WO2020225077A1

WO2020225077A1 - Pyrimido[4,5-b]indol derivatives as pdhk1 inhibitors

Info

Publication number: WO2020225077A1
Application number: PCT/EP2020/061994
Authority: WO
Inventors: Christoph Boss; Stefan Diethelm; Giorgio Guido FERRARI; Philippe Guerry; Laurence JUNG; Thierry Kimmerlin; Cédric LEROY; Hervé SIENDT
Original assignee: Idorsia Pharmaceuticals Ltd
Priority date: 2019-05-03
Filing date: 2020-04-30
Publication date: 2020-11-12

Abstract

The present invention relates to piperidine derivatives of formula (I) wherein R¹, and R² are as described in the description, their preparation, to pharmaceutically acceptable salts thereof, and to their use as pharmaceuticals, to pharmaceutical compositions containing one or more compounds of formula (I), and especially to their use as inhibitors of the pyruvate dehydrogenase kinase PDHK1 and/or as modulators of the immunometabolism.

Description

PYRIMIDO[4,5-B]INDOL DERIVATIVES AS PDHK1 INHIBITORS

The present invention relates to novel piperidine derivatives of formula (I) which are suited as pharmaceuticals which are inhibitors of the pyruvate dehydrogenase kinase PDHK1 , and to related aspects including processes for the preparation of the compounds of formula (I), pharmaceutical compositions containing one or more compounds of formula (I), and to the use of the compounds of formula (I) as inhibitors of the pyruvate dehydrogenase kinase PDHK1 and/or modulators of the immunometabolism. The invention further relates to the compounds of formula (I) and their use as pharmaceuticals in combination with one or more therapeutic agents and/or radiotherapy and/or targeted therapy in the treatment of cancers.

Glucose metabolism is the most important pathway to provide ATP in human body. After glucose is transported into cells, it is metabolized by several steps to pyruvate by glycolysis. Majority of cancer cells transform most pyruvate into lactate in cytoplasm even in the presence of adequate oxygen rather than oxidized via tricarboxylic acid (TCA) cycle. This phenomenon has become known as the 'Warburg effect¹ (Warburg, et al., The metabolism of tumors in the body, J gen Physiol, 1927, 8(6):519-30) or referred to as aerobic glycolysis, which is the most prominent metabolic difference between normal and tumor cells. The Warburg effect' is now widely considered to be one of the hallmarks of cancer biology (Hanahan and Weinberg, Hallmarks of cancer: the next generation, Cell, 201 1 , 144(5):646-74). In summary, non-neoplastic cells depend predominantly on ATP/energy produced by pyruvate oxidation in the mitochondria whereas proliferating cancer cells predominately rely on aerobic glycolysis in the cytoplasm. The Warburg phenotype in cancer cells is thought to be important for cancer growth and survival for a number of reasons. Firstly, although ATP generation via glycolysis is less efficient than oxidative phosphorylation, it is considerably more rapid. This may be more suited to supplying the energetic needs of a rapidly proliferating cell. Similarly, elevated glycolytic activity can enable cancer cells to increase flux through pathways which supply metabolites for anabolic metabolism required for growth and proliferation (such as the pentose phosphate pathway for nucleotide synthesis). Another potential advantage is that the decreased extracellular pH resulting from increased lactate production in cancer cells with a Warburg phenotype may facilitate local invasion as a result of increased activity of matrix degrading enzymes as well as contributing to suppression of the immune system. Greater reliance on oxygen-independent generation of ATP via glycolysis will also favour survival in hypoxic regions of the tumour microenvironment.

In the past decade there has been a resurgence of interest in cancer metabolism as a promising field for the development of novel therapeutic agents (Martinez-Outschoorn et al, Cancer metabolism: a therapeutic perspective, Nature Rev Clin Oncol, 2017 Jan; 14(1):1 1 -31). This has resulted in a number of discoveries that have greatly increased our understanding of the altered metabolic state in cancer cells as well as the genetic alterations that drive this process (Cairns et al., Cancer cell metabolism, Cold Spring Harb Symp Quant Biol, 201 1 , 76:299- 31 1). Most human tumors are genetically distinct with numerous oncogenes being activated and with loss of multiple tumor suppressors. Treating tumors on the basis of their unique genetic profile has been a daunting task because of this extreme variation. Despite this vast heterogeneity, alterations in many oncogenes and tumor suppressor genes induce a common metabolic phenotype. Therapy predicated on this shared characteristic might prove to be better anticancer strategy than treatment based on the complex and highly variable genetic profiles of tumors. The challenge within the field of cancer metabolism is to identify critical nodes in metabolic pathways which are central to the maintenance of this altered metabolic state as well as being characterized by limited cellular capacity for compensation when their activity is inhibited. Naturally, targets which fulfill these characteristics should also demonstrate selectivity for cancer cells such that a reasonable therapeutic window can be achieved.

Pyruvate dehydrogenase kinases (PDHKs), members of the GHKL ATPase/kinase superfamily, are key regulators of the activity of the pyruvate dehydrogenase (PDH). The PDHK family is composed of four members: PDHK1 , PDHK2, PDHK3 and PDHK4 in mammals (gene names: PDK-1 , PDK-2, PDK-3 and PDK-4). PDHK1 should not be confused with Phosphoinositide-dependent kinase-1 , which is also sometimes referred to as "PDK1 ".

PDH is a multienzyme complex consisting of three enzyme components (E1 , E2 and E3) localized in the mitochondria matrix. The E1 , E2 and E3 subunits are respectively responsible for pyruvate decarboxylation, acetyl- CoA production and NAD to NADH reduction. PDHKs and PDH phosphatases are responsible for PDH regulation via phosphorylation and dephosphorylation of the PDH E1 subunit. More precisely, the role of PDHKs, protein kinases having specificity to PDH, is to inactivate the PDH E1 subunit of the complex by phosphorylation whereas PDH phosphatases specificaly activate PDH via dephosphorylation of the PDH E1 subunit. The proportion of PDH in its active (dephosphorylated) state is determined by the balance of kinase activity and phosphatase activity. The kinase activity is regulated by relative concentrations of metabolic substrates. For example, the kinase activity is activated by an increase in the NADH/NAD, acetyl-CoA/CoA or ATP/adenosine diphosphate (ADP) ratios and inhibited by pyruvate.

PDHKs inactivate PDH by phosphorylating it using ATP. Both PDHKs and PDH are located in the mitochondrial matrix of eukaryotic cells. PDH represents a central control point in cellular energy metabolism in that it links glycolysis to the TCA cycle by catalyzing the oxidative decarboxylation of pyruvate to acetyl-CoA in the matrix of the mitochondria. Therefore, PDH controls the degree to which glycolytically-derived pyruvate is utilized for ATP generation via oxidative phosphorylation or whether it is subjected to alternative metabolic fates such as oxidation to Lactate or transamination to Alanine.

PDHK reduces PDH activity by phosphorylating three serine residues on the E1 subunit (an a2b2 heterodimer): Ser 293 (site 1 ), Ser 300 (site 2), and Ser 232 (site 3) (Mann et al, Diverse mechanisms of inhibition of pyruvate dehydrogenase kinase by structurally distinct inhibitors, Biochim Biophys Acta, 2000, 1480(1 -2):283-92). Among the four PDHK isozymes known to exist in mammals, Ser 293 and Ser 300 are phosphorylated equally well by all four isozymes; however, phosphorylation of Ser 232 is isoenzyme specific being only phosphorylated by PDHK1 (Korotchkina et al, Site specificity of four pyruvate dehydrogenase kinase isoenzymes toward the three phosphorylation sites of human pyruvate dehydrogenase, J Biol Chem, 2001 , 276(40) : 37223-9) . Reactivation of PDH is controlled by the activity of two PDH phosphatase isozymes, PDP-1 and PDP-2, which can dephosphorylate all three of the above phosphoryated serines on the PDH E1 subunit.

The four isomeric forms of PDHKs are expressed in a tissue specific manner in mammalian cells. PDHK1 is dominantly found in heart and pancreatic islet. PDHK2 is most abundantly and constitutively expressed in all tissues, particularly in the liver and kidney. PDHK3 is for the most part expressed in the testis whereas its expression level is extremely low in other tissues. PDHK4 is present in small amounts in skeletal muscle, heart and liver but its expression is dramatically changed by physiological conditions. (Zhang et al,“Targeting tumor metabolism for cancer treatment: Is pyruvate dehydrogenase kinases (PDKs) a viable anticancer target?”, Int J Biol Sci, 2015, 11 (12): 1390-400 and Jeoung,“Pyruvate dehydrogenase kinases: therapeutic targets for diabetes and cancers”, Diabetes and Metabolism Journal, 2015, 39: 188-97).

The expression of PDHKs varies in different pathological conditions. Starvation, diabetes and hyperthyroidism could promote the expression of PDHK2 and PDHK4. The expression of PDHK1 and PDHK3 are stimulated in cancer cells or hypoxia microenvironment, while insulin increases the expression of PDHK4.

PDHKs have been shown to be therapeutic targets related to multiple diseases and disorders. In cancer cells, ATP production by oxidative phosphorylation in mitochondria decreases whereas ATP production via the anaerobic glycolysis in the cytoplasm increases. Activation of PDH by inhibiting PDHKs is therefore expected to promote oxidative phosphorylation in mitochondria leading to apoptosis of cancer cells. Accordingly, there is now a considerable body of evidence which points to an important role for PDHKs in cancer.

Firstly, PDHK isozymes have been shown to be over-expressed in clinical cancer specimens compared to normal counterpart tissues and this augmented expression has been correlated with poor prognosis as well as drug resistance (Lu et al, Overexpression of pyruvate dehydrogenase kinase 3 increases drug resistance and early recurrence in colon cancer, Am J Pathol, 2011 , 179(3): 1405-1414 ; Wigfield et al, PDK-1 regulates lactate production in hypoxia and is associated with poor prognosis in head and neck squamous cancer. Br J Cancer, 2008, 98(12): 1975-84; Koukourakis et al, Pyruvate dehydrogenase and Pyruvate dehydrogenase kinase expression in non-small cell lung cancer and tumour- associated stroma, Neoplasia, 2005, 7(1 ): 1-6). Furthermore, PDHKs gene expression has been shown to be up-regulated under conditions relevant to the tumor microenvironment such as hypoxia ( PDK-1 & PDK-3) or by inactivating mutations in common tumor suppressor genes such as p53 ( PDK-2 ) and pRB ( PDK-4) (Contractor and Harris, p53 negatively regulates transcription of the pyruvate dehydrogenase kinase PDK2, Cancer Res, 201 1 , 72(2): 560-67 ; Hsieh et al., Regulation of the PDK4 isozyme by the Rb-E2F1 complex, J Biol Chem, 2008, 283(41): 27401 -7). Both knock-down and pharmacological approaches have been employed to study the role of PDHKs in cancer both in vitro and in murine tumour xenograft studies. Pharmacological approaches have mainly employed Dichloroacetate (DCA) as an allosteric small molecule inhibitor of pan-PDHK, albeit a non-specific one. Both DCA treatment and PDHK1 knock-down have been shown to inhibit the growth of tumours in murine xenograft studies (Bonnet et al., A mitochondrial-K+ channel axis is suppressed in cancer and its normalization promotes apoptosis and inhibits cancer growth, Cancer Cell, 2007, 1 (1 ) : 37-51 ; Sun et al., Reversal of the glycolytic phenotype by dichloroacetate inhibits metastatic breast cancer cell growth in vitro and in vivo, Breast Can Res Treat, 2010, 120(1): 253-60; Papandreou et al., Anticancer drugs that target metabolism: Is dichloroacetate the new paradigm?, Int J Cancer, 2011 , 128(5): 1001 -8; McFate et al., Pyruvate dehydrogenase complex activity controls metabolic and malignant phenotype in cancer cells, J Biol Chem, 2008, 283(33): 22700-8; Michelakis et al, Michelakis et al, Metabolic modulation of glioblastoma with dichloroacetate, Sc Trans Med, 2010, 2(31 ):31 ra34; Fujiwara S et al, PDK1 inhibition is a novel therapeutic target in multiple myeloma, Br J Cancer, 2013, 108(1): 170-8; Xintaropoulou et al, A comparative analysis of inhibitors of the glycolysis pathway in breast and ovarian cancer cell line models, Oncotarget, 2015, 6(28):25677-95; Chae et al, Mitochondrial Akt Regulation of Hypoxic Tumor Reprogramming, Cancer Cell, 2016, 30(2):257-72; Golias et al, Hypoxic repression of pyruvate dehydrogenase activity is necessary for metabolic reprogramming and growth of model tumours, Sci Report, 2016, 6:31146; Li et al, Mitochondria-Translocated PGK1 Functions as a Protein Kinase to Coordinate Glycolysis and the TCA Cycle in Tumorigenesis, Mol Cell, 2016, 61 (5):705-19). These studies have demonstrated the ability of DCA to depolarize the electrochemical gradient across the inner mitochondrial membrane of cancer cells, to induce apoptosis as well as a reversal of the Warburg phenotype as evidenced by a decrease in lactate production and an increase in glucose oxidation (Bonnet et al., A mitochondrial-K+ channel axis is suppressed in cancer and its normalization promotes apoptosis and inhibits cancer growth, Cancer Cell, 2007, 1 (1 ) : 37-51 ; Wong et al., Dichloroacetate induces apoptosis in endometrial cancer cells, Gynecologic Oncology, 2008, 109: 394-402 ; Sun et al., Reversal of the glycolytic phenotype by dichloroacetate inhibits metastatic breast cancer cell growth in vitro and in vivo, Breast Can Res Treat, 2010, 120(1): 253-60). In addition, RNA interference studies have demonstrated that PDHK1 knock-down results in increased cell death under hypoxic conditions in Flead and Neck Squamous Cell Carcinoma (HNSCC) and colon cancer cell lines and, similar to the DCA studies above, mitochondrial inner membrane depolarization and reversal of the Warburg phenotype (Papandreou et al., Anticancer drugs that target metabolism: Is dichloroacetate the new paradigm?, Int J Cancer, 201 1 , 128(5): 1001 - 8; McFate et al., Pyruvate dehydrogenase complex activity controls metabolic and malignant phenotype in cancer cells, J Biol Chem, 2008, 283(33): 22700-8). Furthermore, DCA treatment has also been shown to synergize with other anti-cancer agents such as Vemurafenib (Kaplon et al., A key role for mitochondrial gatekeeper pyruvate dehydrogenase in oncogene-induced senescence, Nature, 2014, 498(7452) : 109- 12 and Abildgaard et al., Bioenergetic modulation with dichloroacetate reduces the growth of melanoma cells and potentiates their response to BRAFV600E inhibition, J Transl Med, 2014 12:247) Sorafenib (Shen et al., Activating oxidative phosphorylation by a pyruvate dehydrogenase kinase inhibitor overcomes Sorafenib resistance of hepatocellular carcinoma, Br J Cancer, 2012, 108(1 ): 72-81 ), Gefitnib or Erlotinib (Yang and Tam, Anti-cancer synergy of dichloroacetate and EGFR tyrosine kinase inhibitors in NSCLC cell lines, Eur J Pharmacol. 2016, 789:458-67), Metformin (Li et al., Dichloroacetate and metformin synergistically suppress the growth of ovarian cancer cells, Oncotarget, 2016, 7(37):59458-59470) and Ecesclemol (Kluza et al., Inactivation of the HIF-1 a/PDHK-3 signaling axis drives melanoma toward mitochondrial oxidative metabolism and potentiates the therapeutic activity of pro-oxidants, Cancer Res, 2012, 72(19): 5035-47). Another interesting observation is that PDHK1 knock-down has been shown to result in a substantial reduction in Hypoxia-Inducible Factor (HIF)-1 a expression under both normoxic and hypoxic conditions (McFate et al., Pyruvate dehydrogenase complex activity controls metabolic and malignant phenotype in cancer cells, J Biol Chem, 2008, 283(33): 22700-8). This is an attractive outcome of PDHK inhibition as HIF-1 a has been implicated as an important factor in cancer progression in several cancer types based on studies with clinical specimens as well as murine xenografts using cell lines in which HIF-1 a level has been genetically manipulated (Semenza, Defining the role of hypoxia-inducible factor 1 in cancer biology and therapeutics, Oncogene, 2010, 29(5): 625-34).

In addition to cancer, PDHK has been shown to be a potential therapeutic target for several other indications.

Immune cell activation and differentiation occurs concurrently with metabolic reprogramming. This ensures that activated cells generate the energy and substrates necessary to perform their specified function. There are several studies demonstrating how inhibitors of metabolism (e.g., glycolysis, glutamine metabolism, and fatty acid oxidation) can regulate immune responses and treat immune-mediated pathogenesis. Inhibitors of metabolism can be employed to regulate immune responses in both autoimmunity and transplantation (Bettencourt and Powell, Targeting metabolism as a novel therapeutic approach to autoimmunity, inflammation, and transplantation, J Immunol, 2017, 198(3):999-1005). The metabolism of a naive lymphocyte is different from that of a memory cell and is different from that of an effector (and indeed, even effector subsets have great differences in their metabolic profiles) (Pearce et al, Fueling immunity: insights into metabolism and lymphocyte function, Science, 2013, 342(6155): 1242454). Naive lymphocytes resemble many of the somatic cells in the body and progress through metabolic pathways, relying on glycolysis and subsequent TCA cycle to produce a maximum amount of ATP. However, upon activation, there is a dramatic shift in the metabolism of lymphocytes. Similar to the Warburg effect, there is a tremendous increase in glycolysis, even in the presence of abundant oxygen (Pearce and Pearce, Metabolic pathways in immune cell activation and quiescence, Immunity, 2013, 38(4):633-43). This aerobic glycolysis is necessary for activation, proliferation, and effector function. Effector cells also have differences in their metabolism between different subsets, with Th1 , Th2, and Th17 tending to be more glycolytic, whereas regulatory T cells (Tregs) rely more on lipid metabolism (Michalek et al, Cutting edge: distinct glycolytic and lipid oxidative metabolic programs are essential for effector and regulatory CD4+ T cell subsets, J. Immunol, 201 1 , 186: 3299— 3303).

The shift in the metabolism of innate immune cells upon activation is similar yet distinct from that which occurs in the adaptive immune system (Kelly and O’Neill, Metabolic reprogramming in macrophages and dendritic cells in innate immunity, Cell Res, 2015, 25: 771-784). Upon activation of macrophages and dendritic cells (DCs) in an inflammatory context, there is a shift from the quiescent state to a Warburg phenotype that is similar to that of activated lymphocytes (O’Neill and Pearce, Immunometabolism governs dendritic cell and macrophage function, J. Exp. Med, 2016, 213: 15-23).

In this context, inhibition of PDHK1 modulated immunity and protected animals against experimental autoimmune encephalomyelitis decreasing Th17 cells and increasing Tregs (Gerriets et al, Metabolic programming and PDHK1 control CD4+ T-cell subsets and inflammation, JCI, 2015, 125( 1 ) : 194-207) . Furthermore, Dichloroacetate delays the onset and alleviates the progression of rheumatoid arthritis, an autoimmune disease, in a murine collagen II- induced arthritis model in an estrogen-dependent manner as well as by down regulating B cells producing anti- Collagen II antibodies (Bian et al, Dichloroacetate alleviates development of collagen ll-induced arthritis in female DBA/1 mice, Arthritis Res Ther, 2009, 1 1 (5):R132). Hence, PDHK inhibitors is expected to control specific immune cell population such as T-cells and macrophages in autoimmune and inflammatory diseases, such as multiple sclerosis (MS), systemic lupus erythematosus (SLE), Sjogren's syndrome, rheumatic disorders, granulomatosis with polyangiitis, idiopathic thrombocytopenic purpura, pemphigus vulgaris, myasthenia gravis, vitiligo, psoriasis, autoimmune hepatitis, diabetes type I, juvenile arthritis, psoriatic arthritis, nephritis, in particular glomerular nephritis and interstitial nephritis, vasculitis, rheumatic fever, familial Mediterranean fever.

PDHK1 also plays a crucial role in macrophage polarization because it is required for M1 macrophage generation and activation in response to the TLR2 agonist PAM, as well as bacterial pathogens that are dependent on TLR2 signaling to induce a response (Tan et al, Pyruvate dehydrogenase kinase 1 participates in macrophage polarization via regulating glucose metabolism, J. Immunol, 2015, 194: 6082-6089). Knockdown of PDHK1 increases the expression of M2 signature genes at early time points after activation and increases the oxidative respiration that preferentially leads to the M2 polarization.

Furthermore, in the case of solid organ transplantation, metabolic therapy is currently evaluated. For solid organ transplant, it appears that there is far less reliance on lipid metabolism for the generation of ATP, and rejecting cells appear to employ aerobic glycolysis (Priyadharshini and Turka T-cell energy metabolism as a controller of cell fate in transplantation, Curr. Opin. Organ Transplant, 2015, 20: 21-28). The metabolic demands of the effector cells promoting graft rejection are somewhat different from those observed in bone marrow transplant which rely on fatty acid beta-oxidation. CD4+ T cell activation, in the setting of solid organ transplant, more closely resembles the classical metabolic shift that is seen during the normal activation of lymphocytes with a switch to aerobic glycolysis. Modulating the aerobic glycolysis with PDHK inhibitors should decrease T cell activation and by extension its cytokine production and proliferation resulting in inhibition of MHC-mismatched allograft rejection after solid organ transplantation.

B cells have emerged as effective targets for therapeutic intervention in autoimmune disorders in which either auto antibodies or T cells are primary drivers of inflammation (Franks et al, Targeting B cells in treatment of autoimmunity, Curr Opin Immunol. 2016 12; 43:39-45). It has been shown that the PDHK inhibitor DCA suppressed B cell proliferation and antibody secretion in vitro and in vivo (Caro-Maldano et al, Metabolic reprogramming is required for antibody production that is suppressed in anergic but exaggerated in chronically BAFF-exposed B cells, J Immunol. 2014 Apr 15; 192(8) : 3626-36) . It can therefore be reasoned that PDHK inhibition may be beneficial in autoimmune diseases for which B cell targeting therapies (e.g. such as the B cell targeting antibody rituximab or the B-cell activating factor neutralizing antibody belimumab) are currently in clinical use, such as multiple sclerosis, systemic lupus erythematosus, rheumatoid arthritis, granulomatosis with polyangiitis, idiopathic thrombocytopenic purpura, pemphigus vulgaris, myasthenia gravis.

The dysregulation of glucose metabolism by the decrease of PDH activity causes various metabolic diseases including diabetes (Del Prato et al, Characterization of cellular defects of insulin action in type II (non insulin dependent) diabetes mellitus, Journal of Clin Invest, 1993, 91 :484-94 and Mondon et al, Lactate production and pyruvate dehydrogenase activity in fat and skeletal muscle from diabetic rats, Diabetes, 1992, 41 : 1547-54). For instance, type II diabetes mellitus is associated with alterations in the balance between glucose and lipid metabolic pathway (Randle et al, Mechanisms modifying glucose oxidation in diabetes mellitus, Diabetologia, 1994, 37 Suppl 2:S155-61 ). Activation of PDH should benefit the diabetic state by inhibiting gluconeogenesis and promoting glucose disposal in peripheral tissues. Decreasing the supply of gluconeogenic substrates, by increasing the oxidation of pyruvate in peripheral tissues, is an attractive mechanism for lowering this excessive gluconeogenic rate.

Preliminary evidence in support of this proposal was obtained using DCA (Stacpoole et al, Pharmacokinetics, metabolism and toxicology of dichloroacetate, Drug Metab, 1998, 30(3):499-539). In addition, DCA decreases alanine flux and lactate levels in humans by increasing pyruvate oxidation rate in peripheral tissues. (Shangraw and Jahoor, Mechanism of dichloroacetate-induced hypolactatemia in humans with or without cirrhosis, Metabolism, 2004, 53(8): 1087-94). In a limited study in Type II diabetic patients, DCA decreased glucose concentration in association with a reduction in lactate and alanine and this was most marked in patients with high glucose levels (Stacpoole et al, Metabolic effects of dichloroacetate in patients with diabetes mellitus and hyperlipoproteinemia, New Engl J Med, 1978, 298(10):526-30). The role of PDH in the pancreatic b-cell is less clear. Increasing glucose oxidation and ATP production may be important in promoting glucose-stimulated insulin secretion from the pancreas through the activation of ATP sensitive K+ channels (Sugden and Holness, Potential role of peroxisome proliferator-activated receptor-alpha in the modulation of glucose-stimulated insulin secretion, Diabetes, 2004, 53 Suppl 1 :S71 -81 ). Therefore, it is critical to adequately maintain PDH to prevent the occurrence of metabolic diseases (Jeoung, Pyruvate dehydrogenase kinases: therapeutic targets for diabetes and cancers, Obesity and metab Syndrome, 2015, 39: 188-97). DCA dosed to 12-week-old Zucker Diabetic fatty rats increased PDH activity in tibialis anterior, cardiac muscle, kidney and liver and decreased glucose levels with sustained efficacy after 25 days of dosing (Islam et al, Effect of Dichloroacetate on Glucose Metabolism and Tissue Pyruvate Dehydrogenase Activity in Zucker Diabetic Fatty Rats, Diabetes, 1999, 48. Sup2 2012-P).

PDHK4 is of particular interest for diabetes as it is expressed at high levels in heart and skeletal muscle and to a lesser extent in liver and is rapidly upregulated in response to starvation in human tissues. Trace of PDHK1 are detected in skeletal muscle, whereas PDHK3 appears in heart and skeletal muscle (Rowles et al, Cloning and characterization of PDHK4 on 7q21.3 encoding a fourth pyruvate dehydrogenase kinase isoenzyme in human, J Biol Chem, 1996, 271 (37): 22376-82 and Gudi et al, Diversity of the pyruvate dehydrogenase kinase gene family in humans, J Biol Chem, 1995, 270(48) :28989-94) . PDHK4 is markedly upregulated in skeletal muscle in animal model of type I diabetes (Wu et al, Mechanism responsible for inactivation of skeletal muscle pyruvate dehydrogenase complex in starvation and diabetes, Diabetes, 1999, 48(8): 1593-9). High fat feeding of Wistar rats increases PDHK expression particularly PDHK4 in soleus muscle (Holness et al, Targeted upregulation of pyruvate dehydrogenase kinase (PDK)-4 in slow-twitch skeletal muscle underlies the stable modification of the regulatory characteristics of PDHK induced by high-fat feeding, Diabetes, 2000, 49(5)775-81 ). Similarly, the mildly hyperglycaemic but highly insulin resistant Otsuka Long-Evans Tokushima Fatty rat shows increased levels of both mRNA and protein for PDHK2 and PDHK4 (Bajotto et al, Downregulation of the skeletal muscle pyruvate dehydrogenase complex in the Otsuka Long-Evans Tokushima Fatty rat both before and after the onset of diabetes mellitus, Life Sci, 2004, 75(17):2117-30). A previous study has shown that PDHK4 expression increases in the skeletal muscle of rats receiving a continuous infusion of intralipids indicating a disruption in the suppression of PDHK4 by insulin. This indicates a direct relationship between free fatty acid levels and PDHK4 expression in the muscle (Kim et al, Insulin regulation of skeletal muscle PDHK4 mRNA expression is impaired in acute insulin- resistant states, Diabetes, 2006, 55(8) :2311 -7). PDHK4 levels are also elevated in fasting and diabetic individuals (Wu et al, Starvation increases the amount of pyruvate dehydrogenase kinase in several mammalian tissues, Arch Biochem Biophys, 2000, 381 ( 1 ) : 1 -7 and Sugden and Holness, Therapeutic potential of the mammalian pyruvate dehydrogenase kinases in the prevention of hyperglycaemia, Curr Drug Targets Immune endocr Metabol Disord, 2002, 2(2): 151-65). In mice that are null for the hepatic insulin receptor substrate 1 and 2, which is a novel model for type II diabetes, additional KO of the PDHK4 gene improved glycemic control and glucose tolerance (Tao et al, Genetic inactivation of pyruvate dehydrogenase kinases improves hepatic insulin resistance induced diabetes, Plos One, 2013, 8(8):e71997). Overall, PDHK are likely to play a key role in controlling the balance between glucose and lipid oxidation suggesting inhibition of PDHK as a potential effective therapy for metabolic diseases.

The pyruvate dehydrogenase complex further plays an important role in energy homeostasis in the heart by providing the link between glycolysis and the tricarboxylic acid cycle. Studies in coronary artery disease patients show that several actions take place when angina is induced by cardiac pacing including a switch from myocardial lactate uptake to lactate production. During a demand induced myocardial ischemia, there is a high rate of anaerobic glycolysis despite a high rate of residual myocardial oxygen consumption. A relationship between myocardial recovery during post ischemic reperfusion and glycolytic activity exists. Indeed, increased glucose oxidation relative to fatty acids improves blood flow outcome after myocardial ischemia and reperfusion.

During myocardial ischemia, there is a switch from net lactate uptake to net lactate production which activates glycolysis. The flux of pyruvate is a key determinant of the rate of lactate production. Studies in myocardial ischemia and reperfusion on dogs and pigs show that an increase in the NADH to NAD+ and acetyl-coA to free coA ratios inhibits the rate of pyruvate flux through PDH at a given phosphorylation state (Clanachan, Contribution of protons to post-ischemic Na(+) and Ca(2+) overload and left ventricular mechanical dysfunction, J. Cardiovasc. Electrophysiol, 2006, 17 (Suppl. 1 ) S141-S148; Imahashi et al, Cardiac-specific ablation of the Na+-Ca2+ exchanger confers protection against ischemia/reperfusion injury, Circ. Res., 2005, 97 916-921 ). During the first 10 to 15 min of reperfusion following transient ischemia in the heart, PDH is predominantly in the phosphorylated inactive form (Kobayashi and Neely, Effects of ischemia and reperfusion on pyruvate dehydrogenase activity in isolated rat hearts, J. Mol. Cell. Cardiol., 1983, 15 359-367; Patel and Olson, Regulation of pyruvate dehydrogenase complex in ischemic rat heart, Am. J. Physiol., 1984, 246 H858-H864). Cardiac efficiency and recovery of contractile function in post-ischemic hearts can be improved by pharmacological stimulation of PDH with DCA (Barak et al, Effects of dichloroacetate on mechanical recovery and oxidation of physiologic substrates after ischemia and reperfusion in the isolated heart, J. Cardiovasc. Pharmacol., 1998, 31 336-344; Stanley et al, Pyruvate dehydrogenase activity and malonyl CoA levels in normal and ischemic swine myocardium: effects of dichloroacetate, J. Mol. Cell. Cardiol., 1996, 28, 905-914), or the infusion of pyruvate (De Groot and Van der Vusse, The effects of exogenous lactate and pyruvate on the recovery of coronary flow in the rat heart after ischaemia, Cardiovasc. Res., 1993, 27, 1088-1093; Mallet et al, Pyruvate restores contractile function and antioxidant defenses of hydrogen peroxide-challenged myocardium, J. Mol. Cell. Cardiol. ,2002, 34, 1 173-1184). There is already a substantial body of evidence demonstrating that activating PDH through inhibiting PDHK activity pharmacologically is a useful therapeutic target for avoiding heart diseases such as cardiomyopathy, particularly during heart surgery, and partial ischemia (Lloyd et al, Differential modulation of glucose, lactate, and pyruvate oxidation by insulin and dichloroacetate in the rat heart, Am. J. Physiol. Heart. Circ. Physiol., 2003, 285 H163- H172; Taegtmeyer, Cardiac metabolism as a target for the treatment of heart failure, Circulation, 2004, 110 894— 896; Wolff et al, Metabolic approaches to the treatment of ischemic heart disease: the clinicians' perspective, Heart Fail. Rev., 2002, 7 187-203; Sun et al, The role of pyruvate dehydrogenase complex in cardiovascular diseases, Life Sciences, 2015, 121 :97-103).

In animal models, the hypertrophied heart possesses an altered metabolic profile that is similar to a fetal heart with a reduced fatty acid and an increased preference for carbohydrate sources (Barger, and Kelly, Fatty acid utilization in the hypertrophied and failing heart: molecular regulatory mechanisms, Am. J. Med. Sci., 1999, 31836-42; Doenst et al, Decreased rates of substrate oxidation ex vivo predict the onset of heart failure and contractile dysfunction in rats with pressure overload, Cardiovasc. Res., 2010, 86 461-470). Based on transcription of PDHK4 which is stimulated by the nuclear fatty acid receptor PPAR-a, increased PPAR-a activity in the heart can cause cardiomyopathy (Finck et al, The cardiac phenotype induced by PPARalpha overexpression mimics that caused by diabetes mellitus, J. Clin. Invest., 2002, 109 121-130; Young et al, Reactivation of peroxisome proliferator- activated receptor alpha is associated with contractile dysfunction in hypertrophied rat heart, J. Biol. Chem., 2001 , 276 44390-44395). Zhao et al. (Zhao et al, Overexpression of pyruvate dehydrogenase kinase 4 in heart perturbs metabolism and exacerbates calcineurin-induced cardiomyopathy, Am. J. Physiol. Heart Circ. Physiol., 2008, 294 H936-H943) observed a marked inhibition of PDH activity in the hearts of transgenic mice through overexpressing PDHK4. Overexpression of PDHK4 alone was sufficient to cause metabolic inflexibility and to exacerbate preexisting cardiomyopathy.

Under ischemic conditions, therefore, when energy metabolism becomes glucose oxidation dominant by activation of PDH, the ability to maintain ATP level is considered to be enhanced. In addition, since activation of PDH causes oxidation of pyruvate produced by glycolysis, and reducing production of lactate, the net proton burden is considered to be reduced in ischemic tissues. Accordingly, PDH activation by inhibition of PDHK is expected to protectively act in ischemic diseases such as cardiac muscle ischemia. In that direction, DCA has been demonstrated to have a cardioprotective effect in animal models of ventricular hypertrophy (Atherton et al, Validation of the in vivo assessment of pyruvate dehydrogenase activity using hyperpolarised 13C MRS, NMR Biomed, 201 1 , 24(2):201 -8; Kato et al, Analysis of metabolic remodeling in compensated left ventricular hypertrophy and heart failure, Circ Heart Fail, 2010, 3(3):420-30).

Defects in energy metabolism are potential pathogenic mechanisms in amyotrophic lateral sclerosis (ALS), a rapidly fatal neuron disease in adults. Several studies indicate that ALS is a systemic disease that affects whole body phsysiology and metabolic homeostasis. Metabolomics and stable isotope tracers in a cellular model of familial ALS have shown an increase of glucose metabolism associated with death, aerobic glycolysis and dysregulation of amino acid homeostasis. Aerobic glycolysis was mainly due to the induction of PDHK1 (Valbuena et al, Metabolomic analysis reveals increased aerobic glycolysis and amino acid deficit in a cellular model of amyotrophic lateral sclerosis, Mol Neuobiol, 2016, 53:2222-40). Using mouse model of the disease, induction of PDHK4 has been reported in glycolytic muscles. Inhibition of PDHK4 with DCA delayed symptom onset while improving mitochondrial dysfunction and ameliorating muscle denervation (Palamiuc et al, A metabolic switch toward lipid use in glycolytic muscle is an early pathologic event in a mouse model of amyotrophic lateral sclerosis, EM BO Mol Med, 2015, 7:526-546).

A drug that activates PDH by inhibition of PDHK is considered to decrease lactate production since it promotes pyruvate metabolism. Hence, such drug is expected to be useful for the treatment of hyperlactacidemia such as mitochondrial disease, mitochondrial encephalomyopathy and sepsis (Lang et al, Glucose kinetics and pyruvate dehydrogenase activity in septic rats treated with dichloroacetate, Circ Shock, 1987, 23(2): 131 -41 ).

The present invention provides novel pyrimido[4,5-b]indol derivatives of formula (I) which are inhibitors of PDHK1 , and are useful for the prevention or treatment of diseases which respond to the inhibition of PDHK1 and/or to a modulated immunometabolism, especially cancer, autoimmune diseases and disorders or inflammatory diseases and disorders. In the prevention or treatment of cancers the compounds of formula (I) may also be used in combination with one or more chemotherapy agents and / or radiotherapy and / or targeted therapy.

1) A first aspect of the invention relates to novel pyrimido[4,5-b]indol derivatives of formula (I);

Formula (I)

wherein

• R¹ and R² together represent a group -CH2-CH(CN)-* wherein the asterisk represents the bond with which R² is attached to the rest of the molecule; or

• R¹ represents

> (Ci-4)alkyl (especially methyl);

> hydroxy-(C2-6)alkylene-, wherein said (C2-6)alkylene group is unsubstituted; or mono-substituted with (C i)f I uoroal kyl , or phenyl;

> hydroxy-(C3-6)cycloalkylene-CH2-, wherein said (C3-6)cycloalkylene optionally contains a ring oxygen atom [especially such group is 4-hydroxy-tetrahydro-pyran-4-yl-methyl];

> -CH2-CH2-O-R⁰¹, wherein R⁰¹ represents (Cujalkyl, hydroxy-(C2-6)alkylene-, or (Ci_3)alkoxy- (C2-3)alkylene-;

> -CH2-CH2-NR^N1R^N2, wherein R^N1 and R^N2 together with the nitrogen to which they are attached form a saturated 4- to 6-membered ring optionally containing one oxygen ring heteroatom; wherein said ring is unsubstituted, or mono- or di-substituted with fluoro;

> -CH2-CO-NR^N3R^N4, wherein R^N1 and R^N2 independently represent hydrogen or (Cujalkyl; and

R² represents -CH2-CN.

The compounds of formula (I) may contain one or more further stereogenic or asymmetric centers, such as one or more additional asymmetric carbon atoms. The compounds of formula (I) may thus be present as mixtures of stereoisomers or preferably as pure stereoisomers. Mixtures of stereoisomers may be separated in a manner known to a person skilled in the art.

In case a particular compound (or generic structure) is designated as (R)- or (S)-enantiomer / as having an absolute (R)- or (S)-configuration, such designation is to be understood as referring to the respective compound (or generic structure) in enriched, especially essentially pure, enantiomeric form. Likewise, in case a specific asymmetric center in a compound is designated as being in (R)- or (S)-configuration or as being in a certain relative configuration, such designation is to be understood as referring to the compound that is in enriched, especially essentially pure, form with regard to the respective configuration of said asymmetric center. In analogy, c/s- or frans-designations (or (R* R*) designations) are to be understood as referring to the respective stereoisomer of the respective relative configuration in enriched form, especially in essentially pure form.

The term "enriched", when used in the context of stereoisomers, is to be understood in the context of the present invention to mean that the respective stereoisomer is present in a ratio of at least 70:30, especially of at least 90: 10 (i.e., in a purity of at least 70% by weight, especially of at least 90% by weight), with regard to the respective other stereoisomer / the entirety of the respective other stereoisomers.

The term“essentially pure”, when used in the context of stereoisomers, is to be understood in the context of the present invention to mean that the respective stereoisomer is present in a purity of at least 95% by weight, especially of at least 99% by weight, with regard to the respective other stereoisomer / the entirety of the respective other stereoisomers.

In some instances, the compounds of formula (I) may contain tautomeric forms. Such tautomeric forms are encompassed in the scope of the present invention.

The present invention also includes isotopically labelled, especially ²H (deuterium) labelled compounds of formula (I), which compounds are identical to the compounds of formula (I) except that one or more atoms have each been replaced by an atom having the same atomic number but an atomic mass different from the atomic mass usually found in nature. Isotopically labelled, especially ²H (deuterium) labelled compounds of formula (I) and salts thereof are within the scope of the present invention. Substitution of hydrogen with the heavier isotope ²H (deuterium) may lead to greater metabolic stability, resulting e.g. in increased in-vivo half-life or reduced dosage requirements, or may lead to reduced inhibition of cytochrome P450 enzymes, resulting e.g. in an improved safety profile. In one embodiment of the invention, the compounds of formula (I) are not isotopically labelled, or they are labelled only with one or more deuterium atoms. In a sub-embodiment, the compounds of formula (I) are not isotopically labelled at all. Isotopically labelled compounds of formula (I) may be prepared in analogy to the methods described hereinafter but using the appropriate isotopic variation of suitable reagents or starting materials.

Where the plural form is used for compounds, salts, pharmaceutical compositions, diseases and the like, this is intended to mean also a single compound, salt, or the like.

Any reference to compounds of formula (I) is to be understood as referring also to the salts (and especially the pharmaceutically acceptable salts) of such compounds, as appropriate and expedient.

The term "pharmaceutically acceptable salts" refers to salts that retain the desired biological activity of the subject compound and exhibit minimal undesired toxicological effects. Such salts include inorganic or organic acid and/or base addition salts depending on the presence of basic and/or acidic groups in the subject compound. For reference see for example“Handbook of Pharmaceutical Salts. Properties, Selection and Use.”, P. Heinrich Stahl, Camille G. Wermuth (Eds.), Wiley-VCH, 2008; and“Pharmaceutical Salts and Co-crystals”, Johan Wouters and Luc Quere (Eds.), RSC Publishing, 2012. Definitions provided herein are intended to apply uniformly to the compounds of formula (I), as defined in any one of embodiments 1) to 7), and, mutatis mutandis, throughout the description and the claims unless an otherwise expressly set out definition provides a broader or narrower definition. It is well understood that a definition or preferred definition of a term defines and may replace the respective term independently of (and in combination with) any definition or preferred definition of any or all other terms as defined herein. If not explicitly defined otherwise in the respective embodiment or claim, groups defined herein are unsubstituted.

The term“halogen” means fluorine, chlorine, bromine, or iodine, preferably fluorine or chlorine, especially fluorine.

The term“alkyl”, used alone or in combination, refers to a saturated straight or branched chain hydrocarbon group containing one to six (especially one to four) carbon atoms. The term“(Cx-y)alkyl” (x and y each being an integer), refers to an alkyl group as defined before, containing x to y carbon atoms. For example a (C^alkyl group contains from one to four carbon atoms. Examples of alkyl groups are methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec.- butyl, tert-butyl, n-pentyl, 1 , 1 -dimethyl-propyl, 2,2-dimethyl-propyl, 3-methyl-butyl, and n-hexyl. An example of (Ci_4)alkyl group as used for R¹ is methyl. An example of (C^Jalkyl group as used for R⁰¹, R^N1 or R^N2 is methyl.

The term“-(C_x-y)alkylene-”, used alone or in combination, refers to bivalently bound alkyl group as defined before containing x to y carbon atoms. Preferably, the points of attachment of any bivalently bound alkyl group are in 1 , 1 - diyl, 1 ,2-diyl, or in 1 ,3-diyl arrangement. Examples of -(C2-6)alkylene- are ethylene, propan-1 ,2-diyl, butan-1 ,2-diyl, 2-methyl-propan-1 ,2-diyl, 2,2-dimethyl-propan-1 ,3-diyl, 3-methyl-butan-1 ,3-diyl, and 3, 3-dimethyl-butan-1 ,2-diyl.

The term“alkoxy”, used alone or in combination, refers to an alkyl-O- group wherein the alkyl group is as defined before. The term“(C_x-y)alkoxy” (x and y each being an integer) refers to an alkoxy group as defined before containing x to y carbon atoms. For example a (Ci-3)alkoxy group means a group of the formula (Cujalkyl-O- in which the term“(Ci_3)alkyl” has the previously given significance. Examples of alkoxy groups are methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec.-butoxy and tert.-butoxy. A preferred example is methoxy.

The term "fluoroalkyl” refers to an alkyl group as defined before containing one to five carbon atoms in which one or more (especially 1 , 2, or 3; and possibly all) hydrogen atoms have been replaced with fluorine. The term“(C_x. yjfluoroalkyl” (x and y each being an integer) refers to a fluoroalkyl group as defined before containing x to y carbon atoms. For example a (Cujfluoroalkyl group contains from one to three carbon atoms in which one to seven hydrogen atoms have been replaced with fluorine. Representative examples of the (Ci)fluoroalkyl group are fluoromethyl and trifluoromethyl.

The term "cyano" refers to a group -CN.

The term "cycloalkyl", used alone or in combination, refers to a saturated mono- or bicyclic carbocyclic ring containing three to eight carbon atoms, wherein the term "bicyclic cycloalkyl" includes fused, bridged, and spiro- bicyclic cycloalkyl groups. The term "(C_x-y)cycloalkyl" (x and y each being an integer), refers to a cycloalkyl group as defined before containing x to y carbon atoms. For example a (C^cydoalkyl group contains from three to six carbon atoms. Examples are cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. The term“-(C_x-y)cycloalkylene-”, used alone or in combination, refers to bivalently bound cycloalkyl group as defined before containing x to y carbon atoms. Preferably, the points of attachment of any bivalently bound cycloalkyl group are in 1 , 1 -diyl, or in 1 ,2-diyl arrangement. An example of hydroxy-(C3-6)cycloalkylene-CH2- as used for R¹ is 4- hydroxy-tetrahydro-pyran-4-yl-methyl.

Further embodiments of the invention are presented hereinafter:

2) A second embodiment of the present invention relates to the compounds of Formula (I) according to embodiment 1), wherein

• R¹ represents

> methyl, or -C FI 2-(C 1-3) alkyl (especially methyl);

> hydroxy-(C2-6)alkylene-, wherein said (C2-6)alkylene group represents

^■ ethylene which is unsubstituted, or mono-substituted with (Ci_4)alkyl, or di-substituted with methyl;

^■ n-propylene which is unsubstituted, or mono-substituted with (Ci-3)alkyl, or di- substituted with methyl; or

^■ ethylene which is mono-substituted with fluoromethyl, trifluoromethyl, or phenyl;

> (4-hydroxy-tetrahydro-pyran-4-yl)-methyl;

> -CFI2-CFI2 -R⁰¹, wherein R⁰¹ represents methyl; methoxy-(C2-3)alkylene-; or hydroxy- (C2-6)alkylene- wherein said -(C2-6)alkylene- represents ethylene, or n-propylene which is unsubstituted or mono- or di-substituted with methyl;

> -CH2-CH₂-NR^N1R^N2, wherein the group -NR^N1R^N2 represents morpholin-4-yl or 3-fluoro-azetidin- 1 -yl; or

> -CFl2-CO-NR^N3R^N4, wherein R^N1 represents hydrogen and R^N2 represents (Ci_3)alkyl; and R² represents -CH2-CN.

3) A further embodiment relates to the compounds of Formula (I) according to embodiment 1 ), wherein

• R¹ represents

> methyl, or -C FI 2-(C 1-3) alkyl (especially methyl);

> hydroxy-(C2-6)alkylene-, wherein said (C2-6)alkylene group represents ^■ ethylene which is unsubstituted, or mono-substituted with (Ci-4)alkyl, or di-substituted with methyl; or

^■ n-propylene which is unsubstituted, or mono-substituted with (Cu)alkyl, or di- substituted with methyl;

> hydroxy-(C2-6)alkylene-, wherein said (C2-6)alkylene group represents

^■ ethylene which is mono-substituted with fluoromethyl, or trifluoromethyl; or

> -CH2-CH2-O-R⁰¹, wherein R⁰¹ represents methyl; methoxy-(C2-3)alkylene-; or hydroxy- (C2-6)alkylene- wherein said -(C2-6)alkylene- represents ethylene, or n-propylene which is unsubstituted or mono- or di-substituted with methyl; and

R² represents -CH2-CN. ) A further embodiment relates to the compounds according to embodiment 1), wherein

• R¹ represents

> methyl or -C H 2-(C 1 -3) al ky I (especially methyl);

> 2-hydroxyethyl, 2-hydroxy-propyl, 2-hydroxy-2-methyl-propyl, 3-hy d roxy-2 ,2-dimethyl-propyl, 2- hydroxy-butyl, 3-hydroxy-3-methyl-butyl, 2-hydroxy-3, 3-dimethyl-butyl;

> 3,3,3-trifluoro-2-hydroxy-propyl, 3-fluoro-2-hydroxy-propyl, 2-hydroxy-2-phenyl-ethyl;

> (4-hydroxy-tetrahydro-pyran-4-yl)-methyl;

> 2-methoxy-ethyl, 2-(2-hydroxy-ethoxy)-ethyl, 2-(2-methoxy-ethoxy)-ethyl, 2-(3-hydroxy-3- methy I -butoxy ) -ethyl ; or

> 2-(methylamino)-2-oxoethyl, 2-(3-fluoro-azetidin-1 -yl)-ethyl, or 2-(morpholin-4-yl)-ethyl, and R² represents -CH2-CN. ) A further embodiment relates to the compounds according to embodiment 1), wherein

• R¹ represents

> methyl;

> 2-hydroxyethyl, 2-hydroxy-propyl, 2-hydroxy-2-methyl-propyl, 3-hydroxy-2, 2-dimethyl-propyl, 2- hydroxy-butyl, 3-hydroxy-3-methyl-butyl; > 3,3,3-trifluoro-2-hydroxy-propyl, 3-fluoro-2-hydroxy-propyl; or

> 2-methoxy-ethyl, 2-(2-hydroxy-ethoxy)-ethyl, 2-(2-methoxy-ethoxy)-ethyl, 2-(3-hydroxy-3- methy I -bu toxy ) -ethyl ; and

R² represents -CH2-CIM.

6) A further embodiment relates to the compounds according to embodiment 1 ), wherein R¹ and R² together represent a group -CH2-CH(CN)-* wherein the asterisk represents the bond with which R² is attached to the rest of the molecule.

7) A further embodiment relates to the compounds according to embodiment 1), wherein R¹ represents

> methyl;

> 2-hydroxyethyl, 2-hydroxy-propyl, 2-hydroxy-2-methyl-propyl, 3-hydroxy-2, 2-dimethyl-propyl, 2- hydroxy-butyl, 3-hydroxy-3-methyl-butyl, 2-hydroxy-3, 3-dimethyl-butyl;

> 3,3,3-trifluoro-2-hydroxy-propyl, 3-fluoro-2-hydroxy-propyl;

> 2-methoxy-ethyl, 2-(2-hydroxy-ethoxy)-ethyl, 2-(2-methoxy-ethoxy)-ethyl; or

> 2-(3-f I uoro-azetid i n - 1 -yl ) -ethyl , or 2-(m orp hoi i n-4-y I ) -ethyl , and

R² represents -CH2-CIM.

8) Another embodiment relates to compounds according to embodiment 1 ) which are selected from the following compounds:

[5-(6-Fluoro-2-methyl-8-methylamino-9H-pyrimido[4,5-b]indol-4-yl)-2-methoxy-phenoxy]-acetonitrile;

[5-(6-Fluoro-2-methyl-8-methylamino-9H-pyrimido[4,5-b]indol-4-yl)-2-(2-hydroxy-2-methyl-propoxy)-phenoxy]- acetonitrile;

2-[2-Cyanomethoxy-4-(6-fluoro-2-methyl-8-methylamino-9FI-pyrimido[4,5-b]indol-4-yl)-phenoxy]-N-methyl- acetamide;

[5-(6-Fluoro-2-methyl-8-methylamino-9H-pyrimido[4,5-b]indol-4-yl)-2-(2-hydroxy-3,3-dimethyl-butoxy)-phenoxy]- acetonitrile;

[5-(6-Fluoro-2-methyl-8-methylamino-9H-pyrimido[4,5-b]indol-4-yl)-2-(2-hydroxy-2-phenyl-ethoxy)-phenoxy]- acetonitrile;

[5-(6-Fluoro-2-methyl-8-methylamino-9H-pyrimido[4,5-b]indol-4-yl)-2-(3-hydroxy-3-methyl-butoxy)-phenoxy]- acetonitrile;

[5-(6-Fluoro-2-methyl-8-methylamino-9H-pyrimido[4,5-b]indol-4-yl)-2-(3,3,3-trifluoro-2-hydroxy-propoxy)- phenoxyj-acetonitrile;

[5-(6-Fluoro-2-methyl-8-methylamino-9H-pyrimido[4,5-b]indol-4-yl)-2-(2-hydroxy-butoxy)-phenoxy]-acetonitrile;

[5-(6-Fluoro-2-methyl-8-methylamino-9H-pyrimido[4,5-b]indol-4-yl)-2-(2-hydroxy-propoxy)-phenoxy]-acetonitrile; [5-(6-Fluoro-2-methyl-8-methylamino-9H-pyrimido[4,5-b]indol-4-yl)-2-(4-hydroxy-tetrahydro-pyran-4-ylmethoxy)- phenoxyj-acetonitrile;

[5-(6-Fluoro-2-methyl-8-methylamino-9H-pyrimido[4,5-b]indol-4-yl)-2-(2-methoxy-ethoxy)-phenoxy]-acetonitrile;

[2-(3-Fluoro-2-hydroxy-propoxy)-5-(6-fluoro-2-methyl-8-methylamino-9H-pyrimido[4,5-b]indol-4-yl)-phenoxy]- acetonitrile;

[5-(6-Fluoro-2-methyl-8-methylamino-9H-pyrimido[4,5-b]indol-4-yl)-2-(2-hydroxy-ethoxy)-phenoxy]-acetonitrile;

{5-(6-Fluoro-2-methyl-8-methylamino-9FI-pyrimido[4,5-b]indol-4-yl)-2-[2-(2-methoxy-ethoxy)-ethoxy]-phenoxy}- acetonitrile;

[5-(6-Fluoro-2-methyl-8-methylamino-9H-pyrimido[4,5-b]indol-4-yl)-2-(3-hydroxy-2,2-dimethyl-propoxy)-phenoxy]- acetonitrile;

[5-(6-Fluoro-2-methyl-8-methylamino-9H-pyrimido[4,5-b]indol-4-yl)-2-(2-morpholin-4-yl-ethoxy)-phenoxy]- acetonitrile;

{5-(6-Fluoro-2-methyl-8-methylamino-9H-pyrimido[4,5-b]indol-4-yl)-2-[2-(3-hydroxy-3-methyl-butoxy)-ethoxy]- phenoxyj-acetonitrile;

{5-(6-Fluoro-2-methyl-8-methylamino-9FI-pyrimido[4,5-b]indol-4-yl)-2-[2-(2-hydroxy-ethoxy)-ethoxy]-phenoxy}- acetonitrile;

[2-[2-(3-Fluoro-azetidin-1-yl)-ethoxy]-5-(6-fluoro-2-methyl-8-methylamino-9H-pyrimido[4,5-b]indol-4-yl)-phenoxy]- acetonitrile; and

7-(6-Fluoro-2-methyl-8-methylamino-9FI-pyrimido[4,5-b]indol-4-yl)-2,3-dihydro-benzo[1 ,4]dioxine-2-carbonitrile.

9) Another embodiment relates to compounds according to embodiment 1 ) which are selected from the following compounds:

(R)-[5-(6-Fluoro-2-methyl-8-methylamino-9H-pyrimido[4,5-b]indol-4-yl)-2-(2-hydroxy-3,3-dimethyl-butoxy)- phenoxyj-acetonitrile;

(S)-[5-(6-Fluoro-2-methyl-8-methylamino-9H-pyrimido[4,5-b]indol-4-yl)-2-(2-hydroxy-3,3-dimethyl-butoxy)- phenoxyj-acetonitrile;

(R)-[5-(6-Fluoro-2-methyl-8-methylamino-9H-pyrimido[4,5-b]indol-4-yl)-2-(2-hydroxy-2-phenyl-ethoxy)-phenoxy]- acetonitrile;

(S)-[5-(6-Fluoro-2-methyl-8-methylamino-9H-pyrimido[4,5-b]indol-4-yl)-2-(2-hydroxy-2-phenyl-ethoxy)-phenoxy]- acetonitrile;

[5-(6-Fluoro-2-methyl-8-methylamino-9H-pyrimido[4,5-b]indol-4-yl)-2-(3-hydroxy-3-methyl-butoxy)-phenoxy]- acetonitrile; (R)-[5-(6-Fluoro-2-methyl-8-methylamino-9H-pyrimido[4,5-b]indol-4-yl)-2-(3,3,3-trifluoro-2-hydroxy-propoxy)- phenoxyj-acetonitrile;

(S)-[5-(6-Fluoro-2-methyl-8-methylamino-9H-pyrimido[4,5-b]indol-4-yl)-2-(3,3,3-trifluoro-2-hydroxy-propoxy)- phenoxyj-acetonitrile;

(R)-[5-(6-Fluoro-2-methyl-8-methylamino-9H-pyrimido[4,5-b]indol-4-yl)-2-(2-hydroxy-butoxy)-phenoxy]- acetonitrile;

(S)-[5-(6-Fluoro-2-methyl-8-methylamino-9H-pyrimido[4,5-b]indol-4-yl)-2-(2-hydroxy-butoxy)-phenoxy]- acetonitrile;

(R)-[5-(6-Fluoro-2-methyl-8-methylamino-9FI-pyrimido[4,5-b]indol-4-yl)-2-(2-hydroxy-propoxy)-phenoxy]- acetonitrile;

(S)-[5-(6-Fluoro-2-methyl-8-methylamino-9FI-pyrimido[4,5-b]indol-4-yl)-2-(2-hydroxy-propoxy)-phenoxy]- acetonitrile;

[5-(6-Fluoro-2-methyl-8-methylamino-9FI-pyrimido[4,5-b]indol-4-yl)-2-(4-hydroxy-tetrahydro-pyran-4-ylmethoxy)- phenoxyj-acetonitrile;

[5-(6-Fluoro-2-methyl-8-methylamino-9FI-pyrimido[4,5-b]indol-4-yl)-2-(2-methoxy-ethoxy)-phenoxy]-acetonitrile;

(R)-[2-(3-Fluoro-2-hydroxy-propoxy)-5-(6-fluoro-2-methyl-8-methylamino-9FI-pyrimido[4,5-b]indol-4-yl)-phenoxy]- acetonitrile;

(S)-[2-(3-Fluoro-2-hydroxy-propoxy)-5-(6-fluoro-2-methyl-8-methylamino-9FI-pyrimido[4,5-b]indol-4-yl)-phenoxy]- acetonitrile;

[5-(6-Fluoro-2-methyl-8-methylamino-9FI-pyrimido[4,5-b]indol-4-yl)-2-(2-hydroxy-ethoxy)-phenoxy]-acetonitrile;

[5-(6-Fluoro-2-methyl-8-methylamino-9FI-pyrimido[4,5-b]indol-4-yl)-2-(3-hydroxy-2,2-dimethyl-propoxy)-phenoxy]- acetonitrile;

[5-(6-Fluoro-2-methyl-8-methylamino-9FI-pyrimido[4,5-b]indol-4-yl)-2-(2-morpholin-4-yl-ethoxy)-phenoxy]- acetonitrile;

{5-(6-Fluoro-2-methyl-8-methylamino-9FI-pyrimido[4,5-b]indol-4-yl)-2-[2-(3-hydroxy-3-methyl-butoxy)-ethoxy]- phenoxyj-acetonitrile;

[2-[2-(3-Fluoro-azetidin-1-yl)-ethoxy]-5-(6-fluoro-2-methyl-8-methylamino-9FI-pyrimido[4,5-b]indol-4-yl)-phenoxy]- acetonitrile;

(R)-7-(6-Fluoro-2-methyl-8-methylamino-9FI-pyrimido[4,5-b]indol-4-yl)-2,3-dihydro-benzo[1 ,4]dioxine-2- carbonitrile; and

(S)-7-(6-Fluoro-2-methyl-8-methylamino-9FI-pyrimido[4,5-b]indol-4-yl)-2,3-dihydro-benzo[1 ,4]dioxine-2- carbonitrile. The compounds of formula (I) according to embodiments 1) to 9) and their pharmaceutically acceptable salts can be used as medicaments, e.g. in the form of pharmaceutical compositions for enteral (such especially oral) or parenteral administration (including topical application or inhalation).

The production of the pharmaceutical compositions can be effected in a manner which will be familiar to any person skilled in the art (see for example Remington, The Science and Practice of Pharmacy, 21 st Edition (2005), Part 5, “Pharmaceutical Manufacturing” [published by Lippincott Williams & Wilkins]) by bringing the described compounds of formula (I) or (II), or their pharmaceutically acceptable salts, optionally in combination with other therapeutically valuable substances, into a galenical administration form together with suitable, non-toxic, inert, therapeutically compatible solid or liquid carrier materials and, if desired, usual pharmaceutical adjuvants.

The present invention also relates to a method for the prevention or treatment of a disease or disorder mentioned herein comprising administering to a subject a pharmaceutically active amount of a compound of formula (I) as defined in any one of embodiments 1 ) to 9).

In a further embodiment of the invention, the administered amount is comprised between 1 mg and 1000 mg per day.

Whenever the word“between” is used to describe a numerical range, it is to be understood that the end points of the indicated range are explicitly included in the range. For example: if a temperature range is described to be between 40 °C and 80 °C, this means that the end points 40 °C and 80 °C are included in the range; or if a variable is defined as being an integer between 1 and 4, this means that the variable is the integer 1 , 2, 3, or 4.

Unless used regarding temperatures, the term“about” placed before a numerical value“X” refers in the current application to an interval extending from X minus 10% of X to X plus 10% of X, and preferably to an interval extending from X minus 5% of X to X plus 5% of X. In the particular case of temperatures, the term“about” placed before a temperature Ύ” refers in the current application to an interval extending from the temperature Y minus 10 °C to Y plus 10 °C, and preferably to an interval extending from Y minus 5 °C to Y plus 5 °C.

For avoidance of any doubt, if compounds are described as useful for the prevention or treatment of certain diseases, such compounds are likewise suitable for use in the preparation of a medicament for the prevention or treatment of said diseases.

The compounds of formula (I) as defined in any one of embodiments 1 ) to 9) are useful for the prevention / prophylaxis or treatment of diseases and disorders responding to the inhibition of PDHK1 and/or to a modulated immunometabolism.

Diseases or disorders responding to the inhibition of PDHK1 and/or to a modulated immunometabolism are especially:

• cancer;

• inflammatory diseases (notably inflammatory diseases which are T-cell and/or macrophage mediated; and may be defined as comprising especially inflammatory kidney diseases such as nephritis, in particular glomerular nephritis and interstitial nephritis; vasculitis; rheumatic fever; and familial Mediterranean Fever);

• autoimmune disorders (notably (inflammatory) demyelinating diseases; multiple sclerosis (MS), systemic lupus erythematosus (SLE), Sjogren's syndrome, rheumatic disorders including rheumatoid arthritis (RA), juvenile arthritis, psoriatic arthritis granulomatosis with polyangiitis, (idiopathic) thrombocytopenic purpura, pemphigus vulgaris, myasthenia gravis, vitiligo, psoriasis, autoimmune hepatitis and diabetes type I).

In addition, further diseases or disorders responding to the inhibition of PDHK1 and/or to a modulated immunometabolism are

• transplant rejection, notably rejection of solid organ transplantation and complications from hematopoietic stem cell transplantation such as graft versus host disease;

• diabetic complications such as diabetic neuropathy, diabetic retinopathy, diabetic nephropathy, diabetic kidney disease, diabetic cataract;

• cardiovascular diseases caused by limited energy substrate supply to the tissues such as cardiac failure, cardiomyopathy, myocardial ischemia, dyslipidemia or atherosclerosis; or

• neurodegenerative disorders such as amyotrophic lateral sclerosis (ALS), cerebral ischemia or cerebral apoplexy;

• fibrotic diseases such as pulmonary fibrosis (especially idiopathic pulmonary fibrosis, or liver fibrosis).

The term "cancer" refers to all sorts of cancers such as carcinomas; adenocarcinomas; leukemias; sarcomas; lymphomas; myelomas; metastatic cancers; brain tumors; neuroblastomas; pancreatic cancers; gastro-intestinal cancers; lung cancers; breast cancers; prostate cancers; endometrial cancers; skin cancers; bladder cancers; head and neck cancers; neuroendocrine tumors; ovarian cancers; cervical cancers; oral tumors; nasopharyngeal tumors; thoracic cancers; and virally induced tumors.

Notably the term“cancer” refers to brain tumors including brain metastases, malignant gliomas, glioblastoma multiforme, medulloblastoma, meningiomas; neuroblastoma; pancreatic cancer including pancreatic adenocarcinoma/pancreatic ductal adenocarcinoma; gastro-intestinal cancers including colon carcinoma, colorectal adenoma, colorectal adenocarcinoma, metastatic colorectal cancer, familial adenomatous polyposis (FAP), gastric cancer, gallbladder cancer, cholangiocarcinoma, hepatocellular carcinoma; Kaposi’s sarcoma; leukemias including acute myeloid leukemia, adult T-cell leukemia; lymphomas including Burkitt’s lymphoma, Hodgkin’s lymphoma, MALT lymphoma, and primary intra-ocular B-Cell lymphoma; lung cancer including non-small cell lung cancer; breast cancer including triple negative breast carcinoma; rhabdomyosarcoma; prostate cancer including castrate-resistant prostate cancer; esophageal squamous cancer; (oral) squamous cell carcinoma; endometrial cancer; thyroid carcinoma including papillary thyroid carcinoma; metastatic cancers; lung metastasis; skin cancer including melanoma and metastatic melanoma; bladder cancer including urinary bladder cancer, urothelial cell carcinoma; multiple myelomas; osteosarcoma; head and neck cancer; and renal carcinomas including renal cell carcinoma renal clear cell carcinoma, metastatic renal cell carcinoma, metastatic renal clear cell carcinoma; as well as neuroendocrine tumors; ovarian cancer; cervical cancer; oral tumors; nasopharyngeal tumors; thoracic cancer; choriocarcinoma; Ewing’s sarcoma; and virally induced tumors.

Especially the term "cancer" refers to malignant glioma in particular glioblastoma multiforme, neuroblastoma; pancreatic cancers in particular pancreatic ductal adenocarcinoma; Kaposi’s sarcoma; adult T-cell leukemia, lymphoma; lung cancer; breast cancer; rhabdomyosarcoma; prostate cancer; esophageal squamous cancer; (oral) squamous cell carcinoma; endometrial cancer; papillary thyroid carcinoma; metastatic cancer; lung metastasis; melanoma; bladder cancer; multiple myelomas; osteosarcoma; gastro-intestinal cancers, in particular colon carcinoma, hepatocellular carcinoma; head and neck cancer; and renal clear cell carcinoma. Preferably the term "cancer" refers to malignant glioma, in particular glioblastoma multiforme; pancreatic cancers, in particular pancreatic ductal adenocarcinoma; papillary thyroid carcinoma; hepatocellular carcinoma; lung cancer; breast cancer; metastatic cancers; lung metastasis; melanoma; colon carcinoma; and head and neck cancer.

The compounds of formula (I) as defined in any one of embodiments 1 ) to 9) may in particular be useful as therapeutic agents for the prevention / prophylaxis or treatment of a cancer as defined before, which cancer is a metastatic cancer / a cancer which forms metastasis.

The compounds of formula (I) as defined in any one of embodiments 1) to 9) are in particular useful as therapeutic agents for the prevention / prophylaxis or treatment of a cancer. They can be used as single therapeutic agents or in combination with one or more chemotherapy agents and / or radiotherapy and / or targeted therapy. In a sub embodiment, when a compound of formula (I) is used for the prevention / prophylaxis or treatment of a cancer in combination with one or more chemotherapy agents and / or radiotherapy and / or targeted therapy, such cancer is especially a malignant glioma, in particular a glioblastoma multiforme; pancreatic cancer, especially pancreatic ductal adenocarcinoma; papillary thyroid carcinoma; lung metastasis; melanoma; lung cancer; metastatic cancers; hepatocellular carcinoma; breast cancer; colorectal cancer; or head and neck cancer. Such combined treatment may be effected simultaneously, separately, or over a period of time.

The invention, thus, also relates to pharmaceutical compositions comprising a pharmaceutically acceptable carrier material, and:

• a compound of formula (I) as defined in any one of embodiments 1 ) to 9);

• and one or more cytotoxic chemotherapy agents.

The invention, thus, further relates to a kit comprising

• a pharmaceutical composition, said composition comprising a pharmaceutically acceptable carrier material, and a compound of formula (I) as defined in any one of embodiments 1 ) to 9);

• and instructions how to use said pharmaceutical composition for the prevention or the treatment of a cancer (especially of a malignant glioma, in particular of a glioblastoma multiforme), in combination with chemotherapy and / or radiotherapy and / or targeted therapy. The terms "radiotherapy" or "radiation therapy" or "radiation oncology", refer to the medical use of ionizing radiation in the prevention (adjuvant therapy) and / or treatment of cancer; including external and internal radiotherapy.

The term "targeted therapy" refers to the prevention / prophylaxis (adjuvant therapy) and / or treatment of cancer with one or more anti-neoplastic agents such as small molecules or antibodies which act on specific types of cancer cells or stromal cells. Some targeted therapies block the action of certain enzymes, proteins, or other molecules involved in the growth and spread of cancer cells. Other types of targeted therapies help the immune system kill cancer cells (immunotherapies); or deliver toxic substances directly to cancer cells and kill them. An example of a targeted therapy which is in particular suitable to be combined with the compounds of the present invention is immunotherapy, especially immunotherapy targeting the progammed cell death receptor 1 (PD-1 receptor) or its ligand PD-L1 (Feig C et al, PNAS 2013).

When used in combination with the compounds of formula (I), the term "targeted therapy" especially refers to agents such as:

a) Epidermal growth factor receptor (EGFR) inhibitors or blocking antibodies (for example Gefitinib, Erlotinib, Afatinib, lcotinib, Lapatinib, Panitumumab, Zalutumumab, Nimotuzumab, Matuzumab and Cetuximab);

b) Anti-angiogeneic therapies (for example Axitinib, Bevacizumab, Cabozantinib, Everolimus, Lenalidomide, Lenvatinib mesylate, Pazopanib, Ramucirumab, Regorafenib, Sorafenib, Sunitinib, Thalidomide, Vandetanib, Ziv- aflibercept.

c) B-RAF inhibitors (for example Vemurafenib, Sorafenib, Dabrafenib,GDC-0879, PLX-4720, LGX818);d) Aromatase inhibitors (for example Exemestane, Letrozole, Anastrozole, Vorozole, Formestane,

Fadrozole);

e) Immune Checkpoint inhibitors (for example, anti-PD1 antibodies such as Pembrolizumab (Lambrolizumab, MK-3475), Nivolumab, Pidilizumab, AM P-514/M ED 10680; small molecule anti PD1 agents such as for example compounds disclosed in WO2015/033299, W02015/044900 and WO2015/034820; anti-PD1 L antibodies, such as BMS-936559, atezolizumab (MPDL3280A), MEDI4736, avelumab (MSB0010718C); anti-PDL2, such as AMP224, anti-CTLA-4 antibodies, such as ipilimumab, tremilmumab);

f) Vaccination approaches (for example dendritic cell vaccination, peptide or protein vaccination (for example with gp100 peptide or MAGE-A3 peptide);

g) Re-introduction of patient derived or allogenic (non-self) cancer cells genetically modified to secrete immunomodulatory factors such as granulocyte monocyte colony stimulating factor (GMCSF) gene-transfected tumor cell vaccine (GVAX) or Fms-related tyrosine kinase 3 (Flt-3) ligand gene-transfected tumor cell vaccine (FVAX),or Toll like receptor enhanced GM-CSF tumor based vaccine (TEGVAX);

h) T-cell based adoptive immunotherapies, including chimeric antigen receptor (CAR) engineered T-cells (for example CTL019);

i) Cytokine or immunocytokine based therapy (for example Interferon alpha, interferon beta, interferon gamma, interleukin 2, interleukin 15); j) Toll-like receptor (TLR) agonists (for example resiquimod, imiquimod, glucopyranosyl lipid A, CpG oligodesoxynucleotides);

k) Thalidomide analogues (for example Lenalidomide, Pomalidomide);

L) lndoleamin-2,3-Dioxgenase (IDO) and/or Tryptophane-2, 3-Dioxygenase (TDO) inhibitors (for example NLG919/lndoximod, 1 MT (1 -methyltryptophan), INCB024360);

m) Activators of T-cell co-stimulatory receptors (for example anti- Lymphocyte-activation gene 3 (LAG-3) antibodies (such as BMS-986016); anti T cell immunoglobulin mucin-3 (TIM-3) antibodies, anti-CD137/4-1 BB antibodies (for example BMS-663513/ urelumab), anti- Killer-cell immunoglobulin-like receptors (KIR) for example Lirilumab (IPH2102/BMS-986015); anti-OX40/CD134 (Tumor necrosis factor receptor superfamily, member 4), anti OX40-Ligand/CD252; anti-glucocorticoid-induced TNFR family related gene (GITR) (such as TRX518) , anti-CD40 (TNF receptor superfamily member 5) antibodies (such as CP-870,893); anti-CD40-Ligand antibodies (such as BG9588); anti-CD28 antibodies);

n) Molecules binding a tumor specific antigen as well as a T-cell surface marker such as bispecific antibodies or antibody fragments, antibody mimetic proteins such as designed ankyrin repeat proteins (DARPINS), bispecific T-cell engager (BITE, for example AMG103, AMG330);

o) Antibodies or small molecular weight inhibitors targeting colony-stimulating factor-1 receptor (CSF-1 R) (for example RG7155 or PLX3397).

When used in combination with the compounds of formula (I), immune checkpoint inhibitors such as those listed under e), and especially those targeting the progammed cell death receptor 1 (PD-1 receptor) or its ligand PD-L1 , are preferred.

The term "chemotherapy" refers to the treatment of cancer with one or more cytotoxic anti-neoplastic agents ("cytotoxic chemotherapy agents"). Chemotherapy is often used in conjunction with other cancer treatments, such as radiation therapy or surgery. The term especially refers to conventional chemotherapeutic agents which act by killing cells that divide rapidly, one of the main properties of most cancer cells. Chemotherapy may use one drug at a time (single-agent chemotherapy) or several drugs at once (combination chemotherapy or polychemotherapy). Chemotherapy using drugs that convert to cytotoxic activity only upon light exposure is called photochemotherapy or photodynamic therapy.

The term“cytotoxic chemotherapy agent” or“chemotherapy agent” as used herein refers to an active anti-neoplastic agent inducing apoptosis or necrotic cell death. When used in combination with the compounds of formula (I), the term especially refers to conventional cytotoxic chemotherapy agents such as:

a) alkylating agents (for example mechlorethamine, chlorambucil, cyclophosphamide, ifosfamide, streptozocin, carmustine, lomustine, melphalan, busulfan, dacarbazine, temozolomide, thiotepa or altretamine; in particular temozolomide);

b) platinum drugs (for example cisplatin, carboplatin or oxaliplatin); c) antimetabolite drugs (for example 5-fluorouracil, capecitabine, 6-mercaptopurine, methotrexate, gemcitabine, cytarabine, fludarabine or pemetrexed);

d) anti-tumor antibiotics (for example daunorubicin, doxorubicin, epirubicin, idarubicin, actinomycin-D, bleomycin, mitomycin-C or mitoxantrone);

e) mitotic inhibitors (for example paclitaxel, docetaxel, ixabepilone, vinblastine, vincristine, vinorelbine, vindesine or estramustine); or

f) topoisomerase inhibitors (for example etoposide, teniposide, topotecan, irinotecan, diflomotecan or elomotecan).

When used in combination with the compounds of formula (I), preferred cytotoxic chemotherapy agents are the above-mentioned alkylating agents (notably mechlorethamine, chlorambucil, cyclophosphamide, ifosfamide, streptozocin, carmustine, lomustine, melphalan, busulfan, dacarbazine, 3-methyl-(triazen-1 -yl)imidazole-4- carboxamide (MTIC) and prodrugs thereof such as especially temozolomide, thiotepa, altretamine; or pharmaceutically acceptable salts of these compounds; in particular temozolomide); and mitotic inhibitors (notably paclitaxel, docetaxel, ixabepilone, vinblastine, vincristine, vinorelbine, vindesine, estramustine; or pharmaceutically acceptable salts of these compounds; in particular paclitaxel). Most preferred cytotoxic chemotherapy agents to be used in combination with the compounds of formula (I) are those routinely used in the treament of glioblastoma multiforme, in particular temozolomide. Equally preferred is radiotherapy.

Chemotherapy may be given with a curative intent or it may aim to prolong life or to palliate symptoms.

a) Combined modality chemotherapy is the use of drugs with other cancer treatments, such as radiation therapy or surgery.

b) Induction chemotherapy is the first line treatment of cancer with a chemotherapeutic drug. This type of chemotherapy is used for curative intent.

c) Consolidation chemotherapy is the given after remission in order to prolong the overall disease free time and improve overall survival. The drug that is administered is the same as the drug that achieved remission. d) Intensification chemotherapy is identical to consolidation chemotherapy but a different drug than the induction chemotherapy is used.

e) Combination chemotherapy involves treating a patient with a number of different drugs simultaneously. The drugs differ in their mechanism and side effects. The biggest advantage is minimising the chances of resistance developing to any one agent. Also, the drugs can often be used at lower doses, reducing toxicity.

f) Neoadjuvant chemotherapy is given prior to a local treatment such as surgery, and is designed to shrink the primary tumor. It is also given to cancers with a high risk of micrometastatic disease.

g) Adjuvant chemotherapy is given after a local treatment (radiotherapy or surgery). It can be used when there is little evidence of cancer present, but there is risk of recurrence. It is also useful in killing any cancerous cells that have spread to other parts of the body. These micrometastases can be treated with adjuvant chemotherapy and can reduce relapse rates caused by these disseminated cells. h) Maintenance chemotherapy is a repeated low-dose treatment to prolong remission.

i) Salvage chemotherapy or palliative chemotherapy is given without curative intent, but simply to decrease tumor load and increase life expectancy. For these regimens, a better toxicity profile is generally expected.

When combined with the compounds of formula (I), preventive or curative forms of chemotherapy (or mutatis mutandis : radiotherapy) such as those listed under a), b) c), d), e), and especially g) and / or h) above are preferred.

“Simultaneously”, when referring to an administration type, means in the present application that the administration type concerned consists in the administration of two or more active ingredients and/or treatments at approximately the same time; wherein it is understood that a simultaneous administration will lead to exposure of the subject to the two or more active ingredients and/or treatments at the same time. When administered simultaneously, said two or more active ingredients may be administered in a fixed dose combination, or in an equivalent non-fixed dose combination (e.g. by using two or more different pharmaceutical compositions to be administered by the same route of administration at approximately the same time), or by a non-fixed dose combination using two or more different routes of administration; wherein said administration leads to essentially simultaneous exposure of the subject to the two or more active ingredients and/or treatments.

“Fixed dose combination”, when referring to an administration type, means in the present application that the administration type concerned consists in the administration of one single pharmaceutical composition comprising the two or more active ingredients.

“Separately”, when referring to an administration type, means in the present application that the administration type concerned consists in the administration of two or more active ingredients and/or treatments at different points in time; wherein it is understood that a separate administration will lead to a treatment phase (e.g. at least 1 hour, notably at least 6 hours, especially at least 12 hours) where the subject is exposed to the two or more active ingredients and/or treatments at the same time; wherein such "separate administration" may under certain circumstances also encompass a treatment phase where for a certain period of time (e.g. at least 12 hours, especially at least one day) the subject is exposed to only one of the two or more active ingredients and/or treatments. Separate administration thus especially refers to situations wherein one active ingredient and/or treatment is given e.g. once a day, and another is given e.g. twice a day, thrice a day, every other day, wherein as a consequence of such administration type the subject is exposed to the two or more active ingredients and/or treatments the same time during essentially the whole treatment period. Separate administration also refers to situations wherein at least one of the active ingredients and/or treatments is given with a periodicity substantially longer than daily (such as once or twice daily) administration (e.g. wherein one active ingredient and/or treatment is given e.g. once or twice a day, and another is given once a week). For example when used in combination with (e.g. weekly or bi-weekly) radiotherapy the present PDHK1 inhibitors would possibly be used "separately".

By administration“over a period of time” is meant in the present application the subsequent administration of two or more active ingredients and/or treatments at different times. The term in particular refers to an administration method according to which the entire administration of one of the active ingredients and/or treatments is completed before the administration of the other / the others begins. In this way it is possible to administer one of the active ingredients and/or treatments for several months before administering the other active ingredient(s) and/or treatment(s).

Administration“over a period of time” also encompasses situations wherein the PDHK1 inhibitors of formula (I) or (II) would be used in a treatment that starts after termination of an initial chemotherapeutic or radiotherapeutic treatment or targeted therapy (for example an induction chemotherapy), wherein optionally said treatment would be in combination with a further / an ongoing chemotherapeutic or radiotherapeutic treatment or targeted therapy treatment (for example in combination with a consolidation chemotherapy, an intensification chemotherapy, an adjuvant chemotherapy, or a maintenance chemotherapy; or radiotherapeutic equivalents thereof); wherein such further / ongoing chemotherapeutic or radiotherapeutic treatment or targeted therapy would be simultaneously or separately with the treatment using the PDHK1 inhibitor.

Autoimmune disorders may be defined as comprising multiple sclerosis (MS), systemic lupus erythematosus (SLE), Sjogren's syndrome, rheumatic disorders including rheumatoid arthritis (RA), juvenile arthritis, psoriatic arthritis granulomatosis with polyangiitis, (idiopathic) thrombocytopenic purpura, pemphigus vulgaris, myasthenia gravis, vitiligo, psoriasis, autoimmune hepatitis and diabetes type I.

In a sub-embodiment, autoimmune disorders especially refer to autoimmune disorders which have an inflammatory component, wherein particular examples are (inflammatory) demyelinating diseases, multiple sclerosis (MS), rheumatoid arthritis (RA), juvenile arthritis and psoriatic arthritis, and systemic lupus erythematosus (SLE).

Inflammatory diseases especially refer to inflammatory diseases which are T-cell and/or macrophage mediated; and may be defined as comprising especially inflammatory kidney diseases such as nephritis, in particular glomerular nephritis and interstitial nephritis; vasculitis; rheumatic fever; and familial Mediterranean Fever.

The compounds of formula (I) according to embodiments 1 ) to 9) are also useful in method of prophylaxis or treating tumors comprising administering an effective amount of the compound of formula (I) wherein said effective amount leads to a change of tumor properties, and wherein said modification is achieved by modulating PDHK1 activity and/or immunometabolism; wherein said prophylaxis or treatment may optionally be effected in combination with a conventional chemotherapeutic or radiotherapeutic treatment (in which case the tumor is notably a malignant glioma, in particular a glioblastoma multiforme). Such combined treatment may be effected simultaneously, separately, and/or over a period of time.

The compounds of formula (I) are also useful in method of modulating an immune response comprising the administration of an effective amount of the compound of formula (I) to a subject (especially a human) in need thereof, wherein said subject has been diagnosed to have an autoimmune disease or an inflammatory disease, wherein said immune response is mediated by PDHK1 activity and/or immunometabolism. Preparation of compounds of formula (I):

Compounds of Formula (I) can be prepared from commercially available or well-known starting materials according to the methods described in the experimental part, by analogous methods; or according to the general sequence of reactions outlined below, wherein R¹ and R² are as defined for Formula (I).

Optimum reaction conditions may vary with particular reactants or solvents used, but such conditions can be determined by a person skilled in the art by routine optimisation procedures. Other abbreviations used herein are explicitly defined or are as defined in the experimental section.

In some instances, the generic groups R¹ and R² might be incompatible with the assembly illustrated in the schemes below and so will require the use of protecting groups (PG). The use of protecting groups is well known in the art (see for example“Protective Groups in Organic Synthesis", T.W. Greene, P.G.M. Wuts, Wiley-lnterscience, 1999). For the purposes of this discussion, it will be assumed that such protecting groups as necessary are in place.

In some cases, the final product may be further modified, for example, by manipulation of substituents to give a new final product. These manipulations may include, but are not limited to, reduction, oxidation, alkylation, acylation, and hydrolysis reactions which are commonly known to those skilled in the art. The compounds obtained may also be converted into salts, especially pharmaceutically acceptable salts in a manner known per se.

General Procedures:

In a specific embodiment, compounds of formula (I) of the present invention can be prepared according to the general sequence of reactions outlined below in Reaction Scheme A. Examples of formula (I) may be obtained by the procedure illustrated in Reaction Scheme A. N-methyl allyl amine can be introduced by displacement of an ortho-fluoro atom on 2,4,6-trifluoronitrobenzene (A) to give the allyl protected N-methyl amine (B) in a solvent like THF or DCM at RT. Treatment of (B) with cyano ethyl acetate in the presence of a base like NaH in a DMF at temperature between 0°C and RT gives the substituted cyano-acetic ester derivative (C). Reduction of the nitro group of (C) with zinc in glacial acetic acid at temperature between 0°C and RT delivers the 2-aminoindole-3- ethylester (D). The indole intermediate (D) is converted to the tricyclic compound (E) through condensation of acetonitrile with the 2-aminoindole-3-ethylester (D), in a 2 step sequences, first in acidic condition such as HCI 4N in dioxane at RT and then in soft basic condition such as NaOFI (0.25N) in EtOH (96%) at temperature between RT and 60°C. Compound (F) can be prepared from the tricyclic hydroxypyrimidine precursor (E) with an activating reagent such as triflic anhydride in pyridine to yield the corresponding trifluoromethylsulfonate (Fi) as leaving group or with an activating reagent such as POCI3 in toluene at 1 10°C to yield the corresponding chloro derivative (F2) (LG2) according to standard conditions described in literature for similar chemical transformations. The trifluoromethylsulfonate derivative (Fi) can also be transformed into the chloride (F2) by treatment with LiCI in DMF at temperature between RT and 150°C. Coupling of the tricyclic compound (F) bearing a leaving group (LG) such as a trifluoromethylsulfonate or a chloro atom, with an organometallic reagent (G) such as a boronic acid or boronic ester using transition metal catalyst such as Pd catalysts in a solvent such as dioxane or its like at temperature ranging from RT to 125 °C, preferably above 100°C. Loss of the allyl protection can be observed along with the coupling step at high temperature; otherwise a final deprotection step on the coupling product (H) according to conditions well known in the art like treatment with 1 ,3-dimethylbarbituric acid and palladium tetrakis triphenyl phosphine in an alcohol like MeOH at RT may be required for reaching the final derivative of formula (I).

Reaction scheme A

Compounds of formula (I) may alternatively be prepared as illustrated in Reaction Scheme B. Compound (F2) is further N-Boc protected by treatment with di-tert-butyl decarbonate in a solvent like THF or DCM in the presence of DMAP and DIPEA to yield the intermediate (J). Coupling of the deprotected tricyclic compound (J) with an organometallic reagent (G) such as a boronic acid or boronic ester using transition metal catalyst such as Pd catalysts in a solvent such as dioxane or its like at temperature ranging from RT to 125 °C, preferably above 100°C in the presence of a base like aq. K2CO3 or aq. K3PO4 yields the coupling product (K). The N-Boc protecting group is first removed by treatment with an acid like TFA in DCM at RT or 4M HCI in dioxane. The second protecting allyl group is cleaved by treatment with 1 ,3-dimethylbarbituric acid and palladium tetrakis triphenyl phosphine in an alcohol like MeOH at RT to give the final derivative of formula (I). Reaction scheme B

Whenever the compounds of formula (I) are obtained in the form of mixtures of enantiomers, the enantiomers can be separated using methods known to one skilled in the art: e.g. by formation and separation of diastereomeric salts or by HPLC over a chiral stationary phase such as a Regis Whelk-01 (R,R) (10 mhh) column, a Daicel ChiralCel OD-H (5-10 mhh) column, or a Daicel ChiralPak IA (10 mhh), IA, IB, IC, IE, or IF (5 mhh) or AD-H (5 mhh) column. Typical conditions of chiral HPLC are an isocratic mixture of eluent A (EtOH, in presence or absence of an amine such as triethylamine or diethylamine) and eluent B (heptane), at a flow rate of 0.8 to 150 mL/min.

Experimental Part

I. Chemistry

All temperatures are stated in °C. Commercially available starting materials were used as received without further purification. Unless otherwise specified, all reactions were carried out in oven-dried glassware under an atmosphere of nitrogen or argon. Compounds were purified by flash column chromatography on silica gel or by preparative HPLC. Compounds described in the invention are characterised by LC-MS data (retention time tR is given in min; molecular weight obtained from the mass spectrum is given in g/mol) using the conditions listed below. In cases where compounds of the present invention appear as a mixture of conformational isomers, particularly visible in their LC-MS spectra, the retention time of the most abundant conformer is given. NMR spectroscopy

Bruker Avarice II spectrometer equipped with a 400 MHz (¹H) Ultrashield™ Magnet and a BBO 5mm probehead or a PAXTI 1 mm probehead, or a Bruker Avance III HD Ascend 500 MHz (¹H), magnet equiped with DCH cryoprobe. Chemical shifts (d) are reported in parts per million (ppm) relative to proton resonances resulting from incomplete deuteration of the NMR solvent, e.g. for dimethylsulfoxide d(H) 2.49 ppm, for chloroform d(H) 7.24 ppm. The abbreviations s, d, f, q and m refer to singlet, doublet, triplet, quartet, multiplet and br to broad, respectively. Coupling constants J are reported in Hz. In case NMR spectra are measured using 1 mm Microprobe® tubes and a PAXTI 1 mm probehead, the compounds are dissolved in non-deuterated DMSO. The spectra are then measured with double irradiation for suppression of the DMSO and H2O peaks. In that case only a selection of representative NMR peaks of the compound is given.

Quality control (QC) analytical LC-MS:

Equipment and conditions:

Pump: Waters Acquity Binary, Solvent Manager, MS: Waters SQ Detector, DAD: Acquity UPLC PDA Detector, ELSD: Acquity UPLC ELSD. Columns: Acquity UPLC CSH C18 1.7 pm 2.1x50 mm or Acquity UPLC HSS T3 C18 1.8 m 2.1x50 mm from Waters, thermostated in the Acquity UPLC Column Manager at 60°C. Eluents: A1 : H20 + 0.05% FA; B1 : AcCN + 0.045% FA. Method: Gradient: 2% B 98% B over 2.0 min. Flow: 1.0 mL/min. Detection: UV 214nm and ELSD, and MS, tR is given in min.

-Waters Acquity UPLC (ACQ-CM, - ACQ-BSM - ACD-SM) Injection volume: 0.20 uL, partial loop 2 uL. Column Oven Temp (°C): 60°C. Eluent A1 : H20 + 0.05% v/v formic Acid, Eluent B1 : acetonitrile + 0.045% v/v formic Acid. Column: ACQUITY UPLC CSH C18 1.7 urn, 2.1 x 50 mm.

-PDA Detector (ACQ-PDA), Wavelengh: 200-300 nm, Resolution: 3.6 nm, Sampling Rate: 20 points/sec. Filter Time Constant: Normal, Exposure Time: Automatic.

-Xevo TQD, Source Temp(°C): 150. Desolvatation Temp (°C): 500. Desolvatation Gas Flow (L/hr): 650. Cone Gas Flow (L/hr): 10. Extractor (V): 3. RF Lens (V): 0.1. Cone (V): 25. Capillary (kV): 2.5. LM Resolution: 15. HM Resolution: 9.5. Ion Energy: 0.1. Gain: 1.0. Positive-Negative Switching Mode: 0.1 sec per scan, 120-1000 amu in Full Scan.

Analytical LC-MS

Equipment: Binary gradient pump Agilent G4220A or equivalent with mass spectrometry detection (single quadrupole mass analyser, Thermo Finnigan MSQPIus or equivalent).

Conditions:

Method A (acidic conditions): Column: Zorbax SB-aq (3.5 Dm, 4.6 x 50 mm); conditions: CH3CN [eluent A]; water + 0.04% TFA [eluent B]; gradient: 95% B— > 5% B over 1.5 min (flow: 4.5 mL/min). Detection: UVA/is + MS. Method B (acidic conditions): Nucleodur C8 ec column, 4.6 x 100 mm from Macherey-Nagel. Eluents: A: H O + 0.1 % HCOOH; B: acetonitrile + 0.1 % HCOOH. Gradient: 5% B to 95%B over 5 min. Flow: 1.3 mL/min. Detection: UV/Vis + MS.

Method C (acidic conditions): UPLC-MS: Nucleoshell RP18 ec column, 3.0 x 50 mm from Macherey-Nagel. Eluents: A: H O + 0.1 % HCOOH; B: acetonitrile + 0.1 % HCOOH. Gradient: 5% B to 95% B over 0.6 min. Flow: 1 mL/min. Detection: UV/Vis + MS.

Preparative LC-MS

Equipment: Binary gradient pump Gilson 333/334 or equivalent with mass spectrometry detection (single quadrupole mass analyser, Thermo Finnigan MSQPIus or equivalent).

Conditions: Method B (basic conditions): Column: Waters XBridge C18 (10 Dm, 30 x 75 mm); conditions: CH₃CN [eluent A]; water + 0.5% NH₄OH (25% aq.) [eluent B]; gradient: 95% B— > 5% B, over 6.5 min (flow: 75 mL/min). Detection: UV/Vis + MS.

Abbreviations (as used hereinbefore or hereinafter):

AcOH acetic acid

aq. aqueous

Boc tert-butoxycarbonyle

CH₃CN acetonitrile

DCM dichloromethane

DIEA diisopropyl-ethylamine, HOnig's base, ethyl-diisopropylamine

dioxane 1 ,4-dioxane

DMAP 4-dimethylaminopyridine

DME 1 ,2-dimethoxyethane

DMF dimethylformamide

DMSO dimethylsulfoxide

DTT DL-dithiothreitol

EA ethyl acetate

Et ethyl

Et₂0 diethyl ether

EtOH ethanol

FC flash chromatography

HPLC high performance liquid chromatography

HV high vacuum conditions

KOAc potassium acetate

K₂CO₃ potassium carbonate

LC-MS liquid chromatography - mass spectrometry M molarity of a solution

mCPBA 3-chloroperbenzoic acid

Me methyl

MeOH methanol

N normality of a solution

MS mass spectroscopy

MTCF Methyl thiourea ethyl sulfide ethyl Silica 60-200 m (PhosphonicS MTCF)

NMR nuclear magnetic resonance spectroscopy

Pd/C palladium on carbon

PdCI₂(dppf).CH₂CI₂ [1 , 1 '-Bis(diphenylphosphino)ferrocene]dichloropalladium(l I), complex with DCM

Pd(PPh₃)₄ Palladium tetrakistriphenylphosphine

rac racemic

RT room temperature

sat. saturated

STA3 Triamine ethyl sulfide amide Silica 60-200 pm (PhosphonicS STA3)

TFA trifluoroacetic acid

THF tetrahydrofuran

fR retention time

Zn Zinc

Intermediate B01 : [2-Methoxy-5-(4,4,5,5-tetramethyl-[1 ,3,2]dioxaborolan-2-yl)-phenoxy]-acetonitrile

To a solution of 2-methoxy-5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenol (0.4 g, 1.6 mmol) in CH3CN (5 mL) are added Cs₂C03 (0.65 g, 4.8 mmol) and bromoacetonitrile (0.28 mL, 4 mmol). The reaction mixture is stirred at RT for 30h and evaporated. EA (10 mL) and H₂0 (10mL) are added. The organic layer is washed twice with H₂0 (2 X 10 mL), dried over MgS0₄, filtered and evaporated to dryness. Purification by FC on silica gel (cyclohexane/EA 100:0 to 50:50) yields the title compound as a white powder. LC-MSmethod B: tR = 5.15 min; [M+FI]⁺ = 290.3.

Intermediate B02: [2-(2-Hydroxy-2-methyl-propoxy)-5-(4,4,5,5-tetramethyl-[1 ,3,2]dioxaborolan-2-yl)- phenoxy]-acetonitrile

Step 1 : 1-[5-Bromo-2-(2-hydroxy-2-methyl-propoxy)-phenyl]-ethanone

To a solution of 5’-bromo-2’-hydroxyacetophenone (1.0 g, 4.6 mmol) in DMF (20 mL) are added 1-chloro-2-methyl- propanol (0.95 mL, 9.2 mmol) and K₂C0₃ (1.3 g, 9.2 mmol). The mixture is heated in a sealed tube at 140°C for 20h and evaporated. The residue is partitioned between sat. NaFICOa solution (25 mL) and EA (25 mL) and the organic layer is washed with sat. NaFICOa solution (3x 25 mL)), dried (MgS0₄), filtered and evaporated. Purification by FC on silica gel (cyclohexane/EA 100:0 to 50:50) yields the title compound as a dark orange oil (830 mg). LC- MS method C: tR = 1.56 min; [M+Na]⁺ = 31 1.0. Step 2: Acetic acid 5-bromo-2-(2-hydroxy-2-methyl-propoxy)-phenyl ester

To a solution of 1 -[5-bromo-2-(2-hydroxy-2-methyl-propoxy)-phenyl]-ethanone (830 mg, 2.9 mmol) in DCM (6 mL) is added 77% mCPBA (1.62 g, 7.2 mmol). The reaction mixture is heated at 50°C for 20h, cooled to 0°C and quenched with sat. Na₂S₂0s solution (25 mL). The mixture is stirred at 0°C for 30 min and filtered. The filtrate is diluted with DCM (50 mL) and the organic layer is washed with sat. NaHCCh solution (3x 25 mL)), dried (MgSC ), filtered and evaporated. Purification by FC on silica gel (cyclohexane/EA 100:0 to 50:50) yields the title compound as a yellow oil (695 mg). LC-MS method B: tR = 4.74 min; [M+Na]⁺ = 327.0.

Step 3: 5-Bromo-2-(2-hydroxy-2-methyl-propoxy)-phenol

To a solution of acetic acid 5-bromo-2-(2-hydroxy-2-methyl-propoxy)-phenyl ester (690 mg, 2.3 mmol) in methanol (6.6 mL) is added 2.5M NaOH solution in H₂0 (1.25 mL). The reaction mixture is heated at 50°C for 20h and is evaporated. The residue is partitioned between H₂0 (25 mL) and EA (25 mL) and the aqueous layer is extracted with EA (2x 25 mL). The organic fractions are combined, washed successively with 1 N NaOH solution (25 mL), sat. NaCI solution (25 mL) and then dried (MgSO^, filtered and evaporated to yield the title compound as white solid (448 mg). LC-MS method B: t_R = 4.55 min; [M+Na]⁺ = 285.0.

Step 4: [5-Bromo-2-(2-hydroxy-2-methyl-propoxy)-phenoxy]-acetonitrile

[5-Bromo-2-(2-hydroxy-2-methyl-propoxy)-phenoxy]-acetonitrile is prepared according to the method of intermediate B01 using 5-bromo-2-(2-hydroxy-2-methyl-propoxy)-phenol and bromoacetonitrile as reagents, Cs₂C03 as base and by stirring the reaction mixture at RT for 20h to yield the title compound as a brown oil. LC- MS method C: t_R = 1.52 min; [M+Na]⁺ = 324.0.

Step 5: [2-(2-Hydroxy-2-methyl-propoxy)-5-(4,4,5,5-tetramethyl-[1 ,3,2]dioxaborolan-2-yl)-phenoxy]-acetonitrile

B02

To a purged solution of [5-bromo-2-(2-hydroxy-2-methyl-propoxy)-phenoxy]-acetonitrile (440 mg, 1.46 mmol), bis(pinacolato)diboron (375 mg, 1.46 mmol) and KOAc (432 mg, 4.39 mmol) in dioxane (3 mL) is added PdCI₂(dppf). DCM (12 mg, 0.014 mmol). The reaction mixture is heated at 80°C for 20h. EA is added, and the organic layer is washed with H₂0 (3X 25 mL), dried (MgSO^, filtered and evaporated. Purification by FC on silica gel (cyclohexane/EA 100:0 to 50:50) yields the title compound as a yellow oil (443 mg). LC-MS method C: t_R = 1.60 min; [M+Na]⁺ = 370.2.

Intermediate B03: 2-(2-(Cyanomethoxy)-4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenoxy)-N- methylacetamide

Step 1 : 2-(5-Bromo-2-formylphenoxy)acetonitrile

2-(5-Bromo-2-formylphenoxy)acetonitrile is prepared according to the method of intermediate B01 using 4-bromo- 2-hydroxy-benzaldehyde and bromoacetonitrile as reagents, Cs₂C03 as base and by stirring the reaction mixture at RT for 20h to yield the title compound as a beige solid. LC-MS method B: t_R = 4.67; [M+Na]⁺ = 242.1

Step 2: 4-Bromo-2-(cyanomethoxy)phenyl formate To a suspension of 2-(5-bromo-2-formylphenoxy)acetonitrile (9.15 g, 38.1 mmol) in DCM (80 mL) is added portionwise mCPBA 77% (21.3 , 95.25 mmol). The reaction mixture is heated at 50°C in a sealed tube for 20h. The mixture is filtered and the filtrate is cooled to 0°C then quenched with Na2S20s sat (100 mL). The mixture is then stirred at RT for 30 min and the 2 phases are separated. The organic layer is washed with NaHCCh sat (5X 25 mL), dried (Na2S04), filtered and evaporated. Purification by FC on silica gel (cyclohexane/EA 100:0 to 60:40) yields the title compound as a white powder (2.79 g) of the title product and 2.06g formation of 2-(5-bromo-2- hydroxyphenoxyjacetonitrile (synthesized in step 3) as a white powder. LC-MS method B: tR = 4.69; [M+Na]⁺ = 279.9.

Step 3: 2-(5-Bromo-2-hydroxyphenoxy)acetonitrile

To a solution of 4-bromo-2-(cyanomethoxy)phenyl formate (2.68 g, 10.47 mmol) in DCM (27 mL) are added AcOH (4.02 mL, 70.22 mmol) and FLO (1 mL). The reaction mixture is heated at 50°C for 90h. DCM (25 mL) and FLO (25 mL) are added at RT and the 2 phases are separated. The organic layer is washed with FLO (2X 25 mL), dried (MgSO^, filtered and evaporated to yield the title compound as a beige powder (2.44 g). LC-MS methodB: tR = 4.42 min; [M+H]⁺ = 230.0.

Step 4: 2-(4-Bromo-2-(cyanomethoxy)phenoxy)-N-methylacetamide

2-(4-Bromo-2-(cyanomethoxy)phenoxy)-N-methylacetamide is prepared according to the method of intermediate B01 using 2-(5-bromo-2-hydroxyphenoxy)acetonitrile and then 2-chloro-n-methylacetamide as reagents, CS2CO3 as base and by stirring the reaction mixture at RT for 48h. Cyclohexane/EA 100:0 to 30:70 as gradient for the purification step to yield the title compound as a white powder. LC-MS method -B: tR = 4.31 min; [M+Na]⁺ = 323.1.

Step 5: 2-(2-(Cyanomethoxy)-4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenoxy)-N-methylacetamide B03 Intermediate B03 is prepared according to the method of intermediate B02 (step 5) using 2-(4-bromo-2- (cyanomethoxy)phenoxy)-N-methylacetamide as starting material and cyclohexane/EA 100:0 to 50:50 as gradient for the purification step to yield the title compound as a white powder .LC-MS method C: tR = 4.71 min; [M+Na]⁺ = 347.2.

Intermediate B04: Rac-2-(2-(2-hydroxy-3,3-dimethylbutoxy)-5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2- yl)phenoxy)acetonitrile

Step 4: Rac-2-(5-bromo-2-(2-hydroxy-3,3-dimethylbutoxy)phenoxy)acetonitrile

To a solution of 2-(5-bromo-2-hydroxyphenoxy)acetonitrile B03 (step 3) (500 mg, 2.19 mmol) and 3,3-dimethyl- 1 , 2-epoxybutane (300 uL, 2.41 mmol) in CFI₃CN (10 mL) is added K₂CO₃ (450 mg, 3.29 mmol). The reaction mixture is heated at 80°C for 20h. 3, 3-dimethyl-1 , 2-epoxybutane (150 uL, 1.2 mmol) is added again at RT then the reaction mixture is heated at 80°C for 20h. The mixture is evaporated to dryness then EA (20 mL) and NaFICOs sat (20 mL) are added. The aqueous layer is extracted with EA (2X 20 mL), and the combined organic layers are dried (MgS04), filtered and evaporated. Purification by FC on silica gel (cyclohexane/EA 100:0 to 30:70) yields the title compound as a colorless oil (465 mg). LC-MS method B: tR = 5.22 min; [M+Na]⁺ = 352.3. Step 5: Rac-2-(2-(2-hydroxy-3,3-dimethylbutoxy)-5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2- yl)phenoxy)acetonitrile B04

Intermediate B04 is prepared according to the method of intermediate B02 (step 5) using 2-(5-bromo-2-(2-hydroxy- 3,3-dimethylbutoxy)phenoxy)acetonitrile as starting material and cyclohexane/EA 100:0 to 60:40 as gradient for the purification step to yield the title compound as a yellow oil. LC-MS method B: tR = 5.47 2-(4-Bromo-2- (cyanomethoxy)phenoxy)-N-methylacetamide min; [M+Na]⁺ = 398.3.

Intermediate B05: Rac-2-(2-(2-hydroxy-2-phenylethoxy)-5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2- yl)phenoxy)acetonitrile

Step 4: Rac-2-(5-Bromo-2-(2-hydroxy-2-phenylethoxy)phenoxy)acetonitrile

To a solution of 2-(5-bromo-2-hydroxyphenoxy)acetonitrile B03 (step 3) (500 mg, 2.20 mmol) and styrene oxide (245 uL, 3.06 mmol) in DMF (10 mL) is added K2CO3 (450 mg, 3.30 mmol). The reaction mixture is heated at 80°C for 20h. Styrene oxide (150 uL, 1.15 mmol) is added again at RT then the reaction mixture is heated at 80°C for 24h. The mixture is evaporated to dryness then EA (20 mL) and NaHCCh sat (20 mL) are added. The aqueous layer is extracted with EA (2X 20 mL), and the combined organic layers are dried (MgSC ), filtered and evaporated. Purification by FC on silica gel (cyclohexane/EA 100:0 to 70:30) yields the title compound as a yellow oil (393 mg). LC-MS method B: t_R = 5.06 min; [M+Na]⁺ = 372.2.

Step 5: Rac-2-(2-(2-hydroxy-2-phenylethoxy)-5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenoxy)acetonitrile

B05

Intermediate B05 is prepared according to the method of intermediate B02 (step 5) using 2-(5-bromo-2-(2-hydroxy- 2-phenylethoxy)phenoxy)acetonitrile as starting material and cyclohexane/EA 100:0 to 70:30 as gradient for the purification step to yield the title compound as a yellow oil. LC-MS method B: t_R = 5.33 min; [M+Na]⁺ = 418.2.

Intermediate B06: 2-(2-(3-Hydroxy-3-methylbutoxy)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)phenoxy)acetonitrile

Step 4: 2-(5-Bromo-2-(3-hydroxy-3-methylbutoxy)phenoxy)acetonitrile

To a solution of 2-(5-bromo-2-hydroxyphenoxy)acetonitrile B03 (step 3) (50 mg, 0.22 mmol) in CFI3CN (2 mL) is added CS2CO3 (79 mg, 0.24 mmol). The mixture is stirred at RT for 15 min then 4-chloro-2-methylbutan-2-ol (39 uL, 0.29 mmol) is added. The reaction mixture is heated at 80°C in a sealed tube for 20h. The mixture is cooled to RT and CS2CO3 (50 mg, 0.15 mmol) and chloro-2-methylbutan-2-ol (40 uL, 0.29 mmol) are added. The reaction mixture is heated at 80°C for 4h. The mixture is cooled to RT and EA (10 mL) and H2O (10 mL) are added. The aqueous layer is extracted with EA (2X 10 mL), and the combined organic layers are dried (MgSO^, filtered and evaporated. Purification by FC on silica gel (cyclohexane/EA 100:0 to 50:50) yields to the title compound as an orange oil (45 mg). LC-MS-method B: t_R = 4.80 min; [M+Na]⁺ = 338.

Step 5: 2-(2-(3-hydroxy-3-methylbutoxy)-5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenoxy)acetonitrile B06 Intermediate B06 is prepared according to the method of intermediate B02 (step 5) using 2-(5-bromo-2-(3-hydroxy- 3-methylbutoxy)phenoxy)acetonitrile as starting material and cyclohexane/EA 100:0 to 60:40 as gradient for the purification step to yield the title compound as a yellow oil. LC-MS method B: tR = 5.10 min; [M+Na]⁺ = 384.2.

Intermediate B07 : Rac-2-(5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-2-(3,3,3-trifluoro-2- hydroxypropoxy)phenoxy)acetonitrile

Step 4: Rac-2-(5-bromo-2-(3,3,3-trifluoro-2-hydroxypropoxy)phenoxy)acetonitrile

Rac-2-(5-bromo-2-(3,3,3-trifluoro-2-hydroxypropoxy)phenoxy)acetonitrile is prepared according to the method of intermediate B05 (step 4) using 2-(5-bromo-2-hydroxyphenoxy)acetonitrile B03 (step 3) and 1 , 1 , 1 -trifluoro-2,3- epoxypropane as reagents, K2CO3 as base and by heating the reaction mixture at 80°C overnight; cyclohexane/EA 100:0 to 70:30 as gradient for the purification step to yield the title compound as a brown oil. LC-MS method C: tR = 1.60 min; [M+Na]⁺ = 363.9

Step 5: Rac-2-(5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-2-(3,3,3-trifluoro-2- hydroxypropoxy)phenoxy)acetonitrile B07

Intermediate B07 is prepared according to the method of intermediate B02 (step 5) using rac-2-(5-bromo-2-(3,3,3- trifluoro-2-hydroxypropoxy)phenoxy)acetonitrile as starting material and cyclohexane/EA 100:0 to 70:30 as gradient for the purification step to yield the title compound as a colorless oil. LC-MS method B: tR = 5.19 min; [M+Na]⁺ = 410.1.

Intermediate B08: Rac-2-(2-(2-hydroxybutoxy)-5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2- yl)phenoxy)acetonitrile

Step 4: Rac-2-(5-bromo-2-(2-hydroxybutoxy)phenoxy)acetonitrile

Rac-2-(5-bromo-2-(2-hydroxybutoxy)phenoxy)acetonitrile is prepared according to the method of intermediate B05 (step 4) using 2-(5-bromo-2-hydroxyphenoxy)acetonitrile B03 (step 3) and 1 ,2-epoxybutane as reagents, K2CO3 as base and by heating the reaction mixture at 80°C for 20h, to yield the title compound as a brown oil. LC-MS method B: t_R = 4.78 min; [M+Na]⁺ = 324.0.

Step 5: Rac-2-(2-(2-hydroxybutoxy)-5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenoxy)acetonitrile B08 Intermediate B08 is prepared according to the method of intermediate B02 (step 5) using 2-(5-bromo-2-(2- hydroxybutoxy)phenoxy)acetonitrile as starting material and cyclohexane/EA 100:0 to 80:20 as gradient for the purification step to yield the title compound as a yellow oil. LC-MS method B: tR = 5.09 min; [M+Na]⁺ = 370.2

Intermediate B09: Rac-2-(2-(2-hydroxypropoxy)-5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2- yl)phenoxy)acetonitrile

Step 4: Rac-2-(5-bromo-2-(2-hydroxypropoxy)phenoxy)acetonitrile

Rac-2-(5-bromo-2-(2-hydroxypropoxy)phenoxy)acetonitrile is prepared according to the method of intermediate B05 (step 4) using 2-(5-bromo-2-hydroxyphenoxy)acetonitrile B03 (step 3) and propylene oxide as reagents, K2CO3 as base and by heating the reaction mixture at 80°C for 40h; cyclohexane/EA 100:0 to 50:50 as gradient for the purification step to yield the title compound as a yellow oil . LC-MS method B: tR = 4.57 min; [M+Na]⁺ = 309.9. Step 5: Rac-2-(2-(2-hydroxypropoxy)-5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenoxy)acetonitrile B09 Intermediate B09 is prepared according to the method of intermediate B02 (step 5) using rac-2-(5-bromo-2-(2- hydroxypropoxy)phenoxy)acetonitrile as starting material and cyclohexane/EA 100:0 to 75:25 as gradient for the purification step to yield the title compound as a yellow oil. LC-MS method B: tR = 4.91 min ; [M+Na]⁺ = 356.1

Intermediate B10: 2-(2-((4-Hydroxytetrahydro-2H-pyran-4-yl)methoxy)-5-(4,4,5,5-tetramethyl-1 ,3,2- dioxaborolan-2-yl)phenoxy)acetonitrile

Step 4: 2-(5-Bromo-2-((4-hydroxytetrahydro-2H-pyran-4-yl)methoxy)phenoxy)acetonitrile

2-(5-bromo-2-((4-hydroxytetrahydro-2H-pyran-4-yl)methoxy)phenoxy)acetonitrile is prepared according to the method of intermediate B05 (step 4) using 2-(5-bromo-2-hydroxyphenoxy)acetonitrile B03 (step 3) and 1 ,6- dioxaspiro[2,5]octane as reagents, K2CO3 as base and by heating the reaction mixture at 80°C overnight; cyclohexane/EA 100:0 to 75:25 as gradient for the purification step to yield the title compound as a colorless oil . LC-MS method C: t_R = 1.48 min; [M+Na]⁺ = 365.9.

Step 5: 2-(2-((4-Hydroxytetrahydro-2H-pyran-4-yl)methoxy)-5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2- yl)phenoxy)acetonitrile B10

Intermediate B10 is prepared according to the method of intermediate B02 (step 5) using 2-(5-bromo-2-((4- hydroxytetrahydro-2H-pyran-4-yl)methoxy)phenoxy)acetonitrile as starting material and cyclohexane/EA 100:0 to 50:50 as gradient for the purification step to yield the title compound as ayellow gum. LC-MS method B: tR = 4.88 min; [M+Na]⁺ = 412.2.

Intermediate B11 : 2-(2-(2-Methoxyethoxy)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)phenoxy)acetonitrile

Step 4: 2-(5-Bromo-2-(2-methoxyethoxy)phenoxy)acetonitrile

2-(5-Bromo-2-(2-methoxyethoxy)phenoxy)acetonitrile is prepared according to the method of intermediate B06 (step 4) using 2-(5-bromo-2-hydroxyphenoxy)acetonitrile B03 (step 3) and bromoethyl methyl ether as reagents, CS2CO3 as base and by stirring the reaction mixture at 80°C for 20h. Cyclohexane/EA 100:0 to 70:30 as gradient for the purification step to yield the title compound as a colorless oil. LC-MS method B: tR = 4.92 min; [M+H]⁺ = 288.1.

Step 5: 2-(2-(2-methoxyethoxy)-5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenoxy)acetonitrile B11

Intermediate B11 is prepared according to the method of intermediate B02 (step 5) using 2-(5-bromo-2-(2- methoxyethoxy)phenoxy)acetonitrile as starting material and cyclohexane/EA 100:0 to 70:30 as gradient for the purification step to yield the title compound as a colorless oil. LC-MS method B: tR = 5.18 min; [M+H]⁺ = 334.2.

Intermediate B12: Rac-2-(2-(3-fluoro-2-hydroxypropoxy)-5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2- yl)phenoxy)acetonitrile

Step 4: Rac-2-(5-bromo-2-(3-fluoro-2-hydroxypropoxy)phenoxy)acetonitrile

Rac-2-(5-Bromo-2-(3-fluoro-2-hydroxypropoxy)phenoxy)acetonitrile is prepared according to the method of intermediate B05 (step 4) using 2-(5-bromo-2-hydroxyphenoxy)acetonitrile B03 (step 3) and 3-fluoro-1 ,2- propenoxide as reagents, K₂CO₃ as base and by heating the reaction mixture at 80°C for 20h to yield the title compound as a brown oil. LC-MS method B: tR = 4.56 min; [M+Na]⁺ = 327.9.

Step 5: Rac-2-(2-(3-fluoro-2-hydroxypropoxy)-5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenoxy)acetonitrile

B12

Intermediate B12 is prepared according to the method of intermediate B02 (step 5) using rac-2-(5-bromo-2-(3- fluoro-2-hydroxypropoxy)phenoxy)acetonitrile as starting material and cyclohexane/EA 100:0 to 70:30 as gradient for the purification step to yield the title compound as a colorless oil. LC-MS method C: tR = 1.55 min; [M+Na]⁺ = 374.1.

Intermediate B13: 2-(2-(2-Hydroxyethoxy)-5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2- yl)phenoxy)acetonitrile

Step 4: 2-(5-Bromo-2-(2-hydroxyethoxy)phenoxy)acetonitrile

To a suspension of 2-(5-bromo-2-hydroxyphenoxy)acetonitrile B03 (step 3) (50 mg, 0.21 mmol) and ethylene carbonate (77 mg, 0.87 mmol) in toluene (1.2 mL) is added K2CO3 (60 mg, 0.44 mmol). The reaction mixture is heated at 115°C for 2h. The mixture is cooled to RT and EA (10 mL) and H2O (10 mL) are added. The aqueous layer is extracted with EA (2 X 10 mL), and the combined organic layers are dried (MgSC ), filtered and evaporated. Purification by FC on silica gel (cyclohexane/EA 100:0 to 50:50) yields to the title compound as a colorless oil. LC- MS methodB: t_R = 4.40 min; [M+Na]⁺ = 296.1.

Step 5: 2-(2-(2-Hydroxyethoxy)-5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenoxy)acetonitrile B13

Intermediate B13 is prepared according to the method of intermediate B02 (step 5) using 2-(5-bromo-2-(2- hydroxyethoxy)phenoxy)acetonitrile as starting material and cyclohexane/EA 100:0 to 50:50 as gradient for the purification step to yield the title compound as a colorless oil. LC-MS method B: t_R = 4.74 min ; [M+Na]⁺ = 342.2.

Intermediate B14: 2-(2-(2-(2-Methoxyethoxy)ethoxy)-5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2- yl)phenoxy)acetonitrile

Step 4: 2-(5-Bromo-2-(2-(2-methoxyethoxy)ethoxy)phenoxy)acetonitrile

2-(5-Bromo-2-(2-(2-methoxyethoxy)ethoxy)phenoxy)acetonitrile is prepared according to the method of intermediate B11 (step 4) using 2-(5-bromo-2-hydroxyphenoxy)acetonitrile B03 (step 3)and 1 -bromo-2(2- methoxyethoxy)ethane as reagents, CS2CO3 as base and by heating the reaction mixture at 80°C for 20h; cyclohexane/EA 100:0 to 60:40 as gradient for the purification step to yield the title compound as a colorless oil. LC-MS method B: t_R = 4.97 min; [M+H]⁺ = 332.1.

Step 5: 2-(2-(2-(2-Methoxyethoxy)ethoxy)-5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenoxy)acetonitrile B14 Intermediate B14 is prepared according to the method of intermediate B02 (step 5) using 2-(5-bromo-2-(2-(2- methoxyethoxy)ethoxy)phenoxy)acetonitrile as starting material and 100% cyclohexane for the purification step to yield the title compound as a(brown oil. LC-MS method B: t_R = 5.20; [M+Na]⁺ = 400.2. Intermediate B15: 2-(2-(3-Hydroxy-2,2-dimethylpropoxy)-5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2- yl)phenoxy)acetonitrile

Step 4: 2-(5-Bromo-2-(3-hydroxy-2,2-dimethylpropoxy)phenoxy)acetonitrile

2-(5-Bromo-2-(3-hydroxy-2,2-dimethylpropoxy)phenoxy)acetonitrile is prepared according to the method of intermediate B05 (step 4) using 2-(5-bromo-2-hydroxyphenoxy)acetonitrile B03 (step 3) and 3-bromo-2,2-dimethyl-

1 -propanol as reagents, K2CO3 as base and by heating the reaction mixture at 80°C for 6h; cyclohexane/EA 100:0 to 80:20 as gradient for the purification step to yield the title compound as acolorless oil. LC-MS method B: tR = 5.10 min; [M+Na]⁺ = 338.1.

Step 5: 2-(2-(3-Hydroxy-2,2-dimethylpropoxy)-5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenoxy)acetonitrile

B15

Intermediate B15 is prepared according to the method of intermediate B02 (step 5) using 2-(5-bromo-2-(3-hydroxy- 2,2-dimethylpropoxy)phenoxy)acetonitrile as starting material and cyclohexane/EA 100:0 to 60:40 as gradient for the purification step to yield the title compound as colorless oil. LC-MS method B: tR = 5.30 min ; [M+H]⁺ = 362.2.

Intermediate B16: 2-(2-(2-Morpholinoethoxy)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)phenoxy)acetonitrile

Step 4: 2-(5-Bromo-2-(2-morpholinoethoxy)phenoxy)acetonitrile

2-(5-Bromo-2-(2-(2-methoxyethoxy)ethoxy)phenoxy)acetonitrile is prepared according to the method of intermediate B11 (step 4) using 2-(5-bromo-2-hydroxyphenoxy)acetonitrile B03 (step 3) and 4-(2- chloroethyl)morpholine hydrochloride as reagents, CS2CO3 as base and by heating the reaction mixture at 80°C overnight; cyclohexane/EA 100:0 to 80:20 as gradient for the purification step to yield the title compound as colorless crystalline compound. LC-MS methodB: tR =3.32 min; [M+H]⁺ = 343.0.

Step 5: 2-(2-(2-Morpholinoethoxy)-5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenoxy)acetonitrile B16

Intermediate B16 is prepared according to the method of intermediate B02 (step 5) using 2-(5-bromo-2-(2- morpholinoethoxy)phenoxy)acetonitrile as starting material and cyclohexane/EA 100:0 to 97:3 as gradient for the purification step to yield the title compound as ayellow gum. LC-MS methodB: tR = 3.67 min; [M+H]⁺ = 389.2.

Intermediate B17: 2-(2-(2-(3-Hydroxy-3-methylbutoxy)ethoxy)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)phenoxy)acetonitrile

Step 4: 2-(5-Bromo-2-(2-(3-hydroxy-3-methylbutoxy)ethoxy)phenoxy)acetonitrile

2-(5-Bromo-2-(2-(2-methoxyethoxy)ethoxy)phenoxy)acetonitrile is prepared according to the method of intermediate B11 (step 4) using 2-(5-bromo-2-hydroxyphenoxy)acetonitrile B03 (step 3) and 1 -(2-bromoethoxy)-3- methoxy-3-methylbutane as reagents, CS2CO3 as base and by heating the reaction mixture at 80°C for 20h; cyclohexane/EA 100:0 to 50:50 as gradient for the purification step to yield the title compound as ayellow oil. LC- MS method -B: tR = 4.57 min; [M+Na]⁺ = 380.9.

Step 5: 2-(2-(2-(3-Hydroxy-3-methylbutoxy)ethoxy)-5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2- yl)phenoxy)acetonitrile B17 Intermediate B17 is prepared according to the method of intermediate B02 (step 5) using 2-(5-bromo-2-(2-(3- hydroxy-3-methylbutoxy)ethoxy)phenoxy)acetonitrile as starting material and cyclohexane/EA 100:0 to 50:50 as gradient for the purification step to yield the title compound as ayellow oil. LC-MS method B: tR = 4.84 min; [M+Na]⁺= 428.0. Preparation of 1 -(2-bromoethoxy)-3-methoxy-3-methylbutane:

Step 1 : Methyl 3-(2-(benzyloxy)ethoxy)propanoate

To a solution of 2(benzyloxy)ethanol (4.2 mL, 29.56 mmol) in THF (50 mL) is added methyl acrylate (2.13 g, 23.65 mmol) followed by sodium (catalytic amount) (6 mg). The reaction mixture is stirred at RT for 20h then quenched with iced H2O. The aqueous layer is extracted with EA (2X 25 mL) and the combined organic layers are dried (MgSC ), filtered and evaporated. Purification by FC on silica gel (cyclohexane/EA 100:0 to 90: 10) yields the title compound as a colorless oil (1.2 g). LC-MS method B: tR = 4.73 min; [M+Na]⁺ = 261.0.

Step 2: ((2-(3-Methoxy-3-methylbutoxy)ethoxy)methyl)benzene:

To a solution of methyl 3-(2-(benzyloxy)ethoxy)propanoate (1.2 g, 5.03 mmol) in THF (24 mL) at -78°C is added methyl magnesiumbromide(in Et20 (5 mL, 15.11 mmol). The reaction mixture is stirred at -78°C for 30min then at RT for 3h. The mixture is cooled to 0°C and quenched with sat. NH4CI, (25 mL), diluted in H2O (50 mL) and extracted with EA (2X 50 mL). The combined organic layers are dried (MgSC ), filtered and evaporated to yield to the crude title compound as a yellow oil (1.05 g). LC-MS method B: tR = 4.58 min; [M+Na]⁺ = 261.0.

Step 3: 2-(3-Methoxy-3-methylbutoxy)ethan-1-ol:

To a solution of ((2-(3-methoxy-3-methylbutoxy)ethoxy)methyl)benzene (1.05 g, 4.40 mmol) in EA (13 mL) is added Pd/C (310 mg). The reaction mixture is purged with H2 and stirred under H2 atmosphere at RT for 20h. The mixture is filtered through celite, rinced with EA and evaporated to yield to the titled compound as a colorless oil (620 mg).

LC-MS method B: tR = no UV absorption. [M+Na]⁺ = 171.0

Step 4: 1-(2-Bromoethoxy)-3-methoxy-3-methylbutane:

To a solution of 2-(3-methoxy-3-methylbutoxy)ethan-1 -ol (570 mg, 3.85 mmol) in THF (17 mL) are added triphenylphosphine (1.25 g, 4.61 mmol) and tetrabromomethane (1.55 g, 4.61 mmol). The reaction mixture is stirred at RT for 4h then filtered to remove triphenylphosphine oxide. The filtrate is quenched with cold H2O (25 mL) then extracted with EA (2X 25 mL). The combined organic layers are dried (MgSO^, filtered and evaporated. Purification by FC on silica gel (cyclohexane/EA 100:0 to 50:50) yields the title compound as a colorless oil (530 mg). LC-MS method B: t_R = 3.90 min; [M+NaFM = 234.9.

Intermediate B18: 2-(2-(2-(2-Hydroxyethoxy)ethoxy)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)phenoxy)acetonitrile

Step 4: 2-(5-Bromo-2-(2-(2-hydroxyethoxy)ethoxy)phenoxy)acetonitrile

2-(5-Bromo-2-(2-(2-methoxyethoxy)ethoxy)phenoxy)acetonitrile is prepared according to the method of intermediate B11 (step 4) using 2-(5-bromo-2-hydroxyphenoxy)acetonitrile B03 (step 3) and 2-(2- chloroethoxyjethanol as reagents, CS2CO3 as base and by heating the reaction mixture at 80°C for 20h; cyclohexane/EA 100:0 to 20:80 as gradient for the purification step to yield to the titled compound ascolorless oil. LC-MS method B: tR = 4.36 min; [M+Na]⁺ = 339.9.

Step 5: 2-(2-(2-(2-hydroxyethoxy)ethoxy)-5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenoxy)acetonitrile B18 Intermediate B18 is prepared according to the method of intermediate B02 (step 5) using 2-(5-bromo-2-(2-(2- hydroxyethoxy)ethoxy)phenoxy)acetonitrile as starting material and cyclohexane/EA 75:25 to 20:80 as gradient for the purification step to yield to the titled compound as a colorless oil. LC-MS method B: tR = 4.69 min; [M+Na]⁺ = 386.2.

Intermediate B19: 2-(2-(2-(3-Fluoroazetidin-1-yl)ethoxy)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)phenoxy)acetonitrile

Step 1 : (2-Benzyloxy-5-bromo-phenoxy)-acetonitrile

(2-Benzyloxy-5-bromo-phenoxy)-acetonitrile is prepared according to the method of intermediate B01 using 2- benzyloxy-5-bromo-phenol and bromoacetonitrile as reagents, CS2CO3 as base and by stirring the reaction mixture at RT for 20h to yield the title compound as beige solid. LC-MS method A: tR = 1.04 min; [M+H]⁺ = 318.04.

Step 2: 5-Bromo-2-hydroxyphenoxy)acetonitrile

(5-Bromo-2-hydroxyphenoxy)acetonitrile is prepared by treatment of (2-benzyloxy-5-bromo-phenoxy)-acetonitrile with boron trichloride in DCM (10 mL) at 0°C, the reaction mixture is washed with NaHCOa sat. (25 mL), evaporated and the crude is purified by FC on silica gel with heptane/EA 95:5 to 20:80 as gradient to deliver the title compound as white solid; LC-MS method A: tR = 0.77 min; [M+H]⁺ = no mass.

Step 3: 2-(5-Bromo-2-(2-chloroethoxy)phenoxy)acetonitrile

2-(5-Bromo-2-(2-chloroethoxy)phenoxy)acetonitrile is prepared according to the method of intermediate B11 (step 4) using 2-(5-bromo-2-hydroxyphenoxy)acetonitrile and dichloroethane as reagents, CS₂CO₃ as base and by heating the reaction mixture at 60°C for 5h; cyclohexane/EA 95:5 to 20:80 as gradient for the purification step to yield the title compound as white solid. LC-MS method A: tR = 0.95; [M+H]⁺ = no mass.

Step 4: 2-(5-Bromo-2-(2-(3-fluoroazetidin-1-yl)ethoxy)phenoxy)acetonitrile

To a solution of 2-(5-bromo-2-(2-chloroethoxy)phenoxy)acetonitrile (550 mg, 1.89mmol) in CH₃CN (10 mL) are added 3-fluoroazetidine hydrochloride (422 mg, 3.79 mmol), tretabutylammonium iodide (69.9 mg, 0.189 mmol) and CS2C03 (2.16 g, 6.63 mmol). The reaction mixture is stirred at 60°C for 24h. The mixture is cooled to RT and EA (25 mL) and H2O (25 mL) are added. The aqueous layer is extracted with EA (2X 25 mL), and the combined organic layers are dried (MgSO^, filtered and evaporated to yield to the title crude compound as a colorless oil (500 mg). LC-MS method A: t_R = 0.62 min; [M+H]⁺ = 329.15.

Step 5: 2-(2-(2-(3-Fluoroazetidin-1 -yl)ethoxy)-5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenoxy)acetonitrile

B19

Intermediate B19 is prepared according to the method of intermediate B02 (step 5) using 2-(5-bromo-2-(2-(3- fluoroazetidin-1-yl)ethoxy)phenoxy)acetonitrile as starting material and DCM/MeOFI 100:0 to 80:20 as gradient for the purification step to deliver the title compound as brown oil. LC-MS method A: tR = 0.72 min; [M+FI]⁺ = 377.26. Intermediate B20: 7-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-2,3-dihydro-benzo[1 ,4]dioxine-2- carbonitrile

Step 1 : 7-Bromo-2,3-dihydro-benzo[1 ,4]dioxine-2-carbonitrile

To a solution of 4-bromocatechol (1.0 g, 5.3 mmol) in acetone (10 mL) were added K₂CO₃ (730 mg, 2.6 mmol) and 2-chloroacrylonitrile (470 mI_, 2.6 mmol). The reaction mixture was refluxed in a sealed tube for 20h and evaporated. The residue was partitioned between DCM and H2O and the aqueous layer was extracted with DCM (3x). The organic layers were combined, dried (MgSC ) filtered and evaporated. Purification by FC on silica gel (cyclohexane/EA 100:0 to 80:20) yielded the title compound as transparent oil (990 mg). LC-MS method C: tR = 1.62 min; [M+Na]⁺ = 241.9.

Step 2: 7-(4,4,5,5-Tetramethyl-[1 ,3,2]dioxaborolan-2-yl)-2,3-dihydro-benzo[1 ,4]dioxine-2-carbonitrile B20

Intermediate B20 is prepared according to the method of intermediate B13 (step 1 ) using 7-Bromo-2,3-dihydro- benzo[1 ,4]dioxine-2-carbonitrile as starting material and (cyclohexane/EA 100:0 to 85: 15) as gradient for the purification step to yield the tilte compound as transparent oil. ). LC-MS method C: tR = 1.70 min; [M+H]⁺ = 288.1.

Intermediate D: 7-(Allyl-methyl-amino)-2-amino-5-fluoro-1 H-indole-3-carboxylic acid ethyl ester

Step 1 : Intermediate B: Allyl-(3,5-difluoro-2-nitro-phenyl)-methyl-amine

To a cold (0°C) solution of 2,4,6-trifluoronitrobenzene (16.5 g, 93 mmol) in THF (230 mL) are added N-methyl allylamine (10 mL, 102 mmol) and K2CO3 (17.0 g, 121 mmol). The reaction mixture is stirred at RT for 20h and is filtered. The filtrate is evaporated, and the crude is purified by FC on silica gel (cyclohexane/EA 100:0 to 95:5) to yield the title compound as a yellow oil (19.07 g). LC-MS method A: tR = 0.93 min; [M+FI]⁺ = 229.17.

Step 2: Intermediate C: [3-(Allyl-methyl-amino)-5-fluoro-2-nitro-phenyl]-cyano-acetic acid ethyl ester

To a cold (0°C) solution of allyl-(3,5-difluoro-2-nitro-phenyl)-methyl-amine (19.1 g, 83 mmol) in dry DMF (320 mL) is added ethyl cyanoacetate (17.8 mL, 166 mmol) followed by 60% NaH (6.7 g, 166 mmol) portionwise. The reaction mixture is stirred at RT for 20h and poured on a cooled (0°C) sat. solution of NH₄CI (200 mL). After 30 min of stirring, EA (100 mL) is added and the aqueous phase is extracted with EA (3x 100 mL). The organic phases are combined, washed with sat. NH₄CI (3x 100 mL), dried (MgSO^, filtered and evaporated. Purification by FC on silica gel (cyclohexane/EA 100:0 to 90: 10) yields the title compound as an orange oil (21.9 g). LC-MS method A: tR = 0.93 min; [M+H]⁺ = 322.05.

Step 3: Intermediate D: 7-(Allyl-methyl-amino)-2-amino-5-fluoro-1 H-indole-3-carboxylic acid ethyl ester C1

To a cold (0°C) solution of [3-(allyl-methyl-amino)-5-fluoro-2-nitro-phenyl]-cyano-acetic acid ethyl ester (21.9 g, 68 mmol) in glacial AcOFI (200 mL) is added portionwise Zn dust (44.5 g, 680 mmol). The reaction mixture is stirred at RT for 1 h30 and is filtered over a celite pad. The filtrate is evaporated, and the resulting residue dissolved in EA (200 mL). The cooled (0°C) solution is neutralized with a sat. NaFICOs solution and the organic phase is washed with sat. NaFICOs (3x 100 mL), dried (MgSO^, filtered and concentrated. Purification by FC on silica gel (cyclohexane/EA 100:0 to 60:40) yields the title compound as a beige powder (7.4 g). LC-MS-C: tR = 5.04 min; [M+H]⁺ = 292.2 . Intermediate E: 8-(Allyl-methyl-amino)-6-fluoro-2-methyl-9H-pyrimido[4,5-b] indol-4-ol

To a solution of intermediate D (6.0 g, 20 mmol) in CH3CN (100 mL) is added a 4N HCI solution in dioxane (100 mL). The mixture is stirred ar RT for 20h and is evaporated. The resulting brown foam is dissolved in a mixture of EtOH (92 mL) and H2O (5.6 mL) and NaOH powder (2.0 g, 49 mmol) is added. The reaction mixture is stirred at 50°C for 20h. After cooling at RT, a sat. NH4CI solution is added (30 mL). After 15 min of stirring, the suspension is filtered and the resulting cake is washed successively with H2O (25 mL), EA (25 mL) and Et20 (50 mL). The solid is dried under vacuum over P2O5 for 20h to yield the title compound as a beige solid (5.2 g). LC-MS method A: tR = 0.77 min; [M+H]⁺ = 287.13 .

Intemediate F1 : Trifluoro-methanesulfonic acid 8-(allyl-methyl-amino)-6-fluoro-2-methyl-9H-pyrimido[4,5- b]indol-4-yl ester

To a cooled (0°C) suspension of intermediate E (2.6 g, 9.1 mmol) in dry DCM (100 mL) are added dry pyridine (2.9 mL, 36.3 mmol) and trifluromethanesulfonic anhydride (2.3 mL, 13.6 mmol). The reaction mixture is stirred at 0°C for 1 h30 and is poured on a cooled (0°C) sat. NH₄CI solution (100 mL). The aqueous layer is extracted with DCM (3x 100 mL) and the organic layers are combined, dried (MgSC ), filtered and gently evaporated. Purification by FC on silica gel (cyclohexane/DCM 100:0 to 55:45) yields the title compound as an orange sticky solid (3.4 g). LC- MS method A: t_R = 1.04 min; [M+H]⁺ = 419.02 .

Intermediate F2: Allyl-(4-chloro-6-fluoro-2-methyl-9H-pyrimido[4,5-b]indol-8-yl)-methyl-amine

To a suspension of intermediate E (620 mg, 2.2 mmol) in dry toluene (4.2 mL) is added POCI3 (4.2 mL). The reaction mixture is heated at 110°C for 1 h and is evaporated. The residue is partitioned between EA (50 mL) and a sat. NaHC03 (50 mL) solution and the organic layer is washed with a sat. NaHC03 solution (3x 100 mL), dried (MgS04) filtered and evaporated. Purification by FC on silica gel (cyclohexane/EA 100:0 to 70:30) yields the title compound as a light yellow solid (475 mg). LC-MS method A: t_R = 1.04 min; [M+FI]⁺ = 305.15 .

Intermediate J: 8-(Allyl-methyl-amino)-4-chloro-6-fluoro-2-methyl-pyrimido[4,5-b]indole-9-carboxylic acid tert-butyl ester

To a solution of intermediate F2 (1.04 g, 3.28 mmol) in THF (20 mL) are added successively B0C2O (1.07 g, 4.92 mmol), DMAP (40 mg, 0.32 mmol) and DIEA (0.85 mL, 4.92 mmol). The reaction mixture is stirred at 60°C for 3h and is evaporated. Purification by FC on silica gel (cyclohexane/EA 100:0 to 80:20) yields the title compound as a light-yellow solid (928 mg). LC-MS method A: t_R = 1.22 min; [M+H]⁺ = 405.21.

Example 1.01 [5-(6-Fluoro-2-methyl-8-methylamino-9H-pyrimido[4,5-b]indol-4-yl)-2-methoxy-phenoxy]- acetonitrile

1.01 a: 2-(5-(8-(allyl(methyl)amino)-6-fluoro-2-methyl-9H-pyrimido[4,5-b]indol-4-yl)-2-methoxyphenoxy) acetonitrile To a purged solution of intermediate F1 trifluoro-methanesulfonic acid 8-(allyl-methyl-amino)-6-fluoro-2-methyl-9H- pyrimido[4,5-b]indol-4-yl este r(5.5 g, 13.3 mmol) and [2-methoxy-5-(4,4,5,5-tetramethyl-[1 ,3,2]dioxaborolan-2-yl)- p h e n oxy]- aceto n i tri I e B01 (4.9 g, 16.9 mmol) in dry DME (60 mL) with nitrogen are added a 2M solution of aq. K2CO3 (20 mL, 40 mmol) and PdCLidppfJ.DCM (537 mg, 0.657 mmol). The reaction mixture is stirred at 90°C for 2h. The mixture is cooled to RT, diluted with EA (60 mL and washed with H2O (100 mL) and brine (100mL). The combined organic phases are dried over MgS04, filtered and evaporated. The crude is purified by FC on silica gel (DCM / MeOH, 100/0 to 85/15) to yield the title compound as a yellow oil (2.87 g). LC-MS method A: tR = 0.82 min; [M+H]⁺ = 432.17 .

1.01 b: [5-(6-Fluoro-2-methyl-8-methylamino-9H-pyrimido[4,5-b]indol-4-yl)-2-methoxy-phenoxy]-acetonitrile A solution of 2-(5-(8-(allyl(methyl)amino)-6-fluoro-2-methyl-9H-pyrimido[4,5-b]indol-4-yl)-2- methoxyphenoxy)acetonitrile (2.87 g, 6.65 mmol) in MeOFI (100 mL) mL) is treated with 1 ,3-dimethylbarbituric acid (2098 mg, 13.3 mmol) and Pd(PPh3)4 (396 mg, 0.333 mmol). The reaction mixture is stirred at rt for 16 hrs. The mixture is evaporated to dryness. The crude is purified by FC on silica gel (DCM/MeOFI 100/0 to 95/5) to yield the title compound as yellow powder (1 82g). The product is dissolved in DCM/MeOF1 1 :1 (80 mL) then Pd scavengers STA3 (0.91 g) and MTCF (0.91 g) are added. The mixture is shaken at 50°C overnight then filtered. The solution is concentrated and the resulting yellowish product (1.72 g) is dried under HV for one week. LC-MS method A: tR = 0.74 min; [M+H]⁺ = 392.37. ¹H NMR (400 MHz, DMSO) <5: 11.77 (s, 1 H), 7.60 (d, J = 8.4 Hz, 1 H), 7.56 (s, 1 H), 7.33 (d, J = 8.4 Hz, 1 H), 6.70 (d, J = 8.5 Hz, 1 H), 6.45 (d, J = 1 1.8 Hz, 1 H), 5.91 (d, J = A1 Hz, 1 H), 5.22 (s, 2 H), 3.94 (s, 3 H), 2.91 (d, J = A1 Hz, 3 H), 2.72 (s, 3 H) .

Example 1.02: [5-(6-Fluoro-2-methyl-8-methylamino-9H-pyrimido[4,5-b]indol-4-yl)-2-(2-hydroxy-2- methyl-propoxy)-phenoxy]-acetonitrile

1.02a: 8-(Allyl-methyl-amino)-4-[3-cyanomethoxy-4-(2-hydroxy-2-methyl-propoxy)-phenyl]-6-fluoro-2-methyl- pyrimido[4,5-b]indole-9-carboxylic acid tert-butyl ester

To a solution of 8-(allyl-methyl-amino)-4-chloro-6-fluoro-2-methyl-pyrimido[4,5-b]indole-9-carboxylic acid tert-butyl ester J J 8-(allyl-methyl-amino)-4-chloro-6-fluoro-2-methyl-pyrimido[4,5-b]indole-9-carboxylic acid tert-butyl ester (3.5 g, 8.21 mmol) and [2-(2-3ydroxy-2-methyl-propoxy)-5-(4,4,5,5-tetramethyl-[1 ,3,2]dioxaborolan-2-yl)-phenoxy]- acetonitrile B02 (3.42 g, 9.85 mmol) in dry dioxane (70 mL) purged with nitrogen are added a 2M solution of aq. K2CO3 (8.2 mL, 16.4 mmol) and Pd(Pfi3)4 (719 mg, 0.616 mmol). The reaction mixture is stirred at 80°C for 48h. The mixture is cooled to RT, diluted with EA (60 mL) and washed with H2O (100 mL) and brine (100mL). The combined organic phases are dried over Na2S04, filtered and evaporated. The crude is purified by FC on silica gel (heptane / EA, 100/0 to 50/50) to yield the title compound as a yellow oil (4.077 g, 84%). LC-MS method A: tR = 1.10 min; [M+H]⁺ = 590.39.

1.02b: [5-[8-(Allyl-methyl-amino)-6-fluoro-2-methyl-9H-pyrimido[4,5-b]indol-4-yl]-2-(2-hydroxy-2-methyl-propoxy)- p h e n oxy]- aceto n i tri I e

TFA (2.43 mL, 31.1 mmol) is added to a solution of 8-(allyl-methyl-amino)-4-[3-cyanomethoxy-4-(2-hydroxy-2- methyl-propoxy)-phenyl]-6-fluoro-2-methyl-pyrimido[4,5-b]indole-9-carboxylic acid tert-butyl ester (4077 mg, 6.22 mmol) in DCM (130 mL) at 0°C. The mixture is stirred at RT for 2h30. The mixture is concentrated under reduced pressure then diluted again with DCM (100 mL) and washed twice with aq. 10% NaHC03 (2 X 100 mL). The combined organic layers are dried over Na2S04, filtered and concentrated. The crude is used for the next step. LC- MS method A: t_R = 0.84 min; [M+H]⁺ = 490.41.

1.03c: [5-(6-Fluoro-2-methyl-8-methylamino-9H-pyrimido[4,5-b]indol-4-yl)-2-(2-hydroxy-2-methyl-propoxy)- p h e n oxy]- aceto n i tri I e

A solution of [5-[8-(allyl-methyl-amino)-6-fluoro-2-methyl-9H-pyrimido[4,5-b]indol-4-yl]-2-(2-hydroxy-2-methyl- propoxy)-phenoxy]-acetonitrile (3.4 g, 6.25 mmol) in MeOH (125 mL) mL) is treated with 1 ,3-dimethylbarbituric acid (1.972 g, 12.5 mmol) and tetrakis(triphenylphosphine)palladium(0) (365 mg, 0.313 mmol). The reaction mixture is stirred at RT for 3 hrs. The mixture is evaporated to dryness. The crude is purified by FC on silica gel (DCM/MeOFI 100/0 to 90/10) to yield the title compound as yellow powder (2.43 g). The scavenging of the Pd residue is then performed using phosphonic MTCF & STA3 resins. The pure product is dissolved in DCM/MeOFI 9: 1 (15 mL) then scavengers STA3 (1.21 g) and MTCF (1.21 g) are added. The mixture is shaken at 50°C overnight then filtered. The solution is concentrated, and the resulting product is dried under HV for one week to yield 2.23 g (79%) of a yellowish powder. LC-MS method A: t_R = 0.76 min; [M+H]⁺ = 450.13. ¹H NMR (400 MHz, DMSO) <5: 1 1.74-11.77 (m, 1 H), 7.58 (m, 2 H), 7.35 (d, J = 8.3 Hz, 1 H), 6.71 (dd, Ji = 2.0 Hz, J₂ = 9.6 Hz, 1 H), 6.45 (dd, Ji = 1.7 Hz, J₂ = 12.0 Hz, 1 H), 5.89-5.90 (m, 1 H), 5.24 (s, 2 H), 4.72 (s, 1 H), 3.91 (s, 2 H), 2.91 (d, J = 4.8 Hz, 3 H), 2.72 (s, 3 H), 1.28 (s, 6 H).

Example 1.03 2-[2-Cyanomethoxy-4-(6-fluoro-2-methyl-8-methylamino-9H-pyrimido[4,5-b]indol-4-yl)- phenoxy]-N-methyl-acetamide

1.03a: 8-(Allyl-methyl-amino)-4-(3-cyanomethoxy-4-methylcarbamoylmethoxy-phenyl)-6-fluoro-2-methyl- pyrimido[4,5-b]indole-9-carboxylic acid tert-butyl ester is prepared according to the procedure 1.02a, starting from intermediates J 8-(allyl-methyl-amino)-4-chloro-6-fluoro-2-methyl-pyrimido[4,5-b]indole-9-carboxylic acid tert-butyl ester and B03 2-(2-(cyanomethoxy)-4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenoxy)-N-methylacetamide; LC-MS method B: t_R = 5.62 min; [M+H]⁺ = 589.4 .

1.03b: 2-{4-[8-(Allyl-methyl-amino)-6-fluoro-2-methyl-9H-pyrimido[4,5-b]indol-4-yl]-2-cyanomethoxy-phenoxy}-N- methyl-acetamide is prepared according to the procedure 1 02b, starting from intermediate 1 03a; LC-MS method B: t_R = 4.39 min; [M+H]⁺ = 489.3.

1.03: The title compound is prepared according to the procedure 1.02c, starting from intermediate 1.03b; QC LC- MS: t_R = 0.77 min; [M+H]⁺ = 449.2.

Example 1.04 Rac-[5-(6-fluoro-2-methyl-8-methylamino-9H-pyrimido[4,5-b]indol-4-yl)-2-(2-hydroxy-3,3- dimethyl-butoxy)-phenoxy]-acetonitrile

1.04a: Rac-8-(allyl-methyl-amino)-4-[3-cyanomethoxy-4-(2-hydroxy-3,3-dimethyl-butoxy)-phenyl]-6-fluoro-2- methyl-pyrimido[4,5-b]indole-9-carboxylic acid tert-butyl ester is prepared according to procedure 1 02a, starting from intermediates J 8-(allyl-methyl-amino)-4-chloro-6-fluoro-2-methyl-pyrimido[4,5-b]indole-9-carboxylic acid tert- butyl ester and B04 rac-2-(2-(2-hydroxy-3,3-dimethylbutoxy)-5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2- yl)phenoxy)acetonitrile; LC-MS method B: t_R = 6.07 min; [M+H]⁺ = 8.4. 1.04b: Rac-[5-[8-(allyl-methyl-amino)-6-fluoro-2-methyl-9H-pyrimido[4,5-b]indol-4-yl]-2-(2-hydroxy-3, 3-dimethyl- butoxy)-phenoxy]-acetonitrile is prepared according to procedure 1 02b, starting from intermediate 1 04a ; LC-MS method B: t_R = 5.09 min; [M+H]⁺ = 518.4.

1.04: the title compound is obtained according to the procedure 1.02c, starting from intermediate 1.04b; QC LC- MS: t_R = 1.05 min; [M+H]⁺ = 478.3.

Example 1.05 Rac-[5-(6-fluoro-2-methyl-8-methylamino-9H-pyrimido[4,5-b]indol-4-yl)-2-(2-hydroxy-2- phenyl-ethoxy)-phenoxy]-acetonitrile

1.05a: Rac-8-(allyl-methyl-amino)-4-[3-cyanomethoxy-4-(2-hydroxy-2-phenyl-ethoxy)-phenyl]-6-fluoro-2-methyl- pyrimido[4,5-b]indole-9-carboxylic acid tert-butyl ester is prepared according to procedure 1.02a, starting from intermediates J 8-(allyl-methyl-amino)-4-chloro-6-fluoro-2-methyl-pyrimido[4,5-b]indole-9-carboxylic acid tert-butyl ester and B05 rac-2-(2-(2-hydroxy-2-phenylethoxy)-5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2- yl)phenoxy)acetonitrile; LC-MS method B: t_R =5.93 min; [M+H]⁺ = 638.4.

1.05b: Rac-[5-[8-(allyl-methyl-amino)-6-fluoro-2-methyl-9H-pyrimido[4,5-b]indol-4-yl]-2-(2-hydroxy-2-phenyl- ethoxy)-phenoxy]-acetonitrile is prepared according to procedure 1.02b, starting from intermediate 1.05a; LC-MS method B: t_R = 4.95 min; [M+H]⁺ = 538.3.

1.05: The title compound is prepared according to the procedure 1.02c, starting from intermediate 1.05b; QC LC- MS: t_R = 0.99 min; [M+H]⁺ = 498.3.

Example 1.06 [5-(6-Fluoro-2-methyl-8-methylamino-9H-pyrimido[4,5-b]indol-4-yl)-2-(3-hydroxy-3- methyl-butoxy)-phenoxy]-acetonitrile

1.06a: 8-(Allyl-methyl-amino)-4-[3-cyanomethoxy-4-(3-hydroxy-3-methyl-butoxy)-phenyl]-6-fluoro-2-methyl- pyrimido[4,5-b]indole-9-carboxylic acid tert-butyl ester is prepared according to procedure 1.02a, starting from intermediates J 8-(allyl-methyl-amino)-4-chloro-6-fluoro-2-methyl-pyrimido[4,5-b]indole-9-carboxylic acid tert-butyl ester and B06 2-(2-(3-hydroxy-3-methylbutoxy)-5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2- yl)phenoxy)acetonitrile; LC-MS method B: t_R = 5.84 min; [M+H]⁺ = 604.4.

1.06b: [5-[8-(Allyl-methyl-amino)-6-fluoro-2-methyl-9H-pyrimido[4,5-b]indol-4-yl]-2-(3-hydroxy-3-methyl-butoxy)- phenoxyj-acetonitrile is prepared according to procedure 1 02b, starting from intermediate 1 06a; LC-MS method B: t_R = 4.68 min; [M+H]⁺ = 504.4.

1.06: the title compound is prepared according to procedure 1 02c, starting from intermediate 1 06b; QC LC-MS: t_R = 0.89 min; [M+H]⁺ = 464.3; ¹H NMR (400 MHz, DMSO) <5: 11.77 (s, 1 H), 7.59 (d, J = 8.4 Hz, 1 H), 7.57 (s, 1 H), 7.35 (d, J = 8.4 Hz, 1 H), 6.71 (d, J = 8.3 Hz, 1 H), 6.45 (d, J = 1 1.8 Hz, 1 H), 5.89 (d, J = 4.5 Hz, 1 H), 5.21 (s, 2 H), 4.45 (s, 1 H), 4.26 (t, J = 7.1 Hz, 2 H), 2.91 (d, J = A1 Hz, 3 H), 2.72 (s, 3 H), 1.96 (t, J = 7.1 Hz, 2 H), 1.22 (s, 6 H). Example 1.07 Rac-[5-(6-fluoro-2-methyl-8-methylamino-9H-pyrimido[4,5-b]indol-4-yl)-2-(3,3,3-trifluoro- 2-hydroxy-propoxy)-phenoxy]-acetonitrile

1.07 a: Rac-8-(allyl-methyl-amino)-4-[3-cyanomethoxy-4-(3,3,3-trifluoro-2-hydroxy-propoxy)-phenyl]-6-fluoro-2- methyl-pyrimido[4,5-b]indole-9-carboxylic acid tert-butyl ester is prepared according to procedure 1 02a, starting from intermediates J 8-(allyl-methyl-amino)-4-chloro-6-fluoro-2-methyl-pyrimido[4,5-b]indole-9-carboxylic acid tert- butyl ester and B07 rac-2-(5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-2-(3,3,3-trifluoro-2- hydroxypropoxy)phenoxy)acetonitrile; LC-MS method B: tR = 5.78 min; [M+H]⁺ = 630.3.

1.07b: Rac-[5-[8-(allyl-methyl-amino)-6-fluoro-2-methyl-9H-pyrimido[4,5-b]indol-4-yl]-2-(3,3,3-trifluoro-2-hydroxy- propoxy)-phenoxy]-acetonitrile is prepared according to procedure 1 02b, starting from intermediate 1 07a; LC-MS method B: tR = 4.89 min; [M+H]⁺ = 530.3.

1.07: the title compound is prepared according to procedure 1.02c, starting from intermediate 1.07b; QC LC-MS: tR = 0.95 min; [M+H]⁺ = 490.2.

Example 1.08 Rac-[5-(6-fluoro-2-methyl-8-methylamino-9H-pyrimido[4,5-b]indol-4-yl)-2-(2-hydroxy- butoxy)-phenoxy]-acetonitrile

1.08a: Rac-8-(allyl-methyl-amino)-4-[3-cyanomethoxy-4-(2-hydroxy-butoxy)-phenyl]-6-fluoro-2-methyl- pyrimido[4,5-b]indole-9-carboxylic acid tert-butyl ester is prepared according to procedure 1.02a, starting from intermediates J 8-(allyl-methyl-amino)-4-chloro-6-fluoro-2-methyl-pyrimido[4,5-b]indole-9-carboxylic acid tert-butyl ester and B08 rac-2-(2-(2-hydroxybutoxy)-5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenoxy)acetonitrile; LC- MS method B: tR = 5.82 min; [M+H]⁺ = 590.3.

1.08b: Rac-[5-[8-(allyl-methyl-amino)-6-fluoro-2-methyl-9H-pyrimido[4,5-b]indol-4-yl]-2-(2-hydroxy-butoxy)- phenoxyj-acetonitrile is prepared according to procedure 1.02b, starting from intermediate 1.8a; LC-MS method B: tR = 4.73 min; [M+H]⁺ = 490.4.1.08: the title compound is prepared according to procedure 1.02c, starting from intermediate 1.08b; QC LC-MS: tR = 0.90 min; [M+H]⁺ = 450.3.

Example 1.09 Rac-[5-(6-fluoro-2-methyl-8-methylamino-9H-pyrimido[4,5-b]indol-4-yl)-2-(2-hydroxy- propoxy)-phenoxy]-acetonitrile

1.09a: Rac-8-(allyl-methyl-amino)-4-[3-cyanomethoxy-4-(2-hydroxy-propoxy)-phenyl]-6-fluoro-2-methyl- pyrimido[4,5-b]indole-9-carboxylic acid tert-butyl ester is prepared according to procedure 1.02a, starting from intermediates J 8-(allyl-methyl-amino)-4-chloro-6-fluoro-2-methyl-pyrimido[4,5-b]indole-9-carboxylic acid tert-butyl ester and B09 rac-2-(2-(2-hydroxypropoxy)-5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenoxy)acetonitrile; LC-MS method B: t_R = 5.71 min; [M+H]⁺ = 576.3.

1.09b: Rac-[5-[8-(allyl-methyl-amino)-6-fluoro-2-methyl-9H-pyrimido[4,5-b]indol-4-yl]-2-(2-hydroxy-propoxy)- phenoxyj-acetonitrile is prepared according to procedure 1.02b, starting from intermediate 1.09a;LC-Ms method B: tR = 4.53 min; [M+H]⁺ = 476.3. 1.09: the title compound is prepared according to procedure 1 02c, starting from intermediate 1 09b; QC LC-MS: tR = 0.82 min; [M+H]⁺ = 436.3.

Example 1.10 [5-(6-Fluoro-2-methyl-8-methylamino-9H-pyrimido[4,5-b]indol-4-yl)-2-(4-hydroxy- tetrahydro-pyran-4-ylmethoxy)-phenoxy]-acetonitrile

1.10a: 8-(Allyl-methyl-amino)-4-[3-cyanomethoxy-4-(4-hydroxy-tetrahydro-pyran-4-ylmethoxy)-phenyl]-6-fluoro-2- methyl-pyrimido[4,5-b]indole-9-carboxylic acid tert-butyl ester is prepared according to procedure 1 02a, starting from intermediates J 8-(allyl-methyl-amino)-4-chloro-6-fluoro-2-methyl-pyrimido[4,5-b]indole-9-carboxylic acid tert- butyl ester and B10 2-(2-((4-hydroxytetrahydro-2H-pyran-4-yl)methoxy)-5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan- 2-yl)phenoxy)acetonitrile; LC-MS method B: tR = 5.72 min; [M+H]⁺ = 632.3.

1.10b: [5-[8-(Allyl-methyl-amino)-6-fluoro-2-methyl-9H-pyrimido[4,5-b]indol-4-yl]-2-(4-hydroxy-tetrahydro-pyran-4- ylmethoxy)-phenoxy]-acetonitrile is prepared according to procedure 1.02b, starting from intermediate 1.10a; LC- MS method B: t_R = 4.43min; [M+H]⁺ = 532.4.

1.10: the title compound is prepared according to procedure 1 02c, starting from intermediate 1.10b; QC LC-MS: t_R = 0.81 min; [M+H]⁺ = 492.3.

Example 1.11 [5-(6-Fluoro-2-methyl-8-methylamino-9H-pyrimido[4,5-b]indol-4-yl)-2-(2-methoxy-ethoxy)- phenoxy]-acetonitrile

1.1 1 a: 8-(Allyl-methyl-amino)-4-[3-cyanomethoxy-4-(2-methoxy-ethoxy)-phenyl]-6-fluoro-2-methyl-pyrimido[4,5- b]indole-9-carboxylic acid tert-butyl ester is prepared according to procedure 1 02a, starting from intermediates J 8-(allyl-methyl-amino)-4-chloro-6-fluoro-2-methyl-pyrimido[4,5-b]indole-9-carboxylic acid tert-butyl ester and B11 2-(2-(2-methoxyethoxy)-5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenoxy)acetonitrile; LC-MS method B: t_R = 5.92 min; [M+H]⁺ = 576.3.

1.1 1 b: [5-[8-(Allyl-methyl-amino)-6-fluoro-2-methyl-9H-pyrimido[4,5-b]indol-4-yl]-2-(2-methoxy-ethoxy)-phenoxy]- acetonitrile is prepared according to procedure 1 02b, starting from intermediate 1.1 1 a; LC-MS method B: t_R = 4.82 min; [M+H]⁺ = 476.3.

1.1 1 : the title compound is prepared according to procedure 1 02c, starting from intermediate 1.1 1 b; QC LC-MS: t_R = 0.90 min; [M+H]⁺ = 436.3.

Example 1.12 Rac-[2-(3-fluoro-2-hydroxy-propoxy)-5-(6-fluoro-2-methyl-8-methylamino-9H- pyrimido[4,5-b]indol-4-yl)-phenoxy]-acetonitrile

1.12a: Rac-8-(allyl-methyl-amino)-4-[3-cyanomethoxy-4-(3-fluoro-2-hydroxy-propoxy)-phenyl]-6-fluoro-2-methyl- pyrimido[4,5-b]indole-9-carboxylic acid tert-butyl ester is prepared according to procedure 1.02a, starting from intermediates J 8-(allyl-methyl-amino)-4-chloro-6-fluoro-2-methyl-pyrimido[4,5-b]indole-9-carboxylic acid tert-butyl ester and B12 rac-2-(2-(3-fluoro-2-hydroxypropoxy)-5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2- yl)phenoxy)acetonitrile; LC-MS method B: t_R = 5.62 min; [M+H]⁺ = 594.4 1.12b: Rac-[5-[8-(allyl-methyl-amino)-6-fluoro-2-methyl-9H-pyrimido[4,5-b]indol-4-yl]-2-(3-fluoro-2-hydroxy- propoxy)-phenoxy]-acetonitrile is prepared according to procedure 1.02b, starting from intermediate 1.12a; LC-MS method B: t_R = 4.54 min; [M+H]⁺ = 494.4.

1.12: the title compound is prepared according to procedure 1 02c, starting from intermediate 1.12b; QC LC-MS: t_R = 0.81 min; [M+H]⁺ = 454.3.

Example 1.13 [5-(6-Fluoro-2-methyl-8-methylamino-9H-pyrimido[4,5-b]indol-4-yl)-2-(2-hydroxy-ethoxy)- phenoxy]-acetonitrile

1.13a: 8-(Allyl-methyl-amino)-4-[3-cyanomethoxy-4-(2-hydroxy-ethoxy)-phenyl]-6-fluoro-2-methyl-pyrimido[4,5- b]indole-9-carboxylic acid tert-butyl ester ester is prepared according to procedure 1.02a, starting from intermediates J 8-(allyl-methyl-amino)-4-chloro-6-fluoro-2-methyl-pyrimido[4,5-b]indole-9-carboxylic acid tert-butyl ester and B13 2-(2-(2-hydroxyethoxy)-5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenoxy)acetonitrile; LC-MS method B: t_R = 5.58 min; [M+H]⁺ = 562.4.

1.13b: [5-[8-(Allyl-methyl-amino)-6-fluoro-2-methyl-9H-pyrimido[4,5-b]indol-4-yl]-2-(2-hydroxy-ethoxy)-phenoxy]- acetonitrile is prepared according to procedure 1 02b, starting from intermediate 1 13a; LC-MS method B: t_R = 4.36 min; [M+H]⁺ = 462.3

1.13: the title compound is prepared according to procedure 1 02c, starting from intermediate 1.13b; QC LC-MS: t_R = 0.75 min; [M+H]⁺ = 422.2.

Example 1.14 {5-(6-Fluoro-2-methyl-8-methylamino-9H-pyrimido[4,5-b]indol-4-yl)-2-[2-(2-methoxy- eth oxy )-eth oxy]-ph enoxy}-aceton itri le

1.14a: 8-(Allyl-methyl-amino)-4-{3-cyanomethoxy-4-[2-(2-methoxy-ethoxy)-ethoxy]-phenyl}-6-fluoro-2-methyl- pyrimido[4,5-b]indole-9-carboxylic acid tert-butyl ester is prepared according to procedure 1.02a, starting from intermediates J 8-(allyl-methyl-amino)-4-chloro-6-fluoro-2-methyl-pyrimido[4,5-b]indole-9-carboxylic acid tert-butyl ester and B14 2-(2-(2-(2-methoxyethoxy)ethoxy)-5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2- yl)phenoxy)acetonitrile; LC-MS method B t_R = 5.88 min; [M+H]⁺ = 620.3.

1.14b: {5-[8-(Allyl-methyl-amino)-6-fluoro-2-methyl-9H-pyrimido[4,5-b]indol-4-yl]-2-[2-(2-methoxy-ethoxy)-ethoxy]- phenoxyj-acetonitrile is prepared according to procedure 1.02b, starting from intermediate 1.14a; LC-MSmethod B: t_R = 4.76 min; [M+H]⁺ = 520.3.

1.14: the title compound is prepared according to procedure 1 02c, starting from intermediate 1.14b; QC LC-MS: t_R = 0.90 min; [M+H]⁺ = 480.3.

Example 1.15 [5-(6-Fluoro-2-methyl-8-methylamino-9H-pyrimido[4,5-b]indol-4-yl)-2-(3-hydroxy-2,2- dimethyl-propoxy)-phenoxy]-acetonitrile

1.15a: 8-(Allyl-methyl-amino)-4-[3-cyanomethoxy-4-(3-hydroxy-2,2-dimethyl-propoxy)-phenyl]-6-fluoro-2-methyl- pyrimido[4,5-b]indole-9-carboxylic acid tert-butyl ester is prepared according to procedure 1.02a, starting from intermediates J 8-(allyl-methyl-amino)-4-chloro-6-fluoro-2-methyl-pyrimido[4,5-b]indole-9-carboxylic acid tert-butyl ester and B15 2-(2-(3-hydroxy-2,2-dimethylpropoxy)-5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2- yl)phenoxy)acetonitrile; LC-MS method B: tR = 5.97 min; [M+H]⁺ = 604.4.

1.15b: [5-[8-(Allyl-methyl-amino)-6-fluoro-2-methyl-9H-pyrimido[4,5-b]indol-4-yl]-2-(3-hydroxy-2, 2-dimethyl- propoxy)-phenoxy]-acetonitrile is prepared according to procedure 1.02b, starting from intermediate 1.15a; ; LC- MS method B: t_R = 4.91 min; [M+H]⁺ = 504.4.

1.15: the title compound is prepared according to procedure 1 02c, starting from intermediate 1.15b; QC LC-MS: t_R = 0.94 min; [M+H]⁺ = 464.3.

Example 1.16 [5-(6-Fluoro-2-methyl-8-methylamino-9H-pyrimido[4,5-b]indol-4-yl)-2-(2-morpholin-4-yl- ethoxy)-phenoxy]-acetonitrile

1.16a: 8-(Allyl-methyl-amino)-4-[3-cyanomethoxy-4-(2-morpholin-4-yl-ethoxy)-phenyl]-6-fluoro-2-methyl- pyrimido[4,5-b]indole-9-carboxylic acid tert-butyl ester ester is prepared according to procedure 1 02a, starting from intermediates J 8-(allyl-methyl-amino)-4-chloro-6-fluoro-2-methyl-pyrimido[4,5-b]indole-9-carboxylic acid tert-butyl ester and B16 2-(2-(2-morpholinoethoxy)-5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenoxy)acetonitrile; LC- MS method B t_R = 4.67 min; [M+H]⁺ = 631.3.

1.16b: [5-[8-(Allyl-methyl-amino)-6-fluoro-2-methyl-9H-pyrimido[4,5-b]indol-4-yl]-2-(2-morpholin-4-yl-ethoxy)- phenoxyj-acetonitrile is prepared according to procedure 1.02b, starting from intermediate 1.16a; LC-MS method B: t_R =3.76 min; [M+H]⁺ = 531.3.

1.16: the title compound is prepared according to procedure 1 02c, starting from intermediate 1.16b; QC LC-MS: t_R = 0.59 min; [M+H]⁺ = 491.2.

Example 1.17 {5-(6-Fluoro-2-methyl-8-methylamino-9H-pyrimido[4,5-b]indol-4-yl)-2-[2-(3-hydroxy-3- methyl-butoxy)-ethoxy]-phenoxy}-acetonitrile

1.17a: 8-(Allyl-methyl-amino)-4-{3-cyanomethoxy-4-[2-(3-hydroxy-3-methyl-butoxy)-ethoxy]-phenyl}-6-fluoro-2- methyl-pyrimido[4,5-b]indole-9-carboxylic acid tert-butyl ester ester is prepared according to procedure 1 02a, starting from intermediates J 8-(allyl-methyl-amino)-4-chloro-6-fluoro-2-methyl-pyrimido[4,5-b]indole-9-carboxylic acid tert-butyl ester and B17 2-(2-(2-(3-hydroxy-3-methylbutoxy)ethoxy)-5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan- 2-yl)phenoxy)acetonitrile; LC-MS method B: t_R = 5.64 min; [M+H]⁺ = 648.2.

1.17b: {5-[8-(Allyl-methyl-amino)-6-fluoro-2-methyl-9H-pyrimido[4,5-b]indol-4-yl]-2-[2-(3-hydroxy-3-methyl-butoxy)- ethoxy]-phenoxy}-acetonitrile is prepared according to procedure 1.02b, starting from intermediate 1.17a; LC-MS method B: t_R = 4.47 min; [M+H]⁺ = 548.1.

1.17: the title compound is prepared according to procedure 1.02c, starting from intermediate 1.17b; QC LC-MS: t_R = 0.91 min; [M+H]⁺ = 508.3. Example 1.18 {5-(6-Fluoro-2-methyl-8-methylamino-9H-pyrimido[4,5-b]indol-4-yl)-2-[2-(2-hydroxy- eth oxy )-eth oxy]-ph enoxy}-aceton itri le

1.18a: 8-(Allyl-methyl-amino)-4-{3-cyanomethoxy-4-[2-(2-hydroxy-ethoxy)-ethoxy]-phenyl}-6-fluoro-2-methyl- pyrimido[4,5-b]indole-9-carboxylic acid tert-butyl ester is prepared according to procedure 1.02a, starting from intermediates J 8-(allyl-methyl-amino)-4-chloro-6-fluoro-2-methyl-pyrimido[4,5-b]indole-9-carboxylic acid tert-butyl ester and B18 2-(2-(2-(2-hydroxyethoxy)ethoxy)-5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2- yl)phenoxy)acetonitrile; LC-MS method B: tR = 5.57 min; [M+H]⁺ = 606.3.

1.18b: {5-[8-(Allyl-methyl-amino)-6-fluoro-2-methyl-9H-pyrimido[4,5-b]indol-4-yl]-2-[2-(2-hydroxy-ethoxy)-ethoxy]- phenoxyj-acetonitrile is prepared according to procedure 1.02b, starting from intermediate 1.18a; LC-MS method B: t_R = 4.38 min; [M+H]⁺ = 506.3.

1.18: the title compound is prepared according to procedure 1 02c, starting from intermediate 1.18b; QC LC-MS: t_R = 0.78 min; [M+H]⁺ = 466.3. ¹H NMR (400 MHz, DMSO) <5: 11.75-11.83 (s, 1 H), 7.57-7.60 (m, 2 H), 7.36 (d, J = 8.3 Hz, 1 H), 6.70 (dd, Ji = 1.9 Hz, J₂ = 9.6 Hz, 1 H), 6.45 (dd, Ji = 1.9 Hz, J₂ = 12.0 Hz, 1 H), 5.90-5.91 (m, 1 H), 5.24 (s, 2 H), 4.62-4.69 (s, 1 H), 4.29 (m, 2 H), 3.84 (m, 2 H), 3.55 (s, 4 H), 2.91 (d, J = 4.6 Hz, 3 H), 2.72 (s, 3 H).

Example 1.19 [2-[2-(3-Fluoro-azetidin-1-yl)-ethoxy]-5-(6-fluoro-2-methyl-8-methylamino-9H- pyrimido[4,5-b]indol-4-yl)-phenoxy]-acetonitrile

1.19a: 8-(Allyl-methyl-amino)-4-{3-cyanomethoxy-4-[2-(3-fluoro-azetidin-1-yl)-ethoxy]-phenyl}-6-fluoro-2-methyl- pyrimido[4,5-b]indole-9-carboxylic acid tert-butyl ester is prepared according to procedure 1 02a, starting from intermediates J 8-(allyl-methyl-amino)-4-chloro-6-fluoro-2-methyl-pyrimido[4,5-b]indole-9-carboxylic acid tert-butyl ester and B19 2-(2-(2-(3-fluoroazetidin-1 -yl)ethoxy)-5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2- yl)phenoxy)acetonitrile; LC-MS method A: t_R = 0.92 min; [M+H]⁺ = 619.4

1.19b: {5-[8-(Allyl-methyl-amino)-6-fluoro-2-methyl-9H-pyrimido[4,5-b]indol-4-yl]-2-[2-(3-fluoro-azetidin-1 -yl)- ethoxy]-phenoxy}-acetonitrile is prepared according to procedure 1.02b, starting from intermediate 1.19a; LC-MS method A: t_R = 0.69 min; [M+H]⁺ = 519.3.1.19: the title compound is prepared according to procedure 1.02c, starting from intermediate 1.19b; QC LC-MS: t_R = 0.59 min; [M+H]⁺ = 479.2.

Example 1.20 Rac-7-(6-fluoro-2-methyl-8-methylamino-9H-pyrimido[4,5-b]indol-4-yl)-2, 3-dihydro- benzo[1,4]dioxine-2-carbonitrile

1.20: Rac-7-(6-fluoro-2-methyl-8-methylamino-9H-pyrimido[4,5-b]indol-4-yl)-2,3-dihydro-benzo[1 ,4]dioxine-2- carbonitrile is prepared according to procedure 1 01 a, starting from intermediates F1 trifluoro-methanesulfonic acid 8-(allyl-methyl-amino)-6-fluoro-2-methyl-9H-pyrimido[4,5-b]indol-4-yl ester and B20 rac-7-(4,4,5,5-tetramethyl- [1 ,3,2]dioxaborolan-2-yl)-2,3-dihydro-benzo[1 ,4]dioxine-2-carbonitrile. The allyl group is cleaved under the reaction conditions, delivering the title compound; QC LC-MS: t_R = 0.91 min; [M+H]⁺ = 390.2. Assay methods

Synthesis of the fluorescence polarization probe N-{4-[5-(1-Cyclopropylmethyl-piperidin-4-ylcarbamoyl)- 3-(2,4-dihydroxy-phenyl)-3H-[1,2,3]triazol-4-yl]-benzyl}-6-(6-hydroxy-3-oxo-3H-xanthen-9-yl)-isophthalamic acid (FP probe)

Step 1 : 2, 4-Bis-benzyloxy-1 -nitrobenzene

To a solution of 2,4-difluoro-nitrobenzene (3.45 mL, 31.1 mmol) in DMF (100 mL) at 0°C is added portionwise sodium hydride, 60% suspension in oil, (2.7 g, 68.5 mmol). A solution of benzyl alcohol (6.79 mL, 65.3 mmol) in DMF (40 mL) is slowly added and the reaction mixture is stirred at 0°C for 30min then at RT for 2h. The mixture is poured into ice-water and extracted with EA (3 X 50 mL) and the combined organic layers are dried (MgSC ), filtered and evaporated. Purification by FC on silica gel (Fleptane/EA 100:0 to 80:20) yields the title compound as a yellow solid (7.34 g). LC-MS method A: t_R = 1.01 ; [M+H]⁺ = 336.3.

Step 2: 1-Azido-2,4-bis-benzyloxy-benzene

Tin(ll) chloride dihydrate (2.42 g, 105 mmol) and HCI 37% (20.6 mL, 311 mmol) are added to a suspension of 2,4- bis-benzyloxy-1-nitro-benzene (7.34 g, 17.5 mmol) in EtOH (180 mL). The mixture is heated at 80°C for 1 h. The mixture is cooled to 0°C and NaOFI 8M (43.7 mL, 350 mmol) is slowly added. The salts are filtered through Celite and washed with EA (200 mL) and the solvent are evaporated. The residue is dissolved in AcOFI 90% (360 mL), cooled to 0°C and protected from light with an aluminium foil. Sodium nitrite (1.34 g, 19.3 mmol) dissolved in cold H2O (36 mL) is added dropwise and the mixture is stirred for 10min. Sodium azide (1.26 g, 19.3 mmol) dissolved in cold H2O (36 mL) is then added dropwise. The reaction mixture is stirred at 0°C for 1 h then poured into water/EA (50 mL) and extracted with EtOAc (3 X 100 mL). The combined organic layers are dried (Na2S04), filtered and concentrated. Purification by FC on silica gel (Fleptane/EA 100:0 to 80:20) yields the title compound as an orange solid (4.43 g). LC-MS method A: t_R = 1.05; [M+FI]⁺ = no MS signal.

Step 3: 3-[4-(tert-Butoxycarbonylamino-methyl)-phenyl]-3-oxo-propionic acid ethyl ester

To a solution of 4-(boc-aminomethyl)benzoic acid (3 g, 1 1.6 mmol), 2,2-dimethyl-1 ,3-dioxane-4,6-dione (1.87 g, 12.7 mmol) and DMAP (2.26 g, 18.5 mmol) in DCM (40 mL) at 0°C is added DCC (2.75 g, 13.3 mmol) in DCM (20 mL) over 60 min. The reaction mixture is stirred at 0°C for 30min then at RT for 4h. DCM (50 mL) is added and the solution is washed with H₂0 (4 X 50 mL), dried (MgSO^ and evaporated. The residue is dissolved in EtOH (40 mL) and heated at reflux for 48h. The mixture is evaporated and purified by FC on silica gel (Fleptane / EA 100:0 to 80:20) to yield the title compound as a colorless oil (1 g). LC-MS method A: t_R = 0.85; [M+FI]⁺ = 322.3.

Step 4: 1-(2,4-Bis-benzyloxy-phenyl)-5-[4-(tert-butoxycarbonylamino-methyl)-phenyl]-1 H-[1 ,2,3]triazole-4- carboxylic acid ethyl ester

To a solution of 1-azido-2,4-bis-benzyloxy-benzene (630 mg, 1.52 mmol) and 3-[4-(tert-butoxycarbonylamino- methyl)-phenyl]-3-oxo-propionic acid ethyl ester (488 mg, 1.52 mmol) in DMF (10 mL) is added K2CO3 (424 mg, 3.04 mmol). The reaction mixture is stirred at 80°C overnight then cooled down to RT and concentrated. Purification by FC on silica gel (Heptane/EA 50:50 to 0: 100) yields the title compound as a red oil (610 mg). LC-MS method A: tR = 1.04; [M+H]⁺ = 635.16.

Step 5: 1-(2,4-Bis-benzyloxy-phenyl)-5-[4-(tert-butoxycarbonylamino-methyl)-phenyl]-1 H-[1 ,2,3]triazole-4- carboxylic acid

To a solution of 1 1 -(2,4-bis-benzyloxy-phenyl)-5-[4-(tert-butoxycarbonylamino-methyl)-phenyl]-1 H-[1 ,2,3]triazole- 4-carboxylic acid ethyl ester (610 mg, 0.961 mmol) in MeOH (5 mL) and THF (5 mL) is added NaOFI 1 M (2.9 mL, 2.88 mmol). The reaction is stirred at RT overnight. The mixture is concentrated to remove the organic solvents and the resulting aqueous layer is acidified to pH 2-5 using 1 N HCI then extracted with EA (2 X 25 mL). The combined organic layers are washed with brine, dried (MgS04), filtered and evaporated to afford the crude title compound as a brown foam (500 mg). LC-MS method A: tR = 0.96; [M+FI]⁺ = 607.15.

Step 6: {4-[3-(2,4-Bis-benzyloxy-phenyl)-5-(1-cyclopropylmethyl-piperidin-4-ylcarbamoyl)-3H-[1 ,2,3]triazol-4-yl]- benzyl)-carbamic acid tert-butyl ester

A solution of 1 -(2,4-bis-benzyloxy-phenyl)-5-[4-(tert-butoxycarbonylamino-methyl)-phenyl]-1 H-[1 ,2,3]triazole-4- carboxylic acid (250 mg, 0.412 mmol), 1 -cyclopropylmethyl-piperidin-4-ylamine (76.3 mg, 0.495 mmol), DIPEA (0.215 mL, 1.24 mmol) and HATU (188 mg, 0.494 mmol) in DMF (3 mL) is stirred in a sealed tube at RT overnight. The reaction mixture is then filtered and purified by preparative HPLC to afford the title compound as a white solid (215 mg). LC-MS method A: t_R = 0.88; [M+H]⁺ = 743.28.

Step 7: 5-(4-Aminomethyl-phenyl)-1 -(2,4-bis-benzyloxy-phenyl)-1 H-[1 ,2,3]triazole-4-carboxylic acid (1- cyclopropylmethyl-piperidin-4-yl)-amide

To a solution of {4-[3-(2,4-bis-benzyloxy-phenyl)-5-(1 -cyclopropylmethyl-piperidin-4-ylcarbamoyl)-3H-[1 ,2,3]triazol- 4-yl]-benzyl)-carbamic acid tert-butyl ester (215 mg, 0.289 mmol) in dioxane (5 mL) is added HCI 4M in dioxane (0.722 mL, 2.89 mmol). The reaction mixture is stirred at RT overnight then concentrated. The residue is dissolved in EtOH (5 mL) then concentrated to yield to the title compound as a beige foam (178 mg). LC-MS method A: t_R = 0.69; [M+H]⁺ = 643.19.

Step 8: 4-(6-Hydroxy-3-oxo-3H-xanthen-9-yl)-isophthalic acid 1-(2,5-dioxo-pyrrolidin-1 -yl) ester

To an orange suspension of 5-carboxyfluorescein (500 mg, 1.33 mmol) in THF (0.26 mL) are added DCC (6.03 mg, 0.0292 mmol) and N-hydroxysuccinimid (3.36 mg, 0.0292 mmol). The reaction mixture is stirred at RT for 1 h then concentrated to yield to the crude title compound as a red solid (314 mg). LC-MS method A: t_R = 0.74[M+FI]⁺ = 473.95.

Step 9: N-{4-[3-(2,4-Bis-benzyloxy-phenyl)-5-(1 -cyclopropylmethyl-piperidin-4-ylcarbamoyl)-3H-[1 ,2,3]triazol-4-yl]- benzyl}-6-(6-hydroxy-3-oxo-3H-xanthen-9-yl)-isophthalamic acid

To a solution of 4-(6-hydroxy-3-oxo-3H-xanthen-9-yl)-isophthalic acid 1 -(2,5-dioxo-pyrrolidin-1 -yl) ester (78 mg, 0.165 mmol) in CFI₃CN (5 mL) are added 5-(4-aminomethyl-phenyl)-1 -(2,4-bis-benzyloxy-phenyl)-1 H- [1 ,2,3]triazole-4-carboxylic acid (1-cyclopropylmethyl-piperidin-4-yl)-amide (1 17 mg, 0.181 mmol) and DIPEA (31.7 uL, 0.181 mmol). The reaction mixture is stirred at RT over the weekend. The mixture is filtered, washed with CH₃CN (2X5 mL) to afford the title compound as a red solid (200 mg). LC-MS method A: tR = 0.63; [M+H]⁺ = no MS signal.

Step 10: N-{4-[5-(1-Cyclopropylmethyl-piperidin-4-ylcarbamoyl)-3-(2,4-dihydroxy-phenyl)-3H-[1 ,2,3]triazol-4-yl]- benzyl}-6-(6-hydroxy-3-oxo-3H-xanthen-9-yl)-isophthalamic acid

To a solution of N-{4-[3-(2,4-bis-benzyloxy-phenyl)-5-(1-cyclopropylmethyl-piperidin-4-ylcarbamoyl)-3H- [1 ,2,3]triazol-4-yl]-benzyl}-6-(6-hydroxy-3-oxo-3H-xanthen-9-yl)-isophthalamic acid (200 mg, 0.2 mmol) in DCM (30 mL) at 0°C is added boron trichloride 1 M in DCM (0.56 mL, 0.999 mmol). The reaction mixture is stirred at 0°C for 30 min then at RT overnight. The mixture is diluted in DCM (30 mL) and washed with sat. NaHC03 (3 X 25 mL) until complete dissolution of the solid. The organic layer is dried (MgS04), filtered and evaporated. Purification by preparative HPLC affords the title compound as an orange solid (20 mg). LC-MS method A: tR = 0.67; [M+H]⁺ = 821.1.

PDHK1 Fluorescence Polarization Assay

Fluorescence polarization is a homogenous method to analyze molecular binding events in solution. When a small fluorescent molecule (probe) is excited with plane-polarized light, the emitted light is largely depolarized because molecules tumble rapidly in solution during its fluorescence lifetime. However, if the probe is bound by a larger molecule (eg PDHK1 ) its effective molecular volume is increased. The rotation of the probe is slowed so that the emitted light is in the same plane as the excitation energy.

The bound and the free states of the probe each have an intrinsic polarization value: a high value for the bound state and a low value for the free state. The polarization value provides a direct measure of the fraction of bound probe.

The FP assay set-up for PDHK1 is based on a probe which is labelled with fluorescein [N-{4-[5-(1 - Cyclopropylmethyl-piperidin-4-ylcarbamoyl)-3-(2,4-dihydroxy-phenyl)-3H-[1 ,2,3]triazol-4-yl]-benzyl}-6-(6-hydroxy- 3-oxo-3H-xanthen-9-yl)-isophthalamic acid (FP probe)]. The FP probe binds to the ATP binding site of PDHK1. If compounds compete with the FP probe for binding to this site, more unbound FP probe is in solution represented by a lower polarization value. The polarization values are the basis for IC₅₀ calculation of compounds.

The assay tolerates a DMSO concentration of 2%, so stock solutions are made up at 50X. 1 mI/well of serially diluted compounds are added into 384 well-plates. 50 mI of FP Probe [10 nM] and PDHK1 [10 nM] pre-mixture is dispensed over the 1 ul dry-compound (Pre-mixture was tested to be stable for at least 1 h at RT without any impact on signal, quality and inhibitory potency). Plates are then incubated for 120 minutes in the dark at room temperature. Fluorescent counts and polarization value (mP) are determined on the Pherastar plate reader.

Assay buffer contains 50 mM MOPS / 50 mM K₂PO₄ / 150 mM NaCI / 1 mM DTT / 5% Glycerol / 0.1 % Octyl b-D- glucopyranoside, pH=>7.5 with NaOH. The calculated IC50 values may fluctuate depending on the daily assay performance. Fluctuations of this kind are known to those skilled in the art. Average IC50 values from several measurements are given as geometric mean values.

Table 1: Biological activity of example compounds against PDHK1 enzyme, measured by Fluorescence Polarization:

Compounds of the present invention may be further characterized with regard to their general pharmacokinetic and pharmacological properties using conventional assays well known in the art; for example relating to their bioavailablility in different species (such as rat or dog); or for their properties with regard to drug safety and/or toxicological properties using conventional assays well known in the art, for example relating to cytochrome P450 enzyme inhibition and time dependent inhibition, pregnane X receptor (PXR) activation, glutathione binding, or phototoxic behavior.

Claims

1. A compound of formula (I)

Formula (I)

wherein

• R¹ represents

> (Ci-₄)alkyl;

> hydroxy-(C3-6)cycloalkylene-CH2-, wherein said (C3-6)cycloalkylene optionally contains a ring oxygen atom;

> -CH2-CH2-O-R⁰¹, wherein R⁰¹ represents (Cujalkyl, hydroxy-(C2-6)alkylene-, or (Ci-3)alkoxy- (C2-3)alkylene-;

> -CH₂-CO-NR^N3R^N4, wherein R^N1 and R^N2 independently represent hydrogen or (Ci-₃)alkyl; and

R² represents -CH2-CN;

or a pharmaceutically acceptable salt thereof.

2. A compound according to claim 1 ; wherein

• R¹ represents

> methyl, or -C H ₂-(C ₁ -₃) al kyl;

> hydroxy-(C2-6)alkylene-, wherein said (C2-6)alkylene group represents ^■ ethylene which is unsubstituted, or mono-substituted with (Ci-4)alkyl, or di-substituted with methyl;

^■ n-propylene which is unsubstituted, or mono-substituted with (Cu)alkyl, or di- substituted with methyl; or

> (4-hydroxy-tetrahydro-pyran-4-yl)-methyl;

> -CH2-CH2-O-R⁰¹, wherein R⁰¹ represents methyl; methoxy-(C2-3)alkylene-; or hydroxy- (C2-6)alkylene- wherein said -(C2-6)alkylene- represents ethylene, or n-propylene which is unsubstituted or mono- or di-substituted with methyl;

> -CH₂-CH₂-NR^N1R^N2, wherein the group -NR^N1R^N2 represents morpholin-4-yl or 3-fluoro-azetidin- 1 -yl; or

> -CH2-CO-NR^N3R^N4, wherein R^N1 represents hydrogen and R^N2 represents (Ci-3)alkyl; and R² represents -CH2-CN.

or a pharmaceutically acceptable salt thereof.

3. A compound according to claim 1 ; wherein;

• R¹ represents

> methyl or -C H 2-(C 1 -3) al ky I;

> 2-hy d roxy ethyl , 2-hydroxy-propyl, 2-hydroxy-2-methyl-propyl, 3-hydroxy-2, 2-dimethyl-propyl, 2- hydroxy-butyl, 3-hydroxy-3-methyl-butyl, 2-hydroxy-3, 3-dimethyl-butyl;

> (4-hydroxy-tetrahydro-pyran-4-yl)-methyl;

> 2-(methylamino)-2-oxoethyl, 2-(3-fluoro-azetidin-1 -yl)-ethyl, or 2-(morpholin-4-yl)-ethyl, and R² represents -CH2-CN;

or a pharmaceutically acceptable salt thereof.

4. A compound according to claim 1 ; wherein

R¹ represents

> methyl;

> 2-hydroxyethyl, 2-hydroxy-propyl, 2-hydroxy-2-methyl-propyl, 3-hydroxy-2, 2-dimethyl-propyl, 2- hydroxy-butyl, 3-hydroxy-3-methyl-butyl, 2-hydroxy-3, 3-dimethyl-butyl; > 3,3,3-trifluoro-2-hydroxy-propyl, 3-fluoro-2-hydroxy-propyl;

> 2-methoxy-ethyl, 2-(2-hydroxy-ethoxy)-ethyl, 2-(2-methoxy-ethoxy)-ethyl; or

R² represents -CH2-CN;

or a pharmaceutically acceptable salt thereof.

5. A compound according to claim 1 which is:

(R)-[5-(6-Fluoro-2-methyl-8-methylamino-9H-pyrimido[4,5-b]indol-4-yl)-2-(3,3,3-trifluoro-2-hydroxy-propoxy)- phenoxyj-acetonitrile;

(R)-[5-(6-Fluoro-2-methyl-8-methylamino-9H-pyrimido[4,5-b]indol-4-yl)-2-(2-hydroxy-propoxy)-phenoxy]- acetonitrile;

(S)-[5-(6-Fluoro-2-methyl-8-methylamino-9H-pyrimido[4,5-b]indol-4-yl)-2-(2-hydroxy-propoxy)-phenoxy]- acetonitrile;

[5-(6-Fluoro-2-methyl-8-methylamino-9H-pyrimido[4,5-b]indol-4-yl)-2-(4-hydroxy-tetrahydro-pyran-4-ylmethoxy)- phenoxyj-acetonitrile; [5-(6-Fluoro-2-methyl-8-methylamino-9H-pyrimido[4,5-b]indol-4-yl)-2-(2-methoxy-ethoxy)-phenoxy]-acetonitrile;

(R)-[2-(3-Fluoro-2-hydroxy-propoxy)-5-(6-fluoro-2-methyl-8-methylamino-9H-pyrimido[4,5-b]indol-4-yl)-phenoxy]- acetonitrile;

[2-[2-(3-Fluoro-azetidin-1-yl)-ethoxy]-5-(6-fluoro-2-methyl-8-methylamino-9H-pyrimido[4,5-b]indol-4-yl)-phenoxy]- acetonitrile;

(R)-7-(6-Fluoro-2-methyl-8-methylamino-9H-pyrimido[4,5-b]indol-4-yl)-2,3-dihydro-benzo[1 ,4]dioxine-2- carbonitrile; or

(S)-7-(6-Fluoro-2-methyl-8-methylamino-9FI-pyrimido[4,5-b]indol-4-yl)-2,3-dihydro-benzo[1 ,4]dioxine-2- carbonitrile;

or a pharmaceutically acceptable salt thereof.

6. A pharmaceutical composition comprising, as active principle, one or more compounds according to any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof, and at least one therapeutically inert excipient.

7. A compound according to any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof, for use as a medicament.

8. A compound according to any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof, for use in the prevention or treatment of a cancer, an autoimmune disorder, or an inflammatory disease.

9. Use of a compound as defined in claim 1 , or of a pharmaceutically acceptable salt thereof, in the preparation of a medicament for the prevention or treatment of a cancer, an autoimmune disorder, or an inflammatory disease.

10. A method for the prophylaxis or treatment of a cancer, an autoimmune disorder, or an inflammatory disease; comprising administering to a subject in need thereof an effective amount of a compound as defined in any one of claims 1 to 5, or of a pharmaceutically acceptable salt thereof.

11. A method of modulating an immune response; comprising administering to a subject in need thereof an effective amount of a compound as defined in any one of claims 1 to 5, or of a pharmaceutically acceptable salt thereof; wherein said subject has been diagnosed to have an autoimmune disease or an inflammatory disease, wherein said immune response is mediated by PDHK1 activity and/or immunometabolism.

12. A method of treatment of a tumor in a subject having been diagnosed to have cancer; comprising administering to said subject an effective amount of a compound as defined in any one of claims 1 to 5, or of a pharmaceutically acceptable salt thereof; wherein said effective amount leads to a change of tumor properties, and wherein said modification is achieved by modulating PDHK1 activity and/or immunometabolism; wherein said prophylaxis or treatment may optionally be effected in combination with one or more chemotherapy agents and / or radiotherapy and / or targeted therapy.