Carbonyl-substituted diazaspiro compounds and uses thereof

Abstract

The present disclosure relates to compounds of Formula I, wherein the variables are as defined in the specification; pharmaceutical compositions containing them, processes for preparing them, and their uses.

Description

[0001] Cross-references to related applications

[0002] This application claims priority to international application PCT / CN2021 / 135427, filed on December 3, 2021, and international application PCT / CN2022 / 115162, filed on August 26, 2022; the entire contents of these two applications are incorporated herein by reference. Technical Field

[0003] This disclosure provides carbonyl-substituted diazaspirolides that inhibit the interaction of menin with MLL and MLL fusion proteins. This disclosure also provides methods for preparing these compounds, pharmaceutical compositions comprising these compounds, and their use for the prevention or treatment of cancer and other diseases mediated by the interaction of menin with MLL and / or MLL fusion proteins.

[0004] background

[0005] Mixed lineage leukemia (MLL, also known as MLL1 or KMT2A) gene rearrangements occur in approximately 10% of acute leukemias and are particularly prevalent in infantile acute leukemia, accounting for up to ~70% of infantile acute lymphoblastic leukemia (ALL) cases (Issa, GC et al., Leukemia, 2021, 35, 2482). MLLr (MLL rearrangement) is also found in 85% of secondary acute myeloid (AML) leukemia cases, occurring in patients treated with topoisomerase II inhibitors. More than 80 partner genes are involved in MLL fusions, and six major partner genes account for approximately 80% of cases, including AF4 (ALL-1 fusion gene from chromosome 4), AF6, AF9, AF10, ENL (11-19 leukemia), and ELL (11-19 lysine-rich leukemia) (Meyer, C. et al., 2018, Leukemia, 32, 273). MLL translocation leads to the expression of MLL fusion proteins, which enhance proliferation and block hematopoietic differentiation, ultimately driving the development of leukemia. MLLr leukemia is one of the high-risk types of leukemia, characterized by its aggressiveness, treatment resistance, high frequency of early relapse, and a 5-year survival rate of only about 35% (Marschalek, R.Br JHaematol. 2011, 152, 141). Therefore, there is a huge unmet medical need for treatment of MLLr leukemia.

[0006] The protein-protein interaction (PPI) between menin and MLLr is crucial to the pathogenesis of MLLr-driven leukemia through dysregulation 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 nucleophosphoprotein 1 (NPM1) gene mutations. NPM1 mutations (NMP1c) are found in over 30% of AML patients with poor 5-year overall survival and are also associated with upregulated expression of the HOXA and MEIS1 genes (Kuhn, MW, et al., Cancer Discov. 2016, 6, 1166). Menin inhibitors have been reported to block the interaction between menin and MLLr and MLL wt, demonstrating their potential use in the treatment of MLLr-related acute leukemia and NPM-mutant AML (Klossowski, S., et al., J Clin Invest. 2020, 130, 981). Invention Overview

[0008] This overview is provided to introduce some concepts in a simplified form, which are further explained in detail below. This overview is not intended to identify key or essential features of the claimed subject matter, nor is it intended to limit the scope of the claimed subject matter.

[0009] This disclosure provides compounds of formula I:

[0010]

[0011] Or its pharmaceutically acceptable salts or stereoisomers, racemates, tautomers, hydrates or solvates, wherein:

[0012] X is a halogenated group or CN;

[0013] Y is either N or CH;

[0014] Z is selected from CH2, O, S, and NH;

[0015] R1 is selected from:

[0016] 1)-(C=O)-NRaRb, where:

[0017] Ra and Rb are each independently selected from C 1-6 Alkyl, 3-6 membered cycloalkyl rings and 5-9 membered heterocyclic rings, optionally with

[0018] 1, 2, or 3 are selected from deuterium, halogenated groups, OH, CN, and C. 1-6 Substitution of alkoxy groups;

[0019] Alternatively, Ra and Rb, together with the nitrogen atoms to which they are attached, form a 5-9 membered heterocyclic ring, which is optionally composed of 1, 2, or 3 atoms selected from C. 1-6 Alkyl, halogroup, OH and CN substituents;

[0020] 2) 5-10 membered heteroaryl rings or C 6-10 The aryl ring is optionally substituted by one, two, or three substituents selected from the following:

[0021] The halogenated group, CN, is optionally substituted by one, two, or three substituents selected from the halogenated group, CN, and OH. 1-6 Alkyl, 3-5 membered alkyl rings, oxo and C 1-6 Alkoxy;

[0022] R2 and R3 are each independently H or D;

[0023] R4 groups are independently selected from halogen groups, CN, OH, oxo groups, and C groups. 1-6 alkylsulfonyl-, C 1-6 alkylsulfonylamino-, C 1-6 Alkyl carbonyl amino-, C 6-10 Aryl ring, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, 3-9 membered cycloalkyl, 5-10 membered heteroaryl, and 4-9 membered heterocyclic rings, wherein the alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, heteroaryl, or heterocyclic rings are optionally substituted by 1, 2, or 3 substituents selected from halogen, CN, and OH.

[0024] Two adjacent R4 atoms, together with the carbon atoms they are attached to, optionally form a 3-9 membered alkyl ring, which is optionally surrounded by 1, 2, or 3 carbon atoms selected from C. 1-6 Alkyl, -C 1-6 Alkyl-OH, C 1-6 Alkoxy-C 1-6 Alkyl, halo, CN, and OH substituents;

[0025] Alternatively, two R4 atoms attached to the same carbon atom may optionally form a 3-6 membered cycloalkyl ring or a 4-6 membered heterocyclic ring together with the carbon atom, optionally surrounded by one, two, or three C atoms. 1-6 Alkyl, -C 1-6 Alkyl-OH, C 1-6 Alkoxy-C 1-6 Alkyl, halo, CN, and OH substituents;

[0026] Alternatively, two adjacent R4 atoms, together with the carbon atoms they are attached to, may optionally form a 5-10 membered heteroaryl ring, C6-10 An aryl ring or a 5-9 membered heterocyclic ring, wherein the heteroaryl ring or aryl ring is optionally composed of 1, 2 or 3 members selected from C 1-6 Alkyl, C 1-6 Halogenated alkyl, -C 1-6 Alkyl-OH, C 1-6 Alkoxy-C 1-6 The alkyl group is substituted with a alkyl group, a halogroup, a CN group, or an OH group, wherein the alkyl group is optionally substituted with a 3-6 membered alkyl ring or a phenyl group; the heterocyclic ring is optionally substituted with one, two, or three substituents selected from C10. 1-6 Alkyl, C 1-6 Halogenated alkyl, -C 1-6 Alkyl-OH, C 1-6 Alkoxy-C 1-6 Alkyl, oxo, halo, CN and OH substituents;

[0027] R5 is selected from H, a halogroup, a methyl group optionally substituted with 1, 2 or 3 deuterium or halogroups, a methoxy group optionally substituted with 1, 2 or 3 deuterium or halogroups, NH2, CH3NH or (CH3)2N.

[0028] a, b, c, and d are each 1 or 2 independently;

[0029] n is 0, 1, or 2; and

[0030] m is 0, 1, 2, 3 or 4;

[0031] The condition is that R4, if present, substitutes for any chemically permissible position on the heterocyclic group, except for the N atom adjacent to the junction of the heterocyclic group and the rest of the compound structure.

[0032] The compounds of Formula I or their stereoisomers, racemates, tautomers, hydrates or solvates or pharmaceutically acceptable salts, as well as specific compounds disclosed in the context of this invention and covered by the scope of the above-described compounds, are collectively referred to as "the compounds disclosed herein".

[0033] This disclosure provides compounds of this disclosure for use as pharmaceuticals.

[0034] This disclosure provides compounds of this disclosure for the treatment or prevention of cancer or diabetes.

[0035] This disclosure provides pharmaceutical compositions comprising the compounds of this disclosure and optionally a pharmaceutically acceptable carrier.

[0036] This disclosure also provides kits for treating or preventing cancer or diabetes, which contain the pharmaceutical compositions of this disclosure and instructions for use.

[0037] This disclosure also provides the use of the compounds disclosed herein for the treatment or prevention of cancer or diabetes.

[0038] This disclosure also provides the use of the compounds disclosed herein in the preparation of medicaments for the treatment or prevention of cancer or diabetes.

[0039] This disclosure also provides a method for inhibiting the interaction of menin with MLL and / or MLL fusion proteins in vivo or in vitro, comprising contacting an effective amount of the disclosed compound with menin.

[0040] This disclosure also provides methods for treating or preventing cancer or diabetes, which include administering an effective amount of the compound of this disclosure to an individual in need.

[0041] This disclosure also provides combinations comprising the compounds of this disclosure and at least one additional therapeutic agent.

[0042] This disclosure also provides methods for preparing the compounds of this disclosure, and intermediates for preparing the compounds of this disclosure. Invention Details

[0044] The implementation scheme of this disclosure – Part A

[0045] Implementation Scheme 1. Compound of Formula I:

[0046]

[0047]

[0048] Or its stereoisomers, racemates, tautomers, hydrates or solvates or pharmaceutically acceptable salts, wherein:

[0049] X is a halogenated group or CN;

[0050] Y is either N or CH;

[0051] Z is selected from CH2, O, S, and NH;

[0052] R1 is selected from:

[0053] 1)-(C=O)-NRaRb, where:

[0054] Ra and Rb are each independently selected from C 1-6 Alkyl, 3-6 membered cycloalkyl rings and 5-9 membered heterocyclic rings, optionally with

[0055] 1, 2, or 3 are selected from deuterium, halogenated groups, OH, CN, and C. 1-6 Substitution of alkoxy groups;

[0056] Alternatively, Ra and Rb, together with the nitrogen atoms to which they are attached, form a 5-9 membered heterocyclic ring, which is optionally composed of 1, 2, or 3 atoms selected from C. 1-6 Alkyl, halogroup, OH and CN substituents;

[0057] 2) 5-10 membered heteroaryl rings or C 6-10 The aryl ring is optionally substituted by one, two, or three substituents selected from the following:

[0058] The halogenated group, CN, is optionally substituted by one, two, or three substituents selected from the halogenated group, CN, and OH. 1-6 Alkyl, 3-5 membered alkyl rings, oxo and C 1-6 Alkoxy;

[0059] R2 and R3 are each independently H or D;

[0060] R4 groups are independently selected from halogen groups, CN, OH, oxo groups, and C groups. 1-6 alkylsulfonyl-, C 1-6 alkylsulfonylamino-, C 1-6 Alkyl carbonyl amino-, C 6-10 Aryl ring, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, 3-9 membered cycloalkyl, 5-10 membered heteroaryl, and 4-9 membered heterocyclic rings, wherein the alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, heteroaryl, or heterocyclic rings are optionally substituted by 1, 2, or 3 substituents selected from halogen, CN, and OH.

[0061] Two adjacent R4 atoms, together with the carbon atoms they are attached to, optionally form a 3-9 membered alkyl ring, which is optionally surrounded by 1, 2, or 3 carbon atoms selected from C. 1-6 Alkyl, -C 1-6 Alkyl-OH, C 1-6 Alkoxy-C 1-6 Alkyl, halo, CN, and OH substituents;

[0062] Alternatively, two R4 atoms attached to the same carbon atom may optionally form a 3-6 membered cycloalkyl ring or a 4-6 membered heterocyclic ring together with the carbon atom, optionally surrounded by one, two, or three C atoms. 1-6 Alkyl, -C 1-6 Alkyl-OH, C 1-6 Alkoxy-C 1-6 Alkyl, halo, CN, and OH substituents;

[0063] Alternatively, two adjacent R4 atoms, together with the carbon atoms they are attached to, may optionally form a 5-10 membered heteroaryl ring, C6-10 An aryl ring or a 5-9 membered heterocyclic ring, wherein the heteroaryl ring or aryl ring is optionally composed of 1, 2 or 3 members selected from C 1-6 Alkyl, C 1-6 Halogenated alkyl, -C 1-6 Alkyl-OH, C 1-6 Alkoxy-C 1-6 The alkyl group is substituted with a alkyl group, a halogroup, a CN group, or an OH group, wherein the alkyl group is optionally substituted with a 3-6 membered alkyl ring or a phenyl group; the heterocyclic ring is optionally substituted with 1, 2, or 3 C1-membered alkyl groups. 1-6 Alkyl, C 1-6 Halogenated alkyl, -C 1-6 Alkyl-OH, C 1-6 Alkoxy-C 1-6 Alkyl, oxo, halogen

[0064] Substitution by substituents of alkyl groups, CN, and OH;

[0065] R5 is selected from H, a halogroup, a methyl group optionally substituted with 1, 2 or 3 deuterium or halogroups, a methoxy group optionally substituted with 1, 2 or 3 deuterium or halogroups, NH2, CH3NH or (CH3)2N.

[0066] a, b, c, and d are each 1 or 2 independently;

[0067] n is 0, 1, or 2; and

[0068] m is 0, 1, 2, 3 or 4;

[0069] The condition is that R4, if present, substitutes for any chemically permissible position on the heterocyclic group, except for the N atom adjacent to the junction of the heterocyclic group and the rest of the compound structure.

[0070] Implementation Scheme 2. The compound according to Implementation Scheme 1 or its stereoisomers, racemates, tautomers, hydrates or solvates or pharmaceutically acceptable salts, wherein:

[0071] X is F, Cl, or CN;

[0072] Y is either N or CH;

[0073] Z is selected from CH2, O, S, and NH;

[0074] R1 is selected from:

[0075] 1)-(C=O)-NRaRb, where:

[0076] Ra and Rb are each independently selected from C 1-6 Alkyl and 3-5 membered cycloalkyl rings, wherein C 1-6Alkyl groups are optionally surrounded by one, two, or three groups selected from deuterium, halogroup, OH, and C. 1-6 Substitution of alkoxy groups;

[0077] Alternatively, Ra and Rb, together with the nitrogen atoms to which they are attached, form a 5-6 membered monocyclic or 7-9 membered bicyclic heterocyclic ring, optionally composed of 1, 2, or 3 atoms selected from C. 1-6 Substitution of alkyl and halogroups;

[0078] 2) A 5-6 membered heteroaryl ring, optionally substituted with 1, 2, or 3 substituents selected from the following: a halogenated group, CN, and a C substituent optionally substituted with 1, 2, or 3 substituents selected from the halogenated group and CN. 1-6 Alkyl, 3-5 membered alkyl rings, oxo and C 1-6 Alkoxy;

[0079] 3)C 6-10 An aryl ring, which is substituted by 1, 2, or 3 substituents selected from: halogen, CN, and C optionally substituted by 1, 2, or 3 substituents selected from the halogen and CN. 1-6 Alkyl, 3-5 membered cycloalkyl rings and C 1-6 Alkoxy;

[0080] R2 and R3 are each independently H or D;

[0081] R4 groups are independently selected from halogen groups, CN, OH, and C. 1-6 alkylsulfonyl-, C 1-6 alkylsulfonylamino-, C 1-6 Alkyl carbonyl amino-, phenyl, C 1-6 Alkyl, C 1-6 Alkoxy, 3-6 membered cycloalkyl, 5-10 membered heteroaryl, and 5-9 membered heterocyclic rings, wherein the alkyl, alkoxy, cycloalkyl, heteroaryl, or heterocyclic rings are optionally substituted by 1, 2, or 3 substituents selected from halogen, CN, and OH;

[0082] Two adjacent R4 atoms, together with the carbon atoms they are attached to, optionally form a 3-6 membered alkyl ring, which is optionally surrounded by 1, 2, or 3 carbon atoms selected from C14. 1-6 Alkyl, -C 1-6 Alkyl-OH, C 1-6 Alkoxy-C 1-6 Alkyl and haloyl substituents;

[0083] Alternatively, two R4s attached to the same carbon atom may optionally form a 3-6 membered cycloalkyl ring together with the carbon atom, which may optionally be substituted by one, two or three substituents selected from halogens, CN and OH;

[0084] Alternatively, two adjacent R4s, together with the carbon atoms they are attached to, may optionally form a 5-10 membered heteroaryl ring, a phenyl ring, or a 5-9 membered heterocyclic ring, which may optionally be surrounded by one, two, or three groups selected from halogenated groups, C, and D. 1-6 Alkyl and C 1-6 The alkyl group is substituted with a substituent, wherein the alkyl group is optionally substituted with a 3-6 membered cycloalkyl ring or a phenyl group;

[0085] R5 is an H or a halogenated group;

[0086] a, b, c, and d are each 1 or 2 independently;

[0087] n is 0 or 1; and

[0088] m is 0, 1, 2, or 3;

[0089] The condition is that R4, if present, substitutes for any chemically permissible position on the heterocyclic group, except for the N atom adjacent to the junction of the heterocyclic group and the rest of the compound structure.

[0090] Implementation Scheme 3. The compound or its stereoisomer, racemate, tautomer, hydrate or solvate or pharmaceutically acceptable salt according to any of the foregoing implementation schemes, wherein:

[0091] R4 groups are independently selected from halogen groups, CN, OH, and C. 1-6 alkylsulfonyl-, C 1-6 Alkylsulfonylamino-, phenyl, C 1-6 Alkyl, C 1-6 Alkoxy and 3-6 membered cycloalkyl ring, wherein the alkyl or alkoxy group is optionally substituted by 1, 2 or 3 substituents selected from halogen, CN and OH;

[0092] Two adjacent R4 atoms, together with the carbon atoms they are attached to, optionally form a 3-6 membered alkyl ring, which is optionally surrounded by 1, 2, or 3 carbon atoms selected from C14. 1-6 Alkyl, -C 1-6 Alkyl-OH, C 1-6 Alkoxy-C 1-6 Alkyl and haloyl substituents;

[0093] Alternatively, two R4s attached to the same carbon atom may optionally form a 3-6 membered cycloalkyl ring together with the carbon atom, which may optionally be substituted by one, two or three substituents selected from halogens, CN and OH;

[0094] Alternatively, two adjacent R4 atoms, together with the carbon atoms they are attached to, may optionally form a 5-10 membered heteroaryl ring or a phenyl group, which may optionally be surrounded by 1, 2, or 3 carbon atoms selected from C4. 1-6 Alkyl substituents, wherein the alkyl group is optionally substituted with a 3-6 membered cycloalkyl ring or a phenyl group.

[0095] Implementation Scheme 4. A compound or its stereoisomer, racemate, tautomer, hydrate or solvate or pharmaceutically acceptable salt according to any of the foregoing implementation schemes, wherein R5 is H.

[0096] Implementation Scheme 5. A compound according to any of the foregoing implementation schemes, or a stereoisomer, racemate, tautomer, hydrate, solvate, or pharmaceutically acceptable salt thereof, wherein the compound has Formula II:

[0097]

[0098] Preferably, the compound has formula IIa:

[0099]

[0100] Its preferred

[0101]

[0102] More preferably:

[0103]

[0104] Where p is independently 0 or 1; q is 0, 1 or 2; R 4a It is C 1-3 Alkyl or halogroup;

[0105] The best option is:

[0106]

[0107] Where p is independently 0 or 1; q is 0, 1 or 2; R 4a It is C 1-3 Alkyl or halogroup.

[0108] Implementation Scheme 6. A compound or its stereoisomer, racemate, tautomer, hydrate or solvate or pharmaceutically acceptable salt according to any one of Implementation Schemes 1 to 4, wherein the compound has Formula III:

[0109]

[0110] Implementation Scheme 7. A compound or its stereoisomer, racemate, tautomer, hydrate or solvate or pharmaceutically acceptable salt according to any of the foregoing implementation schemes, wherein X is F.

[0111] Implementation Scheme 8. A compound or its stereoisomer, racemate, tautomer, hydrate or solvate or pharmaceutically acceptable salt according to any of the foregoing implementation schemes, wherein Z is selected from CH2, O and S, preferably CH2.

[0112] Implementation Scheme 9. A compound or its stereoisomer, racemate, tautomer, hydrate or solvate or pharmaceutically acceptable salt according to any of the foregoing implementation schemes, wherein R2 and R3 are each independently H.

[0113] Implementation Scheme 10. The compound or its stereoisomer, racemate, tautomer, hydrate or solvate or pharmaceutically acceptable salt according to any of the foregoing implementation schemes, wherein:

[0114] R1 is -(C=O)-NRaRb, where:

[0115] Ra and Rb are each independently selected from C 1-6 Alkyl and 3-5 membered cycloalkyl rings, wherein the C 1-6 The alkyl group is optionally replaced by one, two, or three substituents selected from deuterium, halogroup, OH, and C. 1-6 Substitution of alkoxy groups; or

[0116] Ra and Rb, together with the nitrogen atom to which they are attached, form a 5-6 membered monocyclic or 7-9 membered bicyclic heterocyclic ring having another cyclic heteroatom selected from N, O, and S, optionally surrounded by 1, 2, or 3 cyclic heteroatoms selected from C. 1-6 Substitution of alkyl and halogen groups.

[0117] Implementation Scheme 11. A compound or its stereoisomer, racemate, tautomer, hydrate, solvate, or pharmaceutically acceptable salt according to any one of Implementation Schemes 1-9, wherein:

[0118] R1 is -(C=O)-NRaRb, where Ra and Rb are each C that is optionally replaced by an OH group. 1-3 Alkyl; preferably Ra is ethyl, and Rb is isopropyl; or

[0119] R1 is determined by 1, 2, or 3 groups selected from halogenated groups, CN, C, and C. 1-3 A 5-6 membered heteroaryl ring substituted with alkyl and cyclopropyl substituents; or a phenyl group substituted with 1, 2 or 3 substituents selected from halogen, CN and cyclopropyl groups.

[0120] Implementation Scheme 12. The compound according to Implementation Scheme 11 or its stereoisomers, racemates, tautomers, hydrates or solvates or pharmaceutically acceptable salts, wherein:

[0121] R1 is -(C=O)-NRaRb, where Ra and Rb are each C that is optionally replaced by an OH group. 1-3 Alkyl; preferably Ra is ethyl, and Rb is isopropyl; or

[0122] R1 is a pyridinyl, pyrimidinyl, or pyrazolyl group, which is surrounded by one, two, or three groups selected from halogenated groups, CN, C. 1-3 Alkyl and cyclopropyl substituents; or phenyl, which is substituted by one, two or three substituents selected from halogen, CN and cyclopropyl.

[0123] Implementation Scheme 13. A compound or its stereoisomer, racemate, tautomer, hydrate or solvate or pharmaceutically acceptable salt according to any one of Implementation Schemes 1-9, wherein:

[0124] R1 is -(C=O)-NRaRb, where Ra and Rb are each C 1-3 Alkyl group, preferably Ra is ethyl, and Rb is isopropyl; or

[0125] R1 is a 6-membered heteroaryl or phenyl ring, which is substituted by 1, 2 or 3 substituents selected from halogenated, CN and cyclopropyl groups.

[0126] Implementation Scheme 14. A compound or its stereoisomer, racemate, tautomer, hydrate or solvate or pharmaceutically acceptable salt according to any one of Implementation Schemes 1-9, wherein:

[0127] R1 is -(C=O)-NRaRb, where Ra is ethyl and Rb is isopropyl.

[0128] Implementation Scheme 15. A compound or its stereoisomer, racemate, tautomer, hydrate or solvate or pharmaceutically acceptable salt according to any one of Implementation Schemes 1-9, wherein:

[0129] R1 is pyridyl, pyrimidinyl, or phenyl, which is substituted by one, two, or three substituents selected from halogenated, CN, and cyclopropyl groups.

[0130] Implementation Scheme 16. A compound or its stereoisomer, racemate, tautomer, hydrate, solvate, or pharmaceutically acceptable salt according to any one of Implementation Schemes 1-9, wherein:

[0131] R1 is Wherein A1 or A2 is N or CH; R6 is selected from halogenated group, CN, and cyclopropyl; and R7 is selected from H, halogenated group, CN, and cyclopropyl; preferably, R1 is

[0132] Or R1 is Where A3 is N or C substituted with a halogenated group, and R8 is C. 1-3 Alkyl; preferably, R1 is

[0133] Implementation Scheme 17. The compound according to Implementation Scheme 16, or a stereoisomer, racemate, tautomer, hydrate, solvate, or pharmaceutically acceptable salt thereof, wherein the compound has formula IIb:

[0134]

[0135] Implementation Scheme 18. A compound or its stereoisomer, racemate, tautomer, hydrate or solvate or pharmaceutically acceptable salt according to any one of Implementation Schemes 1-9, wherein:

[0136] R1 is -(C=O)-NRaRb, where Ra and Rb are each C 1-3 Alkyl; preferably Ra is ethyl, and Rb is isopropyl; or

[0137] R1 is a 6-membered heteroaryl ring, which is substituted by 1, 2 or 3 substituents selected from halogenated groups, CN and cyclopropyl groups.

[0138] Implementation Scheme 19. The compound or its stereoisomers, racemates, tautomers, hydrates or solvates or pharmaceutically acceptable salts according to Implementation Schemes 1-9, wherein:

[0139] R1 is -(C=O)-NRaRb, where Ra and Rb are each C 1-3 Alkyl; preferably Ra is ethyl, and Rb is isopropyl; or

[0140] R1 is a pyridinyl or pyrimidinyl group, which is substituted by one, two, or three substituents selected from halogenated groups, CN, and cyclopropyl groups.

[0141] Implementation Scheme 20. A compound or its stereoisomer, racemate, tautomer, hydrate, solvate, or pharmaceutically acceptable salt according to any one of Implementation Schemes 1-9 above, wherein:

[0142] R1 is selected from:

[0143]

[0144] Implementation Scheme 21. The compound or its stereoisomer, racemate, tautomer, hydrate or solvate or pharmaceutically acceptable salt according to any of the foregoing implementation schemes, wherein:

[0145] Each of a and b is 1; and

[0146] Each of c and d is 1 or 2.

[0147] Implementation Scheme 22. The compound or its stereoisomer, racemate, tautomer, hydrate or solvate or pharmaceutically acceptable salt according to any of the foregoing implementation schemes, wherein:

[0148] n can be 0 or 1, preferably 0.

[0149] Implementation Scheme 23. A compound or its stereoisomer, racemate, tautomer, hydrate or solvate or pharmaceutically acceptable salt according to any one of Implementation Schemes 1-15, wherein n is 0.

[0150] Implementation Scheme 24. A compound or its stereoisomer, racemate, tautomer, hydrate or solvate or pharmaceutically acceptable salt according to any one of Implementation Schemes 1-15, wherein n is 1.

[0151] Implementation Scheme 25. The compound or its stereoisomer, racemate, tautomer, hydrate or solvate or pharmaceutically acceptable salt according to any of the foregoing implementation schemes, wherein m is 0, 1 or 2.

[0152] Implementation Scheme 26. The compound or its stereoisomer, racemate, tautomer, hydrate or solvate or pharmaceutically acceptable salt according to any of the foregoing implementation schemes, wherein:

[0153] Each of a and b is 1.

[0154] Implementation Scheme 27. A compound or its stereoisomer, racemate, tautomer, hydrate, solvate, or pharmaceutically acceptable salt according to any of the foregoing implementation schemes, wherein:

[0155] The value of each of c and d is 2.

[0156] Implementation Scheme 28. A compound or its stereoisomer, racemate, tautomer, hydrate, solvate, or pharmaceutically acceptable salt according to any of the foregoing implementation schemes, wherein:

[0157] m is 1 or 2.

[0158] Implementation Scheme 29. A compound or its stereoisomer, racemate, tautomer, hydrate or solvate or pharmaceutically acceptable salt according to any one of Implementation Schemes 1-16, wherein:

[0159] Each of a and b is 1;

[0160] Each of c and d is 2;

[0161] n is either 0 or 1, preferably 0; and

[0162] m can be 0, 1, or 2.

[0163] Implementation Scheme 30. The compound or its stereoisomer, racemate, tautomer, hydrate or solvate or pharmaceutically acceptable salt according to any of the foregoing implementation schemes, wherein:

[0164] R4 groups are independently selected from halogenated groups; CN; OH; C. 1-6 alkylsulfonyl-; C 1-6 Alkylsulfonylamino-; phenyl; C substituted with 1, 2 or 3 substituents selected from halogen groups, CN and OH. 1-6 Alkyl group; C group optionally substituted with 1, 2 or 3 halogroups 1-6 alkoxy; and cyclopropyl,

[0165] Two adjacent R4 atoms, together with the carbon atoms they are attached to, optionally form a 3-6 membered alkyl ring, which is optionally surrounded by 1, 2, or 3 carbon atoms selected from C14. 1-6 Alkyl, -C 1-6 Alkyl-OH, C 1-6 Alkoxy-C 1-6 Alkyl and haloyl substituents;

[0166] Alternatively, two R4s attached to the same carbon atom may optionally form a 3-6 membered cycloalkyl ring together with the carbon atom, which may optionally be substituted with 1, 2 or 3 halogen groups;

[0167] Alternatively, two adjacent R4 atoms, together with the carbon atoms they are attached to, may optionally form a 5-6 membered heteroaryl ring, which may optionally be bounded by 1, 2, or 3 carbon atoms. 1-6 Alkyl substitution, wherein the alkyl group is optionally substituted with a 3-6 membered cycloalkyl ring or a phenyl group;

[0168] Alternatively, two adjacent R4 atoms, together with the carbon atoms they are attached to, may optionally form a phenyl group.

[0169] Implementation Scheme 31. The compound or its stereoisomer, racemate, tautomer, hydrate or solvate or pharmaceutically acceptable salt according to any of the foregoing implementation schemes, wherein:

[0170] R4 groups are independently selected from halogenated groups; CN; OH; C. 1-3 alkylsulfonyl-; C 1-3 Alkylsulfonylamino-; phenyl; C optionally substituted with 1, 2 or 3 substituents selected from halogen, CN and OH 1-3 Alkyl group; C group optionally substituted with 1, 2 or 3 halogroups 1-3 alkoxy; and cyclopropyl,

[0171] Two adjacent R4 atoms, together with the carbon atoms they are attached to, optionally form a 3-6 membered alkyl ring, which is optionally surrounded by 1, 2, or 3 carbon atoms selected from C14. 1-3 Alkyl, -C 1-3 Alkyl-OH, C 1-3 Alkoxy-C 1-3 Alkyl and haloyl substituents;

[0172] Alternatively, two R4s attached to the same carbon atom may optionally form a 3-6 membered cycloalkyl ring together with the carbon atom, which may optionally be substituted with 1, 2 or 3 halogen groups;

[0173] Alternatively, two adjacent R4 atoms, together with the carbon atoms they are attached to, may optionally form a 5-6 membered heteroaryl ring, which may optionally be bounded by 1, 2, or 3 carbon atoms. 1-3 Alkyl substitution, wherein the alkyl group is optionally substituted with a 3-6 membered cycloalkyl ring or a phenyl group;

[0174] Alternatively, two adjacent R4 atoms, together with the carbon atoms they are attached to, may optionally form a phenyl group.

[0175] Implementation Scheme 32. The compound or its stereoisomer, racemate, tautomer, hydrate or solvate or pharmaceutically acceptable salt according to any of the foregoing implementation schemes, wherein:

[0176] Structural parts Selected from:

[0177]

[0178]

[0179] Implementation Scheme 33. A compound or its stereoisomer, racemate, tautomer, hydrate, solvate, or pharmaceutically acceptable salt according to any one of Implementation Schemes 1-5, wherein:

[0180] X is F;

[0181] Z is CH2;

[0182] R1 is selected from:

[0183] 1)-(C=O)-NRaRb, where:

[0184] Ra and Rb are each independently selected from C atoms that are optionally replaced by 1, 2, or 3 deuterium atoms. 1-6 alkyl;

[0185] Alternatively, Ra and Rb, together with the nitrogen atoms to which they are attached, form a 5-6 membered monocyclic or 7-9 membered bicyclic heterocyclic ring, optionally bounded by 1, 2, or 3 carbon atoms. 1-6 Alkyl substitution;

[0186] 2) Selected by 1, 2 or 3 halogenated groups, CN, C 1-6 Alkyl, CF3, 3-5 membered cycloalkyl rings, oxo and C 1-6 5-6 membered heteroaryl rings substituted with alkoxy groups;

[0187] 3) Selected by 1, 2 or 3 halogenated groups, CN, C 1-6Alkyl, CF3, 3-5 membered cycloalkyl rings and C 1-6 alkoxy substituents of C 6-10 Aryl ring;

[0188] R2 and R3 are each H independently;

[0189] R4 groups are independently selected from halogenated groups; CN; OH; C. 1-6 alkylsulfonyl-; C 1-6 Alkylsulfonylamino-; phenyl; C substituted with 1, 2 or 3 substituents selected from halogen groups, CN and OH. 1-6 Alkyl group; C group optionally substituted with 1, 2 or 3 halogroups 1-6 alkoxy groups; and 3-6 membered cycloalkyl rings,

[0190] Two adjacent R4 atoms, together with the carbon atoms they are attached to, optionally form a 3-6 membered alkyl ring, which is optionally surrounded by 1, 2, or 3 carbon atoms selected from C14. 1-6 Substitution of alkyl and halogroups;

[0191] Alternatively, two adjacent R4 atoms, together with the carbon atoms they are attached to, may optionally form a phenyl group;

[0192] R5 is an H or a halogenated group;

[0193] Each of a and b is 1;

[0194] Each of c and d is 2;

[0195] n is 0; and

[0196] m is 0, 1, or 2;

[0197] The condition is that R4, if present, substitutes for any chemically permissible position on the heterocyclic group, except for the N atom adjacent to the junction of the heterocyclic group and the rest of the compound structure.

[0198] Implementation Scheme 34. The compound or its stereoisomer, racemate, tautomer, hydrate or solvate or pharmaceutically acceptable salt according to Implementation Scheme 33, wherein R5 is H.

[0199] Implementation Scheme 35. A compound or its stereoisomer, racemate, tautomer, hydrate or solvate or pharmaceutically acceptable salt according to any one of Implementation Schemes 33-34, wherein R1 is -(C=O)-NRaRb, and Ra and Rb are each independently selected from ethyl or isopropyl.

[0200] Implementation Scheme 36. A compound or its stereoisomer, racemate, tautomer, hydrate, solvate, or pharmaceutically acceptable salt according to any one of Implementation Schemes 33-34, wherein R1 is a 5- or 6-membered heteroaryl ring or phenyl ring, which is surrounded by one or two groups selected from halogenated groups, CN, C 1-3 Alkyl, CF3, cyclopropyl, oxo and C 1-3 Substitution of alkoxy groups.

[0201] Implementation Scheme 37. A compound or its stereoisomer, racemate, tautomer, hydrate, solvate, or pharmaceutically acceptable salt according to any one of Implementation Schemes 33-34, wherein:

[0202] R1 is selected from:

[0203]

[0204] Implementation Scheme 38. A compound or its stereoisomer, racemate, tautomer, hydrate or solvate or pharmaceutically acceptable salt according to any one of Implementation Schemes 33-37, wherein...

[0205] R4 groups are independently selected from halogenated groups; CN; OH; C. 1-3 alkylsulfonyl-; C 1-3 Alkylsulfonylamino-; phenyl; C optionally substituted with 1, 2 or 3 substituents selected from halogen, CN and OH 1-3 Alkyl group; C group optionally substituted with 1, 2 or 3 halogroups 1-3 alkoxy; and cyclopropyl;

[0206] Two adjacent R4 atoms, together with the carbon atoms they are attached to, optionally form a 3-6 membered alkyl ring, which is optionally surrounded by 1, 2, or 3 carbon atoms selected from C14. 1-3 Substitution of alkyl and halogroups;

[0207] Alternatively, two adjacent R4 atoms, together with the carbon atoms they are attached to, may optionally form a phenyl group.

[0208] Implementation Scheme 39. A compound or its stereoisomer, racemate, tautomer, hydrate or solvate or pharmaceutically acceptable salt according to any one of Implementation Schemes 33-38, wherein:

[0209] Structural parts Selected from:

[0210]

[0211] Implementation Scheme 40. A compound or its stereoisomers, racemates, tautomers, hydrates or solvates or pharmaceutically acceptable salts according to any one of Implementation Schemes 1-30 and 34-38, wherein:

[0212] R4 groups are independently selected from halogenated groups, CN, and C. 1-3 Alkoxy and cyclopropyl,

[0213] Or two adjacent R4 atoms together with the carbon atoms they are attached to form a cyclopropyl group; and

[0214] m is 1 or 2.

[0215] Implementation Scheme 41. A compound or its stereoisomer, racemate, tautomer, hydrate or solvate or pharmaceutically acceptable salt according to any one of Implementation Schemes 1-29 and 33-38, wherein the structural moiety is... yes

[0216] R4', R4”, and R4”' are independently selected from H; a halogroup; CN; OH; and a C group optionally substituted with 1, 2, or 3 substituents selected from the halogroup and CN. 1-6 Alkyl; C 1-6 alkoxy; and cyclopropyl; or

[0217] R4' and R4" together with the carbon atoms they are attached to optionally form a 3-6 membered alkyl ring, which is optionally composed of 1, 2 or 3 carbon atoms selected from C1 to C2. 1-6 Alkyl and haloyl substituents; and R4”' is H.

[0218] Implementation Scheme 42. A compound or its stereoisomer, racemate, tautomer, hydrate or solvate or pharmaceutically acceptable salt according to any one of Implementation Schemes 1-29 and 33-38, wherein the structural moiety is... yes

[0219] R4', R4”, and R4”' are independently selected from H; a halogenated group; CN; OH; and a C group optionally substituted with a halogenated group. 1-6 Alkyl; and C 1-6 alkoxy; or

[0220] R4' and R4" together with the carbon atoms they are attached to optionally form a 3-6 membered alkyl ring, which is optionally bounded by one or two carbon atoms. 1-6 Alkyl substitution; and R4”' is H.

[0221] Implementation Scheme 43. A compound or its stereoisomer, racemate, tautomer, hydrate or solvate or pharmaceutically acceptable salt according to any one of Implementation Schemes 1-29 and 33-38, wherein the structural moiety is... yes

[0222] R4', R4”, and R4”' are independently selected from H; a halogenated group; CN; and a C that is optionally substituted with a halogenated group. 1-3 Alkyl; and C 1-3 alkoxy; or

[0223] R4' and R4" together with the carbon atoms they are attached to optionally form a 3- to 5-membered alkyl ring, which is optionally bounded by 1 or 2 carbon atoms. 1-3 Alkyl substitution; and R4”' is H.

[0224] Implementation Scheme 44. A compound or its stereoisomers, racemates, tautomers, hydrates or solvates or pharmaceutically acceptable salts according to any one of Implementation Schemes 1-29 and 33-38, wherein:

[0225] Structural parts yes

[0226] Implementation Scheme 45. A compound or its stereoisomer, racemate, tautomer, hydrate or solvate or pharmaceutically acceptable salt according to any one of Implementation Schemes 41-44, wherein:

[0227] R4', R4”, and R4”' are independently selected from H; a halogenated group; CN; OH; and a C group optionally substituted with a halogenated group. 1-3 Alkyl; and C 1-3 Alkyl group.

[0228] Implementation Scheme 46. A compound or its stereoisomer, racemate, tautomer, hydrate or solvate or pharmaceutically acceptable salt according to any one of Implementation Schemes 41-44, wherein:

[0229] R4' and R4" together with the carbon atoms they are attached to optionally form a 3- to 5-membered alkyl ring, which is optionally bounded by 1 or 2 carbon atoms. 1-3 Alkyl substitution; and R4”' is H.

[0230] Implementation Scheme 47. A compound or its stereoisomer, racemate, tautomer, hydrate, solvate, or pharmaceutically acceptable salt according to any one of Implementation Schemes 41-44, wherein:

[0231] Each of R4' and R4"' is H; and R4" is C substituted with a halogenated group. 1-3 alkyl.

[0232] Implementation Scheme 48. A compound or its stereoisomer, racemate, tautomer, hydrate or solvate or pharmaceutically acceptable salt according to any one of Implementation Schemes 41-44, wherein:

[0233] R4' and R4” together with the carbon atoms to which they are attached optionally form a 3- or 5-membered alkyl ring, which is optionally substituted with 1 or 2 methyl groups; and R4”' is H.

[0234] Implementation Scheme 49. A compound or its stereoisomers, racemates, tautomers, hydrates or solvates or pharmaceutically acceptable salts according to any one of 1-29 and 33-38, wherein:

[0235] Structural parts yes

[0236] Where R4”’ is H; and

[0237] R4' and R4" are independently selected from H; halogenated group; C optionally substituted with one halogenated group. 1-6 Alkyl; and C 1-6 alkoxy group; condition is that one of R4' and R4" is not H; or,

[0238] R4' and R4" together with the carbon atoms they are attached to form a group optionally bounded by one or two C atoms. 1-3 Alkyl-substituted 3- or 5-membered alkyl rings, or forming phenyl rings.

[0239] Implementation Scheme 50. The compounds according to 1-29 and 33-38, or their stereoisomers, racemates, tautomers, hydrates or solvates or pharmaceutically acceptable salts, wherein:

[0240] Structural parts yes

[0241] Where R4”’ is H; and

[0242] R4' and R4" are independently selected from H; halogenated group; C optionally substituted with one halogenated group. 1-6 Alkyl; and C 1-6 alkoxy group; condition is that one of R4' and R4" is not H; or,

[0243] R4' and R4" together with the carbon atoms they are attached to form a group optionally bounded by one or two C atoms. 1-3 Alkyl-substituted 3- or 5-membered alkyl rings.

[0244] Implementation Scheme 51. A compound or its stereoisomers, racemates, tautomers, hydrates or solvates or pharmaceutically acceptable salts according to any one of Implementation Schemes 1-29 and 33-38, wherein:

[0245] Structural parts yes Where R4' is H; and R4” and R4”' are independently C. 1-3 alkyl.

[0246] Implementation Scheme 52. A compound or its stereoisomer, racemate, tautomer, hydrate or solvate or pharmaceutically acceptable salt according to any one of Implementation Schemes 1-29 and 33-38, wherein the structural moiety is... yes

[0247] One of R4' and R4" is H; and the other is C. 1-6 Alkyl; or

[0248] R4' and R4" together with the carbon atoms they are attached to optionally form a 3- or 5-membered cycloalkyl ring, which is optionally bounded by 1 or 2 carbon atoms. 1-3 Alkyl substitution.

[0249] Implementation Scheme 53. A compound or its stereoisomer, racemate, tautomer, hydrate, solvate, or pharmaceutically acceptable salt according to any one of Implementation Schemes 1-29 and 33-38, wherein the structural moiety is... yes

[0250] Where R4' is H; and R4” is C substituted with a halogenated group. 1-6 Alkyl; or

[0251] R4' and R4”, together with the carbon atoms they are attached to, optionally form 3- or 5-membered alkyl rings.

[0252] Implementation Scheme 54. A compound or its stereoisomer, racemate, tautomer, hydrate or solvate or pharmaceutically acceptable salt according to any one of Implementation Schemes 1-29 and 33-38, wherein the structural moiety is... yes

[0253] Where R4' is H; and R4” is C replaced by an F. 1-3 Alkyl; or

[0254] R4' and R4”, together with the carbon atoms they are attached to, optionally form 3- or 5-membered alkyl rings.

[0255] Implementation Scheme 55. A compound or its stereoisomer, racemate, tautomer, hydrate or solvate or pharmaceutically acceptable salt according to any one of Implementation Schemes 1-29 and 33-38, wherein the structural moiety is... yes

[0256] Each p is independently 0 or 1; preferably, all p are 0 or all p are 1.

[0257] q is 0, 1, or 2; preferably q is 0 or 2.

[0258] R 4a It is C 1-3 Alkyl group, preferably methyl group.

[0259] Implementation Scheme 56. The compound according to Implementation Scheme 55, or a stereoisomer, racemate, tautomer, hydrate, solvate, or pharmaceutically acceptable salt thereof, wherein the structural moiety is... yes

[0260] Implementation Scheme 57. A compound or its stereoisomer, racemate, tautomer, hydrate or solvate or pharmaceutically acceptable salt according to any one of Implementation Schemes 1 to 2, wherein said compound is selected from:

[0261]

[0262]

[0263]

[0264]

[0265]

[0266]

[0267]

[0268]

[0269]

[0270]

[0271]

[0272]

[0273]

[0274]

[0275]

[0276]

[0277]

[0278]

[0279]

[0280]

[0281]

[0282]

[0283]

[0284]

[0285]

[0286]

[0287]

[0288]

[0289] Implementation Scheme 58. The compound of any one of Implementation Schemes 1-57 or its stereoisomers, racemates, tautomers, hydrates or solvates or pharmaceutically acceptable salts thereof, used as a medicine.

[0290] Implementation Scheme 59. The compound of any one of Implementation Schemes 1-57 or its stereoisomers, racemates, tautomers, hydrates or solvates or pharmaceutically acceptable salts thereof, for the treatment or prevention of cancer and other diseases mediated by the interaction of menin with MLL and / or MLL fusion proteins.

[0291] Implementation Scheme 60. The compound of any one of Implementation Schemes 1-57 or its stereoisomers, racemates, tautomers, hydrates or solvates or pharmaceutically acceptable salts, used for the treatment or prevention of cancer or diabetes;

[0292] Preferably, the cancer is a hematologic 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;

[0293] More preferably, the leukemia is selected from acute leukemia, chronic leukemia, myeloid leukemia, lymphoblastic leukemia, lymphocytic leukemia, acute myeloid leukemia (AML), chronic myeloid leukemia (CML), acute lymphoblastic leukemia (ALL), chronic lymphocytic leukemia (CLL), T-cell prolymphoblastic leukemia (T-PLL), large granular lymphocytic leukemia, hairy cell leukemia (HCL), and mixed lineage leukemia (M). MLL, MLL rearrangement leukemia (MLLr leukemia), MLL-PTD leukemia, MLL amplified leukemia, MLL positive leukemia, nucleophosphorus protein (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.

[0294] Implementation Scheme 61. A pharmaceutical composition comprising a compound of any one of Implementation Schemes 1-57 or a stereoisomer, racemate, tautomer, hydrate or solvate or pharmaceutically acceptable salt thereof, and optionally a pharmaceutically acceptable carrier.

[0295] Implementation Scheme 62. Use of any compound of any of Implementation Schemes 1-57 or its stereoisomers, racemates, tautomers, hydrates or solvates or pharmaceutically acceptable salts in the preparation of medicaments for the treatment or prevention of cancer or diabetes;

[0296] Preferably, the cancer is a hematologic 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;

[0297] More preferably, the leukemia is selected from acute leukemia, chronic leukemia, myeloid leukemia, lymphoblastic leukemia, lymphocytic leukemia, acute myeloid leukemia (AML), chronic myeloid leukemia (CML), acute lymphoblastic leukemia (ALL), chronic lymphocytic leukemia (CLL), T-cell prolymphoblastic leukemia (T-PLL), large granular lymphocytic leukemia, hairy cell leukemia (HCL), and mixed lineage leukemia (M). MLL, MLL rearrangement leukemia (MLLr leukemia), MLL-PTD leukemia, MLL amplified leukemia, MLL positive leukemia, nucleophosphorus protein (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.

[0298] Implementation Scheme 63. A method for inhibiting the interaction of menin with MLL and / or MLL fusion protein in vivo or in vitro, said method comprising contacting an effective amount of the compound of any one of Implementation Schemes 1-57 or a pharmaceutically acceptable salt thereof with menin and MLL and / or MLL fusion protein.

[0299] Implementation Scheme 64. A method for treating or preventing cancer or diabetes, said method comprising administering to an individual in need an effective amount of any of the compounds of Implementation Schemes 1-57 or their stereoisomers, racemates, tautomers, hydrates or solvates or pharmaceutically acceptable salts.

[0300] Preferably, the cancer is a hematologic 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;

[0301] More preferably, the leukemia is selected from acute leukemia, chronic leukemia, myeloid leukemia, lymphoblastic leukemia, lymphocytic leukemia, acute myeloid leukemia (AML), chronic myeloid leukemia (CML), acute lymphoblastic leukemia (ALL), chronic lymphocytic leukemia (CLL), T-cell prolymphoblastic leukemia (T-PLL), large granular lymphocytic leukemia, hairy cell leukemia (HCL), and mixed lineage leukemia (M). MLL, MLL rearrangement leukemia (MLLr leukemia), MLL-PTD leukemia, MLL amplified leukemia, MLL positive leukemia, nucleophosphorus protein (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.

[0302] Implementation Scheme 65. Combination comprising a compound or stereoisomer, racemate, tautomer, hydrate or solvate or pharmaceutically acceptable salt of any one of Implementation Schemes 1-57, and at least one additional therapeutic agent, wherein the additional therapeutic agent is preferably an antitumor agent, such as a radiotherapy agent, a chemotherapy agent, an immunotherapy agent or a targeted therapy agent.

[0303] The implementation scheme of this disclosure – Part B

[0304] Implementation Scheme 1. Compound of Formula I:

[0305]

[0306] Or its stereoisomers, racemates, tautomers, hydrates or solvates or pharmaceutically acceptable salts, wherein:

[0307] X is a halogenated group or CN;

[0308] Y is either N or CH;

[0309] Z is selected from CH2, O, S, and NH;

[0310] R1 is selected from:

[0311] 1)-(C=O)-NRaRb, where:

[0312] Ra and Rb are each independently selected from C 1-6 Alkyl, 3-6 membered cycloalkyl rings, and 5-9 membered heterocyclic rings, optionally surrounded by 1, 2, or 3 groups selected from halogenated groups, OH, CN, and C. 1-6 Substitution of alkoxy groups;

[0313] Alternatively, Ra and Rb, together with the nitrogen atoms to which they are attached, form a 5-9 membered heterocyclic ring, which is optionally composed of 1, 2, or 3 atoms selected from C. 1-6 Alkyl, halogroup, OH and CN substituents;

[0314] 2) 5-10 membered heteroaryl rings or C 6-10 An aryl ring, optionally substituted by one, two, or three substituents selected from the following: halogenated, CN, C. 1-6 Alkyl and 3-5 membered alkyl rings;

[0315] R2 and R3 are each independently H or D;

[0316] R4 groups are independently selected from halogen groups, CN, OH, oxo groups, and C groups. 1-6 alkylsulfonyl-, C 1-6 alkylsulfonylamino-, C 1-6 Alkyl carbonyl amino-, C 6-10 Aryl ring, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, 3-9 membered cycloalkyl, 5-10 membered heteroaryl, and 4-9 membered heterocyclic rings, wherein the alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, heteroaryl, or heterocyclic rings are optionally substituted by 1, 2, or 3 substituents selected from halogen, CN, and OH.

[0317] Two adjacent R4 atoms, together with the carbon atoms they are attached to, optionally form a 3-9 membered alkyl ring, which is optionally surrounded by 1, 2, or 3 carbon atoms selected from C. 1-6 Alkyl, -C 1-6 Alkyl-OH, C 1-6 Alkoxy-C 1-6 Alkyl, halo, CN, and OH substituents;

[0318] Alternatively, two R4 atoms attached to the same carbon atom may optionally form a 3-6 membered cycloalkyl ring or a 4-6 membered heterocyclic ring together with the carbon atom, optionally surrounded by one, two, or three C atoms. 1-6 Alkyl, -C 1-6 Alkyl-OH, C 1-6 Alkoxy-C 1-6 Alkyl, halo, CN, and OH substituents;

[0319] Alternatively, two adjacent R4 atoms, together with the carbon atoms they are attached to, may optionally form a 5-10 membered heteroaryl ring, C 6-10 An aryl ring or a 5-9 membered heterocyclic ring, wherein the heteroaryl ring or aryl ring is optionally substituented by 1, 2 or 3 substituents selected from C. 1-6 Alkyl, C 1-6Halogenated alkyl, -C 1-6 Alkyl-OH, C 1-6 Alkoxy-C 1-6 The alkyl group is substituted with a alkyl group, a halogroup, a CN group, or an OH group, wherein the alkyl group is optionally substituted with a 3-6 membered alkyl ring or a phenyl group; the heterocyclic ring is optionally substituted with 1, 2, or 3 C1-membered alkyl groups. 1-6 Alkyl, C 1-6 Halogenated alkyl, -C 1-6 Alkyl-OH, C 1-6 Alkoxy-C 1-6 Alkyl, oxo, halo, CN and OH substituents;

[0320] R5 is selected from H, a halogroup, a methyl group optionally substituted with 1, 2 or 3 deuterium or halogroups, a methoxy group optionally substituted with 1, 2 or 3 deuterium or halogroups, NH2, CH3NH or (CH3)2N.

[0321] a, b, c, and d are each 1 or 2 independently;

[0322] n is 0, 1, or 2; and

[0323] m can be 0, 1, 2, 3, or 4.

[0324] Implementation Scheme 2. The compound according to Implementation Scheme 1 or its stereoisomers, racemates, tautomers, hydrates or solvates or pharmaceutically acceptable salts, wherein:

[0325] X is F, Cl, or CN;

[0326] Y is either N or CH;

[0327] Z is selected from CH2, O, S, and NH;

[0328] R1 is selected from:

[0329] 1)-(C=O)-NRaRb, where:

[0330] Ra and Rb are each independently selected from C 1-6 Alkyl and 3-5 membered cycloalkyl rings, wherein the C 1-6 Alkyl groups are optionally surrounded by one, two, or three groups selected from halogen groups, OH groups, and C groups. 1-6 Substitution of alkoxy groups;

[0331] Alternatively, Ra and Rb, together with the nitrogen atoms to which they are attached, form a 5-6 membered monocyclic or 7-9 membered bicyclic heterocyclic ring, optionally composed of 1, 2, or 3 atoms selected from C. 1-6 Substitution of alkyl and halogroups;

[0332] 2) A 5-6 membered heteroaryl ring, optionally substituted by 1, 2 or 3 substituents selected from the following: halogenated, CN, C 1-6 Alkyl and 3-5 membered alkyl rings;

[0333] 3)C 6-10 An aryl ring, which is surrounded by 1, 2 or 3 groups selected from halogenated groups, CN, C 1-6 Substitution of alkyl groups and 3-5 membered alkyl rings;

[0334] R2 and R3 are each independently H or D;

[0335] R4 groups are independently selected from halogen groups, CN, OH, and C. 1-6 alkylsulfonyl-, C 1-6 alkylsulfonylamino-, C 1-6 Alkyl carbonyl amino-, phenyl, C 1-6 Alkyl, C 1-6 Alkoxy, 3-6 membered cycloalkyl, 5-10 membered heteroaryl, and 5-9 membered heterocyclic rings, wherein the alkyl, alkoxy, cycloalkyl, heteroaryl, or heterocyclic rings are optionally substituted by 1, 2, or 3 substituents selected from halogen, CN, and OH;

[0336] Two adjacent R4 atoms, together with the carbon atoms they are attached to, optionally form a 3-6 membered alkyl ring, which is optionally surrounded by 1, 2, or 3 carbon atoms selected from C14. 1-6 Alkyl, -C 1-6 Alkyl-OH, C 1-6 Alkoxy-C 1-6 Alkyl and haloyl substituents;

[0337] Alternatively, two R4s attached to the same carbon atom may optionally form a 3-6 membered cycloalkyl ring together with the carbon atom, which may optionally be substituted by one, two or three substituents selected from halogens, CN and OH;

[0338] Alternatively, two adjacent R4s, together with the carbon atoms they are attached to, may optionally form a 5-10 membered heteroaryl ring, a phenyl ring, or a 5-9 membered heterocyclic ring, which may optionally be surrounded by one, two, or three groups selected from halogenated groups, C, and D. 1-6 Alkyl and C 1-6 The alkyl group is substituted with a substituent, wherein the alkyl group is optionally substituted with a 3-6 membered cycloalkyl ring or a phenyl group;

[0339] R5 is an H or a halogenated group;

[0340] a, b, c, and d are each 1 or 2 independently;

[0341] n is 0 or 1; and

[0342] m can be 0, 1, 2, or 3.

[0343] Implementation Scheme 3. The compound or its stereoisomer, racemate, tautomer, hydrate or solvate or pharmaceutically acceptable salt according to any of the foregoing implementation schemes, wherein:

[0344] R4 groups are independently selected from halogen groups, CN, OH, and C. 1-6 alkylsulfonyl-, C 1-6 Alkylsulfonylamino-, phenyl, C 1-6 Alkyl, C 1-6 Alkoxy and 3-6 membered cycloalkyl ring, wherein the alkyl or alkoxy group is optionally substituted by 1, 2 or 3 substituents selected from halogen, CN and OH;

[0345] Two adjacent R4 atoms, together with the carbon atoms they are attached to, optionally form a 3-6 membered alkyl ring, which is optionally surrounded by 1, 2, or 3 carbon atoms selected from C14. 1-6 Alkyl, -C 1-6 Alkyl-OH, C 1-6 Alkoxy-C 1-6 Alkyl and haloyl substituents;

[0346] Alternatively, two R4s attached to the same carbon atom may optionally form a 3-6 membered cycloalkyl ring together with the carbon atom, which may optionally be substituted by one, two or three substituents selected from halogens, CN and OH;

[0347] Alternatively, two adjacent R4 atoms, together with the carbon atoms they are attached to, may optionally form a 5-10 membered heteroaryl ring or a phenyl group, which may optionally be surrounded by 1, 2, or 3 carbon atoms selected from C4. 1-6 Alkyl substituents, wherein the alkyl group is optionally substituted with a 3-6 membered cycloalkyl ring or a phenyl group.

[0348] Implementation Scheme 4. The compound or its stereoisomer, racemate, tautomer, hydrate or solvate or pharmaceutically acceptable salt according to any of the foregoing implementation schemes, wherein:

[0349] R4 groups are independently selected from halogen groups, CN, OH, and C. 1-6 alkylsulfonyl-, C 1-6 Alkylsulfonylamino-, phenyl, C 1-6 Alkyl and C 1-6 Alkoxy group, wherein the alkyl or alkoxy group is optionally substituted with one, two or three substituents selected from halogen, CN and OH;

[0350] Two adjacent R4 atoms, together with the carbon atoms they are attached to, optionally form a 3-6 membered alkyl ring, which is optionally surrounded by 1, 2, or 3 carbon atoms selected from C14. 1-6 Alkyl, -C 1-6 Alkyl-OH, C 1-6 Alkoxy-C1-6 Alkyl and haloyl substituents;

[0351] Alternatively, two R4s attached to the same carbon atom may optionally form a 3-6 membered cycloalkyl ring together with the carbon atom, which may optionally be substituted by one, two or three substituents selected from halogens, CN and OH;

[0352] Alternatively, two adjacent R4 atoms, together with the carbon atoms they are attached to, may optionally form a 5-10 membered heteroaryl ring or a phenyl group, which may optionally be surrounded by 1, 2, or 3 carbon atoms selected from C4. 1-6 Alkyl substituents, wherein the alkyl group is optionally substituted with a 3-6 membered cycloalkyl ring or a phenyl group.

[0353] Implementation Scheme 5. A compound or its stereoisomer, racemate, tautomer, hydrate, solvate, or pharmaceutically acceptable salt according to any of the foregoing implementation schemes, wherein the compound has Formula II:

[0354]

[0355] Preferably, the compound has formula IIa:

[0356]

[0357] Its preferred

[0358]

[0359] More preferably:

[0360]

[0361] Where p is independently 0 or 1; q is 0, 1 or 2; R 4a It is C 1-3 Alkyl or halogroup;

[0362] The best option is:

[0363]

[0364] Where p is independently 0 or 1; q is 0, 1 or 2; R 4a It is C 1-3 Alkyl or halogroup.

[0365] Implementation Scheme 6. A compound or its stereoisomer, racemate, tautomer, hydrate or solvate or pharmaceutically acceptable salt according to any one of Implementation Schemes 1 to 4, wherein the compound has Formula III:

[0366]

[0367] Implementation Scheme 7. A compound or its stereoisomer, racemate, tautomer, hydrate or solvate or pharmaceutically acceptable salt according to any of the foregoing implementation schemes, wherein X is F.

[0368] Implementation Scheme 8. A compound or its stereoisomer, racemate, tautomer, hydrate or solvate or pharmaceutically acceptable salt according to any of the foregoing implementation schemes, wherein Z is selected from CH2, O and S, preferably CH2.

[0369] Implementation Scheme 9. A compound or its stereoisomer, racemate, tautomer, hydrate or solvate or pharmaceutically acceptable salt according to any of the foregoing implementation schemes, wherein R2 and R3 are each independently H.

[0370] Implementation Scheme 10. The compound or its stereoisomer, racemate, tautomer, hydrate or solvate or pharmaceutically acceptable salt according to any of the foregoing implementation schemes, wherein:

[0371] R1 is -(C=O)-NRaRb, where:

[0372] Ra and Rb are each independently selected from C 1-6 Alkyl and 3-5 membered cycloalkyl rings, wherein the C 1-6 Alkyl groups are optionally surrounded by one, two, or three groups selected from halogen groups, OH groups, and C groups. 1-6 Substitution of alkoxy groups; or

[0373] Ra and Rb, together with the nitrogen atom to which they are attached, form a 5-6 membered monocyclic or 7-9 membered bicyclic heterocyclic ring having another cyclic heteroatom selected from N, O, and S, optionally surrounded by 1, 2, or 3 cyclic heteroatoms selected from C. 1-6 Substitution of alkyl and halogen groups.

[0374] Implementation Scheme 11. A compound or its stereoisomer, racemate, tautomer, hydrate or solvate or pharmaceutically acceptable salt according to any of the foregoing implementation schemes, wherein:

[0375] R1 is -(C=O)-NRaRb, where Ra and Rb are each C 1-6 Alkyl group, preferably Ra is ethyl and Rb is isopropyl; or

[0376] R1 is a 5-6 membered heteroaryl ring, optionally substituted by 1, 2, or 3 substituents selected from the following: halogenated, CN, C. 1-6 Alkyl and 3-5 membered cycloalkyl rings; or phenyl, which is surrounded by 1, 2 or 3 groups selected from halogenated, C1, C2, ... 1-6 Substitution of alkyl groups and 3-5 membered alkyl rings.

[0377] Implementation Scheme 12. The compound or its stereoisomer, racemate, tautomer, hydrate or solvate or pharmaceutically acceptable salt according to any of the foregoing implementation schemes, wherein:

[0378] R1 is -(C=O)-NRaRb, where Ra is ethyl and Rb is isopropyl.

[0379] Implementation Scheme 13. The compound or its stereoisomer, racemate, tautomer, hydrate or solvate or pharmaceutically acceptable salt according to any of the foregoing implementation schemes, wherein:

[0380] R1 is a 5-6 membered heteroaryl ring, optionally substituted by 1, 2, or 3 substituents selected from the following: halogenated, CN, C. 1-6 Alkyl and 3-5 membered cycloalkyl rings; or phenyl, which is surrounded by 1, 2 or 3 groups selected from halogenated, C1, C2, ... 1-6 Substitution of alkyl groups and 3-5 membered alkyl rings.

[0381] Implementation Scheme 14. The compound or its stereoisomer, racemate, tautomer, hydrate or solvate or pharmaceutically acceptable salt according to any of the foregoing implementation schemes, wherein:

[0382] R1 is Where A1 or A2 is N or CH; R6 is selected from halogenated groups, CN, and C. 1-6 Alkyl groups and 3-5 membered cycloalkyl rings; and R7 is selected from H, halogroup, CN, C. 1-6 Alkyl and 3-5 membered alkyl rings; preferably, R1 is

[0383] Or R1 is Where A3 is N or C substituted with a halogenated group, and R8 is C. 1-6 Alkyl; preferably, R1 is

[0384] Implementation Scheme 15. The compound according to Implementation Scheme 14, or its stereoisomers, racemates, tautomers, hydrates or solvates or pharmaceutically acceptable salts, wherein the compound has formula IIb:

[0385]

[0386] Implementation Scheme 16. The compound or its stereoisomer, racemate, tautomer, hydrate or solvate or pharmaceutically acceptable salt according to any of the foregoing implementation schemes, wherein:

[0387] Each of a and b is 1; and

[0388] Each of c and d is 1 or 2;

[0389] Implementation Scheme 17. A compound or its stereoisomer, racemate, tautomer, hydrate or solvate or pharmaceutically acceptable salt according to any of the foregoing implementation schemes, wherein:

[0390] n can be 0 or 1, preferably 0.

[0391] Implementation Scheme 18. A compound or its stereoisomer, racemate, tautomer, hydrate or solvate or pharmaceutically acceptable salt according to any of the foregoing implementation schemes, wherein n is 0.

[0392] Implementation Scheme 19. A compound or its stereoisomer, racemate, tautomer, hydrate or solvate or pharmaceutically acceptable salt according to any of the foregoing implementation schemes, wherein n is 1.

[0393] Implementation Scheme 20. The compound or its stereoisomer, racemate, tautomer, hydrate or solvate or pharmaceutically acceptable salt according to any of the foregoing implementation schemes, wherein m is 0, 1 or 2.

[0394] Implementation Scheme 21. The compound or its stereoisomer, racemate, tautomer, hydrate or solvate or pharmaceutically acceptable salt according to any of the foregoing implementation schemes, wherein:

[0395] Each of a and b is 1.

[0396] Implementation Scheme 22. The compound or its stereoisomer, racemate, tautomer, hydrate or solvate or pharmaceutically acceptable salt according to any of the foregoing implementation schemes, wherein:

[0397] The value of each of c and d is 2.

[0398] Implementation Scheme 23. The compound or its stereoisomer, racemate, tautomer, hydrate or solvate or pharmaceutically acceptable salt according to any of the foregoing implementation schemes, wherein:

[0399] m is 1 or 2.

[0400] Implementation Scheme 24. The compound or its stereoisomer, racemate, tautomer, hydrate or solvate or pharmaceutically acceptable salt according to any of the foregoing implementation schemes, wherein:

[0401] Each of a and b is 1;

[0402] Each of c and d is 2;

[0403] n is either 0 or 1, preferably 0; and

[0404] m can be 0, 1, or 2.

[0405] Implementation Scheme 25. The compound or its stereoisomer, racemate, tautomer, hydrate or solvate or pharmaceutically acceptable salt according to any of the foregoing implementation schemes, wherein:

[0406] R4 groups are independently selected from halogenated groups; CN; OH; C. 1-6 alkylsulfonyl-; C 1-6 Alkylsulfonylamino-; phenyl; C substituted with 1, 2 or 3 substituents selected from halogen groups, CN and OH. 1-6 Alkyl groups; and C groups optionally substituted with halogen groups. 1-6 Alkoxy

[0407] Two adjacent R4 atoms, together with the carbon atoms they are attached to, optionally form a 3-6 membered alkyl ring, which is optionally surrounded by 1, 2, or 3 carbon atoms selected from C14. 1-6 Alkyl, -C 1-6 Alkyl-OH, C 1-6 Alkoxy-C 1-6 Alkyl and haloyl substituents;

[0408] Alternatively, two R4s attached to the same carbon atom may optionally form a 3-6 membered cycloalkyl ring together with the carbon atom, which may optionally be substituted with 1, 2 or 3 halogen groups;

[0409] Alternatively, two adjacent R4 atoms, together with the carbon atoms they are attached to, may optionally form a 5-6 membered heteroaryl ring, which may optionally be bounded by 1, 2, or 3 carbon atoms. 1-6 Alkyl substitution, wherein the alkyl group is optionally substituted with a 3-6 membered cycloalkyl ring or a phenyl group;

[0410] Alternatively, two adjacent R4 atoms, together with the carbon atoms they are attached to, may optionally form a phenyl group.

[0411] Implementation Scheme 26. The compound or its stereoisomer, racemate, tautomer, hydrate or solvate or pharmaceutically acceptable salt according to any of the foregoing implementation schemes, wherein:

[0412] R1 is selected from:

[0413]

[0414] Implementation Scheme 27. A compound or its stereoisomer, racemate, tautomer, hydrate, solvate, or pharmaceutically acceptable salt according to any of the foregoing implementation schemes, wherein:

[0415] R1 is selected from:

[0416]

[0417] Implementation Scheme 28. A compound or its stereoisomer, racemate, tautomer, hydrate, solvate, or pharmaceutically acceptable salt according to any of the foregoing implementation schemes, wherein:

[0418] Structural parts Selected from:

[0419]

[0420]

[0421] Implementation Scheme 29. The compound or its stereoisomer, racemate, tautomer, hydrate or solvate or pharmaceutically acceptable salt according to any of the foregoing implementation schemes, wherein:

[0422] Structural parts Selected from:

[0423]

[0424] Implementation Scheme 30. The compound or its stereoisomer, racemate, tautomer, hydrate or solvate or pharmaceutically acceptable salt according to any of the foregoing implementation schemes, wherein:

[0425] X is F;

[0426] Z is CH2;

[0427] R1 is selected from:

[0428] 1)-(C=O)-NRaRb, where:

[0429] Ra and Rb are each independently selected from C 1-6 alkyl;

[0430] Alternatively, Ra and Rb, together with the nitrogen atoms to which they are attached, form a 5-6 membered monocyclic or 7-9 membered bicyclic heterocyclic ring, optionally bounded by 1, 2, or 3 carbon atoms. 1-6 Alkyl substitution;

[0431] 2) Selected by 1, 2 or 3 halogenated groups, CN, C 1-6 5-6 membered heteroaryl rings substituted with alkyl and 3-5 membered alkyl rings;

[0432] 3) Selected by 1, 2 or 3 halogenated groups, CN, C 1-6 Substituents of alkyl and 3-5 membered alkyl rings with C-shaped substituents 6-10 Aryl ring;

[0433] R2 and R3 are each H independently;

[0434] R4 groups are independently selected from halogenated groups; CN; OH; C. 1-6alkylsulfonyl-; C 1-6 Alkylsulfonylamino-; phenyl; C substituted with 1, 2 or 3 substituents selected from halogen groups, CN and OH. 1-6 Alkyl groups; and C groups optionally substituted with 1, 2, or 3 halogroups. 1-6 Alkoxy groups; and 3-6 membered cycloalkyl rings,

[0435] Two adjacent R4 atoms, together with the carbon atoms they are attached to, optionally form a 3-6 membered alkyl ring, which is optionally surrounded by 1, 2, or 3 carbon atoms selected from C14. 1-6 Alkyl, -C 1-6 Alkyl-OH, C 1-6 Alkoxy-C 1-6 Alkyl and haloyl substituents;

[0436] Alternatively, two adjacent R4 atoms, together with the carbon atoms they are attached to, may optionally form a phenyl group.

[0437] R5 is an H or a halogenated group;

[0438] Each of a and b is 1;

[0439] Each of c and d is 2;

[0440] n is 0; and

[0441] m can be 0, 1, or 2.

[0442] Implementation Scheme 31. A compound or its stereoisomer, racemate, tautomer, hydrate or solvate or pharmaceutically acceptable salt according to any of the foregoing implementation schemes, wherein R5 is H or a halogroup; preferably H.

[0443] Implementation Scheme 32. The compound or its stereoisomer, racemate, tautomer, hydrate or solvate or pharmaceutically acceptable salt according to any of the foregoing implementation schemes, wherein...

[0444] R4 groups are independently selected from halogenated groups; CN; OH; C. 1-6 alkylsulfonyl-; C 1-6 Alkylsulfonylamino-; phenyl; C substituted with 1, 2 or 3 substituents selected from halogen groups, CN and OH. 1-6 Alkyl groups; and C groups optionally substituted with 1, 2, or 3 halogroups. 1-6 Alkoxy

[0445] Two adjacent R4 atoms, together with the carbon atoms they are attached to, optionally form a 3-6 membered alkyl ring, which is optionally substituted by one, two, or three substituents selected from: C 1-6 Alkyl, -C 1-6 Alkyl-OH and C 1-6 Alkoxy-C1-6 alkyl-;

[0446] Alternatively, two adjacent R4 atoms, together with the carbon atoms they are attached to, may optionally form a phenyl group.

[0447] Implementation Scheme 33. The compound or its stereoisomer, racemate, tautomer, hydrate or solvate or pharmaceutically acceptable salt according to any of the foregoing implementation schemes, wherein R1 is -(C=O)-NRaRb, and Ra and Rb are each independently selected from ethyl or isopropyl.

[0448] Implementation Scheme 34. A compound or its stereoisomer, racemate, tautomer, hydrate, solvate, or pharmaceutically acceptable salt according to any of the foregoing implementation schemes, wherein R1 is a 5- or 6-membered heteroaryl ring or a C 6-10 An aryl ring, which is surrounded by one or two groups selected from halogenated groups, CN, C 1-6 Alkyl and cyclopropyl substituents.

[0449] Implementation Scheme 35. A compound or its stereoisomer, racemate, tautomer, hydrate or solvate or pharmaceutically acceptable salt according to any of the foregoing implementation schemes, wherein the structural moiety is... yes

[0450] R4', R4”, and R4”' are independently selected from H; a halogroup; CN; OH; and a C group optionally substituted with 1, 2, or 3 substituents selected from the halogroup and CN. 1-6 Alkyl; C 1-6 alkoxy groups; and 3-6 membered cycloalkyl rings; or

[0451] R4' and R4" together with the carbon atoms they are attached to optionally form a 3-6 membered alkyl ring, which is optionally composed of 1, 2 or 3 carbon atoms selected from C1 to C2. 1-6 Alkyl, -C 1-6 Alkyl-OH, C 1-6 Alkoxy-C 1-6 Alkyl and haloyl substituents; and R4”' is H.

[0452] Implementation Scheme 36. A compound or its stereoisomer, racemate, tautomer, hydrate, solvate, or pharmaceutically acceptable salt according to any of the foregoing implementation schemes, wherein the structural moiety is... yes

[0453] R4', R4”, and R4”' are independently selected from H; a halogroup; CN; OH; and a C group optionally substituted with 1, 2, or 3 substituents selected from the halogroup and CN. 1-6 Alkyl; C 1-6 alkoxy; and cyclopropyl; or

[0454] R4' and R4" together with the carbon atoms they are attached to optionally form a 3-6 membered alkyl ring, which is optionally composed of 1, 2 or 3 carbon atoms selected from C1 to C2. 1-6 Alkyl, -C 1-6 Alkyl-OH, C 1-6 Alkoxy-C 1-6 Alkyl and haloyl substituents; and R4”' is H.

[0455] Implementation Scheme 37. A compound or its stereoisomer, racemate, tautomer, hydrate, solvate, or pharmaceutically acceptable salt according to any of the foregoing implementation schemes, wherein the structural moiety is... yes

[0456] R4', R4”, and R4”' are independently selected from H; a halogenated group; CN; and a C group optionally substituted with 1, 2, or 3 substituents selected from the halogenated group and CN. 1-6 Alkyl; and C 1-6 alkoxy; or

[0457] R4' and R4" together with the carbon atoms they are attached to optionally form a 3-6 membered alkyl ring, which is optionally composed of 1, 2 or 3 carbon atoms selected from C1 to C2. 1-6 Alkyl, -C 1-6 Alkyl-OH, C 1-6 Alkoxy-C 1-6 Alkyl and haloyl substituents; and R4”' is H.

[0458] Implementation Scheme 38. A compound or its stereoisomer, racemate, tautomer, hydrate, solvate, or pharmaceutically acceptable salt according to any of the foregoing implementation schemes, wherein:

[0459] R4', R4”, and R4”' are independently selected from H; a halogroup; CN; OH; and a C group optionally substituted with 1, 2, or 3 substituents selected from the halogroup and CN. 1-6 Alkyl; and C 1-6 Alkyl group.

[0460] Implementation Scheme 39. A compound or its stereoisomer, racemate, tautomer, hydrate, solvate, or pharmaceutically acceptable salt according to any of the foregoing implementation schemes, wherein:

[0461] R4' and R4" together with the carbon atoms they are attached to optionally form a 3-6 membered alkyl ring, which is optionally composed of 1, 2 or 3 carbon atoms selected from C1 to C2. 1-6 Alkyl, -C 1-6 Alkyl-OH and C 1-6 Alkoxy-C 1-6Alkyl-substituents; and R4”' is H.

[0462] Implementation Scheme 40. A compound or its stereoisomer, racemate, tautomer, hydrate or solvate or pharmaceutically acceptable salt according to any of the foregoing implementation schemes, wherein:

[0463] Each of R4' and R4"' is H; and R4" is C substituted with 1, 2 or 3 halogenated groups. 1-6 alkyl.

[0464] Implementation Scheme 41. The compound or its stereoisomer, racemate, tautomer, hydrate or solvate or pharmaceutically acceptable salt according to any of the foregoing implementation schemes, wherein:

[0465] R4' and R4” together with the carbon atoms to which they are attached optionally form a 3- or 5-membered cycloalkyl ring, which is optionally substituted with 1, 2 or 3 halogroups; and R4”' is H.

[0466] Implementation Scheme 42. The compound or its stereoisomer, racemate, tautomer, hydrate or solvate or pharmaceutically acceptable salt according to any of the foregoing implementation schemes, wherein:

[0467] Structural parts yes

[0468] Implementation Scheme 43. The compound or its stereoisomer, racemate, tautomer, hydrate or solvate or pharmaceutically acceptable salt according to any of the foregoing implementation schemes, wherein:

[0469] Structural parts yes

[0470] Where R4”’ is H; and

[0471] R4' and R4” are independently selected from H; halogenated group; C optionally substituted with 1, 2 or 3 halogenated groups. 1-6 Alkyl; and C 1-6 Alkyl group; provided that one of R4' and R4" is not H; or R4' and R4" together with the carbon atoms to which they are attached form a 3- or 5-membered alkyl ring, optionally bounded by 1, 2, or 3 carbon atoms. 1-3 Alkyl substitution.

[0472] Implementation Scheme 44. The compound or its stereoisomer, racemate, tautomer, hydrate or solvate or pharmaceutically acceptable salt according to any of the foregoing implementation schemes, wherein:

[0473] Structural parts yes Where R4' is H; and R4” and R4”' are independently C. 1-3 alkyl.

[0474] Implementation Scheme 45. A compound or its stereoisomer, racemate, tautomer, hydrate or solvate or pharmaceutically acceptable salt according to any of the foregoing implementation schemes, wherein the structural moiety is... yes

[0475]

[0476] One of R4' and R4" is H; and the other is C. 1-6 Alkyl; or

[0477] R4' and R4" together with the carbon atoms they are attached to optionally form a 3- or 5-membered cycloalkyl ring, which is optionally bounded by 1 or 2 carbon atoms. 1-6 Alkyl substitution.

[0478] Implementation Scheme 46. A compound or its stereoisomer, racemate, tautomer, hydrate, solvate, or pharmaceutically acceptable salt according to any of the foregoing implementation schemes, wherein the structural moiety is... yes

[0479]

[0480] Where R4' is H; and R4” is C substituted with 1 or 2 halogenated groups. 1-6 Alkyl; or

[0481] R4' and R4" together with the carbon atoms to which they are attached optionally form a 3- or 5-membered cycloalkyl ring, which is optionally substituted with one or two halogroups.

[0482] Implementation Scheme 47. A compound or its stereoisomer, racemate, tautomer, hydrate or solvate or pharmaceutically acceptable salt according to any of the foregoing implementation schemes, wherein the structural moiety is... yes

[0483] Where R4' is H; and R4” is C substituted with 1, 2 or 3 halogenated groups. 1-6 Alkyl; or

[0484] R4' and R4”, together with the carbon atoms they are attached to, optionally form 3- or 5-membered alkyl rings.

[0485] Implementation Scheme 48. A compound or its stereoisomer, racemate, tautomer, hydrate or solvate or pharmaceutically acceptable salt according to any of the foregoing implementation schemes, wherein the structural moiety is... yes

[0486] Each p is independently 0 or 1; preferably, all p are 0 or all p are 1.

[0487] q is 0, 1, or 2; preferably q is 0 or 2.

[0488] R 4a It is C 1-3 Alkyl or halogroup; preferably R 4a It is methyl or F.

[0489] Implementation Scheme 49. The compound according to Implementation Scheme 48, or a stereoisomer, racemate, tautomer, hydrate, solvate, or pharmaceutically acceptable salt thereof, wherein the structural moiety is... yes

[0490] Implementation Scheme 50. A compound or its stereoisomer, racemate, tautomer, hydrate or solvate or pharmaceutically acceptable salt according to any one of Implementation Schemes 1 to 2, wherein the compound is selected from Examples 2 to 100.

[0491] Implementation Scheme 51. The compound of any one of Implementation Schemes 1-50 or its stereoisomer, racemate, tautomer, hydrate or solvate or pharmaceutically acceptable salt thereof, used as a medicine.

[0492] Implementation Scheme 52. The compound of any one of Implementation Schemes 1-50 or its stereoisomers, racemates, tautomers, hydrates or solvates or pharmaceutically acceptable salts thereof, for the treatment or prevention of cancer and other diseases mediated by the interaction of menin with MLL and / or MLL fusion proteins.

[0493] Implementation Scheme 53. The compound of any one of Implementation Schemes 1-50 or its stereoisomers, racemates, tautomers, hydrates or solvates or pharmaceutically acceptable salts, used for the treatment or prevention of cancer or diabetes;

[0494] Preferably, the cancer is a hematologic 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;

[0495] More preferably, the leukemia is selected from acute leukemia, chronic leukemia, myeloid leukemia, lymphoblastic leukemia, lymphocytic leukemia, acute myeloid leukemia (AML), chronic myeloid leukemia (CML), acute lymphoblastic leukemia (ALL), chronic lymphocytic leukemia (CLL), T-cell prolymphoblastic leukemia (T-PLL), large granular lymphocytic leukemia, hairy cell leukemia (HCL), and mixed lineage leukemia (M). MLL, MLL rearrangement leukemia (MLLr leukemia), MLL-PTD leukemia, MLL amplified leukemia, MLL positive leukemia, nucleophosphorus protein (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.

[0496] Implementation Scheme 54. A pharmaceutical composition comprising a compound of any one of Implementation Schemes 1-50, or a stereoisomer, racemate, tautomer, hydrate, solvate, or pharmaceutically acceptable salt thereof, and optionally a pharmaceutically acceptable carrier.

[0497] Implementation Scheme 55. Use of any compound of any one of Implementation Schemes 1-50, or a stereoisomer, racemate, tautomer, hydrate, solvate, or pharmaceutically acceptable salt thereof, in the preparation of a medicament for the treatment or prevention of cancer or diabetes.

[0498] Preferably, the cancer is a hematologic 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;

[0499] More preferably, the leukemia is selected from acute leukemia, chronic leukemia, myeloid leukemia, lymphoblastic leukemia, lymphocytic leukemia, acute myeloid leukemia (AML), chronic myeloid leukemia (CML), acute lymphoblastic leukemia (ALL), chronic lymphocytic leukemia (CLL), T-cell prolymphoblastic leukemia (T-PLL), large granular lymphocytic leukemia, hairy cell leukemia (HCL), and mixed lineage leukemia (M). MLL, MLL rearrangement leukemia (MLLr leukemia), MLL-PTD leukemia, MLL amplified leukemia, MLL positive leukemia, nucleophosphorus protein (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.

[0500] Implementation Scheme 56. A method for inhibiting the interaction of menin with MLL and / or MLL fusion protein in vivo or in vitro, said method comprising contacting an effective amount of the compound of any one of Implementation Schemes 1-50 or a pharmaceutically acceptable salt thereof with menin and MLL and / or MLL fusion protein.

[0501] Implementation Scheme 57. A method for treating or preventing cancer or diabetes, the method comprising administering to an individual in need an effective amount of any of the compounds of Implementation Schemes 1-50 or their stereoisomers, racemates, tautomers, hydrates or solvates or pharmaceutically acceptable salts thereof.

[0502] Preferably, the cancer is a hematologic 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;

[0503] More preferably, the leukemia is selected from acute leukemia, chronic leukemia, myeloid leukemia, lymphoblastic leukemia, lymphocytic leukemia, acute myeloid leukemia (AML), chronic myeloid leukemia (CML), acute lymphoblastic leukemia (ALL), chronic lymphocytic leukemia (CLL), T-cell prolymphoblastic leukemia (T-PLL), large granular lymphocytic leukemia, hairy cell leukemia (HCL), and mixed lineage leukemia (M). MLL, MLL rearrangement leukemia (MLLr leukemia), MLL-PTD leukemia, MLL amplified leukemia, MLL positive leukemia, nucleophosphorus protein (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.

[0504] Implementation Scheme 58. Combination comprising a compound of any one of Implementation Schemes 1-50 or a stereoisomer, racemate, tautomer, hydrate or solvate or pharmaceutically acceptable salt thereof, and at least one additional therapeutic agent, wherein the additional therapeutic agent is preferably an antitumor agent, such as a radiotherapy agent, a chemotherapy agent, an immunotherapy agent or a targeted therapy agent.

[0505] definition

[0506] The following words, phrases and symbols used in this disclosure have the meanings described below, unless otherwise stated in the context.

[0507] As used herein, the singular form and "the" and "the" are intended to include the plural form as well, unless the context clearly indicates otherwise.

[0508] A hyphen ("-") not located between two letters or symbols indicates the junction of substituents. For example, -C 1-6 Alkyl-OH is attached to the rest of the molecule through the alkyl group.

[0509] As used herein, the term "alkyl" refers to a straight-chain or branched saturated hydrocarbon group having 1–10 carbon atoms (C1-C2). 1-10 Preferably, 1-6 carbon atoms (C 1-6 ), and more preferably 1-4 carbon atoms (C 1-4 ) or 1-3 carbon atoms (C 1-3 For example, "C" 1-6 "alkyl" means an alkyl group having 1 to 6 (1, 2, 3, 4, 5 or 6) carbon atoms. Examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl and tert-butyl.

[0510] As used herein, the term "alkenyl" refers to a straight-chain or branched unsaturated hydrocarbon group containing one or more, for example, 1, 2, or 3 carbon-carbon double bonds (C=C) and having 2-10 carbon atoms (C1, C2, C3). 2-10 Preferably, 2-6 carbon atoms (C 2-6 ), more preferably 2-4 carbon atoms (C 2-4 For example, "C" 2-6 "Alkenyl" indicates an alkenyl group having 2-6 (2, 3, 4, 5 or 6) carbon atoms, preferably having 1 or 2 carbon-carbon double bonds; "C 2-4 "Alkenyl" refers to an alkenyl group having 2-4 carbon atoms, preferably having one carbon-carbon double bond. Examples of alkenyl groups include, but are not limited to, vinyl, 2-propenyl, and 2-butenyl. The alkenyl group may or may not be attached to the double bond.

[0511] As used herein, the term "alkynyl" refers to a straight-chain or branched unsaturated hydrocarbon group containing one or more, for example, 1, 2, or 3 carbon-carbon triple bonds (C≡C), and having 2–10 carbon atoms (C≡C). 2-10 Preferably, 2-6 carbon atoms (C 2-6 ), more preferably 2-4 carbon atoms (C 2-4 For example, "C" 2-6 "Alkyne group" indicates an alkynyl group having 2-6 (2, 3, 4, 5 or 6) carbon atoms, preferably having 1 or 2 carbon-carbon triple bonds; "C 2-4 "Alynyl" refers to an alkynyl group having 2-4 carbon atoms, preferably having one carbon-carbon triple bond. Examples of alkynyl groups include, but are not limited to, ethynyl, 2-propynyl, and 2-butynyl. The alkynyl group may or may not be attached to the triple bond.

[0512] As used herein, the term "halogen" or "halogenated" refers to fluorine, chlorine, bromine, and iodine, preferably fluorine, chlorine, and bromine, more preferably fluorine and chlorine, and most preferably fluorine.

[0513] As used herein, the term "haloalkyl" refers to an alkyl group as defined herein, wherein one or more hydrogen atoms, such as 1, 2, 3, 4, or 5 hydrogen atoms, are replaced by halogen atoms, and when more than one hydrogen atom is replaced by a halogen atom, the halogen atoms may be the same as or different from each other. In one embodiment, the term "haloalkyl" as used herein refers to an alkyl group as defined herein, wherein two or more hydrogen atoms, such as 2, 3, 4, or 5 hydrogen atoms, are replaced by halogen atoms, wherein the halogen atoms are the same as each other. In another embodiment, the term "haloalkyl" as used herein refers to an alkyl group as defined herein, wherein two or more hydrogen atoms, such as 2, 3, 4, or 5 hydrogen atoms, are replaced by halogen atoms, wherein the halogen atoms are different from each other. Examples of haloalkyl groups include, but are not limited to, -CF3, -CHF2, -CH2F, -CH2CF3, -CF2CF3, -CF2CH3, etc. Preferred haloalkyl groups are C16-C ... 1-6 Trifluoroalkyl, more preferably -CF3.

[0514] The term "alkyl group substituted with 1, 2, or 3... halogen groups" refers to an alkyl group as defined herein, wherein one or more, for example, 1, 2, or 3 hydrogen atoms are substituted with halogen atoms, and when more than one hydrogen atom is substituted with a halogen atom, the halogen atoms may be the same or different from each other, including but not limited to -CF3, -CHF2, -CH2F, -CH2CF3, -CH2CH2F, -CF2CH3, etc. Similarly, the term "alkyl group substituted with 1, 2, or 3... CN groups" includes but is not limited to -CH2CN and -CH2CH2CN. The term "alkoxy group substituted with 1, 2, or 3... halogen groups" includes but is not limited to -OCH2F, -OCHF2, -OCHF3, -OCH2CHF3.

[0515] As used herein, the term "alkoxy" refers to the -O-alkyl group, where the alkyl group is as defined above. Examples of alkoxy groups include, but are not limited to, C... 1-6 Alkoxy groups, such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, pentoxy, and hexoxy, including their isomers. Preferably, the alkoxy group is methoxy.

[0516] As used in this article, the term "cycloalkyl" refers to a ring containing 3-10 carbon atoms (C1-C2). 3-10 ), such as 3-9 ring carbon atoms (C 3-9 ), 3-7 ring carbon atoms (C 3-7 ), 3-6 ring carbon atoms (C 3-6 ), 3-5 ring carbon atoms (C 3-5 ) or 5-6 ring carbon atoms (C 5-6 A saturated cyclic hydrocarbon group, which may have one or more rings, for example, one or two rings. For example, the cycloalkyl group is a monocyclic cycloalkyl group, preferably a monocyclic C14.3-7 Cycloalkyl, preferably monocyclic C 3-6 Cycloalkyl (e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl) or monocyclic C 3-5 Cycloalkyl (e.g., cyclopropyl, cyclobutyl, cyclopentyl) ring. For example, the cycloalkyl group is a bicyclic cycloalkyl ring, preferably a bicyclic C5-C6 ring. 10 Cycloalkyl rings. Bicyclic cycloalkyl groups include fused rings, bridged rings, or spiro rings.

[0517] As used herein, the term "heterocyclic group" refers to a saturated or partially unsaturated ring having 3-10 ring atoms (3-10 members), such as 5-9 ring atoms (5-9 members), 6-8 ring atoms (6-8 members), 5-6 ring atoms (5-6 members), or 7-9 ring atoms (7-9 members), wherein one or more, such as 1, 2, or 3, preferably 1 or 2, are heteroatoms independently selected from N, O, and S, and the remaining ring atoms are carbon atoms; it may have one or more rings, such as 1, 2, or 3, preferably 1 or 2 rings, wherein the N and S heteroatoms may optionally be oxidized to various oxidation states. The bonding point of the heterocyclic group may be on the N heteroatom or on the carbon atom. The ring of the heterocyclic group also includes fused rings, bridged rings, or spirocyclic rings. The ring of the heterocyclic group may be saturated or contain one or more, such as one or two double bonds (i.e., partially unsaturated), but it is not fully conjugated and is not a heteroaryl group as defined herein. For example, "5-9 membered heterocyclic group" refers to a monocyclic or bicyclic heterocyclic group having 5-9 ring atoms and containing 1, 2, or 3, preferably 1 or 2 ring heteroatoms independently selected from N, O, and S, preferably a saturated 5-6 membered monocyclic or 7-9 membered bicyclic heterocyclic group. Examples of heterocyclic groups include, but are not limited to, pyrrolidinyl, imidazoalkyl, morpholinyl, thiomorpholinyl, piperidinyl, piperazinyl, hexahydropyrimidinyl, oxazacyclohexyl, 3-oxa-6-azabicyclo[3.2.1]octyl, 3-azabicyclo[3.1.0]hexyl, 3,6-diazabicyclo[3.1.1]heptyl, 6-azabicyclo[3.1.1]heptyl, 3-azabicyclo[3.1.1]heptyl, and 3-azabicyclo[3.1.2]heptyl. Cyclo[3.1.1]heptyl, 3-azabicyclo[4.1.0]heptyl, azabicyclo[2.2.2]hexyl, 2-azabicyclo[3.2.1]octyl, 8-azabicyclo[3.2.1]octyl, 2-azabicyclo[2.2.2]octyl, 8-azabicyclo[2.2.2]octyl, azaspiro[3.5]nonyl, or azaspiro[2.5]octyl ring. Preferably, the heterocyclic group is morpholino or 3-oxa-6-azabicyclo[3.2.1]octyl ring.

[0518] As used in this article, "aryl" refers to a group consisting of one or more fused rings with 6-14 carbon atoms (C6, C ... 6-14 Preferably, 6-10 carbon atoms (C 6-10The aryl group is a carbocyclic hydrocarbon group, wherein at least one ring is an aromatic ring. Examples of aryl groups include, but are not limited to, phenyl, naphthyl, 1,2,3,4-tetrahydronaphthyl, phenanthryl, indene, indanyl, azulel, preferably phenyl or naphthyl rings, more preferably phenyl rings.

[0519] As used herein, the term "heteroaryl" refers to a monocyclic, bicyclic, or tricyclic ring system having 5-12 ring atoms (5-12 members), such as 5-10 ring atoms (5-10 members), 5-9 ring atoms (5-9 members), 8-10 ring atoms (8-10 members), 5-6 ring atoms (5-6 members), 5 ring atoms (5 members), or 6 ring atoms (6 members), wherein at least one ring is a 5- or 6-membered aromatic ring, wherein one or more, for example, 1, 2, or 3, preferably 1 or 2 ring atoms are heteroatoms independently selected from N, O, and S, and the remaining ring atoms are carbon, wherein the N or S heteroatoms are optionally oxidized to various oxidation states. For example, a 5-10 membered heteroaryl is:

[0520] -5-6-membered monocyclic heteroaryl, that is, a monocyclic aromatic hydrocarbon group having 5 or 6 ring atoms (5 or 6-membered), wherein one or more, for example 1, 2 or 3, preferably 1 or 2 ring atoms are heteroatoms independently selected from N, O and S (preferably N), and the remaining ring atoms are carbon; preferably a monocyclic aromatic hydrocarbon group having 6 ring atoms (6-membered), wherein 1, 2 or 3, preferably 1 or 2 ring atoms are heteroatoms independently selected from N, O and S (preferably N);

[0521] or

[0522] -8-10-membered bicyclic heteroaryl, that is, 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 ring atoms are independently selected from N, O and S (preferably N) and the remaining ring atoms are carbon, wherein at least one ring is aromatic.

[0523] Examples of heteroaryl groups include, but are not limited to, 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), and imidazoleyl (e.g., imidazole-1-yl, imidazole-5-yl, imidazole-3-yl, imidazole-4-yl, imidazole-5-yl). (e.g., triazolyl, 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, thiophenyl, furanyl, pyranyl, pyrroleyl, benzo[m]dioxacyclopentenyl, benzo[oxazolyl, benzo[isooxazolyl, benzo[thiophenyl, benzo[thiazolyl, benzo[isothiazolyl, imidazo[pyridyl, imidazo[pyrroleyl, triazol[pyridyl, indazole, pyrrole[pyridyl, pyrrole[pyrimidinyl, pyrazol[pyridyl, pyrazol[pyrimidinyl, tetrazol[pyridyl, tetrahydropyrazol[pyridyl, benzo[furanyl, benzo[imidazolinyl, or indoleyl)).) Preferably, the heteroaryl group is a pyrazolyl, triazolyl, or pyrimidinyl ring, more preferably a 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, or triazol-5-yl.

[0524] The term "oxo" as used in this article refers to the =O group.

[0525] The group "D" indicates that the hydrogen atom on the group has been replaced by its isotope deuterium.

[0526] When the structure of the compound in this article contains wavy lines When a bond is indicated, it refers to a mixture of isomers of the compound in any proportion.

[0527] When the bond of the group carries a wavy line When the wavy line is used, it indicates the connection point between the group and the rest of the molecule.

[0528] As used herein, a bond through the ring means that a group having that bond is attached to the ring at any chemically permissible position on the ring, unless otherwise stated.

[0529] Z, n, m, and R4 are groups as defined in the general formula of this paper. This indicates that (R4) is applied at any chemically permissible position on the ring (e.g., at Z when Z is CH2 or NH).m Substituted heterocyclic ring. Preferably, in this disclosure, R4 substitution does not occur on the N atom adjacent to the junction of the heterocyclic ring group and the rest of the compound structure.

[0530] As used herein, the terms “optional,” “optionally,” or “optionally” indicate that an event or condition subsequently described may or may not occur, and the description includes both cases where the event or condition occurs and cases where it does not occur. For example, “optionally substituted by…” includes “unsubstituted” and “substituted by 1, 2, 3, or more…” as defined herein. Those skilled in the art will understand that, for any group containing one or more substituents, the group does not include any substitution or substitution pattern that is spatially impractical, chemically incorrect, synthetically infeasible, and / or inherently unstable.

[0531] As used herein, the terms “substitution” or “replaced by” mean that one or more hydrogen atoms on a given atom or group are replaced by one or more substituents independently selected from the specified group of substituents, provided that the substitution does not exceed the normal valence of the given atom. The terms “replaced by 1, 2, or 3” mean that 1, 2, or 3 hydrogen atoms on a given atom or group are replaced by 1, 2, or 3 substituents independently selected from the specified group of substituents, provided that the substitution does not exceed the normal valence of the specified atom. When the substituent is an oxo group (i.e., =O), two hydrogen atoms on a single atom are replaced. Such combinations are permitted only if the combination of substituents and / or variables results in a chemically correct and stable compound. A chemically correct and stable compound means that the compound is robust enough to be isolated from the reaction mixture.

[0532] Those skilled in the art will understand that some of the compounds disclosed herein may contain one or more chiral centers or rings, and thus have two or more stereoisomers. Racemic mixtures of these isomers, mixtures of single isomers and enantiomer-enriched mixtures, and mixtures of diastereomers and specific diastereomer-enriched mixtures when there are two chiral centers are all within the scope of this disclosure. Those skilled in the art will also understand that this disclosure includes all single stereoisomers of the compounds of formula (I) (e.g., enantiomers, diastereomers, cis- or trans-isomers (e.g., substituent configurations on divalent cyclic saturated or partially saturated groups) or trans-blocking isomers, as chemically possible), racemic compounds of the disclosed compounds, mixtures thereof, and, where appropriate, their individual tautomer forms.

[0533] Racemic or other mixtures of isomers can be used in their own form or can be resolved into their individual isomers. Resolution yields stereochemically pure compounds or mixtures enriched with one or more isomers. Methods for isomer separation are well known (e.g., see Allinger NL and Eliel EL, "Topics in Stereochemistry", Vol. 6, Wiley Interscience, 1971).

[0534] When the structure in this article contains "(R)" and / or "(S)", it means that the chiral center of the compound marked with "(R)" or "(S)" is a single configuration of R-configuration or S-configuration. The R-configuration or S-configuration of the chiral center of the compound can also be determined solely by [the specific configuration in the text]. or This indicates that, for example, the compounds of this disclosure have an enantiomeric purity of at least 60%ee (e.g., 60%, 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9%ee (enantiomer excess), or any value between those enumerated values), or have a diastereomeric purity of at least 60%de (diastereomer excess) (e.g., 60%, 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9%de, or any value between those enumerated values).

[0535] The term "pharmaceutically acceptable salt" includes, but is not limited to: acid addition salts formed by the compounds disclosed herein with inorganic acids, such as hydrochlorides, hydrobroms, carbonates, bicarbonates, phosphates, sulfates, sulfites, nitrates, etc.; and acid addition salts formed by the compounds disclosed herein with organic acids, such as formates, acetates, malates, maleates, fumarates, tartrates, succinates, citrates, lactates, methanesulfonates, p-toluenesulfonates, 2-hydroxyethanesulfonates, benzoates, salicylates, stearates, and salts with the formula HOOC-(CH2). n Salts formed from alkyl dicarboxylic acids of the -COOH group (where n is 0-4), etc. "Pharmaceutically acceptable salts" also include base addition salts formed from compounds of this disclosure with acidic groups and pharmaceutically acceptable cations such as sodium, potassium, calcium, aluminum, lithium, and ammonium.

[0536] Furthermore, if the compound described herein is obtained as an acid addition salt, its free base form can be obtained by alkalizing the solution of the acid addition salt. Conversely, if the product is in the form of a free base, its acid addition salt, particularly a pharmaceutically acceptable acid addition salt, can be obtained by following the conventional procedure for preparing acid addition salts from basic compounds, by dissolving the free base in a suitable solvent and treating the solution with acid. Those skilled in the art can determine various synthetic methods for preparing non-toxic, pharmaceutically acceptable acid or base addition salts without extensive experimentation.

[0537] The term "protecting group" or "PG" refers to a substituent that is typically used to block or protect a specific functional group when other functional groups on a compound 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), triphenylmethyl (Trt), acetyl, trifluoroacetyl, phthalimide, tert-butoxycarbonyl (BOC), benzyloxycarbonyl (CBz), and 9-fluorenylmethoxycarbonyl (Fmoc). Similarly, a "hydroxyl protecting group" refers to a substituent that blocks or protects the hydroxyl group of a hydroxyl functional group. Suitable hydroxyl protecting groups include methoxymethyl, benzyl, benzyloxymethyl, methyl, triarylmethyl, acetyl, trialkylsilyl, dialkylphenylsilyl, benzoyl, and tetrahydropyranyl. For a general description of protecting groups and their uses, see TWGreene and PGMWuts, “Protective Groups in Organic Synthesis”, 5th ed., Wiley, New York, 2014.

[0538] As used herein, the term "drug combination" or "combination" refers to a product resulting from a mixture or combination of more than one therapeutic agent, and includes fixed and non-fixed combinations of therapeutic agents, such as a pillbox or pharmaceutical composition. The term "fixed combination" refers to the simultaneous administration of a therapeutic agent, such as a compound of this disclosure, and another therapeutic agent to an individual in the form of a single entity or dose. The term "non-fixed combination" refers to the simultaneous, parallel, or sequential administration of a therapeutic agent, such as a compound of this disclosure, and another therapeutic agent as separate entities to an individual in need, wherein such administration provides an effective level of the compound within the individual.

[0539] The term "treatment" or "disposition" refers to the administration of one or more pharmaceutical substances, particularly compounds of this disclosure or pharmaceutically acceptable salts thereof, to an individual suffering from or exhibiting symptoms of said disease or disorder, in order to cure, heal, alleviate, reduce, alter, treat, improve, enhance, or influence said disease or disorder or its symptoms. In some embodiments, said disease or disorder is cancer or diabetes.

[0540] The term "disease prevention" refers to the administration of one or more pharmaceutical substances, particularly compounds of this disclosure, to an individual who is susceptible to or at risk of developing the disease or disorder, in order to prevent or slow the onset of the disease or disorder in that individual.

[0541] As used herein, the term "effective amount" refers to the amount of a compound of this disclosure that is effective in "treating" or "preventing" cancer or diabetes in an individual. An effective amount may cause any visible or detectable change in the individual described in the preceding definition of "treatment," "treatment," or "prevention." For example, in the case of cancer, an effective amount may reduce the number of cancer or tumor cells; shrink the size of the tumor; inhibit or prevent the invasion of tumor cells into surrounding organs; inhibit or prevent tumor metastasis; inhibit or prevent tumor growth; alleviate one or more cancer-related symptoms to a certain extent; reduce morbidity and mortality; improve quality of life; or a combination of the above effects. An effective amount may be sufficient to reduce cancer symptoms. The term "effective amount" may also refer to the amount of a compound of this disclosure that effectively inhibits the interaction of menin with MLL and / or MLL fusion proteins.

[0542] The term "inhibition" refers to a reduction in the baseline activity of a biological activity or process.

[0543] As used herein, the term "individual" refers to both mammals and non-mammals. Mammals include any member of the mammal class, including but not limited to humans; non-human primates such as chimpanzees and other apes and monkeys; farm animals such as cattle, horses, sheep, goats, and pigs; domesticated animals such as rabbits, dogs, and cats; laboratory animals, including rodents such as rats, mice, and guinea pigs; etc. In some embodiments, an individual is a human being.

[0544] The term "pharmaceutical acceptable" means that the substance specified after the term can be used to prepare a pharmaceutical composition, which is generally safe, non-toxic, and has no undesirable properties in a biological or other sense, especially for human medicinal use.

[0545] The term "cancer" as used herein refers to a cellular disease characterized by uncontrolled or disordered cell proliferation, reduced cell differentiation, inappropriate invasion of surrounding tissues, and / or the ability to establish new growth in other sites. The term "cancer" includes, but is not limited to, hematologic malignancies and solid tumors, preferably leukemia. The term "cancer" includes cancers of the skin, tissues, organs, bones, cartilage, blood, and blood vessels. The term "cancer" also includes primary cancers, metastatic cancers, recurrent cancers, and refractory cancers. The term "cancer" includes, but is not limited to, leukemia, lymphoma, myeloma (e.g., multiple myeloma), myelodysplastic syndromes (MDS) and myeloproliferative neoplasms (MPN), polycythemia vera; prostate cancer, lung cancer, breast cancer, pancreatic cancer, colon cancer, liver cancer, melanoma, and glioblastoma. The term "leukemia" in this article includes, but is not limited to, acute leukemia, chronic leukemia, myeloid leukemia, lymphoblastic leukemia, acute myeloid leukemia (AML), chronic myeloid leukemia (CML), acute lymphoblastic leukemia (ALL), chronic lymphocytic leukemia (CLL), T-cell prolymphoblastic leukemia (T-PLL), large granular lymphoblastic leukemia, hairy cell leukemia (HCL), mixed lineage leukemia (MLL), MLL rearrangement leukemia (MLLr leukemia), and MLL partial tandem duplication leukemia (MLL-PTD leukemia). MLL amplified leukemia, MLL-positive leukemia, nucleophosphorus protein (NPM)-mutant leukemia (NPM1-mutant leukemia, NPM1c leukemia), MOZ acute leukemia, NUP98 acute leukemia, and clathrin-assembled lymphoid myeloid (CALM) acute leukemia; and MLL-AF4 (ALL-1 fusion gene from chromosome 4) leukemia, MLL-AF6 leukemia, MLL-AF9 leukemia, MLL-AF10 leukemia, MLL-ENL (11-19 leukemia) leukemia, and MLL-ELL (11-19 lysine-enriched leukemia) leukemia.

[0546] All numerical ranges in this document should be understood as disclosing every and all values ​​within that range, as well as every and all subsets of values ​​within that range, regardless of whether they are otherwise specifically disclosed. For example, when referring to any numerical range, it should be considered that it refers to every single value within the numerical range, such as every single integer within the numerical range. This disclosure includes all values ​​falling within these ranges, all smaller ranges, and the upper or lower bound of those ranges.

[0547] Undefined technical and scientific terms used herein have the meanings commonly understood by one of ordinary skill in the art to which this invention pertains.

[0548] Pharmaceutical composition and administration

[0549] The compounds disclosed herein (such as any of the compounds in the examples herein) can be formulated into pharmaceutical compositions, alone or in combination with one or more other therapeutic agents. A 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 other therapeutic agent.

[0550] A pharmaceutically acceptable carrier is an excipient or adjuvant that is compatible with (in some embodiments, stabilizes) the active ingredient in the composition and is harmless to the individual being treated. Suitable pharmaceutically acceptable carriers are disclosed in standard references in the art (e.g., Remington's Pharmaceutical Sciences, Remington: The Science and Practice of Pharmacy) and include one or more buffers, stabilizers, surfactants, wetting agents, lubricants, emulsifiers, suspending agents, preservatives, antioxidants, opacifiers, flow aids, processing aids, colorants, sweeteners, flavoring agents, tasters, diluents, and other known additives to provide a favorable appearance for the medicine (i.e., the compound of this disclosure or a pharmaceutical composition thereof) or to facilitate the manufacture of the pharmaceutical product (i.e., the pharmaceutical preparation).

[0551] The compounds disclosed herein can be administered in a variety of known ways, such as orally, parenterally, by inhalation, or by implantation. As used herein, the term "parenteral" includes subcutaneous, intradermal, intravenous, intramuscular, intra-articular, intra-articular, intrasynovial, intrasternal, intravertebral, intra-affective, and intracranial injection or infusion.

[0552] The compounds disclosed herein can be administered in any convenient formulation, such as tablets, powders, capsules, solutions, dispersants, suspensions, syrups, sprays, suppositories, gels, emulsions, patches, etc.

[0553] In one example, the effective amount of each parenterally administered compound of the present disclosure will be in the range of about 0.01 to 100 mg / kg patient body weight / day, or about 0.1 to 20 mg / kg patient body weight / day, wherein the 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 about 0.1 to about 1000 mg of the compound of the present disclosure.

[0554] Indications and Treatments

[0555] This disclosure relates to methods for treating or preventing diseases or disorders mediated by the interaction of menin with MLL and / or MLL fusion proteins, the methods comprising administering an effective amount of the compound of this disclosure to an individual in need.

[0556] This disclosure relates to methods for treating or preventing cancer or diabetes, said methods comprising administering an effective amount of the compound of this disclosure to an individual in need.

[0557] In one embodiment, the compounds disclosed herein are used to treat or prevent diseases or disorders mediated by the interaction of menin with MLL and / or MLL fusion proteins.

[0558] In one embodiment, the compounds disclosed herein are used to treat or prevent cancer or diabetes.

[0559] In one embodiment, the compounds of this disclosure are used to treat or prevent hematologic malignancies, including but not limited to leukemia, lymphoma, myeloma (e.g., multiple myeloma), myelodysplastic syndrome (MDS) and myeloproliferative neoplasm (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.

[0560] In one embodiment, the compounds disclosed herein are used to treat or prevent acute leukemia, chronic leukemia, myeloid leukemia, lymphoblastic leukemia, lymphocytic leukemia, acute myeloid leukemia (AML), chronic myeloid leukemia (CML), acute lymphoblastic leukemia (ALL), chronic lymphocytic leukemia (CLL), T-cell prolymphocytic leukemia (T-PLL), large granular lymphocytic leukemia, hairy cell leukemia (HCL), mixed lineage leukemia (MLL), MLL rearrangement leukemia (MLLr leukemia), MLL partial tandem duplication leukemia (MLL-PTD leukemia), MLL amplified leukemia, MLL positive leukemia, nucleophosphorus protein (NPM)-mutated leukemia, MOZ acute leukemia, NUP98 acute leukemia, and clathrin-assembled lymphoid myeloid (CALM) acute leukemia.

[0561] Drug combination

[0562] The compounds of this disclosure can be combined with additional therapeutic agents to treat diseases or disorders mediated by the interaction of menin with MLL and / or MLL fusion proteins. The additional therapeutic agents can be administered separately from the compounds of this disclosure or can be included together with the compounds of this disclosure in a pharmaceutical composition according to this disclosure, for example, a fixed-combination product. In some embodiments, the additional therapeutic agents are those known or found to be effective in treating diseases or disorders mediated by the interaction of menin with MLL and / or MLL fusion proteins, or compounds that antagonize additional targets associated with said specific disease. This combination can be used to increase the efficacy of the compounds of this disclosure, reduce one or more side effects, or reduce the required dosage.

[0563] In some embodiments, the compounds of this disclosure are administered in combination with antitumor agents. Antitumor agents include, but are not limited to, radiotherapy agents, chemotherapy agents, immunotherapy agents, and targeted therapy agents.

[0564] General Synthesis Method

[0565] Compounds of the examples having a general structure such as A10 can be synthesized according to process 1. Phenol A1 and 5-bromopyrimidine react under basic conditions to give biaryl ether A2, which can be converted to N-oxide A3 in the presence of mCPBA. The latter reacts readily with a chlorinating agent such as POCl3 to give chloropyrimidine A4. A nucleophilic substitution reaction between chloride A4 and monoprotected spirodiamine A5 gives the key intermediate A6. After deprotection of A7, it forms an amide with an N-protected cyclic amino acid A8, and N-deprotection gives the final compound A10.

[0566] Process 1

[0567]

[0568] Compounds of the examples having the B4 structure can be synthesized according to process 2. B1 can be prepared from a suitable phenol according to a method similar to that described for A6 in process 1. The Suzuki coupling reaction between B1 and (hetero)arylboronic acid yields compound B3. Alternatively, B3 can be prepared using a two-step method, i.e., by a palladium-catalyzed borylation reaction followed by a Suzuki reaction of the latter with a (hetero)aryl halide, converting B1 to the borate ester B2. Subsequently, B3 is deprotected, amidated with the N-protected cyclic amino acid A8, and finally N-deprotected to give compound B4.

[0569] Process 2

[0570]

[0571] Compounds of the examples having a general C6 structure can be synthesized according to procedure 3. A selective nucleophilic substitution reaction between a monoprotected spirodiamine A5 and 3,5,6-trichloro-1,2,4-triazine C1 yields triazine C2. A second nucleophilic substitution with phenol C3 yields monochlorinated C4. Removal of the chlorine atom under reducing conditions yields triazine C5. Again, deprotection is subsequently performed, followed by amidation with an N-protected cyclic amino acid A8, and finally N-deprotection to give compound C6.

[0572] Process 3

[0573]

[0574] The example compounds having the general formula structure shown in D1 of process 4 can be prepared from chloride C4 in three steps: deprotection, amidation with an N-protected cyclic amino acid A8, and N-deprotection. Chloride C4 can also be reacted with a nucleophile under basic conditions or with a boron reagent in the presence of a palladium catalyst to give intermediate D2, which, after deprotection, is amidated with an N-protected cyclic amino acid A8 and then N-deprotected to give the example compounds having the general formula structure shown in D3 (process 4).

[0575]

[0576] The various embodiments and features described in this disclosure should be understood as being able to be combined with each other in any way, and all such combinations are included within the scope of this disclosure as if they were specifically and individually listed herein, unless the context clearly indicates otherwise.

[0577] To the extent permitted by law, the entire contents of all patents, patent applications, publications, and other documents cited or referenced herein are incorporated herein by reference. Discussion of these references is intended only to outline the claims therein. No patent, patent application, publication, or document, or any part thereof, is acknowledged as relevant material or prior art. The right to question the accuracy and relevance of any claim that a patent, patent application, publication, or other document is relevant material or prior art is specifically reserved. Example

[0578] The following embodiments are intended to illustrate the present invention only and should not be construed as limiting the present invention in any way.

[0579] Unless otherwise stated, temperatures are in degrees Celsius and pressures are in atmospheres or near atmospheres. All MS (mass spectrometry) data were obtained using an Agilent 6120B and / or a Shimadzu LCMS2010. 1 H-NMR spectra were obtained using a nuclear magnetic resonance instrument operated at 400 MHz on a Bruker Avance NEO. The following abbreviations were used to represent peak multiplicity: s (singleton), d (doublet), t (triplet), m (multiplet), q (quartet), br (broad peak), dd (double doublet), dt (double triplet). The coupling constants given are in Hertz (Hz).

[0580] All reagents and raw materials used in this invention, except for the intermediates prepared below, are commercially available or prepared according to existing technology.

[0581] All compound names, except for reagents, are generated by Chemdraw. If a compound is given both its name and structural formula, and they are inconsistent, the structural formula shall prevail, unless the context indicates that the structure is incorrect while the name is correct.

[0582] In any structural formula of this application, if there is a vacant valence on any atom, the vacant valence is actually a hydrogen atom that is not specifically described for simplicity.

[0583] Unless otherwise stated, if isomers are separated from the same chromatographic separation conditions in the following examples, they are named in the same order as they were eluted.

[0584] The following abbreviations are used in the following embodiments:

[0585] List of abbreviations

[0586]

[0587]

[0588] Preparation of key intermediates

[0589] Preparation of intermediate 1, 2-((4-(2,7-diazaspiro[3.5]non-2-yl)pyrimidin-5-yl)oxy)-N-ethyl-5-fluoro-N-isopropylbenzamide

[0590]

[0591] Step 1:

[0592] Ethyl(propyl-2-yl)amine (15.4 g, 176 mmol) was added dropwise 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) at 0 °C. The reaction mixture was gradually warmed to room temperature and stirred overnight. The reaction mixture was quenched with saturated NH4Cl solution (50 mL), extracted with EtOAc (100 mL x 3), and the combined organic phases were washed with water and brine, dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by silica gel column chromatography (EtOAc in PE = 0–30%) to give the desired product, N-ethyl-5-fluoro-2-methoxy-N-(propyl-2-yl)benzamide (10.0 g, yield: 94.8%), as a pale yellow solid. LC / MS (ESI) m / z: 240 (M+H) + .

[0593] Step 2:

[0594] BBr3 (37.6 mL, 1.0 M, in DCM) was added dropwise to a solution of N-ethyl-5-fluoro-2-methoxy-N-(propyl-2-yl)benzamide (9.01 g, 37.6 mmol) in DCM (50 mL) at -60 °C under a N2 atmosphere. The resulting mixture was stirred at this temperature for 2 hours. The reaction mixture was then quenched at 0 °C with cooled saturated NaHCO3. The mixture was extracted with DCM (100 mL x 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-5-fluoro-2-hydroxy-N-(propyl-2-yl)benzamide (4.01 g, yield: 47.2%), as a pale yellow solid, which was used in the next step without further purification. LC / MS (ESI) m / z: 226 (M+H) + .

[0595] Step 3:

[0596] 5-Bromopyrimidine (3.40 g, 21.3 mmol) and Cs₂CO₃ (11.6 g, 35.5 mmol) were added to a mixture of N-ethyl-5-fluoro-2-hydroxy-N-(propyl-2-yl)benzamide (4.01 g, 17.7 mmol) in DMF (20 mL). The reaction mixture was heated to 120 °C for 12 hours. After cooling to room temperature, the mixture was quenched with saturated NH4Cl solution (50 mL), extracted with EtOAc (100 mL x 3), and the combined organic layers were washed with water and brine, dried over anhydrous Na2SO4, filtered, and concentrated to obtain a crude product. This crude product was purified by silica gel column chromatography (EtOAc in PE = 0–20%) to give the desired product, N-ethyl-5-fluoro-N-(propyl-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) + .

[0597] Step 4:

[0598] m-CPBA (3.41 g, 19.8 mmol) was added in portions to a solution of N-ethyl-5-fluoro-N-(propyl-2-yl)-2-(pyrimidin-5-yloxy)benzamide (1.99 g, 6.60 mmol) in DCM (20 mL) at 0 °C. The resulting mixture was then stirred at room temperature for 10 hours. The reaction mixture was quenched with saturated NaHCO3, extracted with DCM (50 mL x 3), and the combined organic layers were washed with water and brine, dried over anhydrous Na2SO4, filtered, and concentrated to obtain a crude product. This crude product was purified by silica gel column chromatography (EtOAc = 0–80% in PE) to give the desired product 5-{2-[ethyl(propyl-2-yl)carbamoyl]-4-fluorophenoxy}pyrimidin-1-onthium-1-ol salt (0.901 g, yield: 42.8%) as a creamy white solid. LC / MS (ESI) m / z: 320 (M+H) + .

[0599] Step 5:

[0600] POCl3 (0.80 mL, 8.4 mmol) was added dropwise to a solution of 5-{2-[ethyl(prop-2-yl)carbamoyl]-4-fluorophenoxy}pyrimidin-1-onthium-1-ol (0.90 g, 2.8 mmol) and TEA (0.8 mL, 5.6 mmol) in CHCl3 (10 mL). The reaction mixture was then stirred at room temperature for 12 hours. The reaction mixture was quenched with saturated NaHCO3 and extracted with DCM (100 mL x 3). The combined organic layers were washed with water and brine, dried over anhydrous Na2SO4, filtered, and concentrated under vacuum to give crude product 2-[(4-chloropyrimidin-5-yl)oxy]-N-ethyl-5-fluoro-N-(prop-2-yl)benzamide (320 mg, yield: 33.6%) as a brown oil, which was used in the next step without further purification. LC / MS (ESI) m / z: 338 / 340 (M+H) + .

[0601] Step 6:

[0602] To a solution of 2-[(4-chloropyrimidin-5-yl)oxy]-N-ethyl-5-fluoro-N-(prop-2-yl)benzamide (300 mg, 0.9 mmol) in MeCN (10 mL), tert-butyl 2,7-diazaspiro[3.5]nonane-7-carboxylate (221 mg, 1.00 mmol) and K₂CO₃ (246 mg, 1.80 mmol) were added. The resulting mixture was heated to 80 °C for 5 hours. After cooling to room temperature, the reaction mixture was quenched with saturated NH4Cl solution (10 mL), extracted with EtOAc (20 mL x 3), and the combined organic layers were washed with water and brine, dried over anhydrous Na2SO4, filtered, and concentrated to obtain a crude product. This crude product was purified by silica gel column chromatography (EtOAc in PE = 0–50%) to obtain the desired product, 2-(5-{2-[ethyl(propyl-2-yl)carbamoyl]-4-fluorophenoxy}pyrimidin-4-yl)-2,7-diazaspiro[3.5]nonane-7-carboxylic acid tert-butyl ester (390 mg, yield: 83.2%), as a yellow solid. LC / MS (ESI) m / z: 528 (M+H) + .

[0603] Step 7:

[0604] TFA (2.0 mL) was added dropwise to a solution of 2-(5-{2-[ethyl(prop-2-yl)carbamoyl]-4-fluorophenoxy}pyrimidin-4-yl)-2,7-diazaspiro[3.5]nonane-7-carboxylic acid tert-butyl ester (200 mg, 0.4 mmol) in DCM (5 mL) at room temperature, and the resulting mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated to give crude product 2-[(4-{2,7-diazaspiro[3.5]non-2-yl}pyrimidin-5-yl)oxy]-N-ethyl-5-fluoro-N-(prop-2-yl)benzamide (150 mg, yield: 92.5%), a TFA salt, which was used in the next step without further purification. LC / MS (ESI) m / z: 428 (M+H) + .

[0605] The following intermediates were prepared from the corresponding chemicals according to the experimental procedures used for intermediate 1 (the main different chemicals used are listed in the raw materials column):

[0606]

[0607]

[0608]

[0609] Preparation of intermediate 14, 5-fluoro-2-hydroxy-N,N-diisopropylbenzamide

[0610]

[0611] Step 1:

[0612] Diisopropylamine (712 mg, 7.06 mmol) was added dropwise to a solution of 5-fluoro-2-methoxybenzoic acid (1.00 g, 5.88 mmol) and HATU (2.28 g, 6.00 mmol) in DMF (10 mL) at 0 °C. The reaction mixture was gradually warmed to room temperature and stirred overnight. The reaction mixture was quenched with saturated NH4Cl solution (10 mL) and extracted with EtOAc (30 mL x 3). The combined organic phases were washed with water and brine, dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by silica gel column chromatography (EtOAc in PE = 0–30%) to give the desired product, 5-fluoro-N,N-diisopropyl-2-methoxybenzamide (320 mg, yield: 21.5%), as a pale yellow solid. LC / MS (ESI) m / z: 254 (M+H) + .

[0613] Step 2:

[0614] BBr3 (3 mL, 1.0 M, in DCM) was added dropwise to a solution of 5-fluoro-N,N-diisopropyl-2-methoxybenzamide (320 mg, 1.26 mmol) in DCM (10 mL) at -60 °C under a N2 atmosphere. The resulting mixture was stirred at this temperature for 2 hours. The reaction mixture was then quenched with cooled MeOH at 0 °C. The mixture was extracted with DCM (15 mL x 3). The combined organic layers were washed with water and brine, dried over anhydrous Na2SO4, filtered, and concentrated to obtain a crude product. This crude product was purified by silica gel column chromatography (EtOAc = 0–20% in PE) to give the desired product, N-ethyl-5-fluoro-2-hydroxy-N-(propyl-2-yl)benzamide (260 mg, yield: 86.3%), as a white solid. LC / MS (ESI) m / z: 240 (M+H). + .

[0615] Preparation of intermediate 15, (2S)-4-hydroxy-4-methylpyrrolidine-2-carboxylic acid

[0616]

[0617] Step 1:

[0618] MeMgBr (1.2 mL, 1.23 mmol) was added dropwise to a solution of (2S)-4-oxopyrrolidine-1,2-dicarboxylic acid 1-tert-butyl 2-methyl ester (200 mg, 0.82 mmol) in THF (5 mL) at 0 °C under N2. The resulting mixture was stirred at room temperature for 2 hours. The reaction mixture was quenched with saturated NH4Cl solution (5 mL), extracted with EtOAc (20 mL x 3), and the combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by silica gel column chromatography (EtOAc = 0–30% in PE) to give the desired product (2S)-4-hydroxy-4-methylpyrrolidine-1,2-dicarboxylic acid 1-tert-butyl 2-methyl ester (180 mg, yield: 80.2%) as a pale yellow oil. LC / MS (ESI) m / z: 260 (M+H) + .

[0619] Step 2:

[0620] NaOH (83 mg, 2.1 mmol) was added to a solution of (2S)-4-hydroxy-4-methylpyrrolidine-1,2-dicarboxylic acid 1-tert-butyl 2-methyl ester (180 mg, 0.69 mmol) in MeOH (3 mL) and H₂O (1 mL) at 0 °C. The resulting mixture was stirred at room temperature for 2 hours, 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 x 3), and the combined organic layers were dried over anhydrous Na₂SO₄, filtered, and concentrated to give the desired product (2S)-1-[(tert-butoxy)carbonyl]-4-hydroxy-4-methylpyrrolidine-2-carboxylic acid (150 mg, yield: 83.6%) as a white solid, which could be used directly in the next step without further purification. LC / MS (ESI) m / z: 190 (M-55) + .

[0621] Preparation of intermediate 16, (2S,4R)-1-(tert-butoxycarbonyl)-4-(methylsulfonyl)pyrrolidine-2-carboxylic acid

[0622]

[0623] Step 1:

[0624] MsCl (0.50 g, 4.5 mmol) was added to a solution of (2S,4S)-4-hydroxypyrrolidine-1,2-dicarboxylic acid 1-tert-butyl 2-methyl ester (1.0 g, 4.0 mmol) and TEA (0.83 g, 8.2 mmol) in DCM (15 mL) at 0 °C under N2. The resulting mixture was stirred at room temperature for 1 hour. The mixture was diluted with water (30 mL) and extracted with EtOAc (25 mL x 3). The combined organic phases were washed with brine (25 mL) and concentrated to give crude product (1.1 g, yield: 83.4%) of (2S,4S)-4-(methanesulfonyloxy)pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl 2-methyl ester (1.1 g, yield: 83.4%) as a pale yellow oil, which was used in the next step without further purification. LC / MS (ESI) m / z: 224 (M-100+H) + .

[0625] Step 2:

[0626] To a solution of (2S,4S)-4-(methanesulfonyloxy)pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl 2-methyl ester (1.1 g, 3.4 mmol) in DMF (15 mL), NaSMe (230 mg, 4.0 mmol) was added, and the resulting mixture was stirred at room temperature for 10 hours. The reaction mixture was diluted with water (30 mL) and extracted with EtOAc (25 mL x 3). The combined organic phases were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by silica gel column chromatography (EtOAc in PE = 10–25%) to give the desired product (2S,4R)-4-(methylthio)pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl 2-methyl ester (850 mg, yield: 90.7%) as a solid. 1H NMR (400MHz, CDCl3) δ4.29 (dd, J=23.9, 16.0Hz, 1H), 3.97 (dd, J=10.5, 7.0Hz, 1H), 3.74 (s, 3H), 3. 42–3.12(m,2H),2.60(dd,J=13.0,6.4Hz,1H),2.12(s,3H),1.99–1.88(m,1H),1.47–1.40(m,9H).

[0627] Step 3:

[0628] To a solution of (2S,4R)-4-(methylthio)pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl 2-methyl ester (850 mg, 3.10 mmol) in DCM (20 mL), m-CPBA (1.1 g, 6.2 mmol) was added, and the resulting mixture was stirred overnight at room temperature. The reaction mixture was diluted with DCM (50 mL), washed with brine, dried over anhydrous Na₂SO₄, filtered, and concentrated. The residue was purified by silica gel column chromatography (EtOAc = 5–25% in PE) to give the desired product (2S,4R)-4-(methylsulfonyl)pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl 2-methyl ester (500 mg, yield: 52.7%) as a pale yellow solid. LC / MS (ESI) m / z: 330 (M+Na). + .

[0629] Step 4:

[0630] To a solution of (2S,4R)-4-(methylsulfonyl)pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl 2-methyl ester (500 mg, 1.6 mmol) in EtOH (5 mL), an aqueous solution of NaOH (2.0 mL, 2.0 N) was added, and the resulting mixture was stirred at room temperature for 30 minutes. The reaction mixture was concentrated, and the pH was adjusted to 2–3 with 1.0 N HCl solution, followed by extraction with EtOAc (30 mL x 3). The combined organic layers were washed with water and brine, dried over anhydrous Na₂SO₄, filtered, and concentrated to give 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) + .

[0631] Preparation of intermediate 17, (4S,5S,7R)-6-(tert-butoxycarbonyl)-1-methyl-4,5,6,7-tetrahydro-1H-4,7-methylenepyrazolo[3,4-c]pyridine-5-carboxylic acid

[0632]

[0633] Step 1:

[0634] Add 3.3 g (7.7 mmol) of Desmond reagent to a solution of (1R,3S,4S,6R)-6-hydroxy-2-azabicyclo[2.2.1]heptane-2,3-dicarboxylic acid-2-tert-butyl ester-3-ethyl ester (1.1 g, 3.8 mmol) in DCM (30 mL) at 0 °C, and stir the resulting mixture overnight at room temperature. Dilute the reaction mixture with water (20 mL) and extract with DCM (20 mL x 3). The combined organic phases were washed with water and brine, dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by silica gel column chromatography (EtOAc = 5–20% in PE) to give the desired product (1R,3S,4S)-6-oxo-2-azabicyclo[2.2.1]heptane-2,3-dicarboxylic acid 2-tert-butyl ester 3-ethyl ester (800 mg, yield: 73.2%), as an oil. LC / MS (ESI) m / z: 184 (M-100+H) + .

[0635] Step 2:

[0636] DMF-DMA (5 mL) was added to a solution of (1R,3S,4S)-6-oxo-2-azabicyclo[2.2.1]heptane-2,3-dicarboxylic acid 2-tert-butyl 3-ethyl ester (1.2 g, 4.2 mmol) in toluene (10 mL), and the reaction mixture was heated to 120 °C for 24 hours. The mixture was cooled to room temperature, and the solution was concentrated. The residue was purified by silica gel column chromatography (EtOAc = 50%–100% in PE) to give the desired product (1R,3S,4S)-5-((dimethylamino)methylene)-6-oxo-2-azabicyclo[2.2.1]heptane-2,3-dicarboxylic acid 2-tert-butyl 3-ethyl ester (500 mg, yield: 35.7%) as a pale yellow solid. LC / MS (ESI) m / z: 283 (M-55+H). + .

[0637] Step 3:

[0638] HOAc (0.1 mL) was added to a solution of (1R,3S,4S)-5-((dimethylamino)methylene)-6-oxo-2-azabicyclo[2.2.1]heptane-2,3-dicarboxylic acid 2-tert-butyl ester 3-ethyl ester (300 mg, 0.9 mmol) and methylhydrazine solution (0.2 mL, 1.6 mmol) in MeCN (10 mL), and the resulting mixture was stirred overnight at 80 °C. The reaction mixture was concentrated, and the residue was purified by silica gel column chromatography (EtOAc = 10-30% in PE) to obtain the desired product (4S,5S,7R)-1-methyl-1,4,5,7-tetrahydro-6H-4,7-methylenepyrazolo[3,4-c]pyridine-5,6-dicarboxylic acid 6-(tert-butyl) ester 5-ethyl ester (150 mg, yield: 52%), as a white solid, LC / MS (ESI) m / z: 322(M+H)+.

[0639] Step 4:

[0640] Add 3.0 mL of NaOH solution (2.0 N) to a solution of (4S,5S,7R)-1-methyl-1,4,5,7-tetrahydro-6H-4,7-methylenepyrazolo[3,4-c]pyridine-5,6-dicarboxylic acid 6-(tert-butyl) ester 5-ethyl ester (150 mg, 0.5 mmol) in MeOH (8 mL), and stir the reaction mixture at 60 °C for 1 hour. The mixture was concentrated and the pH was adjusted to 2-3 with 1.0N HCl. The mixture was then extracted with EtOAc (20 mL x 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-methylenepyrazolo[3,4-c]pyridine-5-carboxylic acid (80 mg, yield: 58.4%) as a yellow solid. LC / MS (ESI) m / z: 294 (M+H) + .

[0641] Preparation of Intermediate 18, (S)-N-ethyl-5-fluoro-N-isopropyl-2-((4-(7-(1-methyl-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-4-carbonyl)-2,7-diazaspiro[3,5]non-2-yl)pyrimidin-5-yl)oxy)benzamide

[0642]

[0643] Step 1:

[0644] DMF-DMA (2.8 mL, 24.7 mmol) was added to a solution of (S)-4-oxopyrrolidine-1,2-dicarboxylic acid di-tert-butyl ester (2.0 g, 8.2 mmol) in toluene (20 mL). The resulting mixture was heated to 105 °C for 6 hours. The reaction mixture was cooled to room temperature and concentrated. The residue was purified by silica gel column chromatography (EtOAc = 0–50% in PE) to give the desired product, 3-((dimethylamino)methylene)-4-oxopyrrolidine-1,2-dicarboxylic acid di-tert-butyl ester (2.0 g, yield: 84%), as an oil. LC-MS: m / z 341 (M+H) + .

[0645] Step 2:

[0646] To a solution of 1.3 g (3.8 mmol) of 3-((dimethylamino)methylene)-4-oxopyrrolidine-1,2-dicarboxylic acid di-tert-butyl ester in EtOH (10 mL), a solution of methylhydrazine (0.8 mL, 5.7 mmol) was added. The resulting mixture was heated to 85 °C for 12 hours in a sealed tube. The reaction mixture was concentrated, and the residue was purified by silica gel column chromatography (EtOAc = 0–100% in PE) to give the desired product (S)-1-methyl-4,6-dihydropyrrolo[3,4-c]pyrazole-4,5(1H)-dicarboxylic acid di-tert-butyl ester (700 mg, yield: 57%) as a solid. LC-MS: m / z 324 (M+H) + .

[0647] Step 3:

[0648] TFA (2 mL) was added dropwise to a solution of (S)-1-methyl-4,6-dihydropyrrolo[3,4-c]pyrazole-4,5(1H)-dicarboxylic acid di-tert-butyl ester (300 mg, 0.93 mmol) in DCM (5 mL) at 0 °C, and the resulting mixture was stirred at room temperature for 10 hours. The reaction mixture was concentrated under reduced pressure to give 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) + .

[0649] Step 4:

[0650] Boc₂O (170 mg, 0.71 mmol) was added dropwise to a solution of (S)-1-methyl-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazole-4-carboxylic acid (290 mg, 0.71 mmol) and TEA (0.09 mL, 0.71 mmol) in DCM (5 mL) at 0 °C. The resulting mixture was stirred at room temperature for 2 hours. The reaction mixture was diluted with H₂O (5 mL), extracted with DCM (10 mL x 3), and the combined organic phases were dried over anhydrous Na₂SO₄, filtered, and concentrated to give the desired crude product (S)-5-(tert-butoxycarbonyl)-1-methyl-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazole-4-carboxylic acid (180 mg, yield: 94.6%) as a solid. LC / MS (ESI) m / z: 268 (M+H) + .

[0651] The following intermediates were prepared from the corresponding chemicals according to the experimental procedure used for intermediate 18 (the main different chemicals used are listed in the raw materials column):

[0652]

[0653]

[0654] Preparation of intermediate 22, N-(2,2-difluoroethyl)-5-fluoro-2-hydroxy-N-isopropylbenzamide

[0655]

[0656] Step 1:

[0657] DIPEA (2.56 mL, 15.5 mmol) and HATU (5.0 g, 13.1 mmol) were added to a stirred solution of 5-fluoro-2-methoxybenzoic acid (2.0 g, 11.7 mmol) and 2-[(propyl-2-yl)amino]ethanol-1-ol (1.5 mL, 13.6 mmol) in a DCM (40 mL) at 0 °C. The resulting mixture was then cooled to room temperature and stirred overnight. The reaction mixture was quenched with saturated NH4Cl solution and extracted with EtOAc (50 mL x 3). The combined organic phases were dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by silica gel column chromatography (EtOAc in PE = 5–50%) to give the desired product, 5-fluoro-N-(2-hydroxyethyl)-2-methoxy-N-(propyl-2-yl)benzamide (2.5 g, yield: 83.3%), as a white solid. LC / MS (ESI) m / z: 256 (M+H) + .

[0658] Step 2:

[0659] Add Dysmart reagent (4.5 g, 10.6 mmol) to a solution of 5-fluoro-N-(2-hydroxyethyl)-2-methoxy-N-(propyl-2-yl)benzamide (2.5 g, 9.79 mmol) in DCM (100 mL) at 0 °C. Stir the resulting mixture at 25 °C for 10 hours. Pour the reaction mixture into ice water (50 mL), extract with EtOAc (50 mL x 3), dry the combined organic phases to anhydrous Na₂SO₄, filter and concentrate. Purify the residue by silica gel column chromatography (EtOAc in PE = 5–30%) to give the desired product, 5-fluoro-2-methoxy-N-(2-oxoethyl)-N-(propyl-2-yl)benzamide (2.2 g, yield: 88.7%), as a white solid. LC / MS (ESI) m / z: 254 (M+H) + .

[0660] Step 3:

[0661] DAST (2.87 mL, 21.7 mmol) was slowly added to a solution of 5-fluoro-2-methoxy-N-(2-oxoethyl)-N-(propyl-2-yl)benzamide (2.2 g, 8.69 mmol) in DCM (50 mL) at -10 °C. The reaction mixture was stirred at 25 °C under a N2 atmosphere for 5 hours. The reaction mixture was poured into ice water (50 mL) and extracted with EtOAc (50 mL x 3). The combined organic phases were dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by silica gel column chromatography (EtOAc in PE = 1–30%) to give the desired product N-(2,2-difluoroethyl)-5-fluoro-2-methoxy-N-(propyl-2-yl)benzamide (350 mg, yield: 14.6%) as an oil. LC / MS (ESI) m / z: 276 (M+H) + .

[0662] Step 4:

[0663] BBr3 (3.4 mL, 3.40 mmol) was added dropwise to a solution of N-(2,2-difluoroethyl)-5-fluoro-2-methoxy-N-(propyl-2-yl)benzamide (350 mg, 1.27 mmol) in DCM (10 mL) at -60 °C under a N2 atmosphere. The resulting mixture was stirred at -60 °C for 2 hours. The reaction mixture was quenched at 0 °C with ice-saturated NaHCO3, extracted with DCM (100 mL x 3), and the combined organic layers were washed with water and brine, dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by silica gel column chromatography (EtOAc = 1–20% in PE) to give the desired product N-(2,2-difluoroethyl)-5-fluoro-2-hydroxy-N-(propyl-2-yl)benzamide (300 mg, yield: 90.3%) as a white solid. LC / MS (ESI) m / z: 262 (M+H) + .

[0664] Preparation of intermediate 22-1

[0665] 5-Fluoro-2-hydroxy-N-(2-hydroxyethyl)-N-(propyl-2-yl)benzamide

[0666]

[0667] BBr3 (4 mL, 1.0 M, in DCM) was added dropwise to a solution of 5-fluoro-N-(2-hydroxyethyl)-N-isopropyl-2-methoxybenzamide (510 mg, 2.00 mmol) in DCM (10 mL) at -40 °C under a N2 atmosphere. The resulting mixture was stirred at this temperature for 2 hours. The reaction mixture was then slowly quenched with cooled MeOH at -40 °C and diluted with DCM (50 mL). The organic layer was separated, washed with saturated NaHCO3 solution and brine, dried over anhydrous Na2SO4, filtered, and concentrated to give the desired product, 5-fluoro-2-hydroxy-N-(2-hydroxyethyl)-N-isopropylbenzamide (330 mg, yield: 68.5%), as a yellow solid, which was used in the next step without further purification. LC / MS (ESI) m / z: 242 (M+H) + .

[0668] Preparation of intermediate 23, (6S)-5-(tert-butoxycarbonyl)-1,1-difluoro-5-azaspiro[2.4]heptane-6-carboxylic acid

[0669]

[0670] Step 1:

[0671] TMSCHN2 (225.73 mg, 1.98 mmol) was added to a solution of (2S)-1-[(tert-butoxy)carbonyl]-4-methylenepyrrolidine-2-carboxylic acid (0.25 mL, 1.32 mmol) in DCM (5 mL) at room temperature, and the resulting mixture was stirred for 2 hours. The reaction mixture was quenched with AcOH (1.0 mL), 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 crude product (S)-4-methylenepyrrolidine-1,2-dicarboxylic acid 1-tert-butyl 2-methyl ester (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) + .

[0672] Step 2:

[0673] TMSCF3 (7.5 g, 53.05 mmol) was added to a solution of (S)-4-methylenepyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester (400 mg) and NaI (82 mg, 0.54 mmol) in THF (10 mL) under N2 at room temperature. The resulting mixture was stirred in a sealed tube at 65 °C for 12 hours. The mixture was diluted with H2O (10 mL), extracted with EtOAc (20 mL x 3), and the combined organic layers were washed with water and brine, dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by silica gel column chromatography (EtOAc in PE = 5-30%) to obtain the desired product (6S)-1,1-difluoro-5-azaspiro[2.4]heptane-5,6-dicarboxylic acid 5-tert-butyl 6-methyl ester (150 mg, yield: 29.5%), as a yellow oil; LCMS: ESI m / z 246 (M+1). + .

[0674] Step 3:

[0675] NaOH (80 mg, 2 mmol) was added to a solution of (6S)-1,1-difluoro-5-azaspiro[2,4]heptane-5,6-dicarboxylic acid 5-tert-butyl 6-methyl ester (200 mg, 0.68 mmol) in MeOH (3 mL) and H2O (1 mL) at 0 °C, and the resulting mixture was stirred at room temperature for 30 minutes. The reaction mixture was concentrated, the pH was adjusted to 2–3 with 1.0 N HCl, and extracted with EtOAc (20 mL x 3). The combined organic layers were washed with water and brine, dried over anhydrous Na2SO4, filtered, and concentrated to give crude product (6S)-5-[(tert-butoxy)carbonyl]-1,1-difluoro-5-azaspiro[2,4]heptane-6-carboxylic acid (150 mg, yield: 74.8%) as a white solid, which could be used directly in the next step without further purification. LC / MS(ESI) m / z: 222(M-55) + .

[0676] Preparation of intermediate 24, (3S,5R)-2-(tert-butoxycarbonyl)-5-(methoxymethyl)-2-azabicyclo[3.1.0]hexane-3-carboxylic acid

[0677]

[0678] Step 1:

[0679] To a solution of (1S)-1-(hydroxymethyl)bicyclo[3.1.0]hexane-3-carboxylate (200 mg, 1.28 mmol) in DCE (5 mL), 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) were added. The reaction mixture was then stirred at 100 °C for 1 hour. The reaction mixture was cooled to room temperature, diluted with H2O (5 mL), and extracted with EtOAc (10 mL x 3). The combined organic phases were dried over anhydrous Na₂SO₄, filtered, and concentrated to give the crude product (3S,5R)-5-(methoxymethyl)-2-azabicyclo[3.1.0]hexane-2,3-dicarboxylic acid 2-tert-butyl 3-methyl ester (150 mg, yield: 68%), as a yellow oil. LC / MS (ESI) m / z: 286 (M+1) + .

[0680] Step 2:

[0681] To a solution of 2-tert-butyl 3-methyl hexane-2,3-dicarboxylic acid (3S,5R)-5-(methoxymethyl)-2-azabicyclo[3.1.0]hexane-3-carboxylic acid in MeOH (3.0 mL) and H₂O (1.0 mL), NaOH (200 mg, 5.00 mmol) was added. The resulting mixture was then stirred at 80 °C for 1 hour. The pH of the reaction mixture was then adjusted to 5 with 1.0 N HCl and extracted with EtOAc (15 mL x 3). The combined organic layers were washed with brine, dried over Na₂SO₄, filtered, and concentrated to give 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) + .

[0682] Preparation of intermediate 25, (2S,4S)-1-(tert-butoxycarbonyl)-4-(methylsulfonylamino)pyrrolidine-2-carboxylic acid

[0683]

[0684] Step 1:

[0685] MsCl (0.06 mL, 0.72 mmol) was added to a solution of (2S,4S)-4-aminopyrrolidine-1,2-dicarboxylic acid 1-tert-butyl 2-methyl ester (162 mg, 0.65 mmol) and TEA (0.20 mL, 1.3 mmol) in DCM (5 mL) at 0 °C, and the resulting mixture was stirred at 25 °C for 6 hours. The reaction mixture was quenched with saturated NH4Cl solution (10 mL), extracted with DCM (10 mL x 3), and the combined organic phases were washed with water and brine, dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by silica gel column chromatography (EtOAc = 10–50% in PE) to give the desired product (2S,4S)-4-(methanesulfonamide)pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl 2-methyl ester (160 mg, yield: 75%) as a colorless oil. LC / MS(ESI) m / z: 323(M+1) + .

[0686] Step 2:

[0687] To a solution of (2S,4S)-4-(methylsulfonylamino)pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl 2-methyl ester (160 mg, 0.50 mmol) in MeOH (3.0 mL) and H₂O (1.0 mL), NaOH (80 mg, 2.0 mmol) was added, and the resulting mixture was stirred at 20 °C under N₂ for 1 hour. The pH of the reaction mixture was then adjusted to 5 with 1.0 N HCl, and the mixture was extracted with EtAOc (15 mL x 3). The combined organic layers were dried over Na₂SO₄, filtered, and concentrated to give the crude product (2S,4S)-1-[(tert-butoxy)carbonyl]-4-methanesulfonylaminopyrrolidine-2-carboxylic acid (130 mg, yield: 84%) as a solid. LC / MS (ESI) m / z: 309 (M+1) + .

[0688] The following intermediates were prepared from the appropriate chemicals according to the experimental procedure for intermediate 25 (the main different chemicals used are listed in the raw materials column):

[0689]

[0690] Preparation of intermediate 27, (2S,5R)-1-(tert-butoxycarbonyl)-5-fluoropiperidine-2-carboxylic acid

[0691]

[0692] Step 1:

[0693] SOCl2 (0.30 mL, 4.1 mmol) was added to a solution of (2S,5S)-5-hydroxypiperidine-2-carboxylic acid (301 mg, 2.07 mmol) in MeOH (5.0 mL). The resulting mixture was stirred at 20 °C for 1 hour. The reaction mixture was concentrated to give crude product (2S,5S)-5-hydroxypiperidine-2-carboxylic acid methyl ester (300 mg, yield: 91%) as a pale yellow oil. LC / MS (ESI) m / z: 160 (M+1) + .

[0694] Step 2:

[0695] TEA (0.52 mL, 3.7 mmol) and (Boc)₂O (0.45 g, 2.07 mmol) were added to a solution of methyl (2S,5S)-5-hydroxypiperidine-2-carboxylate (300 mg, 1.88 mmol) in acetone (5.0 mL) and H₂O (1.0 mL) at 0 °C. The resulting mixture was stirred at 20 °C for 3 hours, quenched with saturated NH₄Cl solution (10 mL), extracted with EtOAc (15 mL x 3), and the combined organic layers were washed with brine, dried over Na₂SO₄, filtered, and concentrated to give crude (2S,5S)-5-hydroxypiperidine-1,2-dicarboxylate 1-tert-butyl 2-methyl ester (400 mg, yield: 81%) as a pale yellow solid, which could be used directly in the next step. LC / MS (ESI) m / z: 260 (M+1). + .

[0696] Step 3:

[0697] DAST (0.5 mL, 3.85 mmol) was added to a solution of (2S,5S)-5-hydroxypiperidine-1,2-dicarboxylic acid 1-tert-butyl 2-methyl ester (400 mg, 1.54 mmol) in DCM (10 mL) at -60 °C. The resulting mixture was stirred at room temperature under N2 for 16 hours. The reaction mixture was diluted with saturated NaHCO3 solution (10 mL), extracted with DCM (15 mL x 3), and the combined organic phases were washed with brine, dried over Na2SO4, filtered, and concentrated to give crude (2S,5R)-5-fluoropiperidine-1,2-dicarboxylic acid 1-tert-butyl 2-methyl ester (270 mg, yield: 67.2%) as a yellow oil, which was used in the next step without further purification. LC / MS (ESI) m / z: 262 (M+H) + .

[0698] Step 4:

[0699] To a solution of 2-methyl 1-tert-butyl (270 mg, 1.01 mmol) of (2S,5R)-5-fluoropiperidine-1,2-dicarboxylic acid in MeOH (3.0 mL) and H₂O (1.0 mL), NaOH (120 mg, 3.0 mmol) was added, and the resulting mixture was stirred at room temperature for 1 hour. The pH of the reaction mixture was then adjusted to 5 with 1N HCl, and the mixture was extracted with EtAOc (15 mL x 3). The combined organic layers were washed with brine, dried over Na₂SO₄, filtered, and concentrated to give crude product (2S,5R)-1-(tert-butoxycarbonyl)-5-fluoropiperidine-2-carboxylic acid (130 mg, yield: 48%) as a solid, which was used in the next step without further purification. LC / MS (ESI) m / z: 247 (M+H) + .

[0700] Preparation of intermediate 28, (2S)-1-(tert-butoxycarbonyl)-4-(cyanomethyl)pyrrolidine-2-carboxylic acid

[0701]

[0702] Step 1:

[0703] LiHMDS (9.0 mL, 1.0 M, in THF) was added to a solution of (cyanomethyl)phosphonate diethyl ester (1.5 mL, 9.0 mmol) in THF (20 mL) at 0 °C. The resulting mixture was stirred at 0 °C for 1 hour. Then, at the same temperature, 2.01 g (8.22 mmol) of (2S)-4-oxopyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester in THF (10 mL) was added to the reaction mixture. The reaction mixture was stirred for 16 hours while being cooled to room temperature, quenched with saturated NH4Cl solution (20 mL), and extracted with EtOAc (20 mL x 2). The combined organic phases were dried and concentrated using Na₂SO₄. The residue was purified by silica gel column chromatography (EtOAc = 0–10% in PE) to give the desired product (2S,4Z)-4-(cyanomethylene)pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl 2-methyl ester (900 mg, yield: 41.0%), as a yellow solid. LC / MS (ESI) m / z: 247 (M+H) + .

[0704] Step 2:

[0705] A slurry of Pd / C (90 mg, 10%) in EtOAc (10 mL) was added to a solution of (2S)-4-(cyanomethylene)pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl 2-methyl ester (900 mg, 3.38 mmol) in MeOH (5 mL). The resulting suspension was then stirred at room temperature under an H2 balloon for 16 hours. The reaction mixture was filtered through a celite pad, and the filtrate was concentrated to give crude product (2S)-4-(cyanomethyl)pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl 2-methyl ester (900 mg, yield: 99%) as a colorless oil, which was used in the next step without further purification. LC / MS (ESI) m / z: 269 (M+H) + .

[0706] Step 3:

[0707] To a solution of 2-methyl 1-tert-butyl (2S)-4-(cyanomethyl)pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester (650 mg, 2.29 mmol) in MeOH (5.0 mL) and H₂O (1.0 mL), NaOH (200 mg, 5.00 mmol) was added. The resulting mixture was heated to 65 °C for 1 hour. The reaction mixture was cooled to room temperature and the pH was adjusted to 5 with 1.0 N HCl. The mixture was extracted with EtOAc (10 mL x 3). The combined organic phases were dried over anhydrous Na₂SO₄, filtered, and concentrated under vacuum to give crude product (2S)-1-[(tert-butoxy)carbonyl]-4-(cyanomethyl)pyrrolidine-2-carboxylic acid (400 mg, yield: 47%) as a pale yellow solid. LC / MS (ESI) m / z: 254 (M+H) + .

[0708] Preparation of intermediate 29, 4-isopropyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborhexacyclopentan-2-yl)pyrimidine

[0709]

[0710] KOAc (1.50 g, 15.7 mmol) and Pd(dppf)Cl2 (100 mg) were added 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'-bis(1,3,2-dioxaborhecyclopentane) (1.40 g, 5.47 mmol) in dioxane (10 mL). The resulting mixture was heated to 110 °C for 12 hours under a nitrogen atmosphere. After cooling to room temperature, the mixture was diluted with 10 mL of H₂O, extracted with EtOAc (30 mL x 3), and the combined organic phases were washed with water and brine, dried over anhydrous Na₂SO₄, filtered, and concentrated under vacuum to obtain a crude product. This crude product was purified by silica gel column chromatography (EtOAc in PE = 0–20%) to give the desired product, 4-isopropyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborhexacyclopentan-2-yl)pyrimidine (610 mg, yield: 49%), as a white solid. LC / MS (ESI) m / z: 249 (M+H) + .

[0711] The following intermediates were prepared from the appropriate chemicals according to the experimental procedure for intermediate 29 (the main different chemicals used are listed in the raw materials column):

[0712]

[0713] Preparation of intermediate 31, 2-(4-(7-(tert-butoxycarbonyl)-2,7-diazaspiro[3.5]non-2-yl)pyrimidin-5-yloxy)-5-fluorobenzoic acid

[0714]

[0715] Step 1:

[0716] Cs₂CO₃ (12.8 g, 39.3 mmol) was added 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) at room temperature. The resulting mixture was heated to 120 °C for 12 hours. The reaction mixture was cooled to room temperature, quenched with saturated NH₄Cl solution (50 mL), extracted with EtOAc (100 mL x 3), and the combined organic layers were washed with water and brine, dried over anhydrous Na₂SO₄, filtered, and concentrated. The residue was purified by silica gel column chromatography (EtOAc = 0–30% in PE) 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).+ .

[0717] Step 2:

[0718] Pd(dppf)Cl2 (150 mg) was added to a solution of 5-(2-bromo-4-fluorophenoxy)pyrimidine (1.00 g, 3.70 mmol) and TEA (1.5 mL, 11 mmol) in MeOH (15 mL) at room temperature. The resulting mixture was stirred at 90 °C under a CO (70 psi) atmosphere for 12 h. After cooling to room temperature, the solvent was concentrated under reduced pressure to obtain a crude product, which was purified by silica gel column chromatography (EtOAc = 0–30% in PE) 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) + .

[0719] Step 3:

[0720] Urea·H₂O₂ (800 mg, 8.16 mmol) and TFAA (0.6 mL) were added to a solution of methyl 5-fluoro-2-(pyrimidin-5-yloxy)benzoate (900 mg, 3.63 mmol) in THF (20 mL) at 0 °C under N₂. The resulting mixture was stirred at room temperature for 1 hour. The reaction mixture was quenched with saturated NaHCO₃, extracted with EtOAc (20 mL x 3), and the combined organic layers were washed with water and brine, dried over anhydrous Na₂SO₄, filtered, and concentrated under vacuum to give crude product 5-[4-fluoro-2-(methoxycarbonyl)phenoxy]pyrimidin-1-onthium-1-ol (830 mg, yield: 86.3%) as a yellow oil, which could be used directly in the next step without further purification. LCMS: ESI m / z 265 (M+1) + .

[0721] Step 4:

[0722] POCl3 (0.6 mL, 6.8 mmol) was added to a solution of 5-[4-fluoro-2-(methoxycarbonyl)phenoxy]pyrimidin-1-onthium-1-ol (800 mg, 3.01 mmol) and DIPEA (5.6 mL, 34 mmol) in EtOAc (15 mL) at 0 °C. The resulting mixture was stirred at room temperature for 2 hours. The reaction mixture was quenched with saturated NaHCO3 solution (20 mL), extracted with EtOAc (50 mL x 3), and the combined organic layers were washed with water and brine, dried over anhydrous Na2SO4, filtered, and concentrated under vacuum to give crude product methyl 2-[(4-chloropyrimidin-5-yl)oxy]-5-fluorobenzoate (798 mg, yield: 93%) as a brown oil, which could be used directly in the next step without further purification. LCMS: ESI m / z 283 (M+1) + .

[0723] Step 5:

[0724] At room temperature, tert-butyl 2,7-diazaspiro[3.5]nonane-7-carboxylate (703 mg, 3.11 mmol) was added 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). The resulting mixture was stirred at 65 °C for 3 hours. After cooling to room temperature, the reaction mixture was quenched with saturated NH4Cl solution (10 mL), extracted with EtOAc (30 mL x 3), and the combined organic layers were washed with water and brine, dried over anhydrous Na2SO4, filtered, and concentrated to obtain a crude product. This crude product was purified by silica gel column chromatography (EtOAc in PE = 0–50%) to obtain the desired product, 2-{5-[4-fluoro-2-(methoxycarbonyl)phenoxy]pyrimidin-4-yl}-2,7-diazaspiro[3.5]nonane-7-carboxylic acid tert-butyl ester (610 mg, yield: 45.5%), as a yellow solid. LCMS: ESI m / z 473 (M+1). + .

[0725] Step 6:

[0726] NaOH (228 mg, 5.71 mmol) was added to a solution of 2-{5-[4-fluoro-2-(methoxycarbonyl)phenoxy]pyrimidin-4-yl}-2,7-diazaspiro[3.5]nonane-7-carboxylic acid tert-butyl ester (610 mg, 1.29 mmol) in MeOH (12 mL) and H2O (4.0 mL) at 0 °C. The resulting mixture was stirred at room temperature for 1 hour. The pH of the mixture was then adjusted to 5 with 1.0 N HCl, extracted with EtOAc (20 mL x 3), and the combined organic layers were washed with water and brine, dried over anhydrous Na₂SO₄, filtered, and concentrated to give crude product 2-[(4-{7-[(tert-butoxy)carbonyl]-2,7-diazaspiro[3.5]nonyl-2-yl}pyrimidin-5-yl)oxy]-5-fluorobenzoic acid (560 mg, yield: 94.5%) as a white solid, which was used in the next step without further purification. LC / MS (ESI) m / z: 459 (M+H) + .

[0727] Step 7:

[0728] DIPEA (169 mg, 1.31 mmol) was added to a stirred solution of 2-[(4-{7-[(tert-butoxy)carbonyl]-2,7-diazaspiro[3.5]non-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). The resulting mixture was stirred for 10 min, followed by the addition of 2-[(prop-2-yl)amino]ethanol-1-ol (54 mg, 0.52 mmol). The reaction mixture was stirred at room temperature for 1 h, then diluted with H2O (10 mL) and extracted with EtOAc (30 mL x 3). The combined organic phases were dried over anhydrous Na₂SO₄, filtered, and concentrated to obtain the desired product. This product was then purified by preparative-TLC (MeOH = 9% in DCM) to yield 2-(5-{4-fluoro-2-[(2-hydroxyethyl)(propyl-2-yl)carbamoyl]phenoxy}pyrimidin-4-yl)-2,7-diazaspiro[3.5]nonane-7-carboxylic acid tert-butyl ester (135 mg, yield: 56.9%), a white solid. LCMS: ESI m / z 544 (M+1) + .

[0729] Step 8:

[0730] TFA (1.0 mL) was added to a solution of 2-(5-{4-fluoro-2-[(2-hydroxyethyl)(propyl-2-yl)carbamoyl]phenoxy}pyrimidin-4-yl)-2,7-diazaspiro[3.5]nonane-7-carboxylic acid tert-butyl ester (50 mg, 0.09 mmol) in DCM (3.0 mL). The mixture was stirred at room temperature for 1 hour. The resulting mixture was concentrated under vacuum to give crude product 2-[(4-{2,7-diazaspiro[3.5]non-2-yl}pyrimidin-5-yl)oxy]-5-fluoro-N-(2-hydroxyethyl)-N-(propyl-2-yl)benzamide (40 mg, yield: 98%) as an oil, which could be used directly in the next step without further purification. LC / MS (ESI) m / z: 444 (M+H) + .

[0731] Preparation of intermediate 32, 2-((4-(2,7-diazaspiro[3.5]non-2-yl)pyrimidin-5-yl)oxy)-5-fluoro-N-isopropyl-N-(2-methoxyethyl)benzamide

[0732]

[0733] Step 1:

[0734] NaH (7.0 mg, 0.17 mmol, 60%) was added to a solution of 2-(5-{4-fluoro-2-[(2-hydroxyethyl)(propyl-2-yl)carbamoyl]phenoxy}pyrimidin-4-yl)-2,7-diazaspiro[3.5]nonane-7-carboxylic acid tert-butyl ester (60 mg, 0.11 mmol) in DMF (4 mL) at 0 °C. The reaction mixture was stirred for 10 min, and then MeI (31 mg, 0.22 mmol) was added. The resulting mixture was stirred at room temperature for 1 h, quenched with saturated NH4Cl solution (10 mL), and extracted with EtOAc (30 mL x 3). The combined organic layers were dried over anhydrous Na₂SO₄, filtered, and concentrated to obtain the desired product. This product was then purified by preparative TLC (MeOH = 9% in DCM) to yield 2-(5-{4-fluoro-2-[(2-methoxyethyl)(propyl-2-yl)carbamoyl]phenoxy}pyrimidin-4-yl)-2,7-diazaspiro[3.5]nonane-7-carboxylic acid tert-butyl ester (50 mg, yield: 81.2%), as a yellow solid. LCMS: ESI m / z 558 (M+1) + .

[0735] Step 2:

[0736] TFA (1.0 mL) was added to a solution of 2-(5-{4-fluoro-2-[(2-methoxyethyl)(propyl-2-yl)carbamoyl]phenoxy}pyrimidin-4-yl)-2,7-diazaspiro[3.5]nonane-7-carboxylic acid tert-butyl ester (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 under vacuum to give crude product 2-[(4-{2,7-diazaspiro[3.5]non-2-yl}pyrimidin-5-yl)oxy]-5-fluoro-N-(2-methoxyethyl)-N-(propyl-2-yl)benzamide (30 mg, yield: 73.5%) as a brown oil, which could be used directly in the next step without further purification. LC / MS (ESI) m / z: 458 (M+H) + .

[0737] Preparation of intermediate 33, 2-cyclopropyl-5'-fluoro-2'-hydroxybiphenyl-4-carboxynitrile

[0738]

[0739] Step 1:

[0740] To a solution of 3-bromo-4-hydroxybenzyl nitrile (1.01 g, 5.05 mmol) and cyclopropylboronic acid (520 mg, 6.06 mmol) in toluene (15 mL), PCy3 (280 mg, 1 mmol), Pd(OAc)2 (100 mg), and K3PO4 (3.2 g, 15 mmol) were added at room temperature. The resulting mixture was stirred at 100 °C under N2 for 12 hours. The reaction mixture was cooled to room temperature, quenched with H2O (20 mL), extracted with EtOAc (30 mL x 3), and the combined organic layers were washed with water and brine, dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by silica gel column chromatography (EtOAc in PE = 0–30%) to give the desired product, 3-cyclopropyl-4-hydroxybenzyl nitrile (700 mg, yield: 82.8%), as a yellow oil. LC / MS (ESI) m / z: 158 (MH) + .

[0741] Step 2:

[0742] Tf₂O (1.1 mL, 6.59 mmol) was added to a solution of 3-cyclopropyl-4-hydroxybenzyl nitrile (700 mg, 4.39 mmol) and pyridine (1.12 g, 8.79 mmol) in THF (10 mL) at -5 °C under N₂. The resulting mixture was stirred at 0 °C for 3 hours. The reaction was quenched with saturated NaHCO₃ solution, extracted with DCM (30 mL x 3), and the combined organic layers were washed with water and brine, dried over anhydrous Na₂SO₄, filtered, and concentrated. The residue was purified by silica gel column chromatography (EtOAc = 0–80% in PE) to give the desired product, 4-cyano-2-cyclopropylphenyl trifluoromethanesulfonic acid (1.01 g, yield: 74.2%), as an oil. LC / MS (ESI) m / z: 292 (M+H) + .

[0743] Step 3:

[0744] Pd(dppf)Cl2 (20 mg) and K2CO3 (414 mg, 3.00 mmol) were added to a solution of 4-cyano-2-cyclopropylphenyl trifluoromethanesulfonic acid (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). The resulting mixture was stirred at 100°C under a N2 atmosphere for 10 hours. The reaction mixture was cooled to room temperature, diluted with 10 mL of H₂O, and extracted with EtOAc (20 mL x 3). The combined organic layers were washed with water and brine, dried over anhydrous Na₂SO₄, filtered, and concentrated to obtain a crude product. This crude product was purified by silica gel column chromatography (EtOAc in PE = 0–50%) to give the desired product, 2-cyclopropyl-5'-fluoro-2'-hydroxybiphenyl-4-carboxynitrile (125 mg, yield: 47.7%), as a yellow solid. LC / MS (ESI) m / z: 254 (M+H) + .

[0745] Preparation of intermediate 34, 2-((5-(2,7-diazaspiro[3.5]non-2-yl)-1,2,4-triazin-6-yl)oxy)-N-ethyl-5-fluoro-N-isopropylbenzamide

[0746]

[0747] Step 1:

[0748] 2,7-diazaspiro[3.5]nonane-7-carboxylic acid tert-butyl hydrochloride (1.05 g, 4.01 mmol) was added to a stirred solution of trichloro-1,2,4-triazine (CAS 873-41-6, 0.88 g, 4.80 mmol) and TEA (1.39 mL, 9.99 mmol) in DCM (15 mL). The resulting mixture was stirred at room temperature for 12 hours. The reaction mixture was quenched with H2O (20 mL), extracted with DCM (30 mL x 3), and the combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated to obtain a crude product. This crude product was purified by silica gel column chromatography (EtOAc = 0–25% in PE) to obtain the desired product, tert-butyl 2-(dichloro-1,2,4-triazin-5-yl)-2,7-diazaspiro[3.5]nonane-7-carboxylate (1.10 g, yield: 60.4%), as a white solid. LCMS: ESI m / z 374 (M+1) + .

[0749] Step 2:

[0750] DBU (0.50 mL, 3.37 mmol) was added to a 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-(prop-2-yl)benzamide (0.63 g, 2.81 mmol) in 12 mL of THF under stirring at room temperature. The resulting mixture was stirred at room temperature for 8 hours. The reaction mixture was diluted with H2O (20 mL), extracted with EtOAc (20 mL x 3), and the combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by silica gel column chromatography (EtOAc in PE = 20%–50%) to give the desired product 2-(3-chloro-6-{2-[ethyl(propyl-2-yl)carbamoyl]-4-fluorophenoxy}-1,2,4-triazin-5-yl)-2,7-diazaspiro[3.5]nonane-7-carboxylic acid tert-butyl ester (800 mg, yield: 50.6%) as a white solid. LCMS: ESI m / z 563 (M+1) + .

[0751] Step 3:

[0752] A slurry of TEA (0.24 mL, 1.71 mmol) and Pd / C (10% 80 mg) in EtOAc (5 mL) was added to a stirred solution of 2-(3-chloro-6-{2-[ethyl(prop-2-yl)carbamoyl]-4-fluorophenoxy}-1,2,4-triazin-5-yl)-2,7-diazaspiro[3.5]nonane-7-carboxylic acid tert-butyl ester (0.80 g, 1.42 mmol) in MeOH (10 mL). The resulting suspension was evacuated and refilled with hydrogen gas, and stirred at room temperature under H2 balloon pressure for 8 hours. The reaction mixture was filtered through a celite pad, washed with MeOH (5 mL), and the filtrate was concentrated to give the desired product, 2-(6-{2-[ethyl(propyl-2-yl)carbamoyl]-4-fluorophenoxy}-1,2,4-triazin-5-yl)-2,7-diazaspiro[3.5]nonane-7-carboxylic acid tert-butyl ester (750 mg, yield: 99.8%), as a white solid, which was used in the next step without further purification. LCMS: ESI m / z 529 (M+1) + .

[0753] Step 4:

[0754] TFA (5 mL) was added to a solution of 2-(6-{2-[ethyl(prop-2-yl)carbamoyl]-4-fluorophenoxy}-1,2,4-triazin-5-yl)-2,7-diazaspiro[3.5]nonane-7-carboxylic acid tert-butyl ester (720 mg, 1.36 mmol) in DCM (10 mL) at 0 °C. The resulting mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated under vacuum to give crude product 2-((5-(2,7-diazaspiro[3.5]non-2-yl)-1,2,4-triazin-6-yl)oxy)-N-ethyl-5-fluoro-N-isopropylbenzamide, a TFA salt (580 mg, yield: 99.4%), as a yellow oil, which could be used directly in the next step without further purification. LC / MS (ESI) m / z: 429 (M+H) + .

[0755] The following intermediates were prepared from the appropriate chemicals according to the experimental procedure for intermediate 34 (the main different chemicals used are listed in the raw materials column):

[0756]

[0757]

[0758] Preparation of intermediate 36, 2-(6-(2-(4-chloro-1-isopropyl-1H-pyrazol-5-yl)-4-fluorophenoxy)-1,2,4-triazine-5-yl)-2,7-diazaspiro[3.5]nonane

[0759]

[0760] Step 1:

[0761] At room temperature, K2CO3 (1.08 g, 7.85 mmol) and Pd(dppf)Cl2 (192 mg, 0.26 mmol) were added to a solution of [1-(propyl-2-yl)-1H-pyrazol-5-yl]boric acid (605 mg, 3.93 mmol), 2-bromo-4-fluorophenol (500 mg, 2.62 mmol) in dioxane (10 mL) and H2O (2.0 mL). The resulting mixture was stirred at 100 °C under N2 for 2 hours. The reaction mixture was cooled to room temperature, quenched with 10 mL of H₂O, and extracted with EtOAc (30 mL x 3). The combined organic layers were dried over anhydrous Na₂SO₄, filtered, and concentrated. The residue was purified by silica gel column chromatography (EtOAc in PE = 0–50%) to give the desired product, 4-fluoro-2-(1-isopropyl-1H-pyrazole-5-yl)phenol (200 mg, yield: 34.7%), as a yellow solid. LC / MS (ESI) m / z: 221 (M+H) + .

[0762] Step 2:

[0763] DBU (0.08 mL, 0.53 mmol) was added to a solution of 2-(dichloro-1,2,4-triazin-5-yl)-2,7-diazaspiro[3.5]nonane-7-carboxylic acid tert-butyl ester (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) at room temperature, and the resulting mixture was stirred overnight. The reaction mixture was diluted with H2O (10 mL), extracted with EtOAc (10 mL x 3), and the combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by silica gel column chromatography (EtOAc in PE = 0–40%) to give the desired product 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-carboxylic acid tert-butyl ester (120 mg, yield: 40.2%), as a pale yellow solid. LC / MS (ESI) m / z: 558 (M+H) + .

[0764] Step 3:

[0765] Pd / C (12 mg) was added to a solution of 2-(3-chloro-6-{4-fluoro-2-[1-(propyl-2-yl)-1H-pyrazol-5-yl]phenoxy}-1,2,4-triazin-5-yl)-2,7-diazaspiro[3.5]nonane-7-carboxylic acid tert-butyl ester (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 gas, and stirred at room temperature under an H2 balloon for 2 hours. The reaction mixture was filtered through a celite pad, and the filtrate was concentrated to give crude product 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-carboxylic acid tert-butyl ester (60 mg, yield: 53.3%) as a yellow solid, which was used in the next step without further purification. LC / MS (ESI) m / z: 524 (M+H) + .

[0766] Step 4:

[0767] NCS (17 mg, 0.13 mmol) was added to a solution of 2-(6-{4-fluoro-2-[1-(propyl-2-yl)-1H-pyrazol-5-yl]phenoxy}-1,2,4-triazin-5-yl)-2,7-diazaspiro[3.5]nonane-7-carboxylic acid tert-butyl ester (60 mg, 0.11 mmol) in DMF (2.0 mL) at 0 °C, and the resulting mixture was stirred at the same temperature for 3 hours. The reaction mixture was quenched with H2O (5 mL), extracted with EtOAc (10 mL x 3), and the combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by silica gel column chromatography (EtOAc in PE = 0–80%) to give the desired 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-7-carboxylic acid tert-butyl ester (40 mg, yield: 62.1%), as a pale yellow solid. LC / MS (ESI) m / z: 558 (M+H) + .

[0768] Step 5:

[0769] At room temperature, TFA (1.0 mL) was added to a solution of 2-(6-{2-[4-chloro-1-(propyl-2-yl)-1H-pyrazol-5-yl]-4-fluorophenoxy}-1,2,4-triazin-5-yl)-2,7-diazaspiro[3.5]nonane-7-carboxylic acid tert-butyl ester (40 mg, 0.07 mmol) in DCM (3.0 mL), and the resulting mixture was stirred for 1 hour. The reaction mixture was concentrated to give crude product 2-(6-(2-(4-chloro-1-isopropyl-1H-pyrazol-5-yl)-4-fluorophenoxy)-1,2,4-triazin-5-yl)-2,7-diazaspiro[3.5]nonane (30 mg, yield: 91.4%) as a yellow oil, which was used in the next step without further purification. LC / MS (ESI) m / z: 458 (M+H) + .

[0770] Preparation of intermediate 37, trans-1-(tert-butoxycarbonyl)-3-ethylpyrrolidine-2-carboxylic acid

[0771]

[0772] Step 1:

[0773] TEA (4.3 mL, 31 mmol) and NCS (2.30 g, 17.0 mmol) were added in small batches to a mixture of (2S)-pyrrolidine-2-carboxylate (2.01 g, 15.5 mmol) in DCM (30 mL) at 0 °C. The resulting mixture was stirred at room temperature for 3 hours, followed by the slow addition of pyridine (4.53 g, 35.6 mmol) over 1 hour. The reaction mixture was cooled to -20 °C, and then Cb2Cl (5.81 g, 34.1 mmol) was added. The mixture was gradually warmed to room temperature and stirred for 12 hours. The reaction mixture was diluted with 50 mL of H₂O and extracted with DCM (50 mL x 3). The combined organic layers were washed with water and brine, dried over anhydrous Na₂SO₄, filtered, and concentrated. The residue was purified by silica gel column chromatography (EtOAc = 0–30% in PE) to give the desired product, 2-methyl 4,5-dihydro-1H-pyrrole-1,2-dicarboxylic acid 1-benzyl ester (503 mg, yield: 11.7%), as a yellow oil. LC / MS (ESI) m / z: 262 (M+H) + .

[0774] Step 2:

[0775] Vinyl magnesium bromide (2.8 mL, 1.0 M, in THF) was added dropwise to a solution of Me2S.CuBr (79 mg, 0.38 mmol) in THF (5.0 mL) at -40 °C under N2. The resulting mixture was stirred for 1 hour, and a solution of 2-methyl 1-benzyl 4,5-dihydro-1H-pyrrole-1,2-dicarboxylic acid (500 mg, 1.91 mmol) in THF (5.0 mL) was added dropwise. The reaction mixture was stirred at this temperature for 4 hours. The mixture was quenched with saturated NH4Cl / NH3·H2O (8:1), extracted with EtOAc (20 mL x 3), and the combined organic layers were washed with saturated NH4Cl solution, dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by silica gel column chromatography (EtOAc in PE = 0–30%) to give the desired product, trans-3-vinylpyrrolidine-1,2-dicarboxylic acid 1-benzyl ester 2-methyl ester (505 mg, yield: 85.2%), as an oil. LC / MS (ESI) m / z: 292 (M+H) + .

[0776] Step 3:

[0777] Pd / C (10%, 50 mg) was added to a solution of trans-3-vinylpyrrolidine-1,2-dicarboxylic acid 1-benzyl ester 2-methyl ester (500 mg, 1.72 mmol) and (Boc)₂O (378 mg, 1.75 mmol) in MeOH (7.0 mL) at room temperature. The resulting suspension was evacuated and refilled with hydrogen gas, and stirred under an H₂ balloon for 3 hours. The reaction mixture was filtered through a celite pad, the filtrate was concentrated, and the residue was purified by silica gel column chromatography (EtOAc = 0–30% in PE) to give the desired product, trans-3-ethylpyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester (400 mg, yield: 86.1%), as a pale yellow oil. LC / MS (ESI) m / z: 202 (M+H) + .

[0778] Step 4:

[0779] NaOH (186 mg, 4.66 mmol) was added to a solution of 1-tert-butyl 2-methyl trans-3-ethylpyrrolidine-1,2-dicarboxylic acid (400 mg, 1.55 mmol) in MeOH (6.0 mL) and H₂O (2.0 mL) at 0 °C. 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) and extracted with EtOAc (15 mL x 3). The combined organic phases were dried over anhydrous Na₂SO₄, filtered, and concentrated to give crude trans-1-[(tert-butoxy)carbonyl]-3-ethylpyrrolidine-2-carboxylic acid (350 mg, yield: 87.9%) as a white solid, which was used in the next step without further purification. LC / MS (ESI) m / z: 188 (M+H) + .

[0780] Preparation of intermediate 38, (2S,3R,4R)-1-(tert-butoxycarbonyl)-4-fluoro-3-methylpyrrolidine-2-carboxylic acid

[0781]

[0782] Step 1:

[0783] To a solution of (2S,4S)-4-hydroxypyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester (4.98 g, 20.4 mmol) in DCM (50 mL), imidazole (1.80 g, 26.5 mmol) and TBDPSCl (7.91 g, 30.6 mmol) were added. The resulting mixture was stirred at room temperature for 1 hour. The reaction mixture was quenched with saturated NH4Cl solution (50 mL), extracted with DCM (100 mL x 3), and the combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by silica gel column chromatography (EtOAc = 0–50% in PE) to give the desired product (2S,4S)-4-[(tert-butyldiphenylsilyl)oxy]pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester (8.98 g, yield: 86.7%) as a colorless oil. LC / MS (ESI) m / z: 484 (M+H) + .

[0784] Step 2:

[0785] At room temperature, HCl (100 mL, 4.0 M) in dioxane was slowly added to a solution of (2S,4S)-4-[(tert-butyldiphenylsilyl)oxy]pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl 2-methyl ester (15.0 g, 31.0 mmol) in DCM (100 mL) for 2 hours. The resulting mixture was concentrated to give crude product (2S,4S)-4-[(tert-butyldiphenylsilyl)oxy]pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl 2-methyl ester (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) + .

[0786] Step 3:

[0787] TEA (3.3 mL, 23 mmol) and NCS (1.91 g, 14.3 mmol) were added in small batches to a solution of (2S,4S)-4-[(tert-butyldiphenylsilyl)oxy]pyrrolidine-2-carboxylate (5.00 g, 13.0 mmol) in DCM (50 mL). The resulting mixture was stirred at room temperature for 3 hours, followed by the slow addition of 2,6-rutidine (3 mL, 26.07 mmol) over 1 hour. The reaction mixture was cooled to -20 °C and Cb2Cl (4.70 g, 27.4 mmol) was added. The mixture was then slowly warmed to room temperature and stirred overnight. The reaction mixture was quenched with H₂O (50 mL), extracted with EtOAc (50 mL x 3), and the combined organic layers were washed with water and brine, dried over anhydrous Na₂SO₄, filtered, and concentrated. The residue was purified by silica gel column chromatography (EtOAc in PE = 0–30%) to give the desired product (4S)-4-[(tert-butyldiphenylsilyl)oxy]-4,5-dihydro-1H-pyrrole-1,2-dicarboxylic acid 1-benzyl ester 2-methyl ester (1.01 g, yield: 14.2%) as an oil. LC / MS (ESI) m / z: 516 (M+H) + .

[0788] Step 4:

[0789] MeMgBr (2.9 mL, 1.0 M, in THF) was added dropwise to a solution of CuBr·Me2S (480 mg, 2.33 mmol) in THF (5.0 mL) at -40 °C under N2. The mixture was stirred at -40 °C for 1 hour, followed by the addition of a solution of (4S)-4-[(tert-butyldiphenylsilyl)oxy]-4,5-dihydro-1H-pyrrole-1,2-dicarboxylic acid 1-benzyl ester 2-methyl ester (1 g, 1.94 mmol) in THF (10 mL). The resulting mixture was stirred at -40 °C for 1 hour. The reaction mixture was quenched with saturated NH4Cl solution, extracted with EtOAc (20 mL x 3), and the combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by silica gel column chromatography (EtOAc in PE = 0–30%) to give the desired product (2S,3R,4S)-4-[(tert-butyldiphenylsilyl)oxy]-3-methylpyrrolidine-1,2-dicarboxylic acid 1-benzyl ester 2-methyl ester (300 mg, yield: 27.6%), as a yellow oil. LC / MS (ESI) m / z: 532 (M+H) + .

[0790] Step 5:

[0791] Add TBAF (0.85 mL, 1.0 M, in THF) to a solution of (2S,3R,4S)-4-[(tert-butyldiphenylsilyl)oxy]-3-methylpyrrolidine-1,2-dicarboxylic acid 1-benzyl ester 2-methyl ester (300 mg, 0.56 mmol) in THF (5.0 mL). Stir the resulting mixture at room temperature for 1 hour. The reaction mixture was diluted with saturated NH4Cl solution (5 mL), extracted with EtOAc (10 mL x 3), and the combined organic layers were washed with water and brine, dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by silica gel column chromatography (EtOAc in PE = 0–50%) to give the desired product (2S,3R,4S)-4-hydroxy-3-methylpyrrolidine-1,2-dicarboxylic acid 1-benzyl ester 2-methyl ester (100 mg, yield: 60.4%), as a pale yellow oil. LC / MS (ESI) m / z: 294 (M+H) + .

[0792] Step 6:

[0793] DAST (0.07 mL, 0.51 mmol) was added to a solution of (2S,3R,4S)-4-hydroxy-3-methylpyrrolidine-1,2-dicarboxylic acid 1-benzyl ester 2-methyl ester (100 mg, 0.34 mmol) in DCM (2.0 mL) at 0 °C under N2. The resulting mixture was stirred at room temperature for 16 hours. The reaction mixture was quenched with saturated NaHCO3, extracted with DCM (10 mL x 3), and the combined organic layers were washed with water and brine, dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by silica gel column chromatography (EtOAc = 0–40% in PE) to give the desired product (2S,3R,4R)-4-fluoro-3-methylpyrrolidine-1,2-dicarboxylic acid 1-benzyl ester 2-methyl ester (80 mg, yield: 75%), as a yellow oil; LCMS: ESI m / z 296 (M+H). + .

[0794] Step 7:

[0795] Pd / C (10%, 15 mg) was added to a solution of (2S,3R,4R)-4-fluoro-3-methylpyrrolidine-1,2-dicarboxylic acid 1-benzyl ester 2-methyl ester (80 mg, 0.27 mmol) and (Boc)₂O (0.07 mL, 0.36 mmol) in MeOH (7.0 mL) at room temperature. The resulting suspension was evacuated and refilled with hydrogen gas, and stirred at room temperature under H₂ balloon pressure for 3 hours. The reaction mixture was filtered through a celite pad, the filtrate was concentrated, and the residue was purified by silica gel column chromatography (EtOAc = 0–30% in PE) to obtain the desired product (2S,3R,4R)-4-fluoro-3-methylpyrrolidine-1,2-dicarboxylic acid 1-(tert-butyl) ester 2-methyl ester (60 mg, yield: 80%) as an oil. LC / MS (ESI) m / z: 206 (M+H) + .

[0796] Step 8:

[0797] To a solution of (2S,3R,4R)-4-fluoro-3-methylpyrrolidine-1,2-dicarboxylic acid 1-(tert-butyl) ester 2-methyl ester (60 mg, 0.23 mmol) in MeOH (3 mL) and H₂O (1 mL), NaOH (28 mg, 0.69 mmol) was added at 0 °C. The resulting mixture was stirred at room temperature for 4 hours, concentrated, and the pH was adjusted to 4–5 with 1.0 N HCl solution. Extraction was performed with EtOAc (15 mL x 3). The combined organic layers were washed with water and brine, dried over anhydrous Na₂SO₄, filtered, and concentrated to give crude product (2S,3R,4R)-1-(tert-butoxycarbonyl)-4-fluoro-3-methylpyrrolidine-2-carboxylic acid (50 mg, yield: 83.5%) as a white solid, which could be used directly in the next step without further purification. LC / MS (ESI) m / z: 192 (M+1-56) + .

[0798] Preparation of intermediate 39, (2S,3R,4R)-1-[(tert-butoxy)carbonyl]-3-ethyl-4-fluoropyrrolidine-2-carboxylic acid

[0799]

[0800] Step 1:

[0801] Imidazole (2.50 g, 37.2 mmol) and TBSCl (3.30 g, 22.3 mmol) were added to a solution of (2S,4S)-4-hydroxypyrrolidine-2-carboxylate (2.71 g, 18.6 mmol) in DCM (40 mL). The resulting mixture was stirred at room temperature for 16 hours. The reaction mixture was washed with 10% Na2CO3 aqueous solution (50 mL), the aqueous layer was extracted with DCM (50 mL x 2), and the combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated to give crude product (2S,4S)-4-[(tert-butyldimethylsilyl)oxy]pyrrolidine-2-carboxylate (4.50 g, yield: 88.6%) as a pale yellow oil, which was used in the next step without further purification. LC / MS (ESI) m / z: 260 (M+H)+.

[0802] Step 2:

[0803] H₂O (20 mL) and sodium dichloroisocyanurate (3.60 g, 13.9 mmol) were added to a solution of (2S,4S)-4-[(tert-butyldimethylsilyl)oxy]pyrrolidine-2-carboxylate (4.50 g, 17.3 mmol) in toluene (60 mL) at 0 °C. The resulting mixture was stirred at 0 °C for 16 hours. The reaction mixture was filtered and concentrated to give crude product (2S,4S)-4-[(tert-butyldimethylsilyl)oxy]-1-chloropyrrolidine-2-carboxylate (4.48 g, yield: 83.8%) as an oil, which was used in the next step without further purification. LC / MS (ESI) m / z: 294 (M+H) + .

[0804] Step 3:

[0805] TEA (6.4 mL, 46 mmol) was added to a solution of (2S,4S)-4-[(tert-butyldimethylsilyl)oxy]-1-chloropyrrolidine-2-carboxylate (4.48 g, 15.3 mmol) in toluene (60 mL) at -10 °C, and the resulting mixture was stirred overnight at room temperature. The reaction mixture was washed with water and brine, dried over anhydrous Na2SO4, filtered, and concentrated to give crude intermediate (3S)-3-[(tert-butyldimethylsilyl)oxy]-3,4-dihydro-2H-pyrrole-5-carboxylate (3.5 g) as a clear oil. The crude intermediate was dissolved in DCM (40 mL) and cooled to -10 °C. 2,6-Lutidine (3.2 mL, 27 mmol) and Cb2Cl (2.80 g, 16.3 mmol) were added to the solution in small amounts several times, and the mixture was stirred at room temperature for 24 hours. Then, ethylenediamine (0.25 mL, 3.7 mmol) was added to the mixture and stirred for 15 minutes. The mixture was washed successively with citric acid solution (1.0 N, 30 mL) and HCl aqueous solution (1.0 N, 25 mL). The organic phase was washed with water, NaHCO3 solution (1.5 N), and brine. After drying with anhydrous Na2SO4, the mixture was filtered and concentrated. The residue was purified by silica gel column chromatography (EtOAc = 0–30% in PE) to give the desired product (4S)-4-[(tert-butyldimethylsilyl)oxy]-4,5-dihydro-1H-pyrrole-1,2-dicarboxylic acid 1-benzyl ester 2-methyl ester (1.51 g, yield: 26.7%), as a pale yellow oil. LC / MS (ESI) m / z: 392 (M+H) + .

[0806] Step 4:

[0807] EtMgBr (1.3 mL, 3.0 M, in THF) was added dropwise to a solution of CuBr·Me₂S (630 mg, 3.07 mmol) in THF (5.0 mL) at -40 °C under N₂. The mixture was stirred at -40 °C for 1 hour, followed by the addition of a solution of (4S)-4-[(tert-butyldimethylsilyl)oxy]-4,5-dihydro-1H-pyrrole-1,2-dicarboxylic acid 1-benzyl ester 2-methyl ester (1.00 g, 2.56 mmol) in THF (10 mL). The resulting mixture was stirred at -40 °C for 1 hour. The reaction mixture was quenched with saturated NH4Cl solution, extracted with EtOAc (20 mL x 3), and the combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by silica gel column chromatography (EtOAc in PE = 0–30%) to give the desired product (2S,3R,4S)-4-[(tert-butyldimethylsilyl)oxy]-3-ethylpyrrolidine-1,2-dicarboxylic acid 1-benzyl ester 2-methyl ester (200 mg, yield: 17.6%), as a pale yellow oil. LC / MS (ESI) m / z: 422 (M+H) + .

[0808] Step 5:

[0809] Add TBAF (0.85 mL, 1.0 M, in THF) to a solution of (2S,3R,4S)-4-[(tert-butyldimethylsilyl)oxy]-3-ethylpyrrolidine-1,2-dicarboxylic acid 1-benzyl ester 2-methyl ester (200 mg, 0.48 mmol) in THF (3.0 mL). Stir the resulting mixture at room temperature for 1 hour. The reaction mixture was diluted with saturated NH4Cl solution (5 mL), extracted with EtOAc (10 mL x 3), and the combined organic layers were washed with water and brine, dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by silica gel column chromatography (EtOAc in PE = 0–50%) to give the desired product (2S,3R,4S)-3-ethyl-4-hydroxypyrrolidine-1,2-dicarboxylic acid 1-benzyl ester 2-methyl ester (120 mg, yield: 78.2%), as a pale yellow oil. LC / MS (ESI) m / z: 308 (M+H) + .

[0810] Step 6:

[0811] DAST (0.07 mL, 0.51 mmol) was added to a solution of (2S,3R,4S)-3-ethyl-4-hydroxypyrrolidine-1,2-dicarboxylic acid 1-benzyl ester 2-methyl ester (120 mg, 0.39 mmol) in DCM (3.0 mL) at 0 °C under N2. The resulting mixture was stirred at room temperature for 16 hours. The reaction mixture was quenched with saturated NaHCO3, extracted with DCM (10 mL x 3), and the combined organic layers were washed with water and brine, dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by silica gel column chromatography (EtOAc = 0–40% in PE) to give the desired product (2S,3R,4R)-3-ethyl-4-fluoropyrrolidine-1,2-dicarboxylic acid 1-benzyl ester 2-methyl ester (110 mg, yield: 86.6%), as a yellow oil; LCMS: ESI m / z 310 (M+H). + .

[0812] Step 7:

[0813] Pd / C (10%, 20 mg) was added to a solution of (2S,3R,4R)-3-ethyl-4-fluoropyrrolidine-1,2-dicarboxylic acid 1-benzyl ester 2-methyl ester (110 mg, 0.36 mmol) and (Boc)₂O (78 mg, 0.36 mmol) in MeOH (2.0 mL) at room temperature. The resulting suspension was evacuated and refilled with hydrogen. The mixture was stirred at room temperature under an H₂ balloon for 3 hours. The reaction mixture was filtered through a celite pad, the filtrate was concentrated, and the residue was purified by silica gel column chromatography (EtOAc = 0–30% in PE) to give the desired product (2S,3R,4R)-3-ethyl-4-fluoropyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester (90 mg, yield: 87%) as an oil. LC / MS (ESI) m / z: 276 (M+H) + .

[0814] Step 8:

[0815] NaOH (65 mg, 1.63 mmol) was added to a solution of (2S,3R,4R)-3-ethyl-4-fluoropyrrolidine-1,2-dicarboxylic acid 1-tert-butyl 2-methyl ester (90 mg, 0.38 mmol) in MeOH (3 mL) and H₂O (1 mL) at 0 °C. The resulting mixture was stirred at room temperature for 5 hours, concentrated, and the pH was adjusted to 4–5 with 1.0 N HCl solution. Extraction was performed with EtOAc (15 mL x 3). The combined organic layers were washed with water and brine, dried over anhydrous Na₂SO₄, filtered, and concentrated to give crude product (2S,3R,4R)-1-[(tert-butoxy)carbonyl]-3-ethyl-4-fluoropyrrolidine-2-carboxylic acid (70 mg, 78% yield) as a white solid, which was used in the next step without further purification. LC / MS(ESI) m / z: 206 (M+1-56) + .

[0816] Preparation of intermediate 40, (1-isopropyl-1H-pyrazol-5-yl)boronic acid

[0817]

[0818] n-BuLi (11.0 mL, 27.5 mmol) was added to a solution of 1-(propyl-2-yl)-1H-pyrazole (2.01 g, 18.2 mmol) in THF (40 mL) at -70 °C under N2. The mixture was stirred at -70 °C for 1 hour, followed by the addition of triisopropyl borate (12.5 mL, 54.46 mmol). The resulting mixture was stirred at room temperature for 16 hours. The reaction mixture was quenched at 0 °C with saturated NH4Cl solution, and the pH was adjusted to 6 with 1.0 N HCl. The mixture was extracted with EtOAc (50 mL x 3), and the combined organic phases were washed with water and brine, dried over anhydrous Na2SO4, filtered, and concentrated to give crude product [1-(propyl-2-yl)-1H-pyrazole-5-yl]boronic acid (2 g, yield: 71%) as a white solid, which was used in the next step without further purification. LC / MS (ESI) m / z: 523 (M+H) + .

[0819] Preparation of intermediate 41, 5-fluoro-2-methoxybenzo-3,4-d2 acid

[0820]

[0821] Step 1:

[0822] NBS (464 mg, 2.6 mmol) was added to a solution of methyl 4-bromo-5-fluoro-2-hydroxybenzoate (500 mg, 2 mmol) in DMF (3 mL) at room temperature. The resulting mixture was heated to 700°C for 4 hours. After cooling to room temperature, water (5 mL) was added, and the mixture was extracted with EtOAc (10 mL x 3). The combined organic layers were washed with water and brine, dried over anhydrous Na2SO4, filtered, and concentrated to obtain a crude product. This crude product was purified by silica gel column chromatography (EtOAc in PE = 0–10%) to obtain 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).

[0823] Step 2:

[0824] MeI (0.2 mL, 3.6 mmol) and K₂CO₃ (843 mg, 6.1 mmol) were added to a solution of methyl 3,4-dibromo-5-fluoro-2-hydroxybenzoate (400 mg, 1.2 mmol) in DMF (5 mL). 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 x 3). The combined organic layers were washed with water and brine, dried over Na₂SO₄, filtered, and concentrated to obtain a crude product. This crude product was purified by silica gel column chromatography (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) + .

[0825] Step 3:

[0826] Pd / C (25 mg) was added to a solution of methyl 3,4-dibromo-5-fluoro-2-methoxybenzoate (340 mg, 0.99 mmol) in MeOD (5 mL), and the resulting mixture was stirred at 600°C for 10 hours under a D2 atmosphere. The mixture was filtered and concentrated to give crude methyl 5-fluoro-2-methoxybenzoate-3,4-d2 (85 mg, yield: 45.9%) as a colorless oil, which could be used directly in the next step without further purification. LC / MS (ESI) m / z: 186 (M+H) + .

[0827] Step 4:

[0828] LiOH·H2O (72 mg, 1.72 mmol) was added to a solution of methyl 5-fluoro-2-methoxybenzoate-3,4-d2 (80 mg, 0.43 mmol) in MeOH / H2O (4 mL / 2 mL). The resulting mixture was stirred at room temperature under a N2 atmosphere for 2 hours. The reaction mixture was then diluted with H2O (50 mL), and the pH was adjusted to 3–4. Extraction was performed with EtOAc (20 mL x 3). The combined organic phases were washed with water and brine, dried over anhydrous Na2SO4, filtered, and concentrated under vacuum to give crude 5-fluoro-2-methoxybenzoate-3,4-d2 acid (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) + .

[0829] Preparation of intermediate 42, 2-[(5-{2,7-diazaspiro[3.5]non-2-yl}-1,2,4-triazin-6-yl)oxy]-N-ethyl-5-fluoro-N-(prop-2-yl)benzamide

[0830]

[0831] Step 1:

[0832] Cyclopropylmagnesium bromide (9.43 mL, 9.43 mmol, 1.0 M) was added dropwise to a solution of 5-bromopyrimidine (1.01 g, 6.29 mmol) in THF (15 mL) at -20 °C under N2. The resulting mixture was stirred at room temperature for 2 hours. The reaction mixture was quenched with H2O (0.3 mL), followed by the addition of DDQ (1.60 g, 6.92 mmol), and the mixture was stirred at room temperature for 16 hours. The reaction mixture was diluted with H2O (50 mL), extracted with EtOAc (20 mL x 3), and the combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by silica gel column chromatography (EtOAc in PE = 0–10%) to give the desired product, 5-bromo-4-cyclopropylpyrimidine (1.10 g, yield: 83.5%), as a white solid. LC / MS(ESI) m / z: 199(M+H) + .

[0833] Step 2:

[0834] Pd(dppf)Cl2 (20 mg) and K2CO3 (347 mg, 2.51 mmol) were added 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). The resulting mixture was stirred at 100 °C under N2 for 12 hours. The reaction mixture was cooled to room temperature, diluted with H₂O (20 mL), and extracted with EtOAc (20 mL x 3). The combined organic layers were washed with water and brine, dried over anhydrous Na₂SO₄, filtered, and concentrated. The residue was purified by silica gel column chromatography (EtOAc in PE = 0–30%) to give the desired product, 2-(4-cyclopropylpyrimidin-5-yl)-4-fluorophenol (200 mg, yield: 82.1%), as a pale yellow solid. LC / MS (ESI) m / z: 231 (M+H) + .

[0835] Step 3:

[0836] DBU (1.04 g, 6.90 mmol) was added to a solution of 2-(4-cyclopropylpyrimidin-5-yl)-4-fluorophenol (800 mg, 3.48 mmol) and 2-(3,6-dichloro-1,2,4-triazin-5-yl)-2,7-diazaspiro[3.5]nonane-7-carboxylic acid tert-butyl ester (1.30 g, 3.48 mmol) in THF (20 mL) under stirring. The resulting mixture was stirred at room temperature for 10 hours. The reaction mixture was diluted with H2O (20 mL), extracted with EtOAc (30 mL x 3), and the combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by silica gel column chromatography (EtOAc in PE = 10–50%) to give the desired product 2-(3-chloro-6-(2-(4-cyclopropylpyrimidin-5-yl)-4-fluorophenoxy)-1,2,4-triazin-5-yl)-2,7-diazaspiro[3.5]nonane-7-carboxylic acid tert-butyl ester (849 mg, yield: 43.2%) as a yellow solid. LCMS: ESI m / z 568 (M+1) + .

[0837] Step 4:

[0838] At room temperature, 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) were added to TMEDA (220 mg, 0.53 mmol) and Pd(dppf)Cl2.CH2Cl2 (30 mg). The resulting mixture was stirred overnight at room temperature. The reaction mixture was diluted with H₂O (10 mL), extracted with EtOAc (20 mL x 3), and the combined organic layers were dried over anhydrous Na₂SO₄, filtered, and concentrated. The residue was purified by silica gel column chromatography (EtOAc in PE = 0–50%) to give the desired product 2-{6-[2-(4-cyclopropylpyrimidin-5-yl)-4-fluorophenoxy]-1,2,4-triazin-5-yl}-2,7-diazaspiro[3.5]nonane-7-carboxylic acid tert-butyl ester (250 mg, yield: 84.3%), as a pale yellow solid. LC / MS (ESI) m / z: 534 (M+H) + .

[0839] Step 5:

[0840] TFA (5 mL) was added to a solution of 2-(6-(2-(4-cyclopropylpyrimidin-5-yl)-4-fluorophenoxy)-1,2,4-triazin-5-yl)-2,7-diazaspiro[3.5]nonane-7-carboxylic acid tert-butyl ester (600 mg, 1.12 mmol) in DCM (10 mL) at 0 °C. The resulting mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated to give crude product 2-[(5-{2,7-diazaspiro[3.5]non-2-yl}-1,2,4-triazin-6-yl)oxy]-N-ethyl-5-fluoro-N-(prop-2-yl)benzamide (460 mg, yield: 90%) as a brown oil, which was used in the next step without further purification. LC / MS (ESI) m / z: 434 (M+H) + .

[0841] The following intermediates were prepared from the corresponding chemicals according to the experimental procedure for intermediate 42:

[0842]

[0843] Intermediate 44:

[0844] Preparation of 2-(5-(4-fluoro-2-(1-isopropyl-1H-1,2,4-triazol-5-yl)phenoxy)pyrimidin-4-yl)-2,7-diazaspiro[3.5]nonane

[0845]

[0846] Step 1:

[0847] To a solution of 5-fluoro-2-methoxybenzoic acid (4.01 g, 23.51 mmol) and DIEPA (5.8 mL, 35.33 mmol) in DCM (40 mL), HATU (13.4 g, 35.31 mmol) and NH4Cl (1.72 g, 31.82 mmol) were added. The resulting mixture was stirred at room temperature for 3 hours. The reaction mixture was quenched with saturated NH4Cl solution, extracted with DCM (20 mL x 3), and the combined organic phases were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated to obtain a crude product. This crude product was purified by silica gel column chromatography (EtOAc = 10–30% in PE) to give the desired product, 5-fluoro-2-methoxybenzamide (3.81 g, yield: 95.6%), as a white solid. LC / MS (ESI) m / z: 170 (M+H) + .

[0848] Step 2:

[0849] A solution of 5-fluoro-2-methoxybenzamide (3.81 g, 22.52 mmol) in DMF-DMA (30.1 mL, 224.61 mmol) was heated to 100 °C overnight. The reaction mixture was concentrated under reduced pressure to give crude product N-[(1E)-(dimethylamino)methylene]-5-fluoro-2-methoxybenzamide (4.78 g, yield: 95.2%), a colorless oil that could be used directly in the next step without further purification. LC / MS (ESI) m / z 225 (M+H) + .

[0850] Step 3:

[0851] (Propyl-2-yl)hydrazine (1.61 g, 22.0 mmol) was added to a solution of N-[(1E)-(dimethylamino)methylene]-5-fluoro-2-methoxybenzamide (4.78 g, 21.41 mmol) in AcOH (30 mL). The resulting mixture was stirred at 100 °C for 1 hour. The reaction mixture was concentrated under reduced pressure, and a saturated NaHCO3 solution (30 mL) was added to the residue. The mixture was then extracted with DCM (20 mL x 3), the combined organic phases were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under vacuum to obtain a crude product. This crude product was purified by silica gel column chromatography (EtOAc = 0–40% in PE) to obtain the desired product 5-(5-fluoro-2-methoxyphenyl)-1-(propyl-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) + .

[0852] Step 4:

[0853] BBr3 (10 mL, 1 mol / L, in DCM) was added dropwise to a solution of 5-(5-fluoro-2-methoxyphenyl)-1-(propyl-2-yl)-1H-1,2,4-triazole (1 g, 4.25 mmol) in DCM (10 mL) at -60 °C under a N2 atmosphere. The resulting mixture was stirred at this temperature for 2 hours. The reaction mixture was then quenched at 0 °C with cooled saturated NaHCO3. The mixture was extracted with DCM (30 mL x 3), and 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-(propyl-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) + .

[0854] Step 5:

[0855] 5-Bromopyrimidine (467 mg, 2.91 mmol) was added to a mixture of 4-fluoro-2-[1-(propyl-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). The reaction mixture was heated to 120 °C for 12 hours. After cooling to room temperature, the mixture was quenched with saturated NH4Cl solution (50 mL), extracted with EtOAc (20 mL x 3), and the combined organic layers were washed with water and brine, dried over anhydrous Na2SO4, filtered, and concentrated to obtain a crude product. This crude product was purified by silica gel column chromatography (MeOH = 0–4% in DCM) to give the desired product 5-{4-fluoro-2-[1-(propyl-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) + .

[0856] Step 6:

[0857] Urea hydrogen peroxide (226 mg, 2.42 mmol) and TFAA (0.6 mL, 4.2 mmol) were added to a solution of 5-{4-fluoro-2-[1-(propyl-2-yl)-1H-1,2,4-triazol-5-yl]phenoxy}pyrimidine (240 mg, 0.81 mmol) in THF (10 mL) at 0 °C. The resulting mixture was stirred at 20 °C under N2 for 1 hour. The reaction mixture was washed with saturated NaHCO3 aqueous solution (30 mL) and saturated Na2S2O3 aqueous solution (30 mL). The aqueous phase was extracted with DCM (15 mL x 3). 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-(propyl-2-yl)-1H-1,2,4-triazol-5-yl]phenoxy}pyrimidine-1-onthium-1-ol (160 mg, yield: 63.3%), a brown solid, which was used directly in the next step without further purification. LC / MS (ESI) m / z: 254 (M+H) + .

[0858] Step 7:

[0859] DIEPA (0.7 mL, 4.10 mmol) and POCl3 (0.15 mL, 1.52 mmol) were added to a solution of 5-{4-fluoro-2-[1-(propyl-2-yl)-1H-1,2,4-triazol-5-yl]phenoxy}pyrimidine-1-on-1-ol (160 mg, 0.52 mmol) in EtOAc (10 mL) at 0 °C. The reaction mixture was then stirred at room temperature for 12 hours. The reaction mixture was quenched with saturated NaHCO3, extracted with DCM (15 mL x 3), and the combined organic layers were washed with water and brine, dried over anhydrous Na2SO4, filtered, and concentrated under vacuum to give the crude product 4-chloro-5-{4-fluoro-2-[1-(propyl-2-yl)-1H-1,2,4-triazol-5-yl]phenoxy}pyrimidine (80 mg, yield: 47.2%), a brown oily substance that could be used directly in the next step without further purification. LC / MS (ESI) m / z: 334 (M+H) + .

[0860] Step 8:

[0861] To a solution of 4-chloro-5-{4-fluoro-2-[1-(propyl-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), tert-butyl 2,7-diazaspiro[3.5]nonane-7-carboxylate (59.7 mg, 0.31 mmol) was added. The resulting mixture was heated to 80 °C for 5 hours. After cooling to room temperature, the reaction mixture was quenched with saturated NH4Cl solution (10 mL), extracted with EtOAc (15 mL x 3), and the combined organic layers were washed with water and brine, dried over anhydrous Na2SO4, filtered, and concentrated to obtain a crude product. This crude product was purified by silica gel column chromatography (EtOAc in PE = 0–40%) to obtain the desired product 2-(5-{4-fluoro-2-[1-(propyl-2-yl)-1H-1,2,4-triazol-5-yl]phenoxy}pyrimidin-4-yl)-2,7-diazaspiro[3.5]nonane-7-carboxylic acid tert-butyl ester (30 mg, yield: 23.9%), a white solid. LC / MS (ESI) m / z: 524 (M+H + ).

[0862] Step 9:

[0863] TFA (2 mL) was added dropwise to a solution of 2-(5-{4-fluoro-2-[1-(propyl-2-yl)-1H-1,2,4-triazol-5-yl]phenoxy}pyrimidin-4-yl)-2,7-diazaspiro[3.5]nonane-7-carboxylic acid tert-butyl ester (30 mg, 0.06 mmol) in DCM (5 mL) at room temperature, and the resulting mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated to give crude product 2-(5-{4-fluoro-2-[1-(propyl-2-yl)-1H-1,2,4-triazol-5-yl]phenoxy}pyrimidin-4-yl)-2,7-diazaspiro[3.5]nonane (15 mg, yield: 61.8%), as a pale yellow solid, which could be used directly in the next step without further purification. LC / MS(ESI)m / z:213(1 / 2M+H + ).

[0864] 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

[0865]

[0866] Step 1:

[0867] At room temperature, K2CO3 (1.2 g, 8.9 mmol) and Pd(dppf)Cl2 (217 mg, 0.29 mmol) were added to a solution of [1-(propyl-2-yl)-1H-pyrazol-5-yl]boronic acid (686 mg, 4.46 mmol) and 5-(2-bromo-4-fluorophenoxy)pyrimidine (800 mg, 2.97 mmol) in dioxane (20 mL) and H2O (2.0 mL). The resulting mixture was stirred at 100 °C under N2 for 2 hours. The reaction mixture was cooled to room temperature, quenched with H2O (5 mL), and extracted with EtOAc (30 mL x 3). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated to obtain a crude product. This crude product was purified by silica gel column chromatography (EtOAc in PE = 0–50%) to obtain the desired product 5-{4-fluoro-2-[1-(propyl-2-yl)-1H-pyrazol-5-yl]phenoxy}pyrimidine (602 mg, yield: 68%) as a yellow solid. 1H NMR (400MHz, DMSO) δ8.91 (s, 1H), 8.47 (s, 2H), 7.46 (s, 1H), 7.44-7.40 (m, 1H), 7.39 -7.34 (m, 2H), 6.25 (d, J = 1.2Hz, 1H), 4.39 -4.31(m,1H),1.29(d,J=6.4Hz,6H), LC / MS(ESI)m / z:299(M+H) + .

[0868] Step 2:

[0869] NCS (268 mg, 2.01 mmol) was added dropwise to a solution of 5-{4-fluoro-2-[1-(propyl-2-yl)-1H-pyrazol-5-yl]phenoxy}pyrimidine (600 mg, 2.01 mmol) in DMF (10 mL) at room temperature, and the resulting mixture was stirred for 3 hours. The reaction mixture was quenched with H2O (10 mL), extracted with EtOAc (20 mL x 3), and the combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by silica gel column chromatography (EtOAc in PE = 0–80%) to give the desired product 5-{2-[4-chloro-1-(propyl-2-yl)-1H-pyrazol-5-yl]-4-fluorophenoxy}pyrimidine (401 mg, yield: 65.7%) as a pale yellow solid. 1 H NMR (400MHz, DMSO) δ8.93 (s, 1H), 8.48 (s, 2H), 7.63 (s, 1H), 7.55–7.40 (m, 3H), 4.34–4.25 (m, 1H), 1.28 (dd, J = 11.7, 6.5Hz, 6H). LC / MS(ESI)m / z:333(M+H) + .

[0870] Step 3:

[0871] Urea·H₂O₂ (127 mg, 1.35 mmol) and TFAA (568 mg, 2.71 mmol) were added in portions to a solution of 5-{2-[4-chloro-1-(propyl-2-yl)-1H-pyrazol-5-yl]-4-fluorophenoxy}pyrimidine (150 mg, 0.45 mmol) in THF (5 mL). The resulting mixture was then cooled to room temperature and stirred for 3 hours. The reaction mixture was quenched with saturated NaHCO3, extracted with EtOAc (50 mL x 3), and 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-(propyl-2-yl)-1H-pyrazol-5-yl]-4-fluorophenoxy}pyrimidine-1-onthium-1-ol (120 mg, yield: 76.3%), a brown solid, which was used in the next step without further purification. LC / MS (ESI) m / z: 349 (M+H) + .

[0872] Step 4:

[0873] POCl3 (0.10 mL, 1.0 mmol) and DIPEA (0.23 mL, 1.4 mmol) were added dropwise to a solution of 5-{2-[4-chloro-1-(prop-2-yl)-1H-pyrazol-5-yl]-4-fluorophenoxy}pyrimidine-1-on-1-ol (120 mg, 0.34 mmol) in EtOAc (3 mL) at 0 °C. The resulting mixture was cooled to room temperature and stirred overnight. The reaction mixture was quenched with saturated NaHCO3, extracted with DCM (10 mL x 3), and the combined organic layers were washed with water and brine, dried over anhydrous Na2SO4, filtered, and concentrated to give crude product 4-chloro-5-{2-[4-chloro-1-(propyl-2-yl)-1H-pyrazol-5-yl]-4-fluorophenoxy}pyrimidine (110 mg, yield: 87.1%), a brown oil, which was used in the next step without further purification. LC / MS (ESI) m / z: 367 (M+H) + .

[0874] Step 5:

[0875] To a solution of 4-chloro-5-{2-[4-chloro-1-(propyl-2-yl)-1H-pyrazol-5-yl]-4-fluorophenoxy}pyrimidine (110 mg, 0.30 mmol) in DMF (5 mL), tert-butyl 2,7-diazaspiro[3.5]nonane-7-carboxylate (67 mg, 0.30 mmol) and K₂CO₃ (124 mg, 0.89 mmol) were added. The resulting solution was stirred overnight at room temperature. The reaction mixture was quenched with H₂O (5 mL), extracted with EtOAc (10 mL x 3), and the combined organic layers were washed with water and brine, dried over anhydrous Na₂SO₄, filtered, and concentrated. The residue was purified by silica gel column chromatography (EtOAc in PE = 0–50%) to give the desired 2-(5-{2-[4-chloro-1-(propyl-2-yl)-1H-pyrazol-5-yl]-4-fluorophenoxy}pyrimidin-4-yl)-2,7-diazaspiro[3.5]nonane-7-carboxylic acid tert-butyl ester (100 mg, yield: 59.9%) as a white solid. LC / MS (ESI) m / z: 557 (M+H) + .

[0876] Step 6:

[0877] TFA (1.0 mL) was added dropwise to a solution of 2-(5-(2-(4-chloro-1-isopropyl-1H-pyrazol-5-yl)-4-fluorophenoxy)pyrimidin-4-yl)-2,7-diazaspiro[3.5]nonane-7-carboxylic acid tert-butyl ester (100 mg, 0.18 mmol) in DCM (3.0 mL), and the resulting mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated to give crude product 2-(5-{2-[4-chloro-1-(propyl-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 slurry, which could be used directly in the next step without further purification. LC / MS (ESI) m / z: 457 (M+H) + .

[0878] Preparation of intermediate 46, trans-1-(tert-butoxycarbonyl)-3-(fluoromethyl)pyrrolidine-2-carboxylic acid

[0879]

[0880] Step 1: 2-methyl trans-3-vinylpyrrolidine-1,2-dicarboxylic acid 1-benzyl ester (1.30 g, 4.49 mmol, see Intermediate 37 Synthesis), NaIO4 (3.00 g, 13.48 mmol), and potassium osmium tetroxide dihydrate (0.17 g, 0.45 mmol) were added to a solution of MeOH (30 mL) and H2O (50 mL). The resulting mixture was stirred at room temperature for 4 hours. The reaction mixture was then diluted with H2O (20 mL) and extracted with DCM (50 mL x 3). The combined organic phases were washed with water and brine, dried over anhydrous Na₂SO₄, filtered, and concentrated to obtain a crude product. This crude product was purified by silica gel column chromatography (EtOAc = 0–50% in PE) to obtain the desired product, trans-3-formylpyrrolidine-1,2-dicarboxylic acid 1-benzyl ester 2-methyl ester (700 mg, 2.40 mmol, 53.48%), as a colorless oil. LC / MS (ESI) m / z: 292 (M+H) +

[0881] Step 2:

[0882] NaBH4 (5 mg, 0.14 mmol) was slowly added to a solution of trans-3-formylpyrrolidine-1,2-dicarboxylic acid 1-benzyl ester 2-methyl ester (200 mg, 0.69 mmol) in MeOH (5 mL) at 0 °C. The resulting mixture was stirred at room temperature for 2 hours. The reaction mixture was then quenched with saturated NH4Cl solution (5 mL), extracted with EtOAc (10 mL x 3), and the combined organic phases were washed with water and brine, dried over anhydrous Na2SO4, filtered, and concentrated to give crude product trans-3-(hydroxymethyl)pyrrolidine-1,2-dicarboxylic acid 1-benzyl ester 2-methyl ester (160 mg, 79.4%) as a pale yellow oil. LC / MS (ESI) m / z: 294 (M+H) + .

[0883] Step 3:

[0884] DAST (132 mg, 0.82 mmol) was added to a solution of trans-3-(hydroxymethyl)pyrrolidine-1,2-dicarboxylic acid 1-benzyl ester 2-methyl ester (160 mg, 0.55 mmol) in DCM (5 mL). The resulting mixture was stirred for 16 hours. The reaction mixture was quenched with saturated NaHCO3, extracted with DCM (10 mL x 3), and the combined organic layers were washed with water and brine, dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by silica gel column chromatography (EtOAc = 0–20% in PE) to give the desired product, trans-3-(fluoromethyl)pyrrolidine-1,2-dicarboxylic acid 1-benzyl ester 2-methyl ester (80 mg, 0.27 mmol, 49.6%), as a brown oil; LCMS: ESI m / z 296 (M+H). + .

[0885] Step 4:

[0886] Pd / C (10%, 20 mg) was added to a solution of trans-3-(fluoromethyl)pyrrolidine-1,2-dicarboxylic acid 1-benzyl ester 2-methyl ester (80 mg, 0.27 mmol) and (Boc)₂O (77 mg, 0.35 mmol) in MeOH (5 mL) at room temperature. The resulting suspension was evacuated and refilled with hydrogen. The mixture was stirred at room temperature under an H₂ balloon for 3 hours. The reaction mixture was filtered through a celite pad, the filtrate was concentrated, and the residue was purified by silica gel column chromatography (EtOAc = 0–30% in PE) to obtain the desired product, trans-3-(fluoromethyl)pyrrolidine-1,2-dicarboxylic acid 1-(tert-butyl) ester 2-methyl ester (50 mg, 70.6%), as an oil. LC / MS (ESI) m / z: 262 (M+H) + .

[0887] Step 5:

[0888] NaOH (20 mg, 0.50 mmol) was added to a solution of 2-methyl 1-(tert-butyl)-1,2-dicarboxylic acid (50 mg, 0.19 mmol) in MeOH (3 mL) and H₂O (1 mL) at 0 °C. The resulting mixture was stirred at room temperature for 5 hours, concentrated, and the pH was adjusted to 4–5 with 1.0 N HCl solution. Extraction was performed with EtOAc (15 mL x 3). The combined organic layers were washed with water and brine, dried over anhydrous Na₂SO₄, filtered, and concentrated to give crude trans-1-(tert-butoxycarbonyl)-3-(fluoromethyl)pyrrolidine-2-carboxylic acid (40 mg, 85.2% yield) as a brown solid, which was used in the next step without further purification. LC / MS (ESI) m / z: 248 (M+1–56) + .

[0889] Preparation of intermediate 47, 5-(2-((5-(2,7-diazaspiro[3.5]non-2-yl)-1,2,4-triazin-6-yl)oxy)-5-fluorophenyl)-6-cyclopropyl-2-cyanopyridine compound

[0890]

[0891] Step 1:

[0892] Pd(PPh3)4 (0.38 g, 0.33 mmol) was added to a solution of 6-bromo-2-chloropyridin-3-amine (2.30 g, 11.09 mmol) and Zn(CN)2 (0.98 g, 8.32 mmol) in DMF (25 mL) at room temperature. The resulting mixture was heated to 85 °C for 12 hours under a nitrogen atmosphere. The reaction mixture was quenched with saturated NH4Cl solution, extracted with EtOAc (20 mL x 3), and the combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated to obtain a crude product. This crude product was purified by silica gel column chromatography (EtOAc in PE = 0–30%) to give the desired product, 5-amino-6-chloropyridin-2-carboxynitrile (500 mg, yield: 29.4%), as a pale yellow solid. LC / MS (ESI) m / z: 154 (M+H). + .

[0893] Step 2:

[0894] Pd(AcO)₂ (40 mg, 0.18 mmol) and K₃PO₄ (14.9 g, 70.33 mmol) were added to a solution of 5-amino-6-chloropyridin-2-carboxynitrile (2.71 g, 17.58 mmol), cyclopropylboronic acid (1.96 g, 22.86 mmol), and tricyclohexylphosphine (1.97 g, 7.03 mmol) in toluene (80 mL) and H₂O (10 mL). The resulting mixture was stirred at 100 °C under a nitrogen atmosphere for 10 hours. The reaction mixture was diluted with saturated NH₄Cl solution and extracted with EtOAc (20 mL x 3). The combined organic phases were washed with brine, dried over Na₂SO₄, filtered, and concentrated to obtain a crude product. This crude product was purified by silica gel column chromatography (EtOAc = 5–30% in PE) to give the desired product, 5-amino-6-cyclopropylpyridine-2-carboxynitrile (1.12 g, yield: 40.1%), as a yellow solid. LC / MS (ESI) m / z: 160 (M+H) + .

[0895] Step 3:

[0896] A solution of 5-amino-6-cyclopropylpyridine-2-carboxylonitrile (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). The resulting mixture was stirred at the same temperature for 1 hour. The reaction mixture was quenched with saturated NH4Cl solution (30 mL), extracted with EtOAc (20 mL x 3), the combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by silica gel column chromatography (EtOAc = 0–10% in PE) to give the desired product, 5-bromo-6-cyclopropylpyridine-2-carboxylonitrile (1 g, yield: 63.7%), as a yellow solid. LC / MS(ESI) m / z: 223(M+H) + .

[0897] Step 4:

[0898] Pd(dppf)Cl2 (50 mg) and Cs2CO3 (4.38 g, 13.45 mmol) were added to a solution of 5-bromo-6-cyclopropylpyridine-2-carboxynitrile (1.00 g, 4.48 mmol) and (5-fluoro-2-hydroxyphenyl)boronic acid (1.05 g, 6.72 mmol) in dioxane (10 mL) and H2O (2 mL). The resulting mixture was stirred at 100 °C under N2 for 2 hours. The reaction mixture was cooled to room temperature, quenched with H2O (5 mL), extracted with EtOAc (30 mL x 3), and the combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by silica gel column chromatography (EtOAc = 5–30% in PE) to give the desired product, 6-cyclopropyl-5-(5-fluoro-2-hydroxyphenyl)pyridine-2-carboxynitrile (740 mg, yield: 64.9%), as a colorless oil. LC / MS (ESI) m / z: 255 (M+H) + .

[0899] Step 5:

[0900] DBU (0.65 mL, 4.37 mmol) was added to a stirred solution of 6-cyclopropyl-5-(5-fluoro-2-hydroxyphenyl)pyridine-2-carboxynitrile (740 mg, 2.91 mmol) and 2-(dichloro-1,2,4-triazin-5-yl)-2,7-diazaspiro[3.5]nonane-7-carboxylic acid tert-butyl ester (762 mg, 2.04 mmol, see intermediate 34 synthesis) in THF (15 mL). The resulting mixture was stirred at room temperature for 10 hours. The reaction mixture was diluted with H2O (20 mL), extracted with EtOAc (30 mL x 3), and the combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by silica gel column chromatography (EtOAc = 0–50% in PE) to give the desired product 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-carboxylic acid tert-butyl ester (440 mg, yield: 25.5%), as a white solid. LCMS: ESI m / z 592 (M+H) + .

[0901] Step 6:

[0902] To a solution of 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-carboxylic acid tert-butyl ester (600 mg, 1.01 mmol), [3-(dimethylamino)propyl]dimethylamine (263 mg, 2.03 mmol) in THF (15 mL), NaBH4 (63 mg, 1.86 mmol) and Pd(dppf)Cl2 (30 mg) were added. The reaction mixture was stirred at room temperature under N2 atmosphere for 12 hours, quenched with saturated NH4Cl solution (30 mL), and extracted with EtOAc (20 mL x 3). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated to obtain a crude product. This crude product was purified by silica gel column chromatography (EtOAc = 0–40% in PE) to yield the desired product, 2-{6-[2-(6-cyano-2-cyclopropylpyridin-3-yl)-4-fluorophenoxy]-1,2,4-triazin-5-yl}-2,7-diazaspiro[3.5]nonane-7-carboxylic acid tert-butyl ester (240 mg, yield: 42.5%), as a white solid. LCMS: ESI m / z 558 (M+H) + .

[0903] Step 7:

[0904] TFA (2.0 mL) was added dropwise to a solution of 2-{6-[2-(6-cyano-2-cyclopropylpyridin-3-yl)-4-fluorophenoxy]-1,2,4-triazin-5-yl}-2,7-diazaspiro[3.5]nonane-7-carboxylic acid tert-butyl ester (240 mg, 0.43 mmol) in DCM (5.0 mL) at room temperature, and the resulting mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated to give crude product 5-(2-((5-(2,7-diazaspiro[3.5]non-2-yl)-1,2,4-triazin-6-yl)oxy)-5-fluorophenyl)-6-cyclopropyl-2-cyanopyridine, as a TFA salt (200 mg, yield: 75.1%), which could be used directly in the next step without further purification. LC / MS (ESI) m / z: 458 (M+H) + .

[0905] Preparation of intermediate 48, 2-((3-chloro-5-(2,7-diazaspiro[3.5]non-2-yl)-1,2,4-triazin-6-yl)oxy)-N-ethyl-5-fluoro-N-isopropylbenzamide

[0906]

[0907] TFA (2.0 mL) was added dropwise to a solution of 2-(3-chloro-6-(2-(ethyl(isopropyl)carbamoyl)-4-fluorophenoxy)-1,2,4-triazin-5-yl)-2,7-diazaspiro[3.5]nonane-7-carboxylic acid tert-butyl ester (200 mg, 0.36 mmol, see Intermediate 34 for its synthesis) in DCM (5.0 mL) at room temperature, and the resulting mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated to give crude product 2-((3-chloro-5-(2,7-diazaspiro[3.5]non-2-yl)-1,2,4-triazin-6-yl)oxy)-N-ethyl-5-fluoro-N-isopropylbenzamide, as 2,2,2-trifluoroacetate (150 mg, yield: 74.4%), which could be used directly in the next step without further purification. LC / MS (ESI) m / z: 463 (M+H) + .

[0908] Preparation of intermediate 49, rel-(2R,3R,4S)-1-(tert-butoxycarbonyl)-3,4-dimethylpyrrolidine-2-carboxylic acid

[0909]

[0910] Step 1:

[0911] LiF (2.66 g, 102.31 mmol) was added to a stirred solution of benzyl(methoxymethyl)[(trimethylsilyl)methyl]amine (21.5 mL, 84.24 mmol) and (2Z)-but-2-enedioic acid 1,4-dimethyl ester (10.6 mL, 84.24 mmol) in MeCN (150 mL) at 25 °C, and the resulting mixture was stirred at 25 °C under a N2 atmosphere for 18 hours. The reaction mixture was then diluted with saturated NH4Cl solution (100 mL) and extracted with EtOAc (200 mL x 3). The combined organic phases were washed sequentially with water and brine, dried over anhydrous Na2SO4, filtered, and concentrated to obtain a crude product. This crude product was purified by silica gel column chromatography (EtOAc = 0–30% in PE) to obtain the desired product, cis-1-benzylpyrrolidine-3,4-dicarboxylic acid 3,4-dimethyl ester (22.1 g, yield: 94.2%), which was a pale yellow oil. 1 H NMR (400MHz, CDCl3) δ7.31–7.23(m,5H),3.66(s,8H),3.33–3.28(m,2H),3.17-3.12(m,2H),2.77–2.67(m,2H), LC / MS(ESI)m / z:278(M+H) + .

[0912] Step 2:

[0913] LAH (4.5 g, 118.58 mmol) was added in small, repeated additions to a stirred solution of cis-1-benzylpyrrolidine-3,4-dicarboxylate (10.0 g, 36.06 mmol) in THF (50 mL) at 0 °C. The resulting mixture was stirred at 60 °C under a nitrogen atmosphere for 18 hours, and 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 a celite filter, and the filtrate was extracted with EtOAc (100 mL x 3). The combined organic phases were washed with water and brine, dried over anhydrous Na₂SO₄, filtered, and concentrated to obtain a crude product. This crude product was purified by silica gel column chromatography (MeOH = 1–10% in DCM) to give the desired product, cis-[1-benzyl-4-(hydroxymethyl)pyrrolidine-3-yl]methanol (7.03 g, yield: 87.7%), as a colorless oil. LC / MS (ESI) m / z: 222 (M+H) + .

[0914] Step 3:

[0915] TEA (1.49 g, 14.85 mmol) and 10% Pd / C (500 mg) were slowly added to a stirred solution of cis-[1-benzyl-4-(hydroxymethyl)pyrrolidine-3-yl]methanol (4.00 g, 18.07 mmol) and Boc2O (4.95 g, 22.91 mmol) in MeOH (50 mL) at room temperature. The resulting mixture was stirred at room temperature under H2 atmosphere for 18 hours and then poured into water (200 mL). The mixture was extracted with EtOAc (200 mL x 3), and the combined organic phases were washed with water and brine, dried over anhydrous Na2SO4, filtered, and concentrated to obtain a crude product. This crude product was purified by silica gel column chromatography (EtOAc in PE = 0–20%) to obtain the desired product, cis-3,4-di(hydroxymethyl)pyrrolidine-1-carboxylic acid tert-butyl ester (3.50 g, yield: 83.7%), as a colorless oil. LC / MS (ESI) m / z: 176 (M+H-56) + .

[0916] Step 4:

[0917] MsCl (4.05 mL, 52.38 mmol) was added over 10 minutes to a solution of cis-3,4-di(hydroxymethyl)pyrrolidine-1-carboxylate (4.00 g, 17.29 mmol) and DIPEA (10.2 mL, 61.90 mmol) in a stirred solution of DCM (50 mL). The resulting mixture was stirred at 25 °C for 18 h under a N2 atmosphere, quenched with saturated NH4Cl solution (20 mL), and extracted with DCM (50 mL x 3). The combined organic phases were washed with water and brine, dried over anhydrous Na₂SO₄, filtered, and concentrated to obtain a crude product. This crude product was purified by silica gel column chromatography (EtOAc = 0–20% in PE) to give the desired product, cis-3,4-di(((methanesulfonyl)oxy)methyl)pyrrolidine-1-carboxylic acid tert-butyl ester (5.81 g, yield: 86.6%), as a pale yellow oil. LC / MS (ESI) m / z: 332 (M+H-56) + .

[0918] Step 5:

[0919] LiEt3BH (100 mL, 100 mmol) was added to a stirred solution of cis-3,4-di((((methanesulfonyl)oxy)methyl)pyrrolidine-1-carboxylate (5.81 g, 14.97 mmol) over 30 minutes at 0 °C. The resulting mixture was stirred at 25 °C under a N2 atmosphere for 12 hours, quenched with saturated NH4Cl solution (10 mL), and extracted with EtOAc (50 mL x 3). The combined organic phases were washed with water and brine, dried over anhydrous Na2SO4, filtered, and concentrated. The crude product was purified by silica gel column chromatography (EtOAc = 0–10% in PE) to give the desired product, cis-3,4-dimethylpyrrolidine-1-carboxylate (1.50 g, yield: 50.3%), as a pale yellow oil. 1 H NMR (400MHz, CDCl3) δ3.46-3.42(m,2H),3.04-3.00(m,2H),2.34–2.14(m,2H),1.46(s,9H),0.92(d,J=6.7Hz,6H).

[0920] Step 6:

[0921] s-BuLi (1.5 mL, 1.950 mmol) was added dropwise to a stirred solution of cis-3,4-dimethylpyrrolidine-1-carboxylic acid tert-butyl ester (300 mg, 1.51 mmol) in 3 mL of THF at -78 °C for 30 minutes. The resulting mixture was stirred at the same temperature for 3 hours, and then bubbled with CO2 for 1 hour (keeping the internal temperature below -70 °C). After cooling to room temperature, the mixture was quenched with 1 N HCl to pH 5 and extracted with EtOAc (30 mL x 3). The combined organic phases were washed with water and brine, dried over anhydrous Na2SO4, filtered, and concentrated to give crude product rel-(2S,3S,4R)-1-(tert-butoxycarbonyl)-3,4-dimethylpyrrolidine-2-carboxylic acid (120 mg, yield: 32.8%) as a yellow semi-solid, which could be used directly in the next step without further purification. LC / MS (ESI) m / z: 144 (M+H-100) + .

[0922] Preparation of intermediate 50

[0923] 2-[(tert-butoxy)carbonyl]-5,5-difluoro-octahydrocyclopentadien[c]pyrrole-1-carboxylic acid

[0924]

[0925] Step 1:

[0926] DAST (11.7 mL, 88.77 mmol) was slowly added to a solution of cis-5-oxo-octahydrocyclopentadieno[c]pyrrole-2-carboxylate (5.00 g, 22.19 mmol) in THF (30 mL) at 0 °C. The reaction mixture was stirred at 25 °C under a nitrogen atmosphere for 72 hours. The reaction mixture was quenched with saturated NH4Cl solution (10 mL), extracted with EtOAc (50 mL x 3), and the combined organic phases were washed with water and brine, dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by silica gel column chromatography (EtOAc = 0–40% in PE) to give the desired product, cis-5,5-difluoro-octahydrocyclopentadieno[c]pyrrole-2-carboxylate (4 g, yield: 72.8%), as a pale yellow oil. LC / MS (ESI) m / z: 248 (M+H) + .

[0927] Step 2:

[0928] s-BuLi (29.8 mL, 38.82 mmol) was added to a solution of cis-5,5-difluoro-octahydrocyclopentadieno[c]pyrrole-2-carboxylic acid tert-butyl ester (3.21 g, 12.94 mmol) in THF (20 mL) at -78 °C. The mixture was stirred at -78 °C under N2 atmosphere for 4 hours, and then stirred at -78 °C under CO2 atmosphere for 5 hours. The mixture was then gradually brought to room temperature and stirred at room temperature for another 12 hours. The mixture was quenched with 1N HCl solution, adjusted to pH 4–5, and extracted with EtOAc (30 mL x 3). The combined organic layers were washed with brine, dried over anhydrous Na₂SO₄, filtered, and concentrated to give crude product 2-[(tert-butoxy)carbonyl]-5,5-difluoro-octahydrocyclopentadieno[c]pyrrole-1-carboxylic acid (800 mg, yield: 21.2%), a brown oil, which was used in the next step without further purification. LC / MS (ESI) m / z: 292 (M+H) + .

[0929] Preparation of intermediate 51

[0930] trans-1-((benzyloxy)carbonyl)-3-(difluoromethyl)pyrrolidine-2-carboxylic acid

[0931]

[0932] Step 1:

[0933] 1-Benzyl ester 2-methyl trans-3-vinylpyrrolidine-1,2-dicarboxylic acid (1.30 g, 4.49 mmol, see Intermediate 37 for its synthesis), NaIO4 (2.88 g, 13.48 mmol), and potassium osmium tetroxide dihydrate (170 mg, 0.45 mmol) were added to a solution of MeOH (30 mL) and H2O (50 mL). The resulting mixture was stirred at room temperature for 4 hours. The reaction mixture was then diluted with H2O (20 mL) and extracted with DCM (20 mL x 3). The combined organic phases were washed with water and brine, dried over anhydrous Na₂SO₄, filtered, and concentrated to obtain a crude product. This crude product was purified by silica gel column chromatography (EtOAc = 0–50% in PE) to give the desired product, trans-3-formylpyrrolidine-1,2-dicarboxylic acid 1-benzyl ester 2-methyl ester (700 mg, yield: 53.5%), as a yellow solid. LC / MS (ESI) m / z: 292 (M+H) +

[0934] Step 2:

[0935] Solid (500 mg, 1.72 mmol) of (2S,3S)-3-formylpyrrolidine-1,2-dicarboxylic acid 1-benzyl ester 2-methyl ester was added to DAST (5 mL) at 0 °C, and the resulting mixture was stirred at 40 °C for 24 hours. The reaction mixture was diluted with DCM (50 mL) and washed with saturated NaHCO3. The organic phase was collected, and the aqueous layer was extracted with DCM (20 mL x 3). The combined organic layers were washed with water and brine, dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by silica gel column chromatography (EtOAc = 0–30% in PE) to give the desired product, trans-3-(fluoromethyl)pyrrolidine-1,2-dicarboxylic acid 1-benzyl ester 2-methyl ester (300 mg, yield: 55.7%), as a yellow oil; LCMS: ESI m / z 314 (M+H). + .

[0936] Step 3:

[0937] NaOH (115 mg, 2.88 mmol) was added to a solution of trans-3-(difluoromethyl)pyrrolidine-1,2-dicarboxylic acid 1-benzyl ester 2-methyl ester (300 mg, 0.96 mmol) in MeOH (5 mL) and H₂O (2 mL) at 0 °C. The resulting mixture was stirred at room temperature for 2 hours, concentrated, and the pH was adjusted to 4–5 with 1N HCl solution. Extraction was performed with EtOAc (15 mL x 3). The combined organic layers were washed with water and brine, dried over anhydrous Na₂SO₄, filtered, and concentrated to give the crude product trans-3-(difluoromethyl)pyrrolidine-1,2-dicarboxylic acid 1-benzyl ester 2-methyl ester (250 mg, yield: 82.2%) as a brown solid, which was used in the next step without further purification. LC / MS (ESI) m / z: 300 (M+1) + .

[0938] The following intermediates were prepared from the appropriate chemicals according to the experimental procedure for intermediate 37 (the main different chemicals used are listed in the raw materials column):

[0939]

[0940] Preparation of intermediate 53, N-(ethyl-1,1-d2)-5-fluoro-2-hydroxy-N-isopropylbenzamide

[0941]

[0942] At 0℃, step 1:

[0943] LiAlD4 (620 mg, 14.83 mmol) was added to a solution of N-isopropylacetamide (1 g, 9.89 mmol) in dry THF (10 mL), and the resulting mixture was stirred at 70 °C for 24 h. The reaction mixture was quenched with saturated NH4Cl (10 mL) and extracted with Et2O (20 mL x 3). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated to give crude N-(ethyl-1,1-d2)propyl-2-amine (400 mg, yield: 45.4%) as a colorless liquid, which was used in the next step without further purification. LC / MS (ESI) m / z: 90 (M+H) + .

[0944] Step 2:

[0945] HATU (2.03 g, 5.35 mmol) and DIPEA (1.06 g, 8.23 ​​mmol) were added dropwise to a solution of 5-fluoro-2-methoxybenzoic acid (700 mg, 4.11 mmol) and N-(ethyl-1,1-d2)propyl-2-amine (400 mg, 4.49 mmol) in DMF (5 mL) at 0 °C. The reaction mixture was gradually warmed to room temperature and stirred overnight. The reaction mixture was quenched with saturated NH4Cl solution (10 mL), extracted with EtOAc (50 mL x 3), and the combined organic phases were washed with water and brine, dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by silica gel column chromatography (EtOAc = 0–20% in PE) 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) + .

[0946] Step 3:

[0947] BBr3 (2.2 mL, 1.0 M, in DCM) was added dropwise to a solution of N-[(1,1-d2)ethyl]-5-fluoro-2-methoxy-N-(propyl-2-yl)benzamide (400 mg, 1.66 mmol) in DCM (10 mL) at -60 °C under a N2 atmosphere. The resulting mixture was stirred at this temperature for 7 hours. The reaction mixture was then quenched at 0 °C with cooled saturated NaHCO3. The mixture was extracted with DCM (30 mL x 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, which was used in the next step without further purification. LC / MS (ESI) m / z: 228 (M+H) + .

[0948] Preparation of intermediate 54, 2-(2-cyclopropylpyridin-3-yl)-4-fluorophenol

[0949]

[0950] Pd(dppf)Cl2 (25 mg) and K2CO3 (400 mg, 2.89 mmol) were added to a solution of 3-bromo-2-cyclopropylpyridine (250 mg, 1.26 mmol) and (5-fluoro-2-hydroxyphenyl)boronic acid (220 mg, 1.41 mmol) in dioxane (4.0 mL) and H2O (1.0 mL). The resulting mixture was stirred overnight at 100 °C under N2. The reaction mixture was cooled to room temperature, diluted with H2O (20 mL), and extracted with EtOAc (20 mL x 3). The combined organic layers were washed with water and brine, dried over anhydrous Na₂SO₄, filtered, and concentrated. The residue was purified by silica gel column chromatography (EtOAc = 0–10% in PE) to give the desired product, 2-(2-cyclopropylpyridin-3-yl)-4-fluorophenol (200 mg, yield: 69.1%), as a yellow solid. LC / MS (ESI) m / z: 230 (M+H) + .

[0951] Preparation of intermediate 55, 2-(2-cyclopropyl-6-methoxypyridin-3-yl)-4-fluorophenol

[0952]

[0953] Step 1:

[0954] At room temperature, K3PO4 (13.4 g, 63.1 mmol), tricyclohexylphosphine (1.77 g, 6.31 mmol), and Pd(AcO)2 (40 mg, 0.16 mmol) were added to a solution of 2-chloro-6-methoxypyridin-3-amine (2.5 g, 15.8 mmol), cyclopropylboronic acid (1.76 g, 20.5 mmol), in toluene (20 mL), and H2O (4 mL). The resulting mixture was degassed three times with N2 and stirred overnight at 100 °C under N2 atmosphere. The reaction mixture was cooled to room temperature, quenched with saturated NH4Cl solution (20 mL), and extracted with EtOAc (20 mL x 3). The combined organic layers were washed with water and brine, dried over anhydrous Na₂SO₄, filtered, and concentrated to obtain a crude product. This crude product was purified by silica gel column chromatography (EtOAc = 0–10% in PE) to give the desired product, 2-cyclopropyl-6-methoxypyridine-3-amine (830 mg, yield: 32.1%), as a yellow solid. LC / MS (ESI) m / z: 164 (M+H) + .

[0955] Step 2:

[0956] 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. Then, a solution of 2-cyclopropyl-6-methoxypyridine-3-amine (830 mg, 5.06 mmol) in MeCN (5 mL) was added dropwise to the stirred mixture. The resulting mixture was stirred at 70 °C for another hour. The reaction mixture was quenched with water (10 mL) and extracted with EtOAc (20 mL x 3). The combined organic phases were washed with water and brine, dried over anhydrous Na₂SO₄, filtered, and concentrated to obtain a crude product. This crude product was purified by silica gel column chromatography (PE = 100%) to obtain 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) + .

[0957] Step 3:

[0958] To 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), Cs₂CO₃ (2.57 g, 7.89 mmol) and Pd(dppf)Cl₂ (50 mg) were added. The resulting mixture was stirred overnight at 100 °C under a N₂ atmosphere. The reaction mixture was cooled to room temperature, diluted with H₂O (20 mL), extracted with EtOAc (20 mL x 3), and the combined organic layers were washed with water and brine, dried over anhydrous Na₂SO₄, filtered, and concentrated. The residue was purified by silica gel column chromatography (EtOAc = 0–30% in PE) 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]+.

[0959] Preparation of intermediate 56, 6-cyclopropyl-5-(5-fluoro-2-hydroxyphenyl)pyridine-2(1H)-one

[0960]

[0961] At room temperature, 3 mL of 40% HBr solution was added to a solution of 2-(2-cyclopropyl-6-methoxypyridin-3-yl)-4-fluorophenol (350 mg, 1.35 mmol, intermediate 55) in HOAc (5 mL), and the resulting mixture was stirred overnight at 80 °C. The reaction mixture was cooled to room temperature and concentrated. The residue was suspended in EtOAc (50 mL) and washed with saturated NaHCO3 (10 mL x 3) and brine. The organic phase was dried over anhydrous Na2SO4, filtered, and concentrated to obtain a crude product. This crude product was purified by column chromatography with silica gel (EtOAc = 0–70% in PE) to give the desired product, 6-cyclopropyl-5-(5-fluoro-2-hydroxyphenyl)-1,2-dihydropyridin-2-one (200 mg, yield: 60.4%), as a brown semi-solid. 1 H NMR (400MHz, DMSO) δ10.72(s,1H),9.38(s,1H),7.23(d,J=9.0Hz,1H),7.02–6.92(m,2H),6.89-6.85(m,1H) ,6.21(d,J=8.9Hz,1H),1.75-1.69(m,1H),0.89-0.80(m,2H),0.76-0.72(m,2H),LC / MS(ESI)m / z:246(M+H) + .

[0962] Example

[0963] Example 2:

[0964] Preparation of N-ethyl-5-fluoro-2-[(4-{7-[(2S,4R)-4-fluoropyrrolidine-2-carbonyl]-2,7-diazaspiro[3.5]non-2-yl}pyrimidin-5-yl)oxy]-N-(prop-2-yl)benzamide

[0965]

[0966] Step 1:

[0967] At room temperature, DIPEA (0.1 mL) and HATU (58 mg, 0.15 mmol) were added to a solution of 2-[(4-{2,7-diazaspiro[3.5]non-2-yl}pyrimidin-5-yl)oxy]-N-ethyl-5-fluoro-N-(prop-2-yl)benzamide (intermediate 1, 50 mg, 0.12 mmol) and (2S,4R)-1-[(tert-butoxy)carbonyl]-4-fluoropyrrolidine-2-carboxylic acid (27 mg, 0.12 mmol) in DMF (2 mL). The resulting mixture was stirred at room temperature for 3 hours, quenched with saturated NH4Cl solution (10 mL), and extracted with EtOAc (15 mL x 3). The combined organic phases were washed with water and brine, dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by silica gel column chromatography (MeOH = 0–5% in DCM) to give the desired product (2S,4R)-2-[2-(5-{2-[ethyl(propyl-2-yl)carbamoyl]-4-fluorophenoxy}pyrimidin-4-yl)-2,7-diazaspiro[3.5]nonane-7-carbonyl]-4-fluoropyrrolidine-1-carboxylic acid tert-butyl ester (60 mg, yield: 79%), as a pale yellow solid. LC / MS (ESI) m / z: 643 (M+H) + .

[0968] Step 2:

[0969] TFA (1.0 mL) was added to a solution of (2S,4R)-2-[2-(5-{2-[ethyl(prop-2-yl)carbamoyl]-4-fluorophenoxy}pyrimidin-4-yl)-2,7-diazaspiro[3.5]nonane-7-carbonyl]-4-fluoropyrrolidine-1-carboxylic acid tert-butyl ester (60 mg, 0.1 mmol) in DCM (3 mL). The resulting mixture was stirred at room temperature for 1 hour, concentrated, and the residue was purified by preparative-HPLC to obtain the desired product N-ethyl-5-fluoro-2-[(4-{7-[(2S,4R)-4-fluoropyrrolidine-2-carbonyl]-2,7-diazaspiro[3.5]nonane-2-yl}pyrimidin-5-yl)oxy]-N-(prop-2-yl)benzamide (35 mg, yield: 69%), as a white solid. 1 H NMR (400MHz, CDCl3) δ8.40 (d, J = 3.1Hz, 1H), 7.82–7.80 (m, 1H), 7.04 -7.00 (m, 2H), 6.78–6.72 (m, 1H), 5.35 -5.22 (m, 1H), 4.29 -4.25(m,1H),4.03–3.82(m,5H),3.66 -3.63(m,1H),3.52–3.15(m,7H),2.40 -2.31(m,1H),1.87–1.76(m,5H),1.29 -1.23(m,4H),1.16 -1.07(m,5 hours). LC / MS(ESI)m / z:543(M+H) + .

[0970] The following compounds were prepared from suitable intermediates or commercially available chemicals according to the experimental method of Example 2:

[0971]

[0972]

[0973]

[0974]

[0975]

[0976]

[0977]

[0978]

[0979]

[0980]

[0981]

[0982]

[0983]

[0984] Example 27:

[0985] Preparation of 2-((4-(7-((2S,4R)-4-cyanopyrrolidine-2-carbonyl)-2,7-diazaspiro[3.5]non-2-yl)pyrimidin-5-yl)oxy)-N-ethyl-5-fluoro-N-isopropylbenzamide

[0986]

[0987] Step 1:

[0988] DIPEA (0.8 mL, 3.5 mmol) and HATU (266 mg, 0.70 mmol) were added to a solution of 2-(4-(2,7-diazaspiro[3.5]non-2-yl)pyrimidin-5-yloxy)-N-ethyl-5-fluoro-N-isopropylbenzamide (intermediate 1, 280 mg, 0.53 mmol) and (2S,4S)-1-(tert-butoxycarbonyl)-4-hydroxypyrrolidine-2-carboxylic acid (277 mg, 0.60 mmol) in DMF (5 mL) at 0 °C. The reaction mixture was then cooled to room temperature and stirred overnight. The reaction mixture was quenched with saturated NH4Cl solution, extracted with EtOAc (20 mL x 3), and the combined organic phases were washed with water and brine, dried over anhydrous Na2SO4, filtered, and concentrated under vacuum to obtain a crude product. This crude product was purified by silica gel column chromatography (EtOAc in PE = 0–30%) to obtain the desired product (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-carboxylic acid tert-butyl ester (180 mg, yield: 80%), as a white solid. LCMS: m / z 641 (M+H) +

[0989] Step 2:

[0990] MsCl (0.10 mL, 0.42 mmol) was added to a solution of (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-carboxylic acid tert-butyl ester (180 mg, 0.28 mmol) and DIPEA (72 mg, 0.56 mmol) in DCM (10 mL) at 0 °C. The resulting mixture was stirred at room temperature for 3 hours. The reaction mixture was quenched with saturated NH4Cl (10 mL) solution and extracted with EtOAc (20 mL x 3). The combined organic phases were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by silica gel column chromatography (EtOAc = 0–20% in PE) to give the desired product (2S,4S)-2-(2-(5-(2-(ethyl(isopropyl)carbamoyl)-4-fluorophenoxy)pyrimidin-4-yl)-2,7-diazaspiro[3.5]nonane-7-carbonyl)-4-((methanesulfonyl)oxy)pyrrolidine-1-carboxylic acid tert-butyl ester (150 mg, yield: 80%), as a white solid. LCMS: m / z 719 (M+H) +

[0991] Step 3:

[0992] To a solution of (2S,4S)-2-(2-(5-(2-(ethyl(isopropyl)carbamoyl)-4-fluorophenoxy)pyrimidin-4-yl)-2,7-diazaspiro[3.5]nonane-7-carbonyl)-4-((methanesulfonyl)oxy)pyrrolidine-1-carboxylic acid tert-butyl ester (150 mg, 0.21 mmol) in DMF (5 mL), NaCN (20 mg, 0.40 mmol) was added. The mixture was stirred at 100 °C for 10 hours. The resulting mixture was diluted with water (10 mL) and extracted with EtOAc (15 mL x 3). The combined organic phases were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by silica gel column chromatography (EtOAc = 0–20% in PE) to give the desired product (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-carboxylic acid tert-butyl ester (60 mg, yield: 45%) as a yellow solid. LCMS: m / z 650 (M+H) +

[0993] Step 4:

[0994] TFA (1.0 mL) was added to a solution of (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-carboxylic acid tert-butyl ester (60 mg, 0.09 mmol) in DCM (3 mL). The reaction mixture was stirred at room temperature for 1 hour 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]non-2-yl)pyrimidin-5-yl)oxy)-N-ethyl-5-fluoro-N-isopropylbenzamide (20 mg, yield: 30%), a white solid. 1 H NMR(400MHz,MeOD)δ8.26-8.25(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) + .

[0995] Example 39:

[0996] Preparation of N-ethyl-5-fluoro-2-[(5-{7-[(2S,4R)-4-fluoropyrrolidine-2-carbonyl]-2,7-diazaspiro[3.5]non-2-yl}-1,2,4-triazin-6-yl)oxy]-N-(prop-2-yl)benzamide

[0997]

[0998] Step 1:

[0999] DIPEA (0.68 mL, 4.1 mmol) was added to a stirred solution of (2S,4R)-1-[(tert-butoxy)carbonyl]-4-fluoropyrrolidine-2-carboxylic acid (381 mg, 1.63 mmol) and HATU (517 mg, 1.36 mmol) in 15 mL of DMF. The reaction mixture was stirred at room temperature for 10 min, followed by the addition of 2-[(5-{2,7-diazaspiro[3.5]non-2-yl}-1,2,4-triazin-6-yl)oxy]-N-ethyl-5-fluoro-N-(prop-2-yl)benzamide (583 mg, 1.36 mmol), and the resulting mixture was stirred at room temperature for another 1 h. The reaction mixture was quenched with H₂O (50 mL), extracted with EtOAc (50 mL x 3), and the combined organic layers were dried over anhydrous Na₂SO₄, filtered, and concentrated. The residue was purified by silica gel column chromatography (MeOH = 0–5% in DCM) to give the desired product (2S,4R)-2-[2-(6-{2-[ethyl(propyl-2-yl)carbamoyl]-4-fluorophenoxy}-1,2,4-triazin-5-yl)-2,7-diazaspiro[3.5]nonane-7-carbonyl]-4-fluoropyrrolidine-1-carboxylic acid tert-butyl ester (650 mg, yield: 74.2%), as a white solid. LCMS: ESI m / z 644 (M+H) + .

[1000] Step 2:

[1001] At room temperature, (2S,4R)-2-[2-(6-{2-[ethyl(propyl-2-yl)carbamoyl]-4-fluorophenoxy}-1,2,4-triazine-5-

[1002] 500 mg (0.78 mmol) of tert-butyl ester (500 mg, 0.78 mmol) of tert-butyl ester (5 mL) of TFA was added to a solution in DCM (10 mL). 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 give the desired product N-ethyl-5-fluoro-2-[(5-{7-[(2S,4R)-4-fluoropyrrolidine-2-carbonyl]-2,7-diazaspiro[3.5]non-2-yl}-1,2,4-triazin-6-yl)oxy]-N-(prop-2-yl)benzamide (315 mg, yield: 74.6%) as a white solid. 1H NMR(400MHz,MeOD)δ8.59(d,J=6.6Hz,1H),7.46-7.43(m,1H),7.35–7.22( m,2H),5.56-5.43(m,1H),4.98–4.93(m,1H),4.54(s,2H),4.13(s,2H),3.8 7-3.80(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) + .

[1003] The following compounds were prepared from suitable intermediates or commercially available chemicals according to the experimental method of Example 39:

[1004]

[1005]

[1006]

[1007]

[1008]

[1009]

[1010]

[1011]

[1012]

[1013]

[1014]

[1015]

[1016]

[1017]

[1018]

[1019] Example 98:

[1020] Preparation of 2-((5-(7-5,5-difluorooctanecyclopentadien[c]pyrrole-1-carbonyl)-2,7-diazaspiro[3.5]non-2-yl)-1,2,4-triazin-6-yl)oxy)-N-ethyl-5-fluoro-N-isopropylbenzamide

[1021]

[1022] Step 1:

[1023] At room temperature, DIPEA (50 mg, 0.39 mmol) and HATU (133 mg, 0.35 mmol) were added to a solution of 2-((5-(2,7-diazaspiro[3.5]non-2-yl)-1,2,4-triazin-6-yl)oxy)-N-ethyl-5-fluoro-N-isopropylbenzamide (100 mg, 0.23 mmol, intermediate 34) and 2-(tert-butoxycarbonyl)-5,5-difluorooctahedral[c]pyrrole-1-carboxylic acid (67.9 mg, 0.23 mmol, intermediate 50) in DMF (3 mL). The resulting mixture was stirred at room temperature for 3 hours, quenched with saturated NH4Cl solution (10 mL), and extracted with EtOAc (15 mL x 3). The combined organic phases were washed with water and brine, dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by silica gel column chromatography (MeOH = 0–5% in DCM) to give the desired product, tert-butyl 1-(2-(6-(2-(ethyl(isopropyl)carbamoyl)-4-fluorophenoxy)-1,2,4-triazin-5-yl)-2,7-diazaspiro[3.5]nonane-7-carbonyl)-5,5-difluorohexahydrocyclopentadieno[c]pyrrole-2(1H)-carboxylic acid (40 mg, yield: 24.4%), as a pale yellow solid. LC / MS (ESI) m / z: 702 (M+H) + .

[1024] Step 2:

[1025] TFA (4 mL) was added 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-difluorohexahydrocyclopentadieno[c]pyrrole-2(1H)-carboxylic acid (150 mg, 0.21 mmol) in DCM (10 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 NaHCO3 solution. The organic phase was collected, dried over anhydrous Na2SO4, filtered, and concentrated. The crude product was purified by preparative-HPLC to obtain the desired product 2-((5-(7-5,5-difluorooctanecyclopentadien[c]pyrrole-1-carbonyl)-2,7-diazaspiro[3.5]non-2-yl)-1,2,4-triazin-6-yl)oxy)-N-ethyl-5-fluoro-N-isopropylbenzamide (90 mg, yield: 69.9%), a white solid. SFC chiral separation yielded four isomers. (Two conditions were used; the first condition yielded pure isomers 3 and 4, and a mixture of isomers 1 and 2, respectively; the latter was then subjected to the second condition to yield pure isomers 1 and 2, respectively.)

[1026] Example 98a: Isomer 1 (9.8 mg, yield: 10.8%), a white solid (SFC conditions: SHIMADZAPREP SPLUTION SFC, column: ChiralPak IH, 250 × 21.1 μm, ID, 5 μm; mobile phase: A = CO2, B = EtOH + 0.1% NH3H2O, gradient: B 17%, flow rate: 40 mL / min, back pressure: 100 bar, column temperature: 35 °C, wavelength: 254 nm, circulation time: 18 min, elution time: 3.5 h, retention time: 8.39 min); 1H NMR(400MHz,MeOD)δ8.40(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=7.1Hz,1H),0.82-0.79(m,2H),LC / MS(ESI)m / z:602(M+H) + .

[1027] Example 98b: Isomer 2 (16.3 mg, yield: 18.1%), a white solid (SFC conditions: SHIMADZAPREP SPLUTION SFC, column: ChiralPak IH, 250 × 21.1 μm, ID, 5 μm; mobile phase: A is CO2, B is EtOH + 0.1% NH3H2O, gradient: B 17%, flow rate: 40 mL / min, back pressure: 100 bar, column temperature: 35 °C, wavelength: 254 nm, circulation time: 18 min, elution time: 3.5 h, retention time: 11.09 min); 1H NMR(400MHz,MeOD)δ8.40(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=3.9Hz,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=7.1Hz,1H),0.82-0.78(m,2H),LC / MS(ESI)m / z:602(M+H) + .

[1028] Example 98c: Isomer 3 (8.8 mg, yield: 9.7%), a white solid (SFC conditions: SHIMADZAPREP SPLUTION SFC, column: ChiralPak CIG, 250 × 21.1 μm, ID, 5 μm; mobile phase: A is CO2, B is IPA + 0.1% NH3H2O, gradient: B 50%, flow rate: 40 mL / min, back pressure: 100 bar, column temperature: 35 °C, wavelength: 254 nm, circulation time: 45 min, elution time: 5 h. Retention time: 12.61 min); 1H NMR(400MHz,MeOD)δ8.40(s,1H),7.43-7.38(m,1H),7.31–7.21(m,2H),4. 49–4.41(m,2H),4.13(d,J=7.0Hz,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,1 H),2.03-1.84(m,7H),1.23–1.12(m,6H),1.07(t,J=7.1Hz,1H),0.81(d,J=

[1029] 5.1Hz,2H). LC / MS(ESI)m / z:602(M+H) + .

[1030] Example 98d: Isomer 4 (20.1 mg, yield: 22.3%), a white solid (SFC conditions: SHIMADZAPREP SPLUTION SFC, column: ChiralPak CIG, 250 × 21.1 μm, ID, 5 μm; mobile phase: A is CO2, B is IPA + 0.1% NH3H2O, gradient: B 50%, flow rate: 40 mL / min, back pressure: 100 bar, column temperature: 35 °C, wavelength: 254 nm, circulation time: 45 min, elution time: 5 h. Retention time: 28.06 min); 1H NMR(400MHz,MeOD)δ8.40(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=7.1Hz,1H),0.81(d,J=5.2Hz,2H),HNMR,LC / MS(ESI)m / z:602(M+H) + .

[1031] Example 99 :

[1032] Preparation of 2-((5-(7-(trans-3-(difluoromethyl)pyrrolidine-2-carbonyl)-2,7-diazaspiro[3.5]non-2-yl)-1,2,4-triazin-6-yl)oxy)-N-ethyl-5-fluoro-N-isopropylbenzamide

[1033]

[1034] Step 1:

[1035] HATU (476 mg, 1.25 mmol) and DIPEA (323 mg, 2.51 mmol) were added to a solution of trans-1-[(benzyloxy)carbonyl]-3-(difluoromethyl)pyrrolidine-2-carboxylic acid (250 mg, 0.83 mmol, intermediate 51) and 2-[(5-{2,7-diazaspiro[3.5]non-2-yl}-1,2,4-triazin-6-yl)oxy]-N-ethyl-5-fluoro-N-(prop-2-yl)benzamide (357 mg, 0.83 mmol, intermediate 34) in DMF (5 mL) at room temperature. The resulting mixture was stirred at room temperature for 3 hours, quenched with saturated NH4Cl solution (10 mL), and extracted with EtOAc (20 mL x 3). The combined organic phases were washed with water and brine, dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by silica gel column chromatography (MeOH = 0–5% in DCM) to give the desired product, trans-3-(difluoromethyl)-2-[2-(6-{2-[ethyl(prop-2-yl)carbamoyl]-4-fluorophenoxy}-1,2,4-triazin-5-yl)-2,7-diazaspiro[3.5]nonane-7-carbonyl]pyrrolidine-1-carboxylic acid benzyl ester (200 mg, yield: 33.7%), as a white solid. LC / MS (ESI) m / z: 710 (M+H) + .

[1036] Step 2:

[1037] Pd / C (30 mg, 10% palladium-supported activated carbon) was added to a solution of trans-3-(difluoromethyl)-2-[2-(6-{2-[ethyl(prop-2-yl)carbamoyl]-4-fluorophenoxy}-1,2,4-triazin-5-yl)-2,7-diazaspiro[3.5]nonane-7-carbonyl]pyrrolidine-1-carboxylic acid benzyl ester (200 mg, 0.28 mmol) in MeOH (10 mL) at room temperature. The reaction mixture was stirred at room temperature under a H2 atmosphere (balloon) for 5 hours. The reaction mixture was then filtered and concentrated. The crude product was purified by preparative HPLC to obtain the desired product 2-[(5-{7-[trans-3-(difluoromethyl)pyrrolidine-2-carbonyl]-2,7-diazaspiro[3.5]non-2-yl}-1,2,4-triazin-6-yl)oxy]-N-ethyl-5-fluoro-N-(prop-2-yl)benzamide (30 mg, yield: 36.9%), a white solid. It was then separated by SFC to obtain two isomers. (SFC conditions: Waters Thar 80 prepared SFC, column: ChiralCel, 250×21.1um, ID, 5um; mobile phase: A is CO2, B is MeOH + 0.1% NH3H2O, gradient: B 40%, flow rate: 40mL / min, back pressure: 100bar, column temperature: 35℃, wavelength: 254nm, circulation time: 5 minutes, elution time: 2 hours. Retention time: 5.5 minutes for 99a, 7.8 minutes for 99b)

[1038] Example 99a: 2-((5-(7-((2S,3S)-3-(difluoromethyl)pyrrolidine-2-carbonyl)-2,7-diazaspiro[3.5]nonyl-2-

[1039] 1,2,4-triazine-6-yl)oxy)-N-ethyl-5-fluoro-N-isopropylbenzamide (35.3 mg, yield: 21.4%) is a white solid. 1H NMR(400MHz,MeOD)δ8.40(s,1H),7.43-7.38(m,1H),7.31–7.19(m,2H),6.10- 5.81(m,1H),4.48–4.41(m,2H),4.14(d,J=5.4Hz,1H),4.04–3.97(m,2H),3.8 4–3.80(m,1H),3.71–3.47(m,5H),3.25-3.11(m,2H),2.94–2.78(m,2H),2.06 –1.81(m,6H),1.22–1.12(m,6H),1.07(t,J=7.1Hz,1H),0.81(d,J=4.9Hz,2H). LC / MS (ESI) m / z: 576 (M+H)+ .

[1040] Example 99b: 2-((5-(7-((2R,3R)-3-(difluoromethyl)pyrrolidine-2-carbonyl)-2,7-diazaspiro[3.5]nonyl-2-

[1041] 1,2,4-triazine-6-yl)oxy)-N-ethyl-5-fluoro-N-isopropylbenzamide (36.8 mg, yield: 22.9%) is a white solid. 1 H NMR(400MHz,MeOD)δ8.40(s,1H),7.43-7.38(m,1H),7.31–7.19(m,2H),6.11 -5.82(m,1H),4.48-4.39(m,2H),4.17(d,J=5.2Hz,1H),4.02-3.96(m,2H),3. 85-3.79(m,1H),3.72–3.48(m,5H),3.24–3.11(m,2H),2.97-2.81(m,2H),2. 05–1.84(m,6H),1.22–1.13(m,6H),1.07(t,J=7.1Hz,1H),0.87–0.74(m,2H). LC / MS (ESI) m / z: 576 (M+H) + .

[1042] The following compounds were prepared from suitable intermediates or commercially available chemicals according to the experimental method of Example 99:

[1043]

[1044] Pharmacological Examples

[1045] The SNDX-5613 used for the following analyses was derived from MCE catalog number HY-136175, or prepared according to the method reported in WO2017214367.

[1046] 1. Menin-MLL1 inhibition test

[1047] Prepare a 1x assay buffer (Tris 7.5 50mM, NaCl 50mM, DTT 1mM, Tween-20 0.01%) and transfer the test compound solution (10mM in DMSO, Sigma, catalog number 34869) to an assay plate (384-well plate, Perkin Elmer, catalog number 6007279) via Echo. The final fraction of DMSO is 1%. Add 20 nM of Menin protein (Menin(2-610)isform2, ChemPartner, catalog number 2020111101) in the 1x assay buffer to prepare a 2x enzyme solution. Then add 10 nM of MLL-peptide (Ac-SRWRFPARPGTGRR-Ahx-Ahx-K(FAM)-NH2, GL Biochem (Shanghai), catalog number 833831 / 202009220104) in the 1x assay buffer to prepare a 2x substrate solution. Transfer 10 μL of 2x enzyme solution to the assay plate, or 10 μL of 1x assay buffer to the assay plate for the low control group. Add 10 μL of 2x substrate solution to each well to begin the reaction. Collect mP data on an Envision (Ex480 / Em535(s),Em535(p)) instrument.

[1048] The compound potency was determined by first calculating the inhibition percentage at each compound concentration according to Equation 1:

[1049] Suppression % = (Max - Signal) / (Max - Min) * 100 (Equation 1)

[1050] IC of the compound of the present invention 50 The values ​​were obtained using Equation 2 and are shown in Table 1 below:

[1051] Y = bottom + (top - bottom) / (1 + (IC50 / X) * HillSlope), where Y is the percentage of inhibition and X is the compound concentration (Equation 2).

[1052] The test results for the compounds of this invention are shown in Table 1.

[1053] 2. Cell proliferation assay

[1054] • RPMI1640 (from Invitrogen, catalog number 11875-093; lot number 2327411)

[1055] • IMDM (from Invitrogen, catalog number 12440-053; lot number 2192731)

[1056] • FBS (from Gibco, catalog number 10099141C, lot number 2233792CP)

[1057] • Penicillin-streptomycin solution (from Invitrogen, catalog number 15140-122, batch number 2321118)

[1058] • Glutamax (from Invitrogen, catalog number 35050-061; lot number 2248972)

[1059] • 0.25% Trypsine-EDTA (from Invitrogen, catalog number 25200-072; lot number 2276876)

[1060] • Staurosporine (from Selleck, catalog number S1421, batch number #S142106)

[1061] ·DMSO (from Sigma, catalog number 276855-1L, lot number 276855-1L)

[1062]

[1063] The antiproliferative activity of the test compounds was evaluated in human leukemia cell lines. Cell lines expressing the MLL fusion proteins MLL-AF4 and MLL-AF9, and carrying the NPM1c gene mutation, MV4-11, MOLM13, and OCI-AML3, were tested separately. HL-60 was used as a control cell line containing two wild-type MLL alleles to exclude compounds exhibiting broad cytotoxic effects. MV4-11 cells were cultured in IMDM supplemented with 10% FBS, MOLM13 and OCI-AML3 cells were cultured in RPMI1640 supplemented with 20% FBS, and HL-60 cells were cultured in IMDM supplemented with 20% FBS. The corresponding cell lines (MV4-11, MOLM13, OCI-AML3, or HL-60) were seeded in 96-well plates (white-walled clear bottom, tissue culture treated, Corning, catalog number CLS3903; batch number 30419025) at 100 μL of medium per well. The plate was placed in a CO2 incubator overnight. Compound solutions (2 mM starting, 4-fold serial dilutions) were prepared and added to wells containing 100 μL of medium with HPD300 according to the well distribution map, and centrifuged at 1000 rpm for 1 minute (total 200-fold dilution). MV4-11, MOLM13, OCI-AML3, and HL-60 cells were incubated with the compound at 5% CO2 and 37°C for 4, 12, 5, and 4 days, respectively. 100 μL of CellTiter-Glo reagent (Promega, catalog number G7573, catalog number 0000416710) was added to the assay plate using a Multirop Combi instrument, and the contents were mixed on a oscillator for 10 minutes to induce cell lysis. After incubation at room temperature for 10 minutes, the transparent bottom was affixed with a white back seal, and the luminescence was read using Envision.

[1064] The test results for the compounds of this invention are shown in Table 1.

[1065] Table 1. Biological Data

[1066]

[1067]

[1068]

[1069]

[1070] 3. Study on the stability of liver microsomes

[1071] The study was conducted using liver microsomes (Corning, 0.5 mg / mL). A 10 mM stock solution of the test compound was prepared in DMSO. Aliquots of the stock solution were diluted to 0.5 mM with acetonitrile, and then further diluted to 1.5 μM upon addition of liver microsomes / buffer. 30 μL of the 1.5 μM aliquot was mixed with 15 μL of 6 mM NADPH, preheated to 37 °C, to a final NADPH concentration of 2 mM. The final concentrations of the test compound and ketoselin were 1 μM. The plates were kept in a 37 °C water bath during the experiment. At each time point (0, 5, 15, 30, 45 min), 135 μL of acetonitrile was added to the corresponding well. After quenching with acetonitrile at the last time point, the plate was shaken for 10 min (600 rpm / min) on an IKA (MTS 2 / 4) and then centrifuged at 5,594 g for 15 min (Thermo Multifuge × 3R). Aliquots of the supernatant were diluted 1:1 in distilled water and analyzed by LC-MS / MS. The peak area-to-internal-standard response ratio (PARR) of the compound at 5, 15, 30, and 45 minutes was compared with the PARR at 0 minutes to determine the percentage of the test compound remaining at each time point. The half-life was calculated using Excel software and fitted to a single-phase exponential decay equation.

[1072] Table 2. Stability of human liver microsomes

[1073]

[1074]

[1075] 4. hERG inhibition research

[1076] The inhibitory effect of the test compounds on hERG was investigated in CHO-hERG cells (cell density: 21.5 × 10⁶ / mL). 10 μL of the compound stock solution was added to 20 μL of DMSO solution, and then serially diluted 3-fold to six concentrations. Six different concentrations of the compound solution (4 μL) were added to extracellular solution (996 μL) and diluted to the final test concentration (a total of 250-fold dilutions). The highest test concentration was 40.00 μM, followed by 40.0, 13.3, 4.4, 1.48, 0.49, and 0.16 μM. The DMSO content in the final test concentration did not exceed 0.2%, at which point DMSO had no effect on hERG potassium channels. High-resistance sealing of single cells and formation of whole-cell models were both automated using a Qpatch instrument.

[1077] Table 3. hERG suppression data

[1078] compound hERG(μM) SNDX-5613 9.6 Example 2 >40 Example 55 >40 Example 57 >40 Example 60 >40 Example 68 >40 Example 74 >40 Example 77 >40 Example 82 29.4

Claims

1. Compounds of Formula II: Or its stereoisomers, racemic derivatives, or pharmaceutically acceptable salts, wherein: X is F; Z is CH2; R1 is selected from: 1)-(C=O)-NRaRb, where: Ra and Rb are each independently selected from C atoms that are optionally replaced by 1, 2, or 3 deuterium atoms. 1-6 alkyl; 2) Selected by 1, 2 or 3 halogenated groups, CN, C 1-6 Alkyl, CF3, 3-5 membered cycloalkyl rings, oxo and C 1-6 5-6 membered heteroaryl rings substituted with alkoxy groups; 3) Selected by 1, 2 or 3 halogenated groups, CN, C 1-6 Alkyl, CF3, 3-5 membered cycloalkyl rings and C 1-6 Alkoxy substituents substituted for phenyl rings; R2 and R3 are each H independently; R4 is independently selected from halogenated groups; CN; OH; C optionally substituted by 1, 2 or 3 substituents selected from halogenated groups, CN and OH. 1-6 Alkyl group; C group optionally substituted with 1, 2 or 3 halogroups 1-6 alkoxy groups; and 3-6 membered cycloalkyl rings, Two adjacent R4 atoms, together with the carbon atoms they are attached to, optionally form a 3-6 membered alkyl ring, which is optionally surrounded by 1, 2, or 3 carbon atoms selected from C14. 1-6 Substitution of alkyl and halogroups; Alternatively, two adjacent R4 atoms, together with the carbon atoms they are attached to, may optionally form a phenyl group; R5 is an H or a halogenated group; Each of a and b is 1; Each of c and d is 2; n is 0; and m is 0, 1, or 2; The condition is that R4, if present, substitutes for any chemically permissible position on the heterocyclic group, except for the N atom adjacent to the junction of the heterocyclic group and the rest of the compound structure.

2. The compound according to claim 1, or its stereoisomer, racemate, or pharmaceutically acceptable salt, wherein: R1 is Where A1 or A2 is N or CH; R6 is selected from halogenated group, CN and cyclopropyl; and R7 is selected from H, halogenated group, CN and cyclopropyl. Or R1 is Where A3 is N or C substituted with a halogenated group, and R8 is C. 1-3 alkyl.

3. The compound according to claim 1, or its stereoisomer, racemate, or pharmaceutically acceptable salt, wherein: R1 is 4. The compound according to claim 1, or its stereoisomer, racemate, or pharmaceutically acceptable salt, wherein: R1 is 5. The compound according to claim 1, or its stereoisomer, racemate, or pharmaceutically acceptable salt, wherein: R1 is selected from:

6. The compound according to any one of claims 1-2, or its stereoisomer, racemate, or pharmaceutically acceptable salt, wherein: Structural parts Selected from:

7. The compound or its stereoisomer, racemate or pharmaceutically acceptable salt according to any one of claims 1-2, wherein R5 is H.

8. The compound according to any one of claims 1-2, or a stereoisomer, racemate, or pharmaceutically acceptable salt thereof, wherein the structural moiety is... yes R4', R4”, and R4”' are independently selected from H; a halogenated group; CN; OH; and a C group optionally substituted with a halogenated group. 1-6 Alkyl; and C 1-6 alkoxy or R4' and R4" together with the carbon atoms they are attached to optionally form a 3-6 membered alkyl ring, which is optionally bounded by one or two carbon atoms. 1-6 Alkyl substitution; and R4”' is H.

9. The compound according to any one of claims 1-2, or its stereoisomer, racemate, or pharmaceutically acceptable salt, wherein: Structural parts yes Where R4”’ is H; and R4' and R4" are independently selected from H; halogenated group; C optionally substituted with one halogenated group. 1-6 Alkyl; and C 1-6 alkoxy group; 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 an alkoxy group optionally occupied by one or two carbon atoms. 1-3 Alkyl-substituted 3- or 5-membered alkyl rings, or forming phenyl rings.

10. The compound or its stereoisomer, racemate or pharmaceutically acceptable salt according to any one of claims 1-2, wherein the structural moiety is... yes Where R4' is H; and R4” is C substituted with a halogenated group. 1-6 Alkyl; or R4' and R4”, together with the carbon atoms they are attached to, optionally form 3- or 5-membered alkyl rings.

11. The compound or its stereoisomer, racemate or pharmaceutically acceptable salt according to any one of claims 1-2, wherein the structural moiety is... yes Each p is independently 0 or 1; q is 0, 1, or 2; R 4a It is C 1-3 alkyl.

12. The compound of claim 11 or its stereoisomer, racemate or pharmaceutically acceptable salt, wherein p is 0.

13. The compound of claim 11 or its stereoisomer, racemate or pharmaceutically acceptable salt, wherein p is 1.

14. The compound of claim 13 or its stereoisomer, racemate or pharmaceutically acceptable salt, wherein q is 0.

15. The compound of claim 13 or its stereoisomer, racemate or pharmaceutically acceptable salt, wherein q is 2.

16. The compound of claim 11 or its stereoisomers, racemates, or pharmaceutically acceptable salts, wherein R 4a It is a methyl group.

17. The compound of claim 1 or its stereoisomer, racemate, or pharmaceutically acceptable salt, wherein the compound is selected from:

18. A pharmaceutical composition comprising a compound of any one of claims 1-17 or a stereoisomer thereof, a racemic mixture or a pharmaceutically acceptable salt thereof, and optionally a pharmaceutically acceptable carrier.

19. A combination comprising a compound of any one of claims 1-17 or a stereoisomer thereof, a racemic mixture or a pharmaceutically acceptable salt thereof, and at least one additional therapeutic agent.

20. The combination of claim 19, wherein the additional therapeutic agent is an antitumor agent.

21. The combination of claim 19, wherein the additional therapeutic agent is a radiotherapy agent, a chemotherapy agent, an immunotherapy agent, or a targeted therapy agent.

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