Amide derivatives as WIP1 inhibitors

Abstract

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 compounds of formula (I) for use as a medicament and to pharmaceutical compositions comprising said compounds.

Description

[0001] ANAVO Therapeutics BV A19160WO1 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 A19160WO2 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 A19160WO3 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 A19160WO4 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 A19160WO5 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. In certain embodiments, the compounds of formula (I) exhibit a high stability in human micro-20 some. In certain embodiments, the human microsome stability data are the most relevant datafor drug development. Accordingly, the compounds of formula (I) can advantageously be used as a medicament, in particular for the treatment of one or more diseases selected from the group consisting of amyotrophic lateral sclerosis, attention deficit hyperactivity disorder, autism, Bannayan-Zonana syndrome, bladder cancer, blood cancer, bone cancer, breast cancer, in-25 flammatory breast cancer, brain cancer, cervical cancer, colorectal cancer, Cowden disease,endometrial cancer, ependymoma, esophagus cancer, Ewing's sarcoma, gastric cancer, head and neck cancer, individual allergic asthma, kidney cancer, Lhermitte-Duclos disease, lung can- cer, liver cancer, lymphoma, medulloblastoma, melanoma, mesothelioma, nasopharyngeal car- cinoma, neuroblastoma, neurofibromatosis, ovarian cancer, osteosarcoma, pancreatic cancer,30 prostate cancer, Rhabdomyosarcoma, thyroid cancer, urothelial cancer, and Wilm's tumor.In a first aspect, the present invention relates to a compound of formula (I) 35 or a stereoisomer, tautomer, N-oxide, or pharmaceutically acceptable salt thereof; wherein40 A is -OR1, -NH-R1 or -NRA-R1; oris a moiety selected from ANAVO therapeutics BV A19160WO6 wherein the wavy line marks the connection to the remainder of the molecule; Bis a 5- or 6-membered aromatic carbocyclic or heterocyclic ring, wherein the aforemen-tioned heterocyclic ring 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-oxi- 5dized, and wherein each substitutable carbon or heteroatom in the aforementioned carbo-cyclic or heterocyclic rings is independently unsubstituted or substituted with one or more, same or different substituents RB; R2is H, C1-C2-alkyl, 5- or 6-membered saturated or partially unsaturated carbocyclyl or hete- rocyclyl, or carbocyclyloxy or heterocyclyloxy, or 4- to 12-membered saturated carbobicy-10 clyl or heterobicyclyl, wherein the aforementioned heterocyclyl or heterobicyclyl comprisesone 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 substi- tutable atom in the aforementioned groups is independently unsubstituted or substituted with one or more, same or different substituents RX;15 R3 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-20 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; and RNis H or CH3; and wherein25 R1 is 5- or 6-membered aromatic carbocyclyl, carbocyclylmethyl, heterocyclyl, or heterocy-clylmethyl, wherein the aforementioned heterocyclyl comprises one or more, same or dif- ferent heteroatoms selected from O, N, or S, wherein said N- and / or S-atoms are indepen- dently oxidized or non-oxidized, and wherein each substitutable atom in the aforemen- tioned groups is independently unsubstituted or substituted with one or more, same or dif-30 ferent substituents RZ;RAis H or CH3; RBis halogen, CN, C1-C4-alkyl, C1-C4-haloalkyl, C1-C4-alkoxy, or C1-C4-haloalkoxy; or RNand RBtogether with the atoms to which they are bonded and the atoms in between form a fused 5- or 6-membered heterocyclic ring, wherein said heterocyclic ring comprises the ni-35 trogen atom of the NRN group as heteroatom; orRAand RBtogether with the atoms to which they are bonded and together with the carbon atom to which the nitrogen atom of the NRAgroup is bonded form a fused 5- or 6-membered saturated heterocyclic ring, wherein said heterocyclic ring comprises the nitrogen atom of the NR1group as heteroatom;40 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;45 A1 is a 5- or 6-membered aromatic carbocyclic or heterocyclic ring, wherein the aforemen-tioned heterocyclic ring 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-oxi- dized;ANAVO therapeutics BV A19160WO7 A2is a 5- to 7-membered saturated, partially or fully unsaturated or aromatic carbocyclic or heterocyclic ring, wherein the aforementioned heterocyclic ring 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; 5R4 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; and10 n is 0, 1, 2, 3, or 4;and wherein RZis halogen, CN, C1-C4-alkyl, C1-C4-haloalkyl, C1-C4-alkoxy, C1-C4-haloalkoxy, C1-C4- alkylO-C(=O)-, C1-C4-alkyl-C(=O)-O-, (C1-C4-alkyl)2N-C(=O)-, C1-C4-alkyl-C(=O)-NH-, C3- C6-cycloalkyl, phenyl, or 3- to 6-membered saturated heterocyclyl, wherein said heterocy-15 clyl 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 said heterocyclyl is unsubstituted or substituted with one or more, same or different sub- stituents selected from halogen, C1-C2-alkyl, and C1-C2-haloalkyl; or two RZattached to neighboring atoms together with the atoms to which they are attached20 form a fused 5 or 6-membered saturated, partially or fully unsaturated, or aromatic carbo-cyclic or heterocyclic ring, wherein the aforementioned heterocyclic ring 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 said heterocyclic ring is unsubstituted or substituted with one or more, same or different substituents selected from25 halogen, C1-C2-alkyl, and C1-C2-haloalkyl.In particular, the present invention relates to a compound of formula (I) 30 or a stereoisomer, tautomer, N-oxide, or pharmaceutically acceptable salt thereof; wherein35 A is -OR1, -NH-R1 or -NRA-R1; oris a moiety selected from wherein the wavy line marks the connection to the remainder of the molecule; Bis a 5- or 6-membered aromatic carbocyclic or heterocyclic ring, wherein the aforemen-40 tioned heterocyclic ring comprises one or more, same or different heteroatoms selectedfrom O, N, or S, wherein said N- and / or S-atoms are independently oxidized or non-oxi- dized, and wherein each substitutable carbon or heteroatom in the aforementioned carbo-ANAVO therapeutics BV A19160WO8 cyclic or heterocyclic rings is independently unsubstituted or substituted with one or more, same or different substituents RB; R2is H, C1-C2-alkyl, 5- or 6-membered saturated or partially unsaturated carbocyclyl or hete- rocyclyl, or carbocyclyloxy or heterocyclyloxy, or 4- to 12-membered saturated carbobicy- 5clyl or heterobicyclyl, wherein the aforementioned heterocyclyl or heterobicyclyl comprisesone 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 substi- tutable atom in the aforementioned groups is independently unsubstituted or substituted with one or more, same or different substituents RX;10 R3 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-15 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; and RNis H or CH3; and wherein20 R1 is 3-pyridinyl or 4-pyridinyl, wherein each substitutable carbon or heteroatom in the afore-mentioned rings is independently unsubstituted or substituted with one or more, same or different substituents RZ; RAis H or CH3; RBis halogen, CN, C1-C4-alkyl, C1-C4-haloalkyl, C1-C4-alkoxy, or C1-C4-haloalkoxy; or25 RN and RB together with the atoms to which they are bonded and the atoms in between form afused 5- or 6-membered heterocyclic ring, wherein said heterocyclic ring comprises the ni- trogen atom of the NRNgroup as heteroatom; or RAand RBtogether with the atoms to which they are bonded and together with the carbon atom to which the nitrogen atom of the NRAgroup is bonded form a fused 5- or 6-membered30 saturated heterocyclic ring, wherein said heterocyclic ring comprises the nitrogen atom ofthe NR1group as heteroatom; RXis 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-C4-35 haloalkyl, C1-C4-alkoxy, C1-C4-haloalkoxy, C1-C2-alkoxy-C1-C4-alkyl, C1-C4-hydroxyalkyl, orC3-C4-cycloalkyl; A1is a 5- or 6-membered aromatic carbocyclic or heterocyclic ring, wherein the aforemen- tioned heterocyclic ring 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-oxi-40 dized;A2is a 5- to 7-membered saturated, partially or fully unsaturated or aromatic carbocyclic or heterocyclic ring, wherein the aforementioned heterocyclic ring 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;45 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; andANAVO therapeutics BV A19160WO9 nis 0, 1, 2, 3, or 4;and wherein RZis halogen, CN, C1-C4-alkyl, C1-C4-haloalkyl, C1-C4-alkoxy, C1-C4-haloalkoxy, C1-C4- alkylO-C(=O)-, C1-C4-alkyl-C(=O)-O-, (C1-C4-alkyl)2N-C(=O)-, C1-C4-alkyl-C(=O)-NH-, C3- 5C6-cycloalkyl, phenyl, or 3- to 6-membered saturated heterocyclyl, wherein said heterocy-clyl 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 said heterocyclyl is unsubstituted or substituted with one or more, same or different sub- stituents selected from halogen, C1-C2-alkyl, and C1-C2-haloalkyl;10 or two RZ attached to neighboring atoms together with the atoms to which they are attachedform a fused 5 or 6-membered saturated, partially or fully unsaturated, or aromatic carbo- cyclic or heterocyclic ring, wherein the aforementioned heterocyclic ring 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 said heterocyclic ring is15 unsubstituted or substituted with one or more, same or different substituents selected fromhalogen, C1-C2-alkyl, and C1-C2-haloalkyl. In one embodiment of the compound of formula (I), Ais -OR1, -NH-R1 or -NRA-R1;20 whereinR1is 3-pyridinyl or 4-pyridinyl, wherein each substitutable carbon or heteroatom in the afore- mentioned rings is independently unsubstituted or substituted with one or more, same or different substituents RZ.25 In a preferred embodiment,A is -OR1, -NH-R1 or -NRA-R1;wherein R1is 3-pyridinyl or 4-pyridinyl, wherein each substitutable carbon or heteroatom in the afore- mentioned rings is independently unsubstituted or substituted with one or more, same or30 different substituents RZ;wherein RZis F, Cl, Br, CN, CH3, CF2H, CF3, OCH3, CH3O-C(=O)-, CH3-C(=O)-NH-, cyclopropyl, mor- pholinyl, 4-methylpiperazinyl, or phenyl; or two RZattached to neighboring atoms together with the atoms to which they are attached35 form a fused 5 or 6-membered saturated, partially or fully unsaturated, or aromatic carbocyclicor heterocyclic ring, wherein the aforementioned heterocyclic ring comprises one or more, same or different heteroatoms selected from O, N, or S, wherein said N- and / or S-atoms are indepen- dently oxidized or non-oxidized, and wherein said heterocyclic ring is unsubstituted.40 In a more preferred embodiment of the compound of formula (I),A is -NH-R1 or -N(CH3)-R1;wherein R1is 3-pyridinyl or 4-pyridinyl, wherein each substitutable carbon or heteroatom in the afore- mentioned rings is independently unsubstituted or substituted with one or more, same or differ-45 ent substituents RZ;wherein RZis F, Cl, or CH3. In an even more preferred embodiment of the compound of formula (I),ANAVO therapeutics BV A19160WO10 Ais -NH-R1 or -N(CH3)-R1;wherein R1is 3-pyridinyl or 4-pyridinyl, wherein each substitutable carbon or heteroatom in the afore- mentioned rings is independently unsubstituted or substituted with one or more, same or differ- 5ent substituents RZ;wherein RZis F, or CH3. In another embodiment of the compound of formula (I),10 A is a moiety selected from15 ANAVO therapeutics BV A19160WO11 wherein the wavy line marks the connection to the remainder of the molecule; and and wherein Y1is CH2, NH, NCH3, or O; 5Y2 is CH or N;Y3is CH2; and the remaining variables are as defined above. In another embodiment of the compound of formula (I),10 A is a moiety selected fromR4N N N O andO; wherein the wavy line marks the connection to the remainder of the molecule; and wherein preferably R4is Br, Cl, CN, CH3, CF3, or cyclopropyl. 15 In a more preferred embodiment, wherein the wavy line marks the connection to the remainder of the molecule;20 and whereinR4is Cl, or CF3. In another embodiment of the compound of formula (I), Bis a phenyl, thiophenyl or thiazolyl ring, wherein each substitutable carbon or heteroatom25 in the aforementioned carbocyclic or heterocyclic rings is independently unsubstituted orsubstituted with one or more, same or different substituents RB. In a preferred embodiment,30, wherein the wavy line marks the connection to A and the dotted line marks the connection to the carbon atom of the C(=O) group to which B is attached.ANAVO therapeutics BV A19160WO12 In a more preferred embodiment, Bis wherein the wavy line marks the connection to A and the dotted line marks the connection to the 5carbon atom of the C(=O) group to which B is attached.In another embodiment of the compound of formula (I), R2is cyclohexyl, cyclopentyl or tetrahydrofuranyl, wherein each substitutable carbon atom in the aforementioned rings is independently unsubstituted or substituted with one or more,10 same or different substituents RX.In a preferred embodiment, 15 wherein the wavy line marks the connection to the remainder of the molecule. In another preferred embodiment, R2is20 wherein the wavy line marks the connection to the remainder of the molecule. In another embodiment of the compound of formula (I), R3is CH3;25 or a 3- to 5-membered saturated carbocyclic or heterocyclic ring, wherein the aforemen-tioned heterocyclic ring comprises an oxygen atom as heteroatom, and wherein each sub- stitutable carbon atom in the aforementioned carbocyclic or heterocyclic rings is indepen- dently unsubstituted or substituted with one or more, same or different substituents RY; or a 5- or 6-membered aromatic carbocyclic or heterocyclic ring; wherein the aforemen-30 tioned heterocyclic ring comprises one or more, same or different heteroatoms selectedfrom O, N, or S, wherein said N- and / or S-atoms are independently oxidized or non-oxi- dized, and wherein each substitutable atom in the aforementioned carbocyclic or hetero- cyclic ring is independently unsubstituted or substituted with one or more, same or differ- ent substituents RY;35 or 5- or 6-membered aromatic carbocyclylmethyl or heterocyclylmethyl; wherein the afore-mentioned heterocyclyl 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-oxi- dized, and wherein each substitutable atom in the aforementioned carbocyclylmethyl orANAVO therapeutics BV A19160WO13 heterocyclylmethyl is independently unsubstituted or substituted with one or more, same or different substituents RY. In one preferred embodiment, 5R3 is wherein the wavy line marks the connection to the remainder of the molecule. In another preferred embodiment,10 wherein the wavy line marks the connection to the remainder of the molecule. In one embodiment of the compound of formula (I),15 A is -NH-R1 or -N(CH3)-R1;wherein R1is 3-pyridinyl or 4-pyridinyl, wherein each substitutable carbon or heteroatom in the aforementioned rings is independently unsubstituted or substituted with one or more, same or different substituents RZ;20 whereinRZis F, Cl, or CH3; or 25 wherein the wavy line marks the connection to the remainder of the molecule;and wherein R4is Cl, or CF3; Bis 30 wherein the wavy line marks the connection to A and the dotted line marks the connectionto the carbon atom of the C(=O) group to which B is attached; R2is wherein the wavy line marks the connection to the remainder of the molecule;35 andR3isANAVO therapeutics BV A19160WO14 wherein the wavy line marks the connection to the remainder of the molecule. In another embodiment of the compound of formula (I), Ais -NH-R1 or -N(CH3)-R1;5 whereinR1is 3-pyridinyl or 4-pyridinyl, wherein each substitutable carbon or heteroatom in the aforementioned rings is independently unsubstituted or substituted with one or more, same or different substituents RZ; wherein10 RZ is F, or CH3;or wherein the wavy line marks the connection to the remainder of the molecule;15 and whereinR4is Cl, or CF3; Bis wherein the wavy line marks the connection to A and the dotted line marks the connection20 to the carbon atom of the C(=O) group to which B is attached;R2is wherein the wavy line marks the connection to the remainder of the molecule; and25 R3 is 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) 30 In one embodiment, the compound according to formula (I) is selected from the groupANAVO therapeutics BV A19160WO15 consisting of 5In another embodiment, the compound according to formula (I) is selected from the groupconsisting of 10 ANAVO therapeutics BV A19160WO16 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), (IS), or (IS.a).ANAVO therapeutics BV A19160WO17 The compounds according to the invention may be amorphous or may exist in one or more dif- ferent crystalline states (polymorphs), which may have different macroscopic properties such as stability or show different biological properties such as activities. The present invention relates to amorphous and crystalline forms of compounds of formula (I), mixtures of different crystalline 5states 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- ange 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 a10 basic functionality, or by reacting acidic compounds according to the invention with a suitablebase. Suitable cationic counterions are in particular the ions of the alkali metals, preferably lithium, 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-15 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 comprise methylammonium, isopropylammonium, dimethylammonium, diisopropylammonium, trimethy- lammonium, tetramethylammonium, tetraethylammonium, tetrabutylammonium, 2-hydroxyethy-20 lammonium, 2-(2-hydroxyethoxy)ethylammonium, bis(2-hydroxyethyl)ammonium, ben-zyltrimethylammonium and benzyltriethylammonium, furthermore the cations of 1,4-piperazine, meglumine, benzathine and lysine. Suitable anionic counterions are in particular chloride, bromide, hydrogensulfate, sulfate, dihy- drogenphosphate, hydrogenphosphate, phosphate, nitrate, bicarbonate, carbonate, hexafluo-25 rosilicate, hexafluorophosphate, benzoate, and the anions of C1-C4-alkanoic acids, preferablyformate, acetate, propionate and butyrate, furthermore lactate, gluconate, and the anions of poly acids such as succinate, oxalate, maleate, fumarate, malate, tartrate and citrate, further- more sulfonate anions such as besylate (benzenesulfonate), tosylate (p-toluenesulfonate), nap- sylate (naphthalene-2-sulfonate), mesylate (methanesulfonate), esylate (ethanesulfonate), and30 ethanedisulfonate. They can be formed by reacting compounds according to the invention thathave a basic functionality with an acid of the corresponding anion. Depending on the substitution pattern, the compounds according to the invention may have one or more centers of chirality, including axial chirality. The invention provides both, pure enan- tiomers or pure diastereomers (also referred to as diastereoisomers), of the compounds accord-35 ing to the invention, and their mixtures, including racemic mixtures. Suitable compounds accord-ing to the invention also include all possible 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 amide group. Tautomers may be formed, if a substituent is present at the compound of formula (I), which al-40 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. 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.45 The scope of the invention also embraces the compounds provided herein, particularly thecompounds 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), in which one or more hydrogen atoms (or, e.g., all hydrogen atoms) are replaced by deuterium atoms (i.e.,2H; also referred to as "D"). Accordingly, the invention also embraces compounds ofANAVO therapeutics BV A19160WO18 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), can be increased using deuteration techniques known in the art. For example, a compound of 5formula (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, 2012; 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 deuterium10 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 or 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 designated15 atom is replaced with a specified substituent, provided that the substitution results in a stable orchemically feasible compound. Unless otherwise indicated, a substituted atom may have one or more substituents and each substituent is independently selected. The term "substitutable", when used in reference to a designated atom, means that attached to the atom is a hydrogen, which can be replaced with a suitable substituent.20 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, most 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.25 The organic moieties mentioned in the above definitions of the variables are - like the termhalogen - 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. The term “halo” refers to fluoro, chloro, bromo or iodo, particularly fluoro, chloro or bromo. The term “halogen” denotes in each case fluorine, bromine, chlorine or iodine, in particular fluorine,30 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 group having usually from 1 to 5 carbon atoms, preferably 1 to 4 carbon atoms, more preferably 1 to 3 or 1 or 2 carbon atoms. Examples of an alkyl group are methyl, ethyl, n-propyl, iso-propyl, n-35 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- 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.40 The term "haloalkyl" as used herein denotes in each case a straight-chain or branched alkylgroup 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. 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-45 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 alkyl 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 areANAVO therapeutics BV A19160WO19 methoxy, ethoxy, n-propoxy, iso-propoxy, n-butyloxy, 2-butyloxy, iso-butyloxy, tert.-butyloxy, and the like. 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, 5which 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- cule. Thus, it refers to an alkyl group, which is bonded via oxygen to a further alkyl group, which is then bonded to the remainder of the molecule. Examples of an alkoxyalkyl group are methoxymethyl, methoxyethyl, ethoxymethyl, ethoxyethyl, and the like.10 The term "haloalkoxy" as used herein denotes in each case a straight-chain or branchedalkoxy group having from 1 to 4 carbon atoms, preferably 1 to 2 carbon atoms, more preferably 1 carbon atom, wherein the hydrogen atoms of this group are partially or totally replaced with halogen atoms, in particular fluorine atoms. Preferred haloalkoxy moieties include C1- haloalkoxy, in particular C1-fluoroalkoxy, such as trifluoromethoxy and the like.15 The term “hydroxyalkyl” as used herein denotes in each case a straight-chain or branchedalkyl group having usually from 1 to 4 carbon atoms, preferably from 1 to 3 carbon atoms and being further substituted with 1 to 5, preferably with 1 to 2 hydroxy groups, in particular with 1 hydroxy 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-20 mainder of the molecule. Examples of an hydroxyalkyl group are hydroxymethyl, hydroxyethyl,n-hydroxypropyl, 2-hydroxypropyl, n-hydroxybutyl, 2-hydroxybutyl, 2-hydroxy-2-methylpropyl, and n-hydroxypentyl. Hydroxymethyl, hydroxyethyl, hydroxypropyl, and hydroxybutyl, are pre- ferred, in particular hydroxymethyl and hydroxyethyl. Furthermore, 1-hydroxy-1-methylethyl is a preferred hydroxyalkyl group.25 “=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, more preferably a 5- or 6-membered monocyclic ring comprising 3 to 9, preferably 4 to 8 or 3 to 6 or 5 to 7, more preferably 5 or 6 carbon atoms. The carbocycle may be saturated, partially or30 fully unsaturated, or aromatic, wherein saturated means that only single bonds are present, andpartially 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. The term “carbocylce” or “carbocyclyl”, unless otherwise indi- cated, may therefore cover inter alia cycloalkyl, cycloalkenyl, as well as phenyl. Preferably, the35 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 radical 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-40 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- 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 means45 that only single bonds are present, and partially or fully unsaturated means that one or moredouble 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 term “aromatic” in connection with the carbobicyclic ring means that both rings of the bicyclic moiety are aromatic, so that, e.g., 8 π electrons are present in case of a 10-membered aromatic carbo-ANAVO therapeutics BV A19160WO20 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- clo[2.2.2]octane, bicyclo[3.2.1]octane or bicyclo[4.2.0]octane), bicyclononane (such as bicy- 5clo[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. 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-10 tially or fully unsaturated, or aromatic, wherein saturated means that only single bonds arepresent, 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. 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,15 where S-atoms as ring members may be present as S, SO or SO2. The remaining ring membersare 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-20 vided below in connection with the definition of “hetaryl”. “Hetaryls” or “heteroaryls” are coveredby the term “heterocycles”. The saturated or partially or fully unsaturated heterocycles usually comprise 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-30 ing at least one heteroatom, such as pyrrolidine, tetrahydrothiophene, tetrahydrofuran, piperi-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.35 The term " heterocyclyloxy" as used herein denotes in each case a moiety defined above as“heterocycle” or “heterocyclyl” that is connected to the remainder of the molecule via an oxygen atom. 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- or40 10-membered bicyclic rings. The heterobicycle 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. In principle for being “aromatic” it is sufficient if one of the two rings of the bicyclic45 moieties is aromatic, while the other is non-aromatic. However, it is preferred in connection withthe 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-ANAVO therapeutics BV A19160WO21 cle 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 members are carbon atoms. Examples of heterobicycles include benzofuranyl, benzothienyl, indolyl, indazolyl, benzimidazolyl, benzoxathiazolyl, benzoxadia- 5zolyl, benzothiadiazolyl, benzoxazinyl, quinolinyl, isoquinolinyl, purinyl, 1,8-naphthyridyl,pteridyl, pyrido[3,2-d]pyrimidyl, pyrido[2,3-b]oxazinyl, pyrido[3,4-b]oxazinyl, pyrazolo[1,5- a]pyridinyl, triazolo[4,3-a]pyridinyl, triazolo[1,5-a]pyridinyl, pyridoimidazolyl, dihydropyrido[3,2- e]oxazepinyl, dihydropyrrolo[2,3-c]pyridinyl, imidazo[1,2-a]pyridinyl, triethylenediamine or quinu- clidine and the like. Preferred heterobicycles according to the invention are heterobicycles such10 as indazolyl, and pyrido[2,3-b]oxazinyl.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, 3 or 4 heteroatoms selected from N, O and S, where S-atoms as ring members may be present as S, SO or SO2. Examples of 5- or 6-membered aromatic heterocycles include pyridyl (also re-15 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, 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-20 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- or 2H-tetrazolyl. Unless otherwise indicated, the term “hetaryl” further covers “aromatic heterobicy- cles” as defined above.25 The term “aryl” or “aromatic carbocyclyl” preferably includes 6-membered aromatic carbocyclicrings 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. 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-30 ferred examples include benzyl (i.e. phenylmethyl), cyclohexylmethyl, pyridinylmethyl, andpiperidinomethyl. 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. As used in the specification and the claims, the singular forms of “a” and “an” also include the35 corresponding plurals unless the context clearly dictates otherwise. The same applies for pluralforms used herein, which also include the singular forms unless the context clearly dictates oth- erwise. When it is defined that “each substitutable atom in a group is independently unsubstituted or substituted”, that means that each atom, which can principally be substituted, is independently40 unsubstituted or substituted. For example, in case of “carbocyclylmethyl” or “heterocyclyl-methyl”, not only each substitutable atom in the carbocyclic or heterocyclic ring is independently unsubstituted or substituted, but also the carbon atom of the methyl group is independently un- substituted or substituted. 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 A19160WO22 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 truncation mutants, mutants, fragments, variants, isoforms, and homologs of the full-length wild-type. 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 the15 wild-type gene or gene product. "Mutant" or "modified" also refers to the sequence at a specificnucleotide position or positions, or the sequence at a particular codon position or positions, or 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.20 The term "mutation"' refers to a nucleic acid with at least a single nucleotide variation relativeto the normal sequence or wild-type sequence. In the context of polypeptide, "mutation" refers 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 may25 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 a 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-30 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- stitution or other mutation that creates a premature stop codon without shortening the nucleic acid 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. 35 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 as 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,40 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 on the context. "Inhibit," "inhibition," or "inhibiting" means reducing or suppressing a condition, symptom, or bi-45 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 oral or parenteral administration. A "pharmaceutically acceptable carrier" includes substances used in the preparation or use of pharmaceutical compositions, such as diluents, solvents, dispersionANAVO therapeutics BV A19160WO23 media, surfactants, antioxidants, preservatives, isotonic agents, buffering agents, emulsifiers, and more. The term “pharmaceutically acceptable excipient” as used herein refers to com- pounds commonly comprised in pharmaceutical compositions, which are known to the skilled person. Typically, a pharmaceutically acceptable excipient can be defined as being pharmaceu- 5tically 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 as “treatment and / or prophylaxis” or “treating and / or preventing”. The term "cancer" pertains to a disease characterized by the rapid and uncontrolled growth of10 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. The 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-15 clude premalignant, as well as malignant cancers and tumors.In the following, preferred embodiments of the substituents in the above formula (I) are de- scribed in further detail. It is to be understood that each preferred embodiment is relevant on its own as well as in combination with other preferred embodiments. Furthermore, it is to be under-20 stood that the preferences in each case also apply to the salts, stereoisomers, tautomers, andN-oxides of the compounds of the invention. As indicated above, the present invention relates in a first aspect to a compound of formula (I) 25 or a stereoisomer, tautomer, N-oxide, or pharmaceutically acceptable salt thereof;wherein RNis H or CH3; or RNand RBtogether with the atoms to which they are bonded and the atoms in between form a fused 5- or 6-membered heterocyclic ring, wherein said heterocyclic ring comprises the nitrogen30 atom of the NRN group as heteroatom;and the remaining substituents are as defined above in formula (I). In a preferred embodiment, RNis H or CH3.35 Accordingly, the compound of formula (I) may therefore be a compound of formula (I.a) or (I.b)as shown below: In connection with the compounds according to formula (I.a) and (I.b), it is to be understood that the substituents A, A1, A2, B, R1, R2, R3, R4, R5, RA, RB, RX, RY, RZ, m, and n are as defined40 above in formula (I). Further preferred embodiments regarding these substituents are providedfurther below.ANAVO therapeutics BV A19160WO24 In a preferred embodiment, RNis H. Thus, in a preferred embodiment, the compound of formula (I) is a compound of formula (I.a). 5In 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.10 In connection with the compounds according to formula (IS), it is to be understood that sub-stituents A, A1, A2, B, R1, R2, R3, R4, R5, RA, RB, RX, RY, RZ, m, and n are as defined above in formula (I). 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 two15 amido groups is in S-configuration: In the following, the substituents R1, R2, R3, A, and B (and relevant further substituents in this connection) are defined in further detail in connection with the compound of formula (I). The20 same embodiments are also relevant to a compound of formula (I.a), (I.b), (IS), or (IS.a).In one embodiment of the compound of formula (I), R2is H, C1-C2-alkyl, 5- or 6-membered saturated or partially unsaturated carbocyclyl or hete- rocycly, or carbocyclyloxy or heterocyclyloxy l, or 4- to 12-membered saturated carbobicy-25 clyl or heterobicyclyl, wherein the aforementioned heterocyclyl or heterobicyclyl comprisesone 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 substi- tutable atom in the aforementioned groups is independently unsubstituted or substituted with one or more, same or different substituents RX.30 In a preferred embodiment,R2a 5- or 6-membered saturated or partially unsaturated carbocyclyl or heterocyclyl, or car- bocyclyloxy, 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 in35 the aforementioned groups is independently unsubstituted or substituted with one ormore, 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,ANAVO therapeutics BV A19160WO25 R2is cyclohexyl, cyclopentyl or tetrahydrofuranyl, wherein each substitutable carbon atom in the aforementioned rings is independently unsubstituted or substituted with one or more, same or different substituents RX. In an even more preferred embodiment, 5R2 is cyclohexyl, cyclopentyl or tetrahydrofuranyl, wherein each substitutable carbon atom inthe aforementioned rings is independently unsubstituted or substituted with one or more, same or different substituents RX; wherein RXis halogen, CN or OH. In a particularly preferred embodiment, R2is cyclohexyl, cyclopentyl or tetrahydrofuranyl, wherein each substitutable carbon atom in10 the aforementioned rings is independently unsubstituted or substituted with one or more,same or different substituents RX; wherein RXis F. In another particularly preferred embodiment, 15 wherein the wavy line marks the connection to the remainder of the molecule. In another particularly preferred embodiment, 20 wherein the wavy line marks the connection to the remainder of the molecule.In a most preferred embodiment, wherein the wavy line marks the connection to the remainder of the molecule. 25 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, partially or fully unsaturated, or aromatic carbocyclyl, carbocyclylmethyl, heterocyclyl, or heterocyclylmethyl, or 4- to 12-membered saturated carbobicyclyl or heterobicyclyl,30 wherein the aforementioned heterocyclyl or heterobicyclyl comprises one or more, sameor 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 or different substituents RY.35 In a preferred embodiment,R3is CH3; or a 3- to 5-membered saturated carbocyclic or heterocyclic ring, wherein the aforemen- tioned heterocyclic ring comprises an oxygen atom as heteroatom, and wherein each sub-ANAVO therapeutics BV A19160WO26 stitutable carbon atom in the aforementioned carbocyclic or heterocyclic rings is indepen- dently unsubstituted or substituted with one or more, same or different substituents RY; or a 5- or 6-membered aromatic carbocyclic or heterocyclic ring; wherein the aforemen- tioned heterocyclic ring comprises one or more, same or different heteroatoms selected 5from O, N, or S, wherein said N- and / or S-atoms are independently oxidized or non-oxi-dized, and wherein each substitutable atom in the aforementioned carbocyclic or hetero- cyclic ring is independently unsubstituted or substituted with one or more, same or differ- ent substituents RY; or 5- or 6-membered aromatic carbocyclylmethyl or heterocyclylmethyl; wherein the afore-10 mentioned heterocyclyl comprises one or more, same or different heteroatoms selectedfrom O, N, or S, wherein said N- and / or S-atoms are independently oxidized or non-oxi- dized, and wherein each substitutable atom in the aforementioned carbocyclylmethyl or heterocyclylmethyl is independently unsubstituted or substituted with one or more, same or different substituents RY.15 In connection with the above definitions of R3, it is preferred thatRYis 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. In connection with above definitions of R3, it is even more preferred that20 RY is 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. Thus, in particularly preferred embodiment, R3is CH3; or 3- or 5-membered saturated carbocyclyl or heterocyclyl, wherein the aforementioned25 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 a 5- or 6-membered aromatic carbocyclic or heterocyclic ring; wherein the aforemen- tioned heterocyclic ring comprises one or more, same or different heteroatoms selected30 from O, N, or S, wherein said N- and / or S-atoms are independently oxidized or non-oxi-dized, and wherein each substitutable atom in the aforementioned carbocyclic or hetero- cyclic ring is independently unsubstituted or substituted with one or more, same or differ- ent substituents RY; or 5- or 6-membered aromatic carbocyclylmethyl or heterocyclylmethyl; wherein the afore-35 mentioned heterocyclyl comprises one or more, same or different heteroatoms selectedfrom O, N, or S, wherein said N- and / or S-atoms are independently oxidized or non-oxi- dized, and wherein each substitutable atom in the aforementioned carbocyclylmethyl or heterocyclylmethyl is independently unsubstituted or substituted with one or more, same or different substituents RY.40 whereinRYis 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. It is even more preferred that RYis halogen, CN, OH, C1-C2-alkyl, C1-C2-haloalkyl, C1-C2-alkoxy, or C1-C4-hydroxyalkyl.45 It is yet even more preferred thatRYis F, CN, OH, CH3, CF3, OCH3, or CD3. In one embodiment, R3isANAVO therapeutics BV A19160WO27 5 wherein the wavy line marks the connection to the remainder of the molecule. In a preferred embodiment,10 15 wherein the wavy line marks the connection to the remainder of the molecule.In a more preferred embodiment, R3isANAVO therapeutics BV A19160WO28 5wherein the wavy line marks the connection to the remainder of the molecule.In an especially preferred embodiment, 10 wherein the wavy line marks the connection to the remainder of the molecule.In another especially preferred embodiment, R3is 15 wherein the wavy line marks the connection to the remainder of the molecule.In a most preferred embodiment, R3is 20 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-25 stituent is not enriched in deuterium.In one embodiment of the compound of formula (I), Bis a 5- or 6-membered aromatic carbocyclic or heterocyclic ring, wherein the aforemen-tioned heterocyclic ring comprises one or more, same or different heteroatoms selected30 from O, N, or S, wherein said N- and / or S-atoms are independently oxidized or non-oxi-dized, and wherein each substitutable carbon or heteroatom in the aforementioned carbo-ANAVO therapeutics BV A19160WO29 cyclic or heterocyclic rings is independently unsubstituted or substituted with one or more, same or different substituents RB. In another embodiment, Bis a 5- or 6-membered aromatic carbocyclic or heterocyclic ring, wherein the aforemen-5 tioned heterocyclic ring comprises one or more, same or different heteroatoms selectedfrom O, N, or S, wherein said N- and / or S-atoms are independently oxidized or non-oxi- dized, and wherein each substitutable carbon or heteroatom in the aforementioned carbo- cyclic or heterocyclic rings is independently unsubstituted or substituted with one or more, same or different substituents RB;10 whereinRBis halogen, CN, C1-C4-alkyl, C1-C4-haloalkyl, C1-C4-alkoxy, or C1-C4-haloalkoxy. In a preferred embodiment, Bis a phenyl, thiophenyl or thiazolyl ring, wherein each substitutable carbon or heteroatomin the aforementioned carbocyclic or heterocyclic rings is independently unsubstituted or15 substituted with one or more, same or different substituents RB;wherein RBis halogen, CN, C1-C4-alkyl, C1-C4-haloalkyl, C1-C4-alkoxy, or C1-C4-haloalkoxy. In a more preferred embodiment, Bis a phenyl, thiophenyl or thiazolyl ring, wherein each substitutable carbon or heteroatom20 in the aforementioned carbocyclic or heterocyclic rings is independently unsubstituted orsubstituted with one or more, same or different substituents RB; wherein RBis F, CH3, or OCH3. In an even more preferred embodiment,25 B is, wherein the wavy line marks the connection to A and the dotted line marks the connection to the carbon atom of the C(=O) group to which B is attached.30 In a yet even more preferred embodiment,B is, wherein the wavy line marks the connection to A and the dotted line marks the connection to the35 carbon atom of the C(=O) group to which B is attached.In a yet more preferred embodiment, BisANAVO therapeutics BV A19160WO30 wherein the wavy line marks the connection to A and the dotted line marks the connection to the carbon atom of the C(=O) group to which B is attached. 5In an especially preferred embodiment, wherein the wavy line marks the connection to A and the dotted line marks the connection to the carbon atom of the C(=O) group to which B is attached.10 In a particularly preferred embodiment,B is wherein the wavy line marks the connection to A and the dotted line marks the connection to the carbon atom of the C(=O) group to which B is attached. 15 In one embodiment of the compound of formula (I), Ais -OR1, -NH-R1 or -NRA-R1;wherein R1is 3-pyridinyl or 4-pyridinyl, wherein each substitutable carbon or heteroatom in the afore-20 mentioned rings is independently unsubstituted or substituted with one or more, same ordifferent substituents RZ; and RAis H or CH3; and wherein RZis halogen, CN, C1-C4-alkyl, C1-C4-haloalkyl, C1-C4-alkoxy, C1-C4-haloalkoxy, C1-C4-25 alkylO-C(=O)-, C1-C4-alkyl-C(=O)-O-, (C1-C4-alkyl)2N-C(=O)-, C1-C4-alkyl-C(=O)-NH-, C3-C6-cycloalkyl, phenyl, or 3- to 6-membered saturated heterocyclyl, wherein said heterocy- clyl 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 said heterocyclyl is unsubstituted or substituted with one or more, same or different sub-30 stituents selected from halogen, C1-C2-alkyl, and C1-C2-haloalkyl;or two RZattached to neighboring atoms together with the atoms to which they are attached form a fused 5 or 6-membered saturated, partially or fully unsaturated, or aromatic carbo- cyclic or heterocyclic ring, wherein the aforementioned heterocyclic ring comprises one or more, same or different heteroatoms selected from O, N, or S, wherein said N- and / or S-35 atoms are independently oxidized or non-oxidized, and wherein said heterocyclic ring isunsubstituted or substituted with one or more, same or different substituents selected from halogen, C1-C2-alkyl, and C1-C2-haloalkyl. In one embodiment, Ais -OR1, -NH-R1 or -NRA-R1,40 whereinANAVO therapeutics BV A19160WO31 R1is 3-pyridinyl or 4-pyridinyl, wherein each substitutable carbon or heteroatom in the afore- mentioned rings is independently unsubstituted or substituted with one or more, same or different substituents RZ; and RAis H or CH3. 5 In connection with the above definitions of R1, it is preferred that RZis F, Cl, Br, CN, CH3, CF2H, CF3, OCH3, CH3O-C(=O)-, CH3-C(=O)-NH-, cyclopropyl, mor- pholinyl, 4-methylpiperazinyl, or phenyl; or two RZattached to neighboring atoms together with the atoms to which they are attached10 form a fused 5 or 6-membered saturated, partially or fully unsaturated, or aromatic carbo-cyclic or heterocyclic ring, wherein the aforementioned heterocyclic ring 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 said heterocyclic ring is unsubstituted.15 Thus, in a more preferred embodiment,A is -OR1, -NH-R1 or -NRA-R1,wherein R1is 3-pyridinyl or 4-pyridinyl, wherein each substitutable carbon or heteroatom in the afore- mentioned rings is independently unsubstituted or substituted with one or more, same or20 different substituents RZ; andRAis H or CH3; and wherein RZis F, Cl, Br, CN, CH3, CF2H, CF3, OCH3, CH3O-C(=O)-, CH3-C(=O)-NH-, cyclopropyl, mor- pholinyl, 4-methylpiperazinyl, or phenyl;25 or two RZ attached to neighboring atoms together with the atoms to which they are attachedform a fused 5 or 6-membered saturated, partially or fully unsaturated, or aromatic carbo- cyclic or heterocyclic ring, wherein the aforementioned heterocyclic ring 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 said heterocyclic ring is30 unsubstituted.In a preferred embodiment, A-NH-R1 or -NRA-R1,wherein R1is 3-pyridinyl or 4-pyridinyl, wherein each substitutable carbon or heteroatom in the afore-35 mentioned rings is independently unsubstituted or substituted with one or more, same ordifferent substituents RZ; and RAis CH3; and wherein RZis F, Cl, or CH3. 40 In a particularly preferred embodiment, A-NH-R1 or -NRA-R1,wherein R1is 3-pyridinyl or 4-pyridinyl, wherein each substitutable carbon or heteroatom in the afore-45 mentioned rings is independently unsubstituted or substituted with one or more, same ordifferent substituents RZ; and RAis CH3; and wherein RZis F, or CH3.ANAVO therapeutics BV A19160WO32 In this regard, the skilled person is aware that R1being “3-pyridinyl” as defined above may preferably be reflected by the following moiety: wherein the dashed line marks the connection to the nitrogen atom of the NH or NRAgroup of 5the A-moiety as defined aboveand RZis as defined above; and qis 0, 1, 2, 3, or 4.10 Further, the skilled person is aware that R1 being “4-pyridinyl” as defined above may preferablybe reflected by the following moiety: ; wherein the dashed line marks the connection to the nitrogen atom of the NH or NRAgroup of the A-moiety as defined above15 andRZis as defined above; and qis 0, 1, 2, 3, or 4.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 A1is a 5- or 6-membered aromatic carbocyclic or heterocyclic ring, wherein the aforemen-25 tioned heterocyclic ring comprises one or more, same or different heteroatoms selectedfrom O, N, or S, wherein said N- and / or S-atoms are independently oxidized or non-oxi- dized; A2is a 5- to 7-membered saturated, partially or fully unsaturated or aromatic carbocyclic or heterocyclic ring, wherein the aforementioned heterocyclic ring comprises one or more,30 same or different heteroatoms selected from O, N, or S, wherein said N- and / or S-atomsare independently oxidized or non-oxidized; 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-C4-35 haloalkoxy; or two R5 together form =O;m is 0, 1, or 2; andn is 0, 1, 2, 3, or 4.In a preferred embodiment,40 A is a moiety selected fromANAVO therapeutics BV A19160WO33 5 10 wherein the wavy line marks the connection to the remainder of the molecule; and wherein Y1is CH2, NH, NCH3, or O; Y2is CH or N;15 Y3 is CH2;and the remaining variables are as defined above. In a more preferred embodiment, Ais a moiety selected fromANAVO therapeutics BV A19160WO34 5wherein the wavy line marks the connection to the remainder of the molecule;and wherein Y1is CH2, NH, NCH3, or O; Y2is CH or N; and the remaining variables are as defined above. 10 In an even more preferred embodiment, A is a moiety selected from wherein the wavy line marks the connection to the remainder of the molecule;15 and whereinY2is CH or N; and R4is Br, Cl, CN, CH3, CF3, or cyclopropyl. In another even more preferred embodiment,20 A is a moiety selected from wherein the wavy line marks the connection to the remainder of the molecule and the remaining variables are as defined above.25 In an especially preferred embodiment,A is a moiety selected from ANAVO therapeutics BV A19160WO35 wherein the wavy line marks the connection to the remainder of the molecule; and wherein R4is Br, Cl, CN, CH3, CF3, or cyclopropyl. 5In a particularly preferred embodiment,A is a moiety selected from wherein the wavy line marks the connection to the remainder of the molecule; and wherein10 R4 is Cl, CH3 or CF3.In another particularly preferred embodiment, 15 wherein the wavy line marks the connection to the remainder of the molecule;and wherein R4is Cl, or CF3. In another particularly preferred embodiment,20 A is selected from the group consisting of, wherein the wavy line marks the connection to the remainder of the molecule.25 In one embodiment of the compound of formula (I),A is -NH-R1 or -N(CH3)-R1;wherein R1is 3-pyridinyl or 4-pyridinyl, wherein each substitutable carbon or heteroatom in the afore- mentioned rings is independently unsubstituted or substituted with one or more, same or differ-30 ent substituents RZ;wherein RZis F, Cl, or CH3; or AANAVO therapeutics BV A19160WO36 wherein the wavy line marks the connection to the remainder of the molecule; and wherein R4is Cl, or CF3; 5B is wherein the wavy line marks the connection to A and the dotted line marks the connection to the carbon atom of the C(=O) group to which B is attached; R2is10 wherein the wavy line marks the connection to the remainder of the molecule; and R3is 15 wherein the wavy line marks the connection to the remainder of the molecule.In another embodiment of the compound of formula (I), Ais -NH-R1 or -N(CH3)-R1;wherein20 R1 is 3-pyridinyl or 4-pyridinyl, wherein each substitutable carbon or heteroatom in the afore-mentioned rings is independently unsubstituted or substituted with one or more, same or differ- ent substituents RZ; wherein RZis F, or CH3;25 or wherein the wavy line marks the connection to the remainder of the molecule; and wherein30 R4 is Cl, or CF3;B is ANAVO therapeutics BV A19160WO37 wherein the wavy line marks the connection to A and the dotted line marks the connection to the carbon atom of the C(=O) group to which B is attached; R2is 5wherein the wavy line marks the connection to the remainder of the molecule;and R3is wherein the wavy line marks the connection to the remainder of the molecule. 10 In one embodiment of the compound of formula (I), Ais -NH-R1 or -N(CH3)-R1;wherein R1is 3-pyridinyl or 4-pyridinyl, wherein each substitutable carbon or heteroatom in the afore-15 mentioned rings is independently unsubstituted or substituted with one or more, same or differ-ent substituents RZ; wherein RZis F, Cl or CH3; Bis20 wherein the wavy line marks the connection to A and the dotted line marks the connection to the carbon atom of the C(=O) group to which B is attached; R2is 25 wherein the wavy line marks the connection to the remainder of the molecule;and R3is wherein the wavy line marks the connection to the remainder of the molecule. 30 In one embodiment of the compound of formula (I), Ais -NH-R1 or -N(CH3)-R1;wherein R1is 3-pyridinyl or 4-pyridinyl, wherein each substitutable carbon or heteroatom in the afore-35 mentioned rings is independently unsubstituted or substituted with one or more, same or differ-ent substituents RZ;ANAVO therapeutics BV A19160WO38 wherein 5wherein the wavy line marks the connection to A and the dotted line marks the connection to thecarbon atom of the C(=O) group to which B is attached; R2is wherein the wavy line marks the connection to the remainder of the molecule;10 andR3is wherein the wavy line marks the connection to the remainder of the molecule.15 In another embodiment of the compound of formula (I), wherein the wavy line marks the connection to the remainder of the molecule; and wherein20 R4 is Cl, or CF3;B is wherein the wavy line marks the connection to A and the dotted line marks the connection to the carbon atom of the C(=O) group to which B is attached;25 R2 is wherein the wavy line marks the connection to the remainder of the molecule; and 30 ANAVO therapeutics BV A19160WO39 wherein the wavy line marks the connection to the remainder of the molecule. In another embodiment of the compound of formula (I), 5 wherein the wavy line marks the connection to the remainder of the molecule; and wherein R4is Cl, or CF3; Bis10 wherein the wavy line marks the connection to A and the dotted line marks the connection to the carbon atom of the C(=O) group to which B is attached; R2is 15 wherein the wavy line marks the connection to the remainder of the molecule;and R3is wherein the wavy line marks the connection to the remainder of the molecule. 20 In a preferred embodiment, the compound according to formula (I) is selected from the group consisting of: 25 ,ANAVO therapeutics BV A19160WO40 5 10 ANAVO therapeutics BV A19160WO41 5 10 ANAVO therapeutics BV A19160WO42 In a more preferred embodiment, the compound according to formula (I) is selected from the group consisting of: 5 In an especially preferred embodiment, the compound according to formula (I) is selected from the group consisting of: 10 ANAVO therapeutics BV A19160WO43 5Pharmaceutical 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. 10 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 more15 of subcutaneous, intravenous, intra-muscular, intraarterial, intradermal, intrathecal and epiduraladministrations. 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.20 A 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.25 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, carrier30 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-ANAVO therapeutics BV A19160WO44 plication. Suitable pharmaceutically acceptable carriers include, for instance, water, aqueous salt 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- 5lose, magnesium stearate, surfactants, perfume oil, fatty acid monoglycerides, diglycerides andtriglycerides, polyoxyethylated medium or long chain fatty acids such as ricinoleic acid, and polyoxyethylated 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.10 Preferably, the compounds of the present invention are administered in a pharmaceutical com-position comprising of lipids, interbilayer crosslinked multilamellar vesicles, biodegradeable poly(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-15 somes as drug carriers can increase the therapeutic index of the compounds. Liposomes arecomposed of natural phospholipids and can contain mixed lipid chains with surfactant properties (e.g., egg phosphatidylethanolamine). A liposome design can employ surface ligands for attach- ing to unhealthy tissue. Non-limiting examples of liposomes include the multilamellar vesicle (MLV), the small unilamellar vesicle (SUV), and the large unilamellar vesicle (LUV). Liposomal20 physicochemical properties can be modulated to optimize penetration through biological barriersand retention at the site of administration, and to reduce a likelihood of developing premature degradation 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 the25 liposomes by the liver and spleen, and increases the circulation time, resulting in increased lo-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-30 face of cells associated with the disease.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-35 ceutically 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, methylcellulose40 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 compounds45 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.ANAVO therapeutics BV A19160WO45 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 5a non-toxic parenterally acceptable diluent or solvent. Among the acceptable vehicles and sol-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.10 Suppositories for rectal administration of a compound of formula (I) can be prepared by e.g.mixing the compound with a suitable non-irritating excipient such as cocoa butter, synthetic triglycerides 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.15 For administration by inhalation, the compounds according to the present invention may beconveniently 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.20 Capsules and cartridges of e.g. gelatin for use in an inhaler or insufflator may be formulatedcontaining a powder mix of the compound and a suitable powder base such as lactose or starch. 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 use25 can be obtained as solid excipient, optionally grinding a resulting mixture, and processing themixture of granules, after adding suitable auxiliaries, if desired, to obtain tablets or dragee cores. 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-30 lose, sodium carboxymethylcellulose, and / or polyvinylpyrrolidone (PVP). If desired, disintegrat-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).35 A 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. Suitable40 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 prepared45 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,ANAVO therapeutics BV A19160WO46 if necessary, shaping the product. Liquid dose units are vials or ampoules. Solid dose units are 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 5a 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- 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 3510 mg / kg / day, in single or divided doses. For a 70 kg human, this would amount to about 0.07 toabout 7000 mg / day, preferably about 0.7 to about 2500 mg / day. In some instances, dosage lev- els below the lower limit of the aforesaid range may be more than adequate, while in other cases 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.15 Furthermore, the pharmaceutical composition may also contain the compound of formula (I) asa prodrug such as an ester or amide thereof. A prodrug is any compound, which is converted 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. 20 Indications, for which the compounds of the present invention may be used 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.25 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- sociated with Wip1. In this connection, it is to be understood that the compounds according to the present invention or the pharmaceutical composition according to the present invention are capable to modulate or inhibit Wip1.30 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, 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, more35 preferably selected from the group consisting of cancer, pre-cancerous syndromes, and neuro-logical 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-40 nection, it is to be understood that cancers may be in the form of solid tumors such as sarco-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 lateral45 sclerosis, attention deficit hyperactivity disorder, autism, Bannayan-Zonana syndrome, bladdercancer, 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-ANAVO therapeutics BV A19160WO47 loblastoma, melanoma, mesothelioma, nasopharyngeal carcinoma, neuroblastoma, neurofibro- 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- 5cal composition according to the present invention are suitable for use in the treatment of breastcancer, preferably selected from the group consisting of inflammatory breast cancer, triple neg- 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 blood10 cancers, preferably selected from the group consisting of leukemia, lymphoma and multiplemyeloma. Relevant leukemia include acute lymphocytic leukemia (ALL), Acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), and myelodysplastic syndromes (MDS). Of particular relevance is AML. In a preferred embodiment, compounds according to the present invention or the pharmaceuti-15 cal composition according to the present invention are suitable for use in the treatment of braincancers, preferably selected from the group consisting of glioma, glioblastoma, oligoden- 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-20 cal composition according to the present invention are suitable for use in the treatment of lungcancers, preferably selected from the group consisting of small-cell lung cancer (SCLC) and 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 liver25 cancer, preferably hepatocellular carcinoma (HCC).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 Bannayan-Zonana syndrome, bladder cancer, bone cancer, breast cancer, inflammatory breast cancer, brain cancer, especially glioblastoma and30 glioma, cervical cancer, colorectal cancer, Cowden disease, 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, medulloblastoma, melanoma, mesothelioma, multiple myeloma, nasopharyngeal carcinoma, neuroblastoma, ovarian cancer, osteosarcoma,35 pancreatic cancer, prostate cancer, Rhabdomyosarcoma, thyroid cancer, and Wilm's tumor.Combination Therapies It is to be understood that in connection with the medical uses of the invention it can be pre-40 ferred that the compounds according to the present invention are administered in combinationwith 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-45 cludes both agents, or by administering two distinct compositions at the same time, wherein onecomposition includes a compound of the present invention, and the other includes the second agent(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 appliedANAVO therapeutics BV A19160WO48 separately, one would generally ensure that a significant period of time did not expire between the time of each delivery, such that the agents would still be able to exert an advantageously combined 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 5each 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) lapse between the respective administrations. In some embodiments, the compound of the present 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-10 pound of the present invention.Typically, any anti-neoplastic-agent that has activity versus a susceptible tumor being treated may be co-administered in the treatment of cancer in the present invention. Examples of such agents 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 of15 ordinary skill in the art would be able to discern which combinations of agents would be usefulbased on the particular characteristics of the drugs and the cancer involved. Typical anti-neo- plastic agents useful in the present invention include, but are not limited to, anti-microtubule agents such as diterpenoids and vinca alkaloids; platinum coordination complexes; alkylating agents such as nitrogen mustards, oxazaphosphorines, alkylsulfonates, nitrosoureas, and tri-20 azenes; antibiotic agents such as anthracyclines, such as but not limited to doxorubicin ordonarubicin, actinomycins and bleomycins; topoisomerase II inhibitors such as epipodophyllo- 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-25 munotherapeutic agents; proapoptotic agents; and cell cycle signaling inhibitors. Examples of afurther active ingredient or ingredients for use in combination or co-administered with the 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-30 ited to, diterpenoids and vinca alkaloids.In one embodiment, 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 and35 hormonal 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. 40 Examples The following abbreviations are used hereinafter. ANAVO therapeutics BV A19160WO49 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 in5 °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 wasANAVO therapeutics BV A19160WO50 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 25 °C. Exchangeable NH and OH residues were not identifiable in the1H-NMR spectra in some 5cases. 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 Multisam- pler, 1290 MCT G7116B Column Comp., 1290 G7117B DAD (210-320nm), PDA (210-320nm),10 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. Method B: Instrument: Agilent 1290 Infinity II, 1290 G7120A Bin. Pump, 1290 G7167B Multisam-15 pler, 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 Bicarbonate in Water (pH 9.5), Eluent B: 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 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 5:0:95. Method D: Instrument: Waters Acquity Class H, Column Acquity BEH C181.7 μm, 2.1 x 50 mm;25 temperature: 35 °C; flow rate: 0.50 mL / min; A: 50 mM ammonium formate buffer, pH 4 withHCOOH, 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: Instrument: Waters IClass; Bin. Pump: UPIBSM, SM: UPISMFTN with SO; UPCMA, PDA: UPPDATC, 210-320 nm, SQD: ACQ-SQD2 ESI; column: Waters XSelect CSH C18, 50x2.130 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: Instrument: Waters IClass; Bin. Pump: UPIBSM, SM: UPISMFTN with SO; UPCMA, PDA: UPPDATC, 210-320 nm, SQD: ACQ-SQD2 ESI; column: Waters XSelect CSH C18, 50x2.135 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:40 Method A: Instrument: Agilent 1260 Infinity II, 1260 G7112B Bin. Pump, 1260 G7167A Multisam-pler, 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 in45 Acetonitrile, Gradient: t=0 min 5% B, t=1.6 min 98% B, t=3 min 98% B, Postrun: 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 ammoniumbicarbonateANAVO therapeutics BV A19160WO51 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. Method C: Instrument: Waters Alliance 2795, PDA 2996. MS-ZQ2000; Column SunShell C182.6 μm, 2.1 x 50 mm; temperature: 40 °C; flow rate: 0.50 mL / min; A: 50 mM ammonium formate 5buffer, pH 4 with HCOOH, B: water; C: acetonitrile, gradient A:B:C: 0.3 min in 5:85:10 + from5:85:10 to 5:10:85 in 1.7 min + 3 min in 5:10:85. Preparative HPLC methods: Method A: HPLC instrument type: Agilent Technologies 1200 preparative LC; MS instrument10 type: Agilent Technologies G6120AA Quadrupole; Column: Waters XSelect CSH (C18, 100x30mm, 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 instrument15 type: ACQ-SQD2; Column: Waters XSelect (C18, 100x30 mm, 10µm); flow: 55 ml / min prep 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.20 Synthetic procedures for key intermediates:Intermediate 1: Synthesis of (S)-2-amino-3-cyclopentyl-N-(1-methyl-1H-pyrazol-4- yl)propanamide hydrochloride Intermediate 125 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 over sodiumsulfate and concentrated in vacuo. The residue was purified by silicagel chromatography (hep- tane: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 temperature35 overnight, the reaction mixture was concentrated in vacuo to afford (S)-2-amino-3-cyclopentyl-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 A19160WO52 Intermediate 2This 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), 1.18 5– 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 152025 This intermediate was prepared using procedures analogous to Intermediate 1.1H NMR (400 MHz, DMSO-d6) 8.60 (d, J = 5.0 Hz, 1H), 8.27 (s, 3H), 3.63 (t, J = 6.9 Hz, 1H), 2.64 (d, J = 4.5 Hz, 3H), 1.84 – 1.65 (m, 5H), 1.62 – 1.51 (m, 2H), 1.51 – 1.42 (m, 2H), 1.20 – 0.93 (m, 2H); UPLC (Method D): tR 2.48 min, MS (ESI) 171.2 (M+H)+. 30ANAVO therapeutics BV A19160WO53 Intermediate 6: Synthesis of (S)-2-amino-3-cyclopentyl-N-phenylpropanamide hydrochloride This intermediate was prepared using procedures analogous to Intermediate 1. LCMS (Method B): tR 1.88 min, MS (ESI) 233.2 (M+H)+. 5 Intermediate 7: Synthesis of (S)-2-amino-3-cyclopentyl-N-(5-methyl-1,3,4-thiadiazol-2- yl)propanamide hydrochloride This intermediate was prepared using procedures analogous to Intermediate 1. LCMS (Method10 B): tR 1.58 min, MS (ESI) 255.1 (M+H)+.Intermediate 8: Synthesis of (S)-2-amino-N-cyclopropyl-3-(4,4-difluorocyclohexyl)propanamide hydrochloride 15 This intermediate was prepared using procedures analogous to Intermediate 1. LCMS (MethodB): tR 1.60 min, MS (ESI) 247.1 (M+H)+. Intermediate 9: Synthesis of (S)-2-amino-3-(4,4-difluorocyclohexyl)-N-(1-methyl-1H-pyrazol-4- yl)propanamide hydrochloride 20 This intermediate was prepared using procedures analogous to Intermediate 1. LCMS (Method B): tR 1.60 min, MS (ESI) 287.1 (M+H)+. Intermediate 10: Synthesis of (S)-3-bromo-N-(3-cyclopentyl-1-(cyclopropylamino)-1-oxopropan-25 2-yl)benzamide ANAVO therapeutics BV A19160WO54 To an ice-cooled solution of 3-bromobenzoic acid (2.16 g, 10.7 mmol) and (S)-2-amino-3-cy- clopentyl-N-cyclopropylpropanamide hydrochloride (Intermediate 2, 2.50 g, 10.7 mmol, 1 equiv) in DMF (10 mL) were added DIPEA (5.61 mL, 32.2 mmol, 3 equiv) and HATU (4.49 g, 11.8 mmol, 1.1 equiv). the reaction was allowed to warm to room temperature and stirred for 6 d. The result- 5ing suspension was diluted with EtOAc and water, the layers were separated and the aqueouslayer was extracted with EtOAc (2x). The combined organics were washed with water (3x), aque- ous saturated NaHCO3and brine, dried over Na2SO4concentrated in vacuo. The residue was purified by silicagel chromatography (EtOAc in heptane, 0-50%) to afford (S)-3-bromo-N-(3-cy- clopentyl-1-(cyclopropylamino)-1-oxopropan-2-yl)benzamide (3.39 g, 8.94 mmol, 83%) as a light-10 yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 8.55 (d, J = 8.0 Hz, 1H), 8.14 – 8.02 (m, 2H), 7.89(dt, J = 7.8, 1.3 Hz, 1H), 7.73 (ddd, J = 8.0, 2.0, 1.0 Hz, 1H), 7.43 (t, J = 7.9 Hz, 1H), 4.36 (ddd, J = 9.6, 8.0, 5.1 Hz, 1H), 2.62 (tq, J = 7.8, 4.0 Hz, 1H), 1.88 – 1.37 (m, 9H), 1.19 – 1.03 (m, 2H), 0.66 – 0.51 (m, 2H), 0.49 – 0.32 (m, 2H); LCMS (Method B): tR 2.01 min, MS (ESI) 279.0 (M+H)+.15 Intermediate 11: Synthesis of (S)-3-bromo-N-(3-cyclopentyl-1-(cyclopropylamino)-1-oxopropan-2-yl)benzamide Intermediate 1 Intermediate 11This intermediate was prepared using procedures analogous to Intermediate 10.1H NMR (400 MHz, DMSO-d6) δ 10.11 (s, 1H), 8.74 (d, J = 7.8 Hz, 1H), 8.13 (t, J = 1.8 Hz, 1H), 7.91 (dt, J =20 7.8, 1.3 Hz, 1H), 7.86 (s, 1H), 7.75 (ddd, J = 7.9, 2.1, 1.0 Hz, 1H), 7.48 – 7.39 (m, 2H), 4.53 (ddd,J = 9.3, 7.7, 5.2 Hz, 1H), 3.77 (s, 3H), 1.92 – 1.80 (m, 2H), 1.73 (ddd, J = 14.3, 9.8, 5.1 Hz, 3H), 1.57 (qd, J = 10.6, 6.0 Hz, 2H), 1.48 (ddt, J = 14.8, 7.6, 3.0 Hz, 2H), 1.23 – 1.09 (m, 2H); LCMS (Method B): tR 2.03 min, MS (ESI) 419.1 / 421.1 (M+H)+.25 Intermediate 12: Synthesis of 3-(2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-1-yl)benzoic acidlithium salt To a solution of 2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazine (32 mg, 0.23 mmol) and methyl 3-bro- mobenzoate (50 mg, 0.23 mmol, 1 equiv) in dioxane (1.5 mL) under argon atmosphere were30 added cesium carbonate (0.17 g, 0.51 mmol, 2.2 equiv), RuPhos (7.6 mg, 16 μmol, 0.07 equiv)and Pd2(dba)3(6.4 mg, 7.0 μmol, 0.03 equiv). The resulting mixture was heated in a sealed vial to 90 °C for 15 h. The reaction was allowed to reach room temperature, diluted with MeOH, filtered over a syringe filter and directly purified by preparative reversed phase chromatography (Waters XSelectTMCSH C18 column, ammonium bicarbonate in water / acetonitrile), affording methyl 3-35 (2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-1-yl)benzoate (50.6 mg, 81%). LCMS (Method B): tR1.85 min, MS (ESI) 271.1 (M+H)+. To a solution of methyl 3-(2,3-dihydro-1H-pyrido[2,3-b][1,4]ox- azin-1-yl)benzoate (50 mg, 0.18 mmol) in THF / water / MeOH (1:1:1, 1.5 mL) was added lithium hydroxide monohydrate (7.8 mg 0.18 μmol, 1.0 equiv) and the reaction was stirred at room tem- perature for 72 h. The volatiles were removed in vacuo and the residue co-evaporated twice withANAVO therapeutics BV A19160WO55 DCM / MeCN, to afford 3-(2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-1-yl)benzoic acid lithium salt (49 mg, quant.) as a white solid. LCMS (Method B): tR 1.30 min, MS (ESI) 257.0 (M+H)+. Intermediate 13: Synthesis of 3-(7-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-1-yl)benzoic 5acid lithium salt This intermediate was prepared using procedures analogous to Intermediate 12. LCMS (Method B): tR 1.42 min, MS (ESI) 271.0 (M+H)+.10 Intermediate 14: Synthesis of 3-(7-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-1-yl)benzoicacid lithium salt This intermediate was prepared using procedures analogous to Intermediate 12. LCMS (Method B): tR 1.46 min, MS (ESI) 283.0 (M+H)+. 15 Intermediate 15: Synthesis of 1-(5-methylpyridin-3-yl)indoline-5-carboxylic acid To a solution of 2,3-dihydro-1H-indole-5-carboxylic acid hydrochloride (70 mg, 0.33 mmol) in diox- ane (2 mL), 3-bromo-5-methylpyridine (77 μL, 0.67 mmol, 2 equiv), sodium tert-butoxide (80 mg,20 0.83 mmol, 2.5 equiv), Pd2(dba)3 (6 mg, 0.006 mmol, 0.02 equiv) and RuPhos (8 mg, 0.016 mmol,0.05 equiv) were added The resulting mixture was degassed with N2and stirred at 100 °C for 20 h. The reaction was allowed to reach room temperature, filtered through a plug of celite and the solids were washed with MeOH. The combined filtrates were concentrated in vacuo. Purification of the crude residue by reversed phase chromatography (C18 gold column; water+buffer pH7 in25 acetonitrile) afforded 1-(5-methylpyridin-3-yl)indoline-5-carboxylic acid (37 mg, 44%) as a pinkishsolid.1H NMR (400 MHz, DMSO-d6) δ 8.48 (s, 1H), 8.40 (d, J = 2.6 Hz, 1H), 8.06 (s, 1H), 7.75 – 7.66 (m, 2H), 7.57 – 7.48 (m, 1H), 7.09 (d, J = 8.2 Hz, 1H), 4.04 (t, J = 8.5 Hz, 2H), 3.14 (t, J = 8.4 Hz, 2H), 2.32 (s, 3H); LCMS (Method C): tR 2.72 min, MS (ESI) 255.3 (M+H)+.30 Intermediate 16: Synthesis of 1-(2-methylpyridin-4-yl)indoline-5-carboxylic acid ANAVO therapeutics BV A19160WO56 This intermediate was prepared using procedures analogous to Intermediate 15. LCMS (Method C): tR 1.38 min, MS (ESI) 255.4 (M+H)+. Intermediate 17: Synthesis of 1-(2-methylpyridin-4-yl)indoline-6-carboxylic acid 5 1015 Intermediate 1920 To a suspension of 3-bromo-2,5-dimethylpyridine (0.20 mL, 1.50 mmol), methyl 4-hydroxyben-zoate (343 mg, 2.25 mmol, 1.5 equiv), K3PO4(479 mg, 2.26 mmol, 1.5 equiv) and RockPhos-Pd- G3 (25 mg, 0.029 mmol, 0.02 equiv) in toluene / DME (2:1, 22.5 mL), palladium(ii)(π-cinnamyl) chloride dimer (7 mg, 0.013 mmol, 0.01 equiv) was added. The solution was degassed with N2and stirred at 80 °C for 24 h. After the reaction mixture was cooled to room temperature, water25 and DCM were added. The layers were separated, and the aqueous layer was extracted withDCM (3x). The organic layers were combined, dried over sodium sulfate, and solvents were evap- orated in vacuo. The crude residue was purified by silicagel chromatography (10% EtOAc in hex- ane) to afford methyl 4-((2,5-dimethylpyridin-3-yl)oxy)benzoate (48 mg, 12%) as a colorless oil. 1H NMR (300 MHz, DMSO-d6) δ 8.23 (s, 1H), 7.97 (d, J = 8.4 Hz, 2H), 7.35 (s, 1H), 6.99 (d, J =30 8.1 Hz, 2H), 3.83 (s, 3H), 2.28 (s, 6H); LCMS (Method C): tR 2.96 min, MS (ESI) 257.9 (M+H)+.To a solution of methyl 4-((2,5-dimethylpyridin-3-yl)oxy)benzoate (45 mg, 0.17 mmol) in MeOH / H2O (1:1, 2 mL), lithium hydroxide monohydrate (22 mg, 0.52 mmol, 3.05 equiv) was added. The resulting solution was stirred at room temperature for 16 h and the volatiles were removed in vacuo to yield crude 4-((2,5-dimethylpyridin-3-yl)oxy)benzoic acid lithium salt (45 mg,35 quant.) as a white solid, which was then used in the next step without further purification.1H NMR(300 MHz, DMSO-d6) δ 8.11 (s, 1H), 7.84 (d, J = 8.1 Hz, 2H), 7.11 (s, 1H), 6.78 (d, J = 8.1 Hz, 2H), 2.33 (s, 3H), 2.23 (s, 3H); LCMS (Method C): tR 2.45 min, MS (ESI) 243.9 (M+H)+. Intermediate 20: Synthesis of 3-((2,5-dimethylpyridin-3-yl)oxy)benzoic acid lithium saltANAVO therapeutics BV A19160WO57 This intermediate was prepared using procedures analogous to Intermediate 19. LCMS (Method C): tR 2.36 min, MS (ESI) 243.9 (M+H)+. 5Synthetic procedures for final compounds:Example 1: Synthesis of (S)-N-(3-cyclopentyl-1-((1-methyl-1H-pyrazol-4-yl)amino)-1-oxopropan- 2-yl)-4-(pyridin-3-ylamino)benzamide 10 To a solution of (S)-2-amino-3-cyclopentyl-N-(1-methyl-1H-pyrazol-4-yl)propanamide hydrochlo-ride (Intermediate 1, 15 mg, 55 μmol) and 4-(pyridin-3-ylamino)benzoic acid (14 mg, 55 μmol , 1.2 equiv) in DMF (1.0 mL) was added DIPEA (57 μL, 0.33 mmol, 6 equiv) followed by HATU (31 mg, 82 μmol, 1.5 equiv). The reaction mixture was stirred at room temperature overnight, after which it was directly purified by preparative HPLC (Method B). Product containing fractions were15 concentrated and lyophilized from MeCN / water, affording the title product (10.5 mg, 44%) as awhite solid.1H NMR (400 MHz, DMSO-d6) δ 10.06 (s, 1H), 8.73 (s, 1H), 8.42 (d, J = 2.8 Hz, 1H), 8.29 (d, J = 7.8 Hz, 1H), 8.13 (dd, J = 4.7, 1.4 Hz, 1H), 7.94 – 7.81 (m, 3H), 7.57 (ddd, J = 8.3, 2.8, 1.4 Hz, 1H), 7.42 (s, 1H), 7.30 (dd, J = 8.3, 4.6 Hz, 1H), 7.14 – 7.07 (m, 2H), 4.59 – 4.48 (m, 1H), 3.77 (s, 3H), 1.95 – 1.64 (m, 5H), 1.64 – 1.52 (m, 2H), 1.52 – 1.37 (m, 2H), 1.25 – 1.05 (m,20 2H); UPLC (Method F): tR 1.27 min, 97.1%, MS (ESI) 433.3 (M+H)+.The following examples have been prepared using procedures analogous to Example 1, using the appropriate starting materials and intermediates, and purified by preparative HPLC (Method A or B): 25 ANAVO therapeutics BV A19160WO58 ANAVO therapeutics BV A19160WO59 ANAVO therapeutics BV A19160WO60 ANAVO therapeutics BV A19160WO61 ANAVO therapeutics BV A19160WO62 Example 23: Synthesis of (S)-N-(3-cyclopentyl-1-(cyclopropylamino)-1-oxopropan-2-yl)-3-((3-flu- oropyridin-4-yl)amino)benzamide 1) Pd db X ntPh Example 235 To methyl 3-bromobenzoate (7.0 g, 33 mmol), 3-fluoropyridin-4-amine (4.4 g, 39 mmol, 1.2 equiv),cesium carbonate (21 g, 65 mmol, 2 equiv) and XantPhos (0.75 g, 1.3 mmol, 0.04 equiv) under argon atmosphere was added 1,4-dioxane (160 mL). The resulting suspension was purged with argon for 15 min, after which Pd2(dba)3(0.60 g, 0.65 mmol, 0.02 equiv) was added and purging with argon was continued for 1 min. The reaction mixture was heated to reflux temperature for 16ANAVO therapeutics BV A19160WO63 h, cooled to room temperature and the volatiles were removed in vacuo. The residue was parti- tioned between water and EtOAc, the layers were separated and the aqueous layer was extracted with EtOAc (4x). The combined organic layers were dried over Na2SO4, concentrated in vacuo and the residue was purified by silicagel chromatography (EtOAc in heptane, 0-70%), affording 5methyl 3-((3-fluoropyridin-4-yl)amino)benzoate (4.5 g, 18 mmol, 56%) as an off-white solid. 1HNMR (400 MHz, CDCl3) δ 8.32 (d, J = 3.2 Hz, 1H), 8.14 (d, J = 5.5 Hz, 1H), 7.91 (t, J = 2.0 Hz, 1H), 7.84 (dt, J = 7.6, 1.5 Hz, 1H), 7.48 (t, J = 7.8 Hz, 1H), 7.44 – 7.38 (m, 1H), 7.08 (dd, J = 7.4, 5.5 Hz, 1H), 6.34 – 6.26 (m, 1H), 3.94 (s, 3H); LCMS (Method B): tR 1.81 min, MS (ESI) 247.1 (M+H)+. Methyl 3-((3-fluoropyridin-4-yl)amino)benzoate (4.5 g, 18 mmol) was dissolved in THF10 (30 mL) and methanol (30 mL). A solution of lithium hydroxide monohydrate (0.77 g, 18 mmol, 1equiv) in water (30 mL) was added and the reaction was stirred at room temperature for 16 h. The resulting mixture was concentrated in vacuo and the residue was co-evaporated with toluene and DCM to afford 3-((3-fluoropyridin-4-yl)amino)benzoic acid lithium salt (4.5 g, 17 mmol, 94%) as a white solid.1H NMR (400 MHz, DMSO-d6) δ 8.64 (s, 1H), 8.27 (d, J = 3.7 Hz, 1H), 8.02 (d, J =15 5.5 Hz, 1H), 7.80 (t, J = 1.9 Hz, 1H), 7.62 (dt, J = 7.5, 1.4 Hz, 1H), 7.33 – 7.21 (m, 1H), 7.21 –7.09 (m, 1H), 7.02 (dd, J = 7.8, 5.5 Hz, 1H); LCMS (Method B): tR 0.84 min, MS (ESI) 233.1 (M+H)+. To a solution of (S)-2-amino-3-cyclopentyl-N-cyclopropylpropanamide hydrochloride (In- termediate 2, 13 mg, 56 μmol) and 3-((3-fluoropyridin-4-yl)amino)benzoic acid lithium salt (15 mg, 65 μmol , 1.2 equiv) in DMF (1.0 mL) was added DIPEA (29 μL, 0.17 mmol, 3 equiv) followed20 by HATU (22 mg, 59 μmol, 1.05 equiv). The reaction mixture was stirred at room temperatureovernight, after which it was directly purified by preparative HPLC (Method B). Product containing fractions were concentrated and lyophilized from MeCN / water, affording the title product (8.0 mg, 35%) as a white solid.1H NMR (400 MHz, DMSO-d6) δ 8.82 (s, 1H), 8.38 (d, J = 8.2 Hz, 1H), 8.33 (d, J = 3.6 Hz, 1H), 8.07 (d, J = 5.4 Hz, 1H), 8.05 (d, J = 4.4 Hz, 1H), 7.74 (t, J = 1.9 Hz, 1H), 7.6425 – 7.58 (m, 1H), 7.44 (t, J = 7.8 Hz, 1H), 7.41 – 7.36 (m, 1H), 7.12 (dd, J = 7.7, 5.5 Hz, 1H), 4.42– 4.32 (m, 1H), 2.66 – 2.59 (m, 1H), 1.83 – 1.50 (m, 7H), 1.50 – 1.39 (m, 2H), 1.18 – 1.06 (m, 2H), 0.66 – 0.55 (m, 2H), 0.45 – 0.35 (m, 2H); UPLC (Method B): tR 2.53 min, 100%, MS (ESI) 411.2 (M+H)+.30 The following examples have been prepared using procedures analogous to Example 23, usingthe appropriate starting materials and intermediates, and purified by preparative HPLC (Method A or B): ANAVO therapeutics BV A19160WO64 ANAVO therapeutics BV A19160WO65 ANAVO therapeutics BV A19160WO66 ANAVO therapeutics BV A19160WO67 Example 39: Synthesis of (S)-N-(3-cyclopentyl-1-((1-methyl-1H-pyrazol-4-yl)amino)-1-oxo- propan-2-yl)-3-methoxy-5-(pyridin-4-ylamino)benzamide 5To a solution of methyl 3-amino-5-methoxybenzoate (70 mg, 0.386 mmol) in dioxane (3.5 mL), 4-bromopyridine hydrochloride (75.1 mg, 0.386 mmol, 1.00 eq), Cs2CO3(378 mg, 1.16 mmol, 3.0 equiv), Pd(OAc)2(8.7 mg, 0.038 mmol, 0.10 equiv) and XantPhos (44.7 mg, 0.077 mmol, 0.20 equiv) were added. The resulting mixture was degassed with N2for 5 min and stirred at 100 °C for 16 h. After the reaction mixture was cooled to room temperature, water and EtOAc were10 added. The layers were separated, and the aqueous layer was extracted with EtOAc (3x). Theorganic layers were combined, washed with water (15 mL) and brine (15 mL), dried over sodium sulfate, and concentrated in vacuo. Purification of the crude residue by silicagel chromatography ( MeOH / DCM / NH3, 97:3:1) afforded methyl 3-methoxy-5-(pyridin-4-ylamino)benzoate (85.7 mg, 86%) as a colorless oil.1H NMR (400 MHz, CDCl3) δ 8.34 – 8.32 (m, 2H), 7.46 (ddd, J = 2.1, 1.3,15 0.4 Hz, 1H), 7.31 (dd, J = 2.4, 1.3 Hz, 1H), 6.94 – 6.90 (m, 1H), 6.87 – 6.83 (m, 2H), 6.10 (s, 1H),3.92 (s, 3H), 3.86 (s, 3H); LCMS (Method C): tR 2.25 min, MS (ESI) 259.4 (M+H)+. To a solution of 3-methoxy-5-(pyridin-4-ylamino)benzoate (36 mg, 0.144 mmol) in MeOH and H2O (1:1, 2 mL), lithium hydroxide monohydrate (19 mg, 0.452 mmol, 3.05 equiv) was added. The resulting solu- tion was stirred at room temperature for 16 h. The volatiles were removed under reduced pressure20 to yield crude lithium 3-methoxy-5-(pyridin-4-ylamino)benzoate (54 mg, quant.) as a white solid,which was used in the next step without further purification.1H NMR (400 MHz, DMSO-d6): δ 8.17 – 8.11 (m, 2H), 7.39 (dd, J = 2.1, 1.1 Hz, 1H), 7.15 (dd, J = 2.5, 1.1 Hz, 1H), 6.93 – 6.85 (m, 2H), 6.66 (t, J = 2.3 Hz, 1H), 3.74 (s, 3H). Lithium 3-methoxy-5-(pyridin-4-ylamino)benzoate was sub- sequently coupled with Intermediate 1 using procedures analogous to Example 1, affording (S)-25 N-(3-cyclopentyl-1-((1-methyl-1H-pyrazol-4-yl)amino)-1-oxopropan-2-yl)-3-methoxy-5-(pyridin-4-ANAVO therapeutics BV A19160WO68 ylamino)benzamide (20.5 mg, 42%) as a white solid.1H NMR (400 MHz, DMSO-d6) δ 10.09 (s, 1H), 8.90 (s, 1H), 8.57 (d, J = 8.0 Hz, 1H), 8.19 (d, J = 5.7 Hz, 2H), 7.84 (s, 1H), 7.41 (s, 1H), 7.30 (s, 1H), 7.14 (s, 1H), 6.92 (d, J = 5.6 Hz, 2H), 6.85 (s, 1H), 4.60 – 4.43 (m, 1H), 3.79 (s, 3H), 3.75 (s, 3H),1.93 – 1.35 (m, 9H), 1.33 – 1.06 (s, 2H); UPLC (Method D): tR 2.90 min, 98.8%, MS5 (ESI) 463.4 (M+H)+.The following examples have been prepared using procedures analogous to Example 39, using the appropriate starting materials and intermediates, and purified by preparative HPLC (Method A or B): ANAVO therapeutics BV A19160WO69 ANAVO therapeutics BV A19160WO70 Example 53 [Ref. Ex.]: Synthesis of (S)-N-(3-cyclopentyl-1-((1-methyl-1H-pyrazol-4-yl)amino)-1- oxopropan-2-yl)-3-((4-methylpyridin-2-yl)amino)benzamideANAVO therapeutics BV A19160WO71 3-((4-Methylpyridin-2-yl)amino)benzoic acid lithium salt was prepared using procedures analo- gous to those described in Example 39. To a solution of 3-((4-methylpyridin-2-yl)amino)benzoic acid lithium salt (26.5 mg, 0.11 mmol) in DMF (2 mL) were added (S)-2-amino-3-cyclopentyl-N- 5(1-methyl-1H-pyrazol-4-yl)propanamide hydrochloride (Intermediate 1, 30 mg, 0.11 mmol, 1.05equiv), EDCI (23.6 mg, 0.12 mmol, 1.1 equiv), DIPEA (91 μL, 0.53 mmol, 5.0 equiv) and HOAt (17.4 mg, 0.13 mmol, 1.2 equiv). The reaction mixture was stirred at room temperature for 17 h. Water was added, and the resulting mixture was extracted with DCM (3x). The combined organic layers were washed with a saturated aqueous NaHCO3, dried over Na2SO4and concentrated.10 The residue was purified by reversed phase chromatography (C18 gold column; water+bufferpH7 in acetonitrile) affording (S)-N-(3-cyclopentyl-1-((1-methyl-1H-pyrazol-4-yl)amino)-1-oxo- propan-2-yl)-3-((4-methylpyridin-2-yl)amino)benzamide (25 mg, 53%) as a white solid.1H NMR (300 MHz, DMSO-d6) δ 10.05 (s, 1H), 9.03 (s, 1H), 8.38 (d, J = 7.9 Hz, 1H), 8.08 – 7.97 (m, 2H), 7.96 – 7.88 (m, 1H), 7.86 (s, 1H), 7.46 – 7.36 (m, 2H), 7.32 (t, J = 7.8 Hz, 1H), 6.70 – 6.55 (m,15 2H), 4.64 – 4.46 (m, 1H), 3.78 (s, 3H), 2.23 (s, 3H), 1.97 – 1.33 (m, 9H), 1.32 – 1.02 (m, 2H);UPLC (Method D): tR 3.54 min, 96%, MS (ESI) 447.4 (M+H)+. The following examples have been prepared using procedures analogous to Example 53, using the appropriate starting materials and intermediates, and purified by preparative HPLC (Method20 A or B): ANAVO therapeutics BV A19160WO72 ANAVO therapeutics BV A19160WO73 ANAVO therapeutics BV A19160WO74 ANAVO therapeutics BV A19160WO75 Example 70: Synthesis of (S)-N-(1-(benzylamino)-3-cyclopentyl-1-oxopropan-2-yl)-3-((3-fluo- ropyridin-4-yl)amino)benzamide Example 70A solution of 3-((3-fluoropyridin-4-yl)amino)benzoic acid lithium salt (prepared in Example 23, 2.0 5g, 8.6 mmol), methyl (S)-2-amino-3-cyclopentylpropanoate hydrochloride (1.8 g, 8.6 mmol, 1equiv) and HATU (3.4 g, 9.0 mmol, 1.05 equiv) in DMF (40 mL) was cooled to 0 °C, after which DiPEA (4.5 mL, 26 mmol, 3 equiv) was added. The reaction was allowed to warm to room tem- perature and stirred overnight. The volatiles were removed in vacuo and the residue was parti- tioned between brine and ethyl acetate. The layers were separated and the organic layer was10 washed with 10% aqueous citric acid, saturated aqueous NaHCO3 and brine, dried over Na2SO4and concentrated. The resulting oil was purified by silicagel chromatography (EtOAc in heptane, 0-100%), affording methyl (S)-3-cyclopentyl-2-(3-((3-fluoropyridin-4-yl)amino)benza- mido)propanoate (3.3 g, 7.7 mmol, 89%). LCMS (Method B): tR 1.95 min, MS (ESI) 386.2 (M+H)+. To a solution of methyl (S)-3-cyclopentyl-2-(3-((3-fluoropyridin-4-yl)amino)benza-15 mido)propanoate (3.0 g, 7.7 mmol) in methanol (13 mL) and THF (13 mL) was added a solutionof lithium hydroxide monohydrate (0.32 g, 7.7 mmol, 1 equiv) in water (13 mL) and the reaction was stirred at room temperature overnight. The resulting mixture was slightly acidified with 1M aqueous KHSO4 to pH ~5 and concentrated in vacuo. Co-evaporation of the residue with toluene yielded (S)-3-cyclopentyl-2-(3-((3-fluoropyridin-4-yl)amino)benzamido)propanoic acid (4.66 g,20 7.84 mmol, quant.), which was used as such. LCMS (Method B): tR 1.55 min, MS (ESI) 372.2(M+H)+. To a solution of (S)-3-cyclopentyl-2-(3-((3-fluoropyridin-4-yl)amino)benzamido)propanoic acid (63 mg, 168 μmol), benzylamine (27 mg, 0.25 mmol, 1.5 equiv) and HATU (96.0 mg, 0.25 mmol, 1.5 equiv) in N,N-dimethylformamide (1 mL) was added DiPEA (176 μL, 1.01 mmol, 6 equiv) and the reaction mixture was stirred overnight. The resulting mixture was diluted with25 DMSO, filtered over a syringe filter, and directly purified by preparative HPLC (Method B) to affordthe title product (45 mg, 98 μmol, 58%) as a white solid.1H NMR (400 MHz, DMSO-d6) δ 8.82 (s, 1H), 8.52 – 8.44 (m, 2H), 8.32 (d, J = 3.7 Hz, 1H), 8.07 (d, J = 5.5 Hz, 1H), 7.76 (t, J = 2.0 Hz, 1H), 7.66 – 7.60 (m, 1H), 7.45 (t, J = 7.8 Hz, 1H), 7.42 – 7.36 (m, 1H), 7.34 – 7.27 (m, 2H), 7.27 – 7.18 (m, 3H), 7.12 (dd, J = 7.7, 5.4 Hz, 1H), 4.54 – 4.45 (m, 1H), 4.29 (d, J = 6.0 Hz, 2H), 1.9430 – 1.63 (m, 5H), 1.63 – 1.51 (m, 2H), 1.49 – 1.38 (m, 2H), 1.21 – 1.04 (m, 2H); UPLC (Method B):tR 2.93 min, 100%, MS (ESI) 461.2 (M+H)+. The following examples have been prepared using procedures analogous to Example 70, using the appropriate starting materials and intermediates, and purified by preparative HPLC (Method35 A or B): ANAVO therapeutics BV A19160WO76 ANAVO therapeutics BV A19160WO77 ANAVO therapeutics BV A19160WO78 Example 79: Synthesis of (S)-3-((2-acetamidopyridin-4-yl)amino)-N-(3-cyclopentyl-1-(cyclo- propylamino)-1-oxopropan-2-yl)benzamide 5To an 8 mL reaction vial were added (S)-3-bromo-N-(3-cyclopentyl-1-(cyclopropylamino)-1-oxo-propan-2-yl)benzamide (Intermediate 10, 30 mg, 79 µmol), N-(4-aminopyridin-2-yl)acetamide (14 mg, 95 µmol, 1.2 equiv) and Cs2CO3(52 mg, 0.16 mmol, 2 equiv). Dioxane (1.0 mL) was added and the mixture was flushed with Argon for 5 min. Next, tris(dibenzylideneacetone)dipalla- dium (1.4 mg, 1.6 μmol, 0.02 equiv) and Xantphos (1.8 mg, 3.2 μmol, 0.04 equiv) were added10 and the reaction mixture was heated in a sealed vial to 120 °C overnight. After cooling to roomtemperature, the volatiles were removed in vacuo and the residue was purified preparative HPLC (Method A), affording the title product (12.5 mg, 38%) as a white solid.1H NMR (400 MHz, DMSO- d6) δ 10.23 (s, 1H), 9.00 (s, 1H), 8.35 (d, J = 8.2 Hz, 1H), 8.05 (d, J = 4.4 Hz, 1H), 7.95 (d, J = 5.7 Hz, 1H), 7.81 (s, 1H), 7.66 (t, J = 1.9 Hz, 1H), 7.53 (d, J = 7.7 Hz, 1H), 7.41 (t, J = 7.8 Hz, 1H),15 7.34 (dd, J = 7.7, 2.2 Hz, 1H), 6.67 (dd, J = 5.7, 2.2 Hz, 1H), 4.36 (td, J = 9.1, 5.1 Hz, 1H), 2.66 –2.58 (m, 1H), 2.05 (s, 3H), 1.88 – 1.60 (m, 5H), 1.60 – 1.50 (m, 2H), 1.50 – 1.34 (m, 2H), 1.20 – 1.02 (m, 2H), 0.66 – 0.54 (m, 2H), 0.48 – 0.32 (m, 2H; UPLC (Method F): tR 1.31 min, 99.7%, MS (ESI) 450.2 (M+H)+.20 The following examples have been prepared using procedures analogous to Example 79, usingthe appropriate starting materials and intermediates, and purified by preparative HPLC (Method A or B): ANAVO therapeutics BV A19160WO79 ANAVO therapeutics BV A19160WO80 ANAVO therapeutics BV A19160WO81 ANAVO therapeutics BV A19160WO82 ANAVO therapeutics BV A19160WO83 ANAVO therapeutics BV A19160WO84 ANAVO therapeutics BV A19160WO85 ANAVO therapeutics BV A19160WO86 ANAVO therapeutics BV A19160WO87 ANAVO therapeutics BV A19160WO88 ANAVO therapeutics BV A19160WO89 ANAVO therapeutics BV A19160WO90 ANAVO therapeutics BV A19160WO91 ANAVO therapeutics BV A19160WO92 ANAVO therapeutics BV A19160WO93 ANAVO therapeutics BV A19160WO94 Example 143 [Ref. Ex.]: Synthesis of (S)-N-(3-cyclopentyl-1-((1-methyl-1H-pyrazol-4-yl)amino)- 1-oxopropan-2-yl)-3-((3-fluoropyridin-2-yl)amino)benzamide 5An oven dried vial under argon atmosphere was loaded with anhydrous 1,4-dioxane (0.5 mL) andpurged with argon for 3 min in an ultrasonic bath. Next, Xantphos (2.5 mg 4.3 µmol) and Pd2(dba)3(2.0 mg, 2.1 µmol) were added, the vial was sealed and heated at 90 °C for 5 min to form the active catalyst. An 8 mL reaction vial containing (S)-3-bromo-N-(3-cyclopentyl-1-((1-methyl-1H- pyrazol-4-yl)amino)-1-oxopropan-2-yl)benzamide (Intermediate 11, 30 mg, 72 µmol) and 3-fluo-10 ropyridin-2-amine (9.6 mg, 86 µmol, 1.2 equiv) was placed under an argon atmosphere, degassedanhydrous 1,4-dioxane (1.0 mL) was added and the mixture was purged with argon for 3 min. Next, cesium carbonate (51 mg, 0.16 mmol, 2.2 equiv) was added, followed by the solution of the active catalyst. The reaction vial was heated in a sealed vial at 90 °C overnight, cooled to room temperature and concentrated in vacuo. The residue was purified by preparative HPLC (Method15 B), affording the title product (23 mg, 71%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ10.10 (s, 1H), 8.98 (d, J = 2.1 Hz, 1H), 8.43 (d, J = 7.9 Hz, 1H), 8.22 (t, J = 2.0 Hz, 1H), 7.99 (dt, J = 4.9, 1.2 Hz, 1H), 7.94 (ddd, J = 8.1, 2.4, 1.0 Hz, 1H), 7.87 (s, 1H), 7.57 (ddd, J = 11.7, 7.9, 1.5 Hz, 1H), 7.53 – 7.45 (m, 1H), 7.43 (s, 1H), 7.36 (t, J = 7.9 Hz, 1H), 6.84 (ddd, J = 8.1, 4.9, 3.4 Hz, 1H), 4.59 – 4.48 (m, 1H), 3.78 (s, 3H), 1.97 – 1.65 (m, 5H), 1.65 – 1.53 (m, 2H), 1.53 – 1.3820 (m, 2H), 1.29 – 1.00 (m, 2H); UPLC (Method F): tR 1.46 min, 99.7%, MS (ESI) 451.2 (M+H)+.The following examples have been prepared using procedures analogous to Example 143, using the appropriate starting materials and intermediates, and purified by preparative HPLC (Method A or B): ANAVO therapeutics BV A19160WO95 ANAVO therapeutics BV A19160WO96 ANAVO therapeutics BV A19160WO97 The following compounds were prepared analogously to other exemplified compounds de- scribed herein: 5Example 155: (S)-3-((2-chloro-5-fluoropyridin-4-yl)amino)-N-(3-cyclopentyl-1-((1-methyl-1H-pyrazol-4-yl)amino)-1-oxopropan-2-yl)benzamide Example 156: (S)-N-(3-cyclopentyl-1-((5-methylthiazol-2-yl)amino)-1-oxopropan-2-yl)-3-((3-fluo-10 ropyridin-4-yl)amino)benzamide Example 157: (S)-N-(3-cyclopentyl-1-oxo-1-((pyrimidin-5-ylmethyl)amino)propan-2-yl)-3-((3-flu- oropyridin-4-yl)amino)benzamide 15 ANAVO therapeutics BV A19160WO98 Example 158: N-((S)-3-cyclopentyl-1-(((S)-1-(1-methyl-1H-pyrazol-4-yl)ethyl)amino)-1-oxo- propan-2-yl)-3-((3-fluoropyridin-4-yl)amino)benzamide 5 Example 159: N-((S)-3-cyclopentyl-1-(((R)-1-(1-methyl-1H-pyrazol-4-yl)ethyl)amino)-1-oxo- propan-2-yl)-3-((3-fluoropyridin-4-yl)amino)benzamide10 Example 160: (S)-N-(3-cyclopentyl-1-((4-hydroxyphenyl)amino)-1-oxopropan-2-yl)-3-((3-fluo- ropyridin-4-yl)amino)benzamide and (R)-N-(3-cyclopentyl-1-((4-hydroxyphenyl)amino)-1-oxo-15 propan-2-yl)-3-((3-fluoropyridin-4-yl)amino)benzamide Example 161: (S)-N-(3-cyclopentyl-1-((6-hydroxypyridin-3-yl)amino)-1-oxopropan-2-yl)-3-((3-flu-20 oropyridin-4-yl)amino)benzamide and (R)-N-(3-cyclopentyl-1-((6-hydroxypyridin-3-yl)amino)-1-oxopropan-2-yl)-3-((3-fluoropyridin-4-yl)amino)benzamide 25 Example 162: (S)-N-(3-cyclopentyl-1-oxo-1-((2-(pyridin-3-yl)propan-2-yl)amino)propan-2-yl)-3-((3-fluoropyridin-4-yl)amino)benzamide and (R)-N-(3-cyclopentyl-1-oxo-1-((2-(pyridin-3- yl)propan-2-yl)amino)propan-2-yl)-3-((3-fluoropyridin-4-yl)amino)benzamide 30 Example 163: (S)-N-(3-cyclopentyl-1-((3-(2-hydroxypropan-2-yl)phenyl)amino)-1-oxopropan-2- yl)-3-((3-fluoropyridin-4-yl)amino)benzamide and (R)-N-(3-cyclopentyl-1-((3-(2-hydroxypropan-2- yl)phenyl)amino)-1-oxopropan-2-yl)-3-((3-fluoropyridin-4-yl)amino)benzamideANAVO therapeutics BV A19160WO99 Example 164: (S)-N-(3-cyclopentyl-1-((2-hydroxyphenyl)amino)-1-oxopropan-2-yl)-3-((3-fluo- 5ropyridin-4-yl)amino)benzamide and (R)-N-(3-cyclopentyl-1-((2-hydroxyphenyl)amino)-1-oxo-propan-2-yl)-3-((3-fluoropyridin-4-yl)amino)benzamide 10 Example 165: (S)-N-(3-cyclopentyl-1-((3-hydroxyphenyl)amino)-1-oxopropan-2-yl)-3-((3-fluo-ropyridin-4-yl)amino)benzamide (R)-N-(3-cyclopentyl-1-((3-hydroxyphenyl)amino)-1-oxopropan- 2-yl)-3-((3-fluoropyridin-4-yl)amino)benzamide 15 Example 166: (S)-N-(3-cyclopentyl-1-oxo-1-(o-tolylamino)propan-2-yl)-3-((3-fluoropyridin-4- yl)amino)benzamide and (R)-N-(3-cyclopentyl-1-oxo-1-(o-tolylamino)propan-2-yl)-3-((3-fluoropy- ridin-4-yl)amino)benzamide20 Example 167: (S)-N-(3-cyclopentyl-1-(isoxazol-4-ylamino)-1-oxopropan-2-yl)-3-((3-fluoropyridin- 4-yl)amino)benzamide and (R)-N-(3-cyclopentyl-1-(isoxazol-4-ylamino)-1-oxopropan-2-yl)-3-((3- fluoropyridin-4-yl)amino)benzamide 25 Example 168: (S)-N-(3-cyclopentyl-1-((1-methyl-1H-pyrazol-4-yl)amino)-1-oxopropan-2-yl)-3-(8- (trifluoromethyl)-2,3-dihydropyrido[3,2-e][1,4]oxazepin-1(5H)-yl)benzamide 30 ANAVO therapeutics BV A19160WO100 Example 169: (S)-N-(3-cyclopentyl-1-((1-methyl-1H-pyrazol-4-yl)amino)-1-oxopropan-2-yl)-3- ((5-fluoro-2-methylpyridin-4-yl)(methyl)amino)benzamide 5Example 170: (S)-N-(3-cyclopentyl-1-((5-fluoropyrimidin-2-yl)amino)-1-oxopropan-2-yl)-3-((3-flu-oropyridin-4-yl)amino)benzamide and (R)-N-(3-cyclopentyl-1-((5-fluoropyrimidin-2-yl)amino)-1- oxopropan-2-yl)-3-((3-fluoropyridin-4-yl)amino)benzamide 10 Example 171: (S)-N-(3-cyclopentyl-1-((5-methylpyrazin-2-yl)amino)-1-oxopropan-2-yl)-3-((3-flu- oropyridin-4-yl)amino)benzamide and (R)-N-(3-cyclopentyl-1-((5-methylpyrazin-2-yl)amino)-1- oxopropan-2-yl)-3-((3-fluoropyridin-4-yl)amino)benzamide15 Example 172: (S)-N-(1-((5-cyanopyrazin-2-yl)amino)-3-cyclopentyl-1-oxopropan-2-yl)-3-((3-fluo- ropyridin-4-yl)amino)benzamide and (R)-N-(1-((5-cyanopyrazin-2-yl)amino)-3-cyclopentyl-1-oxo- propan-2-yl)-3-((3-fluoropyridin-4-yl)amino)benzamide 20 Example 173: (S)-N-(3-cyclopentyl-1-((2,6-dimethylpyrimidin-4-yl)amino)-1-oxopropan-2-yl)-3- ((3-fluoropyridin-4-yl)amino)benzamide and (R)-N-(3-cyclopentyl-1-((2,6-dimethylpyrimidin-4-25 yl)amino)-1-oxopropan-2-yl)-3-((3-fluoropyridin-4-yl)amino)benzamide Example 174: (S)-N-(3-cyclopentyl-1-((1-methyl-1H-pyrazol-4-yl)amino)-1-oxopropan-2-yl)-3-30 ((2,6-dimethylpyridin-4-yl)amino)-4-fluorobenzamide, formate salt.ANAVO therapeutics BV A19160WO101 Example 175: 3-((5-fluoro-2-methylpyridin-4-yl)amino)-N-((2S)-1-((1-methyl-1H-pyrazol-4- yl)amino)-3-(3-methylcyclopentyl)-1-oxopropan-2-yl)benzamide 5 Example 176: N-((2S)-3-(3,3-difluorocyclopentyl)-1-((1-methyl-1H-pyrazol-4-yl)amino)-1-oxo- propan-2-yl)-3-((5-fluoro-2-methylpyridin-4-yl)amino)benzamide 10 Example 177: N-((2S)-3-(3-fluorocyclopentyl)-1-((1-methyl-1H-pyrazol-4-yl)amino)-1-oxo- propan-2-yl)-3-(7-(trifluoromethyl)-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-1-yl)benzamide 15 ANAVO therapeutics BV A19160WO102 Example 178: N-((2S)-3-(3,3-difluorocyclopentyl)-1-((1-methyl-1H-pyrazol-4-yl)amino)-1-oxo- propan-2-yl)-3-(7-(trifluoromethyl)-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-1-yl)benzamide 5 Example 179: (S)-3-((5-chloro-2-methylpyridin-4-yl)amino)-N-(3-cyclopentyl-1-((1-methyl-1H-py- razol-4-yl)amino)-1-oxopropan-2-yl)benzamide 10 Example 180: (S)-N-(3-cyclopentyl-1-((1-methyl-1H-pyrazol-4-yl)amino)-1-oxopropan-2-yl)-3- ((2-(trifluoromethyl)pyridin-4-yl)amino)benzamide 15 Example 181: (S)-N-(3-cyclopentyl-1-((1-methyl-1H-pyrazol-4-yl)amino)-1-oxopropan-2-yl)-3-((2-(difluoromethyl)pyridin-4-yl)amino)benzamide Example 182: (S)-N-(3-cyclopentyl-1-((1-methyl-1H-pyrazol-4-yl)amino)-1-oxopropan-2-yl)-3-20 ((2,6-dimethylpyridin-4-yl)amino)benzamide Example 183: (S)-N-(3-cyclopentyl-1-((1-methyl-1H-pyrazol-4-yl)amino)-1-oxopropan-2-yl)-3- ((2-(2-fluoropropan-2-yl)pyridin-4-yl)amino)benzamide 25 ANAVO therapeutics BV A19160WO103 Example 184: (S)-N-(3-cyclopentyl-1-((1-methyl-1H-pyrazol-4-yl)amino)-1-oxopropan-2-yl)-3- ((5-(1,1-difluoroethyl)pyridin-3-yl)amino)benzamide 5Example 185: (S)-N-(3-cyclopentyl-1-((1-methyl-1H-pyrazol-4-yl)amino)-1-oxopropan-2-yl)-3-((5-(difluoromethyl)pyridin-3-yl)amino)benzamide Example 186: (S)-3-((5-chloro-2-methylpyridin-4-yl)amino)-N-(3-cyclopentyl-1-((1-methyl-1H-10 pyrazol-4-yl)amino)-1-oxopropan-2-yl)-4-fluorobenzamide Example 187: (S)-N-(3-cyclopentyl-1-((1-methyl-1H-pyrazol-4-yl)amino)-1-oxopropan-2-yl)-4- fluoro-3-((2-(trifluoromethyl)pyridin-4-yl)amino)benzamide 15 Example 188: (S)-N-(3-cyclopentyl-1-((1-methyl-1H-pyrazol-4-yl)amino)-1-oxopropan-2-yl)-3- ((2-(difluoromethyl)pyridin-4-yl)amino)-4-fluorobenzamide 20 Example 189: (S)-N-(3-cyclopentyl-1-((1-methyl-1H-pyrazol-4-yl)amino)-1-oxopropan-2-yl)-3- ((2-(1,1-difluoroethyl)pyridin-4-yl)amino)-4-fluorobenzamide 25 Example 190: (S)-N-(3-cyclopentyl-1-((1-methyl-1H-pyrazol-4-yl)amino)-1-oxopropan-2-yl)-4-fluoro-3-((2-methoxy-6-methylpyridin-4-yl)amino)benzamideANAVO therapeutics BV A19160WO104 Example 191: (S)-3-((2-cyclobutylpyridin-4-yl)amino)-N-(3-cyclopentyl-1-((1-methyl-1H-pyrazol- 4-yl)amino)-1-oxopropan-2-yl)-4-fluorobenzamide 5 Example 192: (S)-N-(3-cyclopentyl-1-((1-methyl-1H-pyrazol-4-yl)amino)-1-oxopropan-2-yl)-4- fluoro-3-((2-isopropylpyridin-4-yl)amino)benzamide 10 Example 193: (S)-N-(3-cyclopentyl-1-((1-methyl-1H-pyrazol-4-yl)amino)-1-oxopropan-2-yl)-4- fluoro-3-((2-(2-hydroxypropan-2-yl)pyridin-4-yl)amino)benzamide 15 Example 194 [Ref. Ex.]: (S)-N-(3-cyclopentyl-1-((1-methyl-1H-pyrazol-4-yl)amino)-1-oxo-propan-2-yl)-3-((2,5-dimethylphenyl)amino)-4-fluorobenzamide Example 195: (S)-N-(3-cyclopentyl-1-((1-methyl-1H-pyrazol-4-yl)amino)-1-oxopropan-2-yl)-3-20 ((5-cyclopropylpyridin-3-yl)amino)-4-fluorobenzamide Example 196: (S)-N-(3-cyclopentyl-1-((2-methylthiazol-5-yl)amino)-1-oxopropan-2-yl)-3-((3-fluo- ropyridin-4-yl)amino)benzamideANAVO therapeutics BV A19160WO105 Example 197: (S)-N-(3-cyclopentyl-1-((2-methylthiazol-4-yl)amino)-1-oxopropan-2-yl)-3-((3-fluo- ropyridin-4-yl)amino)benzamide 5 Example 198: (S)-N-(3-cyclopentyl-1-((5-methyl-1,2,4-thiadiazol-3-yl)amino)-1-oxopropan-2-yl)- 3-((3-fluoropyridin-4-yl)amino)benzamide and (R)-N-(3-cyclopentyl-1-((5-methyl-1,2,4-thiadiazol- 3-yl)amino)-1-oxopropan-2-yl)-3-((3-fluoropyridin-4-yl)amino)benzamide 10 Example 199: (S)-N-(3-cyclopentyl-1-((1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-4-yl)amino)-1- oxopropan-2-yl)-3-((3-fluoropyridin-4-yl)amino)benzamide 15 Example 200: (S)-N-(3-(cyclopentyloxy)-1-((1-methyl-1H-pyrazol-4-yl)amino)-1-oxopropan-2- yl)-3-(7-(trifluoromethyl)-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-1-yl)benzamide 20 Example 201: (S)-N-(3-(cyclopentyloxy)-1-((1-methyl-1H-pyrazol-4-yl)amino)-1-oxopropan-2- yl)-3-((5-fluoro-2-methylpyridin-4-yl)amino)benzamide 25 Example 202: (S)-N-(3-cyclopentyl-1-((1-methyl-1H-pyrazol-4-yl)amino)-1-oxopropan-2-yl)-4-fluoro-3-(7-(trifluoromethyl)-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-1-yl)benzamideANAVO therapeutics BV A19160WO106 Example 203: (S)-N-(3-cyclopentyl-1-((1-methyl-1H-pyrazol-4-yl)amino)-1-oxopropan-2-yl)-4- methyl-3-(7-(trifluoromethyl)-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-1-yl)benzamide 5 Example 204: (S)-N-(3-cyclopentyl-1-((2-hydroxyphenyl)amino)-1-oxopropan-2-yl)-3-(7-(trifluo- romethyl)-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-1-yl)benzamide 10 Example 205: (S)-N-(3-cyclopentyl-1-((2-hydroxyphenyl)amino)-1-oxopropan-2-yl)-3-((5-fluoro- 2-methylpyridin-4-yl)amino)benzamide 15 Example 206: (S)-N-(3-cyclopentyl-1-((2-hydroxyphenyl)amino)-1-oxopropan-2-yl)-3-((3-fluo-ropyridin-4-yl)amino)benzamide20 ANAVO therapeutics BV A19160WO107 Example 208: N-((S)-3-((1r,3R,4S)-3,4-difluorocyclopentyl)-1-((1-methyl-1H-pyrazol-4- yl)amino)-1-oxopropan-2-yl)-3-(7-(trifluoromethyl)-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-1- yl)benzamide 5 Example 209: (S)-N-(3-cyclopentyl-1-((4-hydroxypyridin-3-yl)amino)-1-oxopropan-2-yl)-3-((3-flu- oropyridin-4-yl)amino)benzamide 10 Example 210: (S)-N-(3-cyclopentyl-1-((2-methoxyphenyl)amino)-1-oxopropan-2-yl)-3-((3-fluo-ropyridin-4-yl)amino)benzamide Example 211: (S)-N-(3-cyclopentyl-1-((3-fluoropyridin-2-yl)amino)-1-oxopropan-2-yl)-3-((3-fluo-15 ropyridin-4-yl)amino)benzamide and (R)-N-(3-cyclopentyl-1-((3-fluoropyridin-2-yl)amino)-1-oxo-propan-2-yl)-3-((3-fluoropyridin-4-yl)amino)benzamide 20 Example 212: (S)-N-(3-cyclopentyl-1-((2-fluorophenyl)amino)-1-oxopropan-2-yl)-3-((3-fluoropy-ridin-4-yl)amino)benzamide Example 213: (S)-N-(3-cyclopentyl-1-oxo-1-((2-(trifluoromethyl)phenyl)amino)propan-2-yl)-3-25 ((3-fluoropyridin-4-yl)amino)benzamide ANAVO therapeutics BV A19160WO108 Example 214: (S)-N-(3-cyclopentyl-1-((5-fluoropyridin-3-yl)amino)-1-oxopropan-2-yl)-3-((3-fluo- ropyridin-4-yl)amino)benzamide and (R)-N-(3-cyclopentyl-1-((5-fluoropyridin-3-yl)amino)-1-oxo- propan-2-yl)-3-((3-fluoropyridin-4-yl)amino)benzamide 5 Example 215: (S)-3-((5-cyanopyridin-3-yl)amino)-N-(3-cyclopentyl-1-((1-methyl-1H-pyrazol-4- yl)amino)-1-oxopropan-2-yl)benzamide 10 Example 216: (S)-N-(3-cyclopentyl-1-((2-hydroxypyridin-3-yl)amino)-1-oxopropan-2-yl)-3-((3-flu- oropyridin-4-yl)amino)benzamide 15 Example 217: (S)-N-(3-cyclopentyl-1-((5-fluoropyrimidin-4-yl)amino)-1-oxopropan-2-yl)-3-((3-fluoropyridin-4-yl)amino)benzamide and (R)-N-(3-cyclopentyl-1-((5-fluoropyrimidin-4-yl)amino)- 1-oxopropan-2-yl)-3-((3-fluoropyridin-4-yl)amino)benzamide 20 Comparative Example: US20240116910, Example 98: (5-((S)-1-((5-chloro-2-methylpyridin-3- yl)amino)ethyl)-N-(3-cyclopentyl-1-((1-methyl-1H-pyrazol-4-yl)amino)-1-oxopropan-2-yl)thio- phene-2-carboxamide 25 1H NMR (400 MHz, DMSO-d6) δ 10.09 (s, 1H), 8.52 (d, J = 8.0 Hz, 1H), 7.84 (s, 1H), 7.75 (d, J= 3.8 Hz, 1H), 7.67 (d, J = 2.0 Hz, 1H), 7.41 (s, 1H), 7.08 (d, J = 3.8 Hz, 1H), 6.83 (d, J = 2.1 Hz, 1H), 5.87 (d, J = 7.1 Hz, 1H), 4.93 (q, J = 6.9 Hz, 1H), 4.50 – 4.40 (m, 1H), 3.77 (s, 3H), 2.37 (s, 3H), 1.92 – 1.71 (m, 3H), 1.71 – 1.61 (m, 2H), 1.59 (d, J = 6.7 Hz, 3H), 1.57 – 1.49 (m, 2H), 1.49 – 1.33 (m, 2H), 1.21 – 1.03 (m, 2H). UPLC (Method F): tR 1.526 min, 99.74%, MS30 (ESI) 515.4 (M+H)+.ANAVO therapeutics BV A19160WO109 Biological data WIP1 (PPM1D) in vitro phosphatase activity assay with Fluorescein Diphosphate (FDP) 5substrateRecombinant WIP1 (amino acids 1-397; SEQ ID NO1: GHMAGLYSLGVSVFSDQG- GRKYMEDVTQIVVEPEPTAEEKPSPRRSLSQPLPPRPSPAALPGGEVSGKGPAVAAREARD- PLPDAGASPAPSRCCRRRSSVAFFAVCDGHGGREAAQFAREHLWGFIKKQKGFTSSEPAKV-10 CAAIRKGFLACHLAMWKKLAEWPKTMTGLPSTSGTTASVVIIRGMKMYVAHVGDSGVVLGIQD-DPKDDFVRAVEVTQDHKPELPKERERIEGLGGSVMNKSGVNRVVWKRPRLTHNG- PVRRSTVIDQIPFLAVARALGDLWSYDFFSGEFVVSPEPDTSVHTLDPQKHKYIILGSDGLWN- MIPPQDAISMCQDQEEKKYLMGEHGQSCAKMLVNRALGRWRQRMLRADNTSAIVICISPEVD- NQGNFTNEDELYLNLTDPSGS) was expressed in E. coli, purified using standard chromato-15 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- croplates in the presence of 20 µM FDP and 10 nM WIP1. Compounds were dissolved in20 DMSO. Serially diluted compounds were added to a maximal final concentration of 10μM in a3.3-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 without 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. Reactions25 were stopped by adding 10 µl 125 mM EDTA. The fluorescence signal was read in an EnVisionMultimode Reader (PerkinElmer) using excitation / emission at 490 / 514 nm. IC50values were cal- culated using GraphPad Prism software. WIP1 Dephosphorylation Assay Measuring Cellular p53 Phospho-Serine 15 Levels30 In the cellular WIP1 (de-)phosphorylation assay the human osteosarcoma cell line U2OS isused. 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 p53Ser15 due to the lack of WIP1-dependent dephosphorylation.35 U2OS cells were plated in DMEM supplemented with 10% FCS in 96 well cell culture platesand 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 minimum 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. 40 The cells were incubated with compounds for 3 hours at 37°C in complete culture medium containing 10% FCS. After cell lysis, quantification of phospho p53Ser15 was assessed in 96well plates via sandwich-ELISA using a p53-specific capture antibody and a phospho- p53Ser15-specific detection antibody. Curves were analyzed using GraphPad Prism and EC5045 values expressed as log Molar“+” represents a fitted IC50value 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.ANAVO therapeutics BV A19160WO110 Table 5: “No.” denotes “Example Number” ANAVO therapeutics BV A19160WO111 ANAVO therapeutics BV A19160WO112 ANAVO therapeutics BV A19160WO113 ANAVO therapeutics BV A19160WO114 ANAVO therapeutics BV A19160WO115 ANAVO therapeutics BV A19160WO116 ANAVO therapeutics BV A19160WO117 ANAVO therapeutics BV A19160WO118 ANAVO therapeutics BV A19160WO119 ANAVO therapeutics BV A19160WO120 ANAVO therapeutics BV A19160WO121 ANAVO therapeutics BV A19160WO122 ANAVO therapeutics BV A19160WO123 ANAVO therapeutics BV A19160WO124 ANAVO therapeutics BV A19160WO125 ANAVO therapeutics BV A19160WO126 ANAVO therapeutics BV A19160WO127 ANAVO therapeutics BV A19160WO128 ANAVO therapeutics BV A19160WO129 ANAVO therapeutics BV A19160WO130 ANAVO therapeutics BV A19160WO131

[0002] ANAVO therapeutics BV A19160WO132 ANAVO therapeutics BV A19160WO133 ANAVO therapeutics BV A19160WO134 ANAVO therapeutics BV A19160WO135 ANAVO therapeutics BV A19160WO136 ANAVO therapeutics BV A19160WO137 ANAVO therapeutics BV A19160WO138 ANAVO therapeutics BV A19160WO139

[0003] ANAVO therapeutics BV A19160WO140 Microsome stability studies: Mouse liver microsome stability study: - Compounds are dissolved in DMSO to a concentration of 10 mM and further diluted to 100 5µM using MeCN.- Mouse liver microsomes are incubated in duplicate with the compound at a final concentra- tion of 1 µM in 0.1 M potassium phosphate buffer (pH 7.4) containing 3.3 mM MgCl2, 0.5 mg / mL microsomal protein, in the presence or absence of NADPH (1 mM). - Incubations are performed at 37 °C in a total volume of 500 µL. Control incubations with ref-10 erence compounds are included for each experiment.- At different time points (0, 5, 15, 30 and 45 min), 50 µL of the incubation mixture is trans- ferred into a quench plate containing acetonitrile and internal standard (200 nM labetalol) cooled to 6 °C. - After the last time point, the quench plates are mixed and centrifuged for 15 minutes at 370015 rpm and 6 °C.- The supernatant is transferred to a new 96-well plates and subjected to LCMS analysis. All sample analysis is performed using a Vanquish Horizon UHPLC-system equipped with an autosampler, a binary pump and a column compartment coupled to a Exactive focus hybrid quadrupole-Orbitrap MS (Thermo Fisher Scientific) equipped with heated electrospray ion20 source. MS settings were optimized for the flow rate.- The percentage of compound remaining is defined as the ratio of compound peak area at a specific time point and the peak area in the t = 0 min samples multiplied by 100%. - The metabolic stability is evaluated by plotting the natural logarirhm of the %compound re- maining versus time and performing linear regression. Using this graph, the elimination con-25 stant, t1 / 2 and in vitro intrinsic clearance are calculated.Human liver microsome stability study: - Compounds are dissolved in DMSO to a concentration of 10 mM and further diluted to 10030 µM using MeCN.- Human liver microsomes are incubated in duplicate with the compound at a final concentra- tion of 1 µM in 0.1 M potassium phosphate buffer (pH 7.4) containing 3.3 mM MgCl2, 0.5 mg / mL microsomal protein, in the presence or absence of NADPH (1 mM). - Incubations are performed at 37 °C in a total volume of 500 µL. Control incubations with ref-35 erence compounds are included for each experiment.- At different time points (0, 5, 15, 30 and 45 min), 50 µL of the incubation mixture is trans- ferred into a quench plate containing acetonitrile and internal standard (200 nM labetalol) cooled to 6 °C. - After the last time point, the quench plates are mixed and centrifuged for 15 minutes at 370040 rpm and 6 °C.- The supernatant is transferred to a new 96-well plates and subjected to LCMS analysis. All sample analysis is performed using a Vanquish Horizon UHPLC-system equipped with an autosampler, a binary pump and a column compartment coupled to a Exactive focus hybrid quadrupole-Orbitrap MS (Thermo Fisher Scientific) equipped with heated electrospray ion45 source. MS settings were optimized for the flow rate.- The percentage of compound remaining is defined as the ratio of compound peak area at a specific time point and the peak area in the t = 0 min samples multiplied by 100%. - The metabolic stability is evaluated by plotting the natural logarithm of the %compound re-ANAVO therapeutics BV A19160WO141 maining versus time and performing linear regression. Using this graph, the elimination con- stant, t1 / 2and in vitro intrinsic clearance are calculated. “A” represents a calculated Clintvalue less than or equal to 10 µl / min / mg; “B” represents a cal- culated Clintvalue greater than 10 µl / min / mg and less than or equal to 50 µl / min / mg; “C” repres-5 ents a calculated Clint value greater than 50 µl / min / mg.Table 3: “No.” denotes “Example Number”; “Comp. Ex.” denotes “Comparative Example” ANAVO therapeutics BV A19160WO142 * US20240116910, Example 98 5

[0004] ANAVO therapeutics BV A19160WO143 In particular, the present invention relates to the following items: 1. A compound of formula (I)5 or a stereoisomer, tautomer, N-oxide, or pharmaceutically acceptable salt thereof; wherein10 A is -OR1, -NH-R1 or -NRA-R1; oris a moiety selected from wherein the wavy line marks the connection to the remainder of the molecule; Bis a 5- or 6-membered aromatic carbocyclic or heterocyclic ring, wherein the aforemen-15 tioned heterocyclic ring comprises one or more, same or different heteroatoms selectedfrom O, N, or S, wherein said N- and / or S-atoms are independently oxidized or non-oxi- dized, and wherein each substitutable carbon or heteroatom in the aforementioned carbo- cyclic or heterocyclic rings is independently unsubstituted or substituted with one or more, same or different substituents RB;20 R2 is H, C1-C2-alkyl, 5- or 6-membered saturated or partially unsaturated carbocyclyl or hete-rocyclyl, or carbocyclyloxy or heterocyclyloxy, or 4- to 12-membered saturated carbobicy- clyl 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 substi-25 tutable atom in the aforementioned groups is independently unsubstituted or substitutedwith 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 heterocyclylmethyl, or 4- to 12-membered saturated carbobicyclyl or heterobicyclyl,30 wherein the aforementioned heterocyclyl or heterobicyclyl comprises one or more, sameor 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 or different substituents RY; and35 RN is H or CH3;and wherein R1is 5- or 6-membered aromatic carbocyclyl, carbocyclylmethyl, heterocyclyl, or heterocy- clylmethyl, wherein the aforementioned heterocyclyl comprises one or more, same or dif- ferent heteroatoms selected from O, N, or S, wherein said N- and / or S-atoms are indepen-40 dently oxidized or non-oxidized, and wherein each substitutable atom in the aforemen-tioned groups is independently unsubstituted or substituted with one or more, same or dif- ferent substituents RZ;ANAVO therapeutics BV A19160WO144 RAis H or CH3; RBis halogen, CN, C1-C4-alkyl, C1-C4-haloalkyl, C1-C4-alkoxy, or C1-C4-haloalkoxy; or RNand RBtogether with the atoms to which they are bonded and the atoms in between form a fused 5- or 6-membered heterocyclic ring, wherein said heterocyclic ring comprises the ni- 5trogen atom of the NRN group as heteroatom; orRAand RBtogether with the atoms to which they are bonded and together with the carbon atom to which the nitrogen atom of the NRAgroup is bonded form a fused 5- or 6-membered saturated heterocyclic ring, wherein said heterocyclic ring comprises the nitrogen atom of the NR1group as heteroatom;10 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 A1 is a 5- or 6-membered aromatic carbocyclic or heterocyclic ring, wherein the aforemen-tioned heterocyclic ring 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-oxi- dized; A2is a 5- to 7-membered saturated, partially or fully unsaturated or aromatic carbocyclic or20 heterocyclic ring, wherein the aforementioned heterocyclic ring 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; 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;25 R5 each 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; andn is 0, 1, 2, 3, or 4;and wherein30 RZ is halogen, CN, C1-C4-alkyl, C1-C4-haloalkyl, C1-C4-alkoxy, C1-C4-haloalkoxy, C1-C4-alkylO-C(=O)-, C1-C4-alkyl-C(=O)-O-, (C1-C4-alkyl)2N-C(=O)-, C1-C4-alkyl-C(=O)-NH-, C3- C6-cycloalkyl, phenyl, or 3- to 6-membered saturated heterocyclyl, wherein said heterocy- clyl 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 wherein35 said heterocyclyl is unsubstituted or substituted with one or more, same or different sub-stituents selected from halogen, C1-C2-alkyl, and C1-C2-haloalkyl; or two RZattached to neighboring atoms together with the atoms to which they are attached form a fused 5 or 6-membered saturated, partially or fully unsaturated, or aromatic carbo- cyclic or heterocyclic ring, wherein the aforementioned heterocyclic ring comprises one or40 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 said heterocyclic ring is unsubstituted or substituted with one or more, same or different substituents selected from halogen, C1-C2-alkyl, and C1-C2-haloalkyl.45 2. The compound according to item 1, whereinA is -OR1, -NH-R1 or -NRA-R1;and whereinANAVO therapeutics BV A19160WO145 R1is pyridinyl, pyrimidinyl, pyridazinyl, phenyl, or pyrazolyl, wherein each substitutable car- bon or heteroatom in the aforementioned rings is independently unsubstituted or substi- tuted with one or more, same or different substituents RZ. 53. The compound according to item 1 or 2, whereinA is -OR1, -NH-R1 or -NRA-R1;and wherein R1is 3-pyridinyl or 4-pyridinyl, wherein each substitutable carbon or heteroatom in the afore- mentioned rings is independently unsubstituted or substituted with one or more, same or10 different substituents RZ;and wherein preferably RZis F, Cl, Br, CN, CH3, CF2H, CF3, OCH3, CH3O-C(=O)-, CH3-C(=O)-NH-, cyclopropyl, mor- pholinyl, 4-methylpiperazinyl, or phenyl; or two RZattached to neighboring atoms together with the atoms to which they are attached15 form a fused 5 or 6-membered saturated, partially or fully unsaturated, or aromatic carbo-cyclic or heterocyclic ring, wherein the aforementioned heterocyclic ring 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 said heterocyclic ring is unsubstituted. 20 4. The compound according to item 1, whereinA is a moiety selected from25 ANAVO therapeutics BV A19160WO146 5wherein the wavy line marks the connection to the remainder of the molecule;and wherein Y1is CH2, NH, NCH3, or O; Y2is CH or N; Y3is CH2;10 and the remaining variables are as defined in item 1.5. The compound according to item 1, whereinA is a moiety selected from 15 wherein the wavy line marks the connection to the remainder of the molecule;and wherein preferably R4is Br, Cl, CN, CH3, CF3, or cyclopropyl. 6. The compound according to any one of items 1 to 5, wherein20 B is a phenyl, thiophenyl or thiazolyl ring, wherein each substitutable carbon or heteroatomin the aforementioned carbocyclic or heterocyclic rings is independently unsubstituted or substituted with one or more, same or different substituents RB. 7. The compound according to any one of items 1 to 6, wherein25 wherein the wavy line marks the connection to A and the dotted line marks the connection to the carbon atom of the C(=O) group to which B is attached.30 8. The compound according to any one of items 1 to 7, whereinANAVO therapeutics BV A19160WO147 R2is cyclohexyl, cyclopentyl or tetrahydrofuranyl, wherein each substitutable carbon atom in the aforementioned rings is independently unsubstituted or substituted with one or more, same or different substituents RX. 59. The compound according to any one of items 1 to 8, whereinR3is CH3; or a 3- to 5-membered saturated carbocyclic or heterocyclic ring, wherein the aforemen- tioned heterocyclic ring comprises an oxygen atom as heteroatom, and wherein each sub- stitutable carbon atom in the aforementioned carbocyclic or heterocyclic rings is indepen-10 dently unsubstituted or substituted with one or more, same or different substituents RY;or a 5- or 6-membered aromatic carbocyclic or heterocyclic ring; wherein the aforemen- tioned heterocyclic ring 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-oxi- dized, and wherein each substitutable atom in the aforementioned carbocyclic or hetero-15 cyclic ring is independently unsubstituted or substituted with one or more, same or differ-ent substituents RY; or 5- or 6-membered aromatic carbocyclylmethyl or heterocyclylmethyl; wherein the afore- mentioned heterocyclyl 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-oxi-20 dized, and wherein each substitutable atom in the aforementioned carbocyclylmethyl orheterocyclylmethyl is independently unsubstituted or substituted with one or more, same or different substituents RY. 10. The compound according to any one of items 1 to 9, wherein the compound of formula (I)25 is a compound of formula (IS) 11. The compound according to any one of items 1 to 10, wherein the compound according to30 formula (I) is selected from the group consisting of 12. A pharmaceutical composition comprising a pharmaceutically effective amount of the35 compound according to any one of items 1 to 11 and optionally a pharmaceutically acceptablecarrier or excipient.ANAVO therapeutics BV A19160WO148 13. A compound according to any one of items 1 to 11 or a pharmaceutical composition ac-cording to item 12 for use in medicine. 14. A compound according to any one of items 1 to 11 or a pharmaceutical composition ac-5 cording to item 12 for use in the treatment of a disease selected from the group consisting ofcancer, pre-cancerous syndromes, autoimmune conditions, neurological diseases, and viral dis- ease, preferably selected from the group consisting of cancer, pre-cancerous syndromes, au- toimmune conditions, and neurological diseases, more preferably selected from the group con- sisting of cancer, pre-cancerous syndromes, and neurological diseases. 10 15. A compound according to any one of items 1 to 11 or a pharmaceutical composition ac-cording to item 12 for use in the treatment of a disease selected from the group consisting of amyotrophic lateral sclerosis, attention deficit hyperactivity disorder, autism, Bannayan-Zonana syndrome, bladder cancer, blood cancer, bone cancer, breast cancer, inflammatory breast can-15 cer, brain cancer, cervical cancer, colorectal cancer, Cowden disease, endometrial cancer,ependymoma, esophagus cancer, Ewing's sarcoma, gastric cancer, head and neck cancer, indi- 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,20 Rhabdomyosarcoma, thyroid cancer, urothelial cancer, and Wilm's tumor.

Claims

ANAVO therapeutics BV A19160WO149 Claims 1. A compound of formula (I)5or a stereoisomer, tautomer, N-oxide, or pharmaceutically acceptable salt thereof; wherein10 A is -OR1, -NH-R1 or -NRA-R1; oris a moiety selected fromwherein the wavy line marks the connection to the remainder of the molecule; Bis a 5- or 6-membered aromatic carbocyclic or heterocyclic ring, wherein the aforemen-15 tioned heterocyclic ring comprises one or more, same or different heteroatoms selectedfrom O, N, or S, wherein said N- and / or S-atoms are independently oxidized or non-oxi- dized, and wherein each substitutable carbon or heteroatom in the aforementioned carbo- cyclic or heterocyclic rings is independently unsubstituted or substituted with one or more, same or different substituents RB;20 R2 is H, C1-C2-alkyl, 5- or 6-membered saturated or partially unsaturated carbocyclyl or hete-rocyclyl, or carbocyclyloxy or heterocyclyloxy, or 4- to 12-membered saturated carbobicy- clyl 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 substi-25 tutable atom in the aforementioned groups is independently unsubstituted or substitutedwith 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 heterocyclylmethyl, or 4- to 12-membered saturated carbobicyclyl or heterobicyclyl,30 wherein the aforementioned heterocyclyl or heterobicyclyl comprises one or more, sameor 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 or different substituents RY; and35 RN is H or CH3;and wherein R1is 3-pyridinyl or 4-pyridinyl, wherein each substitutable carbon or heteroatom in the afore- mentioned rings is independently unsubstituted or substituted with one or more, same or different substituents RZ;40 RA is H or CH3;RBis halogen, CN, C1-C4-alkyl, C1-C4-haloalkyl, C1-C4-alkoxy, or C1-C4-haloalkoxy; orANAVO therapeutics BV A19160WO150 RNand RBtogether with the atoms to which they are bonded and the atoms in between form a fused 5- or 6-membered heterocyclic ring, wherein said heterocyclic ring comprises the ni- trogen atom of the NRNgroup as heteroatom; or RAand RBtogether with the atoms to which they are bonded and together with the carbon atom 5to which the nitrogen atom of the NRA group is bonded form a fused 5- or 6-memberedsaturated heterocyclic ring, wherein said heterocyclic ring comprises the nitrogen atom of the NR1group as heteroatom; RXis halogen, CN, OH, C1-C4-alkyl, C1-C4-haloalkyl, C1-C4-alkoxy, C1-C4-haloalkoxy, or C1- C4-hydroxyalkyl;10 RY is 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; A1is a 5- or 6-membered aromatic carbocyclic or heterocyclic ring, wherein the aforemen- tioned heterocyclic ring comprises one or more, same or different heteroatoms selected15 from O, N, or S, wherein said N- and / or S-atoms are independently oxidized or non-oxi-dized; A2is a 5- to 7-membered saturated, partially or fully unsaturated or aromatic carbocyclic or heterocyclic ring, wherein the aforementioned heterocyclic ring comprises one or more, same or different heteroatoms selected from O, N, or S, wherein said N- and / or S-atoms20 are independently oxidized or non-oxidized;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;25 m is 0, 1, or 2; andn is 0, 1, 2, 3, or 4;and wherein RZis halogen, CN, C1-C4-alkyl, C1-C4-haloalkyl, C1-C4-alkoxy, C1-C4-haloalkoxy, C1-C4- alkylO-C(=O)-, C1-C4-alkyl-C(=O)-O-, (C1-C4-alkyl)2N-C(=O)-, C1-C4-alkyl-C(=O)-NH-, C3-30 C6-cycloalkyl, phenyl, or 3- to 6-membered saturated heterocyclyl, wherein said heterocy-clyl 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 said heterocyclyl is unsubstituted or substituted with one or more, same or different sub- stituents selected from halogen, C1-C2-alkyl, and C1-C2-haloalkyl;35 or two RZ attached to neighboring atoms together with the atoms to which they are attachedform a fused 5 or 6-membered saturated, partially or fully unsaturated, or aromatic carbo- cyclic or heterocyclic ring, wherein the aforementioned heterocyclic ring 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 said heterocyclic ring is40 unsubstituted or substituted with one or more, same or different substituents selected fromhalogen, C1-C2-alkyl, and C1-C2-haloalkyl.

2. The compound according to claim 1, whereinA is -OR1, -NH-R1 or -NRA-R1;45 and whereinR1is 3-pyridinyl or 4-pyridinyl, wherein each substitutable carbon or heteroatom in the afore- mentioned rings is independently unsubstituted or substituted with one or more, same or different substituents RZ.ANAVO therapeutics BV A19160WO151 3. The compound according to claim 1 or 2, whereinA is -OR1, -NH-R1 or -NRA-R1;and wherein R1is 3-pyridinyl or 4-pyridinyl, wherein each substitutable carbon or heteroatom in the afore- 5mentioned rings is independently unsubstituted or substituted with one or more, same ordifferent substituents RZ; and wherein RZis F, Cl, Br, CN, CH3, CF2H, CF3, OCH3, CH3O-C(=O)-, CH3-C(=O)-NH-, cyclopropyl, mor- pholinyl, 4-methylpiperazinyl, or phenyl;10 or two RZ attached to neighboring atoms together with the atoms to which they are attachedform a fused 5 or 6-membered saturated, partially or fully unsaturated, or aromatic carbo- cyclic or heterocyclic ring, wherein the aforementioned heterocyclic ring 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 said heterocyclic ring is15 unsubstituted.

4. The compound according to any of the claims 1 to 3, wherein,A is -NH-R1 or -N(CH3)-R1;wherein20 R1 is 3-pyridinyl or 4-pyridinyl, wherein each substitutable carbon or heteroatom in the afore-mentioned rings is independently unsubstituted or substituted with one or more, same or differ- ent substituents RZ; wherein RZis F, Cl, or CH3. 25 5. The compound according to any of the claims 1 to 4, wherein,A is -NH-R1 or -N(CH3)-R1;wherein R1is 3-pyridinyl or 4-pyridinyl, wherein each substitutable carbon or heteroatom in the afore-30 mentioned rings is independently unsubstituted or substituted with one or more, same or differ-ent substituents RZ; wherein RZis F, or CH3.35 6. The compound according to claim 1, whereinA is a moiety selected fromANAVO therapeutics BV A19160WO152 5wherein the wavy line marks the connection to the remainder of the molecule;10 and whereinY1is CH2, NH, NCH3, or O; Y2is CH or N; Y3is CH2; and the remaining variables are as defined in claim 1. 15 7. The compound according to claim 1, whereinA is a moiety selected fromwherein the wavy line marks the connection to the remainder of the molecule;20 and wherein preferablyR4is Br, Cl, CN, CH3, CF3, or cyclopropyl.

8. The compound according to claim 1, 6, or 7, whereinANAVO therapeutics BV A19160WO153wherein the wavy line marks the connection to the remainder of the molecule; and wherein 5R4 is Cl, or CF3.

9. The compound according to any one of claims 1 to 8, whereinB is a phenyl, thiophenyl or thiazolyl ring, wherein each substitutable carbon or heteroatomin the aforementioned carbocyclic or heterocyclic rings is independently unsubstituted or10 substituted with one or more, same or different substituents RB.

10. The compound according to any one of claims 1 to 9, wherein15wherein the wavy line marks the connection to A and the dotted line marks the connection to the carbon atom of the C(=O) group to which B is attached.

11. The compound according to any one of claims 1 to 10, wherein20wherein the wavy line marks the connection to A and the dotted line marks the connection to the carbon atom of the C(=O) group to which B is attached.25 12. The compound according to any one of claims 1 to 11, whereinR2is cyclohexyl, cyclopentyl or tetrahydrofuranyl, wherein each substitutable carbon atom in the aforementioned rings is independently unsubstituted or substituted with one or more, same or different substituents RX.30 13. The compound according to any one of claims 1 to 12, whereinR2isANAVO therapeutics BV A19160WO154wherein the wavy line marks the connection to the remainder of the molecule.

514. The compound according to any one of claims 1 to 13, whereinR2iswherein the wavy line marks the connection to the remainder of the molecule.10 15. The compound according to any one of claims 1 to 14, whereinR3is CH3; or a 3- to 5-membered saturated carbocyclic or heterocyclic ring, wherein the aforemen- tioned heterocyclic ring comprises an oxygen atom as heteroatom, and wherein each sub- stitutable carbon atom in the aforementioned carbocyclic or heterocyclic rings is indepen-15 dently unsubstituted or substituted with one or more, same or different substituents RY;or a 5- or 6-membered aromatic carbocyclic or heterocyclic ring; wherein the aforemen- tioned heterocyclic ring 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-oxi- dized, and wherein each substitutable atom in the aforementioned carbocyclic or hetero-20 cyclic ring is independently unsubstituted or substituted with one or more, same or differ-ent substituents RY; or 5- or 6-membered aromatic carbocyclylmethyl or heterocyclylmethyl; wherein the afore- mentioned heterocyclyl 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-oxi-25 dized, and wherein each substitutable atom in the aforementioned carbocyclylmethyl orheterocyclylmethyl is independently unsubstituted or substituted with one or more, same or different substituents RY.

16. The compound according to any one of claims 1 to 15, wherein30 R3 iswherein the wavy line marks the connection to the remainder of the molecule.

17. The compound according to any one of claims 1 to 16, wherein35ANAVO therapeutics BV A19160WO155 wherein the wavy line marks the connection to the remainder of the molecule.

18. The compound according to any one of claims 1 to 17, whereinA is -NH-R1 or -N(CH3)-R1;5 whereinR1is 3-pyridinyl or 4-pyridinyl, wherein each substitutable carbon or heteroatom in the afore- mentioned rings is independently unsubstituted or substituted with one or more, same or differ- ent substituents RZ; wherein10wherein the wavy line marks the connection to the remainder of the molecule;15 and whereinR4is Cl, or CF3; Biswherein the wavy line marks the connection to A and the dotted line marks the connection to the20 carbon atom of the C(=O) group to which B is attached;R2iswherein the wavy line marks the connection to the remainder of the molecule; and25 R3 iswherein the wavy line marks the connection to the remainder of the molecule.

19. The compound according to any one of claims 1-4, 6-16, or 18, wherein30 A is -NH-R1 or -N(CH3)-R1;wherein R1is 3-pyridinyl or 4-pyridinyl, wherein each substitutable carbon or heteroatom in the afore- mentioned rings is independently unsubstituted or substituted with one or more, same or differ- ent substituents RZ;35 whereinRZis F, or CH3; or AisANAVO therapeutics BV A19160WO156wherein the wavy line marks the connection to the remainder of the molecule; and wherein R4is Cl, or CF3; 5B iswherein the wavy line marks the connection to A and the dotted line marks the connection to the carbon atom of the C(=O) group to which B is attached; R2is10wherein 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.

20. The compound according to any one of claims 1 to 19, wherein the compound of formula(I) is a compound of formula (IS) 2021. The compound according to any one of claims 1-4, 9 to 16, 18 or 20, wherein the com-pound according to formula (I) is selected from the group consisting of 25ANAVO therapeutics BV A19160WO157 5ANAVO therapeutics BV A19160WO15823. A pharmaceutical composition comprising a pharmaceutically effective amount of the5 compound according to any one of claims 1 to 22 and optionally a pharmaceutically acceptablecarrier or excipient.

24. A compound according to any one of claims 1 to 22 or a pharmaceutical composition ac-cording to claim 23 for use in medicine. 10 25. A compound according to any one of claims 1 to 22 or a pharmaceutical composition ac-cording to claim 23 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-15 toimmune conditions, and neurological diseases, more preferably selected from the group con-sisting of cancer, pre-cancerous syndromes, and neurological diseases.

26. A compound according to any one of claims 1 to 22 or a pharmaceutical composition ac-cording to claim 23 for use in the treatment of a disease selected from the group consisting of20 amyotrophic lateral sclerosis, attention deficit hyperactivity disorder, autism, Bannayan-Zonanasyndrome, 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- vidual allergic asthma, kidney cancer, Lhermitte-Duclos disease, lung cancer, liver cancer, lym-25 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. 30

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