Thiophenecarboxamide derivatives as WIP1 inhibitors

Abstract

The application relates to compounds of formula (I) and stereoisomers, tautomers, N-oxides, and pharmaceutically acceptable salts thereof that act as modulators or inhibitors of Wip1 (PPM1 D) phosphatase useful for the treatment of cancer and neurological diseases. The application further relates to the compounds of formula (I) for use as a medicament and to pharmaceutical compositions comprising said compounds.

Description

[0001]ANAVO Therapeutics BV A19159WO1 ANAVO THERAPEUTICS BV J.H. Oortweg 19 52333 CH LeidenNetherlands Novel compounds as Wip1 inhibitors 10 Field of the Invention15 The present invention relates to compounds of formula (I) and stereoisomers, tautomers, N-oxides, and pharmaceutically acceptable salts thereof that are useful as modulators or inhibitors of Wip1 (PPM1D) phosphatase. The present invention further relates to the compound of for- mula (I) for use as a medicament and to a pharmaceutical composition comprising said com- pounds. 20 Background of the Invention The wild-type p53-induced phosphatase 1 (Wip1; also referred to as serine / threonine phos- phatase PPM1D, protein phosphatase 2C delta (PP2Cδ), PPMID, or IDDGIP) is a negative reg-25 ulator of the tumor suppressor p53 and is overexpressed in several human (solid) tumors. TheWip1 gene (also known as PPM1D gene) is located at 17q23. The expression of this gene is in- duced in a p53-dependent manner in response to various environmental threats and plays an important role in homeostatic down-regulation of various stress response, cell cycle regulation, DNA damage repair and tumor cell metabolism. At present, Wip1 has particularly been found to30 be amplified and overexpressed in various (human) tumors and is currently considered to be anoncogene. Wip1 is a member of the PP2C family of Ser / Thr protein phosphatase that are dependent on Mg2+or Mn2+for their catalytic activity and can be induced by various DNA damaging treatments including ionizing or UV irradiation in a P53 dependent manner (Fiscella et al. PNAS 94, 6048-35 6053 (1997)). Upon its induction, Wip1 acts upon multiple effectors of the DNA damage re-sponse pathway to dephosphorylate and consequently inactivate them. Among its reported sub- strates are UNG2 (Lu et al., Molecular Cell 15, 621-634 (2004)), MDM2 (Lu et al., Cancer Cell 12, 342-354 (2008)), MDMX (Xinna et al., Journal of Biological Chemistry 281, 24847-24862 (2009)), ATM (Shreeram et al., Journal of Experimental Medicine 203, 2793-2799 (2006)),40 yH2AX (Cha et al., Cancer Research 70, 4112-4122 (2010)), p38MAPK (Bulavin et al., NatureGenetics 36, 343-350 (2004)), Chk2 (Fujimoto et al., Cell Death and Differentiation 13, 1170- 1180 (2006)), KPNA2 (P. Wang et al, J. Cell. Biochem. (2019)), Chk1 and p53(Lu et al., Genes and Development 19, 1162-1174 (2005)). In cellular studies, overexpression of Wip1 in E1A transduced rat embryonic fibroblasts was45 sufficient to induce transformation foci (Nannenga et al., Molecular Carcinogenesis 45, 594-604(2006)). Conversely, murine embryonic fibroblasts homozygous for Wip1 deletion showed sig- nificantly reduced tumor growth when co-transfected with the transforming oncogenes HRAS and E1A, HRAS and ErbB2, or HRAS and Myc (Bulavin et.al., Nature Genetics 36, 343-350 (2004)). Wip1- / - mice also demonstrated tumor-resistance to both induced tumor models, usingANAVO therapeutics BV A19159WO2 infection with MMTV driven ErbB2 or HRAS, as well as a decreased incidence of spontaneous leukemias and sarcomas. Similarly, Wip1- / - mice were relatively resistant to Eµ-Myc induced lymphomas (Shreeram et al., Journal of Experimental Medicine 203, 2793-2799 (2006)). Overexpression of Wip1 is reported to result in delay or suppression of base-excision repair by 5inhibition of UNG2 and P53. Similarly, its overexpression suppresses DNA double-strand-breakrepair by inhibition of the ATM response, inhibiting repair by both homologous recombination and non-homologous end joining. Conversely, silencing or knockout of Wip1 has been reported to elevate the activity of multiple stress response pathways, resulting in elevated levels of phos- pho-p38, phospho-p53(S15), p53 response genes p21 / Waf, p16INKAA, and ARF (Bulavin et al.,10 Nature Genetics 36, 343-350 (2004)), and elevated γH2AX and DNA damage-associated nu-clear foci (Moon et al., Journal of Biological Chemistry 285, 12935-12947 (2010)). Further, it is reported that Wip1 overexpression predicts poor prognosis in esophageal squamous cell carci- noma ESCC (K. Li, Y. Liu et al., Pathol. Oncol. Res.: POR (2018)). Amplified or overexpressed Wip1 has also been proposed to promote tumorigenesis in multi-15 ple cancers by suppressing the regulatory activity of a host of its tumor suppressor substrates.Amplification of the Wip1 / PPM1D gene locus on 17q23 has been reported in breast cancer (Li et al., Nature Genetics 31, 133-134 (2002)), ovarian clear cell carcinoma (Hirasawa et al., Clini- cal Cancer Research 9, 1995-2004 (2003)), neuroblastoma (Saito-Ohara et al., Journal of Ex- perimental Medicine 203, 2793-2799 (2003)), and pancreatic adenocarcinoma (Loukopoulos et20 al., Cancer Science 98, 392-400 (2007)). Moreover, elevated expression of Wip1 is reported inmedulloblastomas (Castellino et al., Journal of Neuro-Oncology 86, 245-256 (2008)) and gastric carcinomas (Fuku et al., Pathology International 57, 566-571 (2007)). In several of these tu- mors, gene amplification has been confirmed to correlate with elevated protein expression. Wenhong et al. reviews the role of Wip1 in cancer (Wenhong et al. Biomed. Pharmacother.,25 125, 1-10 (2020)). It is inter alia disclosed that Wip1 gene mutation exists in colon cancer, whichlead to the persistent suppression of p53 and the occurrence of tumors (P. Kleiblova et al., J. Cell Biol., 201 (4), 511-521 (2013)). In addition, Wip1 mutations were associated with hemato- logical diseases such as myelodysplastic syndrome, leukemia and lymphoma (M. Xie et al., Nat. Med., 20 (12), 1472-1478 (2014)), observed in a 3-year-old patient with glioblastoma multiforme30 (A.J. Dodgshun et al., Cancer Genet., 209 (1–2) 53-56 (2016)), and mutant genes in thyroidcancer were identified by Next Generation Gene Sequencing, wherein mutations were found in genes including Wip1 (B. Pekova et al., Endocr. Connect., 796-805 (2019)). Furthermore, Wip1 can be expressed in lung cancer tissues and can also mediate the regulation of amyloid protein- binding protein 2 APPBP2 on lung cancer tissues as an intermediate molecule of pathway.35 Gong et al. observed an ectopic expression of APPBP2, Wip1 and SPOP in human NSCLC tis-sues (H. Gong et al., EBioMedicine, 44138-149 (2019)). Furthermore, it was observed that the expression of Wip1 in nasopharyngeal carcinoma, in hepatocellular carcinoma, and in human renal cell carcinoma is significantly higher than that in normal tissues (G.G. Sun et al., Pathol. Oncol. Res.: POR, 21 (2) 283-291 (2015); G.B. Li et al., PLoS One, 8 (3) e60775 (2013); and S.40 Liu et al., PLoS One, 9 (10) e110218 (2014)). It is also assumed that Wip1 is a target moleculefor bladder cancer treatment (W. Wang et al., Braz. J. Med. Biol. Res., 47 (12) 1044-1049 (2014)). As a final oncogenic example, it was found that the expression of Wip1 in prostate can- cer is significantly higher than that in benign prostatic hyperplasia BPH control group (L. Jiao et al., Anticancer Res., 34 (6) 2919-2925 (2014)).45 In addition, mutations in Wip1 are associated with multiple myeloma (Mouhieddine et al., NatCommun., 11(1) (2020)). Wang et al. discloses that Wip1 also has an important role in cervical cancer (Oncol Res., 22(4) 225-233 (2014) and Zhang at al. report that Wip1 regulates the prolif- eration and invasion of nasopharyngeal carcinoma (Tumour Biol., 35(8) 7651-7 (2014)). Further, Wip1 is associated with osteosarcoma, Ewing's sarcoma (He et al., Eur Rev Med PharmacolANAVO therapeutics BV A19159WO3 Sci., 25(1) 78-85 (2021), Long et al., J Cell Biochem., 120(4) 5652-566 (2019)), Wilm’s tumor (Saliba et al., Pediatr Dev Pathol., 23(2) 167-171 (2020)), mesothelioma (Yu et al., Aging (Al- bany NY), 13(17) 21294–21308 (2021)), and melanoma (Wu et al., Br J Cancer, 118(4) 495-508 (2018)). 5Further to the above-outlined connections of Wip1 and potential indications, Wip1 is associ-ated with the treatment of amyotrophic lateral sclerosis (CN109876143A) and individual allergic asthma (CN105727295A), as well as with the regulation of the adipogenic differentiation capac- ity of mesenchymal stem cells (MSCs) (CN111118046A). Based on the above, inhibition of Wip1 by small molecule inhibitors was investigated10 (JP2021138671A2, JP2018024645A2) and found to provide suitable selectivity(WO2012 / 149102). However, no small molecule inhibitor has reached the market yet. The known in the art small molecule inhibitors are either not potent enough or do not provide satisfy- ing pharmacological properties suitable for drug development, such as but not limited to phar- macokinetic properties, e.g., regarding the metabolic stability, in particular the half-life. Thus,15 there is a need for small molecules that selectively inhibit Wip1 and provide improved pharma-cological properties that are of high relevance in drug development. In connection with the preparation of medicaments, cellular activity is an important differentiat- ing factor in drug development as it defines the functional activity of the compound in a cellular environment, a physiologically relevant setting (Schwaid, A. G. et al J Med Chem, 2018, 61,20 1767-1773). As a consequence, high cellular activity triggered by Wip1 modulation, inhibitionand / or degradation is desirable for a drug. Such cellular activity triggered by Wip1 modulation can for example be measured in a dephos- phorylation assay measuring cellular p53 phospho-serine 15 levels, as reported in the literature (Gilmartin, A. G. et al. Nat Chem Biol 2014,10, 181–187).25 As alternative, cellular activity triggered by Wip1 modulation can be measured in a degradationassay measuring Wip1 protein level for example but not limited to by Western blotting (Gilmartin, A. G. et al. Nat Chem Biol 2014,10, 181–187). Small molecule permeability is one important compound characteristic that is influencing its cellular activity on an intracellular target such as Wip1. Several parameters are impacting small30 molecule permeability, including its physicochemical properties, such as but not limited tomolecular weight, lipophilicity, ionization state and hydrogen-bonding capacity (Miller, R. R. J. Med. Chem.2020, 63, 12156−12170; Desai, P. V. et al. Bioorg. Med. Chem. Lett.2012, 22, 6540–6548). In particular, the hydrogen-bonding capacity of a drug is influencing the solubility and the ability to establish important interaction with its biomolecular targets, driving potency35 binding and selectivity. On the other hand, the number of hydrogen bond donors and acceptorshas a negative impact on its permeability and ultimately on its cellular activity (Kenny, P. W. J. Med. Chem.2022, 65, 21, 14261–14275; Coimbra, J. T. S. et al. RCS Adv.2021, 11, 899-908). The appropriate number of hydrogen-bonding capacity to reach high cellular activity is desirable for a drug. 40 In view of the above, compounds modulating, inhibiting, or degrading Wip1 are useful for treat- ing one or more diseases such as cancer, pre-cancerous syndromes, autoimmune conditions, and neurological diseases. Of particular relevance is the treatment of cancer and pre-cancerous syndromes. Cancers may45 be in the form of solid tumors such as sarcomas, carcinomas, and lymphomas or in the form ofliquid tumors, e.g. leukemia. Compounds modulating or inhibiting Wip1 are particularly useful for the treatment of amy- otrophic lateral sclerosis, attention deficit hyperactivity disorder, autism, Bannayan-Zonana syn- drome, bladder cancer, blood cancer, bone cancer, breast cancer (e.g. inflammatory breastANAVO therapeutics BV A19159WO4 cancer, triple negative breast cancer (TNBC), and HER2+ breast cancer), brain cancer, cervical cancer, colorectal cancer, Cowden disease, endometrial cancer, ependymoma, esophagus can- cer, Ewing's sarcoma, gastric cancer, head and neck cancer, individual allergic asthma, kidney cancer, Lhermitte-Duclos disease, lung cancer, liver cancer, lymphoma, medulloblastoma, 5melanoma, mesothelioma, nasopharyngeal carcinoma, neuroblastoma, neurofibromatosis,ovarian cancer, osteosarcoma, pancreatic cancer, prostate cancer, Rhabdomyosarcoma, thy- roid cancer, urothelial cancer, and Wilm's tumor. Relevant blood cancers include leukemia, lym- phoma, and multiple myeloma. Relevant leukemia include acute lymphocytic leukemia (ALL), Acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), chronic myeloid leukemia10 (CML), and myelodysplastic syndromes (MDS). Of particular relevance is AML. Relevant braincancers include glioblastoma, oligodendroglioma, diffuse intrinsic pontine glioma (DIPG), meningioma. Particularly relevant is glioblastoma. Relevant lung cancers include small-cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC). Particularly relevant is NSCLC. The most relevant liver cancer is hepatocellular carcinoma (HCC). Compounds modulating or inhibit-15 ing Wip1 may be especially useful in the treatment of amyotrophic lateral sclerosis, Bannayan-Zonana syndrome, bladder cancer, bone cancer, breast cancer, inflammatory breast cancer, brain cancer, especially glioblastoma, cervical cancer, colorectal cancer, Cowden disease, en- dometrial cancer, ependymoma, esophagus cancer, Ewing's sarcoma, gastric cancer, head and neck cancer, kidney cancer, leukemia, especially AML, Lhermitte-Duclos disease, lung cancer,20 especially NSCLC and SCLC, liver cancer, especially HCC, lymphoma, medulloblastoma,melanoma, mesothelioma, neuroblastoma, ovarian cancer, osteosarcoma, pancreatic cancer, prostate cancer, Rhabdomyosarcoma, thyroid cancer, and Wilm's tumor. Objects and Summary of the Invention 25 It is therefore an object of the present invention to provide compounds, which modulate Wip1. It is another object of the present invention to provide compounds, which inhibit Wip1. It is an- other object of the present invention to provide compounds which degrade Wip1. It is another object of the present invention to provide compounds, which exhibit a high activity30 regarding the modulation, the inhibition and / or the degradation of Wip1, especially within thecell. It is another object of the present invention to provide compounds, which exhibit satisfying pharmacological properties suitable for drug development, such as but not limited to pharma- cokinetic properties.35 It is another object of the present invention to provide compounds, which are suitable for useas a medicament. It is another object of the present invention to provide compounds, which are suitable for use in the treatment of one or more diseases, which are linked to Wip1, e.g. its over- expression, genomic amplification, gain of function mutations, and / or fusions / translocations. It is another object of the present invention to provide compounds, which are suitable for use in the40 treatment of one or more disease selected from cancer, pre-cancerous syndromes, autoimmuneconditions, neurological disease, and viral disease. It is another object of the present invention to provide compounds, which are suitable for use in the treatment of cancer, in particular in the treatment of solid or liquid tumors. In particular, it is an object of the present invention to provide compounds, which are suitable for the treatment of cancer, especially the treatment of Ban-45 nayan-Zonana syndrome, bladder cancer, bone cancer, breast cancer, inflammatory breastcancer, brain cancer, especially glioblastoma, cervical cancer, colorectal cancer, Cowden dis- ease, endometrial cancer, ependymoma, esophagus cancer, Ewing's sarcoma, gastric cancer, head and neck cancer, kidney cancer, leukemia, especially AML, Lhermitte-Duclos disease, lung cancer, especially NSCLC and SCLC, liver cancer, especially HCC, lymphoma, medul-ANAVO therapeutics BV A19159WO5 loblastoma, melanoma, mesothelioma, neuroblastoma, ovarian cancer, osteosarcoma, pancre- atic cancer, prostate cancer, Rhabdomyosarcoma, thyroid cancer, and Wilm's tumor. It is an- other object of the present invention to provide compounds, which are suitable for use in the treatment of autoimmune conditions such as asthma, in particular of individual allergic asthma. 5It is another object of the present invention to provide compounds, which are suitable for use inthe treatment of neurological diseases such as amyotrophic lateral sclerosis, attention deficit hy- peractivity disorder, or autism. It is another object of the present invention to provide com- pounds, which are suitable for use in the treatment of viral diseases.10 At least one of the above objects can be achieved by the compounds of formula (I) as definedherein as well as pharmaceutical compositions comprising the same, and by the medical uses thereof. The inventors of the present invention inter alia surprisingly found that the compounds of for-15 mula (I) as defined herein inhibit Wip1 with a high potency. In certain embodiments, the com-pounds of formula (I) also reach high cellular activities due to the presence of hydrogen bond donors and acceptors in the molecule. In certain embodiments, the compounds of formula (I) also exhibit advantageous properties regarding the metabolic stability, in particular the half-life. Accordingly, the compounds of formula (I) can advantageously be used as a medicament, in20 particular for the treatment of one or more diseases selected from the group consisting of amy-otrophic lateral sclerosis, attention deficit hyperactivity disorder, autism, Bannayan-Zonana syn- drome, bladder cancer, blood cancer, bone cancer, breast cancer, inflammatory breast cancer, brain cancer, cervical cancer, colorectal cancer, Cowden disease, endometrial cancer, ependy- moma, esophagus cancer, Ewing's sarcoma, gastric cancer, head and neck cancer, individual25 allergic asthma, kidney cancer, Lhermitte-Duclos disease, lung cancer, liver cancer, lymphoma,medulloblastoma, melanoma, mesothelioma, nasopharyngeal carcinoma, neuroblastoma, neu- rofibromatosis, ovarian cancer, osteosarcoma, pancreatic cancer, prostate cancer, Rhab- domyosarcoma, thyroid cancer, urothelial cancer, and Wilm's tumor.30 In a first aspect, the present invention relates to a compound of formula (I) or a stereoisomer, tautomer, N-oxide, or pharmaceutically acceptable salt thereof; 35 wherein X1is CH or N; R1Ais H or C1-C4-alkyl; R1Bis H or C1-C4-alkyl;40 R2 is H, C1-C2-alkyl, 5- or 6-membered saturated or partially unsaturated carbocyclyl, hetero-cyclyl, carbocyclyloxy, or heterocyclyloxy, or 4- to 12-membered saturated carbobicyclyl or heterobicyclyl, wherein the aforementioned heterocyclyl or heterobicyclyl comprises one or more, same or different heteroatoms selected from O, N, or S, wherein said N- and / or S-atoms are independently oxidized or non-oxidized, and wherein each substitutable atomANAVO therapeutics BV A19159WO6 in the aforementioned groups is independently unsubstituted or substituted with one or more, same or different substituents RX; R3is H, C1-C4-alkyl, C1-C4-alkoxy, C1-C2-alkoxy-C1-C4-alkyl, 3- to 6-membered saturated, partially or fully unsaturated, or aromatic carbocyclyl, carbocyclylmethyl, heterocyclyl, or 5heterocyclylmethyl, or 4- to 12-membered saturated carbobicyclyl or heterobicyclyl,wherein the aforementioned heterocyclyl or heterobicyclyl comprises one or more, same or different heteroatoms selected from O, N, or S, wherein said N- and / or S-atoms are in- dependently oxidized or non-oxidized, and wherein each substitutable atom in the afore- mentioned groups is independently unsubstituted or substituted with one or more, same or10 different substituents RY;is a moiety selected from15 20 ANAVO therapeutics BV A19159WO7 wherein the wavy line marks the connection to the remainder of the molecule; and wherein 5RX is halogen, CN, OH, C1-C4-alkyl, C1-C4-haloalkyl, C1-C4-alkoxy, C1-C4-haloalkoxy, or C1-C4-hydroxyalkyl; RYis halogen, CN, OH, S(=O)2CH3, S(=O)(=NH)CH3, NHC(=O)CH3, NH2, C1-C4-alkyl, C1-C4- haloalkyl, C1-C4-alkoxy, C1-C4-haloalkoxy, C1-C2-alkoxy-C1-C4-alkyl, C1-C4-hydroxyalkyl, or C3-C4-cycloalkyl;10 R4 each independently is halogen, CN, OH, C1-C4-alkyl, C1-C4-haloalkyl, C1-C4-alkoxy, C1-C4-haloalkoxy, C1-C4-hydroxyalkyl, or C3-C4-cycloalkyl; R5each independently is halogen, CN, C1-C4-alkyl, C1-C4-haloalkyl, C1-C4-alkoxy, or C1-C4- haloalkoxy; or two R5together form =O; mis 0, 1, or 2;15 n is 0, 1, 2, 3, or 4;Y1is CH2, NH, NRN, or O; Y2is CH or N; Y3is CH2; and wherein20 RN is C1-C6-alkyl or C3-C10-cycloalkyl, wherein optionally one or more -CH2- groups may bereplaced by -O-. In one embodiment of the compound of formula (I),25 ANAVO therapeutics BV A19159WO8 5wherein the wavy line marks the connection to the remainder of the molecule.In a preferred embodiment, Ais a moiety selected from10 wherein the wavy line marks the connection to the remainder of the molecule. In a more preferred embodiment, Ais a moiety selected from15 wherein the wavy line marks the connection to the remainder of the molecule; and wherein preferably R4is Br, Cl, CN, CH3, CF3, or cyclopropyl.20 In another more preferred embodiment,A is a moiety selected from , ; wherein the wavy line marks the connection to the remainder of the molecule;25 and wherein preferablyR4is Br, Cl, CH3, or CF3.ANAVO therapeutics BV A19159WO9 In another embodiment of the compound of formula (I), Ais a moiety selected from 5wherein the wavy line marks the connection to the remainder of the molecule;and wherein preferably Ais a moiety selected from wherein10 R4 is Br, Cl, CN, CH3, CF3, or cyclopropyl.In one embodiment of the compound of formula (I), X1is CH.15 In one embodiment of the compound of formula (I),R1Ais H or CH3; and R1Bis H or CH3. In one embodiment of the compound of formula (I),20 R1A is H; andR1Bis H. In one embodiment of the compound of formula (I), R2is cyclopentyl or tetrahydrofuranyl, wherein each substitutable carbon atom in the afore-25 mentioned rings is independently unsubstituted or substituted with one or more, same ordifferent substituents RX. In one embodiment of the compound of formula (I), R3is 3- or 4-membered saturated carbocyclyl or heterocyclyl, wherein the aforementioned30 heterocyclyl comprises an oxygen atom as heteroatom, and wherein each substitutableatom in the aforementioned groups is independently unsubstituted or substituted with one or more, same or different substituents RY; or 5- or 6-membered aromatic heterocyclyl; wherein the aforementioned heterocyclyl com- prises one or more nitrogen atoms as heteroatom(s), and wherein each substitutable atom35 in the aforementioned groups is independently unsubstituted or substituted with one ormore, same or different substituents RY. In one embodiment of the compound of formula (I), R3isANAVO therapeutics BV A19159WO10 In one embodiment of the compound of formula (I), 5A is a moiety selected from , ; wherein the wavy line marks the connection to the remainder of the molecule; and wherein10 wherein the wavy line marks the connection to the remainder of the molecule; and R3is15 wherein the wavy line marks the connection to the remainder of the molecule. In one embodiment, the compound of formula (I) is a compound of formula (IS) 20 In one embodiment, the compound according to formula (I) is selected from the group consist- ing ofANAVO therapeutics BV A19159WO11 5 ,ANAVO therapeutics BV A19159WO12 5 10 In another embodiment, the compound according to formula (I) is selected from the group con-sisting ofANAVO therapeutics BV A19159WO13 5 ,ANAVO therapeutics BV A19159WO14 5 In another embodiment, the compound according to formula (I) is selected from the group con- sisting of 10 ANAVO therapeutics BV A19159WO15 In a second aspect, the present invention relates to a pharmaceutical composition comprising a 5pharmaceutically effective amount of the compound of formula (I) as defined above and option-ally a pharmaceutically acceptable carrier or excipient. In a third aspect, the present invention relates to a compound of formula (I) as defined above or a pharmaceutical composition as defined above for use in medicine. 10 In a fourth aspect, the present invention relates to a compound of formula (I) as defined above or a pharmaceutical composition as defined above for use in the treatment of a disease se- lected from the group consisting of cancer, pre-cancerous syndromes, autoimmune conditions, neurological diseases, and viral disease, preferably selected from the group consisting of can-15 cer, pre-cancerous syndromes, autoimmune conditions, and neurological diseases, morepreferably selected from the group consisting of cancer, pre-cancerous syndromes, and neuro- logical diseases. In a fifth aspect, the present invention relates to a compound of formula (I) as defined above or20 a pharmaceutical composition as defined above for use in the treatment of a disease selectedfrom the group consisting of amyotrophic lateral sclerosis, attention deficit hyperactivity disor- der, autism, Bannayan-Zonana syndrome, bladder cancer, blood cancer, bone cancer, breast cancer, inflammatory breast cancer, brain cancer, cervical cancer, colorectal cancer, Cowden disease, endometrial cancer, ependymoma, esophagus cancer, Ewing's sarcoma, gastric can-25 cer, head and neck cancer, individual allergic asthma, kidney cancer, Lhermitte-Duclos disease,lung cancer, liver cancer, lymphoma, medulloblastoma, melanoma, mesothelioma, nasopharyn- geal carcinoma, neuroblastoma, neurofibromatosis, ovarian cancer, osteosarcoma, pancreatic cancer, prostate cancer, Rhabdomyosarcoma, thyroid cancer, urothelial cancer, and Wilm's tu- mor. 30 Detailed Description Before describing in detail exemplary embodiments of the present invention, definitions impor- tant for understanding the present invention are given.35 The term “compound(s) of the present invention" is to be understood as equivalent to the term"compound(s) according to the invention", and also covers a salt, stereoisomer, tautomer or N- oxide thereof. The term “compound(s) of the present invention" relates to the compounds of for- mula (I) as well as to compounds of formula (I.a), (I.b), (I.1), (I.1.a), (IS), (IS.a), (IS.1), and (IS.1.a). The compounds according to the invention may be amorphous or may exist in one or more dif-40 ferent crystalline states (polymorphs), which may have different macroscopic properties such asstability or show different biological properties such as activities. The present invention relatesANAVO therapeutics BV A19159WO16 to amorphous and crystalline forms of compounds of formula (I), mixtures of different crystalline states of the compounds of formula (I), as well as amorphous or crystalline salts thereof. Salts of the compounds according to the invention are preferably pharmaceutically acceptable salts, such as those containing counterions present in drug products listed in the US FDA Or- 5ange Book database. They can be formed in a customary manner, e.g., by reacting the com-pound with an acid of the anion in question, if the compounds according to the invention have a basic functionality, or by reacting acidic compounds according to the invention with a suitable base. Suitable cationic counterions are in particular the ions of the alkali metals, preferably lithium,10 sodium and potassium, of the alkaline earth metals, preferably calcium, magnesium and barium,and of the transition metals, preferably manganese, copper, silver, zinc and iron, and also am- monium (NH4+) and substituted ammonium in which one to four of the hydrogen atoms are re- placed by C1-C4-alkyl, C1-C4-hydroxyalkyl, C1-C4-alkoxy, C1-C4-alkoxy-C1-C4-alkyl, hydroxy-C1- C4-alkoxy-C1-C4-alkyl, phenyl or benzyl. Examples of substituted ammonium ions comprise15 methylammonium, isopropylammonium, dimethylammonium, diisopropylammonium, trimethy-lammonium, tetramethylammonium, tetraethylammonium, tetrabutylammonium, 2-hydroxyethy- lammonium, 2-(2-hydroxyethoxy)ethylammonium, bis(2-hydroxyethyl)ammonium, ben- zyltrimethylammonium and benzyltriethylammonium, furthermore the cations of 1,4-piperazine, meglumine, benzathine and lysine.20 Suitable anionic counterions are in particular chloride, bromide, hydrogensulfate, sulfate, dihy-drogenphosphate, hydrogenphosphate, phosphate, nitrate, bicarbonate, carbonate, hexafluo- rosilicate, hexafluorophosphate, benzoate, and the anions of C1-C4-alkanoic acids, preferably formate, acetate, propionate and butyrate, furthermore lactate, gluconate, and the anions of poly acids such as succinate, oxalate, maleate, fumarate, malate, tartrate and citrate, further-25 more sulfonate anions such as besylate (benzenesulfonate), tosylate (p-toluenesulfonate), nap-sylate (naphthalene-2-sulfonate), mesylate (methanesulfonate), esylate (ethanesulfonate), and ethanedisulfonate. They can be formed by reacting compounds according to the invention that have a basic functionality with an acid of the corresponding anion. Depending on the substitution pattern, the compounds according to the invention may have30 one or more centers of chirality, including axial chirality. The invention provides both, pure enan-tiomers or pure diastereomers, of the compounds according to the invention, and their mixtures, including racemic mixtures. Suitable compounds according to the invention also include all pos- sible geometrical stereoisomers (cis / trans isomers or E / Z isomers) and mixtures thereof. E / Z- isomers may be present with respect to, e.g., an alkene, carbon-nitrogen double-bond or amide35 group.Tautomers may be formed, if a substituent is present at the compound of formula (I), which al- lows for the formation of tautomers such as keto-enol tautomers, imine-enamine tautomers, amide-imidic acid tautomers or the like. Furthermore, the core structure comprising the 6-mem- bered ring that contains the =O substituent principally allows for keto-enol-tautomerization.40 The term "N-oxide" includes any compound of the present invention which has at least one ter-tiary nitrogen atom that is oxidized to a N-oxide moiety. The scope of the invention also embraces the compounds provided herein, particularly the compounds of formula (I), in which one or more atoms are replaced by a specific isotope of the corresponding atom. For example, the invention encompasses compounds of formula (I), in45 which one or more hydrogen atoms (or, e.g., all hydrogen atoms) are replaced by deuteriumatoms (i.e.,2H; also referred to as "D"). Accordingly, the invention also embraces compounds of formula (I), which are enriched in deuterium. Naturally occurring hydrogen is an isotopic mixture comprising about 99.98 mol-% hydrogen-1 (1H) and about 0.0156 mol-% deuterium (2H or D). The content of deuterium in one or more hydrogen positions in the compounds of formula (I),ANAVO therapeutics BV A19159WO17 can be increased using deuteration techniques known in the art. For example, a compound of formula (I) or a reactant or precursor to be used in the synthesis of the compound of formula (I) can be subjected to an H / D exchange reaction using, e.g., heavy water (D2O). Further suitable deuteration techniques are described in: Atzrodt J et al., Bioorg Med Chem, 20(18), 5658-5667, 52012; William JS et al., Journal of Labelled Compounds and Radiopharmaceuticals, 53(11-12),635-644, 2010; or Modvig A et al., J Org Chem, 79, 5861-5868, 2014. The content of deuterium can be determined, e.g., using mass spectrometry or NMR spectroscopy. Unless specifically in- dicated otherwise, it is preferred that the compound of formula (I), is not enriched in deuterium. Accordingly, unless indicated otherwise, the presence of naturally occurring hydrogen atoms or10 1H hydrogen atoms in the compounds of formula (I) is preferred.The term "substituted", as used herein, means that a hydrogen atom bonded to a designated atom is replaced with a specified substituent, provided that the substitution results in a stable or chemically feasible compound. Unless otherwise indicated, a substituted atom may have one or more substituents and each substituent is independently selected.15 The term "substitutable", when used in reference to a designated atom, means that attachedto the atom is a hydrogen, which can be replaced with a suitable substituent. When it is referred to certain atoms or moieties being substituted with “one or more” sub- stituents, the term “one or more” is intended to cover at least one substituent, e.g.1 to 10 sub- stituents, preferably 1, 2, 3, 4, or 5 substituents, more preferably 1, 2, or 3 substituents, most20 preferably 1, or 2 substituents. When neither the term “unsubstituted” nor “substituted” is explic-itly mentioned concerning a moiety, said moiety is to be considered as unsubstituted. The organic moieties mentioned in the above definitions of the variables are - like the term halogen - collective terms for individual listings of the individual group members. The prefix Cn- Cmindicates in each case the possible number of carbon atoms in the group.25 The term “halo” refers to fluoro, chloro, bromo or iodo, particularly fluoro, chloro or bromo. Theterm “halogen” denotes in each case fluorine, bromine, chlorine or iodine, in particular fluorine, chlorine, or bromine. The term “cyano” as used herein refers to the group -CN. The term "alkyl" as used herein denotes in each case a straight-chain or branched alkyl group30 having usually from 1 to 5 carbon atoms, preferably 1 to 4 carbon atoms, more preferably 1 to 3or 1 or 2 carbon atoms. Examples of an alkyl group are methyl, ethyl, n-propyl, iso-propyl, n- butyl, 2-butyl, iso-butyl, tert-butyl, n-pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, 2,2-di- methylpropyl, 1-ethylpropyl, n-hexyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 1-methylpentyl, 2- methylpentyl, 3-methylpentyl, 4-methylpentyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethyl-35 butyl, 2,2-dimethylbutyl, 2,3-dimethylbutyl, 3,3-dimethylbutyl, 1-ethylbutyl, 2-ethylbutyl, 1,1,2-trimethylpropyl, 1,2,2-trimethylpropyl, 1-ethyl-1-methylpropyl, and 1-ethyl-2-methylpropyl. The term "haloalkyl" as used herein denotes in each case a straight-chain or branched alkyl group having usually from 1 to 4 carbon atoms, frequently 1 to 3 or 1 or 2 carbon atoms, wherein the hydrogen atoms of this group are partially or totally replaced with halogen atoms.40 Preferred haloalkyl moieties are selected from C1-C4-haloalkyl, more preferably from C1-C3-haloalkyl or C1-C2-haloalkyl, in particular from C1-C2-fluoroalkyl such as fluoromethyl, difluo- romethyl, trifluoromethyl, 1-fluoroethyl, 2-fluoroethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, pentafluoroethyl, and the like. The term "alkoxy" as used herein denotes in each case a straight-chain or branched alkyl45 group which is bonded via an oxygen atom and has usually from 1 to 4 carbon atoms, prefer-ably 1 to 2 carbon atoms, more preferably 1 carbon atom. Examples of an alkoxy group are methoxy, ethoxy, n-propoxy, iso-propoxy, n-butyloxy, 2-butyloxy, iso-butyloxy, tert-butyloxy, and the like.ANAVO therapeutics BV A19159WO18 The term “alkoxyalkyl” as used herein refers to an alkoxy group as defined herein having usu- ally from 1 to 4 carbon atoms, preferably 1 to 2 carbon atoms, more preferably 1 carbon atom, which is bonded via an alkyl group as defined herein having usually from 1 to 4 carbon atoms, preferably 1 to 2 carbon atoms, more preferably 1 carbon atom, to the remainder of the mole- 5cule. Thus, it refers to an alkyl group, which is bonded via oxygen to a further alkyl group, whichis then bonded to the remainder of the molecule. Examples of an alkoxyalkyl group are methoxymethyl, methoxyethyl, ethoxymethyl, ethoxyethyl, and the like. The term "haloalkoxy" as used herein denotes in each case a straight-chain or branched alkoxy group having from 1 to 4 carbon atoms, preferably 1 to 2 carbon atoms, more preferably10 1 carbon atom, wherein the hydrogen atoms of this group are partially or totally replaced withhalogen atoms, in particular fluorine atoms. Preferred haloalkoxy moieties include C1- haloalkoxy, in particular C1-fluoroalkoxy, such as trifluoromethoxy and the like. The term “hydroxyalkyl” as used herein denotes in each case a straight-chain or branched alkyl group having usually from 1 to 4 carbon atoms, preferably from 1 to 3 carbon atoms and15 being further substituted with 1 to 5, preferably with 1 to 2 hydroxy groups, in particular with 1hydroxy group. Preferably, the one hydroxy group is terminating the straight-chain or branched alkyl group so that the hydroxy group is bonded to an alkyl bridge, which is bonded to the re- mainder of the molecule. Examples of an hydroxyalkyl group are hydroxymethyl, hydroxyethyl, n-hydroxypropyl, 2-hydroxypropyl, n-hydroxybutyl, 2-hydroxybutyl, 2-hydroxy-2-methylpropyl,20 and n-hydroxypentyl. Hydroxymethyl, hydroxyethyl, hydroxypropyl, and hydroxybutyl, are pre-ferred, in particular hydroxymethyl and hydroxyethyl. “=O” represents an oxo substituent. The term “carbocyclic” or “carbocyclyl” includes, unless otherwise indicated, in general a 3- to 9-membered, preferably a 4- to 8-membered or a 3- to 6-membered or a 5- to 7-membered,25 more preferably a 5- or 6-membered monocyclic ring comprising 3 to 9, preferably 4 to 8 or 3 to6 or 5 to 7, more preferably 5 or 6 carbon atoms. The carbocycle may be saturated, partially or fully unsaturated, or aromatic, wherein saturated means that only single bonds are present, and partially or fully unsaturated means that one or more double bonds may be present in suitable positions, while the Hückel rule for aromaticity is not fulfilled, whereas aromatic means that the30 Hückel (4n + 2) rule is fulfilled. The term “carbocycle” or “carbocyclyl”, unless otherwise indi-cated, may therefore cover inter alia cycloalkyl, cycloalkenyl, as well as phenyl. Preferably, the term “carbocycle” covers cycloalkyl and cycloalkenyl groups, for example cyclopropane, cy- clobutane, cyclopentane and cyclohexane rings. The term “cycloalkyl” as used herein denotes in each case a monocyclic cycloaliphatic radical35 having usually from 3 to 10 or from 3 to 6 carbon atoms, such as cyclopropyl, cyclobutyl, cy-clopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl and cyclodecyl or cyclopropyl, cy- clobutyl, cyclopentyl and cyclohexyl. The term "carbobicyclic" or “carbobicyclyl” includes in general 6 to 14-membered, preferably 7- to 12-membered or 8- to 10-membered, more preferably 9- or 10-membered bicyclic rings com-40 prising 6 to 14, preferably 7 to 12 or 8 to 10, more preferably 9 or 10 carbon atoms. The carbo-bicycle may be saturated, partially or fully unsaturated, or aromatic, wherein saturated means that only single bonds are present, and partially or fully unsaturated means that one or more double bonds may be present in suitable positions, while the Hückel rule for aromaticity is not fulfilled, whereas aromatic means that the Hückel (4n + 2) rule is fulfilled. Preferably, the term45 “aromatic” in connection with the carbobicyclic ring means that both rings of the bicyclic moietyare aromatic, so that, e.g., 8 π electrons are present in case of a 10-membered aromatic carbo- bicyclic ring. The term “carbobicyclic” or “carbobicyclyl”, unless otherwise indicated, may there- fore cover inter alia bicycloalkyl, bicycloalkenyl, as well as bicyclic aromatic groups, for example bicyclohexane (decalin), bicycloheptane (such as norbornane), bicyclooctane (such as bicy-ANAVO therapeutics BV A19159WO19 clo[2.2.2]octane, bicyclo[3.2.1]octane or bicyclo[4.2.0]octane), bicyclononane (such as bicy- clo[3.3.1]nonane or bicyclo[4.3.0]nonane ), bicyclodecane (such as bicyclo[4.4.0]decane), bicy- cloundecane (such as bicyclo[3.3.3]undecane), norbornene, naphthalene and the like. Prefer- ably, the carbobicycle is a fused carbobicycle, which is preferably aromatic, for example naph- 5thalene.The term “heterocyclic” or “heterocyclyl” includes, unless otherwise indicated, in general a 3- to 9-membered, preferably a 4- to 8-membered or 5- to 7-membered, more preferably 5- or 6- membered, in particular 6-membered monocyclic ring. The heterocycle may be saturated, par- tially or fully unsaturated, or aromatic, wherein saturated means that only single bonds are10 present, and partially or fully unsaturated means that one or more double bonds may be presentin suitable positions, while the Hückel rule for aromaticity is not fulfilled, whereas aromatic means that the Hückel (4n + 2) rule is fulfilled. The heterocycle typically comprises one or more, e.g.1, 2, 3, or 4, preferably 1, 2, or 3 heteroatoms selected from N, O and S as ring members, where S-atoms as ring members may be present as S, SO or SO2. The remaining ring members15 are carbon atoms. In a preferred embodiment, the heterocycle is an aromatic heterocycle,preferably a 5- or 6-membered aromatic heterocycle comprising one or more, e.g.1, 2, 3, or 4, preferably 1, 2, or 3 heteroatoms selected from N, O and S as ring members, where S-atoms as ring members may be present as S, SO or SO2. Examples of aromatic heterocycles are pro- vided below in connection with the definition of “hetaryl”. “Hetaryls” or “heteroaryls” are covered20 by the term “heterocycles”. The saturated or partially or fully unsaturated heterocycles usuallycomprise 1, 2, 3, 4 or 5, preferably 1, 2 or 3 heteroatoms selected from N, O and S as ring members, where S-atoms as ring members may be present as S, SO or SO2. The skilled per- son is aware that S, SO or SO2is to be understood as follows: 25 Further, a skilled person is aware that resonance structures of the oxidized forms may be pos-sible. Saturated heterocycles include, unless otherwise indicated, in general 3- to 9-membered, preferably 4- to 8-membered or 5- to 7-membered, more preferably 5- or 6-membered mono- cyclic rings comprising 3 to 9, preferably 4 to 8 or 5 to 7, more preferably 5 or 6 atoms compris- ing at least one heteroatom, such as pyrrolidine, tetrahydrothiophene, tetrahydrofuran, piperi-30 dine, tetrahydropyran, dioxane, morpholine or piperazine.The term "carbocyclyloxy " as used herein denotes in each case a moiety defined above as “carbocycle” or “carbocyclyl” that is connected to the remainder of the molecule via an oxygen atom. The term " heterocyclyloxy" as used herein denotes in each case a moiety defined above as35 “heterocycle” or “heterocyclyl” that is connected to the remainder of the molecule via an oxygenatom. The term “heterobicyclic” or “heterobicyclyl” includes, unless otherwise indicated, in general 6 to 14-membered, preferably 7- to 12-membered or 8- to 10-membered, more preferably 9- or 10-membered bicyclic rings. The heterobicycle may be saturated, partially or fully unsaturated,40 or aromatic, wherein saturated means that only single bonds are present, and partially or fullyunsaturated means that one or more double bonds may be present in suitable positions, while the Hückel rule for aromaticity is not fulfilled, whereas aromatic means that the Hückel (4n + 2) rule is fulfilled. In principle for being “aromatic” it is sufficient if one of the two rings of the bicyclic moieties is aromatic, while the other is non-aromatic. However, it is preferred in connection with45 the term “aromatic” that both rings of the bicyclic moiety are aromatic, so that, e.g., 8 π elec-trons are present in case of a 9- or 10-membered aromatic heterobicyclic ring. The heterobicy- cle typically comprises one or more, e.g.1, 2, 3, or 4, preferably 1, 2, or 3 heteroatoms selectedANAVO therapeutics BV A19159WO20 from N, O and S as ring members, where S-atoms as ring members may be present as S, SO or SO2. The remaining ring members are carbon atoms. Examples of heterobicycles include benzofuranyl, benzothienyl, indolyl, indazolyl, benzimidazolyl, benzoxathiazolyl, benzoxadia- zolyl, benzothiadiazolyl, benzoxazinyl, quinolinyl, isoquinolinyl, purinyl, 1,8-naphthyridyl, 5pteridyl, pyrido[3,2-d]pyrimidyl, pyridoimidazolyl, triethylenediamine or quinuclidine and the like.Preferred heterobicycles according to the invention are aromatic heterobicycles such as benzo- diazole, benzothiazole, quinoline, and iso-quinoline. The term "hetaryl" or “heteroaryl” or “aromatic heterocycle” or “aromatic heterocyclic ring” in- cludes monocyclic 5- or 6-membered aromatic heterocycles comprising as ring members 1, 2, 310 or 4 heteroatoms selected from N, O and S, where S-atoms as ring members may be presentas S, SO or SO2. Examples of 5- or 6-membered aromatic heterocycles include pyridyl (also re- ferred to as pyridinyl), i.e.2-, 3-, or 4-pyridyl, pyrimidinyl, i.e.2-, 4- or 5-pyrimidinyl, pyrazinyl, pyridazinyl, i.e.3- or 4-pyridazinyl, thienyl, i.e.2- or 3-thienyl, furyl, i.e.2-or 3-furyl, pyrrolyl, i.e. 2- or 3-pyrrolyl, oxazolyl, i.e.2-, 3- or 5-oxazolyl, isoxazolyl, i.e.3-, 4- or 5-isoxazolyl, thiazolyl,15 i.e.2-, 3- or 5-thiazolyl, isothiazolyl, i.e. 3-, 4- or 5-isothiazolyl, pyrazolyl, i.e. 1-, 3-, 4- or 5-pyra-zolyl, i.e.1-, 2-, 4- or 5-imidazolyl, oxadiazolyl, e.g.2- or 5-[1,3,4]oxadiazolyl, 4- or 5-(1,2,3-oxa- diazol)yl, 3- or 5-(1,2,4-oxadiazol)yl, 2- or 5-(1,3,4-thiadiazol)yl, thiadiazolyl, e.g.2- or 5-(1,3,4- thiadiazol)yl, 4- or 5-(1,2,3-thiadiazol)yl, 3- or 5-(1,2,4-thiadiazol)yl, triazolyl, e.g.1H-, 2H- or 3H-1,2,3-triazol-4-yl, 2H-triazol-3-yl, 1H-, 2H-, or 4H-1,2,4-triazolyl and tetrazolyl, i.e.1H- or20 2H-tetrazolyl. Unless otherwise indicated, the term “hetaryl” further covers “aromatic heterobicy-cles” as defined above. The term “aryl” or “aromatic carbocyclyl” preferably includes 6-membered aromatic carbocyclic rings based on carbon atoms as ring members. A preferred example is phenyl. Unless other- wise indicated, the term “aryl” further covers “aromatic carbobicycles” as defined above.25 As used herein, the terms “carbocyclylmethyl” and “heterocyclylmethyl” refer to the corre-sponding groups, which are bonded to the remainder of the molecule via a C1-alkyl group. Pre- ferred examples include benzyl (i.e. phenylmethyl), cyclohexylmethyl, pyridinylmethyl, and piperidinomethyl. As used herein, the term “alkylene chain” refers to a linking straight-chain or branched alky-30 lene group having usually from 1 to 4 carbon atoms, e.g.1, 2, 3, or 4 carbon atoms. The alky-lene group bridges a certain group to the remainder of the molecule. Preferred alkylene groups include methylene (CH2), ethylene (CH2CH2), propylene (CH2CH2CH2) and the like. A skilled person understands that, if it is referred, e.g., to CH2that the carbon atom being tetravalent has two valences left for forming a bridge (-CH2-). Similarly, when it is referred, e.g., to CH2CH2,35 each carbon atom has one valence left for forming a bridge (-CH2CH2-). Furthermore, when it isreferred, e.g., to CH2CH2CH2, each terminal carbon atom has one valence left for forming a bridge (-CH2CH2CH2-). The term “cyclic” moiety can refer to any cyclic groups, which are present in the compounds of formula (I), and which are defined above, e.g., cycloalkyl, cycloalkenyl, carbocycle.40 As used in the specification and the claims, the singular forms of “a” and “an” also include thecorresponding plurals unless the context clearly dictates otherwise. The same applies for plural forms used herein, which also include the singular forms unless the context clearly dictates oth- erwise. The terms “about” and “approximately” in the context of the present invention denotes an inter-45 val of accuracy that a person skilled in the art will understand to still ensure the technical effectof the feature in question. The term typically indicates a deviation from the indicated numerical value of ±10%, preferably ±5%, more preferably ±2%. It needs to be understood that the term “comprising” is not limiting. For the purposes of the present invention, the term “consisting of” is considered to be a preferred embodiment of theANAVO therapeutics BV A19159WO21 term “comprising of”. If hereinafter a group is defined to comprise at least a certain number of embodiments, this is also meant to encompass a group, which preferably consists of these em- bodiments only. The term “half-life” as used herein denotes the time it takes for a substance from its maximum 5concentration (Cmax) to half of its maximum concentration in e.g. the blood plasma and is typi-cally abbreviated by t1 / 2. The half-life can be indicated as the elimination half-life, which is the time required to produce a 50% reduction in blood or plasma concentration. A " Wip1 inhibitor" refers to a compound that inhibits p53-induced phosphatase 1 (Wip1; also referred to as serine / threonine phosphatase PPM1D, protein phosphatase 2C delta (PP2Cδ),10 PPMID, or IDDGIP). The Wip1 gene (also known as PPM1D gene) is located at 17q23. The in-hibition of Wip1 is not limited to the wild-type Wip1 phosphatase but may also include amplifica- tion, mutants, truncation mutants, fragments, variants, isoforms, and homologs of the full-length wild-type. The term “amplification” refers to the increase of the gene copy number resulting in increased15 protein levels compared to the wildtype.The term "mutant" or "modified" refers to a gene or gene product which displays modifications in sequence and or functional properties (i.e., altered characteristics) when compared to the wild-type gene or gene product. "Mutant" or "modified" also refers to the sequence at a specific nucleotide position or positions, or the sequence at a particular codon position or positions, or20 the sequence at a particular amino acid position or positions which displays modifications in se-quence and or functional properties (i.e., altered characteristics) when compared to the wild- type gene or gene product. The term "mutation"' refers to a nucleic acid with at least a single nucleotide variation relative to the normal sequence or wild-type sequence. In the context of polypeptide, "mutation" refers25 to at least a single amino acid variation in a polypeptide sequence relative to the normal se-quence or wild-type sequence. A mutation may include, but is not limited to, a substitution, a deletion, an inversion or an insertion. With respect to an encoded polypeptide, a mutation may be "silent" and result in no change in the encoded polypeptide sequence or a mutation may re- sult in a change in the encoded polypeptide sequence. For example, a mutation may result in a30 substitution in the encoded polypeptide sequence. A mutation may result in a frameshift with re-spect to the encoded polypeptide sequence. The term "truncation" refers to a shortening in the amino acid sequence of protein or the nu- cleotide sequence of a nucleic acid or segment of a nucleic acid (e.g., a gene). A protein trunca- tion may be the result of a truncation in the nucleic acid sequence encoding the protein, a sub-35 stitution or other mutation that creates a premature stop codon without shortening the nucleicacid sequence, or from alternate splicing of RNA in which a substitution or other mutation that does not itself cause a truncation results in aberrant RNA processing. The term "medicine" as used herein is intended to be a generic term inclusive of prescription and non-prescription medications. The compound for use in medicine should be understood as40 being useful in maintaining health or promoting recovery from a disease, preferably cancer. Fur-ther, the term "medicine" includes medicine in any form, including, without limitation, e.g., pills, salves, creams, powders, ointments, capsules, injectable medications, drops, vitamins and sup- positories. The scope of this invention is not limited by the type, form or dosage of the medicine. A "subject" can be a human, primate, dog, rabbit, guinea pig, pig, rat, or mouse, depending on45 the context."Inhibit," "inhibition," or "inhibiting" means reducing or suppressing a condition, symptom, or bi- ological activity. A "pharmaceutical composition" is a compound of the invention or a pharmaceutically accept- able salt thereof, along with at least one pharmaceutically acceptable carrier, prepared for oralANAVO therapeutics BV A19159WO22 or parenteral administration. A "pharmaceutically acceptable carrier" includes substances used in the preparation or use of pharmaceutical compositions, such as diluents, solvents, dispersion media, surfactants, antioxidants, preservatives, isotonic agents, buffering agents, emulsifiers, and more. The term “pharmaceutically acceptable excipient” as used herein refers to com- 5pounds commonly comprised in pharmaceutical compositions, which are known to the skilledperson. Typically, a pharmaceutically acceptable excipient can be defined as being pharmaceu- tically inactive. The term “treatment” is to be understood as also including the option of “prophylaxis”. Thus, whenever reference is made herein to a “treatment” or “treating”, this is to be understood as10 “treatment and / or prophylaxis” or “treating and / or preventing”.The term "cancer" pertains to a disease characterized by the rapid and uncontrolled growth of abnormal cells that can spread locally or through the bloodstream and lymphatic system. Vari- ous cancers, including colorectal, gastric, endometrial, prostate, adrenocortical, uterine, cervi- cal, esophageal, breast, kidney, and ovarian cancer, among others, are described herein. The15 terms "tumor" and "cancer" are used interchangeably and encompass both solid and liquid tu-mors, including diffuse or circulating tumors. As used herein, the terms "tumor" and "cancer" in- clude premalignant, as well as malignant cancers and tumors. In the following, preferred embodiments of the substituents in the above formula (I) are de-20 scribed in further detail. It is to be understood that each preferred embodiment is relevant on itsown as well as in combination with other preferred embodiments. Furthermore, it is to be under- stood that the preferences in each case also apply to the salts, stereoisomers, tautomers, and N-oxides of the compounds of the invention.25 As indicated above, the present invention relates in a first aspect to a compound of formula (I) or a stereoisomer, tautomer, N-oxide, or pharmaceutically acceptable salt thereof; wherein X1is CH or N;30 and the remaining substituents are as defined above.Accordingly, the compound of formula (I) may therefore be a compound of formula (I.a) or (I.b) as shown below: 35 In connection with the compounds according to formula (I.a) and (I.b), it is to be understoodthat the substituents R1A, R1B, R2, R3, R4, R5, m, n, Y1, Y2and Y3are as defined above in formula (I). Further preferred embodiments regarding these substituents are provided further below. In a preferred embodiment, X1is CH.40 Thus, it is preferred that the compound of formula (I) is a compound of formula (I.a).In one embodiment of the compound of formula (I),ANAVO therapeutics BV A19159WO23 R1Ais H or C1-C4-alkyl; R1Bis H or C1-C4-alkyl; In a preferred embodiment, R1Ais H or CH3; and 5R1B is H or CH3.In a more preferred embodiment, R1Ais H; and R1Bis H. Compounds of formula (I), wherein both, R1Aand R1B, are H, are referred to as compounds of10 formula (I.1): In a preferred embodiment, the compound of formula (I) is therefore a compound of formula (I.1). In an even more preferred embodiment, the compound of formula (I) is a compound of formula15 (I.1), wherein X1 is CH. Such compounds are referred to as compounds of formula (I.1.a) In a particularly preferred embodiment, the compound of formula (I) is a compound of formula (I.1.a).20 In a preferred embodiment, the compound of formula (I) is a compound of formula (IS) In these compounds, the stereocenter at the carbon atom between the two amido groups is in S-configuration. Compounds of formula (I), wherein said stereocenter is in S-configuration, are preferred according to the invention.25 In one preferred embodiment, the compound of formula (I) is a compound of formula (IS.a),i.e., a compound of formula (I.a), wherein the stereocenter at the carbon atom between the two amido groups is in S-configuration: In another preferred embodiment, the compound of formula (I) is a compound of formula (IS.1),30 i.e., a compound of formula (I.1), wherein the stereocenter at the carbon atom between the twoamido groups is in S-configuration:ANAVO therapeutics BV A19159WO24 In yet another preferred embodiment, the compound of formula (I) is a compound of formula (IS.1.a), i.e., a compound of formula (I.1.a), wherein the stereocenter at the carbon atom be- tween the two amido groups is in S-configuration: 5 In the following, the substituents R2, R3, and A are defined in further detail in connection with the compound of formula (I). The same embodiments are also relevant to a compound of for- mula (I.a), (I.b), (I.1), (I.1.a), (IS), (IS.a), (IS.1), or (IS.1.a). 10 In one embodiment of the compound of formula (I), R2is H, C1-C2-alkyl, 5- or 6-membered saturated or partially unsaturated carbocyclyl, hetero- cyclyl, carbocyclyloxy, or heterocyclyloxy, or 4- to 12-membered saturated carbobicyclyl or heterobicyclyl, wherein the aforementioned heterocyclyl or heterobicyclyl comprises one15 or more, same or different heteroatoms selected from O, N, or S, wherein said N- and / orS-atoms are independently oxidized or non-oxidized, and wherein each substitutable atom in the aforementioned groups is independently unsubstituted or substituted with one or more, same or different substituents RX. In a preferred embodiment,20 R2 a 5- or 6-membered saturated or partially unsaturated carbocyclyl, heterocyclyl, or carbo-cyclyloxy, wherein the aforementioned heterocyclyl or heterobicyclyl comprises one or more, same or different heteroatoms selected from O, N, or S, wherein said N- and / or S- atoms are independently oxidized or non-oxidized, and wherein each substitutable atom in the aforementioned groups is independently unsubstituted or substituted with one or25 more, same or different substituents RX.In connection with the above definitions of R2, it is preferred that RXis halogen, CN, or OH. In a more preferred embodiment, R2is cyclopentyl or tetrahydrofuranyl, wherein each substitutable carbon atom in the afore-30 mentioned rings is independently unsubstituted or substituted with one or more, same ordifferent substituents RX. In an even more preferred embodiment, R2is cyclopentyl or tetrahydrofuranyl, wherein each substitutable carbon atom in the afore- mentioned rings is independently unsubstituted or substituted with one or more, same or35 different substituents RX; wherein RX is halogen, CN, or OH.In a particularly preferred embodiment, R2is cyclopentyl or tetrahydrofuranyl, wherein each substitutable carbon atom in the afore- mentioned rings is independently unsubstituted or substituted with one or more, same or different substituents RX; wherein RXis F.40 In another particularly preferred embodiment,R2isANAVO therapeutics BV A19159WO25 wherein the wavy line marks the connection to the remainder of the molecule. In another particularly preferred embodiment, 5 wherein the wavy line marks the connection to the remainder of the molecule. In one embodiment of the compound of formula (I), R3is H, C1-C4-alkyl, C1-C4-alkoxy, C1-C2-alkoxy-C1-C4-alkyl, 3- to 6-membered saturated,10 partially or fully unsaturated, or aromatic carbocyclyl, carbocyclylmethyl, heterocyclyl, orheterocyclylmethyl, or 4- to 12-membered saturated carbobicyclyl or heterobicyclyl, wherein the aforementioned heterocyclyl or heterobicyclyl comprises one or more, same or different heteroatoms selected from O, N, or S, wherein said N- and / or S-atoms are in- dependently oxidized or non-oxidized, and wherein each substitutable atom in the afore-15 mentioned groups is independently unsubstituted or substituted with one or more, same ordifferent substituents RY. In a preferred embodiment, R3is H, C1-C4-alkyl, C1-C4-alkoxy, C1-C2-alkoxy-C1-C4-alkyl, 3- to 6-membered saturated car- bocyclyl or heterocyclyl, wherein the aforementioned heterocyclyl comprises an oxygen20 atom as heteroatom, and wherein each substitutable atom in the aforementioned groupsis independently unsubstituted or substituted with one or more, same or different sub- stituents RY; or 5- or 6-membered aromatic heterocyclyl; wherein the aforementioned heterocyclyl com- prises one or more nitrogen atoms as heteroatom(s), and wherein each substitutable atom25 in the aforementioned groups is independently unsubstituted or substituted with one ormore, same or different substituents RY. In connection with the above definitions of R3, it is preferred that RYis halogen, CN, OH, C1-C4-alkyl, C1-C4-haloalkyl, C1-C4-alkoxy, C1-C4-haloalkoxy, C1-C2- alkoxy-C1-C4-alkyl, C1-C4-hydroxyalkyl, or C3-C4-cycloalkyl.30 In a more preferred embodiment,R3is 3- or 4-membered saturated carbocyclyl or heterocyclyl, wherein the aforementioned heterocyclyl comprises an oxygen atom as heteroatom, and wherein each substitutable atom in the aforementioned groups is independently unsubstituted or substituted with one or more, same or different substituents RY;35 or 5- or 6-membered aromatic heterocyclyl; wherein the aforementioned heterocyclyl com-prises one or more nitrogen atoms as heteroatom(s), and wherein each substitutable atom in the aforementioned groups is independently unsubstituted or substituted with one or more, same or different substituents RY. In an even more preferred embodiment,40 R3 is 3- or 4-membered saturated carbocyclyl or heterocyclyl, wherein the aforementionedheterocyclyl comprises an oxygen atom as heteroatom, and wherein each substitutableANAVO therapeutics BV A19159WO26 atom in the aforementioned groups is independently unsubstituted or substituted with one or more, same or different substituents RY; or 5- or 6-membered aromatic heterocyclyl; wherein the aforementioned heterocyclyl com- prises one or more nitrogen atoms as heteroatom(s), and wherein each substitutable atom 5in the aforementioned groups is independently unsubstituted or substituted with one ormore, same or different substituents RY; wherein RYis halogen, CN, OH, C1-C4-alkyl, C1- C4-haloalkyl, C1-C4-alkoxy, C1-C4-haloalkoxy, C1-C2-alkoxy-C1-C4-alkyl, C1-C4-hydrox- yalkyl, or C3-C4-cycloalkyl. In a yet more preferred embodiment,10 R3 is 3- or 4-membered saturated carbocyclyl or heterocyclyl, wherein the aforementionedheterocyclyl comprises an oxygen atom as heteroatom, and wherein each substitutable atom in the aforementioned groups is independently unsubstituted or substituted with one or more, same or different substituents RY; or 5- or 6-membered aromatic heterocyclyl; wherein the aforementioned heterocyclyl com-15 prises one or more nitrogen atoms as heteroatom(s), and wherein each substitutable atomin the aforementioned groups is independently unsubstituted or substituted with one or more, same or different substituents RY; wherein RYis halogen, CN, OH, or C1-C4-alkyl. In a particularly preferred embodiment, R3is 3- or 4-membered saturated carbocyclyl or heterocyclyl, wherein the aforementioned20 heterocyclyl comprises an oxygen atom as heteroatom, and wherein each substitutableatom in the aforementioned groups is independently unsubstituted or substituted with one or more, same or different substituents RY; or 5- or 6-membered aromatic heterocyclyl; wherein the aforementioned heterocyclyl com- prises one or more nitrogen atoms as heteroatom(s), and wherein each substitutable atom25 in the aforementioned groups is independently unsubstituted or substituted with one ormore, same or different substituents RY; wherein RYis F, CN, OH, CH3, or CD3. In another particularly preferred embodiment,30 wherein the wavy line marks the connection to the remainder of the molecule. In connection with R3as defined above, it can in certain embodiments be preferred for a CH3substituent being present as substituent RYthat one or more, preferably all three hydrogen atoms are replaced by deuterium atoms. In other embodiments, it is preferred that the CH3sub-35 stituent is not enriched in deuterium.In another particularly preferred embodiment, ANAVO therapeutics BV A19159WO27 wherein the wavy line marks the connection to the remainder of the molecule. 5 10 15 and whereinANAVO therapeutics BV A19159WO28 R4each independently is halogen, CN, OH, C1-C4-alkyl, C1-C4-haloalkyl, C1-C4-alkoxy, C1-C4- haloalkoxy, C1-C4-hydroxyalkyl, or C3-C4-cycloalkyl; R5each independently is halogen, CN, C1-C4-alkyl, C1-C4-haloalkyl, C1-C4-alkoxy, or C1-C4- haloalkoxy; or two R5together form =O; 5m is 0, 1, or 2;n is 0, 1, 2, 3, or 4;Y1is CH2, NH, NRN, or O; Y2is CH or N; Y3is CH2;10 and whereinRNis C1-C6-alkyl or C3-C10-cycloalkyl, wherein optionally one or more -CH2- groups may be replaced by -O-. In one preferred embodiment,15 A is a moiety selected from20 wherein the wavy line marks the connection to the remainder of the molecule and wherein25 the substituents R4, R5, m, n, Y1, Y2, Y3, and RN are as defined above.ANAVO therapeutics BV A19159WO29 In a more preferred embodiment, Ais a moiety selected from 5wherein the wavy line marks the connection to the remainder of the molecule and whereinthe substituents R4, R5, m, n, Y1, Y2, and RNare as defined above. In an even more preferred embodiment, Ais a moiety selected from 10 wherein the wavy line marks the connection to the remainder of the molecule and whereinthe substituents R4, and Y2are as defined above. In a yet more preferred embodiment, Ais a moiety selected from 15 whereinY2is CH or N; and R4is Br, Cl, CN, CH3, CF3, or cyclopropyl. In another embodiment of the compound of formula (I),20 A is a moiety selected from wherein the wavy line marks the connection to the remainder of the molecule and wherein the substituents R4, R5, m, n, and Y2, are as defined above. In a more preferred embodiment,25 A is a moiety selected from wherein Y2is CH or N; and R4is Br, Cl, CN, CH3, CF3, or cyclopropyl.ANAVO therapeutics BV A19159WO30 In another more preferred embodiment, Ais a moiety selected from5 , ; wherein the wavy line marks the connection to the remainder of the molecule; and wherein preferably R4is Br, Cl, CH3, or CF3.10 In another more preferred embodiment,A is a moiety selected from ; wherein the wavy line marks the connection to the remainder of the molecule;15 and wherein preferablyR4is Br, Cl, CH3, or CF3. In another preferred embodiment, Ais a moiety selected from20 In more preferred embodiment, Ais a moiety selected from25 In one particularly preferred embodiment of the compound of formula (I) Ais a moiety selected from30ANAVO therapeutics BV A19159WO31 , ; wherein the wavy line marks the connection to the remainder of the molecule; and wherein 5 wherein the wavy line marks the connection to the remainder of the molecule; and R3is10 wherein the wavy line marks the connection to the remainder of the molecule. In one particularly preferred embodiment of the invention, the compound according to formula (I) is selected from the group consisting of 15 ANAVO therapeutics BV A19159WO32 5 ANAVO therapeutics BV A19159WO33 5 10 ANAVO therapeutics BV A19159WO34 B B B B5 ,BB 10 In another particular preferred embodiment of the invention, the compound of formula (I) is se-lected from the group consisting ofANAVO therapeutics BV A19159WO35 5 10 Pharmaceutical Compositions of the InventionAs indicated above, the invention relates in a second aspect to a pharmaceutical composition comprising a pharmaceutically effective amount of the compound of formula (I) as defined above and optionally a pharmaceutically acceptable carrier or excipient. 15 A pharmaceutical composition according to the present invention may be formulated for oral, buccal, nasal, rectal, topical, transdermal or parenteral application. Preferred non-parenteral routes include mucosal (e.g., oral, vaginal, nasal, cervical, etc.) routes, of which the oral appli- cation may be preferred. Preferred parenteral routes include, but are not limited to, one or more20 of subcutaneous, intravenous, intra-muscular, intraarterial, intradermal, intrathecal and epiduralANAVO therapeutics BV A19159WO36 administrations. Preferably administration is by subcutaneous, intra-tumoral or peri-tumoral routes. Particularly preferred is intratumoral administration. The compound according to formula (I) should be applied in pharmaceutically effective amounts, for example in the amounts as set out herein below. 5A pharmaceutical composition of the present invention may also be designated as formulationor dosage form. A compound of formula (I) may also be designated in the following as (pharma- ceutically) active agent or active compound. Pharmaceutical compositions may be solid or liquid dosage forms or may have an intermedi- ate, e.g. gel-like character depending inter alia on the route of administration.10 In general, the inventive dosage forms can comprise various pharmaceutically acceptable ex-cipients which will be selected depending on which functionality is to be achieved for the dosage form. A “pharmaceutically acceptable excipient” in the meaning of the present invention can be any substance used for the preparation of pharmaceutical dosage forms, including coating ma- terials, film-forming materials, fillers, disintegrating agents, release-modifying materials, carrier15 materials, diluents, binding agents and other adjuvants. Typical pharmaceutically acceptable ex-cipients include substances like sucrose, mannitol, sorbitol, starch and starch derivatives, lac- tose, and lubricating agents such as magnesium stearate, disintegrants and buffering agents. The term “pharmaceutically acceptable carrier” denotes pharmaceutically acceptable organic or inorganic carrier substances with which the active ingredient is combined to facilitate the ap-20 plication. Suitable pharmaceutically acceptable carriers include, for instance, water, aqueoussalt solutions, alcohols, oils, preferably vegetable oils, propylene glycol, polyoxyethelene sorbi- tans, polyethylene-polypropylene block co-polymers such as poloxamer 188 or poloxamer 407, polyethylene glycols such as polyethylene glycol 200, 300, 400, 600, etc., gelatin, lactose, amy- lose, magnesium stearate, surfactants, perfume oil, fatty acid monoglycerides, diglycerides and25 triglycerides, polyoxyethylated medium or long chain fatty acids such as ricinoleic acid, andpolyoxyethylated fatty acid mono-, di, and triglycerides such as capric or caprilic acids, petroethral fatty acid esters, hydroxymethyl celluloses such as hydroxymethyl, hydroxyethyl, hy- droxypropyl, hydroxypropyl acetate succinate, polyvinylpyrrolidone, crosspovidone and the like. Preferably, the compounds of the present invention are administered in a pharmaceutical com-30 position comprising of lipids, interbilayer crosslinked multilamellar vesicles, biodegradeablepoly(D,L-lactic-co-glycolic acid) [PLGA]-based or poly anhydride-based nanoparticles or mi- croparticles, nanoporous particle-supported lipid bilayers and as a conjugate with an antibody. Compounds of the invention can also be delivered via liposomal technology. The use of lipo- somes as drug carriers can increase the therapeutic index of the compounds. Liposomes are35 composed of natural phospholipids, and can contain mixed lipid chains with surfactant proper-ties (e.g., egg phosphatidylethanolamine). A liposome design can employ surface ligands for at- taching to unhealthy tissue. Non-limiting examples of liposomes include the multilamellar vesicle (MLV), the small unilamellar vesicle (SUV), and the large unilamellar vesicle (LUV). Liposomal physicochemical properties can be modulated to optimize penetration through biological barriers40 and retention at the site of administration, and to reduce a likelihood of developing prematuredegradation and toxicity to non-target tissues. Optimal liposomal properties depend on the ad- ministration route: large-sized liposomes show good retention upon local injection, small-sized liposomes are better suited to achieve passive targeting PEGylation reduces the uptake of the liposomes by the liver and spleen, and increases the circulation time, resulting in increased lo-45 calization at the inflamed site due to the enhanced permeability and retention (EPR) effect. Ad-ditionally, liposomal surfaces can be modified to achieve selective delivery of the encapsulated drug to specific target cells. Non-limiting examples of targeting ligands include monoclonal anti- bodies, vitamins, peptides, and polysaccharides specific for receptors concentrated on the sur- face of cells associated with the disease.ANAVO therapeutics BV A19159WO37 The pharmaceutical compositions can be sterile and, if desired, mixed with auxiliary agents, like lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts for influencing os- motic pressure, buffers, colorings, flavoring and / or aromatic substances and the like which do not deleteriously react with the active compound. It is to be understood that the term “pharma- 5ceutically acceptable carrier” also covers an antibody that delivers the compound of formula (I).If liquid dosage forms are considered for the present invention, these can include pharmaceuti- cally acceptable emulsions, solutions, suspensions and syrups containing inert diluents com- monly used in the art such as water. These dosage forms may contain e.g. microcrystalline cel- lulose for imparting bulk, alginic acid or sodium alginate as a suspending agent, methylcellulose10 as a viscosity enhancer and sweeteners / flavoring agents.For parenteral application, particularly suitable vehicles consist of solutions, preferably oily or aqueous solutions, as well as suspensions, emulsions, or implants. Pharmaceutical formula- tions for parenteral administration are particularly preferred and include aqueous solutions of the compounds of formula (I) in water-soluble form. Additionally, suspensions of the compounds15 of formula (I) may be prepared as appropriate oily injection suspensions. Suitable lipophilic sol-vents or vehicles include fatty oils such as sesame oil, or synthetic fatty acid esters, such as ethyl oleate or triglycerides, or liposomes. Aqueous injection suspensions may contain sub- stances, which increase the viscosity of the suspension, such as sodium carboxymethyl cellu- lose, sorbitol, or dextran.20 Particularly preferred dosage forms are injectable preparations of a compound of formula (I).Thus, sterile injectable aqueous or oleaginous suspensions can for example be formulated ac- cording to the known art using suitable dispersing agents, wetting agents and / or suspending agents. A sterile injectable preparation can also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent. Among the acceptable vehicles and sol-25 vents that can be used are water and isotonic sodium chloride solution. Sterile oils are also con-ventionally used as solvent or suspending medium. Preferred applications for injectable prepa- rations comprising the compounds of the present invention are intravenous, intratumoral and peritumoral administration. Suppositories for rectal administration of a compound of formula (I) can be prepared by e.g.30 mixing the compound with a suitable non-irritating excipient such as cocoa butter, synthetictriglycerides and polyethylene glycols which are solid at room temperature but liquid at rectal temperature such that they will melt in the rectum and release the compound according to for- mula (I) from said suppositories. For administration by inhalation, the compounds according to the present invention may be35 conveniently delivered in the form of an aerosol spray from pressurized packs or a nebulizer,with the use of a suitable propellant, e.g., dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas. In the case of a pressurized aerosol the dosage unit may be determined by providing a valve to deliver a metered amount. Capsules and cartridges of e.g. gelatin for use in an inhaler or insufflator may be formulated40 containing a powder mix of the compound and a suitable powder base such as lactose orstarch. Oral dosage forms may be liquid or solid and include e.g. tablets, troches, pills, capsules, pow- ders, effervescent formulations, dragees and granules. Pharmaceutical preparations for oral use can be obtained as solid excipient, optionally grinding a resulting mixture, and processing the45 mixture of granules, after adding suitable auxiliaries, if desired, to obtain tablets or drageecores. Suitable excipients are, in particular, fillers such as sugars, including lactose, sucrose, mannitol, or sorbitol; cellulose preparations such as, for example, maize starch, wheat starch, rice starch, potato starch, gelatin, gum tragacanth, methyl cellulose, hydroxypropylmethyl-cellu- lose, sodium carboxymethylcellulose, and / or polyvinylpyrrolidone (PVP). If desired, disintegrat-ANAVO therapeutics BV A19159WO38 ing agents may be added, such as the cross-linked polyvinyl pyrrolidone, agar, or alginic acid or a salt thereof such as sodium alginate. The oral dosage forms may be formulated to ensure an immediate release of the compound of formula (I) or a sustained release of the compound of formula (I). 5A solid dosage form may comprise a film coating. For example, the inventive dosage form maybe in the form of a so-called film tablet. A capsule of the invention may be a two-piece hard gelatin capsule, a two-piece hydroxypropylmethylcellulose capsule, a two-piece capsule made of vegetable or plant-based cellulose, or a two-piece capsule made of polysaccharide. The dosage form according to the invention may be formulated for topical application. Suitable10 pharmaceutical application forms for such an application may be a topical nasal spray, sublin-gual administration forms and controlled and / or sustained release skin patches. For buccal ad- ministration, the compositions may take the form of tablets or lozenges formulated in conven- tional manner. The compositions may conveniently be presented in unit dosage forms and may be prepared15 by any of the methods well known in the art of pharmacy. The methods can include the step ofbringing the compounds into association with a carrier, which constitutes one or more accessory ingredients. In general, the compositions are prepared by uniformly and intimately bringing the compounds into association with a liquid carrier, a finely divided solid carrier, or both, and then, if necessary, shaping the product. Liquid dose units are vials or ampoules. Solid dose units are20 tablets, capsules and suppositories.The phrase “effective amount” means an amount of compound (i.e. compound of formula (I)) that, when administered to a mammal in need of such treatment, is sufficient to treat or prevent a particular disease or condition. The amount of the active compound administered will be de- pendent on the subject being treated, the severity of the disorder or condition, the rate of admin-25 istration, the disposition of the compound and the discretion of the prescribing physician. How-ever, an effective amount (also known as effective dosage) is typically in the range of about 0.001 to about 100 mg per kg body weight per day, preferably about 0.01 to about 35 mg / kg / day, in single or divided doses. For a 70 kg human, this would amount to about 0.07 to about 7000 mg / day, preferably about 0.7 to about 2500 mg / day. In some instances, dosage lev-30 els below the lower limit of the aforesaid range may be more than adequate, while in othercases still larger doses may be used without causing any harmful side effect, with such larger doses typically divided into several smaller doses for administration throughout the day. Furthermore, the pharmaceutical composition may also contain the compound of formula (I) as a prodrug such as an ester or amide thereof. A prodrug is any compound, which is converted35 under physiological conditions or by solvolysis to any of the compounds of the invention. A pro-drug may be inactive prior to administration but may be converted to an active compound of the invention in vivo. Indications, for which the compounds of the present invention may be used 40 As indicated above, the compounds of formula (I) as defined herein and the pharmaceutical compositions comprising the same as defined herein are suitable for use in medicine. In particular, the compounds according to the present invention or the pharmaceutical compo- sitions according to the present invention are suitable for use in the treatment of a disease as-45 sociated with Wip1. In this connection, it is to be understood that the compounds according tothe present invention or the pharmaceutical composition according to the present invention are capable to modulate or inhibit Wip1. In a preferred embodiment, compounds according to the present invention or the pharmaceuti- cal composition according to the present invention are suitable for use in the treatment of a dis-ANAVO therapeutics BV A19159WO39 ease selected from the group consisting of cancer, pre-cancerous syndromes, autoimmune con- ditions, neurological diseases, and viral disease, preferably selected from the group consisting of cancer, pre-cancerous syndromes, autoimmune conditions, and neurological diseases, more preferably selected from the group consisting of cancer, pre-cancerous syndromes, and neuro- 5logical diseases.In a preferred embodiment, compounds according to the present invention or the pharmaceuti- cal composition according to the present invention are suitable for use in the treatment of a dis- ease selected from the group consisting of cancer and pre-cancerous syndromes. In this con- nection, it is to be understood that cancers may be in the form of solid tumors such as sarco-10 mas, carcinomas, and lymphomas or in the form of liquid tumors, e.g. leukemia.In a preferred embodiment, compounds according to the present invention or the pharmaceuti- cal composition according to the present invention are suitable for use in the treatment of a dis- ease selected from the group consisting of amyotrophic lateral sclerosis, amyotrophic lateral sclerosis, attention deficit hyperactivity disorder, autism, Bannayan-Zonana syndrome, bladder15 cancer, blood cancer, bone cancer, breast cancer, inflammatory breast cancer, brain cancer,cervical cancer, colorectal cancer, Cowden disease, endometrial cancer, ependymoma, esoph- agus cancer, Ewing's sarcoma, gastric cancer, head and neck cancer, individual allergic asthma, kidney cancer, Lhermitte-Duclos disease, lung cancer, liver cancer, lymphoma, medul- loblastoma, melanoma, mesothelioma, nasopharyngeal carcinoma, neuroblastoma, neurofibro-20 matosis, ovarian cancer, osteosarcoma, pancreatic cancer, prostate cancer, Rhabdomyosar-coma, thyroid cancer, urothelial cancer, and Wilm's tumor. In a preferred embodiment, compounds according to the present invention or the pharmaceuti- cal composition according to the present invention are suitable for use in the treatment of breast cancer, preferably selected from the group consisting of inflammatory breast cancer, triple neg-25 ative breast cancer (TNBC), and HER2+ breast cancer.In a preferred embodiment, compounds according to the present invention or the pharmaceuti- cal composition according to the present invention are suitable for use in the treatment of blood cancers, preferably selected from the group consisting of leukemia, lymphoma and multiple myeloma. Relevant leukemia include acute lymphocytic leukemia (ALL), Acute myeloid30 leukemia (AML), chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), andmyelodysplastic syndromes (MDS). Of particular relevance is AML. In a preferred embodiment, compounds according to the present invention or the pharmaceuti- cal composition according to the present invention are suitable for use in the treatment of brain cancers, preferably selected from the group consisting of glioma, glioblastoma, oligoden-35 droglioma, diffuse intrinsic pontine glioma (DIPG), meningioma. Particularly relevant is glioblas-toma. In a preferred embodiment, compounds according to the present invention or the pharmaceuti- cal composition according to the present invention are suitable for use in the treatment of lung cancers, preferably selected from the group consisting of small-cell lung cancer (SCLC) and40 non-small cell lung cancer (NSCLC). Particularly relevant is NSCLC.In a preferred embodiment, compounds according to the present invention or the pharmaceuti- cal composition according to the present invention are suitable for use in the treatment of liver cancer, preferably hepatocellular carcinoma (HCC). In a preferred embodiment, compounds according to the present invention or the pharmaceuti-45 cal composition according to the present invention are suitable for use in the treatment of a dis-ease selected from the group consisting of Bannayan-Zonana syndrome, bladder cancer, bone cancer, breast cancer, inflammatory breast cancer, brain cancer, especially glioblastoma and glioma, cervical cancer, colorectal cancer, Cowden disease, endometrial cancer, ependymoma, esophagus cancer, Ewing's sarcoma, gastric cancer, head and neck cancer, kidney cancer,ANAVO therapeutics BV A19159WO40 leukemia, especially AML, Lhermitte-Duclos disease, lung cancer, especially NSCLC and SCLC, liver cancer, especially HCC, lymphoma, medulloblastoma, melanoma, mesothelioma, multiple myeloma, nasopharyngeal carcinoma, neuroblastoma, ovarian cancer, osteosarcoma, pancreatic cancer, prostate cancer, Rhabdomyosarcoma, thyroid cancer, and Wilm's tumor. 5 Combination Therapies It is to be understood that in connection with the medical uses of the invention it can be pre- ferred that the compounds according to the present invention are administered in combination10 with antibodies, radiotherapy, surgical therapy, immunotherapy, chemotherapy, toxin therapy,gene therapy, or any other therapy known to those of ordinary skill in the art for treatment of a particular disease. This is particularly relevant in connection with the treatment of cancer. Combination therapy may be achieved by use of a single pharmaceutical composition that in- cludes both agents, or by administering two distinct compositions at the same time, wherein one15 composition includes a compound of the present invention, and the other includes the secondagent(s). The two therapies may be given in either order and may precede or follow the other treatment by intervals ranging from minutes to weeks. In embodiments where the other agents are applied separately, one would generally ensure that a significant period of time did not expire between20 the time of each delivery, such that the agents would still be able to exert an advantageouslycombined effect on the patient. In such instances, it is contemplated that one may administer both modalities within about 12-24 h of each other and, more preferably, within about 6-12 h of each other. In some situations, it may be desirable to extend the time period for treatment signif- icantly, however, where several days (2, 3, 4, 5, 6 or 7) to several weeks (1, 2, 3, 4, 5, 6, 7 or 8)25 lapse between the respective administrations. In some embodiments, the compound of thepresent invention is administered prior to administration of the distinct cancer treatment. In other embodiments, the distinct cancer treatment is administered prior to administration of the com- pound of the present invention. Typically, any anti-neoplastic-agent that has activity versus a susceptible tumor being treated30 may be co-administered in the treatment of cancer in the present invention. Examples of suchagents can be found in Cancer Principles and Practice of Oncology by V. T. Devita and S. Hell- man (editors) 6thedition (Feb.15, 2001), Lippincott Williams & Wilkins Publishers. A person of ordinary skill in the art would be able to discern which combinations of agents would be useful based on the particular characteristics of the drugs and the cancer involved. Typical anti-neo-35 plastic agents useful in the present invention include, but are not limited to, anti-microtubuleagents such as diterpenoids and vinca alkaloids; platinum coordination complexes; alkylating agents such as nitrogen mustards, oxazaphosphorines, alkylsulfonates, nitrosoureas, and tri- azenes; antibiotic agents such as anthracyclines, such as but not limited to doxorubicin or donarubicin, actinomycins and bleomycins; topoisomerase II inhibitors such as epipodophyllo-40 toxins; antimetabolites such as purine and pyrimidine analogues and anti-folate compounds;topoisomerase I inhibitors such as camptothecins; hormones and hormonal analogues; signal transduction pathway inhibitors; non-receptor tyrosine kinase angiogenesis inhibitors; im- munotherapeutic agents; proapoptotic agents; and cell cycle signaling inhibitors. Examples of a further active ingredient or ingredients for use in combination or co-administered with the45 present WIP1 inhibiting compounds are chemotherapeutic agents. Anti-microtubule or anti-mi-totic agents are phase specific agents active against the microtubules of tumor cells during M or the mitosis phase of the cell cycle. Examples of anti-microtubule agents include, but are not lim- ited to, diterpenoids and vinca alkaloids.ANAVO therapeutics BV A19159WO41 In one embodirnent, the claimed invention includes the co-administration a compound of the invention and at least one anti-neoplastic agent, such as one selected from the group consisting of anti-microtubule agents, platinum coordination complexes, alkylating agents, antibiotic agents, topoisomerase II inhibitors, antimetabolites, topoisomerase I inhibitors, hormones and 5hormonal analogues, signal transduction pathway inhibitors, non-receptor tyrosine kinase angio-genesis inhibitors, immunotherapeutic agents, proapoptotic agents, FAS inhibitors, HDAC in- hibitors, and cell cycle signalling inhibitors. The present invention is further illustrated by the following examples. 10 Examples The following abbreviations are used hereinafter. ANAVO therapeutics BV A19159WO42 General experimental details Unless otherwise specified, all starting materials are obtained from commercial suppliers and used without further purification. Unless otherwise specified, all temperatures are expressed in 5°C and all reactions are conducted at room temperature. Reactions were monitored by thin layerchromatography (Merck Millipore TLC Silica Gel 60 F254). Flash column chromatography was performed on Biotage Isolera® or Büchi Reveleris® X2 Flash Chromatography systems using either pre-packed silicagel or C18 columns. NMR spectra were recorded using a Bruker 300 or 400 MHz spectrometer, using residual signal of deuterated solvent as internal reference at 2510 °C. Exchangeable NH and OH residues were not identifiable in the 1H-NMR spectra in somecases. IUPAC names were generated using ChemDraw version 20.1.1.125. UPLC methods: Method A: Instrument: Agilent 1290 Infinity II, 1290 G7120A Bin. Pump, 1290 G7167B Multi-15 sampler, 1290 MCT G7116B Column Comp., 1290 G7117B DAD (210-320nm), PDA (210-320nm), G6135B MSD (ESI pos / neg) mass range: 90-1500, Column: XSelect CSH XP C18 (50x2.1mm, 2.5µ) Flow: 0.8 ml / min Column temp: 40°C, Eluent A: 0.1% Formic acid in Water, Eluent B: 0.1% Formic acid in Acetonitrile, Gradient: t=0 min 5% B, t=0.5 min 5% B, t=4.5 min 98% B; t=5 min 98% B, Postrun: 0.5 min.20 Method B: Instrument: Agilent 1290 Infinity II, 1290 G7120A Bin. Pump, 1290 G7167B Multi-sampler, 1290 MCT G7116B Column Comp., 1290 G7117B DAD (210-320nm), PDA (210- 320nm), G6135B MSD (ESI pos / neg) mass range: 90-1500, Column: XSelect CSH XP C18 (50x2.1mm, 2.5µ) Flow: 0.8 ml / min Column temp: 25°C, Eluent A: 10mM Ammonium Bicarbon- ate in Water (pH 9.5), Eluent B: Acetonitrile, Gradient: t=0 min 5% B, t=0.5 min 5% B, t=4.5 min25 98% B; t=5 min 98% B, Postrun: 0.5 min.Method C: Instrument: Waters Acquity Class H, Column Acquity BEH C181.7 μm, 2.1 x 50 mm; temperature: 35 °C; flow rate: 0.50 mL / min; A: 50 mM ammonium formate buffer, pH 4 with HCOOH, B: water; C: acetonitrile, gradient A:B:C: from 5:85:10 to 5:10:85 in 1.5 min + from 5:10:85 to 5: 0:95 in 0.01 min +1.49 min in 5:0:9530 Method D: Instrument: Waters Acquity Class H, Column Acquity BEH C181.7 μm, 2.1 x 50mm; temperature: 35 °C; flow rate: 0.50 mL / min; A: 50 mM ammonium formate buffer, pH 4 withANAVO therapeutics BV A19159WO43 HCOOH, B: water; C: acetonitrile, gradient A:B:C: 0.5 min in 5:85:10 + from 5:85:10 to 5:10:85 in 4.5 min + 4 min in 5:10:85 Method E: Apparatus: Waters IClass; Bin. Pump: UPIBSM, SM: UPISMFTN with SO; UPCMA, PDA: UPPDATC, 210-320 nm, SQD: ACQ-SQD2 ESI; column: Waters XSelect CSH C18, 550x2.1 mm, 2.5μm, Temp: 40 °C, Flow: 0.6 mL / min, Gradient: t0 = 5% B, t2.0min = 98% B,t2.7min = 98% B, Posttime: 0.3 min, Eluent A: 0.1% formic acid in water, Eluent B: 0.1% formic acid in MeCN. Method F: Apparatus: Waters IClass; Bin. Pump: UPIBSM, SM: UPISMFTN with SO; UPCMA, PDA: UPPDATC, 210-320 nm, SQD: ACQ-SQD2 ESI; column: Waters XSelect CSH C18,10 50x2.1 mm, 2.5μm, Temp: 25 °C, Flow: 0.6 mL / min, Gradient: t0 = 5% B, t2.0min = 98% B,t2.7min = 98% B, Posttime: 0.3 min, Eluent A: 10 mM ammonium bicarbonate in water (pH=9.5), Eluent B: MeCN. LCMS methods: Method A: Instrument: Agilent 1260 Infinity II, 1260 G7112B Bin. Pump, 1260 G7167A Multi-15 sampler, 1290 MCT G7116B Column Comp. 1260 G7115A DAD (210, 220 and 210-320 nm),PDA (210-320 nm), G6135B MSD (ESI pos / neg) mass range 90-1500, 1290 G7102A ELSD (Evap: 50°C, Neb: 50°C, gasflow: 1.3 ml / min), Column: XSelect CSH C18 (30x2.1mm 3.5µ) Flow: 1 ml / min, Column temp.: 40°C, Eluent A: 0.1% Formic acid in Water, Eluent B: 0.1% Formic acid in Acetonitrile, Gradient: t=0 min 5% B, t=1.6 min 98% B, t=3 min 98% B, Postrun:20 1.3 min.Method B: Instrument: Agilent 1260 Infinity, 1260 G1312B Bin. Pump, 1260 G1367E WPS, 1260 TCC G1316A Column Comp.1260 G1315C DAD (210-320 nm, 210 and 220nm), PDA (210-320 nm), G6130B MSD (ESI pos / neg) mass range: 100 - 1000, Column: Waters XSelect CSH C18 (30x2.1mm, 3.5µ) , Flow: 1 ml / min Column temp: 25°C, Eluent A: 10mM ammoni-25 umbicarbonate in water (pH=9), Eluent B: Acetonitrile, Gradient: t=0min 5% B, t=1.6min 98% B,t=3 min 98% B, Postrun: 1.4 min. Preparative HPLC methods: Method A: HPLC instrument type: Agilent Technologies 1200 preparative LC; MS instrument type: Agilent Technologies G6120AA Quadrupole; Column: Waters XSelect CSH (C18, 100x3030 mm, 10µ); Flow: 55 ml / min; Column temp: r.t.; Eluent A: 0.1% formic acid in water; Eluent B:100% MeCN; Detection: DAD (220-320 nm); Detection: MSD (ESI pos / neg) mass range: 100 – 1000; fraction collection based on MS and DAD Method B: HPLC instrument type: Waters Modular Preparative HPLC System; MS instrument type: ACQ-SQD2; Column: Waters XSelect (C18, 100x30 mm, 10µm); flow: 55 ml / min prep35 pump; column temp: r.t.; eluent A: 10 mM ammonium bicarbonate in water pH=9.5, eluent B:100% MeCN; detection: DAD (220-320 nm); detection: MSD (ESI pos / neg) mass range: 100 – 800; fraction collection based on MS and DAD. SFC methods: Method A: Instrument: Waters Acquity UPC2: Waters ACQ-ccBSM Binary Pump; Waters ACQ-40 CCM Convergence Manager; Waters ACQ-SM Sample Manager - Fixed Loop; Waters ACQ-CMColumn Manager - 30S; Waters ACQ-PDA Photodiode Array Detector (210-320 nm); Waters ACQ-ISM Make Up Pump, Waters Acquity QDa MS Detector (ESI pos, mass range 100-650); Column: Phenomenex i-Amylose-3; Column temp: 40°C; Flow: 2.5 ml / min; ABPR: 170 bar; Elu- ent A: CO2, Eluent B: 20 mM Ammonia in Methanol; Linear gradient: t=0 min 5% B, t=5 min45 50% B, t=6 min 50% B; Postrun: 0.5 min.Method B: Instrument: Waters Acquity UPC2: Waters ACQ-ccBSM Binary Pump; Waters ACQ- CCM Convergence Manager; Waters ACQ-SM Sample Manager - Fixed Loop; Waters ACQ-CM Column Manager - 30S; Waters ACQ-PDA Photodiode Array Detector (210-320 nm); Waters ACQ-ISM Make Up Pump, Waters Acquity QDa MS Detector (ESI pos, mass range 100-650);ANAVO therapeutics BV A19159WO44 Column: Phenomenex Cellulose-2; Column temp: 40°C; Flow: 2.5 ml / min; ABPR: 170 bar; Elu- ent A: CO2, Eluent B: 20 mM Ammonia in Methanol; Isocratic method: 50% B for 15 min; Postrun: 0.5 min. Preparative SFC methods: 5Method A: Apparatus: Sepiatec Prep 250 SFC; Column: Phenomenex Lux i-Amylose-3(250x21.2 mm, 5 µm); Column temp: 40°C; Flow: 100 ml / min; ABPR: 120 bar; Eluent A: CO2, Eluent B: 20 mM Ammonia in Methanol; Isocratic method: 40% B for 5 min; Detection: UV 257; Collection: Timed. Method B: Apparatus: Waters Prep 100 SFC UV / MS directed system; Waters 2998 Photodiode10 Array (PDA) Detector; Waters Acquity QDa MS detector; Waters 2767 Sample Manager; Col-umn: Phenomenex Lux Cellulose-2 (250x21.2 mm, 5µm); Column temp: 35°C; Flow: 70 ml / min; ABPR: 120 bar; Eluent A: CO2, Eluent B: 20 mM Ammonia in Methanol; Isocratic method: 50% B for 22 min; Detection: PDA (210-400 nm); Fraction collection: PDA TIC. Method C: Apparatus: Waters Prep 100 SFC UV / MS directed system; Waters 2998 Photodiode15 Array (PDA) Detector; Waters Acquity QDa MS detector; Waters 2767 Sample Manager; Col-umn: Phenomenex Lux Cellulose-2 (250x21.2 mm, 5µm); Column temp: 35°C; Flow: 70 ml / min; ABPR: 120 bar; Eluent A: CO2, Eluent B: 20 mM Ammonia in Methanol; Isocratic method: 50% B for 36 min; Detection: PDA (210-400 nm); Fraction collection: PDA TIC.20 Synthetic procedures for key intermediates:Intermediate 1: Synthesis of (S)-2-amino-3-cyclopentyl-N-(1-methyl-1H-pyrazol-4- yl)propanamide hydrochloride 25 To a solution of (S)-2-((tert-butoxycarbonyl)amino)-3-cyclopentylpropanoic acid (200 mg, 0.78mmol) in DCM (4 mL) were added TEA (0.22 mL, 1.56 mmol, 2 equiv) and HATU (356 mg, 0.94 mmol, 1.2 equiv). After stirring at room temperature for 10 min, 1-methyl-1H-pyrazol-4-amine (0.07 mL, 0.78 mmol, 1 equiv) was added and stirring was continued at room temperature overnight. To the reaction mixture was added aqueous NaHCO3, the layers were separate, the30 aqueous layer was extracted with DCM and the combined organic layers were dried oversodium sulfate and concentrated in vacuo. The residue was purified by silicagel chromatogra- phy (heptane:EtOAc (0->100%), affording tert-butyl (S)-(3-cyclopentyl-1-((1-methyl-1H-pyrazol- 4-yl)amino)-1-oxopropan-2-yl)carbamate. The Boc-protected amide was re-dissolved in DCM (4 mL) and a solution of HCl in dioxane (4N, 2 mL, 15 equiv) was added. After stirring at room tem-35 perature overnight, the reaction mixture was concentrated in vacuo to afford (S)-2-amino-3-cy-clopentyl-N-(1-methyl-1H-pyrazol-4-yl)propanamide hydrochloride (301 mg, 0.78 mmol, quant.) as a white solid.1H NMR (400 MHz, DMSO-d6) δ 10.70 (s, 1H), 8.55 – 8.07 (m, 3H), 7.92 (s, 1H), 7.49 (s, 1H), 3.81 (s, 3H), 1.88 – 1.67 (m, 5H), 1.65 – 1.52 (m, 2H), 1.52 – 1.38 (m, 2H), 1.21 – 0.94 (m, 2H); LCMS (Method A): tR 0.76 min, MS (ESI) 237.2 (M+H)+. 40 Intermediate 2: Synthesis of (S)-2-amino-3-cyclopentyl-N-cyclopropylpropanamide hydrochlo- rideANAVO therapeutics BV A19159WO45 This intermediate was prepared using procedures analogous to Intermediate 1.1H NMR (400 MHz, DMSO-d6) δ 8.63 (d, J = 4.2 Hz, 1H), 8.34 – 8.03 (m, 3H), 3.62 – 3.49 (m, 1H), 2.73 – 2.62 (m, 1H), 1.85 – 1.70 (m, 3H), 1.70 – 1.63 (m, 2H), 1.63 – 1.52 (m, 2H), 1.52 – 1.38 (m, 2H), 51.18 – 0.93 (m, 2H), 0.75 – 0.60 (m, 2H), 0.54 – 0.37 (m, 2H); LCMS (Method B): tR 0.82 min,MS (ESI) 197.5 (M+H)+. Intermediate 3: Synthesis of (S)-2-amino-3-cyclopentyl-N-(pyridin-3-yl)propanamide hydrochlo- ride 10 This intermediate was prepared using procedures analogous to Intermediate 1.1H NMR (400 MHz, DMSO-d6) δ 11.81 (s, 1H), 9.07 (d, J = 2.4 Hz, 1H), 8.61 – 8.35 (m, 5H), 7.76 (dd, J = 8.5, 5.2 Hz, 1H), 4.11 – 4.01 (m, 1H), 1.93 – 1.72 (m, 5H), 1.65 – 1.37 (m, 4H), 1.28 – 1.01 (m, 2H); LCMS (Method A): tR 0.31 min, MS (ESI) 234.2 (M+H)+. 15 Intermediate 4: Synthesis of (S)-2-amino-3-cyclopentyl-N-cyclopropylpropanamide hydrochlo- ride This intermediate was prepared using procedures analogous to Intermediate 1.1H NMR (40020 MHz, DMSO-d6) δ 11.61 (s, 1H), 9.11 (s, 2H), 8.96 (s, 1H), 8.48 (d, J = 5.2 Hz, 3H), 4.19 – 3.91(m, 1H), 1.99 – 1.70 (m, 5H), 1.66 – 1.53 (m, 2H), 1.53 – 1.38 (m, 2H), 1.27 – 1.01 (m, 2H). LCMS (Method B): tR 1.61 min, MS (ESI) 235.2 (M+H)+. Intermediate 5: Synthesis of (2S)-2-amino-N-(1-methyl-1H-pyrazol-4-yl)-3-(tetrahydrofuran-2-25 yl)propanamide hydrochloride (S)-2-Amino-3-(furan-2-yl)propanoic acid hydrochloride (10.0 g, 49.6 mmol), 64.5 mmol, 1.3 equiv) and triethylamine (13.8 mL, 99.2 mmol, 2.0 equiv) were mixed in MeOH (100 mL) and the solution was stirred at 60 °C for 7 h. The volatiles were removed in vacuo,30 aqueous HCl (1N, 50 mL) was added and the aqueous layer was extracted three times withEtOAc. The combined organic layers were dried over sodium sulfate and concentrated in vacuoANAVO therapeutics BV A19159WO46 to afford (S)-2-((tert-butoxycarbonyl)amino)-3-(furan-2-yl)propanoic acid (12.6 g, quant) as a col- orless oil, which was used in the next step without purification. UPLC (Method C): tR 1.56 min, 90.6%, MS (ESI) 256.2 (M+H)+. To a solution of (S)-2-((tert-butoxycarbonyl)amino)-3-(furan-2- yl)propanoic acid (12.7 g, 49.6 mmol) in EtOAc (150 mL) was added PtO2(675 mg, 2.97 mmol, 50.06 equiv). The suspension was degassed and stirred under H2 atmosphere at room tempera-ture for 20 h. The reaction mixture was filtered through celite and the filtrate was in vacuo. The crude residue was purified by silicagel chromatography (MeOH in DCM, 2-5%,) affording (2S)-2- ((tert-butoxycarbonyl)amino)-3-(tetrahydrofuran-2-yl)propanoic acid (mixture of diastereoiso- mers, 7.80 g, 61%) as a colorless oil.1H-NMR (300 MHz, DMSO-d6) δ 12.44 (s, 1H), 7.01 (d,10 8.1 Hz, 1H), 4.03-3.47 (m, 4H), 2.03-1.58 (m, 5H), 1.48-1.28 (m, 10H); UPLC (Method D): tR2.36, 2.42 min, 99.5%, MS (ESI) 260.0 (M+H)+. To a mixture of (2S)-2-((tert-butoxycar- bonyl)amino)-3-(tetrahydrofuran-2-yl)propanoic acid (330 mg, 1.27 mmol), 4-amino-1- methylpyrazole (123 mg, 1.27 mmol, 1.0 equiv) and triethylamine (0.35 mL, 2.54 mmol, 2.00 equiv) in DMF (15 mL) was added HATU (580 mg, 1.53 mmol, 1.2 equiv) and the reaction was15 stirred for 24 h. The resulting mixture was poured into water (15 mL) and DCM (15 mL) wasadded. The layers were separated, the aqueous layer was extracted with DCM (15 mL), the combined organic layers were over sodium sulfate, and concentrated in vacuo.. The crude residue was purified by silicagel chromatography (5% MeOH in DCM) and (15% (EtOH:EtOAc 3:1) in hexanes) , to afford tert-butyl ((2S)-1-((1-methyl-1H-pyrazol-4-yl)amino)-1-oxo-3-(tetrahy-20 drofuran-2-yl)propan-2-yl)carbamate as a white solid. The solids were directly taken up in DCM(10 mL) and HCl in dioxane (4N, 1.23 mL, 4.9 mmol, 5.0 equiv) was added. The reaction was stirred at room temperature for 21 h, after which the volatiles were removed in vacuo and the residue co-evaporated twice with DCM, affording (2S)-2-amino-N-(1-methyl-1H-pyrazol-4-yl)-3- (tetrahydrofuran-2-yl)propanamide hydrochloride (295 mg, quant) as a yellow foam.1H-NMR25 (300 MHz, DMSO-d6) δ 10.72 (s, 1H), 8.28 (bs, 3H), 7.93 (s, 1H), 7.47 (s, 1H), 3.97-3.68 (m,6H), 3.67-3.54 (m, 1H), 2.09-1.69 (m, 5H), 1.55-1.38 (m, 1H); UPLC (Method C): tR 0.44 min, 96.7%, MS (ESI) 239.1 (M+H)+. Intermediate 6: Synthesis of (2S)-2-amino-N-cyclopropyl-3-(tetrahydrofuran-2-yl)propanamide30 hydrochloride Intermediate 6This intermediate was prepared using procedures analogous to Intermediates 1 and 5.1H NMR (400 MHz, DMSO-d6) δ 8.55 (d, J = 4.0 Hz, 1H), 8.05 (br, 3H), 3.86 – 3.57 (m, 4H), 2.66 (qt, J = 7.2, 4.0 Hz, 1H), 2.04 – 1.91 (m, 1H), 1.91 – 1.70 (m, 4H), 1.51 – 1.35 (m, 1H), 0.72 –35 0.61 (m, 2H), 0.51 – 0.38 (m, 2H); LCMS (Method B): tR 0.91 min, MS (ESI) 199.2 (M+H)+.Intermediate 7: Synthesis of (S)-2-amino-3-cyclopentyl-N-(oxetan-3-yl)propanamide (S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-cyclopentylpropanoic acid (2.0 g, 5.340 mmol) and HATU (2.1 g, 5.5 mmol, 1.05 equiv) were dissolved in DMF (10 mL). The reactionwas cooled to 0 °C, DIPEA (2.8 mL, 16 mmol, 3 equiv) and oxetan-3-amine (0.39 g, 5.3 mmol,ANAVO therapeutics BV A19159WO47 1.01 equiv) were added and the reaction was stirred for 30 min. The resulting mixture was parti- tioned between brine and EtOAc, the layers were separated and the organic layer was washed with 10% aqueous citric acid, saturated aqueous NaHCO3(2x) and with brine (2x). The organic layer was dried over Na2SO4and concentrated in vacuo. The residue was purified with silicagel 5chromatography (0-3% MeOH in DCM), affording (9H-fluoren-9-yl)methyl (S)-(3-cyclopentyl-1-(oxetan-3-ylamino)-1-oxopropan-2-yl)carbamate (1.96 g, 4.51 mmol, 86%) as a white solid. Part of this material (300 mg, 690 μmol) was suspended in THF (15 mL), diethylamine (0.5 mL, 5 mmol, 7 equiv) was added and the reaction was stirred at room temperature for 1 h. Additional diethylamine (0.5 mL, 5 mmol, 7 equiv) was added and the reaction mixture was heated to 4310 °C for 3 h and left stirring overnight at room temperature. The volatiles were removed in vacuo,the residue was co-evaporated with toluene and DCM, affording the crude title product as an off-white solid, which was used without further purification. LCMS (Method B): tR 2.23 min, MS (ESI) 213.2 (M+H)+.15 Intermediate 8: Synthesis of (S)-N-(3-cyclopentyl-1-((1-methyl-1H-pyrazol-4-yl)amino)-1-oxo-propan-2-yl)-5-formylthiophene-2-carboxamide To a solution of 5-formylthiophene-2-carboxylic acid (1.52 g, 9.72 mmol) in anhydrous DMF (10 mL) was added HATU (4.44 g, 11.7 mmol). After stirring at room temperature for 15 min, (S)-2-20 amino-3-cyclopentyl-N-(1-methyl-1H-pyrazol-4-yl)propanamide hydrochloride (Intermediate 1,2.65 g, 9.72 mmol) and DIPEA (8.5 mL, 49 mmol) were added and stirring was continued at room temperature for 18h. The reaction mixture was diluted with EtOAc and washed with 1M aq. NaOH, water and brine. The organic layer was dried over sodium sulfate, filtered and con- centrated in vacuo. The residue was purified by silicagel chromatography (heptane:EtOAc, 0-25 100%) and subsequently by preparative reversed phase chromatography (Waters XSelectTMCSH C18 column, ammonium bicarbonate in water / acetonitrile), affording (S)-N-(3-cyclopentyl- 1-((1-methyl-1H-pyrazol-4-yl)amino)-1-oxopropan-2-yl)-5-formylthiophene-2-carboxamide (1.32 g, 3.53 mmol, 36%) as a light-yellow solid.1H NMR (400 MHz, DMSO-d6) δ 10.18 (s, 1H), 9.96 (s, 1H), 9.00 (d, J = 7.9 Hz, 1H), 8.11 – 7.99 (m, 2H), 7.86 (s, 1H), 7.43 (s, 1H), 4.53 (td, J = 8.6,30 5.3 Hz, 1H), 3.78 (s, 3H), 1.90 – 1.64 (m, 5H), 1.63 – 1.39 (m, 4H), 1.16 (dt, J = 9.1, 6.3 Hz,2H); LCMS (Method B): tR 1.85 min, MS (ESI) 375.1 (M+H)+. Intermediate 9: Synthesis of (S)-5-(chloromethyl)-N-(3-cyclopentyl-1-((1-methyl-1H-pyrazol-4- yl)amino)-1-oxopropan-2-yl)thiophene-2-carboxamide 35 To a solution of (S)-N-(3-cyclopentyl-1-((1-methyl-1H-pyrazol-4-yl)amino)-1-oxopropan-2-yl)-5- formylthiophene-2-carboxamide (Intermediate 8, 1.0 g, 2.67 mmol) in methanol (20 mL) was added sodium borohydride (303 mg, 8.01 mmol, 3 equiv) portion wise at room temperature and the reaction mixture was stirred at room temperature overnight. The solvent was removed in40 vacuo and EtOAc (100 mL) and saturated aqueous NaHCO3 (80 mL) were added to theANAVO therapeutics BV A19159WO48 residue. The layers were separated, the organic layer was washed with saturated aqueous NaHCO3, the combined aqueous layers were extracted with EtOAc, the combined organic lay- ers were washed with saturated aqueous NaHCO3and brine, dried over Na2SO4and concen- trate, affording (S)-N-(3-cyclopentyl-1-((1-methyl-1H-pyrazol-4-yl)amino)-1-oxopropan-2-yl)-5- 5(hydroxymethyl)thiophene-2-carboxamide (960 mg, 95%).as a yellow solid.1H NMR (400 MHz,DMSO-d6) δ 10.12 (s, 1H), 8.52 (d, J = 7.9 Hz, 1H), 7.86 (s, 1H), 7.77 (d, J = 3.8 Hz, 1H), 7.42 (s, 1H), 6.96 (dd, J = 3.6, 1.1 Hz, 1H), 5.59 (t, J = 5.7 Hz, 1H), 4.62 (d, J = 4.9 Hz, 2H), 4.53 – 4.44 (m, 1H), 3.77 (s, 3H), 1.89 – 1.63 (m, 5H), 1.61 – 1.51 (m, 2H), 1.45 (dq, J = 7.0, 3.8 Hz, 2H), 1.22 – 1.05 (m, 2H); LCMS (Method B): tR 1.78 min, MS (ESI) 377.1 (M+H)+. A suspension10 of (S)-N-(3-cyclopentyl-1-((1-methyl-1H-pyrazol-4-yl)amino)-1-oxopropan-2-yl)-5-(hydrox-ymethyl)thiophene-2-carboxamide (370 mg, 0.98 mmol) in DCM (10 mL) was cooled to 0 °C, af- ter which thionyl chloride (143 μL, 1.97 mmol, 2 equiv) was added. After stirring for 5 min, the ice bath was removed and the reaction mixture was allowed to warm to room temperature overnight. The reaction mixture was quenched with water (20 mL), the layers were separated,15 the aqueous layer was extracted with DCM (20 mL), the combined organic layers were washedwith brine and filtered over a phase separator. The volume of the resulting solution was reduced under reduced pressure, followed by purification by silicagel chromatography (heptane / EtOAc, 10-100%), affording the title product (345 mg, 88%) as a light-yellow solid.1H NMR (400 MHz, DMSO-d6) δ 10.12 (s, 1H), 8.67 (d, J = 8.0 Hz, 1H), 7.85 (s, 1H), 7.80 (d, J = 3.8 Hz, 1H), 7.4220 (s, 1H), 7.20 (d, J = 3.8 Hz, 1H), 5.02 (s, 2H), 4.54 – 4.45 (m, 1H), 3.77 (s, 3H), 1.89 – 1.61 (m,5H), 1.63 – 1.51 (m, 2H), 1.51 – 1.38 (m, 2H), 1.22 – 1.06 (m, 2H); LCMS (Method B): tR 1.96 min, MS (ESI) 395.2 (M+H)+. Intermediate 10: Synthesis of 5-((7-bromo-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-1-25 yl)methyl)thiophene-2-carboxyic acid To a solution of 7-bromo-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazine (350 mg, 1.63 mmol) in DMF (5.0 mL) was added sodium hydride (60 wt%, 91.1 mg, 2.28 mmol, 1.4 equiv). After stirring at room temperature for 5 min, methyl 5-(bromomethyl)thiophene-2-carboxylate (497 mg, 2.1230 mmol, 1.3 equiv) was added to the reaction mixture and stirring was continued for 2 h. Next,aqueous sodium hydroxide (4M, 1.63 mL, 6.51 mmol, 4.0 equiv) was added dropwise and the reaction mixture was stirred at room temperature for 18 h. Water was added and the mixture was directly purified by preparative reversed phase chromatography (Waters XSelectTMCSH C18 column, formic acid in water / acetonitrile), affording 5-((7-bromo-2,3-dihydro-1H-pyrido[2,3-35 b][1,4]oxazin-1-yl)methyl)thiophene-2-carboxylic acid (391 mg, 1.10 mmol, 68%) as a brownsolid.1H NMR (400 MHz, DMSO-d6) δ 13.09 (s, 1H), 7.61 (d, J = 3.8 Hz, 1H), 7.49 (d, J = 2.1 Hz, 1H), 7.37 (d, J = 2.2 Hz, 1H), 7.13 (d, J = 3.9 Hz, 1H), 4.79 (s, 2H), 4.34 (t, J = 4.5 Hz, 2H), 3.40 (t, J = 4.5 Hz, 2H); LCMS (Method B): tR 1.51 min, MS (ESI) 355.0 (M+H)+.40 Intermediate 11: Synthesis of 5-((7-(trifluoromethyl)-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-1-yl)methyl)thiophene-2-carboxylic acidANAVO therapeutics BV A19159WO49 This intermediate was synthesized using procedures analogous to Intermediate 10. LCMS (Method B): tR 1.52 min, MS (ESI) 345.0 (M+H)+. 5Intermediate 12: Synthesis of 5-((7-chloro-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-1-yl)methyl)thiophene-2-carboxylic acid This intermediate was synthesized using procedures analogous to Intermediate 10.1H NMR (400 MHz, DMSO-d6) δ 13.07 (s, 1H), 7.60 (d, J = 3.7 Hz, 1H), 7.42 (d, J = 2.2 Hz, 1H), 7.28 (d,10 J = 2.3 Hz, 1H), 7.13 (d, J = 3.8 Hz, 1H), 4.79 (s, 2H), 4.34 (t, J = 4.5 Hz, 2H), 3.40 (t, J = 4.5Hz, 2H); LCMS (Method B): tR 1.49 min, MS (ESI) 311.0 (M+H)+. Intermediate 13: Synthesis of 5-((3,3-dimethyl-7-(trifluoromethyl)-2,3-dihydro-1H-pyrido[2,3- b][1,4]oxazin-1-yl)methyl)thiophene-2-carboxylic acid 15 This intermediate was synthesized using procedures analogous to Intermediate 10. LCMS (Method A): tR 1.87 min, MS (ESI) 373.2 (M+H)+. Intermediate 14: Synthesis of 5-((6-chloro-1H-pyrrolo[3,2-b]pyridin-1-yl)methyl)thiophene-2-car-20 boxylic acid To a solution of methyl 5-(bromomethyl)-2-thiophenecarboxylate (77.0 mg, 0.33 mmol) in DMF (1.0 mL) were added 6-chloro-4-azaindole (50.0 mg, 0.33 mmol, 1 equiv) and cesium carbonate (107 mg, 0.33 mmol, 1 equiv). The reaction mixture was heated to 50 °C for 2 h and cooled to25 room temperature. Water (6 mL) and DCM (2 mL) were added, the layers were separated usinga phase separator and the organic layer was concentrated in vacuo. The residue was purified by preparative reversed phase chromatography (Waters XSelectTMCSH C18 column, ammo- nium bicarbonate in water / acetonitrile) to afford methyl 5-((6-chloro-1H-pyrrolo[3,2-b]pyridin-1- yl)methyl)thiophene-2-carboxylate (38 mg, 0.12 mmol, 38%) as a brown oil. LCMS (Method B):30 tR 1.98 min, MS (ESI) 306.9 (M+H)+. To a solution of methyl 5-((6-chloro-1H-pyrrolo[3,2-b]pyridin-1-yl)methyl)thiophene-2-carboxylate (38 mg, 0.12 mmol) in THF (1.0 mL) and waterANAVO therapeutics BV A19159WO50 (0.50mL) was added lithium hydroxide monohydrate (26 mg, 0.62 mmol, 5 equiv). The reaction mixture was stirred for 18 h at room temperature, acidified with aqueous 1N HCl and extracted with EtOAc (3x). The combined organic layers were concentrated to afford 5-((6-chloro-1H- pyrrolo[3,2-b]pyridin-1-yl)methyl)thiophene-2-carboxylic acid (25 mg, 85 μmol, 69%) as a yellow 5solid.1H NMR (400 MHz, DMSO-d6) δ 13.11 (s, 1H), 8.35 (d, J = 2.2 Hz, 1H), 8.27 (d, J = 2.7Hz, 1H), 7.88 (d, J = 3.3 Hz, 1H), 7.56 (d, J = 3.8 Hz, 1H), 7.16 (d, J = 3.8 Hz, 1H), 6.67 (d, J = 3.2 Hz, 1H), 5.71 (s, 2H); LCMS (Method B): tR 1.58 min, MS (ESI) 293.0 (M+H)+. Intermediate 15: Synthesis of 5-((2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-1-yl)methyl)thio-10 phene-2-carboxylic acid This intermediate was synthesized using procedures analogous to Intermediate 14. LCMS (Method B): tR 1.23 min, MS (ESI) 277.0 (M+H)+.15 Intermediate 16: Synthesis of 5-((6-chloro-1H-pyrrolo[3,2-b]pyridin-1-yl)methyl)thiophene-2-car-boxylic acid This intermediate was synthesized using procedures analogous to Intermediate 14. LCMS: (Method A) tR 1.69 min, MS (ESI) 294.0. 20 Intermediates 17 and 18: Synthesis of 5-((6-chloro-1H-benzo[d]imidazol-1-yl)methyl)thio- phene-2-carboxylic acid and 5-((5-chloro-1H-benzo[d]imidazol-1-yl)methyl)thiophene-2-car- boxylic acid 25 A fine suspension of 6-chloro-1H-benzo[d]imidazole (100 mg, 655 μmol) in THF (2.0 mL) wascooled to 0 °C under nitrogen atmosphere, after which NaHMDS (2M in THF, 492 μL, 983 μmol, 1.5 equiv) was added. The reaction mixture was stirred for 5 min, after which methyl 5-(bro- momethyl)thiophene-2-carboxylate (200 mg, 852 μmol ,1.3 equiv) was added. The reaction mix- ture was warmed to room temperature and stirring was continued for 18 h. Aqueous sodium hy-30 droxide (4M, 819 μL, 3.28 mmol, 5.0 equiv) was added and after stirring 4 d, water was addedto the reaction mixture and the mixture was directly purified by preparative reversed phase chro- matography (Waters XSelectTMCSH C18 column, formic acid in water / acetonitrile) to afford the regioisomeric mixture. The regioisomers were separated by preparative SFC (Method A) afford- ing 5-((6-chloro-1H-benzo[d]imidazol-1-yl)methyl)thiophene-2-carboxylic acid (18.5 mg, 61.635 μmol, 9.4%) as an off-white solid and 5-((5-chloro-1H-benzo[d]imidazol-1-yl)methyl)thiophene-2-carboxylic acid (20.9 mg, 71.2 μmol, 10.9%) as an off-white solid.5-((6-Chloro-1H-benzo[d]imi- dazol-1-yl)methyl)thiophene-2-carboxylic acid (Intermediate 17): LCMS (Method B): tR 1.47ANAVO therapeutics BV A19159WO51 min, MS (ESI) 293.0 (M+H)+; SFC (Method A): tR 4.38 min, 100%, MS (ESI) 292.9 (M+H)+.5- ((5-Chloro-1H-benzo[d]imidazol-1-yl)methyl)thiophene-2-carboxylic acid (Intermediate 18): LCMS (Method B): tR 1.46 min, MS (ESI) 293.0 (M+H)+; SFC (Method A): tR 5.08 min, 99.6%, MS (ESI) 292.9 (M+H)+. 5 Intermediates 19 and 20: Synthesis of 5-((6-chloro-1H-imidazo[4,5-b]pyridin-1-yl)methyl)thio- phene-2-carboxylic acid and 5-((5-chloro-1H-imidazo[4,5-b]pyridin-1-yl)methyl)thiophene-2-car- boxylic acid 10 To a suspension of NaH (60 wt%, 54.7 mg, 1.37 mmol, 2.1 equiv) in DMF (3.0 mL) was added6-chloro-1H-imidazo[4,5-b]pyridine (100 mg, 0.65 mmol). The mixture was stirred for 5 min, fol- lowed by the addition of methyl 5-(bromomethyl)thiophene-2-carboxylate (168 mg, 0.72 mmol, 1.1 equiv). The reaction mixture was stirred at room temperature for 5 h, diluted with water and extracted with EtOAc (3x); The combined organic layers were concentrated in vacuo and the15 residue was purified by preparative reversed phase chromatography (Waters XSelectTM CSHC18 column, ammonium bicarbonate in water / acetonitrile) to afford methyl 5-((6-chloro-1H-imi- dazo[4,5-b]pyridin-1-yl)methyl)thiophene-2-carboxylate (23 mg, 0.65 mmol, 11%). LCMS (Method B): tR 1.83 min, MS (ESI) 308.0 (M+H)+, and methyl 5-((6-chloro-3H-imidazo[4,5- b]pyridin-3-yl)methyl)thiophene-2-carboxylate (24 mg, 0.65 mmol, 12%). LCMS (Method B): tR20 1.92 min, MS (ESI) 307.9 (M+H)+. To a solution of methyl 5-((6-chloro-1H-imidazo[4,5-b]pyridin-1-yl)methyl)thiophene-2-carboxylate (23 mg, 75 μmol) in THF (1.0 mL) and water (0.5 mL) was added lithium hydroxide monohydrate (16 mg, 0.37 mmol, 5 equiv). The reaction mixture was stirred at room temperature for 1.5 h, acidified with aqueous 1N HCl and extracted with EtOAc (3x). The combined organic layers were evaporated to afford 5-((6-chloro-1H-imidazo[4,5-25 b]pyridin-1-yl)methyl)thiophene-2-carboxylic acid (Intermediate 19, 15 mg, 0.51 mmol, 68%).LCMS (Method A): tR 1.52 min, MS (ESI) 294.0 (M+H)+. To a solution of methyl 5-((6-chloro- 3H-imidazo[4,5-b]pyridin-3-yl)methyl)thiophene-2-carboxylate (24 mg, 78 μmol) in THF (1.0 mL) and water (0.5 mL) was added lithium hydroxide monohydrate (16 mg, 0.37 mmol, 5 equiv). The reaction mixture was stirred at room temperature for 1.5 h, acidified with aqueous 1N HCl and30 extracted with EtOAc (3x). The combined organic layers were evaporated to afford 5-((6-chloro-3H-imidazo[4,5-b]pyridin-3-yl)methyl)thiophene-2-carboxylic acid (Intermediate 20, 23 mg, 78 μmol, 100 %). LCMS (Method A): tR 1.64 min, MS (ESI) 294.0 (M+H)+. Intermediate 21: Synthesis of 5-((7-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-1-35 yl)methyl)thiophene-2-carboxylic acid To a solution of methyl 5-formylthiophene-2-carboxylate (62.3 mg, 0.37 mmol, 1.1 equiv) and 7- methyl-1H,2H,3H-pyrido[2,3-b][1,4]oxazine (50.0 mg, 0.33 mmol) in DCM (3 mL) was added so- dium triacetoxyborohydride (106 mg, 0.50 mmol, 1,5 equiv). The reaction mixture was stirred for40 24 h, diluted with water and aqueous 1N NaOH. The layers were separated with a phase sepa-ANAVO therapeutics BV A19159WO52 rator and the organic layer concentrated in vacuo. The residue was purified by preparative re- versed phase chromatography (Waters XSelectTMCSH C18 column, ammonium bicarbonate in water / acetonitrile) to afford methyl 5-((7-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-1- yl)methyl)thiophene-2-carboxylate (40 mg, 0.13 mmol, 39%) as a white glass. LCMS (Method 5B): tR 1.87 min, MS (ESI) 305.0 (M+H)+. To a solution of methyl 5-((7-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-1-yl)methyl)thiophene-2-carboxylate (40 mg, 0.13 mmol) in THF (1.0 mL) and water (0.5 mL) was added lithium hydroxide monohydrate (30 mg, 0.73 mmol, 5.6 equiv). The reaction mixture was stirred at room temperature for 16 h and acidified with aque- ous 1N HCl. A solid was formed, which was isolated by filtration and dried in air to afford 5-((7-10 methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-1-yl)methyl)thiophene-2-carboxylic acid (30 mg,0.10 mmol, 79%) as a white solid. LCMS (Method B): tR 1.38 min, MS (ESI) 291.1 (M+H)+. Intermediate 22: Synthesis of 5-((4,7-dimethyl-3,4-dihydropyrido[2,3-b]pyrazin-1(2H)- yl)methyl)thiophene-2-carboxylic acid 15 This compound was synthesized using procedures analogous to Intermediate 21. LCMS (Method B): tR 1.48 min, MS (ESI) 304.1 (M+H)+. Intermediate 23: Synthesis of 5-((6-chloro-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)methyl)thio-20 phene-2-carboxylic acid This intermediate was synthesized using procedures analogous to Intermediate 21. LCMS (Method B): tR 1.63 min, MS (ESI) 310.0 (M+H)+.25 Intermediate 24: Synthesis of 5-((7-cyano-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-1-yl)methyl)thiophene-2-carboxylic acid To a solution of 5-((7-bromo-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-1-yl)methyl)thiophene-2- carboxylic acid (Intermediate 10, 50.0 mg, 0.14 mmol) in DMF (2.0 mL) was added zinc cya-30 nide (34.7 mg, 0.30 mmol, 2.1 equiv). The reaction mixture was flushed with argon for 5 minand tetrakis(triphenylphosphine)palladium(0) (81.3 mg, 70.4 μmol, 0.5 equiv) was added. The reaction mixture was heated to 120 °C for 3 h, after which the volatiles were removed in vacuo, and the residue was purified by preparative reversed phase chromatography (Waters XSelectTMCSH C18 column, ammonium bicarbonate in water / acetonitrile) to afford 5-((7-cyano-2,3-dihy-ANAVO therapeutics BV A19159WO53 dro-1H-pyrido[2,3-b][1,4]oxazin-1-yl)methyl)thiophene-2-carboxylic acid (12 mg, 40 μmol, 28%) as a yellow solid. LCMS (Method B): tR 1.34 min, MS (ESI) 301.8 (M+H)+. Intermediate 25: Synthesis of 7-cyclopropyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazine 100 C 5Intermediate 25To a nitrogen purged solution of 7-bromo-1H,2H,3H-pyrido[2,3-b][1,4]oxazine (50 mg, 0.23 mmol), cyclopropaneboronic acid (60 mg, 0.70 mmol, 3 equiv) and potassium carbonate (96 mg, 0.70 mmol, 3 equiv) in 1,4-dioxane (1.0 mL) and water (0.25 mL) was added PdCl2(dppf).CH2Cl2(9.5 mg, 12 μmol, 0.05 equiv). The reaction mixture was stirred for 4 h at10 100 °C, diluted with water and the aqueous layer was extracted with DCM (2x). The combinedorganic layers were dried over Na2SO4, concentrated in vacuo, and the residue was purified by flash chromatography (EtOAc / heptane, 0-100%) to afford 7-cyclopropyl-2,3-dihydro-1H- pyrido[2,3-b][1,4]oxazine (12 mg, 29%) as an off white solid. UPLC (Method C): tR 1.56 min, MS (ESI) 177.0 (M+H)+. 15 Intermediate 26: Synthesis of 3,3-dimethyl-7-(trifluoromethyl)-2,3-dihydro-1H-pyrido[2,3- b][1,4]oxazine To a solution of methyl 2-hydroxy-2-methylpropanoate (156 mg, 1.32 mmol, 1.2 equiv) in THF20 (4.0 mL) was added sodium hydride (60 wt%, 57.4 mg, 1.43 mmol, 1.3 equiv) and the reactionmixture was stirred at room temperature for 1 h. Next, 5-(trifluoromethyl)-3-nitro-2-chloropyridine (250 mg, 1.10 mmol) was added and the mixture was stirred at room temperature for 16 h. The solution was diluted with water and extracted with EtOAc (3x). The combined organic layers were concentrated in vacuo and the residue was purified by silicagel chromatography (EtOAc in25 heptane, 0-33%) to afford methyl 2-methyl-2-((3-nitro-5-(trifluoromethyl)pyridin-2-yl)oxy)propanoate (157 mg, 509 μmol, 46%). LCMS (Method B) tR 2.08 min, 99.8%, MS (ESI) 308.8 (M+H)+. To a solution of methyl 2-methyl-2-((3-nitro-5-(trifluoromethyl)pyridin-2- yl)oxy)propanoate (157 mg, 509 μmol) in DMF (3 mL) were added 4,4’-bipyridine (3.98 mg, 25.5 μmol, 0.05 equiv) and hypodiboric acid (137 mg, 1.53 mmol, 3 equiv). The reaction mixture is30 stirred for 5 min at room temperature, after which acetic acid (29 μL, 0.51 mmol, 1 equiv) wasadded and the mixture was heated to 80 °C for 2h. After cooling to room temperature water was added, the resulting solids were isolated by filtration and dried on air to afford 3,3-dimethyl-7- (trifluoromethyl)-1H-pyrido[2,3-b][1,4]oxazin-2(3H)-one (82 mg, 0.33 mmol, 65 %) as a yellow solid. LCMS (Method B): tR 1.74 min, 98.1%, MS (ESI) 247.1 (M+H)+. A solution of 3,3-35 dimethyl-7-(trifluoromethyl)-1H-pyrido[2,3-b][1,4]oxazin-2(3H)-one (82.0 mg, 0.33 mmol) in THFANAVO therapeutics BV A19159WO54 (3 mL) under nitrogen atmosphere was cooled to 0 °C, lithium aluminum hydride (2M, 200 μL, 0.40 mmol, 1.2 equiv) was dropwise added and the reaction mixture was stirred at room tem- perature for 2.5 h. The resulting mixture was quenched with methanol and stirred for 30 min. The volatiles were removed in vacuo and the residue was purified by silicagel chromatography 5(EtOAc in heptane, 0-50%) to afford 3,3-dimethyl-7-(trifluoromethyl)-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazine (39 mg, 0.17 mmol, 50 %) as a white solid.1H NMR (400 MHz, CDCl3) δ 7.90 (dd, J = 2.2, 1.1 Hz, 1H), 7.03 (d, J = 2.2 Hz, 1H), 4.10 (s, 1H), 3.16 (t, J = 2.2 Hz, 2H), 1.44 (s, 6H); LCMS (Method B) tR 1.86 min, 100%, MS (ESI) 233.1 (M+H)+10 Synthetic procedures for final compounds:Example 1: Synthesis of (S)-N-(3-cyclopentyl-1-((1-methyl-1H-pyrazol-4-yl)amino)-1-oxo- propan-2-yl)-5-((2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-1-yl)methyl)thiophene-2-carboxamide 15 To a solution of 5-((2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-1-yl)methyl)thiophene-2-carboxylicacid (Intermediate 15, 10.0 mg, 36 μmol), (S)-2-amino-3-cyclopentyl-N-(1-methyl-1H-pyrazol-4- yl)propanamide hydrochloride (Intermediate 1, 12.8 mg, 47 μmol, 1.3 equiv) and DIPEA (18.9 μL 0.11 mmol, 3 equiv) in DMF (0.5 mL) was added HATU (16.5 mg, 43.4 μmol, 1.2 equiv). The reaction mixture was stirred at room temperature for 5 h and purified by preparative reversed20 phase chromatography (Waters XSelectTM CSH C18 column, ammonium bicarbonate in wa-ter / acetonitrile) to afford (S)-N-(3-cyclopentyl-1-((1-methyl-1H-pyrazol-4-yl)amino)-1-oxopropan- 2-yl)-5-((2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-1-yl)methyl)thiophene-2-carboxamide (5.5 mg, 11 μmol, 31%) as a white solid.1H NMR (400 MHz, DMSO-d6) δ 10.10 (s, 1H), 8.56 (d, J = 8.0 Hz, 1H), 7.84 (s, 1H), 7.80 (d, J = 3.7 Hz, 1H), 7.44 – 7.39 (m, 2H), 7.16 (dd, J = 8.0, 1.6 Hz,25 1H), 7.09 (d, J = 3.7 Hz, 1H), 6.82 (dd, J = 7.8, 4.7 Hz, 1H), 4.70 (s, 2H), 4.35 – 4.29 (m, 2H),3.76 (s, 3H), 3.37 (t, J = 4.5 Hz, 2H), 1.87 – 1.74 (m, 3H), 1.74 – 1.61 (m, 3H), 1.55 (d, J = 7.8 Hz, 2H), 1.50 – 1.36 (m, 2H), 1.18 (d, J = 42.4 Hz, 2H); UPLC (Method B): tR 2.54 min, 98.6%, MS (ESI) 495.2 (M+H)+.30 The following examples have been prepared using procedures analogous to Example 1, usingthe appropriate starting materials and intermediates. Table 1: ANAVO therapeutics BV A19159WO55 ANAVO therapeutics BV A19159WO56 ANAVO therapeutics BV A19159WO57 ANAVO therapeutics BV A19159WO58 ANAVO therapeutics BV A19159WO59 ANAVO therapeutics BV A19159WO60 ANAVO therapeutics BV A19159WO61 ANAVO therapeutics BV A19159WO62 Examples 33 and 34: Synthesis of the pure diastereoisomers of 5-((6-chloro-1H-pyrrolo[3,2- b]pyridin-1-yl)methyl)-N-((2S)-1-(cyclopropylamino)-1-oxo-3-(tetrahydrofuran-2-yl)propan-2- yl)thiophene-2-carboxamide 5 The diastereomeric mixture 5-((6-chloro-1H-pyrrolo[3,2-b]pyridin-1-yl)methyl)-N-((2S)-1-(cyclo- propylamino)-1-oxo-3-(tetrahydrofuran-2-yl)propan-2-yl)thiophene-2-carboxamide (Example 20), 31.3 mg, 66.2 μmol) was separated by preparative SFC (Method B). First elution isomer (Example 33): 10.1 mg (32%);1H NMR (400 MHz, DMSO-d6) δ 8.47 (d, J = 8.1 Hz, 1H), 8.3410 (d, J = 2.2 Hz, 1H), 8.26 – 8.20 (m, 1H), 8.01 (d, J = 4.3 Hz, 1H), 7.85 (d, J = 3.3 Hz, 1H), 7.71(d, J = 3.8 Hz, 1H), 7.13 (d, J = 3.8 Hz, 1H), 6.65 (d, J = 3.3 Hz, 1H), 5.67 (s, 2H), 4.30 (td, J = 9.0, 5.7 Hz, 1H), 3.77 – 3.63 (m, 2H), 3.53 (td, J = 7.8, 6.2 Hz, 1H), 2.59 (tq, J = 7.8, 4.1 Hz, 1H), 1.96 – 1.66 (m, 5H), 1.50 – 1.37 (m, 1H), 0.66 – 0.49 (m, 2H), 0.47 – 0.25 (m, 2H); UPLC (Method A): tR 2.18 min, 99.4%, MS (ESI) 473.2 (M+H)+; SFC (Method B): tR 4.15 min, 100%,15 MS (ESI) 473.1 (M+H)+; Second elution isomer (Example 34): 7.0 mg (23%) 1H NMR (400MHz, DMSO-d6) δ 8.42 (d, J = 8.1 Hz, 1H), 8.34 (d, J = 2.2 Hz, 1H), 8.26 – 8.20 (m, 1H), 8.01 (d, J = 4.3 Hz, 1H), 7.85 (d, J = 3.5 Hz, 1H), 7.69 (d, J = 3.8 Hz, 1H), 7.13 (d, J = 3.7 Hz, 1H), 6.67 – 6.62 (m, 1H), 5.68 (s, 2H), 4.40 – 4.30 (m, 1H), 3.78 – 3.64 (m, 2H), 3.53 (td, J = 7.9, 6.2 Hz, 1H), 2.58 (tq, J = 8.0, 3.9 Hz, 1H), 1.94 – 1.67 (m, 5H), 1.47 – 1.33 (m, 1H), 0.61 – 0.50 (m,20 2H), 0.45 – 0.31 (m, 2H); UPLC (Method A): tR 2.20 min, 100%, MS (ESI) 473.2 (M+H)+; SFC(Method B): tR 6.12 min, 97.6%, MS (ESI) 473.1 (M+H)+. Examples 35 and 36: Synthesis of the pure diastereoisomers of 5-((7-bromo-2,3-dihydro-1H- pyrido[2,3-b][1,4]oxazin-1-yl)methyl)-N-((2S)-1-(cyclopropylamino)-1-oxo-3-(tetrahydrofuran-2-25 yl)propan-2-yl)thiophene-2-carboxamideANAVO therapeutics BV A19159WO63 The diastereomeric mixture 5-((7-bromo-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-1-yl)methyl)-N- ((2S)-1-(cyclopropylamino)-1-oxo-3-(tetrahydrofuran-2-yl)propan-2-yl)thiophene-2-carboxamide (Example 21), 27.5 mg, 51.4 μmol) was separated by preparative SFC (Method C). First elution 5isomer (Example 35): 9.4 mg (34%); 1H NMR (400 MHz, DMSO-d6) δ 8.46 (d, J = 8.0 Hz, 1H),8.04 (d, J = 4.4 Hz, 1H), 7.75 (d, J = 3.7 Hz, 1H), 7.47 (d, J = 2.1 Hz, 1H), 7.35 (d, J = 2.0 Hz, 1H), 7.09 (d, J = 3.8 Hz, 1H), 4.75 (s, 2H), 4.38 – 4.25 (m, 3H), 3.79 – 3.66 (m, 2H), 3.63 – 3.47 (m, 1H), 3.41 – 3.37 (m, 2H), 2.61 (tq, J = 7.7, 4.1 Hz, 1H), 1.94 – 1.68 (m, 5H), 1.52 – 1.40 (m, 1H), 0.64 – 0.53 (m, 2H), 0.47 – 0.32 (m, 2H); UPLC (Method B): tR 2.486 min, 99.2%, MS10 (ESI) 535.2 / 537.2 (M+H)+. SFC (Method B): tR 6.50 min, 100%, MS (ESI) 535.1 (M+H)+; Se-cond elution isomer (Example 36): 6.9 mg (25%);1H NMR (400 MHz, DMSO-d6) δ 8.43 (d, J = 8.1 Hz, 1H), 8.04 (d, J = 4.4 Hz, 1H), 7.73 (d, J = 3.8 Hz, 1H), 7.47 (d, J = 2.0 Hz, 1H), 7.35 (d, J = 2.1 Hz, 1H), 7.09 (d, J = 3.8 Hz, 1H), 4.76 (s, 2H), 4.42 – 4.30 (m, 3H), 3.82 – 3.67 (m, 2H), 3.60 – 3.51 (m, 1H), 3.42 – 3.37 (m, 2H), 2.64 – 2.57 (m, 1H), 1.96 – 1.70 (m, 5H), 1.52 – 1.3615 (m, 1H), 0.63 – 0.50 (m, 2H), 0.44 – 0.33 (m, 2H); UPLC (Method B): tR 2.505 min, 99.8%, MS(ESI) 535.2 / 537.2 (M+H)+; SFC (Method B): tR 10.25 min, 97.7%, MS (ESI) 535.0 (M+H)+. Example 37: Synthesis of (S)-5-((7-bromo-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-1-yl)methyl)- N-(3-cyclopentyl-1-(isopropylamino)-1-oxopropan-2-yl)thiophene-2-carboxamide 20 To a solution of 5-((7-bromo-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-1-yl)methyl)thiophene-2- carboxylic acid (Intermediate 10, 47 mg, 0.13 mmol) in DMF (1.0 mL) were added methyl (S)-2- amino-3-cyclopentylpropanoate hydrochloride (27 mg, 0.13 mmol, 1 equiv), DIPEA (51 mg, 69 μL, 0.40 mmol, 3 equiv) and HATU (55 mg, 0.15 mmol, 1.1 equiv). The reaction mixture was25 stirred at room temperature for 16 h and directly purified by preparative reversed phase chro-matography (Waters XSelectTMCSH C18 column, ammonium bicarbonate in water / acetonitrile) to afford methyl (S)-2-(5-((7-bromo-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-1-yl)methyl)thio- phene-2-carboxamido)-3-cyclopentylpropanoate (44 mg, 87 μmol, 65%) as a white glass. LCMS (Method B) tR 2.12 min, MS (ESI) 508. (M+H)+. To a solution of methyl (S)-2-(5-((7-bromo-2,3-30 dihydro-1H-pyrido[2,3-b][1,4]oxazin-1-yl)methyl)thiophene-2-carboxamido)-3-cyclopentyl-propanoate (44 mg, 87 μmol) in THF (0.6 mL) and water (0.3 mL) was added lithium hydroxide monohydrate (18 mg, 0.43 mmol, 5 equiv). The reaction mixture was stirred at room tempera- ture for 16 h, diluted with water and acidified using aqueous 1N HCl. The solids that wereANAVO therapeutics BV A19159WO64 formed were isolated by filtration and dried in air to afford (S)-2-(5-((7-bromo-2,3-dihydro-1H- pyrido[2,3-b][1,4]oxazin-1-yl)methyl)thiophene-2-carboxamido)-3-cyclopentylpropanoic acid (30 mg, 61 μmol, 70%) as an off white solid. LCMS (Method B) tR 1.66 min, MS (ESI) 494. (M+H)+. To a cooled (0 °C) solution of (S)-2-(5-((7-bromo-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-1- 5yl)methyl)thiophene-2-carboxamido)-3-cyclopentylpropanoic acid (28 mg, 57 μmol) in DMF (1.0mL) were added isopropylamine (5.9 μL, 68 μmol, 1.2 equiv), DIPEA (59 μL, 0.35 mmol, 6 equiv) and HATU (35 mg, 85 μmol, 1.5 equiv). The reaction mixture was stirred at 0 °C and sub- sequently at room temperature overnight. The resulting mixture were filtered over a syringe filter and directly purified by preparative HPLC (Method B), to afford (S)-5-((7-bromo-2,3-dihydro-1H-10 pyrido[2,3-b][1,4]oxazin-1-yl)methyl)-N-(3-cyclopentyl-1-(isopropylamino)-1-oxopropan-2-yl)thio-phene-2-carboxamide (18.3 mg, 34.1 μmol, 60%) as an off-white solid.1H NMR (400 MHz, DMSO-d6) δ 8.38 (d, J = 8.5 Hz, 1H), 7.86 (d, J = 7.7 Hz, 1H), 7.79 (d, J = 3.8 Hz, 1H), 7.48 (d, J = 2.2 Hz, 1H), 7.35 (d, J = 2.2 Hz, 1H), 7.09 (d, J = 3.7 Hz, 1H), 4.75 (s, 2H), 4.39 – 4.34 (m, 1H), 4.33 (t, J = 4.6 Hz, 2H), 3.86 – 3.76 (m, 1H), 3.39 (t, J = 4.5 Hz, 2H), 1.86 – 1.58 (m, 5H),15 1.58 – 1.49 (m, 2H), 1.49 – 1.34 (m, 2H), 1.20 – 1.06 (m, 2H), 1.04 (d, J = 6.6 Hz, 3H), 1.02 (d,J = 6.5 Hz, 3H); UPLC (Method E): tR 1.63 min, 100%, MS (ESI) 535.0 / 536.9 (M+H)+. The following examples have been prepared using procedures analogous to Example 37, using the appropriate starting materials and intermediates, and purified by preparative HPLC (Method20 A or B), and / or SFC (Method A or B):Table 2: ANAVO therapeutics BV A19159WO65 ANAVO therapeutics BV A19159WO66 ANAVO therapeutics BV A19159WO67 ANAVO therapeutics BV A19159WO68 ANAVO therapeutics BV A19159WO69 ANAVO therapeutics BV A19159WO70 ANAVO therapeutics BV A19159WO71 Example 65: Synthesis of (S)-N-(3-cyclopentyl-1-((1-methyl-1H-pyrazol-4-yl)amino)-1-oxo- propan-2-yl)-5-((2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)methyl)thiophene-2-carboxamide 5To 3,4-dihydro-2H-benzo[b][1,4]oxazine (18 mg, 0.13 mmol, 1.2 equiv) were added (S)-N-(3-cy-clopentyl-1-((1-methyl-1H-pyrazol-4-yl)amino)-1-oxopropan-2-yl)-5-formylthiophene-2-carboxa- mide (Intermediate 8, 41 mg, 0.11 mmol), anhydrous toluene (2 mL) and acetic acid (19 μL, 0.33 mmol, 3 equiv). The reaction was stirred and heated in a sealed vial at 100 °C for 6 h, cooled to room temperature and sodium triacetoxyborohydride (58 mg, 0.27 mmol, 2.5 equiv)10 was added. The resulting mixture was stirred at room temperature for 3 d and subsequentlyconcentrated in vacuo. The residue was dissolved in DMSO / MeOH, filtered to remove remain- ing solids, and purified by preparative HPLC (Method B), affording (S)-N-(3-cyclopentyl-1-((1-ANAVO therapeutics BV A19159WO72 methyl-1H-pyrazol-4-yl)amino)-1-oxopropan-2-yl)-5-((2,3-dihydro-4H-benzo[b][1,4]oxazin-4- yl)methyl)thiophene-2-carboxamide (13 mg, 0.026 mmol, 24%) as an off-white solid.1H NMR (400 MHz, DMSO-d6) δ 10.11 (s, 1H), 8.56 (d, J = 8.0 Hz, 1H), 7.84 (s, 1H), 7.79 (d, J = 3.8 Hz, 1H), 7.41 (s, 1H), 7.07 (d, J = 3.7 Hz, 1H), 6.83 (dd, J = 8.1, 1.5 Hz, 1H), 6.74 (td, J = 7.7, 1.6 5Hz, 1H), 6.68 (dd, J = 7.8, 1.6 Hz, 1H), 6.55 (td, J = 7.6, 1.5 Hz, 1H), 4.66 (s, 2H), 4.50 – 4.42(m, 1H), 4.24 – 4.11 (m, 2H), 3.76 (s, 3H), 3.38 – 3.34 (m, 2H), 1.90 – 1.62 (m, 5H), 1.62 – 1.50 (m, 2H), 1.50 – 1.35 (m, 2H), 1.21 – 1.04 (m, 2H); UPLC (Method F): tR 1.66 min, 99.8%, MS (ESI) 494.1 (M+H)+.10 The following examples have been prepared using procedures analogous to Example 65, usingthe appropriate starting materials and intermediates, and purified by preparative HPLC (Method A or B): Table 3: ANAVO therapeutics BV A19159WO73 ANAVO therapeutics BV A19159WO74 Example 74: Synthesis of (S)-N-(3-cyclopentyl-1-((1-methyl-1H-pyrazol-4-yl)amino)-1-oxo- propan-2-yl)-5-((4-methyl-3,4-dihydropyrido[2,3-b]pyrazin-1(2H)-yl)methyl)thiophene-2-carbox- amide 5 To an oven-dried reaction vial were added (S)-N-(3-cyclopentyl-1-((1-methyl-1H-pyrazol-4- yl)amino)-1-oxopropan-2-yl)-5-formylthiophene-2-carboxamide (Intermediate 8, 70 mg, 0.19 mmol) and 4-methyl-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine (56 mg, 0.37 mmol, 2 equiv) and anhydrous DCM (6 mL). Under an argon atmosphere, titanium tetraisopropoxide (0.11 g, 0.1110 mL, 0.37 mmol, 2 equiv) was added and the reaction mixture was stirred at 20 °C for 2.5 h.Next, sodium triacetoxyborohydride (0.20 g, 0.93 mmol, 5 equiv) was added and stirring was continued at 20 °C overnight. The reaction mixture was diluted with DCM and aqueous satu- rated NaHCO3was added, followed by the addition of CHCl3 / iPrOH (3 / 1) to facilitate emulsion separation. The layers were separated and the aqueous layer was extracted three times with15 CHCl3 / iPrOH (3 / 1). The remaining aqueous layer was basified (pH10) with solid Na2CO3 and ex-tracted twice with CHCl3 / iPrOH (3 / 1). All combined organic layers were dried over sodium sul- fate and concentrated in vacuo. The residue was purified by silicagel chromatography (DCM / MeOH, 9:1), affording the title product (11 mg, 0.021 mmol, 11%) as an off-white solid.1H NMR (400 MHz, DMSO-d6) δ 10.09 (s, 1H), 8.53 (d, J = 8.0 Hz, 1H), 7.84 (s, 1H), 7.79 (d, J =20 3.8 Hz, 1H), 7.42 – 7.38 (m, 1H), 7.40 (s, 1H); 7.07 (d, J = 3.7 Hz, 1H), 6.73 (dd, J = 7.7, 1.5 Hz,1H), 6.42 (dd, J = 7.7, 4.9 Hz, 1H), 4.60 (s, 2H), 4.47 (td, J = 8.7, 5.4 Hz, 1H), 3.77 (s, 3H), 3.43 – 3.35 (m, 4H), 2.95 (s, 3H), 1.97 – 1.63 (m, 2H), 1.62 – 1.52 (m, 2H), 1.44 (dp, J = 7.2, 3.9 Hz, 2H), 1.21 – 1.07 (m, 2H); UPLC (Method B): tR 2.73 min, 95.4%, MS (ESI) 508.2 (M+H)+.25 Example 75: Synthesis of (S)-N-(3-cyclopentyl-1-((1-methyl-1H-pyrazol-4-yl)amino)-1-oxo-propan-2-yl)-5-((7-methyl-2,3-dihydropyrido[2,3-b]pyrazin-4(1H)-yl)methyl)thiophene-2-carbox- amide This compound was synthesized using procedures analogous to Example 74. After silicagel30 chromatography, the material was subjected to PTLC purification (DCM / MeOH, 10 / 1) to give theANAVO therapeutics BV A19159WO75 pure title product (8 mg, 0.016 mmol, 13%) as an off-white solid.1H NMR (400 MHz, DMSO-d6) δ 10.08 (s, 1H), 8.48 (d, J = 8.0 Hz, 1H), 7.84 (s, 1H), 7.75 (d, J = 3.7 Hz, 1H), 7.41 (s, 1H), 7.22 (t, J = 1.6 Hz, 1H), 7.01 (d, J = 3.8 Hz, 1H), 6.44 (d, J = 1.9 Hz, 1H), 5.65 (s, 1H), 4.82 (d, J = 1.8 Hz, 2H), 4.46 (q, J = 8.1 Hz, 1H), 3.76 (s, 3H), 3.25 (s, 4H), 2.04 (s, 3H), 1.88 – 1.63 (m, 55H), 1.55 (d, J = 7.0 Hz, 2H), 1.48 – 1.40 (m, 2H), 1.16 – 1.06 (m, 2H); UPLC (Method B): tR1.81 min, 95.4%, MS (ESI) 508.2 (M+H)+. Example 76: Synthesis of (S)-5-((6-chloro-1H-indazol-1-yl)methyl)-N-(3-cyclopentyl-1-((1- methyl-1H-pyrazol-4-yl)amino)-1-oxopropan-2-yl)thiophene-2-carboxamide 10 To a solution of (S)-5-(chloromethyl)-N-(3-cyclopentyl-1-((1-methyl-1H-pyrazol-4-yl)amino)-1- oxopropan-2-yl)thiophene-2-carboxamide (Intermediate 9, 45 mg, 0.11 mmol) and 6-chloro-1H- indazole (17 mg, 0.11 mmol, 1 equiv) in DMF (1.0 mL) was added cesium carbonate (74 mg, 0.23 mmol, 2 equiv). The reaction was stirred at room temperature overnight, after which the re-15 action mixture was directly purified by preparative HPLC (Method B), affording the title product(20.5 mg, 35%) as an off-white solid.1H NMR (400 MHz, DMSO-d6) δ 10.08 (s, 1H), 8.59 (d, J = 8.0 Hz, 1H), 8.17 (d, J = 0.9 Hz, 1H), 8.01 (s, 1H), 7.83 (s, 1H), 7.80 (d, J = 8.6 Hz, 1H), 7.76 (d, J = 3.8 Hz, 1H), 7.39 (s, 1H), 7.18 (dd, J = 8.6, 1.7 Hz, 1H), 7.15 (d, J = 3.8 Hz, 1H), 5.87 (s, 2H), 4.49 – 4.39 (m, 1H), 3.76 (s, 3H), 1.85 – 1.60 (m, 5H), 1.60 – 1.48 (m, 2H), 1.48 – 1.35 (m,20 2H), 1.18 – 1.04 (m, 2H); UPLC (Method F): tR 1.71 min, 99.7%, MS (ESI) 511.1 (M+H)+.The following examples have been prepared using procedures analogous to Example 76, using the appropriate starting materials and intermediates, and purified by preparative HPLC (Method A or B):25 Table 4: ANAVO therapeutics BV A19159WO76 ANAVO therapeutics BV A19159WO77 Example 85: Synthesis of (S)-N-(3-cyclopentyl-1-((1-methyl-1H-pyrazol-4-yl)amino)-1-oxo- propan-2-yl)-5-((2-oxo-7-(trifluoromethyl)-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-1- yl)methyl)thiophene-2-carboxamide 5 To a solution of hydroxy-acetic acid methyl ester (119 mg, 101 μL, 1.32 mmol, 1.2 equiv) in THF (4.0 mL) was added sodium hydride (60 wt%, 57.4 mg, 1.43 mmol, 1.3 equiv). The reaction mix- ture was stirred at room temperature for 1 h, after which 5-(trifluoromethyl)-3-nitro-2-chloropyri- dine (250 mg, 1.10 mmol) was added and the reaction mixture was stirred at room temperature10 for 2 h. The resulting mixture was diluted with water and extracted with EtOAc (3x). The com-bined organic layers were concentrated in vacuo to afford methyl 2-((3-nitro-5-(trifluo- romethyl)pyridin-2-yl)oxy)acetate (306 mg, 1.09 mmol, 99%) as a yellow oil.1H NMR (400 MHz, CDCl3) δ 8.65 – 8.54 (m, 2H), 5.15 (s, 2H), 3.79 (s, 3H); LCMS (Method B): tR 1.96 min, MS (ESI) 280.8 (M+H)+. To a solution of methyl 2-((3-nitro-5-(trifluoromethyl)pyridin-2-yl)oxy)acetate15 (306 mg, 1.09 mmol) in acetic acid (5.0 mL) was added iron (305 mg, 5.46 mmol, 5 equiv), thereaction mixture was heated to 80 °C for 2 h, cooled to room temperature and filtered over Celite. The filter cake was washed with EtOAc, the combined organic layers were washed with water (3x) and concentrated in vacuo. The residue was coevaporated with heptane (2x) and with DCM to afford 7-(trifluoromethyl)-1H-pyrido[2,3-b][1,4]oxazin-2(3H)-one (172 mg, 0.7920 mmol, 72%) as a brown / yellow solid. LCMS (Method B) tR 1.52 min, MS (ESI) 218.9 (M+H)+. Toa solution of 7-(trifluoromethyl)-1H-pyrido[2,3-b][1,4]oxazin-2(3H)-one (15.0 mg, 68.8 μmol) in DMF (2 mL) was added sodium hydride (60 wt%, 3.85 mg, 96.3 μmol, 1.4 equiv). The reaction mixture was stirred for 5 min followed by the addition of (S)-5-(chloromethyl)-N-(3-cyclopentyl-1-ANAVO therapeutics BV A19159WO78 ((1-methyl-1H-pyrazol-4-yl)amino)-1-oxopropan-2-yl)thiophene-2-carboxamide (27.2 mg, 68.8 μmol, 1 equiv). The reaction was stirred for 16 h at room temperature, diluted with water and ex- tracted with EtOAc (3x). The combined organic layers were concentrated in vacuo and the residue was purified by preparative HPLC (Method A) to afford (S)-N-(3-cyclopentyl-1-((1- 5methyl-1H-pyrazol-4-yl)amino)-1-oxopropan-2-yl)-5-((2-oxo-7-(trifluoromethyl)-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-1-yl)methyl)thiophene-2-carboxamide (3.8 mg, 6.5 μmol, 9.5%) as a white solid.1H NMR (400 MHz, DMSO-d6) δ 10.10 (s, 1H), 8.60 (d, J = 8.0 Hz, 1H), 8.26 (q, J = 1.1 Hz, 1H), 7.95 (d, J = 2.1 Hz, 1H), 7.83 (s, 1H), 7.77 (d, J = 3.8 Hz, 1H), 7.40 (s, 1H), 7.20 (d, J = 3.8 Hz, 1H), 5.42 (s, 2H), 5.08 (s, 2H), 4.46 (t, J = 7.7 Hz, 1H), 3.76 (s, 3H), 1.85 – 1.61 (m,10 5H), 1.54 (d, J = 7.9 Hz, 2H), 1.49 – 1.38 (m, 2H), 1.12 (s, 2H); UPLC (Method A): tR 2.81 min,99.2%, MS (ESI) 577.2 (M+H)+. The following compounds were prepared analogously to other exemplified compounds de- scribed herein: 15 Example 86: 5-((7-bromo-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-1-yl)methyl)-N-((2S)-3-(3,3- difluorocyclopentyl)-1-((1-methyl-1H-pyrazol-4-yl)amino)-1-oxopropan-2-yl)thiophene-2-carbox- amide20 Example 87: 5-((7-bromo-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-1-yl)methyl)-N-((2S)-3-(3- fluorocyclopentyl)-1-((1-methyl-1H-pyrazol-4-yl)amino)-1-oxopropan-2-yl)thiophene-2-carbox- amide 25 Example 88: (S)-N-(3-cyclopentyl-1-((1-methyl-1H-pyrazol-4-yl)amino)-1-oxopropan-2-yl)-5-((7-30 methoxy-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-1-yl)methyl)thiophene-2-carboxamide ANAVO therapeutics BV A19159WO79 Example 89: (S)-5-((7-cyano-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-1-yl)methyl)-N-(3-cy- clopentyl-1-((1-methyl-1H-pyrazol-4-yl)amino)-1-oxopropan-2-yl)thiophene-2-carboxamide 5Example 90: 5-((7-bromo-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-1-yl)methyl)-N-((S)-3-cyclo-pentyl-1-((-2-hydroxycyclobutyl)amino)-1-oxopropan-2-yl)thiophene-2-carboxamide 10 Example 91: 5-((7-bromo-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-1-yl)methyl)-N-((S)-3-cy-clopentyl-1-((-2-hydroxycyclobutyl)amino)-1-oxopropan-2-yl)thiophene-2-carboxamide 15 Example 92: (S)-5-((7-bromo-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-1-yl)methyl)-N-(1-((3-cy-anobicyclo[1.1.1]pentan-1-yl)amino)-3-cyclopentyl-1-oxopropan-2-yl)thiophene-2-carboxamide Example 93: (S)-5-((7-bromo-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-1-yl)methyl)-N-(3-cy-20 clopentyl-1-((2-hydroxyphenyl)amino)-1-oxopropan-2-yl)thiophene-2-carboxamide Example 94: (S)-5-((7-bromo-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-1-yl)methyl)-N-(3-(cy- clopentyloxy)-1-((1-methyl-1H-pyrazol-4-yl)amino)-1-oxopropan-2-yl)thiophene-2-carboxamideANAVO therapeutics BV A19159WO80 Example 95: 5-(1-(7-bromo-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-1-yl)ethyl)-N-((S)-3-cy- clopentyl-1-((1-methyl-1H-pyrazol-4-yl)amino)-1-oxopropan-2-yl)thiophene-2-carboxamide 5 Example 96: N-((S)-3-((RS)-3,3-difluorocyclopentyl)-1-((1-methyl-1H-pyrazol-4-yl)amino)-1-oxo- propan-2-yl)-5-((7-(trifluoromethyl)-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-1-yl)methyl)thio-10 phene-2-carboxamide 1H NMR (400 MHz, DMSO-d6) δ 10.16 (d, J = 5.8 Hz, 1H), 8.80 – 8.60 (m, 1H), 7.84 (s, 1H),15 7.80 (d, J = 3.7 Hz, 1H), 7.77 (d, J = 1.9 Hz, 1H), 7.42 (d, J = 2.1 Hz, 1H), 7.41 (s, 1H), 7.13 (dd,J = 3.9, 1.5 Hz, 1H), 4.83 (s, 2H), 4.47 (d, J = 7.5 Hz, 1H), 4.44 – 4.39 (m, 2H), 3.77 (s, 3H), 3.44 (t, J = 4.5 Hz, 2H), 2.32 – 1.66 (m, 8H), 1.52 – 1.32 (m, 1H). UPLC (Method B): tR 2.823 min, 100%, MS (ESI) 599.2 (M+H)+.20 Example 97: (S)-5-((7-chloro-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-1-yl)methyl)-N-(3-cy-clopentyl-1-(cyclopropylamino)-1-oxopropan-2-yl)thiophene-2-carboxamide 1H NMR (400 MHz, DMSO-d6) δ 8.41 (d, J = 8.3 Hz, 1H), 8.06 (d, J = 4.3 Hz, 1H), 7.78 (d, J = 3.8 Hz, 1H), 7.41 (d, J = 2.1 Hz, 1H), 7.26 (d, J = 2.2 Hz, 1H), 7.09 (d, J = 3.8 Hz, 1H), 4.75 (s,25 2H), 4.40 – 4.22 (m, 3H), 3.43 – 3.36 (m, 2H), 2.65 – 2.57 (m, 1H), 1.86 – 1.57 (m, 5H), 1.57 –1.36 (m, 4H), 1.16 – 0.99 (m, 2H), 0.65 – 0.53 (m, 2H), 0.44 – 0.32 (m, 2H). UPLC (Method B): tR 2.953 min, 99.31%, MS (ESI) 489.0 (M+H)+.ANAVO therapeutics BV A19159WO81 Example 98: (S)-5-((6-chloro-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)methyl)-N-(3-cyclopentyl- 1-(cyclopropylamino)-1-oxopropan-2-yl)thiophene-2-carboxamide 1H NMR (400 MHz, DMSO-d6) δ 8.39 (d, J = 8.3 Hz, 1H), 8.06 (d, J = 4.5 Hz, 1H), 7.77 (d, J = 53.8 Hz, 1H), 7.06 (d, J = 3.8 Hz, 1H), 6.85 (d, J = 2.4 Hz, 1H), 6.69 (d, J = 8.5 Hz, 1H), 6.55 (dd,J = 8.5, 2.4 Hz, 1H), 4.70 (s, 2H), 4.29 (td, J = 9.1, 5.2 Hz, 1H), 4.23 – 4.12 (m, 2H), 3.38 – 3.37 (m, 2H), 2.65 – 2.57 (m, 1H), 1.85 – 1.57 (m, 5H), 1.57 – 1.35 (m, 4H), 1.18 – 1.01 (m, 2H), 0.64 – 0.53 (m, 2H), 0.44 – 0.33 (m, 2H). UPLC (Method B): tR 3.409 min, 97.60%, MS (ESI) 488.0 (M+H)+. 10 Example 99: (S)-N-(3-cyclopentyl-1-((1-methyl-1H-pyrazol-4-yl)amino)-1-oxopropan-2-yl)-5-((7- hydroxy-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-1-yl)methyl)thiophene-2-carboxamide 1H NMR (300 MHz, DMSO-d6) δ 10.08 (s, 1H), 9.04 (s, 1H), 8.54 (d, J = 8.0 Hz, 1H), 7.84 (s,15 1H), 7.81 (d, J = 3.8 Hz, 1H), 7.42 (s, 1H), 7.07 (d, J = 3.8 Hz, 1H), 6.97 (d, J = 2.5 Hz, 1H),6.60 (d, J = 2.5 Hz, 1H), 4.65 (s, 2H), 4.48 (d, J = 5.5 Hz, 1H), 4.22 (d, J = 5.0 Hz, 2H), 3.77 (s, 3H), 1.87 – 1.44 (m, 10H), 1.16 (s, 1H). UPLC (Method D): tR 3.121 min, 98.71%, MS (ESI) 509.3 (M-H)+.20 Example 100: (S)-5-((7-bromo-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-1-yl)methyl)-N-(3-cy-clopentyl-1-((1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-4-yl)amino)-1-oxopropan-2-yl)thiophene- 2-carboxamide 1H NMR (400 MHz, DMSO-d6) δ 10.14 (s, 1H), 8.62 (d, J = 8.0 Hz, 1H), 7.88 (s, 1H), 7.82 (d, J25 = 3.7 Hz, 1H), 7.48 (d, J = 2.1 Hz, 1H), 7.44 (s, 1H), 7.36 (d, J = 2.1 Hz, 1H), 7.11 (d, J = 3.7Hz, 1H), 4.76 (s, 2H), 4.67 (s, 1H), 4.51 – 4.42 (m, 1H), 4.33 (t, 2H), 3.93 (s, 2H), 3.39 (t, J = 4.5 Hz, 2H), 1.90 – 1.63 (m, 5H), 1.63 – 1.51 (m, 2H), 1.51 – 1.37 (m, 2H), 1.22 – 1.06 (m, 2H), 1.02 (s, 3H), 1.02 (s, 3H). UPLC (Method B): tR 2.834 min, 99.34%, MS (ESI) 631.0 (M+H)+.ANAVO therapeutics BV A19159WO82 Comparative Example CEx01: 5-((S)-1-(7-chloro-3,4-dihydroquinolin-1(2H)-yl)ethyl)-N-((S)-3- cyclopentyl-1-(cyclopropylamino)-1-oxopropan-2-yl)thiophene-2-carboxam- 1H NMR (400 MHz, DMSO) δ 8.40 (d, J = 8.3 Hz, 1H), 8.08 (d, J = 4.3 Hz, 1H), 7.78 (d, J = 3.8 5Hz, 1H), 7.00 (dd, J = 3.8, 1.0 Hz, 1H), 6.92 (d, J = 8.0 Hz, 1H), 6.81 (d, J = 2.1 Hz, 1H), 6.53(dd, J = 7.9, 2.0 Hz, 1H), 5.36 (q, J = 6.8 Hz, 1H), 4.29 (td, J = 9.1, 5.3 Hz, 1H), 3.21 – 3.08 (m, 1H), 3.08 – 2.95 (m, 1H), 2.70 – 2.55 (m, 3H), 1.91 – 1.67 (m, 5H), 1.67 – 1.34 (m, 9H), 1.18 – 1.00 (m, 2H), 0.66 – 0.53 (m, 2H), 0.46 – 0.31 (m, 2H). UPLC (Method B): tR 3.751 min, 97.91%, MS (ESI) 500.2 (M+H)+. 10 Comparative Example CEx02: 5-((R)-1-(7-chloro-3,4-dihydroquinolin-1(2H)-yl)ethyl)-N-((S)-3- cyclopentyl-1-(cyclopropylamino)-1-oxopropan-2-yl)thiophene-2-carboxamide 1H NMR (400 MHz, DMSO) δ 8.39 (d, J = 8.3 Hz, 1H), 8.07 (d, J = 4.4 Hz, 1H), 7.77 (d, J = 3.815 Hz, 1H), 7.00 (dd, J = 3.8, 0.9 Hz, 1H), 6.91 (d, J = 7.9 Hz, 1H), 6.81 (d, J = 2.1 Hz, 1H), 6.53(dd, J = 7.9, 2.0 Hz, 1H), 5.36 (q, J = 6.7 Hz, 1H), 4.30 (td, J = 9.1, 5.3 Hz, 1H), 3.15 (ddd, J = 12.1, 8.6, 3.6 Hz, 1H), 3.09 – 2.97 (m, 1H), 2.71 – 2.54 (m, 3H), 1.90 – 1.67 (m, 5H), 1.67 – 1.35 (m, 9H), 1.19 – 1.00 (m, 2H), 0.64 – 0.51 (m, 2H), 0.47 – 0.30 (m, 2H). UPLC (Method B): tR 3.758 min, 98.47%, MS (ESI) 500.2 (M+H)+. 20 Biological data WIP1 (PPM1D) in vitro phosphatase activity assay with Fluorescein Diphosphate (FDP)25 substrateRecombinant WIP1 (amino acids 1-397; SEQ ID NO1: GHMAGLYSLGVSVFSDQGGRKYMED- VTQIVVEPEPTAEEKPSPRRSLSQPLPPRPSPAALPGGEVSGKGPAVAAREARDPLPDAGAS- PAPSRCCRRRSSVAFFAVCDGHGGREAAQFAREHLWGFIKKQKGFTSSEPAKV-30 CAAIRKGFLACHLAMWKKLAEWPKTMTGLPSTSGTTASVVIIRGMKMYVAHVGDSGVVLGIQD-DPKDDFVRAVEVTQDHKPELPKERERIEGLGGSVMNKSGVNRVVWKRPRLTHNG- PVRRSTVIDQIPFLAVARALGDLWSYDFFSGEFVVSPEPDTSVHTLDPQKHKYIILGSDGLWN- MIPPQDAISMCQDQEEKKYLMGEHGQSCAKMLVNRALGRWRQRMLRADNTSAIVICISPEVD- NQGNFTNEDELYLNLTDPSGS) was expressed in E. coli, purified using standard chromato-35 graphy. The purified protein was stored in 50 mM Tris pH 7.1, 500 mM NaCl, 10 mM MgCl2, 2%glycerol, 1 mM DTT. The FDP phosphatase assay buffer consisted of 50 mM HEPES pH 7.5, 10 mM MgCl2, 1 mM MnCl2, 0.05% Tween20, 1 mM DTT. The activity assay with FDP was per- formed in 40 µl reactions in Corning 96-well Half Area White Flat Bottom Polystyrene NBS Mi-ANAVO therapeutics BV A19159WO83 croplates in the presence of 20 µM FDP and 10 nM WIP1. Compounds were dissolved in DMSO. Serially diluted compounds were added to a maximal final concentration of 10μM in a 3.3-fold drops for 10 points to a minimum concentration of 0.3nM. The maximal final DMSO concentration in the reactions was 1%. Control reactions without compound (1% DMSO) and 5without WIP1 were measured on each plate. After starting the reactions by the addition of WIP1,the microplates were sealed with adhesive foil and incubated for 30 min at 30 °C. Reactions were stopped by adding 10 µl 125 mM EDTA. The fluorescence signal was read in an EnVision Multimode Reader (PerkinElmer) using excitation / emission at 490 / 514 nm. IC50values were cal- culated using GraphPad Prism software. 10 As alternative protocol: Used for Examples 97, 98, CEx01 and CEx02: WIP1 (PPM1D) in vitro phosphatase activity assay with 6,8-Difluor-4-methylumbelliferyl- phosphat (DIFMUP) substrate15Recombinant WIP1 (amino acids 1-397; SEQ ID NO1: "AGLYSLGVSVFSDQGGRKYMED- VTQIVVEPEPTAEEKPSPRRSLSQPLPPRPSPAALPGGEVSGKGPAVAAREARDPLPDAGAS- PAPSRCCRRRSSVAFFAVCDGHGGREAAQFAREHLWGFIKKQKGFTSSEPAKV- CAAIRKGFLACHLAMWKKLAEWPKTMTGLPSTSGTTASVVIIRGMKMYVAHVGDSGVVLGIQD-20 DPKDDFVRAVEVTQDHKPELPKERERIEGLGGSVMNKSGVNRVVWKRPRLTHNG-PVRRSTVIDQIPFLAVARALGDLWSYDFFSGEFVVSPEPDTSVHTLDPQKHKYIILGSDGLWN- MIPPQDAISMCQDQEEKKYLMGEHGQSCAKMLVNRALGRWRQRMLRADNTSAIVICISPEVD- NQGNFTNEDELYLNLTD" was expressed in E. coli, purified using NiNTA chromatography fol- lowed by HisS3 tag cleavage by His-Senp2, a reverse NiNTA and a final size-exclusion chro-25 matography (S200-16 / 600). The purified protein was stored in 50 mM Tris pH 7.5, 350 mMNaCl, 10 mM MgCl2, 2% glycerol, 2 mM DTT. The DIFMUP phosphatase assay buffer consisted of 50 mM HEPES pH7.5, 1 mM MnCl2, 10 mM MgCl2, 1 mM DTT, 0.05% Tween 20 (v / v), 1 µg / ml BSA. The activity assay with DIFMUP30 was performed in 15 µl reactions ProxiPlate-384 Plus F, Black 384-shallow well Microplates inthe presence of 300 µM DIFMUP and 100 nM WIP1. Compounds were dissolved in DMSO. Serially diluted compounds were added to a maximal fi- nal concentration of 50μM in a 3-fold drops for 11 points to a minimum concentration of 0.85 nM. The maximal final DMSO concentration in the reactions was 0.5%. Control reactions with-35 out compound (0.5% DMSO) and without WIP1 were measured on each plate. After starting thereactions by the addition of DIFMUP, the microplates were incubated for 30 min at RT. Reac- tions were stopped by adding 3 µl 125 mM EDTA. The fluorescence signal was read in an EnVi- sion (PerkinElmer) using excitation / emission at 358 / 455 nm. IC50values were calculated using CDD Vault software. 40 WIP1 Dephosphorylation Assay Measuring Cellular p53 Phospho-Serine 15 Levels In the cellular WIP1 (de-)phosphorylation assay the human osteosarcoma cell line U2OS is used. In these cells the direct WIP1 substrate phospho-p53Ser15 is dephosphorylated by the phosphatase WIP1. Inhibition of WIP1 activity results in the accumulation of phospho p53Ser1545 due to the lack of WIP1-dependent dephosphorylation.U2OS cells were plated in DMEM supplemented with 10% FCS in 96 well cell culture plates and incubated over night at 37oC and 5% CO2. The next day, serially diluted compounds were added to a maximal final concentration of 10μM in a 3.3-fold drops for 8 points to a minimumANAVO therapeutics BV A19159WO84 concentration of 3nM. The final DMSO concentration was 0.1%. The diluted compounds were added to the plates using nanodrop dispensing and a Tecan Dispenser. The cells were incubated with compounds for 3 hours at 37°C in complete culture medium con- 5taining 10% FCS. After cell lysis, quantification of phospho p53Ser15 was assessed in 96wellplates via sandwich-ELISA using a p53-specific capture antibody and a phospho-p53Ser15-spe- cific detection antibody. Curves were analyzed using GraphPad Prism and EC50values ex- pressed as log Molar.10 “+” represents a fitted IC50 value less than or equal to 10 µM and greater than 1 µM; “++” rep-resents a fitted IC50value less than or equal to 1 µM and greater than 0.2 µM; “+++” represents a fitted IC50value less than or equal to 0.2 µM and greater than 0.1 µM; “++++” represents a fit- ted IC50value less than or equal to 0.1 µM. 15 Table 5: “No.” denotes “Example Number” ANAVO therapeutics BV A19159WO85 ANAVO therapeutics BV A19159WO86 ANAVO therapeutics BV A19159WO87 ANAVO therapeutics BV A19159WO88 ANAVO therapeutics BV A19159WO89 ANAVO therapeutics BV A19159WO90 ANAVO therapeutics BV A19159WO91 ANAVO therapeutics BV A19159WO92 ANAVO therapeutics BV A19159WO93 ANAVO therapeutics BV A19159WO94 ANAVO therapeutics BV A19159WO95 ANAVO therapeutics BV A19159WO96 ANAVO therapeutics BV A19159WO97 ANAVO therapeutics BV A19159WO98 ANAVO therapeutics BV A19159WO99 ANAVO therapeutics BV A19159WO100 ANAVO therapeutics BV A19159WO101 CEx: comparative example.

Claims

ANAVO therapeutics BV A19159WO102 Claims 1. A compound of formula (I)5or a stereoisomer, tautomer, N-oxide, or pharmaceutically acceptable salt thereof; wherein10alkyl;alkyl; R2is H, C1-C2-alkyl, 5- or 6-membered saturated or partially unsaturated carbocyclyl, hetero- cyclyl, carbocyclyloxy, or heterocyclyloxy, or 4- to 12-membered saturated carbobicyclyl or15 heterobicyclyl, wherein the aforementioned heterocyclyl or heterobicyclyl comprises oneor more, same or different heteroatoms selected from O, N, or S, wherein said N- and / or S-atoms are independently oxidized or non-oxidized, and wherein each substitutable atom in the aforementioned groups is independently unsubstituted or substituted with one or more, same or different substituents RX;20 is H, C1-C4-alkyl, C1-C4-alkoxy, C1-C2-alkoxy-C1-C4-alkyl, 3- to 6-membered saturated,partially or fully unsaturated, or aromatic carbocyclyl, carbocyclylmethyl, heterocyclyl, or heterocyclylmethyl, or 4- to 12-membered saturated carbobicyclyl or heterobicyclyl, wherein the aforementioned heterocyclyl or heterobicyclyl comprises one or more, same or different heteroatoms selected from O, N, or S, wherein said N- and / or S-atoms are in-25 dependently oxidized or non-oxidized, and wherein each substitutable atom in the afore-mentioned groups is independently unsubstituted or substituted with one or more, same or different substituents RY; A30ANAVO therapeutics BV A19159WO103 5wherein the wavy line marks the connection to the remainder of the molecule; and wherein10 RX is halogen, CN, OH, C1-C4-alkyl, C1-C4-haloalkyl, C1-C4-alkoxy, C1-C4-haloalkoxy, or C1-C4-hydroxyalkyl; RYis halogen, CN, OH, S(=O)2CH3, S(=O)(=NH)CH3, NHC(=O)CH3, NH2, C1-C4-alkyl, C1-C4- haloalkyl, C1-C4-alkoxy, C1-C4-haloalkoxy, C1-C2-alkoxy-C1-C4-alkyl, C1-C4-hydroxyalkyl, or C3-C4-cycloalkyl;15 R4 each independently is halogen, CN, OH, C1-C4-alkyl, C1-C4-haloalkyl, C1-C4-alkoxy, C1-C4-haloalkoxy, C1-C4-hydroxyalkyl, or C3-C4-cycloalkyl; R5each independently is halogen, CN, C1-C4-alkyl, C1-C4-haloalkyl, C1-C4-alkoxy, or C1-C4- haloalkoxy; or two R5together form =O; mis 0, 1, or 2;20 n is 0, 1, 2, 3, or 4;Y1is CH2, NH, NRN, or O; Y2is CH or N; Y3is CH2; and wherein25 RN is C1-C6-alkyl or C3-C10-cycloalkyl, wherein optionally one or more -CH2- groups may bereplaced by -O-.

2. The compound according to claim 1, whereinA is a moiety selected fromANAVO therapeutics BV A19159WO104 5wherein the wavy line marks the connection to the remainder of the molecule. 10 3. The compound according to claim 1 or 2, whereinA is a moiety selected from15 wherein the wavy line marks the connection to the remainder of the molecule.

4. The compound according to any one of claims 1 to 3, whereinA is a moiety selected fromANAVO therapeutics BV A19159WO105wherein the wavy line marks the connection to the remainder of the molecule; and wherein preferably R4is Br, Cl, CN, CH3, CF3, or cyclopropyl. 5 5. The compound according to any one of claims 1 to 4, whereinA is a moiety selected from, ;10 wherein the wavy line marks the connection to the remainder of the molecule;and wherein preferably R4is Br, Cl, CH3, or CF3.

6. The compound according to claim 1, wherein15 A is a moiety selected fromwherein the wavy line marks the connection to the remainder of the molecule; and wherein preferably Ais a moiety selected from20wherein R4is Br, Cl, CN, CH3, CF3, or cyclopropyl.

7. The compound according to any one of claims 1 to 6, wherein25 X1 is CH.

8. The compound according to any one of claims 1 to 7, whereinR1Ais H or CH3; and R1Bis H or CH3. 30 9. The compound according to any one of claims 1 to 8, whereinR1Ais H; and R1Bis H.35 10. The compound according to any one of claims 1 to 9, whereinANAVO therapeutics BV A19159WO106 R2is cyclopentyl or tetrahydrofuranyl, wherein each substitutable carbon atom in the afore- mentioned rings is independently unsubstituted or substituted with one or more, same or different substituents RX.

511. The compound according to any one of claims 1 to 10, whereinR3is 3- or 4-membered saturated carbocyclyl or heterocyclyl, wherein the aforementioned heterocyclyl comprises an oxygen atom as heteroatom, and wherein each substitutable atom in the aforementioned groups is independently unsubstituted or substituted with one or more, same or different substituents RY;10 or 5- or 6-membered aromatic heterocyclyl; wherein the aforementioned heterocyclyl com-prises one or more nitrogen atoms as heteroatom(s), and wherein each substitutable atom in the aforementioned groups is independently unsubstituted or substituted with one or more, same or different substituents RY.15 12. The compound according to any one of claims 1 to 11, wherein20 13. The compound according to any one of claims 1 to 12, whereinA is a moiety selected from, ; wherein the wavy line marks the connection to the remainder of the molecule;25 and whereinR2wherein the wavy line marks the connection to the remainder of the molecule;30wherein the wavy line marks the connection to the remainder of the molecule.ANAVO therapeutics BV A19159WO107 14. The compound according to any one of claims 1 to 13, wherein the compound of formula(I) is a compound of formula (IS)5 15. The compound according to any one of claims 1 to 14, wherein the compound accordingto formula (I) is selected from the group consisting of 10ANAVO therapeutics BV A19159WO108 B B B , 5 B B16. The compound according to any one of claims 1 to 14, wherein the compound according10 to formula (I) is selected from the group consisting ofANAVO therapeutics BV A19159WO109 517. A pharmaceutical composition comprising a pharmaceutically effective amount of the10 compound according to any one of claims 1 to 16 and optionally a pharmaceutically acceptablecarrier or excipient.

18. A compound according to any one of claims 1 to 16 or a pharmaceutical composition ac-cording to claim 17 for use in medicine. 15 19. A compound according to any one of claims 1 to 16 or a pharmaceutical composition ac-cording to claim 17 for use in the treatment of a disease selected from the group consisting of cancer, pre-cancerous syndromes, autoimmune conditions, neurological diseases, and viral dis- ease, preferably selected from the group consisting of cancer, pre-cancerous syndromes, au-ANAVO therapeutics BV A19159WO110 toimmune conditions, and neurological diseases, more preferably selected from the group con- sisting of cancer, pre-cancerous syndromes, and neurological diseases.

20. A compound according to any one of claims 1 to 16 or a pharmaceutical composition ac-5 cording to claim 17 for use in the treatment of a disease selected from the group consisting ofamyotrophic lateral sclerosis, attention deficit hyperactivity disorder, autism, Bannayan-Zonana syndrome, bladder cancer, blood cancer, bone cancer, breast cancer, inflammatory breast can- cer, brain cancer, cervical cancer, colorectal cancer, Cowden disease, endometrial cancer, ependymoma, esophagus cancer, Ewing's sarcoma, gastric cancer, head and neck cancer, indi-10 vidual allergic asthma, kidney cancer, Lhermitte-Duclos disease, lung cancer, liver cancer, lym-phoma, medulloblastoma, melanoma, mesothelioma, nasopharyngeal carcinoma, neuroblas- toma, neurofibromatosis, ovarian cancer, osteosarcoma, pancreatic cancer, prostate cancer, Rhabdomyosarcoma, thyroid cancer, urothelial cancer, and Wilm's tumor.

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