Carbonyl-substituted diazaspiro compounds and their use

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 of International Application No. PCT / CN2021 / 135427, filed on December 3, 2021, and International Application No. PCT / CN2022 / 115162, filed on August 26, 2022, both of which are hereby incorporated by reference in their entirety.

[0002] The present disclosure provides a carbonyl - substituted diazaspiro compound that inhibits the interaction between menin and MLL and MLL fusion proteins. The present 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 between menin and MLL and / or MLL fusion proteins.

Background Art

[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 cases of secondary acute myeloid (myelogenous) leukemia (AML) 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, and a high frequency of early relapse, with 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] The protein-protein interaction (PPI) between menin and MLLr is important for the pathogenesis of MLLr-driven leukemia due to deregulation of the HOXA and MEIS1 genes. On the other hand, recent studies have revealed the importance of the menin-MLL1 wild-type (wt) interaction in AML with mutations in the nucleophosmin 1 (NPM1) gene. NPM1 mutations (NPM1c) are observed in more than 30% of AML patients with a low 5-year overall survival rate and are also associated with increased expression of the HOXA and MEIS1 genes (Kuhn, M.W. et al. Cancer Discov. 2016, 6, 1166). Menin inhibitors have been reported to be able to block the interaction between menin and MLLr and MLL wt, indicating the potential for 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 a simplified introduction to the content of the concepts that will be further described later in the "Detailed Description". This summary is not intended to identify the main 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 relates to formula I:

Chemical Formula

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

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

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

[0010] The present disclosure also provides a pharmaceutical composition comprising the compound of the present disclosure and optionally a pharmaceutically acceptable carrier.

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

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

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

[0014] The present disclosure provides a method of inhibiting the interaction of menin with MLL and / or MLL fusion proteins in vivo or in vitro, the method 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, the method 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 a method for the preparation of a compound of the present disclosure, and intermediates for preparing a compound of the present disclosure.

DETAILED DESCRIPTION OF THE INVENTION

[0018] Embodiments of the Present Disclosure - Part A Embodiment 1. Formula I:

CHEMICAL FORMULA

[0019] Embodiment 2. X is F, Cl, or CN, Y is N or CH, Z is selected from the group consisting of CH2, O, S, and NH, R1 is 1)-(C=O)-NRaRb [wherein, Ra and Rb are C1~6 Each independently selected from the group consisting of alkyl and 3- to 5-membered cycloalkyl rings, C 1~6 Alkyl is optionally substituted by one, two or three substituents selected from the group consisting of deuterium, halo, OH and C 1~6 Alkoxyl; or, Ra and Rb, together with the nitrogen atom to which they are attached, form a 5- to 6-membered monocyclic or 7- to 9-membered bicyclic heterocyclyl ring optionally substituted by one, two or three substituents selected from the group consisting of alkyl and halo; 1~6 2) C alkyl optionally substituted by one, two or three substituents selected from the group consisting of halo, CN, halo and CN, 3- to 5-membered cycloalkyl ring, oxo and C Alkoxyl; a 5- to 6-membered heteroaryl ring optionally substituted by one, two or three substituents selected from the group consisting of halo, CN, halo and CN; 1~6 3) C alkyl optionally substituted by one, two or three substituents selected from the group consisting of halo, CN, halo and CN, 3- to 5-membered cycloalkyl ring and C 1~6 An aryl ring substituted by one, two or three substituents selected from the group consisting of alkoxyl; selected from the group consisting of: R2 and R3 are each independently H or D, 1~6 Each R4 is independently selected from the group consisting of halo, CN, OH, C 1~6 Alkylsulfonyl-, C 6~10 Alkylsulfonylamino-, C Alkylcarbonylamino-, phenyl, C Alkyl, C Alkoxyl, 3- to 6-membered cycloalkyl ring, 5- to 10-membered heteroaryl ring and 5- to 9-membered heterocyclyl ring, wherein the alkyl, alkoxyl, cycloalkyl ring, heteroaryl ring or heterocyclyl ring is optionally substituted by one, two or three substituents selected from the group consisting of halo, CN and OH, 1~6 1~6 1~6 1~6 1~6 1~6 1~6 1~6 1~6 1~6 Two adjacent R4s, together with the carbon atom to which they are attached, form a C 1~6 alkyl, -C 1~6 alkyl-OH, C 1~6 alkoxyl-C 1~6 3- to 6-membered cycloalkyl ring, optionally formed by 1, 2 or 3 substituents selected from the group consisting of alkyl, -C Or, two R4s attached to the same carbon atom, together with the carbon atom, optionally form a 3- to 6-membered cycloalkyl ring optionally substituted by 1, 2 or 3 substituents selected from the group consisting of halo, CN and OH Or, two adjacent R4s, together with the carbon atom to which they are attached, form a 5- to 10-membered heteroaryl ring, phenyl or 5- to 9-membered heterocyclyl ring, optionally substituted by 1, 2 or 3 substituents selected from the group consisting of halo, C 1~6 alkyl and C 1~6 haloalkyl, wherein the alkyl is optionally substituted by 1 3- to 6-membered cycloalkyl ring or phenyl R5 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 Provided that when R4 is present, it is substituted at any chemically acceptable position on the heterocyclyl, except for the N atom adjacent to the point of attachment of the heterocyclyl to the remainder of the structure of the compound The compound according to Embodiment 1, or its stereoisomer, racemate, tautomer, hydrate or solvate, or pharmaceutically acceptable salt

[0020] Embodiment 3 Each R4 is halo, CN, OH, C 1~6 alkylsulfonyl-, C 1~6 alkylsulfonylamino-, phenyl, C 1~6 alkyl, C 1~6Independently selected from the group consisting of alkoxyl and 3- to 6-membered cycloalkyl rings, wherein the alkyl or alkoxyl is optionally substituted by 1, 2 or 3 substituents selected from the group consisting of halo, CN and OH, Two adjacent R4s, together with the carbon atom to which they are attached, form a C 1~6 Alkyl, -C 1~6 Alkyl-OH, C 1~6 Alkoxyl-C 1~6 Optionally form a 3- to 6-membered cycloalkyl ring optionally substituted by 1, 2 or 3 substituents selected from the group consisting of alkyl-, and halo, Or, two R4s attached to the same carbon atom, together with the carbon atom, optionally form a 3- to 6-membered cycloalkyl ring optionally substituted by 1, 2 or 3 substituents selected from the group consisting of halo, CN and OH, Or, two adjacent R4s, together with the carbon atom to which they are attached, form a 1~6 5- to 10-membered heteroaryl ring or phenyl optionally substituted by 1, 2 or 3 substituents selected from the group consisting of alkyl, wherein the alkyl is optionally substituted by 1 3- to 6-membered cycloalkyl ring or phenyl, The compound according to Embodiment 1 or 2, or a stereoisomer, racemate, tautomer, hydrate or solvate thereof, or a pharmaceutically acceptable salt.

[0021] Embodiment 4. The compound according to any one of Embodiments 1 to 3, wherein R5 is H, or a stereoisomer, racemate, tautomer, hydrate or solvate thereof, or a pharmaceutically acceptable salt.

[0022] Embodiment 5. The compound is of formula II:

Chemical formula

Chemical formula

[0023] Embodiment 6. The compound is of formula III: [Chemical formula] The compound according to any one of Embodiments 1 to 4, or a stereoisomer, racemate, tautomer, hydrate or solvate thereof, or a pharmaceutically acceptable salt.

[0024] Embodiment 7. The compound according to any one of Embodiments 1 to 6, or a stereoisomer, racemate, tautomer, hydrate or solvate thereof, or a pharmaceutically acceptable salt, wherein X is F.

[0025] Embodiment 8. The compound according to any one of Embodiments 1 to 7, or a stereoisomer, racemate, tautomer, hydrate or solvate thereof, or a pharmaceutically acceptable salt, wherein Z is selected from the group consisting of CH2, O and S, preferably CH2.

[0026] Compound according to any one of Embodiments 1 to 8, or a stereoisomer, racemate, tautomer, hydrate or solvate thereof, or a pharmaceutically acceptable salt thereof, wherein R2 and R3 are each independently H.

[0027] Embodiment 10. R1 is -(C=O)-NRaRb [wherein, Ra and Rb are each independently selected from the group consisting of C 1~6 alkyl and 3- to 5-membered cycloalkyl rings, and C 1~6 alkyl is optionally substituted with 1, 2 or 3 substituents selected from the group consisting of deuterium, halo, OH and C 1~6 alkoxyl, or Ra and Rb, together with the nitrogen atom to which they are attached, form a 5- to 6-membered monocyclic or 7- to 9-membered bicyclic heterocyclyl ring having another ring heteroatom selected from N, O and S, which is optionally substituted with 1, 2 or 3 substituents selected from the group consisting of C 1~6 alkyl and halo] Compound according to any one of Embodiments 1 to 9, or a stereoisomer, racemate, tautomer, hydrate or solvate thereof, or a pharmaceutically acceptable salt thereof.

[0028] Embodiment 11. R1 is -(C=O)-NRaRb [wherein Ra and Rb are each C 1~3 alkyl optionally substituted with one OH, preferably Ra is ethyl and Rb is isopropyl], or R1 is a 5- to 6-membered heteroaryl ring substituted with 1, 2 or 3 substituents selected from the group consisting of halo, CN, C 1~3 alkyl and cyclopropyl, or a phenyl substituted with 1, 2 or 3 substituents selected from the group consisting of halo, CN and cyclopropyl. Compound according to any one of Embodiments 1 to 9, or a stereoisomer, racemate, tautomer, hydrate or solvate thereof, or a pharmaceutically acceptable salt thereof.

[0029] Embodiment 12. R1 is -(C=O)-NRaRb [wherein each of Ra and Rb is C 1~3 alkyl which is optionally substituted by one OH, preferably Ra is ethyl and Rb is isopropyl], or R1 is pyridyl, pyrimidinyl or pyrazolyl substituted by one, two or three substituents selected from the group consisting of halo, CN, C 1~3 alkyl and cyclopropyl, or phenyl substituted by one, two or three substituents selected from the group consisting of halo, CN and cyclopropyl. The compound according to Embodiment 11, or a stereoisomer, racemate, tautomer, hydrate or solvate thereof, or a pharmaceutically acceptable salt.

[0030] Embodiment 13. R1 is -(C=O)-NRaRb [wherein each of Ra and Rb is C 1~3 alkyl, preferably Ra is ethyl and Rb is isopropyl], or R1 is a 6-membered heteroaryl or phenyl ring substituted by one, two or three substituents selected from the group consisting of halo, CN and cyclopropyl. The compound according to any one of Embodiments 1 to 9, or a stereoisomer, racemate, tautomer, hydrate or solvate thereof, or a pharmaceutically acceptable salt.

[0031] Embodiment 14. R1 is -(C=O)-NRaRb [wherein Ra is ethyl and Rb is isopropyl]. The compound according to any one of Embodiments 1 to 9, or a stereoisomer, racemate, tautomer, hydrate or solvate thereof, or a pharmaceutically acceptable salt.

[0032] Embodiment 15. R1 is pyridyl, pyrimidinyl or phenyl substituted with 1, 2 or 3 substituents selected from the group consisting of halo, CN and cyclopropyl, The compound according to any one of Embodiments 1 to 9, or a stereoisomer, racemate, tautomer, hydrate or solvate thereof, or a pharmaceutically acceptable salt.

[0033] Embodiment 16. R1 is [Chemical formula] [wherein, A1 or A2 is N or CH, R6 is selected from the group consisting of halo, CN and cyclopropyl, and R7 is selected from the group consisting of H, halo, CN and cyclopropyl], preferably, R1 is [Chemical formula] or, R1 is [Chemical formula] [wherein, A3 is N or C substituted by halo, and R8 is C 1~3 alkyl], preferably, R1 is [Chemical formula] The compound according to any one of Embodiments 1 to 9, or a stereoisomer, racemate, tautomer, hydrate or solvate thereof, or a pharmaceutically acceptable salt.

[0034] Embodiment 17. The compound is of formula IIb: [Chemical formula] The compound according to Embodiment 16, or a stereoisomer, racemate, tautomer, hydrate or solvate thereof, or a pharmaceutically acceptable salt.

[0035] Embodiment 18. R1 is -(C=O)-NRaRb [wherein each of Ra and Rb is C 1~3 alkyl, preferably Ra is ethyl and Rb is isopropyl], or R1 is a 6-membered heteroaryl ring substituted with one, two or three substituents selected from the group consisting of halo, CN and cyclopropyl, The compound according to any one of Embodiments 1 to 9, or a stereoisomer, racemate, tautomer, hydrate or solvate thereof, or a pharmaceutically acceptable salt.

[0036] Embodiment 19. R1 is -(C=O)-NRaRb [wherein each of Ra and Rb is C 1~3 alkyl, preferably Ra is ethyl and Rb is isopropyl], or R1 is pyridyl or pyrimidinyl substituted with one, two or three substituents selected from the group consisting of halo, CN and cyclopropyl, The compound according to Embodiment 19, or a stereoisomer, racemate, tautomer, hydrate or solvate thereof, or a pharmaceutically acceptable salt.

[0037] Embodiment 20. R1 is

Chemical formula

[0038] Embodiment 21. Each of a and b is 1, Each of c and d is 1 or 2, The compound according to any one of Embodiments 1 to 20, or a stereoisomer, racemate, tautomer, hydrate or solvate thereof, or a pharmaceutically acceptable salt. Embodiment 22. n is 0 or 1, preferably 0, The compound according to any one of Embodiments 1 to 21, or a stereoisomer, racemate, tautomer, hydrate or solvate thereof, or a pharmaceutically acceptable salt.

[0039] Embodiment 23. The compound according to any one of Embodiments 1 to 15, wherein n is 0, or a stereoisomer, racemate, tautomer, hydrate or solvate thereof, or a pharmaceutically acceptable salt.

[0040] Embodiment 24. The compound according to any one of Embodiments 1 to 15, wherein n is 1, or a stereoisomer, racemate, tautomer, hydrate or solvate thereof, or a pharmaceutically acceptable salt.

[0041] Embodiment 25. The compound according to any one of Embodiments 1 to 24, wherein m is 0, 1 or 2, or a stereoisomer, racemate, tautomer, hydrate or solvate thereof, or a pharmaceutically acceptable salt.

[0042] Embodiment 26. wherein each of a and b is 1, The compound according to any one of Embodiments 1 to 25, or a stereoisomer, racemate, tautomer, hydrate or solvate thereof, or a pharmaceutically acceptable salt.

[0043] Embodiment 27. wherein each of c and d is 2, The compound according to any one of Embodiments 1 to 26, or a stereoisomer, racemate, tautomer, hydrate or solvate thereof, or a pharmaceutically acceptable salt.

[0044] Embodiment 28. wherein m is 1 or 2, The compound according to any one of Embodiments 1 to 27, or a stereoisomer, racemate, tautomer, hydrate or solvate thereof, or a pharmaceutically acceptable salt.

[0045] Embodiment 29. wherein 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 pharmaceutically acceptable salt.

[0046] Embodiment 30. each R4 is 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 with 1, 2 or 3 halo 1~6 alkoxyl; and cyclopropyl; independently selected from the group consisting of, two adjacent R4s, together with the carbon atom to which they are attached, optionally form a 3- to 6-membered cycloalkyl ring optionally substituted with 1, 2 or 3 substituents selected from the group consisting of C 1~6 alkyl, -C 1~6 alkyl-OH, C 1~6 alkoxyl-C 1~6 alkyl- and halo; alternatively, two R4s attached to the same carbon atom, together with the carbon atom, optionally form a 3- to 6-membered cycloalkyl ring optionally substituted with 1, 2 or 3 halo, alternatively, two adjacent R4s, together with the carbon atom to which they are attached, optionally form a 5- to 6-membered heteroaryl ring optionally substituted with 1, 2 or 3 C 1~6 alkyl substituents, wherein the alkyl is optionally substituted with one 3- to 6-membered cycloalkyl ring or phenyl, alternatively, two adjacent R4s, together with the carbon atom to which they are attached, optionally form phenyl, The compound according to any one of Embodiments 1 to 29, or a stereoisomer, racemate, tautomer, hydrate or solvate thereof, or a pharmaceutically acceptable salt.

[0047] Embodiment 31. Each R4 is halo; CN; OH; C 1~3 alkylsulfonyl-; C 1~3 alkylsulfonylamino-; phenyl; C optionally substituted with 1, 2 or 3 substituents selected from the group consisting of halo, CN and OH 1~3 alkyl; C optionally substituted with 1, 2 or 3 halo 1~3 alkoxyl; and cyclopropyl; independently selected from the group consisting of, Two adjacent R4s, together with the carbon atom to which they are attached, form optionally a C 1~3 alkyl, -C 1~3 alkyl-OH, C 1~3 alkoxyl-C 1~3 alkyl- and optionally substituted with 1, 2 or 3 substituents selected from the group consisting of halo, optionally forming a 3- to 6-membered cycloalkyl ring, Or, two R4s attached to the same carbon atom, together with the carbon atom, optionally form a 3- to 6-membered cycloalkyl ring optionally substituted with 1, 2 or 3 halo, Or, two adjacent R4s, together with the carbon atom to which they are attached, form optionally a 5- to 6-membered heteroaryl ring optionally substituted with 1, 2 or 3 C 1~3 alkyl substituents, wherein the alkyl is optionally substituted with 1 3- to 6-membered cycloalkyl ring or phenyl, Or, two adjacent R4s, together with the carbon atom to which they are attached, optionally form phenyl, The compound according to any one of Embodiments 1 to 30, or a stereoisomer, racemate, tautomer, hydrate or solvate thereof, or a pharmaceutically acceptable salt.

[0048] Embodiment 32. portion [Chem.] is, [Chem.] a compound according to any one of Embodiments 1 to 31 selected from the group consisting of, or a stereoisomer, racemate, tautomer, hydrate or solvate thereof, or a pharmaceutically acceptable salt.

[0049] Embodiment 33. X is F, Z is CH2, R1 is, 1) -(C=O)-NRaRb [wherein, Ra and Rb are each independently selected from the group consisting of C alkyl optionally substituted with 1, 2 or 3 deuteriums 1~6 or, Ra and Rb together with the nitrogen atom to which they are attached form a 5- to 6-membered monocyclic or 7- to 9-membered bicyclic heterocyclyl ring optionally substituted by C alkyl]; or, Ra and Rb together with the nitrogen atom to which they are attached form a 5- to 6-membered monocyclic or 7- to 9-membered bicyclic heterocyclyl ring optionally substituted by C alkyl]; 1~6 or, Ra and Rb together with the nitrogen atom to which they are attached form a 5- to 6-membered monocyclic or 7- to 9-membered bicyclic heterocyclyl ring optionally substituted by C alkyl]; 2) a 5- to 6-membered heteroaryl ring substituted with 1, 2 or 3 substituents selected from the group consisting of halo, CN, C alkyl, CF3, 3- to 5-membered cycloalkyl ring, oxo and C alkoxyl; 1~6 3) an aryl ring substituted with 1, 2 or 3 substituents selected from the group consisting of halo, CN, C alkyl, CF3, 3- to 5-membered cycloalkyl ring and C alkoxyl; 1~6 4) an aryl ring substituted with 1, 2 or 3 substituents selected from the group consisting of halo, CN, C alkyl, CF3, 3- to 5-membered cycloalkyl ring and C alkoxyl; 3) a C aryl ring substituted with 1, 2 or 3 substituents selected from the group consisting of halo, CN, C alkyl, CF3, 3- to 5-membered cycloalkyl ring and C alkoxyl; 1~6 4) a C aryl ring substituted with 1, 2 or 3 substituents selected from the group consisting of halo, CN, C alkyl, CF3, 3- to 5-membered cycloalkyl ring and C alkoxyl; 1~6 5) a C aryl ring substituted with 1, 2 or 3 substituents selected from the group consisting of halo, CN, C alkyl, CF3, 3- to 5-membered cycloalkyl ring and C alkoxyl; 6~10 aryl ring; selected from the group consisting of, R2 and R3 are each independently H, each R4 is halo; CN; OH; C alkylsulfonyl-; C alkylsulfonylamino-; phenyl; a C aryl ring optionally substituted with 1, 2 or 3 substituents selected from the group consisting of halo, CN and OH; 1~6 alkylsulfonyl-; 1~6 alkylsulfonylamino-; phenyl; a C aryl ring 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 halos 1~6 Alkoxyl; and 3- to 6-membered cycloalkyl ring; independently selected from the group consisting of, Two adjacent R4s, together with the carbon atom to which they are attached, form a C 1~6 Optionally form a 3- to 6-membered cycloalkyl ring optionally substituted by 1, 2 or 3 substituents selected from the group consisting of alkyl and halo, Or, two adjacent R4s, together with the carbon atom to which they are attached, optionally form a phenyl, R5 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, Provided that when R4 is present, it is substituted at any chemically acceptable position on the heterocyclyl, except for the N atom adjacent to the point of attachment of the heterocyclyl to the rest of the structure of the compound. The compound according to any one of Embodiments 1 to 5, or a stereoisomer, racemate, tautomer, hydrate or solvate thereof, or a pharmaceutically acceptable salt.

[0050] Embodiment 34. The compound according to Embodiment 33, wherein R5 is H, or a stereoisomer, racemate, tautomer, hydrate or solvate thereof, or a pharmaceutically acceptable salt.

[0051] Embodiment 35. The compound according to any one of Embodiments 33 to 34, wherein R1 is -(C=O)-NRaRb, and Ra and Rb are each independently selected from the group consisting of ethyl and isopropyl, or a stereoisomer, racemate, tautomer, hydrate or solvate thereof, or a pharmaceutically acceptable salt.

[0052] Embodiment 36. R1 is halo, CN, C 1~3 Alkyl, CF3, cyclopropyl, oxo and C 1~3The compound according to any one of Embodiments 33 to 34, which is a 5- or 6-membered heteroaryl ring or a phenyl ring substituted with 1 or 2 substituents selected from the group consisting of alkoxyl, or a stereoisomer, racemate, tautomer, hydrate or solvate thereof, or a pharmaceutically acceptable salt.

[0053] Embodiment 37. R1 is

Chemical formula

[0054] Embodiment 38. Each R4 is halo; CN; OH; C 1~3 alkylsulfonyl-; C 1~3 alkylsulfonylamino-; phenyl; C optionally substituted with 1, 2 or 3 substituents selected from the group consisting of halo, CN and OH 1~3 alkyl; C optionally substituted with 1, 2 or 3 halo 1~3 alkoxyl; and cyclopropyl; independently selected from the group consisting of, Two adjacent R4s, together with the carbon atom to which they are attached, optionally form a 3- to 6-membered cycloalkyl ring optionally substituted with 1, 2 or 3 substituents selected from the group consisting of alkyl and halo, 1~3 Or, two adjacent R4s, together with the carbon atom to which they are attached, optionally form a phenyl. Or, two adjacent R4s, together with the carbon atom to which they are attached, optionally form a phenyl. The compound according to any one of Embodiments 33 to 37, or a stereoisomer, racemate, tautomer, hydrate or solvate thereof, or a pharmaceutically acceptable salt.

[0055] Embodiment 39. Part

Chemical formula

Chem.

[0056] Embodiment 40. each R4 is independently selected from the group consisting of halo, CN, C1-3 alkoxyl and cyclopropyl, or two adjacent R4s together with the carbon atom to which they are attached form 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 pharmaceutically acceptable salt.

[0057] Embodiment 41. moiety

Chem.

Chem.

[0058] Embodiment 42. Part [Chemical formula] is [Chemical formula] [wherein, R4’, R4’’ and R4’’’ are independently selected from the group consisting of H; halo; CN; OH; C 1~6 alkyl optionally substituted by one halo; and C 1~6 alkoxyl; or R4’ and R4’’ together with the carbon atom to which they are attached optionally form a 3- to 6-membered cycloalkyl ring optionally substituted by one or two C 1~6 alkyl, and R4’’’ is H] The 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.

[0059] Embodiment 43. Part [Chemical formula] is [Chemical formula] [wherein, R4’, R4’’ and R4’’’ are independently selected from the group consisting of H; halo; CN; C 1~3 alkyl optionally substituted by one halo; and C 1~3 alkoxyl; or R4’ and R4’’ together with the carbon atom to which they are attached optionally form a 3- to 6-membered cycloalkyl ring optionally substituted by one or two C 1~3Optionally form a 3- to 5-membered cycloalkyl ring optionally substituted by alkyl, and R4''' is H. 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.

[0060] Embodiment 44. moiety

Chem.

Chem.

[0061] Embodiment 45. [Wherein, R4', R4'' and R4''' are H; halo; CN; OH; C optionally substituted by one halo 1~3 alkyl; and C 1~3 alkoxyl; independently selected from the group consisting of: A compound according to any one of Embodiments 41 to 44, or a stereoisomer, racemate, tautomer, hydrate or solvate thereof, or a pharmaceutically acceptable salt.

[0062] Embodiment 46. R4' and R4'' together with the carbon atom to which they are attached optionally form a 3- to 5-membered cycloalkyl ring optionally substituted by 1 or 2 C 1~3 alkyl, and R4''' is H. A compound according to any one of Embodiments 41 to 44, or a stereoisomer, racemate, tautomer, hydrate or solvate thereof, or a pharmaceutically acceptable salt.

[0063] Embodiment 47. Each of R4’ and R4’’’ is H, and R4’’ is C substituted with one halo 1~3 alkyl, The compound according to any one of Embodiments 41 to 44, or a stereoisomer, racemate, tautomer, hydrate or solvate thereof, or a pharmaceutically acceptable salt.

[0064] Embodiment 48. R4’ and R4’’ together with the carbon atom to which they are attached optionally form a 3- or 5-membered cycloalkyl ring optionally substituted with one or two methyls, and R4’’’ is H, The compound according to any one of Embodiments 41 to 44, or a stereoisomer, racemate, tautomer, hydrate or solvate thereof, or a pharmaceutically acceptable salt.

[0065] Embodiment 49. moiety

Chemical formula

Chemical formula

[0066] Embodiment 50. moiety [Chemical formula] wherein [Chemical formula] [wherein, R4’’’ is H, R4’ and R4’’ are each independently selected from the group consisting of H; halo; C 1~6 alkyl optionally substituted by one halo; and C 1~6 alkoxyl; provided that one of R4’ and R4’’ is not H, or R4’ and R4’’ together with the carbon atom to which they are attached form a 3- or 5-membered cycloalkyl ring optionally substituted by 1 or 2 C 1~3 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 pharmaceutically acceptable salt.

[0067] Embodiment 51. Part [Chemical formula] wherein [Chemical formula] [wherein, R4’ is H, and R4’’ and R4’’’ are each independently C 1~3 alkyl] which is the 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.

[0068] Embodiment 52. Part [Chemical formula] wherein [Chemical formula] [wherein, one of R4’ and R4’’ is H and the other is C 1~6 alkyl, or R4’ and R4’’, 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 C 1~3 alkyl] 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 pharmaceutically acceptable salt.

[0069] Embodiment 53. Part [Chemical formula] is [Chemical formula] [wherein, R4’ is H and R4’’ is C 1~6 alkyl substituted with one halo, or R4’ and R4’’, together with the carbon atom to which they are attached, optionally form a 3- or 5-membered cycloalkyl ring] 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 pharmaceutically acceptable salt.

[0070] Embodiment 54. Part [Chemical formula] is [Chemical formula] [wherein, R4’ is H and R4’’ is C 1~3 alkyl substituted with one F, or R4’ and R4’’, together with the carbon atom to which they are attached, optionally form a 3- or 5-membered cycloalkyl ring] is, The 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. Part

Chemical formula

Chemical formula

[0072] Embodiment 56. Part

Chemical formula

Chemical formula

[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

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

[0074] Embodiment 58. A compound according to any one of Embodiments 1 to 57, or a stereoisomer, racemate, tautomer, hydrate or solvate thereof, or a pharmaceutically acceptable salt, 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 thereof, or a pharmaceutically acceptable salt, 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 acute leukemia, chronic leukemia, myeloid leukemia, myelogeneous 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-PTD leukemia, MLL amplified leukemia, MLL positive leukemia, nucleophosmin (NPM) mutant 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. The compound according to any one of Embodiments 1 to 57, or a stereoisomer, racemate, tautomer, hydrate or solvate thereof, or a pharmaceutically acceptable salt.

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

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

[0080] Embodiment 64. A method for treating or preventing cancer or diabetes, comprising administering to a subject in need thereof an effective amount of the compound according to any one of Embodiments 1 to 57, or a stereoisomer, racemate, tautomer, hydrate or solvate thereof, or a pharmaceutically 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 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-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 thereof, or a pharmaceutically acceptable salt, and at least one additional therapeutic agent, wherein the additional therapeutic agent is preferably an anti-neoplastic agent, for example, a radiotherapy agent, a chemotherapy agent, an immunotherapy agent, or a targeted therapy agent.

[0082] Embodiments of the present disclosure - Part B Embodiment 1. Formula I: [Chemical formula] [Wherein, X is halo or CN, Y is N or CH, Z is selected from the group consisting of CH2, O, S and NH, R1 is 1)-(C=O)-NRaRb (wherein, Ra and Rb are 1, 2 or 3 substituents selected from the group consisting of halo, OH, CN and C 1~6 optionally substituted by alkoxyl, C 1~6Independently selected from the group consisting of alkyl, 3- to 6-membered cycloalkyl rings, and 5- to 9-membered heterocyclyl rings, or Ra and Rb, together with the nitrogen atom to which they are attached, form a C 1~6 5- to 9-membered heterocyclyl ring optionally substituted by 1, 2, or 3 substituents selected from the group consisting of alkyl, halo, OH, and CN); 2) halo, CN, C 1~6 5- to 10-membered heteroaryl ring or C optionally substituted by 1, 2, or 3 substituents selected from the group consisting of alkyl and 3- to 5-membered cycloalkyl rings 6~10 aryl ring; selected from the group consisting of R2 and R3 are each independently H or D, each R4 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 alkoxyl, 3- to 9-membered cycloalkyl ring, 5- to 10-membered heteroaryl ring, and 4- to 9-membered heterocyclyl ring, independently selected, and the alkyl, alkenyl, alkynyl, alkoxyl, cycloalkyl ring, heteroaryl ring, or heterocyclyl ring is optionally substituted by 1, 2, or 3 substituents selected from the group consisting of halo, CN, and OH, two adjacent R4s, together with the carbon atom to which they are attached, form a C 1~6 alkyl, -C 1~6 alkyl-OH, C 1~6 alkoxyl-C 1~6 alkyl-, halo, CN, and OH, optionally forming a 3- to 9-membered cycloalkyl ring optionally substituted by 1, 2, or 3 substituents selected from the group consisting of or two R4s attached to the same carbon atom, together with the carbon atom, form a C 1~6Alkyl, -C 1~6 Alkyl-OH, C 1~6 Alkoxyl-C 1~6 Optionally form 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 R4s together with the carbon atom to which they are attached optionally form a 5- to 10-membered heteroaryl ring, C 6~10 Aryl ring or a 5- to 9-membered heterocyclyl ring, the heteroaryl ring or aryl ring being optionally substituted with 1, 2, or 3 substituents selected from the group consisting of 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, halo, CN, and OH, alkyl being optionally substituted with 1 3- to 6-membered cycloalkyl ring or phenyl, and the heterocyclyl ring being optionally substituted with 1, 2, or 3 substituents selected from the group consisting of 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 R5 is selected from the group consisting of H, halo, methyl optionally substituted with 1, 2, or 3 deuteriums or halo, methoxyl optionally substituted with 1, 2, or 3 deuteriums or halo, NH2, CH3NH, or (CH3)2N 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] Of the compound, or its stereoisomers, racemates, tautomers, hydrates or solvates, or pharmaceutically acceptable salts

[0083] Embodiment 2. X is F, Cl, or CN Y is N or CH, Z is selected from the group consisting of CH2, O, S and NH, R1 is, 1) -(C=O)-NRaRb [wherein, Ra and Rb are 1, 2 or 3 substituents selected from the group consisting of halo, OH and C 1~6 alkyl optionally substituted by 1, 2 or 3 substituents selected from the group consisting of alkoxyl and C 1~6 alkyl and 3- to 5-membered cycloalkyl rings, respectively independently selected from the group consisting of, or Ra and Rb, together with the nitrogen atom to which they are attached, form a 5- to 6-membered monocyclic or 7- to 9-membered bicyclic heterocyclyl ring optionally substituted by 1, 2 or 3 substituents selected from the group consisting of C 1~6 alkyl and halo]; 2) halo, CN, C 1~6 a 5- to 6-membered heteroaryl ring optionally substituted by 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 alkyl, and a C 6~10 aryl ring substituted by 1, 2 or 3 substituents selected from the group consisting of alkyl and 3- to 5-membered cycloalkyl rings, selected from the group consisting of, R2 and R3 are each independently H or D, each R4 is independently selected from the group consisting of halo, CN, OH, C 1~6 alkylsulfonyl-, C 1~6 alkylsulfonylamino-, C 1~6 alkylcarbonylamino-, phenyl, C 1~6 alkyl, C 1~6 alkoxyl, 3- to 6-membered cycloalkyl rings, 5- to 10-membered heteroaryl rings and 5- to 9-membered heterocyclyl rings, wherein the alkyl, alkoxyl, cycloalkyl ring, heteroaryl ring or heterocyclyl ring is optionally substituted by 1, 2 or 3 substituents selected from the group consisting of halo, CN and OH, two adjacent R4s, together with the carbon atom to which they are attached, form a C1~6 Alkyl, -C 1~6 Alkyl-OH, C 1~6 Alkoxyl-C 1~6 Optionally form a 3- to 6-membered cycloalkyl ring optionally substituted by 1, 2 or 3 substituents selected from the group consisting of alkyl- and halo Or, two R4s bonded to the same carbon atom, together with the carbon atom, optionally form a 3- to 6-membered cycloalkyl ring optionally substituted by 1, 2 or 3 substituents selected from the group consisting of halo, CN and OH Or, two adjacent R4s, together with the carbon atoms to which they are attached, optionally form a 5- to 10-membered heteroaryl ring, phenyl or 5- to 9-membered heterocyclyl ring optionally substituted by 1, 2 or 3 substituents selected from the group consisting of halo, C 1~6 Alkyl and C 1~6 Haloalkyl, wherein the alkyl is optionally substituted by one 3- to 6-membered cycloalkyl ring or phenyl R5 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 The compound according to Embodiment 1, or a stereoisomer, racemate, tautomer, hydrate or solvate thereof, or a pharmaceutically acceptable salt

[0084] Embodiment 3 Each R4 is independently selected from the group consisting of halo, CN, OH, C 1~6 Alkylsulfonyl-, C 1~6 Alkylsulfonylamino-, phenyl, C 1~6 Alkyl, C 1~6 Alkoxyl and 3- to 6-membered cycloalkyl ring, wherein the alkyl or alkoxyl is optionally substituted by 1, 2 or 3 substituents selected from the group consisting of halo, CN and OH Two adjacent R4s, together with the carbon atoms to which they are attached, form C 1~6 Alkyl, -C1~6 Alkyl-OH, C 1~6 Alkoxyl-C 1~6 Optionally form a 3- to 6-membered cycloalkyl ring optionally substituted by 1, 2 or 3 substituents selected from the group consisting of alkyl- and halo Or, two R4s bonded to the same carbon atom, together with the carbon atom, optionally form a 3- to 6-membered cycloalkyl ring optionally substituted by 1, 2 or 3 substituents selected from the group consisting of halo, CN and OH Or, two adjacent R4s, together with the carbon atoms to which they are attached, form optionally a 5- to 10-membered heteroaryl ring or phenyl optionally substituted by 1, 2 or 3 substituents selected from the group consisting of C 1~6 Alkyl, wherein the alkyl is optionally substituted by 1 3- to 6-membered cycloalkyl ring or phenyl The compound according to Embodiment 1 or 2, or a stereoisomer, racemate, tautomer, hydrate or solvate thereof, or a pharmaceutically acceptable salt

[0085] Embodiment 4 Each R4 is independently selected from the group consisting of halo, CN, OH, C 1~6 Alkylsulfonyl-, C 1~6 Alkylsulfonylamino-, phenyl, C 1~6 Alkyl, and C 1~6 Alkoxyl, wherein the alkyl or alkoxyl is optionally substituted by 1, 2 or 3 substituents selected from the group consisting of halo, CN and OH Two adjacent R4s, together with the carbon atoms to which they are attached, form C 1~6 Alkyl, -C 1~6 Alkyl-OH, C 1~6 Alkoxyl-C 1~6 Optionally form a 3- to 6-membered cycloalkyl ring optionally substituted by 1, 2 or 3 substituents selected from the group consisting of alkyl- and halo Or, two R4 groups attached to the same carbon atom, together with the carbon atom, optionally form a 3- to 6-membered cycloalkyl ring optionally substituted by one, two or three substituents selected from the group consisting of halo, CN and OH. Or, two adjacent R4 groups, together with the carbon atoms to which they are attached, optionally form a 5- to 10-membered heteroaryl ring or a phenyl optionally substituted by one, two or three substituents selected from the group consisting of C 1~6 alkyl, wherein the alkyl is optionally substituted by one 3- to 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 pharmaceutically acceptable salt.

[0086] Embodiment 5. The compound is of formula II:

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

[0087] Embodiment 6. The compound is of Formula III:

Chemical formula

[0088] Embodiment 7. The compound according to any one of Embodiments 1 to 6, or a stereoisomer, racemate, tautomer, hydrate or solvate thereof, or a pharmaceutically acceptable salt, wherein X is F.

[0089] Embodiment 8. The compound according to any one of Embodiments 1 to 7, or a stereoisomer, racemate, tautomer, hydrate or solvate thereof, or a pharmaceutically acceptable salt, wherein Z is selected from the group consisting of CH2, O and S, preferably CH2.

[0090] Embodiment 9. The compound according to any one of Embodiments 1 to 8, or a stereoisomer, racemate, tautomer, hydrate or solvate thereof, or a pharmaceutically acceptable salt, wherein R2 and R3 are each independently H.

[0091] Embodiment 10. R1 is -(C=O)-NRaRb [wherein, Ra and Rb are each independently selected from the group consisting of halo, OH and C 1~6 alkyl optionally substituted with 1, 2 or 3 substituents selected from the group consisting of alkoxyl and C 1~6 alkyl and 3- to 5-membered cycloalkyl rings, or Ra and Rb, together with the nitrogen atom to which they are attached, form a C 1~6It forms a 5- to 6-membered monocyclic or 7- to 9-membered bicyclic heterocyclyl ring having another ring heteroatom selected from N, O, and S, optionally substituted by 1, 2, or 3 substituents selected from the group consisting of alkyl and halo. The compound according to any one of Embodiments 1 to 9, or a stereoisomer, racemate, tautomer, hydrate or solvate thereof, or a pharmaceutically acceptable salt.

[0092] Embodiment 11. R1 is -(C=O)-NRaRb [wherein Ra and Rb are each C 1~6 alkyl, preferably Ra is ethyl and Rb is isopropyl], or R1 is halo, CN, C 1~6 a 5- to 6-membered heteroaryl ring optionally substituted by 1, 2, or 3 substituents selected from the group consisting of alkyl and a 3- to 5-membered cycloalkyl ring, or halo, CN, C 1~6 phenyl substituted by 1, 2, or 3 substituents selected from the group consisting of alkyl and a 3- to 5-membered cycloalkyl ring. The compound according to any one of Embodiments 1 to 10, or a stereoisomer, racemate, tautomer, hydrate or solvate thereof, or a pharmaceutically acceptable salt.

[0093] Embodiment 12. R1 is -(C=O)-NRaRb [wherein Ra is ethyl and Rb is isopropyl]. The compound according to any one of Embodiments 1 to 11, or a stereoisomer, racemate, tautomer, hydrate or solvate thereof, or a pharmaceutically acceptable salt.

[0094] Embodiment 13. R1 is halo, CN, C 1~6 a 5- to 6-membered heteroaryl ring optionally substituted by 1, 2, or 3 substituents selected from the group consisting of alkyl and a 3- to 5-membered cycloalkyl ring, or halo, CN, C 1~6phenyl substituted with one, two or three substituents selected from the group consisting of alkyl and 3- to 5-membered cycloalkyl rings The compound according to any one of Embodiments 1 to 12, or a stereoisomer, racemate, tautomer, hydrate or solvate thereof, or a pharmaceutically acceptable salt

[0095] Embodiment 14 R1 is [Chemical formula] [wherein, A1 or A2 is N or CH, R6 is halo, CN, C 1~6 selected from the group consisting of alkyl and 3- to 5-membered cycloalkyl rings, and R7 is H, halo, CN, C 1~6 selected from the group consisting of alkyl and 3- to 5-membered cycloalkyl rings], preferably, R1 is [Chemical formula] or, R1 is [Chemical formula] [wherein, A3 is N or C substituted by halo, and R8 is C 1~6 alkyl], preferably, R1 is [Chemical formula] The compound according to any one of Embodiments 1 to 13, or a stereoisomer, racemate, tautomer, hydrate or solvate thereof, or a pharmaceutically acceptable salt

[0096] Embodiment 15. The compound is of Formula IIb: [Chemical formula] The compound according to Embodiment 14, or a stereoisomer, racemate, tautomer, hydrate or solvate thereof, or a pharmaceutically acceptable salt

[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 pharmaceutically 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 pharmaceutically acceptable salt thereof.

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

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

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

[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 pharmaceutically acceptable salt thereof.

[0103] Embodiment 22. each of c and d is 2, The compound according to any one of Embodiments 1 to 21, or a stereoisomer, racemate, tautomer, hydrate or solvate thereof, or a pharmaceutically acceptable salt.

[0104] Embodiment 23. m is 1 or 2, The compound according to any one of Embodiments 1 to 22, or a stereoisomer, racemate, tautomer, hydrate or solvate thereof, or a pharmaceutically acceptable salt.

[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, The compound according to any one of Embodiments 1 to 23, or a stereoisomer, racemate, tautomer, hydrate or solvate thereof, or a pharmaceutically acceptable salt.

[0106] Embodiment 25. Each R4 is halo; CN; OH; C 1~6 alkylsulfonyl-; C 1~6 alkylsulfonylamino-; phenyl; C optionally substituted by 1, 2 or 3 substituents selected from the group consisting of halo, CN and OH 1~6 alkyl; and C optionally substituted by halo 1~6 alkoxyl; independently selected from the group consisting of, Two adjacent R4s, together with the carbon atom to which they are attached, optionally form a 3- to 6-membered cycloalkyl ring optionally substituted by 1, 2 or 3 substituents selected from the group consisting of C 1~6 alkyl, -C 1~6 alkyl-OH, C 1~6 alkoxyl-C 1~6 alkyl- and halo. Or, two R4s attached to the same carbon atom, together with the carbon atom, optionally form a 3- to 6-membered cycloalkyl ring optionally substituted by 1, 2, or 3 halos. Or, two adjacent R4s, together with the carbon atom to which they are attached, form a 5- to 6-membered heteroaryl ring optionally substituted by 1, 2, or 3 C 1~6 alkyl substituents, and the alkyl is optionally substituted by 1 3- to 6-membered cycloalkyl ring or phenyl. Or, two adjacent R4s, together with the carbon atom to which they are attached, optionally form phenyl. A compound according to any one of Embodiments 1 to 24, or a stereoisomer, racemate, tautomer, hydrate or solvate thereof, or a pharmaceutically acceptable salt.

[0107] Embodiment 26. R1 is

Chemical formula

[0108] Embodiment 27. R1 is

Chemical formula

[0109] Embodiment 28. Part

Chemical formula

Chemical formula

[0110] Embodiment 29. moiety

Chem.

Chem.

[0111] Embodiment 30. X is F, Z is CH2, R1 is 1)-(C=O)-NRaRb [wherein Ra and Rb are each independently selected from the group consisting of C 1~6 alkyl, or Ra and Rb, together with the nitrogen atom to which they are attached, form a 5- to 6-membered monocyclic or 7- to 9-membered bicyclic heterocyclyl ring optionally substituted by 1, 2 or 3 C 1~6 alkyl]; 2) a 5- to 6-membered heteroaryl ring substituted with 1, 2 or 3 substituents selected from the group consisting of halo, CN, C 1~6 alkyl and 3- to 5-membered cycloalkyl rings; 3) a C 1~6 aryl ring substituted with 1, 2 or 3 substituents selected from the group consisting of halo, CN, C 6~10 alkyl, and 3- to 5-membered cycloalkyl rings; selected from the group consisting of, R2 and R3 are each independently H, each R4 is halo; CN; OH; C 1~6 alkylsulfonyl-; C1~6 alkylsulfonylamino-; phenyl; optionally substituted with 1, 2 or 3 substituents selected from the group consisting of halo, CN and OH, C 1~6 alkyl; and optionally substituted with 1, 2 or 3 halo, C 1~6 alkoxyl; and a 3- to 6-membered cycloalkyl ring; independently selected from the group consisting of, Two adjacent R4s, together with the carbon atom to which they are attached, form a C 1~6 alkyl, -C 1~6 alkyl-OH, C 1~6 alkoxyl-C 1~6 optionally form a 3- to 6-membered cycloalkyl ring, optionally substituted with 1, 2 or 3 substituents selected from the group consisting of alkyl- and halo, or two adjacent R4s, together with the carbon atom to which they are attached, optionally form a phenyl, R5 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 pharmaceutically acceptable salt.

[0112] Embodiment 31. A compound according to any one of embodiments 1 to 30, or a stereoisomer, racemate, tautomer, hydrate or solvate thereof, or a pharmaceutically acceptable salt, wherein R5 is H or halo, preferably H.

[0113] Embodiment 32. Each R4 is halo; CN; OH; C 1~6 alkylsulfonyl-; C 1~6 alkylsulfonylamino-; phenyl; optionally substituted with 1, 2 or 3 substituents selected from the group consisting of halo, CN and OH, C 1~6 alkyl; and optionally substituted with 1, 2 or 3 halo, C1~6 Independently selected from the group consisting of alkoxyl; Two adjacent R4, together with the carbon atom to which they are attached, form a C 1~6 Alkyl, -C 1~6 Alkyl-OH, and C 1~6 Alkoxyl-C 1~6 Optionally form a 3- to 6-membered cycloalkyl ring, optionally substituted by 1, 2 or 3 substituents selected from the group consisting of alkyl- Or, two adjacent R4, together with the carbon atom to which they are attached, optionally form a phenyl The compound according to any one of Embodiments 1 to 31, or a stereoisomer, racemate, tautomer, hydrate or solvate thereof, or a pharmaceutically acceptable salt.

[0114] Embodiment 33. The compound according to any one of Embodiments 1 to 32, or a stereoisomer, racemate, tautomer, hydrate or solvate thereof, or a pharmaceutically acceptable salt, wherein R1 is -(C=O)-NRaRb, and Ra and Rb are each independently selected from the group consisting of ethyl or isopropyl.

[0115] Embodiment 34. The compound according to any one of Embodiments 1 to 33, or a stereoisomer, racemate, tautomer, hydrate or solvate thereof, or a pharmaceutically acceptable salt, wherein R1 is a 5- or 6-membered heteroaryl ring or a C 1~6 Substituted with 1 or 2 substituents selected from the group consisting of alkyl and cyclopropyl 6~10 Aryl ring.

[0116] Embodiment 35. Moiety

Chemical formula

Chemical formula

[0117] Embodiment 36. Portion

Chemical formula

Chemical formula

[0118] Embodiment 37. Part

Chemical Formula

Chemical Formula

[0119] Embodiment 38. [wherein, R4’, R4’’ and R4’’’ are each independently selected from the group consisting of 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 1~6 alkoxyl; The compound according to any one of Embodiments 1 to 37, or a stereoisomer, racemate, tautomer, hydrate or solvate thereof, or a pharmaceutically acceptable salt.

[0120] Embodiment 39. R4’ and R4’’ together with the carbon atom to which they are attached optionally form a 3- to 6-membered cycloalkyl ring optionally substituted by one, two or three substituents selected from the group consisting of C 1~6 alkyl, -C 1~6 alkyl-OH, and C 1~6 alkoxyl-C 1~6 alkyl-, and R4’’’ is H, A compound according to any one of embodiments 1 to 38, or a stereoisomer, racemate, tautomer, hydrate or solvate thereof, or a pharmaceutically acceptable salt.

[0121] Embodiment 40. Each of R4’ and R4’’’ is H, and R4’’ is C 1~6 alkyl substituted with one, two or three halos, A compound according to any one of embodiments 1 to 39, or a stereoisomer, racemate, tautomer, hydrate or solvate thereof, or a pharmaceutically acceptable salt.

[0122] Embodiment 41. R4’ and R4’’ together with the carbon atom to which they are attached optionally form a 3- or 5-membered cycloalkyl ring optionally substituted by one, two or three halos, and R4’’’ is H, A compound according to any one of embodiments 1 to 40, or a stereoisomer, racemate, tautomer, hydrate or solvate thereof, or a pharmaceutically acceptable salt.

[0123] Embodiment 42. portion

Chemical formula

Chemical formula

[0124] Embodiment 43. portion

Chem.

Chem.

[0125] Embodiment 44. portion

Chem.

Chem.

[0126] Embodiment 45. Portion [Chemistry] wherein, [Chemistry] [wherein, one of R4’ and R4’’ is H and the other is C 1~6 alkyl, or R4’ and R4’’, 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 C 1~6 alkyl] is a compound according to any one of Embodiments 1 to 44, or a stereoisomer, racemate, tautomer, hydrate or solvate thereof, or a pharmaceutically acceptable salt.

[0127] Embodiment 46. Part [Chemistry] wherein, [Chemistry] [wherein, R4’ is H and R4’’ is C 1~6 alkyl substituted with 1 or 2 halos, or R4’ and R4’’, 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 halos] is a compound according to any one of Embodiments 1 to 45, or a stereoisomer, racemate, tautomer, hydrate or solvate thereof, or a pharmaceutically acceptable salt.

[0128] Embodiment 47. Part [Chemistry] wherein, [Chemistry] [wherein, R4’ is H, R4’’ is C substituted with 1 or 3 halos 1、1~6 alkyl, or R4’ and R4’’, together with the carbon atom to which they are attached, optionally form a 3- or 5-membered cycloalkyl ring]. A compound according to any one of Embodiments 1 to 46, or a stereoisomer, racemate, tautomer, hydrate or solvate thereof, or a pharmaceutically acceptable salt.

[0129] Embodiment 48. Part

Chemical Structure

Chemical Structure

[0130] Embodiment 49. Part

Chemical Structure

Chemical Structure

[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 pharmaceutically acceptable salt.

[0132] Embodiment 51. A compound according to any one of Embodiments 1 to 50 for use as a medicament, or a stereoisomer, racemate, tautomer, hydrate or solvate thereof, or a pharmaceutically acceptable salt.

[0133] Embodiment 52. A compound according to any one of Embodiments 1 to 50 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, or a stereoisomer, racemate, tautomer, hydrate or solvate thereof, or a pharmaceutically acceptable salt.

[0134] Embodiment 53. For use in the treatment or prevention of cancer or diabetes Preferably, the cancer is a hematological malignancy, 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 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-PTD leukemia, MLL amplified leukemia, MLL positive leukemia, nucleophosmin (NPM) mutant 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. The compound according to any one of Embodiments 1 to 50, or a stereoisomer, racemate, tautomer, hydrate or solvate thereof, or a pharmaceutically acceptable salt.

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

[0137] Embodiment 56. A method for inhibiting the interaction between menin and MLL and / or an MLL fusion protein in vivo or in vitro, which comprises contacting an effective amount of the compound according to any one of Embodiments 1 to 50 or a pharmaceutically acceptable salt thereof with menin and MLL and / or an MLL fusion protein.

[0138] Embodiment 57. A method for treating or preventing cancer or diabetes, which comprises administering to a subject in need thereof an effective amount of the compound according to any one of Embodiments 1 to 50, or a stereoisomer, racemate, tautomer, hydrate or solvate thereof, or a pharmaceutically acceptable salt thereof, preferably, the cancer is a hematological malignancy, 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 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-PTD leukemia, MLL amplified leukemia, MLL positive leukemia, nucleophosmin (NPM) mutant 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 the compound according to any one of Embodiments 1 to 50, or a stereoisomer, racemate, tautomer, hydrate or solvate thereof, or a pharmaceutically acceptable salt, and at least one additional therapeutic agent, wherein the additional therapeutic agent is preferably an anti-neoplastic agent, for example, a radiotherapy agent, a chemotherapy agent, an immunotherapy agent, or a targeted therapy agent.

[0140] Definition As used herein, the following words, phrases and symbols have the meanings set forth below unless otherwise specified in the context.

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

[0143] As used herein, the term "alkyl" refers to a straight-chain or branched-chain saturated hydrocarbon 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 ). 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] As used herein, the term "alkenyl" contains one or more, for example 1, 2, or 3 carbon-carbon double bonds (C=C) and has 2 to 10 carbon atoms (C2~10 ) and preferably has 2 to 6 carbon atoms (C 2~6 ), more preferably 2 to 4 carbon atoms (C 2~4 ) and refers to a linear or branched 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 and preferably containing 1 or 2 carbon-carbon double bonds. "C 2~4 alkenyl" refers to an alkenyl having 2 to 4 carbon atoms and preferably containing 1 carbon-carbon double bond. Examples of alkenyl include, but are not limited to, vinyl, 2-propenyl, and 2-butenyl. The bonding point of the alkenyl may or may not be on the double bond.

[0145] As used herein, the term "alkynyl" contains one or more, for example, 1, 2, or 3 carbon-carbon triple bonds (C≡C) and has 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 ) and refers to a linear or branched unsaturated hydrocarbon group. For example, "C 2~6 alkynyl" refers to an alkynyl having 2 to 6 (2, 3, 4, 5 or 6) carbon atoms and preferably containing 1 or 2 carbon-carbon triple bonds. "C 2~4 alkynyl" refers to an alkynyl having 2 to 4 carbon atoms and preferably containing 1 carbon-carbon triple bond. Examples of alkynyl include, but are not limited to, ethynyl, 2-propynyl, and 2-butynyl. The bonding point of the alkynyl may or may not be on the triple bond.

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

[0147] As used herein, the term "haloalkyl" refers to an alkyl as defined herein in which one or more, for example 1, 2, 3, 4 or 5, hydrogen atoms are replaced by halogen atoms, and when one or more hydrogen atoms are replaced by 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 by 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 by halogen atoms and the halogen atoms may be different from each other. Examples of haloalkyl include, but are not limited to, -CF3, -CHF2, -CH2F, -CH2CF3, -CF2CF3, -CF2CH3, etc. Preferably, the haloalkyl is C 1~6 trifluoroalkyl, more preferably -CF3 で is.

[0148] The term "alkyl substituted with 1, 2 or 3 halos" refers to an alkyl as defined herein in which one or more, for example 1, 2 or 3, hydrogen atoms are replaced by halogen atoms, and when two or more hydrogen atoms are replaced by halogen atoms, the halogen atoms may be the same or different from each other, for example, -CF3, -CHF2, -CH2F, -CH2CF3, -CH2CH2F, -CF2CH3, etc., but are not limited thereto. Similarly, the term "alkyl substituted with 1, 2 or 3 CNs" includes, but is not limited to, -CH2CN and -CH2CH2CN. The term "alkoxyl substituted with 1, 2 or 3 halos" includes, but is not limited to, -OCH2F, -OCHF2, -OCHF3, -OCH2CHF3.

[0149] As used herein, the term "alkoxyl" refers to the group -O-alkyl where alkyl is as defined above. Examples of alkoxyl include C 1~6 alkoxyls (including their isomers), but are not limited thereto. Preferably, the alkoxyl is methoxy.

[0150] As used herein, the term "cycloalkyl" refers to a saturated cyclic hydrocarbon group having from 3 to 10 ring carbon atoms (C 3~10 ), for example from 3 to 9 ring carbon atoms (C 3~9 ), from 3 to 7 ring carbon atoms (C 3~7 ), from 3 to 6 ring carbon atoms (C 3~6 ), from 3 to 5 ring carbon atoms (C 3~5 ) or from 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 a monocyclic C 3~6 cycloalkyl (e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl) or a monocyclic C 3~5 cycloalkyl (e.g., cyclopropyl, cyclobutyl, cyclopentyl) ring. For example, the cycloalkyl is a bicyclic cycloalkyl ring, preferably a bicyclic C5 - C 10 cycloalkyl ring. Bicyclic cycloalkyls include fused rings, bridged rings, or spiro rings.

[0151] As used herein, the term "heterocyclyl" refers to a saturated or partially unsaturated ring having 3 to 10 ring atoms (3- to 10-membered), such as 5 to 9 ring atoms (5- to 9-membered), 6 to 8 ring atoms (6- to 8-membered), 5 to 6 ring atoms (5- to 6-membered), or 7 to 9 ring atoms (7- to 9-membered), one or more, such as 1, 2, or 3, preferably 1 or 2, of the ring atoms being heteroatoms independently selected from N, O, and S, the remaining ring atoms being carbon, having one or more, such as 1, 2, or 3, preferably 1 or 2, rings, and the N or S heteroatoms being optionally oxidized to various oxidation states. The point of attachment of the heterocyclyl can be on an N heteroatom or a carbon atom. The ring of the heterocyclyl also includes a fused ring, a bridged ring, or a spiro ring. The ring of the heterocyclyl can be saturated or contain one or more, such as one or two, double bonds (i.e., be partially unsaturated), but is not completely conjugated and is not a heteroaryl as defined herein. For example, "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, preferably a saturated 5- to 6-membered monocyclic or 7- to 9-membered bicyclic heterocyclyl. Examples of heterocyclyl include, but are not limited to, pyrrolidinyl, imidazolidinyl, morpholinyl, thiomorpholinyl, piperidinyl, piperazinyl, hexahydropyrimidyl, oxazinananyl, 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[3.1.1]heptanyl, 3-azabicyclo[4.1.0]heptanyl, azabicyclo[2.2.2]hexanyl, 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 rings. 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 a carbocyclic hydrocarbon group having 6 to 14 carbon atoms (C 6~14 ), preferably 6 to 10 carbon atoms (C 6~10 ), consisting of one ring or multiple fused rings, with at least one ring being aromatic. Examples of aryl include, but are not limited to, phenyl, naphthalenyl, 1,2,3,4-tetrahydronaphthalenyl, phenanthryl, indenyl, indanyl, or azulene rings, preferably phenyl or naphthalenyl rings, more preferably phenyl rings.

[0153] As used herein, the term "heteroaryl" refers to a monocyclic, bicyclic, or tricyclic ring system having 5 to 12 ring atoms (5- to 12-membered), such as 5 to 10 ring atoms (5- to 10-membered), 5 to 9 ring atoms (5- to 9-membered), 8 to 10 ring atoms (8- to 10-membered), 5 to 6 ring atoms (5- to 6-membered), 5 ring atoms (5-membered), or 6 ring atoms (6-membered), with at least one ring being a 5- or 6-membered aromatic ring, and one or more, such as 1, 2, or 3, preferably 1 or 2, of the ring atoms being heteroatoms independently selected from N, O, and S, the remaining ring atoms being carbon, and the N or S heteroatoms being optionally oxidized to various oxidation states. For example, 5- to 10-membered heteroaryl is - a 5- to 6-membered monocyclic heteroaryl, i.e., a monocyclic aromatic hydrocarbon group having 5 or 6 ring atoms (5- or 6-membered), with one or more, such as 1, 2, or 3, preferably 1 or 2, of the ring atoms being ring heteroatoms independently selected from N, O, and S (preferably N), and the remaining ring atoms being carbon; preferably, a monocyclic aromatic hydrocarbon group having 6 ring atoms (6-membered), with 1, 2, or 3, preferably 1 or 2, of the ring atoms being 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-membered), wherein one or more, for example, 1, 2, 3 or 4, preferably 1, 2 or 3 of the ring atoms are ring heteroatoms independently selected from N, O and S (preferably N), and 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), oxazolyl, 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, benzoisoxazolyl, benzothienyl, benzothiazolyl, benzoisothiazolyl, imidazopyridyl, imidazopyrrolyl, triazolopyridyl, indazolyl, pyrrolopyridyl, pyrrolopyrimidinyl, pyrazolopyridyl, pyrazolopyrimidinyl, tetrazolopyridyl, tetrahydropyrazolopyridyl, benzofuryl, benzimidazolinyl, or indolyl, but are not limited thereto. 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] As used herein, the term "oxo" refers to the group =O.

[0156] The radical “D” means that the hydrogen atoms in that part are replaced by deuterium, which is an isotope thereof.

[0157] In this specification, when a wavy line

Chem.

[0158] When a radical has a wavy line on the bond

Chem.

[0159] As used herein, a bond through a ring means that, unless otherwise indicated, the group having the bond is attached to the ring at any chemically acceptable position of the ring.

[0160] The radical

Chem.

[0161] As used herein, the term "optional" or "optionally" means that the subsequently recited event or circumstance may or may not occur, and the description includes both the case where the event or circumstance occurs and the case where it does not occur. For example, "optionally substituted by" includes both "unsubstituted" as defined and "substituted by one, two, three or more substituents". One of ordinary skill in the art will understand that for any group containing one or more substituents, such groups do not include any substitutions or substitution patterns that are not sterically practical, chemically incorrect, synthetically infeasible, and / or inherently unstable.

[0162] As used herein, the term "substituted" or "substituted by..." means that one or more hydrogens on the specified atom or group are replaced by 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 by one, two or three..." means that one, two or three hydrogens on the specified atom or group are replaced by 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. When the substituent is oxo (i.e., =O), two hydrogens on a single atom are replaced by oxo. Combinations of substituents and / or variables are permitted only if such combinations result in a chemically correct and stable compound. A chemically correct and stable compound means a compound that is sufficiently robust to withstand adequate isolation from a reaction mixture.

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

[0164] Racemates or other mixtures of isomers can be used as such or can be separated into the individual isomers. By this separation, stereochemically pure compounds or mixtures enriched in one or more isomers can be obtained. Methods for separating isomers are well known (see, for example, Allinger N.L. and Eliel E.L. in "Topics in Stereochemistry", Vol. 6, Wiley Interscience, 1971).

[0165] When the structures herein contain "(R)" and / or "(S)", it means that the chiral center of the compound marked by "(R)" or "(S)" is in a single configuration of either the R-configuration or the S-configuration. Such R-stereoconfiguration or S-stereoconfiguration of the chiral center of the compound is simply

Chemical formula

[0166] The term "pharmaceutically acceptable salt" includes, but is not limited to, acid addition salts formed by the compounds disclosed herein using inorganic acids such as hydrochloride, hydrobromide, carbonate, bicarbonate, phosphate, sulfate, sulfite, nitrate, etc., and similarly, organic acids such as formate, acetate, malate, maleate, fumarate, tartrate, succinate, citrate, lactate, methanesulfonate, p-toluenesulfonate, 2-hydroxyethylsulfonate, benzoate, salicylate, stearate, and salts with alkanedicarboxylic acids of the formula HOOC-(CH2) n -COOH [wherein n is from 0 to 4]. Also, "pharmaceutically acceptable salts" include base addition salts formed by the compounds of the present disclosure having an acidic moiety and a pharmaceutically acceptable cation such as sodium, potassium, calcium, aluminum, lithium, and ammonium.

[0167] In addition, when 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, when the product is a free base, acid addition salts, particularly pharmaceutically acceptable acid addition salts, can be formed from the basic 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. One of ordinary skill in the art will recognize the various synthetic methodologies that can be used without undue experimentation to prepare non-toxic pharmaceutically acceptable acid addition salts or base addition salts.

[0168] The term "protecting group" or "PG" refers to a substituent commonly used to block or protect a particular functional group while allowing other functional groups on the compound to react. For example, an "amino protecting group" is a substituent attached to an amino group that blocks or protects the amino functional group 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-fluorenylmethyloxycarbonyl (Fmoc). Similarly, a "hydroxy protecting group" refers to a substituent on a hydroxy group that blocks or protects the hydroxy functional group. 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 use, see T.W. Greene and P.G.M. Wuts, "Protective Groups in Organic Synthesis", 5th Edition, Wiley, New York, 2014.

[0169] As used herein, the terms "pharmaceutical combination" or "combination" mean a product resulting from the mixing or combining of two or more therapeutic agents, including both fixed and non-fixed combinations of therapeutic agents, e.g., a kit or a pharmaceutical composition. The term "fixed combination" means that both a therapeutic agent, e.g., both a compound of the present disclosure and an additional therapeutic agent, are administered to a subject simultaneously in a single entity or dosage form. The term "non-fixed combination" means that both a therapeutic agent, e.g., both a compound of the present disclosure and an additional therapeutic agent, are administered to a subject as separate entities, simultaneously, concurrently, or sequentially without a specific time limit, and 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 administering one or more pharmaceutical substances, particularly a compound of the present disclosure described herein or a pharmaceutically acceptable salt thereof, to a subject having a disease or disorder or having symptoms of a disease or disorder, for the purpose of restoring, curing, alleviating, reducing, altering, correcting, remitting, 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 terms "prevent" or "prevention" in relation to a disease refer to administering one or more pharmaceutical substances, particularly a compound of the present disclosure, to a subject having a predisposition to a disease or disorder or having a risk of suffering from a disease or disorder, for the purpose of preventing or delaying the occurrence of the disease or disorder in the subject.

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

[0173] As used herein, the term "inhibit" or "inhibiting" refers to a decrease in the baseline activity of a biological activity or process.

[0174] As used herein, the term "subject" means a mammal and a non-mammal. Mammals include humans; non-human primates such as chimpanzees and other apes and monkey species; livestock such as cows, horses, sheep, goats, and pigs; pets such as rabbits, dogs, and cats; laboratory animals such as rodents including rats, mice, and guinea pigs; and any member of the mammalian class including but not limited to the foregoing. In some embodiments, the subject is a human.

[0175] As used herein, the term "pharmaceutically acceptable" means that the substance following this term is useful in the preparation of a pharmaceutical composition, is generally safe, non-toxic, and is neither biologically nor otherwise undesirable, and is particularly suitable for human pharmaceutical use.

[0176] The term "cancer" as used herein refers to a cellular disorder characterized by uncontrolled or unregulated cell growth, reduced cell differentiation, inappropriate invasive ability into surrounding tissues, and / or the ability to form new growths at other sites. The term "cancer" includes, but is not limited to, hematological malignancies and solid tumors, preferably leukemia. The term "cancer" encompasses cancers of the skin, tissue, organs, bone, cartilage, blood, and blood vessels. The term "cancer" further includes primary cancer, metastatic cancer, recurrent cancer, and refractory cancer. 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. The term "leukemia" as used herein includes acute leukemia, chronic leukemia, myeloid leukemia, myelogenous leukemia, lymphoblastic leukemia, lymphocytic leukemia, acute myeloid (myelogenous) leukemia (AML), chronic myeloid (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 (MLLr leukemia), MLL partial tandem duplication leukemia (MLL-PTD leukemia), MLL amplified leukemia, MLL positive leukemia, nucleophosmin (NPM) mutant leukemia (NPM1 mutant leukemia, NPM1c leukemia), MOZ acute leukemia, NUP98 acute leukemia, and class III 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, but is not limited thereto.

[0177] All numerical ranges in this specification are to be understood as disclosing any value within the range and any subset of values within the range, whether or not specifically disclosed otherwise. For example, when referring to any numerical range, it should be considered to refer to any number within the numerical range, such as any integer within the numerical range. This disclosure includes all values falling within these ranges, all smaller ranges, and the upper or lower limits of the range.

[0178] Technical and scientific terms used in this specification and not specifically defined have the meanings generally understood by those skilled in the art to which this disclosure pertains.

[0179] Pharmaceutical Compositions and Administration The compounds of the present disclosure (e.g., any of the compounds of the examples herein) can be formulated into pharmaceutical compositions, either alone or in combination with one or more additional therapeutic agents. The pharmaceutical composition comprises (a) a compound of the present disclosure, (b) a pharmaceutically acceptable carrier (e.g., one or more pharmaceutically acceptable carriers), and optionally (c) at least one additional therapeutic agent.

[0180] A pharmaceutically acceptable carrier refers to an excipient or adjuvant that is compatible with the active ingredient in the composition (and in some embodiments can stabilize the active ingredient) and is not harmful to the subject being treated. Suitable pharmaceutically acceptable carriers are disclosed in standard reference books in the art (e.g., Remington’s Pharmaceutical Sciences, Remington: the Science and Practice of Pharmacy) and include one or more buffering agents, stabilizing agents, surfactants, wetting agents, lubricants, emulsifying agents, suspending agents, preservatives, antioxidants, opacifying agents, flow promoters, processing aids, coloring agents, sweetening agents, flavoring agents, fragrances, diluents, and other known additives, which provide a refined presentation of the drug (i.e., the compound of the present disclosure or its pharmaceutical composition) or assist in the manufacture of a pharmaceutical product (i.e., a medicine).

[0181] The compounds of the present disclosure can be administered in various known modes such as oral, parenteral, inhalation, or implantation. As used herein, the term "parenteral" includes subcutaneous, intradermal, intravenous, intramuscular, intra-articular, intra-arterial, intrasynovial, intrasternal, intramedullary, intralesional, and intracranial injections or infusions.

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

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

[0184] Indications and Treatment Methods The present disclosure relates to a method of treating or preventing a disease or disorder mediated by the interaction of menin with MLL and / or an MLL fusion protein, which comprises 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 of treating or preventing cancer or diabetes, which comprises 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 present disclosure are used for the treatment or prevention of a disease or disorder mediated by the interaction of menin with MLL and / or an MLL fusion protein.

[0187] In one embodiment, the compounds of the present disclosure are used for the treatment or prevention of cancer or diabetes.

[0188] In one embodiment, the compounds of the present disclosure are used for the treatment or prevention of hematological malignancies 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 present disclosure are used for the treatment or prevention of 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) mutant leukemia, MOZ acute leukemia, NUP98 acute leukemia, and class III assembly lymphoid myeloid (CALM) acute leukemia.

[0190] Pharmaceutical 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 agent may be administered separately from the compounds of the present disclosure or may be included together with the compounds of the present disclosure in a pharmaceutical composition according to the present disclosure, e.g., a fixed combination product. In some embodiments, the additional therapeutic agent is one 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 relevant to the particular disease. The combination can serve to increase the effectiveness of the compounds of the present disclosure, reduce one or more side effects, or reduce the dosage required.

[0191] In some embodiments, the compounds of the present disclosure are administered in combination with an anti-neoplastic agent. Examples of anti-neoplastic agents include, but are not limited to, radiation therapy agents, chemotherapy agents, immunotherapy agents, and targeted therapy agents.

[0192] General synthetic method Exemplary compounds having the general structure as A10 can be synthesized according to Scheme 1. The reaction of phenol A1 with 5-bromopyrimidine under basic conditions gave biaryl ether A2, which could be converted to N-oxide A3 in the presence of mCPBA. Subsequently, when the latter was reacted with a chlorinating reagent such as POCl3, chloropyrimidine A4 was readily obtained. A key intermediate A6 was obtained by a nucleophilic substitution reaction between chloride A4 and mono-protected spirodiamine A5. Deprotection of A7, amide formation with N-protected cyclic amino acid A8, and N-deprotection gave the final compound A10.

Chemical formula

[0193] Exemplary compounds having the structure as B4 can be synthesized according to Scheme 2. B1 could be prepared from the appropriate phenol according to the same procedure as A6 shown in Scheme 1. Compound B3 was obtained by a Suzuki coupling reaction of B1 with (hetero)arylboronic acid. Alternatively, B3 could be prepared using a two-step route, i.e., converting B1 to boronate B2 via a palladium-catalyzed borylation reaction, followed by a 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 gave compound B4.

Chemical formula

[0194] Exemplary compounds having the general structure as C6 can be synthesized according to Scheme 3. The triazine C2 was obtained by a selective nucleophilic substitution reaction between the mono-protected spirodiamine A5 and 3,5,6-trichloro-1,2,4-triazine C1. The monochloride C4 was obtained by a second nucleophilic substitution with phenol C3. The chlorine atom was removed under reducing conditions to obtain the triazine C5. Again, through subsequent deprotection, amidation with the N-protected cyclic amino acid A8, and finally N-deprotection, the compound C6 was obtained.

Chem.

[0195] Exemplary compounds having the general structure as D1 in Scheme 4 could be prepared from the chloride C4 in three steps: deprotection, amidation with the N-protected cyclic amino acid A8, and N-deprotection. The chloride C4 can also react with a nucleophile under basic conditions or react with a boronic reagent in the presence of a palladium catalyst to obtain an intermediate D2, which, after deprotection, amidation with the N-protected cyclic amino acid A8, and N-deprotection, can give an exemplary compound having the general structure as D3 (Scheme 4).

Chem.

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

[0197] All patents, patent applications, publications, and other references cited or referred to in this specification are hereby incorporated by reference in their entirety to the extent permitted by law. The discussion of these references is intended solely to summarize the claims made therein. It is not intended to admit that any such patent, patent application, publication, or reference, or any part thereof, is relevant prior art. The right to challenge the accuracy and validity of any such patent, patent application, publication, or reference, or any part thereof, when presented as relevant prior art, is specifically reserved.

Examples

[0198] The following examples are for illustrative purposes only and should not be construed as limiting in any way.

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

[0201] All compound names, except for reagents, were generated using Chemdraw. In the event of a conflict between the structure and name of a compound given in the present invention, the structure shall prevail unless it is shown from the context that the name is correct and the structure is incorrect.

[0202] When the atoms disclosed in this specification have vacant valences, those vacant valences are hydrogen atoms and are omitted for convenience.

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

[0204] In the following examples, the following abbreviations are used. [Table 2-1] [Table 2-2] Preparation of the Main Intermediate Preparation of Intermediate 1, 2-((4-(2,7-Diazaspiro[3.5]nonan-2-yl)pyrimidin-5-yl)oxy)-N-ethyl-5-fluoro-N-isopropylbenzamide [Chemical Formula] 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 dropwise ethyl(propan-2-yl)amine (15.4 g, 176 mmol) at 0 °C. The reaction mixture was gradually warmed to room temperature and stirred overnight. The reaction mixture was quenched with saturated aqueous NH4Cl solution (50 mL), extracted with EtOAc (100 mL × 3), the combined organic phases were washed with water and brine, dried over anhydrous Na2SO4, 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: 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 dropwise with BBr3 (37.6 mL, 1.0 M in DCM) at -60 °C under N2 atmosphere, and the resulting mixture was stirred at this temperature for 2 h. Then, the reaction mixture was quenched with cooled saturated NaHCO3 at 0 °C, the mixture was extracted with DCM (100 mL × 3), the combined organic layers were washed with water and brine, dried over anhydrous Na2SO4, filtered, and concentrated to obtain 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. This 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) were added 5-bromopyrimidine (3.40 g, 21.3 mmol) and Cs2CO3 (11.6 g, 35.5 mmol). The reaction mixture was heated at 120 °C for 12 h, cooled to room temperature, then the mixture was quenched with saturated aqueous NH4Cl (50 mL), extracted with EtOAc (100 mL × 3), the combined organic layers were washed with water and brine, dried over anhydrous Na2SO4, filtered, and concentrated to obtain a crude product, which was purified by column chromatography on silica gel (EtOAc in PE = 0 - 20%) to obtain 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: 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) portionwise at 0 °C, and then the resulting mixture was stirred at room temperature for 10 h. The reaction mixture was quenched with saturated NaHCO3, extracted with DCM (50 mL×3), the combined organic layers were washed with water and brine, dried over anhydrous Na2SO4, filtered, concentrated to give a crude product, which was purified by column chromatography on silica gel (EtOAc in PE = 0 - 80%) to afford 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: 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 CHCl3 (10 mL) was added POCl3 (0.80 mL, 8.4 mmol) dropwise at 0 °C. Then the reaction mixture was stirred at room temperature for 12 h. The reaction mixture was quenched with saturated NaHCO3 and extracted with DCM (100 mL×3). The combined organic layers were washed with water and brine, dried over anhydrous Na2SO4, filtered, concentrated in vacuo to give 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. This could be used in the next step without further purification. LC / MS(ESI) m / z: 338 / 340(M+H) + 。

[0209] Step 6: 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 with tert-butyl 2,7-diazaspiro[3.5]nonane-7-carboxylate (221 mg, 1.00 mmol) and K2CO3 (246 mg, 1.80 mmol). The resulting mixture was heated at 80 °C for 5 h. After cooling to room temperature, the reaction mixture was quenched with saturated aqueous NH4Cl solution (10 mL), extracted with EtOAc (20 mL × 3), and the combined organic layers were washed with water and brine, dried over anhydrous Na2SO4, filtered, and concentrated to obtain a 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: To 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 TFA (2.0 mL) at room temperature, and the resulting mixture was stirred at room temperature for 2 h. 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 could 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 (list the main different chemical substances used in the starting materials column).

Table 3-1

Table 3-2

Table 3-3

Chemical formula

[0212] Step 2: A solution of 5-fluoro-N,N-diisopropyl-2-methoxybenzamide (320 mg, 1.26 mmol) in DCM (10 mL) was added dropwise with BBr3 (3 mL, 1.0 M in DCM) at -60 °C under a N2 atmosphere, and the resulting mixture was stirred at this temperature for 2 h. Subsequently, the reaction mixture was quenched with MeOH cooled to 0 °C, and the mixture was extracted with DCM (15 mL × 3). The combined organic layers were washed with water and brine, dried over anhydrous Na2SO4, filtered, concentrated to obtain a 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

Chemical formula

[0214] Step 2: A solution of 1-tert-butyl 2-methyl (2S)-4-hydroxy-4-methylpyrrolidine-1,2-dicarboxylate (180 mg, 0.69 mmol) in MeOH (3 mL) and H2O (1 mL) was added with NaOH (83 mg, 2.1 mmol) at 0 °C. The resulting mixture was stirred at room temperature for 2 h, the pH of the reaction mixture was adjusted to 4 - 5 with 1.0 N HCl solution, diluted with H2O (10 mL), extracted with DCM (20 mL × 3), the combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated to obtain 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. This 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

Chemical Structure

[0216] Step 2: 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 with 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 phases were washed with brine, dried over anhydrous Na2SO4, filtered, concentrated, and the residue was purified by column chromatography on silica gel (EtOAc in PE = 10 - 25%) 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, CDCl3) δ 4.29 (dd, J = 23.9, 16.0 Hz, 1H), 3.97 (dd, J = 10.5, 7.0 Hz, 1H), 3.74 (s, 3H), 3.42 - 3.12 (m, 2H), 2.60 (dd, J = 13.0, 6.4 Hz, 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, dried over anhydrous Na2SO4, filtered, concentrated, and the residue was purified by column chromatography on silica gel (EtOAc in PE = 5 - 25%) 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: 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 with an aqueous NaOH solution (2.0 mL, 2.0 N), and the resulting mixture was stirred at room temperature for 30 minutes. The reaction mixture was concentrated, adjusted to pH 2 - 3 with 1.0 N HCl solution, and extracted with EtOAc (30 mL × 3). The combined organic layers were washed with water and brine, dried over anhydrous Na2SO4, filtered, and concentrated to obtain 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

Chemical Structure

[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) was added DMF-DMA (5 mL), and the reaction mixture was heated at 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% - 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) was added HOAc (0.1 mL), 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: 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) was added with NaOH solution (3.0 mL, 2.0 N), and the reaction mixture was stirred at 60 °C for 1 hour. The mixture was concentrated, adjusted to pH 2 - 3 with 1.0 N HCl, and the mixture was extracted with EtOAc (20 mL × 3). The combined organic phases were 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

Chemical formula

[0224] Step 2: 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 to a methylhydrazine solution (0.8 mL, 5.7 mmol), and the resulting mixture was heated at 85 °C for 12 h in a sealed tube. 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: TFA (2 mL) was added dropwise 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) 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: 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 dropwise with Boc2O (170 mg, 0.71 mmol) at 0 °C, and the resulting mixture was stirred at room temperature for 2 h. The reaction mixture was diluted with H2O (5 mL), extracted with DCM (10 mL × 3), and the combined organic phases were dried over anhydrous Na2SO4, filtered, and concentrated to obtain 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 chemical substances (listing the main different chemical substances used in the starting material column).

Table 4

Chem.

[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 was added Dess-Martin reagent (4.5 g, 10.6 mmol). The resulting mixture was stirred at 25 °C for 10 h. The reaction mixture was poured into ice-water (50 mL) and extracted with EtOAc (50 mL × 3). The combined organic phases were dried over anhydrous Na2SO4, filtered, concentrated, and the residue was purified by column chromatography on silica gel (EtOAc in PE = 5 - 30%) to afford 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) was slowly added DAST (2.87 mL, 21.7 mmol) at -10 °C, and the reaction mixture was stirred at 25 °C for 5 h under a N2 atmosphere. The reaction mixture was poured into ice water (50 mL), and the mixture was extracted with EtOAc (50 mL × 3). The combined organic phases were dried over anhydrous Na2SO4, 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 dropwise BBr3 (3.4 mL, 3.40 mmol) under a N2 atmosphere, and the resulting mixture was stirred at -60 °C for 2 h. The reaction mixture was quenched with ice-saturated NaHCO3 at 0 °C, extracted with DCM (100 mL × 3), and the combined organic layers were washed with water and brine, dried over anhydrous Na2SO4, 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

Chemical Structure

[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) To a solution of (2S)-1-[(tert-butoxy)carbonyl]-4-methylidenepyrrolidine-2-carboxylic acid (0.25 mL, 1.32 mmol), TMSCHN2 (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), then diluted with H2O (10 mL), extracted with DCM (10 mL x 3), and the combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated to give 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: 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 with TMSCF3 (7.5 g, 53.05 mmol) at room temperature under N2. The resulting mixture was stirred in a sealed tube at 65 °C for 12 h. The mixture was diluted with H2O (10 mL) and extracted with EtOAc (20 mL × 3). The combined organic layers were washed with water and brine, dried over anhydrous Na2SO4, 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: 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 MeOH (3 mL) and H2O (1 mL) was added NaOH (80 mg, 2 mmol) at 0 °C. The resulting mixture was stirred at room temperature for 30 min. The reaction mixture was concentrated, adjusted to pH 2 - 3 with 1.0 N HCl, and extracted with EtOAc (20 mL × 3). The combined organic layers were washed with water and brine, dried over anhydrous Na2SO4, filtered, 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. This 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 [Chemistry] 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) were 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 mixture was then stirred at 100 °C for 1 h. The reaction mixture was cooled to room temperature, diluted with H2O (5 mL), and extracted with EtOAc (10 mL × 3). The combined organic phases were dried over anhydrous Na2SO4, filtered, and concentrated to give 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: To 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 MeOH (3.0 mL) and H2O (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 the mixture was extracted with EtOAc (15 mL × 3). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated to give 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 [Chem.] 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 quenched with saturated aqueous NH4Cl (10 mL), extracted with DCM (10 mL × 3), and the combined organic phases were washed with water and brine, dried over anhydrous Na2SO4, filtered, concentrated, and the residue was purified by column chromatography on silica gel (EtOAc in PE = 10 - 50%) to afford 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: To a solution of (2S,4S)-1-tert-butyl 2-methyl 4-(methylsulfonamido)pyrrolidine-1,2-dicarboxylate (160 mg, 0.50 mmol) in MeOH (3.0 mL) and H2O (1.0 mL) was added NaOH (80 mg, 2.0 mmol), and the resulting mixture was stirred at 20 °C for 1 h under N2. Then, the pH of the reaction mixture was adjusted to 5 with 1.0 N HCl and extracted with EtAOc (15 mL × 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated to give the crude product (2S,4S)-1-[(tert-butoxy)carbonyl]-4-methanesulfonamidopyrrolidine-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 chemical substances (listing the main different chemical substances used in the starting material column).

Table 5

Chem.

[0240] Step 2: To a solution of (2S,5S)-methyl 5-hydroxypiperidine-2-carboxylate (300 mg, 1.88 mmol) in acetone (5.0 mL) and H2O (1.0 mL) were added TEA (0.52 mL, 3.7 mmol) and (Boc)2O (0.45 g, 2.07 mmol) at 0 °C. The resulting mixture was stirred at 20 °C for 3 hours, the reaction mixture was quenched with saturated aqueous NH4Cl solution (10 mL), extracted with EtOAc (15 mL × 3), the combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated to give the crude (2S,5S)-1-tert-butyl 2-methyl 5-hydroxypiperidine-1,2-dicarboxylate (400 mg, yield: 81%) as a pale yellow solid. This could be used directly in the next step. LC / MS (ESI) m / z: 260 (M+1) + 。

[0241] Step 3: 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 with DAST (0.5 mL, 3.85 mmol) at -60 °C. The resulting mixture was stirred at room temperature for 16 h under N2. The reaction mixture was diluted with saturated aqueous NaHCO3 (10 mL), extracted with DCM (15 mL × 3), the combined organic phases were washed with brine, dried over Na2SO4, filtered, and concentrated to give crude (2S,5R)-1-tert-butyl 2-methyl 5-fluoropiperidine-1,2-dicarboxylate (270 mg, yield: 67.2%) as a yellow oil. This can be used in the next step without further purification. LC / MS (ESI) m / z: 262 (M+H) + 。

[0242] Step 4: To a solution of 1-tert-butyl 2-methyl (2S,5R)-5-fluoropiperidine-1,2-dicarboxylate (270 mg, 1.01 mmol) in MeOH (3.0 mL) and H2O (1.0 mL) was added NaOH (120 mg, 3.0 mmol), and the resulting mixture was stirred at room temperature for 1 h. Then, the pH of the reaction mixture was adjusted to 5 with 1 N HCl and extracted with EtAOc (15 mL × 3). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated to give the crude product (2S,5R)-1-(tert-butoxycarbonyl)-5-fluoropiperidine-2-carboxylic acid (130 mg, yield: 48%) as a solid. This 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

Chemical Structure

[0244] Step 2: A slurry of Pd / C (90 mg, 10%) in EtOAc (10 mL) was added to a solution of 1-tert-butyl 2-methyl(2S)-4-(cyanomethylene)pyrrolidine-1,2-dicarboxylate (900 mg, 3.38 mmol) in MeOH (5 mL). Then the resulting suspension was stirred at room temperature for 16 hours under a balloon of H2. The reaction mixture was filtered through a pad of Celite, and the filtrate was concentrated to obtain the crude product (2S)-1-tert-butyl 2-methyl 4-(cyanomethyl)pyrrolidine-1,2-dicarboxylate (900 mg, yield: 99%) as a colorless oil. This could be used in the next step without further purification. LC / MS(ESI) m / z: 269(M+H) + 。

[0245] Step 3: To a solution of (2S)-1-tert-butyl 2-methyl 4-(cyanomethyl)pyrrolidine-1,2-dicarboxylate (650 mg, 2.29 mmol) in MeOH (5.0 mL) and H2O (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, adjusted to pH 5 with 1.0 N HCl, extracted with EtOAc (10 mL × 3), the combined organic phases were dried over anhydrous Na2SO4, filtered, and concentrated 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 [Chemical formula] 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) were added KOAc (1.50 g, 15.7 mmol) and Pd(dppf)Cl2 (100 mg). The resulting mixture was heated to 110 °C for 12 h under a N2 atmosphere. After cooling to room temperature, the mixture was diluted with H2O (10 mL), extracted with EtOAc (30 mL × 3), the combined organic phases were washed with water and brine, dried over anhydrous Na2SO4, filtered, and concentrated in vacuo to give 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 chemical substances (the main different chemical substances used are listed in the starting material column). [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 [Chemical formula] Step 1: To 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 added Cs2CO3 (12.8 g, 39.3 mmol) at room temperature. The resulting mixture was heated at 120 °C for 12 h. The reaction mixture was cooled to room temperature, quenched with saturated aqueous NH4Cl solution (50 mL), extracted with EtOAc (100 mL × 3), and the combined organic layers were washed with water and brine, dried over anhydrous Na2SO4, 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: 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 with Pd(dppf)Cl2 (150 mg) at room temperature. The resulting mixture was stirred at 90 °C for 12 h under a CO (70 psi) atmosphere. After cooling to room temperature, the solvent was concentrated under reduced pressure to obtain a 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 urea·H2O2 (800 mg, 8.16 mmol) and TFAA (0.6 mL) at 0 °C under N2. The resulting mixture was stirred at room temperature for 1 h. The reaction mixture was quenched with saturated NaHCO3, extracted with EtOAc (20 mL × 3), and the combined organic layers were washed with water and brine, dried over anhydrous Na2SO4, filtered, and concentrated in vacuo to give the crude product 5-[4-fluoro-2-(methoxycarbonyl)phenoxy]pyrimidin-1-ium-1-olate (830 mg, yield: 86.3%) as a yellow oil. This 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 with POCl3 (0.6 mL, 6.8 mmol) at 0 °C. The resulting mixture was stirred at room temperature for 2 h. The reaction mixture was quenched with saturated aqueous NaHCO3 (20 mL), extracted with EtOAc (50 mL × 3), and the combined organic layers were washed with water and brine, dried over anhydrous Na2SO4, filtered, and concentrated in vacuo to give the crude product methyl 2-[(4-chloropyrimidin-5-yl)oxy]-5-fluorobenzoate (798 mg, yield: 93%) as a brown oil. This could 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, cooled to room temperature, then the reaction mixture was quenched with saturated aqueous NH4Cl (10 mL), extracted with EtOAc (30 mL × 3), and the combined organic layers were washed with water and brine, dried over anhydrous Na2SO4, filtered, concentrated to give a 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: 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 MeOH (12 mL) and H2O (4.0 mL) was added with NaOH (228 mg, 5.71 mmol) at 0 °C. The resulting mixture was stirred at room temperature for 1 hour. Then, the pH of the mixture was adjusted to 5 with 1.0 N HCl, and the mixture was extracted with EtOAc (20 mL × 3). The combined organic layers were washed with water and brine, dried over anhydrous Na2SO4, filtered, and concentrated to obtain 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. This could 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). After the resulting mixture was stirred for 10 minutes, 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 hour, then diluted with H2O (10 mL) and extracted with EtOAc (30 mL × 3). The combined organic phases were dried over anhydrous Na2SO4, filtered, and concentrated to obtain the desired product, which was purified by preparative TLC (MeOH in DCM = 9%) 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 hour. The resulting mixture was concentrated in vacuo to give the crude product 2-[(4-{2,7-diazaspiro[3.5]nonan-2-yl}pyrimidin-5-yl)oxy]-5-fluoro-N-(2-hydroxyethyl)-N-(propan-2-yl)benzamide (40 mg, yield: 98%) as an oil. This could 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 [Chemical Structure] Step 1: 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 with NaH (7.0 mg, 0.17 mmol, 60%) at 0 °C. The reaction mixture was stirred for 10 minutes and then MeI (31 mg, 0.22 mmol) was added. The resulting mixture was stirred at room temperature for 1 hour, quenched with saturated aqueous NH4Cl solution (10 mL), and extracted with EtOAc (30 mL × 3). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated to obtain the desired product, which was purified by preparative TLC (MeOH in DCM = 9%) 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: TFA (1.0 mL) was added 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). The resulting mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated in vacuo to obtain the crude product 2-[(4-{2,7-diazaspiro[3.5]nonan-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. This 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 [Chemical Formula] Step 1: To 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) were added PCy3 (280 mg, 1 mmol), Pd(OAc)2 (100 mg), and K3PO4 (3.2 g, 15 mmol) at room temperature. The resulting mixture was stirred at 100 °C for 12 h under N2. The reaction mixture was cooled to room temperature, quenched with H2O (20 mL), extracted with EtOAc (30 mL × 3), and the combined organic layers were washed with water and brine, dried over anhydrous Na2SO4, 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 (M-H) + .

[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 Tf2O (1.1 mL, 6.59 mmol) at -5 °C under N2. The resulting mixture was stirred at 0 °C for 3 h. The reaction was quenched with saturated aqueous NaHCO3, extracted with DCM (30 mL × 3), and the combined organic layers were washed with water and brine, dried over anhydrous Na2SO4, 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: 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 dioxane (5.0 mL) and H2O (1.0 mL) was added with Pd(dppf)Cl2 (20 mg) and K2CO3 (414 mg, 3.00 mmol), and the resulting mixture was stirred at 100 °C for 10 h under a N2 atmosphere. The reaction mixture was cooled to room temperature, diluted with H2O (10 mL), extracted with EtOAc (20 mL × 3), and the combined organic layers were washed with water and brine, dried over anhydrous Na2SO4, filtered, concentrated to obtain a 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

Chem.

[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 H2O (20 mL), extracted with EtOAc (20 mL × 3), the combined organic layers were dried over anhydrous Na2SO4, filtered, concentrated, and the residue was purified by chromatography column on silica gel (EtOAc in PE = 20%~50%) to afford 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 at room temperature for 8 h under a balloon pressure of H2. The reaction mixture was filtered through a pad of Celite, washed with MeOH (5 mL), and the filtrate was concentrated to afford 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. This could 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 afford the crude product 2-((5-(2,7-diazaspiro[3.5]nonan-2-yl)-1,2,4-triazin-6-yl)oxy)-N-ethyl-5-fluorobenzamide TFA salt (580 mg, yield: 99.4%) as a yellow oil. This could be used directly in the next step without further purification. LC / MS (ESI) m / z: 429 (M+H) + 。

[0264] Following the experimental procedure for Intermediate 34, the following intermediates were prepared from the corresponding chemical substances (the main different chemical substances used are listed in the column of starting materials).

Table 7-1

Table 7-2

Chem.

[0265] Step 2: 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 with DBU (0.08 mL, 0.53 mmol) at room temperature, and the resulting mixture was stirred overnight. The reaction mixture was diluted with H2O (10 mL), extracted with EtOAc (10 mL × 3), the combined organic layers were dried over anhydrous Na2SO4, filtered, concentrated, and the residue was purified by column chromatography on silica gel (EtOAc in PE = 0 - 40%) to obtain 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: Pd / C (12 mg) was added 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) at room temperature. The reaction mixture was evacuated and refilled with hydrogen, and stirred at room temperature for 2 h under a balloon of H2. The reaction mixture was filtered through a pad of celite, and the filtrate was concentrated to obtain the crude product tert-butyl 2-(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 (60 mg, yield: 53.3%) as a yellow solid. This could be used in the next step without further purification. LC / MS (ESI) m / z: 524 (M + H) + 。

[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 quenched with H2O (5 mL), extracted with EtOAc (10 mL × 3), the combined organic layers were dried over anhydrous Na2SO4, 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. This 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

Chemical formula

[0270] Step 2: A solution of Me2S·CuBr (79 mg, 0.38 mmol) in THF (5.0 mL) at -40 °C was added dropwise with vinylmagnesium bromide (2.8 mL, 1.0 M in THF) under N2. The resulting mixture was stirred for 1 h, and 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. The reaction mixture was stirred at this temperature for 4 h. The mixture was quenched with saturated NH4Cl / NH3·H2O (8:1), extracted with EtOAc (20 mL × 3), the combined organic layers were washed with saturated aqueous NH4Cl solution, dried over anhydrous Na2SO4, 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: To a solution of trans-1-benzyl 2-methyl-3-vinylpyrrolidine-1,2-dicarboxylate (500 mg, 1.72 mmol) and (Boc)2O (378 mg, 1.75 mmol) in MeOH (7.0 mL) was added Pd / C (10%, 50 mg) at room temperature. The resulting suspension was evacuated, refilled with hydrogen, and stirred under a H2 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: A solution of trans-1-tert-butyl 2-methyl-3-ethylpyrrolidine-1,2-dicarboxylate (400 mg, 1.55 mmol) in MeOH (6.0 mL) and H2O (2.0 mL) at 0 °C was added with NaOH (186 mg, 4.66 mmol). The resulting mixture was stirred at room temperature for 1 hour. 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 phases were dried over anhydrous Na2SO4, filtered, concentrated to obtain the crude product trans-1-[(tert-butoxy)carbonyl]-3-ethylpyrrolidine-2-carboxylic acid (350 mg, yield: 87.9%) as a white solid. This 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

Chemical Structure

[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 slowly added HCl in dioxane (100 mL, 4.0 M) at room temperature over 2 hours. 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 were added TEA (3.3 mL, 23 mmol) and NCS (1.91 g, 14.3 mmol) portionwise. The resulting mixture was stirred at room temperature for 3 hours, and then 2,6-lutidine (3 mL, 26.07 mmol) was slowly added within 1 hour. 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 quenched with H2O (50 mL) and extracted with EtOAc (50 mL × 3). The combined organic layers were washed with water and brine, dried over anhydrous Na2SO4, 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: A solution of CuBr·Me₂S (480 mg, 2.33 mmol) in THF (5.0 mL) was added dropwise with MeMgBr (2.9 mL, 1.0 M in THF) at -40 °C under N₂. After the mixture was stirred at -40 °C for 1 hour, 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 hour. The reaction mixture was quenched with saturated aqueous NH₄Cl solution and extracted with EtOAc (20 mL × 3). The combined organic layers were washed with brine, dried over anhydrous Na₂SO₄, filtered, concentrated, and the residue was purified by column chromatography on silica gel (EtOAc in PE = 0 - 30%) to obtain 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 hour. The reaction mixture was diluted with saturated aqueous NH₄Cl solution (5 mL) and extracted with EtOAc (10 mL × 3). The combined organic layers were washed with water and brine, dried over anhydrous Na₂SO₄, filtered, concentrated, and the residue was purified by column chromatography on silica gel (EtOAc in PE = 0 - 50%) to obtain 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) was added DAST (0.07 mL, 0.51 mmol) at 0 °C under N2. The resulting mixture was stirred at room temperature for 16 h. The reaction mixture was quenched with saturated NaHCO3 and extracted with DCM (10 mL × 3). The combined organic layers were washed with water and brine, dried over anhydrous Na2SO4, 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: To a solution of 1-benzyl 2-methyl (2S,3R,4R)-4-fluoro-3-methylpyrrolidine-1,2-dicarboxylate (80 mg, 0.27 mmol) and (Boc)2O (0.07 mL, 0.36 mmol) in MeOH (7.0 mL) was added Pd / C (10%, 15 mg) at room temperature. The resulting suspension was evacuated and refilled with hydrogen, and stirred at room temperature for 3 h under H2 balloon pressure. 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: A solution of 1-(tert-butyl) 2-methyl (2S,3R,4R)-4-fluoro-3-methylpyrrolidine-1,2-dicarboxylate (60 mg, 0.23 mmol) in MeOH (3 mL) and H2O (1 mL) was added with NaOH (28 mg, 0.69 mmol) at 0 °C. The resulting mixture was stirred at room temperature for 4 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 layers were washed with water and brine, dried over anhydrous Na2SO4, filtered, and concentrated to obtain the crude product (2S,3R,4R)-1-[(tert-butoxycarbonyl)]-4-fluoro-3-methylpyrrolidine-2-carboxylic acid (50 mg, yield: 83.5%) as an off-white solid. This 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

Chemical Structure

[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 was added H2O (20 mL) and sodium dichloroisocyanurate (3.60 g, 13.9 mmol), 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. This could be used in the next step without further purification. LC / MS (ESI) m / z: 294 (M+H) + 。

[0283] Step 3: 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 dropwise with 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, dried over anhydrous Na2SO4, 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), cooled to -10 °C, and 2,6-lutidine (3.2 mL, 27 mmol) and CbzCl (2.80 g, 16.3 mmol) were added thereto portionwise, followed by stirring at room temperature for 24 h. Then, ethylenediamine (0.25 mL, 3.7 mmol) was added to the mixture, and the mixture was stirred for 15 min. The mixture was washed successively with citric acid solution (1.0 N, 30 mL) and aqueous HCl solution (1.0 N, 25 mL), and the organic phase was washed with water, aqueous NaHCO3 solution (1.5 N), and brine, dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by column chromatography on silica gel (PE in EtOAc = 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: A solution of CuBr·Me₂S (630 mg, 3.07 mmol) in THF (5.0 mL) was added dropwise with EtMgBr (1.3 mL, 3.0 M in THF) at -40 °C under N₂. After the mixture was stirred at -40 °C for 1 hour, 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 hour. The reaction mixture was quenched with saturated aqueous NH₄Cl solution and extracted with EtOAc (20 mL × 3). The combined organic layers were washed with brine, dried over anhydrous Na₂SO₄, filtered, concentrated, and the residue was purified by column chromatography on silica gel (EtOAc in PE = 0 - 30%) to obtain 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 hour. The reaction mixture was diluted with saturated aqueous NH₄Cl solution (5 mL) and extracted with EtOAc (10 mL × 3). The combined organic layers were washed with water and brine, dried over anhydrous Na₂SO₄, filtered, concentrated, and the residue was purified by column chromatography on silica gel (EtOAc in PE = 0 - 50%) to obtain 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) was added DAST (0.07 mL, 0.51 mmol) at 0 °C under N2. The resulting mixture was stirred at room temperature for 16 h. The reaction mixture was quenched with saturated NaHCO3 and extracted with DCM (10 mL × 3). The combined organic layers were washed with water and brine, dried over anhydrous Na2SO4, 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: To a solution of 1-benzyl 2-methyl (2S,3R,4R)-3-ethyl-4-fluoropyrrolidine-1,2-dicarboxylate (110 mg, 0.36 mmol) and (Boc)2O (78 mg, 0.36 mmol) in MeOH (2.0 mL) was added Pd / C (10%, 20 mg) at room temperature. The resulting suspension was evacuated and refilled with hydrogen, and the mixture was stirred at room temperature for 3 h under a balloon of H2. 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: A solution of 1-tert-butyl 2-methyl (2S,3R,4R)-3-ethyl-4-fluoropyrrolidine-1,2-dicarboxylate (90 mg, 0.38 mmol) in MeOH (3 mL) and H2O (1 mL) was added with 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, adjusted to pH 4 - 5 with 1.0 N HCl solution, and extracted with EtOAc (15 mL × 3). The combined organic layers were washed with water and brine, dried over anhydrous Na2SO4, filtered, and concentrated to obtain the crude product (2S,3R,4R)-1-[(tert-butoxy)carbonyl]-3-ethyl-4-fluoropyrrolidine-2-carboxylic acid (70 mg, yield 78%) as an off-white solid. This could 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

Chemical Structure

[0290] Preparation of Intermediate 41, 5-Fluoro-2-methoxybenzoic Acid-3,4-d2 [Chemical formula] 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 at 70 °C for 4 hours. After cooling to room temperature, water (5 mL) was added, and the mixture was extracted with EtOAc (10 mL × 3). The combined organic layers were washed with water and brine, dried over anhydrous Na2SO4, filtered, and concentrated to obtain a 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) were added MeI (0.2 mL, 3.6 mmol) and K2CO3 (843 mg, 6.1 mmol), and the reaction mixture was stirred at room temperature for 5 hours. Then, water (10 mL) was added, and the mixture was extracted with EtOAc (10 mL × 3). The combined organic layers were washed with water and brine, dried over Na2SO4, filtered, and concentrated to obtain a 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 stirred at 60 °C for 10 h under a D2 atmosphere. It was filtered and concentrated to give the crude product methyl 5-fluoro-2-methoxybenzoate-3,4-d2 (85 mg, yield: 45.9%) as a colorless oil. This could be used directly in the next step without further purification. LC / MS (ESI) m / z: 186 (M+H) + 。

[0293] Step 4: To a solution of methyl 5-fluoro-2-methoxybenzoate-3,4-d2 (80 mg, 0.43 mmol) in MeOH / H2O (4 mL / 2 mL) was added LiOH.H2O (72 mg, 1.72 mmol). The resulting mixture was stirred at room temperature for 2 h under a N2 atmosphere. Then the reaction mixture was diluted with H2O (50 mL), the pH was adjusted to 3 - 4, and it was extracted with EtOAc (20 mL × 3). The combined organic phases were washed with water and brine, dried over anhydrous Na2SO4, filtered, and concentrated in vacuo to give the crude product 5-fluoro-2-methoxybenzoic acid-3,4-d2 (70 mg, yield: 94.6%) 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

Chemical Structure

[0295] Step 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 dioxane (5.0 mL) and H2O (1.0 mL) were added Pd(dppf)Cl2 (20 mg) and K2CO3 (347 mg, 2.51 mmol). The resulting mixture was stirred at 100 °C for 12 h under N2. The reaction mixture was cooled to room temperature, diluted with H2O (20 mL), and extracted with EtOAc (20 mL×3). The combined organic layers were washed with water and brine, dried over anhydrous Na2SO4, filtered, concentrated, and the residue was purified by column chromatography on silica gel (EtOAc in PE = 0~30%) to obtain 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: 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 with 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 diluted with H2O (20 mL), extracted with EtOAc (30 mL×3), the combined organic layers were dried over anhydrous Na2SO4, filtered, concentrated, and the residue was purified by chromatography column on silica gel (EtOAc in PE = 10~50%) to obtain 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: A solution of 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 NaBH4 (20 mg, 0.95 mmol) in THF (5 mL) was added with TMEDA (220 mg, 0.53 mmol) and Pd(dppf)Cl2·CH2Cl2 (30 mg) at room temperature, and the resulting mixture was stirred at room temperature overnight. The reaction mixture was diluted with H2O (10 mL), extracted with EtOAc (20 mL × 3), the combined organic layers were dried over anhydrous Na2SO4, 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: TFA (5 mL) was added 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) 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. This can be used in the next step without further purification. LC / MS (ESI) m / z: 434 (M + H) + 。

[0299] According to the experimental procedure of Intermediate 42, the following intermediates were prepared from the corresponding chemical substances.

Table 8

Chem.

[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 at 100 °C overnight. The reaction mixture was concentrated under reduced pressure to obtain the crude product N-[(1E)-(dimethylamino)methylidene]-5-fluoro-2-methoxybenzamide (4.78 g, yield: 95.2%) as a colorless oil. This 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 saturated NaHCO3 solution (30 mL) was added to the residue. The mixture was then extracted with DCM (20 mL × 3), and the combined organic phases were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated in vacuo to obtain 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) was added BBr3 (10 mL, 1 mol / L in DCM) dropwise at -60 °C under N2 atmosphere, and the resulting mixture was stirred at this temperature for 2 h. Then, the reaction mixture was quenched with cooled saturated NaHCO3 at 0 °C, and the mixture was extracted with DCM (30 mL × 3). The combined organic layers were washed with water and brine, dried over anhydrous Na2SO4, filtered, and concentrated to give the desired product 4-fluoro-2-[1-(propan-2-yl)-1H-1,2,4-triazol-5-yl]phenol (700 mg, yield: 74.4%) as a yellow solid. LC / MS (ESI) m / z: 222 (M+H) + 。

[0303] Step 5: To a mixture of 4-fluoro-2-[1-(propan-2-yl)-1H-1,2,4-triazol-5-yl]phenol (500 mg, 2.30 mmol) and Cs2CO3 (2.21 g, 6.81 mmol) in DMF (10 mL) was added 5-bromopyrimidine (467 mg, 2.91 mmol). The reaction mixture was heated at 120 °C for 12 h, cooled to room temperature, quenched with saturated aqueous NH4Cl solution (50 mL), extracted with EtOAc (20 mL × 3), and the combined organic layers were washed with water and brine, dried over anhydrous Na2SO4, filtered, and concentrated to give a crude product, which was purified by column chromatography on silica gel (MeOH in DCM = 0 - 4%) to afford 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) were added urea hydrogen peroxide (226 mg, 2.42 mmol) and TFAA (0.6 mL, 4.2 mmol) at 0 °C. The resulting mixture was stirred at 20 °C for 1 h under N2. The reaction mixture was washed with saturated aqueous NaHCO3 solution (30 mL) and saturated aqueous Na2S2O3 solution, the aqueous phase was extracted with DCM (15 mL × 3), and the combined organic phases were washed with water and brine, dried over anhydrous Na2SO4, filtered, and concentrated to give 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: 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 with DIEPA (0.7 mL, 4.10 mmol) and POCl3 (0.15 mL, 1.52 mmol) at 0 °C. Next, the reaction mixture was stirred at room temperature for 12 h. It was quenched with NaHCO3 and extracted with DCM (15 mL × 3). The combined organic layers were washed with water and brine, dried over anhydrous Na2SO4, 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. This could be used directly in the next step without further purification. LC / MS (ESI) m / z: 334 (M+H) + 。

[0306] Step 8: To a solution of 4-chloro-5-{4-fluoro-2-[1-(propan-2-yl)-1H-1,2,4-triazol-5-yl]phenoxy}pyrimidine (80 mg, 0.24 mmol) and K2CO3 (132 mg, 0.96 mmol)) in MeCN (10 mL) 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 quenched with saturated aqueous NH4Cl solution (10 mL), extracted with EtOAc (15 mL × 3), the combined organic layers were washed with water and brine, dried over anhydrous Na2SO4, filtered, concentrated to give a 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), TFA (2 mL) was added dropwise at room temperature, and the resulting mixture was stirred at room temperature for 2 hours. 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. This could 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

Chemical Structure

[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 dropwise NCS (268 mg, 2.01 mmol) at room temperature. The resulting mixture was stirred for 3 h. The reaction mixture was quenched with H2O (10 mL), extracted with EtOAc (20 mL × 3), and the combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated. 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 1H 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, 6.5 Hz, 6H). LC / MS (ESI) m / z: 333 (M + H) + 。

[0310] Step 3: To 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), urea·H2O2 (127 mg, 1.35 mmol) and TFAA (568 mg, 2.71 mmol) were added portionwise at 0 °C. The resulting mixture was warmed to room temperature and stirred for 3 h. The reaction mixture was quenched with saturated NaHCO3 and extracted with EtOAc (50 mL × 3). The combined organic layers were washed with water and brine, dried over anhydrous Na2SO4, filtered, and concentrated to give 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. This can be used in the next step without further purification. LC / MS (ESI) m / z: 349 (M + H) + 。

[0311] Step 4: 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 dropwise with POCl3 (0.10 mL, 1.0 mmol) and DIPEA (0.23 mL, 1.4 mmol) at 0 °C. The resulting mixture was warmed to room temperature and stirred overnight. The reaction mixture was quenched with saturated NaHCO3, extracted with DCM (10 mL × 3), and the combined organic layers were washed with water and brine, dried over anhydrous Na2SO4, filtered, and concentrated to give 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. This could 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) were added tert-butyl 2,7-diazaspiro[3.5]nonane-7-carboxylate (67 mg, 0.30 mmol) and K2CO3 (124 mg, 0.89 mmol) at room temperature. The resulting reaction was stirred at room temperature overnight. The reaction mixture was quenched with H2O (5 mL), extracted with EtOAc (10 mL × 3), and the combined organic layers were washed with water and brine, dried over anhydrous Na2SO4, filtered, and concentrated. 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 TFA (1.0 mL) at room temperature, and the resulting mixture was stirred at room temperature for 1 hour. 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. This 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

Chemical Structure

[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 slowly added NaBH4 (5 mg, 0.14 mmol). The resulting mixture was stirred at room temperature for 2 h. The reaction mixture was then quenched with saturated aqueous NH4Cl (5 mL), extracted with EtOAc (10 mL × 3), and the combined organic phases were washed with water and brine, dried over anhydrous Na2SO4, filtered, and concentrated to give 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) was added DAST (132 mg, 0.82 mmol) at 0 °C under N2. The resulting mixture was stirred at room temperature for 16 h. The reaction mixture was quenched with saturated NaHCO3, extracted with DCM (10 mL × 3), and the combined organic layers were washed with water and brine, dried over anhydrous Na2SO4, 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: A solution of 1-benzyl 2-methyl-trans-3-(fluoromethyl)pyrrolidine-1,2-dicarboxylate (80 mg, 0.27 mmol) and (Boc)2O (77 mg, 0.35 mmol) in MeOH (5 mL) was added with Pd / C (10%, 20 mg) at room temperature. The resulting suspension was evacuated and refilled with hydrogen, and the mixture was stirred at room temperature for 3 h under a balloon of H2. 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: To a solution of 1-(tert-butyl) 2-methyl-trans-3-(fluoromethyl)pyrrolidine-1,2-dicarboxylate (50 mg, 0.19 mmol) in MeOH (3 mL) and H2O (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 the mixture was extracted with EtOAc (15 mL×3). The combined organic layers were washed with water and brine, dried over anhydrous Na2SO4, filtered, and concentrated to give the crude product trans-1-(tert-butoxycarbonyl)-3-(fluoromethyl)pyrrolidine-2-carboxylic acid (40 mg, yield 85.2%) as a brown solid. This could 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

Chemical Structure

[0320] Project 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 toluene (80 mL) and H2O (10 mL) were added Pd(AcO)2 (40 mg, 0.18 mmol) and K3PO4 (14.9 g, 70.33 mmol). The resulting mixture was stirred at 100 °C for 10 h under a N2 atmosphere. The reaction mixture was diluted with saturated aqueous NH4Cl and extracted with EtOAc (20 mL × 3). The combined organic phases were washed with brine, dried over Na2SO4, filtered, and concentrated to give a crude product, which was purified by column chromatography on silica gel (EtOAc in PE = 5 - 30%) to afford 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] Project 3: A solution of 5-amino-6-cyclopropylpyridine-2-carbonitrile (1.12 g, 7.04 mmol) in MeCN (10 mL) was added dropwise 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. The resulting mixture was stirred at the same temperature for 1 h. The reaction mixture was quenched with saturated aqueous NH4Cl (30 mL), and the mixture was extracted with EtOAc (20 mL × 3). The combined organic layers were washed with brine, dried over Na2SO4, 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: 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 dioxane (10 mL) and H2O (2 mL), Pd(dppf)Cl2 (50 mg) and Cs2CO3 (4.38 g, 13.45 mmol) were added, and the resulting mixture was stirred at 100 °C for 2 h under N2. The reaction mixture was cooled to room temperature, quenched with H2O (5 mL), extracted with EtOAc (30 mL × 3), and the combined organic layers were dried over anhydrous Na2SO4, 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: 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, see Intermediate 34 for its synthesis) 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 H2O (20 mL) and extracted with EtOAc (30 mL × 3). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by column chromatography 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: 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) solution was added with NaBH4 (63 mg, 1.86 mmol) and Pd(dppf)Cl2 (30 mg). The reaction mixture was stirred at room temperature for 12 h under N2 atmosphere, quenched with saturated aqueous NH4Cl solution (30 mL), and extracted with EtOAc (20 mL×3). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated to obtain 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) 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 obtain the crude product 5-(2-((5-(2,7-diazaspiro[3.5]nonan-2-yl)-1,2,4-triazin-6-yl)oxy)-5-fluorophenyl)-6-cyclopropylpicolinonitrile as the TFA salt (200 mg, yield: 75.1%). This 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

Chem.

[0327] Preparation of Intermediate 49, rel - (2R,3R,4S)-1 - (tert - butoxycarbonyl)-3,4 - dimethylpyrrolidine - 2 - carboxylic acid

Chem.

[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 portionwise. The resulting mixture was stirred at 60 °C for 18 h under a N2 atmosphere, then quenched by dropwise addition of water (4.5 mL), 15% NaOH solution (4.5 mL) and water (13.5 mL). The mixture was filtered through Celite, and the filtrate was extracted with EtOAc (100 mL × 3). The combined organic phases were washed with water and brine, dried over anhydrous Na2SO4, filtered, and concentrated to give a crude product, which was purified by column chromatography on silica gel (MeOH in DCM = 1 - 10%) to afford 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: To a stirred solution of cis-[1-benzyl-4-(hydroxymethyl)pyrrolidin-3-yl]methanol (4.00 g, 18.07 mmol) and Boc2O (4.95 g, 22.91 mmol) in MeOH (50 mL), TEA (1.49 g, 14.85 mmol) and 10% Pd / C (500 mg) were slowly added at room temperature. The resulting mixture was stirred at room temperature for 18 h under a H2 atmosphere, then poured into water (200 mL). The mixture was extracted with EtOAc (200 mL × 3), the combined organic phases were washed with water and brine, dried over anhydrous Na2SO4, filtered, and concentrated to give a crude product, which was purified by column chromatography on silica gel (EtOAc in PE = 0 - 20%) to afford 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 minutes. The resulting mixture was stirred at 25 °C for 18 h under a N2 atmosphere, quenched with saturated aqueous NH4Cl solution (20 mL), and extracted with DCM (50 mL × 3). The combined organic phases were washed with water and brine, dried over anhydrous Na2SO4, filtered, and concentrated to give the crude product, which was purified by column chromatography on silica gel (EtOAc in PE = 0 - 20%) to afford 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 LiEt3BH (100 mL, 100 mmol) at 0 °C over 30 minutes. The resulting mixture was stirred at 25 °C for 12 h under a N2 atmosphere, quenched with saturated aqueous NH4Cl solution (10 mL), and extracted with EtOAc (50 mL × 3). The combined organic phases were washed with water and brine, dried over anhydrous Na2SO4, filtered, and concentrated. The crude product was purified by column chromatography on silica gel (EtOAc in PE = 0 - 10%) to afford 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, CDCl3) 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 = 6.7 Hz, 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 was added dropwise s-BuLi (1.5 mL, 1.950 mmol) over 30 minutes. The resulting mixture was stirred at the same temperature for 3 hours, and then CO2 was bubbled through for 1 hour (maintaining the internal temperature below -70 °C). After warming to room temperature, the mixture was quenched with 1 N HCl to pH = 5 and extracted with EtOAc (30 mL × 3). The combined organic phases were washed with water and brine, dried over anhydrous Na2SO4, filtered, and concentrated to give 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. This could 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

Chemical formula

[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) was added s-BuLi (29.8 mL, 38.82 mmol) at -78 °C. After stirring at -78 °C for 4 h under a N2 atmosphere, the resulting mixture was stirred at -78 °C for 5 h under a CO2 atmosphere, gradually warmed to room temperature, and further stirred at room temperature for 12 h. The mixture was quenched with 1 N HCl solution, adjusted to pH 4 - 5, and extracted with EtOAc (30 mL × 3). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated to give 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

Chem.

[0336] Step 2: To DAST (5 mL) at 0 °C was added solid 1-benzyl 2-methyl(2S,3S)-3-formylpyrrolidine-1,2-dicarboxylate (500 mg, 1.72 mmol), and then the resulting mixture was stirred at 40 °C for 24 h. The reaction mixture was diluted with DCM (50 mL), washed with saturated NaHCO3, the organic phase was collected, and the aqueous layer was extracted with DCM (20 mL × 3). The combined organic layers were washed with water and brine, dried over anhydrous Na2SO4, filtered, concentrated, and the residue was purified by column chromatography on silica gel (EtOAc in PE = 0 - 30%) to afford 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: In MeOH (5 mL) and H2O (2 mL) at 0 °C, NaOH (115 mg, 2.88 mmol) was added to a solution of 1-benzyl 2-methyl-trans-3-(difluoromethyl)pyrrolidine-1,2-dicarboxylate (300 mg, 0.96 mmol). The resulting mixture was stirred at room temperature for 2 h, the reaction mixture was concentrated, the pH was adjusted to 4 - 5 with 1 N HCl solution, and extracted with EtOAc (15 mL × 3). The combined organic layers were washed with water and brine, dried over anhydrous Na2SO4, filtered, and concentrated to obtain the crude product 1-benzyl 2-methyl-trans-3-(difluoromethyl)pyrrolidine-1,2-dicarboxylate (250 mg, yield: 82.2%) as a brown solid. This could be used in the next step without further purification. LC / MS (ESI) m / z: 300 (M+1) + 。

[0338] Following the experimental procedure for Intermediate 37, the following intermediates were prepared from the corresponding chemical substances (listing the main different chemical substances used in the starting material column).

Table 9

Chem.

[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), HATU (2.03 g, 5.35 mmol) and DIPEA (1.06 g, 8.23 mmol) were added dropwise at 0 °C. The reaction mixture was warmed gradually to room temperature and stirred overnight. The reaction mixture was quenched with saturated aqueous NH4Cl (10 mL), extracted with EtOAc (50 mL × 3), and the combined organic phases were washed with water and brine, dried over anhydrous Na2SO4, 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), BBr3 (2.2 mL, 1.0 M in DCM) was added dropwise at -60 °C under N2 atmosphere, and the resulting mixture was stirred at this temperature for 7 h. The reaction mixture was quenched with cooled saturated NaHCO3 at 0 °C, the mixture was extracted with DCM (30 mL × 3), and the combined organic layers were washed with water and brine, dried over anhydrous Na2SO4, filtered, and concentrated to give the desired product N-(ethyl-1,1-d2)-5-fluoro-2-hydroxy-N-isopropylbenzamide (270 mg, yield: 71.6%) as a pale yellow solid. This could 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

Chemical formula

[0342] Preparation of Intermediate 55, 2-(2-cyclopropyl-6-methoxypyridin-3-yl)-4-fluorophenol

Chemical formula

[0343] Step 2: A suspension of tert-butyl nitrite (1.82 mL, 15.2 mmol) and CuBr (2.90 mg, 20.2 mmol) in MeCN (10 mL) was stirred at 70 °C for 30 minutes, and then a solution of 2-cyclopropyl-6-methoxypyridin-3-amine (830 mg, 5.06 mmol) in MeCN (5 mL) was added dropwise to this stirred mixture. The resulting mixture was stirred at 70 °C for an additional 1 hour. The reaction mixture was quenched with water (10 mL) and extracted with EtOAc (20 mL × 3). The combined organic phases were washed with water and brine, dried over anhydrous Na2SO4, filtered, and concentrated to obtain a 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: 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 dioxane (16 mL) and H2O (4 mL) was added with Cs2CO3 (2.57 g, 7.89 mmol) and Pd(dppf)Cl2 (50 mg), and the resulting mixture was stirred at 100 °C overnight under a N2 atmosphere. The reaction mixture was cooled to room temperature, diluted with H2O (20 mL), extracted with EtOAc (20 mL × 3), and the combined organic layers were washed with water and brine, dried over anhydrous Na2SO4, 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

Chemical Structure

[0346] 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

Chemical Structure

[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 hour, concentrated, and the residue was purified by preparative HPLC to give the desired product 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 (35 mg, yield: 69%) as a white solid. 11H NMR (400 MHz, CDCl3) δ 8.40 (d, J = 3.1 Hz, 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 procedure of Example 2, the following compounds were prepared from appropriate intermediates or commercially available chemical substances.

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

Chemical formula

[0349] Step 2: 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 with MsCl (0.10 mL, 0.42 mmol) at 0 °C. The resulting mixture was stirred at room temperature for 3 hours. The reaction mixture was quenched with saturated aqueous NH4Cl solution (10 mL) and extracted with EtOAc (20 mL × 3). The combined organic phases were washed with brine, dried over anhydrous Na2SO4, 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: 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 with 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 phases were washed with brine, dried over anhydrous Na2SO4, filtered, concentrated, and the residue was purified by column chromatography on silica gel (EtOAc in PE = 0 - 20%) to obtain 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: TFA (1.0 mL) was added 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) at 0 °C. The reaction mixture was stirred at room temperature for 1 h and concentrated under reduced pressure to obtain a crude product, which was purified by preparative HPLC to obtain the desired product 2-((4-(7-((2S,4R)-4-cyanopyrrolidine-2-carbonyl)-2,7-diazaspiro[3.5]nonan-2-yl)pyrimidin-5-yl)oxy)-N-ethyl-5-fluorobenzamide (20 mg, yield: 30%) as a white solid. 11H NMR (400 MHz, 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

Chemical Structure

[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 hour. The resulting mixture was concentrated and the residue was purified by preparative HPLC (0.1% formic acid in CH3CN) to afford 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 1H NMR (400 MHz, MeOD) δ 8.59 (d, J = 6.6 Hz, 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 procedure 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

Chemical formula

[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 hour and concentrated. The residue was diluted with EtOAc (20 mL) and the pH was adjusted to 9 with saturated aqueous NaHCO3. The organic phase was collected, dried over anhydrous Na2SO4, filtered, and concentrated. The resulting crude product was purified by preparative HPLC to give the desired product 2-((5-(7-5,5-difluorooctahydrocyclopenta[c]pyrrol-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. Under the first condition, pure isomers 3 and 4, and a mixture of isomers 1 and 2 were obtained, respectively. Then, the latter was subjected to the second condition to give pure isomers 1 and 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, 250×21.1 μm, I.D., 5 μm; mobile phase: A for CO2 and B for EtOH + 0.1% NH3H2O, 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, 250×21.1 um, I.D., 5 um; mobile phase: A for CO2 and B for EtOH + 0.1% NH3H2O, 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), 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 = 7.1 Hz, 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, I.D., 5 um; mobile phase: A with respect to CO2 and B with respect to IPA + 0.1% NH3H2O, gradient: 50% B, flow rate: 40 mL / min, back pressure: 100 bar, column temperature: 35 °C, wavelength: 254 nm, cycle time: 45 minutes, elution time: 5 hours, retention time: 12.61 minutes). 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: A with respect to CO2 and B with respect to IPA + 0.1% NH3H2O, gradient: 50% B, 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

Chemical Structure

[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 under a H2 atmosphere (balloon). The reaction mixture was filtered and concentrated. The crude product obtained 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, I.D., 5 um; mobile phase: A with respect to CO2 and B with respect to MeOH + 0.1% NH3H2O, 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 (400 MHz, 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 = 5.4 Hz, 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 = 7.1 Hz, 1H), 0.81 (d, J = 4.9 Hz, 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 1H 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 = 5.2 Hz, 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 = 7.1 Hz, 1H), 0.87 - 0.74 (m, 2H). LC / MS (ESI) m / z: 576 (M + H) + 。

[0362] Following the experimental procedure of Example 99, the following compounds were prepared from appropriate intermediates or commercially available chemical substances.

Table 12

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

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

[0365] 2. Cell Proliferation Assay · RPMI1640 (manufactured by Invitrogen, catalog number 11875 - 093; lot number 2327411) · IMDM (manufactured by Invitrogen, catalog number 12440 - 053; lot number 2192731) · FBS (manufactured by Gibco, catalog number 10099141C, lot number 2233792CP) · Penicillin - Streptomycin solution (manufactured by Invitrogen, catalog number 15140 - 122, lot number 2321118) · Glutamax (manufactured by Invitrogen, catalog number 35050 - 061; lot number 2248972) · 0.25% Trypsin - EDTA (manufactured by Invitrogen, catalog number 25200 - 072; lot number 2276876) · Staurosporine (manufactured by selleck, catalog number S1421, lot number #S142106) · DMSO (manufactured by Sigma, catalog number 276855 - 1L, lot number 276855 - 1L)

Table 13

[0366] The test results of the compounds of the present disclosure are shown in Table 1.

[0367]

Table 14-1

Table 14-2

Table 14-3

[0368]

Table 15

[0369]

Table 16

Claims

1. Compound of formula I: 【Chemical 1】 or its stereoisomers, racemates, tautomers, hydrates or solvates, or pharmaceutically acceptable salts [wherein, X is halo or CN, Y is N or CH, Z is CH ２ selected from the group consisting of, O, S and NH, R １ is 1)-(C=O)-NRaRb (wherein, Ra and Rb are deuterium, halo, OH, CN and C １～６ alkyl optionally substituted by one, two or three substituents selected from the group consisting of alkoxyl, C １～６ alkyl, 3- to 6-membered cycloalkyl ring and 5- to 9-membered heterocyclyl ring, each independently selected from the group consisting of, or Ra and Rb, together with the nitrogen atom to which they are attached, form a 5- to 9-membered heterocyclyl ring optionally substituted by one, two or three substituents selected from the group consisting of C １～６ alkyl, halo, OH and CN)); 2) halo, CN, C １～６ alkyl which is C １～６ alkyl optionally substituted by one, two or three substituents selected from the group consisting of halo, CN and OH, 3- to 5-membered cycloalkyl ring, oxo and C １～６ alkoxyl, a 5- to 10-membered heteroaryl ring or C ６～１０ aryl ring optionally substituted by one, two or three substituents selected from the group consisting of; 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 １～６Alkylsulfonylamino-, C １～６ Alkylcarbonylamino-, C ６～１０ Aryl ring, C １～６ Alkyl, C ２～６ Alkenyl, C ２～６ Alkynyl, C １～６ Alkoxyl, 3- to 9-membered cycloalkyl ring, 5- to 10-membered heteroaryl ring, and 4- to 9-membered heterocyclyl ring, independently selected from the group consisting of, wherein said alkyl, said alkenyl, said alkynyl, said alkoxyl, said cycloalkyl ring, said heteroaryl ring, or said heterocyclyl ring is optionally substituted by 1, 2, or 3 substituents selected from the group consisting of halo, CN, and OH, Two adjacent Rs ４ together with the carbon atom to which they are attached form a C １～６ Alkyl, -C １～６ Alkyl-OH, C １～６ Alkoxyl-C １～６ Alkyl-, optionally substituted by 1, 2, or 3 substituents selected from the group consisting of halo, CN, and OH, to optionally form a 3- to 9-membered cycloalkyl ring, Or, two Rs attached to the same carbon atom ４ together with the carbon atom form a C １～６ Alkyl, -C １～６ Alkyl-OH, C １～６ Alkoxyl-C １～６ Alkyl-, optionally substituted by 1, 2, or 3 substituents selected from the group consisting of halo, CN, and OH, to optionally form a 3- to 6-membered cycloalkyl ring or a 4- to 6-membered heterocyclyl ring, Or, two adjacent Rs ４ together with the carbon atom to which they are attached optionally form a 5- to 10-membered heteroaryl ring, C ６～１０ Aryl ring, or a 5- to 9-membered heterocyclyl ring, wherein said heteroaryl ring or aryl ring is C １～６ Alkyl, C １～６ Haloalkyl, -C １～６ Alkyl-OH, C １～６ Alkoxyl-C １～６Optionally substituted with 1, 2 or 3 substituents selected from the group consisting of alkyl, halo, CN and OH, wherein the alkyl is optionally substituted by 1 3- to 6-membered cycloalkyl ring or phenyl, and the heterocyclic ring is 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 by 1, 2 or 3 deuteriums or halos, methoxyl optionally substituted by 1, 2 or 3 deuteriums or halos, NH ２ , CH ３ NH, or (CH ３ ) ２ N, and is selected from the group consisting of 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, provided that when R ４ is present, except for the N atom adjacent to the bonding point of the remaining structure of the compound of the moiety [Chemical Formula 2] of, the moiety [Chemical Formula 3] is substituted at any chemically acceptable position above].

2. X is F, Cl or CN, Y is N or CH, Z is CH ２ , O, S and NH, and is selected from the group consisting of R １ is 1)-(C=O)-NRaRb [wherein, Ra and Rb are C １～６Independently selected from the group consisting of alkyl and 3- to 5-membered cycloalkyl rings, said C １～６ alkyl is optionally substituted by 1, 2 or 3 substituents selected from the group consisting of deuterium, halo, OH and C １～６ alkoxyl; or, Ra and Rb, together with the nitrogen atom to which they are attached, form a 5- to 6-membered monocyclic or 7- to 9-membered bicyclic heterocyclyl ring optionally substituted by 1, 2 or 3 substituents selected from the group consisting of C １～６ alkyl and halo]; 2) C optionally substituted by 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 alkoxyl; a 5- to 6-membered heteroaryl ring optionally substituted by 1, 2 or 3 substituents selected from the group consisting of C 3) C optionally substituted by 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 alkoxyl; an aryl ring substituted by 1, 2 or 3 substituents selected from the group consisting of C ６～１０ alkyl; selected from the group consisting of; R ２ and R ３ are each independently H or D; each R ４ is 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, 3- to 6-membered cycloalkyl rings, 5- to 10-membered heteroaryl rings, and 5- to 9-membered heterocyclyl rings, wherein the alkyl, alkoxyl, cycloalkyl ring, heteroaryl ring, or heterocyclyl ring is optionally substituted by 1, 2, or 3 substituents selected from the group consisting of halo, CN, and OH, Two adjacent Rs ４ together with the carbon atom to which they are attached form an optionally substituted 3- to 6-membered cycloalkyl ring selected from the group consisting of C １～６ alkyl, -C １～６ alkyl-OH, C １～６ alkoxyl-C １～６ alkyl- and halo by 1, 2, or 3 substituents optionally selected from the group consisting of Or two Rs attached to the same carbon atom ４ together with the carbon atom form an optionally substituted 3- to 6-membered cycloalkyl ring selected from the group consisting of halo, CN, and OH by 1, 2, or 3 substituents optionally selected from the group consisting of Or two adjacent Rs ４ together with the carbon atom to which they are attached form an optionally substituted 5- to 10-membered heteroaryl ring, phenyl, or 5- to 9-membered heterocyclyl ring selected from the group consisting of halo, C １～６ alkyl and C １～６ haloalkyl by 1, 2, or 3 substituents optionally selected from the group consisting of, wherein the alkyl is optionally substituted by 1 3- to 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, Provided that when R ４ is present, except for the N atom adjacent to the bonding point of the moiety 【Chemical Formula 4】 to the remaining structure of the compound, the moiety 【Chemical Formula 5】 Substituted at any chemically acceptable position above, The compound according to claim 1, or its stereoisomer, racemate, tautomer, hydrate or solvate, or pharmaceutically acceptable salt.

3. The compound is of formula II: 【Chemical Formula 6】 The compound according to claim 1 or 2, or its stereoisomer, racemate, tautomer, hydrate or solvate, or pharmaceutically acceptable salt.

4. The compound is of formula III: 【Chemical Formula 7】 The compound according to any one of claims 1 to 3, or its stereoisomer, racemate, tautomer, hydrate or solvate, or pharmaceutically acceptable salt.

5. X is F, the compound according to any one of claims 1 to 4, or its stereoisomer, racemate, tautomer, hydrate or solvate, or pharmaceutically acceptable salt.

6. Z is CH ２ The compound according to any one of claims 1 to 5, or its stereoisomer, racemate, tautomer, hydrate or solvate, or pharmaceutically acceptable salt.

7. R ２ and R ３ are each independently H, the compound according to any one of claims 1 to 6, or its stereoisomer, racemate, tautomer, hydrate or solvate, or pharmaceutically acceptable salt.

8. R １ is 【Chemical Formula 8】 [wherein, A １ or A ２ is N or CH, and R ６is selected from the group consisting of halo, CN and cyclopropyl, R ７ is selected from the group consisting of H, halo, CN and cyclopropyl], The compound according to any one of claims 1 to 7, or a stereoisomer, racemate, tautomer, hydrate or solvate thereof, or a pharmaceutically acceptable salt.

9. R1 is 【Chemical Formula 9】 is or R1 is 【Chemical Formula 10】 [wherein, A3 is N or C substituted by halo, and R8 is C1-3 alkyl] is The compound according to any one of claims 1 to 8, or a stereoisomer, racemate, tautomer, hydrate or solvate thereof, or a pharmaceutically acceptable salt.

10. R １ is 【Chemical Formula 11】 selected from the group consisting of, the compound according to any one of claims 1 to 7, or a stereoisomer, racemate, tautomer, hydrate or solvate thereof, or a pharmaceutically acceptable salt.

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

12. each R ４ is halo; CN; OH; C １～６ alkylsulfonyl-; C １～６ alkylsulfonylamino-; phenyl; C optionally substituted by 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 halos １～６ Alkoxyl; and cyclopropyl; independently selected from the group consisting of, Two adjacent Rs ４ Together with the carbon atom to which they are attached, form a C １～６ Alkyl, -C １～６ Alkyl-OH, C １～６ Alkoxyl-C １～６ Optionally form a 3- to 6-membered cycloalkyl ring optionally substituted by 1, 2 or 3 substituents selected from the group consisting of alkyl, halo, Or, two Rs attached to the same carbon atom ４ Together with the carbon atom, optionally form a 3- to 6-membered cycloalkyl ring optionally substituted by 1, 2 or 3 halos Or, two adjacent Rs ４ Together with the carbon atom to which they are attached, form a 5- to 6-membered heteroaryl ring optionally substituted by 1, 2 or 3 C １～６ Alkyl substituents, wherein the alkyl is optionally substituted by a 3- to 6-membered cycloalkyl ring or phenyl Or, two adjacent Rs ４ Together with the carbon atom to which they are attached, optionally form phenyl The compound according to any one of claims 1 to 11, or a stereoisomer, racemate, tautomer, hydrate or solvate thereof, or a pharmaceutically acceptable salt.

13. Said moiety 【Chemical Formula 12】 Is 【Chemical Formula 13】 Selected from the group consisting of, the compound according to any one of claims 1 to 12, or a stereoisomer, racemate, tautomer, hydrate or solvate thereof, or a pharmaceutically acceptable salt.

14. X is F, Z is CH ２ and R １ is 1) -(C=O)-NRaRb [wherein Ra and Rb are each independently selected from the group consisting of C １～６ alkyl optionally substituted by 1, 2 or 3 deuteriums, or Ra and Rb, together with the nitrogen atom to which they are attached, form a 5- or 6-membered monocyclic or 7- to 9-membered bicyclic heterocyclyl ring optionally substituted by 1, 2 or 3 C １～６ alkyl]; 2) a 5- to 6-membered heteroaryl ring substituted by 1, 2 or 3 substituents selected from the group consisting of halo, CN, C １～６ alkyl, CF ３ 3- to 5-membered cycloalkyl ring, oxo and C １～６ alkoxyl; 3) a C １～６ aryl ring substituted by 1, 2 or 3 substituents selected from the group consisting of halo, CN, C ３ alkyl, CF １～６ 3- to 5-membered cycloalkyl ring and C ６～１０ alkoxyl; selected from the group consisting of R ２ and R ３ are each independently H, each R ４ is halo; CN; OH; C １～６ alkylsulfonyl-; C １～６ alkylsulfonylamino-; phenyl; C １～６ alkyl optionally substituted by 1, 2 or 3 substituents selected from the group consisting of halo, CN and OH; C １～６ alkoxyl optionally substituted by 1, 2 or 3 halo; and 3- to 6-membered cycloalkyl ring; independently selected from the group consisting of two adjacent R ４ together with the carbon atom to which they are attached form C １～６Optionally forming a 3- to 6-membered cycloalkyl ring optionally substituted by 1, 2 or 3 substituents selected from the group consisting of alkyl and halo or two adjacent Rs ４ together with the carbon atom to which they are attached optionally form 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 provided that when R ４ is present, except for the N atom adjacent to the point of attachment of the moiety 【Chemical Formula 14】 to the remainder of the compound, the moiety 【Chemical Formula 15】 is substituted at any chemically acceptable position thereon The compound according to any one of claims 1 to 3, or a stereoisomer, racemate, tautomer, hydrate or solvate thereof, or a pharmaceutically acceptable salt.

15. R ５ is H, the compound according to any one of claims 1 to 14, or a stereoisomer, racemate, tautomer, hydrate or solvate thereof, or a pharmaceutically acceptable salt.

16. The moiety 【Chemical Formula 16】 is 【Chemical Formula 17】 [wherein R ４ ’, R ４ ’’ and R ４ ’’’ are independently selected from the group consisting of H; halo; CN; OH; C １～６ alkyl optionally substituted by one halo; and C １～６ alkoxyl; or R ４’ and R ４ ’’ together with the carbon atom to which they are attached optionally form a 3- to 6-membered cycloalkyl ring optionally substituted by 1 or 2 C １～６ alkyls, and 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 pharmaceutically acceptable salt.

17. Said moiety 【Chemical Formula 18】 is 【Chemical Formula 19】 [wherein R ４ ’’’ is H, R ４ ’ and R ４ ’’ are independently selected from the group consisting of H; halo; C １～６ alkyl optionally substituted by 1 halo; and C １～６ alkoxyl; provided that one of R ４ ’ and R ４ ’’ is not H, or R ４ ’ and R ４ ’’ together with the carbon atom to which they are attached form a 3- or 5-membered cycloalkyl ring optionally substituted by 1 or 2 C １～３ alkyls or form 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 pharmaceutically acceptable salt.

18. Said moiety 【Chemical Formula 20】 is 【Chemical Formula 21】 [wherein R ４ ’ is H and R ４ ’’ is C １～６ alkyl substituted by 1 halo, or R ４ ’ and R ４ ’’ together with the carbon atom to which they are attached optionally form a 3- or 5-membered cycloalkyl ring]. The 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 pharmaceutically acceptable salt.

19. The said moiety [Chemical Formula 22] is [Chemical Formula 23] [wherein each p is independently 0 or 1, q is 0, 1 or 2, R ４ａ is C １～３ alkyl]. The 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 pharmaceutically acceptable salt.

20. The compound according to claim 19, wherein both p are 1 and q is 0, or a stereoisomer, racemate, tautomer, hydrate or solvate thereof, or a pharmaceutically acceptable salt.

21. The said 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] The compound according to claim 1 or 2, or a stereoisomer, racemate, tautomer, hydrate or solvate thereof, or a pharmaceutically acceptable salt, selected from the group consisting of.

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

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

24. The pharmaceutical composition according to claim 23, wherein the cancer is a hematological tumor or a solid tumor.

25. The pharmaceutical composition according to 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 pharmaceutical composition according to claim 23, wherein the cancer is selected from 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-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. A pharmaceutical composition comprising the compound according to any one of claims 1 to 21, or a stereoisomer, racemate, tautomer, hydrate or solvate thereof, or a pharmaceutically acceptable salt thereof, and optionally a pharmaceutically acceptable carrier.

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

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

30. A pharmaceutical composition for use in a method of treating or preventing cancer or diabetes, comprising a compound according to any one of claims 1 to 21, or a stereoisomer, racemate, tautomer, hydrate or solvate thereof, or a pharmaceutically acceptable salt thereof, 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, or a pharmaceutically acceptable salt thereof.

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

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