Quinolinone compounds and naphthilidinone compounds, and their uses

Abstract

TIFF2026518730000285.tif33161 The present invention belongs to the technical field of biopharmaceuticals and, in particular, to quinolinone compounds and naphthilidinone compounds represented by formula (I) and their uses. Quinolinone compounds and naphthilidinone compounds can be used as molecular glues capable of selectively inducing the formation of PDE3A and SLFN12 complexes and apoptosis of tumor cells, and can be used to treat cancer.

Claims

1. Compounds of formula (I), pharmaceutically acceptable salts thereof, deuterated compounds thereof, stereoisomers thereof, tautomers thereof, or mixtures thereof 【Chemistry 1】 (In the formula, Z is CR 1 Or selected from N, W is C=O, CR 2 R 7 , NR 3 , or selected from O, R 1 is selected from H, halogen, hydroxyl, cyano, alkynyl, C 1 to C 6 alkyl, C 1 to C 6 haloalkyl, C 1 to C 6 alkoxy, or C 3 to C 6 cycloalkyl, R 2 and R 7 These are H, deuterium, and C, respectively, independently. 1 ~C 3 Alkyl, or C 1 ~C 3 Selected from haloalkyls, or R 2 and R 7 They become C together with the carbon atoms to which they bond. 3 ~C 6 Forming a cycloalkyl group, R 3 H, C 1 ~C 6 Alkyl, C 1 ~C 6 Haloalkyl, or C 3 ~C 6 Selected from cycloalkyl groups, n is selected from any integer between 0 and 6. R a Each of these is independently H, halogen, cyano, alkynyl, and optionally substituted C. 1 ~C 6 Alkoxy, C 1 ~C 6 Haloalkyl, and optionally substituted C 6 ~C 10 Aryl, optionally substituted 5- to 10-membered heteroaryl, optionally substituted C 3 ~C 9 Cycloalkyl, and in some cases substituted C 4 ~C 9 Selected from cycloalkenyls, or optionally substituted 3- to 10-membered heterocyclines, Ring A is C 6 ~C 10 Aryl, 5-10 membered heteroaryl, C 4 ~C 10 (Selected from carbocyclyl or 4- to 10-membered heterocyclyl).

2. R a However, each is independent of H, halogen, cyano, and, in some cases, substituted C. 1 ~C 3 Alkoxy, C 1 ~C 3 Haloalkyl, and optionally substituted C 6 ~C 10 Aryl, optionally substituted 5- to 10-membered heteroaryl, optionally substituted C 3 ~C 6 A compound according to claim 1, selected from cycloalkyls or optionally substituted 3- to 10-membered heterocyclines, a pharmaceutically acceptable salt thereof, a deuterated compound thereof, a stereoisomer thereof, a tautomer thereof, or a mixture thereof.

3. Ring A is a benzene ring, C 4 ~C 6 Selected from carbocyclyl or 5-6 membered heterocyclyl, preferably ring A is 【Chemistry 2】 (In the formula, k is selected from 1 or 2) A compound according to claim 1 or 2, a pharmaceutically acceptable salt thereof, a deuterated compound thereof, a stereoisomer thereof, a tautomer thereof, or a mixture thereof, selected from among.

4. The compound is of formula (II), formula (II'), or formula (II") 【Transformation 3】 (In the formula, p is selected from 0, 1, 2, or 3. R 1 H, halogen, hydroxyl, cyano, alkynyl, C 1 ~C 6 Alkyl, C 1 ~C 6 Haloalkyl, C 1 ~C 6 Alkoxy, or C 3 ~C 6 Selected from cycloalkyl groups, R 3 H, C 1 ~C 6 Alkyl, C 1 ~C 6 Haloalkyl, or C 3 ~C 6 Selected from cycloalkyl groups, R 4 and R 5 Each of these is independently H, halogen, cyano, alkynyl, and optionally substituted C. 1 ~C 3 Alkoxy, C 1 ~C 3 Haloalkyl, and optionally substituted C 6 ~C 10 Aryl, optionally substituted 5- to 10-membered heteroaryl, optionally substituted C 3 ~C 6 Cycloalkyl, and in some cases substituted C 4 ~C 6 Selected from cycloalkenyls and optionally substituted 3- to 10-membered heterocyclines, 【Chemistry 4】 (This represents a single bond or a double bond.) A compound according to any one of claims 1 to 3, having the structure represented by, a pharmaceutically acceptable salt thereof, a deuterated compound thereof, a stereoisomer thereof, a tautomer thereof, or a mixture thereof.

5. Each R 4 Each of these independently represents H, halogen, cyano, and C. 1 ~C 3 Haloalkyl, or optionally substituted C 1 ~C 3 Selected from alkoxy, R 5 is optionally substituted C 6 -C 10 -aryl, optionally substituted 5- to 10-membered heteroaryl, cyano, optionally substituted C 3 -C 6 -cycloalkyl, and optionally substituted 3- to 10-membered heterocyclyl, the compound according to claim 4, its pharmaceutically acceptable salts, its deuterated compounds, its stereoisomers, its tautomers, or mixtures thereof.

6. R 5 However, Cyano, 【Transformation 5】 (where m is selected from 0, 1, 2, or 3, and R 6 are each independently H, C 1 to C 3 alkyl, C 1 to C 3 haloalkyl, halogen, cyano, amino, or optionally substituted C 1 to C 3 alkoxy selected from, and optionally substituted C 1 to C 3 alkoxy is -OCH 3 , -OCD 3 , -OCHD 2 , -OCH 2 D, ethoxy, -OCH 2 F, -OCHF 2 , -OCF 3 , or -CH 2 CF 3 selected from) A compound according to claim 5, a pharmaceutically acceptable salt thereof, a deuterated compound thereof, a stereoisomer thereof, a tautomer thereof, or a mixture thereof, selected from among.

7. n is selected from any integer between 1 and 5, R a Each of these is independently replaced by a halogen, and in some cases, C 1 ~C 6 Alkoxy, C 1 ~C 6 Haloalkyl, and optionally substituted C 6 ~C 10 Aryl, optionally substituted 5- to 10-membered heteroaryl, optionally substituted C 3 ~C 6 Selected from cycloalkyl or optionally substituted 3- to 10-membered heterocyclines, and optionally substituted C 1 ~C 6 Alkyl, aryl, heteroaryl, or heterocyclyl is unsubstituted, or deuterium, halogen, cyano, amino, C 1 ~C 6 Alkyl, C 1 ~C 6 Haloalkyl, C 3 ~C 6 Cycloalkyl, 3-6 membered heterocyclyl, hydroxyl, C 1 ~C 6 Alkoxy, C 1 ~C 6 Haloalkoxy, C 1 ~C 6 Alkylamino, C 6 ~C 10 Aryl, 5-10 membered heteroaryl, and C 1 ~C 6 It is substituted with one or more substituents independently selected from hydroxyalkyl groups. Preferably, n is selected from any integer between 1 and 3, and R a Each of these is independently replaced by a halogen, and in some cases, C 1 ~C 6 Alkoxy, C 1 ~C 6 Haloalkyl, and optionally substituted C 6 ~C 10 Selected from aryls, optionally substituted 5- to 10-membered heteroaryls, or optionally substituted 3- to 10-membered heterocyclines, and optionally substituted C 1 ~C 6 Alkyl compounds are either unsubstituted or halogenated, and optionally substituted aryl, heteroaryl, or heterocyclyl compounds are either unsubstituted or halogenated, cyano, amino, or C 1 ~C 6 Alkyl, C 1 ~C 6 Haloalkyl, C 1 ~C 6 Alkoxy, C 1 ~C 6 Haloalkoxy and C 1 ~C 6 It is substituted with one or more substituents independently selected from alkylaminos, More preferably, n is 1 or 2, R a Each of these is independently substituted with F, Cl, Br, and possibly C. 1 ~C 5 Alkoxy, C 1 ~C 5 Haloalkyl, and optionally substituted C 6 Selected from aryls, optionally substituted 5- to 6-membered heteroaryls, or optionally substituted 6- to 8-membered heterocyclines, and optionally substituted C 1 ~C 6 The alkoxy is either unsubstituted or substituted with F, Cl, or Br, and optionally substituted aryl, heteroaryl, or heterocyclyl is F, Cl, Br, cyano, amino, or C 1 ~C 6 Alkyl, C 1 ~C 6 Haloalkyl, C 1 ~C 6 Alkoxy, C 1 ~C 6 Haloalkoxy and C 1 ~C 6 Substituted with one or more substituents independently selected from alkylaminos, A compound according to claim 1, a pharmaceutically acceptable salt thereof, a deuterated compound thereof, a stereoisomer thereof, a tautomer thereof, or a mixture thereof.

8. Ring A is C 6 ~C 10 Aryl, 6-10 member heteroaryl, C 5 ~C 8 Selected from carbocyclyl or 5- to 8-membered heterocyclyl, Preferably, ring A is C 6 aryl, 6-8 membered heteroaryl containing 1-3 heteroatoms selected from N, O, or S, C 5 ~C 7 Selected from carbocyclyl, or 5-7 membered heterocyclyl containing 1-3 heteroatoms selected from N, O, or S, A compound according to claim 1 or 7, a pharmaceutically acceptable salt thereof, a deuterated compound thereof, a stereoisomer thereof, a tautomer thereof, or a mixture thereof.

9. Z is CR 1 Or selected from N, R 1 is H, halogen, hydroxyl, or C 1 ~C 3 Selected from alkyl groups, Preferably, Z is selected from CH or N. A compound according to any one of claims 1 and 7 to 8, a pharmaceutically acceptable salt thereof, a deuterated compound thereof, a stereoisomer thereof, a tautomer thereof, or a mixture thereof.

10. W is C=O, CR 2 R 7 , NR 3 , or selected from O, R 2 and R 7 Each of these independently comprises H, a deuterium atom, or C 1 ~C 3 Selected from alkyl, R 3 However, H, C 1 ~C 6 Alkyl, or C 1 ~C 6 Selected from haloalkyl groups, Preferably, W is C=O, CH 2 , NR 3 , or selected from O, R 3 However, H or C 1 ~C 6 Selected from alkyl groups, A compound according to any one of claims 1 and 7 to 9, a pharmaceutically acceptable salt thereof, a deuterated compound thereof, a stereoisomer thereof, a tautomer thereof, or a mixture thereof.

11. The compound is given by formula (IV): 【Transformation 6】 (In the formula, X is selected from C, CH, or N, R a Each of these independently represents halogen, substituted, or unsubstituted C 1 ~C 6 Alkoxy, C 1 ~C 6 Haloalkyl, substituted, or unsubstituted C 6 ~C 10 Selected from aryls, substituted or unsubstituted 5- to 8-membered heteroaryls, and substituted or unsubstituted 5- to 10-membered heterocyclines, C 1 ~C 6 Alkoxys may be substituted with halogens, and aryl, heteroaryl, or heterocyclyl may be substituted with deuterium, halogen, cyano, amino, or C 1 ~C 6 Alkyl, C 1 ~C 6 Haloalkyl, C 1 ~C 6 Alkoxy, C 1 ~C 6 Haloalkoxy and C 1 ~C 6 The heteroaryl or heterocyclyl may be substituted with one or more substituents independently selected from alkylamino, and each heteroaryl or heterocyclyl contains 1 to 3 heteroatoms selected from N, O, or S. Z is selected from CH or N, and W is C=O, CH 2 , NR 3 , or selected from O, R 3 is H or C 1 ~C 6 Selected from alkyl groups, 【Transformation 7】 (where represents a single or double bond, and - - - indicates the presence or absence of a bond.) A compound according to claim 1, a pharmaceutically acceptable salt thereof, a deuterated compound thereof, a stereoisomer thereof, a tautomer thereof, or a mixture thereof, having the structure represented by .

12. The compound is given by formula (IV-1): 【Transformation 8】 (In the formula, X is C or CH, R a is a substitution or non-substitution C 6 Selected from aryls and substituted or unsubstituted 5- to 6-membered heteroaryls, the aryl or heteroaryl is F, Cl, Br, C 1 ~C 6 Alkyl and C 1 ~C 6 The heteroaryl or heterocyclyl may be substituted with 1 to 3 substituents independently selected from the haloalkyl, and the heteroaryl or heterocyclyl may contain 1 to 3 heteroatoms selected from N, O, or S. Z is CH, and W is NH. 【Chemistry 9】 (where represents a single or double bond, and - - - indicates the presence or absence of a bond.) A compound according to claim 11, a pharmaceutically acceptable salt thereof, a deuterated compound thereof, a stereoisomer thereof, a tautomer thereof, or a mixture thereof, having the structure represented by .

13. The compound, 【Chemistry 10】 【change】 【change】 【change】 【change】 【change】 A compound according to any one of claims 1 to 11, a pharmaceutically acceptable salt thereof, a deuterated compound thereof, a stereoisomer thereof, a tautomer thereof, or a mixture thereof, selected from among.

14. A compound according to any one of claims 1 to 13, a pharmaceutically acceptable salt thereof, a deuterated compound thereof, a stereoisomer thereof, a tautomer thereof, or a mixture thereof, for use as a drug to modulate the interaction between PDE3A and SLFN12, preferably such a drug is capable of enhancing and / or promoting the interaction between PDE3A and SLFN12.

15. A compound, a pharmaceutically acceptable salt thereof, a deuterated compound thereof, a stereoisomer thereof, a tautomer thereof, or a mixture thereof, used to treat and / or prevent a disease, wherein the disease is a hyperproliferative disease, preferably the hyperproliferative disease is a cancerous disease, more preferably the cancerous disease includes brain tumors, breast cancer, cervical cancer, acute myeloid leukemia (AML), lung cancer, skin cancer, esophageal cancer, ovarian cancer, pancreatic cancer, prostate cancer, and sarcoma.

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