Bridged 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

Technical Field

[0001] This disclosure provides bridged diazaspirocyclic compounds 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. background

[0002] 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 J Haematol. 2011, 152, 141). Therefore, there is a huge unmet medical need for treatment of MLLr leukemia.

[0003] 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

[0004] 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.

[0005] This disclosure provides compounds of formula I:

[0006]

[0007] Or its pharmaceutically acceptable salt or stereoisomer, racemate, tautomer, hydrate or solvate, wherein:

[0008] X is a halogenated group or CN;

[0009] Y is either N or CH;

[0010] R1 is selected from:

[0011] 1)-(C=O)-NRaRb, where:

[0012] Ra and Rb are each independently selected from C 1-6 Alkyl, deuterated 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;

[0013] 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. 1-6Substitution of alkyl and halogroups;

[0014] 2) A 5-6 membered heteroaryl ring, optionally 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;

[0015] 3) Phenyl, optionally 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;

[0016] R2 and R3 are each independently H or D;

[0017] Cy is a 5-7 membered heterocyclic group, a 5-7 membered cycloalkyl group, or C. 6-10 Aryl ring, which is coated with (R4) m replace;

[0018] R4 groups are independently selected from halogenated groups, CN, OH, and C. 1-6 Alkyl, C 1-6 Alkoxy, 3-6 membered cycloalkyl ring, C 1-6 Alkyl-S(O)2-NR'-, C 1-6 Alkyl-C(O)-NR'-, C 1-6 Alkyl-S(O)2-, C 1-6 Alkyl-OC(O)-NR'- and C 1-6 Alkyl-NR'-C(O)-NR'-, wherein the alkyl, alkoxy, or cycloalkyl ring is optionally substituted by one, two, or three substituents selected from halogen, CN, and OH, and R' is independently H or C. 1-6 alkyl;

[0019] 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 C. 1-6 Alkyl, -C 1-6 Alkyl-OH, C 1-6 Alkoxy-C 1-6 Alkyl and haloyl substituents;

[0020] 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;

[0021] R5 is an oxo group or H;

[0022] a and b are each independently 1 or 2;

[0023] c is 1, 2, or 3; and

[0024] m can be 0, 1, 2, or 3.

[0025] Compounds of Formula I, or pharmaceutically acceptable salts or stereoisomers, racemates, tautomers, hydrates or solvates thereof, 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 "compounds of this disclosure".

[0026] This disclosure also provides compounds disclosed herein that are used as pharmaceuticals.

[0027] This disclosure also provides compounds disclosed herein for the treatment or prevention of cancer or diabetes.

[0028] This disclosure also provides pharmaceutical compositions comprising the compounds of this disclosure and optionally a pharmaceutically acceptable carrier.

[0029] This disclosure also provides a medicine box for treating or preventing cancer or diabetes, which contains the pharmaceutical composition of this disclosure and instructions for use.

[0030] This disclosure also provides the use of the compounds disclosed herein for the treatment or prevention of cancer or diabetes.

[0031] 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.

[0032] 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.

[0033] This disclosure also provides methods for treating or preventing cancer or diabetes, said methods comprising administering an effective amount of the compound of this disclosure to a subject in need.

[0034] This disclosure also provides combinations comprising the compounds of this disclosure and at least one additional therapeutic agent.

[0035] This disclosure also provides methods for preparing the compounds of this disclosure, and intermediates for preparing the compounds of this disclosure. Invention Details

[0036] Embodiments of the present disclosure

[0037] 1. Compounds of Formula I:

[0038]

[0039] Or its pharmaceutically acceptable salt or stereoisomer, racemate, tautomer, hydrate or solvate, wherein:

[0040] X is a halogenated group or CN;

[0041] Y is either N or CH;

[0042] R1 is selected from:

[0043] 1)-(C=O)-NRaRb, where:

[0044] Ra and Rb are each independently selected from C 1-6 Alkyl, deuterated 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;

[0045] 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;

[0046] 2) A 5-6 membered heteroaryl ring, optionally 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;

[0047] 3) Phenyl, optionally 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;

[0048] R2 and R3 are each independently H or D;

[0049] Cy is a 5-7 membered heterocyclic group, a 5-7 membered cycloalkyl group, or C. 6-10 Aryl ring, which is coated with (R4) m replace;

[0050] R4 groups are independently selected from halogenated groups, CN, OH, and C. 1-6 Alkyl, C 1-6 Alkoxy, 3-6 membered cycloalkyl ring, C 1-6 Alkyl-S(O)2-NR'-, C 1-6 Alkyl-C(O)-NR'-, C 1-6 Alkyl-S(O)2-, C 1-6 Alkyl-OC(O)-NR'- and C 1-6 Alkyl-NR'-C(O)-NR'-, wherein the alkyl, alkoxy, or cycloalkyl ring is optionally substituted by one, two, or three substituents selected from halogen, CN, and OH, and R' is independently H or C. 1-6 alkyl;

[0051] 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 C. 1-6 Alkyl, -C 1-6 Alkyl-OH, C 1-6 Alkoxy-C 1-6 Substitution of alkyl and halogroups

[0052] Base substitution;

[0053] Alternatively, the two R4 atoms attached to the same carbon atom may optionally form a 3-6 membered alkyl ring together with the carbon atom.

[0054] It may be optionally replaced by 1, 2 or 3 halogenated groups;

[0055] R5 is an oxo group or H;

[0056] a and b are each independently 1 or 2;

[0057] c is 1, 2, or 3; and

[0058] m can be 0, 1, 2, or 3.

[0059] 2. The compound according to Scheme 1 or its pharmaceutically acceptable salt or stereoisomer, racemate, tautomer, hydrate or solvate, wherein:

[0060] X is a halogenated group or CN;

[0061] Y is either N or CH;

[0062] R1 is selected from:

[0063] 1)-(C=O)-NRaRb, where:

[0064] Ra and Rb are each independently selected from C 1-6 Alkyl, deuterated C 1-6 alkyl and cyclopropyl, 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;

[0065] 2) A 5-6 membered heteroaryl ring, optionally 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;

[0066] R2 and R3 are each independently H or D;

[0067] Cy is a 5-6 membered heterocyclic group, a 5-6 membered cycloalkyl group, or a phenyl ring, which is bound by (R4). m replace;

[0068] R4 groups are independently selected from halogenated groups, CN, OH, and C. 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkyl-S(O)2-NR'-, C 1-6 Alkyl-C(O)-NR'-, C 1-6 Alkyl-S(O)2-, C 1-6 Alkyl-OC(O)-NR”- and C 1-6 Alkyl-NR'-C(O)-NR'-, wherein the alkyl or alkoxy group is optionally substituted with one, two, or three substituents selected from halogenated and CN groups, and R' is independently H or C. 1-3 alkyl;

[0069] 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 C. 1-6 Alkyl, -C 1-6 Alkyl-OH, C 1-6 Alkoxy-C 1-6 Substitution of alkyl and halogroups

[0070] Base substitution;

[0071] R5 is an oxo group or H;

[0072] a and b are each independently 1 or 2;

[0073] c is 1, 2, or 3; and

[0074] m can be 0, 1, 2, or 3.

[0075] 3. A compound according to any of the foregoing embodiments or a pharmaceutically acceptable salt or stereoisomer, racemate, tautomer, hydrate or solvate thereof, wherein c is 2.

[0076] 4. A compound according to any of the foregoing embodiments or a pharmaceutically acceptable salt or stereoisomer, racemate, tautomer, hydrate or solvate thereof, wherein X is a halogenated group, such as F, Cl or Br.

[0077] 5. A compound according to any of the foregoing embodiments or a pharmaceutically acceptable salt or stereoisomer, racemate, tautomer, hydrate or solvate thereof, wherein X is F.

[0078] 6. A compound according to any of the foregoing embodiments or a pharmaceutically acceptable salt or stereoisomer, racemate, tautomer, hydrate or solvate thereof, wherein R2 and R3 are each independently H.

[0079] 7. A compound according to any of the foregoing embodiments or a pharmaceutically acceptable salt or stereoisomer, racemate, tautomer, hydrate or solvate thereof, wherein R2 and R3 are each independently D.

[0080] 8. A compound according to any of the foregoing embodiments or a pharmaceutically acceptable salt or stereoisomer, racemate, tautomer, hydrate or solvate thereof, wherein a and b are each 1.

[0081] 9. A compound according to any of the foregoing embodiments or a pharmaceutically acceptable salt or stereoisomer, racemate, tautomer, hydrate or solvate thereof, wherein m is 0, 1 or 2.

[0082] 10. A compound according to any of the foregoing embodiments or a pharmaceutically acceptable salt or stereoisomer, racemate, tautomer, hydrate or solvate thereof, wherein m is 1 or 2.

[0083] 11. A compound according to any of the foregoing embodiments, or a pharmaceutically acceptable salt or stereoisomer, racemate, tautomer, hydrate, or solvate thereof, wherein:

[0084] R1 is selected from:

[0085] 1)-(C=O)-NRaRb, where:

[0086] Ra and Rb are each independently C 1-6 Alkyl or deuterated C 1-6 Alkyl groups, optionally surrounded by one, two, or three groups selected from halogenated groups, OH groups, and C groups. 1-6 Substitution of alkoxy groups;

[0087] 2) A 5-6 membered heteroaryl ring, optionally 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.

[0088] 12. A compound according to any of the foregoing embodiments, or a pharmaceutically acceptable salt or stereoisomer, racemate, tautomer, hydrate, or solvate thereof, wherein:

[0089] R1 is selected from:

[0090] 1)-(C=O)-NRaRb, where:

[0091] Ra and Rb are each independently C 1-6 Alkyl groups, optionally surrounded by one, two, or three groups selected from halogenated groups, OH groups, and C groups. 1-6 Substitution of alkoxy groups;

[0092] 2) A 5-6 membered heteroaryl ring, optionally substituted by 1, 2 or 3 substituents selected from halogenated groups, CN and 3-5 membered cycloalkyl rings.

[0093] 13. A compound according to any of the foregoing embodiments, or a pharmaceutically acceptable salt or stereoisomer, racemate, tautomer, hydrate, or solvate thereof, wherein:

[0094] R1 is selected from:

[0095] 1)-(C=O)-NRaRb, where:

[0096] Ra and Rb are each independently C 1-6 Alkyl group, optionally surrounded by a group selected from halogen, OH, and C. 1-6 Substitution of alkoxy groups;

[0097] 2) A 5-6 membered heteroaryl ring, which is optionally substituted by 1, 2 or 3 substituents selected from halogenated groups, CN and cyclopropyl groups.

[0098] 14. A compound according to any of the foregoing embodiments, or a pharmaceutically acceptable salt or stereoisomer, racemate, tautomer, hydrate, or solvate thereof, wherein:

[0099] R1 is selected from:

[0100] 1)-(C=O)-NRaRb, where:

[0101] Ra and Rb are each independently C 1-3 Alkyl group, optionally surrounded by a group selected from halogen, OH, and C. 1-6 Substitution of alkoxy groups;

[0102] 2) A 5-6 membered heteroaryl ring, which is optionally substituted by 1 or 2 cyclopropyl groups.

[0103] 15. A compound according to any of the foregoing embodiments, or a pharmaceutically acceptable salt or stereoisomer, racemate, tautomer, hydrate, or solvate thereof, wherein R1 is -(C=O)-NRaRb, wherein Ra and Rb are each independently C 1-3 Alkyl group, which is optionally replaced by an OH group.

[0104] 16. A compound according to embodiment 14 or a pharmaceutically acceptable salt or stereoisomer, racemate, tautomer, hydrate or solvate thereof, wherein R1 is

[0105] 17. A compound according to any one of embodiments 1-13 or a pharmaceutically acceptable salt or stereoisomer, racemate, tautomer, hydrate or solvate thereof, wherein R1 is a pyrimidinyl or pyridinyl group substituted with one or two cyclopropyl groups, such as a pyrimidin-5-yl group substituted with one cyclopropyl group or a pyridin-3-yl group substituted with one cyclopropyl group.

[0106] 18. A compound according to embodiment 16 or a pharmaceutically acceptable salt or stereoisomer, racemate, tautomer, hydrate or solvate thereof, wherein R1 is

[0107] 19. A compound according to any of the foregoing embodiments, or a pharmaceutically acceptable salt or stereoisomer, racemate, tautomer, hydrate, or solvate thereof, wherein:

[0108] R4 groups are independently selected from halogenated groups, CN, OH, and C. 1-6 alkylsulfonyl-, C 1-6 Alkyl-S(O)2-NR'-, C 1-6 Alkyl-C(O)-NR'-, C 1-6 Alkyl and C 1-6 The alkoxy group, wherein the alkyl or alkoxy group is optionally substituted with one, two, or three substituents selected from halogenated groups and CN, and R' is independently H or C. 1-3 alkyl;

[0109] 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 C. 1-6 Alkyl, -C 1-6 Alkyl-OH, C 1-6 Alkoxy-C 1-6 Alkyl and halogen substituents.

[0110] 20. A compound according to any of the foregoing embodiments, or a pharmaceutically acceptable salt or stereoisomer, racemate, tautomer, hydrate, or solvate thereof, wherein:

[0111] R4 groups are independently selected from halogenated groups, CN, and C. 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Alkyl-S(O)2-NR'-, C 1-3 Alkyl-C(O)-NR'-, C 1-3 Alkyl-S(O)2-, C 1-3 Alkyl-OC(O)-NR”- and C 1-3Alkyl-NR'-C(O)-NR'-, wherein the alkyl or alkoxy group is optionally substituted with one, two, or three substituents selected from halogenated and CN groups, and R' is independently H or C. 1-3 alkyl;

[0112] Two adjacent R4 atoms, together with the carbon atoms they are attached to, optionally form 3-6 membered alkyl rings.

[0113] 21. A compound according to any of the foregoing embodiments, or a pharmaceutically acceptable salt or stereoisomer, racemate, tautomer, hydrate, or solvate thereof, wherein:

[0114] R4 groups are independently selected from halogenated groups, CN, and C. 1-3 Alkyl, C 1-3 Alkoxy and C 1-3 Alkyl-S(O)2-NR'-, wherein the alkyl or alkoxy group is optionally substituted with 1, 2 or 3 halogroups, and R' is H;

[0115] Two adjacent R4 atoms, together with the carbon atoms they are attached to, optionally form 3- to 5-membered alkyl rings.

[0116] 22. A compound according to any of the foregoing embodiments, or a pharmaceutically acceptable salt or stereoisomer, racemate, tautomer, hydrate, or solvate thereof, wherein Cy is a 5-6 membered saturated heterocyclic group, 5-6 membered cycloalkyl group, or phenyl ring in which one or two ring atoms are heteroatoms independently selected from N, O, and S, and is subjected to (R4). m replace.

[0117] 23. A compound according to any of the foregoing embodiments, or a pharmaceutically acceptable salt or stereoisomer, racemate, tautomer, hydrate, or solvate thereof, wherein...

[0118] R5 is an oxo group, and Cy is a structural moiety. Where m is 0, 1, 2, or 3, and n is 0 or 1, provided that R4, if present, substitutes for any chemically permissible position other than the N atom; or

[0119] R5 is H, and Cy is the structural part. Where m is 0 or 1; if the ring with Z is a 6-membered cycloalkyl or phenyl ring, then m is 1; and if the ring with Z is a 6-membered heterocyclic group, such as a 6-membered saturated heterocyclic group, then Z is O or S, and m is 0.

[0120] 24. A compound according to any of the foregoing embodiments, or a pharmaceutically acceptable salt or stereoisomer, racemate, tautomer, hydrate, or solvate thereof, wherein:

[0121] Cy is selected from:

[0122]

[0123] 25. A compound according to any one of embodiments 1-23, or a pharmaceutically acceptable salt or stereoisomer, racemate, tautomer, hydrate, or solvate thereof, wherein said compound has the structure of formula II:

[0124]

[0125] Where m is 0, 1, 2 or 3, and n is 0 or 1;

[0126] The condition is that R4, if present, substitutes for any chemically permissible position other than the N atom.

[0127] 26. A compound according to embodiment 25 or a pharmaceutically acceptable salt or stereoisomer, racemate, tautomer, hydrate or solvate thereof, wherein n is 0.

[0128] 27. A compound according to embodiment 25 or a pharmaceutically acceptable salt or stereoisomer, racemate, tautomer, hydrate or solvate thereof, wherein n is 1.

[0129] 28. A compound according to any one of embodiments 25-27, or a pharmaceutically acceptable salt or stereoisomer, racemate, tautomer, hydrate, or solvate thereof, wherein:

[0130] R4 groups are independently selected from halogenated groups, CN, and 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 and CN;

[0131] 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 C. 1-6 Alkyl, -C 1-6 Alkyl-OH, C 1-6 Alkoxy-C 1-6 Alkyl and halogen substituents.

[0132] 29. A compound according to any one of embodiments 25-27, or a pharmaceutically acceptable salt or stereoisomer, racemate, tautomer, hydrate or solvate thereof, wherein:

[0133] R4 groups are independently selected from halogenated groups, C4 groups, and C4 groups. 1-3 Alkyl and C 1-3 Alkoxy group, wherein the alkyl or alkoxy group is optionally substituted with one, two or three halogroups;

[0134] Two adjacent R4 atoms, together with the carbon atoms they are attached to, optionally form 3- to 5-membered alkyl rings.

[0135] 30. The compound according to embodiment 25 or a pharmaceutically acceptable salt or stereoisomer, racemate, tautomer, hydrate or solvate thereof, wherein:

[0136] X is a halogenated group;

[0137] Y is either N or CH;

[0138] R1 is selected from:

[0139] 1)-(C=O)-NRaRb, where:

[0140] Ra and Rb are each independently C 1-3 Alkyl group, optionally surrounded by a group selected from halogen, OH, and C. 1-6 Substitution of alkoxy groups;

[0141] 2) A 5-6 membered heteroaryl ring, which is optionally substituted with 1 or 2 cyclopropyl groups;

[0142] R4 groups are independently selected from halogenated groups, C4 groups, and C4 groups. 1-3 Alkyl and C 1-3 Alkoxy group, wherein the alkyl or alkoxy group is optionally substituted with one, two or three halogroups;

[0143] Two adjacent R4 atoms, together with the carbon atoms they are attached to, optionally form 3- to 5-membered alkyl rings;

[0144] R5 is an oxo group;

[0145] a and b are both 1;

[0146] c is 2;

[0147] n is 1; and

[0148] m can be 0, 1, or 2.

[0149] 31. A compound or a pharmaceutically acceptable salt or stereoisomer, racemate, tautomer, hydrate or solvate thereof according to any one of embodiments 25-30, wherein Y is CH.

[0150] 32. A compound according to any one of embodiments 25-30, or a pharmaceutically acceptable salt or stereoisomer, racemate, tautomer, hydrate or solvate thereof, wherein Y is N.

[0151] 33. A compound according to any one of embodiments 25-32 or a pharmaceutically acceptable salt or stereoisomer, racemate, tautomer, hydrate or solvate thereof, wherein m is 1 or 2.

[0152] 34. A compound according to any one of embodiments 25-33, or a pharmaceutically acceptable salt or stereoisomer, racemate, tautomer, hydrate, or solvate thereof, wherein m is 1 and R4 is C 1-3 Alkyl groups, such as methyl groups.

[0153] 35. A compound according to any one of embodiments 25-34, or a pharmaceutically acceptable salt or stereoisomer, racemate, tautomer, hydrate, or solvate thereof, wherein the structural part is described above. yes

[0154] 36. A compound according to any one of embodiments 25-33 or a pharmaceutically acceptable salt or stereoisomer, racemate, tautomer, hydrate or solvate thereof, wherein m is 2 and two adjacent R4s together with the carbon atoms to which they are attached form a cyclopentyl or cyclopropyl group.

[0155] 37. A compound according to any one of embodiments 25-33, or a pharmaceutically acceptable salt or stereoisomer, racemate, tautomer, hydrate, or solvate thereof, wherein the structural moiety is... yes

[0156] 38. A compound or a pharmaceutically acceptable salt or stereoisomer, racemate, tautomer, hydrate or solvate thereof according to any one of embodiments 25-33, wherein:

[0157] Structural parts Selected from:

[0158] 39. A compound according to any one of embodiments 1-23 or a pharmaceutically acceptable salt or stereoisomer, racemate, tautomer, hydrate or solvate thereof, wherein R5 is H.

[0159] 40. A compound according to embodiment 39 or a pharmaceutically acceptable salt or stereoisomer, racemate, tautomer, hydrate or solvate thereof, wherein Cy is a structural moiety. R4 groups are independently selected from halogenated groups, CN, OH, and C. 1-6 Alkyl-S(O)2-NR'-, C 1-6 Alkyl-C(O)-NR'-, C 1-6 Alkyl-S(O)2-, C1-6 Alkyl-OC(O)-NR”- and C 1-6 Alkyl-NR'-C(O)-NR'-, m is 0 or 1, and R' is independently H or C. 1-3 alkyl;

[0160] If the ring with Z is a 6-membered cycloalkyl or phenyl ring, then m is 1; and

[0161] If the ring with Z is a 6-membered heterocyclic group, such as a 6-membered saturated heterocyclic group, then Z is O or S, and m is 0.

[0162] 41. A compound according to embodiment 40, or a pharmaceutically acceptable salt or stereoisomer, racemate, tautomer, hydrate, or solvate thereof, wherein said compound has the structure of formula III:

[0163]

[0164] 42. A compound according to any one of embodiments 40-41, or a pharmaceutically acceptable salt or stereoisomer, racemate, tautomer, hydrate, or solvate thereof, wherein m is 1, the ring having Z is a 6-membered cycloalkyl or phenyl ring, and R4 is selected from C 1-3 Alkyl-S(O)2-NR'-, C 1-3 Alkyl-C(O)-NR'-, C 1-3 Alkyl-S(O)2-, C 1-3 Alkyl-OC(O)-NR”-, C 1-3 Alkyl group -NR'-C(O)-NR'-, CN, halogroup and OH, where R' is H.

[0165] 43. A compound according to any one of embodiments 40-41, or a pharmaceutically acceptable salt or stereoisomer, racemate, tautomer, hydrate, or solvate thereof, wherein m is 1, the ring having Z is a 6-membered cycloalkyl group, and R4 is selected from C1. 1-3 Alkyl-S(O)2-NH-, C 1-3 Alkyl-C(O)-NH-, C 1-3 Alkyl-S(O)2-, C 1-3 Alkyl-OC(O)-NH- and C 1-3 Alkyl-NR'-C(O)-NH-.

[0166] 44. A compound according to embodiment 43 or a pharmaceutically acceptable salt or stereoisomer, racemate, tautomer, hydrate or solvate thereof, wherein R4 is C 1-3 Alkyl-S(O)2-NH-, such as ethyl-S(O)2-NH-.

[0167] 45. A compound according to any one of embodiments 40-44, or a pharmaceutically acceptable salt or stereoisomer, racemate, tautomer, hydrate, or solvate thereof, wherein the Z-ring is

[0168] 46. ​​A compound according to any one of embodiments 40-41 or a pharmaceutically acceptable salt or stereoisomer, racemate, tautomer, hydrate or solvate thereof, wherein m is 1, the ring having Z is phenyl, and R4 is selected from CN, halogenated and OH.

[0169] 47. A compound according to embodiment 46 or a pharmaceutically acceptable salt or stereoisomer, racemate, tautomer, hydrate or solvate thereof, wherein R4 is CN.

[0170] 48. The compound according to embodiment 46 or a pharmaceutically acceptable salt or stereoisomer, racemate, tautomer, hydrate or solvate thereof, wherein the Z-ring is

[0171] 49. A compound according to any one of embodiments 40-41 or a pharmaceutically acceptable salt or stereoisomer, racemate, tautomer, hydrate or solvate thereof, wherein m is 0, Z is O or S, and the ring having Z is a 6-membered saturated heterocyclic group.

[0172] 50. The compound according to embodiment 49 or a pharmaceutically acceptable salt or stereoisomer, racemate, tautomer, hydrate or solvate thereof, wherein the ring having Z is

[0173] 51. A compound according to any one of embodiments 1-23, or a pharmaceutically acceptable salt or stereoisomer, racemate, tautomer, hydrate, or solvate thereof, wherein said compound is selected from:

[0174]

[0175]

[0176]

[0177]

[0178] 52. The compound according to embodiment 51 or a pharmaceutically acceptable salt or stereoisomer, racemate, tautomer, hydrate or solvate thereof, wherein the pharmaceutically acceptable salt is a formate.

[0179] 53. A compound of any one of embodiments 1-52 or a pharmaceutically acceptable salt or stereoisomer, racemate, tautomer, hydrate or solvate thereof, used as a medicine.

[0180] 54. A compound of any one of embodiments 1-52 or a pharmaceutically acceptable salt or stereoisomer, racemate, tautomer, hydrate or solvate thereof, for the treatment or prevention of cancer and other diseases mediated by the interaction of menin with MLL and / or MLL fusion proteins.

[0181] 55. A compound of any one of embodiments 1-52 or a pharmaceutically acceptable salt or stereoisomer, racemate, tautomer, hydrate or solvate thereof, for the treatment or prevention of cancer or diabetes;

[0182] 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;

[0183] 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), mixed lineage leukemia (ML). 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.

[0184] 56. A pharmaceutical composition comprising a compound of any one of embodiments 1-52 or a pharmaceutically acceptable salt or stereoisomer, racemate, tautomer, hydrate or solvate thereof, and optionally a pharmaceutically acceptable carrier.

[0185] 57. Use of any compound of any of embodiments 1-52 or a pharmaceutically acceptable salt or stereoisomer, racemate, tautomer, hydrate or solvate thereof in the preparation of a medicament for the treatment or prevention of cancer or diabetes.

[0186] 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;

[0187] 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), mixed lineage leukemia (ML). 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.

[0188] 58. A method for inhibiting the interaction of menin with MLL and / or MLL fusion protein in vivo or in vitro, the method comprising contacting an effective amount of a compound of any one of embodiments 1-52 or a pharmaceutically acceptable salt thereof with menin and MLL and / or MLL fusion protein.

[0189] 59. A method for treating or preventing cancer or diabetes, the method comprising administering to a subject in need an effective amount of any one of embodiments 1-52 of the compound or a pharmaceutically acceptable salt or stereoisomer, racemate, tautomer, hydrate or solvate thereof;

[0190] 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;

[0191] 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), mixed lineage leukemia (ML). 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.

[0192] 60. A combination comprising a compound of any one of embodiments 1-52 or a pharmaceutically acceptable salt or stereoisomer, racemate, tautomer, hydrate or solvate 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.

[0193] Definitions

[0194] The following words, phrases and symbols used in this disclosure have the meanings described below, unless otherwise stated in the context.

[0195] 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.

[0196] 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.

[0197] 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.

[0198] 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.

[0199] 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.

[0200] 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.

[0201] 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.

[0202] 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.

[0203] 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 6-10 The 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.

[0204] 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:

[0205] -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);

[0206] or

[0207] -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.

[0208] 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.

[0209] The term "oxo-group" as used in this article refers to the group =O.

[0210] The group "D" indicates that the hydrogen atom on the group has been replaced by its isotope deuterium.

[0211] 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.

[0212] 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.

[0213] 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.

[0214] 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.

[0215] 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.

[0216] 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).

[0217] 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]. 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).

[0218] 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.

[0219] 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.

[0220] 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.

[0221] 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.

[0222] 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.

[0223] 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.

[0224] 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.

[0225] The term "inhibition" refers to a reduction in the baseline activity of a biological activity or process.

[0226] 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.

[0227] 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.

[0228] 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, 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), mixed lineage leukemia (MLL), MLL rearrangement leukemia (MLLr leukemia), and MLL partial tandem duplication leukemia (MLL-P). TD 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.

[0229] 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.

[0230] 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.

[0231] Pharmaceutical compositions and administration

[0232] 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.

[0233] 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).

[0234] 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.

[0235] 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.

[0236] 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.

[0237] Indications and methods of treatment

[0238] 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.

[0239] 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.

[0240] 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.

[0241] In one embodiment, the compounds disclosed herein are used to treat or prevent cancer or diabetes.

[0242] 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.

[0243] 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.

[0244] Pharmaceutical combinations

[0245] 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.

[0246] 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.

[0247] General synthetic methods

[0248] Compounds of the examples having a general structure such as A10 can be synthesized according to process 1. The reaction of phenol A1 and 5-bromopyrimidine under basic conditions yields diaryl ether A2, which can be converted to N-oxide A3 in the presence of mCPBA. The subsequent reaction of the latter with a chlorinating agent such as POCl3 conveniently yields chloropyrimidine A4. A nucleophilic substitution reaction between chloride A4 and monoprotected spirodiamine A5 yields the key intermediate A6. Subsequently, deprotection occurs, forming an amide with the N-protected cyclic amino acid A8, and N-deprotection of A9 yields the final compound A10.

[0249] Process 1

[0250]

[0251] Compounds of the examples having a general structure such as C6 can be synthesized according to procedure 2. A selective nucleophilic substitution reaction between a monoprotected bridged spirodiamine A5 and 3,5,6-trichloro-1,2,4-triazine C1 yields triazine C2. A second nucleophilic substitution with phenol C3 yields a monohydrate 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.

[0252] Process 2

[0253]

[0254] Examples of compounds having a general formula such as C7 / C8 can be synthesized according to procedure 3. After deprotection, C5 / A7 reacts with A9, A10 or A11 (Ns is 4-nitrobenzene-1-sulfonyl) to give compound C7 / C8.

[0255] Process 3

[0256]

[0257]

[0258] 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.

[0259] 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

[0260] The following embodiments are intended to illustrate the present invention only and should not be construed as limiting the present invention in any way.

[0261] 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).

[0262] All reagents and raw materials used in this invention, except for the intermediates prepared below, are commercially available or prepared according to existing technology.

[0263] 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.

[0264] 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.

[0265] 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.

[0266] The following abbreviations are used in the following embodiments:

[0267] List of abbreviations

[0268]

[0269]

[0270] Preparation of key intermediates

[0271] Preparation of intermediate 1

[0272] 8'-Zazaspiro[azacyclobutane-3,3'-bicyclo[3.2.1]octane]-8'-tert-butyl carboxylate

[0273]

[0274] Step 1:

[0275] LDA (12 mL, 24.0 mmol) was added dropwise to a stirred solution of tert-butyl 3-cyano-8-azabicyclo[3.2.1]octane-8-carboxylate (5.01 g, 21.2 mmol) in THF (30 mL) at -78 °C under N2 atmosphere for 30 minutes. The resulting mixture was stirred for 30 minutes, followed by the addition of BOM-Cl (3.5 mL, 25.5 mmol). The reaction mixture was then stirred at -78 °C for another hour. The reaction mixture was carefully poured into ice water (50 mL), extracted with EtOAc (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 in PE = 1-10%) to obtain the desired product 3-[(benzyloxy)methyl]-3-cyano-8-azabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (4.53 g, yield: 59.6%), a pale yellow solid. 1 H NMR (400MHz, CDCl3) δ7.40-7.29 (m, 5H), 4.57 (s, 2H), 4.27 (d, J = 29.4Hz, 2H), 3.3 4(s,2H),2.23(d,J=7.6Hz,2H),2.03(t,J=20.9Hz,6H),1.58(s,2H),1.42(s,9H).

[0276] Step 2:

[0277] Pd / C (400 mg) was added to a stirred solution of 3-[(benzyloxy)methyl]-3-cyano-8-azabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (3.98 g, 11.2 mmol) in MeOH (50 mL). The resulting mixture was stirred at room temperature under a H2 atmosphere for 18 hours. The reaction mixture was filtered, and the filter cake was washed with EtOAc (50 mL x 3). The combined organic phases were concentrated to give crude product 3-cyano-3-(hydroxymethyl)-8-azabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (2.06 g, yield: 66.9%) as a pale yellow oil, which was used in the next step without further purification. 1H NMR (400MHz, CDCl3) δ 4.43-4.19 (m, 2H), 3.54 (s, 2H), 2.33-2.18 (m, 3H), 2.09 (d, J = 5.0Hz, 2H), 1.97 (s, 2H), 1.85 (s, 2H), 1.45 (s, 9H).

[0278] Step 3:

[0279] 4-Nitrobenzene-1-sulfonyl chloride (NsCl) (600 mg, 2.7 mmol) was added to a stirred solution of 3-cyano-3-(hydroxymethyl)-8-azabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (500 mg, 1.9 mmol) and TEA (0.68 mL, 4.9 mmol) in THF (10 mL). The resulting mixture was stirred at room temperature for 18 hours. The reaction mixture was quenched with saturated NH4Cl solution (10 mL), 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 (EtOAc in PE = 1-30%) to obtain the desired product 3-cyano-3-{[(4-nitrobenzenesulfonyl)oxy]methyl}-8-azabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (200 mg, yield: 23.6%), which is a brown oil. 1 H NMR (400MHz, CDCl3) δ8.44(d,J=8.8Hz,2H),8.14(d,J=8.8Hz,2H),4.31(s, 2H),3.97(s,2H),2.26-2.07(m,4H),1.98(s,2H),1.83(s,2H),1.45(s,9H).

[0280] Step 4:

[0281] Raney nickel (40 mg) was added to a stirred solution of 3-cyano-3-{[(4-nitrobenzenesulfonyl)oxy]methyl}-8-azabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (200 mg, 0.8 mmol) in MeOH (5 mL). The resulting mixture was stirred at room temperature under H2 atmosphere for 12 hours. The reaction mixture was filtered and concentrated to give crude product 8'-azaspiro[azacyclobutane-3,3'-bicyclo[3.2.1]octane]-8'-carboxylic acid tert-butyl ester (60.4 mg, yield: 17.3%) as a grayish-white oil, which could be used directly in the next step without further purification. LC / MS (ESI) m / z: 153 (M+H) + .

[0282] Preparation of intermediate 2,1,2-(2-cyclopropylpyridin-3-yl)-4-fluorophenol

[0283]

[0284] To a stirred solution of 3-bromo-2-cyclopropylpyridine (250 mg, 1.3 mmol) and (5-fluoro-2-hydroxyphenyl)boronic acid (220 mg, 1.4 mmol) in dioxane (4 mL) and H₂O (1 mL), K₂CO₃ (400 mg, 2.9 mmol) and Pd(dppf)Cl₂ (25 mg) were added. The resulting mixture was stirred overnight at 100 °C under a N₂ atmosphere. The reaction mixture was cooled to room temperature, 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 a crude product. This crude product was purified by silica gel column chromatography (EtOAc in PE = 0–20%) to obtain the desired product, 2-(2-cyclopropylpyridin-3-yl)-4-fluorophenol (200 mg, yield: 69.2%), as a pale brown solid. LC / MS (ESI) m / z: 230 (M+H) + .

[0285] Preparation of intermediate 2-2, tert-butyl 1-(dichloro-1,2,4-triazine-5-yl)-8'-azaspiro[azacyclobutane-3,3'-bicyclo[3.2.1]octane]-8'-carboxylic acid ester

[0286]

[0287] To a stirred solution of trichloro-1,2,4-triazine (550 mg, 2.9 mmol) and TEA (905 mg, 8.96 mmol) in a DCM (10 mL), tert-butyl 8'-azaspiro[azacyclobutane-3,3'-bicyclo[3.2.1]octane]-8'-carboxylate (750 mg, 2.9 mmol, intermediate 1) was added. The resulting mixture was stirred at room temperature under a N2 atmosphere for 4 hours. The reaction mixture was quenched 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 obtain a crude product. This crude product was purified by silica gel column chromatography (EtOAc in PE = 0–25%) to obtain the desired product 1-(dichloro-1,2,4-triazine-5-yl)-8'-azaspiro[azacyclobutane-3,3'-bicyclo[3.2.1]octane]-8'-carboxylic acid tert-butyl ester (541 mg, yield: 45.4%), which is a yellow solid. 1H NMR (400MHz, CDCl3) δ4.75 (s, 1H), 4.34 (d, J = 44.0Hz, 4H), 3.90 (s, 1H), 2.04 (t, J = 13.1Hz, 6H), 1.69 (dd, J = 19.5, 7.9Hz, 2H), 1.47 (s, 9H). LCMS:ESI m / z 401(M+1) + .

[0288] Preparation of intermediate 2, 1-{6-[2-(2-cyclopropylpyridin-3-yl)-4-fluorophenoxy]-1,2,4-triazin-5-yl}-8'-azaspiro[azacyclobutane-3,3'-bicyclo[3.2.1]octane]

[0289]

[0290] Step 1:

[0291] DBU (30 mg, 0.3 mmol) was added to a stirred solution of 2-(2-cyclopropylpyridin-3-yl)-4-fluorophenol (60 mg, 0.3 mmol, intermediate 2-2) and 1-(dichloro-1,2,4-triazin-5-yl)-8'-azaspiro[azacyclobutane-3,3'-bicyclo[3.2.1]octane]-8'-carboxylic acid tert-butyl ester (104 mg, 0.3 mmol, intermediate 2-1) in THF (5 mL). The resulting mixture was stirred at room temperature under a nitrogen atmosphere for 12 hours. The reaction mixture was diluted with H2O (10 mL) and extracted with EtOAc (20 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 = 20–50%) to yield the desired product, 1-{3-chloro-6-[2-(2-cyclopropylpyridin-3-yl)-4-fluorophenoxy]-1,2,4-triazin-5-yl}-8'-azaspiro[azacyclobutane-3,3'-bicyclo[3.2.1]octane]-8'-carboxylic acid tert-butyl ester (60 mg, yield: 38.7%), as a brown solid. LC / MS (ESI) m / z: 594 (M+H) + .

[0292] Step 2:

[0293] Pd / C (10 mg) was added to a solution of 1-{3-chloro-6-[2-(2-cyclopropylpyridin-3-yl)-4-fluorophenoxy]-1,2,4-triazin-5-yl}-8'-azaspiro[azacyclobutane-3,3'-bicyclo[3.2.1]octane]-8'-carboxylic acid tert-butyl ester (60 mg, 0.1 mmol) in MeOH (5 mL) under stirring. The resulting mixture was stirred at room temperature under H2 atmosphere for 1 hour. The reaction mixture was filtered and concentrated to give crude product 1-{6-[2-(2-cyclopropylpyridin-3-yl)-4-fluorophenoxy]-1,2,4-triazin-5-yl}-8'-azaspiro[azacyclobutane-3,3'-bicyclo[3.2.1]octane]-8'-carboxylic acid tert-butyl ester (50 mg, yield: 88.5%), as a yellow solid, which was used directly in the next step without further purification. LC / MS (ESI) m / z: 559 (M+H) + .

[0294] Step 3:

[0295] TFA (1 mL) was added to a stirred solution of 1-{6-[2-(2-cyclopropylpyridin-3-yl)-4-fluorophenoxy]-1,2,4-triazin-5-yl}-8'-azaspiro[azacyclobutane-3,3'-bicyclo[3.2.1]octane]-8'-carboxylic acid tert-butyl ester (50 mg, 0.1 mmol) in a DCM (3 mL). The resulting mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated to give crude product 1-{6-[2-(2-cyclopropylpyridin-3-yl)-4-fluorophenoxy]-1,2,4-triazin-5-yl}-8'-azaspiro[azacyclobutane-3,3'-bicyclo[3.2.1]octane] (40 mg, yield: 96.8%), a brown oil, which was used directly in the next step without further purification. LC / MS (ESI) m / z: 459 (M+H) + .

[0296] Preparation of intermediate 3, 2-((5-(8'-azaspiro[azacyclobutane-3,3'-bicyclo[3.2.1]octane]-1-yl)-1,2,4-triazine-6-yl)oxy)-5-fluoro-N-(2-hydroxyethyl)-N-isopropylbenzamide

[0297]

[0298] Step 1:

[0299] 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-[(propane-2-yl)amino]ethane-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, extracted with EtOAc (50 mL x 3), and 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-(propane-2-yl)benzamide (2.5 g, yield: 83.3%), as a white solid. LC / MS (ESI) m / z: 256 (M+H) + .

[0300] Step 2:

[0301] BBr3 (2.79 mL, 2.79 mmol, 1 M in DCM) was added dropwise to a solution of 5-fluoro-N-(2-hydroxyethyl)-2-methoxy-N-(propane-2-yl)benzamide (550 mg, 2.15 mmol) in DCM (10 mL) at -60 °C under a N2 atmosphere. The resulting mixture was stirred at -60 °C for 3 hours. The mixture was then quenched with MeOH at 0 °C and diluted with DCM (20 mL). The organic phase was 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 in PE = 10–50%) to obtain the desired product, 5-fluoro-2-hydroxy-N-(2-hydroxyethyl)-N-(propane-2-yl)benzamide (230 mg, yield: 44.3%), as a pale yellow slurry. LC / MS(ESI) m / z: 242(M+H) + .

[0302] Step 3:

[0303] DBU (100 mg, 0.7 mmol) was added to a stirred solution of 5-fluoro-2-hydroxy-N-(2-hydroxyethyl)-N-(propane-2-yl)benzamide (50 mg, 0.2 mmol) and tert-butyl 1-(dichloro-1,2,4-triazin-5-yl)-8'-azaspiro[azacyclobutane-3,3'-bicyclo[3.2.1]octane]-8'-carboxylate (84 mg, 0.2 mmol, intermediate 2-2) in THF (5 mL), and the resulting mixture was stirred at room temperature under a nitrogen atmosphere for 24 hours. The reaction mixture was quenched with saturated NH4Cl solution (5 mL) and then extracted with EtOAc (10 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 in PE = 10–50%) to obtain the desired product, 1-(3-chloro-6-{4-fluoro-2-[(2-hydroxyethyl)(propane-2-yl)carbamoyl]phenoxy}-1,2,4-triazin-5-yl)-8'-azaspiro[azacyclobutane-3,3'-bicyclo[3.2.1]octane]-8'-carboxylic acid tert-butyl ester (40 mg, yield: 32%), as a brown solid. LC / MS (ESI) m / z: 605(M+H)+.

[0304] Step 4:

[0305] TEA (20 mg, 0.19 mmol) and Pd / C (10 mg) were added to a stirred solution of 1-(3-chloro-6-{4-fluoro-2-[(2-hydroxyethyl)(propane-2-yl)carbamoyl]phenoxy}-1,2,4-triazin-5-yl)-8'-azaspiro[azacyclobutane-3,3'-bicyclo[3.2.1]octane]-8'-carboxylic acid tert-butyl ester (40 mg, 0.06 mmol) in MeOH (5 mL). The resulting mixture was stirred at room temperature under H2 atmosphere for 1 hour, then filtered and concentrated. The crude product was purified by silica gel column chromatography (EtOAc = 0–20% in DCM) to give the desired product 1-(6-{4-fluoro-2-[(2-hydroxyethyl)(propane-2-yl)carbamoyl]phenoxy}-1,2,4-triazin-5-yl)-8'-azaspiro[azacyclobutane-3,3'-bicyclo[3.2.1]octane]-8'-carboxylic acid tert-butyl ester (30 mg, yield: 79.5%), as a white solid. LC / MS (ESI) m / z: 571 (M+H)+.

[0306] Step 5:

[0307] TFA (0.5 mL, 6.73 mmol) was added to a solution of tert-butyl 1-(6-{4-fluoro-2-[(2-hydroxyethyl)(propane-2-yl)carbamoyl]phenoxy}-1,2,4-triazin-5-yl)-8'-azaspiro[azacyclobutane-3,3'-bicyclo[3.2.1]octane]-8'-carboxylic acid (tert-butyl ester) (30 mg, 0.05 mmol) in a stirred DCM (0.5 mL). The mixture was stirred at 25 °C for 1 hour. The reaction mixture was concentrated to give crude product 2-[(5-{8'-azaspiro[azacyclobutane-3,3'-bicyclo[3.2.1]octane]-1-yl}-1,2,4-triazin-6-yl)oxy]-5-fluoro-N-(2-hydroxyethyl)-N-(propane-2-yl)benzamide (20 mg, yield: 80.8%), a brown oil, which was used directly in the next step without further purification. LC / MS (ESI) m / z: 471 (M+H) + .

[0308] Preparation of intermediate 4, 2-[(4-{8'-azaspiro[azacyclobutane-3,3'-bicyclo[3.2.1]octane]-1-yl}pyrimidin-5-yl)oxy]-N-ethyl-5-fluoro-N-(propane-2-yl)benzamide

[0309]

[0310] Step 1:

[0311] Ethyl(propane-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 allowed to cool to room temperature naturally 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-(propane-2-yl)benzamide (10.0 g, yield: 94.8%), as a pale yellow solid. LC / MS (ESI) m / z: 240 (M+H) + .

[0312] Step 2:

[0313] BBr3 (37.6 mL, 1.0 M in DCM) was added dropwise to a solution of N-ethyl-5-fluoro-2-methoxy-N-(propane-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 with saturated NaHCO3 cooled to 0 °C. 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-(propane-2-yl)benzamide (4.01 g, yield: 47.2%), as a pale yellow solid, which could be used in the next step without further purification. LC / MS (ESI) m / z: 226 (M+H) + .

[0314] Step 3:

[0315] 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-(propane-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 obtain the desired product, N-ethyl-5-fluoro-N-(propane-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) + .

[0316] Step 4:

[0317] m-CPBA (3.41 g, 19.8 mmol) was added in portions to a solution of N-ethyl-5-fluoro-N-(propane-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 solution (20 mL), 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 in PE = 0–80%) to obtain the desired product 5-{2-[ethyl(propane-2-yl)carbamoyl]-4-fluorophenoxy}pyrimidin-1-onthium-1-ol salt (900 mg, yield: 42.8%) as a white solid. LC / MS (ESI) m / z: 320 (M+H) + .

[0318] Step 5:

[0319] POCl3 (0.80 mL, 8.4 mmol) was added dropwise to a solution of 5-{2-[ethyl(propane-2-yl)carbamoyl]-4-fluorophenoxy}pyrimidin-1-onyl-1-ol (900 mg, 2.8 mmol) and TEA (566 mg, 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-(propane-2-yl)benzamide (320 mg, yield: 33.6%) as a brown oil, which could be used in the next step without further purification. LC / MS (ESI) m / z: 338 / 340 (M+H) + .

[0320] Step 6:

[0321] DIPEA (40 mg, 0.3 mmol) was added to a solution of tert-butyl 8'-azaspiro[azacyclobutane-3,3'-bicyclo[3.2.1]octane]-8'-carboxylate (25 mg, 0.09 mmol, intermediate 1) and 2-[(4-chloropyrimidin-5-yl)oxy]-N-ethyl-5-fluoro-N-(propane-2-yl)benzamide (50 mg, 0.15 mmol) in a stirred DCM (2 mL) at room temperature. The resulting mixture was stirred at room temperature for 12 hours. The reaction mixture was poured into ice water (10 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 preparative-TLC (MeOH in DCM = 3%) to give the desired product, 1-(5-{2-[ethyl(propane-2-yl)carbamoyl]-4-fluorophenoxy}pyrimidin-4-yl)-8'-azaspiro[azacyclobutane-3,3'-bicyclo[3.2.1]octane]-8'-carboxylic acid tert-butyl ester (35 mg, yield: 63.8%), as a white solid. LC / MS (ESI) m / z: 554 (M+H) + .

[0322] Step 7:

[0323] TFA (1 mL) was added to a stirred solution of 1-(5-{2-[ethyl(propane-2-yl)carbamoyl]-4-fluorophenoxy}pyrimidin-4-yl)-8'-azaspiro[azacyclobutane-3,3'-bicyclo[3.2.1]octane]-8'-carboxylic acid tert-butyl ester (35 mg, 0.06 mmol) in a DCM (2 mL). The resulting mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated to give crude product 2-[(4-{8'-azaspiro[azacyclobutane-3,3'-bicyclo[3.2.1]octane]-1-yl}pyrimidin-5-yl)oxy]-N-ethyl-5-fluoro-N-(propane-2-yl)benzamide (25 mg, yield: 87.2%), a brown oily substance, which can be used directly in the next step without further purification. LC / MS (ESI) m / z: 454 (M+H) + .

[0324] Preparation of intermediate 5

[0325] 4-Methylbenzene-1-sulfonic acid [trans-4-ethanesulfonylaminocyclohexyl]methyl ester

[0326]

[0327] Step 1:

[0328] Ethylenesulfonyl chloride (18.2 mL, 190 mmol) was slowly added to a solution of trans-4-aminocyclohexane-1-carboxylate hydrochloride (25 g, 159 mmol) and TEA (64.3 g, 636 mmol) in DCM (500 mL) at -10 °C. The resulting mixture was stirred at 0 °C for 3 hours and then quenched with saturated NH4Cl solution (50 mL). The organic phase was collected, and the aqueous phase was extracted with DCM (50 mL x 3). The combined organic phases were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated to give crude trans-4-ethanesulfonylaminocyclohexane-1-carboxylate (30 g, yield: 75.6%) as a yellow solid, which was used directly in the next step without further purification. LC / MS (ESI) m / z: 250 (M+H) + .

[0329] Step 2:

[0330] LAH (2.74 g, 72.2 mmol) was slowly added to a solution of trans-4-ethanesulfonamide cyclohexane-1-carboxylate (15 g, 60.2 mmol) in THF (150 mL) at -0 °C, while maintaining the internal temperature below 5 °C during the addition. The resulting mixture was stirred at 0 °C for 3 hours, and then quenched by adding water (5 mL), 15% NaOH (5 mL), and then water (10 mL). The solids formed were removed by filtration through a celite pad, and the filter cake was washed with EtOAc (50 mL x 3). The filtrate was dried over anhydrous Na2SO4, filtered, and concentrated to give crude product N-[trans-4-(hydroxymethyl)cyclohexyl]ethane-1-sulfonamide (9 g, yield: 67.6%) as a yellow oil, which was used directly in the next step without further purification. LC / MS (ESI) m / z: 222 (M+H) + .

[0331] Step 3:

[0332] TsCl (7.8 g, 40.7 mmol) was slowly added to a solution of N-[trans-4-(hydroxymethyl)cyclohexyl]ethane-1-sulfonamide (9 g, 40.7 mmol), TEA (12.3 g, 122 mmol), and DMAP (500 mg, 4.07 mmol) in DCM (100 mL) at 0 °C. The resulting mixture was stirred at 0 °C for 6 hours. The reaction mixture was quenched with saturated NH4Cl solution (30 mL), the DCM layer was collected, and the aqueous phase was extracted with DCM (50 mL x 3). 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 in PE = 5–20%) to obtain the desired product, 4-methylbenzene-1-sulfonic acid [trans-4-ethanesulfonylaminocyclohexyl]methyl ester (10 g, yield: 65.5%), as a yellow solid. LC / MS(ESI) m / z: 376 (1 / 2M+H) + .

[0333] Preparation of intermediate 6

[0334] 1-{6-[2-(4-cyclopropylpyrimidin-5-yl)-4-fluorophenoxy]-1,2,4-triazine-5-yl}-8'-azaspiro[azacyclobutane-3,3'-bicyclo[3.2.1]octane]

[0335]

[0336] Step 1:

[0337] 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) and extracted with EtOAc (20 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 = 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) + .

[0338] Step 2:

[0339] 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 and diluted with 20 mL of H₂O. It was then 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) + .

[0340] Step 3:

[0341] DBU (50 mg, 0.33 mmol) was added to a solution of 2-(4-cyclopropylpyrimidin-5-yl)-4-fluorophenol (60 mg, 0.26 mmol) and 1-(dichloro-1,2,4-triazine-5-yl)-8'-azaspiro[azacyclobutane-3,3'-bicyclo[3.2.1]octane]-8'-carboxylic acid tert-butyl ester (70 mg, 0.17 mmol, intermediate 2-2) in THF (5 mL) at 0 °C. The resulting mixture was stirred at room temperature for 24 h, then quenched with saturated NH4Cl solution (10 mL) and extracted with EtOAc (10 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 = 1–50%) to give the desired product 1-{3-chloro-6-[2-(4-cyclopropylpyrimidin-5-yl)-4-fluorophenoxy]-1,2,4-triazin-5-yl}-8'-azaspiro[azacyclobutane-3,3'-bicyclo[3.2.1]octane]-8'-carboxylic acid tert-butyl ester (60 mg, yield: 38.7%), as a white solid. LC / MS (ESI) m / z: 594 (M+H) + .

[0342] Step 4:

[0343] Pd / C (10 mg) was added to a solution of 1-{3-chloro-6-[2-(4-cyclopropylpyrimidin-5-yl)-4-fluorophenoxy]-1,2,4-triazine-5-yl}-8'-azaspiro[azacyclobutane-3,3'-bicyclo[3.2.1]octane]-8'-carboxylic acid tert-butyl ester (50 mg, 0.08 mmol) in MeOH (5 mL), and the resulting mixture was stirred at room temperature under H2 atmosphere for 1 hour. The reaction mixture was filtered, and the filtrate was concentrated to give the crude product 1-{6-[2-(4-cyclopropylpyrimidin-5-yl)-4-fluorophenoxy]-1,2,4-triazin-5-yl}-8'-azaspiro[azacyclobutane-3,3'-bicyclo[3.2.1]octane]-8'-carboxylic acid tert-butyl ester (35 mg, yield: 74.3%), as a brown oil. LC / MS (ESI) m / z: 560 (M+H) + .

[0344] Step 5:

[0345] TFA (0.5 mL) was added to a solution of 1-{6-[2-(4-cyclopropylpyrimidin-5-yl)-4-fluorophenoxy]-1,2,4-triazine-5-yl}-8'-azaspiro[azacyclobutane-3,3'-bicyclo[3.2.1]octane]-8'-carboxylic acid tert-butyl ester (35 mg, 0.06 mmol) in DCM (1 mL) at 0 °C. The resulting mixture was stirred at room temperature under N2 atmosphere for 1 hour. The reaction mixture was concentrated to give crude product 1-{6-[2-(4-cyclopropylpyrimidin-5-yl)-4-fluorophenoxy]-1,2,4-triazin-5-yl}-8'-azaspiro[azacyclobutane-3,3'-bicyclo[3.2.1]octane] (25 mg, yield: 86.9%), a brown oil, which was used directly in the next step without further purification. LC / MS (ESI) m / z: 460 (M+H) + .

[0346] Preparation of intermediate 7, 2-[(5-{8'-azaspiro[azacyclobutane-3,3'-bicyclo[3.2.1]octane]-1-yl}-1,2,4-triazin-6-yl)oxy]-N-ethyl-5-fluoro-N-(propane-2-yl)benzamide

[0347]

[0348] Step 1:

[0349] DBU (50 mg, 0.33 mmol) was added to a solution of tert-butyl 1-(dichloro-1,2,4-triazin-5-yl)-8'-azaspiro[azacyclobutane-3,3'-bicyclo[3.2.1]octane]-8'-carboxylate (100 mg, 0.25 mmol, intermediate 2-2) and N-ethyl-5-fluoro-2-hydroxy-N-(propane-2-yl)benzamide (60 mg, 0.27 mmol) in THF (3 mL). The reaction mixture was stirred at room temperature under a nitrogen atmosphere for 18 hours. The reaction mixture was then poured into a 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 to obtain a crude product. This crude product was purified by silica gel column chromatography (EtOAc in PE = 1–30%) to obtain the desired product, 1-(3-chloro-6-{2-[ethyl(propane-2-yl)carbamoyl]-4-fluorophenoxy}-1,2,4-triazin-5-yl)-8'-azaspiro[azacyclobutane-3,3'-bicyclo[3.2.1]octane]-8'-carboxylic acid tert-butyl ester (90 mg, yield: 61.2%), as a white solid. LC / MS (ESI) m / z: 589 (M+H)+ .

[0350] Step 2:

[0351] Pd / C (10 mg) was added to a solution of tert-butyl 1-(3-chloro-6-{2-[ethyl(propane-2-yl)carbamoyl]-4-fluorophenoxy}-1,2,4-triazin-5-yl)-8'-azaspiro[azacyclobutane-3,3'-bicyclo[3.2.1]octane]-8'-carboxylate (90 mg, 0.15 mmol) and TEA (30 mg, 0.29 mmol) in MeOH (5 mL) at room temperature. The reaction mixture was stirred at room temperature under H2 atmosphere for 30 minutes. The reaction mixture was filtered, and the filtrate was concentrated to give crude product 1-(6-{2-[ethyl(propane-2-yl)carbamoyl]-4-fluorophenoxy}-1,2,4-triazin-5-yl)-8'-azaspiro[azacyclobutane-3,3'-bicyclo[3.2.1]octane]-8'-carboxylic acid tert-butyl ester (70 mg, yield: 82.6%), as a white solid, which was used directly in the next step without further purification. LC / MS (ESI) m / z: 555 (M+H) + .

[0352] Step 3:

[0353] TFA (1 mL) was added to a solution of 1-(6-{2-[ethyl(propane-2-yl)carbamoyl]-4-fluorophenoxy}-1,2,4-triazin-5-yl)-8'-azaspiro[azacyclobutane-3,3'-bicyclo[3.2.1]octane]-8'-carboxylic acid tert-butyl ester (70 mg, 0.13 mmol) in DCM (2 mL) at 0 °C. The resulting mixture was stirred at room temperature under N2 atmosphere for 1 hour. The reaction mixture was concentrated to give crude product 2-[(5-{8'-azaspiro[azacyclobutane-3,3'-bicyclo[3.2.1]octane]-1-yl}-1,2,4-triazin-6-yl)oxy]-N-ethyl-5-fluoro-N-(propane-2-yl)benzamide (50 mg, yield: 87.2%), a brown oil, which was used directly in the next step without further purification. LC / MS (ESI) m / z: 455 (M+H) + .

[0354] Example 1:

[0355] Synthesis of N-ethyl-5-fluoro-2-((4-(8'-((2S,4R)-4-fluoropyrrolidine-2-carbonyl)-8'-azaspiro[azacyclobutane-3,3'-bicyclo[3.2.1]octane]-1-yl)pyrimidin-5-yl)oxy)-N-isopropylbenzamide

[0356]

[0357] Step 1:

[0358] HATU (30 mg, 0.08 mmol) and DIPEA (19 mg, 0.15 mmol) were added to a stirred solution of 2-[(4-{8'-azaspiro[azacyclobutane-3,3'-bicyclo[3.2.1]octane]-1-yl}pyrimidin-5-yl)oxy]-N-ethyl-5-fluoro-N-(propane-2-yl)benzamide (15 mg, 0.03 mmol, intermediate 4) and (2S,4R)-1-[(tert-butoxy)carbonyl]-4-fluoropyrrolidine-2-carboxylic acid (10 mg, 0.04 mmol) in DMF (1 mL). The resulting mixture was stirred at room temperature under a N2 atmosphere for 1 hour, then quenched with a saturated NH4Cl solution (5 mL) and extracted with EtOAc (10 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 preparative-HPLC to yield the desired product: (2S,4R)-2-(1-(5-(2-(ethyl(isopropyl)carbamoyl)-4-fluorophenoxy)pyrimidin-4-yl)-8'-azaspiro[azacyclobutane-3,3'-bicyclo[3.2.1]octane]-8'-ylcarbonyl)-4-fluoropyrrolidine-1-carboxylic acid tert-butyl ester (12 mg, yield: 54.2%), a pale yellow solid. LC / MS (ESI) m / z: 669 (M+H) + .

[0359] Step 2:

[0360] TFA (1 mL) was added to a stirred solution of (2S,4R)-2-(1-(5-(2-(ethyl(isopropyl)carbamoyl)-4-fluorophenoxy)pyrimidin-4-yl)-8'-azaspiro[azacyclobutane-3,3'-bicyclo[3.2.1]octane]-8'-ylcarbonyl)-4-fluoropyrrolidine-1-carboxylic acid tert-butyl ester (10 mg, 0.01 mmol) in DCM (2 mL). The resulting mixture was stirred at room temperature under N2 atmosphere for 1 hour, and then concentrated. The residue was dissolved in DCM (10 mL) and the pH was adjusted to 10 with saturated NH4Cl solution. The organic layer was collected, dried over anhydrous Na2SO4, filtered, and concentrated to obtain a crude product. This crude product was then purified by preparative-HPLC to obtain the desired product, N-ethyl-5-fluoro-2-((4-(8'-((2S,4R)-4-fluoropyrrolidine-2-carbonyl)-8'-azaspiro[azacyclobutane-3,3'-bicyclo[3.2.1]octane]-1-yl)pyrimidin-5-yl)oxy)-N-isopropylbenzamide (2.8 mg, yield: 32.9%), as a white solid. 1H NMR (400MHz, CDCl3) δ8.39-3.38(m,1H),7.82-7.80(m,1H),7.03-7.00(m, 2H),6.73-6.70(m,1H),5.36-5.20(m,1H),4.76-4.66(m,1H),4.36-4.19( m,3H),4.05-4.00(m,1H),3.85-3.82(m,2H),3.51-3.13(m,4H),2.32-1.8 2(m,10H),1.26-1.24(m,5H),1.15-1.07(m,6H),LC / MS(ESI)m / z:569(M+H) + .

[0361] The following compounds were prepared from suitable intermediates or commercially available chemicals according to the experimental procedure used in Example 1:

[0362]

[0363]

[0364]

[0365] Synthesis of Example 8:

[0366] 2-((5-((1'R,5'S)-8'-(4-cyanobenzyl)-8'-azaspiro[azacyclobutane-3,3'-bicyclo[3.2.1]octane]-1-yl)-1,2,4-triazine-6-yl)oxy)-N-ethyl-5-fluoro-N-isopropylbenzamide

[0367]

[0368] K₂CO₃ (15 mg, 0.11 mmol) and NaI (5 mg) were added to a stirred solution of 2-[(5-{8-azaspiro[bicyclo[3.2.1]octane-3,1'-cyclobutane]-3'-yl}-1,2,4-triazin-6-yl)oxy]-N-ethyl-5-fluoro-N-(propane-2-yl)benzamide (20 mg, 0.04 mmol) and 4-(chloromethyl)benzyl nitrile (10 mg, 0.07 mmol, intermediate 7) in MeCN (3 mL). The resulting mixture was stirred at 50 °C for 12 hours. After cooling to room temperature, the reaction mixture was filtered. The filtrate was concentrated to obtain a crude product, which was then purified by preparative-TLC (MeOH:DCM = 1:10) to obtain the desired product 2-[(5-{8'-[(4-cyanophenyl)methyl]-8'-azaspiro[azacyclobutane-3,3'-bicyclo[3.2.1]octane]-1-yl}-1,2,4-triazin-6-yl)oxy]-N-ethyl-5-fluoro-N-(propane-2-yl)benzamide (5 mg, yield: 13%), a white solid. 1 H NMR (400MHz, MeOD) δ8.37(s,1H),7.69(d,J=8.0Hz,2H),7.60(d,J=8.2Hz,2H),7.42-7.37(m,1H),7.31-7.18(m,2H),4.73-4.66(m,1H),4.34-4. 27(m,2H),3.93-3.89(m,1H),3.84-3.77(m,1H),3.69-3.67(m,2H),2.10 -2.07(m,6H),1.84-1.78(m,2H),1.28-1.04(m,11H),0.82-0.77(m,2H). LC / MS(ESI)m / z:570(M+H) + .

[0369] The following compounds were prepared from suitable intermediates or commercially available chemicals according to the experimental procedure used in Example 8.

[0370]

[0371] Pharmacological examples

[0372] 1. Menin-MLL1 inhibition test

[0373] 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 34869) to an assay plate (384-well plate, Perkin Elmer, catalog 6007279) via Echo. The final DMSO fraction is 1%. Prepare a 2x enzyme solution by adding 20nM of the 1x assay buffer for Menin protein (Menin(2-610)isform2, ChemPartner, catalog 2020111101). Then, 10 nM MLL-peptide (Ac-SRWRFPARPGTGRR-Ahx-Ahx-K(FAM)-NH2, GLBiochem (Shanghai)), catalog number 833831 / 202009220104) was added to 1x assay buffer to prepare a 2x substrate solution. 10 μL of the 2x enzyme solution was transferred to the assay plate, or 10 μL of the 1x assay buffer was transferred to the assay plate for the low control group. 10 μL of the 2x substrate solution was added to each well to begin the reaction. mP data were collected on an Envision (Ex480 / Em535(s),Em535(p)) instrument.

[0374] The compound potency was determined by first calculating the inhibition percentage at each compound concentration according to Equation 1:

[0375] Suppression % = (Max - Signal) / (Max - Min) * 100 (Equation 1)

[0376] IC of the compound of the present invention 50 The values ​​are obtained using Equation 2 and are shown in Table 1 below:

[0377] Y = bottom + (top - bottom) / (1 + (IC50 / X) * HillSlope), where Y is the percentage of inhibition and X is the compound concentration (Equation 2).

[0378] The test results for the compounds of this invention are shown in Table 1.

[0379] 2. Cell proliferation assay

[0380] • RPMI1640 (from Invitrogen, catalog number 11875-093; lot number 2327411)

[0381] • IMDM (from Invitrogen, catalog number 12440-053; lot number 2192731)

[0382] • FBS (from Gibco, catalog number 10099141C, lot number 2233792CP)

[0383] • Penicillin-streptomycin solution (from Invitrogen, catalog number 15140-122, batch number 2321118)

[0384] • Glutamax (from Invitrogen, catalog number 35050-061; lot number 2248972)

[0385] • 0.25% Trypsine-EDTA (from Invitrogen, catalog number 25200-072; lot number 2276876)

[0386] • Staurosporine (from Selleck, catalog number S1421, batch number #S142106)

[0387] ·DMSO (from Sigma, catalog number 276855-1L, lot number 276855-1L)

[0388]

[0389] 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.

[0390] The test results for the compounds of this invention are shown in Table 1.

[0391] Table 1. Biological data

[0392]

[0393] 3. Particle stability study

[0394] 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 solution 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 (MTS2 / 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.

[0395] 4. hERG inhibition research

[0396] 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.

Claims

1. Compounds of Formula I: Or its pharmaceutically acceptable salt, stereoisomer, or racemate, wherein: X is a halogenated group or CN; Y is either N or CH; R1 is selected from: 1)-(C=O)-NRaRb, where: Ra and Rb are each independently selected from C 1-6 Alkyl and deuterated C 1-6 Alkyl, 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; 2) A 5-6 membered heteroaryl ring, which is optionally substituted by 1, 2 or 3 substituents selected from 3-5 membered alkyl rings, wherein one or two of the ring atoms of the heteroaryl ring are heteroatoms independently selected from N, O and S, and the remaining ring atoms are carbon atoms. R2 and R3 are each independently H; Cy is a 5-6 membered heterocyclic group, a 5-6 membered cycloalkyl group, or a phenyl ring, which is bound by (R4). m The substitution is wherein one or two of the ring atoms of the heterocyclic group are heteroatoms independently selected from N, O and S, and the remaining ring atoms are carbon atoms; R4 groups are independently selected from halogenated groups, CN, and C. 1-6 Alkyl, C 1-6 Alkyl-S(O)2-NR'-, C 1-6 Alkyl-C(O)-NR'-, C 1-6 Alkyl-S(O)2-, C 1-6 Alkyl-OC(O)-NR”- and C 1-6 Alkyl-NR'-C(O)-NR'-, wherein R' is independently H or C. 1-3 alkyl; Two adjacent R4 atoms, together with the carbon atoms they are attached to, optionally form 3-6 membered alkyl rings; R5 is an oxo group or H; a and b are each independently 1; c is 2; and m can be 0, 1, or 2.

2. The compound of claim 1 or a pharmaceutically acceptable salt, stereoisomer or racemate thereof, wherein X is F.

3. The compound according to any one of claims 1-2, or a pharmaceutically acceptable salt, stereoisomer, or racemate thereof, wherein: R1 is selected from: 1)-(C=O)-NRaRb, where: Ra and Rb are each independently C 1-3 Alkyl group, which is optionally substituted with an OH group; 2) A 5-6 membered heteroaryl ring, which is optionally substituted by 1 or 2 cyclopropyl groups.

4. The compound according to any one of claims 1-2, or a pharmaceutically acceptable salt, stereoisomer, or racemate thereof, wherein: R4 groups are independently selected from halogenated groups, CN, and C. 1-3 Alkyl and C 1-3 Alkyl-S(O)2-NR'-, where R' is independently H; Two adjacent R4 atoms, together with the carbon atoms they are attached to, optionally form 3-6 membered alkyl rings.

5. The compound according to any one of claims 1-2, or a pharmaceutically acceptable salt, stereoisomer, or racemate thereof, wherein... R5 is an oxo group, and Cy is a structural moiety. Where m is 1 or 2, and n is 0 or 1, provided that R4 substitutes for any chemically permissible position other than the N atom; or R5 is H, and Cy is the structural part. Where m is 0 or 1; if the ring with Z is a 6-membered cycloalkyl or phenyl ring, then m is 1; and if the ring with Z is a 6-membered heterocyclic ring, then Z is O or S, and m is 0.

6. A compound according to any one of claims 1-2, or a pharmaceutically acceptable salt, stereoisomer, or racemate thereof, wherein the compound has the structure of formula II: Where m is 1 or 2, and n is 0 or 1; The condition is that R4 is substituted at any chemically permissible position other than the N atom.

7. The compound of claim 6 or a pharmaceutically acceptable salt, stereoisomer, or racemate thereof, wherein n is 0.

8. The compound of claim 6 or a pharmaceutically acceptable salt, stereoisomer, or racemate thereof, wherein: R4 groups are independently selected from halogenated groups, CN, and C. 1-6 alkyl; Two adjacent R4 atoms, together with the carbon atoms they are attached to, optionally form 3-6 membered alkyl rings.

9. The compound of claim 6 or a pharmaceutically acceptable salt, stereoisomer, or racemate thereof, wherein: X is a halogenated group; Y is either N or CH; R1 is selected from: 1)-(C=O)-NRaRb, where: Ra and Rb are each independently C 1-3 Alkyl group, optionally surrounded by a group selected from halogen, OH, and C. 1-6 Substitution of alkoxy groups; 2) A 5-6 membered heteroaryl ring, which is optionally substituted with 1 or 2 cyclopropyl groups, wherein one or 2 of the ring atoms of the heteroaryl ring are heteroatoms independently selected from N, O and S, and the remaining ring atoms are carbon atoms. R4 groups are independently selected from halogenated groups and C4 groups. 1-3 alkyl; Two adjacent R4 atoms, together with the carbon atoms they are attached to, optionally form 3- to 5-membered alkyl rings; a and b are both 1; c is 2; n is 1; and m is 1 or 2.

10. The compound of claim 6 or a pharmaceutically acceptable salt, stereoisomer, or racemate thereof, wherein m is 1.

11. The compound of claim 6 or a pharmaceutically acceptable salt, stereoisomer, or racemate thereof, wherein the structural moiety is... yes 12. The compound of claim 6 or a pharmaceutically acceptable salt, stereoisomer, or racemate thereof, wherein the structural moiety is... yes 13. A compound according to any one of claims 1-2, or a pharmaceutically acceptable salt, stereoisomer, or racemate thereof, wherein the compound has the structure of formula III: Each R4 group is independently selected from halogenated groups, CN, and C. 1-6 Alkyl-S(O)2-NR'-, C 1-6 Alkyl-C(O)-NR'-, C 1-6 Alkyl-S(O)2-, C 1-6 Alkyl-OC(O)-NR”- and C 1-6 Alkyl-NR'-C(O)-NR'-, m is 0 or 1, and R' is independently H or C. 1-3 alkyl; If the ring with Z is a 6-membered cycloalkyl or phenyl ring, then m is 1; and If the ring with Z is a 6-membered heterocyclic group, then Z is O or S, and m is 0.

14. The compound of claim 13 or a pharmaceutically acceptable salt, stereoisomer, or racemate thereof, wherein m is 1, the ring having Z is a 6-membered cycloalkyl or phenyl ring, and R4 is selected from C10. 1-3 Alkyl-S(O)2-NR'-, C 1-3 Alkyl-C(O)-NR'-, CN and halogroups, where R' is H.

15. The compound of claim 13 or a pharmaceutically acceptable salt, stereoisomer or racemate thereof, wherein m is 0, Z is 0, and the ring having Z is a 6-membered saturated heterocyclic group.

16. The compound of claim 1 or a pharmaceutically acceptable salt, stereoisomer, or racemate thereof, wherein the compound is selected from:

17. A pharmaceutical composition comprising a compound of any one of claims 1-16 or a pharmaceutically acceptable salt, stereoisomer or racemate thereof and optionally a pharmaceutically acceptable carrier.

18. Use of any compound of claims 1-16 or a pharmaceutically acceptable salt, stereoisomer or racemate thereof in the preparation of a medicament for the treatment or prevention of cancer or diabetes.

19. The use according to claim 18, wherein the cancer is a hematologic malignancy or a solid tumor.

20. The use according to claim 18, wherein the cancer is selected from leukemia, lymphoma, myeloma, myelodysplastic syndrome (MDS), myelodysplastic neoplasm (MPN), polycythemia vera, prostate cancer, lung cancer, breast cancer, pancreatic cancer, colon cancer, liver cancer, melanoma, and glioblastoma.

21. The use according to claim 18, wherein the cancer is multiple myeloma.

22. The use according to claim 18, wherein the cancer 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), MLL-positive leukemia, nucleophosphorus protein (NPM)-mutant leukemia, MOZ acute leukemia, NUP98 acute leukemia, and CALM acute leukemia.

23. The use according to claim 18, wherein the cancer is mixed lineage leukemia (MLL).

24. The use according to claim 18, wherein the cancer is selected from MLL rearrangement leukemia (MLLr leukemia), MLL-PTD leukemia, MLL amplified leukemia, MLL-AF4 leukemia, MLL-AF6 leukemia, MLL-AF9 leukemia, MLL-AF10 leukemia, MLL-ENL leukemia, and MLL-ELL leukemia.

25. A method for in vitro inhibition of the interaction between menin and MLL and / or MLL fusion protein for non-therapeutic and non-diagnostic purposes, the method comprising contacting an effective amount of the compound of any one of claims 1-16 or a pharmaceutically acceptable salt thereof with menin and MLL and / or MLL fusion protein.

26. A combination comprising a compound of any one of claims 1-16 or a pharmaceutically acceptable salt, stereoisomer or racemate thereof and at least one additional therapeutic agent.

27. The combination of claims 26, wherein the additional therapeutic agent is an antitumor drug.

28. The combination of claims 26, wherein the additional therapeutic agent is a radiotherapy agent, a chemotherapy agent, an immunotherapy agent, or a targeted therapy agent.

Images