Substituted straight chain spiro derivatives

Abstract

5 20 26 20 52 13 01 J ul 2 02 6 A B S T R A C T 2 0 2 6 2 0 5 2 1 3 0 1 J u l 2 0 2 6 5

Description

INCORPORATION BY CROSS-REFERENCE This application is a divisional application of Australian Application No. 2020404305, which 5 is the national phase entry of PCT / CN2020 / 137266, filed on 17 December 2020, and claims priority to PCT / CN2020 / 126595, filed on 4 November 2020, U.S. Provisional Patent Application No. 62 / 961,775, filed on 16 January 2020, and PCT / CN2019 / 126760, filed on 19 December 2019. The disclosure of each of the aforementioned applications is incorporated herein by reference in its entirety. 10 FIELD OF THE INVENTION The present invention relates to pharmaceutical agents useful for therapy and / or prophylaxis in a mammal, pharmaceutical composition comprising such compounds, and their use as menin / MLL protein / protein interaction inhibitors, useful for treating diseases such as cancer, 15 including but not limited to leukemia, myelodysplastic syndrome (MDS), and myeloproliferative neoplasms (MPN); and diabetes. BACKGROUND OF THE INVENTION Chromosomal rearrangements affecting the mixed lineage leukemia gene (MLL; MLL1; 20   KMT2A) result in aggressive acute leukemias across all age groups and still represent mostly incurable diseases emphasizing the urgent need for novel therapeutic approaches. Acute leukemias harboring these chromosomal translocations of MLL represent as lymphoid, myeloid or biphenotypic disease and constitute 5 to 10% of acute leukemias in adults and approximately 70% in infants (Marschalek, Br J Haematol 2011. 152(2), 141-54; Tomizawa et al., Pediatr 25 Blood Cancer 2007. 49(2), 127-32). MLL is a histone methyltransferase that methylates histone H3 on lysine 4 (H3K4) and functions in multiprotein complexes. Use of inducible loss-of-function alleles of Mll1 demonstrated that Mll1 plays an essential role in sustaining hematopoietic stem cells (HSCs) and developing B cells although its histone methyltransferase activity is dispensable for 30 hematopoiesis (Mishra et al., Cell Rep 2014. 7(4), 1239-47). Fusion of MLL with more than 60 different partners has been reported to date and has been associated with leukemia formation / progression (Meyer et al., Leukemia 2013. 27, 21652176). Interestingly, the SET (Su(var)3-9, enhancer of zeste, and trithorax) domain of MLL is not retained in chimeric proteins but is replaced by the fusion partner (Thiel et al., Bioessays 35   2012. 34, 771-80). Recruitment of chromatin modifying enzymes like Dot1L and / or the pTEFb complex by the fusion partner leads to enhanced transcription and transcriptional elongation of MLL target genes including HOXA genes (e.g. HOXA9) and the HOX cofactor MEIS1 as the 2026205213   01 Jul 2026 most prominent ones. Aberrant expression of these genes in turn blocks hematopoietic differentiation and enhances proliferation. Menin which is encoded by the Multiple Endocrine Neoplasia type 1 (MEN1) gene is expressed ubiquitously and is predominantly localized in the nucleus. It has been shown to interact with 5 numerous proteins and is, therefore, involved in a variety of cellular processes. The best understood function of menin is its role as an oncogenic cofactor of MLL fusion proteins. Menin interacts with two motifs within the N-terminal fragment of MLL that is retained in all fusion proteins, MBM1 (menin-binding motif 1) and MBM2 (Thiel et al., Bioessays 2012. 34, 771- 2026205213   01 Jul 2026 80). Menin / MLL interaction leads to the formation of a new interaction surface for lens epithelium-derived growth factor (LEDGF). Although MLL directly binds to LEDGF, menin is obligatory for the stable interaction between MLL and LEDGF and the gene specific chromatin recruitment of the MLL complex via the PWWP domain of LEDGF (Cermakova et 5 al., Cancer Res 2014. 15, 5139-51; Yokoyama & Cleary, Cancer Cell 2008. 8, 36-46). Furthermore, numerous genetic studies have shown that menin is strictly required for oncogenic transformation by MLL fusion proteins suggesting the menin / MLL interaction as an attractive therapeutic target. For example, conditional deletion of Menl prevents leukomogenesis in bone marrow progenitor cells ectopically expressing MLL fusions (Chen et al., Proc Natl Acad Sci 10   2006. 103, 1018-23). Similarly, genetic disruption of menin / MLL fusion interaction by loss-of- function mutations abrogates the oncogenic properties of the MLL fusion proteins, blocks the development of leukemia in vivo and releases the differentiation block of MLL-transformed leukemic blasts. These studies also showed that menin is required for the maintenance of HOX gene expression by MLL fusion proteins (Yokoyama et al., Cell 2005. 123, 207-18). In addition, 15 small molecule inhibitors of menin / MLL interaction have been developed suggesting druggability of this protein / protein interaction and have also demonstrated efficacy in preclinical models of AML (Borkin et al., Cancer Cell 2015. 27, 589-602; Cierpicki and Grembecka, Future Med Chern 2014. 6, 447-462). Together with the observation that menin is not a requisite cofactor of MLL1 during normal hematopoiesis (Li et al., Blood 2013. 122, 20   2039-2046), these data validate the disruption of menin / MLL interaction as a promising new therapeutic approach for the treatment of MLL rearranged leukemia and other cancers with an active H0X / MEIS1 gene signature. For example, an internal partial tandem duplication (PTD) within the 5’region of the MLL gene represents another major aberration that is found predominantly in de novo and secondary AML as well as myeloid dysplasia syndromes. 25 Although the molecular mechanism and the biological function of MLL-PTD is not well understood, new therapeutic targeting strategies affecting the menin / MLL interaction might also prove effective in the treatment of MLL-PTD-related leukemias. Furthermore, castrationresistant prostate cancer has been shown to be dependent on the menin / MLL interaction (Malik et al., Nat Med 2015. 21, 344-52). 30 MLL protein is also known as Histone-lysine N-methyltransferase 2A (KMT2A) protein in the scientific field (UniProt Accession # Q03164). Several references describe inhibitors targeting the menin-MLL interaction: WO2011029054, 35 J Med Chern 2016, 59, 892-913 describe the preparation of thienopyrimidine and benzodiazepine derivatives; WO2014164543 describes thienopyrimidine and thienopyridine derivatives; Nature Chemical Biology March 2012, 8, 277-284 and Ren, J.; et al. Bioorg Med ChemLett (2016), 26(18), 4472-4476 describe thienopyrimidine derivatives; J Med Chem 2014, 2026205213   01 Jul 2026 57, 1543-1556 describes hydroxy- and aminomethylpiperidine derivatives; Future Med Chem 2014, 6, 447-462 reviews small molecule and peptidomimetic compounds; WO2016195776 describes furo[2,3-d]pyrimidine, 9H-purine, [l,3]oxazolo[5,4-d]pyrimidine, [l,3]oxazolo[4,5-d]pyrimidine,   [l,3]thiazolo[5,4-d]pyrimidine, thieno[2,3-b]pyridine and thieno[2,3- 5   d]pyrimidine   derivatives; WO2016197027 describes 5,6,7,8-tetrahydropyrido[3,4- d]pyrimidine,   5,6,7,8-tetrahydropyrido]4,3-d]pyrimidine, pyrido[2,3-d]pyrimidine and quinoline derivatives; and WO2016040330 describes thienopyrimidine and thienopyridine compounds. WO2017192543 describes piperidines as Menin inhibitors. WO2017112768, WO2017207387, WO2017214367, WO2018053267 and WO2018024602 describe inhibitors 10 of the menin-MLL interaction. WO2017161002 and WO2017161028 describe inhibitors of menin-MLL. WO2018050686, WO2018050684 and WO2018109088 describe inhibitors of the menin-MLL interaction. WO2018226976 describes methods and compositions for inhibiting the interaction of menin with MLL proteins. WO2018175746 provides methods of treatment for hematological malignancies and Ewing’s sarcoma. WO2018106818 and WO2018106820 15 provide methods of promoting proliferation of a pancreatic cell. WO2018153312 discloses azaspiro compounds relating to the field of medicinal chemistry. WO2017132398 discloses methods comprising contacting a leukemia cell exhibiting an NPM1 mutation with a pharmacologic inhibitor of interaction between MLL and Menin. WO2019060365 describes substituted inhibitors of menin-MLL. WO2020069027 describes the treatment of 20 hematological malignancies with inhibitors of menin. Krivtsov et al., Cancer Cell 2019. No.6 Vol.36, 660-673 describes a menin-MLL inhibitor. BRIEF DESCRIPTION OF THE DRAWINGS Fig. 1: Efficacy study in Molm-14 subcutaneous (sc) model. 25 Fig. 2: Efficacy study in disseminated OCI-AML3 model. DESCRIPTION OF THE INVENTION 30 The present invention concerns novel compounds of Formula (I), 2026205213   01 Jul 2026 and the tautomers and the stereoisomeric forms thereof, wherein Rla represents -C(=O)-NRxaRxb; Het; or Het represents a 5- or 6-membered monocyclic aromatic ring containing one, two or three 5 nitrogen atoms and optionally a carbonyl moiety; wherein said 5- or 6-membered monocyclic aromatic ring is optionally substituted with one or two substituents selected from the group consisting of C3-6cycloalkyl and Ci-4alkyl; Rxa and Rxb are each independently selected from the group consisting of hydrogen, 10 Ci-4alkyl and C3-6cycloalkyl; Rlb represents F or Cl; Y1 represents -CR5aR5b-, -O- or -NR5c-; R2 is selected from the group consisting of hydrogen, halo, Ci.4alkyl, -O-Ci.4alkyl, and - NR7aR7b; 15 U represents N or CH; nl, n2, n3 and n4 are each independently selected from 1 and 2; X1 represents CH, and X2 represents N; R4 represents isopropyl; 20 R5a, R5b, R5c, R7a, and R7b, are each independently selected from the group consisting of hydrogen, Ci.4alkyl and C3-6cycloalkyl; R3 represents -Ci-6alkyl-NR8aR8b, -Ci-6alkyl-C(=O)-NR9aR9b, -Ci-6alkyl-OH, or -Ci-6alkyl-NR11-C(=O)-O-Ci.4alkyl-O-C(=O)-Ci.4alkyl; wherein each of the Ci.4alkyl or Ci-ealkyl moi eties in the R3 definitions independently of each 2026205213   01 Jul 2026 other may be substituted with one, two or three substituents each independently selected from the group consisting of cyano, halo, -OH, and -O-Ci-4alkyl; R8a and R8b are each independently selected from the group consisting of hydrogen; Ci-6alkyl; -C(=O)-Ci-4alkyl; -C(=O)-O-Ci-4alkyl; -C(=O)-NR12aR12b; and Ci-6alkyl substituted 5 with one, two or three substituents each independently selected from the group consisting of - OH, cyano, halo, -S(=O)2-Ci-4alkyl, -O-Ci-4alkyl, -C(=O)-NR10aR10b, and -NR10c-C(=O)-Ci-4alkyl; R9a, R9b, R10a, R10b, R10c, R11, R12a, and R12b are each independently selected from the group consisting of hydrogen and Ci-6alkyl; 10 and the pharmaceutically acceptable salts and the solvates thereof. The present invention also relates to a pharmaceutical composition comprising a therapeutically effective amount of a compound of Formula (I), a pharmaceutically acceptable salt, or a solvate thereof, and a pharmaceutically acceptable carrier or excipient. 15   Additionally, the invention relates to a compound of Formula (I), a pharmaceutically acceptable salt, or a solvate thereof, for use as a medicament, and to a compound of Formula (I), a pharmaceutically acceptable salt, or a solvate thereof, for use in the treatment or in the prevention of cancer, including but not limited to leukemia, myelodysplastic syndrome (MDS), and myeloproliferative neoplasms (MPN); and diabetes. 20 In a particular embodiment, the invention relates to a compound of Formula (I), a pharmaceutically acceptable salt, or a solvate thereof, for use in the treatment or in the prevention of cancer. In a specific embodiment said cancer is selected from leukemias, lymphomas, myelomas or solid tumor cancers (e.g. prostate cancer, lung cancer, breast cancer, pancreatic cancer, colon 25 cancer, liver cancer, melanoma and glioblastoma, etc.). In some embodiments, the leukemias include acute leukemias, chronic leukemias, myeloid leukemias, myelogeneous leukemias, lymphoblastic leukemias, lymphocytic leukemias, Acute myelogeneous leukemias (AML), Chronic myelogenous leukemias (CML), Acute lymphoblastic leukemias (ALL), Chronic lymphocytic leukemias (CLL), T cell prolymphocytic leukemias (T-PLL), Large granular 30 lymphocytic leukemia, Hairy cell leukemia (HCL), MLL-rearranged leukemias, MLL-PTD leukemias, MLL amplified leukemias, MLL-positive leukemias, leukemias exhibiting H0XIMEIS1 gene expression signatures etc. In particular, compounds according to the present invention and the pharmaceutical compositions thereof may be useful in the treatment or prevention of leukemias, in particular 35 nucleophosmin (NPMl)-mutated leukemias, e.g. NPMlc. 2026205213   01 Jul 2026 In an embodiment, compounds of Formula (I) and the pharmaceutically acceptable salts, and the solvates thereof, may have improved metabolic stability properties. In an embodiment, compounds of Formula (I) and the pharmaceutically acceptable salts, and the solvates thereof, may have extended in vivo half-life (Tl / 2). 5 In an embodiment, compounds of Formula (I) and the pharmaceutically acceptable salts, and the solvates thereof, may have improved oral bioavailability. In an embodiment, compounds of Formula (I) and the pharmaceutically acceptable salts, and the solvates thereof, may reduce tumor growth e.g., tumours harbouring MLL (KMT2A) gene rearrangements / alterations and / or NPM1 mutations. 10 In an embodiment, compounds of Formula (I) and the pharmaceutically acceptable salts, and the solvates thereof, may have improved PD properties in vivo during a prolonged period of time, e.g. inhibition of target gene expression such as MEIS1 and upregulation of differentiation marker over a period of at least 16 hours. In an embodiment, compounds of Formula (I) and the pharmaceutically acceptable salts, and 15 the solvates thereof, may have an improved safety profile (e.g. reduced hERG inhibition; improved cardiovascular safety). In an embodiment, compounds of Formula (I) and the pharmaceutically acceptable salts, and the solvates thereof, may be suitable for Q.D. dosing (once daily). The invention also relates to the use of a compound of Formula (I), a pharmaceutically 20 acceptable salt, or a solvate thereof, in combination with an additional pharmaceutical agent for use in the treatment or prevention of cancer, including but not limited to leukemia, myelodysplastic syndrome (MDS), and myeloproliferative neoplasms (MPN); and diabetes. Furthermore, the invention relates to a process for preparing a pharmaceutical composition according to the invention, characterized in that a pharmaceutically acceptable carrier is 25 intimately mixed with a therapeutically effective amount of a compound of Formula (I), a pharmaceutically acceptable salt, or a solvate thereof. The invention also relates to a product comprising a compound of Formula (I), a pharmaceutically acceptable salt, or a solvate thereof, and an additional pharmaceutical agent, as a combined preparation for simultaneous, separate or sequential use in the treatment or 30 prevention of cancer, including but not limited to leukemia, myelodysplastic syndrome (MDS), and myeloproliferative neoplasms (MPN); and diabetes . Additionally, the invention relates to a method of treating or preventing a cell proliferative disease in a warm-blooded animal which comprises administering to the said animal an effective amount of a compound of Formula (I), a pharmaceutically acceptable salt, or a solvate 35 thereof, as defined herein, or a pharmaceutical composition or combination as defined herein. 2026205213   01 Jul 2026 DETAILED DESCRIPTION OF THE INVENTION The term ‘halo’ or ‘halogen’ as used herein represents fluoro, chloro, bromo and iodo. The prefix ‘Cx-y’ (where x and y are integers) as used herein refers to the number of carbon atoms in a given group. Thus, a Ci-ealkyl group contains from 1 to 6 carbon atoms, and so on. 5 The term ‘Ci.4alkyl’ as used herein as a group or part of a group represents a straight or branched chain saturated hydrocarbon radical having from 1 to 4 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, / / -butyl, s-butyl, / -butyl and the like. Similar, the term ‘Ci-ealkyl’ as used herein as a group or part of a group represents a straight or branched chain saturated hydrocarbon radical having from 1 to 6 carbon atoms, such as methyl, 10 ethyl, n-propyl, isopropyl, n-butyl, s-butyl, / -butyl, / / -pentyl, / / -hexyl and the like. The term ‘Cs-ecycloalkyl’ as used herein as a group or part of a group defines a saturated, cyclic hydrocarbon radical having from 3 to 6 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. It will be clear for the skilled person that S(=O)2 or SO2 represents a sulfonyl moiety. 15 It will be clear for the skilled person that CO or C(=O) represents a carbonyl moiety. It will be clear for the skilled person that a group such as -CRR- represents R R \ / _ . An example of such a group is -CR5aR5b-. R I It will be clear for the skilled person that a group such as -NR- represents . An example of such a group is -NR5c-. 20 Non-limiting examples of ‘monocyclic 5- or 6-membered aromatic rings containing one, two or three nitrogen atoms and optionally a carbonyl moiety’, include, but are not limited to pyrazolyl, imidazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl or 1,2-dihydro-2-oxo-4-pyridinyl. 25 The skilled person will understand that a 5- or 6-membered monocyclic aromatic ring containing one, two or three nitrogen atoms and a carbonyl moiety includes, but is not limited to 2026205213   01 Jul 2026 , and When any variable occurs more than one time in any constituent, each definition is independent. When any variable occurs more than one time in any formula (e.g. Formula (I)), each definition 5 is independent. In general, whenever the term ‘substituted’ is used in the present invention, it is meant, unless otherwise indicated or clear from the context, to indicate that one or more hydrogens, in particular from 1 to 4 hydrogens, more in particular from 1 to 3 hydrogens, preferably 1 or 2 10 hydrogens, more preferably 1 hydrogen, on the atom or radical indicated in the expression using ‘substituted’ are replaced with a selection from the indicated group, provided that the normal valency is not exceeded, and that the substitution results in a chemically stable compound, i.e. a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture (isolation after a reaction e.g. purification by silica gel chromatography). In a 15 particular embodiment, when the number of substituents is not explicitly specified, the number of substituents is one. Combinations of substituents and / or variables are permissible only if such combinations result in chemically stable compounds. ‘Stable compound’ is in this context meant to indicate a compound that is sufficiently robust to survive isolation to a useful degree of purity from a 20 reaction mixture (isolation after a reaction e.g. purification by silica gel chromatography). The skilled person will understand that the term ‘optionally substituted’ means that the atom or radical indicated in the expression using ‘optionally substituted’ may or may not be substituted (this means substituted or unsubstituted respectively). When two or more substituents are present on a moiety they may, where possible and unless 25 otherwise indicated or clear from the context, replace hydrogens on the same atom or they may replace hydrogen atoms on different atoms in the moiety. Within the context of this invention ‘saturated’ means ‘fully saturated’, if not otherwise specified. Unless otherwise specified or clear from the context, aromatic rings goups, can be attached to 30 the remainder of the molecule of Formula (I) through any available ring carbon atom (C-linked) or nitrogen atom (N-linked). 2026205213   01 Jul 2026 Unless otherwise specified or clear from the context, aromatic rings goups, may optionally be substituted, where possible, on carbon and / or nitrogen atoms according to the embodiments. The term “subject” as used herein, refers to an animal, preferably a mammal (e.g. cat, dog, primate or human), more preferably a human, who is or has been the object of treatment, 5 observation or experiment. The term “therapeutically effective amount” as used herein, means that amount of active compound or pharmaceutical agent that elicits the biological or medicinal response in a tissue system, animal or human that is being sought by a researcher, veterinarian, medicinal doctor or other clinician, which includes alleviation or reversal of the symptoms of the disease or disorder 10 being treated. The term “composition” is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combinations of the specified ingredients in the specified amounts. The term “treatment”, as used herein, is intended to refer to all processes wherein there may be 15 a slowing, interrupting, arresting or stopping of the progression of a disease, but does not necessarily indicate a total elimination of all symptoms. The term “compound(s) of the (present) invention” or “compound(s) according to the (present) invention” as used herein, is meant to include the compounds of Formula (I) and the pharmaceutically acceptable salts, and the solvates thereof. 20 As used herein, any chemical formula with bonds shown only as solid lines and not as solid wedged or hashed wedged bonds, or otherwise indicated as having a particular configuration (e.g. R, S') around one or more atoms, contemplates each possible stereoisomer, or mixture of two or more stereoisomers. Hereinbefore and hereinafter, the term “compound(s) of Formula (1)” is meant to include the 25 tautomers thereof and the stereoisomeric forms thereof. The terms “stereoisomers”, “stereoisomeric forms” or “stereochemically isomeric forms” hereinbefore or hereinafter are used interchangeably. The invention includes all stereoisomers of the compounds of the invention either as a pure stereoisomer or as a mixture of two or more stereoisomers. 30 Enantiomers are stereoisomers that are non-superimposable mirror images of each other. A 1:1 mixture of a pair of enantiomers is a racemate or racemic mixture. Atropisomers (or atropoisomers) are stereoisomers which have a particular spatial configuration, resulting from a restricted rotation about a single bond, due to large steric hindrance. All atropisomeric forms of the compounds of Formula (I) are intended to be included 35 within the scope of the present invention. 2026205213   01 Jul 2026 Diastereomers (or diastereoisomers) are stereoisomers that are not enantiomers, i.e. they are not related as mirror images. If a compound contains a double bond, the substituents may be in the E or the Z configuration. Substituents on bivalent cyclic saturated or partially saturated radicals may have either the cis-5 or trans-configuration; for example if a compound contains a disubstituted cycloalkyl group, the substituents may be in the cis or trans configuration. Therefore, the invention includes enantiomers, atropisomers, diastereomers, racemates, E isomers, Z isomers, cis isomers, trans isomers and mixtures thereof, whenever chemically possible. 10 The meaning of all those terms, i.e. enantiomers, atropisomers, diastereomers, racemates, E isomers, Z isomers, cis isomers, trans isomers and mixtures thereof are known to the skilled person. The absolute configuration is specified according to the Cahn-Ingold-Prelog system. The configuration at an asymmetric atom is specified by either R or S. Resolved stereoisomers 15 whose absolute configuration is not known can be designated by (+) or (-) depending on the direction in which they rotate plane polarized light. For instance, resolved enantiomers whose absolute configuration is not known can be designated by (+) or (-) depending on the direction in which they rotate plane polarized light. When a specific stereoisomer is identified, this means that said stereoisomer is substantially 20 free, i.e. associated with less than 50%, preferably less than 20%, more preferably less than 10%, even more preferably less than 5%, in particular less than 2% and most preferably less than 1%, of the other stereoisomers. Thus, when a compound of Formula (I) is for instance specified as (R), this means that the compound is substantially free of the (5) isomer; when a compound of Formula (I) is for instance specified as E, this means that the compound is 25 substantially free of the Z isomer; when a compound of Formula (I) is for instance specified as cis, this means that the compound is substantially free of the trans isomer. Some of the compounds according to Formula (I) may also exist in their tautomeric form. Such forms in so far as they may exist, although not explicitly indicated in the above Formula (I) are intended to be included within the scope of the present invention. It follows that a single 30 compound may exist in both stereoisomeric and tautomeric form. Pharmaceutically acceptable salts include acid addition salts and base addition salts. Such salts may be formed by conventional means, for example by reaction of a free acid or a free base form with one or more equivalents of an appropriate base or acid, optionally in a solvent, or in a medium in which the salt is insoluble, followed by removal of said solvent, or said medium, 35 using standard techniques (e.g. in vacuo, by freeze-drying or by filtration). Salts may also be 2026205213   01 Jul 2026 prepared by exchanging a counter-ion of a compound of the invention in the form of a salt with another counter-ion, for example using a suitable ion exchange resin. The pharmaceutically acceptable salts as mentioned hereinabove or hereinafter are meant to comprise the therapeutically active non-toxic acid and base salt forms which the compounds of 5 Formula (I) and solvates thereof, are able to form. Appropriate acids comprise, for example, inorganic acids such as hydrohalic acids, e.g. hydrochloric or hydrobromic acid, sulfuric, nitric, phosphoric and the like acids; or organic acids such as, for example, acetic, propanoic, hydroxyacetic, lactic, pyruvic, oxalic (i.e. ethanedioic), malonic, succinic (i.e. butanedioic acid), maleic, fumaric, malic, tartaric, citric, 10 methanesulfonic, ethanesulfonic, benzenesulfonic, p-toluenesulfonic, cyclamic, salicylic, p-aminosalicylic, pamoic and the like acids. Conversely said salt forms can be converted by treatment with an appropriate base into the free base form. The compounds of Formula (I) and solvates thereof containing an acidic proton may also be converted into their non-toxic metal or amine salt forms by treatment with appropriate organic 15    and inorganic bases. Appropriate base salt forms comprise, for example, the ammonium salts, the alkali and earth alkaline metal salts, e.g. the lithium, sodium, potassium, cesium, magnesium, calcium salts and the like, salts with organic bases, e.g. primary, secondary and tertiary aliphatic and aromatic amines such as methylamine, ethylamine, propylamine, isopropylamine, the four butylamine 20 isomers, dimethylamine, diethylamine, diethanolamine, dipropylamine, diisopropylamine, di-n-butylamine, pyrrolidine, piperidine, morpholine, trimethylamine, triethylamine, tripropylamine, quinuclidine, pyridine, quinoline and isoquinoline; the benzathine, N-methyl-D-glucamine, hydrabamine salts, and salts with amino acids such as, for example, arginine, lysine and the like. Conversely the salt form can be converted by treatment with acid into the 25 free acid form. The term “prodrug” includes any compound that, following oral or parenteral administration, in particular oral administration, is metabolised in vivo to a (more) active form in an experimentally-detectable amount, and within a predetermined time (e.g. within a dosing interval of between 0.5 and 24 hours, or e.g. within a dosing interval of between 6 and 24 hours 30    (i.e. once to four times daily)). For the avoidance of doubt, the term “parenteral” administration includes all forms of administration other than oral administration, in particular intravenous (IV), intramuscular (IM), and subcutaneous (SC) injection. Prodrugs may be prepared by modifying functional groups present on a compound in such a way that the modifications are cleaved in vivo when such prodrug is administered to a 35 mammalian subject. The modifications typically are achieved by synthesising the parent compound with a prodrug substituent. In general, prodrugs include compounds wherein a hydroxyl, amino, sulfhydryl, carboxy or carbonyl group is bonded to any group that may be 2026205213   01 Jul 2026 cleaved in vivo to regenerate the free hydroxyl, amino, sulfhydryl, carboxy or carbonyl group, respectively. Examples of prodrugs include, but are not limited to, esters and carbamates of hydroxy functional groups, esters groups of carboxyl functional groups, N-acyl derivatives and N-5 Mannich bases. General information on prodrugs may be found e.g. in Bundegaard, H. “Design of Prodrugs” p. 1-92, Elesevier, New York-Oxford (1985). The term solvate comprises the solvent addition forms as well as the salts thereof, which the compounds of Formula (I) are able to form. Examples of such solvent addition forms are e.g. hydrates, alcoholates and the like. 10 The compounds of the invention as prepared in the processes described below may be synthesized in the form of mixtures of enantiomers, in particular racemic mixtures of enantiomers, that can be separated from one another following art-known resolution procedures. A manner of separating the enantiomeric forms of the compounds of Formula (I), and pharmaceutically acceptable salts, and solvates thereof, involves liquid chromatography using 15 a chiral stationary phase. Said pure stereochemically isomeric forms may also be derived from the corresponding pure stereochemically isomeric forms of the appropriate starting materials, provided that the reaction occurs stereospecifically. Preferably if a specific stereoisomer is desired, said compound would be synthesized by stereospecific methods of preparation. These methods will advantageously employ enantiomerically pure starting materials. 20 The term "enantiomerically pure" as used herein means that the product contains at least 80% by weight of one enantiomer and 20% by weight or less of the other enantiomer. Preferably the product contains at least 90% by weight of one enantiomer and 10% by weight or less of the other enantiomer. In the most preferred embodiment the term "enantiomerically pure" means that the composition contains at least 99% by weight of one enantiomer and 1% or less of the 25 other enantiomer. The present invention also embraces isotopically-labeled compounds of the present invention which are identical to those recited herein, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature (or the most abundant one found in nature). 30 All isotopes and isotopic mixtures of any particular atom or element as specified herein are contemplated within the scope of the compounds of the invention, either naturally occurring or synthetically produced, either with natural abundance or in an isotopically enriched form. Exemplary isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine and iodine, such 35 as 2H, 3H, uC, 13C, 14C , 13N, 15O, 17O, 18O,32P, 33P, 35S, 18F, 36C1, 122I, 123I, 125I, 1311,75Br, 76Br, 77Br and 82Br. Preferably, the isotope is selected from the group of 2H, 3H, nC, 13C and 18F. Preferably, the isotope is selected from the group of 2H, 3H, nC and 18F. More preferably, the 2026205213   01 Jul 2026 isotope is 2H, 3H or 13C. More preferably, the isotope is 2H or 13C. More preferably, the isotope is 2H. In particular, deuterated compounds and 13C-enriched compounds are intended to be included within the scope of the present invention. In particular, deuterated compounds are intended to be included within the scope of the present invention. 5 Certain isotopically-labeled compounds of the present invention (e.g., those labeled with 3H and 14C) may be useful for example in substrate tissue distribution assays. Tritiated (3H) and carbon-14 (14C) isotopes are useful for their ease of preparation and detectability. Further, substitution with heavier isotopes such as deuterium (i.e., 2H) may afford certain therapeutic advantages resulting from greater metabolic stability (e.g., increased in vivo half-life or reduced 10 dosage requirements) and hence may be preferred in some circumstances. Positron emitting isotopes such as 150,13N, nC and 18F are useful for positron emission tomography (PET) studies. PET imaging in cancer finds utility in helping locate and identify tumours, stage the disease and determine suitable treatment. Human cancer cells overexpress many receptors or proteins that are potential disease-specific molecular targets. Radiolabelled tracers that bind with high 15 affinity and specificity to such receptors or proteins on tumour cells have great potential for diagnostic imaging and targeted radionuclide therapy (Charron, Carlie L. et al. Tetrahedron Lett. 2016, 57(37), 4119-4127). Additionally, target-specific PET radiotracers may be used as biomarkers to examine and evaluate pathology, by for example, measuring target expression and treatment response (Austin R. et al. Cancer Letters (2016), doi: 20    10.1016 / j.canlet.2016.05.008). The present invention relates in particular to compounds of Formula (I) as defined herein, and the tautomers and the stereoisomeric forms thereof, wherein 0 Rla represents -C(=O)-NRxaRxb; Het; or 25 Het represents a 5- or 6-membered monocyclic aromatic ring containing one, two or three nitrogen atoms and optionally a carbonyl moiety; wherein said 5- or 6-membered monocyclic aromatic ring is optionally substituted with one or two substituents selected from the group consisting of C3-6cycloalkyl and Ci-4alkyl; 30 Rxa and Rxb are each independently selected from the group consisting of hydrogen, Ci.4alkyl and C3-6cycloalkyl; Rlb represents F or Cl; Y1 represents -CR5aR5b-, -O- or -NR5c-; NRXaRXb 2026205213   01 Jul 2026 R2 is selected from the group consisting of hydrogen, halo, Ci.4alkyl, -O-Ci.4alkyl, and -NR7aR7b; U represents N or CH; nl, n2, n3 and n4 are each independently selected from 1 and 2; 5 X1 represents CH, and X2 represents N; R4 represents isopropyl; R5a, R5b, R5c, R7a, and R7b, are each independently selected from the group consisting of hydrogen, Ci.4alkyl and C3-6cycloalkyl; 10 R3 represents -Ci-6alkyl-NR8aR8b, -Ci-6alkyl-C(=O)-NR9aR9b, -Ci-6alkyl-OH, or -Ci-6alkyl-NR11-C(=O)-O-Ci.4alkyl-O-C(=O)-Ci.4alkyl; wherein each of the Ci.4alkyl or Ci-ealkyl moi eties in the R3 definitions independently of each other may be substituted with one, two or three substituents each independently selected from the group consisting of cyano, halo or -O-Ci.4alkyl; 15 R8a and R8b are each independently selected from the group consisting of hydrogen; Ci-ealkyl; -C(=O)-Ci-4alkyl; -C(=O)-O-Ci-4alkyl; -C(=O)-NR12aR12b; and Ci-ealkyl substituted with one, two or three substituents each independently selected from the group consisting of cyano, halo, -S(=O)2-Ci-4alkyl, -O-Ci-4alkyl, and -C(=O)-NR10aR10b; R9a, R9b, R10a, R10b, R11, R12a, and R12b are each independently selected from the group 20 consisting of hydrogen and Ci-ealkyl; and the pharmaceutically acceptable salts and the solvates thereof. The present invention relates in particular to compounds of Formula (I) as defined herein, and the tautomers and the stereoisomeric forms thereof, wherein 0 25 Rla represents -C(=O)-NRxaRxb; Het; or Het represents a 5- or 6-membered monocyclic aromatic ring containing one, two or three nitrogen atoms and optionally a carbonyl moiety; wherein said 5- or 6-membered monocyclic aromatic ring is optionally substituted with one or two substituents selected from the group consisting of C3-6cycloalkyl and 30 Ci-4alkyl; Rxa and Rxb are each independently selected from the group consisting of hydrogen, Ci.4alkyl and C3-6cycloalkyl; 2026205213   01 Jul 2026 Rlb represents F or Cl; Y1 represents -CR5aR5b-, -O- or -NR5c-; R2 is selected from the group consisting of hydrogen, halo, Ci.4alkyl, -O-Ci-4alkyl, and -NR7aR7b; 5 U represents N or CH; nl, n2, n3 and n4 are each independently selected from 1 and 2; X1 represents CH, and X2 represents N; R4 represents isopropyl; 10 R5a, R5b, R5c, R7a, and R7b, are each independently selected from the group consisting of hydrogen, Ci.4alkyl and C3-6cycloalkyl; R3 represents -Ci-6alkyl-NR8aR8b; wherein the Ci-ealkyl moiety in the R3 definition may be substituted with one, two or three substituents each independently selected from the group consisting of cyano, halo, OH, and -15 O-Ci-4alkyl; R8a and R8b are each independently selected from the group consisting of hydrogen; Ci-ealkyl; and Ci-ealkyl substituted with one, two or three substituents each independently selected from the group consisting of -OH, cyano, halo, -S(=O)2-Ci-4alkyl, -O-Ci-4alkyl, -C(=O)-NR10aR10b, and -NR10c-C(=O)-Ci-4alkyl; 20   R10a, R10b, R10c are each independently selected from the group consisting of hydrogen and Ci- ealkyl; and the pharmaceutically acceptable salts and the solvates thereof. The present invention relates in particular to compounds of Formula (I) as defined herein, and 25 the tautomers and the stereoisomeric forms thereof, wherein 0 ^^|Dxa xb Rla represents-C(=O)-NRxaRxb; Het; or ' NR R . Het represents a 5- or 6-membered monocyclic aromatic ring containing one, two or three nitrogen atoms and optionally a carbonyl moiety; wherein said 5- or 6-membered monocyclic aromatic ring is optionally substituted with one or 30 two substituents selected from the group consisting of C3-6cycloalkyl and Ci-4alkyl; 2026205213   01 Jul 2026 Rxa and Rxb are each independently selected from the group consisting of hydrogen, Ci.4alkyl and C3-6cycloalkyl; Rlb represents F or Cl; Y1 represents -CR5aR5b-, -O- or -NR5c-; 5 R2 is selected from the group consisting of hydrogen, halo, Ci.4alkyl, -O-Ci.4alkyl, and -NR7aR7b; U represents N or CH; nl, n2, n3 and n4 are each independently selected from 1 and 2; 10 X1 represents CH, and X2 represents N; R4 represents isopropyl; R5a, R5b, R5c, R7a, and R7b, are each independently selected from the group consisting of hydrogen, Ci.4alkyl and C3-6cycloalkyl; R3 represents -Ci-6alkyl-NR8aR8b; 15 wherein the Ci-ealkyl moiety in the R3 definition may be substituted with one, two or three substituents each independently selected from the group consisting of cyano, halo and -O-Ci-4alkyl; R8a and R8b are each independently selected from the group consisting of hydrogen; Ci-ealkyl; and Ci-ealkyl substituted with one, two or three substituents each independently 20 selected from the group consisting of cyano, halo, -S(=O)2-Ci-4alkyl, -O-Ci-4alkyl, and -C(=O)-NR10aR10b; R10a and R10b are each independently selected from the group consisting of hydrogen and Ci-ealkyl; and the pharmaceutically acceptable salts and the solvates thereof. 25 The present invention relates in particular to compounds of Formula (I) as defined herein, and the tautomers and the stereoisomeric forms thereof, wherein Rla represents -C(=O)-NRxaRxb or Het; Het represents a 6-membered monocyclic aromatic ring containing two nitrogen atoms; 30 wherein said 6-membered monocyclic aromatic ring is substituted with one C3-6cycloalkyl; Rxa and Rxb represent Ci-4alkyl; Rlb represents F; 2026205213   01 Jul 2026 Y1 represents -O-; R2 represents hydrogen; U represents N or CH; nl, n2, n3 and n4 are each independently selected from 1 and 2; 5 X1 represents CH, and X2 represents N; R4 represents isopropyl; R3 represents -Ci-6alkyl-NR8aR8b, -Ci-6alkyl-C(=O)-NR9aR9b, -Ci-6alkyl-OH, or -Ci-6alkyl-NR11-C(=O)-O-Ci.4alkyl-O-C(=O)-Ci.4alkyl; 10 wherein each of the Ci.4alkyl or Ci-ealkyl moi eties in the R3 definitions independently of each other may be substituted with one, two or three substituents each independently selected from the group consisting of -OH and -O-Ci.4alkyl; R8a and R8b are each independently selected from the group consisting of hydrogen; Ci-ealkyl; -C(=O)-Ci-4alkyl; -C(=O)-O-Ci-4alkyl; -C(=O)-NR12aR12b; and Ci-ealkyl substituted with one, 15 two or three substituents each independently selected from the group consisting of -OH, cyano, halo, -S(=O)2-Ci.4alkyl, -O-Ci-4alkyl, -C(=O)-NR10aR10b, and -NR10c-C(=O)-Ci-4alkyl; R9a, R9b, R10a, R10b, R10c, R11, R12a, and R12b are each independently selected from the group consisting of hydrogen and Ci-ealkyl; and the pharmaceutically acceptable salts and the solvates thereof. 20 The present invention relates in particular to compounds of Formula (I) as defined herein, and the tautomers and the stereoisomeric forms thereof, wherein Rla represents -C(=O)-NRxaRxb or Het; Het represents a 6-membered monocyclic aromatic ring containing two nitrogen atoms; 25 wherein said 6-membered monocyclic aromatic ring is substituted with one Cs-ecycloalkyl; Rxa and Rxb represent Ci-4alkyl; Rlb represents F; Y1 represents -O-; 30 R2 represents hydrogen; U represents N or CH; nl, n2, n3 and n4 are each independently selected from 1 and 2; 2026205213   01 Jul 2026 X1 represents CH, and X2 represents N; R4 represents isopropyl; R3 represents -Ci-6alkyl-NR8aR8b; wherein the Ci-ealkyl moiety in the R3 definition may be substituted with one, two or three 5 substituents each independently selected from the group consisting of -OH and -O-Ci.4alkyl; R8a and R8b are each independently selected from the group consisting of hydrogen; Ci-ealkyl; and Ci-ealkyl substituted with one, two or three substituents each independently selected from the group consisting of -OH, cyano, halo, -S(=O)2-Ci-4alkyl, -O-Ci.4alkyl, -C(=O)-NR10aR10b, and -NR10c-C(=O)-Ci-4alkyl; 10 R10a R10b, and R10c are each independently selected from the group consisting of hydrogen and Ci-ealkyl; and the pharmaceutically acceptable salts and the solvates thereof. The present invention relates in particular to compounds of Formula (I) as defined herein, and 15 the tautomers and the stereoisomeric forms thereof, wherein Rla represents -C(=O)-NRxaRxb; Rxa and Rxb represent Ci.4alkyl; Rlb represents F; Y1 represents -O-; 20 R2 represents hydrogen; U represents N or CH; nl, n2, n3 and n4 are each independently selected from 1 and 2; X1 represents CH, and X2 represents N; 25 R4 represents isopropyl; R3 represents -Ci-6alkyl-NR8aR8b; wherein the Ci-ealkyl moiety in the R3 definition may be substituted with one, two or three substituents each independently selected from the group consisting of -OH and -O-Ci.4alkyl; R8a and R8b are each independently selected from the group consisting of hydrogen; 30 Ci-ealkyl; and Ci-ealkyl substituted with one, two or three substituents each independently selected from the group consisting of -OH, cyano, halo, -S(=O)2-Ci-4alkyl, -O-Ci.4alkyl, -C(=O)-NR10aR10b, and -NR10c-C(=O)-Ci-4alkyl; 2026205213   01 Jul 2026 R10a, R10b, and R10c are each independently selected from the group consisting of hydrogen and Ci-ealkyl; and the pharmaceutically acceptable salts and the solvates thereof. 5 The present invention relates in particular to compounds of Formula (I) as defined herein, and the tautomers and the stereoisomeric forms thereof, wherein Rla represents -C(=O)-NRxaRxb or Het; Het represents pyrimidinyl substituted with one C3-6cycloalkyl; 10 Rxa and Rxb represent Ci.4alkyl; Rlb represents F; Y1 represents -O-; R2 represents hydrogen; U represents N; 15 nl, n2, n3 and n4 are each independently selected from 1 and 2; X1 represents CH, and X2 represents N; R4 represents isopropyl; R3 represents -Ci-6alkyl-NR8aR8b; 20 wherein the Ci-ealkyl moiety in the R3 definition may be substituted with one -OH; R8a and R8b are each independently selected from the group consisting of hydrogen; Ci-ealkyl; and Ci-ealkyl substituted with one or two substituents each independently selected from the group consisting of halo, -O-Ci.4alkyl, and -NR10c-C(=O)-Ci-4alkyl; Ri°a, R10b, and R10c are each independently selected from the group consisting of hydrogen 25 and Ci-ealkyl; and the pharmaceutically acceptable salts and the solvates thereof. The present invention relates in particular to compounds of Formula (I) as defined herein, and the tautomers and the stereoisomeric forms thereof, wherein 30 Rla represents -C(=O)-NRxaRxb or Het; Het represents pyrimidinyl substituted with one C3-6cycloalkyl; Rxa and Rxb represent Ci.4alkyl; 2026205213   01 Jul 2026 Rlb represents F; Y1 represents -O-; R2 represents hydrogen; U represents N; 5 n2 is 2; nl, n3 and n4 are 1; X1 represents CH, and X2 represents N; R4 represents isopropyl; 10 R3 represents -Ci-6alkyl-NR8aR8b; wherein the Ci-ealkyl moiety in the R3 definition may be substituted with one -OH; R8a and R8b are each independently selected from the group consisting of hydrogen; Ci-ealkyl; and Ci-ealkyl substituted with one or two substituents each independently selected from the group consisting of halo, -O-Ci-4alkyl, and -NR10c-C(=O)-Ci-4alkyl; 15   R10a, R10b, and R10c are each independently selected from the group consisting of hydrogen and Ci-ealkyl; and the pharmaceutically acceptable salts and the solvates thereof. The present invention relates in particular to compounds of Formula (I) as defined herein, and 20 the tautomers and the stereoisomeric forms thereof, wherein Rla represents -C(=O)-NRxaRxb; Rxa and Rxb represent Ci.4alkyl; Rlb represents F; Y1 represents -O-; 25 R2 represents hydrogen; U represents N; n2 is 2; nl, n3 and n4 are 1; 30 X1 represents CH, and X2 represents N; R4 represents isopropyl; 2026205213   01 Jul 2026 R3 represents -Ci-6alkyl-NR8aR8b; R8a and R8b are each independently selected from the group consisting of hydrogen; Ci-ealkyl; and Ci-ealkyl substituted with one or two substituents each independently selected from the group consisting of halo, -O-Ci-4alkyl, and -NR10c-C(=O)-Ci-4alkyl; 5   R10a, R10b, and R10c are each independently selected from the group consisting of hydrogen and Ci-6alkyl; and the pharmaceutically acceptable salts and the solvates thereof. The present invention relates in particular to compounds of Formula (I) as defined herein, and 10 the tautomers and the stereoisomeric forms thereof, wherein Rla represents -C(=O)-NRxaRxb; Rxa and Rxb represent Ci-4alkyl; Rlb represents F; Y1 represents -O-; 15 R2 represents hydrogen; U represents N; n2 is 2; nl, n3 and n4 are 1; 20 X1 represents CH, and X2 represents N; R4 represents isopropyl; R3 represents -CH2-CH2-CH2-NR8aR8b; R8a and R8b are each independently selected from the group consisting of hydrogen; 25 Ci-6alkyl; and Ci-ealkyl substituted with one or two substituents each independently selected from the group consisting of halo, -O-Ci-4alkyl, and -NR10c-C(=O)-Ci-4alkyl; R10a, R10b, and R10c are each independently selected from the group consisting of hydrogen and Ci-6alkyl; and the pharmaceutically acceptable salts and the solvates thereof. 30 The present invention relates in particular to compounds of Formula (I) as defined herein, and the tautomers and the stereoisomeric forms thereof, wherein 2026205213   01 Jul 2026 Rla represents -C(=O)-NRxaRxb; Rxa and Rxb represent Ci.4alkyl; Rlb represents F; Y1 represents -O-; 5 R2 represents hydrogen; U represents N; nl, n2, n3 and n4 are each independently selected from 1 and 2; X1 represents CH, and X2 represents N; 10 R4 represents isopropyl; R3 represents -Ci-6alkyl-NR8aR8b; R8a and R8b are each independently selected from the group consisting of hydrogen; Ci-ealkyl; and Ci-ealkyl substituted with one, two or three substituents each independently selected from the group consisting of -OH, cyano, halo, -S(=O)2-Ci-4alkyl, -O-Ci-4alkyl, and -15   C(=O)-NR10aR10b; R10a and R10b are each independently selected from the group consisting of hydrogen and Ci-ealkyl; and the pharmaceutically acceptable salts and the solvates thereof. 20 The present invention relates in particular to compounds of Formula (I) as defined herein, and the tautomers and the stereoisomeric forms thereof, wherein Rla represents -C(=O)-NRxaRxb; Rxa and Rxb represent Ci.4alkyl; Rlb represents F; 25 Y1 represents -O-; R2 represents hydrogen; U represents N; nl, n2, n3 and n4 are each independently selected from 1 and 2; 30 X1 represents CH, and X2 represents N; R4 represents isopropyl; 2026205213   01 Jul 2026 R3 represents -CH2-CH2-CH2-NR8aR8b; R8a and R8b are each independently selected from the group consisting of hydrogen; Ci-ealkyl; and Ci-ealkyl substituted with one, two or three substituents each independently selected from the group consisting of -OH, cyano, halo, -S(=O)2-Ci-4alkyl, -O-Ci.4alkyl, and - 5   C(=O)-NR10aR10b; R10a and R10b are each independently selected from the group consisting of hydrogen and Ci-ealkyl; and the pharmaceutically acceptable salts and the solvates thereof. 10 The present invention relates in particular to compounds of Formula (I) as defined herein, and the tautomers and the stereoisomeric forms thereof, wherein Rla represents -C(=O)-NRxaRxb; Rxa and Rxb represent hydrogen or Ci.4alkyl; Rlb represents F; 15 Y1 represents-O-; R2 represents hydrogen; U represents N; nl, n2, n3 and n4 are each independently selected from 1 and 2; 20 X1 represents CH, and X2 represents N; R4 represents isopropyl; R3 represents -CH2-CH2-CH2-NR8aR8b; R8a and R8b are each independently selected from the group consisting of hydrogen; Ci-ealkyl; and Ci-ealkyl substituted with one, two or three substituents each independently 25 selected from the group consisting of -OH, cyano, halo, -S(=O)2-Ci-4alkyl, -O-Ci-4alkyl, and - C(=O)-NR10aR10b; R10a and R10b are each independently selected from the group consisting of hydrogen and Ci-ealkyl; and the pharmaceutically acceptable salts and the solvates thereof. 30 The present invention relates in particular to compounds of Formula (I) as defined herein, and the tautomers and the stereoisomeric forms thereof, wherein 2026205213   01 Jul 2026 Rla represents -C(=O)-NRxaRxb; Rxa and Rxb represent hydrogen or Ci.4alkyl; Rlb represents F; Y1 represents -O-; 5 R2 represents hydrogen; U represents N; nl, n2, n3 and n4 are each independently selected from 1 and 2; X1 represents CH, and X2 represents N; 10 R4 represents isopropyl; R3 represents -CH2-CH2-CH2-NR8aR8b; R8a and R8b are each independently selected from the group consisting of hydrogen; Ci-ealkyl; and Ci-ealkyl substituted with one, two or three substituents each independently selected from the group consisting of -OH and -O-Ci-4alkyl; 15 and the pharmaceutically acceptable salts and the solvates thereof. The present invention relates in particular to compounds of Formula (I) as defined herein, and the tautomers and the stereoisomeric forms thereof, wherein Rla represents -C(=O)-NRxaRxb; 20 Rxa and Rxb represent Ci.4alkyl; Rlb represents F; Y1 represents -O-; R2 represents hydrogen; U represents N; 25 nl, n2, n3 and n4 are each independently selected from 1 and 2; X1 represents CH, and X2 represents N; R4 represents isopropyl; R3 represents -Ci-6alkyl-NR8aR8b; 30 R8a and R8b are each independently selected from the group consisting of Ci-ealkyl; and Ci-ealkyl substituted with one -O-Ci.4alkyl; 2026205213   01 Jul 2026 and the pharmaceutically acceptable salts and the solvates thereof. The present invention relates in particular to compounds of Formula (I) as defined herein, and the tautomers and the stereoisomeric forms thereof, wherein 5 Rla represents -C(=O)-NRxaRxb; Rxa and Rxb represent Ci.4alkyl; Rlb represents F; Y1 represents -O-; R2 represents hydrogen; 10 U represents N; nl, n2, n3 and n4 are each independently selected from 1 and 2; X1 represents CH, and X2 represents N; R4 represents isopropyl; 15   R3 represents -CH2-CH2-CH2-NR8aR8b; R8a and R8b are each independently selected from the group consisting of Ci.6alkyl; and Ci-ealkyl substituted with one -O-Ci.4alkyl; and the pharmaceutically acceptable salts and the solvates thereof. 20 The present invention relates in particular to compounds of Formula (I) as defined herein, and the tautomers and the stereoisomeric forms thereof, wherein Rla represents -C(=O)-NRxaRxb; or Het; Het represents a 6-membered monocyclic aromatic ring containing two nitrogen atoms; wherein said 6-membered monocyclic aromatic ring is optionally substituted with one C3- 25 ecycloalkyl; Rxa and Rxb represent Ci.4alkyl; Rlb represents F; Y1 represents -O-; R2 is hydrogen; 30 U represents N; nl, n2, n3 and n4 are each independently selected from 1 and 2; 2026205213   01 Jul 2026 X1 represents CH, and X2 represents N; R4 represents isopropyl; R3 represents -Ci-6alkyl-NR8aR8b, -Ci-6alkyl-C(=O)-NR9aR9b, -Ci-6alkyl-OH, or 5 -Ci-6alkyl-NR11-C(=O)-O-Ci.4alkyl-O-C(=O)-Ci.4alkyl; R8a and R8b are each independently selected from the group consisting of hydrogen; Ci-6alkyl; -C(=O)-Ci-4alkyl; -C(=O)-O-Ci-4alkyl; -C(=O)-NR12aR12b; and Ci-ealkyl substituted with one, two or three substituents each independently selected from the group consisting of cyano, halo, -S(=O)2-Ci-4alkyl, and -O-Ci-4alkyl; 10 R9a, R9b, R12a, and R12b are each independently selected from the group consisting of hydrogen and Ci-6alkyl; and the pharmaceutically acceptable salts and the solvates thereof. The present invention relates in particular to compounds of Formula (I) as defined herein, and 15 the tautomers and the stereoisomeric forms thereof, wherein Rla represents -C(=O)-NRxaRxb; Rxa and Rxb represent Ci-4alkyl; Rlb represents F; Y1 represents -O-; 20 R2 is hydrogen; U represents N; nl, n2, n3 and n4 are each independently selected from 1 and 2; X1 represents CH, and X2 represents N; 25 R4 represents isopropyl; R3 represents -Ci-6alkyl-NR8aR8b, -Ci-6alkyl-C(=O)-NR9aR9b, or -Ci-6alkyl-OH; R8a and R8b are each independently selected from the group consisting of hydrogen; Ci-6alkyl; -C(=O)-Ci-4alkyl; -C(=O)-O-Ci-4alkyl; -C(=O)-NR12aR12b; and Ci-ealkyl substituted with one, 30 two or three substituents each independently selected from the group consisting of cyano, halo, -S(=O)2-Ci-4alkyl, and -O-Ci-4alkyl; 2026205213   01 Jul 2026 R9a, R9b, R12a, and R12b are each independently selected from the group consisting of hydrogen and Ci-ealkyl; and the pharmaceutically acceptable salts and the solvates thereof. 5 In an embodiment, the present invention relates to those compounds of Formula (I) and the pharmaceutically acceptable salts, and the solvates thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein Rlb represents F. In an embodiment, the present invention relates to those compounds of Formula (I) and the 10 pharmaceutically acceptable salts, and the solvates thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein R2 represents hydrogen. In an embodiment, the present invention relates to those compounds of Formula (I) and the pharmaceutically acceptable salts, and the solvates thereof, or any subgroup thereof as 15 mentioned in any of the other embodiments, wherein nl is 1, n2 is 2, n3 is 1, and n4 is 1. In an embodiment, the present invention relates to those compounds of Formula (I) and the pharmaceutically acceptable salts, and the solvates thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein Y1 represents -O-. 20 In an embodiment, the present invention relates to those compounds of Formula (I) and the pharmaceutically acceptable salts, and the solvates thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein Y1 represents -O-; and U represents N. 25 In an embodiment, the present invention relates to those compounds of Formula (I) and the pharmaceutically acceptable salts, and the solvates thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein Y1 represents -O-; U represents N; 30 Rlb represents F; and R2 represents hydrogen. In an embodiment, the present invention relates to those compounds of Formula (I) and the pharmaceutically acceptable salts, and the solvates thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein Het represents 2026205213   01 Jul 2026 In an embodiment, the present invention relates to those compounds of Formula (I) and the pharmaceutically acceptable salts, and the solvates thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein Het represents a monocyclic 5- or 65 membered aromatic ring containing one or two nitrogen atoms; wherein said monocyclic 5- or 6-membered aromatic ring is substituted with one C3-6cycloalkyl. In an embodiment, the present invention relates to those compounds of Formula (I) and the pharmaceutically acceptable salts, and the solvates thereof, or any subgroup thereof as 10 mentioned in any of the other embodiments, wherein Het represents a monocyclic 5- or 6membered aromatic ring containing one or two nitrogen atoms; wherein said monocyclic 5- or 6-membered aromatic ring is substituted with one C3-6cycloalkyl; and Rlb represents F. 15 In an embodiment, the present invention relates to those compounds of Formula (I) and the pharmaceutically acceptable salts, and the solvates thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein Het represents a monocyclic 6membered aromatic ring containing one or two nitrogen atoms; wherein said monocyclic 6membered aromatic ring is substituted with one C3-6cycloalkyl. 20 In an embodiment, the present invention relates to those compounds of Formula (I) and the pharmaceutically acceptable salts, and the solvates thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein Het represents a monocyclic 6membered aromatic ring containing one or two nitrogen atoms; wherein said monocyclic 6 25 membered aromatic ring is substituted with one C3-6cycloalkyl; and Rlb represents F. In an embodiment, the present invention relates to those compounds of Formula (I) and the pharmaceutically acceptable salts, and the solvates thereof, or any subgroup thereof as 30 mentioned in any of the other embodiments, wherein R3 represents -Ci-6alkyl-NR8aR8b; wherein the Ci-ealkyl moiety in the R3 definition may be substituted with one, two or three substituents each independently selected from the group consisting of cyano, halo and -O-Ci-4alkyl. 2026205213   01 Jul 2026 In an embodiment, the present invention relates to those compounds of Formula (I) and the pharmaceutically acceptable salts, and the solvates thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein R3 represents -Ci-6alkyl-NR8aR8b; 5 wherein the Ci-ealkyl moiety in the R3 definition may be substituted with one, two or three substituents each independently selected from the group consisting of cyano, halo, -OH, and -O-Ci-4alkyl. In an embodiment, the present invention relates to those compounds of Formula (I) and the 10 pharmaceutically acceptable salts, and the solvates thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein R3 represents -Ci-6alkyl-NR8aR8b. In an embodiment, the present invention relates to those compounds of Formula (I) and the 15 pharmaceutically acceptable salts, and the solvates thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein R3 represents -Ci-6alkyl-NR8aR8b; wherein the Ci-ealkyl moiety in the R3 definition may be substituted with one, two or three substituents each independently selected from the group consisting of cyano, halo and -O-Ci-20 4alkyl; R8a and R8b are each independently selected from the group consisting of hydrogen; Ci-ealkyl; and Ci-ealkyl substituted with one, two or three substituents each independently selected from the group consisting of -OH, cyano, halo, -S(=O)2-Ci-4alkyl, -O-Ci-4alkyl, -C(=O)-NR10aR10b, and -NR10c-C(=O)-Ci-4alkyl. 25 In an embodiment, the present invention relates to those compounds of Formula (I) and the pharmaceutically acceptable salts, and the solvates thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein R3 represents -Ci-6alkyl-NR8aR8b; 30 wherein the Ci-ealkyl moiety in the R3 definition may be substituted with one, two or three substituents each independently selected from the group consisting of cyano, halo, -OH, and -O-Ci-4alkyl; R8a and R8b are each independently selected from the group consisting of hydrogen; Ci-ealkyl; and Ci-ealkyl substituted with one, two or three substituents each independently 35 selected from the group consisting of -OH, cyano, halo, -S(=O)2-Ci-4alkyl, -O-Ci-4alkyl, -C(=O)-NR10aR10b, and -NR10c-C(=O)-Ci-4alkyl. 2026205213   01 Jul 2026 In an embodiment, the present invention relates to those compounds of Formula (I) and the pharmaceutically acceptable salts, and the solvates thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein R3 represents -Ci-6alkyl-NR8aR8b; 5 wherein the Ci-ealkyl moiety in the R3 definition may be substituted with one, two or three substituents each independently selected from the group consisting of cyano, halo and -O-Ci-4alkyl; R8a and R8b are each independently selected from the group consisting of hydrogen; Ci-ealkyl; and Ci-ealkyl substituted with one, two or three substituents each independently 10 selected from the group consisting of cyano, halo, -S(=O)2-Ci-4alkyl, -O-Ci-4alkyl, and -C(=O)-NR10aR10b. In an embodiment, the present invention relates to those compounds of Formula (I) and the pharmaceutically acceptable salts, and the solvates thereof, or any subgroup thereof as 15 mentioned in any of the other embodiments, wherein R3 represents -Ci-6alkyl-NR8aR8b; wherein the Ci-ealkyl moiety in the R3 definition may be substituted with one, two or three substituents each independently selected from the group consisting of cyano, halo and -O-Ci-4alkyl; 20 R8a and R8b are each independently selected from the group consisting of hydrogen; Ci-ealkyl; and Ci-ealkyl substituted with one, two or three substituents each independently selected from the group consisting of cyano, halo, -S(=O)2-Ci-4alkyl, -O-Ci-4alkyl, -C(=O)-NR10aR10b, and -NR10c-C(=O)-Ci-4alkyl. 25 In an embodiment, the present invention relates to those compounds of Formula (I) and the pharmaceutically acceptable salts, and the solvates thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein R3 represents -Ci-6alkyl-NR8aR8b; wherein the Ci-ealkyl moiety in the R3 definition may be substituted with one, two or three 30 substituents each independently selected from the group consisting of cyano, halo, -OH, and -O-Ci-4alkyl; R8a and R8b are each independently selected from the group consisting of hydrogen; Ci-ealkyl; and Ci-ealkyl substituted with one, two or three substituents each independently selected from the group consisting of cyano, halo, -S(=O)2-Ci-4alkyl, -O-Ci-4alkyl, and -35   C(=O)-NR10aR10b. 2026205213   01 Jul 2026 In an embodiment, the present invention relates to those compounds of Formula (I) and the pharmaceutically acceptable salts, and the solvates thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein R3 represents -Ci-6alkyl-NR8aR8b; 5 wherein the Ci-ealkyl moiety in the R3 definition may be substituted with one, two or three substituents each independently selected from the group consisting of cyano, halo, -OH, and -O-Ci-4alkyl; R8a and R8b are each independently selected from the group consisting of hydrogen; Ci-ealkyl; and Ci-ealkyl substituted with one, two or three substituents each independently 10 selected from the group consisting of cyano, halo, -S(=O)2-Ci-4alkyl, -O-Ci-4alkyl, -C(=O)-NR10aR10b, and -NR10c-C(=O)-Ci-4alkyl. In an embodiment, the present invention relates to those compounds of Formula (I) and the pharmaceutically acceptable salts, and the solvates thereof, or any subgroup thereof as 15 mentioned in any of the other embodiments, wherein R3 represents -C2-ealkyl-NR8aR8b; wherein the C2-ealkyl moiety in the R3 definition may be substituted with one, two or three substituents each independently selected from the group consisting of cyano, halo and -O-Ci-4alkyl. 20 In an embodiment, the present invention relates to those compounds of Formula (I) and the pharmaceutically acceptable salts, and the solvates thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein R3 represents -C2-ealkyl-NR8aR8b; 25 wherein the C2-ealkyl moiety in the R3 definition may be substituted with one, two or three substituents each independently selected from the group consisting of cyano, halo, -OH, and -O-Ci-4alkyl. In an embodiment, the present invention relates to those compounds of Formula (I) and the 30 pharmaceutically acceptable salts, and the solvates thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein R3 represents -C2-ealkyl-NR8aR8b; wherein the C2-ealkyl moiety in the R3 definition may be substituted with one, two or three substituents each independently selected from the group consisting of cyano, halo and -O-Ci-35 4alkyl; R8a and R8b are each independently selected from the group consisting of hydrogen; Ci-ealkyl; and Ci-ealkyl substituted with one, two or three substituents each independently 2026205213   01 Jul 2026 selected from the group consisting of -OH, cyano, halo, -S(=O)2-Ci-4alkyl, -O-Ci.4alkyl, -C(=O)-NR10aR10b, and -NR10c-C(=O)-Ci-4alkyl. In an embodiment, the present invention relates to those compounds of Formula (I) and the pharmaceutically acceptable salts, and the solvates thereof, or any subgroup thereof as 5 mentioned in any of the other embodiments, wherein R3 represents -C2-ealkyl-NR8aR8b; wherein the C2-ealkyl moiety in the R3 definition may be substituted with one, two or three substituents each independently selected from the group consisting of cyano, halo, -OH, and -O-Ci-4alkyl; 10 R8a and R8b are each independently selected from the group consisting of hydrogen; Ci-ealkyl; and Ci-ealkyl substituted with one, two or three substituents each independently selected from the group consisting of -OH, cyano, halo, -S(=O)2-Ci-4alkyl, -O-Ci.4alkyl, -C(=O)-NR10aR10b, and -NR10c-C(=O)-Ci-4alkyl. 15 In an embodiment, the present invention relates to those compounds of Formula (I) and the pharmaceutically acceptable salts, and the solvates thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein R3 represents -C2-ealkyl-NR8aR8b; wherein the C2-ealkyl moiety in the R3 definition may be substituted with one, two or three 20 substituents each independently selected from the group consisting of cyano, halo, -OH, and -O-Ci-4alkyl; R8a and R8b are each independently selected from the group consisting of hydrogen; Ci-ealkyl; and Ci-ealkyl substituted with one, two or three substituents each independently selected from the group consisting of cyano, halo, -S(=O)2-Ci-4alkyl, -O-Ci-4alkyl, and - 25   C(=O)-NR10aR10b. In an embodiment, the present invention relates to those compounds of Formula (I) and the pharmaceutically acceptable salts, and the solvates thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein 30 R3 represents -C2-ealkyl-NR8aR8b; wherein the C2-ealkyl moiety in the R3 definition may be substituted with one, two or three substituents each independently selected from the group consisting of cyano, halo and -O-Ci-4alkyl; R8a and R8b are each independently selected from the group consisting of hydrogen; 35 Ci-ealkyl; and Ci-ealkyl substituted with one, two or three substituents each independently selected from the group consisting of cyano, halo, -S(=O)2-Ci-4alkyl, -O-Ci-4alkyl, and -C(=O)-NR10aR10b. 2026205213   01 Jul 2026 In an embodiment, the present invention relates to those compounds of Formula (I) and the pharmaceutically acceptable salts, and the solvates thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein 5 R3 represents -Ci-6alkyl-NR8aR8b; R8a and R8b are each independently selected from the group consisting of Ci-ealkyl; and Ci-ealkyl substituted with one, two or three substituents each independently selected from the group consisting of -OH, cyano, halo, -S(=O)2-Ci-4alkyl, -O-Ci.4alkyl, and -C(=O)-NR10aR10b. 10 In an embodiment, the present invention relates to those compounds of Formula (I) and the pharmaceutically acceptable salts, and the solvates thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein R3 represents -C2-ealkyl-NR8aR8b; wherein the C2-ealkyl moiety in the R3 definition may be substituted with one, two or three 15 substituents each independently selected from the group consisting of cyano, halo, -OH, and -O-Ci-4alkyl; R8a and R8b are each independently selected from the group consisting of hydrogen; Ci-ealkyl; and Ci-ealkyl substituted with one, two or three substituents each independently selected from the group consisting of cyano, halo, -S(=O)2-Ci-4alkyl, -O-Ci-4alkyl, -C(=O)-20 NR10aR10b, and -NR10c-C(=O)-Ci-4alkyl. In an embodiment, the present invention relates to those compounds of Formula (I) and the pharmaceutically acceptable salts, and the solvates thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein 25 R3 represents -C2-ealkyl-NR8aR8b; wherein the C2-ealkyl moiety in the R3 definition may be substituted with one, two or three substituents each independently selected from the group consisting of cyano, halo and -O-Ci-4alkyl; R8a and R8b are each independently selected from the group consisting of hydrogen; 30 Ci-ealkyl; and Ci-ealkyl substituted with one, two or three substituents each independently selected from the group consisting of cyano, halo, -S(=O)2-Ci-4alkyl, -O-Ci-4alkyl, -C(=O)-NR10aR10b, and -NR10c-C(=O)-Ci-4alkyl. In an embodiment, the present invention relates to those compounds of Formula (I) and the 35 pharmaceutically acceptable salts, and the solvates thereof, or any subgroup thereof as 2026205213   01 Jul 2026 mentioned in any of the other embodiments, wherein R3 represents -Ci-6alkyl-NR8aR8b; R8a and R8b are each independently selected from the group consisting of Ci-ealkyl; and Ci-ealkyl substituted with one, two or three substituents each independently selected from the 5 group consisting of -OH, cyano, halo, -S(=O)2-Ci-4alkyl, -O-Ci.4alkyl, -C(=O)-NR10aR10b, and -NR10c-C(=O)-Ci-4alkyl. In an embodiment, the present invention relates to those compounds of Formula (I) and the pharmaceutically acceptable salts, and the solvates thereof, or any subgroup thereof as 10 mentioned in any of the other embodiments, wherein R3 represents -Ci-6alkyl-NR8aR8b; R8a represents Ci-ealkyl; and R8b represents Ci-ealkyl substituted with one -O-Ci.4alkyl. 15 In an embodiment, the present invention relates to those compounds of Formula (I) and the pharmaceutically acceptable salts, and the solvates thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein R3 represents -Ci-6alkyl-NR8aR8b, -Ci-6alkyl-C(=O)-NR9aR9b, -Ci-6alkyl-OH, or -Ci-6alkyl-NR11-C(=O)-O-Ci.4alkyl-O-C(=O)-Ci.4alkyl; 20 wherein each of the Ci.4alkyl or Ci-ealkyl moi eties in the R3 definitions independently of each other may be substituted with one, two or three substituents each independently selected from the group consisting of cyano, halo or -O-Ci.4alkyl. In an embodiment, the present invention relates to those compounds of Formula (I) and the 25 pharmaceutically acceptable salts, and the solvates thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein R3 represents -Ci-6alkyl-NR8aR8b, -Ci-6alkyl-C(=O)-NR9aR9b, or -Ci-6alkyl-NR11-C(=O)-O-Ci.4alkyl-O-C(=O)-Ci.4alkyl; wherein each of the Ci.4alkyl or Ci-ealkyl moi eties in the R3 definitions independently of each 30 other may be substituted with one, two or three substituents each independently selected from the group consisting of cyano, halo, -OH, and -O-Ci.4alkyl. In an embodiment, the present invention relates to those compounds of Formula (I) and the pharmaceutically acceptable salts, and the solvates thereof, or any subgroup thereof as 35 mentioned in any of the other embodiments, wherein R3 represents -CH2-CH2-CH2-NR8aR8b. 2026205213   01 Jul 2026 In an embodiment, the present invention relates to those compounds of Formula (I) and the pharmaceutically acceptable salts, and the solvates thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein 5 R3 represents -CH2-CH2-CH2-NR8aR8b; R8a represents methyl; and R8b represents -CH2-CH2-OCH3. In an embodiment, the present invention relates to those compounds of Formula (I) and the 10 pharmaceutically acceptable salts, and the solvates thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein Ci-ealkyl in the R3 definition -Ci.6alkyl-NR8aR8b is limited to -CH2-CH2-CH2-. In an embodiment, the present invention relates to those compounds of Formula (I) and the 15 pharmaceutically acceptable salts, and the solvates thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein the compounds of Formula (I) are restricted to compounds of Formula (I-y): wherein R3 is as defined for the compounds of Formula (I) or any subgroup thereof as 20 mentioned in any of the other embodiments. In Formula (I-y) nl is 1, n2 is 2, n3 is 1, and n4 is 1. In an embodiment the compound of Formula (I) is 2026205213   01 Jul 2026 and pharmaceutically acceptable addition salts, and solvates thereof. In an embodiment the compound of Formula (I) is In an embodiment the compound of Formula (I) is 10 In an embodiment the compound of Formula (I) is 2026205213   01 Jul 2026 In an embodiment, the present invention relates to a subgroup of Formula (I) as defined in the general reaction schemes. 5 In an embodiment the compound of Formula (I) is selected from the group consisting of any of the exemplified compounds, tautomers and stereoisomeric forms thereof, and the free bases, any pharmaceutically acceptable salts, and the solvates thereof. 10 All possible combinations of the above indicated embodiments are considered to be embraced within the scope of the invention. In another embodiment, the present invention relates to the intermediate 15 tautomers and stereoisomeric forms thereof, and any pharmaceutically acceptable salts, and the solvates thereof. In another embodiment, the present invention relates to a process for the preparation of an 20 intermediate comprising the following steps: 2026205213   01 Jul 2026 n1(A b)"2 N i PG Step 23 r ci Cl l^CO2C1.4alkyl step 24 n1«)^)n2              * N i PG wherein PG is a suitable protecting group such as benzyl; wherein nl and n2 are as defined for formula (I); Cl N i PG 5 Step 23: at a suitable temperature such as for example from -78 °C to -25 °C, in the presence of suitable bases such as for example DIEA and n-BuLi, in a suitable solvent such as for example THF; Step 24: at a suitable temperature such as for example between -55°C and -65 °C, in the presence of suitable reducing agent such as for example DIBAL-H, in a suitable solvent such as for 10 example toluene, conducted in a suitable flow chemistry system. In another embodiment, the present invention relates to a process for the preparation of an intermediate comprising the following steps: CO2Et 7 I Bn 15 DIPEA n-BuLi THF ICH2CI -78 to -60° C Flow ■ DIBAL-H (2.0 eq.) toluene -65 to -55°C first reaction at a suitable temperature such as for example from -78 °C to -25 °C, in the presence of suitable bases such as for example DIEA and n-BuLi, in a suitable solvent such as for example THF; then, reaction at a suitable temperature such as for example between -55°C and -65 °C, in the 20 presence of suitable reducing agent such as for example DIBAL-H, in a suitable solvent such as for example toluene, conducted in a suitable flow chemistry system. In another embodiment, the present invention relates to a process for the preparation of an intermediate comprising the following steps: 2026205213   01 Jul 2026 PG is a suitable protecting group such as benzyl; other variables are as defined for formula (I). In another embodiment, the present invention relates to a process for the preparation of an intermediate comprising the following steps: 2026205213   01 Jul 2026 Step 30 PG is a suitable protecting group such as benzyl; other variables are as defined for formula (I); 5 Step 30: at a suitable temperature such as for example from 5 °C to 30 °C, in the presence of a suitable base such as for example TEA, in the presence of suitable reducing agent such as for example NaBH(OAc)3, in a suitable solvent such as for example toluene; Step 31: at a suitable temperature such as for example from 50 °C to 55 °C, in the presence of a suitable base such as for example K2HPO4, in a suitable solvent such as for example H2O; 10 Step 32: at a suitable temperature such as for example from -5 °C to 45 °C, under a hydrogen atmosphere within a suitable pressure range such as for example from 0.27 to 0.40 MPa, in the presence of palladium hydroxide on carbon, in the presence of MSA in a suitable solvent such as EtOH; 2026205213   01 Jul 2026 Step 33: at a suitable temperature such as for example from -50 °C to -40 °C, in the presence of suitable base such as for example TEA, in a suitable solvent such as 2-methyltetrahydrofuran; Step 34: at a suitable temperature such as for example from 20 °C to 30 °C, in the presence of suitable base such as for example TMG, in a suitable solvent such as 2-methyltetrahydrofuran; 5 Step 35: at a suitable temperature such as for example from 20 °C to 30 °C, under a hydrogen atmosphere within a suitable pressure range such as for example from 0.20 to 0.30 Mpa, in the presence of a suitable catalyst such as for example palladium on carbon, in a suitable solvent such as MeOH. 10 In another embodiment, the present invention relates to a process for the preparation of a compound comprising the following steps: 2026205213   01 Jul 2026 In another embodiment, the present invention relates to a process for the preparation of a compound comprising the following steps: 5 In another embodiment, the present invention relates to a process for the preparation of a compound comprising the following steps: 2026205213   01 Jul 2026 In another embodiment, the present invention relates to a process for the preparation of a compound comprising the following steps: 2026205213   01 Jul 2026 In another embodiment, the present invention relates to a process for the preparation of a compound comprising the following steps: 5 in a first step, at a suitable temperature such as for example from -5 °C to 45 °C, under a hydrogen atmosphere within a suitable pressure range such as for example from 0.27 to 0.40 MPa, in the presence of palladium hydroxide on carbon, in the presence of MSA in a suitable solvent such as EtOH; in a next step at a suitable temperature such as for example from -50 °C to -40 °C, in the 10 presence of suitable base such as for example TEA, in a suitable solvent such as 2-methyltetrahydrofuran; in a next step at a suitable temperature such as for example from 20 °C to 30 °C, in the presence of suitable base such as for example TMG, in a suitable solvent such as 2-methyltetrahydrofuran; in a next step at a suitable temperature such as for example from 20 °C to 30 °C, under a 15 hydrogen atmosphere within a suitable pressure range such as for example from 0.20 to 0.30 Mpa, in the presence of a suitable catalyst such as for example palladium on carbon, in a suitable solvent such as MeOH. In another embodiment, the present invention relates to a process for the preparation of a 20 compound comprising the following steps: 2026205213   01 Jul 2026 In a first step first at a suitable temperature such as for example from 5 °C to 30 °C, in the presence of a suitable base such as for example TEA, in the presence of suitable reducing agent such as for example NaBH(OAc)3, in a suitable solvent such as for example toluene; and then 5 at a suitable temperature such as for example from 50 °C to 55 °C, in the presence of a suitable base such as for example K2HPO4, in a suitable solvent such as for example H2O; in a next step, at a suitable temperature such as for example from -5 °C to 45 °C, under a hydrogen atmosphere within a suitable pressure range such as for example from 0.27 to 0.40 MPa, in the presence of palladium hydroxide on carbon, in the presence of MSA in a suitable 10 solvent such as EtOH; in a next step at a suitable temperature such as for example from -50 °C to -40 °C, in the presence of suitable base such as for example TEA, in a suitable solvent such as 2-methyltetrahydrofuran; in a next step at a suitable temperature such as for example from 20 °C to 30 °C, in the presence 15 of suitable base such as for example TMG, in a suitable solvent such as 2-methyltetrahydrofuran; in a next step at a suitable temperature such as for example from 20 °C to 30 °C, under a hydrogen atmosphere within a suitable pressure range such as for example from 0.20 to 0.30 2026205213   01 Jul 2026 Mpa, in the presence of a suitable catalyst such as for example palladium on carbon, in a suitable solvent such as MeOH. Methods for the Preparation of Compounds of Formula (I) 5 In this section, as in all other sections unless the context indicates otherwise, references to Formula (I) also include all other sub-groups and examples thereof as defined herein. The general preparation of some typical examples of the compounds of Formula (I) is described hereunder and in the specific examples, and are generally prepared from starting materials which are either commercially available or prepared by standard synthetic processes commonly 10 used by those skilled in the art of organic chemistry. The following schemes are only meant to represent examples of the invention and are in no way meant to be a limit of the invention. Alternatively, compounds of the present invention may also be prepared by analogous reaction protocols as described in the general schemes below, combined with standard synthetic processes commonly used by those skilled in the art. 15 The skilled person will realize that in the reactions described in the Schemes, although this is not always explicitly shown, it may be necessary to protect reactive functional groups (for example hydroxy, amino, or carboxy groups) where these are desired in the final product, to avoid their unwanted participation in the reactions. In general, conventional protecting groups (PG) can be used in accordance with standard practice. The protecting groups may be removed 20 at a convenient subsequent stage using methods known from the art. The skilled person will realize that in the reactions described in the Schemes, it may be advisable or necessary to perform the reaction under an inert atmosphere, such as for example under N2-gas atmosphere. It will be apparent for the skilled person that it may be necessary to cool the reaction mixture 25 before reaction work-up (refers to the series of manipulations required to isolate and purify the product(s) of a chemical reaction such as for example quenching, column chromatography, extraction). The skilled person will realize that heating the reaction mixture under stirring may enhance the reaction outcome. In some reactions microwave heating may be used instead of conventional 30 heating to shorten the overall reaction time. The skilled person will realize that another sequence of the chemical reactions shown in the Schemes below, may also result in the desired compound of Formula (I). The skilled person will realize that intermediates and final compounds shown in the Schemes below may be further functionalized according to methods well-known by the person skilled in 35 the art. The intermediates and compounds described herein can be isolated in free form or as a 2026205213   01 Jul 2026 salt, or a solvate thereof. The intermediates and compounds described herein may be synthesized in the form of mixtures of tautomers and stereoisomeric forms that can be separated from one another following art-known resolution procedures. 5 General Synthetic Schemes All abbreviations used in the general schemes are as defined in the Table in the part Examples. Variables are as defined in the scope or as specifically defined in the general Schemes. 10 Part A) Schemes la, lb, 1c, 2a, 2b and 3 Rn = C-t-galkyl-NR^PG or C^galkyl-OPG or C1.6alkyl-C(=O)OR9a, PG = protecting group Scheme 1a O .U PG Z          + Ci.6alkyl' halo R4-Mg Step 1 R4x^Ci.6alkyl-NHPG O Step 2 HO. -Rn-------j H^-Rn        halo A + R4-Mg Step 3 R4x^,Rn OH Step 2 Step 5 halo           . R4-Mg or R4—Li Step 6 O .-II, -pG Step 4 HO^-Rn /  N-, ---Y '.            :                         o Ci.6alkyl' Scheme 1c PG i Step 9 In Scheme la, lb and 1c the following reaction conditions apply: 2026205213   01 Jul 2026 Step 1: at a suitable temperature such as for example -70°C, in the presence of a suitable base such as for example TMEDA and a suitable organometallic reagent such as for example isopropylmagnesium bromide, in a suitable solvent such as for example THF; Step 2: at a suitable temperature such as for example from 0 °C to RT, in the presence of a 5 suitable oxidative reagent such as for example DMP, in a suitable solvent such as for example DCM; Step 3: at a suitable temperature such as for example from -20°C to RT, in the presence of a suitable organometallic reagent such as for example isopropylmagnesium bromide, in a suitable solvent such as for example THF; 10 Step 4: at a suitable temperature such as for example 80°C, in the presence of a suitable base such as for example NaOH, in suitable solvents such as for example THF and H2O; Step 5: at a suitable temperature such as for example RT, in the presence of suitable amide condensation reagents such as for example EDCI and HOBt, in the presence of a suitable base such as for example NMM, in a suitable solvent such as for example DCM; 15 Step 6: at a suitable temperature such as for example -70°C, in the presence of a suitable organometallic reagent such as for example isopropyllithium, in a suitable solvent such as for example THF; Step 7: at a suitable temperature such as for example 90 °C, in the presence of a suitable organometallic catalyst such as for example Pd(dppf)C12, in the presence of a suitable base 20 such as for example Na2CCh, in suitable solvents such as for example 1,4-dioxane and H2O; Step 8: at a suitable temperature such as for example from 0 °C to RT, in the presence of a suitable Lewis acid such as for example BBn, in a suitable solvent such as for example DCM; Step 9: at a suitable temperature such as for example from -78 °C to 40 °C, in particular from 0 °C to RT, in the presence of a suitable base such as for example TEA, DBU or K2CO3, in a 25 suitable solvent such as for example DCM, THF or DMF; 2026205213   01 Jul 2026 Scheme 2a Scheme 2b H )n4 )n2 I PG Step 12 In Scheme 2a and 2b, the following reaction conditions apply: 5 Step 9: See Step 9 in Scheme 1; 2026205213   01 Jul 2026 Step 10: at a suitable temperature such as for example RT, in the presence of a suitable catalyst such as for example Pd / C, in the presence of a suitable reductive reagent such as for example H2, optionally in the presence of a suitable base such as for example TEA, in a suitable solvent such as for example THF; 5 Alternatively, at a suitable temperature such as RT, in the presence of a suitable catalyst such as for example Pd(dppf)C12-DCM complex, a suitable reducing agent such NaBH4, a suitable base such as for example TMEDA, in a suitable solvent such as for example THF. Step 11: for N deprotection, at a suitable temperature such as for example RT, in the presence of a suitable acid as for example TFA, in a suitable solvent such as for example DCM; for O 10 deprotection, at a suitable temperature such as for example RT, in the presence of a suitable acid as for example 4-methylbenzenesulfonic acid, in a suitable solvent such as for example MeOH; Step 12: at a suitable temperature such as for example 80 °C, optionally in the presence of a suitable Lewis acid such as for example ZnCh, in the presence of a suitable reductive reagent 15 such as for example NaBHsCN, in a suitable solvent such as for example MeOH; Step 13: at a suitable temperature such as for example RT, in the presence of a suitable organometallic catalyst such as for example Ag(Phen)2OTf, in the presence of a suitable brominating reagent such as for example 1,3-dibromo-1,3,5-triazinane-2,4,6-trione, in a suitable solvent such as for example DCE; 20 Step 14: at a suitable temperature such as for example RT, in the presence of a suitable chlorinating reagent such as for example oxalyl chloride, in the presence of DMF, in a suitable solvent such as for example DCM. 2026205213   01 Jul 2026 Scheme 3 C1.6alkyl-NR11-C(=O)-O-ClJlalkyl-O-C(=O)-C1.4alkyl R When Rn = C1.6alkyl-C(=O)OR9a R4x.C1.6alkyl-C(=O)OR9a C1.6alkyl-C(=O)-NR9aR9b In Scheme 3, the following reaction conditions apply: Step 11-12: See Step 11-12 in Scheme 2; 5 Step 15: at a suitable temperature such as for example 80 °C, in the presence of a suitable base such as for example CS2CO3, in suitable solvent such as for example DMF; Step 16: at a suitable temperature such as for example 40 °C, in the presence of a suitable base such as for example ammonia, in suitable solvent such as for example 1,4-dioxane. 2026205213   01 Jul 2026 Part B) Schemes 4, 5, 6, 7, 8, 9, 10, 11 and 12 In Scheme 4, the following reaction conditions apply: Step 1: at a suitable temperature such as for example 90 °C, in the presence of a suitable 5 organometallic catalyst such as for example Pd(dppf)C12, in the presence of a suitable base such as for example Na2COs, in suitable solvents such as for example 1,4-di oxane and H2O; Step 2: at a suitable temperature such as for example RT, in the presence of suitable amide condensation reagent such as for example HATU, in the presence of a suitable base such as for example DIEA, in a suitable solvent such as for example DCM; 10 Step 3: at a suitable temperature such as for example from -78 °C to RT, in the presence of a suitable Lewis acid such as for example BBn, in a suitable solvent such as for example DCM; Step 4: at a suitable temperature such as for example from -78 °C to 40 °C, in particular from 0 °C to RT, in the presence of a suitable base such as for example TEA, DBU or K2CO3, in a suitable solvent such as for example DCM, THF or DMF; 15 Step 5: at a suitable temperature such as for example RT, in the presence of a suitable base such as for example LiOH-ELO, in suitable solvents such as for example THF and H2O; Step 6: at a suitable temperature such as for example RT, in the presence of a suitable organometallic catalyst such as for example Ag(Phen)2OTf, in the presence of a suitable brominating reagent such as for example 1,3-dibromo-1,3,5-triazinane-2,4,6-trione, in a 20 suitable solvent such as for example DCE; 2026205213   01 Jul 2026 Step 7: at a suitable temperature such as for example RT, in the presence of a suitable brominating reagent such as 1,3-dibromo-1,3,5-triazinane-2,4,6-trione, in the presence of 2,2,2-trifluoroethan-l-ol as solvent. In Scheme 5, the following reaction conditions apply: Step 8: at a suitable temperature such as for example from -78 °C to 40 °C, in particular from 0 °C to RT, in the presence of a suitable base such as for example TEA, DBU or K2CO3, in a suitable solvent such as for example DCM, THF or DMF; 10 Step 9: at a suitable temperature such as for example from -78 °C to 40 °C, in particular from 0 °C to RT, in the presence of a suitable base such as for example TEA, DBU or K2CO3, in a suitable solvent such as for example DCM, THF or DMF; Step 10: at a suitable temperature such as for example RT, in the presence of a suitable organometallic catalyst as for example Pd / C and a suitable base as for example TEA, in a 15 suitable solvent such as for example MeOH under H2 atmosphere; Step 11: When PG is Boc, at a suitable temperature such as for example RT, in the presence of a suitable acid as for example TFA, in a suitable solvent such as for example DCM. 2026205213   01 Jul 2026 Scheme 6 In Scheme 6, the following reaction conditions apply: Step 12: reductive amination condition, at a suitable temperature such as for example from RT 5 to 80 °C, in the presence or absence of a suitable Lewis acid such as for example ZnCh or an acid for example AcOH, in the presence of a suitable reducing agent such as for example NaBEECN, in a suitable solvent such as for example MeOH; Step 13: at a suitable temperature such as for example 0 °C, in the presence of a suitable electrophile as for example MsCl, in the presence of a suitable base such as for example TEA, 10 in a suitable solvent such as for example DCM; Step 14: at a suitable temperature such as for example from 0 °C to RT, in the presence of a suitable oxidizing agent as for example DMP, in a suitable solvent such as for example DCM; Step 15: at a suitable temperature such as for example 50 °C, in the presence of a suitable acid as for example HC1, in a suitable solvent such as for example ACN; 15 Step 16: at a suitable temperature such as for example RT, in the presence or absence of a suitable base as for example TEA, in a suitable solvent such as for example THF. 2026205213   01 Jul 2026 Scheme 7 m = 1, 2, 3 Rw = H, CN, halo, OH, O-C^alkyl (Rw)m o 0 In Scheme 7, the following reaction conditions apply: Step 11: When PG is Boc, at a suitable temperature such as for example RT, in the presence of a suitable acid as for example TFA, in a suitable solvent such as for example DCM; 5 Step 12: reductive amination condition, at a suitable temperature such as for example from RT to 80 °C, in the presence or absence of a suitable Lewis acid such as for example ZnCh or an acid for example AcOH, in the presence of a suitable reducing agent such as for example NaBHsCN, in a suitable solvent such as for example MeOH; Step 17: at a suitable temperature such as for example from RT to 80 °C, in the presence of a 10 suitable base such as for example DIEA or CS2CO3, in suitable solvent such as for example DCM or DMF; Step 18: at a suitable temperature such as for example 40 °C, in the presence of a suitable base such as for example ammonia, in suitable solvent such as for 1,4-dioxane. 2026205213   01 Jul 2026 Scheme 8 R1a OH In Scheme 8, the following reaction conditions apply: Step 9: at a suitable temperature such as for example from -78 °C to 40 °C, in particular from 0 °C to RT, in the presence of a suitable base such as for example TEA, DBU or K2CO3, in a suitable solvent 5 such as for example DCM, THF or DMF; Step 10: at a suitable temperature such as for example RT, in the presence of a suitable organometallic catalyst as for example Pd / C, optionally in the presence of a suitable base as for example TEA, in a suitable solvent such as for example MeOH under H2 atmosphere; Step 19: at a suitable temperature such as for example RT, in the presence of a suitable 10 chlorinating reagent such as for example oxalyl chloride, in the presence of DMF, in a suitable solvent such as for example DCM; Step 20: at a suitable temperature such as for example 90 °C, in the presence of a suitable nucleophilic amine, in a suitable solvent such as for example EtOH; Step 21: at a suitable temperature such as for example RT, in the presence of a suitable acid 15 such as for example HC1 in dioxane, in a suitable solvent such as for example MeOH; 2026205213   01 Jul 2026 Step 22: at a suitable temperature such as for example 110 °C, in the presence of a suitable boron reagent such as for example trimethylboroxine, in the presence of a suitable organometallic catalyst such as for example tetrakis(triphenylphosphine)palladium(0), in the presence of a suitable base such as for example K2CO3, in a suitable solvent such as for example 5    1,4-di oxane; Scheme 9 N I PG In Scheme 9, the following reaction conditions apply: Step 23: at a suitable temperature such as for example from -78 °C to -25 °C, in the presence of suitable bases such as for example DIEA and n-BuLi, in a suitable solvent such as for example 10 THF;s 2026205213   01 Jul 2026 Step 24: at a suitable temperature such as for example between -65 °C and - 55°C, in the presence of suitable reducing agent such as for example DIBAL-H, in a suitable solvent such as for example toluene, preferably conducted in a suitable flow chemistry system; Step 25: first at a suitable temperature such as for example from -10 °C to 10 °C, in the presence 5 of a suitable base such as for example DMAP, in the presence of a suitable condensation agent such as for example DCC, in a suitable solvent such as for example DCM; then at a suitable temperature such as for example from -10 °C to 0 °C, in the presence of a suitable acid such as for example AcOH, in the presence of a suitable reducing agent such as for example NaBH4, in a suitable solvent such as for example DCM; 10 Step 26: in a suitable solvent such as for example toluene and heated to reflux; Step 27: at a suitable temperature such as for example from -5 °C to 5 °C, in the presence of suitable reducing agent such as for example LiBIE, in a suitable solvent such as for example 2-methyltetrahydrofuran; Step 28: at a suitable temperature such as for example from 15 °C to 25 °C, in the presence of 15 a suitable reducing agent such as for example NaBH(OAc)3, in a suitable solvent such as for example DCM; Step 29: at a suitable temperature such as for example from 15 °C to 25 °C, in the presence of a suitable acid such as for HC1, in a suitable solvent such as for example IPA; Step 30: at a suitable temperature such as for example from 5 °C to 30 °C, in the presence of a 20 suitable base such as for example TEA, in the presence of suitable reducing agent such as for example NaBH(OAc)3, in a suitable solvent such as for example toluene; Step 31: at a suitable temperature such as for example from 50 °C to 55 °C, in the presence of a suitable base such as for example K2HPO4, in a suitable solvent such as for example H2O; Step 32: When PG is Bn at a suitable temperature such as for example from -5 °C to 45 °C, 25 under a hydrogen atmosphere within a suitable pressure range such as for example from 0.27 to 0.40 MPa, in the presence of a suitable catalyst such as for example palladium hydroxide on carbon, in the presence of a suitable acid as for example MSA in a suitable solvent such as EtOH; Step 33: at a suitable temperature such as for example from -50 °C to -40 °C, in the presence 30   of suitable base such as for example TEA, in a suitable solvent such as 2-methyltetrahydrofuran; Step 34: at a suitable temperature such as for example from 20 °C to 30 °C, in the presence of suitable base such as for example TMG, in a suitable solvent such as 2-methyltetrahydrofuran; Step 35: at a suitable temperature such as for example from 20 °C to 30 °C, under a hydrogen atmosphere within a suitable pressure range such as for example from 0.20 to 0.30 Mpa, in the 2026205213   01 Jul 2026 presence of a suitable catalyst such as for example palladium on carbon, in a suitable solvent such as MeOH; alternatively, at a suitable temperature such as room temperature, in the presence of a suitable catalyst such as for example l,l'-Bis(diphenylphosphino)ferrocene-palladium(II)dichloride 5 dichloromethane complex, a suitable reducing agent such sodium borohydride , a suitable base such as for example A,A,A'7V'-tetramethylethylenediamine, in a suitable solvent such as for example tetrahydrofuran. Scheme 10 10 In general, compounds of Formula (I) wherein Y1 is limited to -CH2-, and R2 is limited to W1, hereby named compounds of Formula (la), can be prepared according to the following reaction Scheme 10. In Scheme 10, W1 represents chloro, bromo or iodo; all other variables are defined according to the scope of the present invention. Scheme 10 (la) 15 In Scheme 10, the following reaction conditions apply: Step 36: at a suitable temperature ranged from 60 °C to 100 °C, in presence of a suitable catalyst such as palladium acetate (Pd(OAc)2) or tris(dibenzylideneacetone)dipalladium(0) (Pd2(dba)3) or tetrakis(triphenylphosphine)palladium(0), in a suitable solvent such as for example tetrahydrofuran or dioxane. The skilled person will realize that starting from compound (la), analogous chemistry as reported in step 10 in scheme 5 and in steps 20, 21 and 22 in scheme 8 could be performed. Scheme 11 25 In general, compounds of Formula (I) wherein Y1 is limited to -CR5aR5b- and R2 is limited to W1, hereby named compounds of Formula (lb), can be prepared according to the following 2026205213   01 Jul 2026 reaction Scheme 11. In Scheme 11 at least one of R5a and R5b is other than hydrogen. All other variables are defined according to the scope of the present invention. Scheme 11 (lb) In Scheme 11, the following reaction condition apply: 5 Step 37: at a suitable temperature ranged from 80°C to 200°C, in presence of a suitable catalyst such as palladium acetate (Pd(OAc)2), in the presence of a suitable ligand such as for example triphenylphosphine or tricyclohexylphosphine, in a suitable solvent such as for example dioxane, preferably in sealed conditions, optionally under microwave irradiation. 10 The skilled person will realize that starting from compound (lb), analogous chemistry as reported in step 10 in scheme 5 and in steps 20, 21 and 22 in scheme 8 could be performed. Scheme 12 15 Scheme 12 Step 38 In Scheme 12, the following reaction condition apply: Step 38: at a suitable temperature such as for example from RT to 80 °C, in the presence of a suitable base such as for example DIEA, CS2CO3 or DBU, in suitable solvent such as for 20 example DCM, THF or DMF; 2026205213   01 Jul 2026 Alternatively, at a suitable temperature such as for example RT to 100 °C, in the presence of a suitable catalyst such as for example Pd2dba3, in the presence of a suitable ligand such as for example Xantphos, in the presence of a suitable base such as CS2CO3 or Na2CO3, in a suitable solvent such dioxane or a mixture of dioxane and water 5 The skilled person will realize that starting from intermediate A, analogous chemistry as reported in case Y1 represents O can be performed. 10 It will be appreciated that where appropriate functional groups exist, compounds of various formulae or any intermediates used in their preparation may be further derivatized by one or more standard synthetic methods employing condensation, substitution, oxidation, reduction, or cleavage reactions. Particular substitution approaches include conventional alkylation, arylation, heteroarylation, acylation, sulfonylation, halogenation, nitration, formylation and 15 coupling procedures. The compounds of Formula (I) may be synthesized in the form of racemic mixtures of enantiomers which can be separated from one another following art-known resolution procedures. The racemic compounds of Formula (I) containing a basic nitrogen atom may be converted into the corresponding diastereomeric salt forms by reaction with a suitable chiral 20 acid. Said diastereomeric salt forms are subsequently separated, for example, by selective or fractional crystallization and the enantiomers are liberated therefrom by alkali. An alternative manner of separating the enantiomeric forms of the compounds of Formula (I) involves liquid chromatography using a chiral stationary phase. Said pure stereochemically isomeric forms may also be derived from the corresponding pure stereochemically isomeric forms of the 25 appropriate starting materials, provided that the reaction occurs stereospecifically. In the preparation of compounds of the present invention, protection of remote functionality (e.g., primary or secondary amine) of intermediates may be necessary. The need for such protection will vary depending on the nature of the remote functionality and the conditions of the preparation methods. Suitable amino-protecting groups (NH-Pg) include acetyl, 30 trifluoroacetyl, t-butoxy carbonyl (Boc),    benzyloxy carbonyl    (CBz) and 9- fluorenylmethyleneoxy carbonyl (Fmoc). The need for such protection is readily determined by one skilled in the art. For a general description of protecting groups and their use, see T. W. Greene and P. G. M. Wuts, Protective Groups in Organic Synthesis, 4th ed., Wiley, Hoboken, New Jersey, 2007. 35 2026205213   01 Jul 2026 Pharmacology It has been found that the compounds of the present invention block the interaction of menin with MLL proteins and oncogenic MLL fusion proteins per se, or can undergo metabolism to a (more) active form in vivo (prodrugs). Therefore the compounds according to the present 5 invention and the pharmaceutical compositions comprising such compounds may be useful for the treatment or prevention, in particular treatment, of diseases such as cancer, including but not limited to leukemia, myelodysplastic syndrome (MDS), and myeloproliferative neoplasms (MPN); and diabetes. 10 In particular, the compounds according to the present invention and the pharmaceutical compositions thereof may be useful in the treatment or prevention of cancer. According to one embodiment, cancers that may benefit from a treatment with menin / MLL inhibitors of the invention comprise leukemias, lymphomas, myelomas or solid tumor cancers (e.g. prostate cancer, lung cancer, breast cancer, pancreatic cancer, colon cancer, liver cancer, melanoma and 15 glioblastoma, etc.). In some embodiments, the leukemias include acute leukemias, chronic leukemias, myeloid leukemias, myelogeneous leukemias, lymphoblastic leukemias, lymphocytic leukemias, Acute myelogeneous leukemias (AML), Chronic myelogenous leukemias (CML), Acute lymphoblastic leukemias (ALL), Chronic lymphocytic leukemias (CLL), T cell prolymphocytic leukemias (T-PLL), Large granular lymphocytic leukemia, Hairy 20 cell leukemia (HCL), MLL-rearranged leukemias, MLL-PTD leukemias, MLL amplified leukemias, MLL-positive leukemias, leukemias exhibiting H0XIMEIS1 gene expression signatures etc. In particular, the compounds according to the present invention and the pharmaceutical compositions thereof may be useful in the treatment or prevention of myelodysplastic syndrome 25 (MDS) or myeloproliferative neoplasms (MPN). In particular, compounds according to the present invention and the pharmaceutical compositions thereof may be useful in the treatment or prevention of leukemias, in particular nucleophosmin (NPMl)-mutated leukemias, e.g. NPMlc. In particular, compounds according to the present invention and the pharmaceutical 30 compositions thereof may be useful in the treatment or prevention of AML, in particular nucleophosmin (NPMl)-mutated AML (i.e., NPMlmutAML), more in particular abstract NPM1-mutated AML. In particular, compounds according to the present invention and the pharmaceutical compositions thereof may be useful in the treatment or prevention of MLL-rearranged 35 leukemias, in particular MLL-rearranged AML or ALL. 2026205213   01 Jul 2026 In particular, compounds according to the present invention and the pharmaceutical compositions thereof may be useful in the treatment or prevention of leukemias with MLL gene alterations, in particular AML or ALL with MLL gene alterations. In particular, compounds according to the present invention and the pharmaceutical 5 compositions thereof may be suitable for Q.D. dosing (once daily). In particular, compounds according to the present invention and the pharmaceutical compositions thereof may be useful in the treatment or prevention of hematological cancer in a subject exhibiting NPM1 gene mutations and / or mixed lineage leukemia gene (MLL, MLLi, 10 KMT2A) alterations, mixed lineage leukemia (MLL), MLL-related leukemia, MLL-associated leukemia, MLL-positive leukemia, MLL-induced leukemia, rearranged mixed lineage leukemia, leukemia associated with a MLL, rearrangement / alteration or a rearrangement / alteration of the MLL gene, acute leukemia, chronic leukemia, myelodysplastic syndrome (MDS), myeloproliferative neoplasms (MPN), insulin resistance, pre-diabetes, diabetes, or risk of 15 diabetes, hyperglycemia, chromosomal rearrangement on chromosome 1lq23, type-1 diabetes, type-2 diabetes; promoting proliferation of a pancreatic cell, where pancreatic cell is an islet cell, beta cell, the beta cell proliferation is evidenced by an increase in beta cell production or insulin production; and for inhibiting a menin-MLL interaction, where the MLL fusion protein target gene is HOX or MEIS1 in human. 20 Hence, the invention relates to compounds of Formula (I), the tautomers and the stereoisomeric forms thereof, and the pharmaceutically acceptable salts, and the solvates thereof, for use as a medicament. The invention also relates to the use of a compound of Formula (I), a tautomer or a stereoisomeric form thereof, or a pharmaceutically acceptable salt, or a solvate thereof, or a 25 pharmaceutical composition according to the invention, for the manufacture of a medicament. The present invention also relates to a compound of Formula (I), a tautomer or a stereoisomeric form thereof, or a pharmaceutically acceptable salt, or a solvate thereof, or a pharmaceutical composition according to the invention, for use in the treatment, prevention, amelioration, control or reduction of the risk of disorders associated with the interaction of menin with MLL 30 proteins and oncogenic MLL fusion proteins in a mammal, including a human, the treatment or prevention of which is affected or facilitated by blocking the interaction of menin with MLL proteins and oncogenic MLL fusion proteins. Also, the present invention relates to the use of a compound of Formula (I), a tautomer or a stereoisomeric form thereof, or a pharmaceutically acceptable salt, or a solvate thereof, or a 35 pharmaceutical composition according to the invention, for the manufacture of a medicament for treating, preventing, ameliorating, controlling or reducing the risk of disorders associated 2026205213   01 Jul 2026 with the interaction of menin with MLL proteins and oncogenic MLL fusion proteins in a mammal, including a human, the treatment or prevention of which is affected or facilitated by blocking the interaction of menin with MLL proteins and oncogenic MLL fusion proteins. The invention also relates to a compound of Formula (I), a tautomer or a stereoisomeric form 5 thereof, or a pharmaceutically acceptable salt, or a solvate thereof, for use in the treatment or prevention of any one of the diseases mentioned hereinbefore. The invention also relates to a compound of Formula (I), a tautomer or a stereoisomeric form thereof, or a pharmaceutically acceptable salt, or a solvate thereof, for use in treating or preventing any one of the diseases mentioned hereinbefore. 10 The invention also relates to the use of a compound of Formula (I), a tautomer or a stereoisomeric form thereof, or a pharmaceutically acceptable salt, or a solvate thereof, for the manufacture of a medicament for the treatment or prevention of any one of the disease conditions mentioned hereinbefore. The compounds of the present invention can be administered to mammals, preferably humans, 15 for the treatment or prevention of any one of the diseases mentioned hereinbefore. In view of the utility of the compounds of Formula (I), the tautomers and the stereoisomeric forms thereof, and the pharmaceutically acceptable salts, and the solvates thereof, there is provided a method of treating warm-blooded animals, including humans, suffering from any one of the diseases mentioned hereinbefore. 20 Said method comprises the administration, i.e. the systemic or topical administration, of a therapeutically effective amount of a compound of Formula (I), a tautomer or a stereoisomeric form thereof, or a pharmaceutically acceptable salt, or a solvate thereof, to warm-blooded animals, including humans. Therefore, the invention also relates to a method for the treatment or prevention of any one of 25 the diseases mentioned hereinbefore comprising administering a therapeutically effective amount of compound according to the invention to a patient in need thereof. One skilled in the art will recognize that a therapeutically effective amount of the compounds of the present invention is the amount sufficient to have therapeutic activity and that this amount varies inter alias, depending on the type of disease, the concentration of the compound in the 30 therapeutic formulation, and the condition of the patient. An effective therapeutic daily amount would be from about 0.005 mg / kg to 100 mg / kg. The amount of a compound according to the present invention, also referred to herein as the active ingredient, which is required to achieve a therapeutically effect may vary on case-by-case basis, for example with the particular compound, the route of administration, the age and condition of the recipient, and the particular 35 disorder or disease being treated. A method of treatment may also include administering the active ingredient on a regimen of between one and four intakes per day. In these methods of 2026205213   01 Jul 2026 treatment the compounds according to the invention are preferably formulated prior to administration. The present invention also provides compositions for preventing or treating the disorders referred to herein. Said compositions comprising a therapeutically effective amount of a 5 compound of Formula (I), a tautomer or a stereoisomeric form thereof, or a pharmaceutically acceptable salt, or a solvate thereof, and a pharmaceutically acceptable carrier or diluent. While it is possible for the active ingredient to be administered alone, it is preferable to present it as a pharmaceutical composition. Accordingly, the present invention further provides a pharmaceutical composition comprising a compound according to the present invention, 10 together with a pharmaceutically acceptable carrier or diluent. The carrier or diluent must be “acceptable” in the sense of being compatible with the other ingredients of the composition and not deleterious to the recipients thereof. The pharmaceutical compositions may be prepared by any methods well known in the art of pharmacy, for example, using methods such as those described in Gennaro et al. Remington’s 15 Pharmaceutical Sciences (18th ed., Mack Publishing Company, 1990, see especially Part 8 : Pharmaceutical preparations and their Manufacture). The compounds of the present invention may be administered alone or in combination with one or more additional therapeutic agents. Combination therapy includes administration of a single pharmaceutical dosage formulation which contains a compound according to the present 20 invention and one or more additional therapeutic agents, as well as administration of the compound according to the present invention and each additional therapeutic agent in its own separate pharmaceutical dosage formulation. Therefore, an embodiment of the present invention relates to a product containing as first active ingredient a compound according to the invention and as further active ingredient one or more 25 anticancer agent, as a combined preparation for simultaneous, separate or sequential use in the treatment of patients suffering from cancer. The one or more other medicinal agents and the compound according to the present invention may be administered simultaneously (e.g. in separate or unitary compositions) or sequentially in either order. In the latter case, the two or more compounds will be administered within a 30 period and in an amount and manner that is sufficient to ensure that an advantageous or synergistic effect is achieved. It will be appreciated that the preferred method and order of administration and the respective dosage amounts and regimes for each component of the combination will depend on the particular other medicinal agent and compound of the present invention being administered, their route of administration, the particular condition, in 35 particular tumour, being treated and the particular host being treated. 2026205213   01 Jul 2026 The following examples further illustrate the present invention. Examples Several methods for preparing the compounds of this invention are illustrated in the following examples. Unless otherwise noted, all starting materials were obtained from commercial 5 suppliers and used without further purification, or alternatively can be synthesized by a skilled person by using well-known methods. Abbreviation Meaning Ag(Phen)2OTf silver triflate-bis(l,10-phenanthroline) complex 2-MeTHF 2-methyltetrahydrofuran ACN acetonitrile AcCl acetyl chloride AcOH acetic acid AC2O acetic anhydride aq. aqueous Ar argon BBn tribromoborane bn benzyl Boc tert-butyl oxy carb ony 1 BOC2O di-tert-butyl dicarbonate w-BuLi n-butyllithium Cbz b enzy 1 oxy carb ony 1 CD3OD Methanol-d4 CHCh chloroform CS2CO3 cesium carbonate cone. concentrated DBU l,8-diazabicyclo[5.4.0]undec-7-ene DCC dicyclohexylcarbodiimide DCE di chloroethane DCM dichloromethane DDQ 4,5-dichloro-3,6-dioxocyclohexa-l,4-diene-l,2-dicarbonitrile DEA diethylamine 2026205213   01 Jul 2026 Abbreviation Meaning DIBAL-H diisobutylaluminum hydride DIEA or DIPEA A / 7-diisopropylethylamine DMAP A,A-dimethylpyridin-4-amine DMF A,A-dimethylformamide DMP Dess-Martin periodinane DMSO dimethyl sulfoxide dppf l,l'-ferrocenediyl-bis(diphenylphosphine) EDCI A-(3-Dimethylaminopropyl)-7V'-ethylcarbodiimide hydrochloride EA or EtOAc ethyl acetate EtOH ethanol eq. equivalent(s) FA formic acid FCC flash column chromatography h hour(s) H2 hydrogen HATU l-[bis(dimethylamino)methylene]-17 / -l,2,3- triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate H2O water HC1 hydrochloric acid HOBt 1 -Hydroxybenzotri azole HPLC high performance liquid chromatography ICH2CI chi oroi odom ethane IPA isopropyl alcohol IPAc isopropyl acetate K2CO3 potassium carbonate KI potassium iodide K2HPO4 dipotassium phosphate K3PO4 tripotassium phosphate LiAlD4 lithium aluminum deuteride LAH lithium aluminum hydride LiBH4 lithium borohydride 2026205213   01 Jul 2026 Abbreviation Meaning LDA lithium diisopropylamide LiCl lithium chloride LG leaving group Me methyl MeOH methanol 2-MeTHF 2-methyltetrahydrofuran min minute(s) mL milliliters mmol millimoles mg milligram MgSO4 magnesium sulfate MSA methanesulfonic acid MsCl methanesulfonyl chloride MS molecular sieve MTBE methyl tert-butyl ether N2 nitrogen NA not available NaBH3CN sodium cyanoborohydride NaBH(OAc)3 sodium triacetoxyborohydride NaBD3CN sodium cyanoborodeuteride Na2CO3 sodium carbonate NaH sodium hydride NaHCO3 sodium bicarbonate Nai sodium iodide NaOAc sodium acetate NaOH sodium hydroxide Na2SO3 sodium sulfite Na2SO4 sodium sulfate NH4C1 ammonium chloride NMM 1 -4-Methylmorpholine Pd2dba3 tris(dibenzylideneacetone)dipalladium(0) 2026205213   01 Jul 2026 Abbreviation Meaning Pd(dppf)C12 DCM [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II), complex with dichloromethane Pd(PPh3)4 tetrakis(triphenylphosphine)palladium(0) PE petroleum ether PG protecting group Phen phenanthroline psi pound per square inch / >-TsOH p-toluenesulfonic acid / >-TsOHH2O p-toluenesulfonic acid monohydrate Rt retention time Rochelle’s salt potassium sodium tartrate tetrahydrate RT room temperature sat. saturated SEC supercritical fluid chromatography TBAF tetrabutylammonium fluoride TBDMS / c / V-butyldimethyl silyl TBDPS / c / 7-butyldiphenylsilyl t-BuOK potassium tert-butoxide TEA triethylamine Tf trifluoromethanesulfonyl TFA trifluoroacetic acid THE tetrahydrofuran Ti(OiPr)4 titanium(IV) isopropoxide TLC thin layer chromatography TMEDA -tetramethyl ethyl enedi amine TMG 1,1,3,3 -tetramethylguani dine TMSI iodotrimethylsilane Ts p-toluenesulfonyl TsCl p-toluenesulfonyl chloride v / v volume per volume 2026205213   01 Jul 2026 10 15 20 Abbreviation Meaning vol. volume(s) wt weight Xantphos 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene As understood by a person skilled in the art, compounds synthesized using the protocols as indicated may exist as a solvate e.g. hydrate, and / or contain residual solvent or minor impurities. Compounds or intermediates isolated as a salt form, may be integer stoichiometric i.e. mono-or di-salts, or of intermediate stoichiometry. When an intermediate or compound in the experimental part below is indicated as ‘HC1 salt’ without indication of the number of equivalents of HC1, this means that the number of equivalents of HC1 was not determined. The same principle will also apply to all other salt forms referred to in the experimental part, such O as e.g. ‘oxalate salt’, ‘formate salt’ or ‘ O HO OH salt, The stereochemical configuration for centers in some compounds may be designated “7?” or “5” when the mixture(s) was separated and absolute stereochemistry was known, or when only one enantiomer was obtained and absolute stereochemistry was known; for some compounds, the stereochemical configuration at indicated centers has been designated as “*A” (first eluted from the column in case the column conditions of the separation are described in the synthesis protocol and when only one stereocenter present or indicated) or “*S” (second eluted from the column in case the column conditions of the separation are described in the synthesis protocol and when only one stereocenter present or indicated) when the absolute stereochemistry is undetermined (even if the bonds are drawn stereo specifically) although the compound itself has been isolated as a single stereoisomer and is enantiomerically pure. In case a compound designated as “*R” is converted into another compound, the “*R” indication of the resulting compound is derived from its starting material. For example, it will be clear that Compound 25 2026205213   01 Jul 2026 When “*7?” or “*S” occurs together with a 2nd stereocentre which is designated “7?” or “5” (known absolute stereochemistry for 2nd stereocentre) in the same molecule, the absolute 5 stereochemistry of the stereocentre designated “*7?” or “*S” is undetermined (even if the bonds are drawn stereo specifically) although the compound itself has been isolated as a single stereoisomer and is enantiomerically pure. “*7?” or “*S” is assigned randomly for such molecules. For example, it will be clear that Compound 340 For compounds wherein the stereochemical configuration of two stereocentres is indicated by * (e.g. *R or *S), the absolute stereochemistry of the stereocentres is undetermined (even if the bonds are drawn stereospecifically), although the compound itself has been isolated as a single 15 stereoisomer and is enantiomerically pure. In this case, the configuration of the first stereocentre is independent of the configuration of the second stereocentre in the same compound. “*7?” or “*S” is assigned randomly for such molecules. For example, for Compound 306 2026205213   01 Jul 2026 A skilled person will realize that the paragraphs above about stereochemical configurations, also apply to intermediates. A skilled person will realize that, even where not mentioned explicitly in the experimental protocols below, typically after a column chromatography purification, the desired fractions 10 were collected and the solvent was evaporated. In case no stereochemistry is indicated, this means it is a mixture of stereoisomers, unless otherwise is indicated or is clear from the context. When a stereocenter is indicated with ‘RS’ this means that a racemic mixture was obtained at the indicated centre, unless otherwise indicated. 15 Preparation of intermediates For intermediates that were used in a next reaction step as a crude or as a partially purified 2026205213   01 Jul 2026 intermediate, in some cases no mol amounts are mentioned for such intermediate in the next reaction step or alternatively estimated mol amounts or theoretical mol amounts for such intermediate in the next reaction step are indicated in the reaction protocols described below. 5 Preparation of intermediate 27 A-ethyl-5-fluoro-A-isopropyl-2-methoxybenzamide HO. To the mixture of 5-fluoro-2-methoxybenzoic acid (8.00 g, 47.0 mmol) and A-ethylpropan-2-amine (8.19 g, 94.0 mmol) in dry DCM (150 mL) cooled at 0 °C, were slowly added HATU 10   (21.5 g, 56.5 mmol) and DIEA (9.10 g, 70.4 mmol) in portions. The resulting mixture was slowly warmed to RT and stirred for 8 h. The organic layer was washed with water (20 mL x 3) and dried over anhydrous Na2SO4. After filtration, the solvent was removed under reduced pressure and the crude product was purified by FCC (EtOAc / PE = 0% to 20%) to afford the title intermediate (12.0 g, 96% yield) as a white solid. 15 Preparation of intermediate 67, 235, 246 5-11 uoro-V.V-diisopropyl-2-niethoxy benzamide 5-fluoro-2-methoxy-A-(propan-2-yl-13C3)benzamide 5-fluoro-A-isopropyl-2-methoxy-A-methylbenzamide 20 The following intermediate was synthesized by an analogous method as described above for intermediate 27 Int. No. Structure Starting Materials 67 JL J 5-fluoro-2-methoxybenzoic acid, diisopropylamine 2026205213   01 Jul 2026 Int. No. Structure Starting Materials 235 w p w w m 0-0 ^=\ zx \ O O 5-fluoro-2-methoxybenzoic acid, propan-2-amine-l,2,3-13C3 246 O — 5-fluoro-2-methoxybenzoic acid, 7V-methylpropan-2-amine Preparation of intermediate 28 7V-ethyl-5-fluoro-2-hydroxy-7V- isopropylbenzamide BBr3, DCM OH 10 To the solution of 7V-ethyl-5-fluoro-A-isopropyl-2-methoxybenzamide (intermediate 27) (12.0 g, 50.1 mmol) in dry DCM (100 mL) cooled at -78 °C was slowly added BBrs (14.4 mL, 152 mmol), the resulting mixture was slowly warmed to RT and stirred for 8 h. The mixture was cooled to -78 °C again and MeOH (5 mL) was added dropwise to quench the reaction. The resulting mixture was slowly warmed to RT and the pH value was adjusted to about 8 by adding sat. aq. NaHCOs solution. The aqueous layer was extracted by DCM (50 mL x 3) and the combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give the crude product which was purified by FCC (EtOAc / PE = 0% to 20%) to afford the title intermediate (9.0 g, 78% yield) as a white solid. 15 Preparation of intermediate 68, 237, 247 5-nuoro-2-hydroxy-V.V-diisopropylbenzamide 7V-(ethyl-13C2)-5-fluoro-2-hydroxy-7V-(propan-2-yl-13C3)benzamide 5-fluoro-2-hydroxy-7V-isopropyl-7V-methylbenzamide 2026205213   01 Jul 2026 The following intermediate was synthesized by an analogous method as described above for intermediate 28 Int. No. Structure Starting Materials 68 J J F^^ intermediate 67 237 I O o-z \=< 0 ” b- 0 u. co         co co " b" co T- intermediate 236 247 intermediate 246 5 Preparation of intermediate 60 5-bromo-4-cyclopropylpyrimidine 1) [>—MgBr THF „          2) DDQ Br To a solution of 5-bromopyrimidine (30 g, 189 mmol) in THF (1000 mL) was added cyclopropylmagnesium bromide (396 mL, 198 mmol, 0.5 M in THF) at 0 °C under N2 10 atmosphere. After addition, the reaction mixture was stirred at RT for 4 h, then a solution of DDQ (42.8 g, 189 mmol) in THF (500 mL) was added dropwise into the reaction mixture at 0 °C. After addition, the reaction mixture was stirred at RT for 16 h. The reaction mixture was concentrated in vacuo and the residue was partitioned between EtOAc (200 mL) and water (200 mL), and the aqueous layer was extracted by EtOAc (200 mL x 3). The combined 15 organic layers were washed with IN NaOH (200 mL x 2), brine (200 mL), dried over 2026205213   01 Jul 2026 Na2SO4, filtered. The filtrate was concentrated in vacuo and the residue was purified by FCC (EtOAc / PE = 0% to 15%) to afford the title intermediate (21.4 g, 55% yield) as white solid. Preparation of intermediate 61 5 2-(4-cyclopropylpyrimidin-5-yl)-4-fluorophenol The mixture of 5-bromo-4-cyclopropylpyrimidine (intermediate 60) (20.0 g, 100 mmol), (5-fluoro-2-hydroxyphenyl)boronic acid (18.7 g, 120 mmol), Pd(dppf)C12 (3.68 g, 5.03 mmol) and Na2CO3 (2 M in H2O, 101 mL, 202 mmol) in 1,4-dioxane (350 mL) was heated at 90 °C 10 for 12 h under N2 atmosphere. After cooled to RT, the reaction mixture was filtered through a celite pad, the filtrate was suspended into water (400 mL) and further extracted with EtOAc (200 mL x 3). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give the crude product, which was purified by FCC on silica gel (PE / EtOAc = 1:0 to 3:1) to afford the title intermediate (24.0 g, 95% purity, 98.6% 15 yield) as a brown solid. Preparation of intermediate 13 tert-butyl 6-(3,6-dichloro-l,2,4-triazin-5-yl)-2,6-diazaspiro[3.4]octane-2-carboxylate Cl TEA, DCM 20 To the solution of 3,5,6-trichloro-l,2,4-triazine (10.0 g, 54.2 mmol) and TEA (15.2 mL, 109 mmol) in DCM (100 mL) cooled at 0 °C was added tert-butyl 2,6-diazaspiro[3.4]octane-2-carboxylate (9.21 g, 43.4 mmol), the mixture was warmed to RT and stirred for 1 h. The mixture was diluted with water (20 mL) and extracted with DCM (30 mL x 3). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated under 25 reduced pressure to give the crude product which was purified by FCC on silica gel (PE / EtOAc = 1:0 to 3:1) to afford the title intermediate (12.0 g, 58% yield) as a yellow solid. 2026205213   01 Jul 2026 Preparation of intermediate 69 tert-butyl 6-(3-chloropyridazin-4-yl)-2,6-diazaspiro[3.4]octane-2-carboxylate The following intermediate was synthesized by an analogous method as described above 5 for intermediate 13 Int. No. Structure Starting Materials 69 o 3,4-dichloropyridazine, tert-butyl 2,6-diazaspiro[3,4]octane-2-carboxylate Preparation of intermediate 14 tert-butyl 6-(3-chloro-6-(2-(ethyl(isopropyl)carbamoyl)-4-fluorophenoxy)-l,2,4-triazin-5- 10 yl)-2,6-diazaspiro[3.4]octane-2-carboxylate Boc                                      Boc / / The mixture of tert-butyl 6-(3,6-dichloro-l,2,4-triazin-5-yl)-2,6-diazaspiro[3.4]octane-2-carboxylate (intermediate 13) (12.0 g, 33.3 mmol), 7V-ethyl-5-fluoro-2-hydroxy-N-isopropylbenzamide (intermediate 28) (7.5 g, 33.3 mmol) and DBU (6.1 g, 40.1 mmol) in 15 THF (120 mL) was stirred at 25 °C for 8 h. The mixture was diluted with water (30 mL) and extracted with DCM (30 mL x 3). The combined organic layers were washed with brine, dried overNa2SO4, filtered and concentrated under reduced pressure to give the crude product which was purified by FCC (PE / EtOAc = 1:0 to 3:1) to afford the title intermediate (14.0 g, 73% yield) as green solid. Preparation of intermediates 57, 74, 70, and 83 tert-butyl 6-(3-chloro-6-(2-(4-cyclopropylpyrimidin-5-yl)-4-fluorophenoxy)-l,2,4-triazin- 5-yl)-2,6-diazaspiro [3.4] octane-2-carboxylate tert-butyl 6-(3-(2-(ethyl(isopropyl)carbamoyl)-4-fluorophenoxy)pyridazin-4-yl)-2,6- 5 diazaspiro[3.4]octane-2-carboxylate tert-butyl 6-(3-(2-(diisopropylcarbamoyl)-4-fluorophenoxy)pyridazin-4-yl)-2,6- diazaspiro[3.4]octane-2-carboxylate tert-butyl 6-(3-chloro-6-(2-(diisopropylcarbamoyl)-4-fluorophenoxy)-l,2,4-triazin-5-yl)- 2,6-diazaspiro[3.4]octane-2-carboxylate 10 The following intermediates were synthesized by an analogous method as described above for intermediate 14 2026205213   01 Jul 2026 Int. No. Structure Starting Materials 57 Boc r-N N^N / — Nc. Jk F             N CI intermediate 61, intermediate 13 74 Boc XX v intermediate 28, intermediate 69 70 Boc V rX yny° Q intermediate 68, intermediate 69 2026205213   01 Jul 2026 Int. No. Structure Starting Materials 83 Boc Y r? yY Q A°A N'n^CI intermediate 68, intermediate 13 Preparation of intermediate 2 tert-butyl 6-(6-(2-(ethyl(isopropyl)carbamoyl)-4-fluorophenoxy)-l,2,4-triazin-5-yl)-2,6- diazaspiro[3.4]octane-2-carboxylate To the mixture of tert-butyl 6-(3-chloro-6-(2-(ethyl(isopropyl)carbamoyl)-4-fluorophenoxy)-l,2,4-triazin-5-yl)-2,6-diazaspiro[3.4]octane-2-carboxylate (intermediate 14) (20 g, 36.4 10 mmol), NaBH4 (2.48 g, 65.7 mmol) and TMEDA (8.54 g, 73.5 mmol) in THF (500 mL) was added Pd(dppf)C12-DCM (1.70 g, 2.08 mmol) under N2 atmosphere. After addition, the reaction mixture was stirred at 25 °C for 14 h. The reaction mixture was filtered and the filtrate was concentrated, the residue was purified by FCC on silica gel (EtOAc) to afford the title intermediate (15 g, 93% purity, 74% yield) as brown solid. 15 Method B: Boc / Pd / C, H2 TEA, MeOH 2026205213   01 Jul 2026 To the solution of tert-butyl 6-(3-chloro-6-(2-(ethyl(isopropyl)carbamoyl)-4-fluorophenoxy)-l,2,4-triazin-5-yl)-2,6-diazaspiro[3.4]octane-2-carboxylate (intermediate 14) (22.0 g, 40.1 mmol), TEA (15 mL) in MeOH (100 mL) was added Pd / C (wet, 5.0 g, 10%) The resulting mixture was stirred under EE atmosphere (30 psi) at 25 °C for 8 h. The reaction mixture was 5 filtered through a celite pad and the filtrate was concentrated in vacuo to afford the title intermediate (25.0 g, crude), which was used directly in next step without further purification. Preparation of intermediate 58, 84 tert-butyl 6-(6-(2-(4-cyclopropylpyrimidin-5-yl)-4-fluorophenoxy)-l,2,4-triazin-5-yl)-2,6-10 diazaspiro [3.4]octane-2-carboxylate tert-butyl 6-(6-(2-(diisopropylcarbamoyl)-4-fluorophenoxy)-l,2,4-triazin-5-yl)-2,6-diazaspiro[3.4]octane-2-carboxylate The following intermediates were synthesized by an analogous method described above for intermediate 2 Int. No. Structure Starting Material Conditions 58 o o m 'z—i z \ z \=z o z—<   \—a <zX) z=\ x=\ intermediate 57 NaBH4, TMEDA, Pd(dppf)Cl2-DCM, THF 84 Boc V rV 'YnT° v intermediate 83 Pd / C, H2, TEA, MeOH Preparation of intermediate 3 2-((5-(2,6-diazaspiro[3.4]octan-6-yl)-l,2,4-triazin-6-yl)oxy)-A-ethyl-5-fluoro-A-isopropylbenzamide 2026205213   01 Jul 2026 To the solution of tert-butyl 6-(6-(2-(ethyl(isopropyl)carbamoyl)-4-fluorophenoxy)-1,2,4-triazin-5-yl)-2,6-diazaspiro[3.4]octane-2-carboxylate (intermediate 2) (300 mg, 0.583 mmol) in DCM (5 mL) was added TFA (0.5 mL, 6.4 mmol), the resulting mixture was stirred at RT 5 for 3 h. Then 10% NaOH (5 mL) solution was slowly added into the mixture to adjust the pH value to about 12, the resulting mixture was extracted with DCM (10 mL x 3). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated in vacuo to afford the title intermediate (220 mg, 90% yield) as a white solid. 10 Preparation of intermediate 59, 75, 85 6-(6-(2-(4-cyclopropylpyrimidin-5-yl)-4-fluorophenoxy)-l,2,4-triazin-5-yl)-2,6-diazaspiro[3.4]octane 2-((4-(2,6-diazaspiro[3.4]octan-6-yl)pyridazin-3-yl)oxy)-A-ethyl-5-fluoro-A-isopropylbenzamide 15    2-((5-(2,6-diazaspiro[3.4]octan-6-yl)-l, 2,4-triazin-6-yl)oxy )-5-11 uoro-V.V- diisopropylbenzamide The following intermediates were synthesized by an analogous method described above for intermediate 3 2026205213   01 Jul 2026 Int. No. Structure Starting Material 75 o O \—\=^ intermediate 74 85 o I—z I intermediate 84 Preparation of intermediate 160 7V-methoxy-7V-methyl-4-(methylamino)butanamide hydrochloride HCI / dioxane XO' Boo         DCM HCI salt 5 To a solution of tert-butyl (4-(methoxy(methyl)amino)-4-oxobutyl)(methyl)carbamate (intermediate 8) (220 g, crude) in DCM (200 mL) was slowly added HCl / l,4-di oxane (750 mL, 3 mol) at 0 °C. The resulting mixture was slowly warmed to RT and stirred at this temperature for 2 h. The mixture was concentrated in vacuo to afford the title intermediate (197 g, crude) which was used directly in next step without further purification. 10 Intermediate 164, 238, 243, 244 7V-(2-methoxyethyl)-7V,5-dimethyl-4-(2,6-diazaspiro[3.4]octan-6-yl)hexan-l-amine hydrochloride 2-((3-chloro-5-(2,6-diazaspiro[3.4]octan-6-yl)-l,2,4-triazin-6-yl)oxy)-7V-ethyl-5-fluoro-7V-15 isopropylbenzamide hydrochloride 2-((5-(2,6-diazaspiro[3.4]octan-6-yl)-l,2,4-triazin-6-yl)oxy)-5-fluoro-A^^V-diisopropylbenzamide hydrochloride 2-((5-(2,6-diazaspiro[3.4]octan-6-yl)-l, 2,4-triazin-6-yl)oxy)-7V-ethyl-5-fluoro-7V-isopropylbenzamide hydrochloride 2026205213   01 Jul 2026 The following intermediates were synthesized by an analogous method described above for intermediate 160 Int. No. Structure Starting Material 164 A, \ / ~A  N- /  \ £ H HCI salt intermediate 163 238 HCI salt r-NH CY YA pAX N'N^CI intermediate 14 243 HCI salt r-NH yC° Q A0 A F            N intermediate 84 244 HCI salt r-NH C / 1 A N A° A N. F            N intermediate 2 Preparation of intermediate 71 5   2-((4-(2,6-diazaspiro [3.4] octan-6-yl)pyridazin-3-yl)oxy)-5-fluoro-A^^V- diisopropylbenzamide 2026205213   01 Jul 2026 To the solution of tert-butyl 6-(3-(2-(diisopropylcarbamoyl)-4-fluorophenoxy)pyridazin-4-yl)-2,6-diazaspiro[3.4]octane-2-carboxylate (intermediate 70) (5.0 g, 9.4 mmol) in 1,4-dioxane (30 mL) cooled at 0 °C was slowly added HC1 in 1.4-dioxane (20 mL, 4 M, 80 mmol) The resulting mixture was stirred at RT for 2 h. Then, the mixture was concentrated and the 5 residue was re-dissolved in DCM (50 mL), to which 1 M NaOH (20 mL) was slowly added and the pH value was adjusted to 12, the resulting mixture was extracted by DCM (30 mL x 3). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated in vacuo to afford the title intermediate (4 g, crude) as a yellow solid, which was used in the next step without further purification. 10 Preparation of intermediate 29 tert-butyl 2,2-dimethyl-5-oxopyrrolidine-l-carboxylate TEA, DMAP, DCM     Boc-k,-V Hj \    + (boc)2o ---------------► y \ ¢ / ^7                               CT^7 To a solution of 5,5-dimethylpyrrolidin-2-one (3.00 g, 26.5 mmol) in DCM (30 mL) were 15 added TEA (8.10 g, 80.0 mmol) and DMAP (325 mg, 2.66 mmol), and followed by addition of di-tert-butyl dicarbonate (8.70 g, 39.8 mmol). The reaction was stirred at 40 °C overnight. After cooled to RT, the reaction mixture was washed with brine (30 mL x 2), dried over Na2SO4, filtered and concentrated under reduced pressure to give a crude product. The crude product was further purified by FCC on silica gel (PE / EtOAc = 100:0 to 3:1) to afford the title 20 intermediate (2.8 g, 50% yield) as a yellow powder. Preparation of intermediate 1 tert-butyl (5-methyl-4-oxohexyl)carbamate TMEDA, THF -------► 25 To a solution of tert-butyl 2-oxopyrrolidine-l-carboxylate (5.0 g, 27 mmol) and TMEDA (5.0 mL, 33 mmol) in THF (60 mL) cooled at -70 °C was slowly added isopropylmagnesium bromide solution (19 mL, 55 mmol, 2.9 M in 2-methyltetrahydrofuran), the resulting mixture was slowly warmed to RT and stirred for 12 h. The mixture was poured into sat. aq. NH4CI (50 mL) solution and extracted with EtOAc (50 mL x 3). The combined organic layers were 30 dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give the 2026205213   01 Jul 2026 crude product, which was further purified by FCC (PE / EtOAc = 1:0 to 100:1) to afford the title intermediate (3.7 g, 60% yield) as a yellow oil. Preparation of intermediate 30,110,141 5 tert-butyl (2,6-dimethyl-5-oxoheptan-2-yl)carbamate tert-butyl (6-methyl-5-oxoheptyl)carbamate 6-hydroxy-2,4-dimethylhexan-3-one The following intermediates were synthesized by an analogous method described above for intermediate 1 Int. No. Structure Starting Materials 30 O H ^N'Boc isopropylmagnesium bromide, intermediate 29 110 O ^n-BOC H isopropylmagnesium bromide, tert-butyl 2-oxopiperidine-1 -carboxylate 141 O OH isopropylmagnesium chloride, 3-methyldihydrofuran-2(3rt)-one Preparation of intermediate 34 benzyl 2,2-dimethyl-5-oxopyrrolidine-l-carboxylate To a solution of 5,5-dimethylpyrrolidin-2-one (5.00 g, 44.2 mmol) in THF (150 mL) cooled at 15   0 °C was added NaH (1.94 g, 48.5 mmol, 60%), the resulting mixture was stirred at this temperature for 30 min. Subsequently A-(benzyloxycarbonyloxy)succinimide (12.1 g, 48.6 mmol) was added and the reaction mixture was slowly warmed to RT and stirred for additional 16 h. The solvent was evaporated under reduced pressure, sat. aq. NH4CI solution (30 mL) was added and extracted with EtOAc (2x30 mL). The combined organic layers 20 were washed with brine (40 mL), dried over Na2SO4, filtered, and concentrated under reduced 2026205213   01 Jul 2026 pressure to afford the crude product, which was further purified by FCC (PE / EtOAc = 1:0 to 3: 1) to afford the title intermediate (5.16 g, 39% yield) as colorless oil. Preparation of intermediate 35 5 4-(((benzyloxy)carbonyl)amino)-4-methylpentanoic acid NaOH (4.18 g, 16.9 mmol) was added to a solution of benzyl 2,2-dimethyl-5-oxopyrrolidine-1-carboxylate (intermediate 34) (5.16 g, 20.9 mmol) in THF (60 mL) and H2O (15 mL). The mixture was stirred at 80 °C for 16 h. The reaction mixture was cooled to 25 °C and acidified 10 by 1 M HC1 to adjust the pH value to about 3, then the mixture was extracted by EtOAc (20 x 2 mL). The combined organic layers were washed with brine (20 mL), dried over Na2SO4, filtered, and concentrated in vacuo to afford the title intermediate (4.48 g, crude) as colorless oil, which was used directly in next step without further purification. 15 Preparation of intermediate 7 4-((tert-butoxycarbonyl)(methyl)amino)butanoic acid TEA, MeOH                   Boc 0 H                                               0         1 To a solution of 4-(methylamino)butanoic acid hydrochloride (3.0 g, 19.5 mmol) and TEA (7.78 mL, 58.6 mmol) in MeOH (30 mL) was added BOC2O (4.69 g, 21.5 mmol) dropwise. 20 The mixture was stirred at RT for 2 h. The mixture was concentrated under reduced pressure and the residue was diluted with EtOAc (100 mL), washed with cooled 0.1 N HC1 (70 mL x 2), H2O (50 mL x 2) and brine (50 mL), dried over Na2SO4, filtered and concentrated to afford the title intermediate (1.80 g, crude) as colorless oil. 25 Preparation of intermediate 8 tert-butyl (4-(methoxy(methyl)amino)-4-oxobutyl)(methyl)carbamate HO.           Boc            0 EDCI, HOBt, NMM, CHCI3         1 T V + n x 0   1 H                 S' To a solution of 4-((tert-butoxycarbonyl)(methyl)amino)butanoic acid (intermediate 7) (1.80 g, crude) in CHCL (30 mL) was added MO-dimethylhydroxylamine hydrochloride (960 mg, 30   9.84 mmol), HOBt (1.24 g, 9.18 mmol) and NMM (2.80 mL, 25.1 mmol). And, then EDCI 2026205213   01 Jul 2026 (2.23 g, 11.6 mmol) was added and the reaction mixture was stirred at RT for 4 h. The reaction mixture was diluted with DCM (100 mL), washed with IN HC1 (30 mL x 3), sat. aq. NaHCO, (30 mL x 3) and brine (30 mL), dried over Na2SO4, filtered and concentrated under in vacuo to afford the title intermediate (1.70 g, crude) as colorless oil. 5 Preparation of intermediates 19, 36,189,190, 203, 204 tert-butyl (3-(methoxy(methyl)amino)-3-oxopropyl)carbamate benzyl (5-(methoxy(methyl)amino)-2-methyl-5-oxopentan-2-yl)carbamate (5)-3-((tert-butyldiphenylsilyl)oxy)-4-(ethyl(methyl)amino)-N-methoxy-N- 10 methylbutanamide (K)-3-((tert-butyldiphenylsilyl)oxy)-4-(ethyl(methyl)amino)-7V-methoxy-7V-methylbutanamide (3)-3-((tert-butyldiphenylsilyl)oxy)-7V-methoxy-4-((2-methoxyethyl)(methyl)amino)-7V-methylbutanamide 15 (ft)-3-((tert-butyldiphenylsilyl)oxy)-7V-methoxy-4-((2-methoxyethyl)(methyl)amino)-7V-methylbutanamide The following intermediates were synthesized by an analogous method described above for intermediate 8 Int. No. Structure Starting Materials 19 O CL Jk, 1 ^N,BOC H 3-((tert-butoxycarbonyl)amino)propanoic acid 7V,O-dimethylhydroxylamine hydrochloride 36 H cbz'N^ 0 intermediate 35 7V,O-dimethylhydroxylamine hydrochloride 189 o nA । i TBDPSCT intermediate 187, 7V,O-dimethylhydroxylamine hydrochloride 190 O aA । i TBDPSO' intermediate 188, 7V,O-dimethylhydroxylamine hydrochloride 2026205213   01 Jul 2026 Int. No. Structure Starting Materials 203 O "A' TBDPSO         O intermediate 201, A,O-dimethylhydroxylamine hydrochloride 204 O -°A 1 TBDPSO     ^^ O intermediate 202, A,O-dimethylhydroxylamine hydrochloride Preparation of intermediate 37 benzyl (5-(methoxy(methyl)amino)-2-methyl-5-oxopentan-2-yl)(methyl)carbamate Mel, NaH, DMF To a solution of benzyl (5-(methoxy(methyl)amino)-2-methyl-5-oxopentan-2-yl)carbamate (intermediate 36) (2.30 g, 7.46 mmol) in DMF (30 mL) cooled at 0 °C under N2 atmosphere was added NaH (358 mg, 8.95 mmol, 60%). Then, Mel (8.87 g, 62.5 mmol) was added and the mixture was stirred at 25 °C for 12 h. The mixture was quenched with sat. aq. NH4CI (30 10 mL) and extracted with EtOAc (30 mL x 2). The combined organic layers washed with brine (40 mL), dried over Na2SO4, filtered and concentrated in vacuo to give the crude product, which was further purified by FCC on silica gel (PE / EtOAc = 1:0 to 3:1) to afford the title intermediate (2.15 g, 76% yield) as yellow oil. 15 Preparation of intermediate 236 A-(ethyl-13C2)-5-fluoro-2-methoxy-A-(propan-2-yl-13C3)benzamide The following intermediate was synthesized by an analogous method as described above for intermediate 37 Int. No. Structure Starting Materials Conditions 236 w 0 w w    w -n   0-0  _O \          '    wz / =\ z-° \  0 / O intermediate 235, iodoethane-1,2-13 C2 NaH, DMF, from 0 °C to 90 °C 2026205213   01 Jul 2026 Preparation of intermediate 9 tert-butyl methyl(5-methyl-4-oxohexyl)carbamate 5 To a solution of tert-butyl (4-(methoxy(methyl)amino)-4-oxobutyl)(methyl)carbamate (intermediate 8) (200 mg, crude) in THF (5 mL) cooled at -70°C under N2 atmosphere was added dropwise isopropyllithium (3.2 mL, 2.24 mmol, 0.7M in pentane). The resulting mixture was stirred at -70 °C for 2 h. The mixture was quenched with sat. aq. NH4CI (15 mL), extracted with EtOAc (30 mL x 2). The combined organic layers were washed with brine (30 10 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a crude product. The crude product was further purified by FCC (PE / EtOAc = 10 : 1) to afford the title intermediate (60 mg) as colorless oil. Preparation of intermediates 20, 38,162,191,192, 205, 206 15 tert-butyl (4-methyl-3-oxopentyl)carbamate benzyl (2,6-dimethyl-5-oxoheptan-2-yl)(methyl)carbamate 6-((2-methoxyethyl)(methyl)amino)-2-methylhexan-3-one (5)-5-((tert-butyldiphenylsilyl)oxy)-6-(ethyl(methyl)amino)-2-methylhex-l-en-3-one (K)-5-((tert-butyldiphenylsilyl)oxy)-6-(ethyl(methyl)amino)-2-methylhex-l-en-3-one 20 (3)-5-((tert-butyldiphenylsilyl)oxy)-6-((2-methoxyethyl)(methyl)amino)-2-methylhex-l-en-3-one (K)-5-((tert-butyldiphenylsilyl)oxy)-6-((2-methoxyethyl)(methyl)amino)-2-methylhex-l-en-3-one 25 The following intermediates were synthesized by an analogous method described above for intermediate 9 Int. No. Structure Starting Materials 20 O 1             H intermediate 19, isopropylmagnesium chloride 2026205213   01 Jul 2026 Int. No. Structure Starting Materials 38 O ^'Cbz intermediate 37 isopropylmagnesium chloride 162 O intermediate 161, isopropyllithium 191 O TBDPSO*^ intermediate 189, isopropenylmagnesium bromide 192 O TBDPSO'' x^N^ / intermediate 190, isopropenylmagnesium bromide 205 O TBDPSO*^ intermediate 203, isopropenylmagnesium bromide 206 O TBDPSO'' intermediate 204, isopropenylmagnesium bromide Preparation of intermediate 15 2-(3-methyl-2-oxobutyl)isoindoline-l, 3-dione To the solution of 1-bromo-3-methylbutan-2-one (200 mg, 1.21 mmol) in DMF (4 mL) was added potassium phthalimide (1.12 g, 6.05 mmol) and the mixture was stirred at 80 °C for 12 h. After cooled to RT, water (15 mL) was added and the mixture was extracted with EtOAc (40 mL x 3). The combined organic layers were dried over anhydrous Na2SO4, filtered and 10 concentrated under reduced pressure to afford the crude product, which was further purified 2026205213   01 Jul 2026 by preparative TLC (PE / EtOAc = 3:1) to afford the title intermediate (200 mg, 69% yield) as a white solid. Preparation of intermediate 46 5 methyl 5-methyl-4-oxohexanoate To a solution of ZnEt2 (104 mL, 104 mmol) in DCM (150 mL) at 0 °C under N2 was added dropwise TFA (11.9 g, 104 mmol) slowly via syringe and the mixture was stirred at 0 °C for 30 min. Then, methylene iodide (27.9 g, 104 mmol) was added dropwise with stirring and the 10 suspension was stirred for another 30 min. And, then methyl 4-methyl-3-oxopentanoate (5.00 g, 34.7 mmol) was added rapidly by syringe and the resulting mixture was stirred at RT for 16 h and refluxed at 50 °C for 20 h. After cooled to RT, the reaction mixture was quenched with sat. aq. NH4CI (50 mL) and extracted with EtOAc (30 mL x 3). The combined organic layers were washed with brine, dried over MgSO4, and concentrated under reduced pressure to an oil 15 residue which was purified by FCC (PE / EtOAc = 1:0 to 20:1) to afford the title intermediate (300 mg, 5% yield) as a yellow oil. Preparation of intermediate 22 tert-butyl (4-methyl-3-(2,6-diazaspiro[3.4]octan-2-yl)pentyl)carbamate hydrochloride 20 Cbz Pd / C, H2 MeOH To a solution of benzyl 2-(l-((terLbutoxycarbonyl)amino)-4-methylpentan-3-yl)-2,6-diazaspiro[3.4]octane-6-carboxylate (intermediate 21) (0.580 g, 1.30 mmol) in MeOH (50 mL) were added 1,1,2-trichloroethane (0.260 g, 1.95 mmol) and Pd / C (0.05 g, 10%) under Ar and the reaction was stirred at 35 °C for 8 h under H2 (15 psi) atmosphere. The reaction 25 mixture was filtered. The filtrate was concentrated in vacuo to afford the title intermediate (280 mg, crude) as colorless oil. Preparation of intermediate 23 2026205213   01 Jul 2026 ethyl 6-(2-(ethyl(isopropyl)carbamoyl)-4-fluorophenoxy)-l,2,4-triazine-5-carboxylate To the mixture of ethyl 6-chloro-l,2,4-triazine-5-carboxylate (13 g, 69 mmol) and A-ethyl-5-fluoro-2-hydroxy-A-isopropylbenzamide (intermediate 28) (15.6 g, 69.3 mmol) in DMF (150 5 mL) was added K2CO3 (28.6 g, 204 mmol). The resulting mixture was stirred at RT for 2 h. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure to give the crude residue, which was diluted with water (100 mL) and extracted with EtOAc (100 mL x 2). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give the crude product, which was further purified by 10 FCC (PE / EtOAc = 1:0 to 1:1) to afford the title intermediate (30 g, 81% purity, 92% yield) as a yellow solid. Preparation of intermediate 24 6-(2-(ethyl(isopropyl)carbamoyl)-4-fluorophenoxy)-l,2,4-triazine-5-carboxylic acid To the mixture of ethyl 6-(2-(ethyl(isopropyl)carbamoyl)-4-fluorophenoxy)-l,2,4-triazine-5-carboxylate (intermediate 23) (8.6 g, 23 mmol) in THF (100 mL) and H2O (25 mL) was added LiOEEELO (2.0 g, 48 mmol) and the reaction mixture was stirred at RT for 1 h. The mixture was acidified with 0.5M HC1 to adjust the pH value to 5~6, and further extracted with 20 EtOAc (150 mL). The aqueous phase was purified by preparative HPLC over Boston Prime (column: C18 150x30 mm 5 um; eluent: ACN / H2O (0.225% FA) from 19% to 49%, v / v) to afford the title intermediate (5.0 g, 62% yield). Preparation of intermediates 187,188, 201, 202 25 (5)-3-((tert-butyldiphenylsilyl)oxy)-4-(ethyl(methyl)amino)butanoic acid (l?)-3-((tert-butyldiphenylsilyl)oxy)-4-(ethyl(methyl)amino)butanoic acid (5)-3-((tert-butyldiphenylsilyl)oxy)-4-((2-methoxyethyl)(methyl)amino)butanoic acid 2026205213   01 Jul 2026 (l?)-3-((tert-butyldiphenylsilyl)oxy)-4-((2-methoxyethyl)(methyl)amino)butanoic acid The following intermediates were synthesized by an analogous method as described above for intermediate 24 Int. No. Structure Starting Material Conditions 187 O H0"| | TBDPSO^^ intermediate 185 NaOH, THF / MeOH / H2O, RT 188 O 1 TBDPSO intermediate 186 NaOH, THF / MeOH / H2O, RT 201 O 1 / TBDPSO         O intermediate 199 NaOH, THF / EtOH / H2O, RT 202 O HO^> । TBDPSO'     ^^ 0 intermediate 200 NaOH, THF / MeOH / H2O, RT Preparation of intermediate 25 7V-ethyl-5-fluoro-2-((5-hydroxy-l,2,4-triazin-6-yl)oxy)-7V-isopropylbenzamide o Ag(Phen)2OTf, DCE 10 To the solution of 6-(2-(ethyl(isopropyl)carbamoyl)-4-fluorophenoxy)-l,2,4-triazine-5-carboxylic acid (intermediate 24) (50 mg, 0.14 mmol) and l,3-dibromo-l,3,5-triazinane-2,4,6-trione (50 mg, 0.17 mmol) in DCE (1 mL) was added Ag(Phen)2OTf (30 mg, 0.049 mmol) and the resulting mixture was stirred at RT for 2 h. The reaction mixture was filtered through a celite pad and washed with ACN (10 mL). The filtrate was concentrated under 15 reduced pressure to afford the crude product, which was further purified by preparative HPLC using a Xtimate (column: Cl8 150x40 mm 10 pm; eluent: ACN / H2O (0.2% FA) from 20% to 50% v / v) to afford the title intermediate (20 mg, 41%) as a white solid. 2026205213   01 Jul 2026 Preparation of intermediate 159 7V-ethyl-5-fluoro-7V-isopropyl-2-((5-(2,2,2-trifluoroethoxy)-l,2,4-triazin-6-yl)oxy)benzamide 4A molecular sieve (8 g) was added to the mixture of 6-(2-(ethyl(isopropyl)carbamoyl)-4-fluorophenoxy)-l,2,4-triazine-5-carboxylic acid (intermediate 24) (8.0 g, 23.0 mmol) in 2,2,2-trifluoroethan-l-ol (100 mL). The resulting mixture was stirred under N2 atmosphere at 70 °C for 1 h. Then cooled to RT and 1,3-dibromo-1,3,5-triazinane-2,4,6-trione (13.1 g, 45.7 10 mmol) was added to above mixture. The resulting mixture was further stirred under N2 atmosphere at RT overnight. The reaction mixture was filtered over a celite pad. The filtrate was concentrated under reduced pressure and the crude residue was purified by FCC (PE : EtOAc from 1:0 to 2:1) to afford the title intermediate (3.1 g, purity 84%, yield 28%) as a yellow solid. Preparation of intermediate 51 4-((terCbutyldimethylsilyl)oxy)butan-l-ol + TBDMSCI NaH,THF                o -------'TBDMS To the solution of butane-1,4-diol (5.00 g, 55.5 mmol) in THF (100 mL) cooled at 0 °C was 20 added NaH (1.55 g, 38.8 mmol, 60%), the resulting mixture was stirred at 0 °C for 20 min. Then TBDMSCI (5.85 g, 38.8 mmol) was added to the reaction mixture and the reaction was further stirred at 0 °C for additional 1 h. The mixture was quenched with water (80 mL) and extracted with EtOAc (80 mL x 3). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to afford the crude product which 25 was further purified by FCC (PE / EtOAc = 1:0 to 10:1) to afford the title intermediate (7.2 g, 63%) as a colorless liquid. 2026205213   01 Jul 2026 Preparation of intermediates 183,184 ethyl (5)-3-((tert-butyldiphenylsilyl)oxy)-4-iodobutanoate ethyl (l?)-3-((tert-butyldiphenylsilyl)oxy)-4-iodobutanoate 5 The following intermediates were synthesized by an analogous method as described above for intermediate 51 Int. No. Structure Starting Materials Conditions 183 O TBDPSCT^^1 TBDPSC1, intermediate 181 imidazole, DCM, RT 184 O A- TBDPSO' TBDPSC1, intermediate 182 imidazole, DCM, RT Preparation of intermediate 52 4-((tert-butyldimethylsilyl)oxy)butanal n            DMP,DCM           - n 10                      'TBDMS                              'TBDMS To the solution of 4-((terLbutyldimethylsilyl)oxy)butan-l-ol (intermediate 51) (7.20 g, 35.2 mmol) in DCM (200 mL) cooled at 0 °C was added DMP (22.4 g, 52.8 mmol) and the reaction mixture was slowly warmed to RT and stirred for 2 h. The reaction mixture was diluted with DCM (100 mL) and stirred with of sat. aq. (NaHCO3 / Na2SO3 = 1 / 1, 100 mL) for 15   2 min, the separated organic layer was washed with brine (100 mL x 3), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give the crude product which was further purified by FCC (PE / EtOAc = 1:0 to 12:1) to afford the title intermediate (2.95 g, 41%) as a colorless liquid. 20 Preparation of intermediate 54,145,146,158 6-((tert-butyldimethylsilyl)oxy)-2-methylhexan-3-one 2-((5-(2-(2,4-dimethyl-6-oxohexan-3-yl)-2,6-diazaspiro[3.4]octan-6-yl)-l, 2,4-triazin-6- yl)oxy)- V-ethyl-5-nuoro- V-isopropylbenzamide (mixture of R,S and S,R; or mixture of R,R and 5,5) 2026205213   01 Jul 2026 2-((5-(2-(2,4-dimethyl-6-oxohexan-3-yl)-2,6-diazaspiro[3.4]octan-6-yl)-l,2,4-triazin-6-yl)oxy)-7V-ethyl-5-fluoro-7V-isopropylbenzamide (mixture of R,R and S^S; or mixture of R,S and S,R) (K)-7V-ethyl-5-fluoro-7V-isopropyl-2-((5-(2-(2-methyl-6-oxoheptan-3-yl)-2,6- 5 diazaspiro[3.4]octan-6-yl)-l,2,4-triazin-6-yl)oxy)benzamide The following intermediates were synthesized by an analogous method described above for intermediate 52 Int. No. Structure Starting Material 54 / 0. CT— — TBDMS intermediate 53 145 mixture of R,S and S,R or mixture of R, / ?and S,S Compound 261 N 146 mixture of R, or mixture of R, rN WA N'N^ R and S,S S and S,R -O Compound 262 Int. No. Structure Starting Material 158 r-N*V / L / -P 0 Vr° 'n> (Tn « V n.n<J Compound 298 2026205213   01 Jul 2026 Preparation of intermediate 53 6-((tert-butyldimethylsilyl)oxy)-2-methylhexan-3-ol O         □. Mn / THF        | OX       TBDMS B| / g \          HO^^^^°'TBDMS 5 To the solution of 4-((terLbutyldimethylsilyl)oxy)butanal (intermediate 52) (1.00 g, 4.94 mmol) in THF (4.9 mL) cooled at -20 °C under N2 atmosphere was added dropwise isopropylmagnesium bromide (4.94 mL, 14.8 mmol, 3 M in THF) and the reaction mixture was slowly warmed to RT and stirred for 2 h. The mixture was quenched with sat. aq. NH4CI (20 mL), and extracted with EtOAc (50 mL x 3). The combined organic layers were dried 10 over anhydrous Na2SO4, filtered, and concentrated in vacuo to give the crude product which was further purified by FCC (PE / EtOAc = 1:0 to 20:1) to afford the title intermediate (580 mg, 48%) as a white oil. Preparation of intermediates 16, 21, 39, 47, 55, 94, 98,161,163 15   2-((5-(2-(1-(1,3-dioxoisoindolin-2-yl)-3-methylbutan-2-yl)-2,6-diazaspiro[3.4]octan-6-yl)- l,2,4-triazin-6-yl)oxy)-A-ethyl-5-fluoro-A-isopropylbenzamide benzyl 2-(l-((tert-butoxycarbonyl)amino)-4-methylpentan-3-yl)-2,6-diazaspiro[3.4]octane-6-carboxylate benzyl (5-(6-(6-(2-(ethyl(isopropyl)carbamoyl)-4-fluorophenoxy)-l,2,4-triazin-5-yl)-2,6- 20 diazaspiro[3.4]octan-2-yl)-2,6-dimethylheptan-2-yl)(methyl)carbamate methyl 4-(6-(6-(2-(4-cyclopropylpyrimidin-5-yl)-4-fluorophenoxy)-l,2,4-triazin-5-yl)-2,6-diazaspiro[3.4]octan-2-yl)-5-methylhexanoate 2-((5-(2-(6-((tert-butyldimethylsilyl)oxy)-2-methylhexan-3-yl)-2,6-diazaspiro[3.4]octan-6-yl)-l,2,4-triazin-6-yl)oxy)-A-ethyl-5-fluoro-A-isopropylbenzamide 2026205213   01 Jul 2026 2-((5-(2-(1-(1,3-dioxolan-2-yl)-4-methylpentan-3-yl)-2,6-diazaspiro[3.4]octan-6-yl)-l,2,4-triazin-6-yl)oxy)-7V-ethyl-5-fluoro-7V- isopropylbenzamide 2-((5-(2-(1-(1,3-dioxolan-2-yl)-4-methylpentan-3-yl)-2,6-diazaspiro[3.4]octan-6-yl)-l, 2,4-triazin-6-yl)oxy)-5-fluoro-A^V-diisopropylbenzamide 5 7V-methoxy-4-((2-methoxyethyl)(methyl)amino)-7V-methylbutanamide tert-butyl 6-(6-((2-methoxyethyl)(methyl)amino)-2-methylhexan-3-yl)-2,6- diazaspiro[3.4]octane-2-carboxylate The following intermediates were synthesized by an analogous method as described for 10 Compound 60 and Compound 61 Int. No. Structure Starting Materials Conditions 16 5=\     \ o i J. O o intermediate 3, intermediate 15 ZnCh, NaBH3CN, MeOH, 65 °C 21 Zn^ ^NH Boc N Cbz intermediate 20, benzyl 2,6-diazaspiro[3,4]octan e-6-carboxylate AcOH, NaBH3CN, MeOH, 45 °C 39 r rr / N-Cbz XJ N. J intermediate 3, intermediate 38 ZnCh, NaBH3CN, MeOH, 65 °C 2026205213   01 Jul 2026 Int. No. Structure Starting Materials Conditions 47 \ rN^M° N^N / —V1    0 A°A intermediate 59 intermediate 46 ZnCh, NaBH3CN, MeOH, 80 °C 55 )--1 O-TBDMS r A5 ^NyO Q o° Yn N.^ intermediate 3, intermediate 54 ZnCh, NaBH3CN, MeOH, 80 °C 94 —( O oA> intermediate 3, intermediate 93 AcOH, NaBH3CN, MeOH, 45 °C 98 "A <Ap intermediate 85, intermediate 93 AcOH, NaBH3CN, MeOH, 60 °C 161 i N N O            1 intermediate 160, 1,1,2-trimethoxy ethane, HC1 AcOH, NaBH3CN, EtOH, RT 2026205213   01 Jul 2026 Int. No. Structure Starting Materials Conditions 163 / —\  N- /  \ N 1 Boc intermediate 162, tert-butyl 2,6-diazaspiro[3,4]octan e-2-carboxylate NaOAc, NaBH3CN, MeOH, 55 °C Preparation of intermediate 17 and 18 (*lf)-2-((5-(2-(l-(l,3-dioxoisoindolin-2-yl)-3-methylbutan-2-yl)-2,6-diazaspiro[3.4]octan-6-yl)-l,2,4-triazin-6-yl)oxy)-7V-ethyl-5-fluoro-7V-isopropylbenzamide 5 (*3)-2-((5-(2-(l-(l,3-dioxoisoindolin-2-yl)-3-methylbutan-2-yl)-2,6-diazaspiro[3.4]octan-6-yl)-l,2,4-triazin-6-yl)oxy)-7V-ethyl-5-fluoro-7V-isopropylbenzamide 2-((5-(2-(l-(l,3-dioxoisoindolin-2-yl)-3-methylbutan-2-yl)-2,6-diazaspiro[3.4]octan-6-yl)-l,2,4-triazin-6-yl)oxy)-A-ethyl-5-fluoro-A-isopropylbenzamide (intermediate 16) (200 mg, 10   0.254 mmol) was purified by SFC over DAICEL CHIRALCEL OD (column: 250x50 mm 10pm; Mobile phase: A: Supercritical CO2, B: IPA (0.1% ammonia), A:B =65:35 at 70 mL / min; Column Temp: 38 °C; Nozzle Pressure: 100 Bar; Nozzle Temp: 60 °C; Evaporator Temp: 20 °C; Trimmer Temp: 25 °C; Wavelength: 220 nm) to afford the title intermediates intermediate 17 (100 mg, 95% purity, 42% yield) and intermediate 18 (100 mg, 99% purity, 15    44% yield) both as colorless oil. 2026205213   01 Jul 2026 Preparation of intermediate 40 and 41 benzyl (*l?)-(5-(6-(6-(2-(ethyl(isopropyl)carbamoyl)-4-fluorophenoxy)-l ,2,4-triazin-5-yl)- 2,6-diazaspiro[3.4]octan-2-yl)-2,6-dimethylheptan-2-yl)(methyl)carbamate benzyl (*5)-(5-(6-(6-(2-(ethyl(isopropyl)carbamoyl)-4-fluorophenoxy)-l,2,4-triazin-5-yl)- 5 2,6-diazaspiro[3.4]octan-2-yl)-2,6-dimethylheptan-2-yl)(methyl)carbamate benzyl (5-(6-(6-(2-(ethyl(isopropyl)carbamoyl)-4-fluorophenoxy)-l,2,4-triazin-5-yl)-2,6-diazaspiro[3,4]octan-2-yl)-2,6-dimethylheptan-2-yl)(methyl)carbamate (intermediate 39) (650 mg, 0.923 mmol) was separated by SFC over DAICEL CHIRALPAK AD-H (column: 10   250x30mm 5pm; eluent: 30% (v / v) super critical CO2 in EtOH (0.1% ammonia), flow rate: 60 mL / min) to afford the title intermediates intermediate 40 (250 mg, 96% purity, 37% yield) and intermediate 41 (220 mg, 99.9% purity, 34% yield) both as a colorless oil. Preparation of intermediate 48 and 49 15 methyl (*l?)-4-(6-(6-(2-(4-cyclopropylpyrimidin-5-yl)-4-fluorophenoxy)-l,2,4-triazin-5-yl)-2,6-diazaspiro[3.4]octan-2-yl)-5-methylhexanoate methyl (*5)-4-(6-(6-(2-(4-cyclopropylpyrimidin-5-yl)-4-fluorophenoxy)-l,2,4-triazin-5- yl)-2,6-diazaspiro[3.4]octan-2-yl)-5-methylhexanoate 2026205213   01 Jul 2026 methyl 4-(6-(6-(2-(4-cyclopropylpyrimidin-5-yl)-4-fluorophenoxy)-l,2,4-triazin-5-yl)-2,6-diazaspiro[3.4]octan-2-yl)-5-methylhexanoate (intermediate 47) (360 mg, 0.513 mmol) was purified by SFC over Phenomenex-Cellulose-2 (column: 250x30mm, 10pm; eluent: 35% 5   (v / v) supercritical CO2 in MeOH with 0.1% ammonia) to afford the title intermediates intermediate 48 (110 mg, 35% yield) and intermediate 49 (90 mg, 31% yield) both as white solid. Preparation of intermediate 93 10   1-(1,3-dioxolan-2-yl)-4-methylpentan-3-one To the mixture of magnesium (6.0 g, 247 mmol) and iodine (100 mg, 0.394 mmol) in THF (70 mL) at 25 °C was slowly added a solution of 2-(2-bromoethyl)-1,3-dioxolane (20.0 g, 110 mmol) in THF (30 mL), the resulting mixture was stirred at 25 °C for 1 h. Then, the mixture 15 was slowly added to the solution of 7V-methoxy-7V-methylisobutyramide (10 g, 76.2 mmol) in THF (100 mL) cooled at 0 °C. The reaction mixture was slowly warmed to 25 °C and stirred at this temperature for 8 h. The mixture was quenched by sat. aq. NH4CI (300 mL), extracted with MTBE (200 mL x 3). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure to give the crude product, which was purified by FCC 20 (PE:EtOAc = 1:0 to 20:1) to afford the title intermediate (13 g, crude) as colorless oil which was used directly in next step without further purification. 2026205213   01 Jul 2026 Preparation of intermediate 95 and 96 (ft)-2-((5-(2-(l-(l,3-dioxolan-2-yl)-4-methylpentan-3-yl)-2,6-diazaspiro[3.4]octan-6-yl)-l,2,4-triazin-6-yl)oxy)-7V-ethyl-5-fluoro-7V-isopropylbenzamide 5   (3)-2-((5-(2-(1-(1,3-dioxolan-2-yl)-4-methylpentan-3-yl)-2,6-diazaspiro[3.4]octan-6-yl)- l,2,4-triazin-6-yl)oxy)-7V-ethyl-5-fluoro-7V-isopropylbenzamide 2-((5-(2-(l-(l,3-dioxolan-2-yl)-4-methylpentan-3-yl)-2,6-diazaspiro[3.4]octan-6-yl)-l,2,4-triazin-6-yl)oxy)-7V-ethyl-5-fluoro-A-isopropylbenzamide (intermediate 94) (4.00 g, 7.01 10 mmol) separated by SFC over DAICEL CHIRALCEL OD (column: 250x50mm lOum; Mobile phase: A: Supercritical CO2, B: MeOH (0.1% ammonia), A:B = 75:25 at 200 mL / min; Column Temp: 38 °C; Nozzle Pressure: 100 Bar; Nozzle Temp: 60 °C; Evaporator Temp: 20 °C; Trimmer Temp: 25 °C; Wavelength: 220 nm) to afford the title intermediates intermediate 95 (1.72 g, 98.76% purity, 42.5% yield) and intermediate 96 (1.57 g, 98.09% 15 purity, 38.5% yield) as white solid. Preparation of intermediate 99 and 100 (*l?)-2-((5-(2-(l-(l,3-dioxolan-2-yl)-4-methylpentan-3-yl)-2,6-diazaspiro[3.4]octan-6-yl)-1,2,4-triazin-6-yl)oxy)-5-fluoro-A^V-diisopropylbenzamide 20   (*3)-2-((5-(2-(l-(l,3-dioxolan-2-yl)-4-methylpentan-3-yl)-2,6-diazaspiro[3.4]octan-6-yl)- 1,2,4-triazin-6-yl)oxy)-5-fluoro-A^V-diisopropylbenzamide 2026205213   01 Jul 2026 2-((5-(2-(1-(1,3-dioxolan-2-yl)-4-methylpentan-3-yl)-2,6-diazaspiro[3.4]octan-6-yl)-l,2,4- triazin-6-yl)oxy)-5-fluoro-A,A-diisopropylbenzamide (intermediate 98) (6.5 g) was separated by SFC over DAICEL CHIRALPAK IG (column: 250x50mm lOum; Mobile phase: A: 5 Supercritical CO2, B: MeOH (0.1% ammonia), A:B = 65:35 at 200 mL / min; Column Temp: 38 ; Nozzle Pressure: lOOBar; Nozzle Temp: 60 °C; Evaporator Temp: 20 °C; Trimmer Temp: 25 °C; Wavelength: 220nm) to afford the title intermediates intermediate 99 (2.7 g) and intermediate 100 (2.8 g). 10 Preparation of intermediate 97 (l?)-A-ethyl-5-fluoro-A-isopropyl-2-((5-(2-(2-methyl-6-oxohexan-3-yl)-2,6- diazaspiro[3.4]octan-6-yl)-l,2,4-triazin-6-yl)oxy)benzamide To a solution of (A)-2-((5-(2-(l-(l,3-dioxolan-2-yl)-4-methylpentan-3-yl)-2,6- 15 diazaspiro[3.4]octan-6-yl)-l,2,4-triazin-6-yl)oxy)-A-ethyl-5-fluoro-A-isopropylbenzamide (intermediate 95) (1.00 g, 1.75 mmol) in ACN (10 mL) was added IM HC1 (10.0 mL, 10.0 mmol) and the resulting mixture was stirred at 50 °C for 1 h. After cooling to RT, the reaction mixture was concentrated under reduced pressure. The resulting residue was diluted with 2026205213   01 Jul 2026 DCM (50 mL) and basified to pH = 14 by 10% aq. NaOH. The mixture was further extracted by DCM (30 mL x 3) and the combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated in vacuo to afford the title intermediate (900 mg, 87% purity, 85% yield) as a white solid, which was used directly in next step without further purification. 5 Preparation of intermediates 101,102,103 (*7?)-5-fluoro-A^^V-diisopropyl-2-((5-(2-(2-methyl-6-oxohexan-3-yl)-2,6-diazaspiro[3.4]octan-6-yl)-l,2,4-triazin-6-yl)oxy)benzamide (*5)-5-fluoro-A^^V-diisopropyl-2-((5-(2-(2-methyl-6-oxohexan-3-yl)-2,6- 10 diazaspiro[3.4]octan-6-yl)-l,2,4-triazin-6-yl)oxy)benzamide 7V-ethyl-5-fluoro-7V-isopropyl-2-((5-(2-(2-methyl-6-oxohexan-3-yl)-2,6-diazaspiro[3.4]octan-6-yl)-l,2,4-triazin-6-yl)oxy)benzamide 15 The following intermediates were synthesized by an analogous method as described for intermediate 97 Int. No. Structure Starting Material 101 o intermediate 99 102 o 3^0 intermediate 100 2026205213   01 Jul 2026 Preparation of intermediate 114 methyl 2-(2-isopropyl-l,3-dioxolan-2-yl)acetate 9 9          (ch2oh)2, p-tsoh«h2o               o |         0           toluene, 135°C, 18 h            \    ' 1                                                                 \ O 5 In a 1000 mL flask equipped with a Dean-Stark apparatus, methyl 4-methyl-3-oxopentanoate (50 g, 347 mmol) was added to a solution consisting of ethane- 1,2-diol (43 g, 693 mmol), / >-toluenesulfonic acid monohydrate (597 mg, 3.47 mmol) and toluene (500 mL). The mixture was stirred at 135°C for 18 h. After cooling to RT, IM Na2CCh (300 mL) aqueous solution was added to the reaction mixture. The organic layer was separated and washed with H2O 10   (100 mL), dried over anhydrous Na2SO4, filtered, and concentrated in vacuo to afford the title intermediate (41 g, crude) as a yellow oil which was used directly in next step without further purification. Preparation of intermediate 115 15   2-(2-isopropyl-l,3-dioxolan-2-yl)ethan-l-ol °\ / 0 0        LiAIH4, THF       °y° ' O—                        ' OH LiAlH4 (2.5 g, 66 mmol) was added in portions to THF (250 mL) cooled at 0°C under N2 atmosphere. A solution of methyl 2-(2-isopropyl-l,3-dioxolan-2-yl)acetate (intermediate 114) (10 g, crude) in THF (20 mL) was added drop-wise to above mixture at 0°C under N2 20 atmosphere. The resulting mixture was slowly warmed to RT and stirred at this temperature for 18 h under N2 atmosphere. Then 2.5 mL H2O was slowly added to above mixture, followed with addition of aq. NaOH solution (15%, 7.5 mL). The resulting mixture was 2026205213   01 Jul 2026 stirred at RT for 0.5 h. Then anhydrous MgSO4 was added to above mixture. The suspension was filtered through a celite pad and washed with THF (200 mL). The filtrate was concentrated in vacuo to afford the title intermediate (6.8 g, crude) as a yellow oil which was used directly in next step without further purification. 5 Preparation of intermediate 116 l-hydroxy-4-methylpentan-3-one Oxalic acid (4.2 mL, 10% in water, 4.7 mmol) was added to a mixture of silica gel (27 g, 449 10 mmol) in DCM (230 mL). Once the aqueous layer vanished, a solution of 2-(2-isopropyl-l,3-dioxolan-2-yl)ethan-l-ol (intermediate 115) (3.7 g, crude) in DCM (7 mL) was added and the reaction mixture was stirred at RT for 5 h. Then NaHCOs (800 mg) was added. The resulting mixture was filtered and washed with DCM (50 mL x 3). The filtrate was concentrated in vacuo to afford the title intermediate (2.4 g, crude) as a colorless oil which 15 was used directly in next step without further purification. Preparation of intermediate 124 (*l?)-3-(6-(6-(2-(ethyl(isopropyl)carbamoyl)-4-fluorophenoxy)-l,2,4-triazin-5-yl)-2,6- diazaspiro[3.4]octan-2-yl)-4-methylpentyl methanesulfonate MsCl (250 mg, 2.18 mmol) was added dropwise to a solution of 7V-ethyl-5-fluoro-2-((5-(2-(l-hydroxy-4-methylpentan-3-yl)-2,6-diazaspiro[3.4]octan-6-yl)-l,2,4-triazin-6-yl)oxy)-7V-isopropylbenzamide (Compound 213) (500 mg, 0.972 mmol) and TEA (0.27 mL, 1.9 mmol) 25 in DCM (10 mL) cooled at 0 °C under N2 atmosphere. The resulting mixture was stirred at 0 °C under N2 for 45 min. Then the reaction mixture was quenched with H2O (5 mL) and extracted with DCM (10 mL x 3). The combined organic layers were washed with brine (5 2026205213   01 Jul 2026 mL), dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated in vacuo to afford the title intermediate (400 mg, crude) as a yellow oil which was used directly in next step without further purification. 5 Preparation of intermediate 130,139 methyl 3-methyl-4-(tosyloxy)butanoate 2-methoxypropyl 4-methylbenzenesulfonate The following intermediates were synthesized by an analogous method as described above for intermediate 124 10 Int. No. Structure Starting Materials Conditions 130 O —o )\ ' OTs intermediate 129, TsCl DMAP, TEA, DCM, RT 139 \     ,OTs O 2-methoxypropan-l -ol, TsCl DMAP, TEA, DCM, RT Preparation of intermediate 125 A-benzyl-2-methoxy-Amethylacetamide O To a solution of A-methyl-l-phenylmethanamine (5.5 g, 45.4 mmol) and TEA (14g, 138.4 mmol) in DCM (60 mL) cooled at 0 °C was dropwise added 2-methoxyacetyl chloride (5 g, 46.073 mmol). The resulting mixture was slowly warmed to 25 °C and stirred at this temperature for 1 h. Then, aq. sat. NaHCOs solution (50 mL) was added to above mixture and 20 extracted with DCM (50 mL x 3). The combined organic layers were washed with brine (100 mL), dried over Na2SO4, filtered and concentrated in vacuo give a crude residue which was purified by FCC (EA:PE = from 0 to 80%) to afford the title intermediate (3.4 g, 34% yield) as a colorless oil. 2026205213   01 Jul 2026 Preparation of intermediate 126 A-benzyl-2-methoxy-A-methylethan-l-amine-l,l-^2 To the mixture of Li Al D4 (1.5 g, 35.732 mmol) in THF (25 mL) cooled at 0 °C under N2 5 atmosphere was added dropwise a solution of A-benzyl-2-methoxy-A-methylacetamide (intermediate 125) (3.4 g, 17.6 mmol) in THF (25 mL). The reaction mixture was first stirred at 25 °C for 1 h and at 50 °C for additional 2 h. Then the reaction mixture was cooled to 0 °C and quenched with aq. NaOH (1 M, 10 mL) dropwise. The resulting mixture was filtered and the filter cake was washed with EtOAc (100 mL). The filtrate was washed with H2O (50 mL) 10 and brine (50 mL), dried over Na2SO4, and filtered. The solvent was concentrated under reduced pressure to afford a residue which was purified by FCC (EtOAc:PE = from 0 to 100%) to afford the title intermediate (2.0 g, 60% yield) as a colorless oil. Preparation of intermediate 127 15 2-methoxy-7V-methylethan-l,l-< / 2-l-amine, hydrochloride D D Pd / C, H2          dvd HCI salt To the solution of A-benzyl-2-methoxy-A-methylethan-1 -amine- 1,1-tfe (800 mg, 4.413 mmol) in MeOH (20 mL) and THF (60 mL) was added 1,1,2-trichloroethane (1.2 g, 9.0 mmol) and Pd / C (wet, 10%, 0.5 g). The resulting mixture was stirred under H2 atmosphere (50 psi) at 20    50 °C for 18 h. After cooling to RT, the reaction mixture was filtered by celite and the filtrate was concentrated in vacuo to afford the title intermediate (600 mg, crude) as yellow oil which was used directly in next step without further purification. Preparation of intermediate 128 25 methyl 4-hydroxy-3-methylbut-2-enoate 2026205213   01 Jul 2026 t-BuOK (16.0 g, 143 mmol) was added to a solution of (2-methoxy-2-oxoethyl)triphenylphosphonium bromide (59.0 g, 142 mmol) in THF (220 mL). The resulting mixture was stirred at 50 °C for 1 h. Then l-hydroxypropan-2-one (7.2 g, 97 mmol) in THF 5   (30 mL) was added to above mixture and the reaction mixture was stirred at 50 °C for another 16 h. After cooling to RT, H2O (200 mL) was added and the mixture was extracted with EtOAc (200 mL x 3). The combined organic layers were washed with H2O (300 mL), dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated to in vacuo to afford a crude compound which was purified by FCC (PE: EtOAc = 1:0 to 1:1) to afford the title 10 intermediate (3.4 g, 27% yield ) as a light yellow oil. Preparation of intermediate 129 methyl 4-hydroxy-3-methylbutanoate O,                                         O, A__           Pd / C, H2, MeOH A__v ——O \—\ / OH                          / OH 15 To the solution of methyl 4-hydroxy-3-methylbut-2-enoate (intermediate 128) (3.4 g, 26 mmol) in MeOH (100 mL) was added dry Pd / C (500 mg, 10%) and the suspension was stirred at RT under H2 (15 psi) atmosphere for 4 h. Then the reaction mixture was filtered through a celite pad and washed with MeOH (200 mL). The filtrate was concentrated in vacuo afford the title intermediate (2.3 g, 67% yield) as a yellow oil which was used directly in the next 20 step without further purification. Preparation of intermediates 193,194, 207, 208 (5)-5-((tert-butyldiphenylsilyl)oxy)-6-(ethyl(methyl)amino)-2-methylhexan-3-one (K)-5-((tert-butyldiphenylsilyl)oxy)-6-(ethyl(methyl)amino)-2-methylhexan-3-one 25 (3)-5-((tert-butyldiphenylsilyl)oxy)-6-((2-methoxyethyl)(methyl)amino)-2-methylhexan-3-one (K)-5-((tert-butyldiphenylsilyl)oxy)-6-((2-methoxyethyl)(methyl)amino)-2-methylhexan-3-one 2026205213   01 Jul 2026 The following intermediates were synthesized by an analogous method as described for intermediate 129 Int. No. Structure Starting Material 193 O TBDPSO ^^ intermediate 191 194 O TBDPSO intermediate 192 207 O LI 1 TBDPSO*^^ N ^^^0^ intermediate 205 208 O 11 । / TBDPSO'          0 intermediate 206 Preparation of intermediate 131 and 132 5 methyl (*l?)-3-methyl-4-(tosyloxy)butanoate methyl ( *3)-3-methyl-4-(tosyloxy)butanoate o                          o                    o intermediate 130               intermediate 131         intermediate 132 Methyl 3-methyl-4-(tosyloxy)butanoate (intermediate 130) (3.3 g) was purified by SFC over DAICEL CHIRALPAK AY-H (column: 250x30mm 5um; Mobile phase: A: Supercritical 10 CO2, B: EtOH (0.1% ammonia), A:B = 90:10 at 60 mL / min) to afford the title intermediates (intermediate 131) (1.28 g, 97% purity, 36 % yield) and (intermediate 132) (1.27 g, 85% purity, 33 % yield) both as white solid. Preparation of intermediate 134 15 methyl ( *5)-4-((2-methoxyethyl)(methyl)amino)-3-methylbutanoate 2026205213   01 Jul 2026 A mixture of methyl (*5)-3-methyl-4-(tosyloxy)butanoate (intermediate 132) (1.27 g, 4.44 mmol), 2-methoxy-A-methylethan-l-amine (593 mg, 6.65 mmol), and K2CO3 (1.23 mg, 8.87 mmol) in ACN (5 mL) was stirred at 90 °C overnight. After cooling to RT, the reaction mixture was filtered and the filtrate was concentrated in vacuo to afford the title intermediate 5   (670 mg, crude) as a brown oil which was used directly in next step without further purification. 10 Preparation of intermediates 133,185,186,199, 200, 219 methyl (*l?)-4-((2-methoxyethyl)(methyl)amino)-3-methylbutanoate ethyl (5)-3-((tert-butyldiphenylsilyl)oxy)-4-(ethyl(methyl)amino)butanoate ethyl (l?)-3-((tert-butyldiphenylsilyl)oxy)-4-(ethyl(methyl)amino)butanoate ethyl (5)-3-((tert-butyldiphenylsilyl)oxy)-4-((2-methoxyethyl)(methyl)amino)butanoate ethyl (l?)-3-((tert-butyldiphenylsilyl)oxy)-4-((2-methoxyethyl)(methyl)amino)butanoate A-(2-methoxyethyl)-A,2-dimethylprop-2-en-l-amine The following intermediates were synthesized by an analogous method as described for intermediate 134 Int. No. Structure Starting Materials Conditions 133 Fa / \ / —O )—' / *R intermediate 131, 2-m ethoxy-A-methylethan-1 -amine K2CO3, ACN, 90 °C 185 O A । TBDPSO ^^ intermediate 183, A-methylethanamine K2CO3, ACN, 80 °C 186 O ! TBDPSO intermediate 184, A-methylethanamine K2CO3, ACN, 80 °C 199 O ! / TBDPSO^        O intermediate 183, 2-m ethoxy-A-methylethan-1 -amine K2CO3, ACN, 85 °C 2026205213   01 Jul 2026 Int. No. Structure Starting Materials Conditions 200 O ! TBDPSO —     O intermediate 184, 2-m ethoxy-A-methyl ethan-1 -amine K2CO3, ACN, 85 °C 219 1 1 3 -bromo-2-methylprop-1 -ene, 2-m ethoxy-A-methyl ethan-1 -amine K2CO3, H2O, RT Preparation of intermediate 136 (*5)-6-((2-methoxyethyl)(methyl)amino)-2,5-dimethylhexan-3-one 5 To the solution of methyl (*5)-4-((2-methoxyethyl)(methyl)amino)-3-methylbutanoate (intermediate 134) (670 mg, crude) in THF (5 mL) cooled at 0 °C under N2 was added dropwise isopropylmagnesium chloride (4.94 mL, 9.88 mmol, 2 M, in THF). The resulting mixture was stirred at 50 °C for 5 h under N2. After cooling to RT, the reaction mixture was quenched with sat. aq. NH4CI solution (1.5 mL) and filtered. The filtrate was concentrated in 10 vacuo to afford the title intermediate (507.1 mg, crude) as a yellow oil which was used directly in next step without further purification. Preparation of intermediate 135 (*l?)-6-((2-methoxyethyl)(methyl)amino)-2,5-dimethylhexan-3-one 15 The following intermediate was synthesized by an analogous method as described for intermediate 136 Int. No. Structure Starting Materials Conditions 135 ( \ A-R / N^\ / 0 y17 ^0 intermediate 133, isopropylmagnesium chloride THF, 50 °C Preparation of intermediate 165 tert-butyl (2-hydroxy-5-methyl-4-oxohexyl)(methyl)carbamate 2026205213   01 Jul 2026 LDA, THF -----► To the solution of 3-methylbutan-2-one (6.0 g, 70.0 mmol) in THF (150 mL) cooled at -40 °C under N2 atmosphere was added dropwise LDA (40 mL, 2 M in THF, 80.0 mmol). The resulting mixture was stirred at -40 °C for 1 h. Then a solution of tert-butyl methyl(2- 5 oxoethyl)carbamate (8.0 g, 46.2 mmol) in THF (50 mL) was added dropwise to above mixture and the reaction was further stirred at -40 °C for 2 h. The reaction was quenched by the dropwise addition of H2O (20 mL) at -40 °C. Then the mixture was warmed to RT and concentrated under reduced pressure. The crude residue was diluted with H2O (200 mL) and extracted with EtOAc (200 mL x 2). The combined organic layers were washed with brine 10   (200 mL), dried over anhydrous Na2SO4, filtered and concentrated. The crude product was purified by FCC (PE / EtOAc = 20 / 1 to 3 / 1) to afford the title intermediate (8.8 g, 85% purity, 62% yield) as colorless oil. The following intermediate was synthesized by an analogous method as described for 15 intermediate 165 Int. No. Structure Starting Materials 174 O OH Y        Boc 3 -methylbutan-2-one, tert-butyl ethyl(2-oxoethyl)carbamate Preparation of intermediate 166 tert-butyl (2-methoxy-5-methyl-4-oxohexyl)(methyl)carbamate trimethyloxonium tetrafluoroborate                x II ।    |               1,8-bis(dimethylamino)naphthalene              9   9 I N' 0      ----------------------------►    \ AL A. N - HP           Boc                                                      — Boc 2Q I                                   4A MS, DCM                     I To a solution of tert-butyl (2-hydroxy-5-methyl-4-oxohexyl)(methyl)carbamate (intermediate 165) (4.00 g, 15.4 mmol) in DCM (200 mL) was added 4 A molecular sieve (4 g) under N2 atmosphere and the mixture was stirred at 25 °C for 10 min. Then 1,8-bis(dimethylamino)naphthalene (8.26 g, 38.6 mmol) was added and the mixture was cooled to 25   0 °C, followed with addition of trimethyloxonium tetrafluoroborate (5.93 g, 40.1 mmol). The reaction mixture was first stirred at 0 °C for 2 h, then warmed up to 25 °C and stirred at this 2026205213   01 Jul 2026 temperature for additional 16 h. The suspension was filtered and washed with DCM (40 mL x 2). The filtrate was concentrated in vacuo and the residue was purified by FCC (PE / EtOAc = 5 / 1 to 4 / 1) to afford the title intermediate (2.00 g, 44% yield) as colorless oil. 5 Preparation of intermediate 181 ethyl (5)-3-hydroxy-4-iodobutanoate EtOH, TMSI EtOH / DCM To a solution of (5)-4-hydroxydihydrofuran-2(3J7)-one (5 g, 50.0 mmol) in EtOH (8.6 mL) in DCM (20 mL) under N2 atmosphere was slowly added TMSI (14.8 g, 74.0 mmol). The 10 resulting mixture was stirred at RT for 16 h. A solution of sat. Na2SO3 (40 mL) was added. The organic layer was separated and concentrated in vacuo to afford the title intermediate (8.8 g, crude) as yellow oil which was used directly in next step without further purification. Preparation of intermediate 182 15 ethyl (l?)-3-hydroxy-4-iodobutanoate The following intermediate was synthesized by an analogous method as described above for intermediate 181 Int. No. Structure Starting Material 182 O HO' (A)-4-hydroxydihydrofuran-2(3J7)-one Preparation of intermediate 195 20 (5)-6-(ethyl(methyl)amino)-5-hydroxy-2-methylhexan-3-one To a solution of (S)-5-((terLbutyldiphenylsilyl)oxy)-6-(ethyl(methyl)amino)-2-methylhexan-3-one (intermediate 193) (2.33 g, 5.04 mmol) in THF (3 mL) was added TBAF (0.65 mL, 1.0 M in THF, 0.65 mmol) under N2 atmosphere. The resulting mixture was stirred at RT for 25    16 h. The reaction mixture was concentrated under reduced pressure and the crude residue 2026205213   01 Jul 2026 was diluted with H2O (25 mL) and extracted with DCM (60 mL x 3). The combined organic layers were washed with brine (40 mL x 2), dried over Na2SO4 and filtered. The filtrate was concentrated in vacuo to afford the title intermediate (2.2 g, crude) as yellow oil which was used directly in next step without further purification. Preparation of intermediate 196, 209, 210 (K)-6-(ethyl(methyl)amino)-5-hydroxy-2-methylhexan-3-one (5)-5-hydroxy-6-((2-methoxyethyl)(methyl)amino)-2-methylhexan-3-one (K)-5-hydroxy-6-((2-methoxyethyl)(methyl)amino)-2-methylhexan-3-one The following intermediates were synthesized by an analogous method as described above for intermediate 195 Int. No. Structure Starting Material 196 O OH । intermediate 194 209 O OH । intermediate 207 210 O OH । intermediate 208 Preparation of intermediate 220 15 7V-((3-isopropyl-5-methyl-4,5-dihydroisoxazol-5-yl)methyl)-2-methoxy-7V-methylethan-l-amine To a solution of 7V-(2-methoxyethyl)-7V,2-dimethylprop-2-en-l-amine (intermediate 219) (2.90 g, 20.2 mmol) in DMF (50 mL) cooled at 0 °C were added NaHCOs (6.82 g, 81.2 20 mmol) and (Z)-7V-hydroxyisobutyrimidoyl chloride (2.47 g, 20.3 mmol). The reaction mixture was stirred at 0 °C for 30 min and then at RT for 16 h. The reaction mixture was quenched by 2026205213   01 Jul 2026 H2O (50 mL) and extracted with EtOAc (30 mL x 2). The combined organic layers were washed with sat. aq. LiCl solution (50 mL), dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated in vacuo to give the crude product, which was purified by FCC (MeOH: DCM = 1:10) to afford the title intermediate (1.20 g, 89.9% purity, 25.9% yield) as 5 brown oil. Preparation of intermediate 221 5-hydroxy-6-((2-methoxyethyl)(methyl)amino)-2,5-dimethylhexan-3-one Raney Ni, H2 AcOH, H2O / MeOH / THF 10 To a solution of A-((3-isopropyl-5-methyl-4,5-dihydroisoxazol-5-yl)methyl)-2-methoxy-7V-methylethan-1-amine (intermediate 220) (1.20 g, 5.26 mmol) in MeOH and THF (40 mL, MeOH / THF = 1 / 2) were added AcOH (3.15 g, 52.5 mmol) and H2O (9.50 mL, 572.3 mmol). Raney-Ni (750 mg) was added to the solution under N2 atmosphere at 0 °C. The suspension was degassed and purged with H2 for 3 times and the mixture was stirred under H2 15 atmosphere (30 Psi) at 25 °C overnight. The reaction mixture was filtered through a celite pad and the filtrate was extracted with DCM. The combined organic layers were washed with NaHCO, (20 mL x 2) and brine (20 mL x 2), dried over Na2SO4 and filtered. The filtrate was concentrated in vacuo to afford the title intermediate (1.10 g, crude) as brown oil, which was used directly in next step without 20 further purification. Preparation of intermediate 227 tert-butyl (l?)-(l-(2,2-dimethyl-4,6-dioxo-l,3-dioxan-5-yl)-3-methylbutan-2-yl)carbamate O 25 Boc-L-valine (44.9 kg), 2,2-dimethyl-l,3-dioxane-4,6-dione (32.9 kg) and DMAP (35.5 kg) in DCM (607 kg) pre-cooled at -10 to 0°C were added to a solution of DCC (55.5 kg) in DCM (613 kg) over 3 h and aged for 16 h at -10 to 0°C. 10% citric acid aqueous solution (449 kg) was added whilst maintaining a temperature below 10°C. The resulting slurry was aged for 2 h 2026205213   01 Jul 2026 at 0 to 10°C. then filtered. The filter cake was washed with DCM (91 kg). The filtrate was separated and the organic layer was washed with 10% citric acid aqueous solution (two times 450 kg) and 10% NaCl aqueous solution (449 kg). To organic phase (1200 kg), was added acetic acid (75.0 kg) whilst maintaining a temperature between -10 to 0°C. Sodium Borohydride 5   (18.0 kg) was added in portions over 5 h whilst maintaining a temperature in the range -10 to 0°C and then resulting mixture was aged at -10 to 0°C for an additional 16 h. The mixture was warmed to 15 to 25°C, and aged for 2 h. The mixture was then washed with 14% NaCl aqueous solution (450 kg) followed by a second wash with 14% NaCl aqueous solution (432 kg) and a final water wash (444 kg). The organic phase was concentrated under reduced pressure to 2-4 10 vol. Iso-propanol (143 kg) was added to the residue and concentrated to 4-5 vol. under reduced pressure. After cooling to -10 to 0°C and aging for 8 h, the resulting slurry was filtered, washed with IPA (38 kg) and dried to afford the title intermediate (46.7 kg, 69% yield) as a white solid. Preparation of intermediate 228 15 tert-butyl (l?)-2-isopropyl-5-oxopyrrolidine-l-carboxylate tert-butyl (A)-(l-(2,2-dimethyl-4,6-dioxo-l,3-dioxan-5-yl)-3-methylbutan-2-yl)carbamate (intermediate 227) (46.7 kg) in toluene (333 kg) was heated to reflux and aged for 4 h. The mixture was cooled to ambient temperature, filtered and washed with toluene (20 kg). The 20 combined filtrates were concentrated to dryness at reduced pressure to afford the desired compound (31.05 kg, 96% yield) as an oil which was used directly without further purification. Preparation of intermediate 229 25 tert-butyl (51?)-2-hydroxy-5-isopropylpyrrolidine-l-carboxylate LiBH4 -----► 2-MeTHF tert-butyl (A)-2-isopropyl-5-oxopyrrolidine-l-carboxylate (intermediate 228) (30.9 kg) in 2- MeTHF (26.7 kg) was cooled to -5 to 5°C. A solution of LiBH4 in 2-MeTHF (IM, 45.2 kg, 2026205213   01 Jul 2026 54.4 mol) was added over 3 h and the mixture was aged for 4 h. A cold aqueous solution of 5% NaHCOs (163 kg) was added at -5 to 5°C over 3h and aged for an additional 2 h. The mixture was warmed to ambient temperature and aged for a further 2 h. The aqueous layer was separated and the organic layer was washed with 10% NaCl aqueous solution (170 kg) 5 and water (155 kg). During the water wash, an emulsion formed and solid NaCl (3.1 kg) was added to affect the separation. After removal of the aqueous layer, the organic layer was concentrated under reduced pressure to dryness to afford the desired compound (28.5 kg, 91% yield) as an oil, which was used directly without further purification. 10 Preparation of intermediate 230 tert-butyl (l?)-(6-((2-methoxyethyl)(methyl)amino)-2-methylhexan-3-yl)carbamate tert-butyl (5A)-2-hydroxy-5-isopropylpyrrolidine-l-carboxylate (intermediate 229) (28.55 kg) in DCM (344 kg), at 15 to 25°C was treated with 2-methoxy-A-methylethan-l-amine 15   (12.3 kg, 138.0 mol) and the resulting mixture was aged for 1 h. Sodium triacetoxyborohydride (40.12 kg) was added in portions over 5h whilst maintaining a temperature between 15 to 25°C and the resulting mixture was aged for 48 h. The reaction mixture was quenched by the addition of 8% NaOH aqueous solution (184 kg) over 2 h whilst maintaining a temperature between 15 to 25°C and the mixture was aged for a further 2 h. The 20 water layer was separated, and the organic layer was washed with water (169 kg). The organic layer was then concentrated under reduced pressure to dryness to afford the title intermediate (33.26 kg, 88% yield) as an oil which was used directly without further purification. Preparation of intermediate 231 25 (l?)-A4-(2-methoxyethyl)-A4,5-dimethylhexane-l,4-diamine, dihydrochloride To 4 molar solution of HC1 in iso-propanol (84.80 kg) at ambient temperature was added a solution of tert-butyl (A)-(6-((2-methoxyethyl)(methyl)amino)-2-methylhexan-3-yl)carbamate (intermediate 230) (32.38 kg) in iso-propanol (25.6 kg) over 3 h and the mixture was aged at 2026205213   01 Jul 2026 C|^ VcO2Et Q CO2Et 0 ambient temperature for an additional 19 h. Methyl tert-butyl ether (95.25 kg) was then added over 1 h and the mixture was aged for 2.5 h. The resulting slurry was filtered and washed with MTBE (53 kg). The filter cake was dried to afford the title compound (23.92 kg, 81% yield) as a white solid. Preparation of intermediate 232 ethyl l-benzyl-3-(chloromethyl)pyrrolidine-3-carboxylate DIPEA (1.1 eq.) n-BuLi (1.0 eq.) THF ICH2CI (1.2 eq.) Bn                -78 to -60°C To a solution of DIPEA (952 g, 1.1 eq.) in THF (6 L) which was cooled to -35 to -25°C was 10 added n-BuLi (2.33 kg, 2.5 M in hexane, 1.0 eq.) whilst maintaining a temperature below -25°C. The resulting mixture was aged at -35 to -25°C for an additional 30 min then cooled to between -78 to -60°C. A solution of ethyl l-benzylpyrrolidine-3-carboxylate (2 kg, 1.0 eq.) in THF (2 L) at -78 to -60°C was added and stirred for an addition 30 min. Chloroiodomethane (1.81 kg, 1.2 eq.) was then charged at -78 to -60°C. The reaction mixture was aged at -60 to - 15   40°C for 2 h. To the reaction mixture was added to citric acid aqueous solution (660 g in 6 L H2O) at a temperature between 0 to 10°C and the resulting mixture was aged at 20 to 30°C for an additional 20 min. After separating the layers, the aqueous layer was extracted with EtOAc (6 L) and the combined organic layers washed with brine (6 L) then warmed to 50 to 60°C. Oxalic acid (2.22 kg) was charged at 50 to 60°C. The resulting mixture was stirred at 50 to 20   60°C for 3 h then cooled to 20 to 30°C and aged overnight. The resulting solid was filtered and the cake was washed with ethyl acetate (2 L). The wet cake was added to toluene (4 L), H2O (8 L) and K3PO4 (1.5 eq.) and the resulting mixture was aged at 20 to 30°C for 20 min. After separating the layers, the aqueous layer was extracted with toluene (2 L). The organic layers were combined and washed twice with water (2 L ). The organic phase was 25 concentrated under reduced pressure to afford 4.2 kg of the desired compound as a toluene solution (46 wt % by assay, giving an assay yield of 80%). Preparation of intermediate 233 l-benzyl-3-(chloromethyl)pyrrolidine-3-carbaldehyde 2026205213   01 Jul 2026 ci-, VCO2Et Q I Bn Flow ■ ----------► DIBAL-H (2.0 eq.) toluene -65 to -55°C Bn Reaction conducted in a flow chemistry system: A solution of ethyl l-benzyl-3-(chloromethyl)pyrrolidine-3-carboxylate (intermediate 232) (4.4 kg) in toluene (26 L) was pumped at 26.7 mL / min and cooled to -60°C. After cooling, it was then mixed with a cooled 5 solution of DIBAL-H (28.1 mol) in toluene at -60°C (28 L) with a pumping rate of 32.1 mL / min. The mixture was passed through a Perfluoroalkoxy (PF A) coil tube reactor at -60°C (total flow rate of 58.8 mL / min with a residence time of 5 seconds). The resulting mixture was mixed with cooled MeOH (-60°C) which was pumped at the rate of 15.2 mL / min. This mixed solution was pumped to another PFA coil tube reactor at -60°C (total flow rate of 74 10 mL / min with a residence time of 5 seconds). The resulting mixture was collected into a receiver which contained 20 wt % aq. solution Rochelle’s salt (20 V). The layers were separated, and the organic phase was twice washed with water (2 x 44 L). The organic phase was combined with another 3.0 kg batch prepared in an analogous manner and concentrated under reduced pressure to afford 20.8 kg of a toluene solution of the desired compound (25.5 15 wt % assay by HPLC, giving an assay yield of 85%) which was used directly without further purification. 'H NMR (300 MHz, Chloroform-d): 8 9.62 (s, 1H), 7.39 - 7.20 (m, 5H), 3.83 - 3.57 (m, 4H), 2.96 (d, J = 10.2 Hz, 1H), 2.80 - 2.55 (m, 3H), 2.17 (ddd, J = 13.9, 7.9, 6.1 Hz, 1H), 1.83 (ddd, J =13.4, 7.8, 5.5 Hz, 1H). 20 Preparation of intermediate 234 (l?)-4-(6-benzyl-2,6-diazaspiro[3.4]octan-2-yl)-A-(2-methoxyethyl)-A,5-dimethylhexan-l-amine 25 ci 'X'^o N Bn nh2 Et3N (2.0 eq.) NaBH(OAc)3 (3.2 eq.) toluene 15-25°C ,, / x.OMe N '     2 HCI 30 To a solution of l-benzyl-3-(chloromethyl)pyrrolidine-3-carbaldehyde (intermediate 233) in toluene (3.0 kg, 10 wt %) diluted with toluene (30 L) and (A)-A1-(2-methoxyethyl)-A1,5-dimethylhexane-l,4-diamine, dihydrochloride (intermediate 231) (3.47 kg) was added triethylamine (2.55 kg, 25.2 mol) at 20 to 30°C. The resulting mixture was aged for 2 h at 20 to 30°C. Then sodium triacetoxyborohydride (9.0 kg) was charged at 20 to 30°C and the mixture was aged for 12 h. The reaction mixture was cooled to 5 to 15°C and 25 wt % NaOH 2026205213   01 Jul 2026 aqueous solution (25 L, -16.75 eq.) was added maintaining a temperature below 35°C. The resulting mixture was aged at 20 to 30°C for 25 mins and the layers were separated. The organic layer was washed with 15 wt % aq. NaCl (10 L) and the layers were again separated and water (18 L) was charged to the organic phase. The pH of the aqueous phase was adjusted 5 to 6-7 with 4M aq. HC1 whilst maintaining an internal temperature below 35°C. The organic phase was then discarded and the aqueous phase was separated and basified to pH 8-9 with K2HPO4. The resulting mixture was warmed to 50 to 55°C and aged for 3 h. The reaction mixture was then cooled to ambient temperature and combined with other two batches (2.4 kg + 3.0 kg). 10 The combined streams were washed with methyl tert-butyl ether three times (3 x 40 L). To the resulting aqueous layer was added additional methyl tert-butyl ether (83 L) and the aqueous phase was basified to pH 9-10 using 8 wt % aq. NaOH whilst maintaining a temperature between 15 to 35°C. The aqueous layer was separated, and the organic layer was washed with three times water (3x30 L). The organic layer was then concentrated under 15 reduced pressure to approximately 3 volumes and then flushed with methanol three times (3 x 30 L) and concentrated to dryness to afford the desired compound (12.4 kg, 90% isolated yield) as light-yellow oil, which was used directly without further purification. Preparation of intermediate 224 20 (K)-7V-(2-methoxyethyl)-7V,5-dimethyl-4-(2,6-diazaspiro[3.4]octan-2-yl)hexan-l-amine 1 Bn Pd(OH)2 / C, MSA H2, EtOH H To palladium hydroxide on carbon (1.2kg) in EtOH (1.47 kg) cooled to -5 to 5°C were added methanesulfonic acid (MSA) (11kg), (A)-4-(6-benzyl-2,6-diazaspiro[3.4]octan-2-yl- N-Q- 25 methoxyethyl)-A,5-dimethylhexan-l-amine (intermediate 234) (10kg) and EtOH (250L). The mixture was warmed to 35-45°C and stirred under a hydrogen atmosphere (0.27 to 0.40 MPa) for 16-20h. The mixture was filtered over diatomite (20kg) and the pad was washed with EtOH (24L). The filtrate was concentrated under reduced pressure (<40°C) to 2-3 vol. and then flushed twice with 2-MeTHF (73kg and 47kg) to give a 2-3 vol. solution. After 30 dilution with 2-MeTHF (65kg), 10% aq. sodium sulfate (30kg) was added and the mixture was cooled to 0 to 10°C, followed by the addition of 16% aq. NaOH (50kg) to adjust the pH to 13-14. The temperature was adjusted to 15 to 25°C and stirred for 30 to 60 min. The 2026205213   01 Jul 2026 aqueous layer was separated and extracted twice with 2-MeTHF (47kg x 2). The combined organic layers were concentrated under reduced pressure (<40°C) to 3~4 vol. and 2-MeTHF (950g) was added. After concentration under reduced pressure (<40°C) to 3~4 vol., the resulting solution was diluted with 2-MeTHF (30kg), dried by passing through 4A molecular 5 sieves (25kg) and washed with 2-MeTHF (30kg). The final solution was concentrated to afford the desired compound (6.7kg) as an oil with 90.1% assay purity in a 79% corrected yield. Preparation of intermediate 225 10    (^)-4-(6-(3,6-dichloro-l,2,4-triazin-5-yl)-2,6-diazaspiro[3.4]octan-2-yl)-7V-(2- methoxyethyl)-A,5-dimethylhexan-l-amine To (A)-A-(2-methoxyethyl)-A,5-dimethyl-4-(2,6-diazaspiro[3,4]octan-2-yl)hexan-l -amine (intermediate 224) (100 g) was added 2-MeTHF (430 g) and TEA (68 g) and the mixture 15 was cooled to -50 to -40°C. 3,5,6-trichloro-l,2,4-triazine (62 g) in 2-MeTHF (172 g) was added and the mixture was stirred for 1 to 3 h. The resulting mixture was warmed to -20 to -10°C and a 7% NaHCOs aqueous solution was added, the mixture was warmed to 20 to 30°C and stirred for 30 to 60 min. The aqueous layer was removed and the organic layer was washed with 10% Na2SO4 (500 g). The organic layer was dried by passing through 4A 20 molecular sieves (220 g) and washed with 2-MeTHF (180 g). The title intermediate was afforded in 90% assay yield as a solution 14.8 wt% in 2-MeTHF. Preparation of intermediate 245 (ft)-2-((5-(2-(6-((2-((tert-butyldimethylsilyl)oxy)ethyl)(methyl)amino)-2-methylhexan-3-25 yl)-2,6-diazaspiro[3.4]octan-6-yl)-l ,2,4-triazin-6-yl)oxy)-A-ethyl-5-fluoro-A- isopropylbenzamide 2026205213   01 Jul 2026 NaBHsCN (23.2 mg, 0.37 mmol) was added to a solution of (A)-7V-ethyl-5-fluoro-A-isopropyl-2-((5-(2-(2-methyl-6-(methylamino)hexan-3-yl)-2,6-diazaspiro[3.4]octan-6-yl)-l,2,4-triazin-6-yl)oxy)benzamide hydrochloride (Compound 19) (100 mg, 0.18 mmol), 2 5 ((tert-butyldimethylsilyl)oxy)acetaldehyde (71 pL, 0.37 mmol) and AcOH (11 pL, 0.18 mmol) in MeOH (2 mL). Then, the reaction mixture was stirred at RT for 24 h. The reaction mixture was poured into water, basified with an aqueous solution of K2CO3 and DCM was added. The organic layer was separated, dried over MgSO4, filtered and evaporated till dryness to give a crude (152 mg) which was purified by silica gel chromatography (Stationary 10 phase: irregular bare silica 4g, Mobile phase: 0.5% NH4OH, 95% DCM, 5% MeOH). The fractions containing the product were mixed and concentrated to afford the title intermediate (46 mg, 36% yield). Preparation of Compounds 15 Preparation of Compound 61 tert-butyl (4-(6-(6-(2-(ethyl(isopropyl)carbamoyl)-4-fluorophenoxy)-l,2,4-triazin-5-yl)- 2,6-diazaspiro[3.4]octan-2-yl)-5-methylhexyl)carbamate The mixture 2-((5-(2,6-diazaspiro[3.4]octan-6-yl)-l,2,4-triazin-6-yl)oxy)-7V-ethyl-5-fluoro-A- 20 isopropylbenzamide (intermediate 3) (1.0 g, 2.4 mmol), tert-butyl (5-methyl-4-oxohexyl)carbamate (intermediate 1) (830 mg, 3.62 mmol) and ZnCh (660 mg, 4.84 mmol) in MeOH (15 mL) was stirred at 80 °C for 0.5 h. Then NaBHsCN (310 mg, 4.93 mmol) was added and the resulting mixture was stirred at 80 °C for 6 h. After cooled to RT, the mixture was concentrated under reduced pressure to give the crude product, which was further 25 purified by preparative HPLC using a Waters Xbridge Prep OBD (column: C18 150x40 mm 2026205213   01 Jul 2026 10 um; eluent: ACN / H2O (0.05% ammonia) from 45% to 75% v / v) to afford the title compound (700 mg, 46% yield) as colorless oil. Preparation of Compounds 62 and 63 5 tert-butyl (l?)-(4-(6-(6-(2-(ethyl(isopropyl)carbamoyl)-4-fluorophenoxy)-l,2,4-triazin-5- yl)-2,6-diazaspiro[3.4]octan-2-yl)-5-methylhexyl)carbamate tert-butyl (5)-(4-(6-(6-(2-(ethyl(isopropyl)carbamoyl)-4-fluorophenoxy)-l,2,4-triazin-5- yl)-2,6-diazaspiro[3.4]octan-2-yl)-5-methylhexyl)carbamate Compound 63 10 tert-butyl (4-(6-(6-(2-(ethyl(isopropyl)carbamoyl)-4-fluorophenoxy)-l,2,4-triazin-5-yl)-2,6-diazaspiro[3.4]octan-2-yl)-5-methylhexyl)carbamate (Compound 61) (200 mg, 0.319 mmol) was purified by SFC over DAICEL CHIRALPAK IG (column: 250x30 mm 10 um; isocratic elution: EtOH (containing 0.1% of 25% ammonia): supercritical CO2, 40% : 60% (v / v)) to afford the title compounds (Compound 62) (85 mg, 42% yield) and (Compound 63) (80 mg, 15    40% yield) both as light yellow oil. 2026205213   01 Jul 2026 Compound 207 and 208 te / 7-butyl (*lf)-(5-(6-(6-(2-(ethyl(isopropyl)carbamoyl)-4-fluorophenoxy)-l,2,4-triazin-5- yl)-2,6-diazaspiro[3.4]octan-2-yl)-6-methylheptyl)carbamate te / 7-butyl (*3)-(5-(6-(6-(2-(ethyl(isopropyl)carbamoyl)-4-fluorophenoxy)-l,2,4-triazin-5- 5 yl)-2,6-diazaspiro[3.4]octan-2-yl)-6-methylheptyl)carbamate Compound 208 Tert-butyl (5-(6-(6-(2-(ethyl(isopropyl)carbamoyl)-4-fluorophenoxy)-l,2,4-triazin-5-yl)-2,6-diazaspiro[3.4]octan-2-yl)-6-methylheptyl)carbamate (Compound 206) (1.4 g) was purified by SFC over DAICEL CHIRALPAK IG (column: 250x30 mm, 10 pm; Mobile phase: A: 10 Supercritical CO2, B: MeOH (0.1% ammonia), A:B = 55:45 at 200 mL / min) to afford the title compounds (Compound 207) (700 mg) and (Compound 208) (700 mg) both as white solid. 2026205213   01 Jul 2026 Compound 304 and 305 terf-butyl ((4*l?)-4-(6-(6-(2-(ethyl(isopropyl)carbamoyl)-4-fluorophenoxy)-l,2,4-triazin- 5-yl)-2,6-diazaspiro[3.4]octan-2-yl)-2-methoxy-5-methylhexyl)(methyl)carbamate terf-butyl ((4*5)-4-(6-(6-(2-(ethyl(isopropyl)carbamoyl)-4-fluorophenoxy)-l,2,4-triazin- 5 5-yl)-2,6-diazaspiro[3.4]octan-2-yl)-2-methoxy-5-methylhexyl)(methyl)carbamate Compound 305 tert-butyl (4-(6-(6-(2-(ethyl(isopropyl)carbamoyl)-4-fluorophenoxy)-l,2,4-triazin-5-yl)-2,6- diazaspiro[3.4]octan-2-yl)-2-methoxy-5-methylhexyl)(methyl)carbamate (Compound 303) (250 mg) was separated by SFC over DAICEL CHIRALPAK IG (column: 250x30 mm, 10 10 pm; Mobile phase: A: Supercritical CO2, B: MeOH (0.1% ammonia), A:B = 60:40; Flow rate: 80 mL / min) to afford the title compounds (Compound 304) (124 mg) and (Compound 305) (124 mg) both as colorless sticky oil. 2026205213   01 Jul 2026 Compound 306 and 307 tert-butyl ((2 *R.4 *l?)-4-(6-(6-(2-(ethyl(isopropyl)carbamoyl)-4-fluorophenoxy)-l,2,4- triazin-5-yl)-2,6-diazaspiro[3.4]octan-2-yl)-2-methoxy-5-methylhexyl)(methyl)carbamate tert-butyl ((2 *5,4 *l?)-4-(6-(6-(2-(ethyl(isopropyl)carbamoyl)-4-fluorophenoxy)-1,2,4- 5 triazin-5-yl)-2,6-diazaspiro[3.4]octan-2-yl)-2-methoxy-5-methylhexyl)(methyl)carbamate Compound 304                      Compound 306 Tert-butyl ((4*7?)-4-(6-(6-(2-(ethyl(isopropyl)carbamoyl)-4-fluorophenoxy)-l,2,4-triazin-5-yl)-2,6-diazaspiro[3.4]octan-2-yl)-2-methoxy-5-methylhexyl)(methyl)carbamate (Compound 304) (120 mg) was separated by SFC over DAICEL CHIRALPAK IG (column: 250x30 10 mm,10 um; Mobile phase: A: Supercritical CO2, B: MeOH (0.1% ammonia), A:B = 70:30 at 80 mL / min) to afford the title compounds (Compound 306) (45 mg) and (Compound 307) (46 mg) both as colorless sticky oil. Compound 371 and 372 15 tert-butyl ((2 *5,4 *5)-4-(6-(6-(2-(ethyl(isopropyl)carbamoyl)-4-fluorophenoxy)-l,2,4-triazin-5-yl)-2,6-diazaspiro[3.4]octan-2-yl)-2-methoxy-5-methylhexyl)(methyl)carbamate tert-butyl ((2 *R,4 *5)-4-(6-(6-(2-(ethyl(isopropyl)carbamoyl)-4-fluorophenoxy)-1,2,4-triazin-5-yl)-2,6-diazaspiro[3.4]octan-2-yl)-2-methoxy-5-methylhexyl)(methyl)carbamate 2026205213   01 Jul 2026 Compound 372 Tert-butyl ((4*S)-4-(6-(6-(2-(ethyl(isopropyl)carbamoyl)-4-fluorophenoxy)-l,2,4-triazin-5- yl)-2,6-diazaspiro[3.4]octan-2-yl)-2-methoxy-5-methylhexyl)(methyl)carbamate (Compound 305) (120 mg) was separated by SFC over DAICEL CHIRALPAK IG (column: 250x30 mm, 5   10 pm; Mobile phase: A: Supercritical CO2, B: IPA (0.1% ammonia), A:B = 60:40; Flow rate: 80 mL / min) to afford the title compounds (Compound 371) (45 mg) and (Compound 372) (46 mg) both as colorless sticky oil. Compound 404 and 405 10 tert-butyl (l?)-(4-(6-(3-chloro-6-(2-(ethyl(isopropyl)carbamoyl)-4-fluorophenoxy )-1,2,4-triazin-5-yl)-2,6-diazaspiro[3.4]octan-2-yl)-5-methylhexyl)carbamate tert-butyl (3)-(4-(6-(3-chloro-6-(2-(ethyl(isopropyl)carbamoyl)-4-fluorophenoxy)-l,2,4- triazin-5-yl)-2,6-diazaspiro[3.4]octan-2-yl)-5-methylhexyl)carbamate 2026205213   01 Jul 2026 Compound 403 Compound 405 Tert-butyl (4-(6-(3-chloro-6-(2-(ethyl(isopropyl)carbamoyl)-4-fluorophenoxy)-l,2,4-triazin-5-yl)-2,6-diazaspiro[3.4]octan-2-yl)-5-methylhexyl)carbamate (Compound 403) (19.5 g) was separated by SFC over DAICEL CHIRALPAK IG (column: 250x30 mm, 10 um; Mobile 5 phase: A: Supercritical CO2, B: MeOH (0.1% ammonia), A:B =55:45 at 80 mL / min; Column Temp: 38 °C; Nozzle Pressure: 100 Bar; Nozzle Temp: 60 °C; Evaporator Temp: 20 °C; Trimmer Temp: 25 °C; Wavelength: 220 nm) to afford the title compounds (Compound 404) (8.00 g) and (Compound 405) (7.00 g) both as sticky oil. 10 Compound 1 (ft)-2-((5-(2-(6-amino-2-methylhexan-3-yl)-2,6-diazaspiro[3.4]octan-6-yl)-l,2,4-triazin-6- yl)oxy)-A-ethyl-5-fluoro-A-isopropylbenzamide formate formate salt 2026205213   01 Jul 2026 HCl / l,4-di oxane (0.5 mL, 2.0 mmol) was added to a solution of tert-butyl (R)-(4-(6-(6-(2-(ethyl(isopropyl)carbamoyl)-4-fluorophenoxy)-l,2,4-triazin-5-yl)-2,6-diazaspiro[3.4]octan-2-yl)-5-methylhexyl)carbamate (Compound 62) (85 mg, 0.14 mmol) in 1,4-dioxane (2 mL). The reaction mixture was sitrred at RT for 4 h. The mixture was concentrated under reduced 5 pressure and the residue was first neutralized by ammonia (5 mL) and further purified by preparative HPLC using a Welch Xtimate Cl8 (column: 150x25 mm 5pm; eluent: ACN / H2O (0.225%FA) from 1% to 31% (v / v)) to afford the title compound (32 mg, 41% yield) as a colorless oil. 'H NMR (400 MHz, Methanol-^): 8 = 8.45-8.41 (m, 3H), 7.48-7.13 (m, 3H), 4.50-4.01 (m, 10   6H), 3.98-3.66 (m, 3H), 3.56-3.38 (m, 1H), 3.25-3.12 (m, 1H), 3.10-3.01 (m, 1H), 2.99-2.87 (m, 2H), 2.43-2.18 (m, 2H), 2.13-1.96 (m, 1H), 1.84-1.44 (m, 4H), 1.25-0.92 (m, 13H), 0.870.69 (m, 2H). LC-MS (ESI) (Method 1): Rt = 2.957 min, m / z found 528.3 [M+H]+. SEC (Method 12): Rt= 1.151 min. Preparation of Compound 60 tert-butyl (4-(6-(6-(2-(ethyl(isopropyl)carbamoyl)-4-fluorophenoxy)-l,2,4-triazin-5-yl)- 2,6-diazaspiro[3.4]octan-2-yl)-5-methylhexyl)(methyl)carbamate 20 To a solution of 2-((5-(2,6-diazaspiro[3.4]octan-6-yl)-1,2,4-triazin-6-yl)oxy)-A-ethyl-5-fluoro-A-isopropylbenzamide (intermediate 3) (600 mg, 1.45 mmol) and tert-butyl methyl(5-methyl-4-oxohexyl)carbamate (intermediate 9) (330 mg, 1.37 mmol) in MeOH (50 mL) was added ZnCh (789 mg, 5.79 mmol). The resulting mixture was stirred at 80 °C for 2 h. Then NaBHsCN (729 mg, 11.6 mmol) was added and the reaction mixture was stirred at 80°C 25 overnight. After cooling to RT, the mixture was concentrated under reduced pressure to give a crude residue, which was diluted with DCM (50 mL), quenched with sat. aq. NH4CI (50 mL) and extracted with DCM (50 mL x 3). The combined organic layers were washed with brine (50 mL), dried over Na2SO4, filtered and the filtrate was concentrated under reduced pressure to give a crude product which was further purified by FCC (DCM / MeOH = 10:1) to afford the 30 title compound (400 mg, 42% yield) as white solid. 2026205213   01 Jul 2026 Compound 56 and 57 tert-butyl (ft)-(4-(6-(6-(2-(ethyl(isopropyl)carbamoyl)-4-fluorophenoxy)-l,2,4-triazin-5- yl)-2,6-diazaspiro[3.4]octan-2-yl)-5-methylhexyl)(methyl)carbamate 5 tert-butyl (3)-(4-(6-(6-(2-(ethyl(isopropyl)carbamoyl)-4-fluorophenoxy)-l,2,4-triazin-5- yl)-2,6-diazaspiro[3.4]octan-2-yl)-5-methylhexyl)(methyl)carbamate Compound 57 Tert-butyl (4-(6-(6-(2-(ethyl(isopropyl)carbamoyl)-4-fluorophenoxy)-l,2,4-triazin-5-yl)-2,6-diazaspiro[3.4]octan-2-yl)-5-methylhexyl)(methyl)carbamate (Compound 60) (419 mg, 10   0.653 mmol) was purified by SFC over DAICEL CHIRALPAK AD (column: 250x30 mm 10 pm; Mobile phase: A: Supercritical CO2, B: IPA (0.1% ammonia), A:B = 80:20 at 60 mL / min; Column Temp: 38 °C; Nozzle Pressure: 100 Bar; Nozzle Temp: 60 °C; Evaporator Temp: 20 °C; Trimmer Temp: 25 °C; Wavelength: 220 nm) to afford the title compounds (Compound 56) (146 mg, 34% yield) and (Compound 57) (149 mg, 36% yield) both as 15 white solid. Compound 19 (K)-7V-ethyl-5-fluoro-7V-isopropyl-2-((5-(2-(2-methyl-6-(methylamino)hexan-3-yl)-2,6- diazaspiro[3.4]octan-6-yl)-l,2,4-triazin-6-yl)oxy)benzamide hydrochloride 2026205213   01 Jul 2026 To a solution of tert-butyl ( / ?)-(4-(6-(6-(2-(ethyl(isopropyl)carbamoyl)-4-fluorophenoxy)-l,2,4-triazin-5-yl)-2,6-diazaspiro[3.4]octan-2-yl)-5-methylhexyl)(methyl)carbamate 5 (Compound 56) (130 mg, 0.203 mmol) in 1,4-dioxane (3 mL) was added HCl / l,4-dioxane (5 mL, 20.0 mmol), and the reaction mixture was stirred at RT for 1 h. The reaction mixture was concentrated in vacuo and the residue was purified by preparative HPLC over Phenomenex Gemini-NX (column: 150x30 mm 5um, Mobile Phase A: water (0.05%HCl), Mobile Phase B: ACN, Flow rate: 25 mL / min, gradient condition B / A from 0% B to 26% (0% B to 26% B)) to 10 afford the title compound (105 mg, 84% yield) as colorless oil. LC-MS (ESI) (Method 1): Rt = 2.939 min, m / z found 542.4 [M+H]+. SEC (Method 1): Rt = 1.201 min. Compound 398 15 (K)-7V-ethyl-5-fluoro-A-isopropyl-2-((5-(2-(2-methyl-6-(methylamino)hexan-3-yl)-2,6-diazaspiro[3.4]octan-6-yl)-l,2,4-triazin-6-yl)oxy)benzamide At 5 °C, TFA (0.51 mL, 6.7 mmol) was added dropwise to a solution of tert-butyl (A)-(4-(6-(6-(2-(ethyl(isopropyl)carbamoyl)-4-fluorophenoxy)-l,2,4-triazin-5-yl)-2,6- 20 diazaspiro[3.4]octan-2-yl)-5-methylhexyl)(methyl)carbamate (Compound 56) (287 mg, 0.45 mmol) in DCM (7.5 mL) and the reaction mixture was stirred overnight. The reaction mixture was evaporated to dryness to give a crude mixture (540 mg) which was purified by silica gel chromatography (Stationary phase: irregular bare silica 12g, Mobile phase: Gradient from 95% DCM, 5% MeOH (+10% NH4OH) to 90% DCM, 10% MeOH (+10% NH4OH)). The 2026205213   01 Jul 2026 pure fractions were mixed and concentrated to afford 173 mg of an intermediate fractions which was freeze-dried with ACN / H2O (20 / 80, v / v) to afford of the title compound (170 mg, 70% yield). LC-MS (ESI) (Method 4): Rt = 2.08 min, m / z found 542.6 [M+H]+. Compound 51 tert-butyl (3-(6-(6-(2-(ethyl(isopropyl)carbamoyl)-4-fluorophenoxy)-l,2,4-triazin-5-yl)-2,6-diazaspiro[3.4]octan-2-yl)-4-methylpentyl)carbamate 10 To a solution of A-ethyl-5-fluoro-2-((5-hydroxy-l,2,4-triazin-6-yl)oxy)-A-isopropylbenzamide (intermediate 25) (0.100 g, 0.312 mmol) in DCM (12 mL) was added oxalyl chloride (0.079 g, 0.624 mmol), followed by DMF (0.046 g, 0.624 mmol) at RT. The mixture was stirred at this temperature for 1 h. Then the mixture was added to a solution of tert-butyl (4-methyl-3-(2,6-diazaspiro[3,4]octan-2-yl)pentyl)carbamate hydrochloride 15 (intermediate 22) (0.272 g, crude) and TEA (0.158 g, 1.56 mmol) in DCM (3 mL). The resulting mixture was stirred at 25 °C for 0.5 h. The reaction mixture was concentrated under reduced pressure and the residue was partitioned between DCM (35 mL) and H2O (35 mL), extracted with DCM (35 mL x 3). The combined organic layers were dried over Na2SO4, filtered and concentrated. The residue was purified by FCC (PE / EtOAc (0.5% ammonia) = 20    1 / 1) to afford the title compound (100 mg, 89% purity, 46% yield) as colorless oil. Compound 52 and 53 tert-butyl (*l?)-(5-(6-(6-(2-(4-cyclopropylpyrimidin-5-yl)-4-fluorophenoxy)-l,2,4-triazin-5-yl)-2,6-diazaspiro[3.4]octan-2-yl)-2,6-dimethylheptan-2-yl)carbamate 25 tert-butyl (*3)-(5-(6-(6-(2-(4-cyclopropylpyrimidin-5-yl)-4-fluorophenoxy)-l,2,4-triazin-5-yl)-2,6-diazaspiro[3.4]octan-2-yl)-2,6-dimethylheptan-2-yl)carbamate 2026205213   01 Jul 2026 Compound 52 tert-butyl (5-(6-(6-(2-(4-cyclopropylpyrimidin-5-yl)-4-fluorophenoxy)-l,2,4-triazin-5-yl)-2,6-diazaspiro[3.4]octan-2-yl)-2,6-dimethylheptan-2-yl)carbamate (Compound 58) (150 mg, 0.227 mmol) was purified by SFC over DAICEL CHIRALPAK AD-H (column: 250x30 mm 5   5 pm; Mobile phase: A: Supercritical CO2, B: IPA (0.1% ammonia), A: B = 4:1 at 60 mL / min) to afford the title compounds Compound 52 (47 mg, 96.3% purity, 30.2% yield) and Compound 53 (56 mg, 97.7% purity, 36.5% yield) both as white solids. Compound 54 and 55 10 tert-butyl (*l?)-(5-(6-(6-(2-(ethyl(isopropyl)carbamoyl)-4-fluorophenoxy)-l,2,4-triazin-5-yl)-2,6-diazaspiro[3.4]octan-2-yl)-2,6-dimethylheptan-2-yl)carbamate tert-butyl (*3)-(5-(6-(6-(2-(ethyl(isopropyl)carbamoyl)-4-fluorophenoxy)-l,2,4-triazin-5- yl)-2,6-diazaspiro[3.4]octan-2-yl)-2,6-dimethylheptan-2-yl)carbamate Compound 55 2026205213   01 Jul 2026 tert-butyl (5-(6-(6-(2-(ethyl(isopropyl)carbamoyl)-4-fluorophenoxy)-l,2,4-triazin-5-yl)-2,6-diazaspiro[3.4]octan-2-yl)-2,6-dimethylheptan-2-yl)carbamate (Compound 59) (1.70 g, 2.59 mmol) was separated by SFC over DAICEL CHIRALPAK IG (column: 250x50 mm 10 pm)); Mobile phase: A: Supercritical CO2, B: EtOH (0.1% ammonia), A: B = 3:2 at 150 mL / min) to 5 afford the title compounds Compound 54 (700 mg, 90% purity, 37% yield) and Compound 55 (700 mg, purity: 96% purity, 40% yield) both as a white solid. Compound 408 tert-butyl (l?)-(4-(6-(6-(2-(ethyl(isopropyl)carbamoyl)-4-fluorophenoxy)-3- 10 (methylamino)-l,2,4-triazin-5-yl)-2,6-diazaspiro[3.4]octan-2-yl)-5-methylhexyl)carbamate The following compounds was synthesized by an analogous method as described above for Compound 395 Co. No. Structure Starting Material Conditions 408 —\ HN-Boc YY V A°A F          N N H Compound 404 methanamine in EtOH (33%), 90 °C, 1 h 15 Compound 412 tert-butyl (l?)-(4-(6-(6-(2-(ethyl(isopropyl)carbamoyl)-4-fluorophenoxy)-3-methyl-l,2,4- triazin-5-yl)-2,6-diazaspiro[3.4]octan-2-yl)-5-methylhexyl)carbamate Pd(PPh3)4, K2CO3 dioxane, 110 °C To the mixture of tert-butyl (A)-(4-(6-(3-chloro-6-(2-(ethyl(isopropyl)carbamoyl)-4- 20 fluorophenoxy)-l,2,4-triazin-5-yl)-2,6-diazaspiro[3.4]octan-2-yl)-5-methylhexyl)carbamate (Compound 404) (50.0 mg, 0.076 mmol), 2,4,6-trimethyl-l,3,5,2,4,6-trioxatriborinane (76.0 2026205213   01 Jul 2026 mg, 0.303 mmol, 50% in THF) and K2CO3 (21.0 mg, 0.152 mmol) in anhydrous dioxane (1 mL) was added Pd(PPh3)4 (8.7 mg, 0.008 mmol) and the resulting mixture was stirred at 110 °C for 8 h under N2 atmosphere. After cooled to RT, the mixture was diluted with H2O (40 mL) and extracted with EtOAc (20 mL x 3). The combined organic layers were dried over 5 anhydrous Na2SO4 and filtered. The filtrate was concentrated under reduced pressure to give the crude product which was purified by preparative TLC (DCM / MeOH = 10 / 1) to afford the title compound (30.0 mg, 59.7% yield) as yellow solid. Compounds 2, 3, 20, 30, 31, 37, 38, 26, 80, 209, 210, 218, 220, 221, 308, 309, 317, 328, 359, 10   373,374,409,413 (5)-2-((5-(2-(6-amino-2-methylhexan-3-yl)-2,6-diazaspiro[3.4]octan-6-yl)-l,2,4-triazin-6- yl)oxy)-A-ethyl-5-fluoro-A-isopropylbenzamide formate 2-((5-(2-(6-amino-2-methylhexan-3-yl)-2,6-diazaspiro[3.4]octan-6-yl)-l,2,4-triazin-6-yl)oxy)-A-ethyl-5-fluoro-A-isopropylbenzamide formate 15 (5)-A-ethyl-5-fluoro-A-isopropyl-2-((5-(2-(2-methyl-6-(methylamino)hexan-3-yl)-2,6-diazaspiro[3.4]octan-6-yl)-l,2,4-triazin-6-yl)oxy)benzamide hydrochloride (*lf)-2-((5-(2-(6-amino-2,6-dimethylheptan-3-yl)-2,6-diazaspiro[3.4]octan-6-yl)-l,2,4-triazin-6-yl)oxy)-A-ethyl-5-fluoro-A-isopropylbenzamide (*3)-2-((5-(2-(6-amino-2,6-dimethylheptan-3-yl)-2,6-diazaspiro[3.4]octan-6-yl)-l,2,4- 20 triazin-6-yl)oxy)-A-ethyl-5-fluoro-A-isopropylbenzamide (*l?)-5-(6-(6-(2-(4-cyclopropylpyrimidin-5-yl)-4-fluorophenoxy)-l,2,4-triazin-5-yl)-2,6-diazaspiro[3.4]octan-2-yl)-2,6-dimethylheptan-2-amine (*5)-5-(6-(6-(2-(4-cyclopropylpyrimidin-5-yl)-4-fluorophenoxy)-l,2,4-triazin-5-yl)-2,6-diazaspiro[3.4]octan-2-yl)-2,6-dimethylheptan-2-amine 25 2-((5-(2-(l-amino-4-methylpentan-3-yl)-2,6-diazaspiro[3.4]octan-6-yl)-l,2,4-triazin-6- yl)oxy)-A-ethyl-5-fluoro-A-isopropylbenzamide A-ethyl-5-fluoro-A-isopropyl-2-((4-(2-(2-methyl-6-(methylamino)hexan-3-yl)-2,6-diazaspiro[3.4]octan-6-yl)pyridazin-3-yl)oxy)benzamide (*lf)-2-((5-(2-(7-amino-2-methylheptan-3-yl)-2,6-diazaspiro[3.4]octan-6-yl)-l,2,4-triazin- 30 6-yl)oxy)-A ethyl-5-niioro-A-isopropylbenzamide formate (*5)-2-((5-(2-(7-amino-2-methylheptan-3-yl)-2,6-diazaspiro[3.4]octan-6-yl)-l,2,4-triazin- 6-yl)oxy)-A-ethyl-5-nuoro-A-isopropylbenzamide (*lf)-2-((5-(2-(l-amino-4-methylpentan-3-yl)-2,6-diazaspiro[3.4]octan-6-yl)-l,2,4-triazin- 6-yl)oxy)-A-ethyl-5-nuoro-A-isopropylbenzamide 2026205213   01 Jul 2026 (*l?)-2-((5-(2-(l-amino-4-methylpentan-3-yl)-2,6-diazaspiro[3.4]octan-6-yl)-l,2,4-triazin-6-yl)oxy)-7V-ethyl-5-fluoro-7V-isopropylbenzamide hydrochloride (*3)-2-((5-(2-(l-amino-4-methylpentan-3-yl)-2,6-diazaspiro[3.4]octan-6-yl)-l,2,4-triazin-6-yl)oxy)-7V-ethyl-5-fluoro-7V-isopropylbenzamide hydrochloride 5 7V-ethyl-5-fluoro-7V-isopropyl-2-((5-(2-((3 *R,5 *l?)-5-methoxy-2-methyl-6-(methylamino)hexan-3-yl)-2,6-diazaspiro[3.4]octan-6-yl)-l,2,4-triazin-6-yl)oxy)benzamide hydrochloride ALethyl-5-fluoro-Az-isopropyl-2-((5-(2-((3*l?,5*5)-5-methoxy-2-methyl-6-(methylamino)hexan-3-yl)-2,6-diazaspiro[3.4]octan-6-yl)-l,2,4-triazin-6-10 yl)oxy)benzamide hydrochloride 7V-ethyl-5-fluoro-2-((5-(2-(5-hydroxy-2-methyl-6-(methylamino)hexan-3-yl)-2,6-diazaspiro[3.4]octan-6-yl)-l,2,4-triazin-6-yl)oxy)-7V-isopropylbenzamide hydrochloride 7V-ethyl-2-((5-(2-(6-(ethylamino)-5-hydroxy-2-methylhexan-3-yl)-2,6- diazaspiro[3.4]octan-6-yl)-l,2,4-triazin-6-yl)oxy)-5-fluoro-7V-isopropylbenzamide 15 hydrochloride 5-fluoro-2-((5-(2-(5-hydroxy-2-methyl-6-(methylamino)hexan-3-yl)-2,6-diazaspiro[3.4]octan-6-yl)-l,2,4-triazin-6-yl)oxy)-A^^V-diisopropylbenzamide hydrochloride 7V-ethyl-5-fluoro-7V-isopropyl-2-((5-(2-((3*3',5*3')-5-methoxy-2-methyl-6- 20 (methylamino)hexan-3-yl)-2,6-diazaspiro[3.4]octan-6-yl)-l,2,4-triazin-6-yl)oxy)benzamide hydrochloride 7V-ethyl-5-fluoro-7V-isopropyl-2-((5-(2-((3*3',5*lf)-5-methoxy-2-methyl-6-(methylamino)hexan-3-yl)-2,6-diazaspiro[3.4]octan-6-yl)-l,2,4-triazin-6-yl)oxy)benzamide hydrochloride 25   (l?)-2-((5-(2-(6-amino-2-methylhexan-3-yl)-2,6-diazaspiro[3.4]octan-6-yl)-3- (methylamino)-l,2,4-triazin-6-yl)oxy)-7V-ethyl-5-fluoro-7V-isopropylbenzamide hydrochloride (ft)-2-((5-(2-(6-amino-2-methylhexan-3-yl)-2,6-diazaspiro[3.4]octan-6-yl)-3-methyl-l,2,4-triazin-6-yl)oxy)-7V-ethyl-5-fluoro-7V-isopropylbenzamide formate 30 The following Compounds were synthesized by an analogous method described above for Compound 1 and 19 2026205213   01 Jul 2026 Co. No. Structure Starting Material Conditions Spectra Details 2 1 \         NH2 YNY° n °^jn formate salt Compound 63 HC1 1,4-di oxane LC-MS (ESI) (Method 1): Rt = 3.028 min, m / z found 528.3 [M+H]+. SEC (Method 12): Rt= 1.502 min. 3 \ nh2 Yny° v rM F            N formate salt Compound 61 HC1 1,4-di oxane LC-MS (ESI) (Method 1): Rt = 2.977 min, m / z found 528.4 [M+H]+. 20 )--< HN— N s '—z YV0 V n^N F            N HC1 salt Compound 57 HC1 1,4-di oxane LC-MS (ESI) (Method 1): Rt = 2.890 min, m / z found 542.3 [M+H]+. SEC (Method 1): Rt= 1.697 min. 30 \ \ o o z— /  __ z''   V—z   ] \=z          \     / 1—-z   J. »y z'x X KJ Compound 54 TFA DCM LC-MS (ESI) (Method 1): Rt = 2.931 min, m / z found 556.3 [M+H]+. SEC (Method 2): Rt = 4.431 min. 2026205213   01 Jul 2026 Co. No. Structure Starting Material Conditions Spectra Details 31 \ o o Z— / X X KJ Compound 55 TFA DCM LC-MS (ESI) (Method 1): Rt = 2.897 min, m / z found 556.3 [M+H]+. SEC (Method 2): Rt = 4.997 min. 37 >=\   >=Z O< / > '-- / v_z O z— /  __ z'' y— z | \=z          1 I l—z 2oJ z \ I KJ Compound 52 TFA DCM '11 NMR (400 MHz, Methanol-tfi): 6 8.88 (brs, 1H), 8.46-8.36 (m, 2H), 7.58-7.45 (m, 1H), 7.447.26 (m, 2H), 4.07-3.52 (m, 4H), 3.31-3.11 (m, 4H), 2.242.02 (m, 3H), 1.99-1.78 (m, 2H), 1.55-1.38 (m, 3H), 1.371.20 (m, 2H), 1.14-1.06 (m, 8H), 0.99-0.83 (m, 7H). LC-MS (ESI) (Method 1): Rt = 3.21 min, m / z found 561.3 [M+H]+. SEC (Method 3): Rt= 5.566 min. 2026205213   01 Jul 2026 Co. No. Structure Starting Material Conditions Spectra Details 38 CM t' ^ZT I LUa / z=\ L z "A ,z 2—z o Z—A   \-A z \ x=\ Y.        u. Compound 53 TFA DCM LC-MS (ESI) (Method 1): Rt = 3.26 min, m / z found 561.3 [M+H]+. SEC (Method 3): Rt= 5.929 min. 26 —\ \ o o 1 L—Z^u^ z I M Compound 51 TFA DCM LC-MS (ESI) (Method 1): Rt = 2.98 min, m / z found 514.4 M+H]+. 80 \ . / U NH 1 JU o F             N Compound 79 TFA DCM 209 )—\ ^nh2 \ ^nT^O Cz 1                  N n.n^ formate salt Compound 207 HC1 1,4-di oxane LC-MS (ESI) (Method 1): Rt = 2.950 min, m / z found 542.3 [M+H]+. SEC (Method 18): Rt = 2.021 min. 2026205213   01 Jul 2026 Co. No. Structure Starting Material Conditions Spectra Details 210 / Z— \ o o Z= /   ---, 0-1¾ 1 z I KJ Compound 208 HC1 1,4-di oxane LC-MS (ESI) (Method 1): Rt = 2.919 min, m / z found 542.3 [M+H]+. SEC (Method 18): Rt = 2.201 min. 218 \ o o i—z z I ro Compound 216 TFA DCM 220 r-N^*^^NH2 1        [               N fT uN HC1 salt Compound 216 HC1 1,4-di oxane 221 n / *s>Vnh2 । । n A°^jn n.n<j HC1 salt Compound 217 HC1 1,4-di oxane 2026205213   01 Jul 2026 Co. No. Structure Starting Material Conditions Spectra Details 308 hn— r——N K \___ / 7Y °'" HCl salt Compound 306 HCl / 1,4-di oxane, MeOH 309 hn— r——N K \ / '■ HCl salt Compound 307 HCl / 1,4-di oxane, MeOH 317 nA hn~~ X      / “V HC* 'yny° V HCl salt Compound 316 HCl / 1,4-di oxane, MeOH 2026205213   01 Jul 2026 Co. No. Structure Starting Material Conditions Spectra Details 328 ) \ HN— / X     / “V no YNY° v F         N HC1 salt Compound 327 HCl / 1,4-di oxane, MeOH 359 / —\ HN— r-N  )—7 JIj ho7 Vy° N. F            N HC1 salt Compound 358 HCl / 1,4-di oxane, MeOH 373 Jy '1 W HC1 salt Compound 371 HCl / 1,4-di oxane, MeOH 2026205213   01 Jul 2026 Co. No. Structure Starting Material Conditions Spectra Details 374 HN — p-N ° \__ / F             N HC1 salt Compound 372 HCl / 1,4-di oxane, MeOH 409 Zn^~^—\ C r\      NH2 -yN^O o°A F —     N N H HC1 salt Compound 408 HCl / 1,4-di oxane, ACN LC-MS (ESI) (Method 2): Rt = 1.94 min, m / z found 557.3 [M+H]+. SEC (Method 13): Rt = 2.75 min. 413 —\ C r\      NH2 -yNy° n ya formate salt Compound 412 HCl / 1,4-di oxane, MeOH LC-MS (ESI) (Method 1): Rt = 2.885 min, m / z found 542.3 [M+H]+. SEC (Method 13): Rt = 2.347 min. Compound 4 (ft)-2-((5-(2-(6-(dimethylamino)-2-methylhexan-3-yl)-2,6-diazaspiro[3.4]octan-6-yl)- l,2,4-triazin-6-yl)oxy)-7V-ethyl-5-fluoro- / V-isopropylbenzamide 2026205213   01 Jul 2026 To the mixture of (7?)-2-((5-(2-(6-amino-2-methylhexan-3-yl)-2,6-diazaspiro[3.4]octan-6-yl)-l,2,4-triazin-6-yl)oxy)-A-ethyl-5-fluoro-A-isopropylbenzamide hydrochloride (Compound 65) (180 mg, crude), formaldehyde (0.085 mL, 1.1 mmol) and AcOH (0.043 mL, 0.76 mmol) 5 in MeOH (10 mL) was added NaBFLCN (72.0 mg, 1.14 mmol), the resulting mixture was stirred at RT for 2 h. The mixture was filtered and the filtrate was purified by preparative HPLC over Welch Xtimate (column: C18 150x30mm 5um; eluent: ACN / H2O (0.225% FA) from 5% to 25%, v / v) and the desired fractions were collected and freeze dried. The resulting solid was further neutralized by 25% ammonia (15 mL) and extracted with DCM (20 mL x 2). 10 The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give a residue, which was further dissolved in ACN / water and freeze dried to afford the title compound (37.65 mg) as yellow solid. LC-MS (ESI) (Method 1): Rt = 2.95 min, m / z found 556.3 [M+H]+. SEC (Method 4): Rt = 1.772 min. 15 Compound 5, 32, 33, 74, 81,101, 211, 212, 222, 224, 231, 410 (3)-2-((5-(2-(6-(dimethylamino)-2-methylhexan-3-yl)-2,6-diazaspiro[3.4]octan-6-yl)-l,2,4-triazin-6-yl)oxy)-A-ethyl-5-fluoro-A-isopropylbenzamide formate ( *l?)-2-((5-(2-(6-(dimethylamino)-2,6-dimethylheptan-3-yl)-2,6-diazaspiro [3.4] octan-6 20 yl)-l,2,4-triazin-6-yl)oxy)-A-ethyl-5-fluoro-A-isopropylbenzamide (*3)-2-((5-(2-(6-(dimethylamino)-2,6-dimethylheptan-3-yl)-2,6-diazaspiro[3.4]octan-6-yl)-l,2,4-triazin-6-yl)oxy)-A-ethyl-5-fluoro-A-isopropylbenzamide 2-((4-(2-(6-(dimethylamino)-2-methylhexan-3-yl)-2,6-diazaspiro[3.4]octan-6-yl)pyridazin-3-yl)oxy)-5-fluoro-A^V-diisopropylbenzamide 25 2-((4-(2-(6-(dimethylamino)-2-methylhexan-3-yl)-2,6-diazaspiro[3.4]octan-6-yl)pyridazin-3-yl)oxy)-A-ethyl-5-fluoro-A-isopropylbenzamide 2-((5-(2-(6-(dimethylamino)-2-methylhexan-3-yl)-2,6-diazaspiro[3.4]octan-6-yl)-l,2,4-triazin-6-yl)oxy)-5-fluoro-A^V-diisopropylbenzamide 2026205213   01 Jul 2026 (*l?)-2-((5-(2-(7-(dimethylamino)-2-methylheptan-3-yl)-2,6-diazaspiro[3.4]octan-6-yl)- l,2,4-triazin-6-yl)oxy)-7V-ethyl-5-fluoro- / V-isopropylbenzamide (*3)-2-((5-(2-(7-(dimethylamino)-2-methylheptan-3-yl)-2,6-diazaspiro[3.4]octan-6-yl)- l,2,4-triazin-6-yl)oxy)-7V-ethyl-5-fluoro- / V-isopropylbenzamide 5 (*lf)-2-((5-(2-(l-(dimethylamino)-4-methylpentan-3-yl)-2,6-diazaspiro[3.4]octan-6-yl)- l,2,4-triazin-6-yl)oxy)-7V-ethyl-5-fluoro- / V-isopropylbenzamide (*3)-2-((5-(2-(l-(dimethylamino)-4-methylpentan-3-yl)-2,6-diazaspiro[3.4]octan-6-yl)- l,2,4-triazin-6-yl)oxy)-7V-ethyl-5-fluoro- / V-isopropylbenzamide (*lf)-2-((5-(2-(l-((2-amino-2-oxoethyl)(methyl)amino)-4-methylpentan-3-yl)-2,6- 10 diazaspiro[3.4]octan-6-yl)-l,2,4-triazin-6-yl)oxy)-7V-ethyl-5-fluoro- / V- isopropylbenzamide (ft)-2-((5-(2-(6-(dimethylamino)-2-methylhexan-3-yl)-2,6-diazaspiro[3.4]octan-6-yl)-3-methoxy-l,2,4-triazin-6-yl)oxy)-7V-ethyl-5-fluoro- / V-isopropylbenzamide formate 15 The following Compounds were synthesized by an analogous method described above for Compound 4 Co. No. Structure Starting Materials Spectra Details 5 r \       / N— yny° V   7 formate salt Compound 66 LC-MS (Method 1): Rt = 2.977 min, m / z found 556.4 [M+H]+. SFC (Method 4):Rt= 1 402 min. 32 / Z—\ \ o o Z— / <!                /     1 z   x)—z \=zZ         \     / 1-2 J. 30J "z^ 1 Compound 30 LC-MS (ESI) (Method 2): Rt = 2.043 min, m / z found 584.3 [M+H]+. SFC (Method 2):Rt = 4 431 min. 2026205213   01 Jul 2026 Co. No. Structure Starting Materials Spectra Details 33 y=\   \ o O Z— / Y A Compound 31 LC-MS (ESI) (Method 2): Rt = 2.008 min, m / z found 584.3 [M+H]+. SEC (Method 2): Rt = 4 997 min. 74 r-N '—\ Y A1 Y vV V fjI j F            N Compound 73 LC-MS (ESI) (Method 2): Rt = 1.933 min, m / z found 569.4 [M+H]+. 81 ^z Y>Y o O \—z \= / Y " Compound 80 101 ^z z-n L z\ z Y / )=z o Yb Y " Compound 97 2026205213   01 Jul 2026 Co. No. Structure Starting Materials Spectra Details 211 C— O ^z^ Compound 209 LC-MS (ESI) (Method 2): Rt = 1.946 min, m / z found 570.3 [M+H]+. SEC (Method 8): Rt = 2.243 min. 212 ^z^ rw o O\ \—\=^ Compound 210 LC-MS (ESI) (Method 1): Rt = 3.021 min, m / z found 570.3 [M+H]+. SEC (Method 8): Rt = 2.431 min. 222 / =\ / Z^^ \ o o , L—z * 1 70 1 ^Z^ Compound 220 224 / =\ / Z^^ \ o o ? ^z^ Compound 221 2026205213   01 Jul 2026 Co. No. Structure Starting Materials Spectra Details 231 N R        NH2 rr N'N^ Compound 230 LC-MS (ESI) (Method 1): Rt = 2.858 min, m / z found 585.3 [M+H]+. SEC (Method 6): Rt = 1 454 min. 410 r-NR^—. r A1 r A°A formate salt Compound 407 LC-MS (ESI) (Method 2): Rt = 2.066 min, m / z found 586.3 [M+H]+. SEC (Method 14): Rt = 2.582 min. Compound 75, 76 ( *l?)-2-((4-(2-(6-(dimethylamino)-2-methylhexan-3-yl)-2,6-diazaspiro [3.4] octan-6-yl)pyridazin-3-yl)oxy)-5-flnoro-A^^V-diisopropylbenzamide 5 (*3)-2-((4-(2-(6-(dimethylamino)-2-methylhexan-3-yl)-2,6-diazaspiro[3.4]octan-6- yl)pyridazin-3-yl)oxy)-5-fluoro-A^^V-diisopropylbenzamide 2026205213   01 Jul 2026 Compound 76 2-((4-(2-(6-(dimethylamino)-2-methylhexan-3-yl)-2,6-diazaspiro[3.4]octan-6-yl)pyridazin-3-yl)oxy)-5-fluoro-A,A-diisopropylbenzamide (Compound 74) (600 mg) was separated by chiral HPLC over DAICEL CHIRALPAK IG (column: 250x30mm lOum; Mobile phase: A: 5 Heptane, B: EtOH, A:B from 20% to 70% (v / v); flowrate: 25 mL / min) to afford the title compounds Compound 75 (92 mg, 15%) and Compound 76 (84 mg) as white solid. Compound 75 LC-MS (ESI) (Method 2): Rt = 1.915 min, m / z found 569.3 [M+H]+. Chiral HPLC (Method 4): Rt = 4 842 min 10 Compound 76 LC-MS (ESI) (Method 2): Rt = 1.924 min, m / z found 569.3 [M+H]+. Chiral HPLC (Method 4): Rt = 6 200 min Compound 77, 78 15   ( *l?)-2-((4-(2-(6-(dimethylamino)-2-methylhexan-3-yl)-2,6-diazaspiro [3.4] octan-6- yl)pyridazin-3-yl)oxy)-A-ethyl-5-fluoro-A-isopropylbenzamide (*3)-2-((4-(2-(6-(dimethylamino)-2-methylhexan-3-yl)-2,6-diazaspiro[3.4]octan-6- yl)pyridazin-3-yl)oxy)-A-ethyl-5-fluoro-A-isopropylbenzamide 2026205213   01 Jul 2026 Compound 78 2-((4-(2-(6-(dimethylamino)-2-methylhexan-3-yl)-2,6-diazaspiro[3.4]octan-6-yl)pyridazin-3-yl)oxy)-7V-ethyl-5-fluoro-7V-isopropylbenzamide (Compound 81) (31.0 mg) was separated by SFC over DAICEL CHIRALPAK IE (column: 250x30mm lOum; eluent: 100% MeOH (0.1% 5 ammonia); flowrate: 25 mL / min) to afford the title compounds Compound 77 (4.2 mg) and Compound 78 (1.3 mg) as white solid. Compound 77 LC-MS (ESI) (Method 3): Rt = 5.039 min, m / z found 555.3 [M+H]+. Chiral HPLC (Method 2): Rt = 7 719 min 10 Compound 78 LC-MS (ESI) (Method 3): Rt = 4.870 min, m / z found 555.3 [M+H]+. Chiral HPLC (Method 2): Rt = 8 754 min Compound 105,106 15   ( *l?)-2-((5-(2-(6-(dimethylamino)-2-methylhexan-3-yl)-2,6-diazaspiro [3.4] octan-6-yl)- l,2,4-triazin-6-yl)oxy)-5-fluoro-A^V-diisopropylbenzamide (*3)-2-((5-(2-(6-(dimethylamino)-2-methylhexan-3-yl)-2,6-diazaspiro[3.4]octan-6-yl)- l,2,4-triazin-6-yl)oxy)-5-fluoro-A^V-diisopropylbenzamide 2026205213   01 Jul 2026 Compound 106 2-((5-(2-(6-(dimethylamino)-2-methylhexan-3-yl)-2,6-diazaspiro[3.4]octan-6-yl)-l,2,4-triazin-6-yl)oxy)-5-fluoro-A,A-diisopropylbenzamide (Compound 101) (1.5 g) was obtained by SFC over DAICEL CHIRALPAK IG (column: 250x50mm lOum; Mobile phase: A: 5 Supercritical CO2, B: MeOH (0.1% ammonia), A:B = 55:45 at 200 mL / min; Column Temp: 38 ; Nozzle Pressure: lOOBar; Nozzle Temp: 60 ; Evaporator Temp: 20 ; Trimmer Temp: 25 ; Wavelength: 220nm) to afford the title compounds Compound 105 (600 mg, 40.0 % yield) and Compound 106 (600 mg, 40.0 % yield) as white solid. 10 Compound 102 ( *l?)-2-((5-(2-(6-(dimethylamino)-2-methylhexan-3-yl)-2,6-diazaspiro [3.4] octan-6-yl)- 1,2,4-triazin-6-yl)oxy)-5-fluoro-A^V-diisopropylbenzamide fumarate Compound 105 Compound 102 To a solution of (*A)-2-((5-(2-(6-(dimethylamino)-2-methylhexan-3-yl)-2,6- 15 diazaspiro[3.4]octan-6-yl)-l,2,4-triazin-6-yl)oxy)-5-fluoro-A,A-diisopropylbenzamide (Compound 105) (300 mg, 0.527 mmol) in ACN (12 mL) and water (4 mL) was added 2026205213   01 Jul 2026 fumaric acid (123 mg, 1.06 mmol). After a clear solution was formed, the mixture was concentrated under reduced pressure, the resulting residue was added to a mixture of ACN (3 mL) and water (10 mL). The mixture was lyophilized to dryness to afford the title compound (422 mg) as a white solid. 5 'H NMR(400 MHz, Methanol-* / ^: 6 = 8.50 (s, 1H), 7.50-7.15 (m, 3H), 6.72 (s, 4H), 4.513.89 (m, 7H), 3.86-3.69 (m, 2H), 3.61-3.49 (m, 1H), 3.25-3.07 (m, 3H), 2.88 (s, 6H), 2.502.20 (m, 2H), 2.19-2.06 (m, 1H), 1.97-1.77 (m, 2H), 1.75-1.57 (m, 2H), 1.51 (d, 7=6.8 Hz, 3H), 1.37-1.14 (m, 6H), 1.11-0.97 (m, 6H), 0.78 (d, 7=6.0 Hz, 3H). LC-MS (ESI) (Method 2): Rt = 2.08 min, m / z found 570.3 [M+H]+. 10 SEC (Method 4): Rt = 1.284 min. Compound 103,112,114,122,123,127,128,132,133,135,137,140,142,145,146,148, 150,152,154,157,159,161,165,167,170,172,176,177,179,181,184,185,188,189,191, 193,195,197,199, 201, 203, 205, 219, 223, 225, 227, 233, 240, 241, 242, 243, 245, 256, 265, 15   266, 268, 270, 278, 280, 283, 259,104, 229, 300, 302, 314, 315, 323, 324, 325, 326, 334, 335, 336, 337, 342, 343, 346, 352, 353, 356, 357, 365, 366, 369, 370, 377, 378, 382, 386, 387, 391, 392, 394, 397 (*3)-2-((5-(2-(6-(dimethylamino)-2-methylhexan-3-yl)-2,6-diazaspiro[3.4]octan-6-yl)-1,2,4-triazin-6-yl)oxy)-5-11 uoro- VA-diisopropylbenzamide fumarate 20 7V-ethyl-5-fluoro-A-isopropyl-2-((5-(2-((lO-6-(((lO-l-methoxypropan-2-yl)amino)-2-methylhexan-3-yl)-2,6-diazaspiro[3.41octan-6-yl)-l,2,4-triazin-6-yl)oxy)benzamide fumarate (10-2-((5-(2-(6-((3,3-difluoropropyl)amino)-2-methylhexan-3-yl)-2,6-diazaspiro[3.4]octan-6-yl)-l,2,4-triazin-6-yl)oxy)-A-ethyl-5-fluoro-A-25 isopropylbenzamide fumarate (*lO-A-ethyl-5-fluoro-A-isopropyl-2-((5-(2-(6-(isopropyl(methyl)amino)-2-methylhexan-3-yl)-2,6-diazaspiro[3.41octan-6-yl)-l,2,4-triazin-6-yl)oxy)benzamide fumarate (*5)-A-ethyl-5-fluoro7V-isopropyl-2-((5-(2-(6-(isopropyl(methyl)amino)-2-methylhexan-3-yl)-2,6-diazaspiro[3.41octan-6-yl)-l,2,4-triazin-6-yl)oxy)benzamide fumarate 30 (*l?)-A-ethyl-5-fluoro-A-isopropyl-2-((5-(2-(2-methyl-6-(methyl(propyl)amino)hexan-3-yl)-2,6-diazaspiro[3.4]octan-6-yl)-l,2,4-triazin-6-yl)oxy)benzamide fumarate (*5)-A-ethyl-5-fluoro-A-isopropyl-2-((5-(2-(2-methyl-6-(methyl(propyl)amino)hexan-3-yl)-2,6-diazaspiro[3.4]octan-6-yl)-l,2,4-triazin-6-yl)oxy)benzamide fumarate 2026205213   01 Jul 2026 (*lf)-7V-ethyl-2-((5-(2-(6-(ethyl(methyl)amino)-2-methylhexan-3-yl)-2,6- diazaspiro[3.4]octan-6-yl)-l,2,4-triazin-6-yl)oxy)-5-fluoro-7V-isopropylbenzamide fumarate (*3)-7V-ethyl-2-((5-(2-(6-(ethyl(methyl)amino)-2-methylhexan-3-yl)-2,6- 5 diazaspiro[3.4]octan-6-yl)-l,2,4-triazin-6-yl)oxy)-5-fluoro-7V-isopropylbenzamide fumarate (!O-7V-ethyl-5-fluoro-7V-isoDroDyl-2-((5-(2-(6-((2-methoxy-2-methylDroDyl)amino)-2- methylhexan-3-yl)-2,6-diazasDiro[3.4]octan-6-yl)-l,2,4-triazin-6-yl)oxy)benzamide fumarate 10   (!O-7V-ethyl-5-fluoro-7V-isoDroDyl-2-((5-(2-(6-((2-methoxy-2- methylDroDyl)(methyl)amino)-2-methylhexan-3-yl)-2,6-diazasDiro[3.4]octan-6-yl)-l,2,4-triazin-6-yl)oxy)benzamide fumarate (!O-7V-ethyl-5-fluoro-2-((5-(2-(6-((2-hydroxy-2-methylDroDyl)(methyl)amino)-2- methylhexan-3-yl)-2,6-diazasDiro[3.4]octan-6-yl)-l,2,4-triazin-6-yl)oxy)-7V- 15 isoproDylbenzamide fumarate (!O-7V-ethyl-5-fluoro-7V-isoDroDyl-2-((5-(2-(6-((3-methoxyDroDyl)(methyl)amino)-2-methylhexan-3-yl)-2,6-diazasDiro[3.41octan-6-yl)-l,2,4-triazin-6-yl)oxy)benzamide fumarate (*!O-2-((5-(2-(6-((3-(dimethylamino)-3-oxoDroDyl)(methyl)amino)-2-methylhexan-3-yr)- 20 2,6-diazasDiro[3.41octan-6-yl)-l,2,4-triazin-6-yl)oxy)-5-fluoro-A^^V-diisoDroDylbenzamide fumarate (*5)-2-((5-(2-(6-((3-(dimethylamino)-3-oxoDroDyl)(methyl)amino)-2-methylhexan-3-yl)- 2,6-diazasDiro[3.41octan-6-yl)-l,2,4-triazin-6-yl)oxy)-5-fluoro-A^^V-diisoDroDylbenzamide fumarate 25 (K)-7V-ethyl-5-fluoro-7V-isopropyl-2-((5-(2-(2-methyl-6-(methyl(2-(7V- methylacetamido)ethyl)amino)hexan-3-yl)-2,6-diazaspiro[3.4]octan-6-yl)-l,2,4-triazin-6-yl)oxy)benzamide fumarate (K)-2-((5-(2-(6-((2,2-dimethoxyethyl)(methyl)amino)-2-methylhexan-3-yl)-2,6-diazaspiro[3.4]octan-6-yl)-l,2,4-triazin-6-yl)oxy)-7V-ethyl-5-fluoro-7V- 30 isopropylbenzamide fumarate (K)-2-((5-(2-(6-((4-(dimethylamino)-4-oxobutyl)(methyl)amino)-2-methylhexan-3-yl)-2,6-diazaspiro[3.4]octan-6-yl)-l,2,4-triazin-6-yl)oxy)-7V-ethyl-5-fluoro-7V-isopropylbenzamide fumarate 2026205213   01 Jul 2026 7V-ethyl-5-fluoro-7V-isoDroDyl-2-((5-(2-((lO-6-(((lO-l-methoxyDroDan-2-yl)(methyl)amino)-2-methylhexan-3-yl)-2,6-diazasDiro[3.4]octan-6-yl)-l,2,4-triazin-6-yl)oxy)benzamide fumarate ALethyl-5-fluoro-Az-isoDroDyl-2-((5-(2-((l?)-6-(((5)-l-methoxyDroDan-2- 5 yl)(methyl)amino)-2-methylhexan-3-yl)-2,6-diazasDiro[3.4]octan-6-yl)-l,2,4-triazin-6-yl)oxy)benzamide fumarate (10-2-((5-(2-(6-((1,3-dimethoxyDroDan-2-yl)amino)-2-methylhexan-3-yl)-2,6-diazasDiro[3.4]octan-6-yl)-l,2,4-triazin-6-yl)oxy)-7V-ethyl-5-fluoro-7V-isoDroDylbenzamide fumarate 10   (10-2-((5-(2-(6-((1,3-dimethoxyDroDan-2-yl)(methyl)amino)-2-methylhexan-3-yl)-2,6- diazasDiro[3.4]octan-6-yl)-l,2,4-triazin-6-yl)oxy)-7V-ethyl-5-fluoro-7V-isoDroDylbenzamide fumarate 7V-ethyl-5-fluoro-2-((5-(2-((lO-6-(((lO-l-hydroxy-3-methoxyDroDan-2-yl)(methyl)amino)-2-methylhexan-3-yl)-2,6-diazasDiro[3.4]octan-6-yl)-l,2,4-triazin-6-yl)oxy)-7V- 15 isoproDylbenzamide fumarate 7V-ethyl-5-fluoro-2-((5-(2-((lO-6-(((5)-l-hydroxy-3-methoxyDroDan-2-yl)(methyl)amino)-2-methylhexan-3-yl)-2,6-diazasDiro[3.4]octan-6-yl)-l,2,4-triazin-6-yl)oxy)-7V-isoDroDylbenzamide fumarate 7V-ethyl-5-fluoro-2-((5-(2-((31O-6-((3-hydroxy-2-methoxyDroDyl)(methyl)amino)-2- 20 methylhexan-3-yl)-2,6-diazasDiro[3.4]octan-6-yl)-l,2,4-triazin-6-yl)oxy)-7V-isoDroDylbenzamide fumarate 2-((5-(2-((31?)-6-((2,3-dimethoxypropyl)amino)-2-methylhexan-3-yl)-2,6-diazaspiro[3.4]octan-6-yl)-l,2,4-triazin-6-yl)oxy)-7V-ethyl-5-fluoro-7V-isopropylbenzamide fumarate 25 2-((5-(2-((!O-6-(((*lO-2,3-dimethoxyDroDyl)(methyl)amino)-2-methylhexan-3-yl)-2,6-diazasDiro[3.4]octan-6-yl)-l,2,4-triazin-6-yl)oxy)-7V-ethyl-5-fluoro-7V-isoDroDylbenzamide fumarate 2-((5-(2-((10-6-((^5)-2,3-dimethoxyDroDyl)(methyl)amino)-2-methylhexan-3-yl)-2,6-diazasDiro[3.4]octan-6-yl)-l,2,4-triazin-6-yl)oxy)-7V-ethyl-5-fluoro-7V- 30 isoproDylbenzamide fumarate 2-((5-(2-((310-6-((4-(dimethylamino)-4-oxobutan-2-yl)(methyl)amino)-2-methylhexan-3-yl)-2,6-diazaspiro[3.4]octan-6-yl)-l,2,4-triazin-6-yl)oxy)-7V-ethyl-5-fluoro-7V-isopropylbenzamide fumarate 2026205213   01 Jul 2026 2-((5-(2-((31f)-6-((3-(dimethylamino)-2-methyl-3-oxopropyl)(methyl)amino)-2-methylhexan-3-yl)-2,6-diazaspiro[3.4]octan-6-yl)-l,2,4-triazin-6-yl)oxy)-7V-ethyl-5-fluoro-7V-isopropylbenzamide fumarate 2-((5-(2-((lO-6-(((*lO-4-(dimethylamino)-4-oxobutan-2-yl)(methyl)amino)-2- 5 methylhexan-3-yl)-2,6-diazasDiro[3.4]octan-6-yl)-l,2,4-triazin-6-yl)oxy)-7V-ethyl-5-fluoro-A^isoproDylbenzamide fumarate 2-((5-(2-((lO-6-(((*3')-4-(dimethylamino)-4-oxobutan-2-yl)(methyl)amino)-2-methylhexan-3-yl)-2,6-diazasDiro[3.4]octan-6-yl)-l,2,4-triazin-6-yl)oxy)-7V-ethyl-5-fluoro-A^isoproDylbenzamide fumarate 10 2-((5-(2-((K)-6-(((*lf)-3-(dimethylamino)-2-methyl-3-oxopropyl)(methyl)amino)-2-methylhexan-3-yl)-2,6-diazaspiro[3.4]octan-6-yl)-l,2,4-triazin-6-yl)oxy)-7V-ethyl-5-fluoro-A^-isopropylbenzamide fumarate 2-((5-(2-((1^)-6-((( *3)-3-(dimethylamino)-2-methyl-3-oxopropyl)(methyl)amino)-2-methylhexan-3-yl)-2,6-diazaspiro[3.4]octan-6-yl)-l,2,4-triazin-6-yl)oxy)-7V-ethyl-5- 15 fluoro-A^-isopropylbenzamide fumarate 7V-ethyl-5-fluoro-7V-isopropyl-2-((5-(2-((lf)-2-methyl-6-(methyl((lf)-4-(methylamino)-4-oxobutan-2-yl)amino)hexan-3-yl)-2,6-diazaspiro[3.4]octan-6-yl)-l,2,4-triazin-6-yl)oxy)benzamide fumarate 7V-ethyl-5-fluoro-7V-isopropyl-2-((5-(2-((lf)-2-methyl-6-(methyl((3')-4-(methylamino)-4- 20 oxobutan-2-yl)amino)hexan-3-yl)-2,6-diazaspiro[3.4]octan-6-yl)-l,2,4-triazin-6-yl)oxy)benzamide fumarate 7V-ethyl-5-fluoro-7V-isopropyl-2-((5-(2-((lf)-2-methyl-6-(methyl((lf)-2-methyl-3-(methylamino)-3-oxopropyl)amino)hexan-3-yl)-2,6-diazaspiro[3.4]octan-6-yl)-l,2,4-triazin-6-yl)oxy)benzamide fumarate 25 7V-ethyl-5-fluoro-7V-isopropyl-2-((5-(2-((lf)-2-methyl-6-(methyl((3')-2-methyl-3-(methylamino)-3-oxopropyl)amino)hexan-3-yl)-2,6-diazaspiro[3.4]octan-6-yl)-l,2,4-triazin-6-yl)oxy)benzamide fumarate 2-((5-(2-(( *lf)-6-(((K)-4-amino-4-oxobutan-2-yl)(methyl)amino)-2-methylhexan-3-yl)-2,6-diazaspiro[3.4]octan-6-yl)-l,2,4-triazin-6-yl)oxy)-5-fluoro-A^^V-diisopropylbenzamide 30 fumarate 2-((5-(2-(( *lf)-6-(((S)-4-amino-4-oxobutan-2-yl)(methyl)amino)-2-methylhexan-3-yl)-2,6-diazaspiro[3.4]octan-6-yl)-l,2,4-triazin-6-yl)oxy)-5-fluoro-A^^V-diisopropylbenzamide fumarate 2026205213   01 Jul 2026 2-((5-(2-(( *lf)-6-(((K)-3-amino-2-methyl-3-oxopropyl)(methyl)amino)-2-methylhexan-3-yl)-2,6-diazaspiro[3.4]octan-6-yl)-l,2,4-triazin-6-yl)oxy)-5-fluoro-Af^V-diisopropylbenzamide fumarate 2-((5-(2-(( *lf)-6-(((S)-3-amino-2-methyl-3-oxopropyl)(methyl)amino)-2-methylhexan-3- 5 yl)-2,6-diazaspiro[3.4]octan-6-yl)-l,2,4-triazin-6-yl)oxy)-5-fluoro-Af^V- diisopropylbenzamide fumarate (*lf)-2-((5-(2-(l-amino-4-methylpentan-3-yl)-2,6-diazaspiro[3.4]octan-6-yl)-l,2,4-triazin- 6-yl)oxy)-7V-ethyl-5-fluoro-7V-isopropylbenzamide fumarate (*lf)-2-((5-(2-(l-(dimethylamino)-4-methylpentan-3-yl)-2,6-diazaspiro[3.4]octan-6-yl)- 10 l,2,4-triazin-6-yl)oxy)-7V-ethyl-5-fluoro-7V-isopropylbenzamide fumarate (*3)-2-((5-(2-(l-(dimethylamino)-4-methylpentan-3-yl)-2,6-diazaspiro[3.4]octan-6-yl)-l,2,4-triazin-6-yl)oxy)-7V-ethyl-5-fluoro-7V-isopropylbenzamide fumarate (*!O-7V-ethyl-5-fluoro-7V-isoDroDyl-2-((5-(2-(l-((2-methoxyethyl)amino)-4-methylDentan-3-yl)-2,6-diazasDiro[3.41octan-6-yl)-l,2,4-triazin-6-yl)oxy)benzamide fumarate 15 (K)-7V-ethyl-5-fluoro-7V-isopropyl-2-((5-(2-(6-((2-methoxyethyl-l,l-< / 2)(niethyl)amino)-2-methylhexan-3-yl)-2,6-diazaspiro[3.4]octan-6-yl)-l,2,4-triazin-6-yl)oxy)benzamide fumarate 7V-ethyl-5-fluoro-7V-isopropyl-2-((5-(2-((3*lf,5*lf)-6-((2-methoxyethyl)(methyl)amino)- 2,5-dimethylhexan-3-yl)-2,6-diazaspiro[3.4]octan-6-yl)-l,2,4-triazin-6-yl)oxy)benzamide 20 fumarate 7V-ethyl-5-fluoro-7V-isopropyl-2-((5-(2-((3*3',5*lf)-6-((2-methoxyethyl)(methyl)amino)- 2,5-dimethylhexan-3-yl)-2,6-diazaspiro[3.4]octan-6-yl)-l,2,4-triazin-6-yl)oxy)benzamide fumarate ALethyl-5-fluoro-Az-isopropyl-2-((5-(2-((3*l?,5*5)-6-((2-methoxyethyl)(methyl)amino)- 25 2,5-dimethylhexan-3-yl)-2,6-diazaspiro[3.4]octan-6-yl)-l,2,4-triazin-6-yl)oxy)benzamide fumarate 7V-ethyl-5-fluoro-7V-isopropyl-2-((5-(2-((3*3',5*3)-6-((2-methoxyethyl)(methyl)amino)-2,5-dimethylhexan-3-yl)-2,6-diazaspiro[3.4]octan-6-yl)-l,2,4-triazin-6-yl)oxy)benzamide fumarate 30 (l?)-2-((5-(2-(6-((2-acetamidoethyl)(methyl)amino)-2-methylhexan-3-yl)-2,6-diazaspiro[3.4]octan-6-yl)-l,2,4-triazin-6-yl)oxy)-7V-ethyl-5-fluoro-7V- isopropylbenzamide fumarate 2026205213   01 Jul 2026 (1^)-2-((5-(2-(6-((1,3-dihydroxypropan-2-yl)(methyl)amino)-2-methylhexan-3-yl)-2,6-diazaspiro[3.4]octan-6-yl)-l,2,4-triazin-6-yl)oxy)-7V-ethyl-5-fluoro-7V-isopropylbenzamide fumarate 7V-ethyl-5-fluoro-7V-isopropyl-2-((5-(2-(6-((2-methoxyethyl)(methyl)amino)-2,4- 5 dimethylhexan-3-yl)-2,6-diazaspiro[3.4]octan-6-yl)-l,2,4-triazin-6-yl)oxy)benzamide (mixture of R,S and S,R; or mixture of R,R and S^S) fumarate 7V-ethyl-5-fluoro-7V-isopropyl-2-((5-(2-(6-((2-methoxyethyl)(methyl)amino)-2,4-dimethylhexan-3-yl)-2,6-diazaspiro[3.4]octan-6-yl)-l,2,4-triazin-6-yl)oxy)benzamide (mixture of R,R and S^S; or mixture of R,S and S,R) fumarate 10   (*l?)-Az-ethyl-5-fluoro-2-((5-(2-(l-((2-hydroxyethyl)amino)-4-methylpentan-3-yl)-2,6- diazaspiro[3.4]octan-6-yl)-l,2,4-triazin-6-yl)oxy)-7V-isopropylbenzamide fumarate (*lf)-7V-ethyl-5-fluoro-2-((5-(2-(l-((2-hydroxyethyl)(methyl)amino)-4-methylpentan-3-yl)-2,6-diazaspiro[3.4]octan-6-yl)-l,2,4-triazin-6-yl)oxy)-7V-isopropylbenzamide fumarate 15   (*l?)-2-((5-(2-(l-((3-amino-3-oxopropyl)amino)-4-methylpentan-3-yl)-2,6- diazaspiro[3.4]octan-6-yl)-l,2,4-triazin-6-yl)oxy)-7V-ethyl-5-fluoro-7V-isopropylbenzamide fumarate (*l?)-2-((5-(2-(l-((3-amino-3-oxopropyl)(methyl)amino)-4-methylpentan-3-yl)-2,6-diazaspiro[3.4]octan-6-yl)-l,2,4-triazin-6-yl)oxy)-7V-ethyl-5-fluoro-7V- 20 isopropylbenzamide fumarate 7V-ethyl-5-fluoro-2-((5-(2-((K)-6-(((K)-2-hydroxy-3-methoxypropyl)(methyl)amino)-2-methylhexan-3-yl)-2,6-diazaspiro[3.4]octan-6-yl)-l,2,4-triazin-6-yl)oxy)-7V-isopropylbenzamide fumarate (K)-7V-ethyl-5-fluoro-2-((5-(2-(6-((2-hydroxyethyl)(methyl)amino)-2-methylhexan-3-yl)-25 2,6-diazaspiro[3.4]octan-6-yl)-l,2,4-triazin-6-yl)oxy)-7V-isopropylbenzamide fumarate (K)-2-((5-(2-(6-((2,2-dimethoxyethyl)amino)-2-methylhexan-3-yl)-2,6-diazaspiro[3.4]octan-6-yl)-l,2,4-triazin-6-yl)oxy)-7V-ethyl-5-fluoro-7V-isopropylbenzamide fumarate (*lf)-7V-ethyl-5-fluoro-7V-isopropyl-2-((5-(2-(l-(isopropylamino)-4-methylpentan-3-yl)-30 2,6-diazaspiro[3.4]octan-6-yl)-l,2,4-triazin-6-yl)oxy)benzamide fumarate 7V-ethyl-5-fluoro-7V-isopropyl-2-((5-(2-((31f)-6-((2-methoxyethyl)(methyl)amino)-2-methylheptan-3-yl)-2,6-diazaspiro[3.4]octan-6-yl)-l,2,4-triazin-6-yl)oxy)benzamide fumarate 2026205213   01 Jul 2026 7V-ethyl-5-fluoro-7V-isopropyl-2-((5-(6-(6-((2-methoxyethyl)(methyl)amino)-2-methylhexan-3-yl)-2,6-diazaspiro[3.4]octan-2-yl)-l,2,4-triazin-6-yl)oxy)benzamide fumarate 2-((5-(2-((3 *R, 5 *l?)-6-(dimethylamino)-5-methoxy-2-methylhexan-3-yl)-2,6- 5 diazaspiro[3.4]octan-6-yl)-l,2,4-triazin-6-yl)oxy)-7V-ethyl-5-fluoro-7V-isopropylbenzamide fumarate 2-((5-(2-((3 *R, 5 *5)-6-(dimethylamino)-5-methoxy-2-methylhexan-3-yl)-2,6-diazaspiro[3.4]octan-6-yl)-l,2,4-triazin-6-yl)oxy)-7V-ethyl-5-fluoro-7V-isopropylbenzamide fumarate 10   7V-ethyl-5-fluoro-2-((5-(2-((3 *R,5 *l?)-5-hydroxy-6-(isopropyl(methyl)amino)-2- methylhexan-3-yl)-2,6-diazaspiro[3.4]octan-6-yl)-l,2,4-triazin-6-yl)oxy)-7V-isopropylbenzamide fumarate 7V-ethyl-5-fluoro-2-((5-(2-((3*5,5*5)-5-hydroxy-6-(isopropyl(methyl)amino)-2-methylhexan-3-yl)-2,6-diazaspiro[3.4]octan-6-yl)-l,2,4-triazin-6-yl)oxy)-7V- 15 isopropylbenzamide fumarate ALethyl-5-fluoro-2-((5-(2-((3*l?,5*5)-5-hydroxy-6-(isopropyl(methyl)amino)-2-methylhexan-3-yl)-2,6-diazaspiro[3.4]octan-6-yl)-l,2,4-triazin-6-yl)oxy)-7V-isopropylbenzamide fumarate 7V-ethyl-5-fluoro-2-((5-(2-((3 *S,5*R)~ 5-hydroxy-6-(isopropyl(methyl)amino)-2- 20 methylhexan-3-yl)-2,6-diazaspiro[3.4]octan-6-yl)-l,2,4-triazin-6-yl)oxy)-7V-isopropylbenzamide fumarate 2-((5-(2-((3 *R, 5 *lO-6-(diethylamino)-5-hydroxy-2-methylhexan-3-yl)-2,6-diazasDiro[3.4]octan-6-yl)-l,2,4-triazin-6-yl)oxy)-7V-ethyl-5-fluoro-7V-isoDroDylbenzamide fumarate 25   2-((5-(2-((3 *5,5 *5)-6-(diethylamino)-5-hydroxy-2-methylhexan-3-yl)-2,6- diazasDiro[3.4]octan-6-yl)-l,2,4-triazin-6-yl)oxy)-7V-ethyl-5-fluoro-7V-isoproDylbenzamide fumarate 2-((5-(2-((3 *5,5 *lO-6-(diethylamino)-5-hydroxy-2-methylhexan-3-yl)-2,6-diazasDiro[3.4]octan-6-yl)-l,2,4-triazin-6-yl)oxy)-7V-ethyl-5-fluoro-7V- 30 isoDroDylbenzamide fumarate 2-((5-(2-((3 *R, 5 *5)-6-(diethylamino)-5-hydroxy-2-methylhexan-3-yl)-2,6-diazasDiro[3.4]octan-6-yl)-l,2,4-triazin-6-yl)oxy)-7V-ethyl-5-fluoro-7V-isoproDylbenzamide fumarate 2026205213   01 Jul 2026 I—k                                    I—k O - 161 - ALethyl-5-fluoro-2-((5-(2-((3*5',51?)-5-hydroxy-6-((2-methoxyethyl)(methyl)amino)-2-methylhexan-3-yl)-2,6-diazaspiro[3.4]octan-6-yl)-l,2,4-triazin-6-yl)oxy)-7V-isopropylbenzamide fumarate 2-((5-(2-((3 *R, 5 *l?)-6-(dimethylamino)-5-hydroxy-2-methylhexan-3-yl)-2,6-diazaspiro[3.4]octan-6-yl)-l,2,4-triazin-6-yl)oxy)-5-fluoro-A^^V-diisopropylbenzamide isopropylbenzamide fumarate 9P!mKzu9qiXdojdos!-7v-ojonu-g-(Xxo(iX-9-u!ZEuj-t7‘j‘x-(iX-9-uKpo[t7,£]oj!dsKZE!p -9‘Z-(lX-£-uEX9qiXqpm-^-XxojpXq-s-(ou!mE(iXqpm)iXqp)-9-(ys‘^ £))-^)-5))-^-^9-^ 2026205213   01 Jul 2026 2-((5-(2-((3 *5,5 *5)-6-(dimethylamino)-5-methoxy-2-methylhexan-3-yl)-2,6- diazaspiro[3.4]octan-6-yl)-l,2,4-triazin-6-yl)oxy)-7V-ethyl-5-fluoro-7V-isopropylbenzamide fumarate 2-((5-(2-((3 *5,5 *l?)-6-(dimethylamino)-5-methoxy-2-methylhexan-3-yl)-2,6- 5 diazaspiro[3.4]octan-6-yl)-l,2,4-triazin-6-yl)oxy)-7V-ethyl-5-fluoro-7V-isopropylbenzamide fumarate 7V-ethyl-5-fluoro-2-((5-(2-(5-hydroxy-6-((2-methoxyethyl)(methyl)amino)-2,5-dimethylhexan-3-yl)-2,6-diazaspiro[3.4]octan-6-yl)-l,2,4-triazin-6-yl)oxy)-7V-isopropylbenzamide fumarate 10   7V-ethyl-5-fluoro-2-((5-(2-((3 *R,5 *l?)-5-hydroxy-2-methyl-6- (methyl(propyl)amino)hexan-3-yl)-2,6-diazaspiro[3.4]octan-6-yl)-l,2,4-triazin-6-yl)oxy)-A^-isopropylbenzamide fumarate 7V-ethyl-5-fluoro-2-((5-(2-((3 *5,5 *5)-5-hydroxy-2-methyl-6- (methyl(propyl)amino)hexan-3-yl)-2,6-diazaspiro[3.4]octan-6-yl)-l,2,4-triazin-6-yl)oxy)- 15 A^-isopropylbenzamide fumarate 2-((5-(2-((3 *R, 5 *5)-6-(ethyl(methyl)amino)-5-hydroxy-2-methylhexan-3-yl)-2,6- diazaspiro[3.4]octan-6-yl)-l,2,4-triazin-6-yl)oxy)-5-fluoro-A^^V-diisopropylbenzamide fumarate 2-((5-(2-((3*5,5*5)-6-(ethyl(methyl)amino)-5-hydroxy-2-methylhexan-3-yl)-2,6- 20 diazaspiro[3.4]octan-6-yl)-l,2,4-triazin-6-yl)oxy)-5-fluoro-A^^V-diisopropylbenzamide fumarate (K)-2-((3-chloro-5-(2-(6-((2-methoxyethyl)(methyl)amino)-2-methylhexan-3-yl)-2,6-diazaspiro[3.4]octan-6-yl)-l,2,4-triazin-6-yl)oxy)-7V-ethyl-5-fluoro-7V-isopropylbenzamide fumarate 25 (K)-7V-ethyl-5-fluoro-7V-isopropyl-2-((5-(2-(6-((2-methoxyethyl)amino)-2-methylhexan-3-yl)-2,6-diazaspiro[3.4]octan-6-yl)-l,2,4-triazin-6-yl)oxy)benzamide fumarate The following Compounds were synthesized by an analogous method described above for Compound 102 2026205213   01 Jul 2026 Co. No. Structure Starting Materials Spectra Details 103 '■ \ W V  n XJ Fjn ^Y^oh N'Y     0     salt Compound 106, fumaric acid LC-MS (ESI) (Method 2): Rt = 2.041 min, m / z found 570.3 [M+H]+. SEC (Method 13):Rt = 1.722 min. 112 / / —X       / ~° )—v hn—(r r Y i Xj o hv^ 'N         O        salt Compound 111, fumaric acid '11 NMR (400 MHz, Methanol-tfi): 6 = 8.49 (s, 1H), 7.45-7.22 (m, 3H), 6.71 (s, 4H), 4.203.63 (m, 9H), 3.51-3.40 (m, 6H), 3.31-2.95 (m, 5H), 2.47-2.23 (m, 2H), 2.19-1.98 (m, 1H), 1.941.54 (m, 4H), 1.35 (d, / =5.6 Hz, 3H), 1.19-0.98 (m, 13H), 0.89-0.73 (m, 2H). LC-MS (ESI) (Method 1): Rt = 3.063 min, m / z found 600.5 [M+H]+. SEC (Method 6): Rt = 1.214 min. 2026205213   01 Jul 2026 Co. No. Structure Starting Materials Spectra Details 114 /                  F )—< HN—T N R ynC° Q n no ^y^oh F'^^    N       O     salt Compound 113, fumaric acid '11 NMR (400 MHz, Methanol-tfi): 5 = 8.47 (s, 1H), 7.52-7.07 (m, 3H), 6.69 (s, 4H), 6.305.90 (m, 1H), 4.50-3.39 (m, 10H), 3.25-2.83 (m, 6H), 2.43-1.99 (m, 5H), 1.90-1.49 (m, 4H), 1.230.71 (m, 15H). LC-MS (ESI) (Method 1): Rt = 3.056 min, m / z found 606.3 [M+H]+. SEC (Method 13): Rt = 1.944 min. 122 )--\ N—( YAY i Xj o H0 F^^    n     O     salt Compound 120, fumaric acid LC-MS (ESI) (Method 2): Rt = 2.030 min, m / z found 584.3 [M+H]+. SEC (Method 18): Rt = 2.312 min. 123 Aa Xn^\ N *S '---' \ \ _nT*o CT' Yoj   i o n Y F^^    'N     0     salt Compound 121, fumaric acid LC-MS (ESI) (Method 2): Rt = 2.020 min, m / z found 584.3 [M+H]+. SEC (Method 18): Rt = 2.557 min. 2026205213   01 Jul 2026 Co. No. Structure Starting Materials Spectra Details 127 \ )—\ JU U H0 W'-'N^     0       salt Compound 125, fumaric acid LC-MS (ESI) (Method 2): Rt = 2.065 min, m / z found 584.3 [M+H]+. Chiral HPLC (Method 7): Rt = 3.197 min. 128 \ / —\ r u VY v   „ CY   hoV^oh JJ               M .xJ           11 F            'N       0       salt Compound 126, fumaric acid LC-MS (ESI) (Method 2): Rt = 2.074 min, m / z found 584.3 [M+H]+. Chiral HPLC (Method 7): Rt = 3.805 min. 132 Y \ A yy ? i JU U HO^^OH -n /     o       salt Compound 130, fumaric acid LC-MS (ESI) (Method 2): Rt = 1.954 min, m / z found 570.3 [M+H]+. Chiral HPLC (Method 7): Rt = 3.702 min. 133 \ / —\ r Y yT° Y    o m6 ho^^°h 'U     o      salt Compound 131, fumaric acid LC-MS (ESI) (Method 2): Rt= 1.955 min, m / z found 570.3 [M+H]+. Chiral HPLC (Method 7): Rt = 4.808 min. 2026205213   01 Jul 2026 Co. No. Structure Starting Materials Spectra Details 135 Y / -p 'I °\ Vr° V    n jj o v-a F             'N         0        salt Compound 134, fumaric acid LC-MS (ESI) (Method 2): Rt = 2.083 min, m / z found 614.4 [M+H]+. SEC (Method 6): Rt = 1.346 min. 137 \ k.-rN N—, ■—N K \__ /   \ r rP Y w v „ XX KJ h°^^°h F             N        O       salt Compound 136, fumaric acid LC-MS (ESI) (Method 2): Rt = 2.115 min, m / z found 628.4 [M+H]+. SEC (Method 6): Rt = 0.938 min. 140 °Y / v K° __\k w r>              1 o Compound 139, fumaric acid LC-MS (ESI) (Method 2): Rt = 1.986 min, m / z found 614.4 [M+H]+. SEC (Method 13): Rt = 1.749 min. 142 /         o— \ \ / —7 \^|L ZD Y / TAJ   I HD HO^oh F"^^    'N       0     salt Compound 141, fumaric acid LC-MS (ESI) (Method 2): Rt = 2.039 min, m / z found 614.4 [M+H]+. SEC (Method 6): Rt = 1.171 min. 2026205213   01 Jul 2026 Co. No. Structure Starting Materials Spectra Details 145 4 2 A 1      [            N JL^T F              'N        O       salt Compound 143, fumaric acid LC-MS (ESI) (Method 2): Rt = 2.096 min, m / z found 655.6 [M+H]+. SEC (Method 19): Rt = 3.861 min. 146 \^NxLO            / N~\ / 5 ]   [      N            —\ Il 1 Tr N ho        JL ' AJ X JJ Y^oh F              'N        O       salt Compound 144, fumaric acid LC-MS (ESI) (Method 2): Rt = 2.096 min, m / z found 655.6 [M+H]+. SEC (Method 19): Rt = 4.578 min. 148 \ / / U / )—      X° / yy v 0 fYYS -^OH N         O       salt Compound 147, fumaric acid LC-MS (ESI) (Method 3): Rt = 4.480 min, m / z found 641.6 [M+H]+. SEC (Method 6): Rt = 1.356 min. 150 / / °\ / \ \ / ° / —\ N R '—z V /     n Yy ho^^oh 'n^      o       salt Compound 149, fumaric acid LC-MS (ESI) (Method 3): Rt = 4.836 min, m / z found 630.4 [M+H]+. SEC (Method 6): Rt = 1.067 min. 2026205213   01 Jul 2026 Co. No. Structure Starting Materials Spectra Details 152 \ \ / — / '—\ / r-N R          O X rxA i OO "Y^“ 'N         0       salt Compound 151, fumaric acid LC-MS (ESI) (Method 2): Rt = 2.332 min, m / z found 655.5 [M+H]+. SEC (Method 6): Rt = 1.449 min. 154 / / \   \ r° )—\ N—(r N R '-- / \ v" / V    „ rj m hoW-- 'N^      o       salt Compound 153, fumaric acid LC-MS (ESI) (Method 2): Rt = 2.022 min, m / z found 614.4 [M+H]+. SEC (Method 6): Rt = 1.137 min. 157 o=f V           Z"" )=O    Ps. «> <-> Compound 156, fumaric acid LC-MS (ESI) (Method 2): Rt = 2.049 min, m / z found 614.4 [M+H]+. SEC (Method 20): Rt = 1.001 min. 159 / / —\ / —\ HN—( R '— / TV / ? ' O Kj HO^^oh F              N         0        salt Compound 158, fumaric acid LC-MS (ESI) (Method 1): Rt = 3.102 min, m / z found 630.4 [M+H]+. SEC (Method 6): Rt = 1.194 min. 2026205213   01 Jul 2026 Co. No. Structure Starting Materials Spectra Details 161 / / \   \ rQ / —\ N \ R \ n / / “y^oh N         0        salt Compound 160, fumaric acid LC-MS (ESI) (Method 2): Rt = 2.112 min, m / z found 644.3 [M+H]+. SEC (Method 6): Rt = 1.073 min. 165 / / \   \ rQ / —\ N —\R N R '— / ^OH i ry o “y^oh N          O        salt Compound 164, fumaric acid LC-MS (ESI) (Method 3): Rt = 4.766 min, m / z found 630.3 [M+H]+. SEC (Method 6): Rt = 1.271 min. 167 / / \ “° / —\ N^S N R '-- / '—OH "yV0          o AV? h°^^oh 'N          0        salt Compound 166, fumaric acid LC-MS (ESI) (Method 3): Rt = 4.730 min, m / z found 630.3 [M+H]+. SEC (Method 6): Rt = 1.373 min. 170 / /        0 OH / —\ N R '— / YY0        o AV; HOr^ 'n           0        salt Compound 169, fumaric acid LC-MS (ESI) (Method 3): Rt = 4.652 min, m / z found 630.4 [M+H]+. 2026205213   01 Jul 2026 Co. No. Structure Starting Materials Spectra Details 172 / ,       o o— )—\ HN— / R '—7 'TY        ° JO Vj F"^^    N      0     salt Compound 171, fumaric acid LC-MS (ESI) (Method 3): Rt = 5.073 min, m / z found 630.4 [M+H]+. 176 / /      o o— / —\ N—' R N R '—f vC° V     n JU 17 "“y^oh F^^    N       O     salt Compound 174, fumaric acid LC-MS (ESI) (Method 3): Rt = 5.035 min, m / z found 644.5 [M+H]+. SEC (Method 23): Rt = 4.662 min. 177 / /      Q o- / —\      s N R '--- / Vr° V     . JQ U “Y^O" F ^^    'N         O      salt Compound 175, fumaric acid LC-MS (ESI) (Method 3): Rt = 5.031 min, m / z found 644.5 [M+H]+. SEC (Method 23): Rt = 4.977 min. 179 /         O )—\ N—< N— N R '— / \ / YX°U I JU u Y** F^^    N       O     salt Compound 178, fumaric acid LC-MS (ESI) (Method 5): Rt = 1.72 min, m / z found 655.5 [M+H]+. 181 /      \ O )—V  N—' N— N R '— /     z Q     o jo °y5n "y^ F'^c^     N         O      salt Compound 180, fumaric acid LC-MS (ESI) (Method 5): Rt= 1.61 min, m / z found 655.5 [M+H]+. 2026205213   01 Jul 2026 Co. No. Structure Starting Materials Spectra Details 184 /         0 )—\ N—Cr N— N R '---1 >  / Yr0 V     o 'A vA„ JJ .xj KJ xj                  11 N            0        salt Compound 182, fumaric acid LC-MS (ESI) (Method 2): Rt = 2.041 min, m / z found 655.4 [M+H]+. SEC (Method 8): Rt = 2.752 min. 185 /          0 )—\   N—< *s N— N R '— /   '' / Yy° v     n JO O HO^o„ F^^ n'n        0     salt Compound 183, fumaric acid LC-MS (ESI) (Method 2): Rt = 2.058 min, m / z found 655.4 [M+H]+. SEC (Method 8): Rt = 3.09 min. 188 /      \ o )—s. \^ / *r'n— N R '--- /        / Yy0 V     o jYY "“y^ok F^^   'N        O     salt Compound 186, fumaric acid LC-MS (ESI) (Method 3): Rt = 4.940 min, m / z found 655.4 [M+H]+. SEC (Method 23): Rt = 5.055 min. 189 /            <j.    O ;—\ \i—n— N R '--- /        / VV V    „ JO O "“y^oh N            O        salt Compound 187, fumaric acid LC-MS (ESI) (Method 3): Rt = 4.907 min, m / z found 655.4 [M+H]+. SEC (Method 23): Rt = 5.287 min. 2026205213   01 Jul 2026 Co. No. Structure Starting Materials Spectra Details 191 /         0 \      \ r / ' )—\ nA hn— R '--- /    ' 'yC0 Q      o pAA “ / A JU                    KJ                                  11 'N            O        salt Compound 190, fumaric acid LC-MS (ESI) (Method 5): Rt = 1.66 min, m / z found 641.3 [M+H]+. 193 /         0 \      \ S / ' )—<   N-2: HN— N R '— / Q     o (W "“y^oh F             N            0        salt Compound 192, fumaric acid LC-MS (ESI) (Method 5): Rt = 1.70 min, m / z found 641.3 [M+H]+. 195 / \ / ° 2—\ 'n^'^hn— n R '— / yy      . XT 17 “y^ 'N            0        salt Compound 194, fumaric acid LC-MS (ESI) (Method 5): Rt = 1.67 min, m / z found 641.3 [M+H]+. 197 /          O ' \      \ / s ' )—\ N—' b HN— N R '— / YY v    n IJ 17 "“y^h F-^^    'N        0     salt Compound 196, fumaric acid LC-MS (ESI) (Method 5): Rt= 1.85 min, m / z found 641.3 [M+H]+. 199 /         0 )—\   N—(r NH, N‘R      \ YV° v     M o o h F^^   'N        0     salt Compound 198, fumaric acid LC-MS (ESI) (Method 5): Rt = 1.62 min, m / z found 641.3 [M+H]+. 2026205213   01 Jul 2026 Co. No. Structure Starting Materials Spectra Details 201 /         o )—\ N^S NH, nRV-X --,    2 'N            0        salt Compound 200, fumaric acid LC-MS (ESI) (Method 5): Rt = 1.63 min, m / z found 641.3 [M+H]+. 203 /       <  0 )—\^r^nh n^rVx VV° Q / y N'l<          0       salt Compound 202, fumaric acid LC-MS (ESI) (Method 5): Rt = 1.72 min, m / z found 641.3 [M+H]+. 205 /         O \ x 7r^ )—<       s NH2 N *R W V   „ O O "V^ 'N            0        salt Compound 204, fumaric acid LC-MS (ESI) (Method 5): Rt = 1.66 min, m / z found 641.2 [M+H]+. 219 Zn^R^nh2 vNC0 v 0 ON hoy^oh F              N         o        salt Compound 218, fumaric acid LC-MS (ESI) (Method 6): Rt = 2.67 min, m / z found 514.2 [M+H]+. 223 Zn^Vi / / r ' Xj XX HO^oh F             N        o       salt Compound 222, fumaric acid LC-MS (ESI) (Method 3): Rt = 5.047 min, m / z found 542.3 [M+H]+. SEC (Method 18): Rt = 1.991 min. 2026205213   01 Jul 2026 Co. No. Structure Starting Materials Spectra Details 225 a ' fj O F             N        o       salt Compound 224, fumaric acid LC-MS (ESI) (Method 3): Rt = 4.890 min, m / z found 542.3 [M+H]+. SEC (Method 18): Rt = 2.189 min. 227 °— N *R^NH VNY°         n o n h°^oh N       0       salt Compound 226, fumaric acid LC-MS (ESI) (Method 6): Rt = 3.00 min, m / z found 572.3 [M+H]+. 233 ~Y \ ? )-A nYd / N R '--- / VT0       0 O°I^N “Y" 'N         0        salt Compound 232, fumaric acid LC-MS (ESI) (Method 1): Rt = 3.031 min, m / z found 602.3 [M+H]+. SEC (Method 6): Rt = 1.134 min. 240 “X \ 7TA N^\ Ed '' *R ' vV V   „ Jj O HO^oh o        salt Compound 236, fumaric acid LC-MS (ESI) (Method 3): Rt = 5.301 min, m / z found 614.4 [M+H]+. SEC (Method 4): Rt = 1.241 min. 2026205213   01 Jul 2026 Co. No. Structure Starting Materials Spectra Details 241 —\ / —\  N^\ Cl *R       \ \Y V   n XJ 17 ho^^oh N        o       salt Compound 237, fumaric acid LC-MS (ESI) (Method 3): Rt = 5.194 min, m / z found 614.4 [M+H]+. SEC (Method 4): Rt = 1.347 min. 242 “X \ *R)— / J3       X vm V   „ O o h0^°h 'n         o        salt Compound 238, fumaric acid LC-MS (ESI) (Method 3): Rt = 5.284 min, m / z found 614.4 [M+H]+. SEC (Method 14): Rt = 2.358 min. 243 ( \ *S )--- / Cj / ¥    \ vM V   „ JU 17 H0'OH 'N         0        salt Compound 239, fumaric acid LC-MS (ESI) (Method 3): Rt = 5.244 min, m / z found 614.4 [M+H]+. SEC (Method 14): Rt = 2.450 min. 2026205213   01 Jul 2026 Co. No. Structure Starting Materials Spectra Details 245 \ —\   / — / ^NH R           / i O O "“y^-oh N            0       sal* Compound 244, fumaric acid '11 NMR (400 MHz, Methanol-tfi): 8 = 8.51 (brs, 1H), 7.56-7.16 (m, 3H), 6.74 (s, 4H), 4.573.67 (m, 9H), 3.63-3.40 (m, 3H), 3.30-3.08 (m, 6H), 2.87 (s, 3H), 2.482.28 (m, 2H), 2.20-2.07 (m, 1H), 1.98 (s, 3H), 1.92-1.79 (m, 2H), 1.761.52 (m, 2H), 1.26-0.94 (m, 13H), 0.89-0.74 (m, 2H). LC-MS (ESI) (Method 1): Rt = 2.916 min, m / z found 627.4 [M+H]+. SEC (Method 25): Rt = 1.707 min. 256 — /   \ ^OH / —\ N \ N R '— / ^OH ^C0        0 JiWj Y           'N^       o       salt Compound 255, fumaric acid LC-MS (ESI) (Method 1): Rt = 2.932 min, m / z found 616.3 [M+H]+. SEC (Method 6): Rt = 1.383 min. 2026205213   01 Jul 2026 Co. No. Structure Starting Materials Spectra Details 265 \ / \ / —\ \'—1 6 X \ mixture of R,Sand S,R । A A or || N mixture of R,Rand S,S O O        salt Compound 263, fumaric acid LC-MS (ESI) (Method 2): Rt = 2.043 min, m / z found 614.3 [M+H]+. 266 \ / \ / —\ N^\ \'— / < \ x 'yN^O         mixture of R,R and S,S 1 1 n I or ||             N mixture of R,S and S,R f-V M 0 hoy^A>h O        salt Compound 264, fumaric acid LC-MS (ESI) (Method 2): Rt= 1.988 min, m / z found 614.5 [M+H]+. 268 Z^*rAnh X° X Y 0 !      g O O H0 W' °h F ^    'N     o     salt Compound 267, fumaric acid LC-MS (ESI) (Method 5): Rt = 1.45 min, m / z found 558.2 [M+H]+. 270 Z^*rAnz o °h Xj o H0W'°h F"^^    N     0     salt Compound 269, fumaric acid LC-MS (ESI) (Method 5): Rt = 1.49 min, m / z found 572.3 [M+H]+. 2026205213   01 Jul 2026 Co. No. Structure Starting Materials Spectra Details 278 NH^V- NH2 r A3 0 -- / / A O U ho^oh Compound 277, fumaric acid LC-MS (ESI) (Method 5): Rt = 1.54 min, m / z found 585.2 [M+H]+. 280 1 /     NH, r d? '° -- / / A DU ho^oh F            'N          o       salt Compound 279, fumaric acid LC-MS (ESI) (Method 5): Rt = 1.54 min, m / z found 599.3 [M+H]+. 283 /       HO Xo Yy° Q t JUaX     u nn houA>h 'N         O       salt Compound 282, fumaric acid LC-MS (ESI) (Method 1): Rt = 2.605 min, m / z found 630.3 [M+H]+. SEC (Method 6): Rt = 1.303 min. 259 — /    \ / —OH / —\  N—' N R '— / Vy° Q DD H0^ 'N          O       salt Compound 286, fumaric acid LC-MS (ESI) (Method 1): Rt = 2.900 min, m / z found 586.6 [M+H]+. SEC (Method 6): Rt = 1.301 min. 2026205213   01 Jul 2026 Co. No. Structure Starting Materials Spectra Details 104 / /        °\ / —\        / 0 )-\ HN^ N R '—z VT0       0 1^ / 7 HO^o„ N         0        salt Compound 287, fumaric acid '11 NMR (400 MHz, Methanol-t / t): 5 = 8.45 (s, 1H), 7.50-7.09 (m, 3H), 6.67 (s, 4H), 4.483.60 (m, 10H), 3.45 (s, 6H), 3.23-2.87 (m, 6H), 2.44-2.18 (m, 2H), 2.161.96 (m, 1H), 1.89-1.50 (m, 4H), 1.29-0.91 (m, 14H), 0.87-0.70 (m, 2H). LC-MS (ESI) (Method 1): Rt = 3.025 min, m / z found 616.3 [M+H]+. SEC (Method 6): Rt = 1.305 min. 229 Nh” o n hoWoh F^^    N     0     salt Compound 228, fumaric acid LC-MS (ESI) (Method 6): Rt = 2.95 min, m / z found 556.3 [M+H]+. 300 \ . / dA N—t r—N “ \__ /   \ r A ' ' Vr° V    „ rr h hoWoh F"'^'^     'hr       0       salt Compound 299, fumaric acid LC-MS (ESI) (Method 2): Rt = 2.017 min, m / z found 614.4 [M+H]+. Chiral HPLC (Method 8): Rt = 5.212 min. 2026205213   01 Jul 2026 Co. No. Structure Starting Materials Spectra Details 302 . / A       \ o Y / n    n O O ”'Y" 'N       0       salt Compound 301, fumaric acid LC-MS (ESI) (Method 2): Rt = 2.021 min, m / z found 600.7 [M+H]+. 314 \ / *pA   N-— K \__ / yr     . JU“A "U^H 'N        0       salt Compound 310, fumaric acid LC-MS (ESI) (Method 3): Rt = 4.900 min, m / z found 586.3 [M+H]+. SEC (Method ll):Rt = 4.457 min. 315 \ . / *R~\    N-- r—N K \__ / yr '■ . 1 U^ ? JU U ho^^oh F^^    'N     0     salt Compound 312, fumaric acid LC-MS (ESI) (Method 3): Rt = 4.966 min, m / z found 586.3 [M+H]+. SEC (Method ll):Rt = 4.273 min. 323 Xy U    JJ HO' *R YY0       o Y YN hoT^™ 'tC      8       salt Compound 319, fumaric acid LC-MS (ESI) (Method 2): Rt = 2.006 min, m / z found 600.3 [M+H]+. SEC (Method 27): Rt = 2.598 min. 2026205213   01 Jul 2026 Co. No. Structure Starting Materials Spectra Details 324 Yny° v    o XjlJ -A F'"^ / ^     "hr       0       salt Compound 320, fumaric acid LC-MS (ESI) (Method 2): Rt = 2.012 min, m / z found 600.4 [M+H]+. SEC (Method 27): Rt = 4.487 min. 325 /    aj no *s w v 1 Aa^A     n JU UN A    8     salt Compound 321, fumaric acid LC-MS (ESI) (Method 2): Rt = 2.012 min, m / z found 600.3 [M+H]+. SEC (Method 28): Rt = 2.196 min. 326 JA X     Yy HO' *R Yny° V o A °A “YAh A 8     salt Compound 322, fumaric acid LC-MS (ESI) (Method 1): Rt = 3.045 min, m / z found 600.3 [M+H]+. SEC (Method 28): Rt = 2.677 min. 334 Jay X / —A h<5 *R \Y V 1 AoA    ? ju nN hv^oh F            'N       0       salt Compound 330, fumaric acid LC-MS (ESI) (Method 2): Rt = 2.023 min, m / z found 600.3 [M+H]+. Chiral HPLC (Method 9): Rt = 4.014 min. 2026205213   01 Jul 2026 Co. No. Structure Starting Materials Spectra Details 335 Ao 1 UY   h JU UN "br        6        salt Compound 331, fumaric acid LC-MS (ESI) (Method 2): Rt = 2.028 min, m / z found 600.3 [M+H]+. Chiral HPLC (Method 9): Rt = 4.265 min. 336 X       Y HO'' *R Y u°       o A Y hoyAh 'NT       0        salt Compound 332, fumaric acid LC-MS (ESI) (Method 2): Rt = 1.967 min, m / z found 600.3 [M+H]+. SEC (Method 29): Rt = 4.190 min. 337 U-J-7 X     Y HO *S vM V 1 / UoxA      H JU UN F'^^    N     6     salt Compound 333, fumaric acid LC-MS (ESI) (Method 2): Rt = 1.973 min, m / z found 600.3 [M+H]+. SEC (Method 29): Rt = 4.444 min. 342 A \ rU— / ' |Y    Jj HO® Yy° V    n fY   hoy^oh 1* .Y N <J        II F             N       0       salt Compound 340, fumaric acid LC-MS (ESI) (Method 1): Rt = 2.934 min, m / z found 586.5 [M+H]+. SEC (Method 6): Rt = 1.326 min. 2026205213   01 Jul 2026 Co. No. Structure Starting Materials Spectra Details 343 —\ U s V ' V    o ju °i5 ho^^°h N'hf       0      salt Compound 341, fumaric acid LC-MS (ESI) (Method 1): Rt = 2.976 min, m / z found 586.5 [M+H]+. SEC (Method 6): Rt = 1.285 min. 346 \ )—\ N—\ r^NU—7  ' H° R YY° V    o ju °i5 ho^^°h N'hT       0       salt Compound 344, fumaric acid '11 NMR (400 MHz, Methanol-tfi): 5 = 8.47 (s, 1H), 7.53-7.16 (m, 3H), 6.68 (s, 4H), 4.493.65 (m, 10H), 3.42 (brs, 2H), 3.28-2.99 (m, 5H), 2.88 (s, 3H), 2.34 (brs, 2H), 2.23-2.11 (m, 1H), 1.85-1.63 (m, 2H), 1.400.74 (m, 18H). LC-MS (ESI) (Method 1): Rt = 2.968 min, m / z found 586.3 [M+H]+. SEC (Method 8): Rt = 2.265 min. 2026205213   01 Jul 2026 Co. No. Structure Starting Materials Spectra Details 352 \ *R )-- / HO S Y£o ? i ju U ho^^oh 'n         0        salt Compound 350, fumaric acid LC-MS (ESI) (Method 1): Rt = 3.010 min, m / z found 616.3 [M+H]+. SEC (Method 6): Rt = 1.235 min. 353 —\ rN*Sp Vo JZj HO S      \ Yy°       o JU ° P 'n         o        salt Compound 351, fumaric acid LC-MS (ESI) (Method 1): Rt = 2.967 min, m / z found 616.3 [M+H]+. SEC (Method 6): Rt = 1.261 min. 356 “X \ r-N *R \ /      O O ho' r       \ V Y° V    „ JU u F'^^    'N      0     salt Compound 354, fumaric acid LC-MS (ESI) (Method 1): Rt = 2.959 min, m / z found 616.4 [M+H]+. SEC (Method 28): Rt = 2.014 min. 357 \ r-N *s )--7  ^0 O HO' R      \ Vyo       o JU °PN HO^oh 'tU      O      salt Compound 355, fumaric acid LC-MS (ESI) (Method 1): Rt = 2.906 min, m / z found 616.3 [M+H]+. SEC (Method 28): Rt = 2.973 min. 2026205213   01 Jul 2026 Co. No. Structure Starting Materials Spectra Details 365 “X \ )—\ N— / R\u x^u     ^_uJ ho' *r VY0       0 ho^Uoh 'n        O        salt Compound 363, fumaric acid LC-MS (ESI) (Method 1): Rt = 3.150 min, m / z found 586.3 [M+H]+. SEC (Method 30): Rt = 2.491 min. 366 “X \ / —\ N— v vU° Q JU Ju HO^o„ n'N-^      o       salt Compound 364, fumaric acid LC-MS (ESI) (Method 1): Rt = 3.093 min, m / z found 586.3 [M+H]+. SEC (Method 30): Rt = 3.517 min. 369 —\ / --\ N— *S )— / X^ /           HO *s VNY° V    „ o juN ra™ F V    'N     0     salt Compound 367, fumaric acid LC-MS (ESI) (Method 1): Rt = 3.170 min, m / z found 586.3 [M+H]+. SEC (Method 31): Rt = 1.863 min. 370 ---\ ;—\ n— rNS\— / x^-"      JZ-} ho' *r VnY° V    n JU u “W™ F ^-^    'N      O      salt Compound 368, fumaric acid LC-MS (ESI) (Method 1): Rt = 3.137 min, m / z found 586.3 [M+H]+. SEC (Method 31): Rt = 2.165 min. 2026205213   01 Jul 2026 Co. No. Structure Starting Materials Spectra Details 377 \ N— r X v \Y V   „ T N ho.     A JU nU Y^oh 'N        O        salt Compound 375, fumaric acid LC-MS (ESI) (Method 2): Rt = 1.997 min, m / z found 586.3 [M+H]+. SEC (Method ll):Rt = 4.749 min. 378 rNAsVjN^ '■ . Xj m hoW'oh F              N        O        salt Compound 376, fumaric acid LC-MS (ESI) (Method 3): Rt = 4.923 min, m / z found 586.3 [M+H]+. SEC (Method ll):Rt = 4.663 min. 382 \ PC3 H0 ° Yf     n Xj rj ho^^°h F              N         0        salt Compound 381, fumaric acid LC-MS (ESI) (Method 2): Rt = 2.019 / 2.055 min, m / z found 630.5 [M+H]+. 386 Zn^r\_J^^\ A    XX HO' ‘R Y / V 1 UY   9 JU ON HOO^oh F             "N       0        salt Compound 384, fumaric acid LC-MS (ESI) (Method 2): Rt = 2.062 min, m / z found 600.3 [M+H]+. SEC (Method 27): Rt = 2.111 min. 2026205213   01 Jul 2026 Co. No. Structure Starting Materials Spectra Details 387 V 1°         0 A°r5 F             'N       0        salt Compound 385, fumaric acid LC-MS (ESI) (Method 2): Rt = 2.059 min, m / z found 600.3 [M+H]+. SEC (Method 27): Rt = 3.466 min. 391 "X \ )---K *R )— /   ' VJ HOZ*S Yf V   n O 17 H0 W'°h 'N        0        salt Compound 389, fumaric acid LC-MS (ESI) (Method 2): Rt = 2.159 min, m / z found 600.3 [M+H]+. Chiral HPLC (Method 9): Rt = 3.862 min. 392 —\ Ysp \ fj HO *S Yy° V    n JU 17 HOUU™ 'N        0        salt Compound 390, fumaric acid LC-MS (ESI) (Method 2): Rt = 2.119 min, m / z found 600.3 [M+H]+. SEC (Method 27): Rt = 2.386 min. 394 / r\      \ ■X- 7 o JU Ya hoY« >Tul 0     salt Compound 393, fumaric acid LC-MS (ESI) (Method 2): Rt = 2.442 min, m / z found 634.3 [M+H]+. SEC (Method 6): Rt = 1.232 min. 2026205213   01 Jul 2026 Co. No. Structure Starting Materials Spectra Details 397 —X        / ~° )—\ HN^ \ N R '-- / X 'N         0       salt Compound 11, fumaric acid LC-MS (ESI) (Method 5): Rt= 1.661 min, m / z found 586.2 [M+H]+. Compound 6 (ft)-2-((5-(2-(6-acetamido-2-methylhexan-3-yl)-2,6-diazaspiro[3.4]octan-6-yl)-l,2,4- triazin-6-yl)oxy)-7V-ethyl-5-fluoro- / V-isopropylbenzamide formate formate salt To the solution of (R)-2-((5-(2-(6-amino-2-methylhexan-3-yl)-2,6-diazaspiro[3.4]octan-6-yl)-l,2,4-triazin-6-yl)oxy)-A-ethyl-5-fluoro-A-isopropylbenzamide formate (Compound 1) (30 mg, 0.057 mmol) and TEA (60 uL, 0.43 mmol) in DCM (1 mL) cooled at 0 °C was added AC2O (20 uL, 0.21 mmol), the resulting mixture was stirred at RT under N2 atmosphere for 10   0.5 h. The reaction mixture was concentrated under reduced pressure and the residue was purified by preparative HPLC using a Welch Xtimate (column: Cl8 150x25mm 5um; eluent: ACN / H2O (0.225% FA) from 30% to 50% (v / v)) to afford the title compound (3.31 mg, 9% yield) as a white solid. LC-MS (ESI) (Method 5): Rt = 0.633 min, m / z found 570.4 [M+H]+. 15 SEC (Method 5): Rt= 1.191 min. Compound 7, 29, 34 (3)-2-((5-(2-(6-acetamido-2-methylhexan-3-yl)-2,6-diazaspiro[3.4]octan-6-yl)-l,2,4- triazin-6-yl)oxy)-A-ethyl-5-fluoro-A-isopropylbenzamide 2026205213   01 Jul 2026 2-((5-(2-(l-acetamido-4-methylpentan-3-yl)-2,6-diazaspiro[3.4]octan-6-yl)-l,2,4-triazin- 6-yl)oxy)-A-ethyl-5-nuoro-A- isopropylbenzamide (*lf)-2-((5-(2-(6-acetamido-2,6-dimethylheptan-3-yl)-2,6-diazaspiro[3.4]octan-6-yl)-l,2,4- triazin-6-yl)oxy)-7V-ethyl-5-fluoro- / V- isopropylbenzamide The following Compounds were synthesized by an analogous method described above for Compound 6 Co. No. Structure Starting Materials Conditions Spectra Details 7 \ O O 1 Compound 2 Ac2O, TEA, DCM LC-MS (ESI) (Method 5): Rt = 0.646 min, m / z found 570.3 [M+H]+. SEC (Method 5): Rt = 1.657 min. 29 \ \ O o 1 Z Compound 26 Ac2O, TEA, DCM LC-MS (ESI) (Method 1): Rt = 3.250 min, m / z found 556.4 [M+H]+. 34 \ \ o o z /   __ z'' 7—2 ] \=z         \     / l—z 30 J ll— z \ Compound 30 AcCl, TEA, DCM LC-MS (ESI) (Method 3): Rt = 4.573 min, m / z found 598.3 [M+H]+. Compound 8 (K)-7V-ethyl-5-fluoro- / V-isopropyl-2-((5-(2-(2-methyl-6-(3-methylureido)hexan-3-yl)-2,6- 10 diazaspiro[3.4]octan-6-yl)-l,2,4-triazin-6-yl)oxy)benzamide 2026205213   01 Jul 2026 To the solution of (R)-2-((5-(2-(6-amino-2-methylhexan-3-yl)-2,6-diazaspiro[3.4]octan-6-yl)-l,2,4-triazin-6-yl)oxy)-7V-ethyl-5-fluoro-A-isopropylbenzamide formate (Compound 1) (70 mg, 0.12 mmol) and TEA (0.35 mL, 2.5 mmol) in DCM (10 mL) cooled at 0 °C was added 5 methylcarbamic chloride (18 mg, 0.19 mmo) and the resulting mixture was stirred for 2 h at 0 °C. The reaction mixure was concentrated under reduced pressure and the residue was purified by preparative HPLC over Phenomenex Gemini-NX (column: 150x30mm 5um; eluent: ACN / H2O (0.04% ammonia+lOmM NH4HCO3) from 35% to 65%, v / v) to afford the title compound (50 mg, 70% yield) as a white solid. 10 LC-MS (ESI) (method 1): Rt = 3.34 min, m / z found 585.3 [M+H]+. SEC (Method 6): Rt = 2.222 min Compound 9 (3)-A-ethyl-5-fluoro-7V-isopropyl-2-((5-(2-(2-methyl-6-(3-methylureido)hexan-3-yl)-2,6- 15 diazaspiro[3.4]octan-6-yl)-l,2,4-triazin-6-yl)oxy)benzamide The following Compound was synthesized by an analogous method described above for Compound 8 Co. No. Structure Starting Materials Spectra Details 9 5=x / Z O 1 Compound 2 LC-MS (ESI) (method 1): Rt = 3.38 min, m / z found 585.3 [M+H]+. SEC (Method 6): Rt = 2 418 min. Compound 10 20 methyl (l?)-(4-(6-(6-(2-(ethyl(isopropyl)carbamoyl)-4-fluorophenoxy)-l,2,4-triazin-5-yl)- 2,6-diazaspiro[3.4]octan-2-yl)-5-methylhexyl)carbamate 2026205213   01 Jul 2026 To the mixture of (R)-2-((5-(2-(6-amino-2-methylhexan-3-yl)-2,6-diazaspiro[3.4]octan-6-yl)-l,2,4-triazin-6-yl)oxy)-A-ethyl-5-fluoro-A-isopropylbenzamide hydrochloride (Compound 65) (0.100 g, crude) in THF / H2O (2 mL / 2 mL) cooled at 0 °C were added 2 MNaOH (0.15 5 mL, 0.30 mmol) and methyl carbonochloridate (0.030 g, 0.317 mmol, in 0.1 mL DCM). The resulting mixture was stirred at 0 °C for 0.5 h. The mixture was diluted with water (10 mL) and sat. aq. NaHCO, (15 mL), further extracted with EtOAc (15 mL x 3). The combined organic layers were dried over (Na2SO4), filtered and evaporated in vacuo to give the crude product, which was further purified by preparative HPLC using Phenomenex Gemini NX 10 (column: C18 75x30mm 3um; eluent: ACN / H2O (0.05% ammonia+lOmM NH4HCO3) 35% to 65% (v / v)) to afford the title compound (11.53 mg) as sticky oil. LC-MS (ESI) (Method 1): Rt = 3.283 min, m / z found 586.3 [M+H]+. Compound 22 15 methyl (l?)-(4-(6-(6-(2-(ethyl(isopropyl)carbamoyl)-4-fluorophenoxy)-l,2,4-triazin-5-yl)-2,6-diazaspiro[3.4]octan-2-yl)-5-methylhexyl)(methyl)carbamate The following Compound was synthesized by an analogous method described above for Compound 10 Co. No. Structure Starting Materials Spectra Details 22 1 o^o ^z 1 on 1 z—e   z >=z O '— Compound 19 LC-MS (ESI) (Method 2): Rt = 2.472 min, m / z found 600.3 [M+H]+. 20 Compound 11 (l?)-A-ethyl-5-fluoro-A-isopropyl-2-((5-(2-(6-((2-methoxyethyl)amino)-2-methylhexan-3- yl)-2,6-diazaspiro[3.4]octan-6-yl)-l,2,4-triazin-6-yl)oxy)benzamide 2026205213   01 Jul 2026 The mixture of (A)-2-((5-(2-(6-amino-2-methylhexan-3-yl)-2,6-diazaspiro[3.4]octan-6-yl)-l,2,4-triazin-6-yl)oxy)-A-ethyl-5-fluoro-A-isopropylbenzamide (Compound 64) (120 mg, crude), 1-bromo-2-methoxyethane (32 mg, 0.23 mmol), CS2CO3 (222 mg, 0.681 mmol), Nai 5   (102 mg, 0.680 mmol) in DMF (1 mL) was stirred at 80 °C via microwave irradiation for 1 h. After cooling to RT, the mixture was diluted with H2O (10 mL) and extracted with EtOAc (3 x 10 mL). The combined organic layers were washed with H2O (10 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to afford the crude product which was further purified by HPLC over a Phenomenex Gemini-NX (column: 150x30 mm 5 pm; 10 eluent: ACN / H2O (lOmM NH4HCO3) from 51% to 71% (v / v)) and further purified by SFC overDAICEL CHIRALCEL OD-H (column: 250x30 mm 5 um; eluent: supercritical CO2 in EtOH (0.1% v / v ammonia) 25 / 25, v / v) to afford the title compound (5.13 mg, 96% purity) as yellow solid. LC-MS (ESI) (Method 1): Rt = 2.997 min, m / z found 586.3 [M+H]+. 15 Compound 28, 90, 93, 287,149, 226, 257, 228 (3)- / V-ethyl-5-fluoro- / V-isopropyl-2-((5-(2-(6-((2-methoxyethyl)(methyl)amino)-2-methylhexan-3-yl)-2,6-diazaspiro[3.4]octan-6-yl)-l,2,4-triazin-6-yl)oxy)benzamide (K)-2-((5-(2-(6-(bis(2-methoxyethyl)amino)-2-methylhexan-3-yl)-2,6- 20 diazaspiro[3.4]octan-6-yl)-l,2,4-triazin-6-yl)oxy)-A-ethyl-5-fluoro-A-isopropylbenzamide formate 5-fluoro-A^V-diisopropyl-2-((5-(2-(6-((2-methoxyethyl)(methyl)amino)-2-methylhexan-3-yl)-2,6-diazaspiro[3.4]octan-6-yl)-l,2,4-triazin-6-yl)oxy)benzamide formate (K)-2-((5-(2-(6-((2,2-dimethoxyethyl)amino)-2-methylhexan-3-yl)-2,6- 25 diazaspiro[3.4]octan-6-yl)-l,2,4-triazin-6-yl)oxy)-A-ethyl-5-fluoro-A- isopropylbenzamide (K)-2-((5-(2-(6-((2,2-dimethoxyethyl)(methyl)amino)-2-methylhexan-3-yl)-2,6-diazaspiro[3.4]octan-6-yl)-l,2,4-triazin-6-yl)oxy)-A-ethyl-5-fluoro-A-isopropylbenzamide 2026205213   01 Jul 2026 (*lf)-7V-ethyl-5-fluoro- / V-isopropyl-2-((5-(2-(l-((2-methoxyethyl)amino)-4-methylpentan-3-yl)-2,6-diazaspiro[3.4]octan-6-yl)-l,2,4-triazin-6-yl)oxy)benzamide (K)-2-((5-(2-(6-((2-ethoxyethyl)(methyl)amino)-2-methylhexan-3-yl)-2,6-diazaspiro[3.4]octan-6-yl)-l,2,4-triazin-6-yl)oxy)-7V-ethyl-5-fluoro- / V- 5 isopropylbenzamide (*lf)-7V-ethyl-5-fluoro- / V-isopropyl-2-((5-(2-(l-(isopropylamino)-4-methylpentan-3-yl)- 2,6-diazaspiro[3.4]octan-6-yl)-l,2,4-triazin-6-yl)oxy)benzamide The following Compounds were synthesized by an analogous method described above 10 for Compound 11 Co. No. Structure Starting Materials Conditions Spectra Details 28 J z—\ z O Compound 20, l-bromo-2-methoxy ethane K2CO3, Nai, DMF, 50 °C LC-MS (ESI) (Method 2): Rt = 2.047 min, m / z found 600.3 [M+H]+. SEC (Method 11): Rt = 5.404 min 90 / o N R '-- / r\          X y y   N F             N formate salt Compound 1, l-bromo-2-methoxy ethane CS2CO3, DMF, 80 °C, micro wave LC-MS (ESI) (Method 2): Rt = 2.105 min, m / z found 644.4 [M+H]+. SEC (Method 15): Rt = 1.105 min. 2026205213   01 Jul 2026 Co. No. Structure Starting Materials Conditions Spectra Details 93 / ~°Z . / A  N—' $ fl " T formate salt Compound 92, l-bromo-2-methoxy ethane K2CO3, Nai, DMF, 50 °C 287 5=\   —< Lz z Compound 1, 2-bromo-l,l-dimethoxyethane K2CO3, Nai, DMF, 70 °C 149 / / °\ / \ \ / 0 N R '-- / "yC0 Q W / ? F'^^ N'N^ Compound 19, 2-bromo-l,l-dimethoxyethane K2CO3, KI, DMF, 80 °C 226 5=\    —< o z^ x> 1 Compound 218, l-bromo-2-methoxy ethane DIEA, ACN, 50 °C 257 A    \ / —\       / — n R '— A°^j f'^x^ N'hr Compound 19, l-bromo-2-ethoxy ethane K2CO3, Nai, DMF, 50 °C 2026205213   01 Jul 2026 Co. No. Structure Starting Materials Conditions Spectra Details 228 \  0 0 * Hr ml Z^ / Compound 218, 2-iodopropane DIEA, ACN, RT Compound 12 (ft)-2-((5-(2-(6-((2-cyanoethyl)amino)-2-methylhexan-3-yl)-2,6-diazaspiro[3.4]octan-6- yl)-l,2,4-triazin-6-yl)oxy)-7V-ethyl-5-fluoro-7V-isopropylbenzamide To a solution of (R)-2-((5-(2-(6-amino-2-methylhexan-3-yl)-2,6-diazaspiro[3.4]octan-6-yl)-l,2,4-triazin-6-yl)oxy)-7V-ethyl-5-fluoro-A-isopropylbenzamide hydrochloride (Compound 65) (260 mg, crude) and DIEA (200 mg, 1.98 mmol) in MeOH (15 mL) was added acrylonitrile (580 mg, 10.9 mmol) at 0 °C. After addition, the reaction mixture was stirred at 10 RT for 18 h. The reaction mixture was concentrated in vacuo and the residue was purified by preparative HPLC over Boston Prime (column: C18 150x30mm 5um, Mobile Phase A: water (0.04% ammonia+lOmM NH4HCO3), Mobile Phase B: ACN, Flow rate: 25 mL / min, gradient condition B / A from 40% to 70%) to afford the title compound (120 mg) as colorless oil. LC-MS (ESI) (Method 1): Rt = 2.938 min, m / z found 581.3 [M+H]+. Compound 18, 246 A-ethyl-5-fluoro-A-isopropyl-2-((5-(2-(2-methyl-6-((2- (methylsulfonyl)ethyl)amino)hexan-3-yl)-2,6-diazaspiro[3.4]octan-6-yl)-l,2,4-triazin-6-yl)oxy)benzamide 2026205213   01 Jul 2026 (ft)-2-((5-(2-(6-((3-(dimethylamino)-3-oxopropyl)(methyl)amino)-2-methylhexan-3-yl)- 2,6-diazaspiro[3.4]octan-6-yl)-l,2,4-triazin-6-yl)oxy)-7V-ethyl-5-fluoro- / V-isopropylbenzamide formate The following Compounds were synthesized by an analogous method described above 5 for Compound 12 Co. No. Structure Starting Materials Conditions Spectra Details 18 5=\     \ o 1 Compound 3, (methyl sulfonyl)-ethene TEA, MeOH, RT LC-MS (ESI) (Method 4): Rt = 2.24 min, m / z found 634.7 [M+H]+ 246 \ __ /     N~y / 3 )'          N— R            / YY Q N'N^ formate salt Compound 19, A,A-dimethylacrylami de TEA, MeOH, reflux LC-MS (ESI) (Method 5): Rt = 1.53 min, m / z found 641.5 [M+H]+. Compound 27 (K)-7V-ethyl-5-fluoro- / V-isopropyl-2-((5-(2-(6-((2-methoxyethyl)(methyl)amino)-2- methylhexan-3-yl)-2,6-diazaspiro[3.4]octan-6-yl)-l,2,4-triazin-6-yl)oxy)benzamide Preparation Method A: The mixture of (A)-A-ethyl-5-fluoro-7V-isopropyl-2-((5-(2-(6-((2-methoxyethyl)amino)-2-methylhexan-3-yl)-2,6-diazaspiro[3.4]octan-6-yl)-l,2,4-triazin-6-yl)oxy)benzamide 2026205213   01 Jul 2026 (Compound 11) (40.0 mg, 0.068 mmol), formaldehyde (55.4 mg, 0.683 mol, 37% in water) and AcOH (8.2 mg, 0.137 mmol) in anhydrous MeOH (2 mL) was stirred at 45 °C for 1 h. Then, NaBHaCN (8.6 mg, 0.137 mmol) was added to the mixture and the resulting mixture was stirred at 45 °C for another 1 h. After cooling to RT, the reaction mixture was treated 5 with sat. aq. NaHCOs (40 mL) to adjust the pH value to about 8 and further extracted with DCM (20 mL x 3). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give the crude which was purified by preparative HPLC over Boston Prime (column: C18 150x30mm 5um, Mobile Phase A: H2O (0.04% ammonia+lOmM NH4HCO3), Mobile Phase B: ACN, Flow rate: 25 mL / min, gradient 10 condition B / A from 50% to 80% (50%B to 80% B)) to afford the title compound (9.62 mg, 99.10% purity, 23.3% yield) as yellow oil. Preparation Method B: 15 To the mixture of A-ethyl-5-fluoro-A-isopropyl-2-((5-(2-(2-methyl-6-(methylamino)hexan-3-yl)-2,6-diazaspiro[3.4]octan-6-yl)-l,2,4-triazin-6-yl)oxy)benzamide hydrochloride (Compound 67) (480 mg, crude), K2CO3 (700 mg, 5.07 mmol) and Nai (400 mg, 2.67 mmol) in DMF (5 mL) was added l-bromo-2-m ethoxy ethane (230 mg, 1.65 mmol). The resulting mixture was stirred at 50 °C overnight. After cooled to RT, the reaction mixture was 20 quenched with H2O (30 mL) and extracted with DCM (30 mL x 3). The combined organic layers were washed with brine (30 mL x 3), dried over Na2SO4, filtered and concentrated to give a crude residue. The residue was purified by FCC (DCM / MeOH = 10:1) to afford N- 2026205213   01 Jul 2026 ethyl-5-fluoro-A-isopropyl-2-((5-(2-(6-((2-methoxyethyl)(methyl)amino)-2-methylhexan-3-yl)-2,6-diazaspiro[3.4]octan-6-yl)-l,2,4-triazin-6-yl)oxy)benzamide (Compound 68) (250 mg, 48% yield) as yellow oil. The A-ethyl-5-fluoro-A-isopropyl-2-((5-(2-(6-((2-methoxyethyl)(methyl)amino)-2- 5 methylhexan-3-yl)-2,6-diazaspiro[3.4]octan-6-yl)-l,2,4-triazin-6-yl)oxy)benzamide (Compound 68) (960 mg, combined from several batches obtained by Method B) was first separated by SFC using DAICEL CHIRALPAK IG (column: 250x30mm lOum; Mobile phase: A: Supercritical CO2, B: EtOH (0.1% ammonia), A:B=40:60 at 60 mL / min) and further purified by preparative HPLC using Boston Prime (column: 150x30mm 5um, Mobile 10 Phase A: H2O (lOmM NH4HCO3), Mobile Phase B: ACN, Flow rate: 25 mL / min, gradient condition B / A from 55% to 85%) to afford the title compound (270 mg) as colorless oil. 'H NMR (400 MHz, Methanol-^): 8 = 8.40 (s, 1H), 7.47-7.32 (m, 1H), 7.30-7.10 (m, 2H), 4.24-4.01 (m, 2H), 3.89-3.60 (m, 3H), 3.48 (br s, 3H), 2.63-2.51 (m, 2H), 2.43-2.32 (m, 2H), 2.29-2.07 (m, 6H), 1.86-1.72 (m, 1H), 1.62-1.44 (m, 2H), 1.39-1.02 (m, 10H), 0.99-0.66 (m, 15   9H). Some protons were hidden by the solvent peak and are not reported. LCMS (ESI) (Method 2): Rt = 1.965 min, m / z found 600.3 [M+H]+. SFC (Method 11): Rt = 4.904 min. Preparation Method C: A methanol solution of (A)-2-((3-chloro-5-(2-(6-((2-methoxyethyl)(methyl)amino)-2-methylhexan-3-yl)-2,6-diazaspiro[3.4]octan-6-yl)-l,2,4-triazin-6-yl)oxy-A-ethyl-5-fluoro-A-isopropylbenzamide (Compound 393) (163.93g of a 60.1 wt % solution in MeOH, 100g corrected of Compound 393), palladium on carbon (10 g) and MeOH (316 g) was stirred at 25   20 to 30°C under a hydrogen atmosphere (0.20 to 0.30 Mpa) for 18 h. The mixture was filtered over diatomite (75 g) and the cake was washed with MeOH (158 g). The filtrate was concentrated under reduced pressure (< 40°C) to ~3 vol., then flushed with isopropyl acetate (IP Ac, 870 g) concentrating to ~3 vol. The mixture was then diluted with IP Ac (696 g) and a 20% Na2COs aqueous solution was added (500 g). The mixture was stirred for 30 to 60 min. 30 The aqueous layer was removed. The organic layer was washed with water (500 g) then 2026205213   01 Jul 2026 concentrated under reduced pressure <45°C to ~3 vol. The title intermediate was afforded in approximately 90% assay yield as a 48.1 wt% solution in IP Ac. Compound 70 5 (l?)-A-ethyl-5-fluoro-A-isopropyl-2-((5-(2-(6-((2-methoxyethyl)(methyl)amino)-2-methylhexan-3-yl)-2,6-diazaspiro[3.4]octan-6-yl)-l,2,4-triazin-6-yl)oxy)benzamide oxalate To a solution of (A)-7V-ethyl-5-fluoro-A-isopropyl-2-((5-(2-(6-((2- 10 methoxy ethyl)(methyl)amino)-2-methylhexan-3-yl)-2,6-diazaspiro[3.4]octan-6-yl)-l, 2,4-triazin-6-yl)oxy)benzamide (Compound 27) (270 mg, 0.450 mmol) in 20 mL of ACN (20 mL) was added oxalic acid (81.0 mg, 0.900 mmol). After addition, the reaction mixture was stirred at RT for 1 h. Then the reaction mixture was concentrated, the residue was redissolved in ACN and deionized water, and lyophilized to afford the title compound (350 mg) 15 as white solid. 'H NMR(400 MHz, Methanol-* / ^: 6 = 8.48 (s, 1H), 7.52-7.11 (m, 3H), 4.54-3.64 (m, 12H), 3.40-3.34 (m, 5H), 3.23-3.13 (m, 2H), 2.90 (s, 3H), 2.54-2.27 (m, 2H), 2.19-2.03 (m, 1H), 1.97-1.77 (m, 2H), 1.75-1.50 (m, 2H), 1.35-0.65 (m, 17H). 'H NMR (400 MHz, DMSO-< / 6): 6 = 8.51 (s, 1H), 7.51-7.29 (m, 3H), 4.29-3.34 (m, 12H), 20   3.23-2.84 (m, 7H), 2.70 (s, 3H), 2.35-2.09 (m, 2H), 2.05-1.85 (m, 1H), 1.81-1.58 (m, 2H), 1.56-1.33 (m, 2H), 1.18-0.60 (m, 17H). LCMS (ESI) (Method 2): Rt = 1.969 min, m / z found 600.4 [M+H]+. 2026205213   01 Jul 2026 Preparation of Compound 70a To a solution of Compound 27 (207.90 g of a 48 wt% solution in IP Ac, 100g of active compound 27) in IP Ac (360 g) was added EtOH (63 g) at 20 to 25°C. The solution was then 5 treated with cone. HC1 (32.9 g) in EtOH (49.5 g) over ~15 min. The mixture was seeded with crystalline Compound 70a seed (2 g, 2% seed load) then aged for 18 h. IP Ac (870 g) was added slowly over 4 h at between 20 to 25°C and the slurry was stirred for an additional 18 h. After cooling to ~5°C, the product was filtered, washed with IP Ac (522 g) and dried under vac at 20-30 °C to afford the weakly crystalline Compound 70a as a white solid (91.0% yield, 10    115.4 g). (Note: A small amount of seed material used in the reaction was obtained via an analogous reaction protocol on small-scale.) Recrystallisation: A solution of weakly crystalline Compound 70a (100 g), EtOH (166 g), purified water (21.5 g) and IP Ac (178 g) was stirred at 20 to 30°C for 0.5-2 h to get a clear solution. Extra IP Ac (522 g) was added dropwise over 1~2 h, and then the mixture was 15 seeded with crystalline Compound 70a seed (2 g, 2% seed load). Then the mixture was aged for 18 ~20 h, IP Ac (348 g) was added slowly over 12 h at between 20 to 30°C, and the slurry was stirred for an additional 55-60 h. The product was filtered, washed with IP Ac (158 g) and dried in vacuo at 20~30°C to afford Compound 70a as a white solid (85% yield, 85.0 g, net). 20 'HNMR (DMSO-J6, 400MHz): 6 = 11.60 (1H, brs), 10.8 (1H, brs), 8.52 (1H, s), 7.36 (3H, m), 3.97-4.20 (7H, m), 3.64-3.71 (4H, m), 3.47 (7H, m), 3.25 (2H, m), 3.05 (3H, m), 2.73 (3H, s), 2.10-2.45 (1H, m), 1.99 (1H, m), 1.78 (2H, m), 1.55 (2H, m), 0.83-1.12 (12H, m), 0.70 (2H, m). 25 LCMS (Method 7): Rt = 0.669 min, m / z found 600.5 [M+H]+. 2026205213   01 Jul 2026 Compound 83, 84, 94, 95, 88, 89, 99,100, 250, 251, 252, 254, 258, 396, 402 (*lf)-7V-ethyl-5-fluoro-7V-isopropyl-2-((4-(2-(6-((2-methoxyethyl)(methyl)amino)-2-methylhexan-3-yl)-2,6-diazaspiro[3.4]octan-6-yl)pyridazin-3-yl)oxy)benzamide oxalate (*3)-7V-ethyl-5-fluoro-7V-isopropyl-2-((4-(2-(6-((2-methoxyethyl)(methyl)amino)-2- 5 methylhexan-3-yl)-2,6-diazaspiro[3.4]octan-6-yl)pyridazin-3-yl)oxy)benzamide oxalate (*7?)-5-fluoro-A^^V-diisopropyl-2-((5-(2-(6-((2-methoxyethyl)(methyl)amino)-2-methylhexan-3-yl)-2,6-diazaspiro[3.4]octan-6-yl)-l,2,4-triazin-6-yl)oxy)benzamide oxalate (*3)-5-fluoro-7V,2V-diisopropyl-2-((5-(2-(6-((2-methoxyethyl)(methyl)amino)-2- 10 methylhexan-3-yl)-2,6-diazaspiro[3.4]octan-6-yl)-l,2,4-triazin-6-yl)oxy)benzamide oxalate (*7?)-5-fluoro-A^^V-diisopropyl-2-((4-(2-(6-((2-methoxyethyl)(methyl)amino)-2-methylhexan-3-yl)-2,6-diazaspiro[3.4]octan-6-yl)pyridazin-3-yl)oxy)benzamide oxalate (*5)-5-fluoro-A^^V-diisopropyl-2-((4-(2-(6-((2-methoxyethyl)(methyl)amino)-2- 15   methylhexan-3-yl)-2,6-diazaspiro[3.4]octan-6-yl)pyridazin-3-yl)oxy)benzamide oxalate (*7?)-5-fluoro-A^^V-diisopropyl-2-((5-(2-(6-((2-methoxyethyl)amino)-2-methylhexan-3-yl)-2,6-diazaspiro[3.4]octan-6-yl)-l,2,4-triazin-6-yl)oxy)benzamide oxalate (*5)-5-fluoro-A^^V-diisopropyl-2-((5-(2-(6-((2-methoxyethyl)amino)-2-methylhexan-3-yl)-2,6-diazaspiro[3.4]octan-6-yl)-l,2,4-triazin-6-yl)oxy)benzamide oxalate 20 7V-ethyl-5-fluoro-7V-isopropyl-2-((5-(2-((K)-6-(((*lf)-2-methoxypropyl)(methyl)amino)-2-methylhexan-3-yl)-2,6-diazaspiro[3.4]octan-6-yl)-l,2,4-triazin-6-yl)oxy)benzamide oxalate 7V-ethyl-5-fluoro-7V-isopropyl-2-((5-(2-((lf)-6-(((*3)-2-methoxypropyl)(methyl)amino)-2-methylhexan-3-yl)-2,6-diazaspiro[3.4]octan-6-yl)-l,2,4-triazin-6-yl)oxy)benzamide 25 oxalate 7V-ethyl-5-fluoro-7V-isopropyl-2-((5-(2-((31f)-6-((2-methoxypropyl)(methyl)amino)-2-methylhexan-3-yl)-2,6-diazaspiro[3.4]octan-6-yl)-l,2,4-triazin-6-yl)oxy)benzamide oxalate 7V-ethyl-5-fluoro-7V-isopropyl-2-((5-(2-((33)-6-((2-methoxypropyl)(methyl)amino)-2- 30 methylhexan-3-yl)-2,6-diazaspiro[3.4]octan-6-yl)-l,2,4-triazin-6-yl)oxy)benzamide oxalate (K)-2-((5-(2-(6-((2-ethoxyethyl)(methyl)amino)-2-methylhexan-3-yl)-2,6-diazaspiro[3.4]octan-6-yl)-l,2,4-triazin-6-yl)oxy)-7V-ethyl-5-fluoro-7V-isopropylbenzamide oxalate 2026205213   01 Jul 2026 ( *l?)-2-((5-(2-(6-(dimethylamino)-2-methylhexan-3-yl)-2,6-diazaspiro [3.4] octan-6-yl)- l,2,4-triazin-6-yl)oxy)-5-fluoro-A^^V-diisopropylbenzamide oxalate (K)-7V-(ethyl-13C2)-5-fluoro-2-((5-(2-(6-((2-methoxyethyl)(methyl)amino)-2-methylhexan- 3-yl)-2,6-diazaspiro[3.4]octan-6-yl)-l,2,4-triazin-6-yl)oxy)-7V-(propan-2-yl- 5 13C3)benzamide oxalate The following Compounds were synthesized by an analogous method described above for Compound 70 Co. No. Structure Starting Materials Spectra Details 83 \ r      h yy    o JU °l5 -VH F'^—0 salt Compound 107, oxalic acid LC-MS (ESI) (Method 3): Rt = 5.034 min, m / z found 599.3 [M+H]+. Chiral HPLC (Method 2): Rt = 8.596 min. 84 > F o=( O         J w            r &                   I Compound 108, oxalic acid LC-MS (ESI) (Method 3): Rt = 4.957 min, m / z found 599.3 [M+H]+. Chiral HPLC (Method 2): Rt = 9.726 min. 94 ,—N “ \__ /   \ Y     S Ut0     o o °Jyn h°Vh F^^ N'N        O salt Compound 109, oxalic acid LC-MS (ESI) (Method 2): Rt = 2.431 min, m / z found 614.5 [M+H]+. Chiral HPLC (Method 3): Rt = 4.967 min. 2026205213   01 Jul 2026 Co. No. Structure Starting Materials Spectra Details 95 ..AA TA Y A1 A T°        ° ju / x Aoh —    N'N>        0 salt Compound 110, oxalic acid LC-MS (ESI) (Method 2): Rt = 2.471 min, m / z found 614.5 [M+H]+. Chiral HPLC (Method 3): Rt= 5.947 min. 88 \ mAA TA y A A yy A xj°y5 a™ N'iA        o salt Compound 117, oxalic acid LC-MS (ESI) (Method 1): Rt = 2.243 min, m / z found 613.4 [M+H]+. Chiral HPLC (Method 5): Rt = 4.873 min. 89 '■_____. \ / A\ y A1 A yy A o xxy5 A™ F^AY    NT        O salt Compound 118, oxalic acid LC-MS (ESI) (Method 1): Rt = 2.271 min, m / z found 613.3 [M+H]+. Chiral HPLC (Method 5): Rt= 5.947 min. 99 — /         / \ / ~Q A\ HA R\— / Yi *A o juAb A°"lt F              N             q salt Compound 115, oxalic acid LC-MS (ESI) (Method 2): Rt = 2.224 min, m / z found 600.3 [M+H]+. Chiral HPLC (Method 6): Rt = 3.810 min. 2026205213   01 Jul 2026 Co. No. Structure Starting Materials Spectra Details 100 V\ HtV S \--- / Vr      o OT "“V", F              N             q salt Compound 116, oxalic acid LC-MS (ESI) (Method 2): Rt = 2.21 min, m / z found 600.4 [M+H]+. Chiral HPLC (Method 6): Rt = 5.322 min. 250 / \ / V \ / -° N R '— / A    0 V V ™ VH„ 'n            0 salt Compound 248, oxalic acid LC-MS (ESI) (Method 1): Rt = 3.107 min, m / z found 614.4 [M+H]+. SEC (Method 16): Rt = 4.082 min. 251 —<   \ Y° y^ Nj*s N R \— / V T o V V H°VH „ N            O salt Compound 249, oxalic acid LC-MS (ESI) (Method 1): Rt = 3.141 min, m / z found 614.4 [M+H]+. SEC (Method 16): Rt = 4.287 min. 252 / \ / \ \ / ° / —\ N R '— / vA Ho VH „ N            o salt Compound 247, oxalic acid LC-MS (ESI) (Method 1): Rt = 3.011 min, m / z found 614.4 [M+H]+. 2026205213   01 Jul 2026 Co. No. Structure Starting Materials Spectra Details 254 / \ / \ \ / 0 N S \— / \.fCL.o Cz Y Y 0 I o Xj n -VH „ F             N            0 salt Compound 253, oxalic acid LC-MS (ESI) (Method 1): Rt = 3.054 min, m / z found 614.4 [M+H]+. 258 \ \ / —\       / — N R '— / u ib -Vh lt n               0 salt Compound 257, oxalic acid LC-MS (ESI) (Method 2): Rt = 2.047 min, m / z found 614.4 [M+H]+. SEC (Method 16): Rt = 4.345 min. 396 zN— 1—N rf \__ / I r         n 0 r; H° VH N'hT          0 salt Compound 105, oxalic acid LC-MS (ESI) (Method 2): Rt = 2.071 min, m / z found 570.3 [M+H]+. SEC (Method 4): Rt = 1.364 min. 402 / —\       X A / Y-y Q 13c / L A.         I? Xjr; h°V\ N              O salt Compound 401, oxalic acid LC-MS (ESI) (Method 5): Rt = 1.500 min, m / z found 605.3 [M+H]+. Compound 13,16, 71, 136,139,153,156,160,164,166,169,173, 274, 275, 276, 279, 282, 285,178,180,190,192,194,196,198, 200, 202, 204, 310, 311, 312, 313, 318, 329, 360, 375, 5   376,379,380,383,388,411 O                  Ui -206 - yl)(methyl)amino)-2-methylhexan-3-yl)-2,6-diazaspiro[3.4]octan-6-yl)-l,2,4-triazin-6-20 yl)oxy)benzamide (ft)-2-((5-(2-(6-((l,3-dimethoxypropan-2-yl)(methyl)amino)-2-methylhexan-3-yl)-2,6-diazaspiro[3.4]octan-6-yl)-l,2,4-triazin-6-yl)oxy)-7V-ethyl-5-fluoro-7V-isopropylbenzamide isopropylbenzamide 15 ALethyl-5-fluoro-ALisopropyl-2-((5-(2-((l?)-6-(((l?)-l-methoxypropan-2-yl)(methyl)amino)-2-methylhexan-3-yl)-2,6-diazaspiro[3.4]octan-6-yl)-l,2,4-triazin-6-yl)oxy)benzamide ALethyl-5-fluoro-ALisopropyl-2-((5-(2-((l?)-6-(((5)-l-methoxypropan-2- -7\f-ojon[j-g-iXqj9-7\f-(Xxo(iX-9-uizEijj-^‘j‘x-(iX-9-uKpo[^,g]ojidsKZEip -9‘Z-(lX-g-uExoqiXqj9m-^-(ou!mE(iXqpm)(iXqpouEX3-j))-9)-j)-s))-j-(^) O                  Ut -207- 2-((5-(2-((31?)-6-((4-(dimethylamino)-4-oxobutan-2-yl)(methyl)amino)-2-methylhexan-3-yl)-2,6-diazaspiro[3.4]octan-6-yl)-l,2,4-triazin-6-yl)oxy)-7V-ethyl-5-fluoro-7V-isopropylbenzamide 2-((5-(2-((31f)-6-((3-(dimethylamino)-2-methyl-3-oxopropyl)(methyl)amino)-2-methylhexan-3-yl)-2,6-diazaspiro[3.4]octan-6-yl)-l,2,4-triazin-6-yl)oxy)-7V-ethyl-5- to o methylhexan-3-yl)-2,6-diazaspiro[3.4]octan-6-yl)-l,2,4-triazin-6-yl)oxy)-7V- 15 isopropylbenzamide 7V-ethyl-5-fluoro-2-((5-(2-((lf)-6-(((3)-2-hydroxy-3-methoxypropyl)(methyl)amino)-2-methylhexan-3-yl)-2,6-diazaspiro[3.4]octan-6-yl)-l,2,4-triazin-6-yl)oxy)-7V-isopropylbenzamide formate -7\f-ojon[j-g-iXqj9-7\f-(Xxo(iX-9-uizEijj-^‘j‘x-(iX-9-uEpo[^,g]ojidsKZEip -9‘j-(lX-£-uExoqiXqpm-^-(ou!mE(iXqpm)(iXdojdXxoqpm!p-g‘^))-9-(^g))-^)-s))-^ 2026205213   01 Jul 2026 ALethyl-5-fluoro-Az-isopropyl-2-((5-(2-((l?)-2-methyl-6-(methyl((5)-2-methyl-3-(methylamino)-3-oxopropyl)amino)hexan-3-yl)-2,6-diazaspiro[3.4]octan-6-yl)-l,2,4-triazin-6-yl)oxy)benzamide 2-((5-(2-(( *lf)-6-(((K)-4-amino-4-oxobutan-2-yl)(methyl)amino)-2-methylhexan-3-yl)-2,6- 5 diazaspiro[3.4]octan-6-yl)-l,2,4-triazin-6-yl)oxy)-5-fluoro-A^^V-diisopropylbenzamide 2-((5-(2-(( *lf)-6-(((5)-4-amino-4-oxobutan-2-yl)(methyl)amino)-2-methylhexan-3-yl)-2,6-diazaspiro[3.4]octan-6-yl)-l,2,4-triazin-6-yl)oxy)-5-fluoro-A^^V-diisopropylbenzamide 2-((5-(2-(( *lf)-6-(((K)-3-amino-2-methyl-3-oxopropyl)(methyl)amino)-2-methylhexan-3-yl)-2,6-diazaspiro[3.4]octan-6-yl)-l,2,4-triazin-6-yl)oxy)-5-fluoro-A^^V- 10 diisopropylbenzamide 2-((5-(2-(( *lf)-6-(((5)-3-amino-2-methyl-3-oxopropyl)(methyl)amino)-2-methylhexan-3-yl)-2,6-diazaspiro[3.4]octan-6-yl)-l,2,4-triazin-6-yl)oxy)-5-fluoro-A^^V-diisopropylbenzamide 2-((5-(2-((3 *R, 5 *l?)-6-(dimethylamino)-5-methoxy-2-methylhexan-3-yl)-2,6- 15 diazaspiro[3.4]octan-6-yl)-l,2,4-triazin-6-yl)oxy)-7V-ethyl-5-fluoro-7V-isopropylbenzamide 7V-ethyl-2-((5-(2-((3*lf,5*lf)-6-(ethyl(methyl)amino)-5-methoxy-2-methylhexan-3-yl)-2,6-diazaspiro[3.4]octan-6-yl)-l,2,4-triazin-6-yl)oxy)-5-fluoro-7V-isopropylbenzamide 2-((5-(2-((3 *R, 5 *5)-6-(dimethylamino)-5-methoxy-2-methylhexan-3-yl)-2,6- 20 diazaspiro[3.4]octan-6-yl)-l,2,4-triazin-6-yl)oxy)-7V-ethyl-5-fluoro-7V-isopropylbenzamide ALethyl-2-((5-(2-((3*l?,5*5)-6-(ethyl(methyl)amino)-5-methoxy-2-methylhexan-3-yl)-2,6-diazaspiro[3.4]octan-6-yl)-l,2,4-triazin-6-yl)oxy)-5-fluoro-7V-isopropylbenzamide 7V-ethyl-5-fluoro-2-((5-(2-(5-hydroxy-6-(isopropyl(methyl)amino)-2-methylhexan-3-yl)- 25 2,6-diazaspiro[3.4]octan-6-yl)-l,2,4-triazin-6-yl)oxy)-7V-isopropylbenzamide 2-((5-(2-(6-(diethylamino)-5-hydroxy-2-methylhexan-3-yl)-2,6-diazaspiro[3.4]octan-6-yl)-l,2,4-triazin-6-yl)oxy)-7V-ethyl-5-fluoro-7V-isopropylbenzamide 2-((5-(2-(6-(dimethylamino)-5-hydroxy-2-methylhexan-3-yl)-2,6-diazaspiro[3.4]octan-6-yl)-l,2,4-triazin-6-yl)oxy)-5-fluoro-A^^V-diisopropylbenzamide 30   2-((5-(2-((3 *5,5 *5)-6-(dimethylamino)-5-methoxy-2-methylhexan-3-yl)-2,6- diazaspiro[3.4]octan-6-yl)-l,2,4-triazin-6-yl)oxy)-7V-ethyl-5-fluoro-7V-isopropylbenzamide 2026205213   01 Jul 2026 2-((5-(2-((3 *5,5 *lf)-6-(dimethylamino)-5-methoxy-2-methylhexan-3-yl)-2,6- diazaspiro[3.4]octan-6-yl)-l,2,4-triazin-6-yl)oxy)-7V-ethyl-5-fluoro- / V-isopropylbenzamide / V-ethyl-2-((5-(2-((3*5,5*5)-6-(ethyl(methyl)amino)-5-methoxy-2-methylhexan-3-yl)-2,6- 5 diazaspiro[3.4]octan-6-yl)-l,2,4-triazin-6-yl)oxy)-5-fluoro- / V-isopropylbenzamide / V-ethyl-2-((5-(2-((3*5,5*lf)-6-(ethyl(methyl)amino)-5-methoxy-2-methylhexan-3-yl)-2,6-diazaspiro[3.4]octan-6-yl)-l,2,4-triazin-6-yl)oxy)-5-fluoro- / V-isopropylbenzamide / V-ethyl-5-fluoro-2-((5-(2-(5-hydroxy-2-methyl-6-(methyl(propyl)amino)hexan-3-yl)-2,6-diazaspiro[3.4]octan-6-yl)-l,2,4-triazin-6-yl)oxy)-7V-isopropylbenzamide 10 2-((5-(2-(6-(ethyl(methyl)amino)-5-hydroxy-2-methylhexan-3-yl)-2,6- diazaspiro[3.4]octan-6-yl)-l,2,4-triazin-6-yl)oxy)-5-fluoro-A^V-diisopropylbenzamide (ft)-2-((3-chloro-5-(2-(6-(dimethylamino)-2-methylhexan-3-yl)-2,6-diazaspiro[3.4]octan-6-yl)-l,2,4-triazin-6-yl)oxy)-7V-ethyl-5-fluo...

Claims

2026205213   01 Jul 2026or a tautomer or a stereoisomeric form thereof, wherein0xa xb5 Rla represents-C(=O)-NRxaRxb; Het; or ' NK K .Het represents a 5- or 6-membered monocyclic aromatic ring containing one, two or three nitrogen atoms and optionally a carbonyl moiety;wherein said 5- or 6-membered monocyclic aromatic ring is optionally substituted with one or two substituents selected from the group consisting of C3-6cycloalkyl and10 Ci-4alkyl;Rxa and Rxb are each independently selected from the group consisting of hydrogen, Ci-4alkyl and C3-6cycloalkyl;Rlb represents F or Cl;Y1 represents -CR5aR5b-, -O- or -NR5c-;15 R2 is selected from the group consisting of hydrogen, halo, Ci.4alkyl, -O-Ci.4alkyl, and -NR7aR7b;U represents N or CH;nl, n2, n3 and n4 are each independently selected from 1 and 2;20 X1 represents CH, and X2 represents N;R4 represents isopropyl;R5a, R5b, R5c, R7a, and R7b, are each independently selected from the group consisting of hydrogen, Ci.4alkyl and C3-6cycloalkyl;2026205213   01 Jul 2026R3 represents -Ci-6alkyl-NR8aR8b, -Ci-6alkyl-C(=O)-NR9aR9b, -Ci-6alkyl-OH, or -Ci-6alkyl-NR11-C(=O)-O-Ci.4alkyl-O-C(=O)-Ci.4alkyl;wherein each of the Ci.4alkyl or Ci-ealkyl moi eties in the R3 definitions independently of each other may be substituted with one, two or three substituents each independently selected from 5 the group consisting of cyano, halo, -OH, and -O-Ci-4alkyl;R8a and R8b are each independently selected from the group consisting of hydrogen;Ci-ealkyl; -C(=O)-Ci-4alkyl; -C(=O)-O-Ci-4alkyl; -C(=O)-NR12aR12b; and Ci-ealkyl substituted with one, two or three substituents each independently selected from the group consisting of -OH, cyano, halo, -S(=O)2-Ci-4alkyl, -O-Ci-4alkyl, -C(=O)-NR10aR10b, and -NR10c-C(=O)-Ci-10 4alkyl;R9a, R9b, R10a, R10b, R10c, R11, R12a, and R12b are each independently selected from the group consisting of hydrogen and Ci-ealkyl;or a pharmaceutically acceptable salt or a solvate thereof.15   2. The compound according to claim 1, whereinR3 represents -Ci-6alkyl-NR8aR8b, -Ci-6alkyl-C(=O)-NR9aR9b, -Ci-6alkyl-OH, or -Ci-6alkyl-NR11-C(=O)-O-Ci.4alkyl-O-C(=O)-Ci.4alkyl;wherein each of the Ci.4alkyl or Ci-ealkyl moi eties in the R3 definitions independently of each other may be substituted with one, two or three substituents each independently selected from 20 the group consisting of cyano, halo or -O-Ci-4alkyl;R8a and R8b are each independently selected from the group consisting of hydrogen; Ci-ealkyl; -C(=O)-Ci-4alkyl; -C(=O)-O-Ci-4alkyl; -C(=O)-NR12aR12b; and Ci-ealkyl substituted with one, two or three substituents each independently selected from the group consisting of cyano, halo, -S(=O)2-Ci-4alkyl, -O-Ci-4alkyl, and -C(=O)-NR10aR10b;25 R9a, R9b, R10a, R10b, R11, R12a, and R12b are each independently selected from the group consisting of hydrogen and Ci-ealkyl.

3. The compound according to claim 2, whereinRla represents -C(=O)-NRxaRxb; or Het;30 Het represents a 6-membered monocyclic aromatic ring containing two nitrogen atoms; wherein said 6-membered monocyclic aromatic ring is optionally substituted with one C3-ecycloalkyl;Rxa and Rxb represent Ci-4alkyl;Rlb represents F;2026205213   01 Jul 2026Y1 represents -O-;R2 is hydrogen;U represents N;R3 represents -Ci-6alkyl-NR8aR8b, -Ci-6alkyl-C(=O)-NR9aR9b, -Ci-6alkyl-OH, or5 -Ci-6alkyl-NR11-C(=O)-O-Ci.4alkyl-O-C(=O)-Ci.4alkyl;R8a and R8b are each independently selected from the group consisting of hydrogen; Ci-ealkyl; -C(=O)-Ci-4alkyl; -C(=O)-O-Ci-4alkyl; -C(=O)-NR12aR12b; and Ci-ealkyl substituted with one, two or three substituents each independently selected from the group consisting of cyano, halo, -S(=O)2-Ci-4alkyl, and -O-Ci.4alkyl.

04. The compound according to claim 2, whereinRla represents -C(=O)-NRxaRxb;Rxa and Rxb represent Ci.4alkyl;Rlb represents F;15 Y1 represents-O-;R2 is hydrogen;U represents N;R3 represents -Ci-6alkyl-NR8aR8b, -Ci-6alkyl-C(=O)-NR9aR9b, or -Ci-6alkyl-OH;R8a and R8b are each independently selected from the group consisting of hydrogen; Ci-ealkyl; 20 -C(=O)-Ci-4alkyl; -C(=O)-O-Ci-4alkyl; -C(=O)-NR12aR12b; and Ci-ealkyl substituted with one, two or three substituents each independently selected from the group consisting of cyano, halo, -S(=O)2-Ci-4alkyl, and -O-Ci.4alkyl.

5. The compound according to claim 1, wherein25 Rla represents -C(=O)-NRxaRxb or Het;Het represents a 6-membered monocyclic aromatic ring containing two nitrogen atoms; wherein said 6-membered monocyclic aromatic ring is substituted with one Cs-ecycloalkyl;Rxa and Rxb represent Ci.4alkyl;30 Rlb represents F;Y1 represents -O-;R2 represents hydrogen;2026205213   01 Jul 2026U represents N or CH;nl, n2, n3 and n4 are each independently selected from 1 and 2;X1 represents CH, and X2 represents N;5 R4 represents isopropyl;R3 represents -Ci-6alkyl-NR8aR8b, -Ci-6alkyl-C(=O)-NR9aR9b, -Ci-6alkyl-OH, or -Ci-6alkyl-NR11-C(=O)-O-Ci.4alkyl-O-C(=O)-Ci.4alkyl;wherein each of the Ci.4alkyl or Ci-ealkyl moi eties in the R3 definitions independently of each other may be substituted with one, two or three substituents each independently selected from 10 the group consisting of -OH and -O-Ci.4alkyl;R8a and R8b are each independently selected from the group consisting of hydrogen; Ci-ealkyl; -C(=O)-Ci-4alkyl; -C(=O)-O-Ci-4alkyl; -C(=O)-NR12aR12b; and Ci-ealkyl substituted with one, two or three substituents each independently selected from the group consisting of -OH, cyano, halo, -S(=O)2-Ci.4alkyl, -O-Ci-4alkyl, -C(=O)-NR10aR10b, and -NR10c-C(=O)-Ci-4alkyl;15 R9a, R9b, R10a, R10b, R10c, R11, R12a, and R12b are each independently selected from the group consisting of hydrogen and Ci-ealkyl.

6. The compound according to claim 1, whereinRla represents -C(=O)-NRxaRxb or Het;20 Het represents a 6-membered monocyclic aromatic ring containing two nitrogen atoms; wherein said 6-membered monocyclic aromatic ring is substituted with one Cs-ecycloalkyl;Rxa and Rxb represent Ci-4alkyl;Rlb represents F;25 Y1 represents -O-;R2 represents hydrogen;U represents N or CH;nl, n2, n3 and n4 are each independently selected from 1 and 2;30 X1 represents CH, and X2 represents N;R4 represents isopropyl;2026205213   01 Jul 2026R3 represents -Ci-6alkyl-NR8aR8b;wherein the Ci-ealkyl moiety in the R3 definition may be substituted with one, two or three substituents each independently selected from the group consisting of -OH and -O-Ci.4alkyl;R8a and R8b are each independently selected from the group consisting of hydrogen;5 Ci-ealkyl; and Ci-ealkyl substituted with one, two or three substituents each independently selected from the group consisting of -OH, cyano, halo, -S(=O)2-Ci-4alkyl, -O-Ci.4alkyl, -C(=O)-NR10aR10b, and -NR10c-C(=O)-Ci-4alkyl;R10a R10b, and R10c are each independently selected from the group consisting of hydrogen and Ci-ealkyl.

07. The compound according to claim 1, whereinRla represents -C(=O)-NRxaRxb;Rxa and Rxb represent Ci.4alkyl;Rlb represents F;15 Y1 represents-O-;R2 represents hydrogen;U represents N;nl, n2, n3 and n4 are each independently selected from 1 and 2;20 X1 represents CH, and X2 represents N;R4 represents isopropyl;R3 represents -Ci-6alkyl-NR8aR8b;R8a and R8b are each independently selected from the group consisting of hydrogen;Ci-ealkyl; and Ci-ealkyl substituted with one, two or three substituents each independently25 selected from the group consisting of -OH, cyano, halo, -S(=O)2-Ci-4alkyl, -O-Ci.4alkyl, and -C(=O)-NR10aR10b;R10a and R10b are each independently selected from the group consisting of hydrogen and Ci-ealkyl.30   8. The compound according to claim 1, whereinY1 represents -O-.2026205213   01 Jul 20269. The compound according to claim 1, whereinRlb represents F.

10. A pharmaceutical composition comprising a compound as claimed in any one of claims 1 5 to 9 and a pharmaceutically acceptable carrier or diluent.

11. A process for preparing a pharmaceutical composition as defined in claim 10 comprising mixing a pharmaceutically acceptable carrier with a therapeutically effective amount of a compound according to any one of claims 1 to 9.1012. A compound as claimed in any one of claims 1 to 9 or a pharmaceutical composition as claimed in claim 10 for use as a medicament.

13. A compound as claimed in any one of claims 1 to 9 or a pharmaceutical composition as 15 claimed in claim 10 for use in the prevention or treatment of cancer.

14. A compound as claimed in any one of claims 1 to 9 or a pharmaceutical composition as claimed in claim 10 for use in the prevention or treatment of leukemia, myelodysplastic syndrome (MDS), and myeloproliferative neoplasms (MPN).2015. The compound or a pharmaceutical composition for use according to claim 14 in the prevention or treatment of leukemia wherein the leukemia is (NPMl)-mutated leukemia.

16. The compound or a pharmaceutical composition for use according to claim 13, wherein 25 cancer is selected from leukemias, lymphomas, myelomas or solid tumor cancers such as prostate cancer, lung cancer, breast cancer, pancreatic cancer, colon cancer, liver cancer, melanoma and glioblastoma.

17. The compound or a pharmaceutical composition for use according to claim 14, in the 30 prevention or treatment of leukemia wherein the leukemia is selected from acute leukemias, chronic leukemias, myeloid leukemias, myelogeneous leukemias, lymphoblastic leukemias, lymphocytic leukemias, Acute myelogeneous leukemias (AML), Chronic myelogenous leukemias (CML), Acute lymphoblastic leukemias (ALL), Chronic lymphocytic leukemias (CLL), T cell prolymphocytic leukemias (T-PLL), Large granular lymphocytic leukemia, 35 Hairy cell leukemia (HCL), MLL-rearranged leukemias, MLL-PTD leukemias, MLLamplified leukemias, MLL-positive leukemias, and leukemias exhibiting H0XIMEIS1 gene expression signatures.2026205213   01 Jul 202618. A method of treating or preventing a disorder selected from cancer, comprising administering to a subject in need thereof, a therapeutically effective amount of a compound as claimed in any one of claims 1 to 9 or a pharmaceutical composition as claimed in claim 10.5    19. An intermediate with the structureor a tautomer or a stereoisomeric form thereof;or a pharmaceutically acceptable addition salt or a solvate thereof.10   20. A process for the preparation of an intermediate comprising the following steps:CO2Ci_4alkyl N I PG Cl                               Cl Step 23     L,CO2C1.4alkyl step 24     k / =° ^Cl        *  n1(^ ^)n2             *  n1«^)n2 N                         N I                                                                                                                                                                                                                 I PG                     PGwherein PG is a suitable protecting group such as benzyl;wherein nl and n2 are as defined for formula (I);15    Step 23: at a suitable temperature such as for example from -78 °C to -25 °C, in the presence ofsuitable bases such as for example DIEA and n-BuLi, in a suitable solvent such as for example THF;Step 24: at a suitable temperature such as for example between -55°C and -65 °C, in the presence of suitable reducing agent such as for example DIBAL-H, in a suitable solvent such as for 20 example toluene, conducted in a suitable flow chemistry system.

21. A process for the preparation of an intermediate comprising the following steps:2026205213   01 Jul 2026Step 30PG is a suitable protecting group such as benzyl;other variables are as defined for formula (I);Step 30: at a suitable temperature such as for example from 5 °C to 30 °C, in the presence of a 5 suitable base such as for example TEA, in the presence of suitable reducing agent such as for example NaBH(OAc)3, in a suitable solvent such as for example toluene;Step 31: at a suitable temperature such as for example from 50 °C to 55 °C, in the presence of a suitable base such as for example K2HPO4, in a suitable solvent such as for example H2O;Step 32: at a suitable temperature such as for example from -5 °C to 45 °C, under a hydrogen 10 atmosphere within a suitable pressure range such as for example from 0.27 to 0.40 MPa, in the presence of palladium hydroxide on carbon, in the presence of MSA in a suitable solvent such as EtOH;Step 33: at a suitable temperature such as for example from -50 °C to -40 °C, in the presence of suitable base such as for example TEA, in a suitable solvent such as 2-methyltetrahydrofuran;2026205213   01 Jul 2026Step 34: at a suitable temperature such as for example from 20 °C to 30 °C, in the presence of suitable base such as for example TMG, in a suitable solvent such as 2-methyltetrahydrofuran; Step 35: at a suitable temperature such as for example from 20 °C to 30 °C, under a hydrogen atmosphere within a suitable pressure range such as for example from 0.20 to 0.30 Mpa, in 5 the presence of a suitable catalyst such as for example palladium on carbon, in a suitable solvent such as MeOH.

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