Carbonyl-substituted diazaspiro compounds and uses thereof

Abstract

The present disclosure relates to compounds of Formula I, wherein the variables are as defined herein; pharmaceutical compositions containing them, methods for preparing them, and uses thereof.

Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of priority to International Application No. PCT / CN2021 / 135427, filed December 3, 2021, and International Application No. PCT / CN2022 / 115162, filed August 26, 2022, both of which are incorporated by reference in their entireties herein.

[0002] The present disclosure provides carbonyl-substituted diazaspiro compounds that inhibit the interaction of menin with MLL and MLL fusion proteins. The disclosure also provides methods for preparing these compounds, pharmaceutical compositions containing these compounds, and their use for the prevention or treatment of cancer and other diseases mediated by the interaction of menin with MLL and / or MLL fusion proteins. [Background technology]

[0003] Rearrangements of the Mixed Lineage Leukemia (also known as MLL, MLL1 or KMT2A) gene occur in approximately 10% of acute leukemias, are particularly frequent in infant acute leukemia, and account for up to approximately 70% of infant acute lymphoblastic leukemia (ALL) cases (Issa, G.C. et al., Leukemia, 2021, 35, 2482). MLLr (MLL rearrangement) is also observed in 85% of secondary acute myeloid (myelogenous) leukemia (AML) cases that develop in patients treated with topoisomerase II inhibitors. More than 80 partner genes are involved in MLL fusions, and six major partner genes, including AF4 (ALL-1 fusion gene on chromosome 4), AF6, AF9, AF10, ENL (11-19 leukemia), and ELL (11-19 lysine-rich leukemia), account for approximately 80% of cases (Meyer, C. et al., 2018, Leukemia, 32, 273). MLL translocations lead to the expression of MLL fusion proteins that promote proliferation and inhibit hematopoietic differentiation, ultimately promoting the development of leukemia. MLLr leukemia is one of the high-risk types of leukemia with high aggressiveness, treatment resistance, high frequency of early relapse, and a 5-year survival rate of only approximately 35% (Marschalek, R. Br. J Haematol. 2011, 152, 141). Therefore, there are substantial unmet medical needs in MLLr leukemia.

[0004] Protein-protein interactions (PPIs) between menin and MLLr are important in the pathogenesis of MLLr-driven leukemia through deregulation of HOXA and MEIS1 genes. Meanwhile, recent studies have revealed the importance of menin-MLL1 wild-type (wt) interactions in AML with mutations in the nucleophosmin 1 (NPM1) gene. NPM1 mutations (NMP1c) are found in more than 30% of AML patients with poor 5-year overall survival rates and are also associated with increased expression of HOXA and MEIS1 genes (Kuhn,MW et al. Cancer Discov. 2016,6,1166). Menin inhibitors have been reported to be able to block the interaction of menin with MLLr and MLL wt, suggesting their potential use in the treatment of MLLr-related acute leukemia and NPM-mutated AML (Klossowski,S.et al. J Clin Invest. 2020,130,981). Summary of the Invention

[0005] This summary is provided to introduce a simplified version of concepts that are further described below in the Detailed Description. This summary is not intended to identify key features or essential features of the claimed subject matter, nor is it intended to be used to limit the scope of the claimed subject matter.

[0006] The present disclosure provides compounds of formula I: [ka] [In the formula, X is halo or CN; Y is N or CH; Z is CH 2 , O, S, and NH; R 1 teeth, 1)-(C=O)-NRaRb (in the formula, Ra and Rb are deuterium, halo, OH, CN and C 1~6 C optionally substituted with 1, 2 or 3 substituents selected from the group consisting of alkoxyl 1~6each independently selected from the group consisting of alkyl, a 3- to 6-membered cycloalkyl ring, and a 5- to 9-membered heterocyclyl ring; or Ra and Rb together with the nitrogen atom to which they are attached form C 1~6 forming a 5-9 membered heterocyclyl ring optionally substituted with 1, 2 or 3 substituents selected from the group consisting of alkyl, halo, OH and CN; 2) Halo, CN, C 1~6 C optionally substituted with 1, 2 or 3 substituents selected from the group consisting of alkyl, halo, CN and OH; 1~6 Alkyl, 3- to 5-membered cycloalkyl ring, oxo and C 1~6 a 5-10 membered heteroaryl ring optionally substituted with 1, 2 or 3 substituents selected from the group consisting of alkoxyl or C 6~10 Aryl ring; is selected from the group consisting of R 2 and R 3 are each independently H or D; Each R 4 is halo, CN, OH, oxo, C 1~6 Alkylsulfonyl-, C 1~6 Alkylsulfonylamino-, C 1~6 Alkylcarbonylamino-, C 6~10 Aryl ring, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 1~6 independently selected from the group consisting of alkoxyl, a 3- to 9-membered cycloalkyl ring, a 5- to 10-membered heteroaryl ring, and a 4- to 9-membered heterocyclyl ring, wherein the alkyl, alkenyl, alkynyl, alkoxyl, cycloalkyl ring, heteroaryl ring, or heterocyclyl ring is optionally substituted with 1, 2, or 3 substituents selected from the group consisting of halo, CN, and OH; Two adjacent R 4 together with the carbon atom to which they are attached, C 1~6 Alkyl, -C 1~6 Alkyl-OH, C 1~6 Alkoxyl-C 1~6optionally forming a 3-9 membered cycloalkyl ring, optionally substituted with 1, 2 or 3 substituents selected from the group consisting of alkyl-, halo, CN and OH; Or, two R attached to the same carbon atom 4 together with the carbon atom, C 1~6 Alkyl, -C 1~6 Alkyl-OH, C 1~6 Alkoxy-C 1~6 optionally forming a 3- to 6-membered cycloalkyl ring or a 4- to 6-membered heterocyclyl ring, optionally substituted with 1, 2, or 3 substituents selected from the group consisting of alkyl-, halo, CN, and OH; Or, two adjacent R 4 together with the carbon atom to which they are attached form a 5- to 10-membered heteroaryl ring, C 6~10 Optionally forms an aryl ring or a 5- to 9-membered heterocyclyl ring, the heteroaryl ring or the aryl ring being 1~6 Alkyl, C 1~6 Haloalkyl, -C 1~6 Alkyl-OH, C 1~6 Alkoxy-C 1~6 is optionally substituted by one, two or three substituents selected from the group consisting of alkyl-, halo, CN and OH, the alkyl being optionally substituted by one 3-6 membered cycloalkyl ring or phenyl, and the heterocyclyl ring is 1~6 Alkyl, C 1~6 Haloalkyl, -C 1~6 Alkyl-OH, C 1~6 Alkoxyl-C 1~6 optionally substituted with 1, 2 or 3 substituents selected from the group consisting of alkyl-, oxo, halo, CN and OH; R 5 is H, halo, methyl optionally substituted with 1, 2 or 3 deuterium or halo, methoxyl optionally substituted with 1, 2 or 3 deuterium or halo, NH 2 , C.H. 3 NH, or (CH 3 ) 2 N, a, b, c, and d are each independently 1 or 2; n is 0, 1 or 2; m is 0, 1, 2, 3 or 4; However, R 4 is, if present, substituted at any chemically permissible position on the heterocyclyl, except for the N atom adjacent to the point of attachment of the heterocyclyl to the remainder of the compound. or a pharma- ceutically acceptable salt, or stereoisomer, racemate, tautomer, hydrate or solvate thereof.

[0007] The compounds of formula I, or stereoisomers, racemates, tautomers, hydrates or solvates, or pharma- ceutically acceptable salts thereof, as well as specific compounds disclosed in the context of the present invention and encompassed within the scope of the above compounds, are collectively referred to as "compounds of the present disclosure."

[0008] The present disclosure also provides compounds of the present disclosure for use as a medicament.

[0009] The present disclosure also provides a compound of the present disclosure for use in the treatment or prevention of cancer or diabetes.

[0010] The present disclosure also provides pharmaceutical compositions comprising a compound of the present disclosure, and optionally a pharma- ceutically acceptable carrier.

[0011] The present disclosure also provides a kit for treating or preventing cancer or diabetes comprising a pharmaceutical composition of the present disclosure and instructions for use.

[0012] The present disclosure also provides the use of a compound of the present disclosure for the treatment or prevention of cancer or diabetes.

[0013] The disclosure also provides the use of a compound of the disclosure in the manufacture of a medicament for the treatment or prevention of cancer or diabetes.

[0014] The present disclosure provides a method for inhibiting the interaction of menin with MLL and / or MLL fusion proteins in vivo or in vitro, comprising contacting menin with an effective amount of a compound of the present disclosure.

[0015] The present disclosure also provides a method of treating or preventing cancer or diabetes, comprising administering to a subject in need thereof an effective amount of a compound of the present disclosure.

[0016] The present disclosure also provides a combination comprising a compound of the present disclosure and at least one additional therapeutic agent.

[0017] The present disclosure also provides processes for the preparation of the disclosed compounds, and intermediates for preparing the disclosed compounds. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0018] Embodiments of the Disclosure - Part A Embodiment 1. Formula I: [ka] [In the formula, X is halo or CN; Y is N or CH; Z is CH 2 , O, S, and NH; R 1 teeth, 1)-(C=O)-NRaRb (in the formula, Ra and Rb are deuterium, halo, OH, CN and C 1~6 C optionally substituted with 1, 2 or 3 substituents selected from the group consisting of alkoxyl 1~6 each independently selected from the group consisting of alkyl, a 3- to 6-membered cycloalkyl ring, and a 5- to 9-membered heterocyclyl ring; or Ra and Rb together with the nitrogen atom to which they are attached form C 1~6forming a 5-9 membered heterocyclyl ring optionally substituted with 1, 2 or 3 substituents selected from the group consisting of alkyl, halo, OH and CN; 2) Halo, CN, C 1~6 C optionally substituted with 1, 2 or 3 substituents selected from the group consisting of alkyl, halo, CN and OH; 1~6 Alkyl, 3- to 5-membered cycloalkyl ring, oxo and C 1~6 a 5-10 membered heteroaryl ring optionally substituted with 1, 2 or 3 substituents selected from the group consisting of alkoxyl or C 6~10 Aryl ring; is selected from the group consisting of R 2 and R 3 are each independently H or D; Each R 4 is halo, CN, OH, oxo, C 1~6 Alkylsulfonyl-, C 1~6 Alkylsulfonylamino-, C 1~6 Alkylcarbonylamino-, C 6~10 Aryl ring, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 1~6 independently selected from the group consisting of alkoxyl, a 3- to 9-membered cycloalkyl ring, a 5- to 10-membered heteroaryl ring, and a 4- to 9-membered heterocyclyl ring, wherein the alkyl, alkenyl, alkynyl, alkoxyl, cycloalkyl ring, heteroaryl ring, or heterocyclyl ring is optionally substituted with 1, 2, or 3 substituents selected from the group consisting of halo, CN, and OH; Two adjacent R 4 together with the carbon atom to which they are attached, C 1~6 Alkyl, -C 1~6 Alkyl-OH, C 1~6 Alkoxyl-C 1~6 optionally forming a 3-9 membered cycloalkyl ring, optionally substituted with 1, 2 or 3 substituents selected from the group consisting of alkyl-, halo, CN and OH; Or, two R attached to the same carbon atom4 together with the carbon atom, C 1~6 Alkyl, -C 1~6 Alkyl-OH, C 1~6 Alkoxyl-C 1~6 optionally forming a 3- to 6-membered cycloalkyl ring or a 4- to 6-membered heterocyclyl ring, optionally substituted with 1, 2, or 3 substituents selected from the group consisting of alkyl-, halo, CN, and OH; Or, two adjacent R 4 together with the carbon atom to which they are attached form a 5- to 10-membered heteroaryl ring, C 6~10 Optionally forms an aryl ring or a 5- to 9-membered heterocyclyl ring, the heteroaryl ring or the aryl ring being 1~6 Alkyl, C 1~6 Haloalkyl, -C 1~6 Alkyl-OH, C 1~6 Alkoxy-C 1~6 is optionally substituted by one, two or three substituents selected from the group consisting of alkyl-, halo, CN and OH, the alkyl being optionally substituted by one 3-6 membered cycloalkyl ring or phenyl, and the heterocyclyl ring is 1~6 Alkyl, C 1~6 Haloalkyl, -C 1~6 Alkyl-OH, C 1~6 Alkoxyl-C 1~6 optionally substituted with 1, 2 or 3 substituents selected from the group consisting of alkyl-, oxo, halo, CN and OH; R 5 is H, halo, methyl optionally substituted with 1, 2 or 3 deuterium or halo, methoxyl optionally substituted with 1, 2 or 3 deuterium or halo, NH 2 , C.H. 3 NH, or (CH 3 ) 2 N, a, b, c, and d are each independently 1 or 2; n is 0, 1 or 2; m is 0, 1, 2, 3 or 4; However, R 4is, if present, substituted at any chemically permissible position on the heterocyclyl, except for the N atom adjacent to the point of attachment of the heterocyclyl to the remainder of the compound. or a stereoisomer, racemate, tautomer, hydrate or solvate, or a pharma- ceutically acceptable salt thereof.

[0019] Embodiment 2. X is F, Cl or CN; Y is N or CH; Z is CH 2 , O, S, and NH; R 1 but, 1)-(C=O)-NRaRb [wherein, Ra and Rb are C 1~6 each independently selected from the group consisting of alkyl and 3- to 5-membered cycloalkyl rings; 1~6 Alkyl is deuterium, halo, OH and C 1~6 optionally substituted with 1, 2 or 3 substituents selected from the group consisting of alkoxyl; or Ra and Rb together with the nitrogen atom to which they are attached form C 1~6 forming a 5-6 membered monocyclic or 7-9 membered bicyclic heterocyclyl ring optionally substituted with 1, 2 or 3 substituents selected from the group consisting of alkyl and halo; 2) C optionally substituted with 1, 2 or 3 substituents selected from the group consisting of halo, CN, halo and CN. 1~6 Alkyl, 3- to 5-membered cycloalkyl ring, oxo and C 1~6 a 5-6 membered heteroaryl ring optionally substituted with 1, 2 or 3 substituents selected from the group consisting of alkoxyl; 3) C optionally substituted with 1, 2 or 3 substituents selected from the group consisting of halo, CN, halo and CN. 1~6 Alkyl, 3- to 5-membered cycloalkyl ring and C 1~6 C substituted with 1, 2 or 3 substituents selected from the group consisting of alkoxyl 6~10 Aryl ring; is selected from the group consisting of R 2 and R 3 are each independently H or D; Each R 4 But, halo, CN, OH, C 1~6 Alkylsulfonyl-, C 1~6 Alkylsulfonylamino-, C 1~6 Alkylcarbonylamino-, phenyl, C 1~6 Alkyl, C 1~6 independently selected from the group consisting of alkoxyl, a 3- to 6-membered cycloalkyl ring, a 5- to 10-membered heteroaryl ring, and a 5- to 9-membered heterocyclyl ring, wherein the alkyl, alkoxyl, cycloalkyl ring, heteroaryl ring, or heterocyclyl ring is optionally substituted with 1, 2, or 3 substituents selected from the group consisting of halo, CN, and OH; Two adjacent R 4 together with the carbon atom to which they are attached, C 1~6 Alkyl, -C 1~6 Alkyl-OH, C 1~6 Alkoxyl-C 1~6 optionally forming a 3-6 membered cycloalkyl ring, optionally substituted with 1, 2 or 3 substituents selected from the group consisting of alkyl- and halo; Or, two R attached to the same carbon atom 4 optionally forms, together with the carbon atom, a 3- to 6-membered cycloalkyl ring optionally substituted with 1, 2 or 3 substituents selected from the group consisting of halo, CN and OH; Or, two adjacent R 4 together with the carbon atom to which they are attached, form halo, C 1~6 Alkyl and C 1~6 haloalkyl, optionally forming a 5-10 membered heteroaryl ring, phenyl, or 5-9 membered heterocyclyl ring, optionally substituted by 1, 2, or 3 substituents selected from the group consisting of haloalkyl, wherein the alkyl is optionally substituted by one 3-6 membered cycloalkyl ring or phenyl; R 5 is H or halo, a, b, c, and d are each independently 1 or 2; n is 0 or 1; m is 0, 1, 2 or 3; However, R 4 is, if present, substituted at any chemically permissible position on the heterocyclyl, except for the N atom adjacent to the point of attachment of the heterocyclyl to the remainder of the compound; A compound according to embodiment 1, or a stereoisomer, racemate, tautomer, hydrate or solvate thereof, or a pharma- ceutically acceptable salt thereof.

[0020] Embodiment 3. Each R 4 But, halo, CN, OH, C 1~6 Alkylsulfonyl-, C 1~6 Alkylsulfonylamino-, phenyl, C 1~6 Alkyl, C 1~6 independently selected from the group consisting of alkoxyl and a 3- to 6-membered cycloalkyl ring, wherein the alkyl or alkoxyl is optionally substituted with 1, 2 or 3 substituents selected from the group consisting of halo, CN and OH; Two adjacent R 4 together with the carbon atom to which they are attached, C 1~6 Alkyl, -C 1~6 Alkyl-OH, C 1~6 Alkoxyl-C 1~6 optionally forming a 3-6 membered cycloalkyl ring, optionally substituted with 1, 2 or 3 substituents selected from the group consisting of alkyl- and halo; Or, two R attached to the same carbon atom 4 optionally forms, together with the carbon atom, a 3- to 6-membered cycloalkyl ring optionally substituted with 1, 2 or 3 substituents selected from the group consisting of halo, CN and OH; Or, two adjacent R 4 together with the carbon atom to which they are attached, C 1~6optionally forming a 5-10 membered heteroaryl ring, optionally substituted by 1, 2 or 3 substituents selected from the group consisting of alkyl, optionally substituted by one 3-6 membered cycloalkyl ring or phenyl; A compound according to embodiment 1 or 2, or a stereoisomer, racemate, tautomer, hydrate or solvate thereof, or a pharma- ceutically acceptable salt thereof.

[0021] Embodiment 4. R 5 is H, or a stereoisomer, racemate, tautomer, hydrate or solvate, or a pharma- ceutically acceptable salt thereof.

[0022] Embodiment 5. The compound has Formula II: [ka] and preferably the compound is of formula IIa: [ka] and the compound is preferably [ka] and more preferably [ka] wherein each p is independently 0 or 1; q is 0, 1, or 2; R 4a is C 1~3 alkyl or halo; Most preferably, [ka] wherein each p is independently 0 or 1; q is 0, 1, or 2; R 4a is C 1~3 alkyl or halo; A compound according to any one of embodiments 1 to 3, or a stereoisomer, racemate, tautomer, hydrate or solvate thereof, or a pharma- ceutically acceptable salt thereof.

[0023] Embodiment 6. The compound has Formula III: [ka] or a stereoisomer, racemate, tautomer, hydrate or solvate, or a pharma- ceutically acceptable salt thereof, wherein

[0024] Embodiment 7. A compound according to any one of embodiments 1-6, or a stereoisomer, racemate, tautomer, hydrate or solvate, or a pharma- ceutically acceptable salt thereof, wherein X is F.

[0025] Embodiment 8. Z is CH 2 , O and S, preferably CH 2 or a stereoisomer, racemate, tautomer, hydrate or solvate, or a pharma- ceutically acceptable salt thereof, wherein

[0026] Embodiment 9. R 2 and R 3 is each independently H, or a stereoisomer, racemate, tautomer, hydrate or solvate, or a pharma- ceutically acceptable salt thereof.

[0027] EMBODIMENT 10. R 1 is -(C=O)-NRaRb, Ra and Rb are C 1~6 each independently selected from the group consisting of alkyl and 3- to 5-membered cycloalkyl rings; 1~6 Alkyl is deuterium, halo, OH and C 1~6 optionally substituted with 1, 2 or 3 substituents selected from the group consisting of alkoxyl; Ra and Rb, together with the nitrogen atom to which they are attached, form C 1~6 forming a 5-6 membered monocyclic or 7-9 membered bicyclic heterocyclyl ring with additional ring heteroatoms selected from N, O and S, optionally substituted with 1, 2 or 3 substituents selected from the group consisting of alkyl and halo; A compound according to any one of embodiments 1 to 9, or a stereoisomer, racemate, tautomer, hydrate or solvate thereof, or a pharma- ceutically acceptable salt thereof.

[0028] Embodiment 11. R 1 -(C=O)-NRaRb, wherein Ra and Rb each represent a C optionally substituted by one OH; 1~3 alkyl, preferably, Ra is ethyl and Rb is isopropyl; or R 1 But, Halo, CN, C 1~3 a 5-6 membered heteroaryl ring substituted with 1, 2 or 3 substituents selected from the group consisting of alkyl and cyclopropyl, or a phenyl substituted with 1, 2 or 3 substituents selected from the group consisting of halo, CN and cyclopropyl; A compound according to any one of embodiments 1 to 9, or a stereoisomer, racemate, tautomer, hydrate or solvate thereof, or a pharma- ceutically acceptable salt thereof.

[0029] Embodiment 12. R 1 -(C=O)-NRaRb, wherein Ra and Rb each represent a C optionally substituted by one OH; 1~3 alkyl, preferably, Ra is ethyl and Rb is isopropyl; or R 1 But, Halo, CN, C 1~3pyridyl, pyrimidinyl or pyrazolyl substituted with 1, 2 or 3 substituents selected from the group consisting of alkyl and cyclopropyl, or phenyl substituted with 1, 2 or 3 substituents selected from the group consisting of halo, CN and cyclopropyl; A compound according to embodiment 11, or a stereoisomer, racemate, tautomer, hydrate or solvate, or a pharma- ceutically acceptable salt thereof.

[0030] Embodiment 13. R 1 -(C=O)-NRaRb [wherein Ra and Rb are each C 1~3 alkyl, preferably Ra is ethyl and Rb is isopropyl; or R 1 is a 6-membered heteroaryl or phenyl ring substituted with 1, 2 or 3 substituents selected from the group consisting of halo, CN and cyclopropyl; A compound according to any one of embodiments 1 to 9, or a stereoisomer, racemate, tautomer, hydrate or solvate thereof, or a pharma- ceutically acceptable salt thereof.

[0031] Embodiment 14. R 1 is -(C=O)-NRaRb, where Ra is ethyl and Rb is isopropyl; A compound according to any one of embodiments 1 to 9, or a stereoisomer, racemate, tautomer, hydrate or solvate thereof, or a pharma- ceutically acceptable salt thereof.

[0032] EMBODIMENT 15. R 1 is pyridyl, pyrimidinyl or phenyl substituted with 1, 2 or 3 substituents selected from the group consisting of halo, CN and cyclopropyl; A compound according to any one of embodiments 1 to 9, or a stereoisomer, racemate, tautomer, hydrate or solvate thereof, or a pharma- ceutically acceptable salt thereof.

[0033] EMBODIMENT 16. R 1 but, [ka] [In the formula, A 1 Or A 2 is N or CH, R 6 is selected from the group consisting of halo, CN, and cyclopropyl; R 7 is selected from the group consisting of H, halo, CN and cyclopropyl, preferably R 1 but, [ka] or R 1 but, [ka] [In the formula, A 3 is N or C substituted by halo, R 8 is C 1~3 alkyl, preferably R 1 but, [ka] or a stereoisomer, racemate, tautomer, hydrate or solvate, or a pharma- ceutically acceptable salt thereof, wherein

[0034] Embodiment 17. The compound has formula IIb: [ka] or a stereoisomer, racemate, tautomer, hydrate or solvate, or a pharma- ceutically acceptable salt thereof, wherein

[0035] EMBODIMENT 18. R 1 -(C=O)-NRaRb [wherein Ra and Rb are each C 1~3alkyl, preferably, Ra is ethyl and Rb is isopropyl; or R 1 is a 6-membered heteroaryl ring substituted with 1, 2 or 3 substituents selected from the group consisting of halo, CN and cyclopropyl; A compound according to any one of embodiments 1 to 9, or a stereoisomer, racemate, tautomer, hydrate or solvate thereof, or a pharma- ceutically acceptable salt thereof.

[0036] EMBODIMENT 19. R 1 -(C=O)-NRaRb [wherein Ra and Rb are each C 1~3 alkyl, preferably, Ra is ethyl and Rb is isopropyl; or R 1 is pyridyl or pyrimidinyl substituted with 1, 2 or 3 substituents selected from the group consisting of halo, CN and cyclopropyl; A compound according to embodiment 19, or a stereoisomer, racemate, tautomer, hydrate or solvate, or a pharma- ceutically acceptable salt thereof.

[0037] EMBODIMENT 20. R 1 but, [ka] or a stereoisomer, racemate, tautomer, hydrate or solvate, or a pharma- ceutically acceptable salt thereof, selected from the group consisting of:

[0038] EMBODIMENT 21. each of a and b is 1; each of c and d is 1 or 2; A compound according to any one of embodiments 1 to 20, or a stereoisomer, racemate, tautomer, hydrate or solvate thereof, or a pharma- ceutically acceptable salt thereof. EMBODIMENT 22. n is 0 or 1, preferably 0; A compound according to any one of embodiments 1 to 21, or a stereoisomer, racemate, tautomer, hydrate or solvate thereof, or a pharma- ceutically acceptable salt thereof.

[0039] Embodiment 23. A compound according to any one of embodiments 1 to 15, or a stereoisomer, racemate, tautomer, hydrate or solvate, or a pharma- ceutically acceptable salt thereof, wherein n is 0.

[0040] Embodiment 24. A compound according to any one of embodiments 1 to 15, or a stereoisomer, racemate, tautomer, hydrate or solvate, or a pharma- ceutically acceptable salt thereof, wherein n is 1.

[0041] Embodiment 25. A compound according to any one of embodiments 1 to 24, or a stereoisomer, racemate, tautomer, hydrate or solvate, or a pharma- ceutically acceptable salt thereof, wherein m is 0, 1, or 2.

[0042] 26. each of a and b is 1; A compound according to any one of embodiments 1 to 25, or a stereoisomer, racemate, tautomer, hydrate or solvate thereof, or a pharma- ceutically acceptable salt thereof.

[0043] EMBODIMENT 27. each of c and d is 2; A compound according to any one of embodiments 1 to 26, or a stereoisomer, racemate, tautomer, hydrate or solvate thereof, or a pharma- ceutically acceptable salt thereof.

[0044] 28. m is 1 or 2; A compound according to any one of embodiments 1 to 27, or a stereoisomer, racemate, tautomer, hydrate or solvate thereof, or a pharma- ceutically acceptable salt thereof.

[0045] 29. each of a and b is 1; each of c and d is 2; n is 0 or 1, preferably 0; m is 0, 1 or 2; A compound according to any one of embodiments 1 to 16, or a stereoisomer, racemate, tautomer, hydrate or solvate thereof, or a pharma- ceutically acceptable salt thereof.

[0046] EMBODIMENT 30. Each R 4 But halo;CN;OH;C 1~6 Alkylsulfonyl-;C 1~6 C optionally substituted with 1, 2 or 3 substituents selected from the group consisting of: alkylsulfonylamino-; phenyl; halo, CN and OH 1~6 alkyl; C optionally substituted with 1, 2 or 3 halo 1~6 independently selected from the group consisting of: alkoxyl; and cyclopropyl; Two adjacent R 4 together with the carbon atom to which they are attached, C 1~6 Alkyl, -C 1~6 Alkyl-OH, C 1~6 Alkoxyl-C 1~6 optionally forming a 3-6 membered cycloalkyl ring, optionally substituted with 1, 2 or 3 substituents selected from the group consisting of alkyl- and halo; Or, two R attached to the same carbon atom 4 optionally forms, together with the carbon atom, a 3- to 6-membered cycloalkyl ring, optionally substituted with 1, 2 or 3 halo; Or, two adjacent R 4 together with the carbon atoms to which they are attached, 1, 2 or 3 C 1~6 Optionally forming a 5-6 membered heteroaryl ring optionally substituted by alkyl substituents, the alkyl being optionally substituted by one 3-6 membered cycloalkyl ring or phenyl; Or, two adjacent R 4together with the carbon atom to which they are attached optionally form a phenyl; A compound according to any one of embodiments 1 to 29, or a stereoisomer, racemate, tautomer, hydrate or solvate thereof, or a pharma- ceutically acceptable salt thereof.

[0047] EMBODIMENT 31. Each R 4 But halo;CN;OH;C 1~3 Alkylsulfonyl-;C 1~3 C optionally substituted with 1, 2 or 3 substituents selected from the group consisting of: alkylsulfonylamino-; phenyl; halo, CN and OH 1~3 alkyl; C optionally substituted with 1, 2 or 3 halo 1~3 independently selected from the group consisting of: alkoxyl; and cyclopropyl; Two adjacent R 4 together with the carbon atom to which they are attached, C 1~3 Alkyl, -C 1~3 Alkyl-OH, C 1~3 Alkoxyl-C 1~3 optionally forming a 3-6 membered cycloalkyl ring, optionally substituted with 1, 2 or 3 substituents selected from the group consisting of alkyl- and halo; Or, two R attached to the same carbon atom 4 optionally forms, together with the carbon atom, a 3- to 6-membered cycloalkyl ring, optionally substituted with 1, 2 or 3 halo; Or, two adjacent R 4 together with the carbon atoms to which they are attached, 1, 2 or 3 C 1~3 Optionally forming a 5-6 membered heteroaryl ring optionally substituted by alkyl substituents, the alkyl being optionally substituted by one 3-6 membered cycloalkyl ring or phenyl; Or, two adjacent R 4 together with the carbon atom to which they are attached optionally form a phenyl; A compound according to any one of embodiments 1 to 30, or a stereoisomer, racemate, tautomer, hydrate or solvate thereof, or a pharma- ceutically acceptable salt thereof.

[0048] EMBODIMENT 32. portion [ka] but, [ka] or a stereoisomer, racemate, tautomer, hydrate or solvate, or a pharma- ceutically acceptable salt thereof, selected from the group consisting of:

[0049] EMBODIMENT 33. X is F, Z is CH 2 and R 1 but, 1)-(C=O)-NRaRb [wherein, Ra and Rb are C optionally substituted with 1, 2 or 3 deuterium. 1~6 each independently selected from the group consisting of alkyl, or Ra and Rb together with the nitrogen atom to which they are attached represent 1, 2 or 3 C 1~6 forming a 5-6 membered monocyclic or 7-9 membered bicyclic heterocyclyl ring optionally substituted by alkyl; 2) Halo, CN, C 1~6 Alkyl, CF 3 , 3-5 membered cycloalkyl ring, oxo and C 1~6 a 5-6 membered heteroaryl ring substituted with 1, 2 or 3 substituents selected from the group consisting of alkoxyl; 3) Halo, CN, C 1~6 Alkyl, CF 3 , 3- to 5-membered cycloalkyl ring and C 1~6 C substituted with 1, 2 or 3 substituents selected from the group consisting of alkoxyl 6~10 Aryl ring; is selected from the group consisting of R 2 and R 3 are each independently H; Each R 4 But halo;CN;OH;C 1~6 Alkylsulfonyl-;C 1~6 C optionally substituted with 1, 2 or 3 substituents selected from the group consisting of: alkylsulfonylamino-; phenyl; halo, CN and OH 1~6 alkyl; C optionally substituted with 1, 2 or 3 halo 1~6 alkoxyl; and 3- to 6-membered cycloalkyl ring; Two adjacent R 4 together with the carbon atom to which they are attached, C 1~6 optionally forming a 3-6 membered cycloalkyl ring, optionally substituted with 1, 2 or 3 substituents selected from the group consisting of alkyl and halo; Or, two adjacent R 4 together with the carbon atom to which they are attached optionally form a phenyl; R 5 is H or halo, each of a and b is 1; each of c and d is 2; n is 0, m is 0, 1 or 2; However, R 4 is, if present, substituted at any chemically permissible position on the heterocyclyl, except for the N atom adjacent to the point of attachment of the heterocyclyl to the remainder of the compound; A compound according to any one of embodiments 1 to 5, or a stereoisomer, racemate, tautomer, hydrate or solvate thereof, or a pharma- ceutically acceptable salt thereof.

[0050] Embodiment 34. R 5 is H, or a stereoisomer, racemate, tautomer, hydrate or solvate, or a pharma- ceutically acceptable salt thereof.

[0051] Embodiment 35. R 1 is -(C=O)-NRaRb, and Ra and Rb are each independently selected from the group consisting of ethyl or isopropyl, or a stereoisomer, racemate, tautomer, hydrate or solvate, or a pharma- ceutically acceptable salt thereof.

[0052] Embodiment 36. R 1 But, Halo, CN, C 1~3 Alkyl, CF 3 , cyclopropyl, oxo and C 1~3 and n is 0, 1 or 2. The compound of any one of embodiments 33-34, or a stereoisomer, racemate, tautomer, hydrate or solvate thereof, or a pharma- ceutically acceptable salt thereof, wherein the ring is a 5- or 6-membered heteroaryl or phenyl ring substituted with 1 or 2 substituents selected from the group consisting of alkoxyl.

[0053] 37. R 1 but, [ka] or a stereoisomer, racemate, tautomer, hydrate or solvate, or a pharma- ceutically acceptable salt thereof, selected from the group consisting of:

[0054] 38. Each R 4 But halo;CN;OH;C 1~3 Alkylsulfonyl-;C 1~3 C optionally substituted with 1, 2 or 3 substituents selected from the group consisting of: alkylsulfonylamino-; phenyl; halo, CN and OH 1~3 alkyl; C optionally substituted with 1, 2 or 3 halo 1~3 independently selected from the group consisting of: alkoxyl; and cyclopropyl; Two adjacent R 4 together with the carbon atom to which they are attached, C 1~3optionally forming a 3-6 membered cycloalkyl ring, optionally substituted with 1, 2 or 3 substituents selected from the group consisting of alkyl and halo; Or, two adjacent R 4 together with the carbon atom to which they are attached optionally form a phenyl; A compound according to any one of embodiments 33 to 37, or a stereoisomer, racemate, tautomer, hydrate or solvate thereof, or a pharma- ceutically acceptable salt thereof.

[0055] 39. portion [ka] but, [ka] or a stereoisomer, racemate, tautomer, hydrate or solvate, or a pharma- ceutically acceptable salt thereof, according to any one of embodiments 33-38, independently selected from the group consisting of:

[0056] EMBODIMENT 40. Each R 4 is independently selected from the group consisting of halo, CN, C1-3 alkoxyl, and cyclopropyl; or two adjacent R 4 together with the carbon atom to which they are attached form a cyclopropyl, m is 1 or 2; A compound according to any one of embodiments 1 to 30 and 34 to 38, or a stereoisomer, racemate, tautomer, hydrate or solvate thereof, or a pharma- ceutically acceptable salt thereof.

[0057] 41. Part [ka] but, [ka] [In the formula, R 4 ', R 4 '' and R 4 "" is H; halo; CN; OH; C optionally substituted with 1, 2 or 3 substituents selected from the group consisting of halo and CN. 1~6 Alkyl;C 1~6 alkoxyl; and cyclopropyl; or R 4 ' and R 4 '' together with the carbon atom to which they are attached form C 1~6 optionally forming a 3-6 membered cycloalkyl ring, optionally substituted with 1, 2 or 3 substituents selected from the group consisting of alkyl and halo; R 4 ''' is H] is A compound according to any one of embodiments 1 to 29 and 33 to 38, or a stereoisomer, racemate, tautomer, hydrate or solvate thereof, or a pharma- ceutically acceptable salt thereof.

[0058] 42. Part [ka] but, [ka] [In the formula, R 4 ', R 4 '' and R 4 ''' is H; halo; CN; OH; C optionally substituted with one halo 1~6 Alkyl; and C 1~6 alkoxyl; or R 4 ' and R 4 '' together with the carbon atom to which they are attached, represent one or two C 1~6 optionally forming a 3- to 6-membered cycloalkyl ring, optionally substituted with alkyl, R 4 ''' is H] is A compound according to any one of embodiments 1 to 29 and 33 to 38, or a stereoisomer, racemate, tautomer, hydrate or solvate thereof, or a pharma- ceutically acceptable salt thereof.

[0059] EMBODIMENT 43. portion [ka] but, [ka] [In the formula, R 4 ', R 4 '' and R 4 ''' is H; halo; CN; C optionally replaced by one halo 1~3 Alkyl; and C 1~3 alkoxyl; or R 4 ' and R 4 '' together with the carbon atom to which they are attached, represent one or two C 1~3 optionally forming a 3- to 5-membered cycloalkyl ring, optionally substituted with alkyl, R 4 ''' is H] is A compound according to any one of embodiments 1 to 29 and 33 to 38, or a stereoisomer, racemate, tautomer, hydrate or solvate thereof, or a pharma- ceutically acceptable salt thereof.

[0060] EMBODIMENT 44. portion [ka] but, [ka] or a stereoisomer, racemate, tautomer, hydrate or solvate, or a pharma- ceutically acceptable salt thereof, wherein

[0061] EMBODIMENT 45. [In the formula, R 4 ', R 4 '' and R 4 ''' is H; halo; CN; OH; C optionally substituted with one halo 1~3 Alkyl; and C 1~3 alkoxyl; A compound according to any one of embodiments 41 to 44, or a stereoisomer, racemate, tautomer, hydrate or solvate thereof, or a pharma- ceutically acceptable salt thereof.

[0062] EMBODIMENT 46. R 4 ' and R 4 '' together with the carbon atom to which they are attached, 1 or 2 C 1~3 optionally forming a 3- to 5-membered cycloalkyl ring, optionally substituted with alkyl, R 4 ''' is H, A compound according to any one of embodiments 41 to 44, or a stereoisomer, racemate, tautomer, hydrate or solvate thereof, or a pharma- ceutically acceptable salt thereof.

[0063] EMBODIMENT 47. R 4 ' and R 4 Each of ''' is H and R 4 '' is replaced by one halo 1~3 is alkyl, A compound according to any one of embodiments 41 to 44, or a stereoisomer, racemate, tautomer, hydrate or solvate thereof, or a pharma- ceutically acceptable salt thereof.

[0064] 48. R 4 ' and R 4 " together with the carbon atom to which they are attached optionally form a 3- or 5-membered cycloalkyl ring optionally substituted by 1 or 2 methyl; R 4 ''' is H, A compound according to any one of embodiments 41 to 44, or a stereoisomer, racemate, tautomer, hydrate or solvate thereof, or a pharma- ceutically acceptable salt thereof.

[0065] 49. portion [ka] but, [ka] [In the formula, R 4 ''' is H, R 4 ' and R 4 '' is H; halo; C optionally substituted by 1 halo 1~6 Alkyl; and C 1~6 alkoxyl; with the proviso that R 4 ' and R 4 '' is not H, or R 4 ' and R 4 '' together with the carbon atom to which they are attached, represent one or two C 1~3 forming a 3- or 5-membered cycloalkyl ring optionally substituted by alkyl, or forming a phenyl ring; A compound according to any one of 1 to 29 and 33 to 38, or a stereoisomer, racemate, tautomer, hydrate or solvate thereof, or a pharma- ceutically acceptable salt thereof.

[0066] EMBODIMENT 50. portion [ka] but, [ka] [In the formula, R 4 ''' is H, R 4 ' and R 4'' is H; halo; C optionally substituted by 1 halo 1~6 Alkyl; and C 1~6 alkoxyl; with the proviso that R 4 ' and R 4 '' is not H, or R 4 ' and R 4 '' together with the carbon atom to which they are attached, represent one or two C 1~3 forming a 3- or 5-membered cycloalkyl ring optionally substituted by alkyl; The compound according to any one of 1 to 29 and 33 to 38, or a stereoisomer, racemate, tautomer, hydrate or solvate thereof, or a pharma- ceutically acceptable salt thereof.

[0067] EMBODIMENT 51. portion [ka] but, [ka] [In the formula, R 4 ' is H and R 4 '' and R 4 ''' is C independently 1~3 or a stereoisomer, racemate, tautomer, hydrate or solvate, or a pharma- ceutically acceptable salt thereof.

[0068] EMBODIMENT 52. portion [ka] but, [ka] [In the formula, R 4 ' and R 4 '' one is H and the other is C 1~6 is alkyl, or R4 ' and R 4 '' together with the carbon atom to which they are attached, represent one or two C 1~3 optionally forming a 3- or 5-membered cycloalkyl ring, optionally substituted by alkyl; A compound according to any one of embodiments 1 to 29 and 33 to 38, or a stereoisomer, racemate, tautomer, hydrate or solvate thereof, or a pharma- ceutically acceptable salt thereof.

[0069] 53. Part [ka] but, [ka] [In the formula, R 4 ' is H and R 4 '' is C substituted with one halo 1~6 is alkyl, or R 4 ' and R 4 " optionally form a 3- or 5-membered cycloalkyl ring together with the carbon atom to which they are attached; A compound according to any one of embodiments 1 to 29 and 33 to 38, or a stereoisomer, racemate, tautomer, hydrate or solvate thereof, or a pharma- ceutically acceptable salt thereof.

[0070] 54. Part [ka] but, [ka] [In the formula, R 4 ' is H and R 4 '' is a C replaced by one F 1~3 is alkyl, or R 4 ' and R 4’’ together with the carbon atom to which they are attached optionally forms a 3- or 5-membered cycloalkyl ring A compound according to any one of embodiments 1 to 29 and 33 to 38, or a stereoisomer, racemate, tautomer, hydrate or solvate thereof, or a pharmaceutically acceptable salt.

[0071] Embodiment 55. Portion

Chemical Structure

Chemical Structure

[0072] Embodiment 56. Portion

Chemical Structure

Chemical Structure

[0073] Embodiment 57. The compound is

Table 1-1

Table 1-2

Table 1-3

Table 1-4

Table 1-5

Table 1-6

Table 1-7

Table 1-8

Table 1-9

Table 1-10

Table 1-11

Table 1-12

Table 1-13

Table 1-14

Table 1-15

Table 1-16

Table 1-17

Table 1-18

Table 1-19

[0074] Embodiment 58. A compound according to any one of embodiments 1 to 57, or a stereoisomer, racemate, tautomer, hydrate or solvate, or a pharma- ceutically acceptable salt thereof, for use as a pharmaceutical.

[0075] Embodiment 59. A compound according to any one of embodiments 1 to 57, or a stereoisomer, racemate, tautomer, hydrate or solvate, or a pharma- ceutically acceptable salt thereof, for use in the treatment or prevention of cancer and other diseases mediated by the interaction of menin with MLL and / or MLL fusion proteins.

[0076] Embodiment 60. For use in the treatment or prevention of cancer or diabetes, Preferably, the cancer is a hematological tumor, such as leukemia, lymphoma, myeloma (e.g., multiple myeloma), myelodysplastic syndrome (MDS), and myeloproliferative neoplasm (MPN), polycythemia vera; or a solid tumor, such as prostate cancer, lung cancer, breast cancer, pancreatic cancer, colon cancer, liver cancer, melanoma, and glioblastoma. More preferably, the leukemia is selected from the group consisting of acute leukemia, chronic leukemia, myeloid leukemia, myelogeneous leukemia, lymphoblastic leukemia, lymphocytic leukemia, acute myeloid leukemia (AML), chronic myelogenous leukemia (CML), acute lymphoblastic leukemia (ALL), chronic lymphocytic leukemia (CLL), T-cell prolymphocytic leukemia (T-PLL), large granular lymphocytic leukemia, hairy cell leukemia (HCL), mixed lineage leukemia (MLL), MLL-rearranged leukemia (MLR), and / or AML-rearranged leukemia (AML). Lr leukemia), MLL-PTD leukemia, MLL amplified leukemia, MLL positive leukemia, nucleophosmin (NPM) mutated leukemia, MOZ acute leukemia, NUP98 acute leukemia, CALM acute leukemia, MLL-AF4 leukemia, MLL-AF6 leukemia, MLL-AF9 leukemia, MLL-AF10 leukemia, MLL-ENL leukemia and MLL-ELL leukemia, A compound according to any one of embodiments 1 to 57, or a stereoisomer, racemate, tautomer, hydrate or solvate thereof, or a pharma- ceutically acceptable salt thereof.

[0077] Embodiment 61. A pharmaceutical composition comprising a compound according to any one of embodiments 1 to 57, or a stereoisomer, racemate, tautomer, hydrate or solvate thereof, or a pharma- ceutically acceptable salt thereof, and optionally a pharma- ceutically acceptable carrier.

[0078] Embodiment 62. In the manufacture of a medicament for the treatment or prevention of cancer or diabetes, Preferably, the cancer is a hematological tumor, such as leukemia, lymphoma, myeloma (e.g., multiple myeloma), myelodysplastic syndrome (MDS), and myeloproliferative neoplasm (MPN), polycythemia vera; or a solid tumor, such as prostate cancer, lung cancer, breast cancer, pancreatic cancer, colon cancer, liver cancer, melanoma, and glioblastoma. More preferably, the leukemia is selected from the group consisting of acute leukemia, chronic leukemia, myeloid leukemia, myelogenous leukemia, lymphoblastic leukemia, lymphocytic leukemia, acute myeloid leukemia (AML), chronic myelogenous leukemia (CML), acute lymphoblastic leukemia (ALL), chronic lymphocytic leukemia (CLL), T-cell prolymphocytic leukemia (T-PLL), large granular lymphocytic leukemia, hairy cell leukemia (HCL), mixed lineage leukemia (MLL), and / or leukemia. ), MLL-rearranged leukemia (MLLr leukemia), MLL-PTD leukemia, MLL-amplified leukemia, MLL-positive leukemia, nucleophosmin (NPM) mutated leukemia, MOZ acute leukemia, NUP98 acute leukemia, CALM acute leukemia, MLL-AF4 leukemia, MLL-AF6 leukemia, MLL-AF9 leukemia, MLL-AF10 leukemia, MLL-ENL leukemia, and MLL-ELL leukemia, Use of a compound according to any one of embodiments 1 to 57, or a stereoisomer, racemate, tautomer, hydrate or solvate thereof, or a pharma- ceutically acceptable salt thereof.

[0079] Embodiment 63. A method for inhibiting the interaction of menin with MLL and / or MLL fusion protein in vivo or in vitro, comprising contacting menin and MLL and / or MLL fusion protein with an effective amount of a compound described in any one of embodiments 1 to 57 or a pharma- ceutically acceptable salt thereof.

[0080] Embodiment 64. A method for treating or preventing cancer or diabetes, comprising administering to a subject in need thereof an effective amount of a compound of any one of embodiments 1-57, or a stereoisomer, racemate, tautomer, hydrate or solvate thereof, or a pharma- ceutically acceptable salt thereof; Preferably, the cancer is a hematological tumor, such as leukemia, lymphoma, myeloma (e.g., multiple myeloma), myelodysplastic syndrome (MDS), and myeloproliferative neoplasm (MPN), polycythemia vera; or a solid tumor, such as prostate cancer, lung cancer, breast cancer, pancreatic cancer, colon cancer, liver cancer, melanoma, and glioblastoma. More preferably, the leukemia is selected from the group consisting of acute leukemia, chronic leukemia, myeloid leukemia, myelogenous leukemia, lymphoblastic leukemia, lymphocytic leukemia, acute myeloid leukemia (AML), chronic myelogenous leukemia (CML), acute lymphoblastic leukemia (ALL), chronic lymphocytic leukemia (CLL), T-cell prolymphocytic leukemia (T-PLL), large granular lymphocytic leukemia, hairy cell leukemia (HCL), mixed lineage leukemia (MLL), and / or leukemia. ), MLL-rearranged leukemia (MLLr leukemia), MLL-PTD leukemia, MLL-amplified leukemia, MLL-positive leukemia, nucleophosmin (NPM) mutated leukemia, MOZ acute leukemia, NUP98 acute leukemia, CALM acute leukemia, MLL-AF4 leukemia, MLL-AF6 leukemia, MLL-AF9 leukemia, MLL-AF10 leukemia, MLL-ENL leukemia, and MLL-ELL leukemia, method.

[0081] Embodiment 65. A combination comprising a compound according to any one of embodiments 1 to 57, or a stereoisomer, racemate, tautomer, hydrate or solvate, or a pharma- ceutically acceptable salt thereof, and at least one additional therapeutic agent, wherein the additional therapeutic agent is preferably an anti-neoplastic agent, such as a radiotherapeutic agent, a chemotherapeutic agent, an immunotherapeutic agent, or a targeted therapeutic agent.

[0082] Embodiments of the Disclosure - Part B Embodiment 1. Formula I: [ka] [In the formula, X is halo or CN; Y is N or CH; Z is CH 2 , O, S, and NH; R 1 teeth, 1)-(C=O)-NRaRb (in the formula, Ra and Rb are halo, OH, CN and C 1~6 C optionally substituted with 1, 2 or 3 substituents selected from the group consisting of alkoxyl 1~6each independently selected from the group consisting of alkyl, a 3- to 6-membered cycloalkyl ring, and a 5- to 9-membered heterocyclyl ring; or Ra and Rb together with the nitrogen atom to which they are attached form C 1~6 forming a 5-9 membered heterocyclyl ring optionally substituted with 1, 2 or 3 substituents selected from the group consisting of alkyl, halo, OH and CN; 2) Halo, CN, C 1~6 a 5-10 membered heteroaryl ring, optionally substituted with 1, 2 or 3 substituents selected from the group consisting of alkyl and 3- to 5-membered cycloalkyl rings; 6~10 Aryl ring; is selected from the group consisting of R 2 and R 3 are each independently H or D; Each R 4 is halo, CN, OH, oxo, C 1~6 Alkylsulfonyl-, C 1~6 Alkylsulfonylamino-, C 1~6 Alkylcarbonylamino-, C 6~10 Aryl ring, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 1~6 independently selected from the group consisting of alkoxyl, a 3- to 9-membered cycloalkyl ring, a 5- to 10-membered heteroaryl ring, and a 4- to 9-membered heterocyclyl ring, wherein the alkyl, alkenyl, alkynyl, alkoxyl, cycloalkyl ring, heteroaryl ring, or heterocyclyl ring is optionally substituted with 1, 2, or 3 substituents selected from the group consisting of halo, CN, and OH; Two adjacent R 4 together with the carbon atom to which they are attached, C 1~6 Alkyl, -C 1~6 Alkyl-OH, C 1~6 Alkoxyl-C 1~6 optionally forming a 3-9 membered cycloalkyl ring, optionally substituted with 1, 2 or 3 substituents selected from the group consisting of alkyl-, halo, CN and OH; Or, two R attached to the same carbon atom 4 together with the carbon atom, C 1~6 Alkyl, -C 1~6 Alkyl-OH, C 1~6 Alkoxyl-C 1~6 optionally forming a 3- to 6-membered cycloalkyl ring or a 4- to 6-membered heterocyclyl ring, optionally substituted with 1, 2, or 3 substituents selected from the group consisting of alkyl-, halo, CN, and OH; Or, two adjacent R 4 together with the carbon atom to which they are attached form a 5- to 10-membered heteroaryl ring, C 6~10 Optionally forms an aryl ring or a 5- to 9-membered heterocyclyl ring, the heteroaryl ring or the aryl ring being 1~6 Alkyl, C 1~6 Haloalkyl, -C 1~6 Alkyl-OH, C 1~6 Alkoxyl-C 1~6 is optionally substituted by one, two or three substituents selected from the group consisting of alkyl-, halo, CN and OH, the alkyl being optionally substituted by one 3-6 membered cycloalkyl ring or phenyl, and the heterocyclyl ring is 1~6 Alkyl, C 1~6 Haloalkyl, -C 1~6 Alkyl-OH, C 1~6 Alkoxyl-C 1~6 optionally substituted with 1, 2 or 3 substituents selected from the group consisting of alkyl-, oxo, halo, CN and OH; R 5 is H, halo, methyl optionally substituted with 1, 2 or 3 deuterium or halo, methoxyl optionally substituted with 1, 2 or 3 deuterium or halo, NH 2 , C.H. 3 NH, or (CH 3 ) 2 N, a, b, c, and d are each independently 1 or 2; n is 0, 1 or 2; m is 0, 1, 2, 3 or 4. or a stereoisomer, racemate, tautomer, hydrate or solvate, or a pharma- ceutically acceptable salt thereof.

[0083] Embodiment 2. X is F, Cl or CN; Y is N or CH; Z is CH 2 , O, S, and NH; R 1 but, 1)-(C=O)-NRaRb [wherein, Ra and Rb are halo, OH and C 1~6 C optionally substituted with 1, 2 or 3 substituents selected from the group consisting of alkoxyl 1~6 each independently selected from the group consisting of alkyl and 3- to 5-membered cycloalkyl rings; or Ra and Rb together with the nitrogen atom to which they are attached form C 1~6 forming a 5-6 membered monocyclic or 7-9 membered bicyclic heterocyclyl ring optionally substituted with 1, 2 or 3 substituents selected from the group consisting of alkyl and halo; 2) Halo, CN, C 1~6 a 5-6 membered heteroaryl ring optionally substituted with 1, 2 or 3 substituents selected from the group consisting of alkyl and a 3- to 5-membered cycloalkyl ring; 3) Halo, CN, C 1~6 C substituted with 1, 2 or 3 substituents selected from the group consisting of alkyl, and 3- to 5-membered cycloalkyl rings 6~10 Aryl ring; is selected from the group consisting of R 2 and R 3 are each independently H or D; Each R 4 But, halo, CN, OH, C 1~6 Alkylsulfonyl-, C 1~6 Alkylsulfonylamino-, C 1~6 Alkylcarbonylamino-, phenyl, C 1~6 Alkyl, C 1~6independently selected from the group consisting of alkoxyl, a 3- to 6-membered cycloalkyl ring, a 5- to 10-membered heteroaryl ring, and a 5- to 9-membered heterocyclyl ring, wherein the alkyl, alkoxyl, cycloalkyl ring, heteroaryl ring, or heterocyclyl ring is optionally substituted with 1, 2, or 3 substituents selected from the group consisting of halo, CN, and OH; Two adjacent R 4 together with the carbon atom to which they are attached, C 1~6 Alkyl, -C 1~6 Alkyl-OH, C 1~6 Alkoxyl-C 1~6 optionally forming a 3-6 membered cycloalkyl ring, optionally substituted with 1, 2 or 3 substituents selected from the group consisting of alkyl- and halo; Or, two R attached to the same carbon atom 4 optionally forms, together with the carbon atom, a 3- to 6-membered cycloalkyl ring optionally substituted with 1, 2 or 3 substituents selected from the group consisting of halo, CN and OH; Or, two adjacent R 4 together with the carbon atom to which they are attached, form halo, C 1~6 Alkyl and C 1~6 haloalkyl, optionally forming a 5-10 membered heteroaryl ring, phenyl, or 5-9 membered heterocyclyl ring, optionally substituted by 1, 2, or 3 substituents selected from the group consisting of haloalkyl, wherein the alkyl is optionally substituted by one 3-6 membered cycloalkyl ring or phenyl; R 5 is H or halo, a, b, c, and d are each independently 1 or 2; n is 0 or 1; m is 0, 1, 2 or 3; A compound according to embodiment 1, or a stereoisomer, racemate, tautomer, hydrate or solvate thereof, or a pharma- ceutically acceptable salt thereof.

[0084] Embodiment 3. Each R 4 But, halo, CN, OH, C1~6 Alkylsulfonyl-, C 1~6 Alkylsulfonylamino-, phenyl, C 1~6 Alkyl, C 1~6 independently selected from the group consisting of alkoxyl and a 3- to 6-membered cycloalkyl ring, wherein the alkyl or alkoxyl is optionally substituted with 1, 2 or 3 substituents selected from the group consisting of halo, CN and OH; Two adjacent R 4 together with the carbon atom to which they are attached, C 1~6 Alkyl, -C 1~6 Alkyl-OH, C 1~6 Alkoxyl-C 1~6 optionally forming a 3-6 membered cycloalkyl ring, optionally substituted with 1, 2 or 3 substituents selected from the group consisting of alkyl- and halo; Or, two R attached to the same carbon atom 4 optionally forms, together with the carbon atom, a 3- to 6-membered cycloalkyl ring optionally substituted with 1, 2 or 3 substituents selected from the group consisting of halo, CN and OH; Or, two adjacent R 4 together with the carbon atom to which they are attached, C 1~6 optionally forming a 5-10 membered heteroaryl ring, optionally substituted by 1, 2 or 3 substituents selected from the group consisting of alkyl, optionally substituted by one 3-6 membered cycloalkyl ring or phenyl; A compound according to embodiment 1 or 2, or a stereoisomer, racemate, tautomer, hydrate or solvate, or a pharma- ceutically acceptable salt thereof.

[0085] Embodiment 4. Each R 4 But, halo, CN, OH, C 1~6 Alkylsulfonyl-, C 1~6 Alkylsulfonylamino-, phenyl, C 1~6 Alkyl, and C 1~6alkoxyl, wherein the alkyl or alkoxyl is optionally substituted with 1, 2 or 3 substituents selected from the group consisting of halo, CN and OH; Two adjacent R 4 together with the carbon atom to which they are attached, C 1~6 Alkyl, -C 1~6 Alkyl-OH, C 1~6 Alkoxyl-C 1~6 optionally forming a 3-6 membered cycloalkyl ring, optionally substituted with 1, 2 or 3 substituents selected from the group consisting of alkyl- and halo; Or, two R attached to the same carbon atom 4 optionally forms, together with the carbon atom, a 3- to 6-membered cycloalkyl ring optionally substituted with 1, 2 or 3 substituents selected from the group consisting of halo, CN and OH; Or, two adjacent R 4 together with the carbon atom to which they are attached, C 1~6 optionally forming a 5-10 membered heteroaryl ring, optionally substituted by 1, 2 or 3 substituents selected from the group consisting of alkyl, optionally substituted by one 3-6 membered cycloalkyl ring or phenyl; A compound according to any one of embodiments 1 to 3, or a stereoisomer, racemate, tautomer, hydrate or solvate thereof, or a pharma- ceutically acceptable salt thereof.

[0086] Embodiment 5. The compound has Formula II: [ka] and preferably the compound is of formula IIa: [ka] and the compound is preferably [ka] and more preferably [ka] wherein each p is independently 0 or 1; q is 0, 1, or 2; R 4a is C 1~3 alkyl or halo; Most preferably, [ka] wherein each p is independently 0 or 1; q is 0, 1, or 2; R 4a is C 1~3 alkyl or halo; A compound according to any one of embodiments 1 to 4, or a stereoisomer, racemate, tautomer, hydrate or solvate thereof, or a pharma- ceutically acceptable salt thereof.

[0087] Embodiment 6. The compound has Formula III: [ka] or a stereoisomer, racemate, tautomer, hydrate or solvate, or a pharma- ceutically acceptable salt thereof, wherein

[0088] Embodiment 7. A compound according to any one of embodiments 1-6, or a stereoisomer, racemate, tautomer, hydrate or solvate, or a pharma- ceutically acceptable salt thereof, wherein X is F.

[0089] Embodiment 8. Z is CH 2 , O and S, preferably CH 2 or a stereoisomer, racemate, tautomer, hydrate or solvate, or a pharma- ceutically acceptable salt thereof, wherein

[0090] Embodiment 9. R 2 and R 3is each independently H, or a stereoisomer, racemate, tautomer, hydrate or solvate, or a pharma- ceutically acceptable salt thereof.

[0091] EMBODIMENT 10. R 1 is -(C=O)-NRaRb, Ra and Rb are halo, OH and C 1~6 C optionally substituted with 1, 2 or 3 substituents selected from the group consisting of alkoxyl 1~6 are independently selected from the group consisting of alkyl and 3- to 5-membered cycloalkyl rings; Ra and Rb, together with the nitrogen atom to which they are attached, form C 1~6 forming a 5-6 membered monocyclic or 7-9 membered bicyclic heterocyclyl ring with additional ring heteroatoms selected from N, O and S, optionally substituted with 1, 2 or 3 substituents selected from the group consisting of alkyl and halo; A compound according to any one of embodiments 1 to 9, or a stereoisomer, racemate, tautomer, hydrate or solvate thereof, or a pharma- ceutically acceptable salt thereof.

[0092] Embodiment 11. R 1 -(C=O)-NRaRb [wherein Ra and Rb are each C 1~6 alkyl, preferably Ra is ethyl and Rb is isopropyl; or R 1 But, Halo, CN, C 1~6 is a 5-6 membered heteroaryl ring optionally substituted with 1, 2 or 3 substituents selected from the group consisting of alkyl and 3- to 5-membered cycloalkyl rings, or halo, CN, C 1~6 phenyl substituted with 1, 2 or 3 substituents selected from the group consisting of alkyl and 3- to 5-membered cycloalkyl rings; A compound according to any one of embodiments 1 to 10, or a stereoisomer, racemate, tautomer, hydrate or solvate thereof, or a pharma- ceutically acceptable salt thereof.

[0093] Embodiment 12. R 1 is -(C=O)-NRaRb, where Ra is ethyl and Rb is isopropyl; A compound according to any one of embodiments 1 to 11, or a stereoisomer, racemate, tautomer, hydrate or solvate thereof, or a pharma- ceutically acceptable salt thereof.

[0094] Embodiment 13. R 1 But, Halo, CN, C 1~6 is a 5-6 membered heteroaryl ring optionally substituted with 1, 2 or 3 substituents selected from the group consisting of alkyl and 3- to 5-membered cycloalkyl rings, or halo, CN, C 1~6 phenyl substituted with 1, 2 or 3 substituents selected from the group consisting of alkyl and 3- to 5-membered cycloalkyl rings; A compound according to any one of embodiments 1 to 12, or a stereoisomer, racemate, tautomer, hydrate or solvate thereof, or a pharma- ceutically acceptable salt thereof.

[0095] Embodiment 14. R 1 but, [ka] [In the formula, A 1 Or A 2 is N or CH, R 6 ,Haro,CN,C 1~6 R is selected from the group consisting of alkyl and 3- to 5-membered cycloalkyl rings; 7 H, halo, CN, C 1~6 alkyl and 3- to 5-membered cycloalkyl rings, preferably R 1 but, [ka] or R 1 but, [ka] [In the formula, A 3 is N or C substituted by halo, R 8 is C 1~6 alkyl, preferably R 1 but, [ka] or a stereoisomer, racemate, tautomer, hydrate or solvate, or a pharma- ceutically acceptable salt thereof, wherein

[0096] Embodiment 15. The compound has the formula IIb: [ka] or a stereoisomer, racemate, tautomer, hydrate or solvate, or a pharma- ceutically acceptable salt thereof, wherein

[0097] EMBODIMENT 16. each of a and b is 1; each of c and d is 1 or 2; A compound according to any one of embodiments 1 to 15, or a stereoisomer, racemate, tautomer, hydrate or solvate thereof, or a pharma- ceutically acceptable salt thereof.

[0098] EMBODIMENT 17. n is 0 or 1, preferably 0; A compound according to any one of embodiments 1 to 16, or a stereoisomer, racemate, tautomer, hydrate or solvate thereof, or a pharma- ceutically acceptable salt thereof.

[0099] Embodiment 18. A compound according to any one of embodiments 1 to 17, or a stereoisomer, racemate, tautomer, hydrate or solvate, or a pharma- ceutically acceptable salt thereof, wherein n is 0.

[0100] Embodiment 19. A compound according to any one of embodiments 1 to 18, or a stereoisomer, racemate, tautomer, hydrate or solvate, or a pharma- ceutically acceptable salt thereof, wherein n is 1.

[0101] Embodiment 20. A compound according to any one of embodiments 1 to 19, or a stereoisomer, racemate, tautomer, hydrate or solvate, or a pharma- ceutically acceptable salt thereof, wherein m is 0, 1, or 2.

[0102] EMBODIMENT 21. each of a and b is 1; A compound according to any one of embodiments 1 to 20, or a stereoisomer, racemate, tautomer, hydrate or solvate thereof, or a pharma- ceutically acceptable salt thereof.

[0103] EMBODIMENT 22. each of c and d is 2; A compound according to any one of embodiments 1 to 21, or a stereoisomer, racemate, tautomer, hydrate or solvate thereof, or a pharma- ceutically acceptable salt thereof.

[0104] EMBODIMENT 23. m is 1 or 2; A compound according to any one of embodiments 1 to 22, or a stereoisomer, racemate, tautomer, hydrate or solvate thereof, or a pharma- ceutically acceptable salt thereof.

[0105] EMBODIMENT 24. each of a and b is 1; each of c and d is 2; n is 0 or 1, preferably 0; m is 0, 1 or 2; A compound according to any one of embodiments 1 to 23, or a stereoisomer, racemate, tautomer, hydrate or solvate thereof, or a pharma- ceutically acceptable salt thereof.

[0106] EMBODIMENT 25. Each R 4But halo;CN;OH;C 1~6 Alkylsulfonyl-;C 1~6 C optionally substituted with 1, 2 or 3 substituents selected from the group consisting of: alkylsulfonylamino-; phenyl; halo, CN and OH 1~6 alkyl; and C optionally substituted with halo 1~6 alkoxyl; Two adjacent R 4 together with the carbon atom to which they are attached, C 1~6 Alkyl, -C 1~6 Alkyl-OH, C 1~6 Alkoxyl-C 1~6 optionally forming a 3-6 membered cycloalkyl ring, optionally substituted with 1, 2 or 3 substituents selected from the group consisting of alkyl- and halo; Or, two R attached to the same carbon atom 4 optionally forms, together with the carbon atom, a 3- to 6-membered cycloalkyl ring, optionally substituted with 1, 2 or 3 halo; Or, two adjacent R 4 together with the carbon atoms to which they are attached, 1, 2 or 3 C 1~6 Optionally forming a 5-6 membered heteroaryl ring optionally substituted by alkyl substituents, the alkyl being optionally substituted by one 3-6 membered cycloalkyl ring or phenyl; Or, two adjacent R 4 together with the carbon atom to which they are attached optionally form a phenyl; A compound according to any one of embodiments 1 to 24, or a stereoisomer, racemate, tautomer, hydrate or solvate thereof, or a pharma- ceutically acceptable salt thereof.

[0107] 26. R 1 but, [ka] or a stereoisomer, racemate, tautomer, hydrate or solvate, or a pharma- ceutically acceptable salt thereof, selected from the group consisting of:

[0108] EMBODIMENT 27. R 1 but, [ka] or a stereoisomer, racemate, tautomer, hydrate or solvate, or a pharma- ceutically acceptable salt thereof, selected from the group consisting of:

[0109] 28. portion [ka] but, [ka] or a stereoisomer, racemate, tautomer, hydrate or solvate, or a pharma- ceutically acceptable salt thereof, selected from the group consisting of:

[0110] 29. portion [ka] but, [ka] or a stereoisomer, racemate, tautomer, hydrate or solvate, or a pharma- ceutically acceptable salt thereof, selected from the group consisting of:

[0111] EMBODIMENT 30. X is F, Z is CH 2 and R 1 but, 1)-(C=O)-NRaRb [wherein, Ra and Rb are C 1~6 each independently selected from the group consisting of alkyl, or Ra and Rb together with the nitrogen atom to which they are attached represent 1, 2 or 3 C 1~6 forming a 5-6 membered monocyclic or 7-9 membered bicyclic heterocyclyl ring optionally substituted by alkyl; 2) Halo, CN, C 1~6 a 5- to 6-membered heteroaryl ring substituted with 1, 2, or 3 substituents selected from the group consisting of alkyl and 3- to 5-membered cycloalkyl rings; 3) Halo, CN, C 1~6 C substituted with 1, 2 or 3 substituents selected from the group consisting of alkyl, and 3- to 5-membered cycloalkyl rings 6~10 Aryl ring; is selected from the group consisting of R 2 and R 3 are each independently H; Each R 4 But halo;CN;OH;C 1~6 Alkylsulfonyl-;C 1~6 C optionally substituted with 1, 2 or 3 substituents selected from the group consisting of: alkylsulfonylamino-; phenyl; halo, CN and OH 1~6 alkyl; and C optionally substituted by 1, 2 or 3 halo 1~6 independently selected from the group consisting of: alkoxyl; and 3- to 6-membered cycloalkyl ring; Two adjacent R 4 together with the carbon atom to which they are attached, C 1~6 Alkyl, -C 1~6 Alkyl-OH, C 1~6 Alkoxyl-C 1~6 optionally forming a 3-6 membered cycloalkyl ring, optionally substituted with 1, 2 or 3 substituents selected from the group consisting of alkyl- and halo; Or, two adjacent R 4together with the carbon atom to which they are attached optionally form a phenyl; R 5 is H or halo, each of a and b is 1; each of c and d is 2; n is 0, m is 0, 1 or 2; A compound according to any one of embodiments 1 to 29, or a stereoisomer, racemate, tautomer, hydrate or solvate thereof, or a pharma- ceutically acceptable salt thereof.

[0112] Embodiment 31. R 5 is H or halo, preferably H; or a stereoisomer, racemate, tautomer, hydrate or solvate, or a pharma- ceutically acceptable salt thereof.

[0113] EMBODIMENT 32. Each R 4 But halo;CN;OH;C 1~6 Alkylsulfonyl-;C 1~6 C optionally substituted with 1, 2 or 3 substituents selected from the group consisting of: alkylsulfonylamino-; phenyl; halo, CN and OH 1~6 alkyl; and C optionally substituted by 1, 2 or 3 halo 1~6 alkoxyl; Two adjacent R 4 together with the carbon atom to which they are attached, C 1~6 Alkyl, -C 1~6 Alkyl-OH and C 1~6 Alkoxyl-C 1~6 optionally forming a 3-6 membered cycloalkyl ring, optionally substituted with 1, 2 or 3 substituents selected from the group consisting of alkyl- Or, two adjacent R 4 together with the carbon atom to which they are attached optionally form a phenyl; A compound according to any one of embodiments 1 to 31, or a stereoisomer, racemate, tautomer, hydrate or solvate thereof, or a pharma- ceutically acceptable salt thereof.

[0114] Embodiment 33. R 1 is -(C=O)-NRaRb, and Ra and Rb are each independently selected from the group consisting of ethyl or isopropyl, or a stereoisomer, racemate, tautomer, hydrate or solvate, or a pharma- ceutically acceptable salt thereof.

[0115] Embodiment 34. R 1 But, Halo, CN, C 1~6 a 5- or 6-membered heteroaryl ring substituted with one or two substituents selected from the group consisting of alkyl and cyclopropyl; 6~10 The compound according to any one of embodiments 1 to 33, or a stereoisomer, racemate, tautomer, hydrate or solvate, or a pharma- ceutically acceptable salt thereof, wherein R is an aryl ring.

[0116] 35. Part [ka] but, [ka] [In the formula, R 4 ', R 4 '' and R 4 "" is H; halo; CN; OH; C optionally substituted with 1, 2 or 3 substituents selected from the group consisting of halo and CN. 1~6 Alkyl;C 1~6 alkoxyl; and 3- to 6-membered cycloalkyl ring; or R 4 ' and R 4 '' together with the carbon atom to which they are attached form C 1~6 Alkyl, -C 1~6 Alkyl-OH, C 1~6 Alkoxyl-C1~6 optionally forming a 3-6 membered cycloalkyl ring, optionally substituted with 1, 2 or 3 substituents selected from the group consisting of alkyl- and halo; R 4 ''' is H] is A compound according to any one of embodiments 1 to 34, or a stereoisomer, racemate, tautomer, hydrate or solvate thereof, or a pharma- ceutically acceptable salt thereof.

[0117] 36. Part [ka] but, [ka] [In the formula, R 4 ', R 4 '' and R 4 "" is H; halo; CN; OH; C optionally substituted with 1, 2 or 3 substituents selected from the group consisting of halo and CN. 1~6 Alkyl;C 1~6 alkoxyl; and cyclopropyl; or R 4 ' and R 4 '' together with the carbon atom to which they are attached form C 1~6 Alkyl, -C 1~6 Alkyl-OH, C 1~6 Alkoxyl-C 1~6 optionally forming a 3-6 membered cycloalkyl ring, optionally substituted with 1, 2 or 3 substituents selected from the group consisting of alkyl- and halo; R 4 ''' is H] is A compound according to any one of embodiments 1 to 35, or a stereoisomer, racemate, tautomer, hydrate or solvate thereof, or a pharma- ceutically acceptable salt thereof.

[0118] 37. Part [ka] but, [ka] [In the formula, R 4 ', R 4 '' and R 4 "" is H; halo; CN; C optionally substituted with 1, 2 or 3 substituents selected from the group consisting of halo and CN. 1~6 Alkyl; and C 1~6 alkoxyl; or R 4 ' and R 4 '' together with the carbon atom to which they are attached form C 1~6 Alkyl, -C 1~6 Alkyl-OH, C 1~6 Alkoxyl-C 1~6 optionally forming a 3-6 membered cycloalkyl ring, optionally substituted with 1, 2 or 3 substituents selected from the group consisting of alkyl- and halo; R 4 ''' is H] is A compound according to any one of embodiments 1 to 36, or a stereoisomer, racemate, tautomer, hydrate or solvate thereof, or a pharma- ceutically acceptable salt thereof.

[0119] 38. [In the formula, R 4 ', R 4 '' and R 4 "" is H; halo; CN; OH; C optionally substituted with 1, 2 or 3 substituents selected from the group consisting of halo and CN. 1~6 Alkyl; and C 1~6 alkoxyl; A compound according to any one of embodiments 1 to 37, or a stereoisomer, racemate, tautomer, hydrate or solvate thereof, or a pharma- ceutically acceptable salt thereof.

[0120] 39. R 4 ' and R 4 '' together with the carbon atom to which they are attached, C 1~6Alkyl, -C 1~6 Alkyl-OH and C 1~6 Alkoxyl-C 1~6 optionally forming a 3-6 membered cycloalkyl ring optionally substituted with 1, 2 or 3 substituents selected from the group consisting of alkyl-, R 4 ''' is H, A compound according to any one of embodiments 1 to 38, or a stereoisomer, racemate, tautomer, hydrate or solvate thereof, or a pharma- ceutically acceptable salt thereof.

[0121] EMBODIMENT 40. R 4 ' and R 4 Each of ''' is H and R 4 '' is C substituted with 1, 2 or 3 halo 1~6 is alkyl, A compound according to any one of embodiments 1 to 39, or a stereoisomer, racemate, tautomer, hydrate or solvate thereof, or a pharma- ceutically acceptable salt thereof.

[0122] EMBODIMENT 41. R 4 ' and R 4 " together with the carbon atom to which they are attached optionally form a 3- or 5-membered cycloalkyl ring optionally substituted with 1, 2 or 3 halo; R 4 ''' is H, A compound according to any one of embodiments 1 to 40, or a stereoisomer, racemate, tautomer, hydrate or solvate thereof, or a pharma- ceutically acceptable salt thereof.

[0123] EMBODIMENT 42. portion [ka] but, [ka] That is, A compound according to any one of embodiments 1 to 41, or a stereoisomer, racemate, tautomer, hydrate or solvate thereof, or a pharma- ceutically acceptable salt thereof.

[0124] EMBODIMENT 43. portion [ka] but, [ka] [In the formula, R 4 ''' is H, R 4 ' and R 4 '' is H; halo; C optionally substituted by 1, 2 or 3 halo 1~6 Alkyl; and C 1~6 alkoxyl; with the proviso that R 4 ' and R 4 '' is not H or R 4 ' and R 4 '' together with the carbon atom to which they are attached, represent 1, 2 or 3 C 1~3 forming a 3- or 5-membered cycloalkyl ring, optionally substituted by alkyl; A compound according to any one of embodiments 1 to 42, or a stereoisomer, racemate, tautomer, hydrate or solvate thereof, or a pharma- ceutically acceptable salt thereof.

[0125] EMBODIMENT 44. portion [ka] but, [ka] [In the formula, R 4 ' is H and R 4 '' and R 4 ''' is C independently 1~3 alkyl; A compound according to any one of embodiments 1 to 43, or a stereoisomer, racemate, tautomer, hydrate or solvate thereof, or a pharma- ceutically acceptable salt thereof.

[0126] 45. Part [ka] but, [ka] [In the formula, R 4 ' and R 4 '' one is H and the other is C 1~6 is alkyl, or R 4 ' and R 4 '' together with the carbon atom to which they are attached, represent one or two C 1~6 optionally forming a 3- or 5-membered cycloalkyl ring, optionally substituted by alkyl; A compound according to any one of embodiments 1 to 44, or a stereoisomer, racemate, tautomer, hydrate or solvate thereof, or a pharma- ceutically acceptable salt thereof.

[0127] 46. ​​Part [ka] but, [ka] [In the formula, R 4 ' is H and R 4 '' is C substituted with 1 or 2 halo 1~6 is alkyl, or R 4 ' and R 4 " taken together with the carbon atom to which they are attached optionally form a 3- or 5-membered cycloalkyl ring, optionally substituted with 1 or 2 halo; A compound according to any one of embodiments 1 to 45, or a stereoisomer, racemate, tautomer, hydrate or solvate thereof, or a pharma- ceutically acceptable salt thereof.

[0128] 47. Part [ka] but, [ka] [In the formula, R 4 ' is H and R 4 '' is C substituted with 1 or 3 halo 1、1~6 is alkyl, or R 4 ' and R 4 " optionally form a 3- or 5-membered cycloalkyl ring together with the carbon atom to which they are attached; A compound according to any one of embodiments 1 to 46, or a stereoisomer, racemate, tautomer, hydrate or solvate thereof, or a pharma- ceutically acceptable salt thereof.

[0129] 48. Part [ka] but, [ka] wherein each p is independently 0 or 1, preferably both p's are 0 or both p's are 1; q is 0, 1 or 2, preferably q is 0 or 2; R 4a is C 1~3 alkyl or halo, preferably R 4a is methyl or F; A compound according to any one of embodiments 1 to 47, or a stereoisomer, racemate, tautomer, hydrate or solvate thereof, or a pharma- ceutically acceptable salt thereof.

[0130] 49. Part [ka] but, [ka] or a stereoisomer, racemate, tautomer, hydrate or solvate, or a pharma- ceutically acceptable salt thereof.

[0131] Embodiment 50. A compound according to any one of embodiments 1 to 2 selected from examples 2 to 100, or a stereoisomer, racemate, tautomer, hydrate or solvate thereof, or a pharma- ceutically acceptable salt thereof.

[0132] Embodiment 51. A compound according to any one of embodiments 1 to 50, or a stereoisomer, racemate, tautomer, hydrate or solvate, or a pharma- ceutically acceptable salt thereof, for use as a pharmaceutical.

[0133] Embodiment 52. A compound according to any one of embodiments 1 to 50, or a stereoisomer, racemate, tautomer, hydrate or solvate, or a pharma- ceutically acceptable salt thereof, for use in the treatment or prevention of cancer and other diseases mediated by the interaction of menin with MLL and / or MLL fusion proteins.

[0134] Embodiment 53. For use in the treatment or prevention of cancer or diabetes, Preferably, the cancer is a hematological tumor, such as leukemia, lymphoma, myeloma (e.g., multiple myeloma), myelodysplastic syndrome (MDS), and myeloproliferative neoplasm (MPN), polycythemia vera; or a solid tumor, such as prostate cancer, lung cancer, breast cancer, pancreatic cancer, colon cancer, liver cancer, melanoma, and glioblastoma. More preferably, the leukemia is selected from the group consisting of acute leukemia, chronic leukemia, myeloid leukemia, myelogenous leukemia, lymphoblastic leukemia, lymphocytic leukemia, acute myeloid leukemia (AML), chronic myelogenous leukemia (CML), acute lymphoblastic leukemia (ALL), chronic lymphocytic leukemia (CLL), T-cell prolymphocytic leukemia (T-PLL), large granular lymphocytic leukemia, hairy cell leukemia (HCL), mixed lineage leukemia (MLL), and / or leukemia. ), MLL-rearranged leukemia (MLLr leukemia), MLL-PTD leukemia, MLL-amplified leukemia, MLL-positive leukemia, nucleophosmin (NPM) mutated leukemia, MOZ acute leukemia, NUP98 acute leukemia, CALM acute leukemia, MLL-AF4 leukemia, MLL-AF6 leukemia, MLL-AF9 leukemia, MLL-AF10 leukemia, MLL-ENL leukemia, and MLL-ELL leukemia, A compound according to any one of embodiments 1 to 50, or a stereoisomer, racemate, tautomer, hydrate or solvate thereof, or a pharma- ceutically acceptable salt thereof.

[0135] Embodiment 54. A pharmaceutical composition comprising a compound according to any one of embodiments 1 to 50, or a stereoisomer, racemate, tautomer, hydrate or solvate thereof, or a pharma- ceutically acceptable salt thereof, and optionally a pharma- ceutically acceptable carrier.

[0136] Embodiment 55. In the manufacture of a medicament for the treatment or prevention of cancer or diabetes, Preferably, the cancer is a hematological tumor, such as leukemia, lymphoma, myeloma (e.g., multiple myeloma), myelodysplastic syndrome (MDS), and myeloproliferative neoplasm (MPN), polycythemia vera; or a solid tumor, such as prostate cancer, lung cancer, breast cancer, pancreatic cancer, colon cancer, liver cancer, melanoma, and glioblastoma. More preferably, the leukemia is selected from the group consisting of acute leukemia, chronic leukemia, myeloid leukemia, myelogenous leukemia, lymphoblastic leukemia, lymphocytic leukemia, acute myeloid leukemia (AML), chronic myelogenous leukemia (CML), acute lymphoblastic leukemia (ALL), chronic lymphocytic leukemia (CLL), T-cell prolymphocytic leukemia (T-PLL), large granular lymphocytic leukemia, hairy cell leukemia (HCL), mixed lineage leukemia (MLL), and / or leukemia. ), MLL-rearranged leukemia (MLLr leukemia), MLL-PTD leukemia, MLL-amplified leukemia, MLL-positive leukemia, nucleophosmin (NPM) mutated leukemia, MOZ acute leukemia, NUP98 acute leukemia, CALM acute leukemia, MLL-AF4 leukemia, MLL-AF6 leukemia, MLL-AF9 leukemia, MLL-AF10 leukemia, MLL-ENL leukemia, and MLL-ELL leukemia, Use of a compound according to any one of embodiments 1 to 50, or a stereoisomer, racemate, tautomer, hydrate or solvate thereof, or a pharma- ceutically acceptable salt thereof.

[0137] Embodiment 56. A method for inhibiting the interaction of menin with MLL and / or MLL fusion protein in vivo or in vitro, comprising contacting menin and MLL and / or MLL fusion protein with an effective amount of a compound described in any one of embodiments 1 to 50 or a pharma- ceutically acceptable salt thereof.

[0138] Embodiment 57. A method for treating or preventing cancer or diabetes, comprising administering to a subject in need thereof an effective amount of a compound according to any one of embodiments 1-50, or a stereoisomer, racemate, tautomer, hydrate or solvate thereof, or a pharma- ceutically acceptable salt thereof; Preferably, the cancer is a hematological tumor, such as leukemia, lymphoma, myeloma (e.g., multiple myeloma), myelodysplastic syndrome (MDS), and myeloproliferative neoplasm (MPN), polycythemia vera; or a solid tumor, such as prostate cancer, lung cancer, breast cancer, pancreatic cancer, colon cancer, liver cancer, melanoma, and glioblastoma. More preferably, the leukemia is selected from the group consisting of acute leukemia, chronic leukemia, myeloid leukemia, myelogenous leukemia, lymphoblastic leukemia, lymphocytic leukemia, acute myeloid leukemia (AML), chronic myelogenous leukemia (CML), acute lymphoblastic leukemia (ALL), chronic lymphocytic leukemia (CLL), T-cell prolymphocytic leukemia (T-PLL), large granular lymphocytic leukemia, hairy cell leukemia (HCL), mixed lineage leukemia (MLL), and / or leukemia. ), MLL-rearranged leukemia (MLLr leukemia), MLL-PTD leukemia, MLL-amplified leukemia, MLL-positive leukemia, nucleophosmin (NPM) mutated leukemia, MOZ acute leukemia, NUP98 acute leukemia, CALM acute leukemia, MLL-AF4 leukemia, MLL-AF6 leukemia, MLL-AF9 leukemia, MLL-AF10 leukemia, MLL-ENL leukemia, and MLL-ELL leukemia, method.

[0139] Embodiment 58. A combination comprising a compound according to any one of embodiments 1 to 50, or a stereoisomer, racemate, tautomer, hydrate or solvate, or a pharma- ceutically acceptable salt thereof, and at least one additional therapeutic agent, wherein the additional therapeutic agent is preferably an anti-neoplastic agent, such as a radiotherapeutic agent, a chemotherapeutic agent, an immunotherapeutic agent, or a targeted therapeutic agent.

[0140] definition As used in this disclosure, the following words, phrases and symbols have the meanings set out below, unless the context indicates otherwise.

[0141] As used herein, the singular forms "a," "an," and "the" are intended to include the plural forms as well, unless the context clearly indicates otherwise.

[0142] A dash ("-") that is not between two letters or symbols is used to indicate a point of attachment for a substituent. For example, -C 1~6 The alkyl-OH is attached to the remainder of the molecule via the alkyl.

[0143] As used herein, the term "alkyl" refers to an alkyl group having 1 to 10 carbon atoms (C 1~10 ), preferably 1 to 6 carbon atoms (C 1~6 ), more preferably 1 to 4 carbon atoms (C 1~4 ) or 1 to 3 carbon atoms (C 1~3 ) refers to a linear or branched saturated hydrocarbon group. For example, "C 1~6 "Alkyl" refers to an alkyl having 1 to 6 (1, 2, 3, 4, 5, or 6) carbon atoms. Examples of alkyl include, but are not limited to, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, and t-butyl.

[0144] The term "alkenyl" as used herein refers to an alkyl group containing one or more, e.g., one, two, or three, carbon-carbon double bonds (C=C) and having 2 to 10 carbon atoms (C 2~10 ), preferably 2 to 6 carbon atoms (C 2~6 ), more preferably 2 to 4 carbon atoms (C 2~4 ) refers to a straight-chain or branched-chain unsaturated hydrocarbon group. For example, "C 2~6 "Alkenyl" refers to an alkenyl having 2 to 6 (2, 3, 4, 5 or 6) carbon atoms, preferably containing 1 or 2 carbon-carbon double bonds. 2~4 "Alkenyl" refers to an alkenyl having 2 to 4 carbon atoms and preferably containing one carbon-carbon double bond. Examples of alkenyl include, but are not limited to, vinyl, 2-propenyl, and 2-butenyl. The point of attachment of an alkenyl may or may not be on the double bond.

[0145] The term "alkynyl" as used herein refers to an alkynyl group containing one or more, e.g., one, two, or three, carbon-carbon triple bonds (C≡C) and having 2 to 10 carbon atoms (C 2~10 ), preferably 2 to 6 carbon atoms (C 2~6 ), more preferably 2 to 4 carbon atoms (C 2~4 ) refers to a straight-chain or branched-chain unsaturated hydrocarbon group. For example, "C 2~6"Alkynyl" refers to an alkynyl having from 2 to 6 (2, 3, 4, 5, or 6) carbon atoms, preferably containing 1 or 2 carbon-carbon triple bonds. 2~4 "Alkynyl" refers to an alkynyl having 2 to 4 carbon atoms and preferably containing one carbon-carbon triple bond. Examples of alkynyl include, but are not limited to, ethynyl, 2-propynyl, and 2-butynyl. The point of attachment of an alkynyl may or may not be on the triple bond.

[0146] The term "halogen" or "halo" as used herein refers to fluoro, chloro, bromo, and iodo, preferably fluoro, chloro and bromo, more preferably fluoro and chloro, and most preferably fluoro.

[0147] The term "haloalkyl" as used herein refers to an alkyl as defined herein in which one or more, for example 1, 2, 3, 4 or 5, hydrogen atoms are replaced with halogen atoms, and when one or more hydrogen atoms are replaced with halogen atoms, the halogen atoms may be the same or different from each other. In one embodiment, the term "haloalkyl" as used herein refers to an alkyl as defined herein in which two or more, for example 2, 3, 4 or 5, hydrogen atoms are replaced with halogen atoms, and the halogen atoms are the same as each other. In another embodiment, the term "haloalkyl" as used herein refers to an alkyl as defined herein in which two or more, for example 2, 3, 4 or 5, hydrogen atoms are replaced with halogen atoms, and the halogen atoms may be different from each other. Examples of haloalkyl include -CF 3 , -CHF 2 , -CH 2 F, -CH 2 CF 3 , -CF 2 CF 3 , -CF 2 CH 3 and the like. Preferably, haloalkyl is C 1~6 trifluoroalkyl, more preferably -CF3で be.

[0148] The term "alkyl substituted with 1, 2 or 3 halo" refers to one or more, e.g., 1, 2 or 3, hydrogen atoms being replaced with halogen atoms, and when two or more hydrogen atoms are replaced with halogen atoms, the halogen atoms may be the same or different from each other, e.g., -CF 3 , -CHF 2 , -CH 2 F, -CH 2 CF 3 , -CH 2 CH 2 F, -CF 2 CH 3 Similarly, the term "alkyl substituted with 1, 2 or 3 CN" includes -CH 2 CN and -CH 2 CH 2 The term "alkoxyl substituted with 1, 2 or 3 halo" includes, but is not limited to, -OCH 2 F, -OCHF 2 , -OCHF 3 , -OCH 2 CHF 3 These include, but are not limited to:

[0149] The term "alkoxyl" as used herein refers to the group -O-alkyl, where alkyl is as defined above. Examples of alkoxyl include C alkoxyl, such as methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, i-butoxy, t-butoxy, pentoxy, hexyloxy, etc. 1~6 Examples of alkoxyl include, but are not limited to, alkoxyl (including isomers thereof). Preferably, the alkoxyl is methoxy.

[0150] The term "cycloalkyl" as used herein refers to a cycloalkyl group having 3 to 10 ring carbon atoms (C 3~10 ), e.g., 3 to 9 ring carbon atoms (C 3~9 ), 3 to 7 ring carbon atoms (C 3~7), 3 to 6 ring carbon atoms (C 3~6 ), 3 to 5 ring carbon atoms (C 3~5 ) or 5 to 6 ring carbon atoms (C 5~6 ) and may have one or more rings, for example, one or two rings. For example, the cycloalkyl is a monocyclic cycloalkyl, preferably a monocyclic C 3~7 Cycloalkyl, preferably monocyclic C 3~6 Cycloalkyl (e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl) or monocyclic C 3~5 Cycloalkyl (e.g., cyclopropyl, cyclobutyl, cyclopentyl) rings. For example, the cycloalkyl may be a bicyclic cycloalkyl ring, preferably a bicyclic C 5 ~C 10 Bicyclic cycloalkyl rings include fused, bridged, or spiro rings.

[0151] The term "heterocyclyl" as used herein refers to a saturated or partially unsaturated ring having 3-10 ring atoms (3-10 members), e.g., 5-9 ring atoms (5-9 members), 6-8 ring atoms (6-8 members), 5-6 ring atoms (5-6 members) or 7-9 ring atoms (7-9 members), in which one or more, e.g., 1, 2 or 3, preferably 1 or 2, of the ring atoms are heteroatoms independently selected from N, O and S, and the remaining ring atoms are carbon, and having one or more, e.g., 1, 2 or 3, preferably 1 or 2 rings, in which the N or S heteroatoms are optionally oxidized to various oxidation states. The attachment point of the heterocyclyl may be on the N heteroatom or on a carbon atom. Heterocyclyl rings also include fused, bridged, or spiro rings. The ring of a heterocyclyl may be saturated or may contain one or more, e.g., one or two, double bonds (i.e., partially unsaturated), but is not fully conjugated and is not a heteroaryl as defined herein. For example, a "5- to 9-membered heterocyclyl" refers to a monocyclic or bicyclic heterocyclyl having 5 to 9 ring atoms and containing 1, 2 or 3, preferably 1 or 2, ring heteroatoms independently selected from N, O and S, and is preferably a saturated 5- to 6-membered monocyclic or 7- to 9-membered bicyclic heterocyclyl. Examples of heterocyclyls include pyrrolidinyl, imidazolidinyl, morpholinyl, thiomorpholinyl, piperidinyl, piperazinyl, hexahydropyrimidyl, oxazinanyl, 3-oxa-6-azabicyclo[3.2.1]octanyl, 3-azabicyclo[3.1.0]hexanyl, 3,6-diazabicyclo[3.1.1]heptanyl, 6-azabicyclo[3.1.1]heptanyl, 3-azabicyclo[3.1 Examples of heterocyclyl include, but are not limited to, 2-azabicyclo[3.2.1]octanyl, 8-azabicyclo[3.2.1]octanyl, 2-azabicyclo[2.2.2]octanyl, 8-azabicyclo[2.2.2]octanyl, azaspiro[3.5]nonanyl, or azaspiro[2.5]octanyl ring. Preferably, the heterocyclyl is a morpholinyl or 3-oxa-6-azabicyclo[3.2.1]octanyl ring.

[0152] As used herein, the term "aryl" refers to an aryl group having 6 to 14 carbon atoms (C 6~14 ), preferably 6 to 10 carbon atoms (C 6~10 ) and consisting of one ring or multiple fused rings, in which at least one ring is aromatic. Examples of aryl include, but are not limited to, phenyl, naphthalenyl, 1,2,3,4-tetrahydronaphthalenyl, phenanthryl, indenyl, indanyl, or azulenyl rings, preferably phenyl or naphthalenyl rings, more preferably phenyl rings.

[0153] The term "heteroaryl" as used herein refers to a monocyclic, bicyclic or tricyclic ring system having 5-12 ring atoms (5-12 members), e.g., 5-10 ring atoms (5-10 members), 5-9 ring atoms (5-9 members), 8-10 ring atoms (8-10 members), 5-6 ring atoms (5-6 members), 5 ring atoms (5 members) or 6 ring atoms (6 members), in which at least one ring is a 5- or 6-membered aromatic ring, in which one or more, e.g., 1, 2 or 3, preferably 1 or 2, of the ring atoms are heteroatoms independently selected from N, O and S, and the remaining ring atoms are carbon, with the N or S heteroatoms optionally oxidized to various oxidation states. For example, a 5-10 membered heteroaryl is - 5-6 membered monocyclic heteroaryl, i.e. a monocyclic aromatic hydrocarbon group having 5 or 6 ring atoms (5 or 6 members) in which one or more, for example 1, 2 or 3, preferably 1 or 2, of the ring atoms are ring heteroatoms independently selected from N, O and S (preferably N), and the remaining ring atoms are carbon; preferably a monocyclic aromatic hydrocarbon group having 6 ring atoms (6 members) in which 1, 2 or 3, preferably 1 or 2, of the ring atoms are heteroatoms independently selected from N, O and S, preferably N; or - 8 to 10 membered bicyclic heteroaryl, i.e., a bicyclic aromatic hydrocarbon group having 8, 9 or 10 ring atoms (8, 9 or 10 members) in which one or more of the ring atoms, for example 1, 2, 3 or 4, preferably 1, 2 or 3, are ring heteroatoms independently selected from N, O and S (preferably N), the remaining ring atoms are carbon, and at least one of the rings is aromatic.

[0154] Examples of heteroaryl include pyridyl (e.g., pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, pyridin-5-yl, pyridin-6-yl), pyridyl N-oxide, pyrazinyl (e.g., pyrazin-2-yl, pyrazin-3-yl), pyrimidinyl (e.g., pyrimidin-2-yl, pyrimidin-4-yl, pyrimidin-5-yl, pyrimidin-6-yl), pyridazinyl (e.g., pyridazin-3-yl, pyridazin-4-yl), pyrazolyl (e.g., pyrazol-1-yl, pyrazol-2-yl, pyrazol-3-yl, pyrazol-4-yl, pyrazol-5-yl), imidazolyl (e.g., imidazol-1-yl, imidazol-5-yl, imidazol-3-yl, imidazol-4-yl, imidazol-5-yl), oxazo. Examples of aryl include, but are not limited to, aryl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, triazolyl (e.g., triazol-1-yl, triazol-2-yl, triazol-3-yl, triazol-4-yl, triazol-5-yl), tetrazolyl, triazinyl, thienyl, furyl, pyranyl, pyrrolyl, benzodioxolyl, benzoxazolyl, benzisoxazolyl, benzothienyl, benzothiazolyl, benzisothiazolyl, imidazopyridyl, imidazopyrrolyl, triazolopyridyl, indazolyl, pyrrolopyridyl, pyrrolopyrimidinyl, pyrazolopyridyl, pyrazolopyrimidinyl, tetrazolopyridyl, tetrahydropyrazolopyridyl, benzofuryl, benzimidazolinyl, or indolyl. Preferably, heteroaryl is a pyrazolyl, triazolyl or pyrimidinyl ring, more preferably pyrazol-1-yl, pyrazol-2-yl, pyrazol-3-yl, pyrazol-4-yl, pyrazol-5-yl, pyrimidin-2-yl, pyrimidin-4-yl, pyrimidin-5-yl, pyrimidin-6-yl, triazol-1-yl, triazol-2-yl, triazol-3-yl, triazol-4-yl, triazol-5-yl.

[0155] The term "oxo" as used herein refers to the group ═O.

[0156] The group "D" means that a hydrogen atom of the moiety has been replaced with its isotope, deuterium.

[0157] In this specification, the structures of compounds are indicated with wavy lines. [ka] When the compound contains a bond represented by the formula:

[0158] Groups have wavy lines on bonds [ka] , the wavy line indicates the point of attachment of the group to the remainder of the molecule.

[0159] As used herein, unless otherwise indicated, a bond via a ring means that the group bearing the bond is attached to the ring at any chemically permissible position on the ring.

[0160] base [ka] [Wherein, Z, n, m and R 4 is as defined in the general formula herein] may be at any chemically permissible position on the ring (e.g., Z is CH 2 or NH, in Z) with (R 4 ) m Preferably, in the present disclosure, R 4 Substitution by does not occur on the N atom adjacent to the point of attachment of the group to the remainder of the compound.

[0161] As used herein, the term "optional" or "optionally" means that the subsequently described event or circumstance may or may not occur, and the description includes cases where the event or circumstance occurs and does not occur. For example, "optionally substituted with" encompasses both "unsubstituted" and "substituted with one, two, three or more substituents" as defined. Those of skill in the art will understand that with respect to any group containing one or more substituents, such groups do not include any substitutions or substitution patterns that are sterically impractical, chemically incorrect, synthetically impractical, and / or inherently unstable.

[0162] As used herein, the term "substituted" or "substituted with..." means that one or more hydrogens on the specified atom or group are replaced with one or more substituents independently selected from the group of substituents shown, provided that the normal valence of the specified atom is not exceeded. The term "substituted with 1, 2, or 3..." means that one, two, or three hydrogens on the specified atom or group are replaced with one, two, or three substituents independently selected from the group of substituents shown, provided that the normal valence of the specified atom is not exceeded. If the substituent is oxo (i.e., =O), two hydrogens on a single atom are replaced with oxo. Combinations of substituents and / or variables are permissible only if such combinations result in chemically precise and stable compounds. By chemically precise and stable compounds is meant compounds that are sufficiently robust to withstand adequate isolation from a reaction mixture.

[0163] It will be understood by those skilled in the art that some of the compounds disclosed herein may contain one or more chiral centers or rings and therefore may exist in two or more stereoisomers. Racemates of these isomers, mixtures enriched in individual isomers and one enantiomer, as well as diastereomers and mixtures enriched in a particular diastereomer when two chiral centers are present, are within the scope of the present disclosure. It will be further understood by those skilled in the art that the present disclosure includes all individual stereoisomers (e.g., enantiomers, diastereomers, cis- or trans-isomers (e.g., the arrangement of substituents on a divalent cyclic saturated or partially saturated group), or atropisomers whenever chemically possible), racemates of the compounds disclosed herein, mixtures thereof, and, where appropriate, their individual tautomeric forms.

[0164] Racemates or other mixtures of isomers can be used as is or can be resolved into the individual isomers. This resolution can provide stereochemically pure compounds or mixtures enriched in one or more isomers. Methods for separating isomers are well known (see, for example, Allinger NL and Eliel ELin "Topics in Stereochemistry", Vol. 6, Wiley Interscience, 1971).

[0165] When a structure herein contains "(R)" and / or "(S)", it is meant that the chiral center of the compound marked by "(R)" or "(S)" is in a single configuration, either the R or S configuration. Such R-configuration or S-configuration of the chiral center of the compound may be represented simply in the structure. [ka] For example, the compounds of the present disclosure have an enantiomeric purity of at least 60% ee (e.g., 60%, 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9% ee (enantiomeric excess), or any value between these recited values), or a diastereomeric purity of at least 60% de (diastereomeric excess), or any value between these recited values).

[0166] The term "pharmaceutically acceptable salts" includes salts with inorganic acids, such as, for example, hydrochlorides, hydrobromides, carbonates, bicarbonates, phosphates, sulfates, sulfites, nitrates, and the like, as well as salts with organic acids, such as, formates, acetates, malates, maleates, fumarates, tartrates, succinates, citrates, lactates, methanesulfonates, p-toluenesulfonates, 2-hydroxyethylsulfonates, benzoates, salicylates, stearates, and salts of the formula HOOC-(CH 2 ) n "Pharmaceutically acceptable salts" include, but are not limited to, acid addition salts formed by compounds disclosed herein with alkane-dicarboxylic acids such as -COOH, where n is 0-4. "Pharmaceutically acceptable salts" also include base addition salts formed by compounds of the present disclosure having an acidic moiety and pharmaceutically acceptable cations, such as sodium, potassium, calcium, aluminum, lithium, and ammonium.

[0167] In addition, if the compounds described herein are obtained as acid addition salts, the free base can be obtained by basifying a solution of the acid addition salt. Conversely, if the product is a free base, an acid addition salt, particularly a pharma- ceutically acceptable acid addition salt, can be generated from the base compound by dissolving the free base in a suitable solvent and treating the solution with an acid according to conventional procedures for preparing acid addition salts. Those skilled in the art will recognize various synthetic methodologies that can be used without undue experimentation to prepare non-toxic pharma-ceutically acceptable acid or base addition salts.

[0168] The term "protecting group" or "PG" refers to a substituent that is commonly used to block or protect a particular functional group while reacting other functional groups on a compound. For example, an "amino protecting group" is a substituent attached to an amino group that blocks or protects the amino functionality in a compound. Suitable amino protecting groups include p-methoxybenzyl (PMB), benzyl (Bn), trityl (Trt), acetyl, trifluoroacetyl, phthalimide, t-butoxycarbonyl (BOC), benzyloxycarbonyl (CBz), and 9-fluorenylmethyleneoxycarbonyl (Fmoc). Similarly, a "hydroxy protecting group" refers to a substituent of a hydroxy group that blocks or protects the hydroxy functionality. Suitable hydroxy protecting groups include methoxymethyl, benzyl, benzyloxymethyl, methyl, triarylmethyl, acetyl, trialkylsilyl, dialkylphenylsilyl, benzoyl, and tetrahydropyranyl. For a general description of protecting groups and their uses, see TW Greene and PGM Huts, "Protective Groups in Organic Synthesis", 5th Edition, Wiley, New York, 2014.

[0169] The term "pharmaceutical combination" or "combination" as used herein refers to a product resulting from the mixing or combination of two or more therapeutic agents, including both fixed and non-fixed combinations of therapeutic agents, such as kits or pharmaceutical compositions. The term "fixed combination" means that both therapeutic agents, such as a compound of the present disclosure and an additional therapeutic agent, are administered to a subject at the same time in the form of a single entity or dose. The term "non-fixed combination" means that both therapeutic agents, such as a compound of the present disclosure and an additional therapeutic agent, are administered to a subject as separate entities, simultaneously, in parallel, or sequentially without specific time restrictions, such that such administration provides a therapeutically effective level of the compound in the subject's body.

[0170] The terms "treating," "treat," or "treatment" in relation to a disease refer to the administration of one or more pharmaceutical agents, particularly the compounds of the present disclosure described herein or pharma- ceutically acceptable salts thereof, to a subject having a disease or disorder or having symptoms of a disease or disorder, for the purpose of curing, curing, alleviating, relieving, altering, correcting, ameliorating, improving, or affecting the disease or disorder or the symptoms of the disease or disorder. In some embodiments, the disease or disorder is cancer or diabetes.

[0171] The term "prevent" or "preventing" in relation to a disease refers to the administration of one or more pharmaceutical agents, particularly compounds of the present disclosure, to a subject predisposed to or at risk of contracting a disease or disorder, for the purpose of preventing or delaying the onset of the disease or disorder in the subject.

[0172] The term "effective amount" as used herein refers to an amount of a compound of the present disclosure effective to "treat" or "prevent" cancer or diabetes in a subject. An effective amount may cause any observable or measurable change in a subject, as described above in the definition of "treating", "treat", "treatment", "preventing", or "preventing". For example, in the case of cancer, an effective amount may reduce the number of cancer or tumor cells; reduce tumor size; inhibit or stop tumor cell invasion into peripheral organs; inhibit and stop tumor metastasis; inhibit and stop tumor growth; relieve to some extent one or more symptoms associated with cancer; reduce morbidity and mortality; improve quality of life; or a combination of such effects. An effective amount may be an amount sufficient to relieve the symptoms of cancer. The term "effective amount" may also refer to an amount of a compound of the present disclosure effective to inhibit the interaction of menin with MLL and / or MLL fusion proteins.

[0173] The term "inhibition" or "inhibiting" refers to a decrease in the baseline activity of a biological activity or process.

[0174] The term "subject" as used herein refers to mammals and non-mammals. Mammals refer to any member of the mammalian genus, including, but not limited to, humans; non-human primates, such as chimpanzees and other ape and monkey species; domestic animals, such as cows, horses, sheep, goats, and pigs; domestic animals, such as rabbits, dogs, and cats; laboratory animals, including rodents, such as rats, mice, and guinea pigs; and the like. In some embodiments, the subject is a human.

[0175] The term "pharmaceutical acceptable" means that the material which follows this term is useful in preparing pharmaceutical compositions, is generally safe, non-toxic, and not biologically or otherwise undesirable, and is particularly suitable for human pharmaceutical use.

[0176] The term "cancer" herein refers to a cellular disorder characterized by uncontrolled or unregulated cell proliferation, reduced cell differentiation, inappropriate ability to invade surrounding tissues, and / or new growth at other sites. The term "cancer" includes, but is not limited to, hematological and solid tumors, preferably leukemia. The term "cancer" encompasses cancers of the skin, tissues, organs, bone, cartilage, blood, and blood vessels. The term "cancer" further encompasses primary cancers, metastatic cancers, recurrent cancers, and refractory cancers. The term "cancer" includes, but is not limited to, leukemia, lymphoma, myeloma (e.g., multiple myeloma), myelodysplastic syndromes (MDS), and myeloproliferative neoplasms (MPN), polycythemia vera; prostate cancer, lung cancer, breast cancer, pancreatic cancer, colon cancer, liver cancer, melanoma, and glioblastoma. As used herein, "leukemia" includes acute leukemia, chronic leukemia, myeloid leukemia, myelogenous leukemia, lymphoblastic leukemia, lymphocytic leukemia, acute myeloid (bone marrow) leukemia (AML), chronic myeloid (bone marrow) leukemia (CML), acute lymphoblastic leukemia (ALL), chronic lymphocytic leukemia (CLL), T-cell prolymphocytic leukemia (T-PLL), large granular lymphocytic leukemia, hairy cell leukemia (HCL), mixed lineage leukemia (MLL), MLL-rearranged leukemia (MLLr leukemia), MLL partial tandem duplication leukemia (MLL-PTD leukemia), MLL-amplified leukemia, MLL-positive leukemia, nucleophosmin (NPM)-mutated leukemia (NPM 1 mutant leukemia, NPM1c leukemia, MOZ acute leukemia, NUP98 acute leukemia, and clathrin assembly lymphoid myeloid (CALM) acute leukemia; and MLL-AF4 (ALL-1 fusion gene on chromosome 4) leukemia, MLL-AF6 leukemia, MLL-AF9 leukemia, MLL-AF10 leukemia, MLL-ENL (11-19 leukemia) leukemia, and MLL-ELL (11-19 lysine-rich leukemia) leukemia.

[0177] All numerical ranges herein should be understood to disclose every value within the range and every subset of values ​​within the range, whether or not otherwise specifically disclosed. For example, when any numerical range is referred to, it should be considered to refer to every numerical value within the numerical range, for example, every integer within the numerical range. The present disclosure includes every value within these ranges, every smaller range, and the upper or lower limit of the range.

[0178] Technical and scientific terms used herein and not specifically defined have the meaning commonly understood by one of ordinary skill in the art to which this disclosure pertains.

[0179] Pharmaceutical Compositions and Administration A compound of the present disclosure (e.g., any of the compounds of the Examples herein) can be formulated, alone or in combination with one or more additional therapeutic agents, into a pharmaceutical composition comprising (a) a compound of the present disclosure, (b) a pharma- ceutically acceptable carrier (e.g., one or more pharma- ceutically acceptable carriers), and, optionally, (c) at least one additional therapeutic agent.

[0180] Pharmaceutically acceptable carrier refers to an excipient or adjuvant that is compatible with the active ingredient in the composition (in some embodiments, it can stabilize the active ingredient) and is not harmful to the subject being treated.Suitable pharmaceutically acceptable carriers are disclosed in standard references in the art (e.g., Remington's Pharmaceutical Sciences, Remington: the Science and Practice of Pharmacy), and include one or more buffers, stabilizers, surfactants, wetting agents, lubricants, emulsifiers, suspending agents, preservatives, antioxidants, opacifiers, glidants, processing aids, colorants, sweeteners, aromas, flavorings, diluents, and other known additives that provide an elegant presentation of the drug (i.e., the compound of the present disclosure or its pharmaceutical composition) or aid in the manufacture of a pharmaceutical product (i.e., a drug product).

[0181] The compounds of the present disclosure can be administered in a variety of known ways, such as orally, parenterally, by inhalation, or by implantation. The term "parenteral" as used herein includes subcutaneous, intradermal, intravenous, intramuscular, intraarticular, intraarterial, intrasynovial, intrasternal, intrathecal, intralesional, and intracranial injection or infusion.

[0182] The compounds of the present disclosure may be administered in any convenient formulation, such as tablets, powders, capsules, liquids, dispersions, suspensions, syrups, sprays, suppositories, gels, emulsions, patches, and the like.

[0183] In one example, an effective amount of a compound of the present disclosure administered parenterally per dose ranges from about 0.01 to 100 mg / kg, alternatively about 0.1 to 20 mg / kg of patient body weight per day, with a typical initial range of the compound used being 0.3 to 15 mg / kg / day. In another embodiment, oral dosage unit forms such as tablets and capsules contain from about 0.1 to about 1000 mg of a compound of the present disclosure.

[0184] Indications and Treatment Methods The present disclosure relates to a method for treating or preventing a disease or disorder mediated by the interaction of menin with MLL and / or MLL fusion proteins, comprising administering to a subject in need thereof an effective amount of a compound of the present disclosure.

[0185] The present disclosure relates to a method for treating or preventing cancer or diabetes comprising administering to a subject in need thereof an effective amount of a compound of the present disclosure.

[0186] In one embodiment, the compounds of the disclosure are used to treat or prevent a disease or disorder mediated by the interaction of menin with MLL and / or MLL fusion proteins.

[0187] In one embodiment, the compounds of the disclosure are used to treat or prevent cancer or diabetes.

[0188] In one embodiment, the compounds of the present disclosure are used to treat or prevent hematological tumors, including but not limited to leukemia, lymphoma, myeloma (e.g., multiple myeloma), myelodysplastic syndromes (MDS), and myeloproliferative neoplasms (MPN), polycythemia vera; or solid tumors, including but not limited to prostate cancer, lung cancer, breast cancer, pancreatic cancer, colon cancer, liver cancer, melanoma, and glioblastoma.

[0189] In one embodiment, the compounds of the disclosure are used to treat or prevent acute leukemia, chronic leukemia, myeloid leukemia, myelogenous leukemia, lymphoblastic leukemia, lymphocytic leukemia, acute myeloid leukemia (AML), chronic myeloid leukemia (CML), acute lymphoblastic leukemia (ALL), chronic lymphocytic leukemia (CLL), T-cell prolymphocytic leukemia (T-PLL), large granular lymphocytic leukemia, hairy cell leukemia (HCL), mixed lineage leukemia (MLL), MLL-rearranged leukemia (MLLr leukemia), MLL partial tandem duplication leukemia (MLL-PTD leukemia), MLL-amplified leukemia, MLL-positive leukemia, nucleophosmin (NPM) mutated leukemia, MOZ acute leukemia, NUP98 acute leukemia, and clathrin assembly lymphocytic myeloid (CALM) acute leukemia.

[0190] Drug Combinations The compounds of the present disclosure can be used in combination with additional therapeutic agents in the treatment of diseases or disorders mediated by the interaction of menin with MLL and / or MLL fusion proteins. The additional therapeutic agents may be administered separately from the compounds of the present disclosure or may be included with the compounds of the present disclosure in a pharmaceutical composition according to the present disclosure, such as a fixed combination product. In some embodiments, the additional therapeutic agent is one that is known or discovered to be effective in the treatment of diseases or disorders mediated by the interaction of menin with MLL and / or MLL fusion proteins, or a compound that antagonizes another target associated with the particular disease. The combination may help to increase the effectiveness of the compounds of the present disclosure, reduce one or more side effects, or reduce the required dosage.

[0191] In some embodiments, the compounds of the present disclosure are administered in combination with an anti-neoplastic agent, including, but not limited to, a radiotherapeutic agent, a chemotherapeutic agent, an immunotherapeutic agent, or a targeted therapeutic agent.

[0192] General synthesis method Exemplary compounds with the general structure as A10 can be synthesized according to Scheme 1. Reaction of phenol A1 with 5-bromopyrimidine under basic conditions afforded biaryl ether A2, which could be converted to N-oxide A3 in the presence of mCPBA. Subsequent reaction of the latter with a chlorinating reagent such as POCl3 readily afforded chloropyrimidine A4. Nucleophilic substitution reaction between chloride A4 and monoprotected spirodiamine A5 afforded key intermediate A6. Subsequent deprotection of A7, amide formation with N-protected cyclic amino acid A8, and N-deprotection afforded the final compound A10. [ka]

[0193] An exemplary compound having the structure as B4 can be synthesized according to Scheme 2. B1 could be prepared from the appropriate phenol following a similar procedure as A6 shown in Scheme 1. Suzuki coupling reaction of B1 with (hetero)arylboronic acid gave compound B3. Alternatively, B3 could be prepared using a two-step route, i.e., conversion of B1 to boronate B2 via palladium-catalyzed boronation reaction followed by Suzuki reaction of the latter with (hetero)aryl halide. Subsequent deprotection of B3, amidation with N-protected cyclic amino acid A8, and final N-deprotection could give compound B4. [ka]

[0194] Exemplary compounds with the general structure as C6 can be synthesized according to Scheme 3. Selective nucleophilic substitution reaction between monoprotected spirodiamine A5 and 3,5,6-trichloro-1,2,4-triazine C1 gave triazine C2. A second nucleophilic substitution with phenol C3 gave monochloride C4. Removal of the chlorine atom under reducing conditions gave triazine C5. Again, subsequent deprotection, amidation with N-protected cyclic amino acid A8, and final N-deprotection gave compound C6. [ka]

[0195] Exemplary compounds having the general structure as D1 in Scheme 4 could be prepared from chloride C4 in three steps: deprotection, amidation with N-protected cyclic amino acid A8, and N-deprotection. Chloride C4 could also be reacted with nucleophiles under basic conditions or with boron reagents in the presence of palladium catalyst to give intermediate D2, which could be deprotected, amidated with N-protected cyclic amino acid A8, and N-deprotected to give exemplary compounds having the general structure as D3 (Scheme 4). [ka]

[0196] It should be understood that each embodiment and the features in each embodiment described in the present disclosure can be combined with each other in any manner, and technical solutions obtained by such combinations are all included in the scope of the present disclosure as if every technical solution obtained by such combinations was specifically and individually recited, unless the context clearly indicates otherwise.

[0197] All patents, patent applications, publications, and other references cited or referred to herein are hereby incorporated by reference in their entirety to the extent permitted by law. The discussion of these references is intended merely to summarize the assertions made therein. No admission is made that such patents, patent applications, publications, or references, or any portion thereof, are relevant material or prior art. The right to challenge the accuracy and pertinence of any assertion made of such patents, patent applications, publications, and other references as relevant material or prior art is specifically reserved. EXAMPLES

[0198] The following examples are intended to illustrate the invention and should not be construed as limiting in any sense.

[0199] Unless otherwise indicated, temperature is in degrees Celsius and pressure is at or near atmospheric. All MS (mass spectrometry) data was determined on an Agilent 6120B and / or Shimadzu LCMS2010. 1 H-NMR spectra were recorded on a Bruker AVANCE NEO nuclear magnetic resonance spectrometer operating at 400 MHz. When peak multiplicities are reported, the following abbreviations are used: s (singlet), d (doublet), t (triplet), m (multiplet), q (quarter), br (broad), dd (doublet of doublets), dt (doublet of triplets). Coupling constants, when given, are reported in Hertz (Hz).

[0200] All reagents and starting materials used in the present invention, except for the intermediates prepared below, are either commercially available or prepared according to prior art techniques.

[0201] All compound names, except for reagents, were generated in Chemdraw. In the event of a discrepancy between the structure and name of a compound given in this invention, the structure prevails unless the context indicates that the structure is incorrect and the name is correct.

[0202] When an atom disclosed herein has an open valence, the open valence is a hydrogen atom and has been omitted for convenience.

[0203] In the following examples, where isomers were isolated from the same chromatographic separation conditions, they are named in the same order as they were eluted, unless otherwise specified.

[0204] In the examples below, the following abbreviations are used: [Table 2-1] [Table 2-2] Preparation of key intermediates Preparation of Intermediate 1, 2-((4-(2,7-diazaspiro[3.5]nonan-2-yl)pyrimidin-5-yl)oxy)-N-ethyl-5-fluoro-N-isopropylbenzamide [ka] Step 1: To a solution of 5-fluoro-2-methoxybenzoic acid (7.50 g, 44.1 mmol) and HATU (16.7 g, 44.0 mmol) in DMF (50 mL) was added ethyl(propan-2-yl)amine (15.4 g, 176 mmol) dropwise at 0° C. The reaction mixture was gradually warmed to room temperature and stirred overnight. The reaction mixture was diluted with saturated NH 4 The mixture was quenched with aqueous Cl (50 mL), extracted with EtOAc (100 mL x 3), and the combined organic phase was washed with water and brine, and then cooled to room temperature. 2 SO 4 The mixture was dried at 40° C., filtered, concentrated, and the residue was purified by column chromatography on silica gel (EtOAc in PE=0-30%) to give the desired product N-ethyl-5-fluoro-2-methoxy-N-(propan-2-yl)benzamide (10.0 g, yield: 94.8%) as a pale yellow solid. LC / MS (ESI) m / z: 240 (M+H). + .

[0205] Step 2: To a solution of N-ethyl-5-fluoro-2-methoxy-N-(propan-2-yl)benzamide (9.01 g, 37.6 mmol) in DCM (50 mL) was added 2 BBr at -60℃ under atmospheric pressure 3 (37.6 mL, 1.0 M in DCM) was added dropwise and the resulting mixture was stirred at this temperature for 2 h. The reaction mixture was then cooled and saturated NaHCO 3 The mixture was quenched with DCM (100 mL x 3) and the combined organic layers were washed with water and brine, and diluted with anhydrous Na 2 SO 4 The mixture was dried at 40° C., filtered and concentrated to give the desired product N-ethyl-5-fluoro-2-hydroxy-N-(propan-2-yl)benzamide (4.01 g, yield: 47.2%) as a pale yellow solid, which can be used in the next step without further purification. LC / MS (ESI) m / z: 226 (M+H). + .

[0206] Step 3: To a mixture of N-ethyl-5-fluoro-2-hydroxy-N-(propan-2-yl)benzamide (4.01 g, 17.7 mmol) in DMF (20 mL), 5-bromopyrimidine (3.40 g, 21.3 mmol) and Cs 2 CO 3 (11.6 g, 35.5 mmol) was added. The reaction mixture was heated at 120° C. for 12 h, cooled to room temperature, and then the mixture was diluted with saturated NH 4 The mixture was quenched with aqueous Cl (50 mL), extracted with EtOAc (100 mL x 3), and the combined organic layers were washed with water and brine, and then with anhydrous Na 2 SO 4 Drying at 40° C., filtration and concentration gave the crude product, which was purified by column chromatography on silica gel (EtOAc in PE=0-20%) to give the desired product N-ethyl-5-fluoro-N-(propan-2-yl)-2-(pyrimidin-5-yloxy)benzamide (1.99 g, yield: 37.1%) as a yellow oil. LC / MS (ESI) m / z: 304 (M+H). + .

[0207] Step 4: To a solution of N-ethyl-5-fluoro-N-(propan-2-yl)-2-(pyrimidin-5-yloxy)benzamide (1.99 g, 6.60 mmol) in DCM (20 mL) was added m-CPBA (3.41 g, 19.8 mmol) in portions at 0° C., and the resulting mixture was then stirred at room temperature for 10 h. The reaction mixture was diluted with saturated NaHCO 3 The mixture was quenched with and extracted with DCM (50 mL x 3), and the combined organic layers were washed with water and brine, and then washed with anhydrous Na 2 SO 4 The mixture was dried at 40° C., filtered and concentrated to give the crude product, which was purified by column chromatography on silica gel (EtOAc in PE=0-80%) to give the desired product 5-{2-[ethyl(propan-2-yl)carbamoyl]-4-fluorophenoxy}pyrimidin-1-ium-1-olate (0.901 g, yield: 42.8%) as an off-white solid. LC / MS (ESI) m / z: 320 (M+H). + .

[0208] Step 5: CHCl 3 To a solution of 5-{2-[ethyl(propan-2-yl)carbamoyl]-4-fluorophenoxy}pyrimidin-1-ium-1-olate (0.90 g, 2.8 mmol) and TEA (0.8 mL, 5.6 mmol) in POCl 3 (0.80 mL, 8.4 mmol) was added dropwise at 0° C. The reaction mixture was then stirred at room temperature for 12 h. The reaction mixture was diluted with saturated NaHCO 3 The mixture was quenched with and extracted with DCM (100 mL x 3). The combined organic layers were washed with water and brine, and then washed with anhydrous Na 2 SO 4 Drying at 40° C., filtering and concentrating in vacuo gave the crude product 2-[(4-chloropyrimidin-5-yl)oxy]-N-ethyl-5-fluoro-N-(propan-2-yl)benzamide (320 mg, yield: 33.6%) as a brown oil, which can be used in the next step without further purification. LC / MS (ESI) m / z: 338 / 340 (M+H).+ .

[0209] Step 6: To a solution of 2-[(4-chloropyrimidin-5-yl)oxy]-N-ethyl-5-fluoro-N-(propan-2-yl)benzamide (300 mg, 0.9 mmol) in MeCN (10 mL) was added tert-butyl 2,7-diazaspiro[3.5]nonane-7-carboxylate (221 mg, 1.00 mmol) and K 2 CO 3 (246 mg, 1.80 mmol) was added. The resulting mixture was heated to 80° C. for 5 h. After cooling to room temperature, the reaction mixture was diluted with saturated NH 4 The mixture was quenched with aqueous Cl (10 mL), extracted with EtOAc (20 mL×3), and the combined organic layers were washed with water and brine, and then with anhydrous Na 2 SO 4 Drying at 40° C., filtration and concentration gave the crude product, which was purified by column chromatography on silica gel (EtOAc in PE=0-50%) to give the desired product tert-butyl 2-(5-{2-[ethyl(propan-2-yl)carbamoyl]-4-fluorophenoxy}pyrimidin-4-yl)-2,7-diazaspiro[3.5]nonane-7-carboxylate (390 mg, yield: 83.2%) as a yellow solid. LC / MS (ESI) m / z: 528 (M+H) + .

[0210] Step 7: A solution of tert-butyl 2-(5-{2-[ethyl(propan-2-yl)carbamoyl]-4-fluorophenoxy}pyrimidin-4-yl)-2,7-diazaspiro[3.5]nonane-7-carboxylate (200 mg, 0.4 mmol) in DCM (5 mL) was added dropwise with TFA (2.0 mL) at room temperature, and the resulting mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated to obtain the crude product 2-2-[(4-{2,7-diazaspiro[3.5]nonan-2-yl}pyrimidin-5-yl)oxy]-N-ethyl-5-fluoro-N-(propan-2-yl)benzamide (150 mg, yield: 92.5%) as the TFA salt. This can be used in the next step without further purification. LC / MS (ESI) m / z: 428 (M+H) + 。

[0211] Following the experimental procedure for Intermediate 1, the following intermediates were prepared from the corresponding chemical substances (listing the main different chemical substances used in the starting material column).

Table 3-1

Table 3-2

Table 3-3

Chem.

[0212] Step 2: To a solution of 5-fluoro-N,N-diisopropyl-2-methoxybenzamide (320 mg, 1.26 mmol) in DCM (10 mL), 2 BBr at -60℃ under atmospheric pressure 3 (3 mL, 1.0 M in DCM) was added dropwise and the resulting mixture was stirred at this temperature for 2 h. The reaction mixture was then quenched with MeOH cooled at 0° C., the mixture was extracted with DCM (15 mL×3), and the combined organic layers were washed with water and brine, and anhydrous Na 2 SO 4 The mixture was dried at 40° C., filtered and concentrated to give the crude product, which was purified by column chromatography on silica gel (EtOAc in PE=0-20%) to give the desired product N-ethyl-5-fluoro-2-hydroxy-N-(propan-2-yl)benzamide (260 mg, yield: 86.3%) as a white solid. LC / MS (ESI) m / z: 240 (M+H). + .

[0213] Preparation of Intermediate 15, (2S)-4-Hydroxy-4-methylpyrrolidine-2-carboxylic acid [ka] Step 1: To a solution of 1-tert-butyl 2-methyl(2S)-4-oxopyrrolidine-1,2-dicarboxylate (200 mg, 0.82 mmol) in THF (5 mL) was added MeMgBr (1.2 mL, 1.23 mmol) 2 The resulting mixture was stirred at room temperature for 2 hours. The reaction mixture was diluted with saturated NH 4The mixture was quenched with aqueous Cl (5 mL), extracted with EtOAc (20 mL x 3), and the combined organic layers were washed with anhydrous Na 2 SO 4 The mixture was dried at 40° C., filtered, concentrated, and the residue was purified by column chromatography on silica gel (EtOAc in PE=0-30%) to give the desired product 1-tert-butyl 2-methyl(2S)-4-hydroxy-4-methylpyrrolidine-1,2-dicarboxylate (180 mg, yield: 80.2%) as a pale yellow oil. LC / MS(ESI) m / z: 260(M+H) + .

[0214] Step 2: MeOH (3 mL) and H 2 To a solution of 1-tert-butyl 2-methyl(2S)-4-hydroxy-4-methylpyrrolidine-1,2-dicarboxylate (180 mg, 0.69 mmol) in HO (1 mL) was added NaOH (83 mg, 2.1 mmol) at 0 °C. The resulting mixture was stirred at room temperature for 2 h, and the reaction mixture was adjusted to pH 4-5 with 1.0 N HCl solution and then cooled to 5°C. 2 Dilute with 20 mL of O (10 mL), extract with DCM (20 mL × 3), and wash the combined organic layers with anhydrous NaCl. 2 SO 4 The mixture was dried at 40° C., filtered and concentrated to give the desired product (2S)-1-[(tert-butoxy)carbonyl]-4-hydroxy-4-methylpyrrolidine-2-carboxylic acid (150 mg, yield: 83.6%) as an off-white solid, which can be used directly in the next step without further purification. LC / MS (ESI) m / z: 190 (M-55). + .

[0215] Preparation of Intermediate 16, (2S,4R)-1-(tert-butoxycarbonyl)-4-(methylsulfonyl)pyrrolidine-2-carboxylic acid [ka] Step 1: To a solution of 1-tert-butyl 2-methyl(2S,4S)-4-hydroxypyrrolidine-1,2-dicarboxylate (1.0 g, 4.0 mmol), TEA (0.83 g, 8.2 mmol) in DCM (15 mL) was added MsCl (0.50 g, 4.5 mmol) and N 2 The mixture was added below 0° C. and the resulting mixture was stirred at room temperature for 1 h. The mixture was diluted with water (30 mL) and extracted with EtOAc (25 mL×3). The combined organic phase was washed with brine (25 mL) and concentrated to give the crude product 1-tert-butyl 2-methyl(2S,4S)-4-(methanesulfonyloxy)pyrrolidine-1,2-dicarboxylate (1.1 g, yield: 83.4%) as a pale yellow oil, which was used in the next step without further purification. LC / MS (ESI) m / z: 224 (M-100+H). + .

[0216] Step 2: To a solution of 1-tert-butyl 2-methyl(2S,4S)-4-(methanesulfonyloxy)pyrrolidine-1,2-dicarboxylate (1.1 g, 3.4 mmol) in DMF (15 mL) was added NaSMe (230 mg, 4.0 mmol) and the resulting mixture was stirred at room temperature for 10 h. The reaction mixture was diluted with water (30 mL) and extracted with EtOAc (25 mL×3). The combined organic phase was washed with brine and diluted with anhydrous Na 2 SO 4 The mixture was dried at 400 rpm, filtered, concentrated, and the residue was purified by column chromatography on silica gel (10-25% EtOAc in PE) to give the desired product (2S,4R)-1-tert-butyl 2-methyl 4-(methylthio)pyrrolidine-1,2-dicarboxylate (850 mg, yield: 90.7%) as a solid. 1H NMR (400 MHz, CDCl 3 )δ 4.29(dd,J=23.9,16.0Hz,1H),3.97(dd,J=10.5,7.0Hz,1H),3.74(s,3H),3.42-3.12(m ,2H),2.60(dd,J=13.0,6.4Hz,1H),2.12(s,3H),1.99-1.88(m,1H),1.47-1.40(m,9H).

[0217] Step 3: To a solution of (2S,4R)-1-tert-butyl 2-methyl 4-(methylthio)pyrrolidine-1,2-dicarboxylate (850 mg, 3.10 mmol) in DCM (20 mL) was added m-CPBA (1.1 g, 6.2 mmol) at 0° C., and the resulting mixture was stirred at room temperature overnight. The reaction mixture was diluted with DCM (50 mL), washed with brine, and diluted with anhydrous Na 2 SO 4 The mixture was dried at 40° C., filtered, concentrated, and the residue was purified by column chromatography on silica gel (5% EtOAc in PE) to give the desired product (2S,4R)-1-tert-butyl 2-methyl 4-(methylsulfonyl)pyrrolidine-1,2-dicarboxylate (500 mg, yield: 52.7%) as a pale yellow solid. LC / MS (ESI) m / z: 330 (M+Na). + .

[0218] Step 4: To a solution of (2S,4R)-1-tert-butyl 2-methyl 4-(methylsulfonyl)pyrrolidine-1,2-dicarboxylate (500 mg, 1.6 mmol) in EtOH (5 mL) was added aqueous NaOH (2.0 mL, 2.0 N) and the resulting mixture was stirred at room temperature for 30 min. The reaction mixture was concentrated, the pH was adjusted to 2-3 with 1.0 N HCl solution, and extracted with EtOAc (30 mL x 3). The combined organic layer was washed with water and brine and diluted with anhydrous Na 2 SO 4 Drying at 40° C., filtration and concentration gave the crude product (2S,4R)-1-(tert-butoxycarbonyl)-4-(methylsulfonyl)pyrrolidine-2-carboxylic acid (400 mg, yield: 83.8%) as a pale yellow oil, which was used in the next step without further purification. LC / MS (ESI) m / z: 316 (M+Na). + .

[0219] Preparation of intermediate 17, (4S,5S,7R)-6-(tert-butoxycarbonyl)-1-methyl-4,5,6,7-tetrahydro-1H-4,7-methanopyrazolo[3,4-c]pyridine-5-carboxylic acid [ka] Step 1: To a solution of 2-tert-butyl 3-ethyl (1R,3S,4S,6R)-6-hydroxy-2-azabicyclo[2.2.1]heptane-2,3-dicarboxylate (1.1 g, 3.8 mmol) in DCM (30 mL) was added Dess-Martin reagent (3.3 g, 7.7 mmol) at 0 °C, and the resulting mixture was stirred at room temperature overnight. The reaction mixture was diluted with water (20 mL) and extracted with DCM (20 mL × 3). The combined organic phase was washed with water and brine and diluted with anhydrous Na 2 SO 4 The mixture was dried at 70° C., filtered, concentrated, and the residue was purified by column chromatography on silica gel (EtOAc in PE=5-20%) to give the desired product 2-tert-butyl 3-ethyl (1R,3S,4S)-6-oxo-2-azabicyclo[2.2.1]heptane-2,3-dicarboxylate (800 mg, yield: 73.2%) as an oil. LC / MS (ESI) m / z: 184 (M-100+H). + .

[0220] Step 2: To a solution of 2-tert-butyl 3-ethyl (1R,3S,4S)-6-oxo-2-azabicyclo[2.2.1]heptane-2,3-dicarboxylate (1.2 g, 4.2 mmol) in toluene (10 mL), DMF-DMA (5 mL) was added and the reaction mixture was heated to 120 °C for 24 h. The mixture was cooled to room temperature, the solvent was concentrated, and the residue was purified by column chromatography on silica gel (EtOAc in PE = 50% to 100%) to give the desired product (1R,3S,4S)-2-tert-butyl 3-ethyl 5-((dimethylamino)methylene)-6-oxo-2-azabicyclo[2.2.1]heptane-2,3-dicarboxylate (500 mg, yield: 35.7%) as a pale yellow solid. LC / MS (ESI) m / z: 283 (M-55+H) + .

[0221] Step 3: To a solution of (1R,3S,4S)-2-tert-butyl 3-ethyl 5-((dimethylamino)methylene)-6-oxo-2-azabicyclo[2.2.1]heptane-2,3-dicarboxylate (300 mg, 0.9 mmol) and methylhydrazine solution (0.2 mL, 1.6 mmol) in MeCN (10 mL), HOAc (0.1 mL) was added and the resulting mixture was stirred at 80° C. overnight. The reaction mixture was concentrated and the residue was purified by column chromatography on silica gel (EtOAc in PE=10-30%) to give the desired product 9-tert-butyl 8-ethyl 6-(tert-butyl) 5-ethyl (4S,5S,7R)-1-methyl-1,4,5,7-tetrahydro-6H-4,7-methanopyrazolo[3,4-c]pyridine-5,6-dicarboxylate (150 mg, yield: 52%) as a white solid. LC / MS(ESI) m / z: 322(M+H)+.

[0222] Step 4: To a solution of 6-(tert-butyl)5-ethyl (4S,5S,7R)-1-methyl-1,4,5,7-tetrahydro-6H-4,7-methanopyrazolo[3,4-c]pyridine-5,6-dicarboxylate (150 mg, 0.5 mmol) in MeOH (8 mL), NaOH solution (3.0 mL, 2.0 N) was added and the reaction mixture was stirred at 60° C. for 1 h. The mixture was concentrated, the pH was adjusted to 2-3 with 1.0 N HCl, the mixture was extracted with EtOAc (20 mL×3), and the combined organic phase was dried and concentrated to give the crude product (4S,5S,7R)-6-(tert-butoxycarbonyl)-1-methyl-4,5,6,7-tetrahydro-1H-4,7-methanopyrazolo[3,4-c]pyridine-5-carboxylic acid (80 mg, yield: 58.4%) as a yellow solid. LC / MS(ESI)m / z:294(M+H) + .

[0223] Preparation of intermediate 18, (S)-N-ethyl-5-fluoro-N-isopropyl-2-((4-(7-(1-methyl-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazole-4-carbonyl)-2,7-diazaspiro[3.5]nonan-2-yl)pyrimidin-5-yl)oxy)benzamide [ka] Step 1: To a solution of (S)-di-tert-butyl 4-oxopyrrolidine-1,2-dicarboxylate (2.0 g, 8.2 mmol) in toluene (20 mL) was added DMF-DMA (2.8 mL, 24.7 mmol). The resulting mixture was heated to 105 °C for 6 h. The reaction mixture was cooled to room temperature, concentrated, and the residue was purified by column chromatography on silica gel (EtOAc in PE = 0-50%) to give the desired product di-tert-butyl 3-((dimethylamino)methylene)-4-oxopyrrolidine-1,2-dicarboxylate (2.0 g, yield: 84%) as an oil. LC-MS: m / z 341 (M+H) + .

[0224] Step 2: To a solution of di-tert-butyl 3-((dimethylamino)methylene)-4-oxopyrrolidine-1,2-dicarboxylate (1.3 g, 3.8 mmol) in EtOH (10 mL) was added methylhydrazine solution (0.8 mL, 5.7 mmol) and the resulting mixture was heated to 85 °C in a sealed tube for 12 h. The reaction mixture was concentrated and the residue was purified by column chromatography on silica gel (EtOAc in PE = 0-100%) to give the desired product (S)-di-tert-butyl 1-methyl-4,6-dihydropyrrolo[3,4-c]pyrazole-4,5(1H)-dicarboxylate (700 mg, yield: 57%) as a solid. LC-MS: m / z 324 (M+H) + .

[0225] Step 3: To a solution of (S)-di-tert-butyl 1-methyl-4,6-dihydropyrrolo[3,4-c]pyrazole-4,5(1H)-dicarboxylate (300 mg, 0.93 mmol) in DCM (5 mL) was added TFA (2 mL) dropwise at 0° C., and the resulting mixture was stirred at room temperature for 10 h. The reaction mixture was concentrated under reduced pressure to give the crude product (S)-1-methyl-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazole-4-carboxylic acid (240 mg, yield: 92%) as a pale yellow oil, which was used in the next step without further purification. LC / MS (ESI) m / z: 168 (M+H). + .

[0226] Step 4: To a solution of (S)-1-methyl-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazole-4-carboxylic acid (290 mg, 0.71 mmol) and TEA (0.09 mL, 0.71 mmol) in DCM (5 mL) was added Boc 2 2H2O (170 mg, 0.71 mmol) was added dropwise at 0° C. and the resulting mixture was stirred at room temperature for 2 h. 2 Dilute with 2 mL of O (5 mL), extract with DCM (10 mL × 3), and wash the combined organic phase with anhydrous Na 2 SO 4 The mixture was dried at 40° C., filtered and concentrated to give the desired crude product (S)-5-(tert-butoxycarbonyl)-1-methyl-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazole-4-carboxylic acid (180 mg, yield: 94.6%) as a solid. LC / MS (ESI) m / z: 268 (M+H) + .

[0227] Following the experimental procedure for intermediate 18, the following intermediates were prepared from the corresponding chemicals (the main different chemicals used are listed in the starting material column). [Table 4] Preparation of Intermediate 22, N-(2,2-difluoroethyl)-5-fluoro-2-hydroxy-N-isopropylbenzamide [ka] Step 1: To a stirred solution of 5-fluoro-2-methoxybenzoic acid (2.0 g, 11.7 mmol) and 2-[(propan-2-yl)amino]ethan-1-ol (1.5 mL, 13.6 mmol) in DCM (40 mL) at 0° C., DIPEA (2.56 mL, 15.5 mmol) and HATU (5.0 g, 13.1 mmol) were added, and the resulting mixture was then allowed to warm to room temperature and stirred overnight. The reaction mixture was diluted with saturated NH 4 The mixture was quenched with aqueous Cl, extracted with EtOAc (50 mL x 3), and the combined organic phase was washed with anhydrous Na 2 SO 4 The mixture was dried at 40° C., filtered, concentrated, and the residue was purified by column chromatography on silica gel (EtOAc in PE=5-50%) to give the desired product 5-fluoro-N-(2-hydroxyethyl)-2-methoxy-N-(propan-2-yl)benzamide (2.5 g, yield: 83.3%) as a white solid. LC / MS (ESI) m / z: 256 (M+H). + .

[0228] Step 2: To a solution of 5-fluoro-N-(2-hydroxyethyl)-2-methoxy-N-(propan-2-yl)benzamide (2.5 g, 9.79 mmol) in DCM (100 mL) at 0 °C, Dess-Martin reagent (4.5 g, 10.6 mmol) was added, and the resulting mixture was stirred at 25 °C for 10 h. The reaction mixture was poured into ice water (50 mL), extracted with EtOAc (50 mL × 3), and the combined organic phase was washed with anhydrous Na 2 SO 4 The mixture was dried at 40° C., filtered, concentrated, and the residue was purified by column chromatography on silica gel (EtOAc in PE=5-30%) to give the desired product 5-fluoro-2-methoxy-N-(2-oxoethyl)-N-(propan-2-yl)benzamide (2.2 g, yield: 88.7%) as a white solid. LC / MS (ESI) m / z: 254 (M+H). + .

[0229] Step 3: To a solution of 5-fluoro-2-methoxy-N-(2-oxoethyl)-N-(propan-2-yl)benzamide (2.2 g, 8.69 mmol) in DCM (50 mL) at −10° C., DAST (2.87 mL, 21.7 mmol) was added slowly and the reaction mixture was cooled to 5° C. with N 2 The mixture was stirred under atmospheric pressure at 25° C. for 5 hours. The reaction mixture was poured into ice water (50 mL), and the mixture was extracted with EtOAc (50 mL×3). The combined organic phase was extracted with anhydrous Na 2 SO 4 The mixture was dried at 40° C., filtered, concentrated, and the residue was purified by column chromatography on silica gel (EtOAc in PE=1-30%) to give the desired product N-(2,2-difluoroethyl)-5-fluoro-2-methoxy-N-(propan-2-yl)benzamide (350 mg, yield: 14.6%) as an oil. LC / MS (ESI) m / z: 276 (M+H). + .

[0230] Step 4: To a solution of N-(2,2-difluoroethyl)-5-fluoro-2-methoxy-N-(propan-2-yl)benzamide (350 mg, 1.27 mmol) in DCM (10 mL) at -60 °C, was added BBr 3 (3.4 mL, 3.40 mmol) 2 The mixture was stirred at -60°C for 2 h. The reaction mixture was cooled to -60°C and saturated NaHCO 3 The mixture was quenched with at 0° C. and extracted with DCM (100 mL×3). The combined organic layers were washed with water and brine, and then washed with anhydrous Na 2 SO 4 The mixture was dried at 40° C., filtered, concentrated, and the residue was purified by column chromatography on silica gel (EtOAc in PE=1-20%) to give the desired product N-(2,2-difluoroethyl)-5-fluoro-2-hydroxy-N-(propan-2-yl)benzamide (300 mg, yield: 90.3%) as a white solid. LC / MS (ESI) m / z: 262 (M+H). + .

[0231] Intermediate 22-1, Preparation of 5-fluoro-2-hydroxy-N-(2-hydroxyethyl)-N-(propan-2-yl)benzamide [ka] To a solution of 5-fluoro-N-(2-hydroxyethyl)-N-isopropyl-2-methoxybenzamide (510 mg, 2.00 mmol) in DCM (10 mL), 2 BBr at -40℃ under atmospheric pressure 3 (4 mL, 1.0 M in DCM) was added dropwise and the resulting mixture was stirred at this temperature for 2 h. The reaction mixture was then slowly quenched with MeOH cooled to -40°C and diluted with DCM (50 mL). The organic layer was separated and saturated NaHCO 3 Wash with aqueous solution and brine, and add anhydrous Na 2 SO 4 After drying, filtration and concentration, the desired product 5-fluoro-2-hydroxy-N-(2-hydroxyethyl)-N-isopropylbenzamide (330 mg, yield: 68.5%) was obtained as a yellow solid, which can be used in the next step without further purification. LC / MS (ESI) m / z: 242 (M+H). + .

[0232] Preparation of intermediate 23, (6S)-5-(tert-butoxycarbonyl)-1,1-difluoro-5-azaspiro[2.4]heptane-6-carboxylic acid [ka] Step 1: in DCM (5 mL) A solution of (2S)-1-[(tert-butoxy)carbonyl]-4-methylidenepyrrolidine-2-carboxylic acid (0.25 mL, 1.32 mmol) was added to the solution of TMSCHN 2 (225.73 mg, 1.98 mmol) was added at room temperature and the resulting mixture was stirred for 2 h. The reaction mixture was quenched with AcOH (1.0 mL) and then H 2 Dilute with 2 mL of O (10 mL), extract with DCM (10 mL × 3), and wash the combined organic layers with anhydrous NaCl. 2 SO4 Drying at 40° C., filtration and concentration afforded the crude product (S)-1-tert-butyl 2-methyl 4-methylenepyrrolidine-1,2-dicarboxylate (300 mg, yield: 89.48%) as a colorless oil, which was used in the next step without further purification. LC / MS (ESI) m / z: 242 (M+H). + .

[0233] Step 2: To a stirred solution of (S)-1-tert-butyl 2-methyl 4-methylenepyrrolidine-1,2-dicarboxylate (400 mg) and NaI (82 mg, 0.54 mmol) in THF (10 mL) was added TMSCF (7.5 g, 53.05 mmol) at room temperature with N 2 and the resulting mixture was stirred in a sealed tube at 65° C. for 12 h. 2 The mixture was diluted with 20 mL of 2,000 mL of EtOAc (10 mL x 3), extracted with EtOAc (20 mL x 3), and the combined organic layers were washed with water and brine, and then with anhydrous Na 2 SO 4 The mixture was dried at 40° C., filtered, concentrated, and the residue was purified by column chromatography on silica gel (EtOAc in PE=5-30%) to give the desired product (6S)-5-tert-butyl 6-methyl 1,1-difluoro-5-azaspiro[2.4]heptane-5,6-dicarboxylate (150 mg, yield: 29.5%) as a yellow oil. LCMS: ESI m / z 246 (M+1) + .

[0234] Step 3: MeOH (3 mL) and H 2 To a solution of (6S)-5-tert-butyl 6-methyl-1,1-difluoro-5-azaspiro[2.4]heptane-5,6-dicarboxylate (200 mg, 0.68 mmol) in 2H2O (1 mL) was added NaOH (80 mg, 2 mmol) at 0 °C, and the resulting mixture was stirred at room temperature for 30 min. The reaction mixture was concentrated, the pH was adjusted to 2-3 with 1.0 N HCl, and extracted with EtOAc (20 mL × 3). The combined organic layer was washed with water and brine, and then extracted with anhydrous Na 2 SO 4The mixture was dried at 40° C., filtered and concentrated to give the crude product (6S)-5-[(tert-butoxy)carbonyl]-1,1-difluoro-5-azaspiro[2.4]heptane-6-carboxylic acid (150 mg, yield: 74.8%) as an off-white solid, which can be used directly in the next step without further purification. LC / MS (ESI) m / z: 222 (M-55). + .

[0235] Preparation of Intermediate 24, (3S,5R)-2-(tert-butoxycarbonyl)-5-(methoxymethyl)-2-azabicyclo[3.1.0]hexane-3-carboxylic acid [ka] Step 1: To a solution of methyl (1S)-1-(hydroxymethyl)bicyclo[3.1.0]hexane-3-carboxylate (200 mg, 1.28 mmol) in DCE (5 mL) was added MeI (0.40 mL, 6.40 mmol), silver trifluoromethanesulfonate (1.60 g, 6.40 mmol) and 2,6-di-tert-butylpyridine (1.4 mL, 6.40 mmol). The reaction was then stirred at 100° C. for 1 h. The reaction mixture was cooled to room temperature and purified by H 2 The mixture was diluted with 2 mL of 2H2O (5 mL) and extracted with EtOAc (10 mL x 3). The combined organic phase was washed with anhydrous Na 2 SO 4 Drying at 40° C., filtration and concentration gave the crude product (3S,5R)-2-tert-butyl 3-methyl 5-(methoxymethyl)-2-azabicyclo[3.1.0]hexane-2,3-dicarboxylate (150 mg, yield: 68%) as a yellow oil. LC / MS (ESI) m / z: 286 (M+1). + .

[0236] Step 2: MeOH (3.0 mL) and H 2To a solution of (3S,5R)-2-tert-butyl 3-methyl 5-(methoxymethyl)-2-azabicyclo[3.1.0]hexane-2,3-dicarboxylate (200 mg, 1.17 mmol) in 2H2O (1.0 mL) was added NaOH (200 mg, 5.00 mmol). The resulting mixture was then stirred at 80° C. for 1 h. The pH of the reaction mixture was then adjusted to 5 with 1.0 N HCl and extracted with EtOAc (15 mL×3). The combined organic layers were washed with brine and extracted with Na 2 SO 4 Drying at 40° C., filtration and concentration afforded the crude product (3S,5R)-2-(tert-butoxycarbonyl)-5-(methoxymethyl)-2-azabicyclo[3.1.0]hexane-3-carboxylic acid (150 mg, yield: 81%) as a white solid. LC / MS (ESI) m / z: 271 (M+1). + .

[0237] Preparation of Intermediate 25, (2S,4S)-1-(tert-butoxycarbonyl)-4-(methylsulfonamido)pyrrolidine-2-carboxylic acid [ka] Step 1: To a solution of (2S,4S)-1-tert-butyl 2-methyl 4-aminopyrrolidine-1,2-dicarboxylate (162 mg, 0.65 mmol) and TEA (0.20 mL, 1.3 mmol) in DCM (5 mL) was added MsCl (0.06 mL, 0.72 mmol) at 0° C., and the resulting mixture was stirred at 25° C. for 6 h. The reaction mixture was diluted with saturated NH 4 Quench with aqueous Cl (10 mL), extract with DCM (10 mL x 3), wash the combined organic phase with water and brine, and add anhydrous Na 2 SO 4The mixture was dried at 40° C., filtered, concentrated, and the residue was purified by column chromatography on silica gel (10-50% EtOAc in PE) to give the desired product (2S,4S)-1-tert-butyl 2-methyl 4-(methylsulfonamido)pyrrolidine-1,2-dicarboxylate (160 mg, yield: 75%) as a colorless oil. LC / MS (ESI) m / z: 323 (M+1). + .

[0238] Step 2: MeOH (3.0 mL) and H 2 To a solution of (2S,4S)-1-tert-butyl 2-methyl 4-(methylsulfonamido)pyrrolidine-1,2-dicarboxylate (160 mg, 0.50 mmol) in O (1.0 mL) was added NaOH (80 mg, 2.0 mmol) and the resulting mixture was diluted with N 2 The mixture was stirred at 20° C. for 1 hour under reduced pressure. The pH of the reaction mixture was then adjusted to 5 with 1.0 N HCl and extracted with EtAOc (15 mL×3). The combined organic layer was washed with Na 2 SO 4 Drying at 40° C., filtering and concentrating gave the crude product (2S,4S)-1-[(tert-butoxy)carbonyl]-4-methanesulfonamide pyrrolidine-2-carboxylic acid (130 mg, yield: 84%) as a solid. LC / MS (ESI) m / z: 309 (M+1). + .

[0239] Following the experimental procedure of Intermediate 25, the following intermediates were prepared from the corresponding chemicals (the main different chemicals used are listed in the starting materials column). [Table 5] Preparation of Intermediate 27, (2S,5R)-1-(tert-butoxycarbonyl)-5-fluoropiperidine-2-carboxylic acid [ka] Step 1: To a solution of (2S,5S)-5-hydroxypiperidine-2-carboxylic acid (301 mg, 2.07 mmol) in MeOH (5.0 mL), was added SOCl 2 (0.30 mL, 4.1 mmol) was added. The resulting mixture was stirred at 20° C. for 1 h. The reaction mixture was concentrated to give the crude product (2S,5S)-methyl 5-hydroxypiperidine-2-carboxylate (300 mg, yield: 91%) as a pale yellow oil. LC / MS (ESI) m / z: 160 (M+1). + .

[0240] Step 2: Acetone (5.0 mL) and H 2 To a solution of (2S,5S)-methyl 5-hydroxypiperidine-2-carboxylate (300 mg, 1.88 mmol) in 2H2O (1.0 mL) at 0 °C was added TEA (0.52 mL, 3.7 mmol) and (Boc) 2 O (0.45 g, 2.07 mmol) was added. The resulting mixture was stirred at 20° C. for 3 h, and the reaction mixture was diluted with saturated NH 4 Quench with aqueous Cl (10 mL), extract with EtOAc (15 mL x 3), wash the combined organic layers with brine and 2 SO 4 Drying at 40° C., filtration and concentration afforded crude (2S,5S)-1-tert-butyl 2-methyl 5-hydroxypiperidine-1,2-dicarboxylate (400 mg, yield: 81%) as a pale yellow solid, which can be used directly in the next step. LC / MS (ESI) m / z: 260 (M+1). + .

[0241] Step 3: To a solution of (2S,5S)-1-tert-butyl 2-methyl 5-hydroxypiperidine-1,2-dicarboxylate (400 mg, 1.54 mmol) in DCM (10 mL) was added DAST (0.5 mL, 3.85 mmol) at −60° C. The resulting mixture was cooled to 5° C. with 5% CO. 2 The reaction mixture was stirred at room temperature for 16 h under reduced pressure. 3 The mixture was diluted with aqueous solution (10 mL) and extracted with DCM (15 mL x 3). The combined organic phase was washed with brine and2 SO 4 After drying over 100° C., filtration and concentration, crude (2S,5R)-1-tert-butyl 2-methyl 5-fluoropiperidine-1,2-dicarboxylate (270 mg, yield: 67.2%) was obtained as a yellow oil, which can be used in the next step without further purification. LC / MS (ESI) m / z: 262 (M+H). + .

[0242] Step 4: MeOH (3.0 mL) and H 2 To a solution of 1-tert-butyl 2-methyl(2S,5R)-5-fluoropiperidine-1,2-dicarboxylate (270 mg, 1.01 mmol) in 2H2O (1.0 mL) was added NaOH (120 mg, 3.0 mmol) and the resulting mixture was stirred at room temperature for 1 h. The pH of the reaction mixture was then adjusted to 5 with 1N HCl and extracted with EtAOc (15 mL x 3). The combined organic layers were washed with brine and diluted with Na 2 SO 4 Drying at 40° C., filtration and concentration gave the crude product (2S,5R)-1-(tert-butoxycarbonyl)-5-fluoropiperidine-2-carboxylic acid (130 mg, yield: 48%) as a solid, which can be used in the next step without further purification. LC / MS (ESI) m / z: 247 (M+H). + .

[0243] Preparation of Intermediate 28, (2S)-1-(tert-butoxycarbonyl)-4-(cyanomethyl)pyrrolidine-2-carboxylic acid [ka] Step 1: To a solution of diethyl(cyanomethyl)phosphonate (1.5 mL, 9.0 mmol) in THF (20 mL) was added LiHMDS (9.0 mL, 1.0 M in THF) at 0° C., the resulting mixture was stirred at 0° C. for 1 h, then (2S)-1-tert-butyl 2-methyl 4-oxopyrrolidine-1,2-dicarboxylate (2.01 g, 8.22 mmol) in THF (10 mL) was added to the reaction mixture at the same temperature. The reaction mixture was stirred for 16 h while warming to room temperature and saturated NH 4 The mixture was quenched with aqueous Cl (20 mL) and extracted with EtOAc (20 mL x 2). The combined organic phase was washed with Na 2 SO 4 The mixture was dried at 40° C., concentrated, and the residue was purified by column chromatography on silica gel (EtOAc in PE=0-10%) to give the desired product 1-tert-butyl 2-methyl(2S,4Z)-4-(cyanomethylidene)pyrrolidine-1,2-dicarboxylate (900 mg, yield: 41.0%) as a yellow solid. LC / MS(ESI) m / z: 247(M+H) + .

[0244] Step 2: To a solution of 1-tert-butyl 2-methyl(2S)-4-(cyanomethylidene)pyrrolidine-1,2-dicarboxylate (900 mg, 3.38 mmol) in MeOH (5 mL) was added a slurry of Pd / C (90 mg, 10%) in EtOAc (10 mL). The resulting suspension was then diluted with H 2 The mixture was stirred at room temperature for 16 h under a balloon. The reaction mixture was filtered through a pad of Celite and the filtrate was concentrated to give the crude product (2S)-1-tert-butyl 2-methyl 4-(cyanomethyl)pyrrolidine-1,2-dicarboxylate (900 mg, yield: 99%) as a colorless oil, which can be used in the next step without further purification. LC / MS (ESI) m / z: 269 (M+H). + .

[0245] Step 3: MeOH (5.0 mL) and H 2To a solution of (2S)-1-tert-butyl 2-methyl 4-(cyanomethyl)pyrrolidine-1,2-dicarboxylate (650 mg, 2.29 mmol) in 2H2O (1.0 mL) was added NaOH (200 mg, 5.00 mmol) at 0° C., and the resulting mixture was heated to 65° C. for 1 h. The reaction mixture was cooled to room temperature, the pH was adjusted to 5 with 1.0 N HCl, the mixture was extracted with EtOAc (10 mL×3), and the combined organic phase was washed with anhydrous Na 2 SO 4 Dry at rt, filter and concentrate in vacuo to give the crude product. (2S)-1-[(tert-butoxy)carbonyl]-4-(cyanomethyl)pyrrolidine-2-carboxylic acid (400 mg, yield: 47%) was obtained as a pale yellow solid. LC / MS (ESI) m / z: 254 (M+H) + .

[0246] Preparation of Intermediate 29, 4-Isopropyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidine [ka] To a stirred solution of 5-bromo-4-isopropylpyrimidine (1.00 g, 4.97 mmol) and 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (1.40 g, 5.47 mmol) in dioxane (10 mL) was added KOAc (1.50 g, 15.7 mmol) and Pd(dppf)Cl 2 (100 mg) was added. The resulting mixture was diluted with N 2 The mixture was heated to 110° C. under atmospheric pressure for 12 h. After cooling to room temperature, the mixture was 2 O (10 mL), extracted with EtOAc (30 mL x 3), and the combined organic phase was washed with water and brine, and then with anhydrous Na 2 SO 4Drying at 40° C., filtering and concentrating in vacuo gave the crude product, which was purified by column chromatography on silica gel (EtOAc in PE=0-20%) to give the desired product 4-isopropyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidine (610 mg, yield: 49%) as a white solid. LC / MS (ESI) m / z: 249 (M+H). + .

[0247] Following the experimental procedure for intermediate 29, the following intermediates were prepared from the corresponding chemicals (major different chemicals used are listed in the starting materials section). [Table 6] Preparation of Intermediate 31, 2-(4-(7-(tert-butoxycarbonyl)-2,7-diazaspiro[3.5]nonan-2-yl)pyrimidin-5-yloxy)-5-fluorobenzoic acid [ka] Step 1: A solution of 2-bromo-4-fluorophenol (3.01 g, 15.7 mmol) and 5-bromopyrimidine (2.75 g, 17.3 mmol) in DMF (30 mL) was diluted with Cs 2 CO 3 (12.8 g, 39.3 mmol) was added at room temperature. The resulting mixture was heated at 120° C. for 12 h. The reaction mixture was cooled to room temperature and saturated NH 4 The mixture was quenched with aqueous Cl (50 mL) and extracted with EtOAc (100 mL x 3). The combined organic layers were washed with water and brine, and then diluted with anhydrous Na 2 SO 4 The mixture was dried at 40° C., filtered and concentrated. The residue was purified by column chromatography on silica gel (EtOAc in PE=0-30%) to give the desired product 5-(2-bromo-4-fluorophenoxy)pyrimidine (1.40 g, yield: 29.8%) as a yellow solid. LCMS: ESI m / z 270 (M+1) + .

[0248] Step 2: To a solution of 5-(2-bromo-4-fluorophenoxy)pyrimidine (1.00 g, 3.70 mmol) and TEA (1.5 mL, 11 mmol) in MeOH (15 mL) was added Pd(dppf)Cl 2 (150 mg) was added at room temperature. The resulting mixture was stirred at 90° C. under CO (70 psi) atmosphere for 12 h. After cooling to room temperature, the solvent was concentrated under reduced pressure to give the crude product, which was purified by column chromatography on silica gel (EtOAc in PE=0-30%) to give the desired product methyl 5-fluoro-2-(pyrimidin-5-yloxy)benzoate (900 mg, yield: 92.7%) as a colorless oil. LC / MS (ESI) m / z: 249 (M+H) + .

[0249] Step 3: To a solution of methyl 5-fluoro-2-(pyrimidin-5-yloxy)benzoate (900 mg, 3.63 mmol) in THF (20 mL) was added N 2 Urea·H at 0℃ 2 O 2 (800 mg, 8.16 mmol) and TFAA (0.6 mL) were added. The resulting mixture was stirred at room temperature for 1 h. The reaction mixture was diluted with saturated NaHCO 3 The mixture was quenched with ethyl acetate (20 mL x 3), extracted with EtOAc (20 mL x 3), and the combined organic layers were washed with water and brine, and then washed with anhydrous Na 2 SO 4 Drying at 40° C., filtration and concentration in vacuo afforded the crude product 5-[4-fluoro-2-(methoxycarbonyl)phenoxy]pyrimidin-1-ium-1-olate (830 mg, yield: 86.3%) as a yellow oil, which can be used directly in the next step without further purification. LCMS: ESI m / z 265 (M+1) + .

[0250] Step 4: A solution of 5-[4-fluoro-2-(methoxycarbonyl)phenoxy]pyrimidin-1-ium-1-olate (800 mg, 3.01 mmol) and DIPEA (5.6 mL, 34 mmol) in EtOAc (15 mL) was added at 0 °C with POCl 3 (0.6 mL, 6.8 mmol) was added. The resulting mixture was stirred at room temperature for 2 h. The reaction mixture was diluted with saturated NaHCO 3 The mixture was quenched with aqueous solution (20 mL) and extracted with EtOAc (50 mL×3). The combined organic layers were washed with water and brine, and then washed with anhydrous Na 2 SO 4 Drying at 40° C., filtration and concentration in vacuo afforded the crude product methyl 2-[(4-chloropyrimidin-5-yl)oxy]-5-fluorobenzoate (798 mg, yield: 93%) as a brown oil, which can be used directly in the next step without further purification. LCMS: ESI m / z 283 (M+1). + .

[0251] Step 5: To a solution of methyl 2-[(4-chloropyrimidin-5-yl)oxy]-5-fluorobenzoate (798 mg, 2.82 mmol) and DIPEA (5.3 mL, 32 mmol) in DMF (15 mL) was added tert-butyl 2,7-diazaspiro[3.5]nonane-7-carboxylate (703 mg, 3.11 mmol) at room temperature. The resulting mixture was stirred at 65° C. for 3 h and cooled to room temperature. After that, the reaction mixture was diluted with saturated NH 4 The mixture was quenched with aqueous Cl (10 mL), extracted with EtOAc (30 mL×3), and the combined organic layers were washed with water and brine, and then with anhydrous Na 2 SO 4 Drying at 40° C., filtration and concentration gave the crude product, which was purified by column chromatography on silica gel (EtOAc in PE=0-50%) to give the desired product tert-butyl 2-{5-[4-fluoro-2-(methoxycarbonyl)phenoxy]pyrimidin-4-yl}-2,7-diazaspiro[3.5]nonane-7-carboxylate (610 mg, yield: 45.5%) as a yellow solid. LCMS: ESI m / z 473 (M+1). + .

[0252] Step 6: MeOH (12 mL) and H 2 To a solution of tert-butyl 2-{5-[4-fluoro-2-(methoxycarbonyl)phenoxy]pyrimidin-4-yl}-2,7-diazaspiro[3.5]nonane-7-carboxylate (610 mg, 1.29 mmol) in 2H2O (4.0 mL) was added NaOH (228 mg, 5.71 mmol) at 0° C. The resulting mixture was stirred at room temperature for 1 h. The pH of the mixture was then adjusted to 5 with 1.0 N HCl and extracted with EtOAc (20 mL×3), and the combined organic layer was washed with water and brine and diluted with anhydrous Na 2 SO 4 Drying at 40° C., filtration and concentration afforded the crude product 2-[(4-{7-[(tert-butoxy)carbonyl]-2,7-diazaspiro[3.5]nonan-2-yl}pyrimidin-5-yl)oxy]-5-fluorobenzoic acid (560 mg, yield: 94.5%) as an off-white solid, which can be used in the next step without further purification. LC / MS (ESI) m / z: 459 (M+H). + .

[0253] Step 7: To a stirred solution of 2-[(4-{7-[(tert-butoxy)carbonyl]-2,7-diazaspiro[3.5]nonan-2-yl}pyrimidin-5-yl)oxy]-5-fluorobenzoic acid (200 mg, 0.44 mmol) and HATU (166 mg, 0.44 mmol) in DMF (4 mL) was added DIPEA (169 mg, 1.31 mmol). The resulting mixture was stirred for 10 min, after which 2-[(propan-2-yl)amino]ethan-1-ol (54 mg, 0.52 mmol) was added. The reaction mixture was stirred at room temperature for 1 h and then H 2 The mixture was diluted with 20 mL of 2H2O (10 mL) and extracted with EtOAc (30 mL x 3). The combined organic phase was washed with anhydrous Na 2 SO 4Drying at 40° C., filtration and concentration gave the desired product, which was purified by preparative TLC (MeOH=9% in DCM) to give the desired product tert-butyl 2-(5-{4-fluoro-2-[(2-hydroxyethyl)(propan-2-yl)carbamoyl]phenoxy}pyrimidin-4-yl)-2,7-diazaspiro[3.5]nonane-7-carboxylate (135 mg, yield: 56.9%) as a white solid. LCMS: ESI m / z 544 (M+1). + .

[0254] Step 8: To a solution of tert-butyl 2-(5-{4-fluoro-2-[(2-hydroxyethyl)(propan-2-yl)carbamoyl]phenoxy}pyrimidin-4-yl)-2,7-diazaspiro[3.5]nonane-7-carboxylate (50 mg, 0.09 mmol) in DCM (3.0 mL) was added TFA (1.0 mL). The mixture was stirred at room temperature for 1 h. The resulting mixture was concentrated in vacuo to give the crude product 2-[(4-{2,7-diazaspiro[3.5]nonane-2-yl}pyrimidin-5-yl)oxy]-5-fluoro-N-(2-hydroxyethyl)-N-(propan-2-yl)benzamide (40 mg, yield: 98%) as an oil, which can be used directly in the next step without further purification. LC / MS (ESI) m / z: 444 (M+H) + .

[0255] Preparation of Intermediate 32, 2-((4-(2,7-diazaspiro[3.5]nonan-2-yl)pyrimidin-5-yl)oxy)-5-fluoro-N-isopropyl-N-(2-methoxyethyl)benzamide [ka] Step 1: To a solution of tert-butyl 2-(5-{4-fluoro-2-[(2-hydroxyethyl)(propan-2-yl)carbamoyl]phenoxy}pyrimidin-4-yl)-2,7-diazaspiro[3.5]nonane-7-carboxylate (60 mg, 0.11 mmol) in DMF (4 mL) was added NaH (7.0 mg, 0.17 mmol, 60%) at 0° C. The reaction mixture was stirred for 10 min, then MeI (31 mg, 0.22 mmol) was added. The resulting mixture was stirred at room temperature for 1 h and diluted with saturated NH 4 The mixture was quenched with aqueous Cl (10 mL) and extracted with EtOAc (30 mL×3). The combined organic layers were washed with anhydrous Na 2 SO 4 Drying at 40° C., filtration and concentration gave the desired product, which was purified by preparative TLC (MeOH=9% in DCM) to give the desired product tert-butyl 2-(5-{4-fluoro-2-[(2-methoxyethyl)(propan-2-yl)carbamoyl]phenoxy}pyrimidin-4-yl)-2,7-diazaspiro[3.5]nonane-7-carboxylate (50 mg, yield: 81.2%) as a yellow solid. LCMS: ESI m / z 558 (M+1) + .

[0256] Step 2: To a solution of tert-butyl 2-(5-{4-fluoro-2-[(2-methoxyethyl)(propan-2-yl)carbamoyl]phenoxy}pyrimidin-4-yl)-2,7-diazaspiro[3.5]nonane-7-carboxylate (50 mg, 0.09 mmol) in DCM (3.0 mL) was added TFA (1.0 mL). The resulting mixture was stirred at room temperature for 1 h. The reaction mixture was concentrated in vacuo to give the crude product 2-[(4-{2,7-diazaspiro[3.5]nonane-2-yl}pyrimidin-5-yl)oxy]-5-fluoro-N-(2-methoxyethyl)-N-(propan-2-yl)benzamide (30 mg, yield: 73.5%) as a brown oil, which can be used directly in the next step without further purification. LC / MS (ESI) m / z: 458 (M+H) + .

[0257] Preparation of Intermediate 33, 2-Cyclopropyl-5'-fluoro-2'-hydroxybiphenyl-4-carbonitrile [ka] Step 1: A solution of 3-bromo-4-hydroxybenzonitrile (1.01 g, 5.05 mmol) and cyclopropylboronic acid (520 mg, 6.06 mmol) in toluene (15 mL) was added to PCy 3 (280 mg, 1 mmol), Pd(OAc) 2 (100mg) and K 3 PO 4 (3.2 g, 15 mmol) was added at room temperature. The resulting mixture was diluted with N 2 The reaction mixture was stirred at 100° C. for 12 hours under reduced pressure. 2 The mixture was quenched with O (20 mL), extracted with EtOAc (30 mL x 3), and the combined organic layers were washed with water and brine, and then with anhydrous Na 2 SO 4 The mixture was dried at 40° C., filtered, concentrated, and the residue was purified by column chromatography on silica gel (EtOAc in PE=0-30%) to give the desired product 3-cyclopropyl-4-hydroxybenzonitrile (700 mg, yield: 82.8%) as a yellow oil. LC / MS (ESI) m / z: 158 (MH). + .

[0258] Step 2: To a solution of 3-cyclopropyl-4-hydroxybenzonitrile (700 mg, 4.39 mmol) and pyridine (1.12 g, 8.79 mmol) in THF (10 mL) was added N 2 Bottom, Tf at -5℃ 2 O (1.1 mL, 6.59 mmol) was added. The resulting mixture was stirred at 0 °C for 3 h. The reaction was cooled to 0 °C with saturated NaHCO 3 The mixture was quenched with aqueous solution of 1,000 mL of DCM and extracted with DCM (30 mL x 3). The combined organic layers were washed with water and brine and washed with anhydrous Na 2 SO 4The mixture was dried over 100° C., filtered, concentrated, and the residue was purified by column chromatography on silica gel (EtOAc in PE=0-80%) to give the desired product 4-cyano-2-cyclopropylphenyl trifluoromethanesulfonate (1.01 g, yield: 74.2%) as an oil. LC / MS (ESI) m / z: 292 (M+H). + .

[0259] Step 3: Dioxane (5.0 mL) and H 2 To a solution of 4-cyano-2-cyclopropylphenyl trifluoromethanesulfonate (300 mg, 1.03 mmol) and 5-fluoro-2-hydroxyphenylboronic acid (177 mg, 1.13 mmol) in 2H2O (1.0 mL) was added Pd(dppf)Cl 2 (20mg) and K 2 CO 3 (414 mg, 3.00 mmol) was added and the resulting mixture was treated with N 2 The mixture was stirred at 100° C. for 10 hours under atmospheric pressure. The reaction mixture was cooled to room temperature and 2 The mixture was diluted with 20 mL of EtOAc (10 mL), extracted with EtOAc (20 mL x 3), and the combined organic layers were washed with water and brine, and then with anhydrous Na 2 SO 4 The mixture was dried at 40° C., filtered and concentrated to give the crude product, which was purified by column chromatography on silica gel (EtOAc in PE=0-50%) to give the desired product 2-cyclopropyl-5'-fluoro-2'-hydroxybiphenyl-4-carbonitrile (125 mg, yield: 47.7%) as a yellow solid. LC / MS (ESI) m / z: 254 (M+H). + .

[0260] Preparation of intermediate 34, 2-((5-(2,7-diazaspiro[3.5]nonan-2-yl)-1,2,4-triazin-6-yl)oxy)-N-ethyl-5-fluoro-N-isopropylbenzamide [ka] Step 1: To a stirred solution of trichloro-1,2,4-triazine (CAS 873-41-6, 0.88 g, 4.80 mmol) and TEA (1.39 mL, 9.99 mmol) in DCM (15 mL) was added tert-butyl 2,7-diazaspiro[3.5]nonane-7-carboxylate hydrochloride (1.05 g, 4.01 mmol) at 0° C. The resulting mixture was stirred at room temperature for 12 h. The reaction mixture was diluted with H 2 The mixture was quenched with O (20 mL), extracted with DCM (30 mL × 3), and the combined organic layers were washed with anhydrous Na 2 SO 4 Drying at 40° C., filtration and concentration gave the crude product, which was purified by chromatography column on silica gel (EtOAc in PE=0-25%) to give the desired product tert-butyl 2-(dichloro-1,2,4-triazin-5-yl)-2,7-diazaspiro[3.5]nonane-7-carboxylate (1.10 g, yield: 60.4%) as a white solid. LCMS: ESI m / z 374 (M+1). + .

[0261] Step 2: To a stirred solution of tert-butyl 2-(dichloro-1,2,4-triazin-5-yl)-2,7-diazaspiro[3.5]nonane-7-carboxylate (1.05 g, 2.81 mmol) and N-ethyl-5-fluoro-2-hydroxy-N-(propan-2-yl)benzamide (0.63 g, 2.81 mmol) in THF (12 mL) was added DBU (0.50 mL, 3.37 mmol) at room temperature. The resulting mixture was stirred at room temperature for 8 h. The reaction mixture was diluted with H 2 The mixture was diluted with 20 mL of EtOAc (20 mL × 3), extracted with EtOAc (20 mL × 3), and the combined organic layers were washed with anhydrous Na 2 SO 4The mixture was dried at 40° C., filtered, concentrated, and the residue was purified by chromatography column on silica gel (EtOAc in PE=20%-50%) to give the desired product tert-butyl 2-(3-chloro-6-{2-[ethyl(propan-2-yl)carbamoyl]-4-fluorophenoxy}-1,2,4-triazin-5-yl)-2,7-diazaspiro[3.5]nonane-7-carboxylate (800 mg, yield: 50.6%) as a white solid. LCMS: ESI m / z 563 (M+1) + .

[0262] Step 3: To a stirred solution of tert-butyl 2-(3-chloro-6-{2-[ethyl(propan-2-yl)carbamoyl]-4-fluorophenoxy}-1,2,4-triazin-5-yl)-2,7-diazaspiro[3.5]nonane-7-carboxylate (0.80 g, 1.42 mmol) in MeOH (10 mL) was added a slurry of TEA (0.24 mL, 1.71 mmol) and Pd / C (10%, 80 mg) in EtOAc (5 mL). The resulting suspension was evacuated and refilled with hydrogen and stirred for 1 hour. 2 The mixture was stirred at room temperature for 8 h under balloon pressure. The reaction mixture was filtered through a pad of Celite, washed with MeOH (5 mL) and the filtrate was concentrated to give the desired product tert-butyl 2-(6-{2-[ethyl(propan-2-yl)carbamoyl]-4-fluorophenoxy}-1,2,4-triazin-5-yl)-2,7-diazaspiro[3.5]nonane-7-carboxylate (750 mg, yield: 99.8%) as a white solid, which can be used in the next step without further purification. LCMS: ESI m / z 529 (M+1) + .

[0263] Step 4: To a solution of tert-butyl 2-(6-{2-[ethyl(propan-2-yl)carbamoyl]-4-fluorophenoxy}-1,2,4-triazin-5-yl)-2,7-diazaspiro[3.5]nonane-7-carboxylate (720 mg, 1.36 mmol) in DCM (10 mL) was added TFA (5 mL) at 0° C. The resulting mixture was stirred at room temperature for 2 h. The reaction mixture was concentrated in vacuo to give the crude product 2-((5-(2,7-diazaspiro[3.5]nonan-2-yl)-1,2,4-triazin-6-yl)oxy)-N-ethyl-5-fluoro-N-isopropylbenzamide TFA salt (580 mg, yield: 99.4%) as a yellow oil, which can be used directly in the next step without further purification. LC / MS (ESI) m / z: 429 (M+H) + .

[0264] Following the experimental procedure of Intermediate 34, the following intermediates were prepared from the corresponding chemicals (the main different chemicals used are listed in the starting material column). [Table 7-1] [Table 7-2] Preparation of Intermediate 36, 2-(6-(2-(4-chloro-1-isopropyl-1H-pyrazol-5-yl)-4-fluorophenoxy)-1,2,4-triazin-5-yl)-2,7-diazaspiro[3.5]nonane [ka] Step 1: Dioxane (10 mL) and H 2 To a solution of [1-(propan-2-yl)-1H-pyrazol-5-yl]boronic acid (605 mg, 3.93 mmol), 2-bromo-4-fluorophenol (500 mg, 2.62 mmol) in 2O (2.0 mL) was added K 2 CO 3 (1.08 g, 7.85 mmol) and Pd(dppf)Cl 2(192 mg, 0.26 mmol) was added at room temperature, and the resulting mixture was treated with N 2 The reaction mixture was stirred at 100° C. for 2 hours. The reaction mixture was cooled to room temperature and 2 The mixture was quenched with O (10 mL), extracted with EtOAc (30 mL × 3), and the combined organic layers were washed with anhydrous Na 2 SO 4 The mixture was dried at 40° C., filtered, concentrated, and the residue was purified by column chromatography on silica gel (EtOAc in PE=0-50%) to give the desired product 4-fluoro-2-(1-isopropyl-1H-pyrazol-5-yl)phenol (200 mg, yield: 34.7%) as a yellow solid. LC / MS (ESI) m / z: 221 (M+H). + .

[0265] Step 2: To a solution of tert-butyl 2-(dichloro-1,2,4-triazin-5-yl)-2,7-diazaspiro[3.5]nonane-7-carboxylate (200 mg, 0.53 mmol) and 4-fluoro-2-(1-isopropyl-1H-pyrazol-5-yl)phenol (118 mg, 0.53 mmol) in THF (5 mL) was added DBU (0.08 mL, 0.53 mmol) at room temperature and the resulting mixture was stirred overnight. 2 The mixture was diluted with 20 mL of EtOAc (10 mL × 3), extracted with EtOAc (10 mL × 3), and the combined organic layers were washed with anhydrous Na 2 SO 4 The mixture was dried at 40° C., filtered, concentrated, and the residue was purified by column chromatography on silica gel (EtOAc in PE=0-40%) to give the desired product tert-butyl 2-(3-chloro-6-(4-fluoro-2-(1-isopropyl-1H-pyrazol-5-yl)phenoxy)-1,2,4-triazin-5-yl)-2,7-diazaspiro[3.5]nonane-7-carboxylate (120 mg, yield: 40.2%) as a pale yellow solid. LC / MS(ESI)m / z:558(M+H) + .

[0266] Step 3: To a solution of tert-butyl 2-(3-chloro-6-{4-fluoro-2-[1-(propan-2-yl)-1H-pyrazol-5-yl]phenoxy}-1,2,4-triazin-5-yl)-2,7-diazaspiro[3.5]nonane-7-carboxylate (120 mg, 0.22 mmol) and TEA (0.12 mL, 0.86 mmol) in EtOAc (3 mL) was added Pd / C (12 mg) at room temperature. The reaction mixture was evacuated and refilled with hydrogen and stirred for 1 hour. 2 The mixture was stirred at room temperature for 2 hours under a balloon of 0.1 mL of 10 ... + .

[0267] Step 4: To a solution of tert-butyl 2-(6-{4-fluoro-2-[1-(propan-2-yl)-1H-pyrazol-5-yl]phenoxy}-1,2,4-triazin-5-yl)-2,7-diazaspiro[3.5]nonane-7-carboxylate (60 mg, 0.11 mmol) in DMF (2.0 mL) was added NCS (17 mg, 0.13 mmol) at 0° C., and the resulting mixture was stirred at the same temperature for 3 h. The reaction mixture was stirred at H 2 The mixture was quenched with O (5 mL), extracted with EtOAc (10 mL × 3), and the combined organic layers were washed with anhydrous Na 2 SO 4The mixture was dried at 40° C., filtered, concentrated, and the residue was purified by column chromatography on silica gel (EtOAc in PE=0-80%) to give the desired product tert-butyl 2-(6-(2-(4-chloro-1-isopropyl-1H-pyrazol-5-yl)-4-fluorophenoxy)-1,2,4-triazin-5-yl)-2,7-diazaspiro[3.5]nonane-7-carboxylate (40 mg, yield: 62.1%) as a pale yellow solid. LC / MS(ESI) m / z: 558(M+H) + .

[0268] Step 5: To a solution of tert-butyl 2-(6-{2-[4-chloro-1-(propan-2-yl)-1H-pyrazol-5-yl]-4-fluorophenoxy}-1,2,4-triazin-5-yl)-2,7-diazaspiro[3.5]nonane-7-carboxylate (40 mg, 0.07 mmol) in DCM (3.0 mL) was added TFA (1.0 mL) at room temperature and the resulting mixture was stirred for 1 h. The reaction mixture was concentrated to give the crude product 2-(6-(2-(4-chloro-1-isopropyl-1H-pyrazol-5-yl)-4-fluorophenoxy)-1,2,4-triazin-5-yl)-2,7-diazaspiro[3.5]nonane (30 mg, yield: 91.4%) as a yellow oil, which can be used in the next step without further purification. LC / MS(ESI)m / z:458(M+H) + .

[0269] Preparation of intermediate 37, trans-1-(tert-butoxycarbonyl)-3-ethylpyrrolidine-2-carboxylic acid [ka] Step 1: To a mixture of methyl (2S)-pyrrolidine-2-carboxylate (2.01 g, 15.5 mmol) in DCM (30 mL) at 0° C., TEA (4.3 mL, 31 mmol) and NCS (2.30 g, 17.0 mmol) were added in small portions. The resulting mixture was stirred at room temperature for 3 h, after which pyridine (4.53 g, 35.6 mmol) was added slowly within 1 h, the reaction mixture was cooled to −20° C., then CbzCl (5.81 g, 34.1 mmol) was added, and the mixture was allowed to gradually warm to room temperature and stirred for 12 h. The reaction was cooled to −20° C., and then CbzCl (5.81 g, 34.1 mmol) was added, and the mixture was allowed to gradually warm to room temperature and stirred for 12 h. 2 Dilute with 200 mL of O (50 mL), extract with DCM (50 mL x 3), and wash the combined organic layers with water and brine, and add anhydrous NaCl. 2 SO 4 The mixture was dried at 40° C., filtered, concentrated, and the residue was purified by column chromatography on silica gel (EtOAc in PE=0-30%) to give the desired product 1-benzyl 2-methyl 4,5-dihydro-1H-pyrrole-1,2-dicarboxylate (503 mg, yield: 11.7%) as a yellow oil. LC / MS (ESI) m / z: 262 (M+H). + .

[0270] Step 2: Me in THF (5.0 mL) at -40 °C 2 To a solution of S.CuBr (79 mg, 0.38 mmol), vinylmagnesium bromide (2.8 mL, 1.0 M in THF) was added 2 The resulting mixture was stirred for 1 h, a solution of 1-benzyl 2-methyl 4,5-dihydro-1H-pyrrole-1,2-dicarboxylate (500 mg, 1.91 mmol) in THF (5.0 mL) was added dropwise, and the reaction mixture was stirred at this temperature for 4 h. The mixture was diluted with saturated NH 4 Cl / NH 3 .H 2 O (8:1), extracted with EtOAc (20 mL × 3), and the combined organic layers were washed with saturated NH 4 Wash with aqueous Cl solution and anhydrous Na 2 SO 4The mixture was dried at 40° C., filtered, concentrated, and the residue was purified by column chromatography on silica gel (EtOAc in PE=0-30%) to give the desired product trans-1-benzyl 2-methyl-3-vinylpyrrolidine-1,2-dicarboxylate (505 mg, yield: 85.2%) as an oil. LC / MS (ESI) m / z: 292 (M+H). + .

[0271] Step 3: trans-1-benzyl 2-methyl-3-vinylpyrrolidine-1,2-dicarboxylate (500 mg, 1.72 mmol) and (Boc) in MeOH (7.0 mL). 2 To a solution of 2H2O (378 mg, 1.75 mmol) was added Pd / C (10%, 50 mg) at room temperature, and the resulting suspension was evacuated and refilled with hydrogen and H 2 The mixture was stirred under a balloon for 3 h. The reaction mixture was filtered through a pad of Celite, the filtrate was concentrated, and the residue was purified by column chromatography on silica gel (EtOAc in PE = 0-30%) to give the desired product trans-1-tert-butyl 2-methyl-3-ethylpyrrolidine-1,2-dicarboxylate (400 mg, yield: 86.1%) as a pale yellow oil. LC / MS (ESI) m / z: 202 (M+H) + .

[0272] Step 4: At 0 °C, MeOH (6.0 mL) and H 2 To a solution of trans-1-tert-butyl 2-methyl-3-ethylpyrrolidine-1,2-dicarboxylate (400 mg, 1.55 mmol) in HO (2.0 mL), NaOH (186 mg, 4.66 mmol) was added, and the resulting mixture was stirred at room temperature for 1 h. The reaction mixture was acidified to pH = 4-5 with HCl solution (1.0 N), extracted with EtOAc (15 mL × 3), and the combined organic phase was washed with anhydrous Na 2 SO 4The mixture was dried at 40° C., filtered and concentrated to give the crude product trans-1-[(tert-butoxy)carbonyl]-3-ethylpyrrolidine-2-carboxylic acid (350 mg, yield: 87.9%) as a white solid, which can be used in the next step without further purification. LC / MS (ESI) m / z: 188 (M+H). + .

[0273] Preparation of Intermediate 38, (2S,3R,4R)-1-(tert-butoxycarbonyl)-4-fluoro-3-methylpyrrolidine-2-carboxylic acid [ka] Step 1: To a solution of 1-tert-butyl 2-methyl(2S,4S)-4-hydroxypyrrolidine-1,2-dicarboxylate (4.98 g, 20.4 mmol) in DCM (50 mL) was added imidazole (1.80 g, 26.5 mmol) and TBDPSCl (7.91 g, 30.6 mmol). The resulting mixture was stirred at room temperature for 1 h. The reaction mixture was diluted with saturated NH 4 The mixture was quenched with aqueous Cl (50 mL), extracted with DCM (100 mL x 3), and the combined organic layers were washed with anhydrous Na 2 SO 4 The mixture was dried at 40° C., filtered, concentrated, and the residue was purified by column chromatography on silica gel (EtOAc in PE=0-50%) to give the desired product 1-tert-butyl 2-methyl(2S,4S)-4-[(tert-butyldiphenylsilyl)oxy]pyrrolidine-1,2-dicarboxylate (8.98 g, yield: 86.7%) as a colorless oil. LC / MS (ESI) m / z: 484 (M+H). + .

[0274] Step 2: To a solution of 1-tert-butyl 2-methyl(2S,4S)-4-[(tert-butyldiphenylsilyl)oxy]pyrrolidine-1,2-dicarboxylate (15.0 g, 31.0 mmol) in DCM (100 mL) was added HCl in dioxane (100 mL, 4.0 M) slowly at room temperature over 2 h. The resulting mixture was concentrated to give the crude product 1-tert-butyl 2-methyl(2S,4S)-4-[(tert-butyldiphenylsilyl)oxy]pyrrolidine-1,2-dicarboxylate (11.9 g, yield: 95.8%) as a white solid, which was used in the next step without further purification. LC / MS (ESI) m / z: 384 (M+H). + .

[0275] Step 3: To a solution of methyl (2S,4S)-4-[(tert-butyldiphenylsilyl)oxy]pyrrolidine-2-carboxylate (5.00 g, 13.0 mmol) in DCM (50 mL) at 0° C., TEA (3.3 mL, 23 mmol) and NCS (1.91 g, 14.3 mmol) were added in small portions, and the resulting mixture was stirred at room temperature for 3 h, after which 2,6-lutidine (3 mL, 26.07 mmol) was added slowly within 1 h. The reaction mixture was cooled to −20° C. and CbzCl (4.70 g, 27.4 mmol) was added. The mixture was slowly warmed to room temperature and stirred overnight. The reaction mixture was diluted with H 2 The mixture was quenched with O (50 mL), extracted with EtOAc (50 mL x 3), and the combined organic layers were washed with water and brine, and then with anhydrous Na 2 SO 4 The mixture was dried at 40° C., filtered, concentrated, and the residue was purified by column chromatography on silica gel (EtOAc in PE=0-30%) to give the desired product 1-benzyl 2-methyl(4S)-4-[(tert-butyldiphenylsilyl)oxy]-4,5-dihydro-1H-pyrrole-1,2-dicarboxylate (1.01 g, yield: 14.2%) as an oil. LC / MS(ESI) m / z: 516(M+H) + .

[0276] Step 4: CuBr.Me in THF (5.0 mL) 2 To a solution of S (480 mg, 2.33 mmol), MeMgBr (2.9 mL, 1.0 M in THF) was added 2 The mixture was stirred at -40°C for 1 h, and then a solution of 1-benzyl 2-methyl(4S)-4-[(tert-butyldiphenylsilyl)oxy]-4,5-dihydro-1H-pyrrole-1,2-dicarboxylate (1 g, 1.94 mmol) in THF (10 mL) was added. The resulting mixture was stirred at -40°C for 1 h. The reaction mixture was diluted with saturated NH 4 The mixture was quenched with aqueous Cl and extracted with EtOAc (20 mL x 3). The combined organic layers were washed with brine and anhydrous Na 2 SO 4 The mixture was dried at 40° C., filtered, concentrated, and the residue was purified by column chromatography on silica gel (EtOAc in PE=0-30%) to give the desired product 1-benzyl 2-methyl(2S,3R,4S)-4-[(tert-butyldiphenylsilyl)oxy]-3-methylpyrrolidine-1,2-dicarboxylate (300 mg, yield: 27.6%) as a yellow oil. LC / MS(ESI) m / z: 532(M+H) + .

[0277] Step 5: To a solution of 1-benzyl 2-methyl(2S,3R,4S)-4-[(tert-butyldiphenylsilyl)oxy]-3-methylpyrrolidine-1,2-dicarboxylate (300 mg, 0.56 mmol) in THF (5.0 mL) was added TBAF (0.85 mL, 1.0 M in THF). The resulting mixture was stirred at room temperature for 1 h, and the reaction mixture was diluted with saturated NH 4 It was diluted with aqueous Cl (5 mL), extracted with EtOAc (10 mL x 3), and the combined organic layers were washed with water and brine, and then with anhydrous Na 2 SO 4After drying at 40° C., filtration and concentration, the residue was purified by column chromatography on silica gel (EtOAc in PE=0-50%) to give the desired product 1-benzyl 2-methyl (2S,3R,4S)-4-hydroxy-3-methylpyrrolidine-1,2-dicarboxylate (100 mg, yield: 60.4%) as a pale yellow oil. LC / MS (ESI) m / z: 294 (M+H). + .

[0278] Step 6: To a solution of 1-benzyl 2-methyl (2S,3R,4S)-4-hydroxy-3-methylpyrrolidine-1,2-dicarboxylate (100 mg, 0.34 mmol) in DCM (2.0 mL), N 2 DAST (0.07 mL, 0.51 mmol) was added at 0° C. under reduced pressure. The resulting mixture was stirred at room temperature for 16 h. The reaction mixture was diluted with saturated NaHCO 3 The mixture was quenched with and extracted with DCM (10 mL x 3), and the combined organic layers were washed with water and brine, and then washed with anhydrous Na 2 SO 4 The mixture was dried at 40° C., filtered, concentrated, and the residue was purified by column chromatography on silica gel (EtOAc in PE=0-40%) to give the desired product 1-benzyl 2-methyl (2S,3R,4R)-4-fluoro-3-methylpyrrolidine-1,2-dicarboxylate (80 mg, yield: 75%) as a yellow oil. LCMS: ESI m / z 296 (M+H) + ..

[0279] Step 7: 1-Benzyl 2-methyl (2S,3R,4R)-4-fluoro-3-methylpyrrolidine-1,2-dicarboxylate (80 mg, 0.27 mmol) and (Boc) in MeOH (7.0 mL) 2 To a solution of 2H2O (0.07 mL, 0.36 mmol) was added Pd / C (10%, 15 mg) at room temperature, and the resulting suspension was evacuated and refilled with hydrogen and stirred for 2 h. 2The mixture was stirred at room temperature under balloon pressure for 3 h. The reaction mixture was filtered through a pad of Celite, the filtrate was concentrated, and the residue was purified by column chromatography on silica gel (EtOAc in PE = 0-30%) to give the desired product 1-(tert-butyl) 2-methyl (2S,3R,4R)-4-fluoro-3-methylpyrrolidine-1,2-dicarboxylate (60 mg, yield: 80%) as an oil. LC / MS (ESI) m / z: 206 (M+H). + .

[0280] Step 8: MeOH (3 mL) and H 2 To a solution of 1-(tert-butyl) 2-methyl (2S,3R,4R)-4-fluoro-3-methylpyrrolidine-1,2-dicarboxylate (60 mg, 0.23 mmol) in 2H2O (1 mL) was added NaOH (28 mg, 0.69 mmol) at 0 °C. The resulting mixture was stirred at room temperature for 4 h, and the reaction mixture was concentrated, the pH was adjusted to 4-5 with 1.0 N HCl solution, and extracted with EtOAc (15 mL × 3). The combined organic layer was washed with water and brine, and then extracted with anhydrous Na 2 SO 4 The mixture was dried at 40° C., filtered and concentrated to give the crude product (2S,3R,4R)-1-(,3R,4R)-1-(tert-butoxycarbonyl)-4-fluoro-3-methylpyrrolidine-2-carboxylic acid (50 mg, yield: 83.5%) as an off-white solid, which can be used directly in the next step without further purification. LC / MS (ESI) m / z: 192 (M+1-56). + .

[0281] Preparation of Intermediate 39, (2S,3R,4R)-1-[(tert-butoxy)carbonyl]-3-ethyl-4-fluoropyrrolidine-2-carboxylic acid [ka] Step 1: To a solution of methyl (2S,4S)-4-hydroxypyrrolidine-2-carboxylate (2.71 g, 18.6 mmol) in DCM (40 mL) was added imidazole (2.50 g, 37.2 mmol) and TBSCl (3.30 g, 22.3 mmol). The resulting mixture was stirred at room temperature for 16 h. The reaction mixture was diluted with 10% Na 2 CO 3 The aqueous layer was washed with water (50 mL), the aqueous layer was extracted with DCM (50 mL x 2), and the combined organic layer was washed with anhydrous Na 2 SO 4 Drying at 40° C., filtration and concentration gave the crude product methyl (2S,4S)-4-[(tert-butyldimethylsilyl)oxy]pyrrolidine-2-carboxylate (4.50 g, yield: 88.6%) as a pale yellow oil, which can be used in the next step without further purification. LC / MS (ESI) m / z: 260 (M+H)+.

[0282] Step 2: To a solution of methyl (2S,4S)-4-[(tert-butyldimethylsilyl)oxy]pyrrolidine-2-carboxylate (4.50 g, 17.3 mmol) in toluene (60 mL) at 0 °C, H 2 20 mL of HO and sodium dichloroisocyanurate (3.60 g, 13.9 mmol) were added and the resulting mixture was stirred at 0° C. for 16 h. The reaction mixture was filtered and concentrated to give the crude product methyl (2S,4S)-4-[(tert-butyldimethylsilyl)oxy]-1-chloropyrrolidine-2-carboxylate (4.48 g, yield: 83.8%) as an oil, which can be used in the next step without further purification. LC / MS (ESI) m / z: 294 (M+H). + .

[0283] Step 3: To a solution of methyl (2S,4S)-4-[(tert-butyldimethylsilyl)oxy]-1-chloropyrrolidine-2-carboxylate (4.48 g, 15.3 mmol) in toluene (60 mL) was added TEA (6.4 mL, 46 mmol) at -10°C, and the resulting mixture was stirred at room temperature overnight. The reaction mixture was washed with water and brine, and then diluted with anhydrous Na 2 SO 4 The mixture was dried over 1000 cc, filtered and concentrated to give the crude intermediate methyl (3S)-3-[(tert-butyldimethylsilyl)oxy]-3,4-dihydro-2H-pyrrole-5-carboxylate (3.5 g) as a clear oil. The crude intermediate was dissolved in DCM (40 mL) and cooled to -10°C. To this solution, 2,6-lutidine (3.2 mL, 27 mmol) and CbzCl (2.80 g, 16.3 mmol) were added in small portions and stirred at room temperature for 24 hours. Ethylenediamine (0.25 mL, 3.7 mmol) was then added to the mixture and stirred for 15 minutes. The mixture was washed successively with citric acid solution (1.0 N, 30 mL) and aqueous HCl (1.0 N, 25 mL), and the organic phase was washed with water, NaHCO 3 Wash with aqueous solution (1.5N) and brine, and add anhydrous Na 2 SO 4 The mixture was dried at 40° C., filtered, concentrated, and the residue was purified by column chromatography on silica gel (EtOAc in PE=0-30%) to give the desired product 1-benzyl 2-methyl(4S)-4-[(tert-butyldimethylsilyl)oxy]-4,5-dihydro-1H-pyrrole-1,2-dicarboxylate (1.51 g, yield: 26.7%) as a pale yellow oil. LC / MS(ESI) m / z: 392(M+H) + .

[0284] Step 4: CuBr.Me in THF (5.0 mL) 2 To a solution of S (630 mg, 3.07 mmol), EtMgBr (1.3 mL, 3.0 M in THF) was added 2The mixture was stirred at -40°C for 1 h, and then a solution of 1-benzyl 2-methyl(4S)-4-[(tert-butyldimethylsilyl)oxy]-4,5-dihydro-1H-pyrrole-1,2-dicarboxylate (1.00 g, 2.56 mmol) in THF (10 mL) was added. The resulting mixture was stirred at -40°C for 1 h. The reaction mixture was diluted with saturated NH 4 The mixture was quenched with aqueous Cl and extracted with EtOAc (20 mL x 3). The combined organic layers were washed with brine and anhydrous Na 2 SO 4 After drying at 40° C., filtration and concentration, the residue was purified by column chromatography on silica gel (EtOAc in PE=0-30%) to give the desired product 1-benzyl 2-methyl(2S,3R,4S)-4-[(tert-butyldimethylsilyl)oxy]-3-ethylpyrrolidine-1,2-dicarboxylate (200 mg, yield: 17.6%) as a pale yellow oil. LC / MS(ESI) m / z: 422(M+H) + .

[0285] Step 5: To a solution of 1-benzyl 2-methyl(2S,3R,4S)-4-[(tert-butyldimethylsilyl)oxy]-3-ethylpyrrolidine-1,2-dicarboxylate (200 mg, 0.48 mmol) in THF (3.0 mL) was added TBAF (0.85 mL, 1.0 M in THF). The resulting mixture was stirred at room temperature for 1 h. The reaction mixture was diluted with saturated NH 4 It was diluted with aqueous Cl (5 mL), extracted with EtOAc (10 mL x 3), and the combined organic layers were washed with water and brine, and then with anhydrous Na 2 SO 4 After drying at 40° C., filtration and concentration, the residue was purified by column chromatography on silica gel (EtOAc in PE=0-50%) to give the desired product 1-benzyl 2-methyl(2S,3R,4S)-3-ethyl-4-hydroxypyrrolidine-1,2-dicarboxylate (120 mg, yield: 78.2%) as a pale yellow oil. LC / MS(ESI) m / z: 308(M+H) + .

[0286] Step 6: To a solution of 1-benzyl 2-methyl(2S,3R,4S)-3-ethyl-4-hydroxypyrrolidine-1,2-dicarboxylate (120 mg, 0.39 mmol) in DCM (3.0 mL), 2 DAST (0.07 mL, 0.51 mmol) was added at 0° C. under reduced pressure. The resulting mixture was stirred at room temperature for 16 h. The reaction mixture was diluted with saturated NaHCO 3 The mixture was quenched with and extracted with DCM (10 mL x 3), and the combined organic layers were washed with water and brine, and then washed with anhydrous Na 2 SO 4 The mixture was dried at 40° C., filtered, concentrated and the residue was purified by column chromatography on silica gel (EtOAc in PE=0-40%) to give the desired product 1-benzyl 2-methyl(2S,3R,4R)-3-ethyl-4-fluoropyrrolidine-1,2-dicarboxylate (110 mg, yield: 86.6%) as a yellow oil. LCMS: ESI m / z 310 (M+H) + .

[0287] Step 7: 1-Benzyl 2-methyl(2S,3R,4R)-3-ethyl-4-fluoropyrrolidine-1,2-dicarboxylate (110 mg, 0.36 mmol) and (Boc) in MeOH (2.0 mL) 2 To a solution of 2H2O (78 mg, 0.36 mmol) at room temperature was added Pd / C (10%, 20 mg), the resulting suspension was evacuated and recharged with hydrogen, and the mixture was stirred under a balloon of H2 at room temperature for 3 h. The reaction mixture was filtered through a pad of Celite, the filtrate was concentrated, and the residue was purified by column chromatography on silica gel (EtOAc in PE = 0-30%) to give the desired product 1-tert-butyl 2-methyl(2S,3R,4R)-3-ethyl-4-fluoropyrrolidine-1,2-dicarboxylate (90 mg, yield: 87%) as an oil. LC / MS (ESI) m / z: 276 (M+H) + .

[0288] Step 8: MeOH (3 mL) and H 2To a solution of 1-tert-butyl 2-methyl(2S,3R,4R)-3-ethyl-4-fluoropyrrolidine-1,2-dicarboxylate (90 mg, 0.38 mmol) in 2H2O (1 mL) was added NaOH (65 mg, 1.63 mmol) at 0 °C. The resulting mixture was stirred at room temperature for 5 h. The reaction mixture was concentrated, the pH was adjusted to 4-5 with 1.0 N HCl solution, and extracted with EtOAc (15 mL × 3). The combined organic layer was washed with water and brine, and then extracted with anhydrous Na 2 SO 4 Drying at 40° C., filtration and concentration afforded the crude product (2S,3R,4R)-1-[(tert-butoxy)carbonyl]-3-ethyl-4-fluoropyrrolidine-2-carboxylic acid (70 mg, 78% yield) as an off-white solid, which can be used in the next step without further purification. LC / MS (ESI) m / z: 206 (M+1-56). + .

[0289] Preparation of Intermediate 40, (1-Isopropyl-1H-pyrazol-5-yl)boronic Acid [ka] To a solution of 1-(propan-2-yl)-1H-pyrazole (2.01 g, 18.2 mmol) in THF (40 mL) was added n-BuLi (11.0 mL, 27.5 mmol) at -70 °C. 2 After stirring the mixture at -70°C for 1 h, triisopropyl borate (12.5 mL, 54.46 mmol) was added and the resulting mixture was stirred at room temperature for 16 h. The reaction mixture was diluted with saturated NH 4 The aqueous Cl solution was quenched at 0° C. and the pH was adjusted to 6 with 1.0 N HCl. The mixture was extracted with EtOAc (50 mL×3), and the combined organic phase was washed with water and brine, and diluted with anhydrous Na 2 SO 4 The mixture was dried at 40° C., filtered and concentrated to give the crude product [1-(propan-2-yl)-1H-pyrazol-5-yl]boronic acid (2 g, yield: 71%) as a white solid, which can be used in the next step without further purification. LC / MS (ESI) m / z: 523 (M+H). +。

[0290] Preparation of intermediate 41, 5-fluoro-2-methoxybenzoic acid-3,4-d2 [ka] Step 1: To a solution of methyl 4-bromo-5-fluoro-2-hydroxybenzoate (500 mg, 2 mmol) in DMF (3 mL) was added NBS (464 mg, 2.6 mmol) at room temperature, and the resulting mixture was heated to 70° C. for 4 h. After cooling to room temperature, water (5 mL) was added and extracted with EtOAc (10 mL×3). The combined organic layer was washed with water and brine, and then extracted with anhydrous Na 2 SO 4 The mixture was dried at 40° C., filtered and concentrated to give the crude product, which was purified by column chromatography on silica gel (EtOAc in PE=0-10%) to give the desired product methyl 3,4-dibromo-5-fluoro-2-hydroxybenzoate (410 mg, yield: 62.3%) as a white solid. 1H NMR (400 MHz, DMSO) δ 11.19 (s, 1H), 7.77 (d, J=8.7 Hz, 1H), 3.94 (s, 3H).

[0291] Step 2: To a solution of methyl 3,4-dibromo-5-fluoro-2-hydroxybenzoate (400 mg, 1.2 mmol) in DMF (5 mL) was added MeI (0.2 mL, 3.6 mmol) and K 2 CO 3 (843 mg, 6.1 mmol) was added and the reaction mixture was stirred at room temperature for 5 h, then water (10 mL) was added and extracted with EtOAc (10 mL×3). The combined organic layers were washed with water and brine and diluted with Na 2 SO 4 The mixture was dried at 40° C., filtered and concentrated to give the crude product, which was purified by column chromatography on silica gel (EtOAc in PE=0-10%) to give the desired product methyl 3,4-dibromo-5-fluoro-2-methoxybenzoate (340 mg, yield: 81.5%) as a white solid. LC / MS (ESI) m / z: 417 (M+H).+ 。

[0292] Step 3: To a solution of methyl 3,4-dibromo-5-fluoro-2-methoxybenzoate (340 mg, 0.99 mmol) in MeOD (5 mL) was added Pd / C (25 mg) and the resulting mixture was subjected to D 2 The mixture was stirred at 60° C. for 10 hours under atmospheric pressure. The mixture was filtered and concentrated to give the crude product methyl 5-fluoro-2-methoxybenzoate-3,4-d 2 (85 mg, yield: 45.9%) was obtained as a colorless oil, which can be used directly in the next step without further purification. LC / MS (ESI) m / z: 186 (M+H). + .

[0293] Step 4: MeOH / H 2 Methyl 5-fluoro-2-methoxybenzoate-3,4-d in O (4 mL / 2 mL) 2 (80mg, 0.43mmol) was added to a solution of LiOH.H 2 O (72 mg, 1.72 mmol) was added. The resulting mixture was then cooled to 5°C. 2 The reaction mixture was stirred at room temperature for 2 hours under atmospheric pressure. 2 The mixture was diluted with 20 mL of EtOAc (50 mL), the pH was adjusted to 3-4, extracted with EtOAc (20 mL x 3), and the combined organic phase was washed with water and brine, and then diluted with anhydrous Na 2 SO 4 Dry at 40° C., filter, and concentrate in vacuo to give the crude product 5-fluoro-2-methoxybenzoic acid-3,4-d 2 (70 mg, yield: 94.6%) was obtained as a white solid, which was used directly in the next step without further purification. LC / MS (ESI) m / z: 173 (M+H). + .

[0294] Preparation of intermediate 42, 2-[(5-{2,7-diazaspiro[3.5]nonan-2-yl}-1,2,4-triazin-6-yl)oxy]-N-ethyl-5-fluoro-N-(propan-2-yl)benzamide [ka] Step 1: To a solution of 5-bromopyrimidine (1.01 g, 6.29 mmol) in THF (15 mL) was added cyclopropylmagnesium bromide (9.43 mL, 9.43 mmol, 1.0 M) 2 The resulting mixture was stirred at room temperature for 2 hours. 2 The reaction mixture was quenched with 0.3 mL of H2O, followed by the addition of DDQ (1.60 g, 6.92 mmol) and the reaction mixture was stirred at room temperature for 16 h. 2 The mixture was diluted with 20 mL of EtOAc (50 mL), extracted with EtOAc (20 mL × 3), and the combined organic layers were washed with anhydrous Na 2 SO 4 The mixture was dried at 40° C., filtered, concentrated, and the residue was purified by chromatography column on silica gel (EtOAc in PE=0-10%) to give the desired product 5-bromo-4-cyclopropylpyrimidine (1.10 g, yield: 83.5%) as a white solid. LC / MS (ESI) m / z: 199 (M+H). + .

[0295] Step 2: Dioxane (5.0 mL) and H 2 To a solution of 5-bromo-4-cyclopropylpyrimidine (200 mg, 1.00 mmol) and (5-fluoro-2-hydroxyphenyl)boronic acid (188 mg, 1.21 mmol) in 2HO (1.0 mL) was added Pd(dppf)Cl 2 (20mg) and K 2 CO 3 (347 mg, 2.51 mmol) was added and the resulting mixture was treated with N 2 The reaction mixture was stirred at 100° C. for 12 hours under reduced pressure. 2 The mixture was diluted with 20 mL of 2H2O, extracted with EtOAc (20 mL x 3), and the combined organic layers were washed with water and brine, and then with anhydrous Na2SO4. 2 SO 4The mixture was dried at 40° C., filtered, concentrated, and the residue was purified by column chromatography on silica gel (EtOAc in PE=0-30%) to give the desired product 2-(4-cyclopropylpyrimidin-5-yl)-4-fluorophenol (200 mg, yield: 82.1%) as a pale yellow solid. LC / MS (ESI) m / z: 231 (M+H). + .

[0296] Step 3: To a stirred solution of 2-(4-cyclopropylpyrimidin-5-yl)-4-fluorophenol (800 mg, 3.48 mmol) and tert-butyl 2-(3,6-dichloro-1,2,4-triazin-5-yl)-2,7-diazaspiro[3.5]nonane-7-carboxylate (1.30 g, 3.48 mmol) in THF (20 mL) was added DBU (1.04 g, 6.90 mmol) at 0° C. The resulting mixture was stirred at room temperature for 10 h. The reaction mixture was stirred at H 2 The mixture was diluted with 20 mL of EtOAc (30 mL × 3), extracted with EtOAc (30 mL × 3), and the combined organic layers were washed with anhydrous Na 2 SO 4 The mixture was dried at 40° C., filtered, concentrated and the residue was purified by chromatography column on silica gel (EtOAc in PE=10-50%) to give the desired product tert-butyl 2-(3-chloro-6-(2-(4-cyclopropylpyrimidin-5-yl)-4-fluorophenoxy)-1,2,4-triazin-5-yl)-2,7-diazaspiro[3.5]nonane-7-carboxylate (849 mg, yield: 43.2%) as a yellow solid. LCMS: ESI m / z 568 (M+1) + .

[0297] Step 4: tert-Butyl 2-(3-chloro-6-(2-(4-cyclopropylpyrimidin-5-yl)-4-fluorophenoxy)-1,2,4-triazin-5-yl)-2,7-diazaspiro[3.5]nonane-7-carboxylate (300 mg, 0.53 mmol) and NaBH 4(20 mg, 0.95 mmol) was added to a solution of TMEDA (220 mg, 0.53 mmol) and Pd(dppf)Cl 2 .CH 2 Cl 2 (30 mg) was added at room temperature and the resulting mixture was stirred at room temperature overnight. 2 The mixture was diluted with 20 mL of EtOAc (10 mL), extracted with EtOAc (20 mL x 3), and the combined organic layers were washed with anhydrous Na 2 SO 4 The mixture was dried at 40° C., filtered, concentrated, and the residue was purified by column chromatography on silica gel (EtOAc in PE=0-50%) to give the desired product tert-butyl 2-{6-[2-(4-cyclopropylpyrimidin-5-yl)-4-fluorophenoxy]-1,2,4-triazin-5-yl}-2,7-diazaspiro[3.5]nonane-7-carboxylate (250 mg, yield: 84.3%) as a pale yellow solid. LC / MS (ESI) m / z: 534 (M+H). + .

[0298] Step 5: To a solution of tert-butyl 2-(6-(2-(4-cyclopropylpyrimidin-5-yl)-4-fluorophenoxy)-1,2,4-triazin-5-yl)-2,7-diazaspiro[3.5]nonane-7-carboxylate (600 mg, 1.12 mmol) in DCM (10 mL) was added TFA (5 mL) at 0° C. The resulting mixture was stirred at room temperature for 2 h. The reaction mixture was concentrated to give the crude product 2-[(5-{2,7-diazaspiro[3.5]nonan-2-yl}-1,2,4-triazin-6-yl)oxy]-N-ethyl-5-fluoro-N-(propan-2-yl)benzamide (460 mg, yield: 90%) as a brown oil, which can be used in the next step without further purification. LC / MS (ESI) m / z: 434 (M+H) + .

[0299] The following intermediates were prepared from the corresponding chemicals following the experimental procedure of Intermediate 42. [Table 8] Intermediate 44: Preparation of 2-(5-(4-fluoro-2-(1-isopropyl-1H-1,2,4-triazol-5-yl)phenoxy)pyrimidin-4-yl)-2,7-diazaspiro[3.5]nonane [ka] Step 1: To a solution of 5-fluoro-2-methoxybenzoic acid (4.01 g, 23.51 mmol) and DIEPA (5.8 mL, 35.33 mmol) in DCM (40 mL) was added HATU (13.4 g, 35.31 mmol) and NH 4 Cl (1.72 g, 31.82 mmol) was added. The resulting mixture was stirred at room temperature for 3 h. The reaction mixture was diluted with saturated NH 4 Quench with aqueous Cl, extract with DCM (20 mL x 3), wash the combined organic phase with brine and add anhydrous Na 2 SO 4 The mixture was dried at 40° C., filtered and concentrated to give the crude product, which was purified by column chromatography on silica gel (10-30% EtOAc in PE) to give the desired product 5-fluoro-2-methoxybenzamide (3.81 g, yield: 95.6%) as a white solid. LC / MS (ESI) m / z: 170 (M+H). + .

[0300] Step 2: A solution of 5-fluoro-2-methoxybenzamide (3.81 g, 22.52 mmol) in DMF-DMA (30.1 mL, 224.61 mmol) was heated to 100° C. overnight. The reaction mixture was concentrated under reduced pressure to give the crude product N-[(1E)-(dimethylamino)methylidene]-5-fluoro-2-methoxybenzamide (4.78 g, yield: 95.2%) as a colorless oil, which can be used directly in the next step without further purification. LC / MS (ESI) m / z 225 (M+H) + .

[0301] Step 3: To a solution of N-[(1E)-(dimethylamino)methylidene]-5-fluoro-2-methoxybenzamide (4.78 g, 21.41 mmol) in AcOH (30 mL) was added (propan-2-yl)hydrazine (1.61 g, 22.0 mmol). The resulting mixture was stirred at 100° C. for 1 h. The reaction mixture was concentrated under reduced pressure and the residue was washed with saturated NaHCO 3 Solution (30 mL) was added. The mixture was then extracted with DCM (20 mL×3), and the combined organic phase was washed with brine and anhydrous Na 2 SO 4 Drying at 40° C., filtering and concentrating in vacuo gave the crude product, which was purified by column chromatography on silica gel (EtOAc in PE=0-40%) to give the desired product 5-(5-fluoro-2-methoxyphenyl)-1-(propan-2-yl)-1H-1,2,4-triazole (3.98 g, yield: 79.4%) as a pale yellow solid. LC / MS (ESI) m / z: 236 (M+H). + .

[0302] Step 4: To a solution of 5-(5-fluoro-2-methoxyphenyl)-1-(propan-2-yl)-1H-1,2,4-triazole (1 g, 4.25 mmol) in DCM (10 mL), 2 BBr at -60℃ under atmospheric pressure 3 (10 mL, 1 mol / L in DCM) 2 BBr at -60℃ under atmospheric pressure 3 (10 mL, 1.0 M in DCM) was added dropwise and the resulting mixture was stirred at this temperature for 2 h. The reaction mixture was then diluted with cold saturated NaHCO 3 The mixture was quenched at 0° C. and extracted with DCM (30 mL×3), and the combined organic layers were washed with water and brine, and diluted with anhydrous Na 2 SO 4 After filtration and concentration, the desired product 4-fluoro-2-[1-(propan-2-yl)-1H-1,2,4-triazol-5-yl]phenol (700 mg, yield: 74.4%) was obtained as a yellow solid. LC / MS (ESI) m / z: 222 (M+H). + .

[0303] Step 5: 4-Fluoro-2-[1-(propan-2-yl)-1H-1,2,4-triazol-5-yl]phenol (500 mg, 2.30 mmol) and Cs in DMF (10 mL) 2 CO 3 (2.21 g, 6.81 mmol) was added 5-bromopyrimidine (467 mg, 2.91 mmol). The reaction mixture was heated at 120° C. for 12 h and cooled to room temperature. After that, the mixture was diluted with saturated NH 4 The mixture was quenched with aqueous Cl (50 mL), extracted with EtOAc (20 mL x 3), and the combined organic layers were washed with water and brine, and then with anhydrous Na 2 SO 4 The mixture was dried at 40° C., filtered and concentrated to give the crude product, which was purified by column chromatography on silica gel (MeOH=0-4% in DCM) to give the desired product 5-{4-fluoro-2-[1-(propan-2-yl)-1H-1,2,4-triazol-5-yl]phenoxy}pyrimidine (240 mg, yield: 35.5%) as a pale yellow oil. LC / MS (ESI) m / z: 300 (M+H). + .

[0304] Step 6: To a solution of 5-{4-fluoro-2-[1-(propan-2-yl)-1H-1,2,4-triazol-5-yl]phenoxy}pyrimidine (240 mg, 0.81 mmol) in THF (10 mL) was added urea hydrogen peroxide (226 mg, 2.42 mmol) and TFAA (0.6 mL, 4.2 mmol) at 0° C. The resulting mixture was cooled to 5° C. with 5% CO. 2 The reaction mixture was stirred at 20 °C for 1 h under reduced pressure. 3 aqueous solution (30 mL) and saturated Na 2 S 2 O 3 The aqueous phase was extracted with DCM (15 mL x 3), and the combined organic phase was washed with water and brine, and then with anhydrous Na 2 SO 4Drying at 40° C., filtration and concentration afforded the crude product 5-{4-fluoro-2-[1-(propan-2-yl)-1H-1,2,4-triazol-5-yl]phenoxy}pyrimidin-1-ium-1-olate] (160 mg, yield: 63.3%) as a brown solid, which was used directly in the next step without further purification. LC / MS (ESI) m / z: 254 (M+H). + .

[0305] Step 7: To a solution of 5-{4-fluoro-2-[1-(propan-2-yl)-1H-1,2,4-triazol-5-yl]phenoxy}pyrimidin-1-ium-1-olate (160 mg, 0.52 mmol) in EtOAc (10 mL) was added DIEPA (0.7 mL, 4.10 mmol) and POCl. 3 (0.15 mL, 1.52 mmol) was added at 0° C. The reaction mixture was then stirred at room temperature for 12 h. 3 The mixture was quenched with and extracted with DCM (15 mL x 3), and the combined organic layers were washed with water and brine, and then washed with anhydrous Na 2 SO 4 The mixture was dried at 40° C., filtered, concentrated and concentrated in vacuo to give the crude product 4-chloro-5-{4-fluoro-2-[1-(propan-2-yl)-1H-1,2,4-triazol-5-yl]phenoxy}pyrimidine (80 mg, yield: 47.2%) as a brown oil, which can be used directly in the next step without further purification. LC / MS (ESI) m / z: 334 (M+H). + .

[0306] Step 8: 4-Chloro-5-{4-fluoro-2-[1-(propan-2-yl)-1H-1,2,4-triazol-5-yl]phenoxy}pyrimidine (80 mg, 0.24 mmol) in MeCN (10 mL) and K 2 CO 3(132 mg, 0.96 mmol)) was added tert-butyl 2,7-diazaspiro[3.5]nonane-7-carboxylate (59.7 mg, 0.31 mmol). The resulting mixture was heated to 80° C. for 5 h. After cooling to room temperature, the reaction mixture was diluted with saturated NH 4 The mixture was quenched with aqueous Cl (10 mL), extracted with EtOAc (15 mL×3), and the combined organic layers were washed with water and brine, and then with anhydrous Na 2 SO 4 The mixture was dried at 40° C., filtered and concentrated to give the crude product, which was purified by column chromatography on silica gel (EtOAc in PE=0-40%) to give the desired product tert-butyl 2-(5-{4-fluoro-2-[1-(propan-2-yl)-1H-1,2,4-triazol-5-yl]phenoxy}pyrimidin-4-yl)-2,7-diazaspiro[3.5]nonane-7-carboxylate (30 mg, yield: 23.9%) as a white solid. LC / MS (ESI) m / z: 524 (M+H + ).

[0307] Step 9: To a solution of tert-butyl 2-(5-{4-fluoro-2-[1-(propan-2-yl)-1H-1,2,4-triazol-5-yl]phenoxy}pyrimidin-4-yl)-2,7-diazaspiro[3.5]nonane-7-carboxylate (30 mg, 0.06 mmol) in DCM (5 mL) was added dropwise at room temperature, and the resulting mixture was stirred at room temperature for 2 h. The reaction mixture was concentrated to give the crude product 2-(5-{4-fluoro-2-[1-(propan-2-yl)-1H-1,2,4-triazol-5-yl]phenoxy}pyrimidin-4-yl)-2,7-diazaspiro[3.5]nonane (15 mg, yield: 61.8%) as a pale yellow solid, which can be used directly in the next step without further purification. LC / MS(ESI)m / z:213(1 / 2 M+H + ).

[0308] Preparation of Intermediate 45, 2-(5-(2-(4-chloro-1-isopropyl-1H-pyrazol-5-yl)-4-fluorophenoxy)pyrimidin-4-yl)-2,7-diazaspiro[3.5]nonane [ka] Step 1: Dioxane (20 mL) and H 2 To a solution of [1-(propan-2-yl)-1H-pyrazol-5-yl]boronic acid (686 mg, 4.46 mmol) and 5-(2-bromo-4-fluorophenoxy)pyrimidine (800 mg, 2.97 mmol) in 2O (2.0 mL) was added 2 CO 3 (1.2 g, 8.9 mmol) and Pd(dppf)Cl 2 (217 mg, 0.29 mmol) was added at room temperature, and the resulting mixture was diluted with N 2 The reaction mixture was stirred at 100° C. for 2 hours under reduced pressure. 2 The mixture was quenched with O (5 mL), extracted with EtOAc (30 mL × 3), and the combined organic layers were washed with anhydrous Na 2 SO 4 Drying at 40° C., filtration and concentration gave the crude product, which was purified by column chromatography on silica gel (EtOAc in PE=0-50%) to give the desired product 5-{4-fluoro-2-[1-(propan-2-yl)-1H-pyrazol-5-yl]phenoxy}pyrimidine (602 mg, yield: 68%) as a yellow solid. 1 H NMR(400 MHz,DMSO)δ 8.91(s,1H),8.47(s,2H),7.46(s,1H),7.44-7.40(m,1H),7.39-7.34(m,2H),6.25( d,J=1.2Hz,1H),4.39-4.31(m,1H),1.29(d,J=6.4Hz,6H),LC / MS(ESI)m / z:299(M+H) + .

[0309] Step 2: To a solution of 5-{4-fluoro-2-[1-(propan-2-yl)-1H-pyrazol-5-yl]phenoxy}pyrimidine (600 mg, 2.01 mmol) in DMF (10 mL) was added NCS (268 mg, 2.01 mmol) dropwise at room temperature and the resulting mixture was stirred for 3 h. The reaction mixture was stirred for 3 h. 2 The mixture was quenched with O (10 mL), extracted with EtOAc (20 mL × 3), and the combined organic layers were washed with anhydrous Na 2 SO 4 The mixture was dried at 40° C., filtered and concentrated, and the residue was purified by column chromatography on silica gel (EtOAc in PE=0-80%) to give the desired product 5-{2-[4-chloro-1-(propan-2-yl)-1H-pyrazol-5-yl]-4-fluorophenoxy}pyrimidine (401 mg, yield: 65.7%) as a pale yellow solid. 1 H NMR(400 MHz,DMSO)δ 8.93(s,1H),8.48(s,2H),7.63(s,1H),7.55-7.40(m,3H),4.34-4.25(m,1H),1.28(dd,J=11.7,6.5Hz,6H).LC / MS(ESI)m / z:333(M+H) + .

[0310] Step 3: A solution of 5-{2-[4-chloro-1-(propan-2-yl)-1H-pyrazol-5-yl]-4-fluorophenoxy}pyrimidine (150 mg, 0.45 mmol) in THF (5 mL) was treated with urea·H 2 O 2 (127 mg, 1.35 mmol) and TFAA (568 mg, 2.71 mmol) were added portionwise at 0° C., and the resulting mixture was allowed to warm to room temperature and stirred for 3 h. The reaction mixture was diluted with saturated NaHCO 3 The mixture was quenched with ethyl acetate (50 mL x 3), extracted with EtOAc (50 mL x 3), and the combined organic layers were washed with water and brine, and then washed with anhydrous Na 2 SO 4Drying at 40° C., filtration and concentration gave the crude product 5-{2-[4-chloro-1-(propan-2-yl)-1H-pyrazol-5-yl]-4-fluorophenoxy}pyrimidin-1-ium-1-olate (120 mg, yield: 76.3%) as a brown solid, which can be used in the next step without further purification. LC / MS (ESI) m / z: 349 (M+H). + .

[0311] Step 4: To a solution of 5-{2-[4-chloro-1-(propan-2-yl)-1H-pyrazol-5-yl]-4-fluorophenoxy}pyrimidin-1-ium-1-olate (120 mg, 0.34 mmol) in EtOAc (3 mL) was added POCl 3 (0.10 mL, 1.0 mmol) and DIPEA (0.23 mL, 1.4 mmol) were added dropwise at 0° C. The resulting mixture was allowed to warm to room temperature and stirred overnight. The reaction mixture was diluted with saturated NaHCO 3 The mixture was quenched with and extracted with DCM (10 mL x 3), and the combined organic layers were washed with water and brine, and then washed with anhydrous Na 2 SO 4 Drying at 40° C., filtration and concentration gave the crude product 4-chloro-5-{2-[4-chloro-1-(propan-2-yl)-1H-pyrazol-5-yl]-4-fluorophenoxy}pyrimidine (110 mg, yield: 87.1%) as a brown oil, which can be used in the next step without further purification. LC / MS (ESI) m / z: 367 (M+H). + .

[0312] Step 5: To a solution of 4-chloro-5-{2-[4-chloro-1-(propan-2-yl)-1H-pyrazol-5-yl]-4-fluorophenoxy}pyrimidine (110 mg, 0.30 mmol) in DMF (5 mL) was added tert-butyl 2,7-diazaspiro[3.5]nonane-7-carboxylate (67 mg, 0.30 mmol) and K 2 CO 3 (124 mg, 0.89 mmol) was added at room temperature. The resulting reaction was stirred at room temperature overnight. The reaction mixture was diluted with H2 The mixture was quenched with O (5 mL), extracted with EtOAc (10 mL x 3), and the combined organic layers were washed with water and brine, and then with anhydrous Na 2 SO 4 The mixture was dried at 40° C., filtered, concentrated and the residue was purified by column chromatography on silica gel (EtOAc in PE=0-50%) to give the desired tert-butyl 2-(5-{2-[4-chloro-1-(propan-2-yl)-1H-pyrazol-5-yl]-4-fluorophenoxy}pyrimidin-4-yl)-2,7-diazaspiro[3.5]nonane-7-carboxylate (100 mg, yield: 59.9%) as a white solid. LC / MS (ESI) m / z: 557 (M+H) + .

[0313] Step 6: To a solution of tert-butyl 2-(5-(2-(4-chloro-1-isopropyl-1H-pyrazol-5-yl)-4-fluorophenoxy)pyrimidin-4-yl)-2,7-diazaspiro[3.5]nonane-7-carboxylate (100 mg, 0.18 mmol) in DCM (3.0 mL) was added dropwise at room temperature, and the resulting mixture was stirred at room temperature for 1 h. The reaction mixture was concentrated to give the crude product 2-(5-{2-[4-chloro-1-(propan-2-yl)-1H-pyrazol-5-yl]-4-fluorophenoxy}pyrimidin-4-yl)-2,7-diazaspiro[3.5]nonane (60 mg, yield: 73%) as a pale yellow syrup, which can be used directly in the next step without further purification. LC / MS(ESI)m / z: 457(M+H) + .

[0314] Preparation of intermediate 46, trans-1-(tert-butoxycarbonyl)-3-(fluoromethyl)pyrrolidine-2-carboxylic acid [ka] Step 1: MeOH (30mL) and H 21-Benzyl 2-methyl-trans-3-ethenylpyrrolidine-1,2-dicarboxylate (1.30 g, 4.49 mmol, see Intermediate 37 for its synthesis) in O (50 mL), NaIO 4 (3.00 g, 13.48 mmol) and potassium osmate dihydrate (0.17 g, 0.45 mmol) and the resulting mixture was stirred at room temperature for 4 h. The reaction mixture was then diluted with H 2 The mixture was diluted with 20 mL of O and extracted with DCM (50 mL x 3). The combined organic phase was washed with water and brine, and diluted with anhydrous Na 2 SO 4 Drying at 40° C., filtration and concentration gave the crude product, which was purified by column chromatography on silica gel (EtOAc in PE=0-50%) to give the desired product 1-benzyl 2-methyl-trans-3-formylpyrrolidine-1,2-dicarboxylate (700 mg, 2.40 mmol, 53.48%) as a colorless oil. LC / MS (ESI) m / z: 292 (M+H). 。

[0315] Step 2: To a solution of 1-benzyl 2-methyl-trans-3-formylpyrrolidine-1,2-dicarboxylate (200 mg, 0.69 mmol) in MeOH (5 mL) at 0 °C was added NaBH 4 (5 mg, 0.14 mmol) was slowly added. The resulting mixture was stirred at room temperature for 2 h. The reaction mixture was then diluted with saturated NH 4 The mixture was quenched with aqueous Cl (5 mL), extracted with EtOAc (10 mL x 3), and the combined organic phase was washed with water and brine, and then diluted with anhydrous Na 2 SO 4 Drying at 40° C., filtration and concentration gave the crude product 1-benzyl 2-methyl-trans-3-(hydroxymethyl)pyrrolidine-1,2-dicarboxylate (160 mg, 79.4%) as a pale yellow oil. LC / MS (ESI) m / z: 294 (M+H) + .

[0316] Step 3: To a solution of 1-benzyl 2-methyl-trans-3-(hydroxymethyl)pyrrolidine-1,2-dicarboxylate (160 mg, 0.55 mmol) in DCM (5 mL), DAST (132 mg, 0.82 mmol) was added N 2 The mixture was stirred at room temperature for 16 hours. The reaction mixture was diluted with saturated NaHCO 3 The mixture was quenched with and extracted with DCM (10 mL x 3), and the combined organic layers were washed with water and brine, and then washed with anhydrous Na 2 SO 4 The mixture was dried at 40° C., filtered, concentrated and the residue was purified by column chromatography on silica gel (EtOAc in PE=0-20%) to give the desired product 1-benzyl 2-methyl-trans-3-(fluoromethyl)pyrrolidine-1,2-dicarboxylate (80 mg, 0.27 mmol, 49.6%) as a brown oil. LCMS: ESI m / z 296 (M+H) + .

[0317] Step 4: 1-Benzyl 2-methyl-trans-3-(fluoromethyl)pyrrolidine-1,2-dicarboxylate (80 mg, 0.27 mmol) and (Boc) in MeOH (5 mL) 2 To a solution of 2H2O (77 mg, 0.35 mmol) at room temperature was added Pd / C (10%, 20 mg), the resulting suspension was evacuated and refilled with hydrogen, and the mixture was stirred at room temperature for 3 h with H 2 The mixture was stirred under a balloon of 0.05 ml. The reaction mixture was filtered through a pad of Celite, the filtrate was concentrated, and the residue was purified by column chromatography on silica gel (EtOAc in PE = 0-30%) to give the desired product 1-(tert-butyl) 2-methyl-trans-3-(fluoromethyl)pyrrolidine-1,2-dicarboxylate (50 mg, 70.6%) as an oil. LC / MS (ESI) m / z: 262 (M+H). + .

[0318] Step 5: MeOH (3 mL) and H 2To a solution of 1-(tert-butyl) 2-methyl-trans-3-(fluoromethyl)pyrrolidine-1,2-dicarboxylate (50 mg, 0.19 mmol) in 2H2O (1 mL) was added NaOH (20 mg, 0.50 mmol) at 0 °C. The resulting mixture was stirred at room temperature for 5 h. The reaction mixture was concentrated, the pH was adjusted to 4-5 with 1.0 N HCl solution, and extracted with EtOAc (15 mL x 3). The combined organic layer was washed with water and brine, and then extracted with anhydrous Na 2 SO 4 The mixture was dried at 40° C., filtered and concentrated to give the crude product trans-1-(tert-butoxycarbonyl)-3-(fluoromethyl)pyrrolidine-2-carboxylic acid (40 mg, 85.2% yield) as a brown solid, which can be used in the next step without further purification. LC / MS (ESI) m / z: 248 (M+1-56). + .

[0319] Preparation of intermediate 47, 5-(2-((5-(2,7-diazaspiro[3.5]nonan-2-yl)-1,2,4-triazin-6-yl)oxy)-5-fluorophenyl)-6-cyclopropylpicolinonitrile compound [ka] Step 1: 6-Bromo-2-chloropyridin-3-amine (2.30 g, 11.09 mmol) and Zn(CN) in DMF (25 mL) 2 (0.98 g, 8.32 mmol) was added to a solution of Pd(PPh 3 ) 4 (0.38 g, 0.33 mmol) was added. The resulting mixture was then heated to 40° C. 2 The reaction mixture was heated to 85° C. under atmosphere for 12 h. 4 The mixture was quenched with aqueous Cl and extracted with EtOAc (20 mL x 3), and the combined organic layers were washed with brine and 2 SO 4Drying at 40° C., filtration and concentration gave the crude product, which was purified by column chromatography on silica gel (EtOAc in PE=0-30%) to give the desired product 5-amino-6-chloropyridine-2-carbonitrile (500 mg, yield: 29.4%) as a pale yellow solid. LC / MS (ESI) m / z: 154 (M+H). + .

[0320] Step 2: Toluene (80 mL) and H 2 To a solution of 5-amino-6-chloropyridine-2-carbonitrile (2.71 g, 17.58 mmol), cyclopropylboronic acid (1.96 g, 22.86 mmol) and tricyclohexylphosphane (1.97 g, 7.03 mmol) in 2H2O (10 mL) was added Pd(AcO) 2 (40 mg, 0.18 mmol) and K 3 PO 4 (14.9 g, 70.33 mmol) was added. The resulting mixture was then heated to 100° C. 2 The mixture was stirred at 100° C. for 10 hours under atmospheric conditions. The reaction mixture was diluted with saturated NH 4 The mixture was diluted with aqueous Cl and extracted with EtOAc (20 mL x 3). The combined organic phase was washed with brine and 2 SO 4 Drying at 40° C., filtration and concentration gave the crude product, which was purified by column chromatography on silica gel (EtOAc in PE=5-30%) to give the desired product 5-amino-6-cyclopropylpyridine-2-carbonitrile (1.12 g, yield: 40.1%) as a yellow solid. LC / MS (ESI) m / z: 160 (M+H). + .

[0321] Step 3: To a stirred solution of t-BuONO (2.53 mL, 21.11 mmol) and CuBr (4.04 g, 28.14 mmol) in MeCN (20 mL) at 70° C., a solution of 5-amino-6-cyclopropylpyridine-2-carbonitrile (1.12 g, 7.04 mmol) in MeCN (10 mL) was added dropwise. The resulting mixture was stirred at the same temperature for 1 h. The reaction mixture was diluted with saturated NH 4The mixture was quenched with aqueous Cl (30 mL), extracted with EtOAc (20 mL×3), and the combined organic layers were washed with brine and 2 SO 4 The mixture was dried at 40° C., filtered and concentrated. The residue was purified by column chromatography on silica gel (EtOAc in PE=0-10%) to give the desired product 5-bromo-6-cyclopropylpyridine-2-carbonitrile (1 g, yield: 63.7%) as a yellow solid. LC / MS (ESI) m / z: 223 (M+H). + .

[0322] Step 4: Dioxane (10 mL) and H 2 To a solution of 5-bromo-6-cyclopropylpyridine-2-carbonitrile (1.00 g, 4.48 mmol), (5-fluoro-2-hydroxyphenyl)boronic acid (1.05 g, 6.72 mmol) in 2 mL of HO was added Pd(dppf)Cl 2 (50mg) and Cs 2 CO 3 (4.38 g, 13.45 mmol) was added and the resulting mixture was treated with N 2 The reaction mixture was stirred at 100° C. for 2 hours under reduced pressure. 2 The mixture was quenched with O (5 mL), extracted with EtOAc (30 mL × 3), and the combined organic layers were washed with anhydrous Na 2 SO 4 The mixture was dried at 40° C., filtered and concentrated. The residue was purified by column chromatography on silica gel (EtOAc in PE=5-30%) to give the desired product 6-cyclopropyl-5-(5-fluoro-2-hydroxyphenyl)pyridine-2-carbonitrile (740 mg, yield: 64.9%) as a colorless oil. LC / MS (ESI) m / z: 255 (M+H). + .

[0323] Step 5: To a stirred solution of 6-cyclopropyl-5-(5-fluoro-2-hydroxyphenyl)pyridine-2-carbonitrile (740 mg, 2.91 mmol) and tert-butyl 2-(dichloro-1,2,4-triazin-5-yl)-2,7-diazaspiro[3.5]nonane-7-carboxylate (762 mg, 2.04 mmol, for its synthesis see intermediate 34) in THF (15 mL) was added DBU (0.65 mL, 4.37 mmol) at 0° C. The resulting mixture was stirred at room temperature for 10 h. The reaction mixture was diluted with H 2 The mixture was diluted with 20 mL of EtOAc (30 mL × 3), extracted with EtOAc (30 mL × 3), and the combined organic layers were washed with anhydrous Na 2 SO 4 The mixture was dried at 70° C., filtered and concentrated. The residue was purified by chromatography column on silica gel (EtOAc in PE=0-50%) to give the desired product tert-butyl 2-{3-chloro-6-[2-(6-cyano-2-cyclopropylpyridin-3-yl)-4-fluorophenoxy]-1,2,4-triazin-5-yl}-2,7-diazaspiro[3.5]nonane-7-carboxylate (440 mg, yield: 25.5%) as a white solid. LCMS: ESI m / z 592 (M+H) + .

[0324] Step 6: To a solution of tert-butyl 2-{3-chloro-6-[2-(6-cyano-2-cyclopropylpyridin-3-yl)-4-fluorophenoxy]-1,2,4-triazin-5-yl}-2,7-diazaspiro[3.5]nonane-7-carboxylate (600 mg, 1.01 mmol), [3-(dimethylamino)propyl]dimethylamine (263 mg, 2.03 mmol) in THF (15 mL) was added NaBH 4 (63 mg, 1.86 mmol) and Pd(dppf)Cl 2 (30 mg) was added. The reaction mixture was stirred at room temperature under N2 atmosphere for 12 h and then saturated NH 4 The mixture was quenched with aqueous Cl (30 mL) and extracted with EtOAc (20 mL×3). The combined organic layers were washed with brine and 2 SO 4Drying at 40° C., filtration and concentration gave the crude product, which was purified by column chromatography on silica gel (EtOAc in PE=0-40%) to give the desired product tert-butyl 2-{6-[2-(6-cyano-2-cyclopropylpyridin-3-yl)-4-fluorophenoxy]-1,2,4-triazin-5-yl}-2,7-diazaspiro[3.5]nonane-7-carboxylate (240 mg, yield: 42.5%) as a white solid. LCMS: ESI m / z 558 (M+H) + .

[0325] Step 7: To a solution of tert-butyl 2-{6-[2-(6-cyano-2-cyclopropylpyridin-3-yl)-4-fluorophenoxy]-1,2,4-triazin-5-yl}-2,7-diazaspiro[3.5]nonane-7-carboxylate (240 mg, 0.43 mmol) in DCM (5.0 mL), TFA (2.0 mL) was added dropwise at room temperature, and the resulting mixture was stirred at room temperature for 1 h. The reaction mixture was concentrated to give the crude product 5-(2-((5-(2,7-diazaspiro[3.5]nonane-2-yl)-1,2,4-triazin-6-yl)oxy)-5-fluorophenyl)-6-cyclopropylpicolinonitrile as a TFA salt (200 mg, yield: 75.1%), which can be used directly in the next step without further purification. LC / MS(ESI)m / z: 458(M+H) + .

[0326] Preparation of Intermediate 48, 2-((3-chloro-5-(2,7-diazaspiro[3.5]nonan-2-yl)-1,2,4-triazin-6-yl)oxy)-N-ethyl-5-fluoro-N-isopropylbenzamide [ka] To a solution of tert-butyl 2-(3-chloro-6-(2-(ethyl(isopropyl)carbamoyl)-4-fluorophenoxy)-1,2,4-triazin-5-yl)-2,7-diazaspiro[3.5]nonane-7-carboxylate (200 mg, 0.36 mmol, see intermediate 34 for its synthesis) in DCM (5.0 mL) was added dropwise TFA (2.0 mL) at room temperature, and the resulting mixture was stirred at room temperature for 1 h. The reaction mixture was concentrated to give the crude product 2-((3-chloro-5-(2,7-diazaspiro[3.5]nonan-2-yl)-1,2,4-triazin-6-yl)oxy)-N-ethyl-5-fluoro-N-isopropylbenzamide as the 2,2,2-trifluoroacetic acid salt (150 mg, yield: 74.4%), which can be used directly in the next step without further purification. LC / MS(ESI)m / z:463(M+H) + .

[0327] Preparation of intermediate 49, rel-(2R,3R,4S)-1-(tert-butoxycarbonyl)-3,4-dimethylpyrrolidine-2-carboxylic acid [ka] Step 1: To a stirred solution of benzyl(methoxymethyl)[(trimethylsilyl)methyl]amine (21.5 mL, 84.24 mmol) and 1,4-dimethyl(2Z)-but-2-enedioate (10.6 mL, 84.24 mmol) in MeCN (150 mL) at 25 °C, LiF (2.66 g, 102.31 mmol) was added and the resulting mixture was cooled to 37 °C with N 2 The mixture was stirred under atmospheric conditions at 25° C. for 18 hours. The reaction mixture was diluted with saturated NH 4 The mixture was diluted with aqueous Cl (100 mL) and extracted with EtOAc (200 mL×3). The combined organic phase was washed successively with water and brine, and the organic phase was washed with anhydrous Na 2 SO 4Drying at 40° C., filtration and concentration gave the crude product, which was purified by column chromatography on silica gel (EtOAc in PE=0-30%) to give the desired product cis-3,4-dimethyl 1-benzylpyrrolidine-3,4-dicarboxylate (22.1 g, yield: 94.2%) as a pale yellow oil. 1 H NMR (400 MHz, CDCl 3 )δ 7.31-7.23(m,5H),3.66(s,8H),3.33-3.28(m,2H),3.17-3.12(m,2H),2.77-2.67(m,2H),LC / MS(ESI)m / z:278(M+H) + .

[0328] Step 2: To a stirred solution of cis-dimethyl 1-benzylpyrrolidine-3,4-dicarboxylate (10.0 g, 36.06 mmol) in THF (50 mL) at 0° C., LAH (4.5 g, 118.58 mmol) was added in small portions. The resulting mixture was stirred under reduced pressure with N 2 The mixture was stirred at 60° C. under atmospheric pressure for 18 hours, then quenched by dropwise addition of 4.5 mL of water, 4.5 mL of 15% NaOH solution, and 13.5 mL of water. The mixture was filtered through Celite, and the filtrate was extracted with EtOAc (100 mL×3). The combined organic phase was washed with water and brine, and the organic phase was diluted with anhydrous Na 2 SO 4 The mixture was dried at 40° C., filtered and concentrated to give the crude product, which was purified by column chromatography on silica gel (MeOH=1-10% in DCM) to give the desired product cis-[1-benzyl-4-(hydroxymethyl)pyrrolidin-3-yl]methanol (7.03 g, yield: 87.7%) as a colorless oil. LC / MS (ESI) m / z: 222 (M+H) + .

[0329] Step 3: Cis-[1-benzyl-4-(hydroxymethyl)pyrrolidin-3-yl]methanol (4.00 g, 18.07 mmol) and Boc in MeOH (50 mL) 2To a stirred solution of 2H2O (4.95 g, 22.91 mmol), TEA (1.49 g, 14.85 mmol) and 10% Pd / C (500 mg) were added slowly at room temperature. The resulting mixture was stirred at room temperature for 18 h and then cooled to room temperature. 2 The mixture was stirred under atmospheric pressure and then poured into water (200 mL). The mixture was extracted with EtOAc (200 mL×3), and the combined organic phase was washed with water and brine, and concentrated with anhydrous Na 2 SO 4 The mixture was dried at 40° C., filtered and concentrated to give the crude product, which was purified by column chromatography on silica gel (EtOAc in PE=0-20%) to give the desired product tert-butyl-cis-3,4-bis(hydroxymethyl)pyrrolidine-1-carboxylate (3.50 g, yield: 83.7%) as a colorless oil. LC / MS (ESI) m / z: 176 (M+H-56). + .

[0330] Step 4: To a stirred solution of cis-tert-butyl 3,4-bis(hydroxymethyl)pyrrolidine-1-carboxylate (4.00 g, 17.29 mmol) and DIPEA (10.2 mL, 61.90 mmol) in DCM (50 mL) was added MsCl (4.05 mL, 52.38 mmol) at 0° C. over 10 min. The resulting mixture was irradiated with N 2 The mixture was stirred at 25°C for 18 hours under atmospheric pressure and then diluted with saturated NH 4 The mixture was quenched with aqueous Cl (20 mL) and extracted with DCM (50 mL x 3). The combined organic phase was washed with water and brine, and the organic phase was washed with anhydrous Na 2 SO 4 The mixture was dried at 40° C., filtered and concentrated to give the crude product, which was purified by column chromatography on silica gel (EtOAc in PE=0-20%) to give the desired product tert-butyl-cis-3,4-bis(((methylsulfonyl)oxy)methyl)pyrrolidine-1-carboxylate (5.81 g, yield: 86.6%) as a pale yellow oil. LC / MS (ESI) m / z: 332 (M+H-56). + .

[0331] Step 5: To a stirred solution of tert-butyl-cis-3,4-bis(((methylsulfonyl)oxy)methyl)pyrrolidine-1-carboxylate (5.81 g, 14.97 mmol) was added LiEt 3 BH (100 mL, 100 mmol) was added over 30 min at 0 °C. The resulting mixture was then cooled to 5 °C. 2 The mixture was stirred at 25°C for 12 hours under atmospheric pressure and then diluted with saturated NH 4 The mixture was quenched with aqueous Cl (10 mL) and extracted with EtOAc (50 mL×3). The combined organic phase was washed with water and brine, and diluted with anhydrous Na 2 SO 4 The mixture was dried at 40° C., filtered and concentrated. The crude product was purified by column chromatography on silica gel (EtOAc in PE=0-10%) to give the desired product tert-butyl-cis-3,4-dimethylpyrrolidine-1-carboxylate (1.50 g, yield: 50.3%) as a pale yellow oil. 1 H NMR (400 MHz, CDCl 3 )δ 3.46-3.42(m,2H),3.04-3.00(m,2H),2.34-2.14(m,2H),1.46(s,9H),0.92(d,J = 6.7Hz,6H).

[0332] Step 6: To a stirred solution of tert-butyl-cis-3,4-dimethylpyrrolidine-1-carboxylate (300 mg, 1.51 mmol) in THF (3 mL) at -78 °C, s-BuLi (1.5 mL, 1.950 mmol) was added dropwise over 30 min. The resulting mixture was stirred at the same temperature for 3 h, followed by CO2 bubbling through for 1 h (maintaining the internal temperature below -70 °C). After warming to room temperature, the mixture was quenched with 1N HCl to pH = 5 and extracted with EtOAc (30 mL x 3). The combined organic phase was washed with water and brine, and diluted with anhydrous Na 2 SO 4Drying at 40° C., filtration and concentration gave the crude product rel-(2S,3S,4R)-1-(tert-butoxycarbonyl)-3,4-dimethylpyrrolidine-2-carboxylic acid (120 mg, yield: 32.8%) as a yellow semi-solid, which can be used directly in the next step without further purification. LC / MS (ESI) m / z: 144 (M+H-100). + .

[0333] Intermediate 50, Preparation of 2-[(tert-butoxy)carbonyl]-5,5-difluoro-octahydrocyclopenta[c]pyrrole-1-carboxylic acid [ka] Step 1. To a solution of tert-butyl-cis-5-oxo-octahydrocyclopenta[c]pyrrole-2-carboxylate (5.00 g, 22.19 mmol) in THF (30 mL) at 0° C., DAST (11.7 mL, 88.77 mmol) was added slowly and the reaction mixture was cooled to 5° C. with N 2 The mixture was stirred under atmospheric conditions at 25° C. for 72 hours. The reaction mixture was diluted with saturated NH 4 The mixture was quenched with aqueous Cl (10 mL), extracted with EtOAc (50 mL×3), and the combined organic phase was washed with water and brine, and diluted with anhydrous Na 2 SO 4 The mixture was dried at 70° C., filtered and concentrated. The residue was purified by column chromatography on silica gel (EtOAc in PE=0-40%) to give the desired product tert-butyl-cis-5,5-difluoro-octahydrocyclopenta[c]pyrrole-2-carboxylate (4 g, yield: 72.8%) as a pale yellow oil. LC / MS (ESI) m / z: 248 (M+H). + .

[0334] Step 2. To a solution of tert-butyl-cis-5,5-difluoro-octahydrocyclopenta[c]pyrrole-2-carboxylate (3.21 g, 12.94 mmol) in THF (20 mL) at −78° C. was added s-BuLi (29.8 mL, 38.82 mmol). 2 After stirring at −78° C. for 4 h under atmospheric pressure, the resulting mixture was 2 The mixture was stirred at −78° C. for 5 hours under atmospheric pressure, gradually warmed to room temperature, and further stirred at room temperature for 12 hours. The mixture was quenched with 1N HCl solution, adjusted to pH 4-5, and extracted with EtOAc (30 mL×3). The combined organic layer was washed with brine and diluted with anhydrous Na 2 SO 4 Drying at 40° C., filtration and concentration afforded the crude product 2-[(tert-butoxy)carbonyl]-5,5-difluoro-octahydrocyclopenta[c]pyrrole-1-carboxylic acid (800 mg, yield: 21.2%) as a brown oil, which was used in the next step without further purification. LC / MS (ESI) m / z: 292 (M+H). + .

[0335] Intermediate 51, Preparation of trans-1-((benzyloxy)carbonyl)-3-(difluoromethyl)pyrrolidine-2-carboxylic acid [ka] Step 1: MeOH (30 mL) and H 2 1-Benzyl 2-methyl-trans-3-ethenylpyrrolidine-1,2-dicarboxylate (1.30 g, 4.49 mmol, see Intermediate 37 for its synthesis) in O (50 mL), NaIO 4 (2.88 g, 13.48 mmol) and potassium osmate dihydrate (170 mg, 0.45 mmol) and the resulting mixture was stirred at room temperature for 4 h. The reaction mixture was then diluted with H 2 The mixture was diluted with 20 mL of O and extracted with DCM (20 mL x 3). The combined organic phase was washed with water and brine, and diluted with anhydrous Na 2 SO 4The mixture was dried at 40° C., filtered and concentrated to give the crude product, which was purified by column chromatography on silica gel (EtOAc in PE=0-50%) to give the desired product 1-benzyl 2-methyl-trans-3-formylpyrrolidine-1,2-dicarboxylate (700 mg, yield: 53.5%) as a yellow solid. LC / MS (ESI) m / z: 292 (M+H). 。

[0336] Step 2: To DAST (5 mL) at 0° C. was added 1-benzyl 2-methyl(2S,3S)-3-formylpyrrolidine-1,2-dicarboxylate (500 mg, 1.72 mmol) as a solid, then the resulting mixture was stirred at 40° C. for 24 h. The reaction mixture was diluted with DCM (50 mL) and saturated NaHCO 3 The organic phase was collected and the aqueous layer was extracted with DCM (20 mL x 3). The combined organic layers were washed with water and brine and diluted with anhydrous Na 2 SO 4 After drying at 40° C., filtration and concentration, the residue was purified by column chromatography on silica gel (EtOAc in PE=0-30%) to give the desired product 1-benzyl 2-methyl-trans-3-(fluoromethyl)pyrrolidine-1,2-dicarboxylate (300 mg, yield: 55.7%) as a yellow oil. LCMS: ESI m / z 314 (M+H) + .

[0337] Step 3: MeOH (5 mL) and H 2 To a solution of 1-benzyl 2-methyl-trans-3-(difluoromethyl)pyrrolidine-1,2-dicarboxylate (300 mg, 0.96 mmol) in 2 mL of O was added NaOH (115 mg, 2.88 mmol). The resulting mixture was stirred at room temperature for 2 h, and the reaction mixture was concentrated, the pH was adjusted to 4-5 with 1N HCl solution, and extracted with EtOAc (15 mL×3). The combined organic layer was washed with water and brine, and then extracted with anhydrous Na 2 SO 4The mixture was dried at 40° C., filtered and concentrated to give the crude product 1-benzyl 2-methyl-trans-3-(difluoromethyl)pyrrolidine-1,2-dicarboxylate (250 mg, yield: 82.2%) as a brown solid, which can be used in the next step without further purification. LC / MS (ESI) m / z: 300 (M+1). + .

[0338] Following the experimental procedure of Intermediate 37, the following intermediates were prepared from the corresponding chemicals (the main different chemicals used are listed in the starting material column). [Table 9] Intermediate 53, N-(ethyl-1,1-d 2 Preparation of 5-fluoro-2-hydroxy-N-isopropylbenzamide [ka] Step 1: To a solution of N-isopropylacetamide (1 g, 9.89 mmol) in dry THF (10 mL), LiAlD 4 (620 mg, 14.83 mmol) was added at 0° C., and the resulting mixture was stirred at 70° C. for 24 h. The reaction mixture was diluted with saturated NH 4 Quench with aqueous Cl (10 mL) and Et 2 The combined organic layers were washed with brine and then with anhydrous Na 2 O (20 mL × 3). 2 SO 4 Dry at 40° C., filter, and concentrate to give the crude product N-(ethyl-1,1-d 2 ) Propan-2-amine (400 mg, yield: 45.4%) was obtained as a colorless liquid, which was used in the next step without further purification. LC / MS (ESI) m / z: 90 (M+H) + .

[0339] Step 2: To a solution of 5-fluoro-2-methoxybenzoic acid (700 mg, 4.11 mmol) and N-(ethyl-1,1-d2)propan-2-amine (400 mg, 4.49 mmol) in DMF (5 mL) was added HATU (2.03 g, 5.35 mmol) and DIPEA (1.06 g, 8.23 ​​mmol) dropwise at 0° C. The reaction mixture was gradually warmed to room temperature and stirred overnight. The reaction mixture was diluted with saturated NH 4 Quench with aqueous Cl (10 mL), extract with EtOAc (50 mL x 3), wash the combined organic phase with water and brine, and add anhydrous Na 2 SO 4 The mixture was dried at 40° C., filtered and concentrated. The residue was purified by column chromatography on silica gel (EtOAc in PE=0-20%) to give the desired product N-(ethyl-1,1-d2)-5-fluoro-N-isopropyl-2-methoxybenzamide (400 mg, yield: 40.3%) as a white solid. LC / MS (ESI) m / z: 242 (M+H). + .

[0340] Step 3: To a solution of N-[(1,1-d2)ethyl]-5-fluoro-2-methoxy-N-(propan-2-yl)benzamide (400 mg, 1.66 mmol) in DCM (10 mL), 2 BBr at -60℃ under atmospheric pressure 3 (2.2 mL, 1.0 M in DCM) was added dropwise and the resulting mixture was stirred at this temperature for 7 h. The reaction mixture was cooled to 0.5 mL of saturated NaHCO 3 The mixture was quenched with DCM (30 mL×3) and the combined organic layers were washed with water and brine, and diluted with anhydrous Na 2 SO 4 Dry at 40° C., filter, and concentrate to give the desired product N-(ethyl-1,1-d 2 )-5-Fluoro-2-hydroxy-N-isopropylbenzamide (270 mg, yield: 71.6%) was obtained as a pale yellow solid, which can be used in the next step without further purification. LC / MS (ESI) m / z: 228 (M+H). + .

[0341] Preparation of Intermediate 54, 2-(2-cyclopropylpyridin-3-yl)-4-fluorophenol [ka] Dioxane (4.0 mL) and H 2 To a solution of 3-bromo-2-cyclopropylpyridine (250 mg, 1.26 mmol) and (5-fluoro-2-hydroxyphenyl)boronic acid (220 mg, 1.41 mmol) in 2O (1.0 mL) was added Pd(dppf)Cl 2 (25mg) and K 2 CO 3 (400 mg, 2.89 mmol) was added and the resulting mixture was treated with N 2 The reaction mixture was stirred at 100° C. overnight under reduced pressure. 2 The mixture was diluted with 20 mL of 2H2O and extracted with EtOAc (20 mL x 3). The combined organic layers were washed with water and brine, and diluted with anhydrous Na 2 SO 4 After drying at 40° C., filtration and concentration, the residue was purified by column chromatography on silica gel (EtOAc in PE=0-10%) to give the desired product 2-(2-cyclopropylpyridin-3-yl)-4-fluorophenol (200 mg, yield: 69.1%) as a yellow solid. LC / MS (ESI) m / z: 230 (M+H) + .

[0342] Preparation of Intermediate 55, 2-(2-cyclopropyl-6-methoxypyridin-3-yl)-4-fluorophenol [ka] Step 1: Toluene (20 mL) and H 2 A solution of 2-chloro-6-methoxypyridin-3-amine (2.5 g, 15.8 mmol), cyclopropylboronic acid (1.76 g, 20.5 mmol) in 2O (4 mL) was stirred at room temperature for 1 h at 37° C. 3 PO 4 (13.4 g, 63.1 mmol), tricyclohexylphosphane (1.77 g, 6.31 mmol) and Pd(AcO) 2(40 mg, 0.16 mmol) was added. The resulting mixture was diluted with N 2 Degas three times with N 2 The mixture was stirred overnight at 100° C. under atmospheric pressure. The reaction mixture was cooled to room temperature and saturated NH 4 The mixture was quenched with aqueous Cl (20 mL) and extracted with EtOAc (20 mL×3). The combined organic layers were washed with water and brine, and then washed with anhydrous Na 2 SO 4 Drying at 40° C., filtration and concentration gave the crude product, which was purified by column chromatography on silica gel (EtOAc in PE=0-10%) to give the desired product 2-cyclopropyl-6-methoxypyridin-3-amine (830 mg, yield: 32.1%) as a yellow solid. LC / MS (ESI) m / z: 164 (M+H). + 。

[0343] Step 2: A suspension of tert-butyl nitrite (1.82 mL, 15.2 mmol), CuBr (2.90 mg, 20.2 mmol) in MeCN (10 mL) was stirred at 70° C. for 30 min, and then a solution of 2-cyclopropyl-6-methoxypyridin-3-amine (830 mg, 5.06 mmol) in MeCN (5 mL) was added dropwise to the stirred mixture. The resulting mixture was stirred at 70° C. for an additional 1 h. The reaction mixture was quenched with water (10 mL) and extracted with EtOAc (20 mL×3). The combined organic phase was washed with water and brine and diluted with anhydrous Na 2 SO 4 Drying at 40° C., filtration and concentration gave the crude product, which was purified by column chromatography on silica gel (PE=100%) to give the desired product 3-bromo-2-cyclopropyl-6-methoxypyridine (400 mg, yield: 34.7%) as a pale yellow oil. LC / MS (ESI) m / z: 229 (M+H). + 。

[0344] Step 3: Dioxane (16 mL) and H 2To a solution of 3-bromo-2-cyclopropyl-6-methoxypyridine (600 mg, 2.63 mmol) and (5-fluoro-2-hydroxyphenyl)boronic acid (615 mg, 3.95 mmol) in 20O (4 mL) was added Cs 2 CO 3 (2.57 g, 7.89 mmol) and Pd(dppf)Cl 2 (50 mg) was added and the resulting mixture was cooled to 100° C. 2 The reaction mixture was stirred overnight at 100° C. under atmospheric pressure. The reaction mixture was cooled to room temperature and 2 The mixture was diluted with 20 mL of 2H2O, extracted with EtOAc (20 mL x 3), and the combined organic layers were washed with water and brine, and then with anhydrous Na2SO4. 2 SO 4 The mixture was dried at 40° C., filtered and concentrated. The residue was purified by column chromatography on silica gel (EtOAc in PE=0-30%) to give the desired product 2-(2-cyclopropyl-6-methoxypyridin-3-yl)-4-fluorophenol (550 mg, yield: 80.6%) as a yellow solid. LC / MS (ESI) m / z: 260 [M+1]+.

[0345] Preparation of Intermediate 56, 6-Cyclopropyl-5-(5-fluoro-2-hydroxyphenyl)pyridin-2(1H)-one [ka] To a solution of 2-(2-cyclopropyl-6-methoxypyridin-3-yl)-4-fluorophenol (350 mg, 1.35 mmol, intermediate 55) in HOAc (5 mL) was added 40% HBr solution (3 mL) at room temperature and the resulting mixture was stirred at 80° C. overnight. The reaction mixture was cooled to room temperature and concentrated. The residue was suspended in EtOAc (50 mL) and washed with saturated NaHCO 3 (10 mL x 3) and brine, and the organic phase was extracted with anhydrous Na 2 SO 4The mixture was dried at 40° C., filtered and concentrated to give the crude product, which was purified by silica gel column (EtOAc in PE=0-70%) to give the desired product 6-cyclopropyl-5-(5-fluoro-2-hydroxyphenyl)-1,2-dihydropyridin-2-one (200 mg, yield: 60.4%) as a brown semi-solid. 1 H NMR(400 MHz,DMSO)δ 10.72(s,1H),9.38(s,1H),7.23(d,J=9.0Hz,1H),7.02-6.92(m,2H),6.89-6.85(m,1H),6.21(d, J=8.9Hz,1H),1.75-1.69(m,1H),0.89-0.80(m,2H),0.76-0.72(m,2H),LC / MS(ESI)m / z:246(M+H) + .

[0346] Working Example Example 2: Preparation of N-ethyl-5-fluoro-2-[(4-{7-[(2S,4R)-4-fluoropyrrolidine-2-carbonyl]-2,7-diazaspiro[3.5]nonan-2-yl}pyrimidin-5-yl)oxy]-N-(propan-2-yl)benzamide [ka] Step 1: To a solution of 2-[(4-{2,7-diazaspiro[3.5]nonan-2-yl}pyrimidin-5-yl)oxy]-N-ethyl-5-fluoro-N-(propan-2-yl)benzamide intermediate 1 (50 mg, 0.12 mmol) and (2S,4R)-1-[(tert-butoxy)carbonyl]-4-fluoropyrrolidine-2-carboxylic acid (27 mg, 0.12 mmol) in DMF (2 mL) was added DIPEA (0.1 mL) and HATU (58 mg, 0.15 mmol) at room temperature. The resulting mixture was stirred at room temperature for 3 h and saturated NH 4 The mixture was quenched with aqueous Cl (10 mL), extracted with EtOAc (15 mL x 3), and the combined organic phase was washed with water and brine, and then diluted with anhydrous Na 2 SO 4After drying at 40° C., filtration, concentration and purification of the residue by column chromatography on silica gel (MeOH=0-5% in DCM) afforded the desired product tert-butyl (2S,4R)-2-[2-(5-{2-[ethyl(propan-2-yl)carbamoyl]-4-fluorophenoxy}pyrimidin-4-yl)-2,7-diazaspiro[3.5]nonane-7-carbonyl]-4-fluoropyrrolidine-1-carboxylate (60 mg, yield: 79%) as a pale yellow solid. LC / MS(ESI)m / z: 643(M+H) + .

[0347] Step 2: To a solution of tert-butyl (2S,4R)-2-[2-(5-{2-[ethyl(propan-2-yl)carbamoyl]-4-fluorophenoxy}pyrimidin-4-yl)-2,7-diazaspiro[3.5]nonane-7-carbonyl]-4-fluoropyrrolidine-1-carboxylate (60 mg, 0.1 mmol) in DCM (3 mL) was added TFA (1.0 mL). The resulting mixture was stirred at room temperature for 1 h, concentrated, and the residue was purified by preparative HPLC to obtain the desired product N-ethyl-5-fluoro-2-[(4-{7-[(2S,4R)-4-fluoropyrrolidine-2-carbonyl]-2,7-diazaspiro[3.5]nonane-2-yl}pyrimidin-5-yl)oxy]-N-(propan-2-yl)benzamide (35 mg, yield: 69%) as a white solid. 1 H NMR (400 MHz, CDCl 3 )δ 8.40(d,J=3.1Hz,1H),7.82-7.80(m,1H),7.04-7.00(m,2H),6.78-6.72(m,1H),5.35-5.22(m,1H),4.29-4.25(m,1H),4.03-3.82(m,5H),3 .66-3.63(m,1H),3.52-3.15(m,7H),2.40-2.31(m,1H),1.87-1.76(m,5H),1.29-1.23(m,4H),1.16-1.07(m,5H).LC / MS(ESI)m / z:543(M+H) + .

[0348] Following the experimental procedures in Example 2, the following compounds were prepared from appropriate intermediates or commercially available chemicals. [Table 10-1] [Table 10-2] [Table 10-3] [Table 10-4] [Table 10-5] [Table 10-6] [Table 10-7] [Table 10-8] [Table 10-9] [Table 10-10] [Table 10-11] Example 27: Preparation of 2-((4-(7-((2S,4R)-4-cyanopyrrolidine-2-carbonyl)-2,7-diazaspiro[3.5]nonan-2-yl)pyrimidin-5-yl)oxy)-N-ethyl-5-fluoro-N-isopropylbenzamide [ka] Step 1: To a solution of 2-(4-(2,7-diazaspiro[3.5]nonan-2-yl)pyrimidin-5-yloxy)-N-ethyl-5-fluoro-N-isopropylbenzamide (Intermediate 1, 280 mg, 0.53 mmol) and (2S,4S)-1-(tert-butoxycarbonyl)-4-hydroxypyrrolidine-2-carboxylic acid (277 mg, 0.60 mmol) in DMF (5 mL) was added DIPEA (0.8 mL, 3.5 mmol) and HATU (266 mg, 0.70 mmol) at 0° C. The reaction mixture was then warmed to room temperature and stirred overnight. The reaction mixture was diluted with saturated NH 4 The mixture was quenched with aqueous Cl, extracted with EtOAc (20 mL x 3), and the combined organic phase was washed with water and brine, and diluted with anhydrous Na 2 SO 4 Drying at 40° C., filtration and concentration in vacuo gave the crude product, which was purified by column chromatography on silica gel (EtOAc in PE=0-30%) to give the desired product tert-butyl (2S,4S)-2-(2-(5-(2-(ethyl(isopropyl)carbamoyl)-4-fluorophenoxy)pyrimidin-4-yl)-2,7-diazaspiro[3.5]nonane-7-carbonyl)-4-hydroxypyrrolidine-1-carboxylate (180 mg, yield: 80%) as a white solid. LCMS: m / z 641 (M+H) +

[0349] Step 2: To a solution of tert-butyl (2S,4S)-2-(2-(5-(2-(ethyl(isopropyl)carbamoyl)-4-fluorophenoxy)pyrimidin-4-yl)-2,7-diazaspiro[3.5]nonane-7-carbonyl)-4-hydroxypyrrolidine-1-carboxylate (180 mg, 0.28 mmol) and DIPEA (72 mg, 0.56 mmol) in DCM (10 mL) was added MsCl (0.10 mL, 0.42 mmol) at 0° C. The resulting mixture was stirred at room temperature for 3 h. The reaction mixture was diluted with saturated NH 4 The mixture was quenched with aqueous Cl (10 mL) and extracted with EtOAc (20 mL×3). The combined organic phase was washed with brine and anhydrous Na 2 SO 4It was dried at 40° C., filtered, concentrated and the residue was purified by column chromatography on silica gel (EtOAc in PE=0-20%) to give the desired product tert-butyl (2S,4S)-2-(2-(5-(2-(ethyl(isopropyl)carbamoyl)-4-fluorophenoxy)pyrimidin-4-yl)-2,7-diazaspiro[3.5]nonane-7-carbonyl)-4-((methylsulfonyl)oxy)pyrrolidine-1-carboxylate (150 mg, yield: 80%) as a white solid. LCMS: m / z 719 (M+H) +

[0350] Step 3: To a solution of tert-butyl (2S,4S)-2-(2-(5-(2-(ethyl(isopropyl)carbamoyl)-4-fluorophenoxy)pyrimidin-4-yl)-2,7-diazaspiro[3.5]nonane-7-carbonyl)-4-((methylsulfonyl)oxy)pyrrolidine-1-carboxylate (150 mg, 0.21 mmol) in DMF (5 mL) was added NaCN (20 mg, 0.40 mmol) at 0° C. The mixture was stirred at 100° C. for 10 h. The resulting mixture was diluted with 10 mL of water and extracted with EtOAc (15 mL×3). The combined organic phase was washed with brine and diluted with anhydrous Na 2 SO 4 It was dried at 40° C., filtered, concentrated and the residue was purified by column chromatography on silica gel (EtOAc in PE=0-20%) to give the desired product tert-butyl (2S,4R)-4-cyano-2-(2-(5-(2-(ethyl(isopropyl)carbamoyl)-4-fluorophenoxy)pyrimidin-4-yl)-2,7-diazaspiro[3.5]nonane-7-carbonyl)pyrrolidine-1-carboxylate (60 mg, yield: 45%) as a yellow solid. LCMS: m / z 650 (M+H) +

[0351] Step 4: To a solution of tert-butyl (2S,4R)-4-cyano-2-(2-(5-(2-(ethyl(isopropyl)carbamoyl)-4-fluorophenoxy)pyrimidin-4-yl)-2,7-diazaspiro[3.5]nonane-7-carbonyl)pyrrolidine-1-carboxylate (60 mg, 0.09 mmol) in DCM (3 mL) was added TFA (1.0 mL) at 0° C. The reaction mixture was stirred at room temperature for 1 h and concentrated under reduced pressure to give the crude product, which was purified by preparative HPLC to give the desired product 2-((4-(7-((2S,4R)-4-cyanopyrrolidine-2-carbonyl)-2,7-diazaspiro[3.5]nonane-2-yl)pyrimidin-5-yl)oxy)-N-ethyl-5-fluoro-N-isopropylbenzamide (20 mg, yield: 30%) as a white solid. 1 H NMR(400MHz,MeOD)δ 8.26-8.25(m,1H),7.78-7.74(m,1H),7.21-7.15(m,2H),7.00-6.96(m,1H),4.20-4.16( m,1H),4.06-3.87(m,5H),3.58-3.46(m,5H),3.39-3.36(m,1H),3.27-3.26(m,1H),3.15- 2.91 (m, 2H), 2.40-2.17 (m, 1H), 1.84-1.78 (m, 4H), 1.32-1.09 (m, 10H). LCMS:m / z 550(M+H) + .

[0352] Example 39: Preparation of N-ethyl-5-fluoro-2-[(5-{7-[(2S,4R)-4-fluoropyrrolidine-2-carbonyl]-2,7-diazaspiro[3.5]nonan-2-yl}-1,2,4-triazin-6-yl)oxy]-N-(propan-2-yl)benzamide [ka] Step 1: To a stirred solution of (2S,4R)-1-[(tert-butoxy)carbonyl]-4-fluoropyrrolidine-2-carboxylic acid (381 mg, 1.63 mmol) and HATU (517 mg, 1.36 mmol) in DMF (15 mL) was added DIPEA (0.68 mL, 4.1 mmol). After stirring the reaction mixture at room temperature for 10 min, 2-[(5-{2,7-diazaspiro[3.5]nonan-2-yl}-1,2,4-triazin-6-yl)oxy]-N-ethyl-5-fluoro-N-(propan-2-yl)benzamide (583 mg, 1.36 mmol) was added and the resulting mixture was stirred at room temperature for an additional 1 h. The reaction mixture was stirred at room temperature for 1 h. 2 The mixture was quenched with O (50 mL), extracted with EtOAc (50 mL x 3), and the combined organic layers were washed with anhydrous Na 2 SO 4 The mixture was dried at 40° C., filtered, concentrated and the residue was purified by chromatography column on silica gel (MeOH in DCM=0-5%) to give the desired product tert-butyl (2S,4R)-2-[2-(6-{2-[ethyl(propan-2-yl)carbamoyl]-4-fluorophenoxy}-1,2,4-triazin-5-yl)-2,7-diazaspiro[3.5]nonane-7-carbonyl]-4-fluoropyrrolidine-1-carboxylate (650 mg, yield: 74.2%) as a white solid. LCMS: ESI m / z 644 (M+H) + .

[0353] Step 2: To a solution of tert-butyl (2S,4R)-2-[2-(6-{2-[ethyl(propan-2-yl)carbamoyl]-4-fluorophenoxy}-1,2,4-triazin-5-yl)-2,7-diazaspiro[3.5]nonane-7-carbonyl]-4-fluoropyrrolidine-1-carboxylate (500 mg, 0.78 mmol) in DCM (10 mL) was added TFA (5 mL) at room temperature. The reaction mixture was stirred at room temperature for 1 h. The resulting mixture was concentrated and the residue was purified by preparative HPLC (CH 3Purification with 0.1% formic acid in CN) afforded the desired product N-ethyl-5-fluoro-2-[(5-{7-[(2S,4R)-4-fluoropyrrolidine-2-carbonyl]-2,7-diazaspiro[3.5]nonan-2-yl}-1,2,4-triazin-6-yl)oxy]-N-(propan-2-yl)benzamide (315 mg, yield: 74.6%) as a white solid. 1 H NMR(400 MHz,MeOD)δ 8.59(d,J=6.6Hz,1H),7.46-7.43(m,1H),7.35-7.22(m,2H),5.56-5. 43(m,1H),4.98-4.93(m,1H),4.54(s,2H),4.13(s,2H),3.87-3.80(m, 1H),3.71-3.51(m,7H),3.17(m,1H),2.95-2.85(m,1H),2.29-2.14(m,1H),1.97-1.90(m,4H),1.25-0.87(m,9H),LC / MS(ESI)m / z:544(M+H) + .

[0354] Following the experimental procedures of Example 39, the following compounds were prepared from appropriate intermediates or commercially available chemicals. [Table 11-1] [Table 11-2] [Table 11-3] [Table 11-4] [Table 11-5] [Table 11-6] [Table 11-7] [Table 11-8] [Table 11-9] [Table 11-10] [Table 11-11] [Table 11-12] Example 98 Preparation of 2-((5-(7-5,5-difluorooctahydrocyclopenta[c]pyrrole-1-carbonyl)-2,7-diazaspiro[3.5]nonan-2-yl)-1,2,4-triazin-6-yl)oxy)-N-ethyl-5-fluoro-N-isopropylbenzamide [ka] Step 1: To a solution of 2-((5-(2,7-diazaspiro[3.5]nonan-2-yl)-1,2,4-triazin-6-yl)oxy)-N-ethyl-5-fluoro-N-isopropylbenzamide (100 mg, 0.23 mmol, Intermediate 34) and 2-(tert-butoxycarbonyl)-5,5-difluorooctahydrocyclopenta[c]pyrrole-1-carboxylic acid (67.9 mg, 0.23 mmol, Intermediate 50) in DMF (3 mL) was added DIPEA (50 mg, 0.39 mmol) and HATU (133 mg, 0.35 mmol) at room temperature. The resulting mixture was stirred at room temperature for 3 h and saturated NH 4 The mixture was quenched with aqueous Cl (10 mL), extracted with EtOAc (15 mL x 3), and the combined organic phase was washed with water and brine, and then diluted with anhydrous Na 2 SO 4After drying at 40° C., filtration, concentration and the residue was purified by column chromatography on silica gel (MeOH=0-5% in DCM) to give the desired product tert-butyl-1-(2-(6-(2-(ethyl(isopropyl)carbamoyl)-4-fluorophenoxy)-1,2,4-triazin-5-yl)-2,7-diazaspiro[3.5]nonane-7-carbonyl)-5,5-difluorohexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate (40 mg, yield: 24.4%) as a pale yellow solid. LC / MS(ESI) m / z: 702(M+H) + .

[0355] Step 2: To a solution of tert-butyl-1-(2-(6-(2-(ethyl(isopropyl)carbamoyl)-4-fluorophenoxy)-1,2,4-triazin-5-yl)-2,7-diazaspiro[3.5]nonane-7-carbonyl)-5,5-difluorohexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate (150 mg, 0.21 mmol) in DCM (10 mL) was added TFA (4 mL). The resulting mixture was stirred at room temperature for 1 h and concentrated. The residue was diluted with EtOAc (20 mL) and washed with saturated NaHCO 3 The pH was adjusted to 9 with aqueous NaCl. The organic phase was collected and diluted with anhydrous Na 2 SO 4 The resulting crude product was purified by preparative HPLC to give the desired product 2-((5-(7-5,5-difluorooctahydrocyclopenta[c]pyrrole-1-carbonyl)-2,7-diazaspiro[3.5]nonan-2-yl)-1,2,4-triazin-6-yl)oxy)-N-ethyl-5-fluoro-N-isopropylbenzamide (90 mg, yield: 69.9%) as a white solid, which was subjected to SFC chiral separation to give four isomers. (Two conditions were used. The first condition gave pure isomer 3 and isomer 4, respectively, and a mixture of isomers 1 and 2. The latter was then subjected to the second condition to give pure isomer 1 and isomer 2, respectively.) Example 98a: Isomer 1 (9.8 mg, yield: 10.8%) was obtained as a white solid (SFC conditions: SHIMADZA PREP SPLUTION SFC, column: ChiralPak IH, 250×21.1um, I.D., 5um; mobile phase: CO 2 versus A and EtOH + 0.1% NH 3 H 2 O versus B, gradient: B 17%, flow rate: 40 mL / min, back pressure: 100 bar, column temperature: 35 °C, wavelength: 254 nm, cycle time: 18 min, elution time: 3.5 h, retention time: 8.39 min). 1H NMR (400 MHz, MeOD) δ 8.40 (s, 1H), 7.43 - 7.38 (m, 1H), 7.31 - 7.20 (m, 2H), 4.48 - 4.42 (m, 2H), 4.03 - 3.97 (m, 3H), 3.84 - 3.75 (m, 1H), 3.64 - 3.48 (m, 5H), 3.13 - 3.06 (m, 2H), 2.96 - 2.87 (m, 3H), 2.34 - 2.26 (m, 1H), 2.06 - 1.81 (m, 7H), 1.23 - 1.14 (m, 6H), 1.06 (d, J = 7.1 Hz, 1H), 0.82 - 0.79 (m, 2H), LC / MS (ESI) m / z: 602 (M + H) + .

[0356] Example 98b: Isomer 2 (16.3 mg, yield: 18.1%) was obtained as a white solid (SFC conditions: SHIMADZA PREP SPLUTION SFC, column: ChiralPak IH, 250×21.1um, I.D., 5um; mobile phase: CO 2 versus A and EtOH + 0.1% NH 3 H 2(B vs. O, gradient: B 17%, flow rate: 40 mL / min, back pressure: 100 bar, column temperature: 35 °C, wavelength: 254 nm, cycle time: 18 min, elution time: 3.5 h, retention time: 11.09 min). 1H NMR (400 MHz, MeOD) δ 8.40 (s, 1H), 7.43-7.38 (m, 1H), 7.31-7.20 (m, 2H), 4.48-4.38 (m, 2H), 4.03-4.00 (m, 2H), 3.91 (d, J = 3.9 Hz, 1H), 3.85-3.80 (m, 1H), 3.69-3.45 (m, 5H), 3.40-3.35 (m, 1H), 3.27-3.20 (m, 1H). H),2.80-2.66(m,3H),2.45-2.37(m,1H),2.33-2.24(m,1H),2.20-2.07(m,1H),1.97-1.82(m ,5H),1.22-1.14(m,6H),1.06(d,J=7.1Hz,1H),0.82-0.78(m,2H),LC / MS(ESI)m / z:602(M+H) + .

[0357] Example 98c: Isomer 3, (8.8 mg, yield: 9.7%) was obtained as a white solid (SFC conditions: SHIMADZA PREP SPLUTION SFC, column: ChiralPak CIG, 250×21.1 um, ID, 5 um; mobile phase: CO 2 A and IPA + 0.1% NH 3 H 2For O, B, gradient: B 50%, flow rate: 40 mL / min, back pressure: 100 bar, column temperature: 35 °C, wavelength: 254 nm, cycle time: 45 min, elution time: 5 h, retention time: 12.61 min). 1H NMR (400 MHz, MeOD) δ 8.40 (s, 1H), 7.43 - 7.38 (m, 1H), 7.31 - 7.21 (m, 2H), 4.49 - 4.41 (m, 2H), 4.13 (d, J = 7.0 Hz, 1H), 4.05 - 3.96 (m, 2H), 3.85 - 3.79 (m, 1H), 3.72 - 3.48 (m, 5H), 3.17 - 3.13 (m, 2H), 3.02 - 2.90 (m, 3H), 2.36 - 2.27 (m, 1H), 2.03 - 1.84 (m, 7H), 1.23 - 1.12 (m, 6H), 1.07 (t, J = 7.1 Hz, 1H), 0.81 (d, J = 5.1 Hz, 2H). LC / MS (ESI) m / z: 602 (M + H) + .

[0358] Example 98d: Isomer 4, (20.1 mg, yield: 22.3%) was obtained as a white solid (SFC conditions: SHIMADZA PREP SPLUTION SFC, column: ChiralPak CIG, 250 × 21.1 um, I.D., 5 um; mobile phase: CO 2 to A and IPA + 0.1% NH 3 H 2 For O, B, gradient: B 50%, flow rate: 40 mL / min, back pressure: 100 bar, column temperature: 35 °C, wavelength: 254 nm, cycle time: 45 min, elution time: 5 h, retention time: 28.06 min). 1H NMR (400 MHz, MeOD) δ 8.40 (s, 1H), 7.43 - 7.38 (m, 1H), 7.31 - 7.18 (m, 2H), 4.47 - 4.30 (m, 2H), 4.02 - 3.98 (m, 3H), 3.84 - 3.80 (m, 1H), 3.62 - 3.42 (m, 6H), 3.25 - 3.20 (m, 1H), 2.85 - 2.74 (m, 3H), 2.48 - 2.40 (m, 1H), 2.36 - 2.25 (m, 1H), 2.17 - 2.16 (m, 1H), 2.03 - 1.86 (m, 5H), 1.22 - 1.11 (m, 6H), 1.06 (d, J = 7.1 Hz, 1H), 0.81 (d, J = 5.2 Hz, 2H), HNMR, LC / MS (ESI) m / z: 602 (M + H)+ .

[0359] Example 99 Preparation of 2-((5-(7-(trans-3-(difluoromethyl)pyrrolidine-2-carbonyl)-2,7-diazaspiro[3.5]nonan-2-yl)-1,2,4-triazin-6-yl)oxy)-N-ethyl-5-fluoro-N-isopropylbenzamide [ka] Step 1: To a solution of trans-1-[(benzyloxy)carbonyl]-3-(difluoromethyl)pyrrolidine-2-carboxylic acid (250 mg, 0.83 mmol, intermediate 51) and 2-[(5-{2,7-diazaspiro[3.5]nonan-2-yl}-1,2,4-triazin-6-yl)oxy]-N-ethyl-5-fluoro-N-(propan-2-yl)benzamide (357 mg, 0.83 mmol, intermediate 34) in DMF (5 mL) was added HATU (476 mg, 1.25 mmol) and DIPEA (323 mg, 2.51 mmol) at room temperature. The resulting mixture was stirred at room temperature for 3 h and saturated NH 4 Quench with aqueous Cl (10 mL), extract with EtOAc (20 mL x 3), wash the combined organic phase with water and brine, and add anhydrous Na 2 SO 4 The mixture was dried at 70° C., filtered and concentrated. The residue was purified by column chromatography on silica gel (MeOH=0-5% in DCM) to give the desired product benzyl-trans-3-(difluoromethyl)-2-[2-(6-{2-[ethyl(propan-2-yl)carbamoyl]-4-fluorophenoxy}-1,2,4-triazin-5-yl)-2,7-diazaspiro[3.5]nonane-7-carbonyl]pyrrolidine-1-carboxylate (200 mg, yield: 33.7%) as an off-white solid. LC / MS(ESI)m / z: 710(M+H) + .

[0360] Step 2. To a solution of benzyl-trans-3-(difluoromethyl)-2-[2-(6-{2-[ethyl(propan-2-yl)carbamoyl]-4-fluorophenoxy}-1,2,4-triazin-5-yl)-2,7-diazaspiro[3.5]nonane-7-carbonyl]pyrrolidine-1-carboxylate (200 mg, 0.28 mmol) in MeOH (10 mL) was added Pd / C (30 mg, 10% palladium on activated carbon) at room temperature. The reaction mixture was stirred at room temperature for 5 h with H 2 The mixture was stirred under atmosphere (balloon). The reaction mixture was filtered and concentrated. The resulting crude product was purified by preparative HPLC to give the desired product 2-[(5-{7-[trans-3-(difluoromethyl)pyrrolidine-2-carbonyl]-2,7-diazaspiro[3.5]nonan-2-yl}-1,2,4-triazin-6-yl)oxy]-N-ethyl-5-fluoro-N-(propan-2-yl)benzamide (30 mg, yield: 36.9%) as a white solid. This was separated by SFC to give two isomers. (SFC conditions: Waters Thar 80 preparative SFC, column: ChiralCel, 250×21.1 um, ID, 5 um; mobile phase: CO 2 A and MeOH + 0.1%NH 3 H 2 B vs. O, gradient: B 40%, flow rate: 40 mL / min, back pressure: 100 bar, column temperature: 35° C., wavelength: 254 nm, cycle time: 5 min, elution time: 2 h, retention time: 5.5 min for 99a and 7.8 min for 99b). Example 99a: 2-((5-(7-((2S,3S)-3-(difluoromethyl)pyrrolidine-2-carbonyl)-2,7-diazaspiro[3.5]nonan-2-yl)-1,2,4-triazin-6-yl)oxy)-N-ethyl-5-fluoro-N-isopropylbenzamide 35.3 mg, yield: 21.4%) was obtained as a white solid. 1H NMR(400MHz,MeOD)δ 8.40(s,1H),7.43-7.38(m,1H),7.31-7.19(m,2H),6.10-5.81(m,1H),4. 48-4.41(m,2H),4.14(d,J=5.4Hz,1H),4.04-3.97(m,2H),3.84-3.80(m, 1H),3.71-3.47(m,5H),3.25-3.11(m,2H),2.94-2.78(m,2H),2.06-1.81 (m,6H),1.22-1.12(m,6H),1.07(t,J=7.1Hz,1H),0.81(d,J=4.9Hz,2H). LC / MS(ESI)m / z:576(M+H) + .

[0361] Example 99b: 2-((5-(7-((2R,3R)-3-(difluoromethyl)pyrrolidine-2-carbonyl)-2,7-diazaspiro[3.5]nonan-2-yl)-1,2,4-triazin-6-yl)oxy)-N-ethyl-5-fluoro-N-isopropylbenzamide (36.8 mg, yield: 22.9%) was obtained as a white solid. 1 H NMR(400 MHz,MeOD)δ 8.40(s,1H),7.43-7.38(m,1H),7.31-7.19(m,2H),6.11-5.82(m,1H),4 .48-4.39(m,2H),4.17(d,J=5.2Hz,1H),4.02-3.96(m,2H),3.85-3.79( m,1H),3.72-3.48(m,5H),3.24-3.11(m,2H),2.97-2.81(m,2H),2.05-1 .84(m,6H),1.22-1.13(m,6H),1.07(t,J=7.1Hz,1H),0.87-0.74(m,2H). LC / MS(ESI)m / z:576(M+H) + .

[0362] Following the experimental procedures of Example 99, the following compounds were prepared from the appropriate intermediates or commercially available chemicals. [Table 12] Pharmacological Examples SNDX-5613 used in the following assays was obtained from MCE catalog number HY-136175 or prepared according to the procedures reported in WO2017214367.

[0363] 1. Menin-MLL1 inhibition assay 1x assay buffer (Tris 7.5 50mM, NaCl 50mM, DTT 1mM, Tween-20 0.01%) was prepared and test compound solutions (10mM in DMSO, Sigma, Cat. No. 34869) were transferred to assay plates (384-well plates, Perkin Elmer, Cat. No. 6007279, Echo). The final fraction of DMSO is 1%. 20nM of menin protein (Menin(2-610) isform2, ChemPartner, Cat. No. 2020111101) was added to 1x assay buffer to prepare 2x enzyme solution. Then, 10 nM of MLL-peptide (Ac-SRWRFPARPGTGRR-Ahx-Ahx-K(FAM)-NH2, GL Biochem (Shanghai), Cat. No. 833831 / 202009220104) was added to the 1x assay buffer to prepare 2x substrate solution. 10 μL of 2x enzyme solution was transferred to the assay plate or 10 μL of 1x assay buffer was transferred to the low control. The reaction was started by adding 10 μL of 2x substrate solution to each well. mP data was collected on Envision (Ex480 / Em535(s), Em535(p)).

[0364] Compound potency was determined by first calculating the % inhibition at each compound concentration according to Equation 1. % Inhibition = (Max-Signal) / (Max-Min) * 100 (formula 1) IC of compounds of the present disclosure 00The values ​​were determined using Equation 2 and are shown in Table 1 below. Y=Bottom+(Top-Bottom) / (1+(IC50 / X) * HillSlope), where Y is the % inhibition and X is the compound concentration (Equation 2) Test results for compounds of the present disclosure are shown in Table 1.

[0365] 2. Cell proliferation assay RPMI1640 (Invitrogen, Catalog No. 11875-093; Lot No. 2327411) IMDM (Invitrogen, Catalog No. 12440-053; Lot No. 2192731) FBS (Gibco, Catalog Number 10099141C, Lot Number 2233792CP) Penicillin-streptomycin solution (Invitrogen, Catalog No. 15140-122, Lot No. 2321118) Glutamax (Invitrogen, Catalog No. 35050-061; Lot No. 2248972) 0.25% Trypsin-EDTA (Invitrogen, Catalog No. 25200-072; Lot No. 2276876) Staurosporine (Selleck, Catalog Number S1421, Lot Number #S142106) DMSO (Sigma, Catalog No. 276855-1L, Lot No. 276855-1L) [Table 13] The antiproliferative activity of the test compounds was evaluated in human leukemia cell lines. The cell lines MV4-11, MOLM13 and OCI-AML3, which express the MLL fusion proteins MLL-AF4 and MLL-AF9, respectively, and harbor NPM1c gene mutations, were tested. HL-60 was used as a control cell line containing two MLL wild-type alleles to exclude compounds that exhibited general cytotoxic effects. MV4-11 cells were cultured in IMDM supplemented with 10% FBS, MOLM13 and OCI-AML3 cells were cultured in RPMI1640 supplemented with 20% FBS, and HL-60 cells were cultured in IMDM supplemented with 20% FBS. The corresponding cells (MV4-11, MOLM13, OCI-AML3 or HL-60 cell lines) were seeded in 96-well plates (white wall with clear bottom, tissue culture treated, Corning, Cat. No. CLS3903; Lot No. 30419025) in 100 uL of medium per well. The plates were incubated at 4°C for 24 h at 4°C for 1 h at 4°C. 2 Compound solutions (starting at 2 mM, 4-fold serial dilutions) were prepared and added to wells containing 100 μL of culture medium with HPD300 according to the plate map and centrifuged at 1000 RPM for 1 minute (total dilutions of 200). MV4-11, MOLM13, OCI-AML3 and HL-60 cells were incubated in a 5% CO 2 The plates were incubated with compounds for 4, 12, 5, and 4 days at 37°C under 50°C for 12 h, 12 h, 5 h, and 4 h, respectively. 100 μL of CellTiter-Glo Reagent (Promega, Cat# G7573, Lot# 0000416710) was added to the assay plate by the Multidrop Combi instrument and the contents were mixed for 10 min on an orbital shaker to induce cell lysis. After 10 min incubation at room temperature, a clear bottom with white back seal was attached and luminescence was read on the Envision.

[0366] Test results for compounds of the present disclosure are shown in Table 1.

[0367] [Table 14-1] [Table 14-2] [Table 14-3] 3. Liver microsome stability test Tests were performed in liver microsomes (Corning, 0.5 mg / mL). Stock solutions were prepared at 10 mM in DMSO for the test compounds. An aliquot of the stock solution was diluted to 0.5 mM with acetonitrile and then further diluted to 1.5 μM upon addition of liver microsomes / buffer. An aliquot of 30 μL of the 1.5 μM solution was mixed with 15 μL of 6 mM NADPH, giving a final concentration of 2 mM NADPH, which was pre-warmed to 37° C. The final concentration of test compounds and ketanserin was 1 μM. The plate was kept in a 37° C. water bath for the duration of the experiment. At each time point (0, 5, 15, 30, 45 min), 135 μL of acetonitrile was added to the corresponding well. After quenching the final time point with acetonitrile, the assay plate was shaken (600 RPM / min) on a vibrator (IKA, MTS 2 / 4) for 10 min, then centrifuged (Thermo Multifuge × 3R) at 5,594 g for 15 min. An aliquot of the supernatant was taken, diluted 1:1 with distilled water, and analyzed by LC-MS / MS. The peak area response ratios (PARR) of the compounds to the internal standard at 5, 15, 30, and 45 min were compared to the PARR at time 0 to determine the percent of test compound remaining at each time point. Half-lives were calculated using Excel software and fitted to a single-phase exponential decay equation.

[0368] [Table 15] 4. hERG inhibition test The inhibitory effect of test compounds on hERG was carried out in CHO-hERG cells (cell density: 21.5×10-6 / mL). 10 μL of compound stock solution was added to 20 μL of DMSO solution, then serially diluted to six concentrations by 3-fold. Six different concentrations of compound solution (4 μL) were added to extracellular solution (996 μL) and diluted to the final concentration to be tested (total 250-fold dilution). The highest test concentration was 40.00 μM, followed by 40.0, 13.3, 4.4, 1.48, 0.49 and 0.16 μM. The content of DMSO in the final test concentration did not exceed 0.2%, and at this concentration DMSO had no effect on the hERG potassium channel. The high impedance sealing of single cells and the formation of whole-cell models were all completed automatically by the Qpatch instrument.

[0369] [Table 16]

Claims

1. Formula I: 【Chemistry 1】 or a stereoisomer, racemate, tautomer, hydrate or solvate thereof, or a pharma- ceutically acceptable salt thereof. [In the formula, X is halo or CN; Y is N or CH; Z is CH ２ , O, S, and NH; R １ teeth, 1)-(C=O)-NRaRb (in the formula, Ra and Rb are deuterium, halo, OH, CN and C １～６ C optionally substituted with 1, 2 or 3 substituents selected from the group consisting of alkoxyl １～６ each independently selected from the group consisting of alkyl, a 3- to 6-membered cycloalkyl ring, and a 5- to 9-membered heterocyclyl ring; Or, Ra and Rb together with the nitrogen atom to which they are attached are C １～６ forming a 5-9 membered heterocyclyl ring optionally substituted with 1, 2 or 3 substituents selected from the group consisting of alkyl, halo, OH and CN; 2) Haro, CN, C １～６ C alkyl optionally substituted with 1, 2 or 3 substituents selected from the group consisting of halo, CN and OH; １～６ Alkyl, 3- to 5-membered cycloalkyl ring, oxo and C １～６ a 5-10 membered heteroaryl ring optionally substituted with 1, 2 or 3 substituents selected from the group consisting of alkoxyl or C ６～１０ Aryl ring; is selected from the group consisting of R ２ and R ３ are each independently H or D; Each R ４ is halo, CN, OH, oxo, C １～６ Alkylsulfonyl-, C １～６ Alkylsulfonylamino-, C １～６ Alkylcarbonylamino-, C ６～１０ Aryl ring, C １～６ Alkyl, C ２～６ Alkenyl, C ２～６ Alkynyl, C １～６ independently selected from the group consisting of alkoxyl, a 3- to 9-membered cycloalkyl ring, a 5- to 10-membered heteroaryl ring, and a 4- to 9-membered heterocyclyl ring, wherein said alkyl, alkenyl, alkynyl, alkoxyl, cycloalkyl ring, heteroaryl ring, or heterocyclyl ring is optionally substituted with 1, 2, or 3 substituents selected from the group consisting of halo, CN, and OH; Two adjacent R ４ together with the carbon atom to which they are attached, １～６ Alkyl, -C １～６ Alkyl-OH, C １～６ Alkoxyl-C １～６ optionally forming a 3-9 membered cycloalkyl ring, optionally substituted with 1, 2 or 3 substituents selected from the group consisting of alkyl-, halo, CN and OH; Or, two R bonded to the same carbon atom ４ together with the carbon atom, C １～６ Alkyl, -C １～６ Alkyl-OH, C １～６ Alkoxyl-C １～６ optionally forming a 3- to 6-membered cycloalkyl ring or a 4- to 6-membered heterocyclyl ring, optionally substituted with 1, 2 or 3 substituents selected from the group consisting of alkyl-, halo, CN and OH; Or, two adjacent R ４ together with the carbon atom to which they are attached, a 5- to 10-membered heteroaryl ring, C ６～１０ Optionally forming an aryl ring or a 5- to 9-membered heterocyclyl ring, said heteroaryl ring or aryl ring being １～６ Alkyl, C １～６ Haloalkyl, -C １～６ Alkyl-OH, C １～６ Alkoxyl-C １～６ is optionally substituted by one, two or three substituents selected from the group consisting of alkyl-, halo, CN and OH, said alkyl being optionally substituted by one 3-6 membered cycloalkyl ring or phenyl, said heterocyclyl ring being C １～６ Alkyl, C １～６ Haloalkyl, -C １～６ Alkyl-OH, C １～６ Alkoxyl-C １～６ optionally substituted with 1, 2 or 3 substituents selected from the group consisting of alkyl-, oxo, halo, CN and OH; R ５ is H, halo, methyl optionally substituted with 1, 2 or 3 deuterium or halo, methoxyl optionally substituted with 1, 2 or 3 deuterium or halo, NH ２ , C.H. ３ NH, or (CH ３ ) ２ N, a, b, c and d are each independently 1 or 2; n is 0, 1 or 2; m is 0, 1, 2, 3 or 4; However, R ４ When present, the moiety is attached to the remainder of the compound's structure. 【Chemistry 2】 except for the N atom adjacent to the point of attachment of said moiety 【Chemistry 3】 substituted at any chemically permissible position above.

2. X is F, Cl or CN; Y is N or CH; Z is CH ２ , O, S, and NH; R １ but, 1)-(C=O)-NRaRb [wherein, Ra and Rb are C １～６ each independently selected from the group consisting of alkyl and 3- to 5-membered cycloalkyl rings; １～６ Alkyl includes deuterium, halo, OH and C １～６ optionally substituted with 1, 2 or 3 substituents selected from the group consisting of alkoxyl; Or, Ra and Rb together with the nitrogen atom to which they are attached are C １～６ forming a 5-6 membered monocyclic or 7-9 membered bicyclic heterocyclyl ring optionally substituted with 1, 2 or 3 substituents selected from the group consisting of alkyl and halo; 2) C optionally substituted with 1, 2 or 3 substituents selected from the group consisting of halo, CN, halo and CN. １～６ Alkyl, 3- to 5-membered cycloalkyl ring, oxo and C １～６ a 5-6 membered heteroaryl ring optionally substituted with 1, 2 or 3 substituents selected from the group consisting of alkoxyl; 3) C optionally substituted with 1, 2 or 3 substituents selected from the group consisting of halo, CN, halo and CN. １～６ Alkyl, 3- to 5-membered cycloalkyl ring and C １～６ C substituted with 1, 2 or 3 substituents selected from the group consisting of alkoxyl ６～１０ Aryl ring; is selected from the group consisting of R ２ and R ３ are each independently H or D; Each R ４ But, halo, CN, OH, C １～６ Alkylsulfonyl-, C １～６ Alkylsulfonylamino-, C １～６ Alkylcarbonylamino-, phenyl, C １～６ Alkyl, C １～６ independently selected from the group consisting of alkoxyl, a 3- to 6-membered cycloalkyl ring, a 5- to 10-membered heteroaryl ring, and a 5- to 9-membered heterocyclyl ring, wherein said alkyl, said alkoxyl, said cycloalkyl ring, said heteroaryl ring, or said heterocyclyl ring is optionally substituted with 1, 2, or 3 substituents selected from the group consisting of halo, CN, and OH; Two adjacent R ４ together with the carbon atom to which they are attached, C １～６ Alkyl, -C １～６ Alkyl-OH, C １～６ Alkoxyl-C １～６ optionally forming a 3-6 membered cycloalkyl ring, optionally substituted with 1, 2 or 3 substituents selected from the group consisting of alkyl- and halo; Or, two R bonded to the same carbon atom ４ optionally forms, together with said carbon atom, a 3- to 6-membered cycloalkyl ring optionally substituted with 1, 2 or 3 substituents selected from the group consisting of halo, CN and OH; Or, two adjacent R ４ together with the carbon atom to which they are attached, halo, C １～６ Alkyl and C １～６ optionally forming a 5-10 membered heteroaryl ring, phenyl or 5-9 membered heterocyclyl ring optionally substituted by 1, 2 or 3 substituents selected from the group consisting of haloalkyl, said alkyl being optionally substituted by one 3-6 membered cycloalkyl ring or phenyl; R ５ is H or halo; a, b, c and d are each independently 1 or 2; n is 0 or 1; m is 0, 1, 2 or 3; However, R ４ is present, the moiety to the remainder of the structure of the compound. 【Chemistry 4】 except for the N atom adjacent to the point of attachment of said moiety 【Chemistry 5】 substituted at any chemically permissible position on the 2. A compound according to claim 1, or a stereoisomer, racemate, tautomer, hydrate or solvate thereof, or a pharma- ceutically acceptable salt thereof.

3. The compound has formula II: 【Chemistry 6】 3. The compound of claim 1 or 2, which is:

4. The compound has formula III: 【Chemistry 7】 or a stereoisomer, racemate, tautomer, hydrate or solvate, or a pharma- ceutically acceptable salt thereof, wherein

5. 5. The compound according to any one of claims 1 to 4, wherein X is F, or a stereoisomer, racemate, tautomer, hydrate or solvate, or a pharma- ceutically acceptable salt thereof.

6. Z is CH ２ 6. The compound according to any one of claims 1 to 5, wherein:

7. R ２ and R ３ is each independently H, or a stereoisomer, racemate, tautomer, hydrate or solvate, or a pharma- ceutically acceptable salt thereof.

8. R １ but, 【Chemistry 8】 [In the formula, A １ Or A ２ is N or CH, R ６ is selected from the group consisting of halo, CN and cyclopropyl; R ７ is selected from the group consisting of H, halo, CN and cyclopropyl; 8. The compound according to any one of claims 1 to 7, or a stereoisomer, racemate, tautomer, hydrate or solvate thereof, or a pharma- ceutically acceptable salt thereof.

9. R 1 is 【Chemistry 9】 That is, Or, R 1 is 【Chemistry 10】 wherein A 3 is N or C substituted by halo, and R 8 is C 1-3 alkyl; 9. The compound according to any one of claims 1 to 8, or a stereoisomer, racemate, tautomer, hydrate or solvate thereof, or a pharma- ceutically acceptable salt thereof.

10. R １ but, 【Chemistry 11】 or a stereoisomer, racemate, tautomer, hydrate or solvate, or a pharma- ceutically acceptable salt thereof, selected from the group consisting of:

11. each of a and b is 1; each of c and d is 2; n is 0, m is 0, 1 or 2; 11. The compound according to any one of claims 1 to 10, or a stereoisomer, racemate, tautomer, hydrate or solvate thereof, or a pharma- ceutically acceptable salt thereof.

12. Each R ４ Halo; CN; OH; C １～６ Alkylsulfonyl-; C １～６ alkylsulfonylamino-; phenyl; C optionally substituted with 1, 2 or 3 substituents selected from the group consisting of halo, CN and OH １～６ alkyl; C optionally substituted by 1, 2 or 3 halo １～６ alkoxyl; and cyclopropyl; Two adjacent R ４ together with the carbon atom to which they are attached, C １～６ Alkyl, -C １～６ Alkyl-OH, C １～６ Alkoxyl-C １～６ optionally forming a 3-6 membered cycloalkyl ring, optionally substituted with 1, 2 or 3 substituents selected from the group consisting of alkyl- and halo; Or, two R bonded to the same carbon atom ４ together with said carbon atom optionally forms a 3- to 6-membered cycloalkyl ring, optionally substituted with 1, 2 or 3 halo; Or, two adjacent R ４ together with the carbon atom to which they are attached, 1, 2 or 3 C １～６ Optionally forming a 5-6 membered heteroaryl ring optionally substituted by alkyl substituents, said alkyl being optionally substituted by one 3-6 membered cycloalkyl ring or phenyl; Or, two adjacent R ４ together with the carbon atom to which they are attached optionally form a phenyl; 12. The compound according to any one of claims 1 to 11, or a stereoisomer, racemate, tautomer, hydrate or solvate thereof, or a pharma- ceutically acceptable salt thereof.

13. The part 【Chemistry 12】 but, 【Chemistry 13】 13. The compound according to any one of claims 1 to 12, or a stereoisomer, racemate, tautomer, hydrate or solvate, or a pharma- ceutically acceptable salt thereof, selected from the group consisting of:

14. X is F, Z is CH ２ and R １ but, 1)-(C=O)-NRaRb [wherein, Ra and Rb are C optionally substituted with 1, 2 or 3 deuterium. １～６ each independently selected from the group consisting of alkyl, Or, Ra and Rb together with the nitrogen atom to which they are attached represent 1, 2 or 3 C １～６ forming a 5-6 membered monocyclic or 7-9 membered bicyclic heterocyclyl ring optionally substituted by alkyl; 2) Haro, CN, C １～６ Alkyl, CF ３ , 3- to 5-membered cycloalkyl ring, oxo and C １～６ a 5-6 membered heteroaryl ring substituted with 1, 2 or 3 substituents selected from the group consisting of alkoxyl; 3) Haro, CN, C １～６ Alkyl, CF ３ , 3- to 5-membered cycloalkyl ring and C １～６ C substituted with 1, 2 or 3 substituents selected from the group consisting of alkoxyl ６～１０ Aryl ring; is selected from the group consisting of R ２ and R ３ are each independently H; Each R ４ Halo; CN; OH; C １～６ Alkylsulfonyl-; C １～６ alkylsulfonylamino-; phenyl; C optionally substituted with 1, 2 or 3 substituents selected from the group consisting of halo, CN and OH １～６ alkyl; C optionally substituted by 1, 2 or 3 halo １～６ alkoxyl; and 3- to 6-membered cycloalkyl ring; Two adjacent R ４ together with the carbon atom to which they are attached, C １～６ optionally forming a 3-6 membered cycloalkyl ring, optionally substituted with 1, 2 or 3 substituents selected from the group consisting of alkyl and halo; Or, two adjacent R ４ together with the carbon atom to which they are attached optionally form a phenyl; R ５ is H or halo; each of a and b is 1; each of c and d is 2; n is 0, m is 0, 1 or 2; However, R ４ is present, the moiety to the remainder of the structure of the compound. 【Chemistry 14】 except for the N atom adjacent to the point of attachment of said moiety 【Chemistry 15】 substituted at any chemically permissible position on the 4. The compound according to any one of claims 1 to 3, or a stereoisomer, racemate, tautomer, hydrate or solvate thereof, or a pharma- ceutically acceptable salt thereof.

15. R ５ is H, or a stereoisomer, racemate, tautomer, hydrate or solvate, or a pharma- ceutically acceptable salt thereof.

16. The part 【Chemistry 16】 but, 【Chemistry 17】 [In the formula, R ４ ', R ４ '' and R ４ "" is H; halo; CN; OH; C optionally substituted with one halo １～６ Alkyl; and C １～６ alkoxyl; or R ４ ' and R ４ ", together with the carbon atom to which they are attached, represent one or two C １～６ optionally forming a 3-6 membered cycloalkyl ring, optionally substituted with alkyl; R ４ ''' is H], A compound according to any one of claims 1 to 11 and 14 to 15, or a stereoisomer, racemate, tautomer, hydrate or solvate thereof, or a pharma- ceutically acceptable salt thereof.

17. The part 【Chemistry 18】 but, 【Chemistry 19】 [In the formula, R ４ ''' is H, R ４ ' and R ４ '' is H; halo; C optionally substituted by 1 halo １～６ Alkyl; and C １～６ alkoxyl; with the proviso that R ４ ' and R ４ '' is not H, or R ４ ' and R ４ ", together with the carbon atom to which they are attached, represent one or two C １～３ forming a 3- or 5-membered cycloalkyl ring optionally substituted by alkyl, or forming a phenyl ring; A compound according to any one of claims 1 to 11 and 14 to 15, or a stereoisomer, racemate, tautomer, hydrate or solvate thereof, or a pharma- ceutically acceptable salt thereof.

18. The part 【Chemistry 20】 but, 【Chemistry 21】 [In the formula, R ４ ' is H and R ４ '' is C substituted with one halo １～６ is alkyl, or R ４ ' and R ４ " optionally form a 3- or 5-membered cycloalkyl ring together with the carbon atom to which they are attached; A compound according to any one of claims 1 to 11 and 14 to 15, or a stereoisomer, racemate, tautomer, hydrate or solvate thereof, or a pharma- ceutically acceptable salt thereof.

19. The part 【Chemistry 22】 but, 【Chemistry 23】 wherein each p is independently 0 or 1; q is 0, 1 or 2; R ４ａ is C １～３ alkyl; A compound according to any one of claims 1 to 11 and 14 to 15, or a stereoisomer, racemate, tautomer, hydrate or solvate thereof, or a pharma- ceutically acceptable salt thereof.

20. The compound of claim 19, or a stereoisomer, racemate, tautomer, hydrate or solvate thereof, or a pharma- ceutically acceptable salt thereof, wherein both p's are 1 and q's are 0.

21. The compound is 【Table 1-1】 【Table 1-2】 【Table 1-3】 【Table 1-4】 【Table 1-5】 【Table 1-6】 【Table 1-7】 【Table 1-8】 【Table 1-9】 【Table 1-10】 【Table 1-11】 【Table 1-12】 【Table 1-13】 【Table 1-14】 【Table 1-15】 【Table 1-16】 【Table 1-17】 【Table 1-18】 【Table 1-19】 【Table 1-20】 【Table 1-21】 【Table 1-22】 【Table 1-23】 【Table 1-24】 【Table 1-25】 【Table 1-26】 【Table 1-27】 【Table 1-28】 3. The compound according to claim 1 or 2, selected from the group consisting of:

22. 22. A pharmaceutical composition comprising a compound according to any one of claims 1 to 21, or a stereoisomer, racemate, tautomer, hydrate or solvate thereof, or a pharma- ceutically acceptable salt thereof, for use as a medicament.

23. 22. A pharmaceutical composition comprising a compound according to any one of claims 1 to 21, or a stereoisomer, racemate, tautomer, hydrate or solvate, or a pharma- ceutically acceptable salt thereof, for use in the treatment or prevention of cancer or diabetes.

24. The pharmaceutical composition of claim 23, wherein the cancer is a blood tumor or a solid tumor.

25. The pharmaceutical composition of claim 23, wherein the cancer is selected from leukemia, lymphoma, myeloma, myelodysplastic syndrome (MDS), myeloproliferative neoplasm (MPN), polycythemia vera, prostate cancer, lung cancer, breast cancer, pancreatic cancer, colon cancer, liver cancer, melanoma and glioblastoma.

26. The cancer is acute leukemia, chronic leukemia, myeloid leukemia, myelogenous leukemia, lymphoblastic leukemia, lymphocytic leukemia, acute myeloid leukemia (AML), chronic myeloid leukemia (CML), acute lymphoblastic leukemia (ALL), chronic lymphocytic leukemia (CLL), T-cell prolymphocytic leukemia (T-PLL), large granular lymphocytic leukemia, hairy cell leukemia (HCL), mixed lineage leukemia (MLL), MLL-rearranged leukemia (MLL-R) 24. The pharmaceutical composition of claim 23, wherein the acute leukemia is selected from acute myeloma, MLL-PTD leukemia, MLL amplified leukemia, MLL positive leukemia, nucleophosmin (NPM) mutated leukemia, MOZ acute leukemia, NUP98 acute leukemia, CALM acute leukemia, MLL-AF4 leukemia, MLL-AF6 leukemia, MLL-AF9 leukemia, MLL-AF10 leukemia, MLL-ENL leukemia, MLL-ELL leukemia, and multiple myeloma.

27. 22. A pharmaceutical composition comprising a compound according to any one of claims 1 to 21, or a stereoisomer, racemate, tautomer, hydrate or solvate, or a pharma- ceutically acceptable salt thereof, and optionally a pharma- ceutically acceptable carrier.

28. 22. Use of a compound according to any one of claims 1 to 21, or a stereoisomer, racemate, tautomer, hydrate or solvate, or a pharma- ceutically acceptable salt thereof, in the manufacture of a medicament for the treatment or prevention of cancer or diabetes.

29. 22. A method for inhibiting the interaction of menin with MLL and / or MLL fusion proteins in vitro, comprising contacting menin and MLL and / or MLL fusion proteins with an effective amount of a compound according to any one of claims 1 to 21 or a pharma- ceutically acceptable salt thereof.

30. 22. A pharmaceutical composition comprising a compound according to any one of claims 1 to 21, or a stereoisomer, racemate, tautomer, hydrate or solvate thereof, or a pharma- ceutically acceptable salt thereof, for use in a method for treating or preventing cancer or diabetes, the method comprising administering to a subject in need thereof an effective amount of a compound according to any one of claims 1 to 21, or a stereoisomer, racemate, tautomer, hydrate or solvate thereof.

31. 22. A pharmaceutical combination comprising a compound according to any one of claims 1 to 21, or a stereoisomer, racemate, tautomer, hydrate or solvate, or a pharma- ceutically acceptable salt thereof, and at least one additional therapeutic agent.

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