Substituted linear spiro derivatives

Abstract

To provide compounds, pharmaceutical compositions, and uses thereof as menin / MLL protein / protein interaction inhibitors useful in the treatment of diseases such as cancer and diabetes.SOLUTION: A compound of formula (I): Pharmaceutical compositions comprising such compounds and their use as menin / MLL protein / protein interaction inhibitors useful in the treatment of diseases such as cancer and diabetes, including but not limited to leukemia, myelodysplastic syndromes (MDS) and myeloproliferative neoplasms (MPN) are provided.SELECTED DRAWING: None

Description

[Technical Field]

[0001] The present invention relates to pharmaceuticals useful for the treatment and / or prophylaxis in mammals, and to compounds containing such compounds. and a pharmaceutical composition containing the compound, for the treatment of leukemia, myelodysplastic syndrome (MDS), and myeloproliferative neoplasm (MPN). Menin, which are useful in the treatment of diseases such as, but not limited to, cancer and diabetes and their use as inhibitors of MLL protein / protein interactions. [Background technology]

[0002] Chromosomal rearrangements affecting mixed lineage leukemia genes (MLL; MLL1; KMT2A) It leads to an aggressive form of acute leukemia across all age groups and remains largely incurable. These MLL chromosomal translocations are essential for the treatment of rheumatoid arthritis, and novel therapeutic approaches are urgently needed. Acute leukemia with lymphoid, myeloid, or mixed phenotypes is a type of acute leukemia in adults. 5-10% of acute leukemias in children and approximately 70% of acute leukemias in infants (Marschalek, Br J Haematol 2011.152(2),141-54;Tomizawa et al., Pediatr Blood Cancer 2007.49(2):1 27-32).

[0003] MLL is a histone methyltransferase that methylates histone H3 on lysine 4 (H3K4). It is a transferase that functions in a multiprotein complex. Depending on allele usage, the histone methyltransferase activity of Mll1 is essential for hematopoiesis. Although Mll1 is dispensable for hematopoietic stem cell (HSC) maintenance and B cell development, It has been demonstrated that it plays a role (Mishra et al., Cell Rep 20 14.7(4),1239-47).

[0004] Fusions of MLL with over 60 different partners have been reported to date, These findings are associated with the formation / progression of leukemia (Meyer et al., Leukemi a 2013.27,2165-2176). Interestingly, the SET(Su( var) 3-9, the enhancer of zeste and the trithorax) domain are chimeric It is not retained in the protein but is replaced by the fusion partner (Thiel et al., 2001). (t al., Bioessays 2012.34,771-80). Recruitment of chromatin-modifying enzymes such as Dot1L and / or the pTEFb complex by HO XA genes (e.g., HOXA9) and most notably the HOX cofactor MEIS1 This results in enhanced transcription and transcription elongation of MLL target genes, including α- and β-glucanase (MLL)-dependent cleavage of these genes. Expression blocks hematopoietic differentiation and enhances proliferation.

[0005] Menin, encoded by the multiple endocrine neoplasia type 1 (MEN1) gene, is ubiquitously expressed in It is expressed and localized mainly in the nucleus. It interacts with many proteins and therefore is involved in a wide variety of cell types. The best understood function of menin is the ML process. The role of menin as a cofactor in the oncogenic activity of L fusion proteins. Two motifs in the N-terminal fragment of MLL are conserved in the Thiel 1) and MBM2 (Thiel et al., Bioessay s 2012.34,771-80). Menin / MLL interaction is involved in lens epithelial-derived growth factor receptors (LERs). This results in the formation of a new interaction surface for the LEDGF. Although menin directly binds to F, it mediates the stable interaction between MLL and LEDGF and LED Required for gene-specific chromatin recruitment of MLL complexes via the PWWP domain of GFs (Cermakova et al., Cancer Res 2014.15 ,5139-51;Yokoyama&Cleary,Cancer Cell 200 8,8,36-46). Furthermore, many genetic studies have shown that menin is mediated by MLL fusion proteins. This indicates that the menin / MLL interaction is strictly required for oncogenic transformation. These findings suggest that Men1 is an attractive therapeutic target. ectopically expressing the L fusion prevents leukemogenesis in myeloid progenitor cells (Chen et al. al.,Proc Natl Acad Sci 2006.103,1018-23 Similarly, genetic disruption of the menin / MLL fusion interaction by loss-of-function mutations results in MLL It neutralizes the oncogenic potential of the fusion protein, blocks leukemia development in vivo, and inhibits the MLL-form These studies demonstrated that menin reverses the differentiation block of transformed leukemic blasts. It was also shown that it is necessary for the maintenance of HOX gene expression by protein (Yokoyama et al., Cell 2005.123,207-18). Furthermore, the menin / MLL phase Small molecule inhibitors of this interaction have been developed to inhibit the druggability of this protein / protein interaction. This suggests that the antibody has potential to inhibit AML, and its efficacy has been demonstrated in preclinical models of AML (Bor kin et al.,Cancer Cell 2015.27,589-602;C ierpicki and Grembecka,Future Med Chem 2 Menin is not an essential cofactor for MLL1 during normal hematopoiesis. Along with this observation (Li et al., Blood 2013.122,2039-2 046), these data suggest that disruption of the menin / MLL interaction may contribute to the development of MLL-rearranged leukemias and This appears to be a promising new therapeutic approach for the treatment of cancers with activated HOX / MEIS1 genes and other cancers with activated HOX / MEIS1 gene signatures. For example, partial tandem duplication (PTD) within the 5' region of the MLL gene is associated with myelodysplastic syndromes. Another major abnormality found primarily in primary and secondary AML as well as in AML-associated syndromes The molecular mechanism and biological function of MLL-PTD are not fully understood, but Novel therapeutic targeting strategies that affect the nin / MLL interaction may also be useful for the treatment of MLL-PTD-associated leukemia. Furthermore, the menin / MLL interaction may prove to be effective in treating castration-resistant prostate cancer. It has been shown that the effect depends on the 15.21,344-52).

[0006] MLL proteins are known in the scientific community as histone-lysine N-methyltransferases. Also known as 2A (KMT2A) (UniProt accession number Q03164).

[0007] Several references describe inhibitors that target the menin-MLL interaction: International Publication No. 2011029054, J Med Chem 2016, 5 9,892-913 describes the preparation of thienopyrimidine derivatives and benzodiazepine derivatives. WO 2014164543 discloses thienopyrimidine derivatives and Thienopyridine derivatives are described; Nature Chemical Biology M arch 2012,8,277-284 and Ren, J.;et al.Bioorg Med Chem Lett(2016),26(18),4472-4476 Describes enopyrimidine derivatives; J Med Chem 2014,57,1543-1 556 describes hydroxy and aminomethylpiperidine derivatives; Future Me d Chem 2014,6,447-462 outlines small molecule and peptidomimetic compounds. The pamphlet of International Publication No. 2016195776 describes a furo[2,3-d]pyrimidinyl 9H-purine, [1,3]oxazolo[5,4-d]pyrimidine, [1,3]oxazolo[5,4-d]pyrimidine Thiazolo[4,5-d]pyrimidine, [1,3]thiazolo[5,4-d]pyrimidine, thieno [2,3-b]pyridine and thieno[2,3-d]pyrimidine derivatives are described; International Publication The pamphlet No. 2016197027 is a 5,6,7,8-tetrahydropyridin [3, 4-d]pyrimidine, 5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine, Pyrido[2,3-d]pyrimidine and quinoline derivatives are described; WO 201604 Pamphlet No. 0330 describes thienopyrimidine and thienopyridine compounds. WO 2017192543 pamphlet describes piperidines as menin inhibitors. The following is described in the pamphlet of International Publication No. 2017112768 and International Publication No. 2017 207387 Brochure, International Publication No. 2017214367 Brochure, International Publication Brochure No. 2018053267 and Brochure No. 2018024602 Lett describes inhibitors of menin-MLL interaction. WO 2017161 Pamphlet No. 002 and Pamphlet No. WO 2017161028 are menin- The present invention describes an inhibitor of MLL. Publication No. 2018050684 Brochure and International Publication No. 2018109088 Bread FRET describes inhibitors of menin-MLL interaction. International Publication No. 201822 The 6976 pamphlet describes a method for inhibiting the interaction between menin and MLL proteins. WO 2018175746 describes methods and compositions for treating blood This document provides a method for treating malignant tumors and Ewing's sarcoma. International Publication No. 2018106818 No. 2018106820 and WO 2018106820 disclose the proliferation of pancreatic cells. WO 2018153312 provides a method for promoting This paper discloses azaspiro compounds related to the field of medicinal chemistry. WO 20171323 The 98th issue of the pamphlet examines leukemia cells that exhibit NPM1 mutations, and the interaction between MLL and menin. The present invention discloses a method for treating a leukemia comprising contacting the leukemia virus with a pharmacological inhibitor of the leukemia virus activity. No. 060365 describes substituted inhibitors of menin-MLL. The International Publication No. 2020069027 pamphlet describes the use of menin inhibitors in the treatment of hematological malignancies. Krivtsov et al., Cancer Cell 2 019.No.6 Vol.36,660-673 describes menin-MLL inhibitors There are. [Brief explanation of the drawings]

[0008] [Figure 1] Efficacy study in the Molm-14 subcutaneous (sc) model. [Figure 2] Efficacy study in disseminated OCI-AML3 model. DETAILED DESCRIPTION OF THE INVENTION

[0009] The present invention relates to a compound of formula (I) [ka] and tautomeric and stereoisomeric forms thereof, wherein R 1a is -C(=O)-NR xa R xb , Het, or [ka] represents Het is a 5 or 6 alkyl group containing 1, 2 or 3 nitrogen atoms and optionally a carbonyl moiety. represents a 6-membered monocyclic aromatic ring, wherein the 5- or 6-membered monocyclic aromatic ring is optionally selected from the group consisting of C 3~6 Cycloalkyl and C 1~4 substituted with 1 or 2 substituents selected from the group consisting of alkyl; R xa and R xb are each independently hydrogen, C 1~4 Alkyl and C 3~6 Cycloa selected from the group consisting of rutile and rutile; R 1b represents F or Cl, Y 1 -CR 5a R 5b -, -O-, or -NR 5c - represents R 2 is hydrogen, halo, C 1~4 Alkyl, -OC 1~4 Alkyl and -NR 7a R 7b is selected from the group consisting of 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 isopropyl, R 5a , R 5b , R 5c , R 7a and R 7b are each independently hydrogen, C 1~4 Al Kill and C 3~6 cycloalkyl; R 3 -C 1~6 Alkyl-NR 8a R 8b , -C 1~6 Alkyl-C(=O)-NR 9a R 9b , -C 1~6 Alkyl-OH or -C 1~6 Alkyl-NR 11 -C(=O) -OC 1~4 Alkyl-OC(=O)-C 1~4 represents alkyl, where R 3 C in the definition of 1~4 Alkyl or C 1~6 Each of the alkyl moieties is Independently of each other, cyano, halo, -OH and -OC 1~4 From the group consisting of alkyl may be substituted with 1, 2, or 3 substituents, each independently selected; R 8a and R 8b are each independently hydrogen, C 1~6 Alkyl, -C(=O)-C1 ~4 Alkyl, -C(=O)-OC 1~4 Alkyl, -C(=O)-NR 12a R 12 b and -OH, cyano, halo, -S(=O)2-C 1~4 Alkyl, -OC 1~4 a Rukyr, -C(=O)-NR 10a R 10b and -NR 10c -C(=O)-C 1~4 a substituted with 1, 2, or 3 substituents each independently selected from the group consisting of alkyl, alkyl, aryl, aryl, aryl and alkyl; C 1~6 is selected from the group consisting of alkyl, R 9a , R 9b , R 10a , R 10b , R 10c , R 11 , R 12a and R 12b Ha, so each independently hydrogen and C 1~6 The novel compounds of formula (I) are selected from the group consisting of alkyl and tautomeric and stereoisomeric forms thereof, as well as pharmaceutically acceptable salts and derivatives thereof. and solvates.

[0010] The present invention provides a therapeutically effective amount of a compound of formula (I), a pharmaceutically acceptable salt or solvate thereof and a pharmaceutically acceptable carrier or excipient.

[0011] Furthermore, the present invention relates to a compound of formula (I), its pharmaceutically acceptable salts, for use as a medicament. and its salts or solvates for the treatment of leukemia, myelodysplastic syndromes (MDS) and myeloproliferative neoplasms (MPNs). N) for use in the treatment or prevention of cancer and diabetes (I) and a pharmaceutically acceptable salt or solvate thereof.

[0012] In a particular embodiment, the present invention provides a compound of formula (I) for use in the treatment or prevention of cancer. and pharmaceutically acceptable salts or solvates thereof.

[0013] In certain embodiments, the cancer is a leukemia, lymphoma, myeloma, or solid tumor cancer (e.g., Select from among prostate cancer, lung cancer, breast cancer, pancreatic cancer, colon cancer, liver cancer, melanoma, and glioblastoma In some embodiments, the leukemia includes acute leukemia, chronic leukemia, myeloid leukemia, and the like. Myeloid leukemia, lymphoblastic leukemia, lymphocytic leukemia, acute myeloid leukemia (AML) , chronic myeloid leukemia (CML), acute lymphoblastic leukemia (ALL), chronic lymphocytic leukemia disease (CLL), T-cell prolymphocytic leukemia (T-PLL), large granular lymphocytic leukemia, Hairy cell leukemia (HCL), MLL-rearranged leukemia, MLL-PTD leukemia, MLL-amplified leukemia These include leukemia, MLL-positive leukemia, and leukemia with HOX / MEIS1 gene expression characteristics. can be.

[0014] In particular, the compounds of the present invention and pharmaceutical compositions thereof are useful in treating leukemia, particularly nucleophosmin (NP) M1) mutant leukemia, such as NPM1c.

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

[0016] In one embodiment, the compounds of formula (I) and pharmaceutically acceptable salts and solvates thereof are It may have an in vivo half-life (T1 / 2).

[0017] In one embodiment, the compounds of formula (I) and pharmaceutically acceptable salts and solvates thereof are It may have improved oral bioavailability.

[0018] In one embodiment, the compounds of formula (I) and pharmaceutically acceptable salts and solvates thereof are For example, tumors containing MLL (KMT2A) gene rearrangements / alterations and / or NPM1 mutations This may reduce tumor growth.

[0019] In one embodiment, the compounds of formula (I) and pharmaceutically acceptable salts and solvates thereof are Improved in vivo PD properties over a long period of time, e.g., over a period of at least 16 hours, This may include inhibition of target gene expression such as EIS1 and upregulation of differentiation markers.

[0020] In one embodiment, the compounds of formula (I) and pharmaceutically acceptable salts and solvates thereof are Improved safety profile (e.g., reduced hERG inhibition, improved cardiovascular safety).

[0021] In one embodiment, the compounds of formula (I) and pharmaceutically acceptable salts and solvates thereof are May be suitable for QD dosing (once daily).

[0022] The present invention relates to the treatment of various cancers, including leukemia, myelodysplastic syndromes (MDS), and myeloproliferative neoplasms (MPN). Additional medications for use in the treatment or prevention of cancer and diabetes, including but not limited to: The present invention also relates to the use of a compound of formula (I), a pharmaceutically acceptable salt or solvate thereof, in combination with do.

[0023] The present invention further provides a process for preparing the pharmaceutical composition of the present invention, which is pharmaceutically acceptable. An acceptable carrier is a therapeutically effective amount of a compound of formula (I), a pharmaceutically acceptable salt thereof, or a solvent thereof. The present invention relates to a process characterized in that the compound is intimately mixed with the hydrate.

[0024] The present invention relates to the treatment of various cancers, including leukemia, myelodysplastic syndromes (MDS), and myeloproliferative neoplasms (MPN). Simultaneous, separate or sequential treatment or prevention of cancer and diabetes, including but not limited to Compounds of formula (I) and pharmaceutically acceptable salts thereof as combined preparations for therapeutic use. or a product comprising a solvate and an additional pharmaceutical agent.

[0025] The present invention further provides a method for treating or preventing a cell proliferative disorder in a warm-blooded animal, comprising administering to said animal to the subject, an effective amount of a compound of formula (I), as defined herein, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition or combination as defined herein. The present invention relates to a method comprising administering

[0026] As used herein, the term "halo" or "halogen" refers to fluoro, chloro, bro Represents molybdenum and iodine.

[0027] As used herein, the prefix "C x~y " (where x and y are integers) is refers to the number of carbon atoms in a given group. 1~6 Alkyl groups have 1 to 6 carbon atoms, etc. Includes:

[0028] As used herein as a group or part of a group, the term "C 1~4 "Alkyl" is 1 to 4 a straight or branched chain saturated hydrocarbon radical having 10 carbon atoms, e.g., methyl, ethyl , n-propyl, isopropyl, n-butyl, s-butyl, t-butyl, etc.

[0029] Similarly, when used herein as a group or part of a group, the term "C 1~6 "Alkyl" is , a linear or branched saturated hydrocarbon radical having 1 to 6 carbon atoms, e.g., a methyl group , ethyl group, n-propyl group, isopropyl group, n-butyl group, s-butyl group, t-butyl group It represents an n-alkyl group, an n-pentyl group, an n-hexyl group, etc.

[0030] As used herein as a group or part of a group, the term "C 3~6 "Cycloalkyl" is Saturated cyclic hydrocarbon radicals having 3 to 6 carbon atoms, such as cyclopropyl, The cyclobutyl, cyclopentyl and cyclohexyl groups are defined.

[0031] It will be apparent to one skilled in the art that S(=O)2 or SO2 represents a sulfonyl moiety.

[0032] It will be apparent to one skilled in the art that CO or C(=O) represent a carbonyl moiety.

[0033] Groups such as -CRR- [ka] It will be clear to one skilled in the art that an example of such a group is -CR 5a R 5b -is .

[0034] Groups such as -NR- [ka] It will be clear to one skilled in the art that an example of such a group is -NR 5c -It is.

[0035] "A monocyclic five-ring ring containing one, two, or three nitrogen atoms and optionally a carbonyl moiety Non-limiting examples of "a 6-membered aromatic ring" include pyrazolyl, imidazolyl, pyridinyl, pyridinyl, pyrazol ... ridazinyl, pyrimidinyl, pyrazinyl, triazinyl or 1,2-dihydro-2-oxo and the like. Examples include, but are not limited to, iso-4-pyridinyl.

[0036] Those skilled in the art will recognize that the five or six-membered alkyl esters containing one, two or three nitrogen atoms and a carbonyl moiety As the monocyclic aromatic ring, [ka] It will be understood that these include, but are not limited to:

[0037] When any variable occurs more than one time in any constituent, each definition is independent. .

[0038] When any variable occurs more than one time in any formula (e.g., formula (I)), each definition is independent. This is what was done.

[0039] Generally, when the term "substituted" is used in the present invention, it means that the substituted group is a substituted group, unless otherwise indicated. Unless otherwise specified or clear from the context, the term "substituted" is always used in expressions One or more hydrogens on an atom or group, particularly 1 to 4 hydrogens, more particularly 1 to 3 hydrogens Preferably, one or two hydrogens, more preferably one hydrogen, are selected from the indicated group. Indicates that the atom is replaced by a valence that does not exceed the normal valence and is not affected by the substitution. Chemically stable compounds, i.e., compounds that can be isolated from reaction mixtures with a useful degree of purity (e.g., A robust compound was obtained that was sufficiently resistant to purification by silica gel chromatography and subsequent isolation. In certain embodiments, when the number of substituents is not specified, In this case, the number of substituents is 1.

[0040] Combinations of substituents and / or variables may be selected to provide compounds that are chemically stable due to such combinations. In this context, a "stable compound" is only acceptable if the reaction Isolation of a useful degree of purity from a mixture (e.g., by silica gel chromatography) refers to a compound that is robust enough to withstand subsequent purification (isolation after purification).

[0041] Those skilled in the art will understand that the term "optionally substituted" is used to refer to The atoms or groups shown in the expression may be substituted or unsubstituted (this and "a" will be understood to mean "substituted or unsubstituted," respectively.

[0042] When more than one substituent is present on a moiety, these substituents may be any of the following: May replace hydrogen on the same atom unless otherwise indicated or clear from the context , or may replace a hydrogen atom on a different atom of this moiety.

[0043] In the context of the present invention, "saturated" means "fully saturated" unless otherwise specified. do.

[0044] Unless otherwise specified or apparent from the context, the aromatic ring group may be any available through a ring carbon atom (C-bond) or a ring nitrogen atom (N-bond) of the molecule of formula (I) It can be bonded to the remainder.

[0045] Unless otherwise specified or apparent from the context, aromatic ring groups are preferred where possible. Depending on the embodiment, there may be optional substitutions on the carbon and / or nitrogen atoms.

[0046] As used herein, the term "subject" means an individual who is the object of treatment, observation, or experiment; or an animal, preferably a mammal (e.g., a mouse), that has been the subject of treatment, observation or experiment. "Animal" refers to any animal, animal, species, species of mammal, mammalian animal, mammalian animal, mammalian species, ...

[0047] As used herein, the term "therapeutically effective amount" refers to an amount that effectively alleviates the symptoms of the disease or disorder being treated. the tissue system, animal or human disease sought by researchers, veterinarians, physicians or other clinicians, including palliative or reversal of "Inactive Ingredient" means the amount of an active compound or drug that elicits a biological or medical response in a subject.

[0048] The term "composition" refers to a product containing specific ingredients in specific amounts, as well as to a product containing specific ingredients in specific amounts. It is intended to include any product resulting directly or indirectly from the combination of

[0049] As used herein, the term "treatment" refers to the treatment of a disease that slows, hinders, arrests, or halts the progression of the disease. It is intended to refer to all processes that may cause, but not necessarily the completeness of, all symptoms. This does not imply any exclusion.

[0050] As used herein, the term "compound of the invention" or "compound according to the invention" refers to a compound of the invention. " is meant to include compounds of formula (I) and pharmaceutically acceptable salts and solvates thereof. do.

[0051] As used herein, a solid wedge bond or a dashed wedge bond is Any chemical formula with bonds shown only as solid lines, without a bond around one or more other atoms Any chemical formula shown to have a particular configuration (e.g., R, S) in It is envisaged that the compound may be any of the possible stereoisomers or a mixture of two or more stereoisomers. .

[0052] In the above and below, the term "compounds of formula (I)" refers to the tautomers and stereoisomers thereof. This means that it includes sexual forms.

[0053] The terms "stereoisomer", "stereoisomeric form" or "stereochemically isomeric form" refer to the above or Used interchangeably below.

[0054] The present invention relates to the isomers of the present invention either as pure stereoisomers or as mixtures of two or more stereoisomers. The present invention also includes all stereoisomers of the compounds of the present invention.

[0055] 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.

[0056] Atropisomers (or atropoisomers) are those that have large steric hindrance around a single bond. All of the compounds of formula (I) are stereoisomers with specific spatial configurations resulting from restricted rotation. Atropisomeric forms of are intended to be included within the scope of the present invention.

[0057] Diastereomers (or diastereoisomers) are not enantiomers, i.e., mirror images. If the compound contains a double bond, the substituents may be in the E or E configuration. can be in the Z configuration.

[0058] Substituents on a divalent cyclic saturated or partially saturated group can have a cis or trans configuration. For example, if a compound contains a disubstituted cycloalkyl group, the substituents may be in a cis configuration. The configuration may be trans or tert-.

[0059] Therefore, the present invention provides for the preparation of enantiomers, atropisomers, Diastereomers, racemates, E isomers, Z isomers, cis isomers, trans isomers and others This includes mixtures of these.

[0060] All these terms, i.e. enantiomers, atropisomers, diastereomers, racemates, The meanings of the E isomer, the Z isomer, the cis isomer, the trans isomer and mixtures thereof are known to those skilled in the art.

[0061] The absolute configuration is specified according to the Cahn-Ingold-Prelog system. The resulting configuration is specified as either R or S. Resolved stereoisomers of unknown absolute configuration are , can be designated as (+) or (-) depending on the direction they rotate plane polarized light. For example, resolved enantiomers of unknown absolute configuration are those that rotate plane-polarized light. It can be indicated by (+) or (-) depending on the direction.

[0062] When a particular stereoisomer is identified, this means that said stereoisomer substantially separates the other isomers. Free of other isomers, i.e., less than 50%, preferably less than 20%, more preferably less than 10%. More preferably, it is associated with less than 5%, especially less than 2%, and most preferably less than 1%. Thus, if a compound of formula (I) is specified as, for example, (R), then: This means that the compound is substantially free of the (S) isomer; compounds of formula (I) For example, if is specified as E, this means that the compound is substantially free of the Z isomer. where a compound of formula (I) is specified as, for example, cis, this means that This means that the compound is substantially free of trans isomers.

[0063] Some of the compounds of formula (I) may also exist in their tautomeric forms. are within the scope of the present invention, even if they are not explicitly mentioned in the above formula (I), as long as they exist. Therefore, a single compound may exist in the form of stereoisomeric and tautomeric forms. It can exist in both.

[0064] Pharmaceutically acceptable salts include acid addition salts and base addition salts. is prepared by conventional means, for example by extracting the free acid, optionally in a solvent or medium in which the salt is insoluble. or the free base form may be reacted with one or more equivalents of an appropriate base or acid, followed by standard procedures. Remove the solvent or medium using a method (e.g., by freeze-drying in vacuo or filtration). The salts can be prepared by adding a counter ion of the compound of the present invention in the form of a salt. , for example by exchange with another counterion using a suitable ion exchange resin. It is also possible.

[0065] The pharmaceutically acceptable salts mentioned above or below are compounds of formula (I) and solvates thereof. The term "therapeutic active agent" includes therapeutically active non-toxic acid and base salt forms which may be used in the treatment of various conditions.

[0066] Suitable acids are, for example, inorganic acids, for example hydrohalic acids such as hydrochloric acid or hydrobromic acid; Acids such as sulfuric acid, nitric acid, phosphoric acid, etc.; or organic acids such as acetic acid, propanoic acid, hydroxyacetic acid, lactic acid, etc. Acids, pyruvic acid, oxalic acid (i.e., ethanedioic acid), malonic acid, succinic acid (i.e., butanedioic acid) , maleic acid, fumaric acid, malic acid, tartaric acid, citric acid, methanesulfonic acid, ethanesulfonic acid p-toluenesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, cyclamic acid, salicylic acid, p -aminosalicylic acid, pamoic acid, etc. Conversely, the salt forms can be prepared by the addition of an appropriate base. It can be converted to the free base form by treatment.

[0067] The compounds of formula (I) and their solvates containing acidic protons can be reacted with suitable organic bases and inorganic bases. They can be converted into their non-toxic metal salt or amine salt forms by treatment with organic bases. It can also be done as follows.

[0068] Suitable basic salt forms include, for example, ammonium salts, alkali metal salts and alkaline earth salts. Metal salts, such as lithium salts, sodium salts, potassium salts, cesium salts, magnesium salts, calcium salts, salts with organic bases, e.g., methylamine, ethylamine, propylamine , isopropylamine, four butylamine isomers, dimethylamine, diethylamine, Diethanolamine, dipropylamine, diisopropylamine, di-n-butylamine , pyrrolidine, piperidine, morpholine, trimethylamine, triethylamine, tripeptide Primary, secondary and tertiary propylamines, quinuclidines, pyridines, quinolines and isoquinolines Salts with aliphatic and aromatic amines; benzathine salts, N-methyl-D-glucamine salts , hydrabamine salts and salts with amino acids such as arginine and lysine. For example, a salt form can be converted into the free acid form by treatment with acid.

[0069] The term "prodrug" refers to a drug that undergoes certain reactions in vivo after oral or parenteral administration, especially after oral administration. within a time interval (e.g., within a 0.5 to 24 hour dosing interval or, for example, within a 6 to 24 hour dosing interval ( that is metabolized to a(n) more active form in experimentally detectable amounts within 1-4 times a day. For the avoidance of doubt, the term "parenteral" administration includes all administration other than oral administration. administration forms, particularly intravenous (IV), intramuscular (IM), and subcutaneous (SC) injections.

[0070] Prodrugs are compounds that convert functional groups present on the compound into compounds that are suitable for use in mammals. The compound is prepared by modifying it in such a way that the modification is cleaved in vivo when administered to a subject. This modification is typically performed by synthesizing the parent compound with a prodrug substituent. Generally, prodrugs contain hydroxyl, amino, sulfonyl, or hydroxyl groups. The free hydroxyl, amino, carboxyl, or carbonyl groups are respectively Cleavage in vivo to regenerate a hydroxyl, sulfhydryl, carboxyl, or carbonyl group This includes compounds bonded to any group that can be cleaved.

[0071] Examples of prodrugs include esters and carbamates of hydroxy functional groups, Examples include ester groups of acyl functional groups, N-acyl derivatives and N-Mannich bases. General information regarding prodrugs is available, for example, from Bundegaa rd, H. “Design of Prodrugs” p.1-92, Elesevie r, New York-Oxford (1985).

[0072] The term solvate refers to the solvent addition forms and their analogues which the compounds of formula (I) are able to form. Examples of such solvent addition forms are, for example, hydrates, alcoholates, etc. .

[0073] The compounds of the present invention prepared by the processes described below may be mixtures of enantiomers, In particular, they can be synthesized in the form of racemic mixtures of enantiomers, which are well known in the art. The compounds of formula (I) and their derivatives can be separated from each other according to known resolution procedures. Methods for separating the enantiomeric forms of physiologically acceptable salts and solvates include those using chiral stationary phases. The pure stereochemically isomeric forms can be purified by suitable methods, including liquid chromatography. They may also be derived from the corresponding pure stereochemically isomeric forms of the starting materials, provided that The reaction is expected to occur stereospecifically. Preferably, a specific stereoisomer is desired. In this case, the compounds will be synthesized by stereospecific methods of preparation. In this case, advantageously enantiomerically pure starting materials are used.

[0074] As used herein, the term "enantiomerically pure" means that the product is It contains at least 80% by weight of one enantiomer and not more than 20% by weight of the other enantiomer. This means that the product contains at least 90% by weight of one enantiomer, It is preferred that the other enantiomer is contained in an amount of 10% by weight or less. In this embodiment, the term "enantiomerically pure" means that the composition contains less of one enantiomer. This means that the compound contains 99% by weight of one enantiomer and 1% or less of the other enantiomer.

[0075] The present invention relates to atomic masses or mass numbers commonly found in nature (or the most abundant atoms found in nature). one or more atoms are replaced by atoms having different atomic masses or mass numbers from the Isotopically labeled compounds of the invention which are identical to the compounds described herein except that they are Contains.

[0076] All isotopes and isotopic mixtures of any particular atom or element identified herein Substances may be naturally occurring, synthetically produced, or naturally abundant. Conformationally enriched forms are also contemplated as being within the scope of the compounds of the present invention. Exemplary isotopes that can be incorporated are: 2 H, 3 H, 11 C, 13C, 14C, 13 N , 15 O. 17 O. 18 O. 32 P, 33 P, 35 S, 18 F, 36 Cl, 122 I, 1 23 I, 125 I, 131 I, 75 Br, 76 Br, 77 Br and 82 Hydrogen such as Br, It includes isotopes of carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine and iodine. Preferably, The isotopes are 2 H, 3 H, 11 C. 13 C and 18 Preferably, the same is selected from the group The coordinate system is 2 H, 3 H, 11 C and 18 More preferably, the isotope is selected from the group , 2 H, 3 H or 13 C. More preferably, the isotope is 2 H or 13 It is C. More preferably, the isotope is 2 H. In particular, deuterated compounds and 13 C-enriched compounds are Deuterated compounds are intended to be included within the scope of the present invention. is intended to be included in

[0077] Certain isotopically labeled compounds of the present invention (e.g., 3 H and 14 C) are e.g. For example, tritiated ( 3 H) and carbon-l4( 1 4 C) isotopes are useful for their ease of preparation and detectability. 2 Substitution with heavier isotopes such as H results in greater metabolic stability. provides a predetermined therapeutic benefit (e.g., increased in vivo half-life or reduced dose requirements) This is possible and may therefore be preferable in some circumstances. 15 O. 13 N, 11 C and 18 F etc. Positron-emitting isotopes of are useful in positron emission tomography (PET) studies. PET imaging can locate and identify tumors, determine the stage of disease, and provide appropriate Human cancer cells have potential disease-specific mutations that may be useful in helping to determine treatment. Tumor cells overexpress many receptors or proteins that are potential molecular targets. Radiolabeled tracers that bind with high affinity and specificity to receptors or proteins are useful for diagnostic imaging. Charron, Carlie L .et al.Tetrahedron Lett.2016,57(37),4119 In addition, target-specific PET radiotracers can be used to detect target expression and therapeutic targets, e.g. Used as a biomarker to examine and evaluate pathology by measuring therapeutic response (Austin R. et al. Cancer Letters (2016) , doi:10.1016 / j.canlet.2016.05.008).

[0078] The present invention particularly relates to compounds of formula (I) as defined herein, as well as tautomers and derivatives thereof. and stereoisomeric forms, wherein R 1a is -C(=O)-NR xa R xb , Het, or [ka] represents Het is a 5 or 6 alkyl group containing 1, 2 or 3 nitrogen atoms and optionally a carbonyl moiety. represents a 6-membered monocyclic aromatic ring, wherein the 5- or 6-membered monocyclic aromatic ring is optionally selected from the group consisting of C 3~6 Cycloalkyl and C 1~4 substituted with 1 or 2 substituents selected from the group consisting of alkyl; R xa and R xb are each independently hydrogen, C 1~4 Alkyl and C 3~6 Cycloa selected from the group consisting of rutile and rutile; R 1b represents F or Cl, Y 1 -CR 5a R 5b -, -O-, or -NR 5c - represents R 2 is hydrogen, halo, C 1~4 Alkyl, -OC 1~4 Alkyl and -NR 7 aR 7b is selected from the group consisting of 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 4represents isopropyl, R 5a , R 5b , R 5c , R 7a and R 7b are each independently hydrogen, C 1~4 Al Kill and C 3~6 cycloalkyl; R 3 -C 1~6 Alkyl-NR 8a R 8b , -C 1~6 Alkyl-C(=O)-NR 9a R 9b , -C 1~6 Alkyl-OH or -C 1~6 Alkyl-NR 11 -C(=O) -OC 1~4 Alkyl-OC(=O)-C 1~4 represents alkyl, where R 3 C in the definition of 1~4 Alkyl or C 1~6 Each of the alkyl moieties is Independently of each other, cyano, halo or -OC 1~4 independently from the group consisting of alkyl and may be substituted with 1, 2 or 3 substituents selected from the following: R 8a and R 8b are each independently hydrogen, C 1~6 Alkyl, -C(=O)-C1 ~4 Alkyl, -C(=O)-OC 1~4 Alkyl, -C(=O)-NR 12a R 12 b and cyano, halo, -S(=O)2-C 1~4 Alkyl, -OC 1~4 Alkyl and -C(=O)-NR 10a R 10b 1 and 2 independently selected from the group consisting of or C substituted with 3 substituents 1~6 is selected from the group consisting of alkyl, R 9a , R 9b , R 10a , R 10b , R 11 , R 12a and R 12b are independent of each other and hydrogen and C 1~6 The compounds of formula (I) and The present invention relates to the tautomeric and stereoisomeric forms of benzophenone-3, as well as to the pharmaceutically acceptable salts and solvates thereof. do.

[0079] The present invention particularly relates to compounds of formula (I) as defined herein, as well as tautomers and derivatives thereof. and stereoisomeric forms, wherein R 1a is -C(=O)-NR xa R xb , Het, or [ka] represents Het is a 5 or 6 alkyl group containing 1, 2 or 3 nitrogen atoms and optionally a carbonyl moiety. represents a 6-membered monocyclic aromatic ring, wherein the 5- or 6-membered monocyclic aromatic ring is optionally selected from the group consisting of C 3~6 Cycloalkyl and C 1~4 substituted with 1 or 2 substituents selected from the group consisting of alkyl; R xa and R xb are each independently hydrogen, C 1~4 Alkyl and C 3~6 Cycloa selected from the group consisting of rutile and rutile; R 1b represents F or Cl, Y 1 -CR 5a R 5b -, -O-, or -NR5c - represents R 2 is hydrogen, halo, C 1~4 Alkyl, -OC 1~4 Alkyl and -NR 7a R 7b is selected from the group consisting of 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 isopropyl, R 5a , R 5b , R 5c , R 7a and R 7b are each independently hydrogen, C 1~4 Al Kill and C 3~6 cycloalkyl; R 3 -C 1~6 Alkyl-NR 8 aR 8b represents where R 3 C in the definition of 1~6 Each alkyl moiety is independently selected from cyano, halo, OH and -OC 1~4 and substituted with 1, 2 or 3 substituents selected from the group consisting of alkyl, can be exchanged, R 8a and R 8b are each independently hydrogen, C 1~6 Alkyl and -OH, cyano , halo, -S(=O)2-C 1~4 Alkyl, -OC 1~4 Alkyl, -C(=O)- NR 10a R 10b and -NR 10c -C(=O)-C 1~4 From the group consisting of alkyl C substituted with 1, 2 or 3 independently selected substituents 1~6 From alkyl is selected from the group R 10a , R 10b , R 10c are each independently hydrogen and C 1~6 From alkyl Compounds of formula (I) and their tautomeric and stereoisomeric forms, selected from the group consisting of: and its pharmaceutically acceptable salts and solvates.

[0080] The present invention particularly relates to compounds of formula (I) as defined herein, as well as tautomers and derivatives thereof. and stereoisomeric forms, wherein R 1a is -C(=O)-NR xa R xb , Het, or [ka] represents Het is a 5 or 6 alkyl group containing 1, 2 or 3 nitrogen atoms and optionally a carbonyl moiety. represents a 6-membered monocyclic aromatic ring, wherein the 5- or 6-membered monocyclic aromatic ring is optionally selected from the group consisting of C 3~6 Cycloalkyl and C 1~4 substituted with 1 or 2 substituents selected from the group consisting of alkyl; R xa and R xb are each independently hydrogen, C 1~4 Alkyl and C 3~6 Cycloa selected from the group consisting of rutile and rutile; R 1b represents F or Cl, Y 1 -CR 5a R 5b -, -O-, or -NR 5c - represents R 2is hydrogen, halo, C 1~4 Alkyl, -OC 1~4 Alkyl and -NR 7a R 7b is selected from the group consisting of 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 isopropyl, R 5a , R 5b , R 5c , R 7a and R 7b are each independently hydrogen, C 1~4 Al Kill and C 3~6 cycloalkyl; R 3 -C 1~6 Alkyl-NR 8a R 8b represents where R 3 C in the definition of 1~6 The alkyl moieties are each independently selected from cyano, halo, and Bi-OC 1~4 substituted with 1, 2 or 3 substituents selected from the group consisting of alkyl Gain, R 8a and R 8b are each independently hydrogen, C 1~6 Alkyl as well as cyano, halo, -S(=O)2-C 1~4 Alkyl, -OC 1~4 Alkyl and -C(=O)-NR 1 0a R 10b substituted with 1, 2, or 3 substituents each independently selected from the group consisting of C 1~6 is selected from the group consisting of alkyl, R 10a and R10b are each independently hydrogen and C 1~6 From the group consisting of alkyl Selected compounds of formula (I) and their tautomeric and stereoisomeric forms, and their pharmaceutical compositions The present invention relates to physiologically acceptable salts and solvates thereof.

[0081] The present invention particularly relates to compounds of formula (I) as defined herein, as well as tautomers and derivatives thereof. and stereoisomeric forms, wherein R 1a is -C(=O)-NR xa R xb or Het, Het represents a 6-membered monocyclic aromatic ring containing two nitrogen atoms; wherein the 6-membered monocyclic aromatic ring is 3~6 substituted with cycloalkyl, R xa and R xb is C 1~4 represents 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 isopropyl, R 3 -C 1~6 Alkyl-NR 8 aR 8b , -C 1~6 Alkyl-C(=O)-NR 9a R 9b , -C 1~6 Alkyl-OH or -C 1~6 Alkyl-NR 11 -C(=O) -OC1~4 Alkyl-OC(=O)-C 1~4 represents alkyl, where R 3 C in the definition of 1~4 Alkyl or C 1~6 Each of the alkyl moieties is Independently of each other, -OH and -OC 1~4 alkyl, may be substituted with 12 or 3 substituents selected from R 8a and R 8b are each independently hydrogen, C 1~6 Alkyl, -C(=O)-C1 ~4 Alkyl, -C(=O)-OC 1~4 Alkyl, -C(=O)-NR 12a R 12 b and -OH, cyano, halo, -S(=O)2-C 1~4 Alkyl, -OC 1~4 a Rukyr, -C(=O)-NR 10a R 10b and -NR 10c -C(=O)-C 1~4 a substituted with 1, 2, or 3 substituents each independently selected from the group consisting of alkyl, alkyl, aryl, aryl, aryl and alkyl; C 1~6 is selected from the group consisting of alkyl, R 9a , R 9b , R 10a , R 10b , R 10c , R 11 , R 12a and R 12b Ha, so each independently hydrogen and C 1~6 The compound of formula (I) is selected from the group consisting of alkyl and its tautomeric and stereoisomeric forms, and pharmaceutically acceptable salts and solvents thereof Related to Japanese things.

[0082] The present invention particularly relates to compounds of formula (I) as defined herein, as well as tautomers and derivatives thereof. and stereoisomeric forms, wherein R 1a is -C(=O)-NR xa R xb or Het, Het represents a 6-membered monocyclic aromatic ring containing two nitrogen atoms; wherein the 6-membered monocyclic aromatic ring is 3~6 substituted with cycloalkyl, R xa and R xb is C 1~4 represents 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 isopropyl, R 3 -C 1~6 Alkyl-NR 8a R 8b represents where R 3 C in the definition of 1~6 The alkyl portion is -OH and -OC 1~4 Archi and each of the substituted or unsubstituted alkyl groups may be substituted with one, two, or three substituents each independently selected from the group consisting of: R 8a and R 8b are each independently hydrogen, C 1~6 Alkyl and -OH, cyano , halo, -S(=O)2-C 1~4 Alkyl, -OC 1~4 Alkyl, -C(=O)- NR 10a R10b and -NR 10c -C(=O)-C 1~4 From the group consisting of alkyl C substituted with 1, 2 or 3 independently selected substituents 1~6 From alkyl is selected from the group R 10a , R 10b and R 10c are each independently hydrogen and C 1~6 From alkyl Compounds of formula (I) and their tautomeric and stereoisomeric forms, as well as and pharmaceutically acceptable salts and solvates thereof.

[0083] The present invention particularly relates to compounds of formula (I) as defined herein, as well as tautomers and derivatives thereof. and stereoisomeric forms, wherein R 1a is -C(=O)-NR xa R xb represents R xa and R xb is C 1~4 represents 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 isopropyl, R 3 -C 1~6 Alkyl-NR 8a R 8b represents where R 3 C in the definition of 1~6 The alkyl portion is -OH and -OC1~4 Archi and each of the substituted or unsubstituted alkyl groups may be substituted with one, two, or three substituents each independently selected from the group consisting of: R 8a and R 8b are each independently hydrogen, C 1~6 Alkyl and -OH, cyano , halo, -S(=O)2-C 1~4 Alkyl, -OC 1~4 Alkyl, -C(=O)- NR 10a R 10b and -NR 10c -C(=O)-C 1~4 From the group consisting of alkyl C substituted with 1, 2 or 3 independently selected substituents 1~6 From alkyl is selected from the group R 10a , R 10b and R 10c are each independently hydrogen and C 1~6 From alkyl Compounds of formula (I) and their tautomeric and stereoisomeric forms, as well as and pharmaceutically acceptable salts and solvates thereof.

[0084] The present invention particularly relates to compounds of formula (I) as defined herein, as well as tautomers and derivatives thereof. and stereoisomeric forms, wherein R 1a is -C(=O)-NR xa R xb or Het, Het is one C 3~6 represents pyrimidinyl substituted by cycloalkyl; R xa and R xb is C 1~4 represents alkyl, R 1b represents F, Y 1 represents -O-, R 2 represents hydrogen, U represents 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 isopropyl, R 3 -C 1~6 Alkyl-NR 8a R 8b represents where R 3 C in the definition of 1~6 The alkyl moiety may be substituted with one -OH; R 8a and R 8b are each independently hydrogen, C 1~6 Alkyl and halo, -OC 1~4 Alkyl and -NR 10c -C(=O)-C 1~4 Each of the groups consisting of alkyl C substituted with 1 or 2 independently selected substituents 1~6 From the group consisting of alkyl Selected, R 10a , R 10b and R 10c are each independently hydrogen and C 1~6 From alkyl Compounds of formula (I) and their tautomeric and stereoisomeric forms, as well as and pharmaceutically acceptable salts and solvates thereof.

[0085] The present invention particularly relates to compounds of formula (I) as defined herein, as well as tautomers and derivatives thereof. and stereoisomeric forms, wherein R 1a is -C(=O)-NR xa R xb or Het, Het is one C 3~6 represents pyrimidinyl substituted by cycloalkyl; R xa and R xb is C 1~4 represents alkyl, R 1b represents F, Y 1 represents -O-, R 2 represents hydrogen, U represents N; n2 is 2, n1, n3, and n4 are 1; X 1 represents CH, and X 2 represents N, R 4 represents isopropyl, R 3 -C 1~6 Alkyl-NR 8a R 8b represents where R 3 C in the definition of 1~6 The alkyl moiety may be substituted with one -OH; R 8a and R 8b are each independently hydrogen, C 1~6 Alkyl and halo, -OC 1~4 Alkyl and -NR 10c -C(=O)-C 1~4 Each of the groups consisting of alkyl C substituted with 1 or 2 independently selected substituents 1~6 From the group consisting of alkyl Selected, R 10a , R 10b and R 10c are each independently hydrogen and C 1~6 From alkyl Compounds of formula (I) and their tautomeric and stereoisomeric forms, as well as and pharmaceutically acceptable salts and solvates thereof.

[0086] The present invention particularly relates to compounds of formula (I) as defined herein, as well as tautomers and derivatives thereof. and stereoisomeric forms, wherein R 1a is -C(=O)-NR xa R xb represents R xa and R xb is C 1~4 represents alkyl, R 1b represents F, Y 1 represents -O-, R 2 represents hydrogen, U represents N; n2 is 2, n1, n3, and n4 are 1; X 1 represents CH, and X 2 represents N, R 4 represents isopropyl, R 3 -C 1~6 Alkyl-NR 8a R 8b represents R 8a and R 8b are each independently hydrogen, C 1~6 Alkyl and halo, -OC 1~4 Alkyl and -NR 10c -C(=O)-C 1~4 Each of the groups consisting of alkyl C substituted with 1 or 2 independently selected substituents 1~6 From the group consisting of alkyl Selected, R 10a , R 10b and R 10c are each independently hydrogen and C 1~6 From alkyl Compounds of formula (I) and their tautomeric and stereoisomeric forms, as well as and pharmaceutically acceptable salts and solvates thereof.

[0087] The present invention particularly relates to compounds of formula (I) as defined herein, as well as tautomers and derivatives thereof. and stereoisomeric forms, wherein R 1a is -C(=O)-NR xa R xb represents R xa and R xb is C 1~4 represents alkyl, R 1b represents F, Y 1 represents -O-, R 2 represents hydrogen, U represents N; n2 is 2, n1, n3, and n4 are 1; X 1 represents CH, and X 2 represents N, R 4 represents isopropyl, R 3 is -CH2-CH2-CH2-NR 8a R 8b represents R 8a and R 8b are each independently hydrogen, C 1~6 Alkyl and halo, -OC 1~4 Alkyl and -NR 10c -C(=O)-C 1~4 Each of the groups consisting of alkyl C substituted with 1 or 2 independently selected substituents 1~6 From the group consisting of alkyl Selected, R 10a , R 10b and R 10c are each independently hydrogen and C 1~6 From alkyl Compounds of formula (I) and their tautomeric and stereoisomeric forms, as well as and pharmaceutically acceptable salts and solvates thereof.

[0088] The present invention particularly relates to compounds of formula (I) as defined herein, as well as tautomers and derivatives thereof. and stereoisomeric forms, wherein R 1a is -C(=O)-NR xa R xb represents R xa and R xb is C 1~4 represents alkyl, R 1b represents F, Y 1 represents -O-, R 2 represents hydrogen, U represents 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 isopropyl, R 3 -C 1~6 Alkyl-NR 8a R 8b represents R 8a and R 8b are each independently hydrogen, C 1~6 Alkyl and -OH, cyano , halo, -S(=O)2-C 1~4 Alkyl, -OC 1~4 Alkyl and -C(=O) -NR 10a R 10b one, two, or three substitutions each independently selected from the group consisting of C substituted with a group 1~6 is selected from the group consisting of alkyl, R 10a and R 10b are each independently hydrogen and C 1~6 From the group consisting of alkyl Selected compounds of formula (I) and their tautomeric and stereoisomeric forms, and their pharmaceutical compositions The present invention relates to physiologically acceptable salts and solvates thereof.

[0089] The present invention particularly relates to compounds of formula (I) as defined herein, as well as tautomers and derivatives thereof. and stereoisomeric forms, wherein R 1a is -C(=O)-NR xa R xb represents R xa and R xb is C 1~4 represents alkyl, R 1b represents F, Y 1 represents -O-, R 2 represents hydrogen, U represents 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 isopropyl, R 3 is -CH2-CH2-CH2-NR 8a R 8b represents R 8a and R 8b are each independently hydrogen, C 1~6 Alkyl and -OH, cyano , halo, -S(=O)2-C 1~4 Alkyl, -OC 1~4 Alkyl and -C(=O) -NR 10a R 10b one, two, or three substitutions each independently selected from the group consisting of C substituted with a group 1~6 is selected from the group consisting of alkyl, R 10a and R 10b are each independently hydrogen and C 1~6 From the group consisting of alkyl Selected compounds of formula (I) and their tautomeric and stereoisomeric forms, and their pharmaceutical compositions The present invention relates to physiologically acceptable salts and solvates thereof.

[0090] The present invention particularly relates to compounds of formula (I) as defined herein, as well as tautomers and derivatives thereof. and stereoisomeric forms, wherein R 1a is -C(=O)-NR xa R xb represents R xa and R xb is hydrogen or C 1~4 represents alkyl, R 1b represents F, Y 1 represents -O-, R 2 represents hydrogen, U represents 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 isopropyl, R 3 is -CH2-CH2-CH2-NR 8a R 8b represents R 8a and R 8b are each independently hydrogen, C 1~6 Alkyl and -OH, cyano , halo, -S(=O)2-C 1~4 Alkyl, -OC 1~4 Alkyl and -C(=O) -NR 10a R 10b one, two, or three substitutions each independently selected from the group consisting of C substituted with a group 1~6 is selected from the group consisting of alkyl, R 10a and R 10bare each independently hydrogen and C 1~6 From the group consisting of alkyl Selected compounds of formula (I) and their tautomeric and stereoisomeric forms, and their pharmaceutical compositions The present invention relates to physiologically acceptable salts and solvates thereof.

[0091] The present invention particularly relates to compounds of formula (I) as defined herein, as well as tautomers and derivatives thereof. and stereoisomeric forms, wherein R 1a is -C(=O)-NR xa R xb represents R xa and R xb is hydrogen or C 1~4 represents alkyl, R 1b represents F, Y 1 represents -O-, R 2 represents hydrogen, U represents 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 isopropyl, R 3 is -CH2-CH2-CH2-NR 8a R 8b represents R 8a and R 8b are each independently hydrogen, C 1~6 Alkyl and -OH and -O -C 1~4 one, two, or three substituents each independently selected from the group consisting of alkyl C replaced with 1~6 The compounds of formula (I) and their Tautomeric and stereoisomeric forms, and pharmaceutically acceptable salts and solvates thereof .

[0092] The present invention particularly relates to compounds of formula (I) as defined herein, as well as tautomers and derivatives thereof. and stereoisomeric forms, wherein R 1a is -C(=O)-NR xa R xb represents R xa and R xb is C 1~4 represents alkyl, R 1b represents F, Y 1 represents -O-, R 2 represents hydrogen, U represents 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 isopropyl, R 3 -C 1~6 Alkyl-NR 8a R 8b represents R 8a and R 8b are each independently C 1~6 Alkyl and one -OC 1~4 Al C replaced by kill 1~6 a compound of formula (I) selected from the group consisting of alkyl; Its tautomeric and stereoisomeric forms, as well as its pharmaceutically acceptable salts and solvates do.

[0093] The present invention particularly relates to compounds of formula (I) as defined herein, as well as tautomers and derivatives thereof. and stereoisomeric forms, wherein R 1a is -C(=O)-NR xa R xb represents R xa and R xb is C 1~4 represents alkyl, R 1b represents F, Y 1 represents -O-, R 2 represents hydrogen, U represents 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 isopropyl, R 3 is -CH2-CH2-CH2-NR 8a R 8b represents R 8a and R 8b are each independently C 1~6 Alkyl and one -OC 1~4 Al C replaced by kill 1~6 a compound of formula (I) selected from the group consisting of alkyl; Its tautomeric and stereoisomeric forms, as well as its pharmaceutically acceptable salts and solvates do.

[0094] The present invention particularly relates to compounds of formula (I) as defined herein, as well as tautomers and derivatives thereof. and stereoisomeric forms, wherein R 1a is -C(=O)-NR xa R xb or Het, Het represents a 6-membered monocyclic aromatic ring containing two nitrogen atoms; wherein the 6-membered monocyclic aromatic ring optionally contains one C 3~6 Cycloalkyl It is replaced, R xa and R xb is C 1~4represents alkyl, R 1b represents F, Y 1 represents -O-, R 2 is hydrogen, U represents 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 isopropyl, R 3 -C 1~6 Alkyl-NR 8a R 8b , -C 1~6 Alkyl-C(=O)-NR 9a R 9b , -C 1~6 Alkyl-OH or -C 1~6 Alkyl-NR 11 -C(=O) -OC 1~4 Alkyl-OC(=O)-C 1~4 represents alkyl, R 8a and R 8b are each independently hydrogen, C 1~6 Alkyl, -C(=O)-C1 ~4 Alkyl, -C(=O)-OC 1~4 Alkyl, -C(=O)-NR 12a R 12 b and cyano, halo, -S(=O)2-C 1~4 Alkyl and -OC 1~4 Alkyl C substituted with 1, 2 or 3 substituents each independently selected from the group consisting of 1~ 6 alkyl, R 9a , R 9b , R 12a and R 12bare each independently hydrogen and C 1~6 Archi and tautomeric and stereoisomeric forms thereof of the compounds of formula (I) selected from the group consisting of: and pharmaceutically acceptable salts and solvates thereof.

[0095] The present invention particularly relates to compounds of formula (I) as defined herein, as well as tautomers and derivatives thereof. and stereoisomeric forms, wherein R 1a is -C(=O)-NR xa R xb represents R xa and R xb is C 1~4 represents alkyl, R 1b represents F, Y 1 represents -O-, R 2 is hydrogen, U represents 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 isopropyl, R 3 -C 1~6 Alkyl-NR 8a R 8b , -C 1~6 Alkyl-C(=O)-NR 9a R 9b or -C 1~6 represents alkyl-OH, R 8a and R 8b are each independently hydrogen, C 1~6 Alkyl, -C(=O)-C1 ~4 Alkyl, -C(=O)-OC 1~4 Alkyl, -C(=O)-NR 12a R 12 b and cyano, halo, -S(=O)2-C 1~4 Alkyl and -OC 1~4 Alkyl C substituted with 1, 2 or 3 substituents each independently selected from the group consisting of 1~ 6 alkyl, R 9a , R 9b , R 12a and R 12b are each independently hydrogen and C 1~6 Archi and tautomeric and stereoisomeric forms thereof of the compounds of formula (I) selected from the group consisting of: and pharmaceutically acceptable salts and solvates thereof.

[0096] In one embodiment, the present invention provides these compounds of formula (I) as well as their pharmaceutically acceptable salts. Any of these subgroups mentioned in any of the salts and solvates or other embodiments. where R 1b represents F.

[0097] In one embodiment, the present invention provides these compounds of formula (I) as well as their pharmaceutically acceptable salts. Any of these subgroups mentioned in any of the salts and solvates or other embodiments. where R 2 represents hydrogen.

[0098] In one embodiment, the present invention provides these compounds of formula (I) as well as their pharmaceutically acceptable salts. Any of these subgroups mentioned in any of the salts and solvates or other embodiments. In the formula, n1 is 1, n2 is 2, n3 is 1, and n4 is 1. do.

[0099] In one embodiment, the present invention provides these compounds of formula (I) as well as their pharmaceutically acceptable salts. Any of these subgroups mentioned in any of the salts and solvates or other embodiments. In the formula, Y 1 represents -O-.

[0100] In one embodiment, the present invention provides these compounds of formula (I) as well as their pharmaceutically acceptable salts. Any of these subgroups mentioned in any of the salts and solvates or other embodiments. Regarding, in the formula: Y 1 represents -O-, U represents N.

[0101] In one embodiment, the present invention provides these compounds of formula (I) as well as their pharmaceutically acceptable salts. Any of these subgroups mentioned in any of the salts and solvates or other embodiments. Regarding, in the formula: Y 1 represents -O-, U represents N; R 1b represents F, R 2 represents hydrogen.

[0102] In one embodiment, the present invention provides these compounds of formula (I) as well as their pharmaceutically acceptable salts. Any of these subgroups mentioned in any of the salts and solvates or other embodiments. wherein Het is [ka] Represents.

[0103] In one embodiment, the present invention provides these compounds of formula (I) as well as their pharmaceutically acceptable salts. Any of these subgroups mentioned in any of the salts and solvates or other embodiments. wherein Het is a monocyclic 5- or 6-membered aromatic ring containing 1 or 2 nitrogen atoms. wherein the monocyclic 5- or 6-membered aromatic ring is 3~6 Cycloalkyl It will be exchanged.

[0104] In one embodiment, the present invention provides these compounds of formula (I) as well as their pharmaceutically acceptable salts. Any of these subgroups mentioned in any of the salts and solvates or other embodiments. wherein Het is a monocyclic 5- or 6-membered aromatic ring containing 1 or 2 nitrogen atoms. wherein the monocyclic 5- or 6-membered aromatic ring is 3~6 Cycloalkyl Converted to R 1b represents F.

[0105] In one embodiment, the present invention provides these compounds of formula (I) as well as their pharmaceutically acceptable salts. Any of these subgroups mentioned in any of the salts and solvates or other embodiments. wherein Het represents a monocyclic 6-membered aromatic ring containing 1 or 2 nitrogen atoms; wherein the monocyclic 6-membered aromatic ring is one C 3~6 It is substituted with cycloalkyl.

[0106] In one embodiment, the present invention provides these compounds of formula (I) as well as their pharmaceutically acceptable salts. Any of these subgroups mentioned in any of the salts and solvates or other embodiments. wherein Het represents a monocyclic 6-membered aromatic ring containing 1 or 2 nitrogen atoms; wherein the monocyclic 6-membered aromatic ring is one C 3~6 cycloalkyl-substituted, R 1 b represents F.

[0107] In one embodiment, the present invention provides these compounds of formula (I) as well as their pharmaceutically acceptable salts. Any of these subgroups mentioned in any of the salts and solvates or other embodiments. Regarding, in the formula: R 3 -C 1~6 Alkyl-NR 8a R 8b represents where R 3 C in the definition of 1~6 The alkyl moieties are each independently selected from cyano, halo, and Bi-OC 1~4 substituted with 1, 2 or 3 substituents selected from the group consisting of alkyl obtain.

[0108] In one embodiment, the present invention provides these compounds of formula (I) as well as their pharmaceutically acceptable salts. Any of these subgroups mentioned in any of the salts and solvates or other embodiments. Regarding, in the formula: R 3 -C 1~6 Alkyl-NR 8a R 8b represents where R 3 C in the definition of 1~6 Each alkyl moiety is independently selected from cyano, halo, -OH and -OC 1~4 and one, two or three substituents selected from the group consisting of alkyl, It can be substituted.

[0109] In one embodiment, the present invention provides these compounds of formula (I) as well as their pharmaceutically acceptable salts. Any of these subgroups mentioned in any of the salts and solvates or other embodiments. where R 3 -C 1~6 Alkyl-NR 8a R 8b Represents.

[0110] In one embodiment, the present invention provides these compounds of formula (I) as well as their pharmaceutically acceptable salts. Any of these subgroups mentioned in any of the salts and solvates or other embodiments. Regarding, in the formula: R 3 -C 1~6 Alkyl-NR 8a R 8b represents where R 3 C in the definition of 1~6 The alkyl moieties are each independently selected from cyano, halo, and Bi-OC 1~4 substituted with 1, 2 or 3 substituents selected from the group consisting of alkyl Gain, R 8a and R 8b are each independently hydrogen, C 1~6 Alkyl and -OH, cyano , halo, -S(=O)2-C 1~4 Alkyl, -OC 1~4 Alkyl, -C(=O)- NR 10a R 10b and -NR 10c -C(=O)-C 1~4 From the group consisting of alkyl C substituted with 1, 2 or 3 independently selected substituents 1~6 From alkyl The compound is selected from the group consisting of:

[0111] In one embodiment, the present invention provides these compounds of formula (I) as well as their pharmaceutically acceptable salts. Any of these subgroups mentioned in any of the salts and solvates or other embodiments. Regarding, in the formula: R 3 -C 1~6 Alkyl-NR 8a R 8b represents where R 3 C in the definition of 1~6 Each alkyl moiety is independently selected from cyano, halo, -OH and -OC 1~4 and one, two or three substituents selected from the group consisting of alkyl, may be substituted, R 8a and R 8b are each independently hydrogen, C 1~6 Alkyl and -OH, cyano , halo, -S(=O)2-C 1~4 Alkyl, -OC 1~4 Alkyl, -C(=O)- NR 10a R 10b and -NR 10c -C(=O)-C 1~4 From the group consisting of alkyl C substituted with 1, 2 or 3 independently selected substituents 1~6 From alkyl The compound is selected from the group consisting of:

[0112] In one embodiment, the present invention provides these compounds of formula (I) as well as their pharmaceutically acceptable salts. Any of these subgroups mentioned in any of the salts and solvates or other embodiments. Regarding, in the formula: R 3 -C 1~6 Alkyl-NR 8a R 8b represents where R 3 C in the definition of 1~6 The alkyl moieties are each independently selected from cyano, halo, and Bi-OC 1~4 substituted with 1, 2 or 3 substituents selected from the group consisting of alkyl Gain, R 8a and R 8b are each independently hydrogen, C 1~6 Alkyl as well as cyano, halo, -S(=O)2-C 1~4 Alkyl, -OC 1~4 Alkyl and -C(=O)-NR 1 0a R 10b substituted with 1, 2, or 3 substituents each independently selected from the group consisting of C1~6 alkyl.

[0113] In one embodiment, the present invention provides these compounds of formula (I) as well as their pharmaceutically acceptable salts. Any of these subgroups mentioned in any of the salts and solvates or other embodiments. Regarding, in the formula: R 3 -C 1~6 Alkyl-NR 8a R 8b represents where R 3 C in the definition of 1~6 The alkyl moieties are each independently selected from cyano, halo, and Bi-OC 1~4 substituted with 1, 2 or 3 substituents selected from the group consisting of alkyl Gain, R 8a and R 8b are each independently hydrogen, C 1~6 Alkyl as well as cyano, halo, -S(=O)2-C 1~4 Alkyl, -OC 1~4 Alkyl, -C(=O)-NR 10 a R 10b and -NR 10c -C(=O)-C 1~4 alkyl, C substituted with 1, 2 or 3 substituents selected arbitrarily 1~6 From the group consisting of alkyl be selected.

[0114] In one embodiment, the present invention provides these compounds of formula (I) as well as their pharmaceutically acceptable salts. Any of these subgroups mentioned in any of the salts and solvates or other embodiments. Regarding, in the formula: R 3 -C 1~6 Alkyl-NR 8a R 8b represents where R 3 C in the definition of 1~6 Each alkyl moiety is independently selected from cyano, halo, -OH and -OC 1~4 and one, two or three substituents selected from the group consisting of alkyl, may be substituted, R 8a and R 8b are each independently hydrogen, C 1~6 Alkyl as well as cyano, halo, -S(=O)2-C 1~4 Alkyl, -OC 1~4 Alkyl and -C(=O)-NR 1 0a R 10b substituted with 1, 2, or 3 substituents each independently selected from the group consisting of C 1~6 alkyl.

[0115] In one embodiment, the present invention provides these compounds of formula (I) as well as their pharmaceutically acceptable salts. Any of these subgroups mentioned in any of the salts and solvates or other embodiments. Regarding, in the formula: R 3 -C 1~6 Alkyl-NR 8a R 8b represents where R 3 C in the definition of 1~6 The alkyl moiety can be cyano, halo, -OH, and -O- C 1~4 and 1, 2, or 3 substituents each independently selected from the group consisting of alkyl, may be substituted, R 8a and R 8b are each independently hydrogen, C 1~6 Alkyl as well as cyano, halo, -S(=O)2-C 1~4 Alkyl, -OC 1~4 Alkyl, -C(=O)-NR10 a R 10b and -NR 10c -C(=O)-C 1~4 alkyl, C substituted with 1, 2 or 3 substituents selected arbitrarily 1~6 From the group consisting of alkyl be selected.

[0116] In one embodiment, the present invention provides these compounds of formula (I) as well as their pharmaceutically acceptable salts. Any of these subgroups mentioned in any of the salts and solvates or other embodiments. Regarding, in the formula: R 3 -C 2~6 Alkyl-NR 8a R 8b represents where R 3 C in the definition of 2~6 The alkyl moieties are each independently selected from cyano, halo, and Bi-OC 1~4 substituted with 1, 2 or 3 substituents selected from the group consisting of alkyl obtain.

[0117] In one embodiment, the present invention provides these compounds of formula (I) as well as their pharmaceutically acceptable salts. Any of these subgroups mentioned in any of the salts and solvates or other embodiments. Regarding, in the formula: R 3 -C 2~6 Alkyl-NR 8a R 8b represents where R 3 C in the definition of 2~6 Each alkyl moiety is independently selected from cyano, halo, -OH and -OC 1~4 and one, two or three substituents selected from the group consisting of alkyl, It can be substituted.

[0118] In one embodiment, the present invention provides these compounds of formula (I) as well as their pharmaceutically acceptable salts. Any of these subgroups mentioned in any of the salts and solvates or other embodiments. Regarding, in the formula: R 3 -C 2~6 Alkyl-NR 8a R 8b represents where R 3 C in the definition of 2~6 The alkyl moieties are each independently selected from cyano, halo, and Bi-OC 1~4 substituted with 1, 2 or 3 substituents selected from the group consisting of alkyl Gain, R 8a and R 8b are each independently hydrogen, C 1~6 Alkyl and -OH, cyano , halo, -S(=O)2-C 1~4 Alkyl, -OC 1~4 Alkyl, -C(=O)- NR 10a R 10b and -NR 10c -C(=O)-C 1~4 From the group consisting of alkyl C substituted with 1, 2 or 3 independently selected substituents 1~6 From alkyl The compound is selected from the group consisting of:

[0119] In one embodiment, the present invention provides these compounds of formula (I) as well as their pharmaceutically acceptable salts. Any of these subgroups mentioned in any of the salts and solvates or other embodiments. Regarding, in the formula: R 3 -C 2~6 Alkyl-NR 8a R 8b represents where R 3 C in the definition of 2~6 Each alkyl moiety is independently selected from cyano, halo, -OH and -OC 1~4 and one, two or three substituents selected from the group consisting of alkyl, may be substituted, R 8a and R 8b are each independently hydrogen, C 1~6 Alkyl and -OH, cyano , halo, -S(=O)2-C 1~4 Alkyl, -OC 1~4 Alkyl, -C(=O)- NR 10a R 10b and -NR 10c -C(=O)-C 1~4 From the group consisting of alkyl C substituted with 1, 2 or 3 independently selected substituents 1~6 From alkyl The compound is selected from the group consisting of:

[0120] In one embodiment, the present invention provides these compounds of formula (I) as well as their pharmaceutically acceptable salts. Any of these subgroups mentioned in any of the salts and solvates or other embodiments. Regarding, in the formula: R 3 -C 2~6 Alkyl-NR 8a R 8b represents where R 3 C in the definition of 2~6 Each alkyl moiety is independently selected from cyano, halo, -OH and -OC 1~4 and one, two or three substituents selected from the group consisting of alkyl, may be substituted, R 8a and R 8b are each independently hydrogen, C 1~6 Alkyl as well as cyano, halo, -S(=O)2-C 1~4 Alkyl, -OC 1~4 Alkyl and -C(=O)-NR 1 0a R10b substituted with 1, 2, or 3 substituents each independently selected from the group consisting of C 1~6 alkyl.

[0121] In one embodiment, the present invention provides these compounds of formula (I) as well as their pharmaceutically acceptable salts. Any of these subgroups mentioned in any of the salts and solvates or other embodiments. Regarding, in the formula: R 3 -C 2~6 Alkyl-NR 8a R 8b represents where R 3 C in the definition of 2~6 The alkyl moieties are each independently selected from cyano, halo, and Bi-OC 1~4 substituted with 1, 2 or 3 substituents selected from the group consisting of alkyl Gain, R 8a and R 8b are each independently hydrogen, C 1~6 Alkyl as well as cyano, halo, -S(=O)2-C 1~4 Alkyl, -OC 1~4 Alkyl and -C(=O)-NR 1 0a R 10b substituted with 1, 2, or 3 substituents each independently selected from the group consisting of C 1~6 alkyl.

[0122] In one embodiment, the present invention provides these compounds of formula (I) as well as their pharmaceutically acceptable salts. Any of these subgroups mentioned in any of the salts and solvates or other embodiments. Regarding, in the formula: R 3 -C 1~6 Alkyl-NR 8a R 8b represents R 8a and R 8b are each independently C 1~6 Alkyl and -OH, cyano, halo, -S(=O)2-C 1~4 Alkyl, -OC 1~4 Alkyl and -C(=O)-NR 1 0a R 10b substituted with 1, 2, or 3 substituents each independently selected from the group consisting of C 1~6 alkyl.

[0123] In one embodiment, the present invention provides these compounds of formula (I) as well as their pharmaceutically acceptable salts. Any of these subgroups mentioned in any of the salts and solvates or other embodiments. Regarding, in the formula: R 3 -C 2~6 Alkyl-NR 8a R 8b represents where R 3 C in the definition of 2~6 Each alkyl moiety is independently selected from cyano, halo, -OH and -OC 1~4 and one, two or three substituents selected from the group consisting of alkyl, may be substituted, R 8a and R 8b are each independently hydrogen, C 1~6 Alkyl as well as cyano, halo, -S(=O)2-C 1~4 Alkyl, -OC 1~4 Alkyl, -C(=O)-NR 10 a R 10b and -NR 10c -C(=O)-C 1~4 alkyl, C substituted with 1, 2 or 3 substituents selected arbitrarily 1~6From the group consisting of alkyl be selected.

[0124] In one embodiment, the present invention provides these compounds of formula (I) as well as their pharmaceutically acceptable salts. Any of these subgroups mentioned in any of the salts and solvates or other embodiments. Regarding, in the formula: R 3 -C 2~6 Alkyl-NR 8a R 8b represents where R 3 C in the definition of 2~6 The alkyl moieties are each independently selected from cyano, halo, and Bi-OC 1~4 substituted with 1, 2 or 3 substituents selected from the group consisting of alkyl Gain, R 8a and R 8b are each independently hydrogen, C 1~6 Alkyl as well as cyano, halo, -S(=O)2-C 1~4 Alkyl, -OC 1~4 Alkyl, -C(=O)-NR 10 a R 10b and -NR 10c -C(=O)-C 1~4 alkyl, C substituted with 1, 2 or 3 substituents selected arbitrarily 1~6 From the group consisting of alkyl be selected.

[0125] In one embodiment, the present invention provides these compounds of formula (I) as well as their pharmaceutically acceptable salts. Any of these subgroups mentioned in any of the salts and solvates or other embodiments. Regarding, in the formula: R 3 -C 1~6 Alkyl-NR 8a R 8b represents R 8a and R 8b are each independently C 1~6 Alkyl and -OH, cyano, halo, -S(=O)2-C 1~4 Alkyl, -OC 1~4 Alkyl, -C(=O)-NR 10 a R 10b and -NR 10c -C(=O)-C 1~4 alkyl, C substituted with 1, 2 or 3 substituents selected arbitrarily 1~6 From the group consisting of alkyl be selected.

[0126] In one embodiment, the present invention provides these compounds of formula (I) as well as their pharmaceutically acceptable salts. Any of these subgroups mentioned in any of the salts and solvates or other embodiments. Regarding, in the formula: R 3 -C 1~6 Alkyl-NR 8a R 8b represents R 8a is C 1~6 represents alkyl, R 8b 1 piece of -OC 1~4 Alkyl-substituted C 1~6 Represents alkyl.

[0127] In one embodiment, the present invention provides these compounds of formula (I) as well as their pharmaceutically acceptable salts. Any of these subgroups mentioned in any of the salts and solvates or other embodiments. Regarding, in the formula: R 3 -C 1~6 Alkyl-NR 8a R 8b , -C 1~6 Alkyl-C(=O)-NR 9a R9b , -C 1~6 Alkyl-OH or -C 1~6 Alkyl-NR 11 -C(=O) -OC 1~4 Alkyl-OC(=O)-C 1~4 represents alkyl, where R 3 C in the definition of 1~4 Alkyl or C 1~6 Each of the alkyl moieties is Independently of each other, cyano, halo or -OC 1~4 independently from the group consisting of alkyl The group may be substituted with one, two or three substituents selected from the following:

[0128] In one embodiment, the present invention provides these compounds of formula (I) as well as their pharmaceutically acceptable salts. Any of these subgroups mentioned in any of the salts and solvates or other embodiments. Regarding, in the formula: R 3 -C 1~6 Alkyl-NR 8a R 8b , -C 1~6 Alkyl-C(=O)-NR 9a R 9b or -C 1~6 Alkyl-NR 11 -C(=O)-OC 1~4 Alkyl-O -C(=O)-C 1~4 represents alkyl, where R 3 C in the definition of 1~4 Alkyl or C 1~6 Each of the alkyl moieties is Independently of each other, cyano, halo, -OH and -OC 1~4 From the group consisting of alkyl Each may be substituted with 1, 2, or 3 independently selected substituents.

[0129] In one embodiment, the present invention provides these compounds of formula (I) as well as their pharmaceutically acceptable salts. Any of these subgroups mentioned in any of the salts and solvates or other embodiments. where R 3 is -CH2-CH2-CH2-NR 8a R 8b Represents.

[0130] In one embodiment, the present invention provides these compounds of formula (I) as well as their pharmaceutically acceptable salts. Any of these subgroups mentioned in any of the salts and solvates or other embodiments. Regarding, in the formula: R 3 is -CH2-CH2-CH2-NR 8a R 8b represents R 8a represents methyl, R 8b represents -CH2-CH2-OCH3.

[0131] In one embodiment, the present invention provides these compounds of formula (I) as well as their pharmaceutically acceptable salts. Any of these subgroups mentioned in any of the salts and solvates or other embodiments. where R 3 Definition of -C 1~6 Alkyl-NR 8a R 8b C in 1~6 Alkyl is limited to -CH2-CH2-CH2-.

[0132] In one embodiment, the present invention provides these compounds of formula (I) as well as their pharmaceutically acceptable salts. Any of these subgroups mentioned in any of the salts and solvates or other embodiments. wherein the compound of formula (I) is of formula (Iy): [ka] where R 3 is a compound of formula (I) or any of the other embodiments. As defined with respect to any of these subgroups mentioned.

[0133] In formula (Iy), n1 is 1, n2 is 2, n3 is 1, and n4 is , 1.

[0134] In one embodiment, the compound of formula (I) is [ka] and pharmaceutically acceptable addition salts and solvates thereof.

[0135] In one embodiment, the compound of formula (I) is [ka] is.

[0136] In one embodiment, the compound of formula (I) is [ka] is.

[0137] In one embodiment, the compound of formula (I) is [ka] is.

[0138] In one embodiment, the present invention relates to a subgroup of formula (I) as defined in the general reaction scheme: Regarding.

[0139] In one embodiment, the compound of formula (I) may be any of the exemplified compounds, tautomers thereof and stereoisomeric forms thereof, as well as the free base, any pharmaceutically acceptable salts and solvates thereof. is selected from the group consisting of:

[0140] All possible combinations of the above-described embodiments are within the scope of the present invention. It is considered to be.

[0141] In another embodiment, the present invention provides an intermediate [ka] , its tautomeric and stereoisomeric forms and any pharmaceutically acceptable salts and solvates thereof Pertaining to things.

[0142] In another embodiment, the present invention relates to a process for preparing an intermediate comprising the steps of: Regarding. [ka] wherein PG is a suitable protecting group such as benzyl; n1 and n2 are as defined in relation to formula (I), Step 23: A suitable solvent such as DIEA and n-BuLi is added to a suitable solvent such as THF. in the presence of a suitable base at a suitable temperature, such as from -78°C to -25°C, Step 24: A suitable reduction, such as DIBAL-H, in a suitable solvent, such as toluene In the presence of a suitable flow chemistry, at a suitable temperature, for example, between -55°C and -65°C, It is carried out in a tree system.

[0143] In another embodiment, the present invention relates to a process for preparing an intermediate comprising the steps of: Regarding. [ka] The first reaction is carried out in a suitable solvent such as THF, for example, with DIEA and n-BuLi. in the presence of any suitable base at a suitable temperature, such as from -78°C to -25°C, The reaction is then carried out in a suitable solvent, such as, for example, toluene, in a suitable solvent such as, for example, DIBAL-H. In the presence of a suitable reducing agent, at a suitable temperature, for example, from -55°C to -65°C, a suitable flow This is carried out in a chemistry system.

[0144] In another embodiment, the present invention relates to a process for preparing an intermediate comprising the steps of: Regarding. [ka] PG is a suitable protecting group such as benzyl; The other variables are as defined for formula (I).

[0145] In another embodiment, the present invention relates to a process for preparing an intermediate comprising the steps of: Regarding. [ka] PG is a suitable protecting group such as benzyl; The other variables are as defined for formula (I). Step 30: In a suitable solvent, such as toluene, In the presence of a suitable reducing agent, for example, in the presence of a suitable base such as TEA, for example, at 5°C to 30°C, At a suitable temperature, Step 31: In a suitable solvent, such as H2O, in the presence of a suitable base, such as K2HPO4 At a suitable temperature, for example, 50°C to 55°C, Step 32: Palladium hydroxide on carbon in the presence of MSA in a suitable solvent such as EtOH under a hydrogen atmosphere within a suitable pressure range, for example, 0.27 to 0.40 MPa, for example, At a suitable temperature such as 5℃ to 45℃, Step 33: In a suitable solvent such as 2-methyltetrahydrofuran, for example TEA, in the presence of a suitable base at a suitable temperature, for example, from -50°C to -40°C, Step 34: In a suitable solvent such as 2-methyltetrahydrofuran, for example TMG in the presence of a suitable base at a suitable temperature, for example, 20°C to 30°C, Step 35: In the presence of a suitable catalyst, such as palladium on carbon, in a suitable solvent, such as MeOH under a hydrogen atmosphere within a suitable pressure range, for example, 0.20 to 0.30 MPa, for example, 2 At a suitable temperature such as 0℃ to 30℃.

[0146] In another embodiment, the present invention relates to a process for preparing a compound comprising the steps of: Regarding. [ka]

[0147] In another embodiment, the present invention relates to a process for preparing a compound comprising the steps of: Regarding. [ka]

[0148] In another embodiment, the present invention relates to a process for preparing a compound comprising the steps of: Regarding. [ka]

[0149] In another embodiment, the present invention relates to a process for preparing a compound comprising the steps of: Regarding. [ka]

[0150] In another embodiment, the present invention relates to a process for preparing a compound comprising the steps of: Regarding. [ka] In the first step, palladium hydroxide on carbon is reacted in the presence of MSA in a suitable solvent such as EtOH. In the presence of, for example, under a hydrogen atmosphere in a suitable pressure range of 0.27 to 0.40 MPa, e.g. At a suitable temperature, for example, -5°C to 45°C, In the next step, a suitable solvent such as 2-methyltetrahydrofuran is reacted with 2-methyl-2-methyl-4-hydroxybenzoyl-2-methylbenzoyl-1-methyl ... in the presence of a suitable base at a suitable temperature, such as -50°C to -40°C, In the next step, a compound such as TMG is reacted in a suitable solvent such as 2-methyltetrahydrofuran. In the presence of a suitable base, at a suitable temperature, for example, 20°C to 30°C, In the next step, a suitable catalyst such as palladium on carbon is reacted with 1,2-dichloro-2,4 ... In the presence of hydrogen, for example, under a hydrogen atmosphere within a suitable pressure range of 0.20 to 0.30 MPa, At a suitable temperature such as 20℃ to 30℃.

[0151] In another embodiment, the present invention relates to a process for preparing a compound comprising the steps of: Regarding. [ka] In the first step, a hydroxybenzoate is first prepared by dissolving, for example, NaBH(OAc) in a suitable solvent, for example, toluene. 3, in the presence of a suitable base such as TEA, for example, at 5°C to at a suitable temperature such as 30° C., followed by a suitable solvent such as, for example, HO, in the presence of a suitable base such as PO4 at a suitable temperature, for example 50°C to 55°C, In the next step, palladium hydroxide on carbon in the presence of MSA in a suitable solvent such as EtOH is reacted with In the presence of hydrogen, for example, under a hydrogen atmosphere within a suitable pressure range of 0.27 to 0.40 MPa, At a suitable temperature such as -5°C to 45°C, In the next step, a suitable solvent such as 2-methyltetrahydrofuran is reacted with 2-methyl-2-methyl-4-hydroxybenzoyl-2-methylbenzoyl-1-methyl ... in the presence of a suitable base at a suitable temperature, such as -50°C to -40°C, In the next step, a compound such as TMG is reacted in a suitable solvent such as 2-methyltetrahydrofuran. In the presence of a suitable base, at a suitable temperature, for example, 20°C to 30°C, In the next step, a suitable catalyst such as palladium on carbon is reacted with 1,2-dichloro-2,4 ... In the presence of hydrogen, for example, under a hydrogen atmosphere within a suitable pressure range of 0.20 to 0.30 MPa, At a suitable temperature such as 20℃ to 30℃.

[0152] Process for preparing compounds of formula (I) In this section, as in all other sections, unless the context indicates otherwise, reference to formula (I) Reference to also includes all other subgroups and examples thereof defined herein.

[0153] The general preparation of some representative examples of compounds of formula (I) is illustrated below and in the specific examples. and are commercially available or can be prepared by standard synthetic methods commonly used by those skilled in the art of organic chemistry. The following schemes are illustrative of the present invention and are generally prepared from prepared starting materials. These are merely intended as a guide and are not intended to limit the invention in any way.

[0154] Instead, the compounds of the present invention can be synthesized in combination with standard synthetic methods commonly used by those skilled in the art. They can also be prepared by reaction sequences analogous to those described in the general scheme below.

[0155] Those skilled in the art will recognize that in the reactions depicted in the schemes, However, reactive functional groups (e.g., hydroxy, amino, or carboxy groups) are not present in the final product. If desired, these may be used in the presence of hydroxybenzoates to avoid unnecessary reaction. It will be understood that it may be necessary to protect the hydroxyl group. Generally, conventional protecting groups (PG) are used as standard. Protecting groups can be used according to conventional techniques. and can be removed at a later convenient stage.

[0156] Those skilled in the art will appreciate that the reactions described in the schemes are carried out under an inert atmosphere, such as N2 gas. It will be understood that it may be desirable or necessary to carry out reactions under atmosphere. .

[0157] Post-reaction work-up (the series of operations required to isolate and purify the products of a chemical reaction, e.g., quenching) It is necessary to cool the reaction mixture before use (e.g., centrifugation, column chromatography, extraction, etc.). It will be apparent to those skilled in the art that this may be necessary.

[0158] Those skilled in the art will appreciate that heating the reaction mixture under stirring may improve the reaction outcome. In some reactions, micro-exchange may be used instead of the usual heating to shorten the overall reaction time. Microwave heating may be used.

[0159] Those skilled in the art will appreciate that the desired compounds of formula (I) can be prepared by the alternative sequences of chemical reactions shown in the schemes below. It will be understood that this can also be obtained.

[0160] Those skilled in the art will appreciate that the intermediates and final compounds shown in the schemes below can be synthesized according to methods well known to those skilled in the art. It will be understood that the intermediates and compounds described herein may be further functionalized by can be isolated in its free form or as a salt or solvate. The intermediates and compounds described herein may be separated from one another following resolution procedures known in the art. The compounds may be synthesized in the form of a mixture of the possible tautomeric and stereoisomeric forms.

[0161] General synthetic scheme All abbreviations used in the general scheme are as defined in the tables in the Examples section. The variables are as defined within the ranges or as specifically defined in the general schemes. That's right.

[0162] Part A) Schemes 1a, 1b, 1c, 2a, 2b and 3 [ka] [ka] [ka]

[0163] In Schemes 1a, 1b and 1c, the following reaction conditions apply: Step 1: In a suitable solvent, such as THF, a suitable base, such as TMEDA, and In the presence of a suitable organometallic reagent, such as isopropylmagnesium bromide, for example, -70 At a suitable temperature, such as °C, Step 2: In the presence of a suitable oxidizing reagent, such as, for example, DMP, in a suitable solvent, such as, for example, DCM at a suitable temperature, for example, 0°C to RT, Step 3: In a suitable solvent such as THF, for example, isopropylmagnesium bromide in the presence of any suitable organometallic reagent at a suitable temperature, such as from -20°C to RT, Step 4: A suitable base, such as NaOH, in a suitable solvent, such as THF and HO at a suitable temperature, such as 80°C, in the presence of Step 5: In a suitable solvent, such as DCM, in the presence of a suitable base, such as NMM, e.g. In the presence of a suitable amide condensation reagent, such as EDCI and HOBt, At a temperature Step 6: In a suitable solvent, such as THF, a suitable amine, such as isopropyllithium, in the presence of an organometallic reagent at a suitable temperature, such as -70°C, Step 7: In a suitable solvent such as 1,4-dioxane and HO, for example, NaCO of a suitable organometallic catalyst such as, for example, Pd(dppf)Cl2 in the presence of a suitable base such as in the presence of, at a suitable temperature, for example, 90°C, Step 8: In the presence of a suitable Lewis acid, such as BBr3, in a suitable solvent, such as DCM at a suitable temperature, for example, 0°C to RT, Step 9: In a suitable solvent such as DCM, THF or DMF, for example, TEA, DBU or is carried out in the presence of a suitable base such as K2CO3, for example, at a temperature of -78°C to 40°C, specifically at a temperature of 0°C to R At a suitable temperature such as T [ka] [ka]

[0164] In Schemes 2a and 2b, the following reaction conditions apply: Step 9: See step 9 in Scheme 1. Step 10: In a suitable solvent, such as, for example, THF, optionally with a suitable solvent, such as, for example, TEA In the presence of a base, in the presence of a suitable reducing agent, such as H2, In the presence of a catalyst, at a suitable temperature, such as RT, Alternatively, a Pd(dppf)Cl / DCM complex may be prepared in a suitable solvent, such as THF. a suitable catalyst such as a benzophenone, a suitable reducing agent such as NaBH4, a suitable salt such as TMEDA, in the presence of a group at a suitable temperature, such as RT, Step 11: For N-deprotection, a suitable solvent such as, for example, TFA is used in a suitable solvent such as, for example, DCM. For O-deprotection, for example Me in the presence of a suitable acid at a suitable temperature, for example RT. in the presence of a suitable acid, for example 4-methylbenzenesulfonic acid, in a suitable solvent, such as OH at a suitable temperature, such as RT, Step 12: A suitable reduction such as NaBH3CN in a suitable solvent such as MeOH In the presence of a reagent, optionally in the presence of a suitable Lewis acid, such as ZnCl, e.g. At a suitable temperature such as 80°C, Step 13: In a suitable solvent such as DCE, for example, 1,3-dibromo-1,3,5-trimethylisothiazolinone (1,3-dibromo-1,3,5-trimethylisothiazolinone) is reacted with 1,3-dibromo-1,3,5-trimethylisothiazolinone (1,3-dibromo-1,3,5-trimethylisothiazolinone). In the presence of a suitable brominating reagent such as riazinan-2,4,6-trione, for example Ag(Ph en) in the presence of a suitable organometallic catalyst such as 2OTf at a suitable temperature, e.g., RT hand, Step 14: In the presence of DMF in a suitable solvent such as DCM, for example oxalyl chloride In the presence of any suitable chlorinating reagent, at a suitable temperature such as RT. [ka]

[0165] In Scheme 3, the following reaction conditions apply: Steps 11-12: See steps 11-12 in Scheme 2. Step 15: In a suitable solvent, such as DMF, in the presence of a suitable base, such as Cs2CO3 at a suitable temperature, for example 80°C, Step 16: In a suitable solvent, such as 1,4-dioxane, in the presence of a suitable base at a suitable temperature, for example 40°C.

[0166] Part B) Schemes 4, 5, 6, 7, 8, 9, 10, 11 and 12 [ka]

[0167] In Scheme 4, the following reaction conditions apply: Step 1: In a suitable solvent such as 1,4-dioxane and HO, of a suitable organometallic catalyst such as, for example, Pd(dppf)Cl2 in the presence of a suitable base such as in the presence of, at a suitable temperature, for example, 90°C, Step 2: In the presence of a suitable base, such as DIEA, in a suitable solvent, such as DCM, In the presence of a suitable amide condensation reagent, such as HATU, at a suitable temperature, such as RT, And, Step 3: In the presence of a suitable Lewis acid, such as BBr3, in a suitable solvent, such as DCM at a suitable temperature, such as, for example, -78°C to RT, Step 4: In a suitable solvent such as DCM, THF or DMF, for example, TEA, DBU or is carried out in the presence of a suitable base such as K2CO3, for example, at a temperature of -78°C to 40°C, specifically at a temperature of 0°C to R At a suitable temperature such as T Step 5: In a suitable solvent, such as THF and H2O, In the presence of a suitable base at a suitable temperature, such as RT, Step 6: In a suitable solvent such as DCE, for example, 1,3-dibromo-1,3,5-trimethylisothiazolinone (DCE) is reacted with 1,3-dibromo-1,3,5-trimethylisothiazolinone (DCE). In the presence of a suitable brominating reagent such as azinane-2,4,6-trione, for example Ag(Phe n) in the presence of a suitable organometallic catalyst, such as 2OTf, at a suitable temperature, for example RT , Step 7: 1,3-difluoromethane in the presence of 2,2,2-trifluoroethane-1-ol as a solvent The existence of a suitable brominating reagent such as bromo-1,3,5-triazinane-2,4,6-trione at a suitable temperature, such as RT. [ka]

[0168] In Scheme 5, the following reaction conditions apply: Step 8: In a suitable solvent such as DCM, THF or DMF, for example, TEA, DBU or is carried out in the presence of a suitable base such as K2CO3, for example, at a temperature of -78°C to 40°C, specifically at a temperature of 0°C to R At a suitable temperature such as T Step 9: In a suitable solvent such as DCM, THF or DMF, for example, TEA, DBU or is carried out in the presence of a suitable base such as K2CO3, for example, at a temperature of -78°C to 40°C, specifically at a temperature of 0°C to R At a suitable temperature such as T Step 10: Under H2 atmosphere in a suitable solvent such as MeOH, e.g., as Pd / C In the presence of a suitable organometallic catalyst and a suitable base, such as TEA, a suitable At the right temperature, Step 11: When PG is Boc, a suitable solvent such as DCM can be used, for example TFA. In the presence of any suitable acid, at a suitable temperature such as RT. [ka]

[0169] In Scheme 6, the following reaction conditions apply: Step 12: A suitable reduction such as NaBH3CN in a suitable solvent such as MeOH in the presence of a suitable Lewis acid, such as ZnCl or an acid, such as AcOH reductive amination conditions at a suitable temperature, e.g., RT to 80°C, in the absence or presence of Step 13: In the presence of a suitable base, such as, for example, TEA, in a suitable solvent, such as, for example, DCM, In the presence of a suitable electrophile, for example MsCl, at a suitable temperature, for example 0° C. , Step 14: In the presence of a suitable oxidizing agent, for example DMP, in a suitable solvent, for example DCM at a suitable temperature, for example, 0°C to RT, Step 15: In the presence of a suitable acid, for example HCl, in a suitable solvent, for example ACN, At a suitable temperature, for example 50°C, Step 16: In a suitable solvent such as THF, in the presence of a suitable base, for example TEA or in the absence thereof, at a suitable temperature such as RT. [ka]

[0170] In Scheme 7, the following reaction conditions apply: Step 11: When PG is Boc, a suitable solvent such as DCM can be used, for example TFA. In the presence of any suitable acid, at a suitable temperature, such as RT, Step 12: A suitable reduction such as NaBH3CN in a suitable solvent such as MeOH in the presence of a suitable Lewis acid, such as ZnCl or an acid, such as AcOH reductive amination conditions at a suitable temperature, e.g., RT to 80°C, in the absence or presence of Step 17: In a suitable solvent such as DCM or DMF, e.g., DIEA or CsCO in the presence of a suitable base such as 3 at a suitable temperature such as RT or 80° C. Step 18: In a suitable solvent such as 1,4-dioxane, a suitable hydroxy group such as ammonia is added. In the presence of a suitable base, at a suitable temperature, for example 40°C. [ka]

[0171] In Scheme 8, the following reaction conditions apply: Step 9: In a suitable solvent such as DCM, THF or DMF, for example, TEA, DBU or is carried out in the presence of a suitable base such as K2CO3, for example, at a temperature of -78°C to 40°C, specifically at a temperature of 0°C to R At a suitable temperature such as T Step 10: Under H2 atmosphere in a suitable solvent such as MeOH, optionally in a solvent such as TE in the presence of a suitable base as A, in the presence of a suitable organometallic catalyst as, for example, Pd / C, At a suitable temperature, such as RT, Step 19: In the presence of DMF in a suitable solvent such as DCM, for example oxalyl chloride In the presence of any suitable chlorinating reagent, at a suitable temperature, such as RT, Step 20: In a suitable solvent, such as EtOH, in the presence of a suitable nucleophilic amine, such as 9 At a suitable temperature such as 0°C, Step 21: In a suitable solvent, such as, for example, MeOH, In the presence of an acid, at a suitable temperature, such as RT, Step 22: In a suitable solvent, such as 1,4-dioxane, In the presence of a suitable base, such as tetrakis(triphenylphosphine)palladium(0), In the presence of a suitable organometallic catalyst, in the presence of a suitable boron reagent, such as trimethylboroxine, at a suitable temperature such as, for example, 110°C. [ka]

[0172] In Scheme 9, the following reaction conditions apply: Step 23: A suitable solvent such as DIEA and n-BuLi is added to a suitable solvent such as THF. in the presence of a suitable base at a suitable temperature, such as from -78°C to -25°C, Step 24: A suitable reduction, such as DIBAL-H, in a suitable solvent, such as toluene In the presence of a suitable agent, at a suitable temperature, for example, between -65°C and -55°C, preferably in a suitable flow chemistry implemented in the street system, Step 25: First, a suitable condensing agent, such as DCC, in a suitable solvent, such as DCM In the presence of a suitable base such as DMAP, for example, at a temperature of -10°C to 10°C. at a suitable temperature, followed by addition of a suitable solvent, such as NaBH4, in a suitable solvent, such as DCM. In the presence of a suitable reducing agent, for example in the presence of a suitable acid such as AcOH, for example at -10°C to 0°C At a suitable temperature such as Step 26: heated to reflux in a suitable solvent such as toluene, Step 27: In a suitable solvent such as 2-methyltetrahydrofuran, for example, LiBH at a suitable temperature, for example, from -5°C to 5°C, Step 28: In a suitable solvent, such as DCM, In the presence of a reducing agent, at a suitable temperature, such as 15°C to 25°C, Step 29: In the presence of a suitable acid, such as HCl, in a suitable solvent, such as IPA, At a suitable temperature, for example, 15°C to 25°C, Step 30: In a suitable solvent, such as toluene, In the presence of a suitable reducing agent, for example, in the presence of a suitable base such as TEA, for example, at 5°C to 30°C, At a suitable temperature, Step 31: In a suitable solvent, such as H2O, in the presence of a suitable base, such as K2HPO4 At a suitable temperature, for example, 50°C to 55°C, Step 32: When PG is Bn, a suitable phenyl group such as MSA is added to a suitable solvent such as EtOH. In the presence of a suitable acid, for example in the presence of a suitable catalyst such as palladium hydroxide on carbon, for example 0.2 Under a hydrogen atmosphere within a suitable pressure range of 7 to 0.40 MPa, for example, at -5 to 45°C At a suitable temperature of Step 33: In a suitable solvent such as 2-methyltetrahydrofuran, for example TEA, in the presence of a suitable base at a suitable temperature, for example, from -50°C to -40°C, Step 34: In a suitable solvent such as 2-methyltetrahydrofuran, for example TMG in the presence of a suitable base at a suitable temperature, for example, 20°C to 30°C, Step 35: In the presence of a suitable catalyst, such as palladium on carbon, in a suitable solvent, such as MeOH under a hydrogen atmosphere within a suitable pressure range, for example, 0.20 to 0.30 MPa, for example, 2 At a suitable temperature such as 0℃ to 30℃, Alternatively, 1,1'-bis(diphenyl ether) (phenylphosphino)ferrocene-palladium(II) dichloride dichloromethane complex, etc. a suitable catalyst such as sodium borohydride, a suitable reducing agent such as N,N,N',N' in the presence of a suitable base, such as tetramethylethylenediamine, at a suitable temperature, such as room temperature There.

[0173] Scheme 10 Generally, compounds of formula (Ia) are referred to herein as compounds of formula (Ia), wherein Y 1 is limited to -CH2- and R 2 W 1 Compounds of formula (I) defined as: In Scheme 10, W 1 represents chloro, bromo or iodo, and other All variables are defined according to the scope of the present invention. [ka]

[0174] In Scheme 10, the following reaction conditions apply: Step 36: Palladium acetate in a suitable solvent such as tetrahydrofuran or dioxane (Pd(OAc)2) or tris(dibenzylideneacetone)dipalladium(0) ( Pd2(dba)3) or tetrakis(triphenylphosphine)palladium(0), etc. in the presence of a suitable catalyst at a suitable temperature in the range of 60°C to 100°C.

[0175] Those skilled in the art will recognize that starting from compound (Ia), step 10 of Scheme 5 and step 11 of Scheme 8 Chemical reactions similar to those reported in steps 20, 21 and 22 can be carried out. You will understand that.

[0176] Scheme 11 Generally referred to herein as formula (Ib), wherein Y 1 Ga-CR 5a R5b -Limited to and R 2 W 1 Compounds of formula (I) defined as: In Scheme 11, R 5a and R 5b At least one of these is hydrogen All other variables are defined in accordance with the scope of the present invention. [ka]

[0177] In Scheme 11, the following reaction conditions apply: Step 37: Optionally, under microwave irradiation, preferably under sealed conditions, e.g., in dioxane. In any suitable solvent, such as triphenylphosphine or tricyclohexylphosphine of a suitable catalyst, such as palladium acetate (Pd(OAc)2), in the presence of any suitable ligand. In the presence of, at a suitable temperature in the range of 80°C to 200°C.

[0178] Those skilled in the art will recognize that starting from compound (Ib), step 10 of Scheme 5 and step 11 of Scheme 8 Chemical reactions similar to those reported in steps 20, 21 and 22 can be carried out. You will understand that.

[0179] Scheme 12 [ka] In Scheme 12, the following reaction conditions apply: Step 38: In a suitable solvent such as DCM, THF or DMF, e.g., DIEA, Cs in the presence of a suitable base such as 2CO3 or DBU at a suitable temperature such as RT or 80°C In Alternatively, Cs2CO3 in a suitable solvent such as dioxane or a mixture of dioxane and water can be or in the presence of a suitable base such as Na2CO3, a suitable ligand such as Xantphos in the presence of a suitable catalyst such as Pd2dba3, for example, at RT to 100°C At a suitable temperature.

[0180] Starting from intermediate A, one skilled in the art can easily elucidate Y 1 Similar to what is reported when represents O It will be appreciated that chemical reactions can be carried out.

[0181] When suitable functional groups are present, compounds of various formulae or any compounds used in their preparation may be The intermediate is one or more standard reactions using condensation, substitution, oxidation, reduction or cleavage reactions. It will be understood that the compound may be further derivatized by conventional synthetic methods. These include conventional alkylation, arylation, heteroarylation, acylation, sulfonylation, These include halogenation, nitration, formylation and coupling methods.

[0182] Compounds of formula (I) may be separated into enantiomers which may be separated from each other by art-known resolution procedures. The racemic mixture of thiomers of formula (I) containing a basic nitrogen atom can be synthesized. The compounds may be converted to the corresponding diastereomeric salt forms by reaction with a suitable chiral acid. The diastereomeric salt forms can then be obtained, for example, by selective or fractional crystallization. The compounds of formula (I) are separated by the addition of HCl and then the enantiomers are liberated by alkali. An alternative method for separating the enantiomeric forms of is by liquid chromatography using a chiral stationary phase. Said pure stereochemically isomeric forms can be prepared by the corresponding pure stereochemically isomeric reactions of the appropriate starting materials. It can also be derived from isomeric forms of the compound, but this reaction occurs stereospecifically. This is assumed.

[0183] In preparing the compounds of the present invention, a remote functional group (e.g., a primary amine or a secondary amine) of an intermediate may be It may be necessary to protect the public (e.g., amines). The preferred amino protecting group (NH -Pg) includes acetyl group, trifluoroacetyl group, t-butoxycarbonyl (B oc) group, benzyloxycarbonyl (CBz) group and 9-fluorenylmethyleneoxycarbonyl The need for such protection can be readily determined by one skilled in the art. For a review of protecting groups and their use, see TW Greene and d PGMWuts,Protective Groups in Organi c Synthesis, 4th ed., Wiley, Hoboken, New Je. See rsey, 2007.

[0184] Pharmacology The compounds of the present invention inhibit the interaction of menin with MLL proteins and oncogenic MLL fusion proteins. They can either block the interaction themselves or be metabolized in vivo to a more active form. Therefore, the compounds of the present invention and such compounds The pharmaceutical composition comprising the compound is intended to treat leukemia, myelodysplastic syndrome (MDS), and myeloproliferative neoplasm (MPN). N) in the treatment or prevention of diseases such as cancer and diabetes, especially in the treatment This may be useful in treating

[0185] In particular, the compounds of the present invention and pharmaceutical compositions thereof may be useful in treating or preventing cancer. According to embodiments, patients may benefit from treatment with the menin / MLL inhibitors of the present invention. The cancers that may be affected include leukemia, lymphoma, myeloma, or solid tumor cancers (e.g., prostate, lung, breast, pancreatic). In some embodiments, the tumors include: pancreatic cancer, colon cancer, liver cancer, melanoma, and glioblastoma. Leukemia includes acute leukemia, chronic leukemia, myeloid leukemia, myeloid leukemia, and lymphoblastic leukemia. Hematologic malignancies, lymphocytic leukemia, acute myeloid leukemia (AML), chronic myeloid leukemia (CML), acute myeloid leukemia Myocardial lymphoblastic leukemia (ALL), chronic lymphocytic leukemia (CLL), T-cell prolymphocytic leukemia Leukemia (T-PLL), large granular lymphocytic leukemia, hairy cell leukemia (HCL), MLL Rearranged leukemia, MLL-PTD leukemia, MLL-amplified leukemia, MLL-positive leukemia, HOX / Examples include leukemias that exhibit MEIS1 gene expression characteristics.

[0186] Specifically, the compounds of the present invention and pharmaceutical compositions thereof are useful for treating myelodysplastic syndrome (MDS) or It may be useful in the treatment or prevention of myeloproliferative neoplasms (MPNs).

[0187] Specifically, the compounds of the present invention and pharmaceutical compositions thereof are useful in treating leukemia, particularly nucleophosmin (NPM1) mutant leukemia, such as NPM1c, may be useful in the treatment or prevention of such leukemia.

[0188] Specifically, the compounds of the present invention and pharmaceutical compositions thereof are useful in treating AML, specifically nucleophore Sumin (NPM1)-mutated leukemia (i.e., NPM1 mut AML), more specifically, Abstract These compounds may be useful in the treatment or prevention of lacto-NPM1 mutant AML.

[0189] Specifically, the compounds of the present invention and pharmaceutical compositions thereof are useful in treating MLL-rearranged leukemias, specifically It may be useful in treating or preventing MLL-rearranged AML or ALL.

[0190] Specifically, the compounds of the present invention and pharmaceutical compositions thereof are useful for treating leukemias containing MLL gene alterations, In particular, it may be useful for treating or preventing AML or ALL containing MLL gene alterations.

[0191] Specifically, the compounds of the present invention and pharmaceutical compositions thereof are suitable for QD dosing (once daily). It could be.

[0192] Specifically, the compounds of the present invention and pharmaceutical compositions thereof are useful for treating NPM1 gene mutations and / or disorders. Altered mixed lineage leukemia genes (MLL; MLL1; KMT2A), mixed lineage leukemia (MLL) , MLL-associated leukemia, MLL-associated leukemia, MLL-positive leukemia, MLL-induced leukemia, rearrangement Mixed lineage leukemia, MLL-associated leukemia, rearrangements / alterations, or rearrangements of the MLL gene formation / modification, acute leukemia, chronic leukemia, myelodysplastic syndrome (MDS), myeloproliferative neoplasm ( MPN), insulin resistance, prediabetes, diabetes or diabetes risk, hyperglycemia, 1 Chromosomal rearrangements on chromosome 1q23, type 1 diabetes, and hematological malignancies in subjects with type 2 diabetes Treatment or prevention: Promotion of proliferation of pancreatic cells when the pancreatic cells are beta cells, which are pancreatic islet cells. Therefore, β-cell proliferation is promoted, as evidenced by increased β-cell production or insulin production. and inhibition of menin-MLL interaction, wherein the MLL fusion protein target gene is a human HOX or MEIS1 in mice;

[0193] Accordingly, the present invention provides compounds of formula (I), their tautomers and derivatives, for use as pharmaceuticals. and stereoisomeric forms and pharmaceutically acceptable salts and solvates thereof.

[0194] The present invention relates to the preparation of a compound of formula (I), a tautomer or a stereoisomer thereof, for the preparation of a medicament. or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition of the present invention. It also relates to use.

[0195] The present invention relates to the synthesis of menin and MLL proteins and oncogenic MLL fusion proteins in mammals, including humans. For the treatment, prevention, amelioration, control or reduction of risk of disorders associated with interaction with fusion proteins a compound of formula (I), a tautomeric or stereoisomeric form thereof, or The present invention also relates to a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition of the present invention, and a therapeutic agent thereof. The treatment or prevention involves the interaction of menin with MLL proteins and oncogenic MLL fusion proteins. is affected or promoted by blocking

[0196] The present invention relates to the synthesis of menin and MLL proteins and oncogenic MLL fusion proteins in mammals, including humans. For the treatment, prevention, amelioration, control or reduction of risk of disorders associated with interactions with fusion proteins a compound of formula (I), a tautomeric or stereoisomeric form thereof, for the manufacture of a medicament for or a pharmaceutically acceptable salt or solvate thereof, or use of the pharmaceutical composition of the present invention The treatment or prevention of this disease also relates to the treatment of menin and MLL proteins and oncogenic MLL fusion proteins. The interaction of the ATP with the protein is affected or enhanced by blocking the interaction.

[0197] The present invention relates to a compound of formula (I) for use in the treatment or prevention of any one of the aforementioned diseases. a compound, a tautomer or stereoisomeric form thereof, or a pharmaceutically acceptable salt or solution thereof It also relates to solvents.

[0198] The present invention provides a compound of formula (I) for use in treating or preventing any one of the aforementioned diseases. I), their tautomeric or stereoisomeric forms or pharmaceutically acceptable salts thereof It also relates to solvates.

[0199] The present invention relates to a compound of formula (I) for the manufacture of a medicament for the treatment or prevention of any one of the aforementioned conditions. I), their tautomeric or stereoisomeric forms or pharmaceutically acceptable salts thereof The present invention also relates to the use of the compounds as solvates.

[0200] The compounds of the present invention can be administered to mammals, preferably mammalian cells, to treat or prevent any one of the aforementioned diseases. Preferably, it can be administered to humans.

[0201] Compounds of formula (I), their tautomeric and stereoisomeric forms and pharmaceutically acceptable salts thereof Considering the usefulness of the salts and solvates, The present invention provides a method for treating a warm-blooded animal, including

[0202] The method comprises administering a therapeutically effective amount of a compound of formula (I), a tautomer or a stereoisomeric form thereof The compound or a pharmaceutically acceptable salt or solvate thereof may be administered to a warm-blooded animal, including a human. That is, systemic administration or local administration.

[0203] Accordingly, the present invention provides a method for treating or preventing any one of the aforementioned diseases, comprising: and a therapeutically effective amount of a compound of the present invention. Regarding.

[0204] Those skilled in the art will appreciate that a therapeutically effective amount of a compound of the present invention is an amount sufficient to have therapeutic activity. This amount may vary depending, inter alia, on the type of disease, the concentration of the compound in the therapeutic formulation, and the condition of the patient. The effective therapeutic daily dose is approximately 0.005 mg / kg to 100 mg / kg. g / kg. The amount of the active ingredient, also referred to herein as the active ingredient, required to obtain a therapeutic effect. The amount of a compound according to the invention may vary depending on individual factors, such as the particular compound, the route of administration, and the age of the recipient. Treatment regimens may vary depending on the age and condition of the patient and the particular disorder or disease being treated. These methods of treatment may also include administering the active ingredient in a regimen of 1 to 4 doses. Preferably, the compounds according to the invention are formulated prior to administration.

[0205] The present invention also provides compositions for preventing or treating the disorders mentioned herein. The composition comprises a therapeutically effective amount of a compound of formula (I), a tautomeric or stereoisomeric form thereof, or or a pharmaceutically acceptable salt or solvate thereof and a pharmaceutically acceptable carrier or diluent. include.

[0206] While it is possible for the active ingredient to be administered alone, it is also possible to present it as a pharmaceutical composition. Therefore, the present invention provides a compound of the present invention, which can be administered in a pharmaceutically acceptable carrier or diluent. The present invention further provides a pharmaceutical composition comprising the carrier or diluent in combination with other ingredients of the composition. It must be "acceptable" in the sense of being suitable and not harmful to its recipient. Not possible.

[0207] Pharmaceutical compositions may be prepared by any method known in the art of pharmacy, e.g., by the preparation of pharmaceutical compositions by Genna ro et al.Remington's Pharmaceutical Scie nces(18 th ed., Mack Publishing Company, 199 0, especially Part 8: Pharmaceutical preparations and their Manufacture) It can be prepared using the method.

[0208] The compounds of the present invention may be administered alone or in combination with one or more additional therapeutic agents. Combination therapy includes a single medication containing a compound according to the present invention and one or more additional therapeutic agents. Administration of the pharmaceutical formulation and each separate pharmaceutical formulation of the compound of the present invention and each additional therapeutic agent Administration includes:

[0209] Thus, one embodiment of the present invention is to provide a combination of the above two compounds, either simultaneously, separately or sequentially, for the treatment of a patient suffering from cancer. A combination preparation for use containing a compound according to the present invention as a first active ingredient. and also relates to products containing one or more anti-cancer agents as further active ingredients.

[0210] The one or more other drugs and the compound of the invention may be administered simultaneously (e.g., in separate compositions or units). They may be administered in either order (as a single composition) or sequentially. In the latter case, two or more The above compounds are administered for a period of time, in an amount, and in a manner sufficient to ensure beneficial or synergistic effects. The preferred administration method and order and the respective administration of each component of the combination The amount and regime may vary depending on the particular other drug and compound of the invention being administered, and their administration route. The specific pathology being treated, particularly the tumor, as well as the specific host being treated will vary. It will be understood that

[0211] The following examples further illustrate the present invention. [Example]

[0212] Several methods for preparing the compounds of this invention are illustrated in the following examples. Unless otherwise noted, all starting materials were obtained from commercial suppliers and used without further purification. or alternatively may be synthesized by one skilled in the art using well-known methods.

[0213] [Table 1]

[0214] [Table 2]

[0215] [Table 3]

[0216] [Table 4]

[0217] [Table 5]

[0218] As will be appreciated by those skilled in the art, compounds synthesized using the protocols provided may be prepared in a solvent. may exist as solvates, e.g., hydrates, and / or may contain residual solvents or small amounts of impurities. Compounds or intermediates isolated as salt forms may be stoichiometric integers, i.e., monosalts or It may be a disalt or may be of intermediate stoichiometry. In the experimental section below, intermediate or When a compound is shown as an "HCl salt" without indicating the number of equivalents of HCl, this means that the This means that the number of Cl equivalents was not determined. The same principle applies to, for example, "oxalate." , "formate", or " [ka] This also applies to all other salt forms referred to in the experimental section, such as

[0219] For some compounds, the mixture was separated and the absolute stereochemistry was known or If only one enantiomer is obtained and the absolute stereochemistry is known, the stereochemical configuration of the center are sometimes referred to as "R" or "S", and in some compounds, the compound itself is a single stereoisomer. Although isolated as a compound and enantiomerically pure, the absolute stereochemistry has not been determined. If not (even if the bond is drawn stereospecifically), The stereochemical configuration is indicated by "*R" (the column conditions for separation are described in the synthesis protocol, and one If only the center of the nucleus is present or shown, it elutes first from the column) or *S (The column conditions for the separation are described in the synthesis protocol, and only one stereocenter is present or where indicated, is referred to as "*R" (elutes second from the column). When a compound is converted into another compound, the "*R" designation of the resulting compound is It comes from quality.

[0220] For example, compound 25 [ka] but, [ka] It will become clear that this is the case.

[0221] "*R" or "*S" may be "R" or "S" (known isomers of the second stereocenter) in the same molecule. When a compound appears with a second stereocenter, called an allelic chemistry, the compound itself has a single stereoisomer. Although isolated as a single isomer and enantiomerically pure, The absolute stereochemistry of the stereocenter designated "S" has not been determined (even if the bond is stereospecific). (Even if drawn). "*R" or "*S" is randomly assigned to such molecules. For example, compound 340 [ka] but, [ka] It will become clear that this is the case.

[0222] In the case of compounds where the stereochemical configuration of two stereocenters is indicated by * (e.g. *R or *S), In this case, even if the compound itself is isolated as a single stereoisomer and is enantiomerically pure, However, the absolute stereochemistry of the stereocenter has not been determined (even though the bond is drawn stereospecifically). In this case, the configuration of the first stereocenter may be different from that of the second stereocenter in the same compound. "*R" or "*S" does not depend on the configuration of the stereocenters in the molecule. are assigned to the system.

[0223] For example, compound 306 [ka] In the case of [ka] This means that

[0224] Those skilled in the art will understand that the above paragraphs regarding stereochemical configuration also apply to intermediates. You will understand.

[0225] Those skilled in the art will usually understand that the following experimental protocol does not explicitly mention the After chromatographic purification, the desired fractions are collected and the solvent is evaporated. It will be.

[0226] Where stereochemistry is not shown, this is unless otherwise indicated or clear from the context. Unless otherwise specified, the term "stereoisomer" refers to a mixture of stereoisomers.

[0227] When a stereocenter is designated with "RS," this refers to the stereocenter at the indicated site unless otherwise specified. This means that a racemic mixture was obtained at the center.

[0228] Preparation of intermediates In the case of intermediates that are used in the next reaction step as crude or partially purified intermediates, In some cases, the molar amounts of such intermediates in the following reaction steps are not mentioned, or instead are The estimated or theoretical molar amounts of these intermediates in the reaction steps are shown in the following reaction protocols: is shown.

[0229] Preparation of intermediate 27 N-ethyl-5-fluoro-N-isopropyl-2-methoxybenzamide [ka] 5-Fluoro-2-methoxybenzoic acid ( 8.00 g, 47.0 mmol) and N-ethylpropan-2-amine (8.19 g, 9 4.0 mmol), HATU (21.5 g, 56.5 mmol) and DIEA (9.10 g, 70.4 mmol) was added slowly in small portions. The temperature was slowly raised to room temperature and stirred for 8 hours. The organic layer was washed with water (20 mL × 3) and After filtration, the solvent was removed under reduced pressure and the crude product was purified by FCC. Purification (EtOAc / PE=0% to 20%) gave the title intermediate as a white solid. (12.0 g, 96% yield).

[0230] Preparation of intermediates 67, 235, and 246 5-Fluoro-N,N-diisopropyl-2-methoxybenzamide 5-Fluoro-2-methoxy-N-(propan-2-yl) 13 C3) Benzamide 5-Fluoro-N-isopropyl-2-methoxy-N-methylbenzamide The following intermediates were synthesized by methods similar to those described above for intermediate 27.

[0231] [Table 6]

[0232] Preparation of intermediate 28 N-ethyl-5-fluoro-2-hydroxy-N-isopropylbenzamide [ka] N-ethyl-5-fluoro-N-isopropyl ether in dry DCM (100 mL) cooled to -78 °C Propyl-2-methoxybenzamide (Intermediate 27) (12.0 g, 50.1 mmol) To this solution, BBr3 (14.4 mL, 152 mmol) was slowly added, and the resulting mixture was The mixture was slowly warmed to RT and stirred for 8 h. The mixture was cooled again to -78 °C and M The reaction was quenched by dropwise addition of eOH (5 mL). The resulting mixture was allowed to warm slowly to RT. The mixture was allowed to warm and the pH value was adjusted to about 8 by adding saturated aqueous NaHCO3 solution. The mixture was extracted with DCM (50 mL × 3), and the combined organic layer was dried over anhydrous Na2SO4. The mixture was then cooled, filtered, and concentrated under reduced pressure to give the crude product, which was purified by FCC (EtOAc / PE=0%~20%) to give the title intermediate as a white solid (9.0 g, 78% yield). .

[0233] Preparation of intermediates 68, 237, and 247 5-Fluoro-2-hydroxy-N,N-diisopropylbenzamide N-(ethyl- 13 C2)-5-Fluoro-2-hydroxy-N-(propan-2-yl) - 13 C3) Benzamide 5-Fluoro-2-hydroxy-N-isopropyl-N-methylbenzamide The following intermediates were synthesized by methods similar to those described above for intermediate 28.

[0234] [Table 7]

[0235] Preparation of Intermediate 60 5-Bromo-4-cyclopropylpyrimidine [ka] 5-Bromopyrimidine (30 mL) in THF (1000 mL) was dissolved in 100 mL of THF under N2 atmosphere at 0 °C. g, 189 mmol) was added to a solution of cyclopropylmagnesium bromide (396 mL, 198 After the addition, the reaction mixture was stirred at RT for 4 h. followed by a solution of DDQ (42.8 g, 189 mmol) in THF (500 mL) at 0 °C. was added dropwise to the reaction mixture. After the addition, the reaction mixture was stirred at RT for 16 hours. The mixture was concentrated in vacuo and the residue was partitioned between EtOAc (200 mL) and water (200 mL). The aqueous layer was extracted with EtOAc (200 mL x 3). The combined organic layers were washed with 1N Na OH (200 mL × 2), brine (200 mL), dried over Na2SO4, The filtrate was concentrated in vacuo and the residue was purified by FCC (EtOAc / PE=0 %~15%) to give the title intermediate as a white solid (21.4 g, 55% yield).

[0236] Preparation of Intermediate 61 2-(4-cyclopropylpyrimidin-5-yl)-4-fluorophenol [ka] 5-Bromo-4-cyclopropylpyrimidine (medium) in 1,4-dioxane (350 mL) Intermediate 60) (20.0 g, 100 mmol), (5-fluoro-2-hydroxyphenyl ) boronic acid (18.7 g, 120 mmol), Pd(dppf)Cl2 (3.68 g, 5 A mixture of Na2CO3 (2M in H2O, 101 mL, 202 mmol) and Na2CO3 (2M in H2O, 101 mL, 202 mmol) The mixture was heated at 90 °C under N2 atmosphere for 12 h. After cooling to RT, the reaction mixture was It was filtered through a pad of light, and the filtrate was suspended in water (400 mL) and further extracted with EtOAc. (200 mL x 3). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. Concentration gave the crude product, which was purified by silica gel FCC (PE / EtOAc=1 :0 to 3:1), the title intermediate was obtained as a brown solid (24.0 g, purity 95%, yield 9 8.6%).

[0237] Preparation of intermediate 13 tert-Butyl 6-(3,6-dichloro-1,2,4-triazin-5-yl)-2, 6-Diazaspiro[3.4]octane-2-carboxylate [ka] 3,5,6-Trichloro-1,2,4-trichloro- of gin (10.0 g, 54.2 mmol) and TEA (15.2 mL, 109 mmol) The solution was treated with tert-butyl 2,6-diazaspiro[3.4]octane-2-carboxylate. Glycate (9.21 g, 43.4 mmol) was added and the mixture was allowed to warm to RT and stirred for 1 h. The mixture was diluted with water (20 mL) and extracted with DCM (30 mL x 3). The organic layer was washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure to give the crude product The product was purified by silica gel FCC (PE / EtOAc = 1:0 to 3:1). This afforded the title intermediate as a yellow solid (12.0 g, 58% yield).

[0238] Preparation of intermediate 69 tert-Butyl 6-(3-chloropyridazin-4-yl)-2,6-diazaspiro[3 .4]octane-2-carboxylate The following intermediates were synthesized by methods similar to those described above for intermediate 13.

[0239] [Table 8]

[0240] Preparation of intermediate 14 tert-Butyl 6-(3-chloro-6-(2-ethyl(isopropyl)carbamoyl) )-4-Fluorophenoxy)-1,2,4-triazin-5-yl)-2,6-diaza Spiro[3.4]octane-2-carboxylate [ka] tert-Butyl 6-(3,6-dichloro-1,2,4-trimethylsilyl)propanol in THF (120 mL) Azin-5-yl)-2,6-diazaspiro[3.4]octane-2-carboxylate (Intermediate 13) (12.0 g, 33.3 mmol), N-ethyl-5-fluoro-2-hydroxybenzoate Hydroxy-N-isopropylbenzamide (Intermediate 28) (7.5 g, 33.3 mmol) A mixture of 1,2-dimethyl-3-(2-methyl-2-propanol) and DBU (6.1 g, 40.1 mmol) was stirred at 25°C for 8 hours. The mixture was diluted with water (30 mL) and extracted with DCM (30 mL x 3). Washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure to give the crude product. This was purified by FCC (PE / EtOAc = 1:0 to 3:1) and labeled as a green solid. The title intermediate was obtained (14.0 g, 73% yield).

[0241] Preparation of Intermediates 57, 74, 70 and 83 tert-Butyl 6-(3-chloro-6-(2-(4-cyclopropylpyrimidine-5- (yl)-4-fluorophenoxy)-1,2,4-triazin-5-yl)-2,6-di Azaspiro[3.4]octane-2-carboxylate tert-Butyl 6-(3-(2-(ethyl(isopropyl)carbamoyl))-4-fluoro (Orophenoxy)pyridazin-4-yl)-2,6-diazaspiro[3.4]octane- 2-carboxylate tert-Butyl 6-(3-(2-(diisopropylcarbamoyl)-4-fluorophenyl)- (Noxy)pyridazin-4-yl)-2,6-diazaspiro[3.4]octane-2-carboxamide Boxylate tert-Butyl 6-(3-chloro-6-(2-(diisopropylcarbamoyl)-4- Fluorophenoxy)-1,2,4-triazin-5-yl)-2,6-diazaspiro[ 3.4]octane-2-carboxylate The following intermediates were synthesized by methods similar to those described above for intermediate 14.

[0242] [Table 9]

[0243] Preparation of intermediate 2 tert-Butyl 6-(6-(2-(ethyl(isopropyl)carbamoyl))-4-fluoro orophenoxy)-1,2,4-triazin-5-yl)-2,6-diazaspiro[3. 4]octane-2-carboxylate Method A: [ka] tert-Butyl 6-(3-chloro-) 6-(2-(ethyl(isopropyl)carbamoyl)-4-fluorophenoxy)-1, 2,4-triazin-5-yl)-2,6-diazaspiro[3.4]octane-2-chlor carboxylate (Intermediate 14) (20 g, 36.4 mmol), NaBH4 (2.48 g, A mixture of Pd (dppf)Cl2·DCM (1.70 g, 2.08 mmol) was added. The reaction mixture was stirred at 25° C. for 14 hours. The reaction mixture was filtered, and the filtrate was concentrated to give a residue. Purification by silica gel FCC (EtOAc) gave the title intermediate as a brown solid ( 15g, purity 93%, yield 74%).

[0244] Method B: [ka] tert-Butyl 6-(3-chloro-6-(2-ethyl) Isopropyl)carbamoyl)-4-fluorophenoxy)-1,2,4-triazine- 5-yl)-2,6-diazaspiro[3.4]octane-2-carboxylate (intermediate A solution of 14) (22.0 g, 40.1 mmol) and TEA (15 mL) was added to Pd / C (wet The resulting mixture was heated at 25°C under a H atmosphere (30 p The mixture was stirred at 4°C for 8 hours. The reaction mixture was filtered through a pad of Celite, and the filtrate was concentrated in vacuo. This gave the title intermediate (25.0 g, crude), which was used in the next step without further purification. I used it as is.

[0245] Preparation of intermediates 58 and 84 tert-Butyl 6-(6-(2-(4-cyclopropylpyrimidin-5-yl)-4- Fluorophenoxy)-1,2,4-triazin-5-yl)-2,6-diazaspiro[ 3.4]octane-2-carboxylate tert-Butyl 6-(6-(2-(diisopropylcarbamoyl)-4-fluorophenyl)- (1,2,4-triazin-5-yl)-2,6-diazaspiro[3.4]octyl Tan-2-carboxylate The following intermediates were synthesized by a similar method as described above for intermediate 2.

[0246] [Table 10]

[0247] Preparation of intermediate 3 2-((5-(2,6-diazaspiro[3.4]octan-6-yl)-1,2,4-trimethylolpropane Triazin-6-yl)oxy)-N-ethyl-5-fluoro-N-isopropylbenzaldehyde Mido [ka] tert-Butyl 6-(6-(2-ethyl(isopropyl)carbamate)) in DCM (5 mL) Bamoyl)-4-fluorophenoxy)-1,2,4-triazin-5-yl)-2,6 -diazaspiro[3.4]octane-2-carboxylate (intermediate 2) (300 mg, To a solution of 0.583 mmol of TFA was added (0.5 mL, 6.4 mmol). The resulting mixture was stirred at RT for 3 h. Then, 10% NaOH (5 mL) was added to the mixture. The pH value was adjusted to about 12 by adding 10 mL of water, and the resulting mixture was diluted with DCM (10 mL × 3). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give The title intermediate was obtained as a white solid (220 mg, 90% yield).

[0248] Preparation of intermediates 59, 75, and 85 6-(6-(2-(4-cyclopropylpyrimidin-5-yl)-4-fluorophenoxy) (Ci)-1,2,4-triazin-5-yl)-2,6-diazaspiro[3.4]octane 2-((4-(2,6-diazaspiro[3.4]octan-6-yl)pyridazine-3- (yl)oxy)-N-ethyl-5-fluoro-N-isopropylbenzamide 2-((5-(2,6-diazaspiro[3.4]octan-6-yl)-1,2,4-trimethylolpropane Triazin-6-yl)oxy)-5-fluoro-N,N-diisopropylbenzamide The following intermediates were synthesized by a similar method as described above for intermediate 3.

[0249] [Table 11]

[0250] Preparation of Intermediate 160 N-Methoxy-N-methyl-4-(methylamino)butanamide hydrochloride [ka] tert-Butyl (4-(methoxy(methyl)amino)-4- To a solution of (oxobutyl)(methyl)carbamate (Intermediate 8) (220 g, crude), at 0°C HCl / 1,4-dioxane (750 mL, 3 mol) was added slowly. The mixture was slowly warmed to RT and stirred at this temperature for 2 h. Condensation gave the title intermediate (197 g, crude), which was used in the next step without further purification. It was used as is.

[0251] Intermediates 164, 238, 243, 244 N-(2-methoxyethyl)-N,5-dimethyl-4-(2,6-diazaspiro[3.4 ]octan-6-yl)hexan-1-amine hydrochloride 2-((3-chloro-5-(2,6-diazaspiro[3.4]octan-6-yl)-1 ,2,4-triazin-6-yl)oxy)-N-ethyl-5-fluoro-N-isopropyl Pyrbenzamide hydrochloride 2-((5-(2,6-diazaspiro[3.4]octan-6-yl)-1,2,4-trimethylolpropane Triazin-6-yl)oxy)-5-fluoro-N,N-diisopropylbenzamide salt Acid salts 2-((5-(2,6-diazaspiro[3.4]octan-6-yl)-1,2,4-trimethylolpropane Triazin-6-yl)oxy)-N-ethyl-5-fluoro-N-isopropylbenzaldehyde Mido Hydrochloride The following intermediates were synthesized by methods similar to those described above for intermediate 160.

[0252] [Table 12]

[0253] Preparation of intermediate 71 2-((4-(2,6-diazaspiro[3.4]octan-6-yl)pyridazine-3- (yl)oxy)-5-fluoro-N,N-diisopropylbenzamide [ka] tert-Butyl 6-(3-(2-)- dioxane (30 mL) cooled to 0° C. (Diisopropylcarbamoyl)-4-fluorophenoxy)pyridazin-4-yl)- 2,6-Diazaspiro[3.4]octane-2-carboxylate (Intermediate 70) (5. To a solution of 1000 mg of HCl in 1,4-dioxane (20 mL, 4 M, 80 The resulting mixture was stirred at RT for 2 h. The mixture was concentrated and the residue was redissolved in DCM (50 mL) and to this was added 1 M NaOH (20 mL). The pH value was adjusted to 12 by slowly adding DCM (30 mL × 3). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. Concentration gave the title intermediate (4 g, crude) as a yellow solid, which was carried on without further purification. Used in the next step.

[0254] Preparation of intermediate 29 tert-Butyl 2,2-dimethyl-5-oxopyrrolidine-1-carboxylate [ka] 5,5-Dimethylpyrrolidin-2-one (3.00 g, 26.5 mL) in DCM (30 mL) A solution of 1000 mg of 1000 sucrose (8.10 g, 80.0 mmol) was added to the solution of 1000 mg of 1000 sucrose (8.10 g, 80.0 mmol) of TEA and DMAP (325 m g, 2.66 mmol) was added, followed by di-tert-butyl dicarbonate (8.7 0 g, 39.8 mmol) was added. The reaction was stirred at 40 °C overnight. It was cooled to RT. After that, the reaction mixture was washed with brine (30 mL × 2), dried over Na2SO4, and filtered. The crude product was further purified by silica gel FCC. (PE / EtOAc = 100:0 to 3:1) to give the title intermediate (2. 8g, 50% yield.

[0255] Preparation of Intermediate 1 tert-Butyl (5-methyl-4-oxohexyl)carbamate [ka] tert-Butyl 2-oxopyrrolidine-1 in THF (60 mL) cooled to -70 °C -carboxylate (5.0 g, 27 mmol) and TMEDA (5.0 mL, 33 mm ol) solution was added to a solution of isopropylmagnesium bromide (19 mL, 55 mmol, 2 -methyl tetrahydrofuran (2.9 M) was slowly added and the resulting mixture was slowly stirred. The mixture was slowly warmed to RT and stirred for 12 h. The mixture was poured into a filtrate and extracted with EtOAc (50 mL x 3). The combined organic layer was dried over anhydrous Na2SO4. Drying, filtration and concentration under reduced pressure gave the crude product which was further purified by FCC (P Et / Et0Ac=1:0 to 100:1) to give the title intermediate as a yellow oil (3.7 g, Yield 60%).

[0256] Preparation of intermediates 30, 110, and 141 tert-Butyl (2,6-dimethyl-5-oxoheptan-2-yl)carbamate tert-Butyl (6-methyl-5-oxoheptane)carbamate 6-Hydroxy-2,4-dimethylhexan-3-one The following intermediates were synthesized by methods similar to those described above for intermediate 1.

[0257] [Table 13]

[0258] Preparation of intermediate 34 Benzyl 2,2-dimethyl-5-oxopyrrolidine-1-carboxylate [ka] 5,5-Dimethylpyrrolidin-2-one (5. 00g, 44.2mmol) to a solution of NaH (1.94g, 48.5mmol, 60% ) was added and the resulting mixture was stirred at this temperature for 30 minutes. (Dicarbonyl)succinimide (12.1 g, 48.6 mmol) was added to the reaction mixture. The mixture was slowly warmed to RT and stirred for an additional 16 h. The solvent was evaporated under reduced pressure and saturated N Aqueous HCl (30 mL) was added and extracted with EtOAc (2×30 mL). The organic layer was washed with brine (40 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. Concentration gave the crude product, which was further purified by FCC (PE / EtOAc = 1:0 to 3:1) to give the title intermediate as a colorless oil (5.16 g, 39% yield).

[0259] Preparation of intermediate 35 4-(((benzyloxy)carbonyl)amino)-4-methylpentanoic acid [ka] NaOH (4.18 g, 16.9 mmol) was dissolved in THF (60 mL) and HO (15 mL) in benzyl 2,2-dimethyl-5-oxopyrrolidine-1-carboxylate (mL) The mixture was heated at 80°C for 16 h. The reaction mixture was cooled to 25°C and acidified with 1M HCl to a pH of The pH was adjusted to about 3, and the mixture was then extracted with EtOAc (20×2 mL). The organic layer was washed with brine (20 mL), dried over Na2SO4, filtered and concentrated in vacuo. Concentration gave the title intermediate (4.48 g, crude) as a colorless oil, which could be further purified. It was used directly in the next step.

[0260] Preparation of Intermediate 7 4-((tert-butoxycarbonyl)(methyl)amino)butanoic acid [ka] 4-(methylamino)butanoic acid hydrochloride (3.0 g, 19.5 m To a solution of BocO (4.6 9 g, 21.5 mmol) was added dropwise. The mixture was stirred at RT for 2 hours. The mixture was then heated under reduced pressure. The residue was diluted with EtOAc (100 mL) and added to cold 0.1 N HCl (70 mL × 2), H2O (50 mL × 2) and brine (50 mL), and then washed with Na2SO4 Drying at 40°C, filtering and concentrating gave the title intermediate as a colorless oil (1.80 g, crude). .

[0261] Preparation of Intermediate 8 tert-Butyl(4-(methoxy(methyl)amino)-4-oxobutyl)(methyl) Carbamates [ka] 4-((tert-butoxycarbonyl)(methyl)amino)- ) To a solution of butanoic acid (Intermediate 7) (1.80 g, crude) was added N,O-dimethylhydroxyl Amine hydrochloride (960 mg, 9.84 mmol), HOBt (1.24 g, 9.18 mmol), ol) and NMM (2.80 mL, 25.1 mmol) were added. 0.23 g, 11.6 mmol) was added and the reaction mixture was stirred at RT for 4 h. The mixture was diluted with DCM (100 mL) and added 1N HCl (30 mL x 3), saturated NaHCO3 Washed with aqueous solution (30 mL x 3) and brine (30 mL), dried over Na2SO4, Filtration and concentration in vacuo gave the title intermediate (1.70 g, crude) as a colorless oil.

[0262] Preparation of intermediates 19, 36, 189, 190, 203, and 204 tert-Butyl(3-(methoxy(methyl)amino)-3-oxopropyl)carbamate Route Benzyl(5-(methoxy(methyl)amino)-2-methyl-5-oxopentane-2- Il)carbamate (S)-3-((tert-butyldiphenylsilyl)oxy)-4-(ethyl(methyl) )Amino)-N-methoxy-N-methylbutanamide (R)-3-((tert-butyldiphenylsilyl)oxy)-4-(ethyl(methyl) )Amino)-N-methoxy-N-methylbutanamide (S)-3-((tert-butyldiphenylsilyl)oxy)-N-methoxy-4-( (2-Methoxyethyl)(methyl)amino)-N-methylbutanamide (R)-3-((tert-butyldiphenylsilyl)oxy)-N-methoxy-4-( (2-Methoxyethyl)(methyl)amino)-N-methylbutanamide The following intermediates were synthesized by methods similar to those described above for intermediate 8.

[0263] [Table 14]

[0264] Preparation of intermediate 37 Benzyl(5-(methoxy(methyl)amino)-2-methyl-5-oxopentane-2- (methyl) carbamate [ka] Benzyl (5-(methoxy)methyl)-2-benzophenone in DMF (30 mL) cooled to 0 °C under N2 atmosphere (amino)-2-methyl-5-oxopentan-2-yl)carbamate (Intermediate 36 ) (2.30 g, 7.46 mmol) was added to a solution of NaH (358 mg, 8.95 mmol) , 60%) was added. Then MeI (8.87 g, 62.5 mmol) was added and mixed. The mixture was stirred at 25° C. for 12 hours. The mixture was quenched with saturated aqueous NH4Cl (30 mL). The combined organic layer was washed with brine (40 mL). Washing, drying over Na2SO4, filtering and concentrating in vacuo gave the crude product, which was The product was further purified by gel FCC (PE / EtOAc = 1:0 to 3:1) as a yellow oil. The title intermediate was obtained (2.15 g, 76% yield).

[0265] Preparation of Intermediate 236 N-(ethyl- 13 C2)-5-Fluoro-2-methoxy-N-(propan-2-yl- 13 C3) Benzamide The following intermediates were synthesized by methods similar to those described above for intermediate 37.

[0266] [Table 15]

[0267] Preparation of Intermediate 9 tert-Butyl methyl (5-methyl-4-oxohexyl)carbamate [ka] Under N2 atmosphere, tert-butyl (4-(methyl)-2- propanol) was dissolved in THF (5 mL) cooled to -70 °C. (4-Oxobutyl)(methyl)carbamate (Intermediate 8) (2 To a solution of 1000 mg (crude) of isopropyl lithium (3.2 mL, 2.24 mmol, A 0.7 M solution of ethanol was added dropwise to the resulting mixture, which was stirred at -70°C for 2 hours. It was quenched with saturated aqueous NH4Cl (15 mL) and extracted with EtOAc (30 mL x 2 The combined organic layers were washed with brine (30 mL), dried over Na2SO4, and filtered. The crude product was further purified by FCC (PE / Et OAc=10:1) to give the title intermediate as a colorless oil (60 mg).

[0268] Preparation of intermediates 20, 38, 162, 191, 192, 205, and 206 tert-Butyl (4-methyl-3-oxopentyl)carbamate Benzyl (2,6-dimethyl-5-oxoheptan-2-yl)(methyl)carbamate 6-((2-methoxyethyl)(methyl)amino)-2-methylhexan-3-one (S)-5-((tert-butyldiphenylsilyl)oxy)-6-(ethyl(methyl) )Amino)-2-methylhex-1-en-3-one (R)-5-((tert-butyldiphenylsilyl)oxy)-6-(ethyl(methyl) )Amino)-2-methylhex-1-en-3-one (S)-5-((tert-butyldiphenylsilyl)oxy)-6-((2-methoxy Ethyl)(methyl)amino)-2-methylhex-1-en-3-one (R)-5-((tert-butyldiphenylsilyl)oxy)-6-((2-methoxy Ethyl)(methyl)amino)-2-methylhex-1-en-3-one The following intermediates were synthesized by methods similar to those described above for intermediate 9.

[0269] [Table 16]

[0270] Preparation of Intermediate 15 2-(3-methyl-2-oxobutyl)isoindoline-1,3-dione [ka] 1-Bromo-3-methylbutan-2-one (200 mg, 1.21 mL) in DMF (4 mL) To a solution of 1.12g (6.05mmol) potassium phthalimide (1.12g, 6.05mmol) was added The mixture was stirred at 80° C. for 12 h. After cooling to RT, water (15 mL) was added and mixed. The product was extracted with EtOAc (40 mL x 3). The combined organic layer was dried over anhydrous Na2SO4. The mixture was evaporated, filtered, and concentrated under reduced pressure to give the crude product, which was further purified by preparative TLC ( PE / EtOAc=3:1) to give the title intermediate as a white solid (200 mg, 6% yield). 9%).

[0271] Preparation of intermediate 46 Methyl 5-methyl-4-oxohexanoate [ka] ZnEt2 (104 mL, 104 mmol) in DCM (150 mL) at 0 °C under N2 TFA (11.9 g, 104 mmol) was slowly added dropwise to the solution via syringe. The mixture was stirred at 0° C. for 30 minutes. Subsequently, methylene iodide (27.9 g) was added with stirring. , 104 mmol) was added dropwise and the suspension was stirred for another 30 minutes. Benzyl-3-oxopentanoate (5.00 g, 34.7 mmol) was added via syringe. The mixture was added quickly and stirred at RT for 16 h and refluxed at 50° C. for 20 h. After cooling to 10°C, the reaction mixture was quenched with saturated aqueous NH4Cl (50 mL) and The combined organic layer was washed with brine and dried over MgSO4. Drying and concentration under reduced pressure gave 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).

[0272] Preparation of intermediate 22 tert-Butyl (4-methyl-3-(2,6-diazaspiro[3.4]octane-2- Il)pentyl)carbamate hydrochloride [ka] Benzyl 2-(1-(tert-butoxycarbonyl)amine) in MeOH (50 mL) (4-methylpentan-3-yl)-2,6-diazaspiro[3.4]octane-6 To a solution of 1,4-dicarboxylate (Intermediate 21) (0.580 g, 1.30 mmol) was added Ar 1,1,2-trichloroethane (0.260 g, 1.95 mmol) and Pd / C ( 0.05 g, 10%) was added and the reaction was stirred at 35 °C for 8 h under H2 (15 psi) atmosphere. The reaction mixture was filtered and the filtrate was concentrated in vacuo to give the title intermediate as a colorless oil. Obtained (280 mg, crude).

[0273] Preparation of intermediate 23 Ethyl 6-(2-(ethyl(isopropyl)carbamoyl)-4-fluorophenoxy) -1,2,4-triazine-5-carboxylate [ka] Ethyl 6-chloro-1,2,4-triazine-5-carboxylate in DMF (150 mL) methylpropanol (13 g, 69 mmol) and N-ethyl-5-fluoro-2-hydroxy-N- To a mixture of isopropylbenzamide (Intermediate 28) (15.6 g, 69.3 mmol) To the resulting mixture was added K2CO3 (28.6 g, 204 mmol). The resulting mixture was stirred at RT for 2 h. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure to give a crude residue which was diluted with water (1 The mixture was diluted with 100 mL of ethyl acetate and extracted with EtOAc (100 mL x 2). Drying over Na2SO4, filtering, and concentrating under reduced pressure gave the crude product, which was purified by FCC. This was further purified by hexane / Et0Ac (PE / Et0Ac=1:0 to 1:1) to give the title intermediate as a yellow solid. (30 g, purity 81%, yield 92%).

[0274] Preparation of intermediate 24 6-(2-(ethyl(isopropyl)carbamoyl)-4-fluorophenoxy)-1, 2,4-triazine-5-carboxylic acid [ka] Ethyl 6-(2-(ethyl)isopropyl)propanol in THF (100 mL) and HO (25 mL) (carbamoyl)-4-fluorophenoxy)-1,2,4-triazine-5-carbamoyl To a mixture of carboxylate (Intermediate 23) (8.6 g, 23 mmol), LiOH HO (2.0 g, 48 mmol) was added and the reaction mixture was stirred at RT for 1 h. Acidify with 0.5 M HCl to adjust the pH to 5-6 and add EtOAc (150 mL) The aqueous phase was purified by preparative HPLC on a Boston Prime column (column Column: C18 150 x 30 mm 5 μm; Eluent: ACN / H2O (0.225% FA) 19% to 49%, v / v) to give the title intermediate (5.0 g, 62% yield).

[0275] Preparation of intermediates 187, 188, 201, and 202 (S)-3-((tert-butyldiphenylsilyl)oxy)-4-(ethyl(methyl) )Amino)butanoic acid (R)-3-((tert-butyldiphenylsilyl)oxy)-4-(ethyl(methyl) )Amino)butanoic acid (S)-3-((tert-butyldiphenylsilyl)oxy)-4-((2-methoxy Ethyl (methyl) amino) butanoic acid (R)-3-((tert-butyldiphenylsilyl)oxy)-4-((2-methoxy Ethyl (methyl) amino) butanoic acid The following intermediates were synthesized by methods similar to those described above for intermediate 24.

[0276] [Table 17]

[0277] Preparation of Intermediate 25 N-ethyl-5-fluoro-2-((5-hydroxy-1,2,4-triazine-6-yl) (per)oxy)-N-isopropylbenzamide [ka] 6-(2-(ethyl(isopropyl)carbamoyl)-4-fluorobenzoate) in DCE (1 mL) 4-triazin-5-carboxylic acid (Intermediate 24) (50 mg, 0.14mmol) and 1,3-dibromo-1,3,5-triazinane-2,4,6-triazinone A solution of Ag(Phen)2OTf (30 mg , 0.049 mmol) was added and the resulting mixture was stirred at RT for 2 h. The mixture was filtered through a pad of Celite and washed with ACN (10 mL). The filtrate was concentrated under reduced pressure to give a crude product. The product was obtained, which was further purified by preparative HPLC using Xtimate (column :C18 150×40mm 10μm; Eluent: ACN / H2O(0.2%FA)20 % to 50% v / v) to afford the title intermediate as a white solid (20 mg, 41% yield).

[0278] Preparation of Intermediate 159 N-ethyl-5-fluoro-N-isopropyl-2-((5-(2,2,2-trifluoro (1,2,4-triazin-6-yl)oxy)benzamide [ka] 4 Å molecular sieves (8 g) were dissolved in 2,2,2-trifluoroethan-1-ol (100 mL ) in 6-(2-(ethyl(isopropyl)carbamoyl)-4-fluorophenoxy)- 1,2,4-Triazine-5-carboxylic acid (Intermediate 24) (8.0 g, 23.0 mmol) The resulting mixture was stirred at 70°C under N2 atmosphere for 1 hour. Cool to RT and add 1,3-dibromo-1,3,5-triazinane-2,4,6-trione (13.1 g, 45.7 mmol) was added to the above mixture. The resulting mixture was heated at RT The mixture was further stirred overnight under a N2 atmosphere. The reaction mixture was filtered through a pad of Celite. Concentration under reduced pressure gave a crude residue which was purified by FCC (PE: EtOAc 1:0 to 2: 1), to give the title intermediate as a yellow solid (3.1 g, 84% purity, 28% yield).

[0279] Preparation of intermediate 51 4-((tert-butyldimethylsilyl)oxy)butan-1-ol [ka] Butane-1,4-diol (5.00 g, 55 mL) in THF (100 mL) cooled to 0 °C To a solution of 0.5 mmol of NaH (1.55 g, 38.8 mmol, 60%) was added The resulting mixture was stirred at 0° C. for 20 min. Then TBDMSCl (5.85 g, 38. 8 mmol) was added to the reaction mixture and the reaction was stirred for an additional 1 h at 0° C. The mixture was diluted with water ( The mixture was quenched with 80 mL of EtOAc and extracted with 80 mL of EtOAc (3). Drying over aqueous Na2SO4, filtering, and concentrating under reduced pressure gave the crude product, which was purified by FCC. This was further purified by hexane / Et0Ac (PE / Et0Ac = 1:0 to 10:1) to give the title intermediate as a colorless liquid. (7.2 g, 63%)

[0280] Preparation of intermediates 183 and 184 Ethyl (S)-3-((tert-butyldiphenylsilyl)oxy)-4-iodobuta Noart Ethyl (R)-3-((tert-butyldiphenylsilyl)oxy)-4-iodobuta Noart The following intermediates were synthesized by methods similar to those described above for intermediate 51.

[0281] [Table 18]

[0282] Preparation of intermediate 52 4-((tert-butyldimethylsilyl)oxy)butanal [ka] 4-((tert-butyldimethylsilyl)isopropyl)-2-(2-methyl-2-propanol)-2-one in DCM (200 mL) cooled to 0 °C To a solution of (oxy)butan-1-ol (Intermediate 51) (7.20 g, 35.2 mmol), DMP (22.4 g, 52.8 mmol) was added and the reaction mixture was allowed to warm slowly to RT. The reaction mixture was diluted with DCM (100 mL) and saturated (NaHCO The mixture was stirred for 2 minutes in a 100 mL (Na2SO4 / Na2SO3 = 1 / 1, 100 mL) aqueous solution, and the separated organic layer was Wash with water (100 mL x 3), dry over anhydrous Na2SO4, filter, and concentrate under reduced pressure. The crude product was further purified by FCC (PE / EtOAc = 1:0-12 :1), to give the title intermediate as a colorless liquid (2.95 g, 41%).

[0283] Preparation of intermediates 54, 145, 146, and 158 6-((tert-butyldimethylsilyl)oxy)-2-methylhexan-3-one 2-((5-(2-(2,4-dimethyl-6-oxohexan-3-yl)-2,6-di Azaspiro[3.4]octan-6-yl)-1,2,4-triazin-6-yl)oxazin (R,S and S,R)-N-ethyl-5-fluoro-N-isopropylbenzamide mixture; or a mixture of R,R and S,S) 2-((5-(2-(2,4-dimethyl-6-oxohexan-3-yl)-2,6-di Azaspiro[3.4]octan-6-yl)-1,2,4-triazin-6-yl)oxazin (R,R and S,S)-N-ethyl-5-fluoro-N-isopropylbenzamide mixture; or a mixture of R,S and S,R) (R)-N-ethyl-5-fluoro-N-isopropyl-2-((5-(2-(2-methyl) (6-oxoheptan-3-yl)-2,6-diazaspiro[3.4]octane-6- (yl)-1,2,4-triazin-6-yl)oxy)benzamide The following intermediates were synthesized by a similar method as described above for intermediate 52.

[0284] [Table 19]

[0285] Preparation of intermediate 53 6-((tert-butyldimethylsilyl)oxy)-2-methylhexan-3-ol [ka] 4-((tert-butyl 2-methyl-2-propanol)-2-one in THF (4.9 mL) cooled to -20 °C under N2 atmosphere Dimethylsilyl)oxy)butanal (Intermediate 52) (1.00 g, 4.94 mmol) To the solution of isopropylmagnesium bromide (4.94 mL, 14.8 mmol, TH Aqueous solution of 1M NaOH in HCl (3M in HCl) was added dropwise and the reaction mixture was allowed to warm slowly to RT and stirred for 2 h. The mixture was quenched with saturated aqueous NH4Cl (20 mL) and extracted with EtOAc (50 mL x 3) The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated in vacuo to give the crude product. This was further purified by FCC (PE / EtOAc = 1:0 to 20:1) to give a white solid. This afforded the title intermediate as a coloured oil (580 mg, 48%).

[0286] Preparation of intermediates 16, 21, 39, 47, 55, 94, 98, 161, and 163 2-((5-(2-(1-(1,3-dioxoisoindolin-2-yl)-3-methyl butan-2-yl)-2,6-diazaspiro[3.4]octan-6-yl)-1,2, 4-triazin-6-yl)oxy)-N-ethyl-5-fluoro-N-isopropylbenzyl Nzuamide Benzyl 2-(1-((tert-butoxycarbonyl)amino)-4-methylpentane -3-yl)-2,6-diazaspiro[3.4]octane-6-carboxylate Benzyl(5-(6-(6-(2-(ethyl(isopropyl)carbamoyl)-4-fluoro) orophenoxy)-1,2,4-triazin-5-yl)-2,6-diazaspiro[3. 4]octan-2-yl)-2,6-dimethylheptan-2-yl)(methyl)carbamate Route Methyl 4-(6-(6-(2-(4-cyclopropylpyrimidin-5-yl)-4-fluoro orophenoxy)-1,2,4-triazin-5-yl)-2,6-diazaspiro[3. 4]octan-2-yl)-5-methylhexanoate 2-((5-(2-(6-((tert-butyldimethylsilyl)oxy)-2-methyl Hexan-3-yl)-2,6-diazaspiro[3.4]octan-6-yl)-1,2 ,4-triazin-6-yl)oxy)-N-ethyl-5-fluoro-N-isopropyl benzamide 2-((5-(2-(1-(1,3-dioxolan-2-yl)-4-methylpentane- 3-yl)-2,6-diazaspiro[3.4]octan-6-yl)-1,2,4-tri Azin-6-yl)oxy)-N-ethyl-5-fluoro-N-isopropylbenzamide Do 2-((5-(2-(1-(1,3-dioxolan-2-yl)-4-methylpentane- 3-yl)-2,6-diazaspiro[3.4]octan-6-yl)-1,2,4-tri Azin-6-yl)oxy)-5-fluoro-N,N-diisopropylbenzamide N-Methoxy-4-((2-methoxyethyl)(methyl)amino)-N-methylbutanal Mido tert-Butyl 6-(6-((2-methoxyethyl)(methyl)amino)-2-methyl Hexane-3-yl)-2,6-diazaspiro[3.4]octane-2-carboxylate to The following intermediates were prepared by methods similar to those described for Compound 60 and Compound 61: and synthesized.

[0287] [Table 20]

[0288] [Table 21]

[0289] [Table 22]

[0290] Preparation of Intermediates 17 and 18 (*R)-2-((5-(2-(1-(1,3-dioxoisoindolin-2-yl)- 3-methylbutan-2-yl)-2,6-diazaspiro[3.4]octan-6-yl) -1,2,4-triazin-6-yl)oxy)-N-ethyl-5-fluoro-N-iso Propylbenzamide (*S)-2-((5-(2-(1-(1,3-dioxoisoindolin-2-yl)- 3-methylbutan-2-yl)-2,6-diazaspiro[3.4]octan-6-yl) -1,2,4-triazin-6-yl)oxy)-N-ethyl-5-fluoro-N-iso Propylbenzamide [ka] 2-((5-(2-(1-(1,3-dioxoisoindolin-2-yl)-3-methyl (2,6-diazaspiro[3.4]octan-6-yl)-1,2-butan-2-yl ,4-triazin-6-yl)oxy)-N-ethyl-5-fluoro-N-isopropyl Benzamide (Intermediate 16) (200 mg, 0.254 mmol) was dissolved in DAICEL C Purification was performed by SFC through HIRALCEL OD (column: 250 x 50 mm 1 0 μm; Mobile phase: A: supercritical CO2, B: IPA (0.1% ammonia), A:B = 65 : 35 (70 mL / min); Column temperature: 38 °C; Nozzle pressure: 100 bar; Nozzle temperature: 60℃; evaporator temperature: 20℃; trimmer temperature: 25℃; wavelength: 220nm) All of the intermediates were obtained as colorless oils, namely, the title intermediate, Intermediate 17 (100 mg, purity 95%, yield 42%). %) and intermediate 18 (100 mg, purity 99%, yield 44%).

[0291] Preparation of Intermediates 40 and 41 Benzyl (*R)-(5-(6-(6-(2-(ethyl(isopropyl)carbamoyl) -4-fluorophenoxy)-1,2,4-triazin-5-yl)-2,6-diazas pyro[3.4]octan-2-yl)-2,6-dimethylheptan-2-yl)(methyl ) Carbamate Benzyl(*S)-(5-(6-(6-(2-(ethyl(isopropyl)carbamoyl) -4-fluorophenoxy)-1,2,4-triazin-5-yl)-2,6-diazas pyro[3.4]octan-2-yl)-2,6-dimethylheptan-2-yl)(methyl ) Carbamate [ka] Benzyl(5-(6-(6-(2-(ethyl(isopropyl)carbamoyl)-4-furan) (fluorophenoxy)-1,2,4-triazin-5-yl)-2,6-diazaspiro[3 .4]octan-2-yl)-2,6-dimethylheptan-2-yl)(methyl)carba Mate (Intermediate 39) (650 mg, 0.923 mmol) was added to DAICEL CHIR Separation was performed by SFC using ALPAK AD-H (column: 250 × 30 mm, 5 μ m; Eluent: 30% (v / v) supercritical CO2 in EtOH (0.1% ammonia), flow rate: 60 mL / min), and the title intermediate, Intermediate 40 (250 mg, pure) was obtained as a colorless oil. and intermediate 41 (220 mg, purity 99.9%, yield 34%). Got it.

[0292] Preparation of Intermediate 48 and Intermediate 49 Methyl(*R)-4-(6-(6-(2-(4-cyclopropylpyrimidin-5-yl) -4-fluorophenoxy)-1,2,4-triazin-5-yl)-2,6-diazas Pyrro[3.4]octan-2-yl)-5-methylhexanoate Methyl(*S)-4-(6-(6-(2-(4-cyclopropylpyrimidin-5-yl) -4-fluorophenoxy)-1,2,4-triazin-5-yl)-2,6-diazas Pyrro[3.4]octan-2-yl)-5-methylhexanoate [ka] Methyl 4-(6-(6-(2-(4-cyclopropylpyrimidin-5-yl)-4-furan (fluorophenoxy)-1,2,4-triazin-5-yl)-2,6-diazaspiro[3 .4]octan-2-yl)-5-methylhexanoate (Intermediate 47) (360 mg, 0.513 mmol) was passed through Phenomenex-Cellulose-2 and SF Purified by C (column: 250 × 30 mm, 10 μm; eluent: MeOH (0.1% ammonia) in 35% (v / v) supercritical CO2), both of which produced the title intermediate as a white solid. Intermediate 48 (110 mg, 35% yield) and Intermediate 49 (90 mg, 31% yield) obtained.

[0293] Preparation of intermediate 93 1-(1,3-dioxolan-2-yl)-4-methylpentan-3-one [ka] Magnesium (6.0 g, 247 mmol) and iodide in THF (70 mL) at 25 °C A mixture of 2-(2-bromo-2-methyl-2-methylpropional)-2-methylpropional (100 mg, 0.394 mmol) in THF (30 mL) was A solution of 20.0 g (110 mmol) of 1,3-dioxolane was slowly added to the was added, and the resulting mixture was stirred at 25°C for 1 hour. The mixture was then cooled to 0°C. N-Methoxy-N-methylisobutyramide (10 g, 76.2 mL) in THF (100 mL) The reaction mixture was slowly warmed to 25°C and the resulting solution was added slowly to a solution of 100 mmol of HCl. The mixture was stirred for 8 hours at a temperature of 100° C. The mixture was quenched with saturated aqueous NH4Cl (300 mL) and Extraction was performed with MTBE (200 mL x 3). The combined organic layer was dried over Na2SO4 and filtered. Filtration and concentration under reduced pressure gave the crude product, which was purified by FCC (PE: EtOAc = 1:0 to 20:1) to give the title intermediate as a colorless oil (13 g, crude), which was further purified. It was used directly in the next step without further purification.

[0294] Preparation of Intermediates 95 and 96 (R)-2-((5-(2-(1-(1,3-dioxolan-2-yl)-4-methylphenyl)- octan-3-yl)-2,6-diazaspiro[3.4]octan-6-yl)-1,2, 4-triazin-6-yl)oxy)-N-ethyl-5-fluoro-N-isopropylbenzyl Nzuamide (S)-2-((5-(2-(1-(1,3-dioxolan-2-yl)-4-methylphenyl)- octan-3-yl)-2,6-diazaspiro[3.4]octan-6-yl)-1,2, 4-triazin-6-yl)oxy)-N-ethyl-5-fluoro-N-isopropylbenzyl Nzuamide [ka] 2-((5-(2-(1-(1,3-dioxolan-2-yl)-4-methylpentane -3-yl)-2,6-diazaspiro[3.4]octan-6-yl)-1,2,4- Triazin-6-yl)oxy)-N-ethyl-5-fluoro-N-isopropylbenzaldehyde 4.00 g (7.01 mmol) of intermediate 94 was added to DAICEL CHIRAL Separation was performed by SFC through a CEL OD (column: 250 × 50 mm, 10 μm; transfer Mobile phase: A: supercritical CO2, B: MeOH (0.1% ammonia), 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: 220nm), white solid The title intermediate, Intermediate 95 (1.72 g, purity 98.76%, yield 42.5%) was obtained as ) and intermediate 96 (1.57 g, purity 98.09%, yield 38.5%) were obtained.

[0295] Preparation of Intermediates 99 and 100 (*R)-2-((5-(2-(1-(1,3-dioxolan-2-yl)-4-methyl Pentan-3-yl)-2,6-diazaspiro[3.4]octan-6-yl)-1,2 ,4-triazin-6-yl)oxy)-5-fluoro-N,N-diisopropylbenz amide (*S)-2-((5-(2-(1-(1,3-dioxolan-2-yl)-4-methyl Pentan-3-yl)-2,6-diazaspiro[3.4]octan-6-yl)-1,2 ,4-triazin-6-yl)oxy)-5-fluoro-N,N-diisopropylbenz amide [ka] 2-((5-(2-(1-(1,3-dioxolan-2-yl)-4-methylpentane -3-yl)-2,6-diazaspiro[3.4]octan-6-yl)-1,2,4- riazin-6-yl)oxy)-5-fluoro-N,N-diisopropylbenzamide ( Intermediate 98) (6.5 g) was subjected to SFC through DAICEL CHIRALPAK IG. Separation was performed by (column: 250 × 50 mm 10 μm; mobile phase: A: supercritical CO2, B: MeOH (0.1% ammonia), A:B = 65:35 (200 mL / min); column temperature Degrees: 38; Nozzle pressure: 100 bar; Nozzle temperature: 60°C; Evaporator temperature: 20°C Trimmer temperature: 25°C; wavelength: 220 nm), intermediate 99 (2.7 g) and intermediate 100 (2.8 g).

[0296] Preparation of intermediate 97 (R)-N-ethyl-5-fluoro-N-isopropyl-2-((5-(2-(2-methyl) (6-oxohexan-3-yl)-2,6-diazaspiro[3.4]octane-6- (yl)-1,2,4-triazin-6-yl)oxy)benzamide [ka] (R)-2-((5-(2-(1-(1,3-dioxolane-2)) in ACN (10 mL) -yl)-4-methylpentan-3-yl)-2,6-diazaspiro[3.4]octane -6-yl)-1,2,4-triazin-6-yl)oxy)-N-ethyl-5-fluoro rho-N-isopropylbenzamide (Intermediate 95) (1.00 g, 1.75 mmol) To the solution was added 1 M HCl (10.0 mL, 10.0 mmol), and the resulting mixture was The mixture was stirred at 50° C. for 1 hour. After cooling to RT, the reaction mixture was concentrated under reduced pressure. The 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 layer was washed with anhydrous N Dry over a2SO4, filter and concentrate in vacuo to give the title intermediate as a white solid ( 900 mg, purity 87%, yield 85%), which was used directly in the next step without further purification. I used it.

[0297] Preparation of intermediates 101, 102, and 103 (*R)-5-Fluoro-N,N-diisopropyl-2-((5-(2-(2-methyl- 6-oxohexan-3-yl)-2,6-diazaspiro[3.4]octan-6-yl )-1,2,4-triazin-6-yl)oxy)benzamide (*S)-5-Fluoro-N,N-diisopropyl-2-((5-(2-(2-methyl- 6-oxohexan-3-yl)-2,6-diazaspiro[3.4]octan-6-yl )-1,2,4-triazin-6-yl)oxy)benzamide N-ethyl-5-fluoro-N-isopropyl-2-((5-(2-(2-methyl-6- Oxohexan-3-yl)-2,6-diazaspiro[3.4]octan-6-yl)- 1,2,4-triazin-6-yl)oxy)benzamide The following intermediates were synthesized by methods similar to those described for intermediate 97.

[0298] [Table 23]

[0299] Preparation of Intermediate 114 Methyl 2-(2-isopropyl-1,3-dioxolan-2-yl)acetate [ka] In a 1000 mL flask equipped with a Dean-Stark apparatus, methyl 4-methyl Dimethyl-3-oxopentanoate (50 g, 347 mmol) was added to ethane-1,2-diol. (43 g, 693 mmol), p-toluenesulfonic acid monohydrate (597 mg, 3.4 The mixture was heated at 135° C. The mixture was stirred for 18 hours. After cooling to room temperature, 1M aqueous Na2CO3 (300 mL) was added to the reaction mixture. The organic layer was separated, washed with H2O (100 mL) and anhydrous Na2SO4 Drying at 40°C, filtering and concentrating in vacuo gave the title intermediate as a yellow oil (41 g, crude). ), which was used directly in the next step without further purification.

[0300] Preparation of Intermediate 115 2-(2-isopropyl-1,3-dioxolan-2-yl)ethan-1-ol [ka] LiAlH4 (2.5 g, 66 mmol) was dissolved in THF ( The mixture was added in small portions to a solution of 100 ml of THF (20 ml) under a N2 atmosphere at 0°C. Methyl 2-(2-isopropyl-1,3-dioxolan-2-yl)acetate (Intermediate A solution of 114) (10 g, crude) was added dropwise to the above mixture. The resulting mixture was allowed to warm slowly to RT and stirred at this temperature for 18 h. HO was slowly added to the above mixture, followed by aqueous NaOH (15%, 7.5 mL The resulting mixture was stirred at RT for 0.5 h. Anhydrous MgSO4 was then added to the 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 was used directly in the next step without further purification.

[0301] Preparation of Intermediate 116 1-hydroxy-4-methylpentan-3-one [ka] To a mixture of silica gel (27 g, 449 mmol) in DCM (230 mL) was added oxalic acid (4.2 mL, 10% in water, 4.7 mmol) was added. After the aqueous layer disappeared, DCM ( 2-(2-isopropyl-1,3-dioxolan-2-yl)ethane-1-ol in 7 mL A solution of ethanol (Intermediate 115) (3.7 g, crude) was added and the reaction mixture was stirred at RT for 5 h. The mixture was stirred. Then, NaHCO3 (800 mg) was added. The resulting mixture was filtered and The filtrate was concentrated in vacuo to give the title intermediate as a colorless oil. (2.4 g, crude), which was used directly in the next step without further purification.

[0302] Preparation of Intermediate 124 (*R)-3-(6-(6-(2-(ethyl(isopropyl)carbamoyl)-4-fluoro) orophenoxy)-1,2,4-triazin-5-yl)-2,6-diazaspiro[3. 4]Octan-2-yl)-4-methylpentyl methanesulfonate [ka] MsCl (250 mg, 2.18 mmol) was dissolved in DCM cooled to 0 °C under a N atmosphere. N-ethyl-5-fluoro-2-((5-(2-(1-hydroxy-4- Methylpentan-3-yl)-2,6-diazaspiro[3.4]octan-6-yl)- 1,2,4-triazin-6-yl)oxy)-N-isopropylbenzamide (compound 213) (500 mg, 0.972 mmol) and TEA (0.27 mL, 1.9 mmol) l) solution. The resulting mixture was stirred at 0 °C under N2 for 45 min. The mixture was quenched with H2O (5 mL) and extracted with DCM (10 mL x 3). The organic layer was washed with brine (5 mL), dried over anhydrous Na2SO4, and filtered. Concentration in vacuo gave the title intermediate (400 mg, crude) as a yellow oil, which was further purified It was used directly in the next step without further purification.

[0303] Preparation of intermediates 130 and 139 Methyl 3-methyl-4-(tosyloxy)butanoate 2-Methoxypropyl 4-methylbenzenesulfonate The following intermediates were synthesized by methods similar to those described above for intermediate 124.

[0304] [Table 24]

[0305] Preparation of Intermediate 125 N-benzyl-2-methoxy-N-methylacetamide [ka] N-methyl-1-phenylmethanamine (5.5 mL) in DCM (60 mL) cooled to 0° C. To a solution of 2-methyl-2-propanol (14 g, 45.4 mmol) and TEA (14 g, 138.4 mmol), Diacetyl chloride (5 g, 46.073 mmol) was added dropwise. The temperature was slowly raised to 25°C and stirred at this temperature for 1 hour. The solution (50 mL) was added to the above mixture and extracted with DCM (50 mL x 3). The organic layer was washed with brine (100 mL), dried over Na2SO4, filtered and concentrated in vacuo Concentration gave a crude residue, which was purified by FCC (EA:PE=0 to 80%). The title intermediate was obtained as a colored oil (3.4 g, 34% yield).

[0306] Preparation of Intermediate 126 N-benzyl-2-methoxy-N-methylethan-1-amine-1,1-d2 [ka] LiAlD4 (1.5 g, 35 mL) in THF (25 mL) cooled to 0 °C under a N2 atmosphere To a mixture of N-benzyl-2-methoxy-N- A solution of methylacetamide (Intermediate 125) (3.4 g, 17.6 mmol) was added dropwise. The reaction mixture was first stirred at 25°C for 1 hour, then at 50°C for an additional 2 hours. The reaction mixture was then cooled to 0°C and quenched by the dropwise addition of aqueous NaOH (1M, 10 mL). The resulting mixture was filtered and the filter cake was washed with EtOAc (100 mL). Wash with H2O (50 mL) and brine (50 mL), dry over Na2SO4 and filter The solvent was concentrated under reduced pressure to give a residue which was purified by FCC (EtOAc:P E=0 to 100%) to give the title intermediate as a colorless oil (2.0 g, 60% yield).

[0307] Preparation of Intermediate 127 2-Methoxy-N-methylethan-1,1-d2-1-amine, hydrochloride [ka] N-benzyl-2-methoxy-N-methyl-N-methyl-2 ... To a solution of ethylethan-1-amine-1,1-d2 (800 mg, 4.413 mmol), 1,1,2-trichloroethane (1.2 g, 9.0 mmol) and Pd / C (wet, 10 %, 0.5 g) was added. The resulting mixture was heated at 50 °C under H atmosphere (50 psi). After stirring for 18 hours, the reaction mixture was cooled to room temperature and filtered through Celite. Concentration in air gave the title intermediate (600 mg, crude) as a yellow oil, which was further purified. It was used directly in the next step without further purification.

[0308] Preparation of Intermediate 128 Methyl 4-hydroxy-3-methylbut-2-enoate [ka] t-BuOK (16.0 g, 143 mmol) in THF (220 mL) (2-oxoethyl)triphenylphosphonium bromide (59.0 g, 142 mm The resulting mixture was stirred at 50°C for 1 hour. 1-hydroxypropan-2-one (7.2 g, 97 mmol) in 30 mL of The mixture was added to the HCl solution and the reaction mixture was stirred at 50° C. for a further 16 h. After cooling to RT, H2O (200 mL) was added and the mixture was extracted with EtOAc (200 mL x 3). The organic layer was washed with H2O (300 mL), dried over anhydrous Na2SO4, and filtered. was concentrated in vacuo to give the crude compound, which was purified by FCC (PE: EtOAc = 1:0 to 1:1) to give the title intermediate as a pale yellow oil (3.4 g, 27% yield).

[0309] Preparation of Intermediate 129 Methyl 4-hydroxy-3-methylbutanoate [ka] Methyl 4-hydroxy-3-methylbut-2-enoate ( To a solution of Intermediate 128) (3.4 g, 26 mmol), dry Pd / C (500 mg, 10 %) was added and the suspension was stirred at RT under an atmosphere of H2 (15 psi) for 4 h. The reaction mixture was filtered through a pad of Celite and washed with MeOH (200 mL). The filtrate was concentrated in vacuo. Concentration at 200°C gave the title intermediate as a yellow oil (2.3 g, 67% yield), which was further purified. It was used directly in the next step without further purification.

[0310] Preparation of intermediates 193, 194, 207, and 208 (S)-5-((tert-butyldiphenylsilyl)oxy)-6-(ethyl(methyl) )Amino)-2-methylhexan-3-one (R)-5-((tert-butyldiphenylsilyl)oxy)-6-(ethyl(methyl) )Amino)-2-methylhexan-3-one (S)-5-((tert-butyldiphenylsilyl)oxy)-6-((2-methoxy Ethyl)(methyl)amino)-2-methylhexan-3-one (R)-5-((tert-butyldiphenylsilyl)oxy)-6-((2-methoxy Ethyl)(methyl)amino)-2-methylhexan-3-one The following intermediates were synthesized by methods similar to those described for intermediate 129.

[0311] [Table 25]

[0312] Preparation of Intermediate 131 and Intermediate 132 Methyl (*R)-3-methyl-4-(tosyloxy)butanoate Methyl (*S)-3-methyl-4-(tosyloxy)butanoate [ka] Methyl 3-methyl-4-(tosyloxy)butanoate (Intermediate 130) (3.3 g) The product was purified by SFC through DAICEL CHIRALPAK AY-H (column Size: 250×30mm 5μm; Mobile phase: A: Supercritical CO2, B: EtOH (0.1% ammonia), A:B=90:10 (60 mL / min)), both of which were obtained as white solids. Intermediate (Intermediate 131) (1.28 g, purity 97%, yield 36%) and (Intermediate 132) ( 1.27 g, 85% purity, 33% yield was obtained.

[0313] Preparation of Intermediate 134 Methyl (*S)-4-((2-methoxyethyl)(methyl)amino)-3-methylbutanoate art [ka] Methyl (*S)-3-methyl-4-(tosyloxy)butanoate in ACN (5 mL) (Intermediate 132) (1.27 g, 4.44 mmol), 2-methoxy-N-methylethane α-1-amine (593 mg, 6.65 mmol) and K2CO3 (1.23 mg, 8.8 7 mmol) was stirred overnight at 90° C. After cooling to RT, the reaction mixture was filtered. The filtrate was concentrated in vacuo to give the title intermediate (670 mg, crude) as a brown oil, which was used directly in the next step without further purification.

[0314] Preparation of intermediates 133, 185, 186, 199, 200, and 219 Methyl (*R)-4-((2-methoxyethyl)(methyl)amino)-3-methylbutanoate Et Ethyl (S)-3-((tert-butyldiphenylsilyl)oxy)-4-(ethyl( Methyl)amino)butanoate Ethyl (R)-3-((tert-butyldiphenylsilyl)oxy)-4-(ethyl( Methyl)amino)butanoate Ethyl (S)-3-((tert-butyldiphenylsilyl)oxy)-4-((2-methylphenyl)silyl (methyl)amino)butanoate Ethyl (R)-3-((tert-butyldiphenylsilyl)oxy)-4-((2-methylphenyl) (methyl)amino)butanoate N-(2-Methoxyethyl)-N,2-dimethylprop-2-en-1-amine The following intermediates were synthesized by methods similar to those described for intermediate 134.

[0315] [Table 26]

[0316] Preparation of Intermediate 136 (*S)-6-((2-methoxyethyl)(methyl)amino)-2,5-dimethylhexa On-3-On [ka] N 2 Methyl (S)-4-((2-methoxyethyl)-2-methyl-2-methyl-1-propanol in THF (5 mL) cooled to 0°C under (methyl)amino)-3-methylbutanoate (Intermediate 134) (670 mg, crude A solution of isopropylmagnesium chloride (4.94 mL, 9.88 mmol, TH Aqueous HCl (2M in F) was added dropwise. The resulting mixture was stirred at 50 °C under N for 5 h. Cooled to RT. After this, the reaction mixture was quenched with saturated aqueous NH4Cl (1.5 mL) and filtered. The solution was concentrated in vacuo to give the title intermediate (507.1 mg, crude) as a yellow oil, which was It was used directly in the next step without further purification.

[0317] Preparation of Intermediate 135 (*R)-6-((2-methoxyethyl)(methyl)amino)-2,5-dimethylhexa On-3-On The following intermediates were synthesized by methods similar to those described for intermediate 136.

[0318] [Table 27]

[0319] Preparation of Intermediate 165 tert-Butyl(2-hydroxy-5-methyl-4-oxohexyl)(methyl)carbamate Bamet [ka] 3-Methylbutan-2-ol in THF (150 mL) cooled to -40 °C under N2 atmosphere A solution of ethanol (6.0 g, 70.0 mmol) was added to LDA (40 mL, 2 M in THF, 80. The resulting mixture was stirred at -40°C for 1 hour. Then, THF tert-Butyl methyl (2-oxoethyl)carbamate (8.0 g, A solution of 46.2 mmol) was added dropwise to the above mixture and the reaction was stirred at -40°C for another 2 hours. The reaction was quenched by adding H2O (20 mL) dropwise at -40 °C. The mixture was then warmed to RT and concentrated under reduced pressure. The crude residue was diluted with H2O (200 mL). The combined organic layer was washed with brine (200 mL). ), dried over anhydrous Na2SO4, filtered and concentrated. The crude product was purified by FCC. The mixture was purified by hexane / Et0Ac (PE / Et0Ac = 20 / 1 to 3 / 1) to give the title intermediate as a colorless oil ( 8.8g, purity 85%, yield 62%).

[0320] The following intermediates were synthesized by methods similar to those described for intermediate 165.

[0321] [Table 28]

[0322] Preparation of Intermediate 166 tert-Butyl(2-methoxy-5-methyl-4-oxohexyl)(methyl)carba Mate [ka] tert-Butyl (2-hydroxy-5-methyl-4-oxo) in DCM (200 mL) (hexyl)(methyl)carbamate (Intermediate 165) (4.00 g, 15.4 mmol) To this solution, 4 Å molecular sieves (4 g) were added under N2 atmosphere, and the mixture was stirred at 25 °C for 10 min. Then, 1,8-bis(dimethylamino)naphthalene (8.26 g, 38.6 mm ol) was added and the mixture was cooled to 0°C, followed by trimethyloxonium tetrafluoro Borate (5.93 g, 40.1 mmol) was added. The reaction mixture was first heated at 0° C. for 2 h. The mixture was stirred for 16 hours, then the temperature was raised to 25°C and the mixture was stirred at this temperature for another 16 hours. The filtrate was concentrated in vacuo and the residue was purified by FCC. The title intermediate was obtained as a colorless oil (2.0 0g, 44% yield.

[0323] Preparation of Intermediate 181 Ethyl (S)-3-hydroxy-4-iodobutanoate [ka] (S)- in EtOH (8.6 mL) in DCM (20 mL) under N2 atmosphere To a solution of 4-hydroxydihydrofuran-2(3H)-one (5 g, 50.0 mmol) TMSI (14.8 g, 74.0 mmol) was slowly added to the resulting mixture. The mixture was stirred at RT for 16 h. A solution of saturated Na2SO3 (40 mL) was added. The organic layer was separated. Release and concentrate in vacuo to give the title intermediate (8.8 g, crude) as a yellow oil, which was further purified It was used directly in the next step without purification.

[0324] Preparation of Intermediate 182 Ethyl (R)-3-hydroxy-4-iodobutanoate The following intermediates were synthesized by methods similar to those described above for intermediate 181.

[0325] [Table 29]

[0326] Preparation of Intermediate 195 (S)-6-(ethyl(methyl)amino)-5-hydroxy-2-methylhexane-3- on [ka] Under N2 atmosphere, (S)-5-((tert-butyldiphenyl)- (Nylsilyl)oxy)-6-(ethyl(methyl)amino)-2-methylhexane-3-ol To a solution of 2.33 g (5.04 mmol) of tetrahydrofuran (Intermediate 193), TBAF (0.65 m L, 1.0 M in THF, 0.65 mmol) was added. 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 H2O (25 mL) and The mixture was extracted with CM (60 mL x 3). The combined organic layers were washed with brine (40 mL x 2). The filtrate was concentrated in vacuo to give the title intermediate as a yellow oil. The compound was obtained (2.2 g, crude) and used directly in the next step without further purification.

[0327] Preparation of intermediates 196, 209, and 210 (R)-6-(ethyl(methyl)amino)-5-hydroxy-2-methylhexane-3- on (S)-5-Hydroxy-6-((2-methoxyethyl)(methyl)amino)-2-methyl Hexan-3-one (R)-5-Hydroxy-6-((2-methoxyethyl)(methyl)amino)-2-methyl Hexan-3-one The following intermediates were synthesized by methods similar to those described above for intermediate 195.

[0328] [Table 30]

[0329] Preparation of Intermediate 220 N-((3-isopropyl-5-methyl-4,5-dihydroisoxazol-5-yl )Methyl)-2-methoxy-N-methylethan-1-amine [ka] N-(2-Methoxyethyl)-N,2-dimethyl in DMF (50 mL) cooled to 0°C A solution of prop-2-en-1-amine (Intermediate 219) (2.90 g, 20.2 mmol) The solution was added with NaHCO3 (6.82 g, 81.2 mmol) and (Z)-N-hydroxyisothiazolinone. Butyrimidoyl chloride (2.47 g, 20.3 mmol) was added. The reaction mixture was stirred at 0 °C for 30 min, followed by stirring at RT for 16 h. The reaction mixture was diluted with H2O (50 mL The mixture was quenched with HCl and extracted with EtOAc (30 mL x 2). The combined organic layers were saturated The filtrate was washed with aqueous LiCl (50 mL), dried over anhydrous Na2SO4, and filtered. Concentration in vacuo gave the crude product, which was purified by FCC (MeOH:DCM=1 :10) to give the title intermediate as a brown oil (1.20 g, purity 89.9%, yield 25. 9%).

[0330] Preparation of Intermediate 221 5-Hydroxy-6-((2-methoxyethyl)(methyl)amino)-2,5-dimethyl Hexan-3-one [ka] N-((3-isopropyl)methylpropional) in MeOH and THF (40 mL, MeOH / THF=1 / 2) (5-methyl-4,5-dihydroisoxazol-5-yl)methyl)-2-meth Dimethyl-N-methylethan-1-amine (Intermediate 220) (1.20 g, 5.26 mmol) ) was added to a solution of AcOH (3.15 g, 52.5 mmol) and HO (9.50 mL, 5 Raney Ni (750 mg) was added under N2 atmosphere at 0°C. ) was added to the solution. The suspension was degassed and purged with H2 three times, and the mixture was placed in an H2 atmosphere at 25 °C. The mixture was stirred under air (30 Psi) overnight.

[0331] The reaction mixture was filtered through a pad of Celite and the filtrate was extracted with DCM. Wash with HCl (20 mL × 2) and brine (20 mL × 2), then dry with NaSO The filtrate was concentrated in vacuo to give the title intermediate as a brown oil (1.10 g). , crude), which was used directly in the next step without further purification.

[0332] Preparation of Intermediate 227 tert-Butyl (R)-(1-(2,2-dimethyl-4,6-dioxo-1,3-dioxo) Xan-5-yl)-3-methylbutan-2-yl)carbamate [ka] Boc-L-valine (44.9 kg) in DCM (607 kg) pre-cooled to -10 to 0 °C ), 2,2-dimethyl-1,3-dioxane-4,6-dione (32.9 kg) and DM AP (35.5 kg) was injected into DCC (55.5 kg) in DCM (613 kg) for 3 hours. g) solution and aged at -10 to 0°C for 16 hours. The temperature was kept below 10°C. While stirring, 10% aqueous citric acid solution (449 kg) was added. The mixture was aged at RT for 2 hours at RT, followed by filtration. The filter cake was washed with DCM (91 kg). The filtrate was separated, and the organic layer was diluted with 10% aqueous citric acid (2 times, 450 kg) and 10% NaCl. The organic phase (120 kg) was washed with 100% aqueous solution (449 kg) of 100% ethanol while maintaining the temperature at -10 to 0°C. Acetic acid (75.0 kg) was added to the mixture (20.0 kg). The temperature was maintained in the range of -10 to 0°C. Sodium borohydride (18.0 kg) was added in small portions over a period of 5 hours, followed by the addition of the obtained The resulting mixture was aged for an additional 16 hours at -10 to 0°C. The mixture was then heated to 15 to 25°C. The mixture was then heated and aged for 2 hours. Washed, then washed a second time with 14% NaCl aqueous solution (432 kg) and a final water wash ( The organic phase was concentrated under reduced pressure to 2-4 vol. Isopropanol (143 kg) was added to the residue and concentrated to 4-5 vol. under reduced pressure. After cooling and aging for 8 hours, the resulting slurry was filtered and washed with IPA (38 kg). and dried to give the title intermediate as a white solid (46.7 kg, 69% yield).

[0333] Preparation of Intermediate 228 tert-Butyl (R)-2-isopropyl-5-oxopyrrolidine-1-carboxylate Route [ka] tert-Butyl (R)-(1-(2,2-dimethyl-4, 6-Dioxo-1,3-dioxan-5-yl)-3-methylbutan-2-yl)carba Mate (Intermediate 227) (46.7 kg) was heated to reflux and aged for 4 hours. The mixture was cooled to ambient temperature, filtered and washed with toluene (20 kg). was concentrated to dryness under reduced pressure to give the desired compound (31.05 kg, 96% yield) as an oil. This was used as is without further purification.

[0334] Preparation of Intermediate 229 tert-Butyl (5R)-2-hydroxy-5-isopropylpyrrolidine-1-carbohydrate Xylate [ka] tert-Butyl (R)-2-isopropyl-5- Oxopyrrolidine-1-carboxylate (Intermediate 228) (30.9 kg) was added to -5 Cool to 5°C. LiBH4 in 2-MeTHF (1M, 45.2 kg, 54.4 mol) A solution of 5% NaHCO3 was added over 3 hours and the mixture was aged for 4 hours. A cold aqueous solution (163 kg) was added over 3 hours at -5 to 5°C, and the mixture was then aged for a further 2 hours. The mixture was allowed to warm to ambient temperature and aged for an additional 2 hours. The aqueous layer was separated and The bed was washed with 10% aqueous NaCl solution (170 kg) and water (155 kg). An emulsion formed and solid NaCl (3.1 kg) was added to affect separation. After removing the aqueous layer, the organic layer was concentrated to dryness under reduced pressure to give the desired compound (28.5%) as an oil. kg, 91% yield, which was used directly without further purification.

[0335] Preparation of Intermediate 230 tert-Butyl (R)-(6-((2-methoxyethyl)(methyl)amino)-2-methyl ethylhexan-3-yl)carbamate [ka] tert-Butyl (5R)-2-hydroxy- in DCM (344 kg) at 15-25°C 5-Isopropylpyrrolidine-1-carboxylate (Intermediate 229) (28.55 kg ) to 2-methoxy-N-methylethan-1-amine (12.3 kg, 138.0 mol The resulting mixture was aged for 1 hour. Then, sodium triacetoxyborohydride (40.12 kg) was added in small amounts over a period of 5 hours. The resulting mixture was aged for 48 hours while maintaining the temperature at 15-25°C. The reaction mixture was stirred for 2 hours by adding 8% aqueous NaOH solution (184 kg). The mixture was quenched and aged for an additional 2 h. The aqueous layer was separated and the organic layer was washed with water (169 The organic layer was then concentrated to dryness under reduced pressure to give the title intermediate (33) as an oil. 0.26 kg, 88% yield, which was used directly without further purification.

[0336] Preparation of Intermediate 231 (R)-N 1 -(2-Methoxyethyl)-N 1 ,5-Dimethylhexane-1,4-diamine Benzene, dihydrochloride [ka] A 4 molar solution of HCl in isopropanol (84.80 kg) at ambient temperature was tert-Butyl (R)-(6-((2-methoxyethyl)methyl)methyl)methylpropional in ethanol (25.6 kg) (Methyl)amino)-2-methylhexan-3-yl)carbamate (Intermediate 230) A solution of 32.38 kg of ethanol was added over 3 hours and the mixture was allowed to evaporate at ambient temperature for a further 19 hours. Then, methyl tert-butyl ether (95.25 kg) was added over 1 hour. The resulting slurry was filtered and MTBE was added. (53 kg). The filter cake was dried to give the title compound as a white solid ( 23.92 kg, 81% yield.

[0337] Preparation of Intermediate 232 Ethyl 1-benzyl-3-(chloromethyl)pyrrolidine-3-carboxylate [ka] DIPEA (952 g, 1.1 eq.) in THF (6 L) cooled to -35 to -25 °C To the solution was added n-BuLi (2.33 kg, in hexane) while maintaining the temperature below -25°C. The resulting mixture was stirred at -35 to -25°C for another 30 minutes. The mixture was aged at -78 to -60 °C and then cooled to -78 to -60 °C. L) in ethyl 1-benzylpyrrolidine-3-carboxylate (2 kg, 1.0 eq.) A solution of 1.81 kg of chloroiodomethane (1.81 kg, 1 0.2 eq.) was added at -78 to -60°C. The reaction mixture was stirred at -60 to -4°C for 2 hours. The reaction mixture was aged at 0°C. An aqueous solution of citric acid (6 L H2O 660 g of ethanol was added, and the resulting mixture was aged at 20 to 30°C for a further 20 minutes. After separating the layers, the aqueous layer was extracted with EtOAc (6 L) and the combined organic layers were washed with brine (6 L). ), and then heated to 50-60°C. Oxalic acid (2.22 kg) was added to the The resulting mixture was stirred at 50-60°C for 3 hours, and then cooled to 20-30°C. The resulting solid was filtered and the cake was washed with ethyl acetate (2 L). The wet cake was dissolved in toluene (4 L), H2O (8 L) and K3PO4 (1.5 eq.). The resulting mixture was aged at 20-30°C for 20 minutes. After separating the layers, The aqueous layer was extracted with toluene (2 L). The organic layers were combined and washed twice with water (2 L). The phase was concentrated under reduced pressure to give 4.2 kg of the desired compound as a toluene solution (80% 46% by weight by assay, given the assay yield.

[0338] Preparation of intermediate 233 1-Benzyl-3-(chloromethyl)pyrrolidine-3-carbaldehyde [ka] The reaction was carried out in a flow chemistry system: ethyl 1-benzyl benzoate in toluene (26 L). Benzyl-3-(chloromethyl)pyrrolidine-3-carboxylate (Intermediate 232) (4 A solution of 0.4 kg was pumped at 26.7 mL / min and cooled to -60°C. This was pumped at 32.1 mL / min and dissolved in toluene (28 L) at -60°C. The mixture was mixed with a cooled solution of perfluoroalkoxy (P FA) through a coiled tube reactor (total flow rate 58.8 mL / min, residence time 5 s) The resulting mixture was added to cooled MeOH (-60 °C) pumped at a rate of 15.2 mL / min. This mixture was pumped into another PFA coiled tube reactor at -60°C. (Total flow rate: 74 mL / min, residence time: 5 seconds). The resulting mixture was mixed with 20 wt. % of the The solution was collected in a receiver containing aqueous Shell's salt solution (20V). The layers were separated and the organic phase was washed twice with water. The organic phase was combined with another 3.0 kg batch prepared in a similar manner. The mixture was concentrated under reduced pressure to give 20.8 kg of a toluene solution of the desired compound (85% assay). Given the yield (25.5% by weight, assayed by HPLC), this was further purified. It was used as is without any modification. 1 H NMR (300 MHz, chloroform-d): δ 9.62 (s, 1H), 7.3 9-7.20(m,5H),3.83-3.57(m,4H),2.96(d,J=10 .2Hz,1H),2.80-2.55(m,3H),2.17(ddd,J=13.9 ,7.9,6.1Hz,1H),1.83(ddd,J=13.4,7.8,5.5Hz ,1H).

[0339] Preparation of Intermediate 234 (R)-4-(6-benzyl-2,6-diazaspiro[3.4]octan-2-yl)- N-(2-Methoxyethyl)-N,5-dimethylhexan-1-amine [ka] Toluene (30 L) and (R)-N 1 -(2-Methoxyethyl)-N 1 ,5-dimethyl Diluted with hexane-1,4-diamine, dihydrochloride (Intermediate 231) (3.47 kg). 1-Benzyl-3-(chloromethyl)pyrrolidine in toluene (3.0 kg, 10 wt%) A solution of 3-carbaldehyde (Intermediate 233) was added to triethylamine (2. The resulting mixture was aged at 20-30°C for 2 hours. Then, sodium triacetoxyborohydride (9.0 kg) was added at 20-30°C. The mixture was aged for 12 hours. The reaction mixture was cooled to 5-15°C. While maintaining the temperature below 35°C, 25 wt% aqueous NaOH solution (25 L, approximately 16.75 eq.) was added. The resulting mixture was aged at 20-30°C for 25 minutes and the layers were separated. The layers were washed with 15% aqueous NaCl (10 L), the layers were separated again, and the organic phase was diluted with water (18 L). While maintaining the internal temperature below 35°C, the pH of the aqueous phase was adjusted to 4 M aqueous HCl. The organic phase was then discarded, and the aqueous phase was separated and adjusted to pH 8-9 with K2HPO4. Basified.

[0340] The resulting mixture was heated to 50-55°C and aged for 3 hours. The mixture was cooled to ambient temperature and combined with the other two batches (2.4 kg + 3.0 kg). The resulting stream was washed three times with methyl tert-butyl ether (3 x 40 L). Add additional methyl tert-butyl ether (83 L) to the layer and bring the temperature to 15-35°C. While maintaining the pH, the aqueous phase was basified to pH 9-10 using an 8 wt% NaOH aqueous solution. The layers were separated and the organic layer was washed three times with water (3 x 30 L). The organic layer was then concentrated under reduced pressure. 3 volumes, followed by three flushes with methanol (3 x 30 L) and concentration to dryness. This gave the desired compound as a pale yellow oil (12.4 kg, 90% isolated yield), which was further purified It was used as is without any modification.

[0341] Preparation of Intermediate 224 (R)-N-(2-methoxyethyl)-N,5-dimethyl-4-(2,6-diazaspiro [3.4]Octan-2-yl)hexan-1-amine [ka] Palladium hydroxide on carbon (1.2 kg) in EtOH (1.47 kg) cooled to -5 to 5°C ) 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 (Intermediate 234) (10 kg) and EtOH (250 L) The mixture was heated to 35-45°C and heated under a hydrogen atmosphere (0.27-0.40 MP). a) for 16-20 hours. The mixture was filtered through diatomaceous earth (20 kg) and the pad was washed with EtO The filtrate was concentrated under reduced pressure (<40°C) to 2-3 vol. It was then flushed twice with 2-MeTHF (73 kg and 47 kg) and dissolved in 2-3 vol. After diluting with 2-MeTHF (65 kg), a 10% aqueous solution of sodium sulfate (3 0 kg) was added and the mixture was cooled to 0-10°C, followed by 16% aqueous NaOH (50 The pH was adjusted to 13-14 by adding 1 kg of ethanol. The temperature was adjusted to 15-25°C, and the The mixture was stirred for 10 minutes. The aqueous layer was separated and extracted twice with 2-MeTHF (47 kg x 2). The organic layer was concentrated under reduced pressure (<40 °C) to 3-4 vol. and diluted with 2-MeTHF (95 After concentrating under reduced pressure (<40°C) to 3-4 vol., the resulting solution was The solution was diluted with 2-MeTHF (30 kg) and passed through 4 Å molecular sieves (25 kg). The final solution was concentrated to give the desired oil. The desired compound (6.7 kg) was obtained (90.1% assay purity in 79% corrected yield).

[0342] Preparation of Intermediate 225 (R)-4-(6-(3,6-dichloro-1,2,4-triazin-5-yl)-2,6 -diazaspiro[3.4]octan-2-yl)-N-(2-methoxyethyl)-N,5 -Dimethylhexan-1-amine [ka] (R)-N-(2-Methoxyethyl)-N,5-dimethyl-4-(2,6-diazaspipril) (3.4)octan-2-yl)hexan-1-amine (Intermediate 224) (100 g) 2-MeTHF (430 g) and TEA (68 g) were added to the mixture, and the temperature was adjusted to -50 to -40 The mixture was cooled to rt. 3,5,6-trichloro-1,2,4-trimethyl-2-methyl-2-propanol (172 g) was added to 2-MeTHF (172 g). Azine (62 g) was added and the mixture was stirred for 1 to 3 hours. The mixture was heated to 10°C, a 7% aqueous solution of NaHCO3 was added, and the mixture was heated to 20-30°C. The aqueous layer was removed, and the organic layer was washed with 10% Na2SO4 (500 g). The organic layer was dried by passing it through 4 Å molecular sieves (220 g) and 2-MeT The title intermediate was dissolved in 2-MeTHF (14.8 wt %) and washed with HF (180 g). The assay yield was 90%.

[0343] Preparation of Intermediate 245 (R)-2-((5-(2-(6-((2-((tert-butyldimethylsilyl)oxy) (Ci)ethyl)(methyl)amino)-2-methylhexan-3-yl)-2,6-diaza Pyrro[3.4]octan-6-yl)-1,2,4-triazin-6-yl)oxy)- N-ethyl-5-fluoro-N-isopropylbenzamide [ka] NaBHCN (23.2 mg, 0.37 mmol) in MeOH (2 mL) (R) -N-ethyl-5-fluoro-N-isopropyl-2-((5-(2-(2-methyl-6 -(methylamino)hexan-3-yl)-2,6-diazaspiro[3.4]octane- 6-yl)-1,2,4-triazin-6-yl)oxy)benzamide hydrochloride (compound 19) (100 mg, 0.18 mmol), 2-((tert-butyldimethylsilyl) (oxy)acetaldehyde (71 μL, 0.37 mmol) and AcOH (11 μL, 0 The reaction mixture was then stirred at RT for 24 hours. The mixture was poured into water, basified with an aqueous solution of K2CO3, and DCM was added. Separation, drying over MgSO4, filtering and evaporation to dryness gave the crude product (152 mg), which This was purified by silica gel chromatography (stationary phase: amorphous bare silica 4 g, Mobile phase: 0.5% NH4OH, 95% DCM, 5% MeOH). The fractions containing the product were Combine and concentrate to give the title intermediate (46 mg, 36% yield).

[0344] Preparation of compounds Preparation of Compound 61 tert-Butyl (4-(6-(6-(2-(ethyl(isopropyl)carbamoyl)- 4-Fluorophenoxy)-1,2,4-triazin-5-yl)-2,6-diazaspirillum (2)(3.4)octan-2-yl)-5-methylhexyl)carbamate [ka] 2-((5-(2,6-diazaspiro[3.4]octane-6)- -yl)-1,2,4-triazin-6-yl)oxy)-N-ethyl-5-fluoro- N-Isopropylbenzamide (Intermediate 3) (1.0 g, 2.4 mmol), tert- Butyl (5-methyl-4-oxohexyl)carbamate (Intermediate 1) (830 mg, 3 A mixture of ZnCl2 (660 mg, 4.84 mmol) and ZnCl2 (660 mg, 4.84 mmol) was heated at 80 °C. The mixture was stirred for 0.5 hours, followed by the addition of NaBH3CN (310 mg, 4.93 mmol). The resulting mixture was stirred at 80° C. for 6 h. After cooling to RT, the mixture was concentrated under reduced pressure. The crude product was purified by HPLC using a Waters Xbridge Prep OBD. Further purification was performed by preparative HPLC (column: C18 150 × 40 mm 10 μm; elution Solution: ACN / H2O (0.05% ammonia) 45% to 75% v / v), as a colorless oil The title compound was obtained (700 mg, 46% yield).

[0345] Preparation of Compounds 62 and 63 tert-Butyl (R)-(4-(6-(6-(2-(ethyl(isopropyl)carbamoyl) (yl)-4-fluorophenoxy)-1,2,4-triazin-5-yl)-2,6-di Azaspiro[3.4]octan-2-yl)-5-methylhexyl)carbamate tert-Butyl (S)-(4-(6-(6-(2-(ethyl(isopropyl)carbamoyl) (yl)-4-fluorophenoxy)-1,2,4-triazin-5-yl)-2,6-di Azaspiro[3.4]octan-2-yl)-5-methylhexyl)carbamate [ka] tert-Butyl(4-(6-(6-(2-(ethyl(isopropyl)carbamoyl) -4-fluorophenoxy)-1,2,4-triazin-5-yl)-2,6-diazas Pyro[3.4]octan-2-yl)-5-methylhexyl)carbamate (Compound 61 ) (200 mg, 0.319 mmol), DAICEL CHIRALPAK IG Purification was performed by SFC (column: 250 x 30 mm 10 μm; isocratic elution: Et OH (containing 0.1% of 25% ammonia):supercritical CO2, 40%:60% (v / v) ), both of which gave the title compound (Compound 62) (85 mg, 42% yield) as a pale yellow oil. (Compound 63) (80 mg, yield 40%) was obtained.

[0346] Compounds 207 and 208 tert-Butyl (R)-(5-(6-(6-(2-(ethyl(isopropyl)carbamoyl)carbamate) 4-fluorophenoxy-1,2,4-triazin-5-yl-2,6- Diazaspiro[3.4]octan-2-yl)-6-methylheptyl)carbamate tert-Butyl (S)-(5-(6-(6-(2-(ethyl(isopropyl)carbamoyl)carbamate) 4-fluorophenoxy-1,2,4-triazin-5-yl-2,6- Diazaspiro[3.4]octan-2-yl)-6-methylheptyl)carbamate [ka] tert-Butyl (5-(6-(6-(2-(ethyl(isopropyl)carbamoyl) -4-fluorophenoxy)-1,2,4-triazin-5-yl)-2,6-diazas pyro[3.4]octan-2-yl)-6-methylheptyl)carbamate (compound 20 6) (1.4g) by SFC through DAICEL CHIRALPAK IG Purified (column: 250 × 30 mm, 10 μm; mobile phase: A: supercritical CO2, B: MeO H (0.1% ammonia), A:B = 55:45 (200 mL / min), both white solids The title compound (compound 207) (700 mg) and (compound 208) (700 mg) ) was obtained.

[0347] Compounds 304 and 305 tert-Butyl ((4*R)-4-(6-(6-(2-(ethyl(isopropyl)carbamate) Bamoyl)-4-fluorophenoxy)-1,2,4-triazin-5-yl)-2,6 -diazaspiro[3.4]octan-2-yl)-2-methoxy-5-methylhexyl (Methyl)carbamate tert-Butyl ((4*S)-4-(6-(6-(2-(ethyl(isopropyl)carbamate) Bamoyl)-4-fluorophenoxy)-1,2,4-triazin-5-yl)-2,6 -diazaspiro[3.4]octan-2-yl)-2-methoxy-5-methylhexyl (Methyl)carbamate [ka] tert-Butyl(4-(6-(6-(2-(ethyl(isopropyl)carbamoyl) -4-fluorophenoxy)-1,2,4-triazin-5-yl)-2,6-diazas Pyrro[3.4]octan-2-yl)-2-methoxy-5-methylhexyl)(methyl Carbamate (compound 303) (250 mg) was added to DAICEL CHIRALPAK Separation was performed by SFC through IG (column: 250 × 30 mm, 10 μm; mobile phase: A :Supercritical CO2, B:MeOH (0.1% ammonia), A:B=60:40;Flow rate: 8 0 mL / min), and the title compound (Compound 304) (124 mg) was obtained as a colorless, viscous oil. ) and (Compound 305) (124 mg) were obtained.

[0348] Compounds 306 and 307 tert-Butyl ((2*R,4*R)-4-(6-(6-(2-(ethyl(isopropyl) (I)carbamoyl)-4-fluorophenoxy)-1,2,4-triazin-5-yl -2,6-diazaspiro[3.4]octan-2-yl)-2-methoxy-5-methyl Xyl)(methyl)carbamate tert-Butyl ((2S,4R)-4-(6-(6-(2-(ethyl(isopropyl) (I)carbamoyl)-4-fluorophenoxy)-1,2,4-triazin-5-yl -2,6-diazaspiro[3.4]octan-2-yl)-2-methoxy-5-methyl Xyl)(methyl)carbamate [ka] tert-Butyl ((4*R)-4-(6-(6-(2-(ethyl(isopropyl)carbonyl)carbonyl) Rubamoyl)-4-fluorophenoxy)-1,2,4-triazin-5-yl)-2, 6-diazaspiro[3.4]octan-2-yl)-2-methoxy-5-methylhexyl ) (methyl) carbamate (compound 304) (120 mg) was added to DAICEL CHIR Separation was performed by SFC using an ALPAK IG column (column: 250 × 30 mm, 10 μm Mobile phase: A: supercritical CO2, B: MeOH (0.1% ammonia), A:B = 70:3 0 (80 mL / min), both of which yielded the title compound (compound 306) (45 mg) and (Compound 307) (46 mg) were obtained.

[0349] Compounds 371 and 372 tert-Butyl ((2S,4S)-4-(6-(6-(2-(ethyl(isopropyl) (I)carbamoyl)-4-fluorophenoxy)-1,2,4-triazin-5-yl -2,6-diazaspiro[3.4]octan-2-yl)-2-methoxy-5-methyl Xyl)(methyl)carbamate tert-Butyl ((2*R,4*S)-4-(6-(6-(2-(ethyl(isopropyl) (I)carbamoyl)-4-fluorophenoxy)-1,2,4-triazin-5-yl -2,6-diazaspiro[3.4]octan-2-yl)-2-methoxy-5-methyl Xyl)(methyl)carbamate [ka] tert-Butyl ((4*S)-4-(6-(6-(2-(ethyl(isopropyl)carbonyl)carbonyl) Rubamoyl)-4-fluorophenoxy)-1,2,4-triazin-5-yl)-2, 6-diazaspiro[3.4]octan-2-yl)-2-methoxy-5-methylhexyl ) (methyl) carbamate (compound 305) (120 mg) was added to DAICEL CHIR Separation was performed by SFC using an ALPAK IG column (column: 250 × 30 mm, 10 μm Mobile phase: A: supercritical CO2, B: IPA (0.1% ammonia), A:B = 60:40 ; flow rate: 80 mL / min), both of which yielded the title compound (Compound 371) ( Compound 372 (46 mg) was obtained.

[0350] Compounds 404 and 405 tert-Butyl (R)-(4-(6-(3-chloro-6-(2-(ethyl)isopropyl (I)carbamoyl)-4-fluorophenoxy)-1,2,4-triazin-5-yl -2,6-diazaspiro[3.4]octan-2-yl)-5-methylhexyl)carba Mate tert-Butyl (S)-(4-(6-(3-chloro-6-(2-(ethyl)isopropyl (I)carbamoyl)-4-fluorophenoxy)-1,2,4-triazin-5-yl -2,6-diazaspiro[3.4]octan-2-yl)-5-methylhexyl)carba Mate [ka] tert-Butyl (4-(6-(3-chloro-6-(2-ethyl(isopropyl)carbonyl) Rubamoyl)-4-fluorophenoxy)-1,2,4-triazin-5-yl)-2, 6-diazaspiro[3.4]octan-2-yl)-5-methylhexyl)carbamate (Compound 403) (19.5 g) was passed through DAICEL CHIRALPAK IG Separation was performed by SFC (column: 250 × 30 mm, 10 μm; mobile phase: A: supercritical CO 2, B: MeOH (0.1% ammonia), A:B = 55:45 (80 mL / min); nozzle pressure: 100 bar; nozzle temperature: 60°C; evaporator temperature: 20°C; trimmer temperature: 25°C; wavelength: 220 nm), both of which were viscous oils. The mixture (compound 404) (8.00 g) and (compound 405) (7.00 g) were obtained.

[0351] compound 1 (R)-2-((5-(2-(6-amino-2-methylhexan-3-yl)-2,6- Diazaspiro[3.4]octan-6-yl)-1,2,4-triazin-6-yl)o (oxy)-N-ethyl-5-fluoro-N-isopropylbenzamide formate [ka] HCl / 1,4-dioxane (0.5 mL, 2.0 mmol) in 1,4-dioxane tert-Butyl (R)-(4-(6-(6-(2-ethyl)isopropyl) (I)carbamoyl)-4-fluorophenoxy)-1,2,4-triazin-5-yl -2,6-diazaspiro[3.4]octan-2-yl)-5-methylhexyl)carba The reaction mixture was added to a solution of mate (compound 62) (85 mg, 0.14 mmol). The mixture was stirred at RT for 4 h. The mixture was concentrated under reduced pressure and the residue was first dissolved in ammonia (5 mL). The mixture was neutralized and further purified by preparative HPLC using a Welch Xtimate C18. The column was purified using a 150 × 25 mm 5 μm column and an eluent of ACN / HO (0.225 %FA) 1% to 31% v / v), affording the title compound as a colorless oil (32 mg, yield 4 1%). 1 H NMR (400 MHz, methanol-d4): 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 measured value: 528.3 [M +H] + . SFC (Method 12):R t =1.151 minutes.

[0352] Preparation of Compound 60 tert-Butyl (4-(6-(6-(2-(ethyl(isopropyl)carbamoyl)- 4-Fluorophenoxy)-1,2,4-triazin-5-yl)-2,6-diazaspirillum (2-[3.4]octan-2-yl)-5-methylhexyl)(methyl)carbamate [ka] 2-((5-(2,6-diazaspiro[3.4]octane-6)- -yl)-1,2,4-triazin-6-yl)oxy)-N-ethyl-5-fluoro- N-isopropylbenzamide (Intermediate 3) (600 mg, 1.45 mmol) and te rt-Butyl methyl (5-methyl-4-oxohexyl)carbamate (Intermediate 9) (3 ZnCl2 (789 mg, 5.79 mmol) in a solution of ZnCl2 (30 mg, 1.37 mmol) The resulting mixture was stirred at 80 °C for 2 h. 9 mg, 11.6 mmol) was added and the reaction mixture was stirred at 80° C. overnight. After this, the mixture was concentrated under reduced pressure to give a crude residue, which was diluted with DCM (50 mL) and It was 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 solution was concentrated under reduced pressure to give the crude product, which was further purified by FCC (DCM / Me OH=10:1) to give the title compound as a white solid (400 mg, 42% yield).

[0353] Compounds 56 and 57 tert-Butyl (R)-(4-(6-(6-(2-(ethyl(isopropyl)carbamoyl) (yl)-4-fluorophenoxy)-1,2,4-triazin-5-yl)-2,6-di Azaspiro[3.4]octan-2-yl)-5-methylhexyl)(methyl)carbamate Route tert-Butyl (S)-(4-(6-(6-(2-(ethyl(isopropyl)carbamoyl) (yl)-4-fluorophenoxy)-1,2,4-triazin-5-yl)-2,6-di Azaspiro[3.4]octan-2-yl)-5-methylhexyl)(methyl)carbamate Route [ka] tert-Butyl(4-(6-(6-(2-(ethyl(isopropyl)carbamoyl) -4-fluorophenoxy)-1,2,4-triazin-5-yl)-2,6-diazas Pyro[3.4]octan-2-yl)-5-methylhexyl)(methyl)carbamate ( Compound 60) (419 mg, 0.653 mmol) was added to DAICEL CHIRALPA Purification was performed by SFC through KAD (column: 250 × 30 mm, 10 μm; mobile phase: A: Supercritical CO2, B: IPA (0.1% ammonia), A:B = 80:20 (60m L / min); column temperature: 38°C; nozzle pressure: 100 bar; nozzle temperature: 60°C; evaporation Temperature: 20°C; Temperature: 25°C; Wavelength: 220 nm) The title compound (Compound 56) (146 mg, 34% yield) and (Compound 57) (1 49 mg, 36% yield was obtained.

[0354] compound 19 (R)-N-ethyl-5-fluoro-N-isopropyl-2-((5-(2-(2-methyl) (6-(methylamino)hexan-3-yl)-2,6-diazaspiro[3.4]octanol Tan-6-yl)-1,2,4-triazin-6-yl)oxy)benzamide hydrochloride [ka] tert-Butyl (R)-(4-(6-(6-(2- (Ethyl(isopropyl)carbamoyl)-4-fluorophenoxy)-1,2,4-trimethyl (riazin-5-yl)-2,6-diazaspiro[3.4]octan-2-yl)-5-methyl (ethylhexyl)(methyl)carbamate (compound 56) (130 mg, 0.203 mmol) To the solution of (I), HCl / 1,4-dioxane (5 mL, 20.0 mmol) was added and the reaction The reaction mixture was stirred at RT for 1 h. The reaction mixture was concentrated in vacuo and the residue was purified by HPLC. The mixture was purified by preparative HPLC through the nex Gemini-NX (column: 150× 30mm 5μm, mobile phase A: water (0.05%HCl), mobile phase B: ACN, flow rate: 25 mL / min, gradient condition B / A 0%B to 26% (0%B to 26%B), standard as colorless oil The title compound was obtained (105 mg, 84% yield). LC-MS(ESI)(Method 1):R t = 2.939 min, m / z measured value: 542.4 [M +H] + . SFC (Method 1):R t =1.201 minutes.

[0355] Compound 398 (R)-N-ethyl-5-fluoro-N-isopropyl-2-((5-(2-(2-methyl) (6-(methylamino)hexan-3-yl)-2,6-diazaspiro[3.4]octanol Tan-6-yl)-1,2,4-triazin-6-yl)oxy)benzamide [ka] At 5 °C, TFA (0.51 mL, 6.7 mmol) was dissolved in tert-butyl ether (DCM) (7.5 mL). t-Butyl (R)-(4-(6-(6-(2-(ethyl(isopropyl)carbamoyl) -4-fluorophenoxy)-1,2,4-triazin-5-yl)-2,6-diazas Pyro[3.4]octan-2-yl)-5-methylhexyl)(methyl)carbamate ( The mixture was added dropwise to a solution of compound 56) (287 mg, 0.45 mmol), 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. The mixture was purified by chromatography (stationary phase: amorphous bare silica 12 g, mobile phase: 95% DCM, 5% MeOH (+10% NH4OH) to 90% DCM, 10% MeOH (+1 The pure fractions were combined and concentrated to give a 173 mg intermediate fraction. This was freeze-dried with ACN / HO (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 measured value: 542.6 [M+ H] + .

[0356] compound 51 tert-Butyl (3-(6-(6-(2-(ethyl(isopropyl)carbamoyl)- 4-Fluorophenoxy)-1,2,4-triazin-5-yl)-2,6-diazaspirillum (3,4)octan-2-yl)-4-methylpentyl)carbamate [ka] N-ethyl-5-fluoro-2-((5-hydroxy-1,2, 4-triazin-6-yl)oxy)-N-isopropylbenzamide (Intermediate 25) ( A solution of oxalyl chloride (0.079 g, 0.6 24 mmol), followed by DMF (0.046 g, 0.624 mmol) was added at RT. The mixture was stirred at this temperature for 1 hour. Then, the mixture was dissolved in tert- Butyl(4-methyl-3-(2,6-diazaspiro[3.4]octan-2-yl)pentan (ethyl)carbamate hydrochloride (Intermediate 22) (0.272 g, crude) and TEA (0.15 The resulting mixture was stirred at 25°C for 0.5 hours. The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in DCM (35 mL) and H2O (35 mL). The mixture was partitioned into 100 ml of ethyl acetate and extracted with DCM (35 mL x 3). The combined organic layer was dried over Na2SO4. The residue was purified by FCC (PE / EtOAc (0.5% ammonium hydroxide)). The title compound was obtained as a colorless oil (100 mg, purity 89%, yield 46%).

[0357] Compounds 52 and 53 tert-Butyl(*R)-(5-(6-(6-(2-(4-cyclopropylpyrimidine -5-yl)-4-fluorophenoxy)-1,2,4-triazin-5-yl)-2, 6-diazaspiro[3.4]octan-2-yl)-2,6-dimethylheptan-2-yl (I) carbamate tert-Butyl(*S)-(5-(6-(6-(2-(4-cyclopropylpyrimidine) -5-yl)-4-fluorophenoxy)-1,2,4-triazin-5-yl)-2, 6-diazaspiro[3.4]octan-2-yl)-2,6-dimethylheptan-2-yl (I) carbamate [ka] tert-Butyl (5-(6-(6-(2-(4-cyclopropylpyrimidin-5-yl) (4-fluorophenoxy)-1,2,4-triazin-5-yl)-2,6-diazonium Zaspiro[3.4]octan-2-yl)-2,6-dimethylheptan-2-yl)carbohydrate Bamate (compound 58) (150 mg, 0.227 mmol) was dissolved in DAICEL CHI The purified product was subjected to SFC through a RALPAK AD-H column (column: 250 x 30 mm, 5 μm; Mobile phase: A: supercritical CO2, B: IPA (0.1% ammonia), A:B = 4:1 (60 mL / min)), and the title compound, Compound 52 (47 mg), both as white solids. , purity 96.3%, yield 30.2%) and compound 53 (56 mg, purity 97.7%, yield 36.5%).

[0358] Compounds 54 and 55 tert-Butyl (R)-(5-(6-(6-(2-(ethyl(isopropyl)carbamoyl)carbamate) 4-fluorophenoxy-1,2,4-triazin-5-yl-2,6- Diazaspiro[3.4]octan-2-yl)-2,6-dimethylheptan-2-yl Carbamates tert-Butyl (S)-(5-(6-(6-(2-(ethyl(isopropyl)carbamoyl)carbamate) 4-fluorophenoxy-1,2,4-triazin-5-yl-2,6- Diazaspiro[3.4]octan-2-yl)-2,6-dimethylheptan-2-yl Carbamates [ka] tert-Butyl (5-(6-(6-(2-(ethyl(isopropyl)carbamoyl) -4-fluorophenoxy)-1,2,4-triazin-5-yl)-2,6-diazas Pyro[3.4]octan-2-yl)-2,6-dimethylheptan-2-yl)carbamate Compound 59 (1.70 g, 2.59 mmol) was added to DAICEL CHIRAL Separation was performed by SFC through PAK IG (column: 250 x 50 mm, 10 μm) Mobile phase: A: supercritical CO2, B: EtOH (0.1% ammonia), A:B = 3:2 ( 150 mL / min), and the title compound, Compound 54 (700 mL), was obtained as a white solid. g, purity 90%, yield 37%) and compound 55 (700 mg, purity 96%, yield 40%) obtained.

[0359] Compound 408 tert-Butyl (R)-(4-(6-(6-(2-(ethyl(isopropyl)carbamoyl) (yl)-4-fluorophenoxy)-3-(methylamino)-1,2,4-triazine- 5-yl)-2,6-diazaspiro[3.4]octan-2-yl)-5-methylhexyl (I) carbamate The following compounds were synthesized by methods similar to those described above for compound 395.

[0360] [Table 31]

[0361] compound 412 tert-Butyl (R)-(4-(6-(6-(2-(ethyl(isopropyl)carbamoyl) (yl)-4-fluorophenoxy)-3-methyl-1,2,4-triazin-5-yl -2,6-diazaspiro[3.4]octan-2-yl)-5-methylhexyl)carba Mate [ka] tert-Butyl (R)-(4-(6-(3-chloro-6-methyl-2 ... -(2-(ethyl(isopropyl)carbamoyl)-4-fluorophenoxy)-1,2 ,4-triazin-5-yl)-2,6-diazaspiro[3.4]octan-2-yl) -5-methylhexyl)carbamate (compound 404) (50.0 mg, 0.076 mm ol), 2,4,6-trimethyl-1,3,5,2,4,6-trioxatriborinane ( 76.0 mg, 0.303 mmol, 50% in THF) and K2CO3 (21.0 mg, 0.152 mmol) was added to a mixture of Pd(PPh3)4 (8.7 mg, 0.008 mmol). l) was added and the resulting mixture was stirred at 110 °C under N atmosphere for 8 h. Cool to RT After that, the mixture was diluted with H2O (40 mL) and extracted with EtOAc (20 mL × 3). The combined organic layers were dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated under reduced pressure to give a crude product. The product was obtained, which was purified by preparative TLC (DCM / MeOH=10 / 1) to give a yellow The title compound was obtained as a solid (30.0 mg, 59.7% yield).

[0362] Compounds 2, 3, 20, 30, 31, 37, 38, 26, 80, 209, 210, 218, 220, 221, 308, 309, 317, 328, 359, 373, 374, 409, 413 (S)-2-((5-(2-(6-amino-2-methylhexan-3-yl)-2,6- Diazaspiro[3.4]octan-6-yl)-1,2,4-triazin-6-yl)o (oxy)-N-ethyl-5-fluoro-N-isopropylbenzamide formate 2-((5-(2-(6-amino-2-methylhexan-3-yl)-2,6-diazonium Pyrro[3.4]octan-6-yl)-1,2,4-triazin-6-yl)oxy)- N-Ethyl-5-fluoro-N-isopropylbenzamide formate (S)-N-ethyl-5-fluoro-N-isopropyl-2-((5-(2-(2-methyl) (6-(methylamino)hexan-3-yl)-2,6-diazaspiro[3.4]octanol Tan-6-yl)-1,2,4-triazin-6-yl)oxy)benzamide hydrochloride (*R)-2-((5-(2-(6-amino-2,6-dimethylheptan-3-yl)- 2,6-Diazaspiro[3.4]octan-6-yl)-1,2,4-triazine-6- (yl)oxy)-N-ethyl-5-fluoro-N-isopropylbenzamide (*S)-2-((5-(2-(6-amino-2,6-dimethylheptan-3-yl)- 2,6-Diazaspiro[3.4]octan-6-yl)-1,2,4-triazine-6- (yl)oxy)-N-ethyl-5-fluoro-N-isopropylbenzamide (*R)-5-(6-(6-(2-(4-cyclopropylpyrimidin-5-yl)-4- Fluorophenoxy)-1,2,4-triazin-5-yl)-2,6-diazaspiro[ 3.4]Octan-2-yl)-2,6-dimethylheptan-2-amine (*S)-5-(6-(6-(2-(4-cyclopropylpyrimidin-5-yl)-4- Fluorophenoxy)-1,2,4-triazin-5-yl)-2,6-diazaspiro[ 3.4]Octan-2-yl)-2,6-dimethylheptan-2-amine 2-((5-(2-(1-amino-4-methylpentan-3-yl)-2,6-diazas Pyrro[3.4]octan-6-yl)-1,2,4-triazin-6-yl)oxy)- N-ethyl-5-fluoro-N-isopropylbenzamide N-ethyl-5-fluoro-N-isopropyl-2-((4-(2-(2-methyl-6- (Methylamino)hexan-3-yl)-2,6-diazaspiro[3.4]octane-6 -yl)pyridazin-3-yl)oxy)benzamide (*R)-2-((5-(2-(7-amino-2-methylheptan-3-yl)-2,6 -diazaspiro[3.4]octan-6-yl)-1,2,4-triazin-6-yl) (oxy)-N-ethyl-5-fluoro-N-isopropylbenzamide formate (*S)-2-((5-(2-(7-amino-2-methylheptan-3-yl)-2,6 -diazaspiro[3.4]octan-6-yl)-1,2,4-triazin-6-yl) (oxy)-N-ethyl-5-fluoro-N-isopropylbenzamide (*R)-2-((5-(2-(1-amino-4-methylpentan-3-yl)-2,6 -diazaspiro[3.4]octan-6-yl)-1,2,4-triazin-6-yl) (oxy)-N-ethyl-5-fluoro-N-isopropylbenzamide (*R)-2-((5-(2-(1-amino-4-methylpentan-3-yl)-2,6 -diazaspiro[3.4]octan-6-yl)-1,2,4-triazin-6-yl) (oxy)-N-ethyl-5-fluoro-N-isopropylbenzamide hydrochloride (*S)-2-((5-(2-(1-amino-4-methylpentan-3-yl)-2,6 -diazaspiro[3.4]octan-6-yl)-1,2,4-triazin-6-yl) (oxy)-N-ethyl-5-fluoro-N-isopropylbenzamide hydrochloride N-ethyl-5-fluoro-N-isopropyl-2-((5-(2-((3*R,5*R )-5-Methoxy-2-methyl-6-(methylamino)hexan-3-yl)-2,6- Diazaspiro[3.4]octan-6-yl)-1,2,4-triazin-6-yl)o (xy)benzamide hydrochloride N-ethyl-5-fluoro-N-isopropyl-2-((5-(2-((3*R,5*S )-5-Methoxy-2-methyl-6-(methylamino)hexan-3-yl)-2,6- Diazaspiro[3.4]octan-6-yl)-1,2,4-triazin-6-yl)o (xy)benzamide hydrochloride N-ethyl-5-fluoro-2-((5-(2-(5-hydroxy-2-methyl-6-( Methylamino)hexan-3-yl)-2,6-diazaspiro[3.4]octane-6- (yl)-1,2,4-triazin-6-yl)oxy)-N-isopropylbenzamide Hydrochloride N-ethyl-2-((5-(2-(6-(ethylamino)-5-hydroxy-2-methyl Hexan-3-yl)-2,6-diazaspiro[3.4]octan-6-yl)-1,2 ,4-triazin-6-yl)oxy)-5-fluoro-N-isopropylbenzamide Hydrochloride 5-Fluoro-2-((5-(2-(5-hydroxy-2-methyl-6-(methylamino) )hexan-3-yl)-2,6-diazaspiro[3.4]octan-6-yl)-1, 2,4-Triazin-6-yl)oxy)-N,N-diisopropylbenzamide hydrochloride N-ethyl-5-fluoro-N-isopropyl-2-((5-(2-((3*S,5*S )-5-Methoxy-2-methyl-6-(methylamino)hexan-3-yl)-2,6- Diazaspiro[3.4]octan-6-yl)-1,2,4-triazin-6-yl)o (xy)benzamide hydrochloride N-ethyl-5-fluoro-N-isopropyl-2-((5-(2-((3S,5R )-5-Methoxy-2-methyl-6-(methylamino)hexan-3-yl)-2,6- Diazaspiro[3.4]octan-6-yl)-1,2,4-triazin-6-yl)o (xy)benzamide hydrochloride (R)-2-((5-(2-(6-amino-2-methylhexan-3-yl)-2,6- Diazaspiro[3.4]octan-6-yl)-3-(methylamino)-1,2,4-trimethyl- Triazin-6-yl)oxy)-N-ethyl-5-fluoro-N-isopropylbenzaldehyde Mido Hydrochloride (R)-2-((5-(2-(6-amino-2-methylhexan-3-yl)-2,6- Diazaspiro[3.4]octan-6-yl)-3-methyl-1,2,4-triazine- 6-yl)oxy)-N-ethyl-5-fluoro-N-isopropylbenzamide formate The following compounds were synthesized by methods similar to those described above for compounds 1 and 19.

[0363] [Table 32]

[0364] [Table 33]

[0365] [Table 34]

[0366] [Table 35]

[0367] [Table 36]

[0368] [Table 37]

[0369] [Table 38]

[0370] compound 4 (R)-2-((5-(2-(6-(dimethylamino)-2-methylhexan-3-yl )-2,6-diazaspiro[3.4]octan-6-yl)-1,2,4-triazine- 6-yl)oxy)-N-ethyl-5-fluoro-N-isopropylbenzamide [ka] (R)-2-((5-(2-(6-amino-2-methylhexyl)methyl)-2-methyl-1,3-dimethyl-2-propanol in MeOH (10 mL) (3-octan-yl)-2,6-diazaspiro[3.4]octan-6-yl)-1,2,4- Triazin-6-yl)oxy)-N-ethyl-5-fluoro-N-isopropylbenz Amide hydrochloride (compound 65) (180 mg, crude), formaldehyde (0.085 mL To a mixture of N aBHCN (72.0 mg, 1.14 mmol) was added and the resulting mixture was stirred at RT for 2 The mixture was filtered and the filtrate was purified by preparative HPLC on a Welch Xtimate. Purification was performed by C (column: C18 150 × 30 mm 5 μm; eluent: ACN / H2 0 (0.225% FA) 5% to 25%, v / v), and the desired fractions were collected and lyophilized. The resulting solid was further neutralized with 25% ammonia (15 mL) and extracted with DCM. (20 mL × 2). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. Concentration gave a residue which was further dissolved in ACN / water and lyophilized to give the title compound as a yellow solid. The compound was obtained (37.65 mg). LC-MS(ESI)(Method 1):R t = 2.95 min, m / z measured value 556.3 [M+H ] + . SFC (Method 4):R t =1.772 minutes.

[0371] Compounds 5, 32, 33, 74, 81, 101, 211, 212, 222, 224, 231 , 410 (S)-2-((5-(2-(6-(dimethylamino)-2-methylhexan-3-yl )-2,6-diazaspiro[3.4]octan-6-yl)-1,2,4-triazine- 6-yl)oxy)-N-ethyl-5-fluoro-N-isopropylbenzamide formate (*R)-2-((5-(2-(6-(dimethylamino)-2,6-dimethylheptane- 3-yl)-2,6-diazaspiro[3.4]octan-6-yl)-1,2,4-tri Azin-6-yl)oxy)-N-ethyl-5-fluoro-N-isopropylbenzamide Do (*S)-2-((5-(2-(6-(dimethylamino)-2,6-dimethylheptane- 3-yl)-2,6-diazaspiro[3.4]octan-6-yl)-1,2,4-tri Azin-6-yl)oxy)-N-ethyl-5-fluoro-N-isopropylbenzamide Do 2-((4-(2-(6-(dimethylamino)-2-methylhexan-3-yl)-2, 6-diazaspiro[3.4]octan-6-yl)pyridazin-3-yl)oxy)-5 -Fluoro-N,N-diisopropylbenzamide 2-((4-(2-(6-(dimethylamino)-2-methylhexan-3-yl)-2, 6-Diazaspiro[3.4]octan-6-yl)pyridazin-3-yl)oxy)-N -Ethyl-5-fluoro-N-isopropylbenzamide 2-((5-(2-(6-(dimethylamino)-2-methylhexan-3-yl)-2, 6-diazaspiro[3.4]octan-6-yl)-1,2,4-triazin-6-yl )Oxy)-5-fluoro-N,N-diisopropylbenzamide (*R)-2-((5-(2-(7-(dimethylamino)-2-methylheptan-3-yl) (2,6-diazaspiro[3.4]octan-6-yl)-1,2,4-triazine -6-yl)oxy)-N-ethyl-5-fluoro-N-isopropylbenzamide (*S)-2-((5-(2-(7-(dimethylamino)-2-methylheptan-3-yl) (2,6-diazaspiro[3.4]octan-6-yl)-1,2,4-triazine -6-yl)oxy)-N-ethyl-5-fluoro-N-isopropylbenzamide (*R)-2-((5-(2-(1-(dimethylamino)-4-methylpentane-3-yl) (2,6-diazaspiro[3.4]octan-6-yl)-1,2,4-triazine -6-yl)oxy)-N-ethyl-5-fluoro-N-isopropylbenzamide (*S)-2-((5-(2-(1-(dimethylamino)-4-methylpentane-3-yl) (2,6-diazaspiro[3.4]octan-6-yl)-1,2,4-triazine -6-yl)oxy)-N-ethyl-5-fluoro-N-isopropylbenzamide (*R)-2-((5-(2-(1-((2-amino-2-oxoethyl)(methyl)amino) (amino)-4-methylpentan-3-yl)-2,6-diazaspiro[3.4]octane- 6-yl)-1,2,4-triazin-6-yl)oxy)-N-ethyl-5-fluoro -N-Isopropylbenzamide (R)-2-((5-(2-(6-(dimethylamino)-2-methylhexan-3-yl )-2,6-diazaspiro[3.4]octan-6-yl)-3-methoxy-1,2,4 -triazin-6-yl)oxy)-N-ethyl-5-fluoro-N-isopropylbenzol azamidoformate The following compounds were synthesized by a method similar to that described above for compound 4.

[0372] [Table 39]

[0373] [Table 40]

[0374] [Table 41]

[0375] [Table 42]

[0376] Compounds 75, 76 (*R)-2-((4-(2-(6-(dimethylamino)-2-methylhexane-3-yl) (2,6-diazaspiro[3.4]octan-6-yl)pyridazin-3-yl)o (xy)-5-fluoro-N,N-diisopropylbenzamide (*S)-2-((4-(2-(6-(dimethylamino)-2-methylhexane-3-yl) (2,6-diazaspiro[3.4]octan-6-yl)pyridazin-3-yl)o (xy)-5-fluoro-N,N-diisopropylbenzamide [ka] 2-((4-(2-(6-(dimethylamino)-2-methylhexan-3-yl)-2 ,6-diazaspiro[3.4]octan-6-yl)pyridazin-3-yl)oxy)- 5-Fluoro-N,N-diisopropylbenzamide (compound 74) (600 mg), Separation was performed by chiral HPLC on DAICEL CHIRALPAK IG (color Column: 250 x 30 mm, 10 μm; Mobile phase: A: heptane, B: EtOH, A:B 20 % to 70% (v / v); flow rate: 25 mL / min), the title compound was obtained as a white solid. Compound 75 (92 mg, 15%) and compound 76 (84 mg) were obtained.

[0377] compound 75 LC-MS(ESI)(Method 2):R t = 1.915 min, m / z measured value 569.3 [M +H] + . Chiral HPLC (Method 4): t =4.842 minutes.

[0378] compound 76 LC-MS(ESI)(Method 2):R t = 1.924 min, m / z measured value 569.3 [M +H] + . Chiral HPLC (Method 4): t =6.200 minutes.

[0379] Compounds 77, 78 (*R)-2-((4-(2-(6-(dimethylamino)-2-methylhexane-3-yl) (2,6-diazaspiro[3.4]octan-6-yl)pyridazin-3-yl)o (xy)-N-ethyl-5-fluoro-N-isopropylbenzamide (*S)-2-((4-(2-(6-(dimethylamino)-2-methylhexane-3-yl) (2,6-diazaspiro[3.4]octan-6-yl)pyridazin-3-yl)o (xy)-N-ethyl-5-fluoro-N-isopropylbenzamide [ka] 2-((4-(2-(6-(dimethylamino)-2-methylhexan-3-yl)-2 ,6-diazaspiro[3.4]octan-6-yl)pyridazin-3-yl)oxy)- N-ethyl-5-fluoro-N-isopropylbenzamide (compound 81) (31.0 m g) was separated by SFC through DAICEL CHIRALPAK IE (collection Column: 250 × 30 mm, 10 μm; Eluent: 100% MeOH (0.1% ammonia); Flow rate: 25 mL / min), the title compound Compound 77 (4.2 mg) and Compound 78 (1.3 mg) was obtained.

[0380] compound 77 LC-MS(ESI)(Method 3):R t = 5.039 min, m / z measured value 555.3 [M +H] + . Chiral HPLC (Method 2): R t =7.719 minutes.

[0381] compound 78 LC-MS(ESI)(Method 3):R t = 4.870 min, m / z measured value 555.3 [M +H] + . Chiral HPLC (Method 2): Rt =8.754 minutes.

[0382] Compounds 105, 106 (*R)-2-((5-(2-(6-(dimethylamino)-2-methylhexane-3-yl) (2,6-diazaspiro[3.4]octan-6-yl)-1,2,4-triazine -6-yl)oxy)-5-fluoro-N,N-diisopropylbenzamide (*S)-2-((5-(2-(6-(dimethylamino)-2-methylhexane-3-yl) (2,6-diazaspiro[3.4]octan-6-yl)-1,2,4-triazine -6-yl)oxy)-5-fluoro-N,N-diisopropylbenzamide [ka] 2-((5-(2-(6-(dimethylamino)-2-methylhexan-3-yl)-2 ,6-diazaspiro[3.4]octan-6-yl)-1,2,4-triazine-6-yl (N,N-diisopropyl)-5-fluoro-N,N-diisopropylbenzamide (compound 101) 1.5g) was obtained by SFC through DAICEL CHIRALPAK IG (Column: 250×50mm 10μm; Mobile phase: A: supercritical CO2, B: MeOH(0 0.1% ammonia), A:B = 55:45 (200 mL / min); column temperature: 38°C; Pressure: 100 bar; Nozzle temperature: 60; Evaporator temperature: 20; Trimmer temperature: 2 5; wavelength: 220 nm), the title compound Compound 105 (600 mg) was obtained as a white solid. , yield 40.0%) and Compound 106 (600 mg, yield 40.0%) were obtained.

[0383] Compound 102 (*R)-2-((5-(2-(6-(dimethylamino)-2-methylhexane-3-yl) (2,6-diazaspiro[3.4]octan-6-yl)-1,2,4-triazine -6-yl)oxy)-5-fluoro-N,N-diisopropylbenzamide fumarate [ka] (*R)-2-((5-(2-(6-(dimethylamino)methyl)methyl)-2-(((5-(2-(6- ...methyl)methyl)methyl)methyl)methyl)methyl)methyl)methyl)methyl)methyl)methyl)methyl)methyl)methyl)methyl)methyl)methyl)methyl (amino)-2-methylhexan-3-yl)-2,6-diazaspiro[3.4]octa N,N-6-yl)-1,2,4-triazin-6-yl)oxy)-5-fluoro-N,N -diisopropylbenzamide (compound 105) (300 mg, 0.527 mmol) To the solution was added fumaric acid (123 mg, 1.06 mmol). A clear solution was formed. Once the mixture was evaporated, the resulting residue was dissolved in ACN (3 mL) and water (10 mL). The mixture was lyophilized to give the title compound (422 mg) as a white solid. Got it. 1 H NMR (400 MHz, methanol-d4): δ = 8.50 (s, 1H), 7.5 0-7.15(m,3H),6.72(s,4H),4.51-3.89(m,7H), 3.86-3.69(m,2H),3.61-3.49(m,1H),3.25-3.0 7(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,2 H),1.51(d,J=6.8Hz,3H),1.37-1.14(m,6H),1. 11-0.97(m,6H),0.78(d,J=6.0Hz,3H). LC-MS(ESI)(Method 2):R t = 2.08 min, m / z measured value 570.3 [M+H ] + . SFC (Method 4): Rt=1.284 minutes.

[0384] Compounds 103, 112, 114, 122, 123, 127, 128, 132, 133, 1 35, 137, 140, 142, 145, 146, 148, 150, 152, 154, 1 57, 159, 161, 165, 167, 170, 172, 176, 177, 179, 1 81, 184, 185, 188, 189, 191, 193, 195, 197, 199, 2 01, 203, 205, 219, 223, 225, 227, 233, 240, 241, 2 42, 243, 245, 256, 265, 266, 268, 270, 278, 280, 2 83, 259, 104, 229, 300, 302, 314, 315, 323, 324, 3 25, 326, 334, 335, 336, 337, 342, 343, 346, 352, 3 53, 356, 357, 365, 366, 369, 370, 377, 378, 382, ​​3 86, 387, 391, 392, 394, 397 (*S)-2-((5-(2-(6-(dimethylamino)-2-methylhexane-3-yl) (2,6-diazaspiro[3.4]octan-6-yl)-1,2,4-triazine -6-yl)oxy)-5-fluoro-N,N-diisopropylbenzamide fumarate N-ethyl-5-fluoro-N-isopropyl-2-((5-(2-((R)-6-(( (R)-1-Methoxypropan-2-yl)amino)-2-methylhexan-3-yl) -2,6-diazaspiro[3.4]octan-6-yl)-1,2,4-triazine-6 -yl)oxy)benzamide fumarate (R)-2-((5-(2-(6-((3,3-difluoropropyl)amino)-2-methyl (ethylhexan-3-yl)-2,6-diazaspiro[3.4]octan-6-yl)-1 ,2,4-triazin-6-yl)oxy)-N-ethyl-5-fluoro-N-isopropyl Pyrbenzamide fumarate (*R)-N-ethyl-5-fluoro-N-isopropyl-2-((5-(2-(6-( Isopropyl(methyl)amino)-2-methylhexan-3-yl)-2,6-diaza Pyro[3.4]octan-6-yl)-1,2,4-triazin-6-yl)oxy)benzyl nzamide fumarate (*S)-N-ethyl-5-fluoro-N-isopropyl-2-((5-(2-(6-( Isopropyl(methyl)amino)-2-methylhexan-3-yl)-2,6-diaza Pyro[3.4]octan-6-yl)-1,2,4-triazin-6-yl)oxy)benzyl nzamide fumarate (*R)-N-ethyl-5-fluoro-N-isopropyl-2-((5-(2-(2-methyl) ethyl-6-(methyl(propyl)amino)hexan-3-yl)-2,6-diazaspiro [3.4]Octan-6-yl)-1,2,4-triazin-6-yl)oxy)benz Amido fumarate (*S)-N-ethyl-5-fluoro-N-isopropyl-2-((5-(2-(2-methyl) ethyl-6-(methyl(propyl)amino)hexan-3-yl)-2,6-diazaspiro [3.4]Octan-6-yl)-1,2,4-triazin-6-yl)oxy)benz Amido fumarate (*R)-N-ethyl-2-((5-(2-(6-(ethyl(methyl)amino)-2-methyl)amino)- (ethylhexan-3-yl)-2,6-diazaspiro[3.4]octan-6-yl)-1 ,2,4-triazin-6-yl)oxy)-5-fluoro-N-isopropylbenzaldehyde Midofumarate (*S)-N-ethyl-2-((5-(2-(6-(ethyl(methyl)amino)-2-methyl)amino)- (ethylhexan-3-yl)-2,6-diazaspiro[3.4]octan-6-yl)-1 ,2,4-triazin-6-yl)oxy)-5-fluoro-N-isopropylbenzaldehyde Midofumarate (R)-N-ethyl-5-fluoro-N-isopropyl-2-((5-(2-(6-(( 2-Methoxy-2-methylpropyl)amino)-2-methylhexan-3-yl)-2, 6-diazaspiro[3.4]octan-6-yl)-1,2,4-triazin-6-yl )Oxy)benzamide fumarate (R)-N-ethyl-5-fluoro-N-isopropyl-2-((5-(2-(6-(( 2-Methoxy-2-methylpropyl)(methyl)amino)-2-methylhexane-3-yl (2,6-diazaspiro[3.4]octan-6-yl)-1,2,4-triazine -6-yl)oxy)benzamide fumarate (R)-N-ethyl-5-fluoro-2-((5-(2-(6-((2-hydroxy-2 -methylpropyl)(methyl)amino)-2-methylhexan-3-yl)-2,6-di Azaspiro[3.4]octan-6-yl)-1,2,4-triazin-6-yl)oxazin β)-N-Isopropylbenzamide fumarate (R)-N-ethyl-5-fluoro-N-isopropyl-2-((5-(2-(6-(( 3-Methoxypropyl)(methyl)amino)-2-methylhexan-3-yl)-2,6 -diazaspiro[3.4]octan-6-yl)-1,2,4-triazin-6-yl) Oxy)benzamide fumarate (*R)-2-((5-(2-(6-((3-(dimethylamino)-3-oxopropyl )(methyl)amino)-2-methylhexan-3-yl)-2,6-diazaspiro[3. 4]octan-6-yl)-1,2,4-triazin-6-yl)oxy)-5-fluoro rho-N,N-diisopropylbenzamide fumarate (*S)-2-((5-(2-(6-((3-(dimethylamino)-3-oxopropyl )(methyl)amino)-2-methylhexan-3-yl)-2,6-diazaspiro[3. 4]octan-6-yl)-1,2,4-triazin-6-yl)oxy)-5-fluoro rho-N,N-diisopropylbenzamide fumarate (R)-N-ethyl-5-fluoro-N-isopropyl-2-((5-(2-(2-methyl) 6-(methyl(2-(N-methylacetamido)ethyl)amino)hexane-3-yl (2,6-diazaspiro[3.4]octan-6-yl)-1,2,4-triazine -6-yl)oxy)benzamide fumarate (R)-2-((5-(2-(6-((2,2-dimethoxyethyl)(methyl)amino) -2-methylhexan-3-yl)-2,6-diazaspiro[3.4]octan-6-yl (1,2,4-triazin-6-yl)oxy)-N-ethyl-5-fluoro-N- Isopropylbenzamide fumarate (R)-2-((5-(2-(6-((4-(dimethylamino)-4-oxobutyl)( Methyl)amino)-2-methylhexan-3-yl)-2,6-diazaspiro[3.4] Octan-6-yl)-1,2,4-triazin-6-yl)oxy)-N-ethyl-5 -Fluoro-N-isopropylbenzamide fumarate N-ethyl-5-fluoro-N-isopropyl-2-((5-(2-((R)-6-(( (R)-1-Methoxypropan-2-yl)(methyl)amino)-2-methylhexane- 3-yl)-2,6-diazaspiro[3.4]octan-6-yl)-1,2,4-tri Azin-6-yl)oxy)benzamide fumarate N-ethyl-5-fluoro-N-isopropyl-2-((5-(2-((R)-6-(( (S)-1-Methoxypropan-2-yl)(methyl)amino)-2-methylhexane- 3-yl)-2,6-diazaspiro[3.4]octan-6-yl)-1,2,4-tri Azin-6-yl)oxy)benzamide fumarate (R)-2-((5-(2-(6-((1,3-dimethoxypropan-2-yl)amino )-2-Methylhexan-3-yl)-2,6-diazaspiro[3.4]octane-6- (yl)-1,2,4-triazin-6-yl)oxy)-N-ethyl-5-fluoro-N -Isopropylbenzamide fumarate (R)-2-((5-(2-(6-((1,3-dimethoxypropan-2-yl)(methyl (amino)-2-methylhexan-3-yl)-2,6-diazaspiro[3.4]octyl Tan-6-yl)-1,2,4-triazin-6-yl)oxy)-N-ethyl-5-furan Fluoro-N-isopropylbenzamide fumarate N-ethyl-5-fluoro-2-((5-(2-((R)-6-(((R)-1-hydro (3-methoxypropan-2-yl)(methyl)amino)-2-methylhexane-3 -yl)-2,6-diazaspiro[3.4]octan-6-yl)-1,2,4-triazamispiro[3.4]octan-6-yl Zin-6-yl)oxy)-N-isopropylbenzamide fumarate N-ethyl-5-fluoro-2-((5-(2-((R)-6-(((S)-1-hydro (3-methoxypropan-2-yl)(methyl)amino)-2-methylhexane-3 -yl)-2,6-diazaspiro[3.4]octan-6-yl)-1,2,4-triazamispiro[3.4]octan-6-yl Zin-6-yl)oxy)-N-isopropylbenzamide fumarate N-ethyl-5-fluoro-2-((5-(2-((3R)-6-((3-hydroxy- 2-Methoxypropyl)(methyl)amino)-2-methylhexan-3-yl)-2,6 -diazaspiro[3.4]octan-6-yl)-1,2,4-triazin-6-yl) (oxy)-N-isopropylbenzamide fumarate 2-((5-(2-((3R)-6-((2,3-dimethoxypropyl)amino)-2- Methylhexan-3-yl)-2,6-diazaspiro[3.4]octan-6-yl)- 1,2,4-triazin-6-yl)oxy)-N-ethyl-5-fluoro-N-isopropyl propyl benzamide fumarate 2-((5-(2-((R)-6-(((*R)-2,3-dimethoxypropyl)(methyl (amino)-2-methylhexan-3-yl)-2,6-diazaspiro[3.4]octyl Tan-6-yl)-1,2,4-triazin-6-yl)oxy)-N-ethyl-5-furan Fluoro-N-isopropylbenzamide fumarate 2-((5-(2-((R)-6-(((*S)-2,3-dimethoxypropyl)(methyl (amino)-2-methylhexan-3-yl)-2,6-diazaspiro[3.4]octyl Tan-6-yl)-1,2,4-triazin-6-yl)oxy)-N-ethyl-5-furan Fluoro-N-isopropylbenzamide fumarate 2-((5-(2-((3R)-6-((4-(dimethylamino)-4-oxobutane- 2-yl)(methyl)amino)-2-methylhexan-3-yl)-2,6-diazaspirillum (3,4)octan-6-yl)-1,2,4-triazin-6-yl)oxy)-N -Ethyl-5-fluoro-N-isopropylbenzamide fumarate 2-((5-(2-((3R)-6-((3-(dimethylamino)-2-methyl-3-o (xopropyl)(methyl)amino)-2-methylhexan-3-yl)-2,6-diaza spiro[3.4]octan-6-yl)-1,2,4-triazin-6-yl)oxy -N-Ethyl-5-fluoro-N-isopropylbenzamide fumarate 2-((5-(2-((R)-6-(((*R)-4-(dimethylamino)-4-oxo (butan-2-yl)(methyl)amino)-2-methylhexan-3-yl)-2,6-di Azaspiro[3.4]octan-6-yl)-1,2,4-triazin-6-yl)oxazin CI)-N-Ethyl-5-fluoro-N-isopropylbenzamide fumarate 2-((5-(2-((R)-6-(((*S)-4-(dimethylamino)-4-oxo (butan-2-yl)(methyl)amino)-2-methylhexan-3-yl)-2,6-di Azaspiro[3.4]octan-6-yl)-1,2,4-triazin-6-yl)oxazin CI)-N-Ethyl-5-fluoro-N-isopropylbenzamide fumarate 2-((5-(2-((R)-6-(((*R)-3-(dimethylamino)-2-methyl -3-oxopropyl)(methyl)amino)-2-methylhexan-3-yl)-2,6 -diazaspiro[3.4]octan-6-yl)-1,2,4-triazin-6-yl) (oxy)-N-ethyl-5-fluoro-N-isopropylbenzamide fumarate 2-((5-(2-((R)-6-(((*S)-3-(dimethylamino)-2-methyl -3-oxopropyl)(methyl)amino)-2-methylhexan-3-yl)-2,6 -diazaspiro[3.4]octan-6-yl)-1,2,4-triazin-6-yl) (oxy)-N-ethyl-5-fluoro-N-isopropylbenzamide fumarate N-ethyl-5-fluoro-N-isopropyl-2-((5-(2-((R)-2-methyl 6-(methyl((R)-4-(methylamino)-4-oxobutan-2-yl)amino)amino (Hexan-3-yl)-2,6-diazaspiro[3.4]octan-6-yl)-1 ,2,4-triazin-6-yl)oxy)benzamide fumarate N-ethyl-5-fluoro-N-isopropyl-2-((5-(2-((R)-2-methyl 6-(methyl((S)-4-(methylamino)-4-oxobutan-2-yl)amino)amino (Hexan-3-yl)-2,6-diazaspiro[3.4]octan-6-yl)-1 ,2,4-triazin-6-yl)oxy)benzamide fumarate N-ethyl-5-fluoro-N-isopropyl-2-((5-(2-((R)-2-methyl 6-(methyl((R)-2-methyl-3-(methylamino)-3-oxopropyl) Amino)hexan-3-yl)-2,6-diazaspiro[3.4]octan-6-yl) -1,2,4-triazin-6-yl)oxy)benzamide fumarate N-ethyl-5-fluoro-N-isopropyl-2-((5-(2-((R)-2-methyl 6-(methyl((S)-2-methyl-3-(methylamino)-3-oxopropyl) Amino)hexan-3-yl)-2,6-diazaspiro[3.4]octan-6-yl) -1,2,4-triazin-6-yl)oxy)benzamide fumarate 2-((5-(2-((*R)-6-(((R)-4-amino-4-oxobutane-2- yl)(methyl)amino)-2-methylhexan-3-yl)-2,6-diazaspiro[ 3.4]octan-6-yl)-1,2,4-triazin-6-yl)oxy)-5-furan Fluoro-N,N-diisopropylbenzamide fumarate 2-((5-(2-((*R)-6-(((S)-4-amino-4-oxobutane-2- yl)(methyl)amino)-2-methylhexan-3-yl)-2,6-diazaspiro[ 3.4]octan-6-yl)-1,2,4-triazin-6-yl)oxy)-5-furan Fluoro-N,N-diisopropylbenzamide fumarate 2-((5-(2-((*R)-6-(((R)-3-amino-2-methyl-3-oxo Propyl)(methyl)amino)-2-methylhexan-3-yl)-2,6-diazaspirillum (3,4)octan-6-yl)-1,2,4-triazin-6-yl)oxy)-5 -Fluoro-N,N-diisopropylbenzamide fumarate 2-((5-(2-((*R)-6-(((S)-3-amino-2-methyl-3-oxo Propyl)(methyl)amino)-2-methylhexan-3-yl)-2,6-diazaspirillum (3,4)octan-6-yl)-1,2,4-triazin-6-yl)oxy)-5 -Fluoro-N,N-diisopropylbenzamide fumarate (*R)-2-((5-(2-(1-amino-4-methylpentan-3-yl)-2,6 -diazaspiro[3.4]octan-6-yl)-1,2,4-triazin-6-yl) (oxy)-N-ethyl-5-fluoro-N-isopropylbenzamide fumarate (*R)-2-((5-(2-(1-(dimethylamino)-4-methylpentane-3-yl) (2,6-diazaspiro[3.4]octan-6-yl)-1,2,4-triazine -6-yl)oxy)-N-ethyl-5-fluoro-N-isopropylbenzamide phosphate (*S)-2-((5-(2-(1-(dimethylamino)-4-methylpentane-3-yl) (2,6-diazaspiro[3.4]octan-6-yl)-1,2,4-triazine -6-yl)oxy)-N-ethyl-5-fluoro-N-isopropylbenzamide phosphate (*R)-N-ethyl-5-fluoro-N-isopropyl-2-((5-(2-(1-( (2-Methoxyethyl)amino)-4-methylpentan-3-yl)-2,6-diaza Pyro[3.4]octan-6-yl)-1,2,4-triazin-6-yl)oxy)benzyl nzamide fumarate (R)-N-ethyl-5-fluoro-N-isopropyl-2-((5-(2-(6-(( 2-Methoxyethyl-1,1-d2)(methyl)amino)-2-methylhexane-3-yl (2,6-diazaspiro[3.4]octan-6-yl)-1,2,4-triazine -6-yl)oxy)benzamide fumarate N-ethyl-5-fluoro-N-isopropyl-2-((5-(2-((3*R,5*R )-6-((2-methoxyethyl)(methyl)amino)-2,5-dimethylhexane-3 -yl)-2,6-diazaspiro[3.4]octan-6-yl)-1,2,4-triazamispiro[3.4]octan-6-yl Zin-6-yl)oxy)benzamide fumarate N-ethyl-5-fluoro-N-isopropyl-2-((5-(2-((3S,5R )-6-((2-methoxyethyl)(methyl)amino)-2,5-dimethylhexane-3 -yl)-2,6-diazaspiro[3.4]octan-6-yl)-1,2,4-triazamispiro[3.4]octan-6-yl Zin-6-yl)oxy)benzamide fumarate N-ethyl-5-fluoro-N-isopropyl-2-((5-(2-((3*R,5*S )-6-((2-methoxyethyl)(methyl)amino)-2,5-dimethylhexane-3 -yl)-2,6-diazaspiro[3.4]octan-6-yl)-1,2,4-triazamispiro[3.4]octan-6-yl Zin-6-yl)oxy)benzamide fumarate N-ethyl-5-fluoro-N-isopropyl-2-((5-(2-((3*S,5*S )-6-((2-methoxyethyl)(methyl)amino)-2,5-dimethylhexane-3 -yl)-2,6-diazaspiro[3.4]octan-6-yl)-1,2,4-triazamispiro[3.4]octan-6-yl Zin-6-yl)oxy)benzamide fumarate (R)-2-((5-(2-(6-((2-acetamidoethyl)(methyl)amino)- 2-Methylhexan-3-yl)-2,6-diazaspiro[3.4]octan-6-yl )-1,2,4-triazin-6-yl)oxy)-N-ethyl-5-fluoro-N-yl Isopropylbenzamide fumarate (R)-2-((5-(2-(6-((1,3-dihydroxypropan-2-yl)(methyl) (ethyl)amino)-2-methylhexan-3-yl)-2,6-diazaspiro[3.4]o N-ethyl-5-(2-methyl-1,2,4-triazin-6-yl)oxy Fluoro-N-isopropylbenzamide fumarate N-ethyl-5-fluoro-N-isopropyl-2-((5-(2-(6-((2-meth (methyl)amino)-2,4-dimethylhexan-3-yl)-2,6-di Azaspiro[3.4]octan-6-yl)-1,2,4-triazin-6-yl)oxazin Benzamide (mixture of R,S and S,R or mixture of R,R and S,S) fumaric acid salt N-ethyl-5-fluoro-N-isopropyl-2-((5-(2-(6-((2-meth (methyl)amino)-2,4-dimethylhexan-3-yl)-2,6-di Azaspiro[3.4]octan-6-yl)-1,2,4-triazin-6-yl)oxazin Benzamide (mixture of R,R and S,S or mixture of R,S and S,R) fumaric acid salt (*R)-N-ethyl-5-fluoro-2-((5-(2-(1-((2-hydroxyethyl) (ethyl)amino)-4-methylpentan-3-yl)-2,6-diazaspiro[3.4]o N-isopropyl 1,2,4-triazin-6-yloxy-N-isopropyl benzamide fumarate (*R)-N-ethyl-5-fluoro-2-((5-(2-(1-((2-hydroxyethyl) (methyl)amino)-4-methylpentan-3-yl)-2,6-diazaspiro[ 3.4]octan-6-yl)-1,2,4-triazin-6-yl)oxy)-N-isopropyl Isopropylbenzamide fumarate (*R)-2-((5-(2-(1-((3-amino-3-oxopropyl)amino)- 4-Methylpentan-3-yl)-2,6-diazaspiro[3.4]octan-6-yl )-1,2,4-triazin-6-yl)oxy)-N-ethyl-5-fluoro-N-yl Isopropylbenzamide fumarate (*R)-2-((5-(2-(1-((3-amino-3-oxopropyl)(methyl) Amino)-4-methylpentan-3-yl)-2,6-diazaspiro[3.4]octane -6-yl)-1,2,4-triazin-6-yl)oxy)-N-ethyl-5-fluoro rho-N-isopropylbenzamide fumarate N-ethyl-5-fluoro-2-((5-(2-((R)-6-(((R)-2-hydro (3-methoxypropyl)(methyl)amino)-2-methylhexan-3-yl)- 2,6-Diazaspiro[3.4]octan-6-yl)-1,2,4-triazine-6- (yl)oxy)-N-isopropylbenzamide fumarate (R)-N-ethyl-5-fluoro-2-((5-(2-(6-((2-hydroxyethyl) (methyl)amino)-2-methylhexan-3-yl)-2,6-diazaspiro[3 .4]octan-6-yl)-1,2,4-triazin-6-yl)oxy)-N-iso Propylbenzamide fumarate (R)-2-((5-(2-(6-((2,2-dimethoxyethyl)amino)-2-methyl (hexan-3-yl)-2,6-diazaspiro[3.4]octan-6-yl)-1, 2,4-triazin-6-yl)oxy)-N-ethyl-5-fluoro-N-isopropyl Rubenzamide fumarate (*R)-N-ethyl-5-fluoro-N-isopropyl-2-((5-(2-(1-( isopropylamino)-4-methylpentan-3-yl)-2,6-diazaspiro[3. 4]Octan-6-yl)-1,2,4-triazin-6-yl)oxy)benzamide Fumarate N-ethyl-5-fluoro-N-isopropyl-2-((5-(2-((3R)-6-( (2-Methoxyethyl)(methyl)amino)-2-methylheptan-3-yl)-2,6 -diazaspiro[3.4]octan-6-yl)-1,2,4-triazin-6-yl) Oxy)benzamide fumarate N-ethyl-5-fluoro-N-isopropyl-2-((5-(6-(6-((2-meth (2-methyl-3-hydroxyethyl)(methyl)amino)-2-methylhexan-3-yl)-2,6-diaz Pyro[3.4]octan-2-yl)-1,2,4-triazin-6-yl)oxy)benzyl nzamide fumarate 2-((5-(2-((3*R,5*R)-6-(dimethylamino)-5-methoxy-2 -methylhexan-3-yl)-2,6-diazaspiro[3.4]octan-6-yl) -1,2,4-triazin-6-yl)oxy)-N-ethyl-5-fluoro-N-iso Propylbenzamide fumarate 2-((5-(2-((3*R,5*S)-6-(dimethylamino)-5-methoxy-2 -methylhexan-3-yl)-2,6-diazaspiro[3.4]octan-6-yl) -1,2,4-triazin-6-yl)oxy)-N-ethyl-5-fluoro-N-iso Propylbenzamide fumarate N-ethyl-5-fluoro-2-((5-(2-((3*R,5*R)-5-hydroxy -6-(isopropyl(methyl)amino)-2-methylhexan-3-yl)-2,6- Diazaspiro[3.4]octan-6-yl)-1,2,4-triazin-6-yl)o (xy)-N-isopropylbenzamide fumarate N-ethyl-5-fluoro-2-((5-(2-((3S,5S)-5-hydroxy -6-(isopropyl(methyl)amino)-2-methylhexan-3-yl)-2,6- Diazaspiro[3.4]octan-6-yl)-1,2,4-triazin-6-yl)o (xy)-N-isopropylbenzamide fumarate N-ethyl-5-fluoro-2-((5-(2-((3R,5S)-5-hydroxy -6-(isopropyl(methyl)amino)-2-methylhexan-3-yl)-2,6- Diazaspiro[3.4]octan-6-yl)-1,2,4-triazin-6-yl)o (xy)-N-isopropylbenzamide fumarate N-ethyl-5-fluoro-2-((5-(2-((3S,5R)-5-hydroxy -6-(isopropyl(methyl)amino)-2-methylhexan-3-yl)-2,6- Diazaspiro[3.4]octan-6-yl)-1,2,4-triazin-6-yl)o (xy)-N-isopropylbenzamide fumarate 2-((5-(2-((3*R,5*R)-6-(diethylamino)-5-hydroxy- 2-Methylhexan-3-yl)-2,6-diazaspiro[3.4]octan-6-yl )-1,2,4-triazin-6-yl)oxy)-N-ethyl-5-fluoro-N-yl Isopropylbenzamide fumarate 2-((5-(2-((3*S,5*S)-6-(diethylamino)-5-hydroxy- 2-Methylhexan-3-yl)-2,6-diazaspiro[3.4]octan-6-yl )-1,2,4-triazin-6-yl)oxy)-N-ethyl-5-fluoro-N-yl Isopropylbenzamide fumarate 2-((5-(2-((3S,5R)-6-(diethylamino)-5-hydroxy- 2-Methylhexan-3-yl)-2,6-diazaspiro[3.4]octan-6-yl )-1,2,4-triazin-6-yl)oxy)-N-ethyl-5-fluoro-N-yl Isopropylbenzamide fumarate 2-((5-(2-((3*R,5*S)-6-(diethylamino)-5-hydroxy- 2-Methylhexan-3-yl)-2,6-diazaspiro[3.4]octan-6-yl )-1,2,4-triazin-6-yl)oxy)-N-ethyl-5-fluoro-N-yl Isopropylbenzamide fumarate N-ethyl-2-((5-(2-((3*R,5S)-6-(ethyl(methyl)amino) -5-hydroxy-2-methylhexan-3-yl)-2,6-diazaspiro[3.4] Octan-6-yl)-1,2,4-triazin-6-yl)oxy)-5-fluoro- N-Isopropylbenzamide fumarate N-ethyl-2-((5-(2-((3*S,5S)-6-(ethyl(methyl)amino) -5-hydroxy-2-methylhexan-3-yl)-2,6-diazaspiro[3.4] Octan-6-yl)-1,2,4-triazin-6-yl)oxy)-5-fluoro- N-Isopropylbenzamide fumarate N-ethyl-2-((5-(2-((3*R,5R)-6-(ethyl(methyl)amino) -5-hydroxy-2-methylhexan-3-yl)-2,6-diazaspiro[3.4] Octan-6-yl)-1,2,4-triazin-6-yl)oxy)-5-fluoro- N-Isopropylbenzamide fumarate N-ethyl-5-fluoro-2-((5-(2-((3*R,5S)-5-hydroxy- 6-((2-methoxyethyl)(methyl)amino)-2-methylhexan-3-yl)- 2,6-Diazaspiro[3.4]octan-6-yl)-1,2,4-triazine-6- (yl)oxy)-N-isopropylbenzamide fumarate N-ethyl-5-fluoro-2-((5-(2-((3S,5S)-5-hydroxy- 6-((2-methoxyethyl)(methyl)amino)-2-methylhexan-3-yl)- 2,6-Diazaspiro[3.4]octan-6-yl)-1,2,4-triazine-6- (yl)oxy)-N-isopropylbenzamide fumarate N-ethyl-5-fluoro-2-((5-(2-((3*R,5R)-5-hydroxy- 6-((2-methoxyethyl)(methyl)amino)-2-methylhexan-3-yl)- 2,6-Diazaspiro[3.4]octan-6-yl)-1,2,4-triazine-6- (yl)oxy)-N-isopropylbenzamide fumarate N-ethyl-5-fluoro-2-((5-(2-((3S,5R)-5-hydroxy- 6-((2-methoxyethyl)(methyl)amino)-2-methylhexan-3-yl)- 2,6-Diazaspiro[3.4]octan-6-yl)-1,2,4-triazine-6- (yl)oxy)-N-isopropylbenzamide fumarate 2-((5-(2-((3*R,5*R)-6-(dimethylamino)-5-hydroxy- 2-Methylhexan-3-yl)-2,6-diazaspiro[3.4]octan-6-yl )-1,2,4-triazin-6-yl)oxy)-5-fluoro-N,N-diisopropyl Pyrbenzamide fumarate 2-((5-(2-((3*R,5*S)-6-(dimethylamino)-5-hydroxy- 2-Methylhexan-3-yl)-2,6-diazaspiro[3.4]octan-6-yl )-1,2,4-triazin-6-yl)oxy)-5-fluoro-N,N-diisopropyl Pyrbenzamide fumarate 2-((5-(2-((3*S,5*S)-6-(dimethylamino)-5-hydroxy- 2-Methylhexan-3-yl)-2,6-diazaspiro[3.4]octan-6-yl )-1,2,4-triazin-6-yl)oxy)-5-fluoro-N,N-diisopropyl Pyrbenzamide fumarate 2-((5-(2-((3S,5R)-6-(dimethylamino)-5-hydroxy- 2-Methylhexan-3-yl)-2,6-diazaspiro[3.4]octan-6-yl )-1,2,4-triazin-6-yl)oxy)-5-fluoro-N,N-diisopropyl Pyrbenzamide fumarate 2-((5-(2-((3*S,5*S)-6-(dimethylamino)-5-methoxy-2 -methylhexan-3-yl)-2,6-diazaspiro[3.4]octan-6-yl) -1,2,4-triazin-6-yl)oxy)-N-ethyl-5-fluoro-N-iso Propylbenzamide fumarate 2-((5-(2-((3*S,5*R)-6-(dimethylamino)-5-methoxy-2 -methylhexan-3-yl)-2,6-diazaspiro[3.4]octan-6-yl) -1,2,4-triazin-6-yl)oxy)-N-ethyl-5-fluoro-N-iso Propylbenzamide fumarate N-ethyl-5-fluoro-2-((5-(2-(5-hydroxy-6-((2-methoxy Diethyl)(methyl)amino)-2,5-dimethylhexan-3-yl)-2,6-diazo Zaspiro[3.4]octan-6-yl)-1,2,4-triazin-6-yl)oxy )-N-Isopropylbenzamide fumarate N-ethyl-5-fluoro-2-((5-(2-((3*R,5*R)-5-hydroxy -2-methyl-6-(methyl(propyl)amino)hexan-3-yl)-2,6-diazo Zaspiro[3.4]octan-6-yl)-1,2,4-triazin-6-yl)oxy )-N-Isopropylbenzamide fumarate N-ethyl-5-fluoro-2-((5-(2-((3S,5S)-5-hydroxy -2-methyl-6-(methyl(propyl)amino)hexan-3-yl)-2,6-diazo Zaspiro[3.4]octan-6-yl)-1,2,4-triazin-6-yl)oxy )-N-Isopropylbenzamide fumarate 2-((5-(2-((3*R,5*S)-6-(ethyl(methyl)amino)-5-hydroxybenzoate (2-methylhexan-3-yl)-2,6-diazaspiro[3.4]octane 6-yl)-1,2,4-triazin-6-yl)oxy)-5-fluoro-N,N-di Isopropylbenzamide fumarate 2-((5-(2-((3S,5S)-6-(ethyl(methyl)amino)-5-hydroxybenzoate (2-methylhexan-3-yl)-2,6-diazaspiro[3.4]octane 6-yl)-1,2,4-triazin-6-yl)oxy)-5-fluoro-N,N-di Isopropylbenzamide fumarate (R)-2-((3-chloro-5-(2-(6-((2-methoxyethyl)(methyl)a (amino)-2-methylhexan-3-yl)-2,6-diazaspiro[3.4]octane- 6-yl)-1,2,4-triazin-6-yl)oxy)-N-ethyl-5-fluoro -N-Isopropylbenzamide fumarate (R)-N-ethyl-5-fluoro-N-isopropyl-2-((5-(2-(6-(( 2-Methoxyethyl)amino)-2-methylhexan-3-yl)-2,6-diazaspirillum (3.4)octan-6-yl)-1,2,4-triazin-6-yl)oxy)benzo Zuamide fumarate The following compounds were synthesized by a method similar to that described above for compound 102.

[0385] [Table 43]

[0386] [Table 44]

[0387] [Table 45]

[0388] [Table 46]

[0389] [Table 47]

[0390] [Table 48]

[0391] [Table 49]

[0392] [Table 50]

[0393] [Table 51]

[0394] Table 52

[0395] Table 53

[0396] Table 54

[0397] Table 55

[0398] Table 56

[0399] Table 57

[0400] Table 58

[0401] Table 59

[0402] Table 60

[0403] Table 61

[0404] [Table 62]

[0405] [Table 63]

[0406] [Table 64]

[0407] [Table 65]

[0408] [Table 66]

[0409] [Table 67]

[0410] [Table 68]

[0411] compound 6 (R)-2-((5-(2-(6-acetamido-2-methylhexan-3-yl)-2 ,6-diazaspiro[3.4]octan-6-yl)-1,2,4-triazine-6-yl (per)oxy)-N-ethyl-5-fluoro-N-isopropylbenzamide formate [ka] (R)-2-((5-(2-(6-amino-2-methyl- (ethylhexan-3-yl)-2,6-diazaspiro[3.4]octan-6-yl)-1 ,2,4-triazin-6-yl)oxy)-N-ethyl-5-fluoro-N-isopropyl Pyrbenzamide formate (Compound 1) (30 mg, 0.057 mmol) and TEA (6 To a solution of 100 μL (0.43 mmol), add AcO (20 μL, 0.21 mmol). The resulting mixture was stirred at room temperature under a N2 atmosphere for 0.5 hours. The mixture was concentrated with HCl and the residue was purified by preparative HPLC using Welch Xtimate ( Column: C18 150 × 25 mm 5 μm; Eluent: ACN / H2O (0.225% F A) 30% to 50% (v / v)), to give the title compound as a white solid (3.31 mg , yield 9%). LC-MS(ESI)(Method 5):R t = 0.633 min, m / z measured value 570.4 [M+ H] + . SFC (Method 5):R t =1.191 minutes.

[0412] Compounds 7, 29, 34 (S)-2-((5-(2-(6-acetamido-2-methylhexan-3-yl)-2 ,6-diazaspiro[3.4]octan-6-yl)-1,2,4-triazine-6-yl (per)oxy)-N-ethyl-5-fluoro-N-isopropylbenzamide 2-((5-(2-(1-acetamido-4-methylpentan-3-yl)-2,6-di Azaspiro[3.4]octan-6-yl)-1,2,4-triazin-6-yl)oxazin CI)-N-ethyl-5-fluoro-N-isopropylbenzamide (*R)-2-((5-(2-(6-acetamido-2,6-dimethylheptane-3-yl) (2,6-diazaspiro[3.4]octan-6-yl)-1,2,4-triazine -6-yl)oxy)-N-ethyl-5-fluoro-N-isopropylbenzamide The following compounds were synthesized by a method similar to that described above for compound 6.

[0413] [Table 69]

[0414] compound 8 (R)-N-ethyl-5-fluoro-N-isopropyl-2-((5-(2-(2-methyl) 6-(3-methylureido)hexan-3-yl)-2,6-diazaspiro[3.4 ]octan-6-yl)-1,2,4-triazin-6-yl)oxy)benzamide [ka] (R)-2-((5-(2-(6-amino-2- Methylhexan-3-yl)-2,6-diazaspiro[3.4]octan-6-yl)- 1,2,4-triazin-6-yl)oxy)-N-ethyl-5-fluoro-N-isopropyl A mixture of propyl benzamido formate (Compound 1) (70 mg, 0.12 mmol) and TEA (0 methylcarbamic acid chloride (18 mg, 0.35 mL, 2.5 mmol) was added to a solution of 19 mmol) was added, and the resulting mixture was stirred at 0° C. for 2 hours. The residue was concentrated and purified by preparative HPLC on a Phenomenex Gemini-NX. The column was 150 × 30 mm, 5 μm; eluent was ACN / HO (0.04% Ammonia + 10 mM NH4HCO3) 35% to 65%, v / v), as a white solid The title compound was obtained (50 mg, 70% yield). LC-MS(ESI)(Method 1):R t = 3.34 min, m / z measured value: 585.3 [M+ H] + . SFC (Method 6):R t =2.222 minutes.

[0415] compound 9 (S)-N-ethyl-5-fluoro-N-isopropyl-2-((5-(2-(2-methyl) 6-(3-methylureido)hexan-3-yl)-2,6-diazaspiro[3.4 ]octan-6-yl)-1,2,4-triazin-6-yl)oxy)benzamide The following compounds were synthesized by a method similar to that described above for compound 8.

[0416] [Table 70]

[0417] compound 10 Methyl (R)-(4-(6-(6-(2-(ethyl(isopropyl)carbamoyl)-4 -fluorophenoxy)-1,2,4-triazin-5-yl)-2,6-diazaspiro [3.4]Octan-2-yl)-5-methylhexyl)carbamate [ka] (R)-2-((5-(2-(6 -amino-2-methylhexan-3-yl)-2,6-diazaspiro[3.4]octane -6-yl)-1,2,4-triazin-6-yl)oxy)-N-ethyl-5-fluoro Mixture of rho-N-isopropylbenzamide hydrochloride (Compound 65) (0.100 g, crude) The material was diluted with 2 M NaOH (0.15 mL, 0.30 mmol) and carbonochloridic acid methyl C1H3 (0.030 g, 0.317 mmol, in 0.1 mL DCM) was added. The mixture was stirred at 0° C. for 0.5 h. The mixture was diluted with water (10 mL) and saturated aqueous NaHCO The combined organic layer was diluted with 15 mL of ethyl acetate and further extracted with EtOAc (15 mL x 3). The layer was dried (Na2SO4), filtered and evaporated in vacuo to give the crude product, which was Further purification was performed by preparative HPLC using Phenomenex Gemini NX ( Column: C18 75 x 30 mm 3 μm; Eluent: ACN / H2O (0.05% ammonia) Nia + 10 mM NH4HCO3 35% to 65% (v / v)), as a viscous oil The compound was obtained (11.53 mg). LC-MS(ESI)(Method 1):R t = 3.283 min, m / z measured value: 586.3 [M +H] + .

[0418] compound 22 Methyl (R)-(4-(6-(6-(2-(ethyl(isopropyl)carbamoyl)-4 -fluorophenoxy)-1,2,4-triazin-5-yl)-2,6-diazaspiro [3.4]Octan-2-yl)-5-methylhexyl)(methyl)carbamate The following compounds were synthesized by a method similar to that described above for compound 10.

[0419] [Table 71]

[0420] compound 11 (R)-N-ethyl-5-fluoro-N-isopropyl-2-((5-(2-(6-(( 2-Methoxyethyl)amino)-2-methylhexan-3-yl)-2,6-diazaspirillum (3.4)octan-6-yl)-1,2,4-triazin-6-yl)oxy)benzo Zuamide [ka] (R)-2-((5-(2-(6-amino-2-methylhexane- 3-yl)-2,6-diazaspiro[3.4]octan-6-yl)-1,2,4-tri Azin-6-yl)oxy)-N-ethyl-5-fluoro-N-isopropylbenzamide Compound 64 (120 mg, crude), 1-bromo-2-methoxyethane (32 mg, 0.23mmol), Cs2CO3(222mg, 0.681mmol), NaI(10 A mixture of 2 mg, 0.680 mmol) was stirred at 80 °C via microwave irradiation for 1 h. After cooling to RT, the mixture was diluted with HO (10 mL) and The combined organic layers were washed with H2O (10 mL) and dried over Na2SO4. Drying, filtration and concentration under reduced pressure gave the crude product which was purified by Phenomenex Ge Further purification was carried out by HPLC through a mini-NX (column: 150 × 30 mm 5 μ Eluent: ACN / H2O (10 mM NH4HCO3) 51% to 71% (v / v) ) and further purified by SFC through DAICEL CHIRALCEL OD-H ( Column: 250 x 30 mm, 5 μm; Eluent: EtOH (0.1% v / v ammonia) Supercritical CO2, 25 / 25, v / v) to give the title compound as a yellow solid (5.13 m g, purity 96%). LC-MS(ESI)(Method 1):R t= 2.997 min, m / z measured value: 586.3 [M +H] + .

[0421] Compounds 28, 90, 93, 287, 149, 226, 257, 228 (S)-N-ethyl-5-fluoro-N-isopropyl-2-((5-(2-(6-(( 2-Methoxyethyl)(methyl)amino)-2-methylhexan-3-yl)-2,6- Diazaspiro[3.4]octan-6-yl)-1,2,4-triazin-6-yl)o (xy)benzamide (R)-2-((5-(2-(6-(bis(2-methoxyethyl)amino)-2-methyl Hexan-3-yl)-2,6-diazaspiro[3.4]octan-6-yl)-1,2 ,4-triazin-6-yl)oxy)-N-ethyl-5-fluoro-N-isopropyl Benzamidoformate 5-Fluoro-N,N-diisopropyl-2-((5-(2-(6-((2-methoxyethyl) (methyl)amino)-2-methylhexan-3-yl)-2,6-diazaspiro[ 3.4]octan-6-yl)-1,2,4-triazin-6-yl)oxy)benzalkonium Midoformate (R)-2-((5-(2-(6-((2,2-dimethoxyethyl)amino)-2-methyl (hexan-3-yl)-2,6-diazaspiro[3.4]octan-6-yl)-1, 2,4-triazin-6-yl)oxy)-N-ethyl-5-fluoro-N-isopropyl Rubenzamide (R)-2-((5-(2-(6-((2,2-dimethoxyethyl)(methyl)amino) -2-methylhexan-3-yl)-2,6-diazaspiro[3.4]octan-6-yl (1,2,4-triazin-6-yl)oxy)-N-ethyl-5-fluoro-N- Isopropylbenzamide (*R)-N-ethyl-5-fluoro-N-isopropyl-2-((5-(2-(1-( (2-Methoxyethyl)amino)-4-methylpentan-3-yl)-2,6-diaza Pyro[3.4]octan-6-yl)-1,2,4-triazin-6-yl)oxy)benzyl Nzuamide (R)-2-((5-(2-(6-((2-ethoxyethyl)(methyl)amino)-2- Methylhexan-3-yl)-2,6-diazaspiro[3.4]octan-6-yl)- 1,2,4-triazin-6-yl)oxy)-N-ethyl-5-fluoro-N-isopropyl propyl benzamide (*R)-N-ethyl-5-fluoro-N-isopropyl-2-((5-(2-(1-( isopropylamino)-4-methylpentan-3-yl)-2,6-diazaspiro[3. 4]Octan-6-yl)-1,2,4-triazin-6-yl)oxy)benzamide The following compounds were synthesized by a method similar to that described above for compound 11.

[0422] [Table 72]

[0423] [Table 73]

[0424] [Table 74]

[0425] compound 12 (R)-2-((5-(2-(6-((2-cyanoethyl)amino)-2-methylhexyl (3-octan-yl)-2,6-diazaspiro[3.4]octan-6-yl)-1,2,4- Triazin-6-yl)oxy)-N-ethyl-5-fluoro-N-isopropylbenz amide [ka] (R)-2-((5-(2-(6-amino-2-methylhexyl)methyl)-2-methyl-1,3-dimethyl-2-propanol in MeOH (15 mL) (3-octan-yl)-2,6-diazaspiro[3.4]octan-6-yl)-1,2,4- Triazin-6-yl)oxy)-N-ethyl-5-fluoro-N-isopropylbenz The amide hydrochloride (compound 65) (260 mg, crude) and DIEA (200 mg, 1.98 To a solution of 100 mmol of acrylonitrile (580 mg, 10.9 mmol) was added at 0 °C. After the addition, the reaction mixture was stirred at RT for 18 h. The reaction mixture was concentrated in vacuo. The residue was purified by preparative HPLC through Boston Prime (column: C 18 150 × 30 mm 5 μm, Mobile phase A: Water (0.04% ammonia + 10 mM N H4HCO3), mobile phase B: ACN, flow rate: 25 mL / min, gradient condition B / A 40% 70%) to give the title compound as a colourless oil (120mg). LC-MS(ESI)(Method 1):R t = 2.938 min, m / z measured value: 581.3 [M +H] + .

[0426] Compound 18, 246 N-ethyl-5-fluoro-N-isopropyl-2-((5-(2-(2-methyl-6- ((2-(methylsulfonyl)ethyl)amino)hexan-3-yl)-2,6-diaza spiro[3.4]octan-6-yl)-1,2,4-triazin-6-yl)oxy benzamide (R)-2-((5-(2-(6-((3-(dimethylamino)-3-oxopropyl) (Methyl)amino)-2-methylhexan-3-yl)-2,6-diazaspiro[3.4 ]octan-6-yl)-1,2,4-triazin-6-yl)oxy)-N-ethyl- 5-Fluoro-N-isopropylbenzamide formate The following compounds were synthesized by a method similar to that described above for compound 12.

[0427] [Table 75]

[0428] compound 27 (R)-N-ethyl-5-fluoro-N-isopropyl-2-((5-(2-(6-(( 2-Methoxyethyl)(methyl)amino)-2-methylhexan-3-yl)-2,6- Diazaspiro[3.4]octan-6-yl)-1,2,4-triazin-6-yl)o (xy)benzamide Preparation method A: [ka] (R)-N-ethyl-5-fluoro-N-isopropyl-2-(2-methyl-2-propanol) in anhydrous MeOH (2 mL) -((5-(2-(6-((2-methoxyethyl)amino)-2-methylhexane-3- (yl)-2,6-diazaspiro[3.4]octan-6-yl)-1,2,4-triazinyl (6-(4-phenyl-6-yl)oxy)benzamide (Compound 11) (40.0 mg, 0.068 mmol) l), formaldehyde (55.4 mg, 0.683 mol, 37% in water) and AcOH (8.2 mg, 0.137 mmol) was stirred at 45°C for 1 hour. H3CN (8.6 mg, 0.137 mmol) was added to the mixture, and the resulting mixture was stirred for 45 The mixture was stirred at RT for another 1 h. After cooling to RT, the reaction mixture was diluted with saturated aqueous NaHCO3 (4 The mixture was treated with 20 mL of DCM to adjust the pH to about 8, and further extracted with DCM (20 mL x 3). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give the crude product, which This was purified by preparative HPLC through Boston Prime (column: C18 150 × 30 mm, 5 μm, Mobile phase A: HO (0.04% ammonia + 10 mM NH 4HCO3), mobile phase B: ACN, flow rate: 25 mL / min, gradient condition B / A 50% to 8 0% (50%B~80%B)), to give the title compound as a yellow oil (9.62 mg, purity 99.10%, yield 23.3%).

[0429] Preparation method B: [ka] 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-triazin-6-yl)oxy)benzalkonium Imidazole hydrochloride (compound 67) (480 mg, crude), K2CO3 (700 mg, 5.07 m mol) and NaI (400 mg, 2.67 mmol), To the mixture was added 230 mg of methyltriethoxyethane (1.65 mmol). The resulting mixture was heated at 50°C. After cooling to RT, the reaction mixture was quenched with H2O (30 mL) and DC The combined organic layer was washed with brine (30 mL x 3), and Dried over Na2SO4, filtered and concentrated to give a crude residue, which was purified by FCC (DCM / MeOH=10:1) to obtain N-ethyl-5-fluoro-N-isopropyl ether as a yellow oil. Propyl-2-((5-(2-(6-((2-methoxyethyl)(methyl)amino)-2 -methylhexan-3-yl)-2,6-diazaspiro[3.4]octan-6-yl) (1,2,4-triazin-6-yl)oxy)benzamide (compound 68) (250 m g, yield 48%).

[0430] N-ethyl-5-fluoro-N-isopropyl-2-((5-(2-(6-((2-methyl (2-methylhexyl)(methyl)amino)-2-methylhexan-3-yl-2,6-diaza spiro[3.4]octan-6-yl)-1,2,4-triazin-6-yl)oxy Benzamide (compound 68) (960 mg, from several batches obtained by method B) The samples were first analyzed by SFC using DAICEL CHIRALPAK IG. (Column: 250 × 30 mm 10 μm; Mobile phase: A: supercritical CO2, B: Et OH (0.1% ammonia), A:B = 40:60 (60 mL / min), Boston The mixture was further purified by preparative HPLC using Prime (column: 150 × 30 mm 5 μ m, Mobile phase A: H2O (10mM NH4HCO3), Mobile phase B: ACN, Flow rate: 25m L / min, gradient condition B / A 55% to 85%) to give the title compound (27 0mg). 1 H NMR (400 MHz, methanol-d4): δ = 8.40 (s, 1H), 7.4 7-7.32(m,1H),7.30-7.10(m,2H),4.24-4.01(m ,2H),3.89-3.60(m,3H),3.48(br s,3H),2.63- 2.51(m,2H),2.43-2.32(m,2H),2.29-2.07(m,6 H),1.86-1.72(m,1H),1.62-1.44(m,2H),1.39- 1.02 (m, 10H), 0.99-0.66 (m, 9H). Some protons are solvent peaks. are hidden by the ' LCMS(ESI)(Method 2):R t = 1.965 min, m / z measured value 600.3 [M+H ] + . SFC (Method 11):R t =4.904 minutes.

[0431] Preparation method C: [ka] (R)-2-((3-chloro-5-(2-(6-((2-methoxyethyl)methyl) Amino)-2-methylhexan-3-yl)-2,6-diazaspiro[3.4]octane -6-yl)-1,2,4-triazin-6-yl)oxy-N-ethyl-5-fluoro -N-Isopropylbenzamide (compound 393) (60 in 163.93 g of MeOH) 1 wt% solution, 100 g corrected for compound 393), palladium on carbon (10 g) and MeOH A solution of (316 g) in methanol was heated at 20-30°C under a hydrogen atmosphere (0.20-0.30 M The mixture was stirred at 250°C for 18 hours. The mixture was filtered through diatomaceous earth (75 g) and the cake was diluted with MeOH (1 The filtrate was concentrated under reduced pressure (≦40° C.) to about 3 vol., and then washed with about 3 vol. The mixture was then flushed with isopropyl acetate (IPAc, 870 g) while concentrating to 100 ml. The mixture was then diluted with IPAc (696 g) and 20% aqueous Na2CO3 was added (5 The mixture was stirred for 30-60 minutes. The aqueous layer was removed. The organic layer was diluted with water (500 g). The title intermediate was washed with IPA and then concentrated to approximately 3 vol. under reduced pressure at <45°C. c) as a 48.1 wt% solution in α-heptane with an assay yield of approximately 90%.

[0432] compound 70 (R)-N-ethyl-5-fluoro-N-isopropyl-2-((5-(2-(6-(( 2-Methoxyethyl)(methyl)amino)-2-methylhexan-3-yl)-2,6- Diazaspiro[3.4]octan-6-yl)-1,2,4-triazin-6-yl)o Benzamide oxalate [ka] (R)-N-ethyl-5-fluoro-N-isopropyl ether in 20 mL of ACN 2-((5-(2-(6-((2-methoxyethyl)(methyl)amino)-2-methyl (hexan-3-yl)-2,6-diazaspiro[3.4]octan-6-yl)-1, 2,4-triazin-6-yl)oxy)benzamide (compound 27) (270 mg, 0 To a solution of 0.450 mmol of oxalic acid (81.0 mg, 0.900 mmol) was added After the addition, the reaction mixture was stirred at RT for 1 h. The reaction mixture was then concentrated and the residue was redissolved in ACN and deionized water and lyophilized to give the title compound as a white solid. (350mg). 1 H NMR (400 MHz, methanol-d4): δ = 8.48 (s, 1H), 7.5 2-7.11(m,3H),4.54-3.64(m,12H),3.40-3.34( m,5H),3.23-3.13(m,2H),2.90(s,3H),2.54-2. 27(m,2H),2.19-2.03(m,1H),1.97-1.77(m,2H) ,1.75-1.50(m,2H),1.35-0.65(m,17H). 1 H NMR(400MHz,DMSO-d6):δ=8.51(s,1H),7.51 -7.29(m,3H),4.29-3.34(m,12H),3.23-2.84(m ,7H),2.70(s,3H),2.35-2.09(m,2H),2.05-1.8 5(m,1H),1.81-1.58(m,2H),1.56-1.33(m,2H), 1.18-0.60(m,17H). LCMS(ESI)(Method 2):R t = 1.969 min, m / z measured value 600.4 [M+H ] + .

[0433] Preparation of Compound 70a [ka] A solution of compound 27 in IPAc (360 g) (48 wt % solution in 207.90 g of IPAc) To 100 g of the active compound 27), EtOH (63 g) was added at 20-25°C. The solution was then washed with concentrated HCl (32.9 g) in EtOH (49.5 g) over approximately 15 minutes. The mixture was seeded with crystalline Compound 70a seeds (2 g, 2% seed amount), and This was followed by aging for 18 hours. IPAc (870 g) was added at 20-25°C for 4 hours. The mixture was added slowly and the slurry was stirred for an additional 18 hours. After cooling to about 5°C, the product was filtered. The solid was filtered, washed with IPAc (522 g), and dried under vacuum at 20-30°C to give a white solid. The resulting weakly crystalline compound 70a was obtained (yield 91.0%, 115.4 g). The small amount of seed material used was obtained via a similar reaction protocol on a smaller scale).

[0434] Recrystallization: Weakly crystalline compound 70a (100 g), EtOH (166 g), purified water (2 A solution of 1.5 g of HCl and 178 g of IPAc was stirred at 20-30°C for 0.5-2 hours to obtain a clear solution. A clear solution was obtained. Additional IPAc (522 g) was added dropwise over 1-2 hours, followed by mixing. The mixture was seeded with crystalline Compound 70a seeds (2 g, 2% seed amount). Aged for 18-20 hours, then added IPAc (348g) at 20-30°C for 12 hours. The mixture was added slowly and the slurry was stirred for an additional 55-60 hours. The product was filtered and (158 g) and dried in vacuo at 20-30°C to give compound 70 as a white solid. a was obtained (yield 85%, net weight 85.0 g). 1 HNMR(DMSO-d6,400MHz):δ=11.60(1H,brs),10 .8(1H,brs),8.52(1H,s),7.36(3H,m),3.97-4. 20(7H,m),3.64-3.71(4H,m),3.47(7H,m),3.25 (2H,m),3.05(3H,m),2.73(3H,s),2.10-2.45(1 H,m),1.99(1H,m),1.78(2H,m),1.55(2H,m),0. 83-1.12(12H,m),0.70(2H,m). LCMS (Method 7):R t = 0.669 min, m / z measured value 600.5 [M+H] + .

[0435] Compounds 83, 84, 94, 95, 88, 89, 99, 100, 250, 251, 252, 254, 258, 396, 402 (*R)-N-ethyl-5-fluoro-N-isopropyl-2-((4-(2-(6-( (2-Methoxyethyl)(methyl)amino)-2-methylhexan-3-yl)-2,6 -diazaspiro[3.4]octan-6-yl)pyridazin-3-yl)oxy)benz Amidooxalate (*S)-N-ethyl-5-fluoro-N-isopropyl-2-((4-(2-(6-( (2-Methoxyethyl)(methyl)amino)-2-methylhexan-3-yl)-2,6 -diazaspiro[3.4]octan-6-yl)pyridazin-3-yl)oxy)benz Amidooxalate (*R)-5-Fluoro-N,N-diisopropyl-2-((5-(2-(6-((2- Methoxyethyl)(methyl)amino)-2-methylhexan-3-yl)-2,6-diazo Zaspiro[3.4]octan-6-yl)-1,2,4-triazin-6-yl)oxy ) Benzamide oxalate (*S)-5-Fluoro-N,N-diisopropyl-2-((5-(2-(6-((2- Methoxyethyl)(methyl)amino)-2-methylhexan-3-yl)-2,6-diazo Zaspiro[3.4]octan-6-yl)-1,2,4-triazin-6-yl)oxy ) Benzamide oxalate (*R)-5-Fluoro-N,N-diisopropyl-2-((4-(2-(6-((2- Methoxyethyl)(methyl)amino)-2-methylhexan-3-yl)-2,6-diazo Zaspiro[3.4]octan-6-yl)pyridazin-3-yl)oxy)benzamide oxalates (*S)-5-Fluoro-N,N-diisopropyl-2-((4-(2-(6-((2- Methoxyethyl)(methyl)amino)-2-methylhexan-3-yl)-2,6-diazo Zaspiro[3.4]octan-6-yl)pyridazin-3-yl)oxy)benzamide oxalates (*R)-5-Fluoro-N,N-diisopropyl-2-((5-(2-(6-((2- Methoxyethyl)amino)-2-methylhexan-3-yl)-2,6-diazaspiro[ 3.4]octan-6-yl)-1,2,4-triazin-6-yl)oxy)benzalkonium Midoxalate (*S)-5-Fluoro-N,N-diisopropyl-2-((5-(2-(6-((2- Methoxyethyl)amino)-2-methylhexan-3-yl)-2,6-diazaspiro[ 3.4]octan-6-yl)-1,2,4-triazin-6-yl)oxy)benzalkonium Midoxalate N-ethyl-5-fluoro-N-isopropyl-2-((5-(2-((R)-6-(( (*R)-2-Methoxypropyl)(methyl)amino)-2-methylhexan-3-yl )-2,6-diazaspiro[3.4]octan-6-yl)-1,2,4-triazine- 6-yl)oxy)benzamide oxalate N-ethyl-5-fluoro-N-isopropyl-2-((5-(2-((R)-6-(( (*S)-2-Methoxypropyl)(methyl)amino)-2-methylhexan-3-yl )-2,6-diazaspiro[3.4]octan-6-yl)-1,2,4-triazine- 6-yl)oxy)benzamide oxalate N-ethyl-5-fluoro-N-isopropyl-2-((5-(2-((3R)-6-( (2-Methoxypropyl)(methyl)amino)-2-methylhexan-3-yl)-2, 6-diazaspiro[3.4]octan-6-yl)-1,2,4-triazin-6-yl )Oxy)benzamide oxalate N-ethyl-5-fluoro-N-isopropyl-2-((5-(2-((3S)-6-( (2-Methoxypropyl)(methyl)amino)-2-methylhexan-3-yl)-2, 6-diazaspiro[3.4]octan-6-yl)-1,2,4-triazin-6-yl )Oxy)benzamide oxalate (R)-2-((5-(2-(6-((2-ethoxyethyl)(methyl)amino)-2- Methylhexan-3-yl)-2,6-diazaspiro[3.4]octan-6-yl)- 1,2,4-triazin-6-yl)oxy)-N-ethyl-5-fluoro-N-isopropyl propyl benzamide oxalate (*R)-2-((5-(2-(6-(dimethylamino)-2-methylhexane-3-yl) (2,6-diazaspiro[3.4]octan-6-yl)-1,2,4-triazine -6-yl)oxy)-5-fluoro-N,N-diisopropylbenzamide oxalate (R)-N-(ethyl- 13 C2)-5-fluoro-2-((5-(2-(6-((2- Methoxyethyl)(methyl)amino)-2-methylhexan-3-yl)-2,6-diazo Zaspiro[3.4]octan-6-yl)-1,2,4-triazin-6-yl)oxy )-N-(propan-2-yl- 13 C3) Benzamide oxalate The following compounds were synthesized by a method similar to that described above for compound 70.

[0436] [Table 76]

[0437] [Table 77]

[0438] [Table 78]

[0439] [Table 79]

[0440] Compounds 13, 16, 71, 136, 139, 153, 156, 160, 164, 166, 169, 173, 274, 275, 276, 279, 282, 285, 178, 180, 190, 192, 194, 196, 198, 200, 202, 204, 310, 311, 312, 313, 318, 329, 360, 375, 376, 379, 380, 383, 388, 411 (R)-2-((5-(2-(6-((2-cyanoethyl)(methyl)amino)-2-methyl (ethylhexan-3-yl)-2,6-diazaspiro[3.4]octan-6-yl)-1 ,2,4-triazin-6-yl)oxy)-N-ethyl-5-fluoro-N-isopropyl Pyrbenzamide (R)-2-((5-(2-(6-((2,2-difluoroethyl)(methyl)amino) -2-methylhexan-3-yl)-2,6-diazaspiro[3.4]octan-6-yl (1,2,4-triazin-6-yl)oxy)-N-ethyl-5-fluoro-N- Isopropylbenzamide (R)-N-ethyl-2-((5-(2-(6-(ethyl(2-methoxyethyl)amino) )-2-Methylhexan-3-yl)-2,6-diazaspiro[3.4]octane-6- (yl)-1,2,4-triazin-6-yl)oxy)-5-fluoro-N-isopropyl Rubenzamide (R)-N-ethyl-5-fluoro-N-isopropyl-2-((5-(2-(6-(( 2-Methoxy-2-methylpropyl)(methyl)amino)-2-methylhexane-3-yl (2,6-diazaspiro[3.4]octan-6-yl)-1,2,4-triazine -6-yl)oxy)benzamide (R)-N-ethyl-5-fluoro-2-((5-(2-(6-((2-hydroxy-2 -methylpropyl)(methyl)amino)-2-methylhexan-3-yl)-2,6-di Azaspiro[3.4]octan-6-yl)-1,2,4-triazin-6-yl)oxazin β)-N-isopropylbenzamide N-ethyl-5-fluoro-N-isopropyl-2-((5-(2-((R)-6-(( (R)-1-Methoxypropan-2-yl)(methyl)amino)-2-methylhexane- 3-yl)-2,6-diazaspiro[3.4]octan-6-yl)-1,2,4-tri Azin-6-yl)oxy)benzamide N-ethyl-5-fluoro-N-isopropyl-2-((5-(2-((R)-6-(( (S)-1-Methoxypropan-2-yl)(methyl)amino)-2-methylhexane- 3-yl)-2,6-diazaspiro[3.4]octan-6-yl)-1,2,4-tri Azin-6-yl)oxy)benzamide (R)-2-((5-(2-(6-((1,3-dimethoxypropan-2-yl)(methyl (amino)-2-methylhexan-3-yl)-2,6-diazaspiro[3.4]octyl Tan-6-yl)-1,2,4-triazin-6-yl)oxy)-N-ethyl-5-furan Fluoro-N-isopropylbenzamide N-ethyl-5-fluoro-2-((5-(2-((R)-6-(((R)-1-hydro (3-methoxypropan-2-yl)(methyl)amino)-2-methylhexane-3 -yl)-2,6-diazaspiro[3.4]octan-6-yl)-1,2,4-triazamispiro[3.4]octan-6-yl Dibenzoyl)diphenyloxy)-N-isopropylbenzamide N-ethyl-5-fluoro-2-((5-(2-((R)-6-(((S)-1-hydro (3-methoxypropan-2-yl)(methyl)amino)-2-methylhexane-3 -yl)-2,6-diazaspiro[3.4]octan-6-yl)-1,2,4-triazamispiro[3.4]octan-6-yl Dibenzoyl)diphenyloxy)-N-isopropylbenzamide N-ethyl-5-fluoro-2-((5-(2-((3R)-6-((3-hydroxy- 2-Methoxypropyl)(methyl)amino)-2-methylhexan-3-yl)-2,6 -diazaspiro[3.4]octan-6-yl)-1,2,4-triazin-6-yl) (oxy)-N-isopropylbenzamide 2-((5-(2-((3R)-6-((2,3-dimethoxypropyl)(methyl)amine (2-methylhexan-3-yl)-2,6-diazaspiro[3.4]octane-6 -yl)-1,2,4-triazin-6-yl)oxy)-N-ethyl-5-fluoro- N-Isopropylbenzamide (*R)-N-ethyl-5-fluoro-2-((5-(2-(1-((3-hydroxypropyl) (propyl)(methyl)amino)-4-methylpentan-3-yl)-2,6-diazaspiro [3.4]octan-6-yl)-1,2,4-triazin-6-yl)oxy)-N- Isopropylbenzamide (*R)-N-ethyl-5-fluoro-N-isopropyl-2-((5-(2-(1-( (3-methoxypropyl)(methyl)amino)-4-methylpentan-3-yl)-2, 6-diazaspiro[3.4]octan-6-yl)-1,2,4-triazin-6-yl )Oxy)benzamide (*R)-N-ethyl-5-fluoro-N-isopropyl-2-((5-(2-(1-( (2-Methoxyethyl)(methyl)amino)-4-methylpentan-3-yl)-2,6 -diazaspiro[3.4]octan-6-yl)-1,2,4-triazin-6-yl) Oxybenzamide (*R)-2-((5-(2-(1-((3-amino-3-oxopropyl)(methyl) Amino)-4-methylpentan-3-yl)-2,6-diazaspiro[3.4]octane -6-yl)-1,2,4-triazin-6-yl)oxy)-N-ethyl-5-fluoro d-N-isopropylbenzamide N-ethyl-5-fluoro-2-((5-(2-((R)-6-(((R)-2-hydro (3-methoxypropyl)(methyl)amino)-2-methylhexan-3-yl)- 2,6-Diazaspiro[3.4]octan-6-yl)-1,2,4-triazine-6- (yl)oxy)-N-isopropylbenzamide N-ethyl-5-fluoro-2-((5-(2-((R)-6-(((S)-2-hydro (3-methoxypropyl)(methyl)amino)-2-methylhexan-3-yl)- 2,6-Diazaspiro[3.4]octan-6-yl)-1,2,4-triazine-6- (yl)oxy)-N-isopropylbenzamide formate 2-((5-(2-((3R)-6-((4-(dimethylamino)-4-oxobutane- 2-yl)(methyl)amino)-2-methylhexan-3-yl)-2,6-diazaspirillum (3,4)octan-6-yl)-1,2,4-triazin-6-yl)oxy)-N -Ethyl-5-fluoro-N-isopropylbenzamide 2-((5-(2-((3R)-6-((3-(dimethylamino)-2-methyl-3-o (xopropyl)(methyl)amino)-2-methylhexan-3-yl)-2,6-diaza spiro[3.4]octan-6-yl)-1,2,4-triazin-6-yl)oxy -N-ethyl-5-fluoro-N-isopropylbenzamide N-ethyl-5-fluoro-N-isopropyl-2-((5-(2-((R)-2-methyl 6-(methyl((R)-4-(methylamino)-4-oxobutan-2-yl)amino)amino (Hexan-3-yl)-2,6-diazaspiro[3.4]octan-6-yl)-1 ,2,4-triazin-6-yl)oxy)benzamide N-ethyl-5-fluoro-N-isopropyl-2-((5-(2-((R)-2-methyl 6-(methyl((S)-4-(methylamino)-4-oxobutan-2-yl)amino)amino (Hexan-3-yl)-2,6-diazaspiro[3.4]octan-6-yl)-1 ,2,4-triazin-6-yl)oxy)benzamide N-ethyl-5-fluoro-N-isopropyl-2-((5-(2-((R)-2-methyl 6-(methyl((R)-2-methyl-3-(methylamino)-3-oxopropyl) Amino)hexan-3-yl)-2,6-diazaspiro[3.4]octan-6-yl) -1,2,4-triazin-6-yl)oxy)benzamide N-ethyl-5-fluoro-N-isopropyl-2-((5-(2-((R)-2-methyl 6-(methyl((S)-2-methyl-3-(methylamino)-3-oxopropyl) Amino)hexan-3-yl)-2,6-diazaspiro[3.4]octan-6-yl) -1,2,4-triazin-6-yl)oxy)benzamide 2-((5-(2-((*R)-6-(((R)-4-amino-4-oxobutane-2- yl)(methyl)amino)-2-methylhexan-3-yl)-2,6-diazaspiro[ 3.4]octan-6-yl)-1,2,4-triazin-6-yl)oxy)-5-furan Fluoro-N,N-diisopropylbenzamide 2-((5-(2-((*R)-6-(((S)-4-amino-4-oxobutane-2- yl)(methyl)amino)-2-methylhexan-3-yl)-2,6-diazaspiro[ 3.4]octan-6-yl)-1,2,4-triazin-6-yl)oxy)-5-furan Fluoro-N,N-diisopropylbenzamide 2-((5-(2-((*R)-6-(((R)-3-amino-2-methyl-3-oxo Propyl)(methyl)amino)-2-methylhexan-3-yl)-2,6-diazaspirillum (3,4)octan-6-yl)-1,2,4-triazin-6-yl)oxy)-5 -Fluoro-N,N-diisopropylbenzamide 2-((5-(2-((*R)-6-(((S)-3-amino-2-methyl-3-oxo Propyl)(methyl)amino)-2-methylhexan-3-yl)-2,6-diazaspirillum (3,4)octan-6-yl)-1,2,4-triazin-6-yl)oxy)-5 -Fluoro-N,N-diisopropylbenzamide 2-((5-(2-((3*R,5*R)-6-(dimethylamino)-5-methoxy-2 -methylhexan-3-yl)-2,6-diazaspiro[3.4]octan-6-yl) -1,2,4-triazin-6-yl)oxy)-N-ethyl-5-fluoro-N-iso Propylbenzamide N-ethyl-2-((5-(2-((3*R,5*R)-6-(ethyl(methyl)amino )-5-Methoxy-2-methylhexan-3-yl)-2,6-diazaspiro[3.4] Octan-6-yl)-1,2,4-triazin-6-yl)oxy)-5-fluoro- N-Isopropylbenzamide 2-((5-(2-((3*R,5*S)-6-(dimethylamino)-5-methoxy-2 -methylhexan-3-yl)-2,6-diazaspiro[3.4]octan-6-yl) -1,2,4-triazin-6-yl)oxy)-N-ethyl-5-fluoro-N-iso Propylbenzamide N-ethyl-2-((5-(2-((3*R,5*S)-6-(ethyl(methyl)amino )-5-Methoxy-2-methylhexan-3-yl)-2,6-diazaspiro[3.4] Octan-6-yl)-1,2,4-triazin-6-yl)oxy)-5-fluoro- N-Isopropylbenzamide N-ethyl-5-fluoro-2-((5-(2-(5-hydroxy-6-(isopropyl (Methyl)amino)-2-methylhexan-3-yl)-2,6-diazaspiro[3.4 ]octan-6-yl)-1,2,4-triazin-6-yl)oxy)-N-isopropyl Pyrbenzamide 2-((5-(2-(6-(diethylamino)-5-hydroxy-2-methylhexane- 3-yl)-2,6-diazaspiro[3.4]octan-6-yl)-1,2,4-tri Azin-6-yl)oxy)-N-ethyl-5-fluoro-N-isopropylbenzamide Do 2-((5-(2-(6-(dimethylamino)-5-hydroxy-2-methylhexane- 3-yl)-2,6-diazaspiro[3.4]octan-6-yl)-1,2,4-tri Azin-6-yl)oxy)-5-fluoro-N,N-diisopropylbenzamide 2-((5-(2-((3*S,5*S)-6-(dimethylamino)-5-methoxy-2 -methylhexan-3-yl)-2,6-diazaspiro[3.4]octan-6-yl) -1,2,4-triazin-6-yl)oxy)-N-ethyl-5-fluoro-N-iso Propylbenzamide 2-((5-(2-((3*S,5*R)-6-(dimethylamino)-5-methoxy-2 -methylhexan-3-yl)-2,6-diazaspiro[3.4]octan-6-yl) -1,2,4-triazin-6-yl)oxy)-N-ethyl-5-fluoro-N-iso Propylbenzamide N-ethyl-2-((5-(2-((3S,5S)-6-(ethyl(methyl)amino )-5-Methoxy-2-methylhexan-3-yl)-2,6-diazaspiro[3.4] Octan-6-yl)-1,2,4-triazin-6-yl)oxy)-5-fluoro- N-Isopropylbenzamide N-ethyl-2-((5-(2-((3S,5R)-6-(ethyl(methyl)amino )-5-Methoxy-2-methylhexan-3-yl)-2,6-diazaspiro[3.4] Octan-6-yl)-1,2,4-triazin-6-yl)oxy)-5-fluoro- N-Isopropylbenzamide N-ethyl-5-fluoro-2-((5-(2-(5-hydroxy-2-methyl-6-( Methyl(propyl)amino)hexan-3-yl)-2,6-diazaspiro[3.4]o N-isopropyl 1,2,4-triazin-6-yloxy-N-isopropyl benzamide 2-((5-(2-(6-(ethyl(methyl)amino)-5-hydroxy-2-methylhe oxan-3-yl)-2,6-diazaspiro[3.4]octan-6-yl)-1,2, 4-triazin-6-yl)oxy)-5-fluoro-N,N-diisopropylbenzaldehyde Mido (R)-2-((3-chloro-5-(2-(6-dimethylamino)-2-methylhexyl (3-octan-yl)-2,6-diazaspiro[3.4]octan-6-yl)-1,2,4- Triazin-6-yl)oxy)-N-ethyl-5-fluoro-N-isopropylbenz Amidoformate The following compounds were synthesized by a method similar to that described above for compound 27 by Method A: did.

[0441] [Table 80]

[0442] [Table 81]

[0443] [Table 82]

[0444] [Table 83]

[0445] [Table 84]

[0446] [Table 85]

[0447] [Table 86]

[0448] [Table 87]

[0449] [Table 88]

[0450] [Table 89]

[0451] Compounds 401, 415 (R)-N-(ethyl- 13 C2)-5-fluoro-2-((5-(2-(6-((2- Methoxyethyl)(methyl)amino)-2-methylhexan-3-yl)-2,6-diazo Zaspiro[3.4]octan-6-yl)-1,2,4-triazin-6-yl)oxy )-N-(propan-2-yl- 13 C3) Benzamide (R)-5-Fluoro-N-isopropyl-2-((5-(2-(6-((2-methoxy Ethyl)(methyl)amino)-2-methylhexan-3-yl)-2,6-diazaspiro [3.4]octan-6-yl)-1,2,4-triazin-6-yl)oxy)-N- Methylbenzamide The following compounds were synthesized by a similar method as described above for compound 27 by Method C: did.

[0452] [Table 90]

[0453] Compounds 107, 108 (*R)-N-ethyl-5-fluoro-N-isopropyl-2-((4-(2-(6-( (2-Methoxyethyl)(methyl)amino)-2-methylhexan-3-yl)-2,6 -diazaspiro[3.4]octan-6-yl)pyridazin-3-yl)oxy)benz amide (*S)-N-ethyl-5-fluoro-N-isopropyl-2-((4-(2-(6-( (2-Methoxyethyl)(methyl)amino)-2-methylhexan-3-yl)-2,6 -diazaspiro[3.4]octan-6-yl)pyridazin-3-yl)oxy)benz amide [ka] N-ethyl-5-fluoro-N-isopropyl-2-((4-(2-(6-((2-methyl (2-methylhexyl)(methyl)amino)-2-methylhexan-3-yl-2,6-diaza Spiro[3.4]octan-6-yl)pyridazin-3-yl)oxy)benzamide ( Compound 82) (47.0 mg) was passed through a DAICEL CHIRALPAK IE Purification was performed by FC (column: 250 × 30 mm 10 μm; eluent: 100% MeOH (0.1% ammonia); flow rate: 25 ml / min), the title compound was obtained as a white solid. Compound 107 (19.0 mg, 40%) and compound 108 (21.2 mg, 45%) were obtained. .

[0454] Compounds 117, 118 (*R)-5-Fluoro-N,N-diisopropyl-2-((4-(2-(6-((2- Methoxyethyl)(methyl)amino)-2-methylhexan-3-yl)-2,6-diazo Zaspiro[3.4]octan-6-yl)pyridazin-3-yl)oxy)benzamide (*S)-5-Fluoro-N,N-diisopropyl-2-((4-(2-(6-((2- Methoxyethyl)(methyl)amino)-2-methylhexan-3-yl)-2,6-diazo Zaspiro[3.4]octan-6-yl)pyridazin-3-yl)oxy)benzamide [ka] 5-Fluoro-N,N-diisopropyl-2-((4-(2-(6-((2-methoxy Ethyl)(methyl)amino)-2-methylhexan-3-yl)-2,6-diazaspiro [3.4]Octan-6-yl)pyridazin-3-yl)oxy)benzamide (compound 87) (300 mg) was purified by chiral HPLC using CHIRALPAK AD-H. The column was purified using a 5 × 25 cm, 10 μm column (isocratic elution: n-hexane / EtOH / D EA = 90 / 10 / 0.1 (v / v / v); flow rate: 60 mL / min; temperature: 35°C), The title compound, Compound 117 (122.8 mg), and Compound 11 were obtained as white solids. 8 (137.0 mg) was obtained.

[0455] Compounds 109, 110 (*R)-5-Fluoro-N,N-diisopropyl-2-((5-(2-(6-((2- Methoxyethyl)(methyl)amino)-2-methylhexan-3-yl)-2,6-diazo Zaspiro[3.4]octan-6-yl)-1,2,4-triazin-6-yl)oxy ) Benzamide (*S)-5-Fluoro-N,N-diisopropyl-2-((5-(2-(6-((2- Methoxyethyl)(methyl)amino)-2-methylhexan-3-yl)-2,6-diazo Zaspiro[3.4]octan-6-yl)-1,2,4-triazin-6-yl)oxy ) Benzamide [ka] 5-Fluoro-N,N-diisopropyl-2-((5-(2-(6-((2-methoxy Ethyl)(methyl)amino)-2-methylhexan-3-yl)-2,6-diazaspiro [3.4]Octan-6-yl)-1,2,4-triazin-6-yl)oxy)benz The amide (compound 93) (110 mg) was first added to DAICEL CHIRALPAK A Separation was performed by preparative chiral HPLC through D (column: 5 × 25 cm, 10 μm; migration Phase: A: n-hexane, B: ethanol / DEA = 10 / 0.1 (v / v), A:B = 9 0:10 (60 mL / min; column temperature: 38°C), Phenomenex Gemin Further purification was performed by preparative HPLC using iNX (column: 75 × 30 mm 3 μm; Mobile phase A: water (0.05%NH3H2O+10mM NH4HCO3), B: ACN, 5 Gradient: 0% B to 80% B; flow rate: 25 mL / min), the title compound, Compound 109 ( Compound 110 (27 mg) and Compound 111 (27 mg) were obtained.

[0456] compound 69 N-ethyl-5-fluoro-N-isopropyl-2-((5-(2-(6-((2-meth (2-methylpropyl)amino)-2-methylhexan-3-yl)-2,6-diazo Zaspiro[3.4]octan-6-yl)-1,2,4-triazin-6-yl)oxy ) Benzamide [ka] NaBH3CN (42 mg, 0.666 mmol) was dissolved in MeOH (5 mL) to give 2-(( 5-(2-(6-amino-2-methylhexan-3-yl)-2,6-diazaspiro[3 .4]octan-6-yl)-1,2,4-triazin-6-yl)oxy)-N-ethyl 5-fluoro-N-isopropylbenzamide (compound 3) (200 mg, 0.33 3mmol) and 2-methoxy-2-methylpropanal (72mg, 0.333mmol l) and the reaction mixture was stirred at RT overnight. The reaction mixture was diluted with DCM The organic layer was decanted and chromatographed using Chromabond. The residue was purified by chromatographing on silica gel. The mixture was purified twice by (amorphous SiOH, 24 g; mobile phase: 0.3% NH4OH, 3% MeOH, 97% DCM to 1% NH4OH, 10% MeOH, 90% DCM gradient). The pure fractions were collected and evaporated to dryness to give the title compound (68 mg, 33% yield). LC-MS(ESI)(Method 4):R t = 2.39 min, m / z measured value: 614.8 [M+ H] + .

[0457] Compounds 14, 17, 255, 82, 87 (R)-N-ethyl-5-fluoro-N-isopropyl-2-((5-(2-(2-methyl) yl-6-((3,3,3-trifluoropropyl)amino)hexan-3-yl)-2, 6-diazaspiro[3.4]octan-6-yl)-1,2,4-triazin-6-yl )Oxy)benzamide (R)-N-ethyl-5-fluoro-N-isopropyl-2-((5-(2-(2-methyl) 6-((2,2,2-trifluoroethyl)amino)hexan-3-yl)-2,6 -diazaspiro[3.4]octan-6-yl)-1,2,4-triazin-6-yl) Oxybenzamide (R)-2-((5-(2-(6-((1,3-dihydroxypropan-2-yl)(methyl) (ethyl)amino)-2-methylhexan-3-yl)-2,6-diazaspiro[3.4]o N-ethyl-5-(2-methyl-1,2,4-triazin-6-yl)oxy Fluoro-N-isopropylbenzamide N-ethyl-5-fluoro-N-isopropyl-2-((4-(2-(6-((2-meth (2-methyl-3-hydroxyethyl)(methyl)amino)-2-methylhexan-3-yl)-2,6-diaz Pyrro[3.4]octan-6-yl)pyridazin-3-yl)oxy)benzamide 5-Fluoro-N,N-diisopropyl-2-((4-(2-(6-((2-methoxyethyl) (methyl)amino)-2-methylhexan-3-yl)-2,6-diazaspiro[ 3.4]Octan-6-yl)pyridazin-3-yl)oxy)benzamide The following compounds were synthesized by a method similar to that described above for compound 69.

[0458] [Table 91]

[0459] [Table 92]

[0460] compound 21 (R)-N-ethyl-5-fluoro-N-isopropyl-2-((5-(2-(2-methyl) 6-(methyl(2,2,2-trifluoroethyl)amino)hexan-3-yl)- 2,6-Diazaspiro[3.4]octan-6-yl)-1,2,4-triazine-6- (I)yl)oxy)benzamide [ka] (R)-N-ethyl-5-fluoro-N-isopropyl-2-(( 5-(2-(2-methyl-6-(methylamino)hexan-3-yl)-2,6-diaza spiro[3.4]octan-6-yl)-1,2,4-triazin-6-yl)oxy Benzamide hydrochloride (compound 19) (50 mg, 0.086 mmol), 2,2,2-trimethylbenzamide hydrochloride Trifluoroethyl trifluoromethanesulfonate (60.2 mg, 0.259 mmol) A mixture of HCl (112 mg, 0.865 mmol) and K2CO3 (112 mg, 0.865 mmol) was stirred at RT for 16 h. The reaction mixture was filtered, and the filtrate was passed through Phenomenex Gemini-NX. The product was purified by preparative HPLC (column: 80 × 40 mm 3 μm, mobile phase A: water (0.0 5% ammonia + 10 mM NH4HCO3), Mobile phase B: ACN, Flow rate: 25 mL / min , gradient condition B / A 52%B to 82%) to give the title compound as a brown oil (12.0 6 mg, purity 97%, yield 22%). LC-MS(ESI)(Method 2):R t = 2.345 min, m / z measured value: 624.3 [M +H] + .

[0461] Compounds 15, 23, 247, 253 (R)-2-((5-(2-(6-((2,2-difluoroethyl)amino)-2-methyl (hexan-3-yl)-2,6-diazaspiro[3.4]octan-6-yl)-1, 2,4-triazin-6-yl)oxy)-N-ethyl-5-fluoro-N-isopropyl Rubenzamide (R)-2-((5-(2-(6-((2-(dimethylamino)-2-oxoethyl)( Methyl)amino)-2-methylhexan-3-yl)-2,6-diazaspiro[3.4] Octan-6-yl)-1,2,4-triazin-6-yl)oxy)-N-ethyl-5 -Fluoro-N-isopropylbenzamide N-ethyl-5-fluoro-N-isopropyl-2-((5-(2-((3R)-6-( (2-Methoxypropyl)(methyl)amino)-2-methylhexan-3-yl)-2, 6-diazaspiro[3.4]octan-6-yl)-1,2,4-triazin-6-yl )Oxy)benzamide N-ethyl-5-fluoro-N-isopropyl-2-((5-(2-((3S)-6-( (2-Methoxypropyl)(methyl)amino)-2-methylhexan-3-yl)-2, 6-diazaspiro[3.4]octan-6-yl)-1,2,4-triazin-6-yl )Oxy)benzamide The following compounds were synthesized by a method similar to that described above for compound 21.

[0462] [Table 93]

[0463] compound 24 (*S)-2-((5-(2-(1-amino-3-methylbutan-2-yl)-2,6- Diazaspiro[3.4]octan-6-yl)-1,2,4-triazin-6-yl)o (xy)-N-ethyl-5-fluoro-N-isopropylbenzamide [ka] (*S)-2-((5-(2-(1-(1,3-dioxoisopropyl) 3-Methylbutan-2-yl)-2,6-diazaspiro[3.4 ]octan-6-yl)-1,2,4-triazin-6-yl)oxy)-N-ethyl- 5-Fluoro-N-isopropylbenzamide (Intermediate 18) (0.05 g, 0.079 To a solution of 1.2 mmol, hydrazinium hydroxide (0.127 g, 3.97 mmol) was added The resulting mixture was stirred at 25° C. for 8 hours. The reaction mixture was concentrated under reduced pressure, and the residue was Purification was performed by preparative HPLC using a Boston Prime column (column: C18 1 50 x 30 mm, 5 μm, Mobile phase A: Water (0.04% ammonia + 10 mM NH4HC O3), Mobile phase B: ACN, Flow rate: 30 mL / min, Gradient condition: B / A 25% to 55%) The title compound was obtained as a white solid (5.74 mg, purity 99.5%, yield 14.4%). ). LC-MS(ESI)(Method 1):R t = 2.94 min, m / z measured value: 500.4 [M+ H] + . SFC (Method 7):R t =5.183 minutes.

[0464] compound 25 (*R)-2-((5-(2-(1-amino-3-methylbutan-2-yl)-2,6- Diazaspiro[3.4]octan-6-yl)-1,2,4-triazin-6-yl)o (xy)-N-ethyl-5-fluoro-N-isopropylbenzamide The following compounds were synthesized by a method similar to that described above for compound 24.

[0465] [Table 94]

[0466] compound 35 (*R)-2-((5-(2-(2,6-dimethyl-6-(methylamino)heptane-3 -yl)-2,6-diazaspiro[3.4]octan-6-yl)-1,2,4-triazamispiro[3.4]octan-6-yl (Di-6-yl)oxy)-N-ethyl-5-fluoro-N-isopropylbenzamide Hydrochloride [ka] Benzyl (R)-(5-(6-(6-(2-ethyl)-isopropyl)-2-propanol in i-PrOH (5 mL) (isopropyl)carbamoyl)-4-fluorophenoxy)-1,2,4-triazine-5 -yl)-2,6-diazaspiro[3.4]octan-2-yl)-2,6-dimethyl (2-butan-2-yl)(methyl)carbamate (Intermediate 40) (210 mg, 0.298 m A mixture of Pd / C (2 mol) and HCl (18 μL, 0.22 mmol) was added under Ar. The resulting mixture was heated at 25°C under H2 (15 PSI) atmosphere. The mixture was stirred for 12 h. The mixture was filtered, and the filtrate was concentrated under reduced pressure to give the crude product, which was then converted into Phe Further purification was performed by preparative HPLC through Nomenex Gemini-NX (column :150×30mm 5μm, Mobile phase A: H2O (0.05%HCl), Mobile phase B: AC N, flow rate: 35 mL / min, gradient conditions B / A 3% to 29%), the title compound was obtained as a white solid. The compound was obtained (170 mg, purity 98%, yield 92%). LC-MS(ESI)(Method 2):R t = 2.040 min, m / z measured value: 570.3 [M +H] + . SFC (Method 8):R t =2.145 minutes.

[0467] compound 36 (*S)-2-((5-(2-(2,6-dimethyl-6-(methylamino)heptane-3 -yl)-2,6-diazaspiro[3.4]octan-6-yl)-1,2,4-triazamispiro[3.4]octan-6-yl (Di-6-yl)oxy)-N-ethyl-5-fluoro-N-isopropylbenzamide Hydrochloride The following compounds were synthesized by a method similar to that described above for compound 35.

[0468] [Table 95]

[0469] compound 39 1-((((R)-4-(6-(6-(2-(ethyl(isopropyl)carbamoyl)- 4-Fluorophenoxy)-1,2,4-triazin-5-yl)-2,6-diazaspirillum (3,4)octan-2-yl)-5-methylhexyl)carbamoyl)oxy)ethyl Isobutyrate [ka] (R)-2-((5-(2-(6-amino-2-methylhexyl)methyl)-2-methyl-2-methylhexyl)methyl (3-octan-yl)-2,6-diazaspiro[3.4]octan-6-yl)-1,2,4- Triazin-6-yl)oxy)-N-ethyl-5-fluoro-N-isopropylbenz Amide (compound 64) (150 mg, crude), 1-(((4-nitrophenoxy)carbo (nyl)oxy)ethyl isobutyrate (102 mg, 0.343 mmol) and TEA ( The mixture was stirred at 25° C. for 2 hours. Concentration with HCl gave the crude product, which was purified by preparative HPLC on a Boston Prime column. The resulting mixture was further purified (column: C18 150 × 30 mm 5 μm, mobile phase A: HO (0.0 4% ammonia + 10 mM NH4HCO3), Mobile phase B: ACN, Flow rate: 25 mL / min , gradient condition B / A 55% to 85%) to give the title compound as a yellow solid (82.2%). 0mg). LC-MS(ESI)(Method 1):R t = 3.901 min, m / z measured value: 686.3 [M +H] + .

[0470] Compounds 40, 41, 42 1-((((R)-4-(6-(6-(2-(ethyl(isopropyl)carbamoyl)- 4-Fluorophenoxy)-1,2,4-triazin-5-yl)-2,6-diazaspirillum (3,4)octan-2-yl)-5-methylhexyl)(methyl)carbamoyl) (oxy)ethyl isobutyrate 1-((((*R)-5-(6-(6-(2-(ethyl(isopropyl)carbamoyl) -4-fluorophenoxy)-1,2,4-triazin-5-yl)-2,6-diazas Pyrro[3.4]octan-2-yl)-2,6-dimethylheptan-2-yl)carbamo (yl)oxy)ethyl isobutyrate formate 1-((((*S)-5-(6-(6-(2-(ethyl(isopropyl)carbamoyl) -4-fluorophenoxy)-1,2,4-triazin-5-yl)-2,6-diazas Pyrro[3.4]octan-2-yl)-2,6-dimethylheptan-2-yl)carbamo (yl)oxy)ethyl isobutyrate The following compounds were synthesized by a method similar to that described above for compound 39.

[0471] [Table 96]

[0472] compound 43 (*R)-4-(6-(6-(2-(4-cyclopropylpyrimidin-5-yl)-4- Fluorophenoxy)-1,2,4-triazin-5-yl)-2,6-diazaspiro[ 3.4]octan-2-yl)-5-methylhexanamide [ka] Methyl (*R)-4-( 6-(6-(2-(4-cyclopropylpyrimidin-5-yl)-4-fluorophenoxy) (Ci)-1,2,4-triazin-5-yl)-2,6-diazaspiro[3.4]octane -2-yl)-5-methylhexanoate (Intermediate 48) (110 mg, 0.178 mm To the mixture of 1.25 mmol, NH4Cl (95 mg, 1.78 mmol) was added. The mixture was stirred for 16 h at 40° C. After cooling to RT, the reaction mixture was concentrated in vacuo to give a residue The residue was purified by preparative HPLC using Boston Prime (column: C1 8 150 × 30 mm 5 μm; Eluent: ACN / H2O (0.04% ammonia + 10 mM NH4HCO3) 30% to 60% (v / v) to obtain the title compound as a white solid. Obtained (34 mg, 34%). LC-MS(ESI)(Method 1):R t = 3.287 min, m / z measured value: 547.2 [M +H] + . SFC (Method 9):R t =6.275 minutes.

[0473] compound 44 The following compounds were synthesized by a method similar to that described above for compound 43.

[0474] [Table 97]

[0475] compound 50 4-(6-(6-(2-(4-cyclopropylpyrimidin-5-yl)-4-fluorophenyl) (phenoxy)-1,2,4-triazin-5-yl)-2,6-diazaspiro[3.4]o (2-octanyl)-N,5-dimethylhexanamide [ka] Methanamine hydrochloride (600 mg, 8.89 mmol) was dissolved in MeNH2 / EtOH (3 Methyl 4-(6-(2-(4-cyclopropylpyrimidine-3%, 20 mL) 5-yl)-4-fluorophenoxy)-1,2,4-triazin-5-yl)-2,6 -diazaspiro[3.4]octan-2-yl)-5-methylhexanoate (Intermediate 4 The reaction mixture was heated to 80° C. After cooling to RT, the reaction mixture was concentrated under reduced pressure to give the crude product, which This was further purified by FCC (DCM / MeOH=10:1) to give the title compound as a yellow solid. (100 mg, 18% yield).

[0476] Compounds 45 and 46 (*S)-4-(6-(6-(2-(4-cyclopropylpyrimidin-5-yl)-4- Fluorophenoxy)-1,2,4-triazin-5-yl)-2,6-diazaspiro[ 3.4]octan-2-yl)-N,5-dimethylhexanamide (*R)-4-(6-(6-(2-(4-cyclopropylpyrimidin-5-yl)-4- Fluorophenoxy)-1,2,4-triazin-5-yl)-2,6-diazaspiro[ 3.4]octan-2-yl)-N,5-dimethylhexanamide [ka] 4-(6-(6-(2-(4-cyclopropylpyrimidin-5-yl)-4-fluoro Phenoxy)-1,2,4-triazin-5-yl)-2,6-diazaspiro[3.4] Octan-2-yl)-N,5-dimethylhexanamide (compound 50) (250 mg, 0.446 mmol) by SFC through DAICEL CHIRALPAK AS The purified solution was collected by filtration (250 × 30 mm, 10 μm) (eluent: EtOH (0.1% v / v ammonia) (near) medium supercritical CO2, 20 / 20, v / v), both of which produced the title compound as a white solid. Compound 45 (81.10 mg, purity 98%, yield 32%) and compound 46 (72.5 3 mg, purity 98%, yield 28%) was obtained.

[0477] compound 45 LC-MS(ESI)(Method 1):R t = 3.323 min, m / z measured value: 561.2 [ M+H] + . SFC (Method 10):R t =3.880 minutes.

[0478] compound 46 LC-MS(ESI)(Method 1):R t = 3.353 min, m / z measured value: 561.2 [ M+H] + . SFC (Method 10):R t =3.707 minutes.

[0479] compound 49 N-ethyl-5-fluoro-2-((5-(2-(6-hydroxy-2-methylhexane -3-yl)-2,6-diazaspiro[3.4]octan-6-yl)-1,2,4- Triazin-6-yloxy)-N-isopropylbenzamide [ka] 2-((5-(2-(6-((tert-butyldimethylsilyl) )oxy)-2-methylhexan-3-yl)-2,6-diazaspiro[3.4]octa (1,2,4-triazin-6-yl)-1,2,4-triazin-6-yl)oxy)-N-ethyl-5-fluoro Oro-N-isopropylbenzamide (Intermediate 55) (217 mg, 0.338 mmol) ) solution was added with 4-methylbenzenesulfonic acid (203 mg, 1.18 mmol). The reaction mixture was stirred at RT overnight. The mixture was concentrated under reduced pressure to give the crude product, which was Further analysis was performed by preparative HPLC using Phenomenex Gemini NX-C18. Purification was performed using a column of 75 × 30 mm (3 μm); eluent: ACN / H2O (0.04% ammonia). Nia + 10 mM NH₄HCO₃) 35% to 60% (v / v)), titled as a white solid (45 mg, 25% yield)

[0480] Compounds 47 and 48 (*R)-N-ethyl-5-fluoro-2-((5-(2-(6-hydroxy-2-methyl) (hexan-3-yl)-2,6-diazaspiro[3.4]octan-6-yl)-1, 2,4-Triazin-6-yl)oxy)-N-isopropylbenzamide (*S)-N-ethyl-5-fluoro-2-((5-(2-(6-hydroxy-2-methyl) (hexan-3-yl)-2,6-diazaspiro[3.4]octan-6-yl)-1, 2,4-Triazin-6-yl)oxy)-N-isopropylbenzamide [ka] N-ethyl-5-fluoro-2-((5-(2-(6-hydroxy-2-methylhexyl) (3-octan-yl)-2,6-diazaspiro[3.4]octan-6-yl)-1,2,4- Triazin-6-yl)oxy)-N-isopropylbenzamide (compound 49) (45 0.0mg, 0.0850mmol) in DAICEL CHIRALPAK IG (25 The product was further purified by SFC through a 0.0 × 30 mm 10 μm filter (eluent: EtOH (0. 1% ammonia) in 40% to 40% (v / v) supercritical CO2), both as white solids The title compound, Compound 47 (17.38 mg, 39% yield) and Compound 48 (15. 79 mg, 35% yield was obtained.

[0481] compound 47 LCMS(ESI)(Method 1):R t = 3.240 min, m / z measured value 529.2 [M+ H] + . SFC (Method 11):R t =4.778 minutes.

[0482] compound 48 LCMS(ESI)(Method 1):R t = 3.212 min, m / z measured value 529.3 [M+ H] + . SFC (Method 11):R t =5.161 minutes.

[0483] compound 64 (R)-2-((5-(2-(6-amino-2-methylhexan-3-yl)-2,6- Diazaspiro[3.4]octan-6-yl)-1,2,4-triazin-6-yl)o (xy)-N-ethyl-5-fluoro-N-isopropylbenzamide [ka] tert-Butyl (R)-(4-(6-(6-(2-ethyl)methyl)methyl)-isopropyl tert-butyl (R)-(4-(6-(6-(2-ethyl)methyl ... (isopropyl)carbamoyl)-4-fluorophenoxy)-1,2,4-triazine-5 -yl)-2,6-diazaspiro[3.4]octan-2-yl)-5-methylhexyl ) carbamate (compound 62) (550 mg, 0.876 mmol) in a solution of TFA ( 4 mL) was slowly added and the resulting mixture was stirred at 25° C. for 1 hour. Concentration under reduced pressure gave a residue. The residue was diluted in DCM (40 mL) and added NaOH (2M, 1 The pH value was adjusted to around 12 with a 6 mL aqueous solution of DCM (10 mL × 2). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give The title compound was obtained as a yellow solid (460 mg, crude) which was carried on to the next step without further purification. It was used as is in the process.

[0484] compound 97 2-((5-(2-(6-amino-2-methylhexan-3-yl)-2,6-diazonium Pyrro[3.4]octan-6-yl)-1,2,4-triazin-6-yl)oxy)- 5-Fluoro-N,N-diisopropylbenzamide The following compounds were synthesized by methods similar to those described above for compound 64.

[0485] [Table 98]

[0486] compound 65 (R)-2-((5-(2-(6-amino-2-methylhexan-3-yl)-2,6- Diazaspiro[3.4]octan-6-yl)-1,2,4-triazin-6-yl)o (xy)-N-ethyl-5-fluoro-N-isopropylbenzamide hydrochloride [ka] tert-Butyl (R)-(4-(6-(6-(2- (Ethyl(isopropyl)carbamoyl)-4-fluorophenoxy)-1,2,4-trimethyl (riazin-5-yl)-2,6-diazaspiro[3.4]octan-2-yl)-5-methyl Solution of (ethylhexyl)carbamate (compound 62) (250 mg, 0.398 mmol) To this was added a solution of 4M HCl in dioxane (10 mL, 40 mmol), and the resulting mixture was The mixture was stirred at RT for 16 h. The reaction mixture was concentrated in vacuo to give the title compound as a yellow oil. The product was obtained (220 mg, crude, HCl salt), which was used directly in the next step without further purification. I used it.

[0487] compound 67 N-ethyl-5-fluoro-N-isopropyl-2-((5-(2-(2-methyl-6- (Methylamino)hexan-3-yl)-2,6-diazaspiro[3.4]octane-6 -yl)-1,2,4-triazin-6-yl)oxy)benzamide hydrochloride [ka] tert-Butyl (4-(6-(2-ethyl)isopropyl)propanol) in DCM (10 mL) (carbamoyl)-4-fluorophenoxy)-1,2,4-triazin-5-yl )-2,6-diazaspiro[3.4]octan-2-yl)-5-methylhexyl)(methyl To a solution of ethyl) carbamate (compound 60) (1 g, 1.56 mmol) in dioxane ( 5 mL, 20 mmol) was added and the resulting mixture was stirred at RT for 1 h. The reaction mixture was concentrated in vacuo to give the title compound (960 mg, crude, HCl salt). This was used directly in the next step without further purification.

[0488] Compounds 66, 73, 92 (S)-2-((5-(2-(6-amino-2-methylhexan-3-yl)-2,6- Diazaspiro[3.4]octan-6-yl)-1,2,4-triazin-6-yl)o (xy)-N-ethyl-5-fluoro-N-isopropylbenzamide hydrochloride 2-((4-(2-(6-amino-2-methylhexan-3-yl)-2,6-diazonium Pyrro[3.4]octan-6-yl)pyridazin-3-yl)oxy)-5-fluoro- N,N-Diisopropylbenzamide hydrochloride 5-Fluoro-N,N-diisopropyl-2-((5-(2-(2-methyl-6-(methyl (amino)hexan-3-yl)-2,6-diazaspiro[3.4]octan-6-yl )-1,2,4-triazin-6-yl)oxy)benzamide hydrochloride The following compounds were prepared by methods similar to those described above for Compound 65 and Compound 67: ...

Claims

1. Formula (I) 【Chemistry 1】 (In the formula, R １ａ is -C(=O)-NR ｘａ R ｘｂ , Het, or 【Chemistry 2】 represents Het is a 5 or 6 alkyl group containing 1, 2 or 3 nitrogen atoms and optionally a carbonyl moiety. represents a 6-membered monocyclic aromatic ring; wherein the 5- or 6-membered monocyclic aromatic ring is optionally ３～６ Cycloalkyl and C １～４ substituted with one or two substituents selected from the group consisting of alkyl; R ｘａ and R ｘｂ are each independently hydrogen, C １～４ Alkyl and C ３～６ Cycloa selected from the group consisting of rutile and rutile; R １ｂ represents F or Cl, Y １ is -CR ５ａ R ５ｂ -, -O- or -NR ５ｃ represents -, R ２ is hydrogen, halo, C １～４ Alkyl, —O—C １～４ Alkyl and -NR ７ａ R ７ｂ is selected from the group consisting of 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 isopropyl, R ５ａ , R ５ｂ , R ５ｃ , R ７ａ and R ７ｂ are each independently hydrogen, C １～４ Al Kill and C ３～６ cycloalkyl; R ３ is -C １～６ Alkyl-NR ８ａ R ８ｂ , -C １～６ Alkyl-C(=O)-NR ９ａ R ９ｂ , -C １～６ Alkyl-OH or -C １～６ Alkyl-NR １１ -C(=O) -O-C １～４ Alkyl-O-C(=O)-C １～４ represents alkyl, Here, R ３ C in the definition of １～４ Alkyl or C １～６ Each of the alkyl moieties is Independently of each other, cyano, halo, —OH and —O—C １～４ From the group consisting of alkyl may be substituted with 1, 2, or 3 substituents, each independently selected; R ８ａ and R ８ｂ are each independently hydrogen, C １～６ Alkyl, —C(═O)—C １ ～４ Alkyl, —C(═O)—O—C １～４ Alkyl, —C(═O)—NR １２ａ R １２ ｂ and -OH, cyano, halo, -S(=O) ２ -C １～４ Alkyl, —O—C １～４ a Rukyr, -C(=O)-NR １０ａ R １０ｂ and -NR １０ｃ -C(=O)-C １～４ a substituted with 1, 2, or 3 substituents each independently selected from the group consisting of alkyl, alkyl, aryl, aryl, aryl and aryl; C １～６ is selected from the group consisting of alkyl, R ９ａ , R ９ｂ , R １０ａ , R １０ｂ , R １０ｃ , R １１ , R １２ａ and R １２ｂ Ha, so each independently hydrogen and C １～６ alkyl) or a tautomeric or stereoisomeric form thereof, or a pharmaceutically acceptable salt thereof, is a solvate.

2. R ３ is -C １～６ Alkyl-NR ８ａ R ８ｂ , -C １～６ Alkyl-C(=O)-N R ９ａ R ９ｂ , -C １～６ Alkyl-OH or -C １～６ Alkyl-NR １１ -C(=O )-O-C １～４ Alkyl-O-C(=O)-C １～４ represents alkyl, Here, R ３ C in the definition of １～４ Alkyl or C １～６ Each of the alkyl moieties is Independently of each other, cyano, halo or —O—C １～４ independently from the group consisting of alkyl and may be substituted with 1, 2 or 3 substituents selected from the following: R ８ａ and R ８ｂ are each independently hydrogen, C １～６ Alkyl, —C(═O)—C １ ～４ Alkyl, —C(═O)—O—C １～４ Alkyl, —C(═O)—NR １２ａ R １２ ｂ and cyano, halo, -S(=O) ２ -C １～４ Alkyl, —O—C １～４ Alkyl and Bi-C(=O)-NR １０ａ R １０ｂ 1 and 2 independently selected from the group consisting of or C substituted with 3 substituents １～６ is selected from the group consisting of alkyl, R ９ａ , R ９ｂ , R １０ａ , R １０ｂ , R １１ , R １２ａ and R １２ｂ are independent of each other and hydrogen and C １～６ 2. The compound of claim 1, wherein the compound is selected from the group consisting of alkyl.

3. R １ａ is -C(=O)-NR ｘａ R ｘｂ or Het, Het represents a 6-membered monocyclic aromatic ring containing two nitrogen atoms; wherein the 6-membered monocyclic aromatic ring optionally contains one C ３～６ Cycloalkyl It is replaced, R ｘａ and R ｘｂ is C １～４ represents alkyl, R １ｂ represents F, Y １ represents —O—, R ２ is hydrogen, U represents N; R ３ is -C １～６ Alkyl-NR ８ａ R ８ｂ , -C １～６ Alkyl-C(=O)-NR ９ａ R ９ｂ , -C １～６ Alkyl-OH or -C １～６ Alkyl-NR １１ -C(=O) -O-C １～４ Alkyl-O-C(=O)-C １～４ represents alkyl, R ８ａ and R ８ｂ are each independently hydrogen, C １～６ Alkyl, —C(═O)—C １ ～４ Alkyl, —C(═O)—O—C １～４ Alkyl, —C(═O)—NR １２ａ R １２ ｂ and cyano, halo, -S(=O) ２ -C １～４ Alkyl and —O—C １～４ Alkyl C substituted with 1, 2 or 3 substituents each independently selected from the group consisting of １～ ６ 3. The compound of claim 2, wherein the compound is selected from the group consisting of alkyl.

4. R １ａ is -C(=O)-NR ｘａ R ｘｂ represents R ｘａ and R ｘｂ is C １～４ represents alkyl, R １ｂ represents F, Y １ represents —O—, R ２ is hydrogen, U represents N; R ３ is -C １～６ Alkyl-NR ８ａ R ８ｂ , -C １～６ Alkyl-C(=O)-NR ９ａ R ９ｂ or -C １～６ represents alkyl-OH, R ８ａ and R ８ｂ are each independently hydrogen, C １～６ Alkyl, —C(═O)—C １ ～４ Alkyl, —C(═O)—O—C １～４ Alkyl, —C(═O)—NR １２ａ R １２ ｂ and cyano, halo, -S(=O) ２ -C １～４ Alkyl and —O—C １～４ Alkyl C substituted with 1, 2 or 3 substituents each independently selected from the group consisting of １～ ６ 3. The compound of claim 2, wherein the compound is selected from the group consisting of alkyl.

5. R １ａ is -C(=O)-NR ｘａ R ｘｂ or Het, Het represents a 6-membered monocyclic aromatic ring containing two nitrogen atoms; wherein the 6-membered monocyclic aromatic ring is ３～６ substituted with cycloalkyl, R ｘａ and R ｘｂ is C １～４ represents 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 isopropyl, R ３ is -C １～６ Alkyl-NR ８ａ R ８ｂ , -C １～６ Alkyl-C(=O)-NR ９ａ R ９ｂ , -C １～６ Alkyl-OH or -C １～６ Alkyl-NR １１ -C(=O) -O-C １～４ Alkyl-O-C(=O)-C １～４ represents alkyl, Here, R ３ C in the definition of １～４ Alkyl or C １～６ Each of the alkyl moieties is Independently of each other, —OH and —O—C １～４ alkyl, may be substituted with 1, 2 or 3 substituents selected from R ８ａ and R ８ｂ are each independently hydrogen, C １～６ Alkyl, —C(═O)—C １ ～４ Alkyl, —C(═O)—O—C １～４ Alkyl, —C(═O)—NR １２ａ R １２ ｂ and -OH, cyano, halo, -S(=O) ２ -C １～４ Alkyl, —O—C １～４ a Rukyr, -C(=O)-NR １０ａ R １０ｂ and -NR １０ｃ -C(=O)-C １～４ a substituted with 1, 2, or 3 substituents each independently selected from the group consisting of alkyl, alkyl, aryl, aryl, aryl and aryl; C １～６ is selected from the group consisting of alkyl, R ９ａ , R ９ｂ , R １０ａ , R １０ｂ , R １０ｃ , R １１ , R １２ａ and R １２ｂ Ha, so each independently hydrogen and C １～６ 10. The method of claim 1, wherein the alkyl group is selected from the group consisting of alkyl. Compound.

6. R １ａ is -C(=O)-NR ｘａ R ｘｂ or Het, Het represents a 6-membered monocyclic aromatic ring containing two nitrogen atoms; wherein the 6-membered monocyclic aromatic ring is ３～６ substituted with cycloalkyl, R ｘａ and R ｘｂ is C １～４ represents 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 isopropyl, R ３ is -C １～６ Alkyl-NR ８ａ R ８ｂ represents Here, R ３ C in the definition of １～６ The alkyl portion is —OH and —O—C １～４ Archi and each of the substituted or unsubstituted alkyl groups may be substituted with one, two, or three substituents each independently selected from the group consisting of: R ８ａ and R ８ｂ are each independently hydrogen, C １～６ Alkyl and -OH, cyano , halo, -S(=O) ２ -C １～４ Alkyl, —O—C １～４ Alkyl, —C(═O)— NR １０ａ R １０ｂ and -NR １０ｃ -C(=O)-C １～４ From the group consisting of alkyl C substituted with 1, 2 or 3 independently selected substituents １～６ From alkyl is selected from the group R １０ａ , R １０ｂ and R １０ｃ are each independently hydrogen and C １～６ From alkyl 2. The compound of claim 1 selected from the group consisting of:

7. R １ａ is -C(=O)-NR ｘａ R ｘｂ represents R ｘａ and R ｘｂ is C １～４ represents alkyl, R １ｂ represents F, Y １ represents —O—, R ２ represents hydrogen, U represents 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 isopropyl, R ３ is -C １～６ Alkyl-NR ８ａ R ８ｂ represents R ８ａ and R ８ｂ are each independently hydrogen, C １～６ Alkyl and -OH, cyano , halo, -S(=O) ２ -C １～４ Alkyl, —O—C １～４ Alkyl and —C(═O) -NR １０ａ R １０ｂ one, two, or three substitutions each independently selected from the group consisting of C substituted with a group １～６ is selected from the group consisting of alkyl, R １０ａ and R １０ｂ are each independently hydrogen and C １～６ From the group consisting of alkyl The compound of claim 1, wherein

8. Y １ The compound according to claim 1, wherein represents —O—.

9. R １ｂ The compound of claim 1 , wherein represents F.

10. A compound according to any one of claims 1 to 9 and a pharmaceutically acceptable carrier or diluent.

10. A pharmaceutical composition comprising:

11. A process for preparing the pharmaceutical composition of claim 10, comprising the steps of: and mixing the carrier with a therapeutically effective amount of a compound according to any one of claims 1 to 9. A process involving:

12. A compound according to any one of claims 1 to 9 or claim 1 for use as a medicament.

10. The pharmaceutical composition according to claim 0.

13. A compound or compound according to any one of claims 1 to 9 for use in the prevention or treatment of cancer. The pharmaceutical composition of claim 10.

14. Prevention or treatment of leukemia, myelodysplastic syndromes (MDS) and myeloproliferative neoplasms (MPN) The compound according to any one of claims 1 to 9 or the compound according to claim 10 for use in Pharmaceutical compositions.

15. The leukemia is (NPM1) mutant leukemia, Item 15. A compound or pharmaceutical composition for use according to item 14.

16. Cancers include leukemia, lymphoma, myeloma, prostate cancer, lung cancer, breast cancer, pancreatic cancer, colon cancer, and liver cancer.

14. The method of claim 13, wherein the cancer is selected from solid tumor cancers such as melanoma and glioblastoma. A compound or pharmaceutical composition for the treatment of

17. The leukemia may be acute leukemia, chronic leukemia, myeloid leukemia, myeloid leukemia, lymphoblastic leukemia, or the like. Hematologic malignancies, lymphocytic leukemia, acute myeloid leukemia (AML), chronic myeloid leukemia (CML), acute Myeloid lymphoblastic leukemia (ALL), chronic lymphocytic leukemia (CLL), T-cell prolymphocytic leukemia Leukemia (T-PLL), large granular lymphocytic leukemia, hairy cell leukemia (HCL), MLL Rearranged leukemia, MLL-PTD leukemia, MLL amplified leukemia, MLL positive leukemia and HOX / MEIS1 gene expression characteristic in the prevention or treatment of leukemia selected from leukemias showing 15. A compound or pharmaceutical composition for use according to claim 14.

18. A method for treating or preventing a disorder selected from cancer, comprising administering to a subject in need thereof a therapeutic agent. A therapeutically effective amount of the compound according to any one of claims 1 to 9 or the medicament according to claim 10. A method comprising administering the composition.

19. structure 【Transformation 3】 or a tautomeric or stereoisomeric form thereof or a pharmaceutically acceptable salt thereof addition salts or solvates thereof.

20. 1. A process for preparing an intermediate comprising the steps of: 【Chemistry 4】 wherein PG is a suitable protecting group such as benzyl; n1 and n2 are as defined in relation to formula (I); Step 23: In a suitable solvent, such as THF, a suitable solution, such as DIEA and n-BuLi in the presence of a suitable base at a suitable temperature, such as from −78° C. to −25° C. Step 24: A suitable reduction such as DIBAL-H in a suitable solvent such as toluene In the presence of a suitable flow chemistry, at a suitable temperature, for example, from -55°C to -65°C, (implemented in a tree system) A process involving:

21. 1. A process for preparing an intermediate comprising the steps of: 【Transformation 5】 wherein PG is a suitable protecting group such as benzyl; The other variables are as defined for formula (I). Step 30: In a suitable solvent such as toluene, for example NaBH(OAc) ３ Suitable for In the presence of a suitable reducing agent, for example, in the presence of a suitable base such as TEA, for example, at 5°C to 30°C, At a suitable temperature, Step 31: For example, H ２ In a suitable solvent such as K ２ HPO ４ In the presence of a suitable base such as at a suitable temperature, for example, 50°C to 55°C, Step 32: Palladium hydroxide on carbon in the presence of MSA in a suitable solvent such as EtOH under a hydrogen atmosphere within a suitable pressure range, for example, 0.27 to 0.40 MPa, for example At a suitable temperature such as 5°C to 45°C, Step 33: In a suitable solvent such as 2-methyltetrahydrofuran, for example, TEA in the presence of a suitable base at a suitable temperature, such as from −50° C. to −40° C. Step 34: In a suitable solvent such as 2-methyltetrahydrofuran, for example TMG in the presence of a suitable base at a suitable temperature, for example, 20°C to 30°C, Step 35: In the presence of a suitable catalyst, such as palladium on carbon, in a suitable solvent, such as MeOH under a hydrogen atmosphere within a suitable pressure range, for example, 0.20 to 0.30 MPa, for example, 2 at a suitable temperature such as 0°C to 30°C A process involving:

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