Substituted straight chain spiro derivatives

Abstract

This invention relates to pharmaceutical agents for treatment and / or prevention in mammals, pharmaceutical compositions comprising such compounds, and their use as menin / MLL protein / protein interaction inhibitors for the treatment of diseases such as cancer, including but not limited to leukemia, myelodysplastic syndrome (MDS), and myeloproliferative neoplasm (MPN); and diabetes.

Description

Technical Field

[0001] The present invention relates to pharmaceutical agents for therapeutic and / or prophylactic treatment in mammals, pharmaceutical compositions comprising such compounds, and their use as inhibitors of menin / MLL protein / protein interactions for the treatment of diseases such as cancer, including but not limited to leukemia, myelodysplastic syndrome (MDS), and myeloproliferative neoplasms (MPN); and diabetes. Prior Art

[0002] Chromosomal rearrangements affecting the mixed lineage leukemia genes (MLL; MLL1; KMT2A) cause aggressive acute leukemias in all age groups and remain a predominantly incurable disease, emphasizing the urgent need for novel therapeutic approaches. Acute leukemias harboring these MLL chromosomal translocations represent lymphoid, myeloid, or biphenotypic diseases and account for 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 Blood Cancer 2007. 49(2), 127-32).

[0003] MLL is a histone methyltransferase that methylates histone H3 at lysine 4 (H3K4) and functions in a multiprotein complex. Using an inducible loss-of-function allele of Mll1, it was shown that Mll1 plays an important role in maintaining hematopoietic stem cells (HSCs) and developing B cells, although its histone methyltransferase activity is dispensable for the hematopoietic lineage (Mishra et al., Cell Rep. 2014. 7(4), 1239-47).

[0004] To date, MLL has been reported to fuse with over 60 different partners and has been linked to leukemia development and progression (Meyer et al., Leukemia 2013. 27, 2165-2176). Interestingly, the SET (Su(var)3-9, enhancer of zeste, and trithorax) domain of MLL is not retained in the chimeric protein but is replaced by the fusion partner (Thiel et al., Bioessays 2012. 34, 771-80). Recruitment of chromatin-modifying enzymes such as Dot1L and / or the pTEFb complex by the fusion partner leads to enhanced transcription and transcriptional elongation of MLL target genes, including, most notably, HOXA genes (e.g., HOXA9) and the HOX cofactor MEIS1. Aberrant expression of these genes, in turn, blocks hematopoietic differentiation and enhances proliferation.

[0005] Menin, encoded by the multiple endocrine neoplasia type 1 (MEN1) gene, is ubiquitously expressed and primarily localized in the cell nucleus. It has been shown to interact with numerous proteins and, therefore, is involved in a variety of cellular processes. Menin's best understood function is as an oncogenic cofactor for MLL fusion proteins. Menin interacts with two motifs within the N-terminal fragment of MLL that are conserved in all fusion proteins, MBM1 (menin binding motif 1) and MBM2 (Thiel et al., Bioessays 2012, 34, 771-80). The menin / MLL interaction leads to the formation of a novel interaction surface for lens epithelium-derived growth factor (LEDGF). Although MLL directly binds to LEDGF, menin is required for a stable interaction between MLL and LEDGF and for gene-specific chromatin recruitment of the MLL complex via the PWWP domain of LEDGF (Cermakova et al., Cancer Res 2014. 15, 5139-51; Yokoyama & Cleary, Cancer Cell 2008. 8, 36-46). Furthermore, numerous genetic studies have demonstrated that menin is critically required for oncogenic transformation via MLL fusion proteins, suggesting that the menin / MLL interaction is an attractive therapeutic target. For example, conditional deletion of Men1 prevents leukemogenesis in myeloid progenitor cells that ectopically express MLL fusions (Chen et al., Proc Natl Acad Sci 2006. 103, 1018-23). Similarly, genetic disruption of the menin / MLL fusion interaction through loss-of-function mutations abolished the oncogenic properties of the MLL fusion protein, blocked leukemia development in vivo, and released the differentiation block of MLL-transformed leukemic blasts. These studies also demonstrated that menin is required for the maintenance of HOX gene expression by the MLL fusion protein (Yokoyama et al., Cell, 2005, 123, 207-18). Furthermore, druggable small-molecule inhibitors of the menin / MLL interaction have been developed and demonstrated efficacy in preclinical models of AML (Borkin et al., Cancer Cell, 2015, 27, 589-602; Cierpicki and Grembecka, Future Med Chem, 2014, 6, 447-462).Together with the observation that menin is not an essential cofactor for MLL1 during normal hematopoiesis (Li et al., Blood 2013. 122, 2039-2046), these data suggest that disruption of the menin / MLL interaction represents a promising new therapeutic approach for the treatment of MLL-rearranged leukemias and other cancer lines characterized by active HOX / MEIS1 genes. For example, internal partial tandem duplications (PTDs) within the 5' region of the MLL gene represent another major aberration that occurs predominantly in de novo and secondary AML, as well as myelodysplastic syndromes. Although the molecular mechanisms and biological functions of MLL-PTDs are not fully understood, novel therapeutic targeting strategies that influence the menin / MLL interaction may also prove effective in the treatment of MLL-PTD-associated leukemias. Furthermore, castration-resistant prostate cancer has been shown to be dependent on the menin / MLL interaction (Malik et al., Nat Med 2015. 21, 344-52).

[0006] Several references describe inhibitors targeting the menin-MLL interaction: WO 2011029054, J Med Chem 2016, 59, 892-913 describe the preparation of thienopyrimidine and benzodiazepine derivatives; WO 2014164543 describes thienopyrimidine and thienopyridine derivatives; Nature Chemical Biology 2012, March, 8, 277-284 and Ren, J. et al. Bioorg Med Chem Lett (2016), 26(18), 4472-4476 describe thienopyrimidine derivatives; J Med Chem 2014, 57, 1543-1556 describe hydroxy- and aminomethylpiperidine derivatives; Future Med Chem 2014, 6, 447-462 review small molecules and peptidomimetic compounds; WO 2016195776 describes furo[2,3-d]pyrimidine, 9H-purine, [1,3]oxazolo[5,4-d]pyrimidine, [1,3]oxazolo[4,5-d]pyrimidine, [1,3]thiazolo[5,4-d]pyrimidine, thieno[2,3-b]pyridine and thieno[2,3-d]pyrimidine derivatives; WO 2016197027 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 WO 2016040330 describes thienopyrimidine and thienopyridine compounds. WO 2017192543 describes piperidines as menin inhibitors. WO 2017112768, WO 2017207387, WO 2017214367, WO 2018053267, and WO 2018024602 describe inhibitors of the menin-MLL interaction. WO 2017161002 and WO 2017161028 describe inhibitors of menin-MLL. WO 2018050686, WO 2018050684, and WO 2018109088 describe inhibitors of the menin-MLL interaction. WO 2018226976 describes methods and compositions for inhibiting the interaction of menin with the MLL protein. WO 2018175746 provides a method for treating hematological malignancies and Ewing's sarcoma. WO 2018106818 and WO 2018106820 provide methods for promoting pancreatic cell proliferation.WO 2018153312 discloses azaspiro compounds in the field of medicinal chemistry. WO 2017132398 discloses a method comprising contacting leukemia cells displaying an NPM1 mutation with a pharmacological inhibitor of the interaction between MLL and Menin. WO 2019060365 describes substituted menin-MLL inhibitors. WO 2020069027 describes the use of menin inhibitors to treat hematological malignancies. Summary of the Invention

[0007] The present invention relates to novel compounds having formula (I), , and its tautomeric and stereoisomeric forms, wherein R 1a represents -C(=O)-NR xaR xb;Het; or ; Het represents a 5-membered or 6-membered monocyclic aromatic ring containing one, two or three nitrogen atoms and optionally a carbonyl moiety; wherein the 5-membered or 6-membered monocyclic aromatic ring is optionally substituted by one or two substituents selected from the following group, the group consisting of: C 3-6 cycloalkyl and C 1-4 alkyl; Rxa and Rxb are each independently selected from the following group, the group consisting of: hydrogen, C1-4 alkyl and C3-6 cycloalkyl; R 1b represents F or Cl; Y 1 represents -CR 5aR 5b-, -O- or -NR 5c-; R 2 is selected from the following group, the group consisting of: hydrogen, halo, C 1-4 alkyl, -OC 1-4 alkyl and -NR 7aR 7b; U represents N or CH; n1, n2, n3 and n4 are each independently selected from 1 and 2; X 1 represents CH, and X 2 represents N; R 4 represents an isopropyl group; R 5a, R 5b, R 5c, R 7a, and R 7b are each independently selected from the following group, the group consisting of: hydrogen, C 1-4 alkyl and C 3-6 cycloalkyl; R 3 represents -C 1-6 alkyl-NR 8aR 8b, -C 1-6 alkyl-C(=O)-NR 9aR 9b, -C 1-6 alkyl-OH, or -C 1-6 alkyl-NR 11-C(=O)-OC 1-4 alkyl-OC(=O)-C 1-4 alkyl; wherein each of the C 1-4 alkyl or C 1-6 alkyl moieties in the definition of R 3 may be independently substituted by one, two, or three substituents, each of which is independently selected from the following group consisting of: cyano, halo, -OH, and -OC 1-4 alkyl; R 8a and R 8b are each independently selected from the following group, the group consisting of: hydrogen; C 1-6 alkyl; -C(=O)-C 1-4 alkyl; -C(=O)-OC 1-4 alkyl; -C(=O)-NR 12aR 12b; and C 1-6 alkyl substituted by one, two, or three substituents, each of which is independently selected from the group consisting of: -OH, cyano, halo, -S(=O) 2-C 1-4 alkyl, -OC 1-4 alkyl, -C(=O)-NR 10aR 10b, and -NR 10c-C(=O)-C 1-4 alkyl; R 9a, R 9b, R 10a, R 10b, R 10c, R 11, R 12a and R 12b are each independently selected from the group consisting of: hydrogen and C 1-6 alkyl; and pharmaceutically acceptable salts and solvates thereof.

[0008] 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 solvate thereof, and a pharmaceutically acceptable carrier or excipient.

[0009] In addition, the present invention relates to a compound of formula (I), a pharmaceutically acceptable salt or solvate thereof, for use as a medicament, and to a compound of formula (I), a pharmaceutically acceptable salt or solvate thereof, for use in treating or preventing cancer, including but not limited to leukemia, myelodysplastic syndrome (MDS), and myeloproliferative neoplasms (MPN); and diabetes.

[0010] In a specific embodiment, the present invention relates to a compound of formula (I), a pharmaceutically acceptable salt or solvate thereof, for use in treating or preventing cancer.

[0011] In a specific embodiment, the cancer is selected from the group consisting of leukemia, lymphoma, myeloma, or solid tumor cancer (e.g., prostate cancer, lung cancer, breast cancer, pancreatic cancer, colorectal cancer, liver cancer, melanoma, and glioblastoma). In some embodiments, the leukemia includes acute leukemia, chronic leukemia, myeloid leukemia, myeloid leukemia, lymphoblastic leukemia, lymphocytic leukemia, acute myeloid leukemia (AML), chronic myeloid leukemia (CML), acute lymphoblastic leukemia (ALL), chronic lymphocytic leukemia (CLL), T-cell prolymphocytic leukemia (T-PLL), large granular lymphocytic leukemia, hairy cell leukemia (HCL), MLL-rearranged leukemia, MLL-PTD leukemia, MLL-amplified leukemia, MLL-positive leukemia, leukemias displaying HOX / MEIS1 gene expression signatures, and the like.

[0012] In particular, the compounds according to the present invention and their pharmaceutical compositions can be used to treat or prevent leukemia, in particular nucleophosmin (NPM1)-mutant leukemia, such as NPM1c.

[0013] In one embodiment, the compounds of Formula (I) and pharmaceutically acceptable salts and solvates thereof may have improved metabolic stability properties.

[0014] In one embodiment, the compound of formula (I) and pharmaceutically acceptable salts and solvates thereof may have a prolonged half-life (T1 / 2) in vivo.

[0015] In one embodiment, the compounds of formula (I) and pharmaceutically acceptable salts and solvates thereof may have improved oral bioavailability.

[0016] In one embodiment, compounds of formula (I) and pharmaceutically acceptable salts and solvates thereof can reduce tumor growth, such as tumors carrying MLL (KMT2A) gene rearrangements / alterations and / or NPM1 mutations.

[0017] In one embodiment, compounds of formula (I) and pharmaceutically acceptable salts and solvates thereof can have improved PD properties in vivo over an extended period of time, such as inhibition of target gene (e.g., MEIS1) expression and upregulation of differentiation markers over a period of at least 16 hours.

[0018] In one embodiment, compounds of Formula (I) and pharmaceutically acceptable salts and solvates thereof may have improved safety (eg, reduced hERG inhibition; improved cardiovascular safety).

[0019] In one embodiment, the compound of formula (I) and pharmaceutically acceptable salts and solvates thereof may be suitable for QD dosing (once daily).

[0020] The present invention also relates to the use of a compound of formula (I), a pharmaceutically acceptable salt or solvate thereof, in combination with another pharmaceutical agent for treating or preventing cancer, including but not limited to leukemia, myelodysplastic syndrome (MDS), and myeloproliferative neoplasms (MPN); and diabetes.

[0021] Furthermore, the present invention relates to a method for preparing the pharmaceutical composition according to the present invention, characterized in that a pharmaceutically acceptable carrier is intimately mixed with a therapeutically effective amount of a compound of formula (I), a pharmaceutically acceptable salt or solvate thereof.

[0022] The present invention also relates to a product comprising a compound of formula (I), a pharmaceutically acceptable salt or solvate thereof, and another pharmaceutical agent, as a combined preparation for simultaneous, separate or sequential use in the treatment or prevention of cancer, including but not limited to leukemia, myelodysplastic syndrome (MDS), and myeloproliferative neoplasms (MPN); and diabetes.

[0023] In addition, the present invention relates to a method for treating or preventing a cell proliferative disease in a warm-blooded animal, which method comprises administering to the animal an effective amount of a compound of formula (I) as defined herein, a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition or combination as defined herein. Simple diagram description

[0024] Figure 1: Efficacy study of Molm-14 in the subcutaneous (sc) model.

[0025] Figure 2: Efficacy study in the disseminated OCI-AML3 model. Implementation Method

[0026] The term "halo" or "halogen" as used herein represents fluoro, chloro, bromo and iodo.

[0027] As used herein, the prefix "Cxy" (wherein x and y are integers) refers to the number of carbon atoms in a given group. Thus, a C1-6 alkyl group contains from 1 to 6 carbon atoms, and so on.

[0028] The term "C 1-4 alkyl" as used herein as a group or a part of a group represents a straight or branched chain saturated hydrocarbon group having from 1 to 4 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, secondary butyl, tertiary butyl, etc.

[0029] The term "C 3-6 cycloalkyl" as used herein as a group or part of a group defines a saturated, cyclic hydrocarbon group having from 3 to 6 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.

[0030] It will be clear to those skilled in the art that S(=0) 2 or SO 2 represents a sulfonyl moiety.

[0031] It will be clear to the skilled person that CO or C(=0) represents a carbonyl moiety.

[0032] It will be clear to those skilled in the art that a group such as -CRR- represents An example of such a group is -CR 5aR 5b-.

[0033] It will be clear to those skilled in the art that a group such as -NR- represents An example of such a group is -NR 5c-.

[0034] Non-limiting examples of a monocyclic 5- or 6-membered aromatic ring containing one, two, or three nitrogen atoms and optionally a carbonyl moiety include, but are not limited to, pyrazolyl, imidazolyl, pyridinyl, pyrimidinyl, pyrimidinyl, trithiophene, or 1,2-dihydro-2-oxo-4-pyridinyl.

[0035] The skilled artisan will appreciate that 5- or 6-membered monocyclic aromatic rings containing one, two, or three nitrogen atoms and a carbonyl moiety include, but are not limited to 、 ,and .

[0036] When any variable occurs more than once in any constituent, each definition is independent.

[0037] When any variable occurs more than one time in any formula (eg, Formula (I)), each definition is independent.

[0038] In general, whenever the term "substituted" is used herein, unless otherwise indicated or clear from the context, it is intended to indicate that one or more hydrogens (particularly from 1 to 4 hydrogens, more particularly from 1 to 3 hydrogens, preferably 1 or 2 hydrogens, more preferably 1 hydrogen) on the atom or group indicated by the expression "substituted" are replaced with an alternative selected from the indicated group, provided that the normal valence is not exceeded and that the substitution results in a chemically stable compound, i.e., a compound that is sufficiently robust to withstand isolation from the reaction mixture to a useful degree of purity (after the reaction, for example, by purification by silica gel chromatography). In certain embodiments, when the number of substituents is not explicitly specified, the number of substituents is one.

[0039] Combinations of substituents and / or variables are permissible only if such combinations result in chemically stable compounds. "Stable compound" in this context is intended to indicate a compound that is sufficiently robust to survive isolation from a reaction mixture (and post-reaction isolation, e.g., purification by silica gel chromatography) to a useful degree of purity.

[0040] The skilled artisan will understand that the term "optionally substituted" means that the atom or group indicated by "optionally substituted" may or may not be substituted (which means substituted or unsubstituted, respectively).

[0041] When two or more substituents are present on a moiety, where possible and unless otherwise specified or clear from the context, the substituents may replace a hydrogen on the same atom, or the substituents may replace hydrogen atoms on different atoms of the moiety.

[0042] In the context of the present invention, "saturated" means "completely saturated" unless otherwise specified.

[0043] Unless otherwise specified or clear from the context, an aromatic ring group may be attached to the remainder of the molecule having formula (I) through any available ring carbon atom (C-linked) or nitrogen atom (N-linked).

[0044] Unless otherwise specified or clear from the context, aromatic ring groups may be optionally substituted on the carbon and / or nitrogen atoms according to the embodiments, where possible.

[0045] As used herein, the term "subject" refers to an animal that is or has been the object of treatment, observation, or experiment, preferably a mammal (eg, a cat, dog, primate, or human), more preferably a human.

[0046] As used herein, the term "therapeutically effective amount" means that amount of an active compound or pharmaceutical agent that elicits the biological or medicinal response in a tissue system (animal or human) that is being sought by the researcher, veterinarian, medical doctor or other clinician, including alleviation or reversal of symptoms of the disease or disorder being treated.

[0047] 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 combination of the specified ingredients in the specified amounts.

[0048] As used herein, the term "treatment" is intended to refer to all procedures in which the progression of the disease may be slowed, interrupted, suppressed or prevented, but does not necessarily imply the complete elimination of all symptoms.

[0049] As used herein, the term "compound(s) of the invention" or "compound(s) according to the invention" is intended to include compounds of formula (I) and pharmaceutically acceptable salts and solvates thereof.

[0050] As used herein, any chemical formula having bonds shown only as solid lines and not as solid or dashed wedges, or otherwise expressed as a chemical formula having a particular configuration (e.g., R, S) around one or more atoms, contemplates every possible stereoisomer, or mixture of two or more stereoisomers.

[0051] Above and below, the term "one or more compounds of formula (I)" is intended to include tautomers and stereoisomeric forms thereof.

[0052] The terms "stereoisomer", "stereoisomeric form" or "stereochemically isomeric form" are used interchangeably above and below.

[0053] The present invention includes all stereoisomers of the compounds of the present invention as pure stereoisomers or as mixtures of two or more stereoisomers.

[0054] 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.

[0055] Atropisomers (or atropoisomers) are stereoisomers with a specific spatial configuration resulting from 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 within the scope of the present invention.

[0056] Diastereoisomers are stereoisomers that are not mirror images. If the compound contains a double bond, the substituents may be in the E or Z configuration.

[0057] Substituents on a divalent cyclic saturated or partially saturated group may have a cis or trans configuration; for example, if the compound contains a disubstituted cycloalkyl group, such substituents may be in a cis or trans configuration.

[0058] Therefore, the present invention includes enantiomers, conformational isomers, diastereomers, racemates, E isomers, Z isomers, cis isomers, trans isomers, and mixtures thereof, as far as chemically possible.

[0059] The meanings of all those terms (ie, enantiomers, conformational isomers, diastereomers, racemates, E isomers, Z isomers, cis isomers, trans isomers and mixtures thereof) are known to the skilled artisan.

[0060] Absolute configuration is assigned according to the Cahn-Ingold-Prelog system. Configuration at asymmetric atoms is designated by R or S. Resolved stereoisomers whose absolute configuration is unknown can be designated by (+) or (-) depending on the direction in which they rotate plane-polarized light. For example, resolved mirror image isomers whose absolute configuration is unknown can be designated by (+) or (-) depending on the direction in which they rotate plane-polarized light.

[0061] When a specific stereoisomer is identified, this means that the stereoisomer is substantially free of other stereoisomers, i.e., associated with less than 50%, preferably less than 20%, more preferably less than 10%, even more preferably less than 5%, particularly less than 2%, and most preferably less than 1% of other stereoisomers. Thus, when a compound of formula (I) is designated, for example, as (R), this means that the compound is substantially free of the (S) isomer; when a compound of formula (I) is designated, for example, as E, this means that the compound is substantially free of the Z isomer; when a compound of formula (I) is designated, for example, as cis, this means that the compound is substantially free of the trans isomer.

[0062] Some compounds according to formula (I) may also exist in tautomeric forms. Although not explicitly indicated in formula (I) above, such forms, where they may exist, are intended to be included within the scope of the present invention. It follows that a single compound may exist in stereoisomeric and tautomeric forms.

[0063] Pharmaceutically acceptable salts include acid addition salts and base addition salts. Such salts can be formed by conventional means, for example, by reacting the free acid or free base form with one or more equivalents of the appropriate base or acid, optionally in a solvent or a medium in which the salt is insoluble, followed by removal of the solvent or medium using standard techniques (e.g., in vacuo, by freeze drying, or by filtration). Salts can also be prepared by exchanging the counterion of a compound of the invention in salt form with another counterion, for example, using a suitable ion exchange resin.

[0064] The pharmaceutically acceptable salts as mentioned above or hereinafter are intended to comprise the therapeutically active non-toxic acid and base salt forms that the compounds of formula (I) and their solvates are able to form.

[0065] Suitable acids include, for example, inorganic acids such as hydrohalic acids (e.g., hydrochloric acid or hydrobromic acid), sulfuric acid, nitric acid, phosphoric acid and the like; or organic acids such as acetic acid, propionic acid, glycolic acid, lactic acid, pyruvic acid, oxalic acid (i.e., oxalic acid), malonic acid, succinic acid (i.e., succinic acid), maleic acid, fumaric acid, malic acid, tartaric acid, citric acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, cyclohexanesulfonic acid, salicylic acid, p-aminosalicylic acid, pamoic acid and the like. Conversely, the salt form can be converted into the free base form by treatment with an appropriate base.

[0066] Compounds of formula (I) containing acidic protons and their solvates may also be converted into their non-toxic metal or amine salt forms by treatment with appropriate organic and inorganic bases.

[0067] Suitable base salt forms include, for example, ammonium salts, alkali metal and alkaline earth metal salts such as 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, tetrabutylamine isomers, dimethylamine, diethylamine, diethanolamine, dipropylamine, diisopropylamine, di-n-butylamine, pyrrolidine, piperidine, morpholine, trimethylamine, triethylamine, tripropylamine, quinuclidine, pyridine, quinoline, and isoquinoline); benzathine, N-methyl-D-glucamine, hydrazine salts, and salts with amino acids such as arginine, lysine, and the like. Conversely, the salt form can be converted into the free acid form by treatment with an acid.

[0068] The term "prodrug" includes any compound that, following oral or parenteral administration (particularly oral administration), is metabolized in vivo to an experimentally detectable amount of the (more) active form within a predetermined time period (e.g., between 0.5 and 24 hours of dosing interval, or, for example, between 6 and 24 hours of dosing interval (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, specifically intravenous (IV), intramuscular (IM), and subcutaneous (SC) injections.

[0069] Prodrugs can be prepared by modifying functional groups present on a compound in such a way that the modifications are cleaved in vivo when the prodrug is administered to a mammalian subject. Typically, such modifications are accomplished by synthesizing a parent compound with prodrug substituents. Typically, prodrugs include compounds in which a hydroxyl, amine, sulfhydryl, carboxyl, or carbonyl group is attached to any group that can be cleaved in vivo to regenerate a free hydroxyl, amine, sulfhydryl, carboxyl, or carbonyl group, respectively.

[0070] Examples of prodrugs include, but are not limited to, esters and carbamates of hydroxyl functional groups, esters of carboxyl functional groups, N-acyl derivatives, and N-Mannich bases. General information on prodrugs can be found, for example, in Bundegaard, H. "Design of Prodrugs," pp. 1-92, Elesevier, New York-Oxford (1985).

[0071] 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 eg hydrates, alcoholates and the like.

[0072] The compounds of the present invention, as prepared by the methods described below, can be synthesized as mixtures of enantiomers, particularly racemic mixtures of enantiomers, which can be separated from one another using resolution procedures known in the art. Methods for separating enantiomerically isomeric forms of compounds of Formula (I) and pharmaceutically acceptable salts and solvates thereof involve liquid chromatography using a chiral stationary phase. The stereochemically pure isomeric forms can also be derived from the correspondingly pure stereochemically isomeric forms of appropriate starting materials, provided that the reaction occurs stereospecifically. Preferably, if a specific stereoisomer is desired, the compound will be synthesized by stereospecific preparation methods. Such methods advantageously employ enantiomerically pure starting materials.

[0073] As used herein, the term "enantiomerically pure" means that the product contains at least 80% by weight of one enantiomer and 20% or less by weight of the other enantiomer. Preferably, the product contains at least 90% by weight of one enantiomer and 10% or less by weight of the other enantiomer. In a most preferred embodiment, the term "enantiomerically pure" means that the composition contains at least 99% by weight of one enantiomer and 1% or less by weight of the other enantiomer.

[0074] The present invention also encompasses 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 one most commonly found in nature).

[0075] All isotopes and isotopic mixtures of any specific atom or element as specified herein are considered within the scope of the compounds of the present invention, whether naturally occurring or synthetically produced, and whether at natural abundance or in isotopically enriched form. Exemplary isotopes that may be included in the compounds of the present invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, and iodine, such as 2H, 3H, 11C, 13C, 14C, 13N, 15O, 17O, 18O, 32P, 33P, 35S, 18F, 36Cl, 122I, 123I, 125I, 131I, 75Br, 76Br, 77Br, and 82Br. Preferably, the isotope is selected from the group consisting of 2H, 3H, 11C, 13C, and 18F. Preferably, the isotope is selected from the group consisting of 2H, 3H, 11C, and 18F. More preferably, the 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 within the scope of the present invention. In particular, deuterated compounds are intended to be within the scope of the present invention.

[0076] 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 because they are easy to prepare and detect. Furthermore, substitution with heavier isotopes such as deuterium (i.e., 2H) may offer certain therapeutic advantages resulting from greater metabolic stability (e.g., increased in vivo half-life or reduced dosage requirements) and may therefore be preferred in some circumstances. Positron-emitting isotopes such as 15O, 13N, 11C, and 18F are useful for positron emission tomography (PET) studies. PET imaging in cancer is effective in helping to localize and identify tumors, stage the disease, and determine appropriate treatments. Human cancer cells overexpress receptors or proteins for many potential disease-specific molecular targets. Radiolabeled tracers that bind to such receptors or proteins on tumor cells with high affinity and specificity have great potential for diagnostic imaging and targeted radionuclide therapy (Charron, Carlie L. et al. Tetrahedron Lett. 2016, 57(37), 4119-4127). In addition, target-specific PET radiotracers can be used as biomarkers to examine and assess pathology, for example, by measuring target expression and treatment response (Austin R. et al. Cancer Letters (2016), doi:10.1016 / j.canlet.2016.05.008).

[0077] The present invention particularly relates to compounds of formula (I) as defined herein, and tautomeric and stereoisomeric forms thereof, wherein R 1a represents -C(=O)-NR xaR xb;Het; or ; Het represents a 5-membered or 6-membered monocyclic aromatic ring containing one, two or three nitrogen atoms and optionally a carbonyl moiety; wherein the 5-membered or 6-membered monocyclic aromatic ring is optionally substituted by one or two substituents selected from the following group, the group consisting of: C 3-6 cycloalkyl and C 1-4 alkyl; Rxa and Rxb are each independently selected from the following group, the group consisting of: hydrogen, C1-4 alkyl and C3-6 cycloalkyl; R 1b represents F or Cl; Y 1 represents -CR 5aR 5b-, -O- or -NR 5c-; R 2 is selected from the following group, the group consisting of: hydrogen, halo, C 1-4 alkyl, -OC 1-4 alkyl and -NR 7aR 7b; U represents N or CH; n1, n2, n3 and n4 are each independently selected from 1 and 2; X 1 represents CH, and X 2 represents N; R 4 represents an isopropyl group; R 5a, R 5b, R 5c, R 7a, and R 7b are each independently selected from the following group, the group consisting of: hydrogen, C 1-4 alkyl and C 3-6 cycloalkyl; R 3 represents -C 1-6 alkyl-NR 8aR 8b, -C 1-6 alkyl-C(=O)-NR 9aR 9b, -C 1-6 alkyl-OH, or -C 1-6 alkyl-NR 11-C(=O)-OC 1-4 alkyl-OC(=O)-C 1-4 alkyl; wherein each of the C 1-4 alkyl or C 1-6 alkyl moieties in the definition of R 3 may be independently substituted by one, two, or three substituents, each of which is independently selected from the following group, the group consisting of: cyano, halo, or -OC 1-4 alkyl; R 8a and R 8b are each independently selected from the group consisting of: hydrogen; C 1-6 alkyl; -C(=O)-C 1-4 alkyl; -C(=O)-OC 1-4 alkyl; -C(=O)-NR 12aR 12b; and C 1-6 alkyl substituted with one, two, or three substituents, each of which is independently selected from the group consisting of: cyano, halo, -S(=O) 2-C 1-4 alkyl, -OC 1-4 alkyl, and -C(=O)-NR 10aR 10b; R 9a, R 9b, R 10a, R 10b, R 11, R 12a, and R 12b are each independently selected from the group consisting of: hydrogen and C 1-6 alkyl; and pharmaceutically acceptable salts and solvates thereof.

[0078] The present invention particularly relates to compounds of formula (I) as defined herein, and tautomeric and stereoisomeric forms thereof, wherein R 1a represents -C(=O)-NR xaR xb;Het; or ; Het represents a 5-membered or 6-membered monocyclic aromatic ring containing one, two or three nitrogen atoms and optionally a carbonyl moiety; wherein the 5-membered or 6-membered monocyclic aromatic ring is optionally substituted by one or two substituents selected from the following group, the group consisting of: C 3-6 cycloalkyl and C 1-4 alkyl; Rxa and Rxb are each independently selected from the following group, the group consisting of: hydrogen, C1-4 alkyl and C3-6 cycloalkyl; R 1b represents F or Cl; Y 1 represents -CR 5aR 5b-, -O- or -NR 5c-; R 2 is selected from the following group, the group consisting of: hydrogen, halo, C 1-4 alkyl, -OC 1-4 alkyl and -NR 7aR 7b; U represents N or CH; n1, n2, n3 and n4 are each independently selected from 1 and 2; X 1 represents CH, and X 2 represents N; R 4 represents an isopropyl group; R 5a, R 5b, R 5c, R 7a, and R 7b are each independently selected from the following group, the group consisting of: hydrogen, C 1-4 alkyl and C 3-6 cycloalkyl; R 3 represents -C 1-6 alkyl-NR 8aR 8b; wherein the C 1-6 alkyl moiety in the definition of R 3 may be substituted by one, two, or three substituents, each of which is independently selected from the following group, the group consisting of: cyano, halo, OH, and -OC 1-4 alkyl; R 8a and R 8b are each independently selected from the following group, the group consisting of: hydrogen; C 1-6 alkyl; and C 1-6 alkyl substituted by one, two, or three substituents, each of which is independently selected from the group consisting of: -OH, cyano, halo, -S(=O) 2-C 1-4 alkyl, -OC 1-4 alkyl, -C(=O)-NR 10aR 10b, and -NR 10c-C(=O)-C 1-4 alkyl; R 10a, R 10b, R 10c are each independently selected from the following group, the group consisting of: hydrogen and C 1-6 alkyl; and pharmaceutically acceptable salts and solvates thereof.

[0079] The present invention particularly relates to compounds of formula (I) as defined herein, and tautomeric and stereoisomeric forms thereof, wherein R 1a represents -C(=O)-NR xaR xb;Het; or ; Het represents a 5-membered or 6-membered monocyclic aromatic ring containing one, two or three nitrogen atoms and optionally a carbonyl moiety; wherein the 5-membered or 6-membered monocyclic aromatic ring is optionally substituted by one or two substituents selected from the following group, the group consisting of: C 3-6 cycloalkyl and C 1-4 alkyl; Rxa and Rxb are each independently selected from the following group, the group consisting of: hydrogen, C1-4 alkyl and C3-6 cycloalkyl; R 1b represents F or Cl; Y 1 represents -CR 5aR 5b-, -O- or -NR 5c-; R 2 is selected from the following group, the group consisting of: hydrogen, halo, C 1-4 alkyl, -OC 1-4 alkyl and -NR 7aR 7b; U represents N or CH; n1, n2, n3 and n4 are each independently selected from 1 and 2; X 1 represents CH, and X 2 represents N; R 4 represents an isopropyl group; R 5a, R 5b, R 5c, R 7a, and R 7b are each independently selected from the following group, the group consisting of: hydrogen, C 1-4 alkyl and C 3-6 cycloalkyl; R 3 represents -C 1-6 alkyl-NR 8aR 8b; wherein the C 1-6 alkyl moiety in the definition of R 3 may be substituted by one, two, or three substituents, each of which is independently selected from the following group, the group consisting of: cyano, halo, and -OC 1-4 alkyl; R 8a and R 8b are each independently selected from the following group, the group consisting of: hydrogen; C 1-6 alkyl; and C 1-6 alkyl substituted by one, two, or three substituents, each of which is independently selected from the group consisting of cyano, halo, -S(=O) 2-C 1-4 alkyl, -OC 1-4 alkyl, and -C(=O)-NR 10aR 10b; R 10a and R 10b are each independently selected from the following group, the group consisting of: hydrogen and C 1-6 alkyl; and pharmaceutically acceptable salts and solvates thereof.

[0080] The present invention particularly relates to compounds of formula (I) as defined herein, and tautomeric and stereoisomeric forms thereof, wherein R 1a represents -C(=O)-NR xaR xb or Het; Het represents a 6-membered monocyclic aromatic ring containing two nitrogen atoms; Wherein the 6-membered monocyclic aromatic ring is substituted by a C 3-6 cycloalkyl group; R xa and R xb represent C 1-4 alkyl; R 1b represents F; Y 1 represents -O-; R 2 represents hydrogen; U represents N or CH; n1, n2, n3 and n4 are each independently selected from 1 and 2; X 1 represents CH, and X 2 represents N; R 4 represents an isopropyl group; R 3 represents -C 1-6 alkyl-NR 8aR 8b, -C 1-6 alkyl-C(=O)-NR 9aR 9b, -C 1-6 alkyl-OH, or -C 1-6 alkyl-NR 11-C(=O)-OC 1-4 alkyl-OC(=O)-C 1-4 alkyl; wherein each of the C 1-4 alkyl or C 1-6 alkyl moieties in the definition of R 3 may be independently substituted by one, two, or three substituents, each of which is independently selected from the following group, the group consisting of: -OH and -OC 1-4 alkyl; R 8a and R 8b are each independently selected from the group consisting of: hydrogen; C 1-6 alkyl; -C(=O)-C 1-4 alkyl; -C(=O)-OC 1-4 alkyl; -C(=O)-NR 12aR 12b; and C 1-6 alkyl substituted with one, two, or three substituents, each of which is independently selected from the group consisting of: -OH, cyano, halo, -S(=O) 2-C 1-4 alkyl, -OC 1-4 alkyl, -C(=O)-NR 10aR 10b, and -NR 10c-C(=O)-C 1-4 alkyl; R 9a, R 9b, R 10a, R 10b, R 10c, R 11, R 12a and R 12b are each independently selected from the group consisting of: hydrogen and C 1-6 alkyl; and pharmaceutically acceptable salts and solvates thereof.

[0081] The present invention particularly relates to compounds of formula (I) as defined herein, and tautomeric and stereoisomeric forms thereof, wherein R 1a represents -C(=O)-NR xaR xb or Het; Het represents a 6-membered monocyclic aromatic ring containing two nitrogen atoms; Wherein the 6-membered monocyclic aromatic ring is substituted by a C 3-6 cycloalkyl group; R xa and R xb represent C 1-4 alkyl; R 1b represents F; Y 1 represents -O-; R 2 represents hydrogen; U represents N or CH; n1, n2, n3 and n4 are each independently selected from 1 and 2; X 1 represents CH, and X 2 represents N; R 4 represents an isopropyl group; R 3 represents -C 1-6 alkyl-NR 8aR 8b; wherein the C 1-6 alkyl moiety in the definition of R 3 may be substituted by one, two, or three substituents, each of which is independently selected from the following group, the group consisting of: -OH and -OC 1-4 alkyl; R 8a and R 8b are each independently selected from the following group, the group consisting of: hydrogen; C 1-6 alkyl; and C 1-6 alkyl substituted by one, two, or three substituents, each of which is independently selected from the group consisting of: -OH, cyano, halo, -S(=O) 2-C 1-4 alkyl, -OC 1-4 alkyl, -C(=O)-NR 10aR 10b, and -NR 10c-C(=O)-C 1-4 alkyl; R 10a, R 10b, and R 10c are each independently selected from the following group, the group consisting of: hydrogen and C 1-6 alkyl; and pharmaceutically acceptable salts and solvates thereof.

[0082] The present invention particularly relates to compounds of formula (I) as defined herein, and tautomeric and stereoisomeric forms thereof, wherein R 1a represents -C(=O)-NR xaR xb; R xa and R xb represent C 1-4 alkyl; R 1b represents F; Y 1 represents -O-; R 2 represents hydrogen; U represents N or CH; n1, n2, n3 and n4 are each independently selected from 1 and 2; X 1 represents CH, and X 2 represents N; R 4 represents an isopropyl group; R 3 represents -C 1-6 alkyl-NR 8aR 8b; wherein the C 1-6 alkyl moiety in the definition of R 3 may be substituted by one, two, or three substituents, each of which is independently selected from the following group, the group consisting of: -OH and -OC 1-4 alkyl; R 8a and R 8b are each independently selected from the following group, the group consisting of: hydrogen; C 1-6 alkyl; and C 1-6 alkyl substituted by one, two, or three substituents, each of which is independently selected from the group consisting of: -OH, cyano, halo, -S(=O) 2-C 1-4 alkyl, -OC 1-4 alkyl, -C(=O)-NR 10aR 10b, and -NR 10c-C(=O)-C 1-4 alkyl; R 10a, R 10b, and R 10c are each independently selected from the following group, the group consisting of: hydrogen and C 1-6 alkyl; and pharmaceutically acceptable salts and solvates thereof.

[0083] The present invention particularly relates to compounds of formula (I) as defined herein, and tautomeric and stereoisomeric forms thereof, wherein R 1a represents -C(=O)-NR xaR xb or Het; Het represents a pyrimidinyl group substituted by a C 3-6 cycloalkyl group; R xa and R xb represent C 1-4 alkyl; R 1b represents F; Y 1 represents -O-; R 2 represents hydrogen; U means N; n1, n2, n3 and n4 are each independently selected from 1 and 2; X 1 represents CH, and X 2 represents N; R 4 represents an isopropyl group; R 3 represents -C 1-6 alkyl-NR 8aR 8b; Wherein the C 1-6 alkyl moiety defined in R 3 may be substituted with a -OH; R 8a and R 8b are each independently selected from the following group, the group consisting of: hydrogen; C 1-6 alkyl; and C 1-6 alkyl substituted with one or two substituents each independently selected from the group consisting of: halo, -OC 1-4 alkyl, and -NR 10c-C(=O)-C 1-4 alkyl; R 10a, R 10b, and R 10c are each independently selected from the following group, the group consisting of: hydrogen and C 1-6 alkyl; and pharmaceutically acceptable salts and solvates thereof.

[0084] The present invention particularly relates to compounds of formula (I) as defined herein, and tautomeric and stereoisomeric forms thereof, wherein R 1a represents -C(=O)-NR xaR xb or Het; Het represents a pyrimidinyl group substituted by a C 3-6 cycloalkyl group; R xa and R xb represent C 1-4 alkyl; R 1b represents F; Y 1 represents -O-; R 2 represents hydrogen; U means N; n2 series 2; n1, n3 and n4 are 1; X 1 represents CH, and X 2 represents N; R 4 represents an isopropyl group; R 3 represents -C 1-6 alkyl-NR 8aR 8b; Wherein the C 1-6 alkyl moiety defined in R 3 may be substituted with a -OH; R 8a and R 8b are each independently selected from the following group, the group consisting of: hydrogen; C 1-6 alkyl; and C 1-6 alkyl substituted with one or two substituents each independently selected from the group consisting of: halo, -OC 1-4 alkyl, and -NR 10c-C(=O)-C 1-4 alkyl; R 10a, R 10b, and R 10c are each independently selected from the following group, the group consisting of: hydrogen and C 1-6 alkyl; and pharmaceutically acceptable salts and solvates thereof.

[0085] The present invention particularly relates to compounds of formula (I) as defined herein, and tautomeric and stereoisomeric forms thereof, wherein R 1a represents -C(=O)-NR xaR xb; R xa and R xb represent C 1-4 alkyl; R 1b represents F; Y 1 represents -O-; R 2 represents hydrogen; U means N; n2 series 2; n1, n3 and n4 are 1; X 1 represents CH, and X 2 represents N; R 4 represents an isopropyl group; R 3 represents -C 1-6 alkyl-NR 8aR 8b; R 8a and R 8b are each independently selected from the following group, the group consisting of: hydrogen; C 1-6 alkyl; and C 1-6 alkyl substituted with one or two substituents each independently selected from the group consisting of: halo, -OC 1-4 alkyl, and -NR 10c-C(=O)-C 1-4 alkyl; R 10a, R 10b, and R 10c are each independently selected from the following group, the group consisting of: hydrogen and C 1-6 alkyl; and pharmaceutically acceptable salts and solvates thereof.

[0086] The present invention particularly relates to compounds of formula (I) as defined herein, and tautomeric and stereoisomeric forms thereof, wherein R 1a represents -C(=O)-NR xaR xb; R xa and R xb represent C 1-4 alkyl; R 1b represents F; Y 1 represents -O-; R 2 represents hydrogen; U means N; n2 series 2; n1, n3 and n4 are 1; X 1 represents CH, and X 2 represents N; R 4 represents an isopropyl group; R 3 represents -CH 2 -CH 2 -CH 2 -NR 8aR 8b; R 8a and R 8b are each independently selected from the following group, the group consisting of: hydrogen; C 1-6 alkyl; and C 1-6 alkyl substituted with one or two substituents each independently selected from the group consisting of: halo, -OC 1-4 alkyl, and -NR 10c-C(=O)-C 1-4 alkyl; R 10a, R 10b, and R 10c are each independently selected from the following group, the group consisting of: hydrogen and C 1-6 alkyl; and pharmaceutically acceptable salts and solvates thereof.

[0087] The present invention particularly relates to compounds of formula (I) as defined herein, and tautomeric and stereoisomeric forms thereof, wherein R 1a represents -C(=O)-NR xaR xb; R xa and R xb represent C 1-4 alkyl; R 1b represents F; Y 1 represents -O-; R 2 represents hydrogen; U means N; n1, n2, n3 and n4 are each independently selected from 1 and 2; X 1 represents CH, and X 2 represents N; R 4 represents an isopropyl group; R 3 represents -C 1-6 alkyl-NR 8aR 8b; R 8a and R 8b are each independently selected from the following group, the group consisting of: hydrogen; C 1-6 alkyl; and C 1-6 alkyl substituted by one, two, or three substituents, each of which is independently selected from the group consisting of: -OH, cyano, halo, -S(=O) 2-C 1-4 alkyl, -OC 1-4 alkyl, and -C(=O)-NR 10aR 10b; R 10a and R 10b are each independently selected from the following group, the group consisting of: hydrogen and C 1-6 alkyl; and pharmaceutically acceptable salts and solvates thereof.

[0088] The present invention particularly relates to compounds of formula (I) as defined herein, and tautomeric and stereoisomeric forms thereof, wherein R 1a represents -C(=O)-NR xaR xb; R xa and R xb represent C 1-4 alkyl; R 1b represents F; Y 1 represents -O-; R 2 represents hydrogen; U means N; n1, n2, n3 and n4 are each independently selected from 1 and 2; X 1 represents CH, and X 2 represents N; R 4 represents an isopropyl group; R 3 represents -CH 2 -CH 2 -CH 2 -NR 8aR 8b; R 8a and R 8b are each independently selected from the following group, the group consisting of: hydrogen; C 1-6 alkyl; and C 1-6 alkyl substituted by one, two, or three substituents, each of which is independently selected from the group consisting of: -OH, cyano, halo, -S(=O) 2-C 1-4 alkyl, -OC 1-4 alkyl, and -C(=O)-NR 10aR 10b; R 10a and R 10b are each independently selected from the following group, the group consisting of: hydrogen and C 1-6 alkyl; and pharmaceutically acceptable salts and solvates thereof.

[0089] The present invention particularly relates to compounds of formula (I) as defined herein, and tautomeric and stereoisomeric forms thereof, wherein R 1a represents -C(=O)-NR xaR xb; R xa and R xb represent C 1-4 alkyl; R 1b represents F; Y 1 represents -O-; R 2 represents hydrogen; U means N; n1, n2, n3 and n4 are each independently selected from 1 and 2; X 1 represents CH, and X 2 represents N; R 4 represents an isopropyl group; R 3 represents -C 1-6 alkyl-NR 8aR 8b; R 8a and R 8b are each independently selected from the following group, the group consisting of: C 1-6 alkyl; and C 1-6 alkyl substituted by one -OC 1-4 alkyl; and pharmaceutically acceptable salts and solvates thereof.

[0090] The present invention particularly relates to compounds of formula (I) as defined herein, and tautomeric and stereoisomeric forms thereof, wherein R 1a represents -C(=O)-NR xaR xb; R xa and R xb represent C 1-4 alkyl; R 1b represents F; Y 1 represents -O-; R 2 represents hydrogen; U means N; n1, n2, n3 and n4 are each independently selected from 1 and 2; X 1 represents CH, and X 2 represents N; R 4 represents an isopropyl group; R 3 represents -CH 2 -CH 2 -CH 2 -NR 8aR 8b; R 8a and R 8b are each independently selected from the following group, the group consisting of: C 1-6 alkyl; and C 1-6 alkyl substituted by one -OC 1-4 alkyl; and pharmaceutically acceptable salts and solvates thereof.

[0091] The present invention particularly relates to compounds of formula (I) as defined herein, and tautomeric and stereoisomeric forms thereof, wherein R 1a represents -C(=O)-NR xaR xb; or Het; Het represents a 6-membered monocyclic aromatic ring containing two nitrogen atoms; Wherein the 6-membered monocyclic aromatic ring is required to be substituted by a C 3-6 cycloalkyl group; R xa and R xb represent C 1-4 alkyl; R 1b represents F; Y 1 represents -O-; R 2 is hydrogen; U means N; n1, n2, n3 and n4 are each independently selected from 1 and 2; X 1 represents CH, and X 2 represents N; R 4 represents an isopropyl group; R 3 represents -C 1-6 alkyl-NR 8aR 8b, -C 1-6 alkyl-C(=O)-NR 9aR 9b, -C 1-6 alkyl-OH, or -C 1-6 alkyl-NR 11-C(=O)-OC 1-4 alkyl-OC(=O)-C 1-4 alkyl; R 8a and R 8b are each independently selected from the group consisting of: hydrogen; C 1-6 alkyl; -C(=O)-C 1-4 alkyl; -C(=O)-OC 1-4 alkyl; -C(=O)-NR 12aR 12b; and C 1-6 alkyl substituted with one, two, or three substituents, each of which is independently selected from the group consisting of: cyano, halo, -S(=O) 2-C 1-4 alkyl, and -OC 1-4 alkyl; R 9a, R 9b, R 12a, and R 12b are each independently selected from the group consisting of: hydrogen and C 1-6 alkyl; and pharmaceutically acceptable salts and solvates thereof.

[0092] The present invention particularly relates to compounds of formula (I) as defined herein, and tautomeric and stereoisomeric forms thereof, wherein R 1a represents -C(=O)-NR xaR xb; R xa and R xb represent C 1-4 alkyl; R 1b represents F; Y 1 represents -O-; R 2 is hydrogen; U means N; n1, n2, n3 and n4 are each independently selected from 1 and 2; X 1 represents CH, and X 2 represents N; R 4 represents an isopropyl group; R 3 represents -C 1-6 alkyl-NR 8aR 8b, -C 1-6 alkyl-C(=O)-NR 9aR 9b, or -C 1-6 alkyl-OH; R 8a and R 8b are each independently selected from the group consisting of: hydrogen; C 1-6 alkyl; -C(=O)-C 1-4 alkyl; -C(=O)-OC 1-4 alkyl; -C(=O)-NR 12aR 12b; and C 1-6 alkyl substituted with one, two, or three substituents, each of which is independently selected from the group consisting of: cyano, halo, -S(=O) 2-C 1-4 alkyl, and -OC 1-4 alkyl; R 9a, R 9b, R 12a, and R 12b are each independently selected from the group consisting of: hydrogen and C 1-6 alkyl; and pharmaceutically acceptable salts and solvates thereof.

[0093] In one embodiment, the present invention relates to compounds of formula (I) as mentioned in any other embodiment and pharmaceutically acceptable salts and solvates thereof, or any subgroup thereof, wherein R 1b represents F.

[0094] In one embodiment, the present invention relates to compounds of formula (I) as mentioned in any other embodiment and pharmaceutically acceptable salts and solvates thereof, or any subgroup thereof, wherein R2 represents hydrogen.

[0095] In one embodiment, the present invention relates to compounds of formula (I) as mentioned in any other embodiment, and pharmaceutically acceptable salts and solvates thereof, or any subgroup thereof, wherein n1 is 1, n2 is 2, n3 is 1, and n4 is 1.

[0096] In one embodiment, the present invention relates to compounds of formula (I) as mentioned in any other embodiment and pharmaceutically acceptable salts and solvates thereof, or any subgroup thereof, wherein Y1 represents -O-.

[0097] In one embodiment, the present invention relates to compounds of formula (I) as mentioned in any other embodiment and pharmaceutically acceptable salts and solvates thereof, or any subgroup thereof, wherein Y represents -O-; and U stands for N.

[0098] In one embodiment, the present invention relates to compounds of formula (I) as mentioned in any other embodiment and pharmaceutically acceptable salts and solvates thereof, or any subgroup thereof, wherein Y 1 represents -O-; U means N; R 1b represents F; and R2 represents hydrogen.

[0099] In one embodiment, the present invention relates to compounds of formula (I) as mentioned in any other embodiment and pharmaceutically acceptable salts and solvates thereof, or any subgroup thereof, wherein Het represents .

[0100] In one embodiment, the present invention relates to compounds of formula (I) as mentioned in any other embodiment, and pharmaceutically acceptable salts and solvates thereof, or any subgroup thereof, wherein Het represents a monocyclic 5-membered or 6-membered aromatic ring containing one or two nitrogen atoms; wherein the monocyclic 5-membered or 6-membered aromatic ring is substituted by a C 3-6 cycloalkyl group.

[0101] In one embodiment, the present invention relates to compounds of formula (I) as mentioned in any other embodiment and pharmaceutically acceptable salts and solvates thereof, or any subgroup thereof, wherein Het represents a monocyclic 5-membered or 6-membered aromatic ring containing one or two nitrogen atoms; wherein the monocyclic 5-membered or 6-membered aromatic ring is substituted with a C 3-6 cycloalkyl group; and R 1b represents F.

[0102] In one embodiment, the present invention relates to compounds of formula (I) as mentioned in any other embodiment, and pharmaceutically acceptable salts and solvates thereof, or any subgroup thereof, wherein Het represents a monocyclic 6-membered aromatic ring containing one or two nitrogen atoms; wherein the monocyclic 6-membered aromatic ring is substituted by a C3-6 cycloalkyl group.

[0103] In one embodiment, the present invention relates to compounds of formula (I) as mentioned in any other embodiment and pharmaceutically acceptable salts and solvates thereof, or any subgroup thereof, wherein Het represents a monocyclic 6-membered aromatic ring containing one or two nitrogen atoms; wherein the monocyclic 6-membered aromatic ring is substituted with one C 3-6 cycloalkyl; and R 1b represents F.

[0104] In one embodiment, the present invention relates to compounds of formula (I) as mentioned in any other embodiment and pharmaceutically acceptable salts and solvates thereof, or any subgroup thereof, wherein R 3 represents -C 1-6 alkyl-NR 8aR 8b; The C 1-6 alkyl moiety in the definition of R 3 may be substituted by one, two, or three substituents, each of which is independently selected from the following group, the group consisting of: cyano, halo, and -OC 1-4 alkyl.

[0105] In one embodiment, the present invention relates to compounds of formula (I) as mentioned in any other embodiment and pharmaceutically acceptable salts and solvates thereof, or any subgroup thereof, wherein R 3 represents -C 1-6 alkyl-NR 8aR 8b; The C 1-6 alkyl moiety in the definition of R 3 may be substituted by one, two, or three substituents, each of which is independently selected from the following group, the group consisting of: cyano, halo, -OH, and -OC 1-4 alkyl.

[0106] In one embodiment, the present invention relates to compounds of formula (I) as mentioned in any other embodiment and pharmaceutically acceptable salts and solvates thereof, or any subgroup thereof, wherein R 3 represents -C 1-6 alkyl-NR 8a R 8b.

[0107] In one embodiment, the present invention relates to compounds of formula (I) as mentioned in any other embodiment and pharmaceutically acceptable salts and solvates thereof, or any subgroup thereof, wherein R 3 represents -C 1-6 alkyl-NR 8aR 8b; wherein the C 1-6 alkyl moiety in the definition of R 3 may be substituted by one, two, or three substituents, each of which is independently selected from the following group, the group consisting of: cyano, halo, and -OC 1-4 alkyl; R 8a and R 8b are each independently selected from the following group, the group consisting of: hydrogen; C 1-6 alkyl; and C 1-6 alkyl substituted by one, two, or three substituents, each of which is independently selected from the group consisting of -OH, cyano, halo, -S(=O) 2-C 1-4 alkyl, -OC 1-4 alkyl, -C(=O)-NR 10aR 10b, and -NR 10c-C(=O)-C 1-4 alkyl.

[0108] In one embodiment, the present invention relates to compounds of formula (I) as mentioned in any other embodiment and pharmaceutically acceptable salts and solvates thereof, or any subgroup thereof, wherein R 3 represents -C 1-6 alkyl-NR 8aR 8b; wherein the C 1-6 alkyl moiety in the definition of R 3 may be substituted by one, two, or three substituents, each of which is independently selected from the following group, the group consisting of: cyano, halo, -OH, and -OC 1-4 alkyl; R 8a and R 8b are each independently selected from the following group, the group consisting of: hydrogen; C 1-6 alkyl; and C 1-6 alkyl substituted by one, two, or three substituents, each of which is independently selected from the group consisting of -OH, cyano, halo, -S(=O) 2-C 1-4 alkyl, -OC 1-4 alkyl, -C(=O)-NR 10aR 10b, and -NR 10c-C(=O)-C 1-4 alkyl.

[0109] In one embodiment, the present invention relates to compounds of formula (I) as mentioned in any other embodiment and pharmaceutically acceptable salts and solvates thereof, or any subgroup thereof, wherein R 3 represents -C 1-6 alkyl-NR 8aR 8b; wherein the C 1-6 alkyl moiety in the definition of R 3 may be substituted by one, two, or three substituents, each of which is independently selected from the following group, the group consisting of: cyano, halo, and -OC 1-4 alkyl; R 8a and R 8b are each independently selected from the following group, the group consisting of: hydrogen; C 1-6 alkyl; and C 1-6 alkyl substituted by one, two, or three substituents, each of which is independently selected from the group consisting of cyano, halo, -S(═O) 2 -C 1-4 alkyl, -OC 1-4 alkyl, and -C(═O)-NR 10a R 10b.

[0110] In one embodiment, the present invention relates to compounds of formula (I) as mentioned in any other embodiment and pharmaceutically acceptable salts and solvates thereof, or any subgroup thereof, wherein R 3 represents -C 1-6 alkyl-NR 8aR 8b; wherein the C 1-6 alkyl moiety in the definition of R 3 may be substituted by one, two, or three substituents, each of which is independently selected from the following group, the group consisting of: cyano, halo, and -OC 1-4 alkyl; R 8a and R 8b are each independently selected from the following group, the group consisting of: hydrogen; C 1-6 alkyl; and C 1-6 alkyl substituted by one, two, or three substituents, each of which is independently selected from the group consisting of cyano, halo, -S(=O) 2 -C 1-4 alkyl, -OC 1-4 alkyl, -C(=O)-NR 10aR 10b, and -NR 10c-C(=O)-C 1-4 alkyl.

[0111] In one embodiment, the present invention relates to compounds of formula (I) as mentioned in any other embodiment and pharmaceutically acceptable salts and solvates thereof, or any subgroup thereof, wherein R 3 represents -C 1-6 alkyl-NR 8aR 8b; wherein the C 1-6 alkyl moiety in the definition of R 3 may be substituted by one, two, or three substituents, each of which is independently selected from the following group, the group consisting of: cyano, halo, -OH, and -OC 1-4 alkyl; R 8a and R 8b are each independently selected from the following group, the group consisting of: hydrogen; C 1-6 alkyl; and C 1-6 alkyl substituted by one, two, or three substituents, each of which is independently selected from the group consisting of cyano, halo, -S(═O) 2 -C 1-4 alkyl, -OC 1-4 alkyl, and -C(═O)-NR 10a R 10b.

[0112] In one embodiment, the present invention relates to compounds of formula (I) as mentioned in any other embodiment and pharmaceutically acceptable salts and solvates thereof, or any subgroup thereof, wherein R 3 represents -C 1-6 alkyl-NR 8aR 8b; wherein the C 1-6 alkyl moiety in the definition of R 3 may be substituted by one, two, or three substituents, each of which is independently selected from the following group, the group consisting of: cyano, halo, -OH, and -OC 1-4 alkyl; R 8a and R 8b are each independently selected from the following group, the group consisting of: hydrogen; C 1-6 alkyl; and C 1-6 alkyl substituted by one, two, or three substituents, each of which is independently selected from the group consisting of cyano, halo, -S(=O) 2 -C 1-4 alkyl, -OC 1-4 alkyl, -C(=O)-NR 10aR 10b, and -NR 10c-C(=O)-C 1-4 alkyl.

[0113] In one embodiment, the present invention relates to compounds of formula (I) as mentioned in any other embodiment and pharmaceutically acceptable salts and solvates thereof, or any subgroup thereof, wherein R 3 represents -C 2-6 alkyl-NR 8aR 8b; The C 2-6 alkyl moiety in the definition of R 3 may be substituted by one, two, or three substituents, each of which is independently selected from the following group, the group consisting of cyano, halo, and -OC 1-4 alkyl.

[0114] In one embodiment, the present invention relates to compounds of formula (I) as mentioned in any other embodiment and pharmaceutically acceptable salts and solvates thereof, or any subgroup thereof, wherein R 3 represents -C 2-6 alkyl-NR 8aR 8b; The C 2-6 alkyl moiety in the definition of R 3 may be substituted by one, two, or three substituents, each of which is independently selected from the following group, the group consisting of: cyano, halo, -OH, and -OC 1-4 alkyl.

[0115] In one embodiment, the present invention relates to compounds of formula (I) as mentioned in any other embodiment and pharmaceutically acceptable salts and solvates thereof, or any subgroup thereof, wherein R 3 represents -C 2-6 alkyl-NR 8aR 8b; wherein the C 2-6 alkyl moiety in the definition of R 3 may be substituted by one, two, or three substituents, each of which is independently selected from the following group, the group consisting of: cyano, halo, and -OC 1-4 alkyl; R 8a and R 8b are each independently selected from the following group, the group consisting of: hydrogen; C 1-6 alkyl; and C 1-6 alkyl substituted by one, two, or three substituents, each of which is independently selected from the group consisting of -OH, cyano, halo, -S(=O) 2-C 1-4 alkyl, -OC 1-4 alkyl, -C(=O)-NR 10aR 10b, and -NR 10c-C(=O)-C 1-4 alkyl.

[0116] In one embodiment, the present invention relates to compounds of formula (I) as mentioned in any other embodiment and pharmaceutically acceptable salts and solvates thereof, or any subgroup thereof, wherein R 3 represents -C 2-6 alkyl-NR 8aR 8b; wherein the C 2-6 alkyl moiety in the definition of R 3 may be substituted by one, two, or three substituents, each of which is independently selected from the following group, the group consisting of: cyano, halo, -OH, and -OC 1-4 alkyl; R 8a and R 8b are each independently selected from the following group, the group consisting of: hydrogen; C 1-6 alkyl; and C 1-6 alkyl substituted by one, two, or three substituents, each of which is independently selected from the group consisting of -OH, cyano, halo, -S(=O) 2-C 1-4 alkyl, -OC 1-4 alkyl, -C(=O)-NR 10aR 10b, and -NR 10c-C(=O)-C 1-4 alkyl.

[0117] In one embodiment, the present invention relates to compounds of formula (I) as mentioned in any other embodiment and pharmaceutically acceptable salts and solvates thereof, or any subgroup thereof, wherein R 3 represents -C 2-6 alkyl-NR 8aR 8b; wherein the C 2-6 alkyl moiety in the definition of R 3 may be substituted by one, two, or three substituents, each of which is independently selected from the following group, the group consisting of: cyano, halo, -OH, and -OC 1-4 alkyl; R 8a and R 8b are each independently selected from the following group, the group consisting of: hydrogen; C 1-6 alkyl; and C 1-6 alkyl substituted by one, two, or three substituents, each of which is independently selected from the group consisting of cyano, halo, -S(═O) 2 -C 1-4 alkyl, -OC 1-4 alkyl, and -C(═O)-NR 10a R 10b.

[0118] In one embodiment, the present invention relates to compounds of formula (I) as mentioned in any other embodiment and pharmaceutically acceptable salts and solvates thereof, or any subgroup thereof, wherein R 3 represents -C 2-6 alkyl-NR 8aR 8b; wherein the C 2-6 alkyl moiety in the definition of R 3 may be substituted by one, two, or three substituents, each of which is independently selected from the following group, the group consisting of: cyano, halo, and -OC 1-4 alkyl; R 8a and R 8b are each independently selected from the following group, the group consisting of: hydrogen; C 1-6 alkyl; and C 1-6 alkyl substituted by one, two, or three substituents, each of which is independently selected from the group consisting of cyano, halo, -S(═O) 2 -C 1-4 alkyl, -OC 1-4 alkyl, and -C(═O)-NR 10a R 10b.

[0119] In one embodiment, the present invention relates to compounds of formula (I) as mentioned in any other embodiment and pharmaceutically acceptable salts and solvates thereof, or any subgroup thereof, wherein R 3 represents -C 1-6 alkyl-NR 8aR 8b; R 8a and R 8b are each independently selected from the group consisting of C 1-6 alkyl; and C 1-6 alkyl substituted with one, two, or three substituents, each of which is independently selected from the group consisting of -OH, cyano, halo, -S(═O) 2 -C 1-4 alkyl, -OC 1-4 alkyl, and -C(═O)-NR 10aR 10b.

[0120] In one embodiment, the present invention relates to compounds of formula (I) as mentioned in any other embodiment and pharmaceutically acceptable salts and solvates thereof, or any subgroup thereof, wherein R 3 represents -C 2-6 alkyl-NR 8aR 8b; wherein the C 2-6 alkyl moiety in the definition of R 3 may be substituted by one, two, or three substituents, each of which is independently selected from the following group, the group consisting of: cyano, halo, -OH, and -OC 1-4 alkyl; R 8a and R 8b are each independently selected from the following group, the group consisting of: hydrogen; C 1-6 alkyl; and C 1-6 alkyl substituted by one, two, or three substituents, each of which is independently selected from the group consisting of cyano, halo, -S(=O) 2 -C 1-4 alkyl, -OC 1-4 alkyl, -C(=O)-NR 10aR 10b, and -NR 10c-C(=O)-C 1-4 alkyl.

[0121] In one embodiment, the present invention relates to compounds of formula (I) as mentioned in any other embodiment and pharmaceutically acceptable salts and solvates thereof, or any subgroup thereof, wherein R 3 represents -C 2-6 alkyl-NR 8aR 8b; wherein the C 2-6 alkyl moiety in the definition of R 3 may be substituted by one, two, or three substituents, each of which is independently selected from the following group, the group consisting of: cyano, halo, and -OC 1-4 alkyl; R 8a and R 8b are each independently selected from the following group, the group consisting of: hydrogen; C 1-6 alkyl; and C 1-6 alkyl substituted by one, two, or three substituents, each of which is independently selected from the group consisting of cyano, halo, -S(=O) 2 -C 1-4 alkyl, -OC 1-4 alkyl, -C(=O)-NR 10aR 10b, and -NR 10c-C(=O)-C 1-4 alkyl.

[0122] In one embodiment, the present invention relates to compounds of formula (I) as mentioned in any other embodiment and pharmaceutically acceptable salts and solvates thereof, or any subgroup thereof, wherein R 3 represents -C 1-6 alkyl-NR 8aR 8b; R 8a and R 8b are each independently selected from the group consisting of C 1-6 alkyl; and C 1-6 alkyl substituted with one, two, or three substituents, each of which is independently selected from the group consisting of -OH, cyano, halo, -S(═O) 2-C 1-4 alkyl, -OC 1-4 alkyl, -C(═O)-NR 10aR 10b, and -NR 10c-C(═O)-C 1-4 alkyl.

[0123] In one embodiment, the present invention relates to compounds of formula (I) as mentioned in any other embodiment and pharmaceutically acceptable salts and solvates thereof, or any subgroup thereof, wherein R 3 represents -C 1-6 alkyl-NR 8aR 8b; R 8a represents a C 1-6 alkyl group; and R 8b represents a C 1-6 alkyl group substituted by one -OC 1-4 alkyl group.

[0124] In one embodiment, the present invention relates to compounds of formula (I) as mentioned in any other embodiment and pharmaceutically acceptable salts and solvates thereof, or any subgroup thereof, wherein R 3 represents -C 1-6 alkyl-NR 8aR 8b, -C 1-6 alkyl-C(=O)-NR 9aR 9b, -C 1-6 alkyl-OH, or -C 1-6 alkyl-NR 11-C(=O)-OC 1-4 alkyl-OC(=O)-C 1-4 alkyl; wherein each of the C 1-4 alkyl or C 1-6 alkyl moieties in the definition of R 3 may be independently substituted by one, two, or three substituents, each of which is independently selected from the following group consisting of cyano, halo, or -OC 1-4 alkyl.

[0125] In one embodiment, the present invention relates to compounds of formula (I) as mentioned in any other embodiment and pharmaceutically acceptable salts and solvates thereof, or any subgroup thereof, wherein R 3 represents -CH 2 -CH 2 -CH 2 -NR 8a R 8b .

[0126] In one embodiment, the present invention relates to compounds of formula (I) as mentioned in any other embodiment and pharmaceutically acceptable salts and solvates thereof, or any subgroup thereof, wherein R 3 represents -CH 2 -CH 2 -CH 2 -NR 8aR 8b; R 8a represents a methyl group; and R 8b represents -CH 2 -CH 2 -OCH 3 .

[0127] In one embodiment, the present invention relates to those compounds of formula (I) as mentioned in any other embodiment, and pharmaceutically acceptable salts and solvates thereof, or any subgroup thereof, wherein the C 1-6 alkyl-C 1-6 alkyl-NR 8aR 8b in the definition of R 3 is limited to -CH 2-CH 2-CH 2-.

[0128] In one embodiment, the present invention relates to those compounds of formula (I) as mentioned in any other embodiment and pharmaceutically acceptable salts and solvates thereof, or any subgroup thereof, wherein the compounds of formula (I) are limited to compounds of formula (Iy): , wherein R 3 is as defined for the compound of formula (I) as mentioned in any other embodiment or any subgroup thereof.

[0129] In Formula (Iy), n1 is 1, n2 is 2, n3 is 1, and n4 is 1.

[0130] In one embodiment, the compound of formula (I) is and pharmaceutically acceptable addition salts and solvates thereof.

[0131] In one embodiment, the compound of formula (I) is .

[0132] In one embodiment, the compound of formula (I) is .

[0133] In one embodiment, the compound of formula (I) is .

[0134] In one embodiment, the present invention relates to a subgroup of compounds having formula (I) as defined in the general reaction scheme.

[0135] In one embodiment, the compound of formula (I) is selected from the group consisting of any one of the exemplary compounds, its tautomeric and stereoisomeric forms, and its free base, any pharmaceutically acceptable salt and solvate.

[0136] All possible combinations of the above-described embodiments are considered to be included within the scope of the present invention.

[0137] In another embodiment, the present invention relates to an intermediate its tautomeric and stereoisomeric forms, and any pharmaceutically acceptable salts and solvates thereof.

[0138] In another embodiment, the present invention relates to a method for preparing an intermediate, the method comprising the following steps: Wherein PG is a suitable protecting group, such as benzyl; Wherein n1 and n2 are as defined in formula (I); Step 23: at a suitable temperature (such as, for example, from -78 ° C to -25 ° C), in the presence of a suitable base (such as, for example, DIEA and n-BuLi), in a suitable solvent (such as, for example, THF); Step 24: is carried out in a suitable flow chemistry system in the presence of a suitable reducing agent (such as, for example, DIBAL-H) in a suitable solvent (such as, for example, toluene) at a suitable temperature (such as, for example, between -55°C and -65°C).

[0139] In another embodiment, the present invention relates to a method for preparing an intermediate, the method comprising the following steps:

[0140] The first reaction is carried out at a suitable temperature (such as, for example, from -78°C to -25°C) in the presence of a suitable base (such as, for example, DIEA and n-BuLi) in a suitable solvent (such as, for example, THF);

[0141] The reaction is then carried out at a suitable temperature (such as, for example, between -55°C and -65°C) in the presence of a suitable reducing agent (such as, for example, DIBAL-H) in a suitable solvent (such as, for example, toluene) in a suitable flow chemistry system.

[0142] In another embodiment, the present invention relates to a method for preparing an intermediate, the method comprising the following steps: PG is a suitable protecting group, such as benzyl; The other variables are as defined for Formula (I).

[0143] In another embodiment, the present invention relates to a method for preparing an intermediate, the method comprising the following steps: PG is a suitable protecting group, such as benzyl; The 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 suitable base (such as, for example, TEA), in the presence of a 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, K 2HPO 4), in a suitable solvent (such as, for example, H 2O); Step 32: at a suitable temperature (such as, for example, from -5°C to 45°C), under a hydrogen atmosphere in 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 a 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 a 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 presence of a suitable catalyst (such as, for example, palladium on carbon), in a suitable solvent (such as MeOH).

[0144] In another embodiment, the present invention relates to a method for preparing a compound, comprising the following steps: .

[0145] In another embodiment, the present invention relates to a method for preparing a compound, comprising the following steps: .

[0146] In another embodiment, the present invention relates to a method for preparing a compound, comprising the following steps:

[0147] In another embodiment, the present invention relates to a method for preparing a compound, comprising the following steps: .

[0148] In another embodiment, the present invention relates to a method for preparing a compound, comprising the following steps: In the first step, at a suitable temperature (such as, for example, from -5°C to 45°C), under a hydrogen atmosphere in 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 the next step, at a suitable temperature (such as, for example, from -50°C to -40°C), in the presence of a suitable base (such as, for example, TEA), in a suitable solvent (such as 2-methyltetrahydrofuran); In the next step, at a suitable temperature (such as, for example, from 20°C to 30°C), in the presence of a suitable base (such as, for example, TMG), in a suitable solvent (such as 2-methyltetrahydrofuran); In the 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 MPa), in the presence of a suitable catalyst (such as, for example, palladium on carbon), in a suitable solvent (such as MeOH).

[0149] In another embodiment, the present invention relates to a method for preparing a compound, comprising the following steps: 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 a suitable reducing agent (such as, for example, NaBH(OAc) 3), in a suitable solvent (such as, for example, toluene); and then 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, K 2HPO 4), in a suitable solvent (such as, for example, H 2O); In the next step, at a suitable temperature (such as, for example, from -5°C to 45°C), under a hydrogen atmosphere in 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 the next step, at a suitable temperature (such as, for example, from -50°C to -40°C), in the presence of a suitable base (such as, for example, TEA), in a suitable solvent (such as 2-methyltetrahydrofuran); In the next step, at a suitable temperature (such as, for example, from 20°C to 30°C), in the presence of a suitable base (such as, for example, TMG), in a suitable solvent (such as 2-methyltetrahydrofuran); In the 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 MPa), in the presence of a suitable catalyst (such as, for example, palladium on carbon), in a suitable solvent (such as MeOH). Method for preparing a compound of formula (I)

[0150] In this section, as in all other sections, unless the context indicates otherwise, references to formula (I) also include all other subgroups and instances thereof as defined herein.

[0151] The general preparation of some representative examples of compounds of formula (I) is described below and in the specific examples, and is generally prepared from starting materials that are commercially available or prepared by standard synthetic techniques commonly used by those skilled in the art of organic chemistry. The following schemes are intended only to represent examples of the present invention and are in no way intended to limit the present invention.

[0152] Alternatively, the compounds of the present invention can also be prepared by combining analogous reaction schemes as described in the following general schemes with standard synthetic techniques commonly used by those skilled in the art.

[0153] The skilled artisan will recognize that in the reactions described in the schemes, although not always explicitly shown, it may be necessary to protect the desired reactive functional groups (e.g., hydroxyl, amine, or carboxyl groups) in the final product to prevent them from participating in undesired reactions. Typically, conventional protecting groups (PG) can be used according to standard practice. The protecting groups can be removed at a convenient subsequent stage using methods known in the art.

[0154] The skilled artisan will recognize that in the reactions described in the schemes, it may be desirable or necessary to carry out the reactions under an inert atmosphere, such as, for example, under a N 2 atmosphere.

[0155] It will be clear to the skilled person that it may be necessary to cool the reaction mixture prior to reaction work-up (referring to the series of operations necessary to separate and purify one or more products of a chemical reaction, such as, for example, quenching, column chromatography, extraction).

[0156] The skilled person will recognize that heating the reaction mixture under stirring can increase the reaction yield.In some reactions, microwave heating can be used to replace conventional heating to shorten the overall reaction time.

[0157] The skilled artisan will recognize that an alternative sequence of the chemical reactions shown in the following schemes may also produce the desired compounds of formula (I).

[0158] The skilled artisan will recognize that the intermediates and final compounds shown in the following schemes can be further functionalized according to methods well known to those skilled in the art. The intermediates and compounds described herein can be isolated in free form or as salts or solvates thereof. The intermediates and compounds described herein can be synthesized as mixtures of tautomeric and stereoisomeric forms, which can be separated from one another following resolution procedures known in the art. [General Synthesis Scheme] []

[0159] All abbreviations used in the general schemes are as defined in the table in the Examples section. Variables are as defined within or as specifically defined in the general schemes. Part A) Options 1a, 1b, 1c, 2a, 2b and 3

[0160] In Schemes 1a, 1b, and 1c, the following reaction conditions apply: 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 suitable oxidizing agent (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); 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 a suitable solvent (such as, for example, THF and H 2 O); Step 5: at a suitable temperature (such as, for example, RT), in the presence of a suitable amide condensation reagent (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); Step 6: at a suitable temperature (such as, for example, -70 ° C), in the presence of a suitable organometallic reagent (such as, for example, isopropyl lithium) 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)Cl 2), in the presence of a suitable base (such as, for example, Na 2CO 3), in a suitable solvent (such as, for example, 1,4-dioxane and H 2O); 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, BBr 3), 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 K 2 CO 3), in a suitable solvent (such as, for example, DCM, THF, or DMF);

[0161] In Schemes 2a and 2b, the following reaction conditions apply: Step 9: See step 9 in scheme 1; Step 10: at a suitable temperature (such as RT), in the presence of a suitable catalyst (such as Pd / C), in the presence of a suitable reducing agent (such as H 2 ), optionally in the presence of a suitable base (such as TEA), in a suitable solvent (such as THF); Alternatively, at a suitable temperature (such as, for example, RT) in the presence of a suitable catalyst (such as, for example, Pd(dppf)Cl2.DCM complex), a suitable reducing agent (such as, for example, 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 (such as, for example, TFA), in a suitable solvent (such as, for example, DCM); for O deprotection, at a suitable temperature (such as, for example, RT), in the presence of a suitable acid (such 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, ZnCl 2), in the presence of a suitable reducing agent (such as, for example, NaBH 3CN), 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 agent (such as, for example, 1,3-dibromo-1,3,5-trioxane-2,4,6-trione), in a suitable solvent (such as, for example, DCE); Step 14: In the presence of a suitable chlorinating agent (such as for example oxalyl chloride) in the presence of DMF in a suitable solvent (such as for example DCM) at a suitable temperature (such as for example RT).

[0162] In Scheme 3, the following reaction conditions apply: Steps 11-12: See steps 11-12 in Scheme 2; Step 15: at a suitable temperature (such as, for example, 80 ° C), in the presence of a suitable base (such as, for example, Cs 2CO 3), in a 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, an amine) in a suitable solvent (such as 1,4-dioxane). Part B) Options 4, 5, 6, 7, 8, 9, 10, 11 and 12

[0163] 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 organometallic catalyst (such as, for example, Pd(dppf)Cl2), in the presence of a suitable base (such as, for example, Na2CO3), in a suitable solvent (such as, for example, 1,4-dioxane and H2O); Step 2: at a suitable temperature (such as, for example, RT), in the presence of a 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); 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, BBr 3), 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 K 2 CO 3), in a suitable solvent (such as, for example, DCM, THF, or DMF); Step 5: at a suitable temperature (such as, for example, RT), in the presence of a suitable base (such as, for example, LiOH·H 2 O), in a suitable solvent (such as, for example, THF and H 2 O); 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 agent (such as, for example, 1,3-dibromo-1,3,5-trioxane-2,4,6-trione), in a suitable solvent (such as, for example, DCE); Step 7: At a suitable temperature (such as, for example, RT), in the presence of a suitable brominating reagent, 1,3-dibromo-1,3,5-trioxane-2,4,6-trione, in the presence of 2,2,2-trifluoroethane-1-ol as solvent.

[0164] 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 K 2 CO 3), in a suitable solvent (such as, for example, DCM, THF, or DMF); 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 K 2 CO 3), 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 (such as, for example, Pd / C) and a suitable base (such as, for example, TEA), in a suitable solvent such as, for example, MeOH, under an atmosphere of H 2 ; Step 11: When PG is Boc, in the presence of a suitable acid (such as for example TFA) in a suitable solvent (such as for example DCM) at a suitable temperature (such as for example RT).

[0165] In Scheme 6, the following reaction conditions apply: Step 12: reductive amination conditions, 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, ZnCl2) or acid (such as AcOH), in the presence of a suitable reducing agent (such as, for example, NaBH3CN), 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 (such as, for example, MsCl), in the presence of a suitable base (such as, for example, TEA), 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 (such 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 (such as, for example, HCl), in a suitable solvent (such as, for example, ACN); Step 16: At a suitable temperature (such as eg RT) in the presence or absence of a suitable base (such as eg TEA) in a suitable solvent (such as eg THF).

[0166] In Scheme 7, the following reaction conditions apply: Step 11: When PG is Boc, at a suitable temperature (such as RT), in the presence of a suitable acid (such as TFA), in a suitable solvent (such as DCM); Step 12: reductive amination conditions, 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, ZnCl2) or acid (such as AcOH), in the presence of a suitable reducing agent (such as, for example, NaBH3CN), 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 suitable base (such as, for example, DIEA or Cs 2 CO 3), in a 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, an amine) in a suitable solvent (such as 1,4-dioxane).

[0167] 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 K 2 CO 3), in a suitable solvent (such as, for example, DCM, THF, or DMF); Step 10: at a suitable temperature (such as RT), in the presence of a suitable organometallic catalyst (such as Pd / C), optionally in the presence of a suitable base (such as TEA), in a suitable solvent (such as MeOH), under an atmosphere of H2; Step 19: at a suitable temperature (such as, for example, RT), in the presence of a suitable chlorinating agent (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 (such as, for example, HCl in dioxane), in a suitable solvent (such as, for example, MeOH); Step 22: at a suitable temperature (such as, for example, 110° C.), in the presence of a suitable boron reagent (such as, for example, trimethylboroxane), 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, K 2 CO 3), in a suitable solvent (such as, for example, 1,4-dioxane);

[0168] 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 a suitable base (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 -65°C and -55°C), in the presence of a suitable reducing agent (such as, for example, DIBAL-H), in a suitable solvent (such as, for example, toluene), preferably 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 of a suitable base (such as, for example, DMAP), in the presence of a suitable condensing 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, NaBH 4), in a suitable solvent (such as, for example, DCM); Step 26: in a suitable solvent (such as, for example, toluene) and heating to reflux; Step 27: at a suitable temperature (such as, for example, from -5 ° C to 5 ° C), in the presence of a suitable reducing agent (such as, for example, LiBH 4 ), 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 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 HCl), 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 suitable base (such as, for example, TEA), in the presence of a 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, K 2HPO 4), in a suitable solvent (such as, for example, H 2O); Step 32: When PG is Bn, 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 a suitable catalyst (such as, for example, palladium hydroxide on carbon), in the presence of a suitable acid (such 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 of a 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 a 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 in 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); Alternatively, at a suitable temperature (such as room temperature), in the presence of a suitable catalyst (such as, for example, 1,1'-bis(diphenylphosphino)ferrocene-dichloropalladium(II) dichloromethane complex), a suitable reducing agent (such as sodium borohydride), a suitable base (such as, for example, N,N,N',N'-tetramethylethylenediamine), in a suitable solvent (such as, for example, tetrahydrofuran). Plan 10

[0169] Generally, compounds of formula (I) (wherein Y is limited to -CH- and R is limited to W, herein designated as compounds of formula (Ia)) can be prepared according to the following reaction scheme 10. In scheme 10, W represents chlorine, bromine, or iodine; all other variables are defined within the scope of the present invention.

[0170] In Scheme 10, the following reaction conditions apply: Step 36: At a suitable temperature range (from 60°C to 100°C) in the 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 tetrahydrofuran or dioxane.

[0171] The skilled artisan will recognize that similar chemistry as reported in Step 10 in Scheme 5 and Steps 20, 21 and 22 in Scheme 8 can be performed starting from compound (Ia). Plan 11

[0172] Generally, compounds of formula (I) (wherein Y is limited to -CR 5aR 5b- and R 2 is limited to W 1, herein designated as compounds of formula (Ib)) can be prepared according to the following reaction scheme 11. In scheme 11, at least one of R 5a and R 5b is not hydrogen. All other variables are defined according to the scope of the present invention.

[0173] In Scheme 11, the following reaction conditions apply: Step 37: At a suitable temperature range (from 80° C. to 200° C.), in the presence of a suitable catalyst (e.g., palladium acetate (Pd(OAc) 2)), in the presence of a suitable ligand (e.g., triphenylphosphine or tricyclohexylphosphine), in a suitable solvent (e.g., dioxane), preferably under sealed conditions, optionally under microwave irradiation.

[0174] The skilled artisan will recognize that similar chemistry as reported in Step 10 in Scheme 5 and Steps 20, 21 and 22 in Scheme 8 can be performed starting from compound (Ib). Plan 12

[0175] In Scheme 12, the following reaction conditions 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, Cs 2 CO 3, or DBU), in a suitable solvent (such as, for example, DCM, THF or DMF);

[0176] Alternatively, at a suitable temperature (such as, for example, RT to 100° C.), in the presence of a suitable catalyst (such as, for example, Pd 2dba 3), in the presence of a suitable ligand (such as, for example, Xantphos), in the presence of a suitable base (such as Cs 2CO 3 or Na 2CO 3), in a suitable solvent (such as dioxane or a mixture of dioxane and water).

[0177] The skilled person will recognize that similar chemistry as reported in the case where Y 1 represents O can be carried out starting from intermediate A.

[0178] It will be understood that compounds of various formulae or any intermediates used in their preparation can be further derivatized by one or more standard synthetic methods employing condensation, substitution, oxidation, reduction, or cleavage reactions, provided that appropriate functional groups are present. Specific substitution methods include conventional alkylation, arylation, heteroarylation, acylation, sulfonylation, halogenation, nitration, formylation, and coupling procedures.

[0179] Compounds of formula (I) can be synthesized as racemic mixtures of enantiomeric forms that can be separated from one another following art-known resolution procedures. Racemic compounds of formula (I) (containing an essential nitrogen atom) can be converted into the corresponding diastereomeric salt forms by reaction with a suitable chiral acid. The diastereomeric forms are then separated, for example, by selective or fractional crystallization, and the enantiomeric forms are liberated therefrom by base. An alternative means of separating the enantiomeric forms of compounds of formula (I) involves liquid chromatography using a chiral stationary phase. The pure stereochemically isomeric forms can also be derived from the corresponding pure stereochemically isomeric forms of appropriate starting materials, provided that the reaction occurs stereospecifically.

[0180] During the preparation of the compounds of the present invention, protection of the distal functional groups of the intermediates (e.g., primary or secondary amines) may be necessary. The need for such protection will depend on the nature of the distal functional group and the conditions of the preparation method. Suitable amino protecting groups (NH-Pg) include acetyl, trifluoroacetyl, tertiary butoxycarbonyl (Boc), benzyloxycarbonyl (CBz), and 9-fluorenylmethyleneoxycarbonyl (Fmoc). The need for such protection is readily determined by one skilled in the art. For a general description of protecting groups and their uses, see TW Greene and PGM Wuts, Protective Groups in Organic Synthesis, 4th ed., Wiley, Hoboken, New Jersey, 2007. Pharmacology

[0181] It has been discovered that the compounds of the present invention themselves block the interaction of menin with MLL proteins and oncogenic MLL fusion proteins, or can be metabolized in vivo to a (more) active form (prodrug). Therefore, the compounds according to the present invention and pharmaceutical compositions containing such compounds can be used to treat or prevent (particularly treat) diseases such as cancer, including but not limited to leukemia, myelodysplastic syndrome (MDS), and myeloproliferative neoplasms (MPN); and diabetes.

[0182] In particular, the compounds and pharmaceutical compositions according to the present invention can be used to treat or prevent cancer. According to one embodiment, cancers that may benefit from treatment with the menin / MLL inhibitors of the present invention include leukemias, lymphomas, myelomas, or solid tumor cancers (e.g., prostate cancer, lung cancer, breast cancer, pancreatic cancer, colorectal cancer, liver cancer, melanoma, and glioblastoma). In some embodiments, the leukemia comprises acute leukemia, chronic leukemia, myeloid leukemia, myeloid leukemia, lymphoblastic leukemia, lymphocytic leukemia, acute myeloid leukemia (AML), chronic myeloid leukemia (CML), acute lymphoblastic leukemia (ALL), chronic lymphocytic leukemia (CLL), T-cell prolymphocytic leukemia (T-PLL), large granular lymphocytic leukemia, hairy cell leukemia (HCL), MLL-rearranged leukemia, MLL-PTD leukemia, MLL-amplified leukemia, MLL-positive leukemia, leukemia displaying a HOX / MEIS1 gene expression signature, and the like.

[0183] In particular, the compounds and pharmaceutical compositions according to the present invention can be used to treat or prevent myelodysplastic syndrome (MDS) or myeloproliferative neoplasms (MPN).

[0184] In particular, the compounds according to the present invention and their pharmaceutical compositions can be used to treat or prevent leukemia, in particular nucleophosmin (NPM1)-mutant leukemia, such as NPM1c.

[0185] In particular, the compounds and pharmaceutical compositions according to the present invention can be used to treat or prevent AML, in particular nucleophosmin (NPM1)-mutant AML (ie, NPM1 mutAML), more particularly theoretical NPM1-mutant AML.

[0186] In particular, the compounds according to the present invention and their pharmaceutical compositions can be used to treat or prevent MLL-rearranged leukemia, in particular MLL-rearranged AML or ALL.

[0187] In particular, the compounds and pharmaceutical compositions according to the present invention can be used to treat or prevent leukemias with MLL gene mutations, in particular AML or ALL with MLL gene mutations.

[0188] In particular, the compounds according to the present invention and their pharmaceutical compositions may be suitable for QD administration (once daily).

[0189] In particular, the compounds and pharmaceutical compositions according to the present invention can be used to treat or prevent hematological cancers in subjects who exhibit mutations in the NPM1 gene and / or the mixed lineage leukemia gene (MLL; MLL1; 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 MLL, rearrangement / alteration, or rearrangement / alteration of the MLL gene, acute leukemia, chronic leukemia, myelodysplastic syndrome (MDS), myeloproliferative neoplasms (MPN), insulin resistance, prediabetes, diabetes, or risk of diabetes, hyperglycemia, chromosomal rearrangement on chromosome 11q23, type 1 diabetes, type 2 diabetes; for promoting the proliferation of pancreatic cells, wherein the pancreatic cells are pancreatic islet cells, beta cells, and the beta cell proliferation is confirmed by increased beta cell production or insulin production; and for inhibiting menin-MLL interaction, wherein the MLL fusion protein target gene is HOX or MEIS1 in humans.

[0190] Therefore, the present invention relates to compounds of formula (I), their tautomeric and stereoisomeric forms and their pharmaceutically acceptable salts and solvates, for use as medicaments.

[0191] The present invention also relates to the use of a compound of formula (I), a tautomer or stereoisomeric form thereof, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition according to the invention, for the manufacture of a medicament.

[0192] The present invention also relates to a compound of formula (I) according to the present invention, a tautomer or stereoisomeric form thereof, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition for use in treating, preventing, ameliorating, controlling or reducing the risk of a disorder associated with the interaction between menin and MLL protein and oncogenic MLL fusion protein in a mammal (including a human), wherein the treatment or prevention of the disorder is affected or promoted by blocking the interaction between menin and MLL protein and oncogenic MLL fusion protein.

[0193] Likewise, the present invention relates to the use of a compound of formula (I) according to the present invention, its tautomer or stereoisomeric form, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition, for the manufacture of a medicament for treating, preventing, ameliorating, controlling or reducing the risk of a disorder associated with the interaction between menin and MLL protein and oncogenic MLL fusion protein in mammals (including humans), wherein the treatment or prevention of such a disorder is affected or promoted by blocking the interaction between menin and MLL protein and oncogenic MLL fusion protein.

[0194] The present invention also relates to a compound of formula (I), a tautomer or stereoisomeric form thereof, or a pharmaceutically acceptable salt or solvate thereof, for use in the treatment or prevention of any of the diseases mentioned above.

[0195] The present invention also relates to a compound of formula (I), a tautomer or stereoisomeric form thereof, or a pharmaceutically acceptable salt or solvate thereof, for use in the treatment or prevention of any of the diseases mentioned above.

[0196] The present invention also relates to the use of a compound of formula (I), its tautomer or stereoisomeric form, or a pharmaceutically acceptable salt or solvate thereof, for the manufacture of a medicament for the treatment or prevention of any of the above-mentioned disease conditions.

[0197] The compounds of the present invention can be administered to mammals (preferably humans) to treat or prevent any of the diseases mentioned above.

[0198] In view of the utility of compounds of formula (I), their tautomeric or stereoisomeric forms, and their pharmaceutically acceptable salts and solvates, there is provided a method of treating a warm-blooded animal (including humans) suffering from any of the diseases mentioned above.

[0199] The method comprises administering (ie, systemically or topically) to a warm-blooded animal (including humans) a therapeutically effective amount of a compound of formula (I), a tautomeric or stereoisomeric form thereof, or a pharmaceutically acceptable salt or solvate thereof.

[0200] Therefore, the present invention also relates to a method for treating or preventing any of the diseases mentioned above, which method comprises administering to a patient in need thereof a therapeutically effective amount of a compound according to the present invention.

[0201] Those skilled in the art will recognize that a therapeutically effective amount of a compound of the present invention is an amount sufficient to be therapeutically active, and this amount varies depending on the type of disease, the concentration of the compound in the therapeutic formulation, and the patient's condition. A therapeutically effective daily dose ranges 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) required to achieve a therapeutic effect can vary depending on, for example, the specific compound, the route of administration, the age and condition of the recipient, and the specific disorder or disease being treated. Treatment methods may also include administering the active ingredient in a regimen of between one and four daily intakes. In such treatment methods, the compound according to the present invention is preferably formulated prior to administration.

[0202] The present invention also provides a composition for preventing or treating the disorders mentioned herein, comprising a therapeutically effective amount of a compound of formula (I), a tautomer or stereoisomeric form thereof, or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable carrier or diluent.

[0203] While the active ingredient can be administered alone, it is preferably presented as a pharmaceutical composition. Accordingly, the present invention further provides a pharmaceutical composition comprising a compound according to the present invention and 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 recipient thereof.

[0204] The pharmaceutical compositions may be prepared by any method well known in the art of pharmacy, for example, using methods such as those described in Gennaro et al., Remington's Pharmaceutical Sciences (18th ed., Mack Publishing Company, 1990, see especially Part 8: Pharmaceutical preparations and their Manufacture).

[0205] 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 containing a compound according to the present invention and one or more additional therapeutic agents, as well as administration of a compound according to the present invention and each additional therapeutic agent in its own separate pharmaceutical dosage formulation.

[0206] Therefore, an embodiment of the present invention relates to a product containing a compound according to the present invention as a first active ingredient and one or more anticancer agents as a further active ingredient, as a combined preparation for simultaneous, separate or sequential use in the treatment of a patient suffering from cancer.

[0207] One or more other pharmaceutical agents and the compounds according to the present invention may be administered simultaneously (e.g., in the form of separate compositions or a whole composition) or sequentially in either order. In the latter case, the two or more compounds will be administered within a time period and in an amount and manner sufficient to ensure a beneficial or synergistic effect. It will be understood that the preferred method and order of administration of each component of the combination, as well as the corresponding dosage and regimen, will depend on the specific other pharmaceutical agent and compound of the present invention being administered, their route of administration, the specific condition being treated (particularly a tumor), and the specific host being treated.

[0208] The following examples further illustrate the present invention. Examples

[0209] Several methods for preparing the compounds of the present invention are described in the following examples. Unless otherwise specified, all starting materials were obtained from commercial suppliers and used without further purification, or alternatively, they were synthesized by the skilled artisan using methods well known in the art. [abbreviation] [meaning] [Ag(Phen) , 2, OTf ] Silver trifluoromethanesulfonate-bis(1,10-phenanthroline) complex [2-MeTHF] 2-Methyltetrahydrofuran [ACN] Acetonitrile [AcCl] Acetyl chloride [AcOH] Acetic acid [Ac , 2, O ] Acetic anhydride [aq.] aqueous solution [Ar] Argon [BBr , 3, ] tribromoborane [bn] benzyl [Boc] tertiary butoxycarbonyl [Boc , 2, O ] Dibutyl dicarbonate [ , n , ] [-BuLi] n-Butyllithium [Cbz] benzyloxycarbonyl [CD , 3, OD ] Methanol-d 4 [CHCl , 3, ] Chloroform [Cs , 2, CO , 3, ] Cesium carbonate [conc.] Concentrated [DBU] 1,8-diazabicyclo[5.4.0]undec-7-ene [DCC] dicyclohexylcarbodiimide [DCE] Ethylene dichloride [DCM] dichloromethane [DDQ] 4,5-Dichloro-3,6-dioxacyclohexa-1,4-diene-1,2-dicarbonitrile [DEA] Diethylamine [DIBAL-H] Diisobutylaluminum hydride [DIEA] [or] [DIPEA] N, N-Diisopropylethylamine [DMAP] N, N-Dimethylpyridin-4-amine [DMF] N, N-dimethylformamide [DMP] Dess-Martin periodinane [DMSO] Dimethyl sulfoxide [dppf] 1,1′-Ferrocenediyl-bis(diphenylphosphine) [EDCI] N-(3-Dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride [EA] [or] [EtOAc] Ethyl acetate [EtOH] ethanol [eq.] equivalent [FA] Formic acid [FCC] Flash column chromatography [h] Hour [H , 2, ] hydrogen [HATU] 1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5- b] Pyridinium cation 3-oxide hexafluorophosphate [H , 2, O ] water [HCl] hydrochloric acid [HOBt] 1-Hydroxybenzotriazole [HPLC] High-performance liquid chromatography [ICH , 2, Cl ] Chloroiodomethane [IPA] Isopropyl alcohol [IPAc] Isopropyl acetate [K , 2, CO , 3, ] potassium carbonate [KI] Potassium iodide [K , 2, HPO , 4, ] Dipotassium hydrogen phosphate [K , 3, PO , 4, ] Tripotassium phosphate [LiAlD , 4, ] Lithium aluminum deuteride [LAH] Lithium aluminum hydride [LiBH , 4, ] lithium borohydride [LDA] Lithium diisopropylamide [LiCl] lithium chloride [LG] Leaving group [Me] methyl [MeOH] Methanol [2-MeTHF] 2-Methyltetrahydrofuran [min] minute [mL] milliliters [mmol] millimoles [mg] mg [MgSO , 4, ] magnesium sulfate [MSA] Methanesulfonic acid [MsCl] Methanesulfonyl chloride [MS] molecular sieves [MTBE] Methyl tertiary butyl ether [N , 2, ] Nitrogen [NA] Unavailable [NaBH , 3, CN ] Sodium cyanoborohydride [NaBH(OAc) , 3, ] Sodium triacetoxyborohydride [NaBD , 3, CN ] Sodium cyanoborodeuteride [Na , 2, CO , 3, ] sodium carbonate [NaH] Sodium hydride [NaHCO , 3, ] Sodium bicarbonate [NaI] Sodium iodide [NaOAc] Sodium acetate [NaOH] Sodium hydroxide [Na , 2, SO , 3, ] sodium sulfite [Na , 2, SO , 4, ] sodium sulfate [NH , 4, Cl ] Ammonium chloride [NMM] 1-4-Methylmorpholine [Pd , 2, dba , 3, ] Tris(dibenzylideneacetone)dipalladium(0) [Pd(dppf)Cl , 2, ]· [DCM] [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) Dichloromethane complex [Pd(PPh , 3, ) , 4, ] Tetrakis(triphenylphosphine)palladium(0) [PE] Petroleum ether [PG] Protecting groups [Phen] Phenanthroline [psi] pounds per square inch [ , p , ] [-TsOH] p-Toluenesulfonic acid [ , p , ] [-TsOH] [H , 2, O , , ] p-Toluenesulfonic acid hydrate [R , t , ] Detention time [Rochelle Salt] [(] [Rochelle] ['] [s salt] [)] Potassium sodium tartrate tetrahydrate [RT] Room temperature [sat.] Saturated [SFC] Supercritical fluid chromatography [TBAF] Tetrabutylammonium fluoride [TBDMS] Tertiary butyl dimethyl silyl [TBDPS] Tertiary butyl diphenylsilyl [ , t , ] [-BuOK] Potassium tertiary butoxide [TEA] Triethylamine [Tf] trifluoromethanesulfonyl [TFA] Trifluoroacetic acid [THF] Tetrahydrofuran [Ti(OiPr) , 4, ] Titanium(IV) isopropoxide [TLC] Thin layer chromatography [TMEDA] N, N, N ', N '-Tetramethylethylenediamine [TMG] 1,1,3,3-Tetramethylguanidine [TMSI] Iodotrimethylsilane [Ts] p-Toluenesulfonyl [TsCl] p-Toluenesulfonyl chloride [v / v] Volume / Volume [vol.] volume [wt] weight [Xantphos] 4,5-Bis(diphenylphosphino)-9,9-dimethyldibenzopyran

[0210] As will be appreciated by those skilled in the art, compounds synthesized using the schemes shown may exist as solvates (e.g., hydrates) and / or contain residual solvents or trace impurities. Compounds or intermediates isolated as salts may be in whole number stoichiometry, i.e., mono- or di-salts, or in intermediate stoichiometry. When an intermediate or compound in the following experimental section is indicated as an "HCl salt" without indicating the number of equivalents of HCl, this means that no equivalents of HCl were determined. The same rule applies to all other salt forms mentioned in the experimental section, such as, for example, "oxalates," "formates," or "oxalates." ".

[0211] When one or more compounds are separated and the absolute stereochemistry is known, or when only one enantiomer is obtained and the absolute stereochemistry is known, the stereochemical configuration of a center in some compounds is designated as "R" or "S." For some compounds, when the absolute stereochemistry is undetermined (even if the bonds are drawn stereospecifically), even though the compound itself has been separated into a single stereoisomer and is enantiomerically pure, the stereochemical configuration at the designated center is designated as "*R" (first eluted from the column under the separated column conditions described in the synthetic scheme and when only one stereocenter is present or specified) or "*S" (second eluted from the column under the separated column conditions described in the synthetic scheme and when only one stereocenter is present or specified). In the case of a compound designated as "*R" being converted to another compound, the "*R" of the resulting compound indicates that it is derived from the starting material.

[0212] For example, it will be clear that compound 25 Tie .

[0213] When "*R" or "*S" occurs with a second stereocenter (denoted "R" or "S") in the same molecule (where the absolute stereochemistry of the second stereocenter is known), even though the compound itself has been isolated as a single stereoisomer and is enantiomerically pure, the absolute stereochemistry of the stereocenter denoted "*R" or "*S" is undetermined (even though the bonds are drawn stereospecifically). For such molecules, "*R" or "*S" is assigned randomly. For example, it will be clear that compound 340 Tie .

[0214] For compounds in which the stereochemical configuration of two stereocenters is indicated by * (e.g., *R or *S), the absolute stereochemistry of these stereocenters is undetermined (even if the bonds are drawn stereospecifically), even though the compound itself has been isolated as a single stereoisomer and is enantiomerically pure. In this case, the configuration of the first stereocenter is independent of the configuration of the second stereocenter in the same compound. For such molecules, "*R" or "*S" is assigned randomly.

[0215] For example, for compound 306

[0216] This means that the compound is

[0217] The skilled person will appreciate that the above paragraphs regarding stereochemical configuration also apply to intermediates.

[0218] The skilled person will appreciate that, even where not explicitly mentioned in the following experimental schemes, typically following column chromatography purification, the desired fractions are collected and the solvent evaporated.

[0219] Where no stereochemistry is indicated, this means it is a mixture of stereoisomers unless otherwise specified or clear from the context.

[0220] When "RS" is used to designate a stereocenter, this means that a racemic mixture is obtained at the designated center, unless otherwise indicated. [Preparation of intermediates] []

[0221] For the intermediates used as crude products or as partially purified intermediates in the next reaction step, in some cases, the molar amount of such intermediates in the next reaction step is not mentioned, or an alternative estimated molar amount or theoretical molar amount of this intermediate in the next reaction step is indicated in the reaction schemes described below. [Intermediates]

[27] Preparation [] [ , N , ] [-] [Ethyl] [-5-] [fluorine] [- , N , - ] [Isopropyl] [-2-] [Methoxybenzamide] []

[0222] To a mixture of 5-fluoro-2-methoxybenzoic acid (8.00 g, 47.0 mmol) and N-ethylpropan-2-amine (8.19 g, 94.0 mmol) in dry DCM (150 mL) cooled at 0°C, HATU (21.5 g, 56.5 mmol) and DIEA (9.10 g, 70.4 mmol) were slowly added portionwise. The resulting mixture was slowly warmed to room temperature and stirred for 8 h. The organic layer was washed with water (20 mL x 3) and dried over anhydrous NaSO. After filtration, the solvent was removed under reduced pressure, and the crude product was purified by FCC (EtOAc / PE = 0% to 20%) to give the title intermediate (12.0 g, 96% yield) as a white solid. [Intermediates]

[67] [、]

[0235] Preparation [] [5-] [fluorine] [-] [ , N , ] [,] [ , N , ] [-] [Diisopropyl] [-2-] [Methoxybenzamide] [] [5-] [fluorine] [-2-] [Methoxy] [-] [ ,N , ] [-(] [C] [-2-] [base] [- , 13 , ] [ , C , ] [ , 3, ] [)] [Benzamide] [] [By targeting the intermediate]

[27] [The following intermediates were synthesized by a similar method as described above] [] [Intermediates] [serial number] [structure] [Starting materials] 67 5-Fluoro-2-methoxybenzoic acid, diisopropylamine 235 5-Fluoro-2-methoxybenzoic acid, Propan-2-amine-1,2,3- 13 C 3 [Intermediates]

[28] Preparation [] [ , N , ] [-] [Ethyl] [-5-] [fluorine] [-2-] [Hydroxy] [- , N , - ] [Cymene] [] []

[0223] To N-ethyl-5-fluoro-N-isopropyl-2-methoxybenzamide ( [Intermediates] To a solution of

[27] ) (12.0 g, 50.1 mmol) in dry DCM (100 mL) was slowly added BBr 3 (14.4 mL, 152 mmol), and 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 was adjusted to about 8 by adding saturated aqueous NaHCO 3 solution. The aqueous layer was extracted with DCM (50 mL x 3) and the combined organic layers were dried over anhydrous Na 2 SO 4, filtered and concentrated under reduced pressure to give the crude product, which was purified by FCC (EtOAc / PE = 0% to 20%) to give the title intermediate (9.0 g, 78% yield) as a white solid. [Intermediates]

[68] [、]

[0237] Preparation [] [5-] [fluorine] [-2-] [Hydroxy] [-] [ , N , ] [,] [ , N , ] [-] [Diisopropylbenzamide] [] [ , N , ] [-(] [Ethyl] [- , 13 , ] [ , C , ] [ , 2, ] [)-5-] [fluorine] [-2-] [Hydroxy] [-] [ , N , ] [-(] [C] [-2-] [base] [- , 13 , ] [ , C , ] [ , 3, ] [)] [Benzamide] [] [By targeting the intermediate]

[28] [The following intermediates were synthesized by a similar method as described above] [] [Intermediate number] [structure] [Starting materials] 68 Intermediate 67 237 Intermediate 236 [Intermediates]

[60] Preparation [] [5-] [bromine] [-4-] [Cyclopropylpyrimidine] [] []

[0224] To a solution of 5-bromopyrimidine (30 g, 189 mmol) in THF (1000 mL) at 0°C under an N₂ atmosphere was added cyclopropylmagnesium bromide (396 mL, 198 mmol, 0.5 M in THF). After the addition, the reaction mixture was stirred at room temperature for 4 h, then a solution of DDQ (42.8 g, 189 mmol) in THF (500 mL) was added dropwise to the reaction mixture at 0°C. After the addition, the reaction mixture was stirred at room temperature 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 with EtOAc (200 mL x 3). The combined organic layers were washed with 1N NaOH (200 mL x 2), brine (200 mL), dried over Na₂SO₄, and filtered. The filtrate was concentrated in vacuo and the residue was purified by FCC (EtOAc / PE = 0% to 15%) to give the title intermediate as a white solid (21.4 g, 55% yield). [Intermediates]

[61] Preparation [] [2-(4-] [Cyclopropylpyrimidine] [-5-] [base] [)-4-] [Fluorophenol] [] []

[0225] Under N2 atmosphere, 5-bromo-4-cyclopropylpyrimidine ( [Intermediates] A mixture of

[60] ) (20.0 g, 100 mmol), (5-fluoro-2-hydroxyphenyl)boronic acid (18.7 g, 120 mmol), Pd(dppf)Cl 2 (3.68 g, 5.03 mmol), and Na 2CO 3 (2 M in H 2 O, 101 mL, 202 mmol) in 1,4-dioxane (350 mL) was heated at 90 ° C for 12 h. After cooling to RT, the reaction mixture was filtered through a celite pad, and the filtrate was suspended in water (400 mL) and extracted with EtOAc (200 mL x 3). The combined organic layers were dried over anhydrous Na 2 SO 4 , 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% yield) as a brown solid. [Intermediates]

[13] Preparation [] [Tertiary butyl] [6-(3,6-] [Dichloro] [-1,2,4-] [Three] [-5-] [base] [)-2,6-] [Diazaspiro] [[3.4]] [Octane] [-2-] [Formate] []

[0226] To a solution of 3,5,6-trichloro-1,2,4-trioxane (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 room temperature 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 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. [Intermediates]

[69] Preparation [] [Tertiary butyl] [6-(3-] [Chlorine]𠯤 [-4-] [base] [)-2,6-] [Diazaspiro] [[3.4]] [Octane] [-2-] [Formate] [] [By targeting the intermediate]

[13] [The following intermediates were synthesized by a similar method as described above] [] [Intermediate number] [structure] [Starting materials] 69 3,4-Dichlorothiazolium, Tertiary butyl 2,6-diazaspiro[3.4] Octane-2-carboxylate [Intermediates]

[14] Preparation [] [Tertiary butyl] [6-(3-] [chlorine] [-6-(2-(] [Ethyl] [(] [Isopropyl] [)] [Carbamoyl] [)-4-] [Fluorophenoxy] [)-1,2,4-] [Three] [-5-] [base] [)-2,6-] [Diazaspiro] [[3.4]] [Octane] [-2-] [Formate] []

[0227] The tertiary butyl 6-(3,6-dichloro-1,2,4-trioxan-5-yl)-2,6-diazaspiro[3.4]octane-2-carboxylate ( [Intermediates]

[13] )(12.0 g, 33.3 mmol), N-ethyl-5-fluoro-2-hydroxy-N-isopropylbenzamide ( [Intermediates] A mixture of

[28] ) (7.5 g, 33.3 mmol) and DBU (6.1 g, 40.1 mmol) in 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 over Na 2 SO 4, filtered and concentrated under reduced pressure to give the crude product, which was purified by FCC (PE / EtOAc = 1: 0 to 3: 1) to give the title intermediate as a green solid (14.0 g, 73% yield). [Intermediates]

[57] [、]

[74] [、]

[70] [and]

[83] Preparation [] [Tertiary butyl] [6-(3-] [chlorine] [-6-(2-(4-] [Cyclopropylpyrimidine] [-5-] [base] [)-4-] [Fluorophenoxy] [)-1,2,4-] [Three] [-5-] [base] [)-2,6-] [Diazaspiro] [[3.4]] [Octane] [-2-] [Formate] [] [Tertiary butyl] [6-(3-(2-(] [Ethyl] [(] [Isopropyl] [)] [Carbamoyl] [)-4-] [Fluorophenoxy] [)] [Da]𠯤 [-4-] [base] [)-2,6-] [Diazaspiro] [[3.4]] [Octane] [-2-] [Formate] [] [Tertiary butyl] [6-(3-(2-(] [Diisopropylaminoformyl] [)-4-] [Fluorophenoxy] [)] [Da]𠯤 [-4-] [base] [)-2,6-] [Diazaspiro] [[3.4]] [Octane] [-2-] [Formate] [] [Tertiary butyl] [6-(3-] [chlorine] [-6-(2-(] [Diisopropylaminoformyl] [)-4-] [Fluorophenoxy] [)-1,2,4-] [Three] [-5-] [base] [)-2,6-] [Diazaspiro] [[3.4]] [Octane] [-2-] [Formate] [] [By targeting the intermediate]

[14] [The following intermediates were synthesized by a similar method as described above] [] [Intermediate number] [structure] [Starting materials] 57 Intermediate 61, Intermediate 13 74 Intermediate 28, Intermediate 69 70 Intermediate 68, Intermediate 69 83 Intermediate 68, Intermediate 13 [Intermediates] [2] Preparation [] [Tertiary butyl] [6-(6-(2-(] [Ethyl] [(] [Isopropyl] [)] [Carbamoyl] [)-4-] [Fluorophenoxy] [)-1,2,4-] [Three] [-5-] [base] [)-2,6-] [Diazaspiro] [[3.4]] [Octane] [-2-] [Formate] [] Method A:

[0228] Under N2 atmosphere, tertiary butyl 6-(3-chloro-6-(2-(ethyl(isopropyl)aminoformyl)-4-fluorophenoxy)-1,2,4-triazol-5-yl)-2,6-diazaspiro[3.4]octane-2-carboxylate ( [Intermediates] To a mixture of

[14] (20 g, 36.4 mmol), NaBH 4 (2.48 g, 65.7 mmol) and TMEDA (8.54 g, 73.5 mmol) in THF (500 mL) was added Pd(dppf)Cl 2·DCM (1.70 g, 2.08 mmol). After addition, the reaction mixture was stirred at 25°C for 14 h. The reaction mixture was filtered, and the filtrate was concentrated, and the residue was purified by FCC on silica gel (EtOAc) to give the title intermediate (15 g, 93% purity, 74% yield) as a brown solid. Method B:

[0229] To tertiary butyl 6-(3-chloro-6-(2-(ethyl(isopropyl)aminoformyl)-4-fluorophenoxy)-1,2,4-triazol-5-yl)-2,6-diazaspiro[3.4]octane-2-carboxylate ( [Intermediates]

[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 at 25 ° C for 8 h under H 2 atmosphere (30 psi). The reaction mixture was filtered through a celite pad and the filtrate was concentrated in vacuo to give the title intermediate (25.0 g, crude), which was used directly in the next step without further purification. [Intermediates]

[58] [、]

[84] Preparation [] [Tertiary butyl] [6-(6-(2-(4-] [Cyclopropylpyrimidine] [-5-] [base] [)-4-] [Fluorophenoxy] [)-1,2,4-] [Three] [-5-] [base] [)-2,6-] [Diazaspiro] [[3.4]] [Octane] [-2-] [Formate] [] [Tertiary butyl] [6-(6-(2-(] [Diisopropylaminoformyl] [)-4-] [Fluorophenoxy] [)-1,2,4-] [Three] [-5-] [base] [)-2,6-] [Diazaspiro] [[3.4]] [Octane] [-2-] [Formate] [] [By targeting the intermediate] [2] [The following intermediates were synthesized by a similar method as described above] [] [Intermediate number] [structure] [Starting materials] [condition] 58 Intermediate 57 NaBH 4,TMEDA, Pd(dppf)Cl 2·DCM, THF 84 Intermediate 83 Pd / C,H 2, TEA,MeOH [Intermediates] [3] Preparation [] [2-((5-(2,6-] [Diazaspiro] [[3.4]] [pungent] [-6-] [base] [)-1,2,4-] [Three] [-6-] [base] [)] [oxyl] [)- , N , - ] [Ethyl] [-5-] [fluorine] [- , N , - ] [Cymene] []

[0230] To tertiary butyl 6-(6-(2-(ethyl(isopropyl)aminoformyl)-4-fluorophenoxy)-1,2,4-trioxan-5-yl)-2,6-diazaspiro[3.4]octane-2-carboxylate ( [Intermediates] To a solution of [2]) (300 mg, 0.583 mmol) in DCM (5 mL) was added TFA (0.5 mL, 6.4 mmol, and the resulting mixture was stirred at RT for 3 h. Then 10% NaOH (5 mL) solution was slowly added to the mixture to adjust the pH to about 12, and the resulting mixture was extracted with DCM (10 mL x 3). The combined organic layers were dried over anhydrous Na 2 SO 4, filtered and concentrated in vacuo to give the title intermediate (220 mg, 90% yield) as a white solid. [Intermediates]

[59] [、]

[75] [、]

[85] Preparation [] [6-(6-(2-(4-] [Cyclopropylpyrimidine] [-5-] [base] [)-4-] [Fluorophenoxy] [)-1,2,4-] [Three] [-5-] [base] [)-2,6-] [Diazaspiro] [[3.4]] [Octane] [] [2-((4-(2,6-] [Diazaspiro] [[3.4]] [pungent] [-6-] [base] [)] [Da]𠯤 [-3-] [base] [)] [oxyl] [)- , N , - ] [Ethyl] [-5-] [fluorine] [- , N , - ] [Cymene] [] [2-((5-(2,6-] [Diazaspiro] [[3.4]] [pungent] [-6-] [base] [)-1,2,4-] [Three] [-6-] [base] [)] [oxyl] [)-5-] [fluorine] [- , N , , ,N , - ] [Diisopropylbenzamide] [] [By targeting the intermediate] [3] [The following intermediates were synthesized by a similar method as described above] [] [Intermediate number] [structure] [Starting materials] 59 Intermediate 58 75 Intermediate 74 85 Intermediate 84 [Intermediates]

[0160] Preparation [] [ , N , ] [-] [Methoxy] [- , N , - ] [methyl] [-4-(] [Methylamino] [)] [Butyramide hydrochloride] [] []

[0231] At 0 ° C, tert-butyl (4-(methoxy(methyl)amino)-4-oxobutyl)(methyl)carbamate ( [Intermediates] To a solution of [8]) (220 g, crude) in DCM (200 mL) was slowly added HCl / 1,4-dioxane (750 mL, 3 mol). The resulting mixture was slowly warmed to RT and stirred at this temperature for 2 h. The mixture was concentrated in vacuo to give the title intermediate (197 g, crude), which was used in the next step without further purification. [Intermediates]

[0164] [、]

[0238] [、]

[0243] [、]

[0244] [ , N , ] [-(2-] [Methoxyethyl] [)- , N , ,5- ] [Dimethyl] [-4-(2,6-] [Diazaspiro] [[3.4]] [pungent] [-6-] [base] [)] [Self] [-1-] [Amine hydrochloride] [] [2-((3-] [chlorine] [-5-(2,6-] [Diazaspiro] [[3.4]] [pungent] [-6-] [base] [)-1,2,4-] [Three] [-6-] [base] [)] [oxyl] [)- , N, - ] [Ethyl] [-5-] [fluorine] [- , N , - ] [Isopropylbenzamide hydrochloride] [] [2-((5-(2,6-] [Diazaspiro] [[3.4]] [pungent] [-6-] [base] [)-1,2,4-] [Three] [-6-] [base] [)] [oxyl] [)-5-] [fluorine] [- , N , , , N , - ] [Diisopropylbenzamide hydrochloride] [] [2-((5-(2,6-] [Diazaspiro] [[3.4]] [pungent] [-6-] [base] [)-1,2,4-] [Three] [-6-] [base] [)] [oxyl] [)- , N , - ] [Ethyl] [-5-] [fluorine] [- , N , - ] [Isopropylbenzamide hydrochloride] [] [By targeting the intermediate]

[0160] [The following intermediates were synthesized by a similar method as described above] [] [Intermediate number] [structure] [Starting materials] 164 Intermediate 163 238 Intermediate 14 243 Intermediate 84 244 Intermediate 2 [Intermediates]

[71] Preparation [] [2-((4-(2,6-] [Diazaspiro] [[3.4]] [pungent] [-6-] [base] [)] [Da]𠯤 [-3-] [base] [)] [oxyl] [)-5-] [fluorine] [- , N , , , N , - ] [Diisopropylbenzamide] [] []

[0232] To tertiary butyl 6-(3-(2-(diisopropylaminoformyl)-4-fluorophenoxy)thiazol-4-yl)-2,6-diazaspiro[3.4]octane-2-carboxylate ( [Intermediates] To a solution of

[70] ) (5.0 g, 9.4 mmol) in 1,4-dioxane (30 mL) was slowly added HCl in 1,4-dioxane (20 mL, 4 M, 80 mmol), and the resulting mixture was stirred at RT for 2 h. Then, the mixture was concentrated and the residue was redissolved in DCM (50 mL), to which 1 M NaOH (20 mL) was slowly added and the pH value was adjusted to 12, and the resulting mixture was extracted with DCM (30 mL x 3). The combined organic layers were dried over anhydrous Na 2 SO 4, filtered, and concentrated in vacuo to give the title intermediate (4 g, crude) as a yellow solid, which was used in the next step without further purification. [Intermediates]

[29] Preparation [] [Tertiary butyl] [2,2-] [Dimethyl] [-5-] [Pen-oxide pyrrolidine] [-1-] [Formate] []

[0233] To a solution of 5,5-dimethylpyrrolidin-2-one (3.00 g, 26.5 mmol) in DCM (30 mL) was added TEA (8.10 g, 80.0 mmol) and DMAP (325 mg, 2.66 mmol), followed by di-tert-butyl dicarbonate (8.70 g, 39.8 mmol). The reaction was stirred at 40°C overnight. After cooling to room temperature, the reaction mixture was washed with brine (30 mL x 2), dried over Na2SO4, filtered, and concentrated under reduced pressure to give the crude product. The crude product was further purified by FCC on silica gel (PE / EtOAc = 100:0 to 3:1) to give the title intermediate as a yellow powder (2.8 g, 50% yield). [Intermediates] [1] Preparation [] [Tertiary butyl] [(5-] [methyl] [-4-] [Pendant oxyhexyl] [)] [Urethane] []

[0234] To a solution of tert-butyl 2-oxopyrrolidine-1-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 room temperature and stirred for 12 h. The mixture was poured into a saturated aqueous NH4Cl solution (50 mL) and extracted with EtOAc (50 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 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. [Intermediates]

[30] [、]

[0110] [、]

[0141] Preparation [] [Tertiary butyl] [(2,6-] [Dimethyl] [-5-] [Heptyl Pendant Oxide] [-2-] [base] [)] [Urethane] [] [Tertiary butyl] [(6-] [methyl] [-5-] [Heptyl Pendant] [)] [Urethane] [] [6-] [Hydroxy] [-2,4-] [Dimethylhexane] [-3-] [ketone] [] [By targeting the intermediate] [1] [The following intermediates were synthesized by a similar method as described above] [] [Intermediate number] [structure] [Starting materials] 30 Isopropylmagnesium bromide, Intermediate 29 110 Isopropylmagnesium bromide, Tertiary butyl 2-oxopiperidin-1-carboxylate 141 Isopropylmagnesium chloride, 3-Methyldihydrofuran-2(3H)-one [Intermediates]

[34] Preparation [] [Benzyl] [2,2-] [Dimethyl] [-5-] [Pen-oxide pyrrolidine] [-1-] [Formate] []

[0235] To a solution of 5,5-dimethylpyrrolidin-2-one (5.00 g, 44.2 mmol) in THF (150 mL) cooled at 0°C was added NaH (1.94 g, 48.5 mmol, 60%), and the resulting mixture was stirred at this temperature for 30 min. Subsequently, N-(benzyloxycarbonyloxy)succinimide (12.1 g, 48.6 mmol) was added, and the reaction mixture was slowly warmed to room temperature and stirred for an additional 16 h. The solvent was evaporated under reduced pressure, saturated aqueous NH4Cl solution (30 mL) was added, and the mixture was extracted with EtOAc (2 x 30 mL). The combined organic layers were washed with brine (40 mL), dried over Na 2 SO 4 , filtered and concentrated under reduced pressure to give the crude product, which was further purified by FCC (PE / EtOAc = 1:0 to 3:1) to give the title intermediate (5.16 g, 39% yield) as a colorless oil. [Intermediates]

[35] Preparation [] [4-(((] [Benzyloxy] [)] [Carbonyl] [)] [Amine] [)-4-] [Methylvaleric acid] [] []

[0236] NaOH (4.18 g, 16.9 mmol) was added to benzyl 2,2-dimethyl-5-oxopyrrolidine-1-carboxylate ( [Intermediates]

[34] ) (5.16 g, 20.9 mmol) in THF (60 mL) and H 2 O (15 mL). The mixture was stirred at 80°C for 16 h. The reaction mixture was cooled to 25°C and acidified with 1 M HCl to adjust the pH to about 3, and then the mixture was extracted with EtOAc (20 x 2 mL). The combined organic layers were washed with brine (20 mL), dried over Na 2 SO 4, filtered and concentrated in vacuo to give the title intermediate (4.48 g, crude) as a colorless oil, which was used directly in the next step without further purification. [Intermediates] [7] Preparation [] [4-((] [ , Level 3 Ding , ] [Oxycarbonyl] [)(] [methyl] [)] [Amine] [)] [Butyric acid] []

[0237] To a solution of 4-(methylamino)butyric acid hydrochloride (3.0 g, 19.5 mmol) and TEA (7.78 mL, 58.6 mmol) in MeOH (30 mL) was added Boc 2 O (4.69 g, 21.5 mmol) dropwise. The mixture was stirred at room temperature 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 HCl (70 mL x 2), H 2 O (50 mL x 2), and brine (50 mL), dried over Na 2 SO 4, filtered, and concentrated to give the title intermediate (1.80 g, crude) as a colorless oil. [Intermediates] [8] Preparation [] [Tertiary butyl] [(4-(] [Methoxy] [(] [methyl] [)] [Amine] [)-4-] [Pendant oxybutyl] [)(] [methyl] [)] [Urethane] [] []

[0238] To 4-((tert-butyloxycarbonyl)(methyl)amino)butanoic acid ( [Intermediates] [7]) (1.80 g, crude) was added to a solution of N, O-dimethylhydroxylamine hydrochloride (960 mg, 9.84 mmol), HOBt (1.24 g, 9.18 mmol) and NMM (2.80 mL, 25.1 mmol) in CHCl 3 (30 mL). EDCI (2.23 g, 11.6 mmol) was then added and the reaction mixture was stirred at RT for 4 h. The reaction mixture was diluted with DCM (100 mL), washed with 1N HCl (30 mL x 3), saturated aqueous NaHCO 3 (30 mL x 3) and brine (30 mL), dried over Na 2 SO 4, filtered and concentrated in vacuo to give the title intermediate (1.70 g, crude) as a colorless oil. [Intermediates]

[19] [、]

[36] [、]

[0189] [、]

[0190] [、]

[0203] [、]

[0204] Preparation [] [Tertiary butyl] [(3-(] [Methoxy] [(] [methyl] [)] [Amine] [)-3-] [Pendant oxypropyl] [)] [Urethane] [] [Benzyl] [(5-(] [Methoxy] [(] [methyl] [)] [Amine] [)-2-] [methyl] [-5-] [Pendyl] [-2-] [base] [)] [Urethane] [] [( , S , )-3-(( ] [tertiary butyldiphenylsilyl] [)] [oxyl] [)-4-(] [Ethyl] [(] [methyl] [)] [Amine] [)- , N , - ] [Methoxy] [- , N , - ] [Methylbutyramide] [] [( , R , )-3-(( ] [tertiary butyldiphenylsilyl] [)] [oxyl] [)-4-(] [Ethyl] [(] [methyl] [)] [Amine] [)- , N , - ] [Methoxy] [- , N , - ] [Methylbutyramide] [] [( , S , )-3-(( ] [tertiary butyldiphenylsilyl] [)] [oxyl] [)- , N , - ] [Methoxy] [-4-((2-] [Methoxyethyl] [)(] [methyl] [)] [Amine] [)- , N , - ] [Methylbutyramide] [] [( , R , )-3-(( ] [tertiary butyldiphenylsilyl] [)] [oxyl] [)- , N , - ] [Methoxy] [-4-((2-] [Methoxyethyl] [)(] [methyl] [)] [Amine] [)- , N , - ] [Methylbutyramide] [] [By targeting the intermediate] [8] [The following intermediates were synthesized by a similar method as described above] [] [Intermediate number] [structure] [Starting materials] 19 3-((tert-butyloxycarbonyl)amino)propionic acid N, O-Dimethylhydroxylamine hydrochloride 36 Intermediate 35 N, O-Dimethylhydroxylamine hydrochloride 189 Intermediate 187, N, O-Dimethylhydroxylamine hydrochloride 190 Intermediate 188, N, O-Dimethylhydroxylamine hydrochloride 203 Intermediate 201, N, O-Dimethylhydroxylamine hydrochloride 204 Intermediate 202, N, O-Dimethylhydroxylamine hydrochloride [Intermediates]

[37] Preparation [] [Benzyl] [(5-(] [Methoxy] [(] [methyl] [)] [Amine] [)-2-] [methyl] [-5-] [Pendyl] [-2-] [base] [)(] [methyl] [)] [Urethane] []

[0239] Under N2 atmosphere, benzyl (5-(methoxy(methyl)amino)-2-methyl-5-oxopentan-2-yl)carbamate ( [Intermediates] To a solution of

[36] ) (2.30 g, 7.46 mmol) in DMF (30 mL) was added NaH (358 mg, 8.95 mmol, 60%). Then, MeI (8.87 g, 62.5 mmol) was added and the mixture was stirred at 25 °C for 12 h. The mixture was quenched with saturated aqueous NH4Cl (30 mL) and extracted with EtOAc (30 mL x 2). The combined organic layers were 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 a yellow oil. [Intermediates]

[0236] Preparation [] [ , N , ] [-(] [Ethyl] [- , 13 , ] [ , C , ] [ , 2, ] [)-5-] [fluorine] [-2-] [Methoxy] [-] [ , N , ] [-(] [C] [-2-] [base] [- , 13 , ] [ , C , ] [ , 3, ] [)] [Benzamide] [] [By targeting the intermediate]

[37] [The following intermediates were synthesized by a similar method as described above] [] [Intermediate number] [structure] [Starting materials] [condition] 236 Intermediate 235, Iodoethane-1,2- 13 C 2 NaH,DMF, From 0°C to 90°C [Intermediates] [9] Preparation [] [Tertiary butyl] [] [methyl] [(5-] [methyl] [-4-] [Pendant oxyhexyl] [)] [Urethane] [] []

[0240] Under N2 atmosphere, tert-butyl (4-(methoxy(methyl)amino)-4-oxobutyl)(methyl)carbamate ( [Intermediates] To a solution of [8] (200 mg, crude) in THF (5 mL) was added isopropyl lithium (3.2 mL, 2.24 mmol, 0.7 M in pentane) dropwise. The resulting mixture was stirred at -70 ° C for 2 h. The mixture was quenched with saturated aqueous NH 4 Cl (15 mL) and extracted with EtOAc (30 mL x 2). The combined organic layers were washed with brine (30 mL), dried over Na 2 SO 4, filtered and concentrated under reduced pressure to give the crude product. The crude product was further purified by FCC (PE / EtOAc = 10: 1) to give the title intermediate (60 mg) as a colorless oil. [Intermediates]

[20] [、]

[38] [、]

[0162] [、]

[0191] [、]

[0192] [、]

[0205] [、]

[0206] Preparation [] [Tertiary butyl] [(4-] [methyl] [-3-] [Pendyloxy] [)] [Urethane] [] [Benzyl] [(2,6-] [Dimethyl] [-5-] [Heptyl Pendant Oxide] [-2-] [base] [)(] [methyl] [)] [Urethane] [] [6-((2-] [Methoxyethyl] [)(] [methyl] [)] [Amine] [)-2-] [Methylhexane] [-3-] [ketone] [] [( , S , )-5-(( ] [tertiary butyldiphenylsilyl] [)] [oxyl] [)-6-(] [Ethyl] [(] [methyl] [)] [Amine] [)-2-] [Methylhexane] [-1-] [ene] [-3-] [ketone] [] [( , R , )-5-(( ] [tertiary butyldiphenylsilyl] [)] [oxyl] [)-6-(] [Ethyl] [(] [methyl] [)] [Amine] [)-2-] [Methylhexane] [-1-] [ene] [-3-] [ketone] [] [( , S , )-5-(( ] [tertiary butyldiphenylsilyl] [)] [oxyl] [)-6-((2-] [Methoxyethyl] [)(] [methyl] [)] [Amine] [)-2-] [Methylhexane] [-1-] [ene] [-3-] [ketone] [] [( , R , )-5-(( ] [tertiary butyldiphenylsilyl] [)] [oxyl] [)-6-((2-] [Methoxyethyl] [)(] [methyl] [)] [Amine] [)-2-] [Methylhexane] [-1-] [ene] [-3-] [ketone] [] [By targeting the intermediate] [9] [The following intermediates were synthesized by a similar method as described above] [] [Intermediate number] [structure] [Starting materials] 20 Intermediate 19, Isopropylmagnesium chloride 38 Intermediate 37 Isopropylmagnesium chloride 162 Intermediate 161, Isopropyl lithium 191 Intermediate 189, Isopropenylmagnesium bromide 192 Intermediate 190, Isopropenylmagnesium bromide 205 Intermediate 203, Isopropenylmagnesium bromide 206 Intermediate 204, Isopropenylmagnesium bromide [Intermediates]

[15] Preparation [] [2-(3-] [methyl] [-2-] [Pendant oxybutyl] [)] [Isoindoline] [-1,3-] [Diketone] [] []

[0241] To a 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 hours. After cooling to room temperature, water (15 mL) was added, and the mixture was extracted with EtOAc (40 mL x 3). The combined organic layers were dried over anhydrous NaSO, filtered, and concentrated under reduced pressure to afford the crude product, which was further purified by preparative TLC (PE / EtOAc = 3:1) to afford the title intermediate (200 mg, 69% yield) as a white solid. [Intermediates]

[46] Preparation [] [methyl] [5-] [methyl] [-4-] [Pendulous hexanoate] [] []

[0242] To a solution of ZnEt (104 mL, 104 mmol) in DCM (150 mL) at 0°C under N₂ was added TFA (11.9 g, 104 mmol) dropwise via syringe, and the mixture was stirred at 0°C for 30 min. Diiodomethane (27.9 g, 104 mmol) was then added dropwise with stirring, and the suspension was stirred for an additional 30 min. Methyl 4-methyl-3-oxopentanoate (5.00 g, 34.7 mmol) was then added quickly via syringe, and the resulting mixture was stirred at room temperature for 16 h and refluxed at 50°C for 20 h. After cooling to room temperature, the reaction mixture was quenched with saturated aqueous NH₄Cl (50 mL) and extracted with EtOAc (30 mL x 3). The combined organic layers were washed with brine, dried over MgSO 4 and concentrated under reduced pressure to an oily residue, which was purified by FCC (PE / EtOAc=1:0 to 20:1) to give the title intermediate as a yellow oil (300 mg, 5% yield). [Intermediates] [twenty two] Preparation [] [Tertiary butyl] [(4-] [methyl] [-3-(2,6-] [Diazaspiro] [[3.4]] [pungent] [-2-] [base] [)] [pentyl] [)] [Carbamate hydrochloride] [] HCl salt []

[0243] Under Ar, benzyl 2-(1-((tert-butyloxycarbonyl)amino)-4-methylpentan-3-yl)-2,6-diazaspiro[3.4]octane-6-carboxylate ( [Intermediates] To a solution of

[21] ) (0.580 g, 1.30 mmol) in MeOH (50 mL) was added 1,1,2-trichloroethane (0.260 g, 1.95 mmol) and Pd / C (0.05 g, 10%), and the reaction was stirred at 35 °C under an atmosphere of H2 (15 psi) for 8 h. The reaction mixture was filtered. The filtrate was concentrated in vacuo to give the title intermediate (280 mg, crude) as a colorless oil. [Intermediates] [twenty three] Preparation [] [Ethyl] [6-(2-(] [Ethyl] [(] [Isopropyl] [)] [Carbamoyl] [)-4-] [Fluorophenoxy] [)-1,2,4-] [Three] [-5-] [Formate] [] []

[0244] To ethyl 6-chloro-1,2,4-trioxan-5-carboxylate (13 g, 69 mmol) and N-ethyl-5-fluoro-2-hydroxy-N-isopropylbenzamide ( [Intermediate] To a mixture of

[28] ) (15.6 g, 69.3 mmol) in DMF (150 mL) was added K 2 CO 3 (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 a 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 Na 2 SO 4 , filtered and concentrated under reduced pressure to give a crude product, which was further purified by FCC (PE / EtOAc = 1:0 to 1:1) to give the title intermediate as a yellow solid (30 g, 81% purity, 92% yield). [Intermediate] [twenty four] Preparation [] [6-(2-(] [Ethyl] [(] [Isopropyl] [)] [Carbamoyl] [)-4-] [Fluorophenoxy] [)-1,2,4-] [Three] [-5-] [Formic acid] [] []

[0245] To ethyl 6-(2-(ethyl(isopropyl)aminoformyl)-4-fluorophenoxy)-1,2,4-triazine-5-carboxylate ( [Intermediate]

[23] ) (8.6 g, 23 mmol) was added to a mixture of THF (100 mL) and H 2 O (25 mL) and LiOH·H 2 O (2.0 g, 48 mmol), and the reaction mixture was stirred at RT for 1 h. The mixture was acidified with 0.5 M HCl to adjust the pH to 5-6 and further extracted with EtOAc (150 mL). The aqueous phase was purified by preparative HPLC on Boston Prime (column: C18 150×30 mm 5 um; eluent: ACN / H 2 O (0.225% FA) from 19% to 49%, v / v) to give the title intermediate (5.0 g, 62% yield). [Intermediates]

[0187] [、]

[0188] [、]

[0201] [、]

[0202] Preparation [] [(] [ , S , ] [)-3-((] [tertiary butyldiphenylsilyl] [)] [oxyl] [)-4-(] [Ethyl] [(] [methyl] [)] [Amine] [)] [Butyric acid] [] [(] [ , R , ] [)-3-((] [tertiary butyldiphenylsilyl] [)] [oxyl] [)-4-(] [Ethyl] [(] [methyl] [)] [Amine] [)] [Butyric acid] [] [(] [ , S , ] [)-3-((] [tertiary butyldiphenylsilyl] [)] [oxyl] [)-4-((2-] [Methoxyethyl] [)(] [methyl] [)] [Amine] [)] [Butyric acid] [] [(] [ , R , ] [)-3-((] [tertiary butyldiphenylsilyl] [)] [oxyl] [)-4-((2-] [Methoxyethyl] [)(] [methyl] [)] [Amine] [)] [Butyric acid] [] [By targeting the intermediate] [twenty four] [The following intermediates were synthesized by a similar method as described above] [] [Intermediate number] [structure] [Starting materials] [condition] 187 Intermediate 185 NaOH,THF / MeOH / H 2O, RT 188 Intermediate 186 NaOH,THF / MeOH / H 2O, RT 201 Intermediate 199 NaOH,THF / EtOH / H 2O, RT 202 Intermediate 200 NaOH,THF / MeOH / H 2O, RT [Intermediates]

[25] Preparation [] [ , N , ] [-] [Ethyl] [-5-] [fluorine] [-2-((5-] [Hydroxy] [-1,2,4-] [Three] [-6-] [base] [)] [oxyl] [)- , N , - ] [Cymene] [] []

[0246] To 6-(2-(ethyl(isopropyl)aminoformyl)-4-fluorophenoxy)-1,2,4-triazine-5-carboxylic acid ( [Intermediates] To a solution of

[24] ) (50 mg, 0.14 mmol) and 1,3-dibromo-1,3,5-trioxane-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 pad of celite and washed with ACN (10 mL). The filtrate was concentrated under reduced pressure to give the crude product, which was further purified by preparative HPLC using Xtimate (column: C18 150×40 mm 10 μm; eluent: ACN / H 2 O (0.2% FA) from 20% to 50% v / v) to give the title intermediate (20 mg, 41%) as a white solid. [Intermediates]

[0159] Preparation [] [ , N , ] [-] [Ethyl] [-5-] [fluorine] [- , N , - ] [Isopropyl] [-2-((5-(2,2,2-] [Trifluoroethoxy] [)-1,2,4-] [Three] [-6-] [base] [)] [oxyl] [)] [Benzamide] []

[0247] 4Å molecular sieves (8 g) were added to 6-(2-(ethyl(isopropyl)aminoformyl)-4-fluorophenoxy)-1,2,4-triazine-5-carboxylic acid ( [Intermediates]

[24] ) (8.0 g, 23.0 mmol) in 2,2,2-trifluoroethane-1-ol (100 mL). The resulting mixture was stirred at 70 ° C for 1 h under N 2 atmosphere. It was then cooled to RT and 1,3-dibromo-1,3,5-trioxane-2,4,6-trione (13.1 g, 45.7 mmol) was added to the above mixture. The resulting mixture was stirred at RT under N 2 atmosphere overnight. The reaction mixture was filtered through 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 give the title intermediate (3.1 g, 84% purity, 28% yield) as a yellow solid. [Intermediates]

[51] Preparation [] [4-((] [tertiary butyl dimethyl silyl] [)] [oxyl] [)] [Man] [-1-] [alcohol] [] []

[0248] To a solution of butane-1,4-diol (5.00 g, 55.5 mmol) in THF (100 mL) cooled at 0°C was added NaH (1.55 g, 38.8 mmol, 60%), and the resulting mixture was stirred at 0°C for 20 min. TBDMSCl (5.85 g, 38.8 mmol) was then added to the reaction mixture, and the reaction was further stirred at 0°C for an 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 NaSO, filtered, and concentrated under reduced pressure to afford the crude product, which 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. [Intermediates]

[0183] [、]

[0184] Preparation [] [Ethyl] [( , S , )-3-(( ] [tertiary butyldiphenylsilyl] [)] [oxyl] [)-4-] [Iodobutyrate] [] [Ethyl] [( , R , )-3-(( ] [tertiary butyldiphenylsilyl] [)] [oxyl] [)-4-] [Iodobutyrate] [] [By targeting the intermediate]

[51] [The following intermediates were synthesized by a similar method as described above] [] [Intermediate number] [structure] [Starting materials] [condition] 183 TBDPSCl, Intermediate 181 Imidazole, DCM, RT 184 TBDPSCl, Intermediate 182 Imidazole, DCM, RT [Intermediates]

[52] Preparation [] [4-((] [tertiary butyl dimethyl silyl] [)] [oxyl] [)] [Butyraldehyde] []

[0249] To 4-((tert-butyldimethylsilyl)oxy)butan-1-ol ( [Intermediates] To a solution of

[51] (7.20 g, 35.2 mmol) in DCM (200 mL) 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 saturated aqueous (NaHCO 3 / Na 2 SO 3 = 1 / 1, 100 mL) for 2 min. The separated organic layer was washed with brine (100 mL x 3), dried over anhydrous Na 2 SO 4, filtered, and concentrated under reduced pressure to give a crude product, which was further purified by FCC (PE / EtOAc = 1: 0 to 12: 1) to give the title intermediate (2.95 g, 41%) as a colorless liquid. [Intermediates]

[54] [、]

[0145] [、]

[0146] [、]

[0158] Preparation [] [6-((] [tertiary butyl dimethyl silyl] [)] [oxyl] [)-2-] [Methylhexane] [-3-] [ketone] [] [2-((5-(2-(2,4-] [Dimethyl] [-6-] [Pen-side oxyhexane] [-3-] [base] [)-2,6-] [Diazaspiro] [[3.4]] [pungent] [-6-] [base] [)-1,2,4-] [Three] [-6-] [base] [)] [oxyl] [)- , N , - ] [Ethyl] [-5-] [fluorine] [- , N , - ] [Isopropylbenzamide(] [ , R , ] [, , S , ] [and] [ , S , ] [, , R , ] [a mixture of; or] [ , R , ] [, , R , ] [and] [ , S , ] [, , S , ] [Mixture of)] [] [2-((5-(2-(2,4-] [Dimethyl] [-6-] [Pen-side oxyhexane] [-3-] [base] [)-2,6-] [Diazaspiro] [[3.4]] [pungent] [-6-] [base] [)-1,2,4-] [Three] [-6-] [base] [)] [oxyl] [)- , N , - ] [Ethyl] [-5-] [fluorine] [- , N , - ] [Isopropylbenzamide(] [ , R , ] [, , R , ] [and] [ , S , ] [, , S , ] [a mixture of; or] [ , R , ] [, , S , ] [and] [ , S , ] [, , R , ] [Mixture of)] [] [( , R , )- , N , - ] [Ethyl] [-5-] [fluorine] [- , N , - ] [Isopropyl] [-2-((5-(2-(2-] [methyl] [-6-] [Heptyl Pendant Oxide] [-3-] [base] [)-2,6-] [Diazaspiro] [[3.4]] [pungent] [-6-] [base] [)-1,2,4-] [Three] [-6-] [base] [)] [oxyl] [)] [Benzamide] [] [By targeting the intermediate]

[52] [The following intermediates were synthesized by a similar method as described above] [] [Intermediate number] [structure] [Starting materials] 54 Intermediate 53 145 Compound 261 146 Compound 262 158 Compound 298 [Intermediates]

[53] Preparation [] [6-((] [tertiary butyl dimethyl silyl] [)] [oxyl] [)-2-] [Methylhexane] [-3-] [alcohol] []

[0250] Under N2 atmosphere, 4-((tert-butyldimethylsilyl)oxy)butyraldehyde ( [Intermediates] To a solution of

[52] (1.00 g, 4.94 mmol) in THF (4.9 mL) was added isopropylmagnesium bromide (4.94 mL, 14.8 mmol, 3 M in THF) dropwise, and the reaction mixture was slowly warmed to RT and stirred for 2 h. The mixture was quenched with saturated aqueous NH 4 Cl (20 mL) and extracted with EtOAc (50 mL x 3). The combined organic layers were dried over anhydrous Na 2 SO 4, 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. [Intermediates]

[16] [、] [twenty one] [、]

[39] [、]

[47] [、]

[55] [、]

[94] [、]

[98] [、]

[0161] [、]

[0163] Preparation [] [2-((5-(2-(1-(1,3-] [Dioxoisoindoline] [-2-] [base] [)-3-] [Methylbutyl] [-2-] [base] [)-2,6-] [Diazaspiro] [[3.4]] [pungent] [-6-] [base] [)-1,2,4-] [Three] [-6-] [base] [)] [oxyl] [)- , N , - ] [Ethyl] [-5-] [fluorine] [- , N , - ] [Cymene] [] [Benzyl] [2-(1-((] [ , Level 3 Ding , ] [Oxycarbonyl] [)] [Amine] [)-4-] [Methylpentyl] [-3-] [base] [)-2,6-] [Diazaspiro] [[3.4]] [Octane] [-6-] [Formate] [] [Benzyl] [(5-(6-(6-(2-(] [Ethyl] [(] [Isopropyl] [)] [Carbamoyl] [)-4-] [Fluorophenoxy] [)-1,2,4-] [Three] [-5-] [base] [)-2,6-] [Diazaspiro] [[3.4]] [pungent] [-2-] [base] [)-2,6-] [Dimethylheptyl] [-2-] [base] [)(] [methyl] [)] [Urethane] [] [methyl] [4-(6-(6-(2-(4-] [Cyclopropylpyrimidine] [-5-] [base] [)-4-] [Fluorophenoxy] [)-1,2,4-] [Three] [-5-] [base] [)-2,6-] [Diazaspiro] [[3.4]] [pungent] [-2-] [base] [)-5-] [Methyl hexanoate] [] [2-((5-(2-(6-((] [tertiary butyl dimethyl silyl] [)] [oxyl] [)-2-] [Methylhexane] [-3-] [base] [)-2,6-] [Diazaspiro] [[3.4]] [pungent] [-6-] [base] [)-1,2,4-] [Three] [-6-] [base] [)] [oxyl] [)- , N , - ] [Ethyl] [-5-] [fluorine] [- , N , - ] [Isopropylbenzamide] [] [2-((5-(2-(1-(1,3-] [Dioxolane] [-2-] [base] [)-4-] [Methylpentyl] [-3-] [base] [)-2,6-] [Diazaspiro] [[3.4]] [pungent] [-6-] [base] [)-1,2,4-] [Three] [-6-] [base] [)] [oxyl] [)- , N , - ] [Ethyl] [-5-] [fluorine] [- , N , - ] [Isopropylbenzamide] [] [2-((5-(2-(1-(1,3-] [Dioxolane] [-2-] [base] [)-4-] [Methylpentyl] [-3-] [base] [)-2,6-] [Diazaspiro] [[3.4]] [pungent] [-6-] [base] [)-1,2,4-] [Three] [-6-] [base] [)] [oxyl] [)-5-] [fluorine] [- , N , , , N , - ] [Diisopropylbenzamide] [] [ , N , ] [-] [Methoxy] [-4-((2-] [Methoxyethyl] [)(] [methyl] [)] [Amine] [)- , N , - ] [Methylbutyramide] [] [Tertiary butyl] [6-(6-((2-] [Methoxyethyl] [)(] [methyl] [)] [Amine] [)-2-] [Methylhexane] [-3-] [base] [)-2,6-] [Diazaspiro] [[3.4]] [Octane] [-2-] [Formate] [] [By targeting compounds]

[60] [and compounds]

[61] [The following intermediates were synthesized by a similar method as described above] [] [Intermediate number] [structure] [Starting materials] [condition] 16 Intermediate 3, Intermediate 15 ZnCl 2,NaBH 3CN,MeOH, 65°C twenty one Intermediate 20, Benzyl 2,6-diazaspiro [3.4] Octane-6-carboxylate AcOH,NaBH 3CN,MeOH, 45°C 39 Intermediate 3, Intermediate 38 ZnCl 2,NaBH 3CN,MeOH, 65°C 47 Intermediate 59 Intermediate 46 ZnCl 2,NaBH 3CN,MeOH, 80°C 55 Intermediate 3, Intermediate 54 ZnCl 2,NaBH 3CN,MeOH, 80°C 94 Intermediate 3, Intermediate 93 AcOH,NaBH 3CN,MeOH, 45°C 98 Intermediate 85, Intermediate 93 AcOH,NaBH 3CN,MeOH, 60°C 161 Intermediate 160, 1,1,2-Trimethoxyethane, HCl AcOH,NaBH 3CN,EtOH, RT 163 Intermediate 162, Tertiary butyl 2,6-diazaspiro [3.4] Octane-2-carboxylate NaOAc,NaBH 3CN,MeOH, 55°C [Intermediates]

[17] [and]

[18] Preparation [] [( , *R , )-2-((5-(2-(1-(1,3- ] [Dioxoisoindoline] [-2-] [base] [)-3-] [Methylbutyl] [-2-] [base] [)-2,6-] [Diazaspiro] [[3.4]] [pungent] [-6-] [base] [)-1,2,4-] [Three] [-6-] [base] [)] [oxyl] [)- , N , - ] [Ethyl] [-5-] [fluorine] [- , N , - ] [Cymene] [] [( , *S , )-2-((5-(2-(1-(1,3- ] [Dioxoisoindoline] [-2-] [base] [)-3-] [Methylbutyl] [-2-] [base] [)-2,6-] [Diazaspiro] [[3.4]] [pungent] [-6-] [base] [)-1,2,4-] [Three] [-6-] [base] [)] [oxyl] [)- , N , - ] [Ethyl] [-5-] [fluorine] [- , N , - ] [Cymene] []

[0251] 2-((5-(2-(1-(1,3-dioxoisoindolin-2-yl)-3-methylbutan-2-yl)-2,6-diazaspiro[3.4]octan-6-yl)-1,2,4-trioxan-6-yl)oxy)-N-ethyl-5-fluoro-N-isopropylbenzamide ( [Intermediates]

[16] ) (200 mg, 0.254 mmol) was purified by SFC on a DAICEL CHIRALCEL OD column (column: 250 x 50 mm 10 µm; mobile phase: A: supercritical CO 2 , B: IPA (0.1% amine), A : B = 65 : 35, 70 mL / min; column temperature: 38°C; nozzle pressure: 100 bar; nozzle temperature: 60°C; evaporator temperature: 20°C; trimmer temperature: 25°C; wavelength: 220 nm) to give the title intermediate as a colorless oil. [Intermediates]

[17] (100 mg, 95% purity, 42% yield) and [Intermediates]

[18] (100 mg, 99% purity, 44% yield). [Intermediates]

[40] [and]

[41] Preparation [] [Benzyl] [( , *R , )-(5-(6-(6-(2-( ] [Ethyl] [(] [Isopropyl] [)] [Carbamoyl] [)-4-] [Fluorophenoxy] [)-1,2,4-] [Three] [-5-] [base] [)-2,6-] [Diazaspiro] [[3.4]] [pungent] [-2-] [base] [)-2,6-] [Dimethylheptyl] [-2-] [base] [)(] [methyl] [)] [Urethane] [] [Benzyl] [( , *S , )-(5-(6-(6-(2-( ] [Ethyl] [(] [Isopropyl] [)] [Carbamoyl] [)-4-] [Fluorophenoxy] [)-1,2,4-] [Three] [-5-] [base] [)-2,6-] [Diazaspiro] [[3.4]] [pungent] [-2-] [base] [)-2,6-] [Dimethylheptyl] [-2-] [base] [)(] [methyl] [)] [Urethane] [] []

[0252] Benzyl (5-(6-(6-(2-(ethyl(isopropyl)carbamoyl)-4-fluorophenoxy)-1,2,4-trioxan-5-yl)-2,6-diazaspiro[3.4]octan-2-yl)-2,6-dimethylhept-2-yl)(methyl)carbamate ( [Intermediates]

[39] ) (650 mg, 0.923 mmol) was separated by SFC on a CHIRALPAK AD-H column (column: 250 x 30 mm 5 µm; eluent: 30% (v / v) supercritical CO 2 in EtOH (0.1% amine), flow rate: 60 mL / min) to afford the title intermediate as a colorless oil. [Intermediates]

[40] (250 mg, 96% purity, 37% yield) and [Intermediates]

[41] (220 mg, 99.9% purity, 34% yield). [] [Intermediates]

[48] [and]

[49] Preparation [] [methyl] [( , *R , )-4-(6-(6-(2-(4- ] [Cyclopropylpyrimidine] [-5-] [base] [)-4-] [Fluorophenoxy] [)-1,2,4-] [Three] [-5-] [base] [)-2,6-] [Diazaspiro] [[3.4]] [pungent] [-2-] [base] [)-5-] [Methyl hexanoate] [] [methyl] [( , *S , )-4-(6-(6-(2-(4- ] [Cyclopropylpyrimidine] [-5-] [base] [)-4-] [Fluorophenoxy] [)-1,2,4-] [Three] [-5-] [base] [)-2,6-] [Diazaspiro] [[3.4]] [pungent] [-2-] [base] [)-5-] [Methyl hexanoate] [] []

[0253] Methyl 4-(6-(6-(2-(4-cyclopropylpyrimidin-5-yl)-4-fluorophenoxy)-1,2,4-triazol-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: 250x30 mm, 10 μm; eluent: 35% (v / v) supercritical CO2 in MeOH with 0.1% amine) to afford the title intermediate as a white solid. [Intermediate]

[48] (110 mg, 35% yield) and [Intermediate]

[49] (90 mg, 31% yield). [Intermediate]

[93] Preparation [] [1-(1,3-] [Dioxolane] [-2-] [base] [)-4-] [Methylpentyl] [-3-] [ketone] [] []

[0254] To a 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 hour. This mixture was then slowly added to a solution of N-methoxy-N-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 hours. The mixture was quenched with saturated aqueous NH4Cl (300 mL) and extracted with MTBE (200 mL x 3). The combined organic layers were dried over Na 2 SO 4 , filtered and concentrated under reduced pressure to give the crude product, which was purified by FCC (PE:EtOAc=1:0 to 20:1) to afford the title intermediate (13 g, crude) as a colorless oil, which was used directly in the next step without further purification. [Intermediates]

[95] [and]

[96] Preparation [] [( , R , )-2-((5-(2-(1-(1,3- ] [Dioxolane] [-2-] [base] [)-4-] [Methylpentyl] [-3-] [base] [)-2,6-] [Diazaspiro] [[3.4]] [pungent] [-6-] [base] [)-1,2,4-] [Three] [-6-] [base] [)] [oxyl] [)- , N , - ] [Ethyl] [-5-] [fluorine] [- , N , - ] [Cymene] [] [( , S , )-2-((5-(2-(1-(1,3- ] [Dioxolane] [-2-] [base] [)-4-] [Methylpentyl] [-3-] [base] [)-2,6-] [Diazaspiro] [[3.4]] [pungent] [-6-] [base] [)-1,2,4-] [Three] [-6-] [base] [)] [oxyl] [)- , N , - ] [Ethyl] [-5-] [fluorine] [- , N , - ] [Cymene] []

[0255] 2-((5-(2-(1-(1,3-dioxolan-2-yl)-4-methylpentan-3-yl)-2,6-diazaspiro[3.4]octan-6-yl)-1,2,4-trioxan-6-yl)oxy)-N-ethyl-5-fluoro-N-isopropylbenzamide ( [Intermediates]

[94] ) (4.00 g, 7.01 mmol) was separated by SFC on a Chiralcel OD column (column: 250 x 50 mm 10 μm; mobile phase: A: supercritical CO 2 , B: MeOH (0.1% amine), A: B = 75:25, 200 mL / min; column temperature: 38°C; nozzle pressure: 100 bar; nozzle temperature: 60°C; evaporator temperature: 20°C; trimmer temperature: 25°C; wavelength: 220 nm) to give the title intermediate as a white solid. [Intermediates]

[95] (1.72 g, 98.76% purity, 42.5% yield) and [Intermediates]

[96] (1.57 g, 98.09% purity, 38.5% yield). [Intermediates]

[99] [and]

[0100] Preparation [] [( , *R , )-2-((5-(2-(1-(1,3- ] [Dioxolane] [-2-] [base] [)-4-] [Methylpentyl] [-3-] [base] [)-2,6-] [Diazaspiro] [[3.4]] [pungent] [-6-] [base] [)-1,2,4-] [Three] [-6-] [base] [)] [oxyl] [)-5-] [fluorine] [- , N , , , N , - ] [Diisopropylbenzamide] [] [( , *S , )-2-((5-(2-(1-(1,3- ] [Dioxolane] [-2-] [base] [)-4-] [Methylpentyl] [-3-] [base] [)-2,6-] [Diazaspiro] [[3.4]] [pungent] [-6-] [base] [)-1,2,4-] [Three] [-6-] [base] [)] [oxyl] [)-5-] [fluorine] [- , N , , , N , - ] [Diisopropylbenzamide] []

[0256] 2-((5-(2-(1-(1,3-dioxolan-2-yl)-4-methylpentan-3-yl)-2,6-diazaspiro[3.4]octan-6-yl)-1,2,4-trioxan-6-yl)oxy)-5-fluoro-N, N-diisopropylbenzamide ( [Intermediates]

[98] ) (6.5 g) was separated by SFC on a Chiralpak IG (column: 250 x 50 mm 10 μm; mobile phase: A: supercritical CO 2, B: MeOH (0.1% amine), A: B = 65:35, 200 mL / min; column temperature: 38; nozzle pressure: 100 bar; nozzle temperature: 60°C; evaporator temperature: 20°C; trimmer temperature: 25°C; wavelength: 220 nm) to obtain the title intermediate. [Intermediates]

[99] (2.7 g) and [Intermediates]

[0100] (2.8 g). [Intermediates]

[97] Preparation [] [( , R , )- , N , - ] [Ethyl] [-5-] [fluorine] [- , N , - ] [Isopropyl] [-2-((5-(2-(2-] [methyl] [-6-] [Pen-side oxyhexane] [-3-] [base] [)-2,6-] [Diazaspiro] [[3.4]] [pungent] [-6-] [base] [)-1,2,4-] [Three] [-6-] [base] [)] [oxyl] [)] [Benzamide] []

[0257] (R)-2-((5-(2-(1-(1,3-dioxolan-2-yl)-4-methylpentan-3-yl)-2,6-diazaspiro[3.4]octan-6-yl)-1,2,4-trioxan-6-yl)oxy)-N-ethyl-5-fluoro-N-isopropylbenzamide ( [Intermediates] To a solution of

[95] ) (1.00 g, 1.75 mmol) in ACN (10 mL) was added 1 M HCl (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 DCM (50 mL) and basified to pH = 14 with 10% aqueous NaOH. The mixture was further extracted with DCM (30 mL x 3) and the combined organic layers were dried over anhydrous Na 2 SO 4, filtered and concentrated in vacuo to give the title intermediate as a white solid (900 mg, 87% purity, 85% yield), which was used directly in the next step without further purification. [Intermediates]

[0101] [、]

[0102] [、]

[0103] Preparation [] [( , *R , )-5- ] [fluorine] [- , N , , , N , - ] [Diisopropyl] [-2-((5-(2-(2-] [methyl] [-6-] [Pen-side oxyhexane] [-3-] [base] [)-2,6-] [Diazaspiro] [[3.4]] [pungent] [-6-] [base] [)-1,2,4-] [Three] [-6-] [base] [)] [oxyl] [)] [Benzamide] [] [( , *S , )-5- ] [fluorine] [- , N , , , N , - ] [Diisopropyl] [-2-((5-(2-(2-] [methyl] [-6-] [Pen-side oxyhexane] [-3-] [base] [)-2,6-] [Diazaspiro] [[3.4]] [pungent] [-6-] [base] [)-1,2,4-] [Three] [-6-] [base] [)] [oxyl] [)] [Benzamide] [] [ , N , ] [-] [Ethyl] [-5-] [fluorine] [- , N , - ] [Isopropyl] [-2-((5-(2-(2-] [methyl] [-6-] [Pen-side oxyhexane] [-3-] [base] [)-2,6-] [Diazaspiro] [[3.4]] [pungent] [-6-] [base] [)-1,2,4-] [Three] [-6-] [base] [)] [oxyl] [)] [Benzamide] [] [By targeting intermediaries]

[97] [The following intermediates were synthesized by similar methods as described above] [] [Intermediate Body Number] [Structure] [Starting materials] 101 Intermediate 99 102 Intermediate 100 103 Intermediate 94 [Intermediate]

[0114] Preparation [] [methyl] [2-(2-] [Isopropyl] [-1,3-] [Dioxolane] [-2-] [base] [)] [Acetate] []

[0258] 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), p-toluenesulfonic acid hydrate (597 mg, 3.47 mmol), and toluene (500 mL). The mixture was stirred at 135°C for 18 h. After cooling to room temperature, a 1M aqueous solution of Na2CO3 (300 mL) was added to the reaction mixture. The organic layer was separated and washed with H2O (100 mL), dried over anhydrous Na2SO4, filtered, and concentrated in vacuo to afford the title intermediate (41 g, crude product) as a yellow oil, which was used directly in the next step without further purification. [Intermediates]

[0115] Preparation [] [2-(2-] [Isopropyl] [-1,3-] [Dioxolane] [-2-] [base] [)] [Second] [-1-] [alcohol] []

[0259] Under N2 atmosphere, LiAlH4 (2.5 g, 66 mmol) was added portionwise to THF (250 mL) cooled at 0 °C. At 0 °C, under N2 atmosphere, methyl 2-(2-isopropyl-1,3-dioxolan-2-yl)acetate ( [Intermediates]

[0114] (10 g, crude) in THF (20 mL) was added dropwise to the above mixture. Under an N atmosphere, the resulting mixture was slowly warmed to room temperature and stirred at this temperature for 18 h. 2.5 mL of H 2 O was then slowly added to the above mixture, followed by an aqueous NaOH solution (15%, 7.5 mL). The resulting mixture was stirred at room temperature for 0.5 h. Anhydrous MgSO 4 was then added to the above mixture. The suspension was filtered through a pad of celite and washed with THF (200 mL). The filtrate was concentrated in vacuo to give the title intermediate (6.8 g, crude) as a yellow oil, which was used directly in the next step without further purification. [Intermediates]

[0116] Preparation [] [1-] [Hydroxy] [-4-] [Methylpentyl] [-3-] [ketone] []

[0260] Oxalic acid (4.2 mL, 10% in water, 4.7 mmol) was added to a mixture of silica gel (27 g, 449 mmol) in DCM (230 mL). Once the aqueous layer disappeared, 2-(2-isopropyl-1,3-dioxolan-2-yl)ethan-1-ol ( [Intermediates]

[0115] (3.7 g, crude) in DCM (7 mL) and the reaction mixture was stirred at RT for 5 h. NaHCO 3 (800 mg) was then added. The resulting mixture was filtered and washed with DCM (50 mL x 3). The filtrate was concentrated in vacuo to give the title intermediate (2.4 g, crude) as a colorless oil, which was used directly in the next step without further purification. [Intermediates]

[0124] Preparation [] [( , *R , )-3-(6-(6-(2-( ] [Ethyl] [(] [Isopropyl] [)] [Carbamoyl] [)-4-] [Fluorophenoxy] [)-1,2,4-] [Three] [-5-] [base] [)-2,6-] [Diazaspiro] [[3.4]] [pungent] [-2-] [base] [)-4-] [Methylpentyl] [] [Methanesulfonate] []

[0261] Under N2 atmosphere, MsCl (250 mg, 2.18 mmol) was added dropwise to N-ethyl-5-fluoro-2-((5-(2-(1-hydroxy-4-methylpentan-3-yl)-2,6-diazaspiro[3.4]octan-6-yl)-1,2,4-trioxan-6-yl)oxy)-N-isopropylbenzamide ( [Compound]

[0213] To a solution of 4-[ ... [Intermediates]

[0130] [、]

[0139] Preparation [] [methyl] [3-] [methyl] [-4-(] [Tosyloxy] [)] [Butyrate] [] [2-] [Methoxypropyl] [4-] [Methylbenzenesulfonate] [] [By targeting the intermediate]

[0124] [The following intermediates were synthesized by a similar method as described above] [] [Intermediate number] [structure] [Starting materials] [condition] 130 Intermediate 129, TsCl DMAP,TEA,DCM,RT 139 2-Methoxypropan-1-ol, TsCl DMAP,TEA,DCM,RT [Intermediates]

[0125] Preparation [] [ , N , ] [-] [Benzyl] [-2-] [Methoxy] [- ,N , - ] [Methylacetamide] []

[0262] To a solution of N-methyl-1-phenylmethanamine (5.5 g, 45.4 mmol) and TEA (14 g, 138.4 mmol) in DCM (60 mL) cooled at 0°C was added 2-methoxyacetyl chloride (5 g, 46.073 mmol) dropwise. The resulting mixture was slowly warmed to 25°C and stirred at this temperature for 1 h. An aqueous saturated NaHCO solution (50 mL) was then added to the mixture and extracted with DCM (50 mL x 3). The combined organic layers were washed with brine (100 mL), dried over NaSO, filtered, and concentrated in vacuo to give a crude residue, which was purified by FCC (EA:PE = 0-80%) to afford the title intermediate (3.4 g, 34% yield) as a colorless oil. [Intermediates]

[0126] Preparation [] [ , N , ] [-] [Benzyl] [-2-] [Methoxy] [- , N , - ] [Methyl Ethyl] [-1-] [amine] [-1,1- , d , , 2, ]

[0263] To a mixture of LiAlD 4 (1.5 g, 35.732 mmol) in THF (25 mL) cooled at 0° C. was added N-benzyl-2-methoxy-N-methylacetamide ( [Intermediates]

[0125] (3.4 g, 17.6 mmol) in THF (25 mL). The reaction mixture was stirred at 25 ° C for 1 h and at 50 ° C for another 2 h. The reaction mixture was then cooled to 0 ° C and quenched dropwise with aqueous NaOH (1 M, 10 mL). The resulting mixture was filtered and the filter cake was washed with EtOAc (100 mL). The filtrate was washed with H 2 O (50 mL) and brine (50 mL), dried over Na 2 SO 4, and filtered. The solvent was concentrated under reduced pressure to give a residue, which was purified by FCC (EtOAc: PE = from 0 to 100%) to give the title intermediate (2.0 g, 60% yield) as a colorless oil. [Intermediates]

[0127] Preparation [] [2-] [Methoxy] [- , N , - ] [Methyl Ethyl] [-1,1- , d , , twenty one- ] [amine] [,] [Hydrochloride] []

[0264] To a solution of N-benzyl-2-methoxy-N-methylethan-1-amine-1,1-d2 (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 at 50° C. under a H2 atmosphere (50 psi) for 18 h. After cooling to RT, the reaction mixture was filtered through celite, and the filtrate was concentrated in vacuo to give the title intermediate as a yellow oil (600 mg, crude), which was used directly in the next step without further purification. [Intermediates]

[0128] Preparation [] [methyl] [4-] [Hydroxy] [-3-] [Methylbutyl] [-2-] [Alkenyl esters] []

[0265] 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. 1-Hydroxypropan-2-one (7.2 g, 97 mmol) in THF (30 mL) was then added to the mixture, and the reaction mixture was stirred at 50°C for an additional 16 h. After cooling to room temperature, 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 in vacuo to give the crude compound, which was purified by FCC (PE:EtOAc = 1:0 to 1:1) to afford the title intermediate (3.4 g, 27% yield) as a pale yellow oil. [Intermediates]

[0129] Preparation [] [methyl] [4-] [Hydroxy] [-3-] [Methylbutyrate] []

[0266] To methyl 4-hydroxy-3-methylbut-2-enoate ( [Intermediates] To a solution of

[0128] (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 an atmosphere of H 2 (15 psi) for 4 h. The reaction mixture was then filtered through a pad of celite and washed with MeOH (200 mL). The filtrate was concentrated in vacuo to give the title intermediate (2.3 g, 67% yield) as a yellow oil, which was used directly in the next step without further purification. [Intermediates]

[0193] [、]

[0194] [、]

[0207] [、]

[0208] Preparation [] [( , S , )-5-(( ] [tertiary butyldiphenylsilyl] [)] [oxyl] [)-6-(] [Ethyl] [(] [methyl] [)] [Amine] [)-2-] [Methylhexane] [-3-] [ketone] [] [( , R , )-5-(( ] [tertiary butyldiphenylsilyl] [)] [oxyl] [)-6-(] [Ethyl] [(] [methyl] [)] [Amine] [)-2-] [Methylhexane] [-3-] [ketone] [] [( , S , )-5-(( ] [tertiary butyldiphenylsilyl] [)] [oxyl] [)-6-((2-] [Methoxyethyl] [)(] [methyl] [)] [Amine] [)-2-] [Methylhexane] [-3-] [ketone] [] [( , R , )-5-(( ] [tertiary butyldiphenylsilyl] [)] [oxyl] [)-6-((2-] [Methoxyethyl] [)(] [methyl] [)] [Amine] [)-2-] [Methylhexane] [-3-] [ketone] [] [By targeting the intermediate]

[0129] [The following intermediates were synthesized by similar methods as described above] [] [Intermediate number] [structure] [Starting materials] 193 Intermediate 191 194 Intermediate 192 207 Intermediate 205 208 Intermediate 206 [Intermediates]

[0131] [and]

[0132] Preparation [] [methyl] [( , *R , )-3- ] [methyl] [-4-(] [Tosyloxy] [)] [Butyrate] [] [methyl] [( , *S , )-3- ] [methyl] [-4-(] [Tosyloxy] [)] [Butyrate] []

[0267] Methyl 3-methyl-4-(toluenesulfonyloxy)butyrate ( [Intermediates]

[0130] ) (3.3 g) was purified by SFC on a CHIRALPAK AY-H (column: 250 x 30 mm, 5 μm; mobile phase: A: supercritical CO 2 , B: EtOH (0.1% amine), A: B = 90:10, 60 mL / min) to obtain the title intermediate ( [Intermediates]

[0131] ) (1.28 g, 97% purity, 36% yield) and ( [Intermediates]

[0132] ) (1.27 g, 85% purity, 33% yield). [Intermediates]

[0134] Preparation [] [methyl] [( , *S , )-4-((2- ] [Methoxyethyl] [)(] [methyl] [)] [Amine] [)-3-] [Methylbutyrate] [] []

[0268] Methyl (* S)-3-methyl-4-(tosyloxy)butyrate ( [Intermediates] A mixture of 4-[4-[4-[4-[4-(4-[4-b]-[4-oxo-2-yl]-1-piperidin-1-yl]-1-nitropropane ... [Intermediates]

[0133] [、]

[0185] [、]

[0186] [、]

[0199] [、]

[0200] [、]

[0219] Preparation [] [methyl] [( , *R , )-4-((2- ] [Methoxyethyl] [)(] [methyl] [)] [Amine] [)-3-] [Methylbutyrate] [] [Ethyl] [( , S , )-3-(( ] [tertiary butyldiphenylsilyl] [)] [oxyl] [)-4-(] [Ethyl] [(] [methyl] [)] [Amine] [)] [Butyrate] [] [Ethyl] [( , R , )-3-(( ] [tertiary butyldiphenylsilyl] [)] [oxyl] [)-4-(] [Ethyl] [(] [methyl] [)] [Amine] [)] [Butyrate] [] [Ethyl] [( , S , )-3-(( ] [tertiary butyldiphenylsilyl] [)] [oxyl] [)-4-((2-] [Methoxyethyl] [)(] [methyl] [)] [Amine] [)] [Butyrate] [] [Ethyl] [( , R , )-3-(( ] [tertiary butyldiphenylsilyl] [)] [oxyl] [)-4-((2-] [Methoxyethyl] [)(] [methyl] [)] [Amine] [)] [Butyrate] [] [ , N , ] [-(2-] [Methoxyethyl] [)- , N , ,2- ] [Dimethylpropane] [-2-] [ene] [-1-] [amine] [] [By targeting the intermediate]

[0134] [The following intermediates were synthesized by similar methods as described above] [] [Intermediate number] [structure] [Starting materials] [condition] 133 Intermediate 131, 2-Methoxy-N-methylethan-1-amine K 2CO 3,ACN,90°C 185 Intermediate 183, N-Methylethylamine K 2CO 3,ACN,80°C 186 Intermediate 184, N-Methylethylamine K 2CO 3,ACN,80°C 199 Intermediate 183, 2-Methoxy-N-methylethan-1-amine K 2CO 3,ACN,85°C 200 Intermediate 184, 2-Methoxy-N-methylethan-1-amine K 2CO 3,ACN,85°C 219 3-Bromo-2-methylprop-1-ene, 2-Methoxy-N-methylethan-1-amine K 2CO 3, H 2O,RT [Intermediates]

[0136] Preparation [] [( , *S , )-6-((2- ] [Methoxyethyl] [)(] [methyl] [)] [Amine] [)-2,5-] [Dimethylhexane] [-3-] [ketone] []

[0269] Under N2, methyl (*S)-4-((2-methoxyethyl)(methyl)amino)-3-methylbutanoate ( [Intermediates] To a solution of

[0134] (670 mg, crude) in THF (5 mL) was added isopropylmagnesium chloride (4.94 mL, 9.88 mmol, 2 M in THF) dropwise. The resulting mixture was stirred at 50° C. under N 2 for 5 h. After cooling to RT, the reaction mixture was quenched with saturated aqueous NH 4 Cl solution (1.5 mL) and filtered. The filtrate was concentrated in vacuo to give the title intermediate (507.1 mg, crude) as a yellow oil, which was used directly in the next step without further purification. [Intermediates]

[0135] Preparation [] [( , *R , )-6-((2- ] [Methoxyethyl] [)(] [methyl] [)] [Amine] [)-2,5-] [Dimethylhexane] [-3-] [ketone] [] [By targeting the intermediate]

[0136] [The following intermediates were synthesized by similar methods as described above] [] [Intermediate number] [structure] [Starting materials] [condition] 135 Intermediate 133, Isopropylmagnesium chloride THF, 50°C [Intermediates]

[0165] Preparation [] [Tertiary butyl] [(2-] [Hydroxy] [-5-] [methyl] [-4-] [Pendant oxyhexyl] [)(] [methyl] [)] [Urethane] []

[0270] To a solution of 3-methylbutan-2-one (6.0 g, 70.0 mmol) in THF (150 mL) cooled at -40°C under an N atmosphere was added LDA (40 mL, 2 M in THF, 80.0 mmol) dropwise. The resulting mixture was stirred at -40°C for 1 h. A solution of tert-butylmethyl(2-oxoethyl)carbamate (8.0 g, 46.2 mmol) in THF (50 mL) was then added dropwise to the above mixture, and the reaction was stirred at -40°C for 2 h. The reaction was quenched at -40°C by the dropwise addition of H₂O (20 mL). The mixture was then warmed to room temperature and concentrated under reduced pressure. The crude residue was diluted with H₂O (200 mL) and extracted with EtOAc (200 mL × 2). The combined organic layers were washed with brine (200 mL), dried over anhydrous Na 2 SO 4 , filtered and concentrated. The crude product was purified by FCC (PE / EtOAc = 20 / 1 to 3 / 1) to give the title intermediate (8.8 g, 85% purity, 62% yield) as a colorless oil. [By targeting the intermediate]

[0165] [The following intermediates were synthesized by similar methods as described above] [] [Intermediate number] [structure] [Starting materials] 174 3-Methylbutan-2-one, Tertiary butylethyl (2-oxoethyl) Urethane [Intermediates]

[0166] Preparation [] [Tertiary butyl] [(2-] [Methoxy] [-5-] [methyl] [-4-] [Pendant oxyhexyl] [)(] [methyl] [)] [Urethane] []

[0271] Under N2 atmosphere, tertiary butyl (2-hydroxy-5-methyl-4-oxohexyl) (methyl) carbamate ( [Intermediates] To a solution of 4-nitro-1-oxo-1-nitro-2-nitro-1-oxo-1-nitro-2-nitro-1-oxo-1-nitro-2-nitro-3 ... [Intermediates]

[0181] Preparation [] [Ethyl] [( , S , )-3- ] [Hydroxy] [-4-] [Iodobutyrate] [] []

[0272] To a solution of (S)-4-hydroxydihydrofuran-2(3H)-one (5 g, 50.0 mmol) in EtOH (8.6 mL) in DCM (20 mL) was slowly added TMSI (14.8 g, 74.0 mmol) under N₂ atmosphere. The resulting mixture was stirred at room temperature for 16 h. A saturated solution of Na₂SO₃ (40 mL) was added. The organic layer was separated and concentrated in vacuo to afford the title intermediate (8.8 g, crude) as a yellow oil, which was used directly in the next step without further purification. [Intermediates]

[0182] Preparation [] [Ethyl] [( , R , )-3- ] [Hydroxy] [-4-] [Iodobutyrate] [] [By targeting the intermediate]

[0181] [The following intermediates were synthesized by a similar method as described above] [] [Intermediate number] [structure] [Starting materials] 182 ( R )-4-Hydroxydihydrofuran-2(3 H)-one [Intermediates]

[0195] Preparation [] [( , S , )-6-( ] [Ethyl] [(] [methyl] [)] [Amine] [)-5-] [Hydroxy] [-2-] [Methylhexane] [-3-] [ketone] []

[0273] Under N2 atmosphere, (S)-5-((tertiary butyldiphenylsilyl)oxy)-6-(ethyl(methyl)amino)-2-methylhexan-3-one ( [Intermediates]

[0193] (2.33 g, 5.04 mmol) in THF (3 mL) was added TBAF (0.65 mL, 1.0 M in THF, 0.65 mmol). The resulting mixture was stirred at RT for 16 h. The reaction mixture was concentrated under reduced pressure and the crude residue was diluted with H 2 O (25 mL) and extracted with DCM (60 mL × 3). The combined organic layers were washed with brine (40 mL × 2), dried over Na 2 SO 4 and filtered. The filtrate was concentrated in vacuo to give the title intermediate (2.2 g, crude) as a yellow oil, which was used directly in the next step without further purification. [Intermediates]

[0196] [、]

[0209] [、]

[0210] Preparation [] [( ,R , )-6-( ] [Ethyl] [(] [methyl] [)] [Amine] [)-5-] [Hydroxy] [-2-] [Methylhexane] [-3-] [ketone] [] [( , S , )-5- ] [Hydroxy] [-6-((2-] [Methoxyethyl] [)(] [methyl] [)] [Amine] [)-2-] [Methylhexane] [-3-] [ketone] [] [( , R , )-5- ] [Hydroxy] [-6-((2-] [Methoxyethyl] [)(] [methyl] [)] [Amine] [)-2-] [Methylhexane] [-3-] [ketone] [] [By targeting the intermediate]

[0195] [The following intermediates were synthesized by a similar method as described above] [] [Intermediate number] [structure] [Starting materials] 196 Intermediate 194 209 Intermediate 207 210 Intermediate 208 [Intermediates]

[0220] Preparation [] [ , N , ] [-((3-] [Isopropyl] [-5-] [methyl] [-4,5-] [Dihydroisoxazole] [-5-] [base] [)] [methyl] [)-2-] [Methoxy] [- , N , - ] [Methyl Ethyl] [-1-] [amine] []

[0274] To N-(2-methoxyethyl)-N,2-dimethylprop-2-en-1-amine ( [Intermediates] To a solution of

[0219] (2.90 g, 20.2 mmol) in DMF (50 mL) was added NaHCO 3 (6.82 g, 81.2 mmol) and (Z)-N-hydroxyisobutyrimidinyl chloride (2.47 g, 20.3 mmol). The reaction mixture was stirred at 0° C. for 30 min and then at room temperature for 16 h. The reaction mixture was quenched with H 2 O (50 mL) and extracted with EtOAc (30 mL×2). The combined organic layers were washed with saturated aqueous LiCl solution (50 mL), dried over anhydrous Na 2 SO 4 and filtered. The filtrate was concentrated in vacuo to give the crude product, which was purified by FCC (MeOH:DCM = 1:10) to give the title intermediate (1.20 g, 89.9% purity, 25.9% yield) as a brown oil. [Intermediates]

[0221] Preparation [] [5-] [Hydroxy] [-6-((2-] [Methoxyethyl] [)(] [methyl] [)] [Amine] [)-2,5-] [Dimethylhexane] [-3-] [ketone] []

[0275] To N-((3-isopropyl-5-methyl-4,5-dihydroisoxazol-5-yl)methyl)-2-methoxy-N-methylethan-1-amine ( [Intermediates] To a solution of 4-[4-[4-[4-[4-(4-oxo-1-yl)-1-oxo ...

[0276] The reaction mixture was filtered through a pad of celite and the filtrate was extracted with DCM. The combined organic layers were washed with NaHCO (20 mL × 2) and brine (20 mL × 2), dried over NaSO, and filtered. The filtrate was concentrated in vacuo to give the title intermediate (1.10 g, crude) as a brown oil, which was used directly in the next step without further purification. [Intermediates]

[0227] Preparation [] [Tertiary butyl] [( , R , )-(1-(2,2- ] [Dimethyl] [-4,6-] [Two-side oxygen groups] [-1,3-] [Dioxane] [-5-] [base] [)-3-] [Methylbutyl] [-2-] [base] [)] [Urethane] []

[0277] A pre-cooled solution of Boc-L-valine (44.9 kg), 2,2-dimethyl-1,3-dioxane-4,6-dione (32.9 kg), and DMAP (35.5 kg) in DCM (607 kg) was added over 3 hours to a solution of DCC (55.5 kg) in DCM (613 kg) and aged at -10°C to 0°C for 16 hours. A 10% aqueous citric acid solution (449 kg) was added while maintaining the temperature below 10°C. The resulting slurry was aged at 0°C to 10°C for 2 hours and then filtered. The filter cake was washed with DCM (91 kg). The filtrate was separated and the organic layer was washed with 10% aqueous citric acid (two 450 kg solutions) and 10% aqueous NaCl (449 kg). Acetic acid (75.0 kg) was added to the organic phase (1200 kg) while maintaining the temperature between -10°C and 0°C. Sodium borohydride (18.0 kg) was added portionwise over 5 hours while maintaining the temperature between -10°C and 0°C, and the resulting mixture was then aged at -10°C to 0°C for an additional 16 hours. The mixture was warmed to 15°C to 25°C and aged for 2 hours. The mixture was then washed with a 14% aqueous NaCl solution (450 kg), followed by a second wash with a 14% aqueous NaCl solution (432 kg), and finally washed with water (444 kg). The organic phase was concentrated under reduced pressure to 2-4 volumes. Isopropyl alcohol (143 kg) was added to the residue and concentrated under reduced pressure to 4-5 volumes. 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 give the title intermediate as a white solid (46.7 kg, 69% yield). [Intermediates]

[0228] Preparation [] [Tertiary butyl] [( , R , )-2- ] [Isopropyl] [-5-] [Pen-oxide pyrrolidine] [-1-] [Formate] [] []

[0278] Tertiary butyl (R)-(1-(2,2-dimethyl-4,6-dioxol-1,3-dioxane-5-yl)-3-methylbutan-2-yl)carbamate ( [Intermediates]

[0227] (46.7 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 combined filtrate was concentrated to dryness under reduced pressure to obtain the desired compound (31.05 kg, 96% yield) as an oil, which was used directly without further purification. [Intermediates]

[0229] Preparation [] [Tertiary butyl] [(5 , R , )-2- ] [Hydroxy] [-5-] [Isopropylpyrrolidine] [-1-] [Formate] []

[0279] Tertiary butyl (R)-2-isopropyl-5-oxopyrrolidine-1-carboxylate ( [Intermediates]

[0228] ) (30.9 kg) was cooled to -5 ° C to 5 ° C. A solution of LiBH 4 in 2-MeTHF (1 M, 45.2 kg, 54.4 mol) was added over 3 h and the mixture was aged for 4 h. A cooled aqueous solution of 5% NaHCO 3 (163 kg) was added at -5 ° C to 5 ° C over 3 h and aged for another 2 h. The mixture was warmed to ambient temperature and aged for another 2 h. The aqueous layer was separated and the organic layer was washed with 10% NaCl aqueous solution (170 kg) and water (155 kg). During the water wash, an emulsion formed and solid NaCl (3.1 kg) was added to effect separation. After removing the aqueous layer, the organic layer was concentrated to dryness under reduced pressure to obtain the desired compound (28.5 kg, 91% yield) as an oil, which was used directly without further purification. [Intermediates]

[0230] Preparation [] [Tertiary butyl] [( , R , )-(6-((2- ] [Methoxyethyl] [)(] [methyl] [)] [Amine] [)-2-] [Methylhexane] [-3-] [base] [)] [Urethane] []

[0280] Tert-butyl (5R)-2-hydroxy-5-isopropylpyrrolidine-1-carboxylate ( [Intermediates]

[0229] (28.55 kg) was treated with 2-methoxy-N-methylethan-1-amine (12.3 kg, 138.0 mol) and the resulting mixture was aged for 1 h. Sodium triacetoxyborohydride (40.12 kg) was added portionwise over 5 h while maintaining the temperature between 15°C and 25°C, and the resulting mixture was aged for 48 h. The reaction mixture was quenched by adding 8% aqueous NaOH (184 kg) over 2 h while maintaining the temperature between 15°C and 25°C, and the resulting mixture was aged for an additional 2 h. The aqueous layer was separated, and the organic layer was washed with water (169 kg). The organic layer was then concentrated to dryness under reduced pressure to give the title intermediate (33.26 kg, 88% yield) as an oil, which was used directly without further purification. [Intermediates]

[0231] Preparation [] [( , R , )- , N , , 1 , -(2- ] [Methoxyethyl] [)- , N , , 1 , ,5- ] [Dimethylhexane] [-1,4-] [Diamine, dihydrochloride] []

[0281] To a 4 molar solution of HCl in isopropanol (84.80 kg) was added tert-butyl (R)-(6-((2-methoxyethyl)(methyl)amino)-2-methylhexan-3-yl)carbamate ( [Intermediates]

[0230] (32.38 kg) in isopropanol (25.6 kg) was added and the mixture was aged at 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 give the title compound as a white solid (23.92 kg, 81% yield). [] [Intermediates]

[0232] Preparation [] [Ethyl] [1-] [Benzyl] [-3-(] [Chloromethyl] [)] [Pyrrolidine] [-3-] [Formate] []

[0282] To a solution of DIPEA (952 g, 1.1 equiv) in THF (6 L) cooled to -35°C to 25°C was added n-BuLi (2.33 kg, 2.5 M in hexanes, 1.0 equiv) while maintaining the temperature below -25°C. The resulting mixture was aged at -35°C to -25°C for an additional 30 min and then cooled to between -78°C and -60°C. A solution of ethyl 1-benzylpyrrolidine-3-carboxylate (2 kg, 1.0 equiv) in THF (2 L) was added at -78°C to -60°C and stirred for an additional 30 min. Chloroiodomethane (1.81 kg, 1.2 equiv) was then added at -78°C to -60°C. The reaction mixture was aged at -60°C to -40°C for 2 h. To the reaction mixture, aqueous citric acid (660 g in 6 L of H 2 O) was added at a temperature between 0°C and 10°C, and the resulting mixture was aged for an additional 20 min at 20°C to 30°C. After separation of the layers, the aqueous layer was extracted with EtOAc (6 L), and the combined organic layers were washed with brine (6 L) and then warmed to 50°C to 60°C. Oxalic acid (2.22 kg) was added at 50°C to 60°C. The resulting mixture was stirred at 50°C to 60°C for 3 h, then cooled to 20°C 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), H 2 O (8 L), and K 3 PO 4 (1.5 equivalents), and the resulting mixture was aged for 20 min at 20°C to 30°C. After separation of 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 concentrated under reduced pressure to give 4.2 kg of the desired compound as a toluene solution (assay 46 wt %, giving an assay yield of 80%). [Intermediates]

[0233] Preparation [] [1-] [Benzyl] [-3-(] [Chloromethyl] [)] [Pyrrolidine] [-3-] [formaldehyde] []

[0283] The reaction was carried out in a flow chemistry system: ethyl 1-benzyl-3-(chloromethyl)pyrrolidine-3-carboxylate ( [Intermediates]

[0232] (4.4 kg) in toluene (26 L) was pumped in at 26.7 mL / min and cooled to -60°C. After cooling, it was then mixed with a cooled solution of DIBAL-H (28.1 mol) in toluene (28 L) at a pumping rate of 32.1 mL / min at -60°C. The mixture was passed through a perfluoroalkoxy (PFA) coil reactor at a total flow rate of 58.8 mL / min and a residence time of 5 seconds at -60°C. The resulting mixture was mixed with cooled MeOH (-60°C) (pumped in at a rate of 15.2 mL / min). This mixed solution was pumped into another PFA coil reactor at a total flow rate of 74 mL / min and a residence time of 5 seconds at -60°C. The resulting mixture was collected in a receiver containing a 20 wt% Rochelle salt solution (20 L). The layers were separated and the organic phase was washed twice with water (2 x 44 L). The organic phase was combined with another 3.0 kg batch prepared in a similar manner and concentrated under reduced pressure to give 20.8 kg of a toluene solution of the desired compound (25.5 wt % by HPLC, giving an assay yield of 85%), which was used directly without further purification. [Intermediates]

[0234] Preparation [] [( , R , )-4-(6- ] [Benzyl] [-2,6-] [Diazaspiro] [[3.4]] [pungent] [-2-] [base] [)- , N , -(2- ] [Methoxyethyl] [)- , N , ,5- ] [Dimethylhexane] [-1-] [amine] [] []

[0284] At 20°C to 30°C, 1-benzyl-3-(chloromethyl)pyrrolidine-3-carbaldehyde ( [Intermediates]

[0233] ) in toluene (3.0 kg, 10 wt%) (diluted with toluene (30 L)) and (R)-N 1-(2-methoxyethyl)-N 1,5-dimethylhexane-1,4-diamine, dihydrochloride ( [Intermediates]

[0231] (3.47 kg) was added triethylamine (2.55 kg, 25.2 mol). The resulting mixture was aged for 2 hours at 20 ° C to 30 ° C. Then, sodium triacetoxyborohydride (9.0 kg) was filled at 20 ° C to 30 ° C and the mixture was aged for 12 h. The reaction mixture was cooled to 5 ° C to 15 ° C and a 25 wt% NaOH aqueous solution (25 L, about 16.75 equivalents) was added (maintaining temperature below 35 ° C). The resulting mixture was aged for 25 min at 20 ° C to 30 ° C and each layer was separated. The organic layer was washed with 15 wt% aqueous NaCl (10 L) and each layer was separated again, and water (18 L) was filled into the organic phase. The pH of the aqueous phase was adjusted to 6 to 7 with 4M aqueous HCl while maintaining an internal temperature below 35 ° C. The organic phase was then discarded and the aqueous phase was separated and basified to pH 8 to 9 with K 2 HPO 4 .

[0285] The obtained mixture is warmed to 50 ℃ to 55 ℃ and aged for 3 h.Then the reaction mixture is cooled to ambient temperature and merged with other two batches (2.4 kg + 3.0 kg).The merged stream is washed three times with methyl tertiary butyl ether (3 x 40 L).In the water layer of gained, add other methyl tertiary butyl ether (83 L) and use 8 wt% aqueous NaOH that water is alkalized to pH 9 to 10 while maintaining the temperature between 15 ℃ to 35 ℃.Separate water layer, and organic layer is washed three times with water (3 x 30 L).Then the organic layer is concentrated to approximately 3 volumes under reduced pressure and then rinsed three times with methanol (3 x 30 L) and concentrated to dryness to obtain the desired compound (12.4 kg, 90% isolated yield) as light yellow oil, which is directly used without further purification. [Intermediates]

[0224] Preparation [] [( , R , )- , N , -(2- ] [Methoxyethyl] [)- , N , ,5- ] [Dimethyl] [-4-(2,6-] [Diazaspiro] [[3.4]] [pungent] [-2-] [base] [)] [Self] [-1-] [amine] [] []

[0286] To palladium hydroxide on carbon (1.2 kg) in EtOH (1.47 kg) cooled to -5°C to 5°C were added methanesulfonic acid (MSA) (11 kg), (R)-4-(6-benzyl-2,6-diazaspiro[3.4]octan-2-yl-N-(2-methoxyethyl)-N,5-dimethylhexan-1-amine ( [Intermediates]

[0234] ) (10 kg) and EtOH (250 L). The mixture is warmed to 35 ℃-45 ℃ and under hydrogen atmosphere (0.27 to 0.40 MPa) stirs 16-20h. The mixture is filtered through diatomite (20 kg) and the pad is washed with EtOH (24 L). The filtrate is concentrated under reduced pressure (<40 ℃) to 2 to 3 volumes and then rinsed twice with 2-MeTHF (73 kg and 47 kg) to provide a solution of 2 to 3 volumes. After diluting with 2-MeTHF (65 kg), 10% aqueous sodium sulfate (30 kg) is added and the mixture is cooled to 0 ℃ to 10 ℃, 16% aqueous NaOH (50 kg) is added subsequently to regulate pH to 13 to 14. The temperature is adjusted to 15 ℃ to 25 ℃ and stirred for 30 to 60 min. The water layer is separated and extracted with 2-MeTHF (47 kg x 2). The combined organic layers were concentrated under reduced pressure (<40°C) to 3-4 volumes, and 2-MeTHF (950 g) was added. After concentration under reduced pressure (<40°C) to 3-4 volumes, the resulting solution was diluted with 2-MeTHF (30 kg), dried by passing through 4A molecular sieves (25 kg), and washed with 2-MeTHF (30 kg). The final solution was concentrated to give the desired compound (6.7 kg) as an oil with an assay purity of 90.1% in a 79% corrected yield. [Intermediates]

[0225] Preparation [] [( , R , )-4-(6-(3,6- ] [Dichloro] [-1,2,4-] [Three] [-5-] [base] [)-2,6-] [Diazaspiro] [[3.4]] [pungent] [-2-] [base] [)- , N , -(2- ] [Methoxyethyl] [)- , N , ,5- ] [Dimethylhexane] [-1-] [amine] [] []

[0287] To (R)-N-(2-methoxyethyl)-N,5-dimethyl-4-(2,6-diazaspiro[3.4]octan-2-yl)hexan-1-amine ( [Intermediates]

[0224] (100 g) was added 2-MeTHF (430 g) and TEA (68 g) and the mixture was cooled to -50 ° C to -40 ° C. 3,5,6-trichloro-1,2,4-trioxane (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 ° C to -10 ° C and a 7% NaHCO 3 aqueous solution was added, the mixture was warmed to 20 ° C to 30 ° C and stirred for 30 to 60 min. The aqueous layer was removed and the organic layer was washed with 10% Na 2SO 4 (500 g). The organic layer was dried by passing through 4Å molecular sieves (220 g) and washed with 2-MeTHF (180 g). The title intermediate was obtained as a 14.8 wt % solution in 2-MeTHF with a 90% assay yield. [Intermediates]

[0245] Preparation [] [( , R , )-2-((5-(2-(6-((2-(( ] [tertiary butyl dimethyl silyl] [)] [oxyl] [)] [Ethyl] [)(] [methyl] [)] [Amine] [)-2-] [Methylhexane] [-3-] [base] [)-2,6-] [Diazaspiro] [[3.4]] [pungent] [-6-] [base] [)-1,2,4-] [Three] [-6-] [base] [)] [oxyl] [)- , N , - ] [Ethyl] [-5-] [fluorine] [- , N , - ] [Isopropylbenzamide] []

[0288] NaBH 3CN (23.2 mg, 0.37 mmol) was added to ( R )- N -ethyl-5-fluoro- N -isopropyl-2-((5-(2-(2-methyl-6-(methylamino)hexan-3-yl)-2,6-diazaspiro[3.4]octan-6-yl)-1,2,4-trioxan-6-yl)oxy)benzamide hydrochloride ( [Compound]

[19] )(100 mg, 0.18 mmol), 2-((tributyldimethylsilyl)oxy)acetaldehyde (71 µL, 0.37 mmol) and AcOH (11 µL, 0.18 mmol) in MeOH (2 mL). The reaction mixture was then stirred at RT for 24 h. The reaction mixture was poured into water, basified with aqueous K 2 CO 3 solution and DCM was added. The organic layer was separated, dried over MgSO 4 , filtered and evaporated to dryness to give the crude product (152 mg), which was purified by silica gel chromatography (stationary phase: irregular bare silica 4 g, mobile phase: 0.5% NH 4 OH, 95% DCM, 5% MeOH). Product-containing fractions were combined and concentrated to give the title intermediate (46 mg, 36% yield). [Preparation of compounds] [] [Compound]

[61] Preparation [] [Tertiary butyl] [(4-(6-(6-(2-(] [Ethyl] [(] [Isopropyl] [)] [Carbamoyl] [)-4-] [Fluorophenoxy] [)-1,2,4-] [Three] [-5-] [base] [)-2,6-] [Diazaspiro] [[3.4]] [pungent] [-2-] [base] [)-5-] [Methylhexyl] [)] [Urethane] []

[0289] 2-((5-(2,6-diazaspiro[3.4]octan-6-yl)-1,2,4-trioxan-6-yl)oxy)-N-ethyl-5-fluoro-N-isopropylbenzamide ( [Intermediates] [3])(1.0 g, 2.4 mmol), tert-butyl (5-methyl-4-oxohexyl) carbamate ( [Intermediates] A mixture of [1]) (830 mg, 3.62 mmol) and ZnCl2 (660 mg, 4.84 mmol) in MeOH (15 mL) was stirred at 80 ° C for 0.5 h. Then NaBH3CN (310 mg, 4.93 mmol) was added and the resulting mixture was stirred at 80 ° C for 6 h. After cooling to RT, the mixture was concentrated under reduced pressure to give the crude product, which was further purified by preparative HPLC using Waters Xbridge Prep OBD (column: C18 150 x 40 mm 10 um; eluent: ACN / H2O (0.05% amine) from 45% to 75% v / v) to give the title compound (700 mg, 46% yield) as a colorless oil. [Compound]

[62] [and]

[63] Preparation [] [Tertiary butyl] [( , R , )-(4-(6-(6-(2-( ] [Ethyl] [(] [Isopropyl] [)] [Carbamoyl] [)-4-] [Fluorophenoxy] [)-1,2,4-] [Three] [-5-] [base] [)-2,6-] [Diazaspiro] [[3.4]] [pungent] [-2-] [base] [)-5-] [Methylhexyl] [)] [Urethane] [] [Tertiary butyl] [( , S , )-(4-(6-(6-(2-( ] [Ethyl] [(] [Isopropyl] [)] [Carbamoyl] [)-4-] [Fluorophenoxy] [)-1,2,4-] [Three] [-5-] [base] [)-2,6-] [Diazaspiro] [[3.4]] [pungent] [-2-] [base] [)-5-] [Methylhexyl] [)] [Urethane] []

[0290] Tributyl (4-(6-(6-(2-(ethyl(isopropyl)carbamoyl)-4-fluorophenoxy)-1,2,4-trioxan-5-yl)-2,6-diazaspiro[3.4]octan-2-yl)-5-methylhexyl)carbamate ( [Compound]

[61] ) (200 mg, 0.319 mmol) was purified by SFC on a Chiralpak IG (column: 250 x 30 mm 10 um; isocratic elution: EtOH (0.1% with 25% amine): supercritical CO 2, 40%: 60% (v / v)) to give the title compound ( [Compound]

[62] )(85 mg, 42% yield) and ( [Compound]

[63] ) (80 mg, 40% yield). [Compound]

[0207] [and]

[0208] [Tertiary butyl] [( , *R , )-(5-(6-(6-(2-( ] [Ethyl] [(] [Isopropyl] [)] [Carbamoyl] [)-4-] [Fluorophenoxy] [)-1,2,4-] [Three] [-5-] [base] [)-2,6-] [Diazaspiro] [[3.4]] [pungent] [-2-] [base] [)-6-] [Methylheptyl] [)] [Urethane] [] [Tertiary butyl] [( , *S , )-(5-(6-(6-(2-( ] [Ethyl] [(] [Isopropyl] [)] [Carbamoyl] [)-4-] [Fluorophenoxy] [)-1,2,4-] [Three] [-5-] [base] [)-2,6-] [Diazaspiro] [[3.4]] [pungent] [-2-] [base] [)-6-] [Methylheptyl] [)] [Urethane] []

[0291] Tributyl (5-(6-(6-(2-(ethyl(isopropyl)carbamoyl)-4-fluorophenoxy)-1,2,4-trioxan-5-yl)-2,6-diazaspiro[3.4]octan-2-yl)-6-methylheptyl)carbamate ( [Compound]

[0206] ) (1.4 g) was purified by SFC on a CHIRALPAK IG column (column: 250 × 30 mm, 10 μm; mobile phase: A: supercritical CO 2 , B: MeOH (0.1% amine), A: B = 55:45, 200 mL / min) to obtain the title compound ( [Compound]

[0207] ) (700 mg) and ( [Compound]

[0208] ) (700 mg). [Compound]

[0304] [and]

[0305] [Tertiary butyl] [((4 , *R , )-4-(6-(6-(2-( ] [Ethyl] [(] [Isopropyl] [)] [Carbamoyl] [)-4-] [Fluorophenoxy] [)-1,2,4-] [Three] [-5-] [base] [)-2,6-] [Diazaspiro] [[3.4]] [pungent] [-2-] [base] [)-2-] [Methoxy] [-5-] [Methylhexyl] [)(] [methyl] [)] [Urethane] [] [Tertiary butyl] [((4 , *S , )-4-(6-(6-(2-( ] [Ethyl] [(] [Isopropyl] [)] [Carbamoyl] [)-4-] [Fluorophenoxy] [)-1,2,4-] [Three] [-5-] [base] [)-2,6-] [Diazaspiro] [[3.4]] [pungent] [-2-] [base] [)-2-] [Methoxy] [-5-] [Methylhexyl] [)(] [methyl] [)] [Urethane] []

[0292] Tributyl (4-(6-(6-(2-(ethyl(isopropyl)aminoformyl)-4-fluorophenoxy)-1,2,4-triazol-5-yl)-2,6-diazaspiro[3.4]octan-2-yl)-2-methoxy-5-methylhexyl)(methyl)carbamate ( [Compound]

[0303] ) (250 mg) were separated by SFC on a Chiralpak IG column (column: 250 × 30 mm, 10 µm; mobile phase: A: supercritical CO 2 , B: MeOH (0.1% amine), A: B = 60:40; flow rate: 80 mL / min) to afford the title compound ( [Compound]

[0304] ) (124 mg) and ( [Compound]

[0305] ) (124 mg). [Compound]

[0306] [and]

[0307] [ , uncle , ] [ , - , ] [ , Butyl , ] [((2 , *R , ,4 , *R , )-4-(6-(6-(2-( ] [Ethyl] [(] [Isopropyl] [)] [Carbamoyl] [)-4-] [Fluorophenoxy] [)-1,2,4-] [Three] [-5-] [base] [)-2,6-] [Diazaspiro] [[3.4]] [pungent] [-2-] [base] [)-2-] [Methoxy] [-5-] [Methylhexyl] [)(] [methyl] [)] [Urethane] [] [ , uncle , ] [ , - , ] [ , Butyl , ] [((2 , *S , ,4 , *R , )-4-(6-(6-(2-( ] [Ethyl] [(] [Isopropyl] [)] [Carbamoyl] [)-4-] [Fluorophenoxy] [)-1,2,4-] [Three] [-5-] [base] [)-2,6-] [Diazaspiro] [[3.4]] [pungent] [-2-] [base] [)-2-] [Methoxy] [-5-] [Methylhexyl] [)(] [methyl] [)] [Urethane] [] []

[0293] Tertiary butyl ((4 * R)-4-(6-(6-(2-(ethyl(isopropyl)carbamoyl)-4-fluorophenoxy)-1,2,4-trioxan-5-yl)-2,6-diazaspiro[3.4]octan-2-yl)-2-methoxy-5-methylhexyl)(methyl)carbamate ( [Compound]

[0304] ) (120 mg) was separated by SFC on a Chiralpak IG column (column: 250 × 30 mm, 10 μm; mobile phase: A: supercritical CO 2 , B: MeOH (0.1% amine), A: B = 70:30, 80 mL / min) to obtain the title compound ( [Compound]

[0306] ) (45 mg) and ( [Compound]

[0307] ) (46 mg). [Compound]

[0371] [and]

[0372] [Tertiary butyl] [((2 , *S , ,4 , *S , )-4-(6-(6-(2-( ] [Ethyl] [(] [Isopropyl] [)] [Carbamoyl] [)-4-] [Fluorophenoxy] [)-1,2,4-] [Three] [-5-] [base] [)-2,6-] [Diazaspiro] [[3.4]] [pungent] [-2-] [base] [)-2-] [Methoxy] [-5-] [Methylhexyl] [)(] [methyl] [)] [Urethane] [] [Tertiary butyl] [((2 , *R , ,4 , *S , )-4-(6-(6-(2-( ] [Ethyl] [(] [Isopropyl] [)] [Carbamoyl] [)-4-] [Fluorophenoxy] [)-1,2,4-] [Three] [-5-] [base] [)-2,6-] [Diazaspiro] [[3.4]] [pungent] [-2-] [base] [)-2-] [Methoxy] [-5-] [Methylhexyl] [)(] [methyl] [)] [Urethane] []

[0294] Tributyl ((4 * S)-4-(6-(6-(2-(ethyl(isopropyl)carbamoyl)-4-fluorophenoxy)-1,2,4-trioxan-5-yl)-2,6-diazaspiro[3.4]octan-2-yl)-2-methoxy-5-methylhexyl)(methyl)carbamate ( [Compound]

[0305] ) (120 mg) were separated by SFC on a CHIRALPAK IG column (column: 250 × 30 mm, 10 μm; mobile phase: A: supercritical CO 2 , B: IPA (0.1% amine), A: B = 60:40; flow rate: 80 mL / min) to obtain the title compound ( [Compound]

[0371] ) (45 mg) and ( [Compound]

[0372] ) (46 mg). [Compound]

[0404] [and]

[0405] [Tertiary butyl] [( , R , )-(4-(6-(3- ] [chlorine] [-6-(2-(] [Ethyl] [(] [Isopropyl] [)] [Carbamoyl] [)-4-] [Fluorophenoxy] [)-1,2,4-] [Three] [-5-] [base] [)-2,6-] [Diazaspiro] [[3.4]] [pungent] [-2-] [base] [)-5-] [Methylhexyl] [)] [Urethane] [] [Tertiary butyl] [( , S , )-(4-(6-(3- ] [chlorine] [-6-(2-(] [Ethyl] [(] [Isopropyl] [)] [Carbamoyl] [)-4-] [Fluorophenoxy] [)-1,2,4-] [Three] [-5-] [base] [)-2,6-] [Diazaspiro] [[3.4]] [pungent] [-2-] [base] [)-5-] [Methylhexyl] [)] [Urethane] []

[0295] Tributyl (4-(6-(3-chloro-6-(2-(ethyl(isopropyl)carbamoyl)-4-fluorophenoxy)-1,2,4-trioxan-5-yl)-2,6-diazaspiro[3.4]octan-2-yl)-5-methylhexyl)carbamate ( [Compound]

[0403] ) (19.5 g) were separated by SFC on a Chiralpak IG column (column: 250 × 30 mm, 10 μm; mobile phase: A: supercritical CO 2 , B: MeOH (0.1% amine), A: B = 55:45, 80 mL / min; column temperature: 38° C.; nozzle pressure: 100 bar; nozzle temperature: 60° C.; evaporator temperature: 20° C.; trimmer temperature: 25° C.; wavelength: 220 nm) to give the title compound ( [Compound]

[0404] ) (8.00 g) and ( [Compound]

[0405] ) (7.00 g). [] [Compound] [1] [( , R , )-2-((5-(2-(6- ] [Amine] [-2-] [Methylhexane] [-3-] [base] [)-2,6-] [Diazaspiro] [[3.4]] [pungent] [-6-] [base] [)-1,2,4-] [Three] [-6-] [base] [)] [oxyl] [)- , N , - ] [Ethyl] [-5-] [fluorine] [- , N , - ] [Cymene] [] [Formate] [] []

[0296] HCl / 1,4-dioxane (0.5 mL, 2.0 mmol) was added to the tert-butyl (R)-(4-(6-(6-(2-(ethyl(isopropyl)carbamoyl)-4-fluorophenoxy)-1,2,4-trioxan-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 stirred at RT for 4 h. The mixture was concentrated under reduced pressure and the residue was first neutralized with amine (5 mL) and further purified by preparative HPLC using Welch Xtimate C18 (column: 150 x 25 mm 5 µm; eluent: ACN / H 2 O (0.225% FA) from 1% to 31% (v / v)) to give the title compound (32 mg, 41% yield) as a colorless oil. [ , 1 , ] [H NMR] [(] [400 MHz] [,methanol] [- , d , , 4, ] [):]δ = 8.45-8.41 (m, 3H), 7.48-7.13 (m, 3H), 4.50-4.01 (m, 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), 0.87-0.69 (m, 2H). [LC-MS] [(] [ESI] [)(method] [1] [):]R t= 2.957 min, m / z found 528.3 [M+H] +. [SFC] [(method]

[12] [):]R t= 1.151 min. [Compound]

[60] Preparation [] [Tertiary butyl] [(4-(6-(6-(2-(] [Ethyl] [(] [Isopropyl] [)] [Carbamoyl] [)-4-] [Fluorophenoxy] [)-1,2,4-] [Three] [-5-] [base] [)-2,6-] [Diazaspiro] [[3.4]] [pungent] [-2-] [base] [)-5-] [Methylhexyl] [)(] [methyl] [)] [Urethane] [] []

[0297] 2-((5-(2,6-diazaspiro[3.4]octan-6-yl)-1,2,4-trioxan-6-yl)oxy)-N-ethyl-5-fluoro-N-isopropylbenzamide ( [Intermediates] [3])(600 mg, 1.45 mmol) and tert-butyl methyl (5-methyl-4-oxohexyl) carbamate ( [Intermediates] To a solution of [9]) (330 mg, 1.37 mmol) in MeOH (50 mL) was added ZnCl2 (789 mg, 5.79 mmol). The resulting mixture was stirred at 80 °C for 2 h. Then NaBH3CN (729 mg, 11.6 mmol) was added and the reaction mixture was stirred at 80 °C 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 saturated aqueous NH4Cl (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 the crude product, which was further purified by FCC (DCM / MeOH = 10: 1) to give the title compound (400 mg, 42% yield) as a white solid. [Compound]

[56] [and]

[57] [Tertiary butyl] [( , R , )-(4-(6-(6-(2-( ] [Ethyl] [(] [Isopropyl] [)] [Carbamoyl] [)-4-] [Fluorophenoxy] [)-1,2,4-] [Three] [-5-] [base] [)-2,6-] [Diazaspiro] [[3.4]] [pungent] [-2-] [base] [)-5-] [Methylhexyl] [)(] [methyl] [)] [Urethane] [] [Tertiary butyl] [( , S , )-(4-(6-(6-(2-( ] [Ethyl] [(] [Isopropyl] [)] [Carbamoyl] [)-4-] [Fluorophenoxy] [)-1,2,4-] [Three] [-5-] [base] [)-2,6-] [Diazaspiro] [[3.4]] [pungent] [-2-] [base] [)-5-] [Methylhexyl] [)(] [methyl] [)] [Urethane] []

[0298] Tributyl (4-(6-(6-(2-(ethyl(isopropyl)carbamoyl)-4-fluorophenoxy)-1,2,4-trioxan-5-yl)-2,6-diazaspiro[3.4]octan-2-yl)-5-methylhexyl)(methyl)carbamate ( [Compound]

[60] ) (419 mg, 0.653 mmol) was purified by SFC on a CHIRALPAK AD column (column: 250 x 30 mm 10 µm; mobile phase: A: supercritical CO 2 , B: IPA (0.1% amine), A: B = 80:20, 60 mL / min; column temperature: 38°C; nozzle pressure: 100 bar; nozzle temperature: 60°C; evaporator temperature: 20°C; trimmer temperature: 25°C; wavelength: 220 nm) to give the title compound ( [Compound]

[56] )(146 mg, 34% yield) and ( [Compound]

[57] ) (149 mg, 36% yield). [Compound]

[19] [( , R , )- , N , - ] [Ethyl] [-5-] [fluorine] [- , N , - ] [Isopropyl] [-2-((5-(2-(2-] [methyl] [-6-(] [Methylamino] [)] [Self] [-3-] [base] [)-2,6-] [Diazaspiro] [[3.4]] [pungent] [-6-] [base] [)-1,2,4-] [Three] [-6-] [base] [)] [oxyl] [)] [Benzamide hydrochloride] [] []

[0299] To tertiary butyl (R)-(4-(6-(6-(2-(ethyl(isopropyl)carbamoyl)-4-fluorophenoxy)-1,2,4-trioxan-5-yl)-2,6-diazaspiro[3.4]octan-2-yl)-5-methylhexyl)(methyl)carbamate ( [Compound] To a solution of

[56] ) (130 mg, 0.203 mmol) in 1,4-dioxane (3 mL) was added HCl / 1,4-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 on a Phenomenon Gemini-NX (column: 150x30 mm 5 μm, mobile phase A: water (0.05% HCl), mobile phase B: ACN, flow rate: 25 mL / min, gradient conditions B / A from 0% B to 26% (0% B to 26% B)) to give the title compound (105 mg, 84% yield) as a colorless oil. [LC-MS] [(] [ESI] [)(method] [1] [):]R t= 2.939 min, m / z found 542.4 [M+H] +. [SFC] [(method] [1] [):]R t= 1.201 min. [Compound]

[0398] [( , R , )- , N , - ] [Ethyl] [-5-] [fluorine] [- , N , - ] [Isopropyl] [-2-((5-(2-(2-] [methyl] [-6-(] [Methylamino] [)] [Self] [-3-] [base] [)-2,6-] [Diazaspiro] [[3.4]] [pungent] [-6-] [base] [)-1,2,4-] [Three] [-6-] [base] [)] [oxyl] [)] [Benzamide] [] []

[0300] At 5°C, TFA (0.51 mL, 6.7 mmol) was added dropwise to tert-butyl (R)-(4-(6-(6-(2-(ethyl(isopropyl)carbamoyl)-4-fluorophenoxy)-1,2,4-triazol-5-yl)-2,6-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 12 g, mobile phase: gradient from 95% DCM, 5% MeOH (+10% NH 4OH) to 90% DCM, 10% MeOH (+10% NH 4OH)). The pure fractions were combined and concentrated to give 173 mg of an intermediate fraction, which was freeze-dried over ACN / H 2O (20 / 80, v / v) to give the title compound (170 mg, 70% yield). [LC-MS] [(] [ESI] [)(method] [4] [):]R t= 2.08 min, m / z found 542.6 [M+H] +. [Compound]

[51] [Tertiary butyl] [(3-(6-(6-(2-(] [Ethyl] [(] [Isopropyl] [)] [Carbamoyl] [)-4-] [Fluorophenoxy] [)-1,2,4-] [Three] [-5-] [base] [)-2,6-] [Diazaspiro] [[3.4]] [pungent] [-2-] [base] [)-4-] [Methylpentyl] [)] [Urethane] []

[0301] To N-ethyl-5-fluoro-2-((5-hydroxy-1,2,4-trioxan-6-yl)oxy)-N-isopropylbenzamide ( [Intermediates] To a solution of

[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 hour. The mixture was then added to tert-butyl (4-methyl-3-(2,6-diazaspiro[3.4]octan-2-yl)pentyl)carbamate hydrochloride ( [Intermediates]

[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 H 2 O (35 mL) and extracted with DCM (35 mL x 3). The combined organic layers were dried over Na 2 SO 4, filtered and concentrated. The residue was purified by FCC (PE / EtOAc (0.5% amine) = 1 / 1) to give the title compound (100 mg, 89% purity, 46% yield) as a colorless oil. [Compound]

[52] [and]

[53] [Tertiary butyl] [( , *R , )-(5-(6-(6-(2-(4- ] [Cyclopropylpyrimidine] [-5-] [base] [)-4-] [Fluorophenoxy] [)-1,2,4-] [Three] [-5-] [base] [)-2,6-] [Diazaspiro] [[3.4]] [pungent] [-2-] [base] [)-2,6-] [Dimethylheptyl] [-2-] [base] [)] [Urethane] [] [Tertiary butyl] [( , *S , )-(5-(6-(6-(2-(4- ] [Cyclopropylpyrimidine] [-5-] [base] [)-4-] [Fluorophenoxy] [)-1,2,4-] [Three] [-5-] [base] [)-2,6-] [Diazaspiro] [[3.4]] [pungent] [-2-] [base] [)-2,6-] [Dimethylheptyl] [-2-] [base] [)] [Urethane] []

[0302] Tributyl (5-(6-(6-(2-(4-cyclopropylpyrimidin-5-yl)-4-fluorophenoxy)-1,2,4-trioxan-5-yl)-2,6-diazaspiro[3.4]octan-2-yl)-2,6-dimethylhept-2-yl)carbamate ( [Compound]

[58] ) (150 mg, 0.227 mmol) was purified by SFC on a CHIRALPAK AD-H column (column: 250 x 30 mm 5 µm; mobile phase: A: supercritical CO 2 , B: IPA (0.1% amine), A: B = 4: 1, 60 mL / min) to give the title compound as a white solid. [Compound]

[52] (47 mg, 96.3% purity, 30.2% yield) and [Compound]

[53] (56 mg, 97.7% purity, 36.5% yield). [Compound]

[54] [and]

[55] [Tertiary butyl] [( , *R , )-(5-(6-(6-(2-( ] [Ethyl] [(] [Isopropyl] [)] [Carbamoyl] [)-4-] [Fluorophenoxy] [)-1,2,4-] [Three] [-5-] [base] [)-2,6-] [Diazaspiro] [[3.4]] [pungent] [-2-] [base] [)-2,6-] [Dimethylheptyl] [-2-] [base] [)] [Urethane] [] [Tertiary butyl] [( , *S , )-(5-(6-(6-(2-( ] [Ethyl] [(] [Isopropyl] [)] [Carbamoyl] [)-4-] [Fluorophenoxy] [)-1,2,4-] [Three] [-5-] [base] [)-2,6-] [Diazaspiro] [[3.4]] [pungent] [-2-] [base] [)-2,6-] [Dimethylheptyl] [-2-] [base] [)] [Urethane] []

[0303] Tributyl (5-(6-(6-(2-(ethyl(isopropyl)carbamoyl)-4-fluorophenoxy)-1,2,4-trioxan-5-yl)-2,6-diazaspiro[3.4]octan-2-yl)-2,6-dimethylhept-2-yl)carbamate ( [Compound]

[59] ) (1.70 g, 2.59 mmol) was separated by SFC on a CHIRALPAK IG column (column: 250 x 50 mm 10 μm); mobile phase: A: supercritical CO 2 , B: EtOH (0.1% amine), A: B = 3: 2, 150 mL / min) to obtain the title compound as a white solid. [Compound]

[54] (700 mg, 90% purity, 37% yield) and [Compound]

[55] (700 mg, purity: 96% purity, 40% yield). [Compound]

[0408] [Tertiary butyl] [( , R , )-(4-(6-(6-(2-( ] [Ethyl] [(] [Isopropyl] [)] [Carbamoyl] [)-4-] [Fluorophenoxy] [)-3-(] [Methylamino] [)-1,2,4-] [Three] [-5-] [base] [)-2,6-] [Diazaspiro] [[3.4]] [pungent] [-2-] [base] [)-5-] [Methylhexyl] [)] [Urethane] [] [By targeting compounds]

[0395] The following compounds were synthesized by a similar method as described above: [] [Compound number] [structure] [Starting materials] [condition] 408 Compound 404 EtOH (33%) Methylamine in 90°C, 1 h [Compound]

[0412] [Tertiary butyl] [( , R , )-(4-(6-(6-(2-( ] [Ethyl] [(] [Isopropyl] [)] [Carbamoyl] [)-4-] [Fluorophenoxy] [)-3-] [methyl] [-1,2,4-] [Three] [-5-] [base] [)-2,6-] [Diazaspiro] [[3.4]] [pungent] [-2-] [base] [)-5-] [Methylhexyl] [)] [Urethane] []

[0304] To tertiary butyl (R)-(4-(6-(3-chloro-6-(2-(ethyl(isopropyl)carbamoyl)-4-fluorophenoxy)-1,2,4-trioxan-5-yl)-2,6-diazaspiro[3.4]octan-2-yl)-5-methylhexyl)carbamate ( [Compound] To a mixture of 2,4,6-trimethyl-1,3,5,2,4,6-trioxatriborinane (50.0 mg, 0.076 mmol), 2,4,6-trimethyl-1,3,5,2,4,6-trioxatriborinane (76.0 mg, 0.303 mmol, 50% in THF), and KCO (21.0 mg, 0.152 mmol) in anhydrous dioxane (1 mL) was added Pd(PPh) (8.7 mg, 0.008 mmol) and the resulting mixture was stirred at 110 ° C. under N atmosphere for 8 h. After cooling to RT, the mixture was diluted with H O (40 mL) and extracted with EtOAc (20 mL × 3). The combined organic layers were dried over anhydrous Na SO 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 give the title compound (30.0 mg, 59.7% yield) as a yellow solid. [] [Compound] [2] [、] [3] [、]

[20] [、]

[30] [、]

[31] [、]

[37] [、]

[38] [、]

[26] [、]

[80] [、]

[0209] [、]

[0210] [、]

[0218] [、]

[0220] [、]

[0221] [、]

[0308] [、]

[0309] [、]

[0317] [、]

[0328] [、]

[0359] [、]

[0373] [、]

[0374] [、]

[0409] [、]

[0413] [( , S , )-2-((5-(2-(6- ] [Amine] [-2-] [Methylhexane] [-3-] [base] [)-2,6-] [Diazaspiro] [[3.4]] [pungent] [-6-] [base] [)-1,2,4-] [Three] [-6-] [base] [)] [oxyl] [)- , N , - ] [Ethyl] [-5-] [fluorine] [- , N , - ] [Isopropylbenzamide] [] [Formate] [] [2-((5-(2-(6-] [Amine] [-2-] [Methylhexane] [-3-] [base] [)-2,6-] [Diazaspiro] [[3.4]] [pungent] [-6-] [base] [)-1,2,4-] [Three] [-6-] [base] [)] [oxyl] [)- , N , - ] [Ethyl] [-5-] [fluorine] [- , N , - ] [Cymene] [] [Formate] [] [( , S , )- , N , - ] [Ethyl] [-5-] [fluorine] [- , N , - ] [Isopropyl] [-2-((5-(2-(2-] [methyl] [-6-(] [Methylamino] [)] [Self] [-3-] [base] [)-2,6-] [Diazaspiro] [[3.4]] [pungent] [-6-] [base] [)-1,2,4-] [Three] [6-] [base] [)] [oxyl] [)] [Benzamide hydrochloride] [] [( , *R , )-2-((5-(2-(6- ] [Amine] [-2,6-] [Dimethylheptyl] [-3-] [base] [)-2,6-] [Diazaspiro] [[3.4]] [pungent] [-6-] [base] [)-1,2,4-] [Three] [-6-] [base] [)] [oxyl] [)- , N , - ] [Ethyl] [-5-] [fluorine] [- , N , - ] [Isopropylbenzamide] [] [( , *S , )-2-((5-(2-(6- ] [Amine] [-2,6-] [Dimethylheptyl] [-3-] [base] [)-2,6-] [Diazaspiro] [[3.4]] [pungent] [-6-] [base] [)-1,2,4-] [Three] [-6-] [base] [)] [oxyl] [)- , N , - ] [Ethyl] [-5-] [fluorine] [- , N , - ] [Isopropylbenzamide] [] [( , *R , )-5-(6-(6-(2-(4- ] [Cyclopropylpyrimidine] [-5-] [base] [)-4-] [Fluorophenoxy] [)-1,2,4-] [Three] [-5-] [base] [)-2,6-] [Diazaspiro] [[3.4]] [pungent] [-2-] [base] [)-2,6-] [Dimethylheptyl] [-2-] [amine] [] [( , *S , )-5-(6-(6-(2-(4- ] [Cyclopropylpyrimidine] [-5-] [base] [)-4-] [Fluorophenoxy] [)-1,2,4-] [Three] [-5-] [base] [)-2,6-] [Diazaspiro] [[3.4]] [pungent] [-2-] [base] [)-2,6-] [Dimethylheptyl] [-2-] [amine] [] [2-((5-(2-(1-] [Amine] [-4-] [Methylpentyl] [-3-] [base] [)-2,6-] [Diazaspiro] [[3.4]] [pungent] [-6-] [base] [)-1,2,4-] [Three] [-6-] [base] [)] [oxyl] [)- , N , - ] [Ethyl] [-5-] [fluorine] [- , N , - ] [Cymene] [] [ , N , ] [-] [Ethyl] [-5-] [fluorine] [- , N , - ] [Isopropyl] [-2-((4-(2-(2-] [methyl] [-6-(] [Methylamino] [)] [Self] [-3-] [base] [)-2,6-] [Diazaspiro] [[3.4]] [pungent] [-6-] [base] [)] [Da]𠯤 [-3-] [base] [)] [oxyl] [)] [Benzamide] [] [( , *R , )-2-((5-(2-(7- ] [Amine] [-2-] [Methylheptyl] [-3-] [base] [)-2,6-] [Diazaspiro] [[3.4]] [pungent] [-6-] [base] [)-1,2,4-] [Three] [-6-] [base] [)] [oxyl] [)- , N , - ] [Ethyl] [-5-] [fluorine] [- , N , - ] [Cymene] [] [Formate] [] [( , *S, )-2-((5-(2-(7- ] [Amine] [-2-] [Methylheptyl] [-3-] [base] [)-2,6-] [Diazaspiro] [[3.4]] [pungent] [-6-] [base] [)-1,2,4-] [Three] [-6-] [base] [)] [oxyl] [)- , N , - ] [Ethyl] [-5-] [fluorine] [- , N , - ] [Cymene] [] [( , *R , )-2-((5-(2-(1- ] [Amine] [-4-] [Methylpentyl] [-3-] [base] [)-2,6-] [Diazaspiro] [[3.4]] [pungent] [-6-] [base] [)-1,2,4-] [Three] [-6-] [base] [)] [oxyl] [)- , N , - ] [Ethyl] [-5-] [fluorine] [- , N , - ] [Cymene] [] [( , *R , )-2-((5-(2-(1- ] [Amine] [-4-] [Methylpentyl] [-3-] [base] [)-2,6-] [Diazaspiro] [[3.4]] [pungent] [-6-] [base] [)-1,2,4-] [Three] [-6-] [base] [)] [oxyl] [)- , N , - ] [Ethyl] [-5-] [fluorine] [- , N , - ] [Isopropylbenzamide hydrochloride] [] [( , *S , )-2-((5-(2-(1- ] [Amine] [-4-] [Methylpentyl] [-3-] [base] [)-2,6-] [Diazaspiro] [[3.4]] [pungent] [-6-] [base] [)-1,2,4-] [Three] [-6-] [base] [)] [oxyl] [)- , N , - ] [Ethyl] [-5-] [fluorine] [- , N , - ] [Isopropylbenzamide hydrochloride] [] [ , N , ] [-] [Ethyl] [-5-] [fluorine] [- , N , - ] [Isopropyl] [-2-((5-(2-((3 , *R , ,5 , *R , )-5- ] [Methoxy] [-2-] [methyl] [-6-(] [Methylamino] [)] [Self] [-3-] [base] [)-2,6-] [Diazaspiro] [[3.4]] [pungent] [-6-] [base] [)-1,2,4-] [Three] [-6-] [base] [)] [oxyl] [)] [Benzamide hydrochloride] [] [ , N , ] [-] [Ethyl] [-5-] [fluorine] [- , N , - ] [Isopropyl] [-2-((5-(2-((3 , *R , ,5 , *S , )-5- ] [Methoxy] [-2-] [methyl] [-6-(] [Methylamino] [)] [Self] [-3-] [base] [)-2,6-] [Diazaspiro] [[3.4]] [pungent] [-6-] [base] [)-1,2,4-] [Three] [-6-] [base] [)] [oxyl] [)] [Benzamide hydrochloride] [] [ , N , ] [-] [Ethyl] [-5-] [fluorine] [-2-((5-(2-(5-] [Hydroxy] [-2-] [methyl] [-6-(] [Methylamino] [)] [Self] [-3-] [base] [)-2,6-] [Diazaspiro] [[3.4]] [pungent] [-6-] [base] [)-1,2,4-] [Three] [-6-] [base] [)] [oxyl] [)- , N , - ] [Isopropylbenzamide hydrochloride] [] [ , N , ] [-] [Ethyl] [-2-((5-(2-(6-(] [Ethylamino] [)-5-] [Hydroxy] [-2-] [Methylhexane] [-3-] [base] [)-2,6-] [Diazaspiro] [[3.4]] [pungent] [-6-] [base] [)-1,2,4-] [Three] [-6-] [base] [)] [oxyl] [)-5-] [fluorine] [- , N , - ] [Isopropylbenzamide hydrochloride] [] [5-] [fluorine] [-2-((5-(2-(5-] [Hydroxy] [-2-] [methyl] [-6-(] [Methylamino] [)] [Self] [-3-] [base] [)-2,6-] [Diazaspiro] [[3.4]] [pungent] [-6-] [base] [)-1,2,4-] [Three] [-6-] [base] [)] [oxyl] [)- , N , , , N , - ] [Diisopropylbenzamide hydrochloride] [] [ , N , ] [-] [Ethyl] [-5-] [fluorine] [- , N , - ] [Isopropyl] [-2-((5-(2-((3 , *S , ,5 , *S , )-5- ] [Methoxy] [-2-] [methyl] [-6-(] [Methylamino] [)] [Self] [-3-] [base] [)-2,6-] [Diazaspiro] [[3.4]] [pungent] [-6-] [base] [)-1,2,4-] [Three] [-6-] [base] [)] [oxyl] [)] [Benzamide hydrochloride] [] [ , N , ] [-] [Ethyl] [-5-] [fluorine] [- , N , - ] [Isopropyl] [-2-((5-(2-((3 , *S , ,5 , *R , )-5- ] [Methoxy] [-2-] [methyl] [-6-(] [Methylamino] [)] [Self] [-3-] [base] [)-2,6-] [Diazaspiro] [[3.4]] [pungent] [-6-] [base] [)-1,2,4-] [Three] [-6-] [base] [)] [oxyl] [)] [Benzamide hydrochloride] [] [( , R , )-2-((5-(2-(6- ] [Amine] [-2-] [Methylhexane] [-3-] [base] [)-2,6-] [Diazaspiro] [[3.4]] [pungent] [-6-] [base] [)-3-(] [Methylamino] [)-1,2,4-] [Three] [-6-] [base] [)] [oxyl] [)- , N , - ] [Ethyl] [-5-] [fluorine] [- , N , - ] [Isopropylbenzamide hydrochloride] [] [( , R , )-2-((5-(2-(6- ] [Amine] [-2-] [Methylhexane] [-3-] [base] [)-2,6-] [Diazaspiro] [[3.4]] [pungent] [-6-] [base] [)-3-] [methyl] [-1,2,4-] [Three] [-6-] [base] [)] [oxyl] [)- , N , - ] [Ethyl] [-5-] [fluorine] [- , N , - ] [Isopropylbenzamide] [] [Formate] [] [By targeting compounds] [1] [and]

[19] [The following compounds were synthesized by a similar method as described above] [] [Compound number] [structure] [Start] [Material] [condition] [Spectrum Detailed Information] 2 Formate Compound 63 HCl 1,4- dioxane [LC-MS] [(] [ESI] [)] [(method] [1] [):] R t = 3.028 min, m / z found 528.3 [M+H] +. [SFC] [(] [method]

[12] [):] R t= 1.502 min. 3 Formate Compound 61 HCl 1,4- dioxane [LC-MS] [(] [ESI] [)] [(method] [1] [):] R t = 2.977 min, m / z found 528.4 [M+H] +. 20 HCl salt Compound 57 HCl 1,4- dioxane [LC-MS] [(] [ESI] [)] [(method] [1] [):] R t = 2.890 min, m / z found 542.3 [M+H] +. [SFC] [(] [method] [1] [):] R t= 1.697 min. 30 Compound 54 TFA DCM [LC-MS] [(] [ESI] [)] [(method] [1]): R t = 2.931 min, m / z found 556.3 [M+H] +. [SFC] [(] [method] [2] [):] R t = 4.431 min. 31 Compound 55 TFA DCM [LC-MS] [(] [ESI] [)] [(method] [1]): R t = 2.897 min, m / z found 556.3 [M+H] +. [SFC] [(] [method] [2] [):] R t = 4.997 min. 37 Compound 52 TFA DCM [ , 1 , ] [H NMR] [(] [400 MHz] [,] [Methanol] [- , d , , 4, ] [):] δ8.88 (brs, 1H), 8.46-8.36 (m, 2H), 7.58-7.45 (m, 1H), 7.44-7.26 (m, 2H), 4.07-3.52 (m, 4H), 3.31-3.11 (m, 4H), 2.24-2.02 (m, 3H), 1.99-1.78 (m, 2H), 1.55-1.38 (m, 3H), 1.37-1.20 (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] +. [SFC] [(] [method] [3] [):] R t= 5.566 min. 38 Compound 53 TFA DCM [LC-MS] [(] [ESI] [)] [(method] [1]): R t = 3.26 min, m / z found 561.3 [M+H] +. [SFC] [(] [method] [3] [):] R t= 5.929 min. 26 Compound 51 TFA DCM [LC-MS] [(] [ESI] [)] [(] [method] [1]): R t = 2.98 min, m / z found 514.4 M+H] +. 80 Compound 79 TFA DCM 209 Formate Compound 207 HCl 1,4- dioxane [LC-MS] [(] [ESI] [)] [(method] [1] [):] R t= 2.950 min, m / z found 542.3 [M+H] +. [SFC] [(] [method]

[18] [):] R t= 2.021 min. 210 Compound 208 HCl 1,4- dioxane [LC-MS] [(] [ESI] [)] [(method] [1] [):] R t = 2.919 min, m / z found 542.3 [M+H] +. [SFC] [(] [method]

[18] [):] R t= 2.201 min. 218 Compound 216 TFA DCM 220 HCl salt Compound 216 HCl 1,4- dioxane 221 HCl salt Compound 217 HCl 1,4- dioxane 308 HCl salt Compound 306 HCl / 1, 4- dioxane, MeOH 309 HCl salt Compound 307 HCl / 1, 4- dioxane, MeOH 317 HCl salt Compound 316 HCl / 1, 4- dioxane, MeOH 328 HCl salt Compound 327 HCl / 1, 4- dioxane, MeOH 359 HCl salt Compound 358 HCl / 1, 4- dioxane, MeOH 373 HCl salt Compound 371 HCl / 1, 4- dioxane, MeOH 374 HCl salt Compound 372 HCl / 1, 4- dioxane, MeOH 409 HCl salt Compound 408 HCl / 1, 4- dioxane, ACN [LC-MS] [(] [ESI] [)] [(method] [2]): R t = 1.94 min, m / z found 557.3 [M+H] +. [SFC] [(] [method]

[13] [):] R t = 2.75 min. 413 Formate Compound 412 HCl / 1, 4- dioxane, MeOH [LC-MS] [(] [ESI] [)] [(method] [1]): R t = 2.885 min, m / z found 542.3 [M+H] +. [SFC] [(] [method]

[13] [):] R t = 2.347 min. [Compound] [4] [( , R , )-2-((5-(2-(6-( ] [Dimethylamino] [)-2-] [Methylhexane] [-3-] [base] [)-2,6-] [Diazaspiro] [[3.4]] [pungent] [-6-] [base] [)-1,2,4-] [Three] [-6-] [base] [)] [oxyl] [)- , N , - ] [Ethyl] [-5-] [fluorine] [- , N , - ] [Cymene] []

[0305] (R)-2-((5-(2-(6-amino-2-methylhexan-3-yl)-2,6-diazaspiro[3.4]octan-6-yl)-1,2,4-trioxan-6-yl)oxy)-N-ethyl-5-fluoro-N-isopropylbenzamide hydrochloride ( [Compound] To a mixture of

[65] (180 mg, crude), formaldehyde (0.085 mL, 1.1 mmol) and AcOH (0.043 mL, 0.76 mmol) in MeOH (10 mL) was added NaBH 3CN (72.0 mg, 1.14 mmol), and the resulting mixture was stirred at RT for 2 h. The mixture was filtered and the filtrate was purified by preparative HPLC on Welch Xtimate (column: C18 150 x 30 mm 5 um; eluent: ACN / H 2O (0.225% FA) from 5% to 25%, v / v), and the desired fractions were collected and freeze-dried. The resulting solid was further neutralized with 25% amine (15 mL) and extracted with DCM (20 mL x 2). The combined organic layers were dried over anhydrous Na 2 SO 4 , 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 a yellow solid. [LC-MS] [(] [ESI] [)(method] [1] [):]R t= 2.95 min, m / z found 556.3 [M+H] +. [SFC] [(method] [4] [):]R t= 1.772 min. [Compound] [5] [、]

[32] [、]

[33] [、]

[74] [、]

[81] [、]

[0101] [、]

[0211] [、]

[0212] [、]

[0222] [、]

[0224] [、]

[0231] [、]

[0410] [( , S , )-2-((5-(2-(6-( ] [Dimethylamino] [)-2-] [Methylhexane] [-3-] [base] [)-2,6-] [Diazaspiro] [[3.4]] [pungent] [-6-] [base] [)-1,2,4-] [Three] [-6-] [base] [)] [oxyl] [)- , N , - ] [Ethyl] [-5-] [fluorine] [- , N , - ] [Isopropylbenzamide] [] [Formate] [] [( , *R , )-2-((5-(2-(6-( ] [Dimethylamino] [)-2,6-] [Dimethylheptyl] [-3-] [base] [)-2,6-] [Diazaspiro] [[3.4]] [pungent] [-6-] [base] [)-1,2,4-] [Three] [-6-] [base] [)] [oxyl] [)- , N , - ] [Ethyl] [-5-] [fluorine] [- , N , - ] [Cymene] [] [( , *S , )-2-((5-(2-(6-( ] [Dimethylamino] [)-2,6-] [Dimethylheptyl] [-3-] [base] [)-2,6-] [Diazaspiro] [[3.4]] [pungent] [-6-] [base] [)-1,2,4-] [Three] [-6-] [base] [)] [oxyl] [)- ,N , - ] [Ethyl] [-5-] [fluorine] [- , N , - ] [Cymene] [] [2-((4-(2-(6-(] [Dimethylamino] [)-2-] [Methylhexane] [-3-] [base] [)-2,6-] [Diazaspiro] [[3.4]] [pungent] [-6-] [base] [)] [Da]𠯤 [-3-] [base] [)] [oxyl] [)-5-] [fluorine] [- , N , , , N , - ] [Diisopropylbenzamide] [] [2-((4-(2-(6-(] [Dimethylamino] [)-2-] [Methylhexane] [-3-] [base] [)-2,6-] [Diazaspiro] [[3.4]] [pungent] [-6-] [base] [)] [Da]𠯤 [-3-] [base] [)] [oxyl] [)- , N , - ] [Ethyl] [-5-] [fluorine] [- , N , - ] [Cymene] [] [2-((5-(2-(6-(] [Dimethylamino] [)-2-] [Methylhexane] [-3-] [base] [)-2,6-] [Diazaspiro] [[3.4]] [pungent] [-6-] [base] [)-1,2,4-] [Three] [-6-] [base] [)] [oxyl] [)-5-] [fluorine] [- , N , , , N , - ] [Diisopropylbenzamide] [] [( , *R , )-2-((5-(2-(7-( ] [Dimethylamino] [)-2-] [Methylheptyl] [-3-] [base] [)-2,6-] [Diazaspiro] [[3.4]] [pungent] [-6-] [base] [)-1,2,4-] [Three] [-6-] [base] [)] [oxyl] [)- , N , - ] [Ethyl] [-5-] [fluorine] [- , N , - ] [Cymene] [] [( , *S , )-2-((5-(2-(7-( ] [Dimethylamino] [)-2-] [Methylheptyl] [-3-] [base] [)-2,6-] [Diazaspiro] [[3.4]] [pungent] [-6-] [base] [)-1,2,4-] [Three] [-6-] [base] [)] [oxyl] [)- , N , - ] [Ethyl] [-5-] [fluorine] [- , N , - ] [Cymene] [] [( , *R , )-2-((5-(2-(1-( ] [Dimethylamino] [)-4-] [Methylpentyl] [-3-] [base] [)-2,6-] [Diazaspiro] [[3.4]] [pungent] [-6-] [base] [)-1,2,4-] [Three] [-6-] [base] [)] [oxyl] [)- , N , - ] [Ethyl] [-5-] [fluorine] [- , N , - ] [Isopropylbenzamide] [] [( , *S , )-2-((5-(2-(1-( ] [Dimethylamino] [)-4-] [Methylpentyl] [-3-] [base] [)-2,6-] [Diazaspiro] [[3.4]] [pungent] [-6-] [base] [)-1,2,4-] [Three] [-6-] [base] [)] [oxyl] [)- , N , - ] [Ethyl] [-5-] [fluorine] [- , N , - ] [Isopropylbenzamide] [] [( , *R , )-2-((5-(2-(1-((2- ] [Amine] [-2-] [Pendant oxyethyl] [)(] [methyl] [)] [Amine] [)-4-] [Methylpentyl] [-3-] [base] [)-2,6-] [Diazaspiro] [[3.4]] [pungent] [-6-] [base] [)-1,2,4-] [Three] [-6-] [base] [)] [oxyl] [)- , N , - ] [Ethyl] [-5-] [fluorine] [- , N , - ] [Cymene] [] [( , R , )-2-((5-(2-(6-( ] [Dimethylamino] [)-2-] [Methylhexane] [-3-] [base] [)-2,6-] [Diazaspiro] [[3.4]] [pungent] [-6-] [base] [)-3-] [Methoxy] [-1,2,4-] [Three] [-6-] [base] [)] [oxyl] [)- , N , - ] [Ethyl] [-5-] [fluorine] [- , N , - ] [Cymene] [] [Formate] [] [By targeting compounds] [4] [The following compounds were synthesized by a similar method as described above] [] [Compound number] [structure] [Start] [Material] [Spectrum Detailed Information] 5 Formate Compound 66 [LC-MS] [(method] [1] [):] R t = 2.977 min, m / z found 556.4 [M+H] + . [SFC] [(] [method] [4] [):] R t= 1.402 min. 32 Compound 30 [LC-MS] [(] [ESI] [)] [(method] [2] [):] R t = 2.043 min, m / z found 584.3 [M+H] + . [SFC] [(] [method] [2] [):] R t = 4.431 min. 33 Compound 31 [LC-MS] [(] [ESI] [)] [(method] [2] [):] R t = 2.008 min, m / z found 584.3 [M+H] + . [SFC] [(] [method] [2] [):] R t = 4.997 min. 74 Compound 73 [LC-MS] [(] [ESI] [)] [(method] [2] [):] R t = 1.933 min, m / z found 569.4 [M+H] + . 81 Compound 80 [] 101 Compound 97 [] 211 Compound 209 [LC-MS] [(] [ESI] [)] [(method] [2] [):] R t = 1.946 min, m / z found 570.3 [M+H] + . [SFC] [(] [method] [8] [):] R t = 2.243 min. 212 Compound 210 [LC-MS] [(] [ESI] [)] [(method] [1] [):] R t = 3.021 min, m / z found 570.3 [M+H] + . [SFC] [(] [method] [8] [):] R t= 2.431 min. 222 Compound 220 [] 224 Compound 221 [] 231 Compound 230 [LC-MS] [(] [ESI] [)] [(method] [1] [):] R t = 2.858 min, m / z found 585.3 [M+H] +. [SFC] [(] [method] [6] [):] R t= 1.454 min. 410 Formate Compound 407 [LC-MS] [(] [ESI] [)] [(method] [2] [):] R t = 2.066 min, m / z found 586.3 [M+H] + . [SFC] [(] [method]

[14] [):] R t= 2.582 min. [Compound]

[75] [、]

[76] [( , *R , )-2-((4-(2-(6-( ] [Dimethylamino] [)-2-] [Methylhexane] [-3-] [base] [)-2,6-] [Diazaspiro] [[3.4]] [pungent] [-6-] [base] [)] [Da]𠯤 [-3-] [base] [)] [oxyl] [)-5-] [fluorine] [- , N , , , N , - ] [Diisopropylbenzamide] [] [( , *S , )-2-((4-(2-(6-( ] [Dimethylamino] [)-2-] [Methylhexane] [-3-] [base] [)-2,6-] [Diazaspiro] [[3.4]] [pungent] [-6-] [base] [)] [Da]𠯤 [-3-] [base] [)] [oxyl] [)-5-] [fluorine] [- , N , , , N , - ] [Diisopropylbenzamide] []

[0306] 2-((4-(2-(6-(dimethylamino)-2-methylhexan-3-yl)-2,6-diazaspiro[3.4]octan-6-yl)thiazolin-3-yl)oxy)-5-fluoro-N, N-diisopropylbenzamide ( [Compound]

[74] ) (600 mg) was separated by chiral HPLC on a CHIRALPAK IG (column: 250 x 30 mm 10 μm; mobile phase: A: heptane, B: EtOH, A: B from 20% to 70% (v / v); flow rate: 25 mL / min) to give the title compound as a white solid. [Compound]

[75] (92 mg, 15%) and [Compound]

[76] (84 mg). [Compound]

[75] [LC-MS] [(] [ESI] [)(method] [2] [):]R t= 1.915 min, m / z found 569.3 [M+H] +. [Chirality] [HPLC] [(method] [4] [):]R t= 4.842 min. [Compound]

[76] [LC-MS] [(] [ESI] [)(method] [2] [):]R t= 1.924 min, m / z found 569.3 [M+H] +. [Chirality] [HPLC] [(method] [4] [):]R t= 6.200 min. [Compound]

[77] [、]

[78] [( , *R , )-2-((4-(2-(6-( ] [Dimethylamino] [)-2-] [Methylhexane] [-3-] [base] [)-2,6-] [Diazaspiro] [[3.4]] [pungent] [-6-] [base] [)] [Da]𠯤 [-3-] [base] [)] [oxyl] [)- , N , - ] [Ethyl] [-5-] [fluorine] [- ,N , - ] [Cymene] [] [( , *S , )-2-((4-(2-(6-( ] [Dimethylamino] [)-2-] [Methylhexane] [-3-] [base] [)-2,6-] [Diazaspiro] [[3.4]] [pungent] [-6-] [base] [)] [Da]𠯤 [-3-] [base] [)] [oxyl] [)- , N , - ] [Ethyl] [-5-] [fluorine] [- , N , - ] [Cymene]

[0307] 2-((4-(2-(6-(dimethylamino)-2-methylhexan-3-yl)-2,6-diazaspiro[3.4]octan-6-yl)thiazolin-3-yl)oxy)-N-ethyl-5-fluoro-N-isopropylbenzamide ( [Compound]

[81] ) (31.0 mg) was separated by SFC on a Chiralpak IE (column: 250 x 30 mm 10 μm; eluent: 100% MeOH (0.1% amine); flow rate: 25 mL / min) to give the title compound as a white solid. [Compound]

[77] (4.2 mg) and [Compound]

[78] (1.3 mg). [Compound]

[77] [LC-MS] [(] [ESI] [)(method] [3] [):]R t= 5.039 min, m / z found 555.3 [M+H] +. [Chirality] [HPLC] [(method] [2] [):]R t= 7.719 min. [Compound]

[78] [LC-MS] [(] [ESI] [)(method] [3] [):]R t= 4.870 min, m / z found 555.3 [M+H] +. [Chirality] [HPLC] [(method] [2] [):]R t= 8.754 min. [Compound]

[0105] [、]

[0106] [( , *R , )-2-((5-(2-(6-( ] [Dimethylamino] [)-2-] [Methylhexane] [-3-] [base] [)-2,6-] [Diazaspiro] [[3.4]] [pungent] [-6-] [base] [)-1,2,4-] [Three] [-6-] [base] [)] [oxyl] [)-5-] [fluorine] [- , N , , , N , - ] [Diisopropylbenzamide] [] [( , *S , )-2-((5-(2-(6-( ] [Dimethylamino] [)-2-] [Methylhexane] [-3-] [base] [)-2,6-] [Diazaspiro] [[3.4]] [pungent] [-6-] [base] [)-1,2,4-] [Three] [-6-] [base] [)] [oxyl] [)-5-] [fluorine] [- , N , , , N , - ] [Diisopropylbenzamide] []

[0308] 2-((5-(2-(6-(dimethylamino)-2-methylhexan-3-yl)-2,6-diazaspiro[3.4]octan-6-yl)-1,2,4-trioxan-6-yl)oxy)-5-fluoro- N, N-diisopropylbenzamide ( [Compound]

[0101] ) (1.5 g) was obtained by SFC on a Chiralpak IG (column: 250 x 50 mm, 10 μm; mobile phase: A: supercritical CO 2 , B: MeOH (0.1% amine), A: B = 55:45, 200 mL / min; column temperature: 38; nozzle pressure: 100 bar; nozzle temperature: 60; evaporator temperature: 20; trimmer temperature: 25; wavelength: 220 nm) to give the title compound as a white solid. [Compound] (600 mg, 40.0% yield) and [Compound]

[0106] (600 mg, 40.0% yield). [Compound]

[0102] [( , *R , )-2-((5-(2-(6-( ] [Dimethylamino] [)-2-] [Methylhexane] [-3-] [base] [)-2,6-] [Diazaspiro] [[3.4]] [pungent] [-6-] [base] [)-1,2,4-] [Three] [-6-] [base] [)] [oxyl] [)-5-] [fluorine] [- , N , , , N , - ] [Diisopropylbenzamide] [] [Fumarate] []

[0309] (*R)-2-((5-(2-(6-(dimethylamino)-2-methylhexan-3-yl)-2,6-diazaspiro[3.4]octan-6-yl)-1,2,4-trioxan-6-yl)oxy)-5-fluoro-N, N-diisopropylbenzamide ( [Compound] To a solution of

[0105] (300 mg, 0.527 mmol) in ACN (12 mL) and water (4 mL) was added fumaric acid (123 mg, 1.06 mmol). After a clear solution was formed, the mixture was concentrated under reduced pressure, and the resulting residue was added to a mixture of ACN (3 mL) and water (10 mL). The mixture was lyophilized to dryness to give the title compound (422 mg) as a white solid. [ , 1 , ] [H NMR] [(] [400 MHz] [,methanol] [- , d , , 4, ] [):]δ = 8.50 (s, 1H), 7.50-7.15 (m, 3H), 6.72 (s, 4H), 4.51-3.89 (m, 7H), 3.86-3.69 (m, 2H), 3.61-3.49 (m, 1H), 3.25-3.07 (m, 3H), 2.88 (s, 6H), 2.50-2.20 (m, 2H), 2.19-2.06 (m, 1H), 1.97-1.77 (m, 2H), 1.75-1.57 (m, 2H), 1.51 (d, J=6.8 Hz, 3H), 1.37-1.14 (m, 6H), 1.11-0.97 (m, 6H), 0.78 (d, J=6.0 Hz, 3H). [LC-MS] [(] [ESI] [)(method] [2] [):]R t= 2.08 min, m / z found 570.3 [M+H] +. [SFC] [(method] [4] [):]Rt = 1.284 min. [Compound]

[0103] [、]

[0112] [、]

[0114] [、]

[0122] [、]

[0123] [、]

[0127] [、]

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[0386] [、]

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[0394] [、]

[0397] [( , *S , )-2-((5-(2-(6-( ] [Dimethylamino] [)-2-] [Methylhexane] [-3-] [base] [)-2,6-] [Diazaspiro] [[3.4]] [pungent] [-6-] [base] [)-1,2,4-] [Three] [-6-] [base] [)] [oxyl] [)-5-] [fluorine] [- , N , , , N , - ] [Diisopropylbenzamide] [] [Fumarate] [] [ , N , ] [-] [Ethyl] [-5-] [fluorine] [- , N , - ] [Isopropyl] [-2-((5-(2-(( , R , )-6-((( , R , )-1- ] [Methoxypropyl] [-2-] [base] [)] [Amine] [)-2-] [Methylhexane] [-3-] [base] [)-2,6-] [Diazaspiro] [[3.4]] [pungent] [-6-] [base] [)-1,2,4-] [Three] [-6-] [base] [)] [oxyl] [)] [Benzamide] [Fumarate] [( , R , )-2-((5-(2-(6-((3,3- ] [Difluoropropyl] [)] [Amine] [)-2-] [Methylhexane] [-3-] [base] [)-2,6-] [Diazaspiro] [[3.4]] [pungent] [-6-] [base] [)-1,2,4-] [Three] [-6-] [base] [)] [oxyl] [)- , N , - ] [Ethyl] [-5-] [fluorine] [- , N , - ] [Cymene] [] [Fumarate] [] [( , *R , )- ,N , - ] [Ethyl] [-5-] [fluorine] [- , N , - ] [Isopropyl] [-2-((5-(2-(6-(] [Isopropyl] [(] [methyl] [)] [Amine] [)-2-] [Methylhexane] [-3-] [base] [)-2,6-] [Diazaspiro] [[3.4]] [pungent] [-6-] [base] [)-1,2,4-] [Three] [-6-] [base] [)] [oxyl] [)] [Benzamide] [] [Fumarate] [] [( , *S , )- , N , - ] [Ethyl] [-5-] [fluorine] [- , N , - ] [Isopropyl] [-2-((5-(2-(6-(] [Isopropyl] [(] [methyl] [)] [Amine] [)-2-] [Methylhexane] [-3-] [base] [)-2,6-] [Diazaspiro] [[3.4]] [pungent] [-6-] [base] [)-1,2,4-] [Three] [-6-] [base] [)] [oxyl] [)] [Benzamide] [] [Fumarate] [] [( , *R , )- , N , - ] [Ethyl] [-5-] [fluorine] [- , N , - ] [Isopropyl] [-2-((5-(2-(2-] [methyl] [-6-(] [methyl] [(] [Propyl] [)] [Amine] [)] [Self] [-3-] [base] [)-2,6-] [Diazaspiro] [[3.4]] [pungent] [-6-] [base] [)-1,2,4-] [Three] [-6-] [base] [)] [oxyl] [)] [Benzamide] [] [Fumarate] [] [( , *S , )- , N , - ] [Ethyl] [-5-] [fluorine] [- , N , - ] [Isopropyl] [-2-((5-(2-(2-] [methyl] [-6-(] [methyl] [(] [Propyl] [)] [Amine] [)] [Self] [-3-] [base] [)-2,6-] [Diazaspiro] [[3.4]] [pungent] [-6-] [base] [)-1,2,4-] [Three] [-6-] [base] [)] [oxyl] [)] [Benzamide] [] [Fumarate] [] [( , *R , )- , N , - ] [Ethyl] [-2-((5-(2-(6-(] [Ethyl] [(] [methyl] [)] [Amine] [)-2-] [Methylhexane] [-3-] [base] [)-2,6-] [Diazaspiro] [[3.4]] [pungent] [-6-] [base] [)-1,2,4-] [Three] [-6-] [base] [)] [oxyl] [)-5-] [fluorine] [- , N , - ] [Cymene] [] [Fumarate] [] [( , *S , )- , N , - ] [Ethyl] [-2-((5-(2-(6-(] [Ethyl] [(] [methyl] [)] [Amine] [)-2-] [Methylhexane] [-3-] [base] [)-2,6-] [Diazaspiro] [[3.4]] [pungent] [-6-] [base] [)-1,2,4-] [Three] [-6-] [base] [)] [oxyl] [)-5-] [fluorine] [- , N , - ] [Cymene] [] [Fumarate] [] [( , R , )- , N , - ] [Ethyl] [-5-] [fluorine] [- , N , - ] [Isopropyl] [-2-((5-(2-(6-((2-] [Methoxy] [-2-] [Methylpropyl] [)] [Amine] [)-2-] [Methylhexane] [-3-] [base] [)-2,6-] [Diazaspiro] [[3.4]] [pungent] [-6-] [base] [)-1,2,4-] [Three] [-6-] [base] [)] [oxyl] [)] [Benzamide] [] [Fumarate] [] [( , R , )- , N , - ] [Ethyl] [-5-] [fluorine] [- , N , - ] [Isopropyl] [-2-((5-(2-(6-((2-] [Methoxy] [-2-] [Methylpropyl] [)(] [methyl] [)] [Amine] [)-2-] [Methylhexane] [-3-] [base] [)-2,6-] [Diazaspiro] [[3.4]] [pungent] [-6-] [base] [)-1,2,4-] [Three] [-6-] [base] [)] [oxyl] [)] [Benzamide] [] [Fumarate] [] [( , R , )- , N , - ] [Ethyl] [-5-] [fluorine] [-2-((5-(2-(6-((2-] [Hydroxy] [-2-] [Methylpropyl] [)(] [methyl] [)] [Amine] [)-2-] [Methylhexane] [-3-] [base] [)-2,6-] [Diazaspiro] [[3.4]] [pungent] [-6-] [base] [)-1,2,4-] [Three] [-6-] [base] [)] [oxyl] [)- , N , - ] [Isopropylbenzamide] [] [Fumarate] [] [( , R , )- , N , - ] [Ethyl] [-5-] [fluorine] [- , N , - ] [Isopropyl] [-2-((5-(2-(6-((3-] [Methoxypropyl] [)(] [methyl] [)] [Amine] [)-2-] [Methylhexane] [-3-] [base] [)-2,6-] [Diazaspiro] [[3.4]] [pungent] [-6-] [base] [)-1,2,4-] [Three] [-6-] [base] [)] [oxyl] [)] [Benzamide] [] [Fumarate] [] [( ,*R , )-2-((5-(2-(6-((3-( ] [Dimethylamino] [)-3-] [Pendant oxypropyl] [)(] [methyl] [)] [Amine] [)-2-] [Methylhexane] [-3-] [base] [)-2,6-] [Diazaspiro] [[3.4]] [pungent] [-6-] [base] [)-1,2,4-] [Three] [-6-] [base] [)] [oxyl] [)-5-] [fluorine] [- , N , , , N , - ] [Diisopropylbenzamide] [] [Fumarate] [] [( , *S , )-2-((5-(2-(6-((3-( ] [Dimethylamino] [)-3-] [Pendant oxypropyl] [)(] [methyl] [)] [Amine] [)-2-] [Methylhexane] [-3-] [base] [)-2,6-] [Diazaspiro] [[3.4]] [pungent] [-6-] [base] [)-1,2,4-] [Three] [-6-] [base] [)] [oxyl] [)-5-] [fluorine] [- , N , , , N , - ] [Diisopropylbenzamide] [] [Fumarate] [] [( , R , )- , N , - ] [Ethyl] [-5-] [fluorine] [- , N , - ] [Isopropyl] [-2-((5-(2-(2-] [methyl] [-6-(] [methyl] [(2-( , N , - ] [Methylacetamido] [)] [Ethyl] [)] [Amine] [)] [Self] [-3-] [base] [)-2,6-] [Diazaspiro] [[3.4]] [pungent] [-6-] [base] [)-1,2,4-] [Three] [-6-] [base] [)] [oxyl] [)] [Benzamide] [] [Fumarate] [] [( , R , )-2-((5-(2-(6-((2,2- ] [Dimethoxyethyl] [)(] [methyl] [)] [Amine] [)-2-] [Methylhexane] [-3-] [base] [)-2,6-] [Diazaspiro] [[3.4]] [pungent] [-6-] [base] [)-1,2,4-] [Three] [6-] [base] [)] [oxyl] [)- , N , - ] [Ethyl] [-5-] [fluorine] [- , N , - ] [Cymene] [] [Fumarate] [] [( , R , )-2-((5-(2-(6-((4-( ] [Dimethylamino] [)-4-] [Pendant oxybutyl] [)(] [methyl] [)] [Amine] [)-2-] [Methylhexane] [-3-] [base] [)-2,6-] [Diazaspiro] [[3.4]] [pungent] [-6-] [base] [)-1,2,4-] [Three] [-6-] [base] [)] [oxyl] [)- , N , - ] [Ethyl] [-5-] [fluorine] [- , N , - ] [Cymene] [] [Fumarate] [] [ , N , ] [-] [Ethyl] [-5-] [fluorine] [- , N , - ] [Isopropyl] [-2-((5-(2-(( , R , )-6-((( , R , )-1- ] [Methoxypropyl] [-2-] [base] [)(] [methyl] [)] [Amine] [)-2-] [Methylhexane] [-3-] [base] [)-2,6-] [Diazaspiro] [[3.4]] [pungent] [-6-] [base] [)-1,2,4-] [Three] [-6-] [base] [)] [oxyl] [)] [Benzamide] [] [Fumarate] [] [ , N , ] [-] [Ethyl] [-5-] [fluorine] [- , N , - ] [Isopropyl] [-2-((5-(2-(( , R , )-6-((( , S , )-1- ] [Methoxypropyl] [-2-] [base] [)(] [methyl] [)] [Amine] [)-2-] [Methylhexane] [-3-] [base] [)-2,6-] [Diazaspiro] [[3.4]] [pungent] [-6-] [base] [)-1,2,4-] [Three] [-6-] [base] [)] [oxyl] [)] [Benzamide] [] [Fumarate] [] [( , R , )-2-((5-(2-(6-((1,3- ] [Dimethoxypropane] [-2-] [base] [)] [Amine] [)-2-] [Methylhexane] [-3-] [base] [)-2,6-] [Diazaspiro] [[3.4]] [pungent] [-6-] [base] [)-1,2,4-] [Three] [-6-] [base] [)] [oxyl] [)- , N , - ] [Ethyl] [-5-] [fluorine] [- , N , - ] [Cymene] [] [Fumarate] [] [( , R , )-2-((5-(2-(6-((1,3- ] [Dimethoxypropane] [-2-] [base] [)(] [methyl] [)] [Amine] [)-2-] [Methylhexane] [-3-] [base] [)-2,6-] [Diazaspiro] [[3.4]] [pungent] [-6-] [base] [)-1,2,4-] [Three] [-6-] [base] [)] [oxyl] [)- , N , - ] [Ethyl] [-5-] [fluorine] [- , N , - ] [Cymene] [] [Fumarate] [] [ , N , ] [-] [Ethyl] [-5-] [fluorine] [-2-((5-(2-(( , R , )-6-((( , R , )-1- ] [Hydroxy] [-3-] [Methoxypropyl] [-2-] [base] [)(] [methyl] [)] [Amine] [)-2-] [Methylhexane] [-3-] [base] [)-2,6-] [Diazaspiro] [[3.4]] [pungent] [-6-] [base] [)-1,2,4-] [Three] [-6-] [base] [)] [oxyl] [)- , N , - ] [Isopropylbenzamide] [] [Fumarate] [] [ , N , ] [-] [Ethyl] [-5-] [fluorine] [-2-((5-(2-(( , R , )-6-((( , S , )-1- ] [Hydroxy] [-3-] [Methoxypropyl] [-2-] [base] [)(] [methyl] [)] [Amine] [)-2-] [Methylhexane] [-3-] [base] [)-2,6-] [Diazaspiro] [[3.4]] [pungent] [-6-] [base] [)-1,2,4-] [Three] [-6-] [base] [)] [oxyl] [)- , N , - ] [Isopropylbenzamide] [] [Fumarate] [] [ , N , ] [-] [Ethyl] [-5-] [fluorine] [-2-((5-(2-((3 , R , )-6-((3- ] [Hydroxy] [-2-] [Methoxypropyl] [)(] [methyl] [)] [Amine] [)-2-] [Methylhexane] [-3-] [base] [)-2,6-] [Diazaspiro] [[3.4]] [pungent] [-6-] [base] [)-1,2,4-] [Three] [-6-] [base] [)] [oxyl] [)- , N , - ] [Cymene] [] [Fumarate] [] [2-((5-(2-((3 , R , )-6-((2,3- ] [Dimethoxypropyl] [)] [Amine] [)-2-] [Methylhexane] [-3-] [base] [)-2,6-] [Diazaspiro] [[3.4]] [pungent] [-6-] [base] [)-1,2,4-] [Three] [-6-] [base] [)] [oxyl] [)- , N , - ] [Ethyl] [-5-] [fluorine] [- , N , - ] [Isopropylbenzamide] [] [Fumarate] [] [2-((5-(2-(( , R , )-6-(((* , R , )-2,3- ] [Dimethoxypropyl] [)(] [methyl] [)] [Amine] [)-2-] [Methylhexane] [-3-] [base] [)-2,6-] [Diazaspiro] [[3.4]] [pungent] [-6-] [base] [)-1,2,4-] [Three] [-6-] [base] [)] [oxyl] [)- , N , - ] [Ethyl] [-5-] [fluorine] [- , N , - ] [Isopropylbenzamide] [] [Fumarate] [] [2-((5-(2-(( , R , )-6-(((* , S , )-2,3- ] [Dimethoxypropyl] [)(] [methyl] [)] [Amine] [)-2-] [Methylhexane] [-3-] [base] [)-2,6-] [Diazaspiro] [[3.4]] [pungent] [-6-] [base] [)-1,2,4-] [Three] [-6-] [base] [)] [oxyl] [)- , N , - ] [Ethyl] [-5-] [fluorine] [- , N , - ] [Cymene] [] [Fumarate] [] [2-((5-(2-((3 , R , )-6-((4-( ] [Dimethylamino] [)-4-] [Side oxide] [-2-] [base] [)(] [methyl] [)] [Amine] [)-2-] [Methylhexane] [-3-] [base] [)-2,6-] [Diazaspiro] [[3.4]] [pungent] [-6-] [base] [)-1,2,4-] [Three] [-6-] [base] [)] [oxyl] [)- , N , - ] [Ethyl] [-5-] [fluorine] [- , N , - ] [Cymene] [] [Fumarate] [] [2-((5-(2-((3 , R , )-6-((3-( ] [Dimethylamino] [)-2-] [methyl] [-3-] [Pendant oxypropyl] [)(] [methyl] [)] [Amine] [)-2-] [Methylhexane] [-3-] [base] [)-2,6-] [Diazaspiro] [[3.4]] [pungent] [-6-] [base] [)-1,2,4-] [Three] [-6-] [base] [)] [oxyl] [)- , N , - ] [Ethyl] [-5-] [fluorine] [- , N , - ] [Cymene] [] [Fumarate] [] [2-((5-(2-(( , R , )-6-((( , *R , )-4-( ] [Dimethylamino] [)-4-] [Side oxide] [-2-] [base] [)(] [methyl] [)] [Amine] [)-2-] [Methylhexane] [-3-] [base] [)-2,6-] [Diazaspiro] [[3.4]] [pungent] [-6-] [base] [)-1,2,4-] [Three] [-6-] [base] [)] [oxyl] [)- , N , - ] [Ethyl] [-5-] [fluorine] [- , N , - ] [Cymene] [] [Fumarate] [] [2-((5-(2-(( , R , )-6-((( , *S , )-4-( ] [Dimethylamino] [)-4-] [Side oxide] [-2-] [base] [)(] [methyl] [)] [Amine] [)-2-] [Methylhexane] [-3-] [base] [)-2,6-] [Diazaspiro] [[3.4]] [pungent] [-6-] [base] [)-1,2,4-] [Three] [-6-] [base] [)] [oxyl] [)- , N , - ] [Ethyl] [-5-] [fluorine] [- , N , - ] [Cymene] [] [Fumarate] [] [2-((5-(2-(( , R , )-6-((( , *R , )-3-( ] [Dimethylamino] [)-2-] [methyl] [-3-] [Pendant oxypropyl] [)(] [methyl] [)] [Amine] [)-2-] [Methylhexane] [-3-] [base] [)-2,6-] [Diazaspiro] [[3.4]] [pungent] [-6-] [base] [)-1,2,4-] [Three] [-6-] [base] [)] [oxyl] [)- , N , - ] [Ethyl] [-5-] [fluorine] [- , N , - ] [Cymene] [] [Fumarate] [] [2-((5-(2-(( , R , )-6-((( , *S , )-3-( ] [Dimethylamino] [)-2-] [methyl] [-3-] [Pendant oxypropyl] [)(] [methyl] [)] [Amine] [)-2-] [Methylhexane] [-3-] [base] [)-2,6-] [Diazaspiro] [[3.4]] [pungent] [-6-] [base] [)-1,2,4-] [Three] [-6-] [base] [)] [oxyl] [)- , N , - ] [Ethyl] [-5-] [fluorine] [- , N , - ] [Isopropylbenzamide] [] [Fumarate] [] [ , N , ] [-] [Ethyl] [-5-] [fluorine] [- , N , - ] [Isopropyl] [-2-((5-(2-(( , R , )-2- ] [methyl] [-6-(] [methyl] [(( , R , )-4-( ] [Methylamino] [)-4-] [Sideoxybutane] [-2-] [base] [)] [Amine] [)] [Self] [-3-] [base] [)-2,6-] [Diazaspiro] [[3.4]] [pungent] [-6-] [base] [)-1,2,4-] [Three] [-6-] [base] [)] [oxyl] [)] [Benzamide] [] [Fumarate] [] [ , N , ] [-] [Ethyl] [-5-] [fluorine] [- , N , - ] [Isopropyl] [-2-((5-(2-(( , R , )-2- ] [methyl] [-6-(] [methyl] [(( , S , )-4-( ] [Methylamino] [)-4-] [Side oxide] [-2-] [base] [)] [Amine] [)] [Self] [-3-] [base] [)-2,6-] [Diazaspiro] [[3.4]] [pungent] [-6-] [base] [)-1,2,4-] [Three] [-6-] [base] [)] [oxyl] [)] [Benzamide] [] [Fumarate] [] [ , N , ] [-] [Ethyl] [-5-] [fluorine] [- , N , - ] [Isopropyl] [-2-((5-(2-(( , R , )-2- ] [methyl] [-6-(] [methyl] [(( , R , )-2- ] [methyl] [-3-(] [Methylamino] [)-3-] [Pendant oxypropyl] [)] [Amine] [)] [Self] [-3-] [base] [)-2,6-] [Diazaspiro] [[3.4]] [pungent] [-6-] [base] [)-1,2,4-] [Three] [-6-] [base] [)] [oxyl] [)] [Benzamide] [] [Fumarate] [] [ , N , ] [-] [Ethyl] [-5-] [fluorine] [- , N, - ] [Isopropyl] [-2-((5-(2-(( , R , )-2- ] [methyl] [-6-(] [methyl] [(( , S , )-2- ] [methyl] [-3-(] [Methylamino] [)-3-] [Pendant oxypropyl] [)] [Amine] [)] [Self] [-3-] [base] [)-2,6-] [Diazaspiro] [[3.4]] [pungent] [-6-] [base] [)-1,2,4-] [Three] [-6-] [base] [)] [oxyl] [)] [Benzamide] [] [Fumarate] [] [2-((5-(2-(( , *R , )-6-((( , R , )-4- ] [Amine] [-4-] [Side oxide] [-2-] [base] [)(] [methyl] [)] [Amine] [)-2-] [Methylhexane] [-3-] [base] [)-2,6-] [Diazaspiro] [[3.4]] [pungent] [-6-] [base] [)-1,2,4-] [Three] [-6-] [base] [)] [oxyl] [)-5-] [fluorine] [- , N , , , N , - ] [Diisopropylbenzamide] [] [Fumarate] [] [2-((5-(2-(( , *R , )-6-(((S)-4- ] [Amine] [-4-] [Side oxide] [-2-] [base] [)(] [methyl] [)] [Amine] [)-2-] [Methylhexane] [-3-] [base] [)-2,6-] [Diazaspiro] [[3.4]] [pungent] [-6-] [base] [)-1,2,4-] [Three] [-6-] [base] [)] [oxyl] [)-5-] [fluorine] [- , N , , , N , - ] [Diisopropylbenzamide] [] [Fumarate] [] [2-((5-(2-(( , *R , )-6-((( , R , )-3- ] [Amine] [-2-] [methyl] [-3-] [Pendant oxypropyl] [)(] [methyl] [)] [Amine] [)-2-] [Methylhexane] [-3-] [base] [)-2,6-] [Diazaspiro] [[3.4]] [pungent] [-6-] [base] [)-1,2,4-] [Three] [-6-] [base] [)] [oxyl] [)-5-] [fluorine] [- , N , , , N , - ] [Diisopropylbenzamide] [] [Fumarate] [] [2-((5-(2-(( , *R , )-6-(((S)-3- ] [Amine] [-2-] [methyl] [-3-] [Pendant oxypropyl] [)(] [methyl] [)] [Amine] [)-2-] [Methylhexane] [-3-] [base] [)-2,6-] [Diazaspiro] [[3.4]] [pungent] [-6-] [base] [)-1,2,4-] [Three] [-6-] [base] [)] [oxyl] [)-5-] [fluorine] [- , N , , , N , - ] [Diisopropylbenzamide] [] [Fumarate] [] [( , *R , )-2-((5-(2-(1- ] [Amine] [-4-] [Methylpentyl] [-3-] [base] [)-2,6-] [Diazaspiro] [[3.4]] [pungent] [-6-] [base] [)-1,2,4-] [Three] [-6-] [base] [)] [oxyl] [)- , N , - ] [Ethyl] [-5-] [fluorine] [- , N , - ] [Cymene] [] [Fumarate] [] [( , *R , )-2-((5-(2-(1-( ] [Dimethylamino] [)-4-] [Methylpentyl] [-3-] [base] [)-2,6-] [Diazaspiro] [[3.4]] [pungent] [-6-] [base] [)-1,2,4-] [Three] [-6-] [base] [)] [oxyl] [)- , N , - ] [Ethyl] [-5-] [fluorine] [- , N , - ] [Cymene] [] [Fumarate] [] [( , *S , )-2-((5-(2-(1-( ] [Dimethylamino] [)-4-] [Methylpentyl] [-3-] [base] [)-2,6-] [Diazaspiro] [[3.4]] [pungent] [-6-] [base] [)-1,2,4-] [Three] [-6-] [base] [)] [oxyl] [)- , N , - ] [Ethyl] [-5-] [fluorine] [- , N , - ] [Isopropylbenzamide] [] [Fumarate] [] [( , *R , )- , N , - ] [Ethyl] [-5-] [fluorine] [- , N , - ] [Isopropyl] [-2-((5-(2-(1-((2-] [Methoxyethyl] [)] [Amine] [)-4-] [Methylpentyl] [-3-] [base] [)-2,6-] [Diazaspiro] [[3.4]] [pungent] [-6-] [base] [)-1,2,4-] [Three] [-6-] [base] [)] [oxyl] [)] [Benzamide] [] [Fumarate] [] [( , R , )- , N , - ] [Ethyl] [-5-] [fluorine] [- , N , - ] [Isopropyl] [-2-((5-(2-(6-((2-] [Methoxyethyl] [-1,1- , d , , 2, )( ] [methyl] [)] [Amine] [)-2-] [Methylhexane] [-3-] [base] [)-2,6-] [Diazaspiro] [[3.4]] [pungent] [-6-] [base] [)-1,2,4-] [Three] [-6-] [base] [)] [oxyl] [)] [Benzamide] [] [Fumarate] [] [ , N , ] [-] [Ethyl] [-5-] [fluorine] [- , N , - ] [Isopropyl] [-2-((5-(2-((3 , *R , ,5 , *R, )-6-((2- ] [Methoxyethyl] [)(] [methyl] [)] [Amine] [)-2,5-] [Dimethylhexane] [-3-] [base] [)-2,6-] [Diazaspiro] [[3.4]] [pungent] [-6-] [base] [)-1,2,4-] [Three] [-6-] [base] [)] [oxyl] [)] [Benzamide] [] [Fumarate] [] [ , N , ] [-] [Ethyl] [-5-] [fluorine] [- , N , - ] [Isopropyl] [-2-((5-(2-((3 , *S , ,5 , *R , )-6-((2- ] [Methoxyethyl] [)(] [methyl] [)] [Amine] [)-2,5-] [Dimethylhexane] [-3-] [base] [)-2,6-] [Diazaspiro] [[3.4]] [pungent] [-6-] [base] [)-1,2,4-] [Three] [-6-] [base] [)] [oxyl] [)] [Benzamide] [] [Fumarate] [] [ , N , ] [-] [Ethyl] [-5-] [fluorine] [- , N , - ] [Isopropyl] [-2-((5-(2-((3 , *R , ,5 , *S , )-6-((2- ] [Methoxyethyl] [)(] [methyl] [)] [Amine] [)-2,5-] [Dimethylhexane] [-3-] [base] [)-2,6-] [Diazaspiro] [[3.4]] [pungent] [-6-] [base] [)-1,2,4-] [Three] [-6-] [base] [)] [oxyl] [)] [Benzamide] [] [Fumarate] [] [ , N , ] [-] [Ethyl] [-5-] [fluorine] [- , N , - ] [Isopropyl] [-2-((5-(2-((3 , *S , ,5 , *S , )-6-((2- ] [Methoxyethyl] [)(] [methyl] [)] [Amine] [)-2,5-] [Dimethylhexane] [-3-] [base] [)-2,6-] [Diazaspiro] [[3.4]] [pungent] [-6-] [base] [)-1,2,4-] [Three] [-6-] [base] [)] [oxyl] [)] [Benzamide] [] [Fumarate] [] [( , R , )-2-((5-(2-(6-((2- ] [Acetamidoethyl] [)(] [methyl] [)] [Amine] [)-2-] [Methylhexane] [-3-] [base] [)-2,6-] [Diazaspiro] [[3.4]] [pungent] [-6-] [base] [)-1,2,4-] [Three] [-6-] [base] [)] [oxyl] [)- , N , - ] [Ethyl] [-5-] [fluorine] [- , N , - ] [Cymene] [] [Fumarate] [] [( , R , )-2-((5-(2-(6-((1,3- ] [Dihydroxypropyl] [-2-] [base] [)(] [methyl] [)] [Amine] [)-2-] [Methylhexane] [-3-] [base] [)-2,6-] [Diazaspiro] [[3.4]] [pungent] [-6-] [base] [)-1,2,4-] [Three] [-6-] [base] [)] [oxyl] [)- , N , - ] [Ethyl] [-5-] [fluorine] [- , N , - ] [Cymene] [] [Fumarate] [] [ , N , ] [-] [Ethyl] [-5-] [fluorine] [- , N , - ] [Isopropyl] [-2-((5-(2-(6-((2-] [Methoxyethyl] [)(] [methyl] [)] [Amine] [)-2,4-] [Dimethylhexane] [-3-] [base] [)-2,6-] [Diazaspiro] [[3.4]] [pungent] [-6-] [base] [)-1,2,4-] [Three] [-6-] [base] [)] [oxyl] [)] [Benzamide] [(] [ , R , ] [, , S , ] [and] [ , S , ] [, , R , ] [Mixture of] [;] [or] [ ,R , ] [, , R , ] [and] [ , S , ] [, , S , ] [Mixture of] [)] [Fumarate] [] [ , N , ] [-] [Ethyl] [-5-] [fluorine] [- , N , - ] [Isopropyl] [-2-((5-(2-(6-((2-] [Methoxyethyl] [)(] [methyl] [)] [Amine] [)-2,4-] [Dimethylhexane] [-3-] [base] [)-2,6-] [Diazaspiro] [[3.4]] [pungent] [-6-] [base] [)-1,2,4-] [Three] [-6-] [base] [)] [oxyl] [)] [Benzamide] [(] [ , R , ] [, , R , ] [and] [ , S , ] [, , S , ] [Mixture of] [;] [or] [ , R , ] [, , S , ] [and] [ , S , ] [, , R , ] [Mixture of] [)] [Fumarate] [] [( , *R , )- , N , - ] [Ethyl] [-5-] [fluorine] [-2-((5-(2-(1-((2-] [Hydroxyethyl] [)] [Amine] [)-4-] [Methylpentyl] [-3-] [base] [)-2,6-] [Diazaspiro] [[3.4]] [pungent] [-6-] [base] [)-1,2,4-] [Three] [-6-] [base] [)] [oxyl] [)- , N , - ] [Cymene] [] [Fumarate] [] [( , *R , )- ,N , - ] [Ethyl] [-5-] [fluorine] [-2-((5-(2-(1-((2-] [Hydroxyethyl] [)(] [methyl] [)] [Amine] [)-4-] [Methylpentyl] [-3-] [base] [)-2,6-] [Diazaspiro] [[3.4]] [pungent] [-6-] [base] [)-1,2,4-] [Three] [-6-] [base] [)] [oxyl] [)- , N , - ] [Cymene] [] [Fumarate] [] [( , *R , )-2-((5-(2-(1-((3- ] [Amine] [-3-] [Pendant oxypropyl] [)] [Amine] [)-4-] [Methylpentyl] [-3-] [base] [)-2,6-] [Diazaspiro] [[3.4]] [pungent] [-6-] [base] [)-1,2,4-] [Three] [-6-] [base] [)] [oxyl] [)- , N , - ] [Ethyl] [-5-] [fluorine] [- , N , - ] [Isopropylbenzamide] [] [Fumarate] [] [( , *R , )-2-((5-(2-(1-((3- ] [Amine] [-3-] [Sulfoxypropyl] [)(] [methyl] [)] [Amine] [)-4-] [Methylpentyl] [-3-] [base] [)-2,6-] [Diazaspiro] [[3.4]] [pungent] [-6-] [base] [)-1,2,4-] [Three] [-6-] [base] [)] [oxyl] [)- , N , - ] [Ethyl] [-5-] [fluorine] [- , N , - ] [Isopropylbenzamide] [] [Fumarate] [] [ , N , ] [-] [Ethyl] [-5-] [fluorine] [-2-((5-(2-(( , R , )-6-((( , R , )-2- ] [Hydroxy] [-3-] [Methoxypropyl] [)(] [methyl] [)] [Amine] [)-2-] [Methylhexane] [-3-] [base] [)-2,6-] [Diazaspiro] [[3.4]] [pungent] [-6-] [base] [)-1,2,4-] [Three] [-6-] [base] [)] [oxyl] [)- , N , - ] [Cymene] [] [Fumarate] [] [( , R , )- , N , - ] [Ethyl] [-5-] [fluorine] [-2-((5-(2-(6-((2-] [Hydroxyethyl] [)(] [methyl] [)] [Amine] [)-2-] [Methylhexane] [-3-] [base] [)-2,6-] [Diazaspiro] [[3.4]] [pungent] [-6-] [base] [)-1,2,4-] [Three] [-6-] [base] [)] [oxyl] [)- , N , - ] [Cymene] [] [Fumarate] [] [( , R , )-2-((5-(2-(6-((2,2- ] [Dimethoxyethyl] [)] [Amine] [)-2-] [Methylhexane] [-3-] [base] [)-2,6-] [Diazaspiro] [[3.4]] [pungent] [-6-] [base] [)-1,2,4-] [Three] [-6-] [base] [)] [oxyl] [)- , N , - ] [Ethyl] [-5-] [fluorine] [- , N , - ] [Cymene] [] [Fumarate] [] [( , *R , )- , N , - ] [Ethyl] [-5-] [fluorine] [- , N , - ] [Isopropyl] [-2-((5-(2-(1-(] [Isopropylamino] [)-4-] [Methylpentyl] [-3-] [base] [)-2,6-] [Diazaspiro] [[3.4]] [pungent] [-6-] [base] [)-1,2,4-] [Three] [-6-] [base] [)] [oxyl] [)] [Benzamide] [] [Fumarate] [] [ , N , ] [-] [Ethyl] [-5-] [fluorine] [- , N , - ] [Isopropyl] [-2-((5-(2-((3 , R , )-6-((2- ] [Methoxyethyl] [)(] [methyl] [)] [Amine] [)-2-] [Methylheptyl] [-3-] [base] [)-2,6-] [Diazaspiro] [[3.4]] [pungent] [-6-] [base] [)-1,2,4-] [Three] [-6-] [base] [)] [oxyl] [)] [Benzamide] [] [Fumarate] [] [ , N , ] [-] [Ethyl] [-5-] [fluorine] [- , N , - ] [Isopropyl] [-2-((5-(6-(6-((2-] [Methoxyethyl] [)(] [methyl] [)] [Amine] [)-2-] [Methylhexane] [-3-] [base] [)-2,6-] [Diazaspiro] [[3.4]] [pungent] [-2-] [base] [)-1,2,4-] [Three] [-6-] [base] [)] [oxyl] [)] [Benzamide] [] [Fumarate] [] [2-((5-(2-((3 , *R , ,5 , *R , )-6-( ] [Dimethylamino] [)-5-] [Methoxy] [-2-] [Methylhexane] [-3-] [base] [)-2,6-] [Diazaspiro] [[3.4]] [pungent] [-6-] [base] [)-1,2,4-] [Three] [-6-] [base] [)] [oxyl] [)- , N , - ] [Ethyl] [-5-] [fluorine] [- , N , - ] [Cymene] [] [Fumarate] [] [2-((5-(2-((3 , *R , ,5 , *S , )-6-( ] [Dimethylamino] [)-5-] [Methoxy] [-2-] [Methylhexane] [-3-] [base] [)-2,6-] [Diazaspiro] [[3.4]] [pungent] [-6-] [base] [)-1,2,4-] [Three] [-6-] [base] [)] [oxyl] [)- , N , - ] [Ethyl] [-5-] [fluorine] [- , N , - ] [Isopropylbenzamide] [] [Fumarate] [] [ , N , ] [-] [Ethyl] [-5-] [fluorine] [-2-((5-(2-((3 , *R , ,5 , *R , )-5- ] [Hydroxy] [-6-(] [Isopropyl] [(] [methyl] [)] [Amine] [)-2-] [Methylhexane] [-3-] [base] [)-2,6-] [Diazaspiro] [[3.4]] [pungent] [-6-] [base] [)-1,2,4-] [Three] [-6-] [base] [)] [oxyl] [)- , N , - ] [Cymene] [] [Fumarate] [] [ , N , ] [-] [Ethyl] [-5-] [fluorine] [-2-((5-(2-((3 , *S , ,5 , *S , )-5- ] [Hydroxy] [-6-(] [Isopropyl] [(] [methyl] [)] [Amine] [)-2-] [Methylhexane] [-3-] [base] [)-2,6-] [Diazaspiro] [[3.4]] [pungent] [-6-] [base] [)-1,2,4-] [Three] [-6-] [base] [)] [oxyl] [)- , N , - ] [Cymene] [] [Fumarate] [] [ , N , ] [-] [Ethyl] [-5-] [fluorine] [-2-((5-(2-((3 , *R , ,5 , *S , )-5- ] [Hydroxy] [-6-(] [Isopropyl] [(] [methyl] [)] [Amine] [)-2-] [Methylhexane] [-3-] [base] [)-2,6-] [Diazaspiro] [[3.4]] [pungent] [-6-] [base] [)-1,2,4-] [Three] [-6-] [base] [)] [oxyl] [)- , N , - ] [Cymene] [] [Fumarate] [] [ , N , ] [-] [Ethyl] [-5-] [fluorine] [-2-((5-(2-((3 , *S , ,5 , *R , )-5- ] [Hydroxy] [-6-(] [Isopropyl] [(] [methyl] [)] [Amine] [)-2-] [Methylhexane] [-3-] [base] [)-2,6-] [Diazaspiro] [[3.4]] [pungent] [-6-] [base] [)-1,2,4-] [Three] [-6-] [base] [)] [oxyl] [)- , N , - ] [Cymene] [] [Fumarate] [] [2-((5-(2-((3 , *R , ,5 , *R , )-6-( ] [Diethylamino] [)-5-] [Hydroxy] [-2-] [Methylhexane] [-3-] [base] [)-2,6-] [Diazaspiro] [[3.4]] [pungent] [-6-] [base] [)-1,2,4-] [Three] [-6-] [base] [)] [oxyl] [)- , N , - ] [Ethyl] [-5-] [fluorine] [- , N , - ] [Cymene] [] [Fumarate] [] [2-((5-(2-((3 , *S , ,5 , *S , )-6-( ] [Diethylamino] [)-5-] [Hydroxy] [-2-] [Methylhexane] [-3-] [base] [)-2,6-] [Diazaspiro] [[3.4]] [pungent] [-6-] [base] [)-1,2,4-] [Three] [-6-] [base] [)] [oxyl] [)- , N , - ] [Ethyl] [-5-] [fluorine] [- , N , - ] [Cymene] [] [Fumarate] [] [2-((5-(2-((3 , *S , ,5 , *R , )-6-( ] [Diethylamino] [)-5-] [Hydroxy] [-2-] [Methylhexane] [-3-] [base] [)-2,6-] [Diazaspiro] [[3.4]] [pungent] [-6-] [base] [)-1,2,4-] [Three] [-6-] [base] [)] [oxyl] [)- , N , - ] [Ethyl] [-5-] [fluorine] [- , N , - ] [Isopropylbenzamide] [] [Fumarate] [] [2-((5-(2-((3 , *R , ,5 , *S , )-6-( ] [Diethylamino] [)-5-] [Hydroxy] [-2-] [Methylhexane] [-3-] [base] [)-2,6-] [Diazaspiro] [[3.4]] [pungent] [-6-] [base] [)-1,2,4-] [Three] [-6-] [base] [)] [oxyl] [)- , N , - ] [Ethyl] [-5-] [fluorine] [- , N , - ] [Isopropylbenzamide] [] [Fumarate] [] [ ,N , ] [-] [Ethyl] [-2-((5-(2-((3 , *R , ,5 , S , )-6-( ] [Ethyl] [(] [methyl] [)] [Amine] [)-5-] [Hydroxy] [-2-] [Methylhexane] [-3-] [base] [)-2,6-] [Diazaspiro] [[3.4]] [pungent] [-6-] [base] [)-1,2,4-] [Three] [-6-] [base] [)] [oxyl] [)-5-] [fluorine] [- , N , - ] [Cymene] [] [Fumarate] [] [ , N , ] [-] [Ethyl] [-2-((5-(2-((3 , *S , ,5 , S , )-6-( ] [Ethyl] [(] [methyl] [)] [Amine] [)-5-] [Hydroxy] [-2-] [Methylhexane] [-3-] [base] [)-2,6-] [Diazaspiro] [[3.4]] [pungent] [-6-] [base] [)-1,2,4-] [Three] [-6-] [base] [)] [oxyl] [)-5-] [fluorine] [- , N , - ] [Cymene] [] [Fumarate] [] [ , N , ] [-] [Ethyl] [-2-((5-(2-((3 , *R , ,5 , R , )-6-( ] [Ethyl] [(] [methyl] [)] [Amine] [)-5-] [Hydroxy] [-2-] [Methylhexane] [-3-] [base] [)-2,6-] [Diazaspiro] [[3.4]] [pungent] [-6-] [base] [)-1,2,4-] [Three] [-6-] [base] [)] [oxyl] [)-5-] [fluorine] [- , N , - ] [Cymene] [] [Fumarate] [] [ , N , ] [-] [Ethyl] [-5-] [fluorine] [-2-((5-(2-((3 , *R , ,5 , S , )-5- ] [Hydroxy] [-6-((2-] [Methoxyethyl] [)(] [methyl] [)] [Amine] [)-2-] [Methylhexane] [-3-] [base] [)-2,6-] [Diazaspiro] [[3.4]] [pungent] [-6-] [base] [)-1,2,4-] [Three] [-6-] [base] [)] [oxyl] [)- , N , - ] [Cymene] [] [Fumarate] [] [ , N , ] [-] [Ethyl] [-5-] [fluorine] [-2-((5-(2-((3 , *S , ,5 , S , )-5- ] [Hydroxy] [-6-((2-] [Methoxyethyl] [)(] [methyl] [)] [Amine] [)-2-] [Methylhexane] [-3-] [base] [)-2,6-] [Diazaspiro] [[3.4]] [pungent] [-6-] [base] [)-1,2,4-] [Three] [-6-] [base] [)] [oxyl] [)- , N , - ] [Cymene] [] [Fumarate] [] [ , N , ] [-] [Ethyl] [-5-] [fluorine] [-2-((5-(2-((3 , *R , ,5 , R , )-5- ] [Hydroxy] [-6-((2-] [Methoxyethyl] [)(] [methyl] [)] [Amine] [)-2-] [Methylhexane] [-3-] [base] [)-2,6-] [Diazaspiro] [[3.4]] [pungent] [-6-] [base] [)-1,2,4-] [Three] [-6-] [base] [)] [oxyl] [)- , N , - ] [Cymene] [] [Fumarate] [] [ , N , ] [-] [Ethyl] [-5-] [fluorine] [-2-((5-(2-((3 , *S , ,5 , R , )-5- ] [Hydroxy] [-6-((2-] [Methoxyethyl] [)(] [methyl] [)] [Amine] [)-2-] [Methylhexane] [-3-] [base] [)-2,6-] [Diazaspiro] [[3.4]] [pungent] [-6-] [base] [)-1,2,4-] [Three] [-6-] [base] [)] [oxyl] [)- , N , - ] [Cymene] [] [Fumarate] [] [2-((5-(2-((3 , *R , ,5 , *R , )-6-( ] [Dimethylamino] [)-5-] [Hydroxy] [-2-] [Methylhexane] [-3-] [base] [)-2,6-] [Diazaspiro] [[3.4]] [pungent] [-6-] [base] [)-1,2,4-] [Three] [-6-] [base] [)] [oxyl] [)-5-] [fluorine] [- , N , , , N , - ] [Diisopropylbenzamide] [] [Fumarate] [] [2-((5-(2-((3 , *R , ,5 , *S , )-6-( ] [Dimethylamino] [)-5-] [Hydroxy] [-2-] [Methylhexane] [-3-] [base] [)-2,6-] [Diazaspiro] [[3.4]] [pungent] [-6-] [base] [)-1,2,4-] [Three] [-6-] [base] [)] [oxyl] [)-5-] [fluorine] [- , N , , , N , - ] [Diisopropylbenzamide] [] [Fumarate] [] [2-((5-(2-((3 , *S , ,5 , *S , )-6-( ] [Dimethylamino] [)-5-] [Hydroxy] [-2-] [Methylhexane] [-3-] [base] [)-2,6-] [Diazaspiro] [[3.4]] [pungent] [-6-] [base] [)-1,2,4-] [Three] [-6-] [base] [)] [oxyl] [)-5-] [fluorine] [- , N , , , N , - ] [Diisopropylbenzamide] [] [Fumarate] [] [2-((5-(2-((3 , *S , ,5 , *R , )-6-( ] [Dimethylamino] [)-5-] [Hydroxy] [-2-] [Methylhexane] [-3-] [base] [)-2,6-] [Diazaspiro] [[3.4]] [pungent] [-6-] [base] [)-1,2,4-] [Three] [-6-] [base] [)] [oxyl] [)-5-] [fluorine] [- , N , , , N , - ] [Diisopropylbenzamide] [] [Fumarate] [] [2-((5-(2-((3 , *S , ,5 , *S , )-6-( ] [Dimethylamino] [)-5-] [Methoxy] [-2-] [Methylhexane] [-3-] [base] [)-2,6-] [Diazaspiro] [[3.4]] [pungent] [-6-] [base] [)-1,2,4-] [Three] [-6-] [base] [)] [oxyl] [)- , N , - ] [Ethyl] [-5-] [fluorine] [- , N , - ] [Isopropylbenzamide] [] [Fumarate] [] [2-((5-(2-((3 , *S , ,5 , *R , )-6-( ] [Dimethylamino] [)-5-] [Methoxy] [-2-] [Methylhexane] [-3-] [base] [)-2,6-] [Diazaspiro] [[3.4]] [pungent] [-6-] [base] [)-1,2,4-] [Three] [-6-] [base] [)] [oxyl] [)- , N , - ] [Ethyl] [-5-] [fluorine] [- , N , - ] [Isopropylbenzamide] [] [Fumarate] [] [ ,N , ] [-] [Ethyl] [-5-] [fluorine] [-2-((5-(2-(5-] [Hydroxy] [-6-((2-] [Methoxyethyl] [)(] [methyl] [)] [Amine] [)-2,5-] [Dimethylhexane] [-3-] [base] [)-2,6-] [Diazaspiro] [[3.4]] [pungent] [-6-] [base] [)-1,2,4-] [Three] [-6-] [base] [)] [oxyl] [)- , N , - ] [Cymene] [] [Fumarate] [] [ , N , ] [-] [Ethyl] [-5-] [fluorine] [-2-((5-(2-((3 , *R , ,5 , *R , )-5- ] [Hydroxy] [-2-] [methyl] [-6-(] [methyl] [(] [Propyl] [)] [Amine] [)] [Self] [-3-] [base] [)-2,6-] [Diazaspiro] [[3.4]] [pungent] [-6-] [base] [)-1,2,4-] [three] [𠯤] [-6-] [base] [)] [oxyl] [)- , N , - ] [Cymene] [] [Fumarate] [] [ , N , ] [-] [Ethyl] [-5-] [fluorine] [-2-((5-(2-((3 , *S , ,5 , *S , )-5- ] [Hydroxy] [-2-] [methyl] [-6-(] [methyl] [(] [Propyl] [)] [Amine] [)] [Self] [-3-] [base] [)-2,6-] [Diazaspiro] [[3.4]] [pungent] [-6-] [base] [)-1,2,4-] [three] [𠯤] [-6-] [base] [)] [oxyl] [)- , N , - ] [Isopropylbenzamide] [] [Fumarate] [] [2-((5-(2-((3 , *R , ,5 , *S , )-6-( ] [Ethyl] [(] [methyl] [)] [Amine] [)-5-] [Hydroxy] [-2-] [Methylhexane] [-3-] [base] [)-2,6-] [Diazaspiro] [[3.4]] [pungent] [-6-] [base] [)-1,2,4-] [three] [𠯤] [-6-] [base] [)] [oxyl] [)-5-] [fluorine] [- , N , , , N , - ] [Diisopropylbenzamide] [] [Fumarate] [] [2-((5-(2-((3* , S, ,5* , S , )-6-( ] [Ethyl] [(] [methyl] [)] [Amine] [)-5-] [Hydroxy] [-2-] [Methylhexane] [-3-] [base] [)-2,6-] [Diazaspiro] [[3.4]] [pungent] [-6-] [base] [)-1,2,4-] [three] [𠯤] [-6-] [base] [)] [oxyl] [)-5-] [fluorine] [- , N , , , N , - ] [Diisopropylbenzamide] [] [Fumarate] [] [( , R , )-2-((3- ] [chlorine] [-5-(2-(6-((2-] [Methoxyethyl] [)(] [methyl] [)] [Amine] [)-2-] [Methylhexane] [-3-] [base] [)-2,6-] [Diazaspiro] [[3.4]] [pungent] [-6-] [base] [)-1,2,4-] [three] [𠯤] [-6-] [base] [)] [oxyl] [)- , N , - ] [Ethyl] [-5-] [fluorine] [- , N , - ] [Isopropylbenzamide] [] [Fumarate] [] [( , R , )- , N , - ] [Ethyl] [-5-] [fluorine] [- , N , - ] [Isopropyl] [-2-((5-(2-(6-((2-] [Methoxyethyl] [)] [Amine] [)-2-] [Methylhexane] [-3-] [base] [)-2,6-] [Diazaspiro] [[3.4]] [pungent] [-6-] [base] [)-1,2,4-] [three] [𠯤] [-6-] [base] [)] [oxyl] [)] [Benzamide] [] [Fumarate] [] [By targeting compounds]

[0102] [The following compounds were synthesized by a similar method as described above] [] [Compound] [serial number] [structure] [Start] [Material] [Spectrum Detailed Information] 103 Compound 106, Fumaric acid [LC-MS] [(] [ESI] [)(method] [2] [):]R t= 2.041 min, m / z found 570.3 [M+H] +. [SFC] [(] [method]

[13] [):]R t= 1.722 min. 112 Compound 111, Fumaric acid [ , 1 , ] [H NMR] [(] [400 MHz] [,methanol] [- , d , , 4, ] [):]δ = 8.49 (s, 1H), 7.45-7.22 (m, 3H), 6.71 (s, 4H), 4.20-3.63 (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), 1.94-1.54 (m, 4H), 1.35 (d, J=5.6 Hz, 3H), 1.19-0.98 (m, 13H), 0.89-0.73 (m, 2H). [LC-MS] [(] [ESI] [)(method] [1] [):]R t= 3.063 min, m / z found 600.5 [M+H] +. [SFC] [(method] [6] [):]R t= 1.214 min. 114 Compound 113, Fumaric acid [ , 1 , ] [H NMR] [(] [400 MHz] [,methanol] [- , d , , 4, ] [):]δ = 8.47 (s, 1H), 7.52-7.07 (m, 3H), 6.69 (s, 4H), 6.30-5.90 (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), 1.23-0.71 (m, 15H). [LC-MS] [(] [ESI] [)(method] [1] [):]R t= 3.056 min, m / z found 606.3 [M+H] +. [SFC] [(] [method]

[13] [):]R t= 1.944 min. 122 Compound 120, Fumaric acid [LC-MS] [(] [ESI] [)(method] [2] [):]R t= 2.030 min, m / z found 584.3 [M+H] +. [SFC] [(] [method]

[18] [):]R t= 2.312 min. 123 Compound 121, Fumaric acid [LC-MS] [(] [ESI] [)(method] [2] [):]R t= 2.020 min, m / z found 584.3 [M+H] +. [SFC] [(] [method]

[18] [):]R t= 2.557 min. 127 Compound 125, Fumaric acid [LC-MS] [(] [ESI] [)(method] [2] [):]R t= 2.065 min, m / z found 584.3 [M+H] +. [Chirality] [HPLC] [(] [method] [7] [):]R t= 3.197 min. 128 Compound 126, Fumaric acid [LC-MS] [(] [ESI] [)(method] [2] [):]R t= 2.074 min, m / z found 584.3 [M+H] +. [Chirality] [HPLC] [(] [method] [7] [):]R t= 3.805 min. 132 Compound 130, Fumaric acid [LC-MS] [(] [ESI] [)(method] [2] [):]R t= 1.954 min, m / z found 570.3 [M+H] +. [Chirality] [HPLC] [(] [method] [7] [):]R t= 3.702 min. 133 Compound 131, Fumaric acid [LC-MS] [(] [ESI] [)(method] [2] [):]R t= 1.955 min, m / z found 570.3 [M+H] +. [Chirality] [HPLC] [(] [method] [7] [):]R t= 4.808 min. 135 Compound 134, Fumaric acid [LC-MS] [(] [ESI] [)(method] [2] [):]R t= 2.083 min, m / z found 614.4 [M+H] +. [SFC] [(] [method] [6] [):]R t= 1.346 min. 137 Compound 136, Fumaric acid [LC-MS] [(] [ESI] [)(method] [2] [):]R t= 2.115 min, m / z found 628.4 [M+H] +. [SFC] [(] [method] [6] [):]R t= 0.938 min. 140 Compound 139, Fumaric acid [LC-MS] [(] [ESI] [)(method] [2] [):]R t= 1.986 min, m / z found 614.4 [M+H] +. [SFC] [(] [method]

[13] [):]R t= 1.749 min. 142 Compound 141, Fumaric acid [LC-MS] [(] [ESI] [)(method] [2] [):]R t= 2.039 min, m / z found 614.4 [M+H] +. [SFC] [(] [method] [6] [):]R t= 1.171 min. 145 Compound 143, Fumaric acid [LC-MS] [(] [ESI] [)(method] [2] [):]R t= 2.096 min, m / z found 655.6 [M+H] +. [SFC] [(] [method]

[19] [):]R t= 3.861 min. 146 Compound 144, Fumaric acid [LC-MS] [(] [ESI] [)(method] [2] [):]R t= 2.096 min, m / z found 655.6 [M+H] +. [SFC] [(] [method]

[19] [):]R t= 4.578 min. 148 Compound 147, Fumaric acid [LC-MS] [(] [ESI] [)(method] [3] [):]R t= 4.480 min, m / z found 641.6 [M+H] +. [SFC] [(] [method] [6] [):]R t= 1.356 min. 150 Compound 149, Fumaric acid [LC-MS] [(] [ESI] [)(method] [3] [):]R t= 4.836 min, m / z found 630.4 [M+H] +. [SFC] [(] [method] [6] [):]R t= 1.067 min. 152 Compound 151, Fumaric acid [LC-MS] [(] [ESI] [)(method] [2] [):]R t= 2.332 min, m / z found 655.5 [M+H] +. [SFC] [(] [method] [6] [):]R t= 1.449 min. 154 Compound 153, Fumaric acid [LC-MS] [(] [ESI] [)(method] [2] [):]R t= 2.022 min, m / z found 614.4 [M+H] +. [SFC] [(] [method] [6] [):]R t= 1.137 min. 157 Compound 156, Fumaric acid [LC-MS] [(] [ESI] [)(method] [2] [):]R t= 2.049 min, m / z found 614.4 [M+H] +. [SFC] [(] [method]

[20] [):]R t= 1.001 min. 159 Compound 158, Fumaric acid [LC-MS] [(] [ESI] [)(method] [1] [):]R t= 3.102 min, m / z found 630.4 [M+H] +. [SFC] [(] [method] [6] [):]R t= 1.194 min. 161 Compound 160, Fumaric acid [LC-MS] [(] [ESI] [)(method] [2] [):]R t= 2.112 min, m / z found 644.3 [M+H] +. [SFC] [(] [method] [6] [):]R t= 1.073 min. 165 Compound 164, Fumaric acid [LC-MS] [(] [ESI] [)(method] [3] [):]R t= 4.766 min, m / z found 630.3 [M+H] +. [SFC] [(] [method] [6] [):]R t= 1.271 min. 167 Compound 166, Fumaric acid [LC-MS] [(] [ESI] [)(method] [3] [):]R t= 4.730 min, m / z found 630.3 [M+H] +. [SFC] [(] [method] [6] [):]R t= 1.373 min. 170 Compound 169, Fumaric acid [LC-MS] [(] [ESI] [)(method] [3] [):]R t= 4.652 min, m / z found 630.4 [M+H] +. 172 Compound 171, Fumaric acid [LC-MS] [(] [ESI] [)(method] [3] [):]R t= 5.073 min, m / z found 630.4 [M+H] +. 176 Compound 174, Fumaric acid [LC-MS] [(] [ESI] [)(method] [3] [):]R t= 5.035 min, m / z found 644.5 [M+H] +. [SFC] [(] [method] [twenty three] [):]R t= 4.662 min. 177 Compound 175, Fumaric acid [LC-MS] [(] [ESI] [)(method] [3] [):]R t= 5.031 min, m / z found 644.5 [M+H] +. [SFC] [(] [method] [twenty three] [):]R t= 4.977 min. 179 Compound 178, Fumaric acid [LC-MS] [(] [ESI] [)(method] [5] [):]R t= 1.72 min, m / z found 655.5 [M+H] +. 181 Compound 180, Fumaric acid [LC-MS] [(] [ESI] [)(method] [5] [):]R t= 1.61 min, m / z found 655.5 [M+H] +. 184 Compound 182, Fumaric acid [LC-MS] [(] [ESI] [)(method] [2] [):]R t= 2.041 min, m / z found 655.4 [M+H] +. [SFC] [(] [method] [8] [):]R t= 2.752 min. 185 Compound 183, Fumaric acid [LC-MS] [(] [ESI] ...

Claims

1. A compound having formula (I), or a tautomer or stereoisomer thereof, wherein R1a represents -C(=O)-NRxaRxb or Het, and Het represents a 6-membered monocyclic aromatic ring containing two nitrogen atoms; wherein the 6-membered monocyclic aromatic ring is to be substituted with a C3-6 cycloalkyl group; Rxa and Rxb represent C1-4 alkyl groups; R1b represents F; Y1 represents -O-; R2 is hydrogen or a halogroup; U represents N or CH; n1, n2, n3 and n4 are each independently selected from 1 and 2; X1 represents CH, and X2 represents N; R4 represents isopropyl; R3 represents -C1-6 alkyl-NR8aR8b, -C1-6 alkyl-C(=O)-NR9aR9b, -C1-6 alkyl-OH, or -C1-6 alkyl-NR11-C(=O)-O-C1-4 alkyl-OC(=O)-C1-4 alkyl; Each of the C1-4 alkyl or C1-6 alkyl moieties in the definition of R3 may be independently substituted by one, two, or three substituents, each of which is independently selected from the group consisting of: -OH, and -O-C1-4 alkyl; R8a and R8b are each independently selected from the group consisting of: hydrogen; C1-6 alkyl; -C(=O)-C1-4 alkyl; -C(=O)-O-C1-4 alkyl; -C(=O)-NR12aR12b; and C1-6 alkyl substituted by one, two, or three substituents, each of which is independently selected from the group consisting of: -OH, cyano, halogroup, -S(=O)2-C1-4 alkyl, -O-C1-4 alkyl, -C(=O)-NR10aR10b, and -NR10c-C(=O)-C1-4 alkyl; R9a, R9b, R10a, R10b, R10c, R11, R12a, and R12b are each independently selected from the group consisting of hydrogen and C1-6 alkyl groups; or pharmaceutically acceptable salts or hydrates thereof.

2. The compound as claimed in claim 1, wherein R2 is hydrogen.

3. The compound as claimed in claim 1 or 2, wherein R3 represents -C1-6 alkyl-NR8aR8b, -C1-6 alkyl-C(=O)-NR9aR9b, -C1-6 alkyl-OH, or -C1-6 alkyl-NR11-C(=O)-O-C1-4 alkyl-OC(=O)-C1-4 alkyl; wherein each of the C1-4 alkyl or C1-6 alkyl moieties as defined in R3 may be independently substituted by one, two, or three substituents, each of which is independently selected from the group consisting of -O-C1-4 alkyl; R8a and R8b are each independently selected from the group consisting of: hydrogen; C1-6 alkyl; -C(=O)-C1-4 alkyl; -C(=O)-O-C1-4 alkyl; -C(=O)-NR12aR12b; and C1-6 alkyl substituted with one, two, or three substituents, each independently selected from the group consisting of: cyano, halo, -S(=O)2-C1-4 alkyl, -O-C1-4 alkyl, and -C(=O)-NR10aR10b; R9a, R9b, R10a, R10b, R11, R12a, and R12b are each independently selected from the group consisting of: hydrogen and C1-6 alkyl.

4. The compound as claimed in claim 3, wherein R2 is hydrogen; U represents N; R3 represents -C1-6 alkyl-NR8aR8b, -C1-6 alkyl-C(=O)-NR9aR9b, -C1-6 alkyl-OH, or -C1-6 alkyl-NR11-C(=O)-O-C1-4 alkyl-OC(=O)-C1-4 alkyl; R8a and R8b are each independently selected from the group consisting of: hydrogen; C1-6 alkyl; -C(=O)-C1-4 alkyl; -C(=O)-O-C1-4 alkyl; -C(=O)-NR12aR12b; and C1-6 alkyl substituted with one, two, or three substituents, each independently selected from the group consisting of: cyano, halo, -S(=O)2-C1-4 alkyl, and -O-C1-4 alkyl.

5. The compound as claimed in claim 3, wherein R1a represents -C(=O)-NRxaRxb; Rxa and Rxb represent C1-4 alkyl; R1b represents F; Y1 represents -O-; R2 is hydrogen; U represents N; R3 represents -C1-6 alkyl-NR8aR8b, -C1-6 alkyl-C(=O)-NR9aR9b, or -C1-6 alkyl-OH; R8a and R8b are each independently selected from the group consisting of: hydrogen; C1-6 alkyl; -C(=O)-C1-4 alkyl; -C(=O)-O-C1-4 alkyl; -C(=O)-NR12aR12b; and C1-6 alkyl substituted with one, two, or three substituents, each independently selected from the group consisting of: cyano, halo, -S(=O)2-C1-4 alkyl, and -O-C1-4 alkyl.

6. The compound as claimed in claim 1, wherein R1a represents -C(=O)-NRxaRxb or Het; Het represents a 6-membered monocyclic aromatic ring containing two nitrogen atoms; wherein the 6-membered monocyclic aromatic ring is substituted by a C3-6 cycloalkyl group; Rxa and Rxb represent C1-4 alkyl groups; R1b represents F; Y1 represents -O-; R2 represents hydrogen; U represents N or CH; n1, n2, n3 and n4 are each independently selected from 1 and 2; X1 represents CH and X2 represents N; R4 represents isopropyl; R3 represents -C1-6 alkyl-NR8aR8b; wherein the C1-6 alkyl portion of R3 may be substituted by one, two or three substituents, each of which is independently selected from the group consisting of -OH and -O-C1-4 alkyl groups; R8a and R8b are each independently selected from the group consisting of: hydrogen; C1-6 alkyl; and C1-6 alkyl substituted with one, two, or three substituents, each independently selected from the group consisting of: -OH, cyano, halo, -S(=O)2-C1-4 alkyl, -O-C1-4 alkyl, -C(=O)-NR10aR10b, and -NR10c-C(=O)-C1-4 alkyl; R10a, R10b, and R10c are each independently selected from the group consisting of: hydrogen and C1-6 alkyl.

7. The compound as claimed in claim 1, wherein R1a represents -C(=O)-NRxaRxb; Rxa and Rxb represent C1-4 alkyl; R1b represents F; Y1 represents -O-; R2 represents hydrogen; U represents N; n1, n2, n3 and n4 are each independently selected from 1 and 2; X1 represents CH and X2 represents N; R4 represents isopropyl; R3 represents -C1-6 alkyl-NR8aR8b; R8a and R8b are each independently selected from the group consisting of: hydrogen; C1-6 alkyl; and C1-6 alkyl substituted with one, two or three substituents, each of which is independently selected from the group consisting of: -OH, cyano, halogroup, -S(=O)2-C1-4 alkyl, -O-C1-4 alkyl, and -C(=O)-NR10aR10b; R10a and R10b are each independently selected from the group consisting of hydrogen and C1-6 alkyl groups.

8. The compound as claimed in claim 1, wherein Y1 represents -O-.

9. The compound as claimed in claim 1, wherein R1b represents F.

10. The compound as claimed in claim 1, wherein the compound is...

11. The compound as claimed in claim 1, wherein the compound is...

12. The compound as claimed in claim 1, wherein the compound is...

13. The compound as claimed in claim 1, wherein the compound is...

14. The compound as claimed in claim 1, wherein the compound is...

15. The compound as claimed in claim 1, wherein the compound is...

16. The compound as claimed in claim 1, wherein the compound is...

17. The compound as claimed in claim 1, wherein the compound is...

18. The compound as claimed in claim 1, wherein the compound is...

19. A pharmaceutical composition comprising a compound as described in any one of claims 1 to 18 and a pharmaceutically acceptable carrier or diluent.

20. A method for preparing a pharmaceutical composition as described in claim 19, the method comprising: A pharmaceutically acceptable carrier is mixed with a therapeutically effective amount of a compound as described in any one of claims 1 to 18.

21. A compound as described in any one of claims 1 to 18 or a pharmaceutical composition as described in claim 19, for use as a medicine.

22. Use of a compound as described in any one of claims 1 to 18 or a pharmaceutical composition as described in claim 19 for the preparation of a medicament for treating cancer.

23. Use of a compound as described in any one of claims 1 to 18 or a pharmaceutical composition as described in claim 19 for the preparation of a medicament for the treatment of leukemia, myelodysplastic syndrome (MDS), and myeloproliferative neoplasm (MPN).

24. The use as described in claim 23, for preparing a medicine for treating leukemia, wherein the leukemia is (NPM1)-mutant leukemia.

25. The use as described in claim 22, wherein the cancer is selected from: leukemia, lymphoma, myeloma and solid tumor cancer.

26. The use as described in claim 22, wherein the cancer is selected from prostate cancer, lung cancer, breast cancer, pancreatic cancer, colorectal cancer, liver cancer, melanoma, and glioblastoma.

27. The use as described in claim 23, for treating leukemia, wherein the leukemia is selected from: acute leukemia, chronic leukemia, myeloid leukemia, myeloid leukemia, lymphoblastic leukemia, and lymphocytic leukemia.

28. The use as described in claim 23, for the treatment of leukemia, wherein the leukemia is selected from: acute myeloid leukemia (AML), chronic myeloid leukemia (CML), acute lymphoblastic leukemia (ALL), chronic lymphocytic leukemia (CLL), T-cell prolymphocytic leukemia (T-PLL), large granular lymphocytic leukemia, hairy cell leukemia (HCL), MLL-rearranged leukemia, MLL-PTD leukemia, MLL-amplified leukemia, MLL-positive leukemia, and leukemia displaying the HOX / MEIS1 gene expression marker.

29. The use as described in claim 23, for treating leukemia, wherein the leukemia is acute leukemia.

30. The use as described in claim 29, wherein the acute leukemia is AML.

31. The use as described in claim 29, wherein the acute leukemia is ALL.

32. The use as described in claims 29, 30 or 31, wherein the acute leukemia has a KMT2A gene alteration or an NPM1 mutation.

33. The use as described in claim 29, 30 or 31, wherein the acute leukemia has a KMT2A gene rearrangement.

34. The use as described in claims 29, 30 or 31, wherein the acute leukemia has an NPM1 mutation.

35. The use as described in claim 34, wherein the NPM1 mutation is NPM1c.

36. The use as described in claim 24, wherein the (NPM1)-mutant leukemia lineage (NPM1c)-mutant leukemia.

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