Carbonyl-substituted diazaspiro compound and application 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 their preparation and their use. (I)

Description

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 their preparation and their use.

Claims

1. Compounds of Formula I: I Or its stereoisomers, racemates, tautomers, hydrates or solvates or pharmaceutically acceptable salts, wherein: X is a halogenated group or CN; Y is either N or CH; Z is selected from CH2, O, S, and NH; R1 is selected from: 1)-(C=O)-NRaRb, where: Ra and Rb are each independently selected from C 1-6 Alkyl, 3-6 membered cycloalkyl rings, and 5-9 membered heterocyclic rings, optionally surrounded by 1, 2, or 3 groups selected from deuterium, halogroup, OH, CN, and C. 1-6 Substitution of alkoxy groups; Alternatively, Ra and Rb, together with the nitrogen atoms to which they are attached, form a 5-9 membered heterocyclic ring, which is optionally composed of 1, 2, or 3 atoms selected from C. 1-6 Alkyl, halogroup, OH and CN substituents; 2) 5-10 membered heteroaryl rings or C 6-10 An aryl ring, optionally substituted with 1, 2, or 3 substituents selected from: a halogroup, CN, and C optionally substituted with 1, 2, or 3 substituents selected from the halogroup, CN, and OH. 1-6 Alkyl, 3-5 membered alkyl rings, oxo and C 1-6 Alkoxy; R2 and R3 are each independently H or D; R4 groups are independently selected from halogen groups, CN, OH, oxo groups, and C groups. 1-6 alkylsulfonyl-, C 1-6 alkylsulfonylamino-, C 1-6 Alkyl carbonyl amino-, C 6-10 Aryl ring, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, 3-9 membered cycloalkyl, 5-10 membered heteroaryl, and 4-9 membered heterocyclic rings, wherein the alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, heteroaryl, or heterocyclic rings are optionally substituted by 1, 2, or 3 substituents selected from halogen, CN, and OH. Two adjacent R4 atoms, together with the carbon atoms they are attached to, optionally form a 3-9 membered alkyl ring, which is optionally surrounded by 1, 2, or 3 carbon atoms selected from C. 1-6 Alkyl, -C 1-6 Alkyl-OH, C 1-6 Alkoxy-C 1-6 Alkyl, halo, CN, and OH substituents; Alternatively, two R4 atoms attached to the same carbon atom may optionally form a 3-6 membered cycloalkyl ring or a 4-6 membered heterocyclic ring together with the carbon atom, optionally surrounded by one, two, or three C atoms. 1-6 Alkyl, -C 1-6 Alkyl-OH, C 1-6 Alkoxy-C 1-6 Alkyl, halo, CN, and OH substituents; Alternatively, two adjacent R4 atoms, together with the carbon atoms they are attached to, may optionally form a 5-10 membered heteroaryl ring, C 6-10 An aryl ring or a 5-9 membered heterocyclic ring, wherein the heteroaryl ring or aryl ring is optionally composed of 1, 2 or 3 members selected from C 1-6 Alkyl, C 1-6 Haloalkyl, -C 1-6 Alkyl-OH, C 1-6 Alkoxy-C 1-6 The alkyl group is substituted with a alkyl group, a halogroup, a CN group, or an OH group, wherein the alkyl group is optionally substituted with a 3-6 membered alkyl ring or a phenyl group; the heterocyclic ring is optionally substituted with 1, 2, or 3 C1-membered alkyl groups. 1-6 Alkyl, C 1-6 Haloalkyl, -C 1-6 Alkyl-OH, C 1-6 Alkoxy-C 1-6 Alkyl, oxo, halo, CN and OH substituents; R5 is selected from H, a halogroup, a methyl group optionally substituted with 1, 2 or 3 deuterium or halogroups, a methoxy group optionally substituted with 1, 2 or 3 deuterium or halogroups, NH2, CH3NH or (CH3)2N. a, b, c, and d are each 1 or 2 independently; n is 0, 1, or 2; and m is 0, 1, 2, 3 or 4; The condition is that R4, if present, substitutes for any chemically permissible position on the heterocyclic group, except for the N atom adjacent to the junction of the heterocyclic group and the rest of the compound structure.

2. The compound according to claim 1, or its stereoisomers, racemates, tautomers, hydrates, solvates, or pharmaceutically acceptable salts, wherein: X is F, Cl, or CN; Y is either N or CH; Z is selected from CH2, O, S, and NH; R1 is selected from: 1)-(C=O)-NRaRb, where: Ra and Rb are each independently selected from C 1-6 Alkyl and 3-5 membered cycloalkyl rings, wherein C 1-6 Alkyl groups are optionally surrounded by one, two, or three groups selected from deuterium, halogroup, OH, and C. 1-6 Substitution of alkoxy groups; 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; 2) A 5-6 membered heteroaryl ring, optionally substituted with 1, 2, or 3 substituents selected from the following: a halogenated group, CN, and a C substituent optionally substituted with 1, 2, or 3 substituents selected from the halogenated group and CN. 1-6 Alkyl, 3-5 membered alkyl rings, oxo and C 1-6 Alkoxy; 3)C 6-10 An aryl ring, which is substituted by 1, 2, or 3 substituents selected from: halogen, CN, and C optionally substituted by 1, 2, or 3 substituents selected from the halogen and CN. 1-6 Alkyl, 3-5 membered cycloalkyl rings and C 1-6 Alkoxy; R2 and R3 are each independently H or D; R4 groups are independently selected from halogenated groups, CN, OH, and C. 1-6 alkylsulfonyl-, C 1-6 alkylsulfonylamino-, C 1-6 Alkyl carbonyl amino-, phenyl, C 1-6 Alkyl, C 1-6 Alkoxy, 3-6 membered cycloalkyl, 5-10 membered heteroaryl, and 5-9 membered heterocyclic rings, wherein the alkyl, alkoxy, cycloalkyl, heteroaryl, or heterocyclic rings are optionally substituted by 1, 2, or 3 substituents selected from halogen, CN, and OH; Two adjacent R4 atoms, together with the carbon atoms they are attached to, optionally form a 3-6 membered alkyl ring, which is optionally surrounded by 1, 2, or 3 carbon atoms selected from C14. 1-6 Alkyl, -C 1-6 Alkyl-OH, C 1-6 Alkoxy-C 1-6 Alkyl and haloyl substituents; Alternatively, two R4s attached to the same carbon atom may optionally form a 3-6 membered cycloalkyl ring together with the carbon atom, which may optionally be substituted by one, two or three substituents selected from halogens, CN and OH; Alternatively, two adjacent R4s, together with the carbon atoms they are attached to, may optionally form a 5-10 membered heteroaryl ring, a phenyl ring, or a 5-9 membered heterocyclic ring, which may optionally be surrounded by one, two, or three groups selected from halogenated groups, C... 1-6 Alkyl and C 1-6 The alkyl group is substituted with a substituent, wherein the alkyl group is optionally substituted with a 3-6 membered cycloalkyl ring or a phenyl group; R5 is an H or a halogenated group; a, b, c, and d are each 1 or 2 independently; n is 0 or 1; and m is 0, 1, 2, or 3; The condition is that R4, if present, substitutes for any chemically permissible position on the heterocyclic group, except for the N atom adjacent to the junction of the heterocyclic group and the rest of the compound structure.

3. A compound according to any one of the preceding claims, or a stereoisomer, racemate, tautomer, hydrate, solvate, or pharmaceutically acceptable salt thereof, wherein the compound has formula II: II。 4. A compound according to any one of the preceding claims, or a stereoisomer, racemate, tautomer, hydrate, solvate, or pharmaceutically acceptable salt thereof, wherein the compound has formula III: III。 5. A compound or stereoisomer, racemate, tautomer, hydrate or solvate or pharmaceutically acceptable salt thereof according to any one of the preceding claims, wherein X is F.

6. A compound or a stereoisomer, racemate, tautomer, hydrate or solvate or pharmaceutically acceptable salt thereof according to any one of the preceding claims, wherein Z is selected from CH2, O and S, preferably CH2.

7. A compound or stereoisomer, racemate, tautomer, hydrate or solvate or pharmaceutically acceptable salt thereof according to any one of the preceding claims, wherein R2 and R3 are each independently H.

8. The compound or its stereoisomer, racemate, tautomer, hydrate, solvate, or pharmaceutically acceptable salt according to any one of the preceding claims, wherein: R1 is Where A1 or A2 is N or CH; R6 is selected from halogenated groups, CN, and cyclopropyl groups; and R7 is selected from H, halogenated groups, CN, and cyclopropyl groups; preferably, R1 is , or ; Or R1 is Where A3 is N or C substituted with a halogenated group, and R8 is C. 1-3 Alkyl; preferably, R1 is .

9. The compound according to any one of claims 1-7, or a stereoisomer, racemate, tautomer, hydrate, solvate, or pharmaceutically acceptable salt thereof, wherein: R1 is selected from: , , , , , , , , , , , , , , , , and .

10. A compound according to any one of the preceding claims, or a stereoisomer, racemate, tautomer, hydrate, solvate, or pharmaceutically acceptable salt thereof, wherein: Each of a and b is 1; Each of c and d is 2; n is either 0 or 1, preferably 0; and m can be 0, 1, or 2.

11. The compound or its stereoisomer, racemate, tautomer, hydrate, solvate, or pharmaceutically acceptable salt according to any one of the preceding claims, wherein: R4 groups are independently selected from halogenated groups; CN; OH; C. 1-6 alkylsulfonyl-; C 1-6 Alkylsulfonylamino-; phenyl; C substituted with 1, 2 or 3 substituents selected from halogen groups, CN and OH. 1-6 Alkyl group; C group optionally substituted with 1, 2 or 3 halogroups 1-6 alkoxy; and cyclopropyl, Two adjacent R4 atoms, together with the carbon atoms they are attached to, optionally form a 3-6 membered alkyl ring, which is optionally surrounded by 1, 2, or 3 carbon atoms selected from C14. 1-6 Alkyl, -C 1-6 Alkyl-OH, C 1-6 Alkoxy-C 1-6 Alkyl and haloyl substituents; 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; Alternatively, two adjacent R4 atoms, together with the carbon atoms they are attached to, may optionally form a 5-6 membered heteroaryl ring, which may optionally be bounded by 1, 2, or 3 carbon atoms. 1-6 Alkyl substitution, wherein the alkyl group is optionally substituted with a 3-6 membered cycloalkyl ring or a phenyl group; Alternatively, two adjacent R4 atoms, together with the carbon atoms they are attached to, may optionally form a phenyl group.

12. The compound or its stereoisomer, racemate, tautomer, hydrate, solvate, or pharmaceutically acceptable salt according to any one of the preceding claims, wherein: Structural parts Selected from: , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , and .

13. The compound according to any one of claims 1 to 3, or a stereoisomer, racemate, tautomer, hydrate, solvate, or pharmaceutically acceptable salt thereof, wherein: X is F; Z is CH2; R1 is selected from: 1)-(C=O)-NRaRb, where: Ra and Rb are each independently selected from C atoms that are optionally replaced by 1, 2, or 3 deuterium atoms. 1-6 alkyl; Alternatively, Ra and Rb, together with the nitrogen atoms to which they are attached, form a 5-6 membered monocyclic or 7-9 membered bicyclic heterocyclic ring, optionally bounded by 1, 2, or 3 carbon atoms. 1-6 Alkyl substitution; 2) Selected by 1, 2 or 3 halogenated groups, CN, C 1-6 Alkyl, CF3, 3-5 membered cycloalkyl rings, oxo and C 1-6 5-6 membered heteroaryl rings substituted with alkoxy groups; 3) Selected by 1, 2 or 3 halogenated groups, CN, C 1-6 Alkyl, CF3, 3-5 membered cycloalkyl rings and C 1-6 alkoxy substituents of C 6-10 Aryl ring; R2 and R3 are each H independently; R4 groups are independently selected from halogenated groups; CN; OH; C. 1-6 alkylsulfonyl-; C 1-6 Alkylsulfonylamino-; phenyl; C substituted with 1, 2 or 3 substituents selected from halogen groups, CN and OH. 1-6 Alkyl group; C group optionally substituted with 1, 2 or 3 halogroups 1-6 alkoxy groups; and 3-6 membered cycloalkyl rings, Two adjacent R4 atoms, together with the carbon atoms they are attached to, optionally form a 3-6 membered alkyl ring, which is optionally surrounded by 1, 2, or 3 carbon atoms selected from C14. 1-6 Substitution of alkyl and halogroups; Alternatively, two adjacent R4 atoms, together with the carbon atoms they are attached to, may optionally form a phenyl group; R5 is an H or a halogenated group; Each of a and b is 1; Each of c and d is 2; n is 0; and m is 0, 1, or 2; The condition is that R4, if present, substitutes for any chemically permissible position on the heterocyclic group, except for the N atom adjacent to the junction of the heterocyclic group and the rest of the compound structure.

14. A compound or stereoisomer, racemate, tautomer, hydrate or solvate or pharmaceutically acceptable salt thereof according to any one of the preceding claims, wherein R5 is H.

15. The compound or its stereoisomer, racemate, tautomer, hydrate, solvate, or pharmaceutically acceptable salt according to any one of claims 1-10 and 13-14, wherein the structural moiety is... yes , R4', R4'', and R4''' are independently selected from H; a halogroup; CN; OH; and a C group optionally substituted with a halogroup. 1-6 Alkyl; and C 1-6 alkoxy or R4' and R4'' together with the carbon atoms they are attached to optionally form a 3-6 membered alkyl ring, which is optionally bounded by 1 or 2 carbon atoms. 1-6 Alkyl substitution; and R4''' is H.

16. The compound or its stereoisomer, racemate, tautomer, hydrate, solvate, or pharmaceutically acceptable salt according to any one of claims 1-10 and 13-14, wherein: Structural parts yes , Where R4''' is H; and R4' and R4'' are independently selected from H; a halogenated group; and a C group optionally substituted with a halogenated group. 1-6 Alkyl; and C 1-6 alkoxy group; provided that one of R4' and R4'' is not H; or R4' and R4'' together with the carbon atom to which they are attached form an alkoxy group optionally surrounded by one or two carbon atoms. 1-3 Alkyl-substituted 3- or 5-membered alkyl rings, or forming phenyl rings.

17. The compound or its stereoisomer, racemate, tautomer, hydrate, solvate, or pharmaceutically acceptable salt according to any one of claims 1-10 and 13-14, wherein the structural moiety is... yes , Where R4' is H; and R4'' is C substituted with a halogenated group. 1-6 Alkyl; or R4' and R4'', together with the carbon atoms they are attached to, optionally form 3- or 5-membered alkyl rings.

18. The compound or its stereoisomer, racemate, tautomer, hydrate, solvate, or pharmaceutically acceptable salt according to any one of claims 1-10 and 13-14, wherein the structural moiety is... yes , Each p is independently 0 or 1; preferably, all p are 0 or all p are 1. q is 0, 1, or 2; preferably q is 0 or 2. R 4a It is C 1-3 Alkyl group, preferably methyl group.

19. The compound according to any one of claims 1 to 2, or a stereoisomer, racemate, tautomer, hydrate, solvate, or pharmaceutically acceptable salt thereof, wherein the compound is selected from:

20. The compound of any one of claims 1-19, or a stereoisomer, racemate, tautomer, hydrate, solvate, or pharmaceutically acceptable salt thereof, used as a medicine.

21. The compound of any one of claims 1-19 or its stereoisomers, racemates, tautomers, hydrates or solvates or pharmaceutically acceptable salts thereof, for the treatment or prevention of cancer or diabetes; 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; More preferably, the leukemia is selected from acute leukemia, chronic leukemia, myeloid leukemia, lymphoblastic leukemia, lymphocytic leukemia, acute myeloid leukemia (AML), chronic myeloid leukemia (CML), acute lymphoblastic leukemia (ALL), chronic lymphocytic leukemia (CLL), T-cell prolymphoblastic leukemia (T-PLL), large granular lymphocytic leukemia, hairy cell leukemia (HCL), and mixed lineage leukemia (M). MLL, MLL rearrangement leukemia (MLLr leukemia), MLL-PTD leukemia, MLL amplified leukemia, MLL positive leukemia, nucleophosphorus protein (NPM)-mutated leukemia, MOZ acute leukemia, NUP98 acute leukemia, CALM acute leukemia, MLL-AF4 leukemia, MLL-AF6 leukemia, MLL-AF9 leukemia, MLL-AF10 leukemia, MLL-ENL leukemia, and MLL-ELL leukemia.

22. A pharmaceutical composition comprising the compound of any one of claims 1-19 or a stereoisomer, racemate, tautomer, hydrate or solvate or pharmaceutically acceptable salt thereof, and optionally a pharmaceutically acceptable carrier.

23. Use of the compound of any one of claims 1-19 or its stereoisomers, racemates, tautomers, hydrates or solvates or pharmaceutically acceptable salts in the preparation of a medicament for the treatment or prevention of cancer or diabetes. 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; More preferably, the leukemia is selected from acute leukemia, chronic leukemia, myeloid leukemia, lymphoblastic leukemia, lymphocytic leukemia, acute myeloid leukemia (AML), chronic myeloid leukemia (CML), acute lymphoblastic leukemia (ALL), chronic lymphocytic leukemia (CLL), T-cell prolymphoblastic leukemia (T-PLL), large granular lymphocytic leukemia, hairy cell leukemia (HCL), and mixed lineage leukemia (M). MLL, MLL rearrangement leukemia (MLLr leukemia), MLL-PTD leukemia, MLL amplified leukemia, MLL positive leukemia, nucleophosphorus protein (NPM)-mutated leukemia, MOZ acute leukemia, NUP98 acute leukemia, CALM acute leukemia, MLL-AF4 leukemia, MLL-AF6 leukemia, MLL-AF9 leukemia, MLL-AF10 leukemia, MLL-ENL leukemia, and MLL-ELL leukemia.

24. 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 the compound of any one of claims 1-19 or a pharmaceutically acceptable salt thereof with menin and MLL and / or MLL fusion protein.

25. A method for treating or preventing cancer or diabetes, the method comprising administering to an individual in need an effective amount of the compound of any one of claims 1-19 or a stereoisomer, racemate, tautomer, hydrate or solvate or pharmaceutically acceptable salt thereof. 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; More preferably, the leukemia is selected from acute leukemia, chronic leukemia, myeloid leukemia, lymphoblastic leukemia, lymphocytic leukemia, acute myeloid leukemia (AML), chronic myeloid leukemia (CML), acute lymphoblastic leukemia (ALL), chronic lymphocytic leukemia (CLL), T-cell prolymphoblastic leukemia (T-PLL), large granular lymphocytic leukemia, hairy cell leukemia (HCL), and mixed lineage leukemia (M). MLL, MLL rearrangement leukemia (MLLr leukemia), MLL-PTD leukemia, MLL amplified leukemia, MLL positive leukemia, nucleophosphorus protein (NPM)-mutated leukemia, MOZ acute leukemia, NUP98 acute leukemia, CALM acute leukemia, MLL-AF4 leukemia, MLL-AF6 leukemia, MLL-AF9 leukemia, MLL-AF10 leukemia, MLL-ENL leukemia, and MLL-ELL leukemia.

26. A combination comprising a compound of any one of claims 1-19 or a stereoisomer, racemate, tautomer, hydrate or solvate or pharmaceutically acceptable salt thereof, and at least one additional therapeutic agent, wherein the additional therapeutic agent is preferably an antitumor agent, such as a radiotherapy agent, a chemotherapy agent, an immunotherapy agent or a targeted therapy agent.