl, heteroarylalkenyl, heteroarylalkynyl, heteroarylheteroalkyl, heteroarylheteroalkenyl, heteroarylheteroalkynyl, heterocycle- alkyl, heterocycle-alkenyl, heterocycle- alkynyl, heterocycle-heteroalkyl, heterocycle- heteroalkenyl, or heterocycle-heteroalkynyl can be unsubstituted or substituted with one or more substituents selected from alkyl, cycloalkyl, alkenyl, alkynyl, hydroxyl, =O, h ^{alogen, -SH, =S, -CF} ₃ ^{, -O-alkyl, -OCF} ₃ ^{, -CHF} ₂ ^{, -OCHF} ₂ ^{, cyano, nitro, -C(O)OH; NH} _2; - NHalkyl, and -N(alkyl) ₂ ; _{- each Z} ³ _{, Z} ^3a _{, Z} ⁴ _{, and Z} ^4a _{is independently selected from hydrogen; alkyl; cycloalkyl;} alkenyl; alkynyl; heteroalkyl; heteroalkenyl; heteroalkynyl; aryl; heteroaryl; heterocycle; arylalkyl; arylalkenyl; arylalkynyl; arylheteroalkyl; arylheteroalkenyl; arylheteroalkynyl; heteroarylalkyl; heteroarylalkenyl; heteroarylalkynyl; heteroarylheteroalkyl; heteroarylheteroalkenyl; heteroarylheteroalkynyl; heterocycle-alkyl; heterocycle- alkenyl; heterocycle-alkynyl; heterocycle-heteroalkyl; heterocycle-heteroalkenyl; or heterocycle-heteroalkynyl; wherein said alkyl, cycloalkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, aryl, heteroaryl, heterocycle, cycloalkyl, arylalkyl, arylalkenyl, arylalkynyl, arylheteroalkyl, arylheteroalkenyl, arylheteroalkynyl, heteroarylalkyl, heteroarylalkenyl, heteroarylalkynyl, heteroarylheteroalkyl, heteroarylheteroalkenyl, heteroarylheteroalkynyl, heterocycle-alkyl, heterocycle-alkenyl, heterocycle-alkynyl, heterocycle-heteroalkyl, heterocycle- heteroalkenyl, or heterocycle-heteroalkynyl can be unsubstituted or substituted with one or more substituents selected from alkyl, cycloalkyl, alkenyl, alkynyl, ^{hydroxyl, =O, halogen, -SH, =S, -CF} ₃ ^{, -O-alkyl, -OCF} ₃ ^{, -CHF} ₂ ^{, -OCHF} ₂ ^{, cyano, nitro, -C(O)OH; NH} _2; ^{-NHalkyl, and -N(alkyl)} ₂ ^; and wherein each Z ³ and Z ⁴ or Z ^3a and Z ^4a can be taken together in order to form a (4-, 5-, 6-, or 7-membered) heterocycle which can be unsubstituted or substituted with one or more substituents selected from alkyl, cycloalkyl, a ^{lkenylalkynyl, hydroxyl, =O, halogen, -SH, =S, -CF} ₃ ^{, -O-alkyl, -OCF} ₃ ^{, -CHF} ₂ ^{, -OCHF} ₂ ^{, cyano, nitro, -C(O)OH; NH} _2; ^{-NHalkyl, and -N(alkyl)} ₂ ^. provided that the compounds are not selected from: - Acetamide, N-[1-(1-cyclopentyl-1H-tetrazol-5-yl)-1,2,3,4-tetrahydro-3qu inolinyl]-; - Acetamide, N-[(1,2,3,4-tetrahydro-1-phenyl-3-quinolinyl)methyl]-; - Propanamide, N-(1,2,3,4-tetrahydro-1-phenyl-3-quinolinyl)-; - Cyclopropanecarboxamide, N-[1,2,3,4-tetrahydro-1-(3-methoxyphenyl)-3-quinolinyl]- ; - Cyclohexaneacetamide, N-(6-cyano-1-cyclohexyl-1,2,3,4-tetrahydro-3-quinolinyl)-; - Carbamic acid, N-[1-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-3-quinolinyl]-, 1,1-dimethylethyl ester; Carbamic acid, N-[1-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-3-quinolinyl]-N -methyl-, 1,1- dimethylethyl ester; Carbamic acid, N-[(3S)-1-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-3- quinolinyl]-, 1,1-dimethylethyl ester; Carbamic acid, N-[(3R)-1-(3,4-dichlorophenyl)- 1,2,3,4-tetrahydro-3-quinolinyl]-, 1,1-dimethylethyl ester; Carbamic acid, N-(1,2,3,4-tetrahydro-1- phenyl-3-quinolinyl)-, 1,1-dimethylethyl ester ; - compounds wherein cycle A is N-[1-[1-(2,2-dimethylpropyl)-2,3-dihydro-3-methyl-2-oxo- 1Himidazo[4,5-b]pyridin-5-yl] or N-[1-[1-[(2,2-difluoro-1-methylcyclopropyl)methyl]-2,3-dihyd ro-3- methyl-2-oxo-1H-imidazo[4,5-b]pyridin-5-yl]; and - compounds wherein R ¹ is methyl or pentyl. Preferred or particular statements (features) and embodiments of the compounds of this disclosure are set herein below. Each statement, aspect and embodiment of the disclosure so defined may be combined with any other statement, aspect and/or embodiment, unless clearly indicated to the contrary. In particular, any feature indicated as being preferred, particular or advantageous may be combined with any other features or statements indicated as being preferred, particular or advantageous. Hereto, the present disclosure is in particular captured by any one or any combination of one or more of the below numbered statements and embodiments, with any other statement, aspect and/or embodiment (which are not numbered). 1. A compound of Formula (Ia), or an isomer (preferably a stereo-isomer or a tautomer), a solvate, a salt (preferably a pharmaceutically acceptable salt) or a prodrug thereof, preferably a pharmaceutically acceptable salt, solvate, hydrate, polymorph, tautomer, stereoisomer, or prodrug thereof, wherein: -E is selected from (5-membered) heterocycle which can be unsubstituted or substituted with one or more substituents selected from C _1-6 alkyl, C _3-9 cycloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, hydroxyl, =O, halogen, -SH, =S, trifluoromethyl, -O-C _1-6 alkyl, -OCF ₃ , cyano, nitro, -C(O)OH, -C(O)OC _1-6 alkyl, - C(O)C _1-6 alkyl, -CONH ₂ , -CONHC _1-6 alkyl, -CON(C _1-6 alkyl) ₂ , -SO ₂ C _1-6 alkyl, -SO ₂ NH ₂ , -SO ₂ NHC _{1- 6} alkyl, -SO ₂ N(C _1-6 alkyl) ₂ , -S(O)(NH)C1-6alkyl, -S(O)(NC1-6alkyl)C1-6alkyl, -S(NH)(NH)C1- 6alkyl,-NH ₂ , -NHC _1-6 alkyl, and -N(C _1-6 alkyl) ₂ ; and -(CR ^10a R ^10b ) _n -NR ¹ R ² ; - n is selected from 0; 1; and 2; - m is selected from 0; and 1; - each represents an optional double bond, whereby maximally 3 are a double bond at the same time; - R ¹ is selected from C _1-6 alkyl; C _3-9 cycloalkyl; C _2-6 alkenyl; C _5-9 cycloalkenyl; C _2-6 alkynyl; C _{5- 9} cycloalkynyl; C _1-6 heteroalkyl; C _2-6 heteroalkenyl; C _2-6 heteroalkynyl; -C(O)H; -C(O)R ³ ; -C(O)OR ⁴ ; -C(O)NR ⁵ R ⁶ ; -S(O) ₂ R ^3a ; -S(O)R ^4a ; -S(O) ₂ NR ^5a R ^6a ; -S(O)(NR ^5a )R ^4a ; -S(NR ^5a )(NR ^6a )R ^3a ; and - P(O)R ^5b R ^6b ; wherein said C _1-6 alkyl, C _3-9 cycloalkyl, C _2-6 alkenyl, C _5-9 cycloalkenyl, C _2-6 alkynyl, C _{5- 9} cycloalkynyl, C _1-6 heteroalkyl, C _2-6 heteroalkenyl and C _2-6 heteroalkynyl can be unsubstituted or substituted with one or more substituents selected from C _1-6 alkyl, C _{3- 9} cycloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, hydroxyl, =O, halogen, -SH, =S, trifluoromethyl, -O- C _1-6 alkyl, -OCF ₃ , cyano, nitro, -C(O)OH, -C(O)OC _1-6 alkyl, -C(O)C _1-6 alkyl, -CONH ₂ , - CONHC _1-6 alkyl, -CON(C _1-6 alkyl) ₂ , -SO ₂ C _1-6 alkyl, -SO ₂ NH ₂ , -SO ₂ NHC _1-6 alkyl, -SO ₂ N(C _{1- 6} alkyl) ₂ , -S(O)(NH)C _1-6 alkyl, -S(O)(NC _1-6 alkyl)C _1-6 alkyl, -S(NH)(NH)C _1-6 alkyl, - S(O)(NH)C1-6alkyl, -S(O)(NC1-6alkyl)C1-6alkyl, -S(O) ₂ OH, -S(NH)(NH)C1-6alkyl, -NH ₂ , -NHC _1-6 alkyl, -N(C _1-6 alkyl) ₂ ; - R ² is selected from hydrogen; C _1-6 alkyl; C _3-9 cycloalkyl; and C _1-6 heteroalkyl; - R ¹ and R ² can be taken together to form a (4-; 5-; 6- or 7-membered) heterocycle which can be unsubstituted or substituted with one or more substituents selected from C _1-6 alkyl, C _3-9 cycloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, hydroxyl, =O, halogen, -SH, =S, trifluoromethyl, -O- C _1-6 alkyl, -OCF ₃ , cyano, nitro, -C(O)OH, -C(O)OC _1-6 alkyl, -C(O)C _1-6 alkyl, -CONH ₂ , - CONHC _1-6 alkyl, -CON(C _1-6 alkyl) ₂ , -SO ₂ C _1-6 alkyl, -SO ₂ NH ₂ , -SO ₂ NHC _1-6 alkyl, -SO ₂ N(C _{1- 6} alkyl) ₂ , -S(O)(NH)C1-6alkyl, -S(O)(NC1-6alkyl)C1-6alkyl, -S(NH)(NH)C1-6alkyl,-NH ₂ , - NHC _1-6 alkyl, -N(C _1-6 alkyl) ₂ ; - each R ³ and R ^3a is independently selected from hydroxyl; C _1-6 alkyl; C _3-9 cycloalkyl; C _{2- 6} alkenyl; C _5-9 cycloalkenyl; C _2-6 alkynyl; C _5-9 cycloalkynyl; C _1-6 heteroalkyl; C _2-6 heteroalkenyl; and C _2-6 heteroalkynyl; wherein said C _1-6 alkyl, C _3-9 cycloalkyl, C _2-6 alkenyl, C _5-9 cycloalkenyl, C _2-6 alkynyl, C _{5- 9} cycloalkynyl, C _1-6 heteroalkyl, C _2-6 heteroalkenyl and C _2-6 heteroalkynyl can be unsubstituted or substituted with one or more substituents selected from alkyl, cycloalkyl, a ^{lkenyl, alkynyl, hydroxyl, =O, halogen, -SH, =S, -CF} ₃ ^{, -O-alkyl, -OCF} ₃ ^{, -CHF} ₂ ^{, -OCHF} ₂ ^{, cyano, nitro, -C(O)OH; NH} _2; ^{-NHalkyl, and -N(alkyl)} ₂ ^; - each R ⁴ and R ^4a is independently selected from C _1-6 alkyl; C _3-9 cycloalkyl; C _2-6 alkenyl; C _{5- 9} cycloalkenyl; C _2-6 alkynyl; C _5-9 cycloalkynyl; C _1-6 heteroalkyl; C _2-6 heteroalkenyl; and C _{2- 6} heteroalkynyl; wherein said C _1-6 alkyl, C _3-9 cycloalkyl, C _2-6 alkenyl, C _5-9 cycloalkenyl, C _2-6 alkynyl, C _{5- 9} cycloalkynyl, C _1-6 heteroalkyl, C _2-6 heteroalkenyl and C _2-6 heteroalkynyl can be unsubstituted or substituted with one or more substituents selected from alkyl, c ^{ycloalkyl, alkenyl, alkynyl, hydroxyl, =O, halogen, -SH, =S, -CF} ₃ ^{, -O-alkyl, -OCF} ₃ ^{, - CHF} ₂ ^{, -OCHF} ₂ ^{, cyano, nitro, -C(O)OH; NH} _2; ^{-NHalkyl, and -N(alkyl)} ₂ ^; - each R ⁵ , R ^5a , R ^5b , R ⁶ , R ^6a and R ^6b is independently selected from hydrogen; C _1-6 alkyl; C _{3- 9} cycloalkyl; C _2-6 alkenyl; C _5-9 cycloalkenyl; C _2-6 alkynyl; C _5-9 cycloalkynyl; C _1-6 heteroalkyl; C _{2- 6} heteroalkenyl; and C _2-6 heteroalkynyl; wherein said C _1-6 alkyl, C _3-9 cycloalkyl, C _2-6 alkenyl, C _5-9 cycloalkenyl, C _2-6 alkynyl, C _5-9 cycloalkynyl, C _1-6 heteroalkyl, C _2-6 heteroalkenyl and C _2-6 heteroalkynyl can be unsubstituted or substituted with one or more substituents selected from alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, hydroxyl, =O, halogen, - S ^{H, =S, -CF} ₃ ^{, -O-alkyl, -OCF} ₃ ^{, -CHF} ₂ ^{, -OCHF} ₂ ^{, cyano, nitro, -C(O)OH; NH} _2; - NHalkyl, and -N(alkyl) ₂ ; and wherein each R ⁵ and R ⁶ or R ^5a and R ^6a can be taken together in order to form a (4-, 5-, 6-, or 7-membered) heterocycle which can be unsubstituted or substituted with one or more substituents selected from alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, hydroxyl, =O, halogen, -SH, =S, -CF ₃ , -O- a ^{lkyl, -OCF} ₃ ^{, -CHF} ₂ ^{, -OCHF} ₂ ^{, cyano, nitro, -C(O)OH; NH} _2; ^{-NHalkyl, and -} N(alkyl) ₂ ; - cycle A is selected from aryl; heteroaryl; C _3-9 cycloalkyl; and heterocycle; wherein said aryl, heteroaryl, C _3-9 cycloalkyl and heterocycle is substituted with one or more R ⁷ ; _{- each R} ⁷ _{is independently selected from halogen; hydroxyl; sulfhydryl; =O; =S; -OZ} ¹ _{; -SZ} ¹ _{; - SCF3; -SF5; -CF3; -OCF3; -CHF2; -OCHF2; -NZ} ³ _Z ⁴ _{; -NZ} ³ _C(O)Z ¹ _{; cyano; -C(O)Z} ² _{; --C(O)OZ} ¹ _; -C(O)NZ ³ Z ⁴ ; C _1-6 alkyl; C _3-9 cycloakyl; C _2-6 alkenyl; C _2-6 alkynyl; C _1-6 heteroalkyl; C _2-6 heteroalkenyl; C _2-6 heteroalkynyl; aryl; heteroaryl; heterocycle; arylC _1-6 alkyl; arylC _2-6 alkenyl; arylalkynyl; arylC _{1- 6} heteroalkyl; arylC _2-6 heteroalkenyl; arylC _2-6 heteroalkynyl; heteroarylC _1-6 alkyl; heteroarylC _{2- 6} alkenyl; heteroarylC _2-6 alkynyl; heteroarylC _1-6 heteroalkyl; heteroarylC _2-6 heteroalkenyl; heteroarylC _2-6 heteroalkynyl; heterocycle-C _1-6 alkyl; heterocycle-C _2-6 alkenyl; heterocycle-C _{2- 6} alkynyl; heterocycle-C _1-6 heteroalkyl; heterocycle-C _2-6 heteroalkenyl; and heterocycle-C _{2- 6} heteroalkynyl; wherein said C _1-6 alkyl, C _3-9 cycloakyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 heteroalkyl, C _{2- 6} heteroalkenyl, C _2-6 heteroalkynyl, aryl, heteroaryl, heterocycle, arylC _1-6 alkyl, arylC _{2- 6} alkenyl, arylalkynyl, arylC _1-6 heteroalkyl, arylC _2-6 heteroalkenyl, arylC _2-6 heteroalkynyl, heteroarylC _1-6 alkyl, heteroarylC _2-6 alkenyl, heteroarylC _2-6 alkynyl, heteroarylC _{1- 6} heteroalkyl, heteroarylC _2-6 heteroalkenyl, heteroarylC _2-6 heteroalkynyl, heterocycle- C _1-6 alkyl, heterocycle-C _2-6 alkenyl, heterocycle-C _2-6 alkynyl, heterocycle-C _{1- 6} heteroalkyl, heterocycle-C _2-6 heteroalkenyl and heterocycle-C _2-6 heteroalkynyl can be unsubstituted or substituted with one or more substituents selected from C _1-6 alkyl, C _3-9 cycloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, hydroxyl, =O, halogen, -SH, =S, -CF ₃ , -O-C _{1- 6} alkyl, -OCF ₃ , -CHF ₂ ; -OCHF ₂ , cyano, nitro, -C(O)OH, -NH ₂ , -NHC _1-6 alkyl, and -N(C _{1- 6} alkyl) ₂ ; - X ¹ is selected from CR ⁸ ; N; and NR ^8a ; whereby X ¹ can only be NR ^8a when X ² and/or X ⁴ are C=O or C=S; - X ² is selected from CR ⁹ ; N; and NR ^9a ; whereby X ² can only be NR ^9a when X ¹ and/or X ³ are C=O or C-SH; - X ³ is selected from CH; and N; - X ⁴ is selected from CH; and N; - X ⁵ is selected from -S(=O) ₂ -; -C(=O)-; and -CH ₂ -; -each R ^10a is independently selected from hydrogen; and C _1-4 alkyl ; -each R ^10b is independently selected from hydrogen; and C _1-4 alkyl wherein said alkyl can be unsubstituted or substituted with one or more substituents selected from C _1-6 alkyl, C _3-9 cycloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, hydroxyl, =O, halogen, -SH, =S, -CF ₃ , -O-C _1-6 alkyl, -OCF ₃ , -CHF ₂ ; -OCHF ₂ , cyano, nitro, -C(O)OH, -NH ₂ , -NHC _1-6 alkyl, and -N(C _1-6 alkyl) ₂ ; whereby maximally 2 of X ¹ , X ² , X ³ and X ⁴ can be a N (selected from N and NR ^8a for X ¹ , from N and NR ^9a for X ² , from N for X ³ , and from Nfor X ⁴ respectively) at the same time; - provided that at least one of R ⁸ and R ⁹ is not hydrogen, each R ⁸ and R ⁹ are independently _{selected from hydrogen; halogen; hydroxyl; sulfhydryl; =O; =S; -OZ} ^1a _{; -SZ} ^1a _{; -SCF3; -SF5; - S(O)Z} ^1a _{; -S(O)(NZ} ^3a _)Z ^1a _{; -S(NZ} ^3a _)(NZ ^3a _)Z ^1a _{; -S(O)2Z} ^2a _{; -S(O)2NZ} ^3a _Z ^4a _{; -CF3; -OCF3; - CHF2; -OCHF2; nitro; -NZ} ^3a _Z ^4a _{; -NZ} ^3a _S(O)2Z ^1a _{; -NZ} ^3a _C(O)Z ^1a _{; -NZ} ^3a _C(O)NZ ^3a _Z ^4a _{; cyano; -C(O)Z} ^2a _{; -C(O)OZ} ^1a _{; -C(O)NZ} ^3a _Z ^4a _{; -C(O)H; -P(O)Z} ^3a _Z ^4a _{; C1-6alkyl; C3-9cycloakyl;} C _2-6 alkenyl; C _2-6 alkynyl; C _1-6 heteroalkyl; C _2-6 heteroalkenyl; C _2-6 heteroalkynyl; aryl; heteroaryl; heterocycle; arylC _1-6 alkyl; arylC _2-6 alkenyl; arylC _2-6 alkynyl; arylC _1-6 heteroalkyl; arylC _{2- 6} heteroalkenyl; arylC _2-6 heteroalkynyl; heteroarylC _1-6 alkyl; heteroarylC _2-6 alkenyl; heteroarylC _{2- 6} alkynyl; heteroarylC _1-6 heteroalkyl; heteroarylC _2-6 heteroalkenyl; heteroarylC _2-6 heteroalkynyl; heterocycle-C _1-6 alkyl; heterocycle-C _2-6 alkenyl; heterocycle-C _2-6 alkynyl; heterocycle-C _{1- 6} heteroalkyl; heterocycle- C _2-6 heteroalkenyl; and heterocycle- C _2-6 heteroalkynyl; wherein said C _1-6 alkyl, C _3-9 cycloakyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 heteroalkyl, C _{2- 6} heteroalkenyl, C _2-6 heteroalkynyl, aryl, heteroaryl, heterocycle, arylC _1-6 alkyl, arylC _{2- 6} alkenyl, arylalkynyl, arylC _1-6 heteroalkyl, arylC _2-6 heteroalkenyl, arylC _2-6 heteroalkynyl, heteroarylC _1-6 alkyl, heteroarylC _2-6 alkenyl, heteroarylC _2-6 alkynyl, heteroarylC _{1- 6} heteroalkyl, heteroarylC _2-6 heteroalkenyl, heteroarylC _2-6 heteroalkynyl, heterocycle-C _{1- 6} alkyl, heterocycle-C _2-6 alkenyl, heterocycle-C _2-6 alkynyl, heterocycle-C _1-6 heteroalkyl, heterocycle-C _2-6 heteroalkenyl and heterocycle-C _2-6 heteroalkynyl can be unsubstituted or substituted with one or more substituents selected from C _1-6 alkyl, C _3-9 cycloalkyl, C _{2- 6} alkenyl, C _2-6 alkynyl, hydroxyl, =O, halogen, -SH, =S, -CF ₃ , -O-C _1-6 alkyl, -OCF ₃ , -CHF ₂ ; - OCHF ₂ , cyano, nitro, -C(O)OH, -NH ₂ , -NHC _1-6 alkyl, and -N(C _1-6 alkyl) ₂ ; _{- each R} ^8a _{and R} ^9a _{are independently selected from hydrogen; hydroxyl; sulfhydryl; -OZ} ^1a _{; - SZ} ^1a _{; -SCF3; -SF5; -S(O)Z} ^1a _{; -S(O)(NZ} ^3a _)Z ^1a _{; -S(NZ} ^3a _)(NZ ^3a _)Z ^1a _{; -S(O)2Z} ^2a _{; - S(O)2NZ} ^3a _Z ^4a _{; -CF3; -OCF3; -CHF2; -OCHF2; nitro; -NZ} ^3a _Z ^4a _{; -NZ} ^3a _S(O)2Z ^2a _{; - NZ} ^3a _C(O)Z ^1a _{; -NZ} ^3a _C(O)NZ ^3a _Z ^4a _{; cyano; -C(O)Z} ^2a _{; -C(O)OZ} ^1a _{; -C(O)NZ} ^3a _Z ^4a _{; -C(O)H;} -P(O)Z ^3a Z ^4a ; C _1-6 alkyl; C _3-9 cycloakyl; C _2-6 alkenyl; C _2-6 alkynyl; C _1-6 heteroalkyl; C _2-6 heteroalkenyl; C _2-6 heteroalkynyl; aryl; heteroaryl; heterocycle; arylC _1-6 alkyl; arylC _2-6 alkenyl; arylC _2-6 alkynyl; arylC _1-6 heteroalkyl; arylC _2-6 heteroalkenyl; arylC _2-6 heteroalkynyl; heteroarylC _1-6 alkyl; heteroarylC _2-6 alkenyl; heteroarylC _2-6 alkynyl; heteroarylC _1-6 heteroalkyl; heteroarylC _{2- 6} heteroalkenyl; heteroarylC _2-6 heteroalkynyl; heterocycle-C _1-6 alkyl; heterocycle-C _2-6 alkenyl; heterocycle-C _2-6 alkynyl; heterocycle-C _1-6 heteroalkyl; heterocycle- C _2-6 heteroalkenyl; and heterocycle- C _2-6 heteroalkynyl; wherein said C _1-6 alkyl, C _3-9 cycloakyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 heteroalkyl, C _{2- 6} heteroalkenyl, C _2-6 heteroalkynyl, aryl, heteroaryl, heterocycle, arylC _1-6 alkyl, arylC _{2- 6} alkenyl, arylalkynyl, arylC _1-6 heteroalkyl, arylC _2-6 heteroalkenyl, arylC _2-6 heteroalkynyl, heteroarylC _1-6 alkyl, heteroarylC _2-6 alkenyl, heteroarylC _2-6 alkynyl, heteroarylC _{1- 6} heteroalkyl, heteroarylC _2-6 heteroalkenyl, heteroarylC _2-6 heteroalkynyl, heterocycle-C _{1- 6} alkyl, heterocycle-C _2-6 alkenyl, heterocycle-C _2-6 alkynyl, heterocycle-C _1-6 heteroalkyl, heterocycle-C _2-6 heteroalkenyl and heterocycle-C _2-6 heteroalkynyl can be unsubstituted or substituted with one or more substituents selected from C _1-6 alkyl, C _3-9 cycloalkyl, C _{2- 6} alkenyl, C _2-6 alkynyl, hydroxyl, =O, halogen, -SH, =S, -CF ₃ , -O-C _1-6 alkyl, -OCF ₃ , -CHF ₂ ; - OCHF ₂ , cyano, nitro, -C(O)OH, -NH ₂ , -NHC _1-6 alkyl, and -N(C _1-6 alkyl) ₂ ; - each Z ¹ and Z ^1a is independently selected from C _1-6 alkyl; C _3-9 cycloakyl; C _2-6 alkenyl; C _{5- 9} cycloalkenyl; C _2-6 alkynyl; C _5-9 cycloalkynyl; C _1-6 heteroalkyl; C _2-6 heteroalkenyl; C _2-6 heteroalkynyl; aryl; heteroaryl; heterocycle; arylC _1-6 alkyl; arylC _2-6 alkenyl; arylC _2-6 alkynyl; arylC _1-6 heteroalkyl; arylC _2-6 heteroalkenyl; arylC _2-6 heteroalkynyl; heteroarylC _1-6 alkyl; heteroarylC _2-6 alkenyl; heteroarylC _2-6 alkynyl; heteroarylC _1-6 heteroalkyl; heteroarylC _2-6 heteroalkenyl; heteroarylC _{2- 6} heteroalkynyl; heterocycle-C _1-6 alkyl; heterocycle-C _2-6 alkenyl; heterocycle-C _2-6 alkynyl; heterocycle-C _1-6 heteroalkyl; heterocycle- C _2-6 heteroalkenyl; and heterocycle- C _2-6 heteroalkynyl; wherein said C _1-6 alkyl, C _3-9 cycloakyl, C _2-6 alkenyl, C _5- 9cycloalkenyl, C _2-6 alkynyl, C _{5- 9} cycloalkynyl, C _1-6 heteroalkyl, C _2-6 heteroalkenyl, C _2-6 heteroalkynyl, aryl, heteroaryl, heterocycle, arylC _1-6 alkyl, arylC _2-6 alkenyl, arylC _2-6 alkynyl, arylC _1-6 heteroalkyl, arylC _{2- 6} heteroalkenyl, arylC _2-6 heteroalkynyl, heteroarylC _1-6 alkyl, heteroarylC _2-6 alkenyl, heteroarylC _2-6 alkynyl, heteroarylC _1-6 heteroalkyl, heteroarylC _2-6 heteroalkenyl, heteroarylC _2-6 heteroalkynyl, heterocycle-C _1-6 alkyl, heterocycle-C _2-6 alkenyl, heterocycle-C _2-6 alkynyl, heterocycle-C _1-6 heteroalkyl, heterocycle- C _2-6 heteroalkenyl, and heterocycle- C _2-6 heteroalkynyl can be unsubstituted or substituted with one or more substituents selected from C _1-6 alkyl, C _3-9 cycloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, hydroxyl, =O, halogen, -SH, =S, -CF ₃ , -O-C _1-6 alkyl, -OCF ₃ , -CHF ₂ ; -OCHF ₂ , cyano, nitro, - C(O)OH, -NH ₂ , -NHC _1-6 alkyl, and -N(C _1-6 alkyl) ₂ ; - each Z ² and Z ^2a is independently selected from hydroxyl; C _1-6 alkyl; C _3-9 cycloakyl; C _2-6 alkenyl; C _5- 9cycloalkenyl; C _2-6 alkynyl; C _5-9 cycloalkynyl; C _1-6 heteroalkyl; C _2-6 heteroalkenyl; C _{2- 6} heteroalkynyl; aryl; heteroaryl; heterocycle; arylC _1-6 alkyl; arylC _2-6 alkenyl; arylC _2-6 alkynyl; arylC _1-6 heteroalkyl; arylC _2-6 heteroalkenyl; arylC _2-6 heteroalkynyl; heteroarylC _1-6 alkyl; heteroarylC _2-6 alkenyl; heteroarylC _2-6 alkynyl; heteroarylC _1-6 heteroalkyl; heteroarylC _{2- 6} heteroalkenyl; heteroarylC _2-6 heteroalkynyl; heterocycle-C _1-6 alkyl; heterocycle-C _2-6 alkenyl; heterocycle-C _2-6 alkynyl; heterocycle-C _1-6 heteroalkyl; heterocycle- C _2-6 heteroalkenyl; and heterocycle- C _2-6 heteroalkynyl; wherein said C _1-6 alkyl, C _3-9 cycloakyl, C _2-6 alkenyl, C _5- 9cycloalkenyl, C _2-6 alkynyl, C _{5- 9} cycloalkynyl, C _1-6 heteroalkyl, C _2-6 heteroalkenyl, C _2-6 heteroalkynyl, aryl, heteroaryl, heterocycle, arylC _1-6 alkyl, arylC _2-6 alkenyl, arylC _2-6 alkynyl, arylC _1-6 heteroalkyl, arylC _{2- 6} heteroalkenyl, arylC _2-6 heteroalkynyl, heteroarylC _1-6 alkyl, heteroarylC _2-6 alkenyl, heteroarylC _2-6 alkynyl, heteroarylC _1-6 heteroalkyl, heteroarylC _2-6 heteroalkenyl, heteroarylC _2-6 heteroalkynyl, heterocycle-C _1-6 alkyl, heterocycle-C _2-6 alkenyl, heterocycle- C _2-6 alkynyl, heterocycle-C _1-6 heteroalkyl, heterocycle- C _2-6 heteroalkenyl, and heterocycle- C _2-6 heteroalkynyl can be unsubstituted or substituted with one or more substituents selected from C _1-6 alkyl, C _3-9 cycloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, hydroxyl, =O, halogen, - S ^{H, =S, -CF} ₃ ^{, -O-C} _1-6 ^{alkyl, -OCF} ₃ ^{, -CHF} ₂ ^{, -OCHF} ₂ ^{, cyano, nitro, -C(O)OH; NH} _2; ^-NHC _{1- 6} alkyl, and -N(C _1-6 alkyl) ₂ ; - _{each Z} ³ _{, Z} ^3a _{, Z} ⁴ _{, and Z} ^4a _{is independently selected from hydrogen; C1-6alkyl; C3- 9} cycloakyl; C _2-6 alkenyl; C _5-9 cycloalkenyl; C _2-6 alkynyl; C _5-9 cycloalkynyl; C _1-6 heteroalkyl; C _2-6 heteroalkenyl; C _2-6 heteroalkynyl; aryl; heteroaryl; heterocycle; arylC _1-6 alkyl; arylC _{2- 6} alkenyl; arylC _2-6 alkynyl; arylC _1-6 heteroalkyl; arylC _2-6 heteroalkenyl; arylC _{2- 6} heteroalkynyl; heteroarylC _1-6 alkyl; heteroarylC _2-6 alkenyl; heteroarylC _2-6 alkynyl; heteroarylC _1-6 heteroalkyl; heteroarylC _2-6 heteroalkenyl; heteroarylC _2-6 heteroalkynyl; heterocycle-C _1-6 alkyl; heterocycle-C _2-6 alkenyl; heterocycle-C _2-6 alkynyl; heterocycle- C _1-6 heteroalkyl; heterocycle- C _2-6 heteroalkenyl; and heterocycle- C _2-6 heteroalkynyl; wherein said C _1-6 alkyl, C _3-9 cycloakyl, C _2-6 alkenyl, C _5-9 cycloalkenyl, C _2-6 alkynyl, C _5-9 cycloalkynyl, C _1-6 heteroalkyl, C _2-6 heteroalkenyl, C _2-6 heteroalkynyl, aryl, heteroaryl, heterocycle, arylC _1-6 alkyl, arylC _2-6 alkenyl, arylC _2-6 alkynyl, arylC _{1- 6} heteroalkyl, arylC _2-6 heteroalkenyl, arylC _2-6 heteroalkynyl, heteroarylC _1-6 alkyl, heteroarylC _2-6 alkenyl, heteroarylC _2-6 alkynyl, heteroarylC _1-6 heteroalkyl, heteroarylC _2-6 heteroalkenyl, heteroarylC _2-6 heteroalkynyl, heterocycle-C _1-6 alkyl, heterocycle-C _2-6 alkenyl, heterocycle-C _2-6 alkynyl, heterocycle-C _1-6 heteroalkyl, heterocycle- C _2-6 heteroalkenyl, and heterocycle- C _2-6 heteroalkynyl can be unsubstituted or substituted with one or more substituents selected from C _{1- 6} alkyl, C _3-9 cycloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, hydroxyl, =O, halogen, -SH, =S, - C ^F ₃ ^{, -O-C} _1-6 ^{alkyl, -OCF} ₃ ^{, -CHF} ₂ ^{, -OCHF} ₂ ^{, cyano, nitro, -C(O)OH; NH} _2; ^-NHC _{1- 6} alkyl, and -N(C _1-6 alkyl) ₂ ; and wherein each Z ³ and Z ⁴ or Z ^3a and Z ^4a can be taken together in order to form a (4-, 5-, 6-, or 7-membered) heterocycle which can be unsubstituted or substituted with one or more substituents selected from C _1-6 alkyl, C _3-9 cycloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, hydroxyl, =O, h ^{alogen, -SH, =S, -CF} ₃ ^{, -O-C} _1-6 ^{alkyl, -OCF} ₃ ^{, -CHF} ₂ ^{, -OCHF} ₂ ^{, cyano, nitro, -C(O)OH; NH} _2; - NHC _1-6 alkyl, and -N(C _1-6 alkyl) ₂ . 2. A compound of formula (I), or an isomer (preferably a stereo-isomer or a tautomer), a solvate, a salt (preferably a pharmaceutically acceptable salt) or a prodrug thereof, preferably a pharmaceutically acceptable salt, solvate, hydrate, polymorph, tautomer, stereoisomer, or prodrug thereof, wherein: - n is selected from 0; and 1; - each represents an optional double bond, whereby maximally 3 are a double bond at the same time; - R ¹ is selected from alkyl; cycloalkyl; heteroalkyl; -C(O)R ³ ; -C(O)OR ⁴ ; -C(O)NR ⁵ R ⁶ ; -S(O) ₂ R ^3a ; - ^{S(O)R4a; -S(O)} ₂ ^{NR5aR6a; -S(O)(NR5a)R4a; and -S(NR5a)(NR6a)R3a;} wherein said alkyl, cycloalkyl and heteroalkyl can be unsubstituted or substituted with one or more substituents selected from alkyl, cycloalkyl, hydroxyl, =O, halogen, -SH, =S, trifluoromethyl, -O-alkyl, -OCF ₃ , cyano, -C(O)OH, -CONH ₂ , -CONHalkyl, -CON(alkyl) ₂ , - SO ₂ alkyl, -SO ₂ NH ₂ , -SO ₂ NHalkyl, -SO ₂ N(alkyl) ₂ , -S(O)(NH)alkyl, -S(O)(Nalkyl)alkyl, - S(NH)(NH)alkyl, -NH ₂ , -NHalkyl, -N(alkyl) ₂ ; - R ² is selected from hydrogen; alkyl; cycloalkyl; and heteroalkyl; - R ¹ and R ² can be taken together to form a (4-; 5-; or 6-membered) heterocycle which can be unsubstituted or substituted with one or more substituents selected from alkyl, cycloalkyl, hydroxyl, =O, halogen, -SH, =S, trifluoromethyl, -O-alkyl, -OCF ₃ , cyano, nitro, -C(O)OH, - CONH ₂ , -CONHalkyl, -CON(alkyl) ₂ , -SO ₂ alkyl, -SO ₂ NH ₂ , -SO ₂ NHalkyl, -SO ₂ N(alkyl) ₂ , - S(O)(NH)alkyl, -S(O)(Nalkyl)alkyl, -S(NH)(NH)alkyl, -NH ₂ , -NHalkyl, -N(alkyl) ₂ ; - each R ³ and R ^3a is independently selected from hydroxyl; alkyl; cycloalkyl; alkenyl; cycloalkenyl; alkynyl; cycloalkynyl; heteroalkyl; heteroalkenyl; and heteroalkynyl; wherein said alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, heteroalkyl, heteroalkenyl and heteroalkynyl can be unsubstituted or substituted with one or more substituents selected from alkyl, cycloalkyl, alkenyl, alkynyl, hydroxyl, =O, halogen, -SH, = ^{S, -CF} ₃ ^{, -O-alkyl, -OCF} ₃ ^{, -CHF} ₂ ^{, -OCHF} ₂ ^{, cyano, nitro, -C(O)OH; NH} _2; ^{-NHalkyl, and -} N(alkyl) ₂ ; - each R ⁴ and R ^4a is independently selected from alkyl; alkenyl; cycloalkenyl; alkynyl; cycloalkyl; cycloalkynyl; heteroalkyl; heteroalkenyl; and heteroalkynyl; wherein said alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, heteroalkyl, heteroalkenyl and heteroalkynyl can be unsubstituted or substituted with one or more substituents selected from alkyl, cycloalkyl, alkenyl, alkynyl, hydroxyl, =O, halogen, - S ^{H, =S, -CF} ₃ ^{, -O-alkyl, -OCF} ₃ ^{, -CHF} ₂ ^{, -OCHF} ₂ ^{, cyano, nitro, -C(O)OH; NH} _2; ^-NHalkyl, and -N(alkyl) ₂ ; - each R ⁵ , R ^5a , R ⁶ , and R ^6a is independently selected from hydrogen; alkyl; cycloalkyl; alkenyl; cycloalkenyl; alkynyl; cycloalkynyl; heteroalkyl; heteroalkenyl; and heteroalkynyl; wherein said alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, heteroalkyl, heteroalkenyl and heteroalkynyl can be unsubstituted or substituted with one or more substituents selected from alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, hydroxyl, =O, halogen, -SH, =S, - C ^F ₃ ^{, -O-alkyl, -OCF} ₃ ^{, -CHF} ₂ ^{, -OCHF} ₂ ^{, cyano, nitro, -C(O)OH; NH} _2; ^-NHalkyl, and -N(alkyl) ₂ ; and wherein each R ⁵ and R ⁶ or R ^5a and R ^6a can be taken together in order to form a (4-, 5-, 6-, or 7-membered) heterocycle which can be unsubstituted or substituted with one or more substituents selected from alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, hydroxyl, =O, halogen, -SH, =S, - C ^F ₃ ^{, -O-alkyl, -OCF} ₃ ^{, -CHF} ₂ ^{, -OCHF} ₂ ^{, cyano, nitro, -C(O)OH; NH} _2; ^-NHalkyl, and -N(alkyl) ₂ . - cycle A is selected from aryl; heteroaryl; cycloalkyl; and heterocycle; wherein said aryl, heteroaryl, cycloalkyl and heterocycle can be unsubstituted or substituted with one or more R ⁷ ; - _{each R} ⁷ _{is independently selected from halogen; hydroxyl; sulfhydryl; =O; =S; -OZ} ¹ _{; -SZ} ¹ _{; -} SCF ₃ ; -SF ₅ ; -CF ₃ ; -OCF ₃ ; -CHF ₂ ; -OCHF ₂ ; -NZ ³ Z ⁴ ; cyano; alkyl; cycloakyl; heteroalkyl; aryl; heteroaryl; heterocycle; arylalkyl; arylheteroalkyl; heteroarylalkyl; heteroarylheteroalkyl; heterocycle-alkyl; and heterocycle-heteroalkyl; wherein said alkyl, cycloakyl, heteroalkyl, aryl, heteroaryl, heterocycle, arylalkyl, arylheteroalkyl, heteroarylalkyl, heteroarylheteroalkyl, heterocycle-alkyl or heterocycle-heteroalkyl can be unsubstituted or substituted with one or more substituents selected from alkyl, cycloalkyl, hydroxyl, =O, halogen, -SH, =S, -CF ₃ , - O-alkyl, -OCF ₃ , -CHF ₂ ; -OCHF ₂ , cyano; - X ¹ is selected from CR ⁸ ; N; and NR ^8a ; whereby X ¹ can only be NR ^8a when X ² and/or X ⁴ are C=O or C=S; - X ² is selected from CR ⁹ ; N; and NR ^9a ; whereby X ² can only be NR ^9a when X ¹ and/or X ³ are C=O or C-SH; 35 - X ³ is selected from CH; and N; - X ⁴ is selected from C ^H ; and N; whereby maximally 2 of X ¹ , X ² , X ³ and X ⁴ can be a N (selected from N and NR ^8a for X ¹ , from N and NR ^9a for X ² , from N for X ³ , and from Nfor X ⁴ respectively) at the same time; - each R ⁸ and R ⁹ are independently selected from hydrogen; halogen; hydroxyl; sulfhydryl; =O; _{=S; -OZ} ^1a _{; -SZ} ^1a _{; -SCF3; -SF5; -S(O)Z} ^1a _{; -S(O)(NZ} ^3a _)Z ^1a _{; -S(NZ} ^3a _)(NZ ^3a _)Z ^1a _{; -S(O)2Z} ^2a _{; -S(O)2NZ} ^3a _Z ^4a _{; -CF3; -OCF3; -CHF2; -OCHF2; -NZ} ^3a _Z ^4a _{; -NZ} ^3a _S(O)2Z ^1a _{; -NZ} ^3a _C(O)Z ^1a _{; - NZ} ^3a _C(O)NZ ^3a _Z ^4a _{; cyano; -C(O)Z} ^2a _{; -C(O)OZ} ^1a _{; -C(O)NZ} ^3a _Z ^4a _{; alkyl; cycloakyl;} heteroalkyl; aryl; heteroaryl; heterocycle; arylalkyl; arylheteroalkyl; heteroarylalkyl; heteroarylheteroalkyl; heterocycle-alkyl; and heterocycle-heteroalkyl; wherein said alkyl, cycloakyl, heteroalkyl, aryl, heteroaryl, heterocycle, arylalkyl, arylheteroalkyl, heteroarylalkyl, heteroarylheteroalkyl, heterocycle-alkyl or heterocycle- heteroalkyl can be unsubstituted or substituted with one or more substituents selected from alkyl, cycloalkyl, hydroxyl, =O, halogen, -SH, =S, -CF ₃ , -O-alkyl, -OCF ₃ , -CHF ₂ ; - OCHF2, cyano, -C(O)OH, -NH ₂ , -NHalkyl, and -N(alkyl) ₂ ; _{- each R} ^8a _{and R} ^9a _{are independently selected from hydrogen; hydroxyl; sulfhydryl; -OZ} ^1a _{; - SZ} ^1a _{; -SCF3; -SF5; -S(O)Z} ^1a _{; -S(O)(NZ} ^3a _)Z ^1a _{; -S(NZ} ^3a _)(NZ ^3a _)Z ^1a _{; -S(O)2Z} ^2a _{; - S(O)2NZ} ^3a _Z ^4a _{; -CF3; -OCF3; -CHF2; -OCHF2; -NZ} ^3a _Z ^4a _{; -NZ} ^3a _S(O)2Z ^2a _{; -NZ} ^3a _C(O)Z ^1a _{; - NZ} ^3a _C(O)NZ ^3a _Z ^4a _{; cyano; -C(O)Z} ^2a _{; -C(O)OZ} ^1a _{; -C(O)NZ} ^3a _Z ^4a _{; - alkyl; cycloakyl;} heteroalkyl; aryl; heteroaryl; heterocycle; arylalkyl; arylheteroalkyl; heteroarylalkyl; heteroarylheteroalkyl; heterocycle-alkyl; and heterocycle-heteroalkyl; wherein said alkyl, cycloakyl, heteroalkyl, aryl, heteroaryl, heterocycle, arylalkyl, arylheteroalkyl, heteroarylalkyl, heteroarylheteroalkyl, heterocycle-alkyl or heterocycle- heteroalkyl can be unsubstituted or substituted with one or more substituents selected from alkyl, cycloalkyl, hydroxyl, =O, halogen, -SH, =S, -CF ₃ , -O-alkyl, -OCF ₃ , -CHF ₂ ; - OCHF2, cyano, -C(O)OH, -NH ₂ , -NHalkyl, and -N(alkyl) ₂ ; - each Z ¹ and Z ^1a is independently selected from alkyl; alkenyl; cycloalkenyl; alkynyl; cycloalkyl; cycloalkynyl; heteroalkyl; heteroalkenyl; heteroalkynyl; aryl; heteroaryl; heterocycle; arylalkyl; arylalkenyl; arylalkynyl; arylheteroalkyl; arylheteroalkenyl; arylheteroalkynyl; heteroarylalkyl; heteroarylalkenyl; heteroarylalkynyl; heteroarylheteroalkyl; heteroarylheteroalkenyl; heteroarylheteroalkynyl; heterocycle-alkyl; heterocycle-alkenyl; heterocycle-alkynyl; heterocycle-heteroalkyl; heterocycle-heteroalkenyl; or heterocycle-heteroalkynyl; wherein said alkyl, cycloalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, aryl, heteroaryl, heterocycle, arylalkyl, arylalkenyl, arylalkynyl, arylheteroalkyl, arylheteroalkenyl, arylheteroalkynyl, heteroarylalkyl, heteroarylalkenyl, heteroarylalkynyl, heteroarylheteroalkyl, heteroarylheteroalkenyl, heteroarylheteroalkynyl, heterocycle-alkyl, heterocycle- alkenyl, heterocycle-alkynyl, heterocycle-heteroalkyl, heterocycle-heteroalkenyl, or heterocycle-heteroalkynyl can be unsubstituted or substituted with one or more substituents selected from alkyl, cycloalkyl, alkenyl, alkynyl, hydroxyl, =O, halogen, - S ^{H, =S, -CF} ₃ ^{, -O-alkyl, -OCF} ₃ ^{, -CHF} ₂ ^{, -OCHF} ₂ ^{, cyano, -C(O)OH; NH} _2; ^{-NHalkyl, and -} N(alkyl) ₂ ; - each Z ² and Z ^2a is independently selected from hydroxyl; alkyl; cycloalkyl; alkenyl; cycloalkenyl; alkynyl; cycloalkynyl; heteroalkyl; heteroalkenyl; heteroalkynyl; aryl; heteroaryl; heterocycle; arylalkyl; arylalkenyl; arylalkynyl; arylheteroalkyl; arylheteroalkenyl; arylheteroalkynyl; heteroarylalkyl; heteroarylalkenyl; heteroarylalkynyl; heteroarylheteroalkyl; heteroarylheteroalkenyl; heteroarylheteroalkynyl; heterocycle-alkyl; heterocycle-alkenyl; heterocycle-alkynyl; heterocycle-heteroalkyl; heterocycle-heteroalkenyl; or heterocycle- heteroalkynyl; wherein said alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, aryl, heteroaryl, heterocycle, arylalkyl, arylalkenyl, arylalkynyl, arylheteroalkyl, arylheteroalkenyl, arylheteroalkynyl, heteroarylalkyl, heteroarylalkenyl, heteroarylalkynyl, heteroarylheteroalkyl, heteroarylheteroalkenyl, heteroarylheteroalkynyl, heterocycle-alkyl, heterocycle-alkenyl, heterocycle- alkynyl, heterocycle-heteroalkyl, heterocycle-heteroalkenyl, or heterocycle-heteroalkynyl can be unsubstituted or substituted with one or more substituents selected from alkyl, cycloalkyl, a ^{lkenyl, alkynyl, hydroxyl, =O, halogen, -SH, =S, -CF} ₃ ^{, -O-alkyl, -OCF} ₃ ^{, -CHF} ₂ ^{, -OCHF} ₂ ^{, cyano, -C(O)OH; NH} _2; ^{-NHalkyl, and -N(alkyl)} ₂ ^; _{- each Z} ³ _{, Z} ^3a _{, Z} ⁴ _{, and Z} ^4a _{is independently selected from hydrogen; alkyl; cycloalkyl;} alkenyl; cycloalkenyl; alkynyl; cycloalkynyl; heteroalkyl; heteroalkenyl; heteroalkynyl; aryl; heteroaryl; heterocycle; arylalkyl; arylalkenyl; arylalkynyl; arylheteroalkyl; arylheteroalkenyl; arylheteroalkynyl; heteroarylalkyl; heteroarylalkenyl; heteroarylalkynyl; heteroarylheteroalkyl; heteroarylheteroalkenyl; heteroarylheteroalkynyl; heterocycle-alkyl; heterocycle-alkenyl; heterocycle-alkynyl; heterocycle-heteroalkyl; heterocycle-heteroalkenyl; or heterocycle-heteroalkynyl; wherein said alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, aryl, heteroaryl, heterocycle, arylalkyl, arylalkenyl, arylalkynyl, arylheteroalkyl, arylheteroalkenyl, arylheteroalkynyl, heteroarylalkyl, heteroarylalkenyl, heteroarylalkynyl, heteroarylheteroalkyl, heteroarylheteroalkenyl, heteroarylheteroalkynyl, heterocycle-alkyl, heterocycle-alkenyl, heterocycle-alkynyl, heterocycle- heteroalkyl, heterocycle-heteroalkenyl, or heterocycle-heteroalkynyl can be unsubstituted or substituted with one or more substituents selected from alkyl, cycloalkyl, alkenyl, alkynyl, hydroxyl, =O, halogen, -SH, =S, -CF ₃ , -O-alkyl, - O ^CF ₃ ^{, -CHF} ₂ ^{, -OCHF} ₂ ^{, cyano, nitro, -C(O)OH; NH} _2; ^{-NHalkyl, and -N(alkyl)} ₂ ^; and wherein each Z ³ and Z ⁴ or Z ^3a and Z ^4a can be taken together in order to form a (4-, 5-, 6-, or 7-membered) heterocycle which can be unsubstituted or substituted with one or more substituents selected from alkyl, cycloalkyl, alkenyl, alkynyl, hydroxyl, =O, halogen, -SH, =S, -CF ₃ , -O-alkyl, -OCF ₃ , -CHF ₂ , - ^OCHF ₂ ^{, cyano, nitro, -C(O)OH; NH} _2; ^{-NHalkyl, and -N(alkyl)} ₂ ^. 3. A compound of formula (I), or an isomer (preferably a stereo-isomer or a tautomer), a solvate, a salt (preferably a pharmaceutically acceptable salt) or a prodrug thereof, preferably a pharmaceutically acceptable salt, solvate, hydrate, polymorph, tautomer, stereoisomer, or prodrug thereof, wherein: - n is selected from 0; and 1; - each represents an optional double bond, whereby maximally 3 are a double bond at the same time; - R ¹ is selected from alkyl; -C(O)R ³ ; -C(O)OR ⁴ ; a n d -S(O) ₂ R ^3a ; wherein said alkyl can be unsubstituted or substituted with one or more substituents selected from hydroxyl, cyano, -C(O)OH, -SO ₂ alkyl, -SO ₂ NHalkyl, -NHalkyl, -N(alkyl) ₂ ; - R ² is selected from hydrogen; alkyl; and heteroalkyl; - R ¹ and R ² can be taken together to form a 4-membered) heterocycle which can be unsubstituted or substituted with one or more substituents selected from alkyl, hydroxyl, =O, -O-alkyl, cyano, -C(O)OH, -SO ₂ alkyl, -SO ₂ NHalkyl, -NHalkyl, and -N(alkyl) ₂ ; - each R ³ and R ^3a is independently selected from alkyl; alkenyl; alkynyl; heteroalkyl; heteroalkenyl; heteroalkynyl; wherein said alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl can be unsubstituted or substituted with one or more substituents selected from hydroxyl, =O, h ^{alogen, -SH, =S, -CF} ₃ ^{, -O-alkyl, -OCF} ₃ ^{, -CHF} ₂ ^{, -OCHF} ₂ ^{, cyano, -C(O)OH; NH} _2; - NHalkyl, and -N(alkyl) ₂ ; - R ⁴ is selected from alkyl; alkenyl; alkynyl; heteroalkyl; heteroalkenyl; heteroalkynyl; wherein said alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl or heteroalkynyl can be unsubstituted or substituted with one or more substituents selected from hydroxyl, =O, h ^{alogen, -SH, =S, -CF} ₃ ^{, -O-alkyl, -OCF} ₃ ^{, -CHF} ₂ ^{, -OCHF} ₂ ^{, cyano, -C(O)OH; NH} _2; - NHalkyl, and -N(alkyl) ₂ ; - cycle A is selected from aryl; heteroaryl; and cycloalkyl; wherein said aryl, heteroaryl, cycloalkyl and heterocycle can be unsubstituted or substituted with one or more R ⁷ ; - each R ⁷ is independently selected from halogen; -OZ ¹ ; -SCF ₃ ; -SF ₅ ; -CF ₃ ; -OCF ₃ ; -CHF ₂ ; - OCHF ₂ ; alkyl; cycloakyl; heteroalkyl; aryl; wherein said alkyl, cycloakyl, heteroalkyl and aryl can be unsubstituted or substituted with one or more substituents selected from alkyl, hydroxyl, halogen, -SH, -CF ₃ , -O- alkyl, -OCF ₃ , -CHF ₂ ; -OCHF ₂ , cyano; - X ¹ is selected from CR ⁸ ; N; and NR ^8a ; whereby X ¹ can only be NR ^8a when X ² and/or X ⁴ are C- OH or C-SH; - X ² is selected from CR ⁹ ; and N; - X ³ is selected from CH; and N; - X ⁴ is selected from CH; and N; whereby maximally 2 of X ¹ , X ² , X ³ and X ⁴ can be a N (selected from N and NR ^8a for X ¹ , from N for X ² , from N for X ³ , and from N for X ⁴ respectively) at the same time; - each R ⁸ and R ⁹ are independently selected from hydrogen; halogen; hydroxyl; sulfhydryl; =O; _{=S; -OZ} ^1a _{; -CF3; -OCF3; -CHF2; -OCHF2; -NZ} ^3a _Z ^4a _{; -NZ} ^3a _S(O)2Z ^1a _{; -NZ} ^3a _C(O)Z ^1a _{; cyano; -C(O)OZ} ^1a _{; -C(O)NZ} ^3a _Z ^4a _{; alkyl; heteroalkyl; aryl; heteroaryl; heterocycle; arylalkyl;} heteroarylalkyl; and heterocycle-alkyl; wherein said alkyl, heteroalkyl, aryl, heteroaryl, heterocycle, arylalkyl, heteroarylalkyl or heterocycle-alkyl can be unsubstituted or substituted with one or more substituents selected from alkyl, hydroxyl, halogen, -CF ₃ , -O-alkyl, -OCF ₃ , -CHF ₂ ; -OCHF2, cyano, - NH ₂ ; - R ^8a is independently selected from hydrogen; alkyl; heteroalkyl; aryl; heteroaryl; heterocycle; arylalkyl; heteroarylalkyl; and heterocycle-alkyl; wherein said alkyl, heteroalkyl, aryl, heteroaryl, heterocycle, arylalkyl, heteroarylalkyl or heterocycle-alkyl can be unsubstituted or substituted with one or more substituents selected from alkyl, hydroxyl, halogen, -CF ₃ , -O-alkyl, -OCF ₃ , -CHF ₂ ; -OCHF2, cyano, - NH ₂ ; - each Z ¹ and Z ^1a is independently selected from alkyl; alkenyl; alkynyl; heteroalkyl; heteroalkenyl; heteroalkynyl; wherein said alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl or heteroalkynyl can be unsubstituted or substituted with one or more substituents selected from hydroxyl, =O, h ^{alogen, -SH, =S, -CF} ₃ ^{, -O-alkyl, -OCF} ₃ ^{, -CHF} ₂ ^{, -OCHF} ₂ ^{, cyano, -C(O)OH; NH} _2; - NHalkyl, and -N(alkyl) ₂ ; - _{each Z} ^3a _{and Z} ^4a _{is independently selected from hydrogen; alkyl; alkenyl; alkynyl;} heteroalkyl; heteroalkenyl; heteroalkynyl; aryl; heteroaryl; heterocycle; wherein said alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, aryl, heteroaryl and heterocycle can be unsubstituted or substituted with one or more substituents selected from hydroxyl, =O, halogen, -SH, =S, -CF ₃ , -O-alkyl, - ^OCF ₃ ^{, -CHF} ₂ ^{, -OCHF} ₂ ^{, cyano, nitro, -C(O)OH; NH} _2; ^{-NHalkyl, and -N(alkyl)} ₂ ^; 4. A compound of formula (I), or an isomer (preferably a stereo-isomer or a tautomer), a solvate, a salt (preferably a pharmaceutically acceptable salt) or a prodrug thereof, preferably a pharmaceutically acceptable salt, solvate, hydrate, polymorph, tautomer, stereoisomer, or prodrug thereof, wherein - n, , R ¹ , R ² , cycle A, R ⁷ , X ¹ , X ² , X ³ , X ⁴ , R ^8a , R ⁴ , Z ¹ , Z ^1a , R ³ , R ^3a , Z ^3a and Z ^4a have the same meaning as in statements 1, 2, or 3, or other embodiments, statements or aspects described _{herein; - R} ⁸ _{is selected from hydrogen; halogen; hydroxyl; sulfhydryl; =O; =S; -OZ} ^1a _{; -CF3; -OCF3; - CHF2; -OCHF2; -NZ} ^3a _Z ^4a _{; -NZ} ^3a _S(O)2Z ^1a _{; -NZ} ^3a _C(O)Z ^1a _{; cyano; -C(O)OZ} ^1a _{; - C(O)NZ} ^3a _Z ^4a _{; alkyl; heteroalkyl; aryl; heteroaryl; heterocycle; arylalkyl; heteroarylalkyl; and} heterocycle-alkyl; wherein said alkyl, heteroalkyl, aryl, heteroaryl, heterocycle, arylalkyl, heteroarylalkyl or heterocycle-alkyl can be unsubstituted or substituted with one or more substituents selected from alkyl, hydroxyl, halogen, -CF ₃ , -O-alkyl, -OCF ₃ , -CHF ₂ ; -OCHF2, cyano, - NH ₂ ; _{- R} ⁹ _{is selected from hydrogen; halogen; hydroxyl; sulfhydryl; =O; =S; -OZ} ^1a _{; -CF3; -OCF3; - CHF2; -OCHF2; -NZ} ^3a _Z ^4a _{; alkyl; and heteroalkyl;} wherein said alkyl and heteroalkyl can be unsubstituted or substituted with one or more substituents selected from hydroxyl, halogen, -CF ₃ , -O-alkyl, -OCF ₃ , -CHF ₂ ; -OCHF2, cyano, - NH ₂ . In a specific embodiment of the present disclosure, the compounds have a structure according to formula (Ia) or formula (I) described herein, more in particular according to the other formulas, statements, embodiments and aspects described herein, yet more in particular according to statements 1, 2, 3, and 4 herein, whereby: - each alkyl is C ₁ -C ₁₈ membered alkyl, more in particular is a C ₁ -C ₁₂ membered alkyl; yet more in particular is a C ₁ -C ₉ membered alkyl; still more in particular is a C ₁ -C ₆ membered alkyl; including when such alkyl is linked for example to aryl, heteroaryl or heterocycle as for example in arylalkyl, heteroarylalkyl and heterocycle-alkyl; - each alkenyl is C ₂ -C ₁₈ membered alkenyl, more in particular is a C ₂ -C ₁₂ membered alkenyl; yet more in particular is a C ₂ -C ₉ membered alkenyl; still more in particular is a C ₂ -C ₆ membered alkenyl; including when such alkenyl is linked to for example aryl, heteroaryl or heterocycle as for example in arylalkenyl, heteroarylalkenyl and heterocycle-alkenyl; - each alkynyl is C ₂ -C ₁₈ membered alkynyl, more in particular is a C ₂ -C ₁₂ membered alkynyl; yet more in particular is a C ₂ -C ₉ membered alkynyl; still more in particular is a C ₂ -C ₆ membered alkynyl; including when such alkynyl is linked to for example aryl, heteroaryl or heterocycle as for example in arylalkynyl, heteroarylalkynyl and heterocycle-alkynyl; - each heteroalkyl is C ₁ -C ₁₈ membered alkyl, more in particular is a C ₁ -C ₁₂ membered heteroalkyl; yet more in particular is a C ₁ -C ₉ membered heteroalkyl; still more in particular is a C ₁ -C ₆ membered heteroalkyl; including when such heteroalkyl is linked for example to aryl, heteroaryl or heterocycle as for example in arylheteroalkyl, heteroarylheteroalkyl and heterocycle-heteroalkyl; - each heteroalkenyl is C ₂ -C ₁₈ membered alkenyl, more in particular is a C ₂ -C ₁₂ membered heteroalkenyl; yet more in particular is a C ₂ -C ₉ membered heteroalkenyl; still more in particular is a C ₂ -C ₆ membered heteroalkenyl; including when such heteroalkenyl is linked to for example aryl, heteroaryl or heterocycle as for example in arylheteroalkenyl, heteroarylheteroalkenyl and heterocycle-heteroalkenyl; and - each heteroalkynyl is C ₂ -C ₁₈ membered alkynyl, more in particular is a C ₂ -C ₁₂ membered heteroalkynyl; yet more in particular is a C ₂ -C ₉ membered heteroalkynyl; still more in particular is a C ₂ -C ₆ membered heteroalkynyl; including when such alkenyl is linked to for example aryl, heteroaryl or heterocycle as for example in arylheteroalkynyl, heteroarylheteroalkynyl and heterocycle-heteroalkynyl. 5. A compound of formula (I), or an isomer (preferably a stereo-isomer or a tautomer), a solvate, a salt (preferably a pharmaceutically acceptable salt) or a prodrug thereof, preferably a pharmaceutically acceptable salt, solvate, hydrate, polymorph, tautomer, stereoisomer, or prodrug thereof, wherein: - n is selected from 0; 1; and 2; - each represents an optional double bond, whereby maximally 3 are a double bond at the same time; - R ¹ is selected from C _1-6 alkyl; C _3-9 cycloalkyl; C _2-6 alkenyl; C _5-9 cycloalkenyl; C _2-6 alkynyl; C _{5- 9} cycloalkynyl; C _1-6 heteroalkyl; C _2-6 heteroalkenyl; C _2-6 heteroalkynyl; -C(O)H; -C(O)R ³ ; -C(O)OR ⁴ ; ^{-C(O)NR5R6; -S(O)} ₂ ^{R3a; -S(O)R4a; -S(O)} ₂ ^{NR5aR6a; -S(O)(NR5a)R4a; -S(NR5a)(NR6a)R3a; and -} P(O)R ^5b R ^6b ; wherein said C _1-6 alkyl, C _3-9 cycloalkyl, C _2-6 alkenyl, C _5-9 cycloalkenyl, C _2-6 alkynyl, C _{5- 9} cycloalkynyl, C _1-6 heteroalkyl, C _2-6 heteroalkenyl and C _2-6 heteroalkynyl can be unsubstituted or substituted with one or more substituents selected from C _1-6 alkyl, C _{3- 9} cycloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, hydroxyl, =O, halogen, -SH, =S, trifluoromethyl, -O- C _1-6 alkyl, -OCF ₃ , cyano, nitro, -C(O)OH, -C(O)OC _1-6 alkyl, -C(O)C _1-6 alkyl, -CONH ₂ , - CONHC _1-6 alkyl, -CON(C _1-6 alkyl) ₂ , -SO ₂ C _1-6 alkyl, -SO ₂ NH ₂ , -SO ₂ NHC _1-6 alkyl, -SO ₂ N(C _{1- 6} alkyl) ₂ , -S(O)(NH)C _1-6 alkyl, -S(O)(NC _1-6 alkyl)C _1-6 alkyl, -S(NH)(NH)C _1-6 alkyl, - S(O)(NH)C1-6alkyl, -S(O)(NC1-6alkyl)C1-6alkyl, -S(NH)(NH)C1-6alkyl, -NH ₂ , -NHC _{1- 6} alkyl, -N(C _1-6 alkyl) ₂ ; - R ² is selected from hydrogen; C _1-6 alkyl; C _3-9 cycloalkyl; and C _1-6 heteroalkyl; - R ¹ and R ² can be taken together to form a (4-; 5-; 6- or 7-membered) heterocycle which can be unsubstituted or substituted with one or more substituents selected from C _1-6 alkyl, C _3-9 cycloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, hydroxyl, =O, halogen, -SH, =S, trifluoromethyl, -O- C _1-6 alkyl, -OCF ₃ , cyano, nitro, -C(O)OH, -C(O)OC _1-6 alkyl, -C(O)C _1-6 alkyl, -CONH ₂ , - CONHC _1-6 alkyl, -CON(C _1-6 alkyl) ₂ , -SO ₂ C _1-6 alkyl, -SO ₂ NH ₂ , -SO ₂ NHC _1-6 alkyl, -SO ₂ N(C _{1- 6} alkyl) ₂ , -S(O)(NH)C1-6alkyl, -S(O)(NC1-6alkyl)C1-6alkyl, -S(NH)(NH)C1-6alkyl,-NH ₂ , - NHC _1-6 alkyl, -N(C _1-6 alkyl) ₂ ; - each R ³ and R ^3a is independently selected from hydroxyl; C _1-6 alkyl; C _3-9 cycloalkyl; C _2-6 alkenyl; C _5-9 cycloalkenyl; C _2-6 alkynyl; C _5-9 cycloalkynyl; C _1-6 heteroalkyl; C _2-6 heteroalkenyl; and C _{2- 6} heteroalkynyl; wherein said C _1-6 alkyl, C _3-9 cycloalkyl, C _2-6 alkenyl, C _5-9 cycloalkenyl, C _2-6 alkynyl, C _{5- 9} cycloalkynyl, C _1-6 heteroalkyl, C _2-6 heteroalkenyl and C _2-6 heteroalkynyl can be unsubstituted or substituted with one or more substituents selected from alkyl, cycloalkyl, a ^{lkenyl, alkynyl, hydroxyl, =O, halogen, -SH, =S, -CF} ₃ ^{, -O-alkyl, -OCF} ₃ ^{, -CHF} ₂ ^{, -OCHF} ₂ ^{, cyano, nitro, -C(O)OH; NH} _2; ^{-NHalkyl, and -N(alkyl)} ₂ ^; - each R ⁴ and R ^4a is independently selected from C _1-6 alkyl; C _3-9 cycloalkyl; C _2-6 alkenyl; C _{5- 9} cycloalkenyl; C _2-6 alkynyl; C _5-9 cycloalkynyl; C _1-6 heteroalkyl; C _2-6 heteroalkenyl; and C _{2- 6} heteroalkynyl; wherein said C _1-6 alkyl, C _3-9 cycloalkyl, C _2-6 alkenyl, C _5-9 cycloalkenyl, C _2-6 alkynyl, C _{5- 9} cycloalkynyl, C _1-6 heteroalkyl, C _2-6 heteroalkenyl and C _2-6 heteroalkynyl can be unsubstituted or substituted with one or more substituents selected from alkyl, cycloalkyl, alkenyl, alkynyl, hydroxyl, =O, halogen, -SH, =S, -CF ₃ , -O-alkyl, -OCF ₃ , - C ^HF ₂ ^{, -OCHF} ₂ ^{, cyano, nitro, -C(O)OH; NH} _2; ^{-NHalkyl, and -N(alkyl)} ₂ ^; - each R ⁵ , R ^5a , R ^5b , R ⁶ , R ^6a and R ^6b is independently selected from hydrogen; C _1-6 alkyl; C _{3- 9} cycloalkyl; C _2-6 alkenyl; C _5-9 cycloalkenyl; C _2-6 alkynyl; C _5-9 cycloalkynyl; C _1-6 heteroalkyl; C _{2- 6} heteroalkenyl; and C _2-6 heteroalkynyl; wherein said C _1-6 alkyl, C _3-9 cycloalkyl, C _2-6 alkenyl, C _5-9 cycloalkenyl, C _2-6 alkynyl, C _5-9 cycloalkynyl, C _1-6 heteroalkyl, C _2-6 heteroalkenyl and C _2-6 heteroalkynyl can be unsubstituted or substituted with one or more substituents selected from alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, hydroxyl, =O, halogen, - S ^{H, =S, -CF} ₃ ^{, -O-alkyl, -OCF} ₃ ^{, -CHF} ₂ ^{, -OCHF} ₂ ^{, cyano, nitro, -C(O)OH; NH} _2; - NHalkyl, and -N(alkyl) ₂ ; and wherein each R ⁵ and R ⁶ or R ^5a and R ^6a can be taken together in order to form a (4-, 5-, 6-, or 7-membered) heterocycle which can be unsubstituted or substituted with one or more substituents selected from alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, hydroxyl, =O, halogen, -SH, =S, -CF ₃ , -O- a ^{lkyl, -OCF} ₃ ^{, -CHF} ₂ ^{, -OCHF} ₂ ^{, cyano, nitro, -C(O)OH; NH} _2; ^{-NHalkyl, and -} N(alkyl) ₂ ; - cycle A is selected from aryl; heteroaryl; C _3-9 cycloalkyl; and heterocycle; wherein said aryl, heteroaryl, C _3-9 cycloalkyl and heterocycle can be unsubstituted or substituted with one or more R ⁷ ; _{- each R} ⁷ _{is independently selected from halogen; hydroxyl; sulfhydryl; =O; =S; -OZ} ¹ _{; -SZ} ¹ _{; - SCF3; -SF5; -CF3; -OCF3; -CHF2; -OCHF2; -NZ} ³ _Z ⁴ _{; -NZ} ³ _C(O)Z ¹ _{; cyano; -C(O)Z} ² _{; --C(O)OZ} ¹ _; -C(O)NZ ³ Z ⁴ ; C _1-6 alkyl; C _3-9 cycloakyl; C _2-6 alkenyl; C _2-6 alkynyl; C _1-6 heteroalkyl; C _2-6 heteroalkenyl; C _2-6 heteroalkynyl; aryl; heteroaryl; heterocycle; arylC _1-6 alkyl; arylC _2-6 alkenyl; arylalkynyl; arylC _{1- 6} heteroalkyl; arylC _2-6 heteroalkenyl; arylC _2-6 heteroalkynyl; heteroarylC _1-6 alkyl; heteroarylC _{2- 6} alkenyl; heteroarylC _2-6 alkynyl; heteroarylC _1-6 heteroalkyl; heteroarylC _2-6 heteroalkenyl; heteroarylC _2-6 heteroalkynyl; heterocycle-C _1-6 alkyl; heterocycle-C _2-6 alkenyl; heterocycle-C _{2- 6} alkynyl; heterocycle-C _1-6 heteroalkyl; heterocycle-C _2-6 heteroalkenyl; and heterocycle-C _{2- 6} heteroalkynyl; wherein said C _1-6 alkyl, C _3-9 cycloakyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 heteroalkyl, C _{2- 6} heteroalkenyl, C _2-6 heteroalkynyl, aryl, heteroaryl, heterocycle, arylC _1-6 alkyl, arylC _{2- 6} alkenyl, arylalkynyl, arylC _1-6 heteroalkyl, arylC _2-6 heteroalkenyl, arylC _2-6 heteroalkynyl, heteroarylC _1-6 alkyl, heteroarylC _2-6 alkenyl, heteroarylC _2-6 alkynyl, heteroarylC _{1- 6} heteroalkyl, heteroarylC _2-6 heteroalkenyl, heteroarylC _2-6 heteroalkynyl, heterocycle- C _1-6 alkyl, heterocycle-C _2-6 alkenyl, heterocycle-C _2-6 alkynyl, heterocycle-C _{1- 6} heteroalkyl, heterocycle-C _2-6 heteroalkenyl and heterocycle-C _2-6 heteroalkynyl can be unsubstituted or substituted with one or more substituents selected from C _1-6 alkyl, C _3-9 cycloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, hydroxyl, =O, halogen, -SH, =S, -CF ₃ , -O-C _{1- 6} alkyl, -OCF ₃ , -CHF ₂ ; -OCHF ₂ , cyano, nitro, -C(O)OH, -NH ₂ , -NHC _1-6 alkyl, and -N(C _{1- 6} alkyl) ₂ ; - X ¹ is selected from CR ⁸ ; N; and NR ^8a ; whereby X ¹ can only be NR ^8a when X ² and/or X ⁴ are C=O or C=S; - X ² is selected from CR ⁹ ; N; and NR ^9a ; whereby X ² can only be NR ^9a when X ¹ and/or X ³ are C=O or C-SH; - X ³ is selected from CH; and N; - X ⁴ is selected from CH; and N; whereby maximally 2 of X ¹ , X ² , X ³ and X ⁴ can be a N (selected from N and NR ^8a for X ¹ , from N and NR ^9a for X ² , from N for X ³ , and from Nfor X ⁴ respectively) at the same time; - each R ⁸ and R ⁹ are independently selected from hydrogen; halogen; hydroxyl; sulfhydryl; =O; _{=S; -OZ} ^1a _{; -SZ} ^1a _{; -SCF3; -SF5; -S(O)Z} ^1a _{; -S(O)(NZ} ^3a _)Z ^1a _{; -S(NZ} ^3a _)(NZ ^3a _)Z ^1a _{; -S(O)2Z} ^2a _{; -S(O)2NZ} ^3a _Z ^4a _{; -CF3; -OCF3; -CHF2; -OCHF2; nitro; -NZ} ^3a _Z ^4a _{; -NZ} ^3a _S(O)2Z ^1a _{; - NZ} ^3a _C(O)Z ^1a _{; -NZ} ^3a _C(O)NZ ^3a _Z ^4a _{; cyano; -C(O)Z} ^2a _{; -C(O)OZ} ^1a _{; -C(O)NZ} ^3a _Z ^4a _{; -C(O)H;} -P(O)Z ^3a Z ^4a ; C _1-6 alkyl; C _3-9 cycloakyl; C _2-6 alkenyl; C _2-6 alkynyl; C _1-6 heteroalkyl; C _2-6 heteroalkenyl; C _2-6 heteroalkynyl; aryl; heteroaryl; heterocycle; arylC _1-6 alkyl; arylC _2-6 alkenyl; arylC _2-6 alkynyl; arylC _1-6 heteroalkyl; arylC _2-6 heteroalkenyl; arylC _2-6 heteroalkynyl; heteroarylC _1-6 alkyl; heteroarylC _2-6 alkenyl; heteroarylC _2-6 alkynyl; heteroarylC _1-6 heteroalkyl; heteroarylC _{2- 6} heteroalkenyl; heteroarylC _2-6 heteroalkynyl; heterocycle-C _1-6 alkyl; heterocycle-C _2-6 alkenyl; heterocycle-C _2-6 alkynyl; heterocycle-C _1-6 heteroalkyl; heterocycle- C _2-6 heteroalkenyl; and heterocycle- C _2-6 heteroalkynyl; wherein said C _1-6 alkyl, C _3-9 cycloakyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 heteroalkyl, C _{2- 6} heteroalkenyl, C _2-6 heteroalkynyl, aryl, heteroaryl, heterocycle, arylC _1-6 alkyl, arylC _{2- 6} alkenyl, arylalkynyl, arylC _1-6 heteroalkyl, arylC _2-6 heteroalkenyl, arylC _2-6 heteroalkynyl, heteroarylC _1-6 alkyl, heteroarylC _2-6 alkenyl, heteroarylC _2-6 alkynyl, heteroarylC _{1- 6} heteroalkyl, heteroarylC _2-6 heteroalkenyl, heteroarylC _2-6 heteroalkynyl, heterocycle-C _{1- 6} alkyl, heterocycle-C _2-6 alkenyl, heterocycle-C _2-6 alkynyl, heterocycle-C _1-6 heteroalkyl, heterocycle-C _2-6 heteroalkenyl and heterocycle-C _2-6 heteroalkynyl can be unsubstituted or substituted with one or more substituents selected from C _1-6 alkyl, C _3-9 cycloalkyl, C _{2- 6} alkenyl, C _2-6 alkynyl, hydroxyl, =O, halogen, -SH, =S, -CF ₃ , -O-C _1-6 alkyl, -OCF ₃ , -CHF ₂ ; - OCHF2, cyano, nitro, -C(O)OH, -NH ₂ , -NHC _1-6 alkyl, and -N(C _1-6 alkyl) ₂ ; _{- each R} ^8a _{and R} ^9a _{are independently selected from hydrogen; hydroxyl; sulfhydryl; -OZ} ^1a _{; - SZ} ^1a _{; -SCF3; -SF5; -S(O)Z} ^1a _{; -S(O)(NZ} ^3a _)Z ^1a _{; -S(NZ} ^3a _)(NZ ^3a _)Z ^1a _{; -S(O)2Z} ^2a _{; - S(O)2NZ} ^3a _Z ^4a _{; -CF3; -OCF3; -CHF2; -OCHF2; nitro; -NZ} ^3a _Z ^4a _{; -NZ} ^3a _S(O)2Z ^2a _{; - NZ} ^3a _C(O)Z ^1a _{; -NZ} ^3a _C(O)NZ ^3a _Z ^4a _{; cyano; -C(O)Z} ^2a _{; -C(O)OZ} ^1a _{; -C(O)NZ} ^3a _Z ^4a _{; -C(O)H;} -P(O)Z ^3a Z ^4a ; C _1-6 alkyl; C _3-9 cycloakyl; C _2-6 alkenyl; C _2-6 alkynyl; C _1-6 heteroalkyl; C _2-6 heteroalkenyl; C _2-6 heteroalkynyl; aryl; heteroaryl; heterocycle; arylC _1-6 alkyl; arylC _2-6 alkenyl; arylC _2-6 alkynyl; arylC _1-6 heteroalkyl; arylC _2-6 heteroalkenyl; arylC _2-6 heteroalkynyl; heteroarylC _1-6 alkyl; heteroarylC _2-6 alkenyl; heteroarylC _2-6 alkynyl; heteroarylC _1-6 heteroalkyl; heteroarylC _{2- 6} heteroalkenyl; heteroarylC _2-6 heteroalkynyl; heterocycle-C _1-6 alkyl; heterocycle-C _2-6 alkenyl; heterocycle-C _2-6 alkynyl; heterocycle-C _1-6 heteroalkyl; heterocycle- C _2-6 heteroalkenyl; and heterocycle- C _2-6 heteroalkynyl; wherein said C _1-6 alkyl, C _3-9 cycloakyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 heteroalkyl, C _{2- 6} heteroalkenyl, C _2-6 heteroalkynyl, aryl, heteroaryl, heterocycle, arylC _1-6 alkyl, arylC _{2- 6} alkenyl, arylalkynyl, arylC _1-6 heteroalkyl, arylC _2-6 heteroalkenyl, arylC _2-6 heteroalkynyl, heteroarylC _1-6 alkyl, heteroarylC _2-6 alkenyl, heteroarylC _2-6 alkynyl, heteroarylC _{1- 6} heteroalkyl, heteroarylC _2-6 heteroalkenyl, heteroarylC _2-6 heteroalkynyl, heterocycle-C _{1- 6} alkyl, heterocycle-C _2-6 alkenyl, heterocycle-C _2-6 alkynyl, heterocycle-C _1-6 heteroalkyl, heterocycle-C _2-6 heteroalkenyl and heterocycle-C _2-6 heteroalkynyl can be unsubstituted or substituted with one or more substituents selected from C _1-6 alkyl, C _3-9 cycloalkyl, C _{2- 6} alkenyl, C _2-6 alkynyl, hydroxyl, =O, halogen, -SH, =S, -CF ₃ , -O-C _1-6 alkyl, -OCF ₃ , -CHF ₂ ; - OCHF2, cyano, nitro, -C(O)OH, -NH ₂ , -NHC _1-6 alkyl, and -N(C _1-6 alkyl) ₂ ; - each Z ¹ and Z ^1a is independently selected from C _1-6 alkyl; C _3-9 cycloakyl; C _2-6 alkenyl; C _5- 9cycloalkenyl; C _2-6 alkynyl; C _5-9 cycloalkynyl; C _1-6 heteroalkyl; C _2-6 heteroalkenyl; C _{2- 6} heteroalkynyl; aryl; heteroaryl; heterocycle; arylC _1-6 alkyl; arylC _2-6 alkenyl; arylC _2-6 alkynyl; arylC _{1- 6} heteroalkyl; arylC _2-6 heteroalkenyl; arylC _2-6 heteroalkynyl; heteroarylC _1-6 alkyl; heteroarylC _{2- 6} alkenyl; heteroarylC _2-6 alkynyl; heteroarylC _1-6 heteroalkyl; heteroarylC _2-6 heteroalkenyl; heteroarylC _2-6 heteroalkynyl; heterocycle-C _1-6 alkyl; heterocycle-C _2-6 alkenyl; heterocycle-C _{2- 6} alkynyl; heterocycle-C _1-6 heteroalkyl; heterocycle- C _2-6 heteroalkenyl; and heterocycle- C _{2- 6} heteroalkynyl; wherein said C _1-6 alkyl, C _3-9 cycloakyl, C _2-6 alkenyl, C _5- 9cycloalkenyl, C _2-6 alkynyl, C _{5- 9} cycloalkynyl, C _1-6 heteroalkyl, C _2-6 heteroalkenyl, C _2-6 heteroalkynyl, aryl, heteroaryl, heterocycle, arylC _1-6 alkyl, arylC _2-6 alkenyl, arylC _2-6 alkynyl, arylC _1-6 heteroalkyl, arylC _{2- 6} heteroalkenyl, arylC _2-6 heteroalkynyl, heteroarylC _1-6 alkyl, heteroarylC _2-6 alkenyl, heteroarylC _2-6 alkynyl, heteroarylC _1-6 heteroalkyl, heteroarylC _2-6 heteroalkenyl, heteroarylC _2-6 heteroalkynyl, heterocycle-C _1-6 alkyl, heterocycle-C _2-6 alkenyl, heterocycle-C _2-6 alkynyl, heterocycle-C _1-6 heteroalkyl, heterocycle- C _2-6 heteroalkenyl, and heterocycle- C _2-6 heteroalkynyl can be unsubstituted or substituted with one or more substituents selected from C _1-6 alkyl, C _3-9 cycloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, hydroxyl, =O, halogen, -SH, =S, -CF ₃ , -O-C _1-6 alkyl, -OCF ₃ , -CHF ₂ ; -OCHF2, cyano, nitro, - C(O)OH, -NH ₂ , -NHC _1-6 alkyl, and -N(C _1-6 alkyl) ₂ ; - each Z ² and Z ^2a is independently selected from hydroxyl; C _1-6 alkyl; C _3-9 cycloakyl; C _2-6 alkenyl; C _5- 9cycloalkenyl; C _2-6 alkynyl; C _5-9 cycloalkynyl; C _1-6 heteroalkyl; C _2-6 heteroalkenyl; C _{2- 6} heteroalkynyl; aryl; heteroaryl; heterocycle; arylC _1-6 alkyl; arylC _2-6 alkenyl; arylC _2-6 alkynyl; arylC _1-6 heteroalkyl; arylC _2-6 heteroalkenyl; arylC _2-6 heteroalkynyl; heteroarylC _1-6 alkyl; heteroarylC _2-6 alkenyl; heteroarylC _2-6 alkynyl; heteroarylC _1-6 heteroalkyl; heteroarylC _{2- 6} heteroalkenyl; heteroarylC _2-6 heteroalkynyl; heterocycle-C _1-6 alkyl; heterocycle-C _2-6 alkenyl; heterocycle-C _2-6 alkynyl; heterocycle-C _1-6 heteroalkyl; heterocycle- C _2-6 heteroalkenyl; and heterocycle- C _2-6 heteroalkynyl; wherein said C _1-6 alkyl, C _3-9 cycloakyl, C _2-6 alkenyl, C _5- 9cycloalkenyl, C _2-6 alkynyl, C _{5- 9} cycloalkynyl, C _1-6 heteroalkyl, C _2-6 heteroalkenyl, C _2-6 heteroalkynyl, aryl, heteroaryl, heterocycle, arylC _1-6 alkyl, arylC _2-6 alkenyl, arylC _2-6 alkynyl, arylC _1-6 heteroalkyl, arylC _{2- 6} heteroalkenyl, arylC _2-6 heteroalkynyl, heteroarylC _1-6 alkyl, heteroarylC _2-6 alkenyl, heteroarylC _2-6 alkynyl, heteroarylC _1-6 heteroalkyl, heteroarylC _2-6 heteroalkenyl, heteroarylC _2-6 heteroalkynyl, heterocycle-C _1-6 alkyl, heterocycle-C _2-6 alkenyl, heterocycle- C _2-6 alkynyl, heterocycle-C _1-6 heteroalkyl, heterocycle- C _2-6 heteroalkenyl, and heterocycle- C _2-6 heteroalkynyl can be unsubstituted or substituted with one or more substituents selected from C _1-6 alkyl, C _3-9 cycloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, hydroxyl, =O, halogen, - S ^{H, =S, -CF} ₃ ^{, -O-C} _1-6 ^{alkyl, -OCF} ₃ ^{, -CHF} ₂ ^{, -OCHF} ₂ ^{, cyano, nitro, -C(O)OH; NH} _2; ^-NHC _{1- 6} alkyl, and -N(C _1-6 alkyl) ₂ ; _{- each Z} ³ _{, Z} ^3a _{, Z} ⁴ _{, and Z} ^4a _{is independently selected from hydrogen; C1-6alkyl; C3- 9} cycloakyl; C _2-6 alkenyl; C _5-9 cycloalkenyl; C _2-6 alkynyl; C _5-9 cycloalkynyl; C _1-6 heteroalkyl; C _2-6 heteroalkenyl; C _2-6 heteroalkynyl; aryl; heteroaryl; heterocycle; arylC _1-6 alkyl; arylC _{2- 6} alkenyl; arylC _2-6 alkynyl; arylC _1-6 heteroalkyl; arylC _2-6 heteroalkenyl; arylC _{2- 6} heteroalkynyl; heteroarylC _1-6 alkyl; heteroarylC _2-6 alkenyl; heteroarylC _2-6 alkynyl; heteroarylC _1-6 heteroalkyl; heteroarylC _2-6 heteroalkenyl; heteroarylC _2-6 heteroalkynyl; heterocycle-C _1-6 alkyl; heterocycle-C _2-6 alkenyl; heterocycle-C _2-6 alkynyl; heterocycle- C _1-6 heteroalkyl; heterocycle- C _2-6 heteroalkenyl; and heterocycle- C _2-6 heteroalkynyl; wherein said C _1-6 alkyl, C _3-9 cycloakyl, C _2-6 alkenyl, C _5-9 cycloalkenyl, C _2-6 alkynyl, C _5-9 cycloalkynyl, C _1-6 heteroalkyl, C _2-6 heteroalkenyl, C _2-6 heteroalkynyl, aryl, heteroaryl, heterocycle, arylC _1-6 alkyl, arylC _2-6 alkenyl, arylC _2-6 alkynyl, arylC _{1- 6} heteroalkyl, arylC _2-6 heteroalkenyl, arylC _2-6 heteroalkynyl, heteroarylC _1-6 alkyl, heteroarylC _2-6 alkenyl, heteroarylC _2-6 alkynyl, heteroarylC _1-6 heteroalkyl, heteroarylC _2-6 heteroalkenyl, heteroarylC _2-6 heteroalkynyl, heterocycle-C _1-6 alkyl, heterocycle-C _2-6 alkenyl, heterocycle-C _2-6 alkynyl, heterocycle-C _1-6 heteroalkyl, heterocycle- C _2-6 heteroalkenyl, and heterocycle- C _2-6 heteroalkynyl can be unsubstituted or substituted with one or more substituents selected from C _{1- 6} alkyl, C _3-9 cycloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, hydroxyl, =O, halogen, -SH, =S, - C ^F ₃ ^{, -O-C} _1-6 ^{alkyl, -OCF} ₃ ^{, -CHF} ₂ ^{, -OCHF} ₂ ^{, cyano, nitro, -C(O)OH; NH} _2; ^-NHC _{1- 6} alkyl, and -N(C _1-6 alkyl) ₂ ; and wherein each Z ³ and Z ⁴ or Z ^3a and Z ^4a can be taken together in order to form a (4-, 5- , 6-, or 7-membered) heterocycle which can be unsubstituted or substituted with one or more substituents selected from C _1-6 alkyl, C _3-9 cycloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, hydroxyl, = ^{O, halogen, -SH, =S, -CF} ₃ ^{, -O-C} _1-6 ^{alkyl, -OCF} ₃ ^{, -CHF} ₂ ^{, -OCHF} ₂ ^{, cyano, nitro, -C(O)OH; NH} _2; ^-NHC _1-6 ^{alkyl, and -N(C} _1-6 ^alkyl) ₂ ^. In a specific embodiment of the present disclosure, the compounds have a structure according to formula I described herein, more in particular according to the formulas, statements, embodiments and aspects described herein, yet more in particular according to statements 1, 2, 3, 4, and 5 herein, whereby: - each aryl is C ₆ -C ₂₀ membered aryl, more in particular is a C ₆ -C ₁₄ membered aryl; yet more in particular is a C ₆ -C ₁₀ membered aryl; including when such aryl is linked to alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl or heteroalkynyl, as in arylalkyl, arylalkenyl, arylalkynyl, arylheteroalkyl, arylheteroalkenyl, arylheteroalkynyl; - each heteroaryl is 5 to 20 membered heteroaryl, more in particular is a 6 to 14 membered heteroaryl; yet more in particular is a 6 to 10 membered heteroaryl; including when such heteroaryl is linked to alkyl, alkenyl or alkynyl such as in heteroarylalkyl, heteroarylalkenyl, heteroarylalkynyl, heteroarylheteroalkyl, heteroarylheteroalkenyl, heteroarylheteroalkynyl; - each heterocycle is 5 to 20 membered heterocycle, more in particular is a 6 to 14 membered heterocycle; yet more in particular is a 6 to 10 membered heterocycle; including when such heterocycle is linked to alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl and heteroalkynyl as in heterocyclealkyl, heterocyclealkenyl, heterocyclealkynyl, heterocycleheteroalkyl, heterocycleheteroalkenyl and heterocycleheteroalkynyl. 6. A compound of formula (I), or an isomer (preferably a stereo-isomer or a tautomer), a solvate, a salt (preferably a pharmaceutically acceptable salt) or a prodrug thereof, preferably a pharmaceutically acceptable salt, solvate, hydrate, polymorph, tautomer, stereoisomer, or prodrug thereof, wherein: - n is selected from 0; and 1; - each represents an optional double bond, whereby maximally 3 are a double bond at the same time; - R ¹ is selected from C _1-6 alkyl; -C(O)R ³ ; -C(O)OR ⁴ ; and -S(O) ₂ R ^3a ; wherein said C _1-6 alkyl can be unsubstituted or substituted with one or more substituents selected from hydroxyl, cyano, -C(O)OH, -SO ₂ C _1-6 alkyl, -SO ₂ NHC _1-6 alkyl, -NHC _1-6 alkyl, - N(C _1-6 alkyl) ₂ ; - R ² is selected from hydrogen; C _1-6 alkyl; and C _1-6 heteroalkyl; - R ¹ and R ² can be taken together to form a 4-membered) heterocycle which can be unsubstituted or substituted with one or more substituents selected from C _1-6 alkyl, hydroxyl, =O, -O-C _1-6 alkyl, cyano, -C(O)OH, -SO ₂ C _1-6 alkyl, -SO ₂ NHC _1-6 alkyl, -NHC _1-6 alkyl, and -N(C _{1- 6} alkyl) ₂ ; - each R ³ and R ^3a is independently selected from C _1-6 alkyl; C _2-6 alkenyl; C _2-6 alkynyl; C _{1- 6} heteroalkyl; C _2-6 heteroalkenyl; C _2-6 heteroalkynyl; wherein said C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 heteroalkyl, C _2-6 heteroalkenyl or C _{2- 6} heteroalkynyl can be unsubstituted or substituted with one or more substituents s ^{elected from hydroxyl, =O, halogen, -SH, =S, -CF} ₃ ^{, -O- C} _1-6 ^{alkyl, -OCF} ₃ ^{, -CHF} ₂ ^{, - OCHF} ₂ ^{, cyano, -C(O)OH; NH} _2; ^-NHC _1-6 ^{alkyl, and -N(C} _1-6 ^alkyl) ₂ ^; - R ⁴ is independently selected from C _1-6 alkyl; C _2-6 alkenyl; C _2-6 alkynyl; C _1-6 heteroalkyl; C _{2- 6} heteroalkenyl; and C _2-6 heteroalkynyl; wherein said C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 heteroalkyl, C _2-6 heteroalkenyl and C _2-6 heteroalkynyl can be unsubstituted or substituted with one or more substituents selected from alkyl, cycloalkyl, alkenyl, alkynyl, hydroxyl, =O, halogen, -SH, =S, -CF ₃ , - O ^{-alkyl, -OCF} ₃ ^{, -CHF} ₂ ^{, -OCHF} ₂ ^{, cyano, nitro, -C(O)OH; NH} _2; ^{-NHalkyl, and -N(alkyl)} ₂ ^; - cycle A is selected from aryl; heteroaryl; and C _3-9 cycloalkyl; wherein said aryl, heteroaryl, C _3-9 cycloalkyl and heterocycle can be unsubstituted or substituted with one or more R ⁷ ; - each R ⁷ is independently selected from halogen; -OZ ¹ ; -SCF ₃ ; -SF ₅ ; -CF ₃ ; -OCF ₃ ; -CHF ₂ ; - OCHF ₂ ; C _1-6 alkyl; C _3-9 cycloakyl; heteroalkyl; aryl; wherein said C _1-6 alkyl, C _3-9 cycloakyl, C _1-6 heteroalkyl and aryl can be unsubstituted or substituted with one or more substituents selected from C _1-6 alkyl, hydroxyl, halogen, -SH, -CF ₃ , -O-C _1-6 alkyl, -OCF ₃ , -CHF ₂ ; -OCHF ₂ , cyano; - X ¹ is selected from CR ⁸ ; N; and NR ^8a ; whereby X ¹ can only be NR ^8a when X ² and/or X ⁴ are C- OH or C-SH; - X ² is selected from CR ⁹ ; and N; - X ³ is selected from CH; and N; - X ⁴ is selected from CH; and N; whereby maximally 2 of X ¹ , X ² , X ³ and X ⁴ can be a N (selected from N and NR ^8a for X ¹ , from N for X ² , from N for X ³ , and from N for X ⁴ respectively) at the same time; _{- R} ⁸ _{is selected from hydrogen; halogen; hydroxyl; sulfhydryl; =O; =S; -OZ} ^1a _{; -CF3; -OCF3; - CHF2; -OCHF2; -NZ} ^3a _Z ^4a _{; -NZ} ^3a _S(O)2Z ^1a _{; -NZ} ^3a _C(O)Z ^1a _{; cyano; -C(O)OZ} ^1a _{; - C(O)NZ} ^3a _Z ^4a _{; C1-6alkyl; C1-6heteroalkyl; aryl; heteroaryl; heterocycle; arylC1-6alkyl;} heteroarylC _1-6 alkyl; and heterocycle-C _1-6 alkyl; wherein said C _1-6 alkyl, C _1-6 heteroalkyl, aryl, heteroaryl, heterocycle, arylC _1-6 alkyl, heteroarylC _1-6 alkyl or heterocycle-C _1-6 alkyl can be unsubstituted or substituted with one or more substituents selected from alkyl, hydroxyl, halogen, -CF ₃ , -O-C _1-6 alkyl, -OCF ₃ , - CHF ₂ ; -OCHF2, cyano, -NH ₂ ; _{- R} ⁹ _{is selected from hydrogen; halogen; hydroxyl; sulfhydryl; =O; =S; -OZ} ^1a _{; -CF3; -OCF3; - CHF2; -OCHF2; -NZ} ^3a _Z ^4a _{; C1-6alkyl; and C1-6heteroalkyl;} wherein said C _1-6 alkyl and C _1-6 heteroalkyl can be unsubstituted or substituted with one or more substituents selected from hydroxyl, halogen, -CF ₃ , -O-C _1-6 alkyl, -OCF ₃ , -CHF ₂ ; -OCHF2, cyano, -NH ₂ ;- R ^8a is independently selected from hydrogen; C _1-6 alkyl; heteroalkyl; aryl; heteroaryl; heterocycle; arylC _1-6 alkyl; heteroarylC _1-6 alkyl; and heterocycle-C _1-6 alkyl; wherein said C _1-6 alkyl, heteroalkyl, aryl, heteroaryl, heterocycle, arylC _1-6 alkyl, heteroarylC _1-6 alkyl or heterocycle-C _1-6 alkyl can be unsubstituted or substituted with one or more substituents selected from C _1-6 alkyl, hydroxyl, halogen, -CF ₃ , -O-C _1-6 alkyl, - OCF ₃ , -CHF ₂ ; -OCHF2, cyano, -NH ₂ ; - each Z ¹ and Z ^1a is independently selected from C _1-6 alkyl; C _2-6 alkenyl; C _2-6 alkynyl; C _{1- 6} heteroalkyl; C _2-6 heteroalkenyl; C _2-6 heteroalkynyl; wherein said C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 heteroalkyl, C _2-6 heteroalkenyl or C _{2- 6} heteroalkynyl can be unsubstituted or substituted with one or more substituents s ^{elected from hydroxyl, =O, halogen, -SH, =S, -CF} ₃ ^{, -O- C} _1-6 ^{alkyl, -OCF} ₃ ^{, -CHF} ₂ ^{, - OCHF} ₂ ^{, cyano, -C(O)OH; NH} _2; ^-NHC _1-6 ^{alkyl, and -N(C} _1-6 ^alkyl) ₂ ^; - _{each Z} ^3a _{and Z} ^4a _{is independently selected from hydrogen; C1-6alkyl; C2-6alkenyl; C2- 6} alkynyl; C _1-6 heteroalkyl; C _2-6 heteroalkenyl; C _2-6 heteroalkynyl; aryl; heteroaryl; heterocycle; wherein said C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 heteroalkyl, C _{2- 6} heteroalkenyl, C _2-6 heteroalkynyl, aryl, heteroaryl and heterocycle can be unsubstituted or substituted with one or more substituents selected from h ^{ydroxyl, =O, halogen, -SH, =S, -CF} ₃ ^{, -O-C} _1-6 ^{alkyl, -OCF} ₃ ^{, -CHF} ₂ ^{, -OCHF} ₂ ^{, cyano, nitro, -C(O)OH; NH} _2; ^-NHC _1-6 ^{alkyl, and -N(C} _1-6 ^alkyl) ₂ ^. 7. A compound of formula (I), or an isomer (preferably a stereo-isomer or a tautomer), a solvate, a salt (preferably a pharmaceutically acceptable salt) or a prodrug thereof, preferably a pharmaceutically acceptable salt, solvate, hydrate, polymorph, tautomer, stereoisomer, or prodrug thereof, wherein - each of n, , R ¹ , R ² , R ⁷ , X ¹ , X ² , X ³ , and X ⁴ have the same meaning as defined herein in the different subgroups, statements, aspects or embodiments described herein; - cycle A is selected from unsubstituted or substituted with one or more R ⁷ phenyl; naphthalenyl; anthracenyl; cyclopropyl; cyclobutyl; cyclopentyl; cyclohexyl; cycloheptyl; cyclooctyl; norbornyl; fenchyl; decalinyl; adamantly; triazolyl; pyridinyl; pyrazolyl; pyrrolyl; furanyl; thiophenyl; imidazolyl; oxazolyl; isoxazolyl; thiazolyl; isothiazolyl; oxadiazolyl; thiadiazolyl; tetrazolyl; oxatriazolyl; pyrimidyl; pyrazinyl; pyridazinyl; triazinyl; indolyl; indolizinyl; isoindolyl; benzofuranyl; benzothiophenyl; indazolyl; benzimidazolyl; benzoxazolyl; benzisoxazolyl; benzothiazolyl; benzoisothiazolyl; dihydro-benzofuranyl; thienopyridinyl; imidazopyridinyl; benzodioxolyl; quinolinyl; isoquinolinyl; cinnolinyl; quinazolinyl; and quinoxalinyl. 8. A compound, or an isomer (preferably a stereo-isomer or a tautomer), a solvate, a salt (preferably a pharmaceutically acceptable salt) or a prodrug thereof, preferably a pharmaceutically acceptable salt, solvate, hydrate, polymorph, tautomer, stereoisomer, or prodrug thereof, selected from one or more of the compounds of Table 1. 9. A compound of formula (I), or an isomer (preferably a stereo-isomer or a tautomer), a solvate, a salt (preferably a pharmaceutically acceptable salt) or a prodrug thereof, preferably a pharmaceutically acceptable salt, solvate, hydrate, polymorph, tautomer, stereoisomer, or prodrug thereof, wherein: - n is selected from 0; and 1; - each represents an optional double bond, whereby maximally 3 are a double bond at the same time; - R ¹ is selected from C _1-6 alkyl; -C(O)R ³ ; -C(O)OR ⁴ ; and -S(O) ₂ R ^3a ; wherein said C _1-6 alkyl can be unsubstituted or substituted with one or more substituents selected from hydroxyl, cyano, -C(O)OH, -SO ₂ C _1-6 alkyl, -SO ₂ NHC _1-6 alkyl, -NHC _1-6 alkyl, - N(C _1-6 alkyl) ₂ ; - R ² is selected from hydrogen; C _1-6 alkyl; and C _1-6 heteroalkyl; - R ¹ and R ² can be taken together to form a 4-membered) heterocycle which can be unsubstituted or substituted with one or more substituents selected from C _1-6 alkyl, hydroxyl, =O, -O-C _1-6 alkyl, cyano, -C(O)OH, -SO ₂ C _1-6 alkyl, -SO ₂ NHC _1-6 alkyl, -NHC _1-6 alkyl, and -N(C _{1- 6} alkyl) ₂ ; - each R ³ and R ^3a is independently selected from C _1-6 alkyl; C _2-6 alkenyl; C _2-6 alkynyl; C _{1- 6} heteroalkyl; C _2-6 heteroalkenyl; C _2-6 heteroalkynyl; wherein said C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 heteroalkyl, C _2-6 heteroalkenyl or C _{2- 6} heteroalkynyl can be unsubstituted or substituted with one or more substituents selected from hydroxyl, =O, halogen, -SH, =S, -CF ₃ , -O- C _1-6 alkyl, -OCF ₃ , -CHF ₂ , - O ^CHF ₂ ^{, cyano, -C(O)OH; NH} _2; ^-NHC _1-6 ^{alkyl, and -N(C} _1-6 ^alkyl) ₂ ^; - R ⁴ is independently selected from C _1-6 alkyl; C _2-6 alkenyl; C _2-6 alkynyl; C _1-6 heteroalkyl; C _{2- 6} heteroalkenyl; and C _2-6 heteroalkynyl; wherein said C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 heteroalkyl, C _2-6 heteroalkenyl and C _2-6 heteroalkynyl can be unsubstituted or substituted with one or more substituents selected from alkyl, cycloalkyl, alkenyl, alkynyl, hydroxyl, =O, halogen, -SH, =S, -CF ₃ , - O ^{-alkyl, -OCF} ₃ ^{, -CHF} ₂ ^{, -OCHF} ₂ ^{, cyano, nitro, -C(O)OH; NH} _2; ^{-NHalkyl, and -N(alkyl)} ₂ ^; - cycle A is selected from phenyl; cyclopentyl; cyclohexyl; cycloheptyl; pyridinyl; pyrimidyl; pyrazinyl; pyridazinyl; indolyl; indolizinyl; isoindolyl; indazolyl; benzimidazolyl; benzoxazolyl; benzisoxazolyl; benzothiazolyl; benzoisothiazolyl;thienopyridinyl; imidazopyridinyl; quinolinyl; isoquinolinyl; cinnolinyl; quinazolinyl; and quinoxalinyl; wherein said phenyl, cyclopentyl, cyclohexyl, cycloheptyl, pyridinyl, pyrimidyl, pyrazinyl, pyridazinyl, indolyl, indolizinyl, isoindolyl, indazolyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzoisothiazolyl, thienopyridinyl, imidazopyridinyl, quinolinyl, isoquinolinyl, cinnolinyl, quinazolinyl, and quinoxalinyl can be unsubstituted or substituted with one or more R ⁷ ; - each R ⁷ is independently selected from halogen; -OZ ¹ ; -SCF ₃ ; -SF ₅ ; -CF ₃ ; -OCF ₃ ; -CHF ₂ ; - OCHF ₂ ; C _1-6 alkyl; C _3-9 cycloakyl; heteroalkyl; aryl; wherein said C _1-6 alkyl, C _3-9 cycloakyl, C _1-6 heteroalkyl and aryl can be unsubstituted or substituted with one or more substituents selected from C _1-6 alkyl, hydroxyl, halogen, -SH, -CF ₃ , -O-C _1-6 alkyl, -OCF ₃ , -CHF ₂ ; -OCHF ₂ , cyano; - X ¹ is selected from CR ⁸ ; N; and NR ^8a ; whereby X ¹ can only be NR ^8a when X ² and/or X ⁴ are C- OH or C-SH; - X ² is selected from CR ⁹ ; and N; - X ³ is selected from CH; and N; - X ⁴ is selected from CH; and N; whereby maximally 2 of X ¹ , X ² , X ³ and X ⁴ can be a N (selected from N and NR ^8a for X ¹ , from N for X ² , from N for X ³ , and from N for X ⁴ respectively) at the same time; _{- R} ⁸ _{is selected from hydrogen; halogen; hydroxyl; sulfhydryl; =O; =S; -OZ} ^1a _{; -CF3; -OCF3; - CHF2; -OCHF2; -NZ} ^3a _Z ^4a _{; -NZ} ^3a _S(O)2Z ^1a _{; -NZ} ^3a _C(O)Z ^1a _{; cyano; -C(O)OZ} ^1a _{; - C(O)NZ} ^3a _Z ^4a _{; C1-6alkyl; C1-6heteroalkyl; aryl; heteroaryl; heterocycle; arylC1-6alkyl;} heteroarylC _1-6 alkyl; and heterocycle-C _1-6 alkyl; wherein said C _1-6 alkyl, C _1-6 heteroalkyl, aryl, heteroaryl, heterocycle, arylC _1-6 alkyl, heteroarylC _1-6 alkyl or heterocycle-C _1-6 alkyl can be unsubstituted or substituted with one or more substituents selected from alkyl, hydroxyl, halogen, -CF ₃ , -O-C _1-6 alkyl, -OCF ₃ , - CHF ₂ ; -OCHF2, cyano, -NH ₂ ; _{- R} ⁹ _{is selected from hydrogen; halogen; hydroxyl; sulfhydryl; =O; =S; -OZ} ^1a _{; -CF3; -OCF3; - CHF2; -OCHF2; -NZ} ^3a _Z ^4a _{; C1-6alkyl; and C1-6heteroalkyl;} wherein said C _1-6 alkyl and C _1-6 heteroalkyl can be unsubstituted or substituted with one or more substituents selected from hydroxyl, halogen, -CF ₃ , -O-C _1-6 alkyl, -OCF ₃ , -CHF ₂ ; -OCHF2, cyano, -NH ₂ ;- R ^8a is independently selected from hydrogen; C _1-6 alkyl; heteroalkyl; aryl; heteroaryl; heterocycle; arylC _1-6 alkyl; heteroarylC _1-6 alkyl; and heterocycle-C _1-6 alkyl; wherein said C _1-6 alkyl, heteroalkyl, aryl, heteroaryl, heterocycle, arylC _1-6 alkyl, heteroarylC _1-6 alkyl or heterocycle-C _1-6 alkyl can be unsubstituted or substituted with one or more substituents selected from C _1-6 alkyl, hydroxyl, halogen, -CF ₃ , -O-C _1-6 alkyl, - OCF ₃ , -CHF ₂ ; -OCHF2, cyano, -NH ₂ ; - each Z ¹ and Z ^1a is independently selected from C _1-6 alkyl; C _2-6 alkenyl; C _2-6 alkynyl; C _{1- 6} heteroalkyl; C _2-6 heteroalkenyl; C _2-6 heteroalkynyl; wherein said C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 heteroalkyl, C _2-6 heteroalkenyl or C _{2- 6} heteroalkynyl can be unsubstituted or substituted with one or more substituents s ^{elected from hydroxyl, =O, halogen, -SH, =S, -CF} ₃ ^{, -O- C} _1-6 ^{alkyl, -OCF} ₃ ^{, -CHF} ₂ ^{, - OCHF} ₂ ^{, cyano, -C(O)OH; NH} _2; ^-NHC _1-6 ^{alkyl, and -N(C} _1-6 ^alkyl) ₂ ^; - _{each Z} ^3a _{and Z} ^4a _{is independently selected from hydrogen; C1-6alkyl; C2-6alkenyl; C2- 6} alkynyl; C _1-6 heteroalkyl; C _2-6 heteroalkenyl; C _2-6 heteroalkynyl; aryl; heteroaryl; heterocycle; wherein said C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 heteroalkyl, C _{2- 6} heteroalkenyl, C _2-6 heteroalkynyl, aryl, heteroaryl and heterocycle can be unsubstituted or substituted with one or more substituents selected from h ^{ydroxyl, =O, halogen, -SH, =S, -CF} ₃ ^{, -O-C} _1-6 ^{alkyl, -OCF} ₃ ^{, -CHF} ₂ ^{, -OCHF} ₂ ^{, cyano, nitro, -C(O)OH; NH} _2; ^-NHC _1-6 ^{alkyl, and -N(C} _1-6 ^alkyl) ₂ ^. 10. A compound of formulas (II), (IIa), (IIb), (IIc), (IId), (IIe), and (IIf) or an isomer (preferably a stereo-isomer or a tautomer), a solvate, a salt (preferably a pharmaceutically acceptable salt) or a prodrug thereof, preferably a pharmaceutically acceptable salt, solvate, hydrate, polymorph, tautomer, stereoisomer, or prodrug thereof, wherein: - n is selected from 0; and 1; - R ¹ is selected from alkyl; cycloalkyl; heteroalkyl; -C(O)R ³ ; -C(O)OR ⁴ ; -S(O) ₂ R ^3a ; -S(O)R ^4a ; - S ^(O) ₂ ^{NR5aR6a; -S(O)(NR5a)R4a; and -S(NR5a)(NR6a)R3a;} wherein said alkyl, cycloalkyl and heteroalkyl can be unsubstituted or substituted with one or more substituents selected from alkyl, cycloalkyl, hydroxyl, =O, halogen, -SH, =S, trifluoromethyl, -O-alkyl, -OCF ₃ , cyano, -C(O)OH, -CONH ₂ , -CONHalkyl, -CON(alkyl) ₂ , - SO ₂ alkyl, -SO ₂ NH ₂ , -SO ₂ NHalkyl, -SO ₂ N(alkyl) ₂ , -S(O)(NH)alkyl, -S(O)(Nalkyl)alkyl, - S(NH)(NH)alkyl, -NH ₂ , -NHalkyl, -N(alkyl) ₂ ; - R ² is selected from hydrogen; alkyl; cycloalkyl; and heteroalkyl; - R ¹ and R ² can be taken together to form a (4-; 5-; or 6-membered) heterocycle which can be unsubstituted or substituted with one or more substituents selected from alkyl, cycloalkyl, hydroxyl, =O, halogen, -SH, =S, trifluoromethyl, -O-alkyl, -OCF ₃ , cyano, nitro, -C(O)OH, - CONH ₂ , -CONHalkyl, -CON(alkyl) ₂ , -SO ₂ alkyl, -SO ₂ NH ₂ , -SO ₂ NHalkyl, -SO ₂ N(alkyl) ₂ , - S(O)(NH)alkyl, -S(O)(Nalkyl)alkyl, -S(NH)(NH)alkyl, -NH ₂ , -NHalkyl, -N(alkyl) ₂ ; - each R ³ and R ^3a is independently selected from hydroxyl; C _1-6 alkyl; C _3-9 cycloalkyl; C _2-6 alkenyl; C _5-9 cycloalkenyl; C _2-6 alkynyl; C _5-9 cycloalkynyl; C _1-6 heteroalkyl; C _2-6 heteroalkenyl; and C _{2- 6} heteroalkynyl; wherein said C _1-6 alkyl, C _3-9 cycloalkyl, C _2-6 alkenyl, C _5-9 cycloalkenyl, C _2-6 alkynyl, C _{5- 9} cycloalkynyl, C _1-6 heteroalkyl, C _2-6 heteroalkenyl and C _2-6 heteroalkynyl can be unsubstituted or substituted with one or more substituents selected from alkyl, cycloalkyl, alkenyl, alkynyl, hydroxyl, =O, halogen, -SH, =S, -CF ₃ , -O-alkyl, -OCF ₃ , -CHF ₂ , -OCHF ₂ , c ^{yano, nitro, -C(O)OH; NH} _2; ^{-NHalkyl, and -N(alkyl)} ₂ ^; - each R ⁴ and R ^4a is independently selected from C _1-6 alkyl; C _3-9 cycloalkyl; C _2-6 alkenyl; C _{5- 9} cycloalkenyl; C _2-6 alkynyl; C _5-9 cycloalkynyl; C _1-6 heteroalkyl; C _2-6 heteroalkenyl; and C _{2- 6} heteroalkynyl; wherein said C _1-6 alkyl, C _3-9 cycloalkyl, C _2-6 alkenyl, C _5-9 cycloalkenyl, C _2-6 alkynyl, C _{5- 9} cycloalkynyl, C _1-6 heteroalkyl, C _2-6 heteroalkenyl and C _2-6 heteroalkynyl can be unsubstituted or substituted with one or more substituents selected from alkyl, cycloalkyl, alkenyl, alkynyl, hydroxyl, =O, halogen, -SH, =S, -CF ₃ , -O-alkyl, -OCF ₃ , - C ^HF ₂ ^{, -OCHF} ₂ ^{, cyano, nitro, -C(O)OH; NH} _2; ^{-NHalkyl, and -N(alkyl)} ₂ ^; - each R ⁵ , R ^5a , R ^5b , R ⁶ , R ^6a and R ^6b is independently selected from hydrogen; C _1-6 alkyl; C _{3- 9} cycloalkyl; C _2-6 alkenyl; C _5-9 cycloalkenyl; C _2-6 alkynyl; C _5-9 cycloalkynyl; C _1-6 heteroalkyl; C _{2- 6} heteroalkenyl; and C _2-6 heteroalkynyl; wherein said C _1-6 alkyl, C _3-9 cycloalkyl, C _2-6 alkenyl, C _5-9 cycloalkenyl, C _2-6 alkynyl, C _5-9 cycloalkynyl, C _1-6 heteroalkyl, C _2-6 heteroalkenyl and C _2-6 heteroalkynyl can be unsubstituted or substituted with one or more substituents selected from alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, hydroxyl, =O, halogen, - ^{35 SH, =S, -CF} ₃ ^{, -O-alkyl, -OCF} ₃ ^{, -CHF} ₂ ^{, -OCHF} ₂ ^{, cyano, nitro, -C(O)OH; NH} _2; - NHalkyl, and -N(alkyl) ₂ ; and wherein each R ⁵ and R ⁶ or R ^5a and R ^6a can be taken together in order to form a (4-, 5-, 6-, or 7-membered) heterocycle which can be unsubstituted or substituted with one or more substituents selected from alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, hydroxyl, =O, halogen, -SH, =S, -CF ₃ , -O- a ^{lkyl, -OCF} ₃ ^{, -CHF} ₂ ^{, -OCHF} ₂ ^{, cyano, nitro, -C(O)OH; NH} _2; ^{-NHalkyl, and -} N(alkyl) ₂ ; - cycle A is selected from aryl; heteroaryl; cycloalkyl; and heterocycle; wherein said aryl, heteroaryl, cycloalkyl and heterocycle can be unsubstituted or substituted with one or more R ⁷ ; _{- each R} ⁷ _{is independently selected from halogen; hydroxyl; sulfhydryl; =O; =S; -OZ} ¹ _{; -SZ} ¹ _{; - SCF3; -SF5; -CF3; -OCF3; -CHF2; -OCHF2; -NZ} ³ _Z ⁴ _{; cyano; alkyl; cycloakyl; heteroalkyl; aryl;} heteroaryl; heterocycle; arylalkyl; arylheteroalkyl; heteroarylalkyl; heteroarylheteroalkyl; heterocycle-alkyl; and heterocycle-heteroalkyl; wherein said alkyl, cycloakyl, heteroalkyl, aryl, heteroaryl, heterocycle, arylalkyl, arylheteroalkyl, heteroarylalkyl, heteroarylheteroalkyl, heterocycle-alkyl or heterocycle-heteroalkyl can be unsubstituted or substituted with one or more substituents selected from alkyl, cycloalkyl, hydroxyl, =O, halogen, -SH, =S, -CF ₃ , - O-alkyl, -OCF ₃ , -CHF ₂ ; -OCHF ₂ , cyano; - each R ⁸ and R ⁹ are independently selected from hydrogen; halogen; hydroxyl; sulfhydryl; =O; _{=S; -OZ} ^1a _{; -SZ} ^1a _{; -SCF3; -SF5; -S(O)Z} ^1a _{; -S(O)(NZ} ^3a _)Z ^1a _{; -S(NZ} ^3a _)(NZ ^3a _)Z ^1a _{; -S(O)2Z} ^2a _{; -S(O)2NZ} ^3a _Z ^4a _{; -CF3; -OCF3; -CHF2; -OCHF2; -NZ} ^3a _Z ^4a _{; -NZ} ^3a _S(O)2Z ^1a _{; -NZ} ^3a _C(O)Z ^1a _{; - NZ} ^3a _C(O)NZ ^3a _Z ^4a _{; cyano; -C(O)Z} ^2a _{; -C(O)OZ} ^1a _{; -C(O)NZ} ^3a _Z ^4a _{; alkyl; cycloakyl;} heteroalkyl; aryl; heteroaryl; heterocycle; arylalkyl; arylheteroalkyl; heteroarylalkyl; heteroarylheteroalkyl; heterocycle-alkyl; and heterocycle-heteroalkyl; wherein said alkyl, cycloakyl, heteroalkyl, aryl, heteroaryl, heterocycle, arylalkyl, arylheteroalkyl, heteroarylalkyl, heteroarylheteroalkyl, heterocycle-alkyl or heterocycle- heteroalkyl can be unsubstituted or substituted with one or more substituents selected from alkyl, cycloalkyl, hydroxyl, =O, halogen, -SH, =S, -CF ₃ , -O-alkyl, -OCF ₃ , -CHF ₂ ; - OCHF2, cyano, -C(O)OH, -NH ₂ , -NHalkyl, and -N(alkyl) ₂ ; _{- each of R} ^8a _{and R} ^9a _{, are independently selected from hydrogen; hydroxyl; sulfhydryl; -OZ} ^1a _{; - SZ} ^1a _{; -SCF3; -SF5; -S(O)Z} ^1a _{; -S(O)(NZ} ^3a _)Z ^1a _{; -S(NZ} ^3a _)(NZ ^3a _)Z ^1a _{; -S(O)2Z} ^2a _{; - S(O)2NZ} ^3a _Z ^4a _{; -CF3; -OCF3; -CHF2; -OCHF2; -NZ} ^3a _Z ^4a _{; -NZ} ^3a _S(O)2Z ^2a _{; -NZ} ^3a _C(O)Z ^1a _{; - NZ} ^3a _C(O)NZ ^3a _Z ^4a _{; cyano; -C(O)Z} ^2a _{; -C(O)OZ} ^1a _{; -C(O)NZ} ^3a _Z ^4a _{; - alkyl; cycloakyl;} heteroalkyl; aryl; heteroaryl; heterocycle; arylalkyl; arylheteroalkyl; heteroarylalkyl; heteroarylheteroalkyl; heterocycle-alkyl; and heterocycle-heteroalkyl; wherein said alkyl, cycloakyl, heteroalkyl, aryl, heteroaryl, heterocycle, arylalkyl, arylheteroalkyl, heteroarylalkyl, heteroarylheteroalkyl, heterocycle-alkyl or heterocycle- heteroalkyl can be unsubstituted or substituted with one or more substituents selected from alkyl, cycloalkyl, hydroxyl, =O, halogen, -SH, =S, -CF ₃ , -O-alkyl, -OCF ₃ , -CHF ₂ ; - OCHF2, cyano, -C(O)OH, -NH ₂ , -NHalkyl, and -N(alkyl) ₂ ; - each Z ¹ and Z ^1a is independently selected from alkyl; alkenyl; cycloalkenyl; alkynyl; cycloalkyl; cycloalkynyl; heteroalkyl; heteroalkenyl; heteroalkynyl; aryl; heteroaryl; heterocycle; arylalkyl; arylalkenyl; arylalkynyl; arylheteroalkyl; arylheteroalkenyl; arylheteroalkynyl; heteroarylalkyl; heteroarylalkenyl; heteroarylalkynyl; heteroarylheteroalkyl; heteroarylheteroalkenyl; heteroarylheteroalkynyl; heterocycle-alkyl; heterocycle-alkenyl; heterocycle-alkynyl; heterocycle-heteroalkyl; heterocycle-heteroalkenyl; or heterocycle-heteroalkynyl; wherein said alkyl, cycloalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, aryl, heteroaryl, heterocycle, arylalkyl, arylalkenyl, arylalkynyl, arylheteroalkyl, arylheteroalkenyl, arylheteroalkynyl, heteroarylalkyl, heteroarylalkenyl, heteroarylalkynyl, heteroarylheteroalkyl, heteroarylheteroalkenyl, heteroarylheteroalkynyl, heterocycle-alkyl, heterocycle- alkenyl, heterocycle-alkynyl, heterocycle-heteroalkyl, heterocycle-heteroalkenyl, or heterocycle-heteroalkynyl can be unsubstituted or substituted with one or more substituents selected from alkyl, cycloalkyl, alkenyl, alkynyl, hydroxyl, =O, halogen, - S ^{H, =S, -CF} ₃ ^{, -O-alkyl, -OCF} ₃ ^{, -CHF} ₂ ^{, -OCHF} ₂ ^{, cyano, -C(O)OH; NH} _2; ^{-NHalkyl, and -} N(alkyl) ₂ ; - each Z ² and Z ^2a is independently selected from hydroxyl; alkyl; cycloalkyl; alkenyl; cycloalkenyl; alkynyl; cycloalkynyl; heteroalkyl; heteroalkenyl; heteroalkynyl; aryl; heteroaryl; heterocycle; arylalkyl; arylalkenyl; arylalkynyl; arylheteroalkyl; arylheteroalkenyl; arylheteroalkynyl; heteroarylalkyl; heteroarylalkenyl; heteroarylalkynyl; heteroarylheteroalkyl; heteroarylheteroalkenyl; heteroarylheteroalkynyl; heterocycle-alkyl; heterocycle-alkenyl; heterocycle-alkynyl; heterocycle-heteroalkyl; heterocycle-heteroalkenyl; or heterocycle- heteroalkynyl; wherein said alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, aryl, heteroaryl, heterocycle, arylalkyl, arylalkenyl, arylalkynyl, arylheteroalkyl, arylheteroalkenyl, arylheteroalkynyl, heteroarylalkyl, heteroarylalkenyl, heteroarylalkynyl, heteroarylheteroalkyl, heteroarylheteroalkenyl, heteroarylheteroalkynyl, heterocycle-alkyl, heterocycle-alkenyl, heterocycle- alkynyl, heterocycle-heteroalkyl, heterocycle-heteroalkenyl, or heterocycle-heteroalkynyl can be unsubstituted or substituted with one or more substituents selected from alkyl, cycloalkyl, a ^{lkenyl, alkynyl, hydroxyl, =O, halogen, -SH, =S, -CF} ₃ ^{, -O-alkyl, -OCF} ₃ ^{, -CHF} ₂ ^{, -OCHF} ₂ ^{, cyano, -C(O)OH; NH} _2; ^{-NHalkyl, and -N(alkyl)} ₂ ^; - _{each Z} ³ _{, Z} ^3a _{, Z} ⁴ _{, and Z} ^4a _{is independently selected from hydrogen; alkyl; cycloalkyl;} alkenyl; cycloalkenyl; alkynyl; cycloalkynyl; heteroalkyl; heteroalkenyl; heteroalkynyl; aryl; heteroaryl; heterocycle; arylalkyl; arylalkenyl; arylalkynyl; arylheteroalkyl; arylheteroalkenyl; arylheteroalkynyl; heteroarylalkyl; heteroarylalkenyl; heteroarylalkynyl; heteroarylheteroalkyl; heteroarylheteroalkenyl; heteroarylheteroalkynyl; heterocycle-alkyl; heterocycle-alkenyl; heterocycle-alkynyl; heterocycle-heteroalkyl; heterocycle-heteroalkenyl; or heterocycle-heteroalkynyl; wherein said alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, aryl, heteroaryl, heterocycle, arylalkyl, arylalkenyl, arylalkynyl, arylheteroalkyl, arylheteroalkenyl, arylheteroalkynyl, heteroarylalkyl, heteroarylalkenyl, heteroarylalkynyl, heteroarylheteroalkyl, heteroarylheteroalkenyl, heteroarylheteroalkynyl, heterocycle-alkyl, heterocycle-alkenyl, heterocycle-alkynyl, heterocycle- heteroalkyl, heterocycle-heteroalkenyl, or heterocycle-heteroalkynyl can be unsubstituted or substituted with one or more substituents selected from alkyl, cycloalkyl, alkenyl, alkynyl, hydroxyl, =O, halogen, -SH, =S, -CF ₃ , -O-alkyl, - O ^CF ₃ ^{, -CHF} ₂ ^{, -OCHF} ₂ ^{, cyano, nitro, -C(O)OH; NH} _2; ^{-NHalkyl, and -N(alkyl)} ₂ ^; and wherein each Z ³ and Z ⁴ or Z ^3a and Z ^4a can be taken together in order to form a (4-, 5-, 6-, or 7-membered) heterocycle which can be unsubstituted or substituted with one or more substituents selected from alkyl, cycloalkyl, a ^{lkenyl, alkynyl, hydroxyl, =O, halogen, -SH, =S, -CF} ₃ ^{, -O-alkyl, -OCF} ₃ ^{, -CHF} ₂ ^{, -OCHF} ₂ ^{, cyano, nitro, -C(O)OH; NH} _2; ^{-NHalkyl, and -N(alkyl)} ₂ ^. In a specific embodiment of the present disclosure, the compounds have a structure according to formulas (II), (IIa), (IIb), (IIc), (IId), (IIe), and (IIf) or an isomer (preferably a stereo-isomer or a tautomer), a solvate, a salt (preferably a pharmaceutically acceptable salt) or a prodrug thereof, whereby the different substituents n, R ¹ , R ² , R ³ , R ^3a , R ⁴ , R ^4a , R ⁵ , R ^5a , R ^5b , R ⁶ , R ^6a , R ^6b , cycle A, R ⁷ , _R ⁸ _{, R} ⁹ _{, R} ^8a _{, R} ^9a _{, Z} ¹ _{, Z} ^1a _Z ² _{, Z} ^2a _{, Z} ³ _{, Z} ^3a _{, Z} ⁴ _{, and Z} ^4a _{have the same meaning as defined herein in} the different statements, aspects or embodiments for formula (I), more specifically as in statement 1, 2, 3, 4, 5, 6, 7, or 8 herein. 11. A compound of formulas (III), (IIIa), (IIIb), (IIIc), (IIId), (IIIe), (IIIf) and (IIIg) or an isomer (preferably a stereo-isomer or a tautomer), a solvate, a salt (preferably a pharmaceutically acceptable salt) or a prodrug thereof, preferably a pharmaceutically acceptable salt, solvate, hydrate, polymorph, tautomer, stereoisomer, or prodrug thereof, wherein: - each of n, R ¹ , R ² , cycle A, R ⁷ , X ¹ , X ² , X ³ , X ⁴ , R ⁸ , R ⁹ , R ^8a and R ^9a have the same meaning as defined herein in the different subgroups, statements, aspects or embodiments; more in particular as in the statements 1, 2, 3, 4, 5, 6, 7, 8, and 9 herein; - m is selected from 0; 1; 2, 3 and 4. 12. A compound of formulas (IV), (IVa), (IVb), (IVc), (IVd), (IVe), (IVf) and (IVg) or an isomer (preferably a stereo-isomer or a tautomer), a solvate, a salt (preferably a pharmaceutically acceptable salt) or a prodrug thereof, preferably a pharmaceutically acceptable salt, solvate, hydrate, polymorph, tautomer, stereoisomer, or prodrug thereof,