Sulfur-containing isoindoline derivatives, methods for preparing the same, and their pharmaceutical applications.

Abstract

This invention provides compounds for the treatment of multiple myeloma. [Solution] The present invention provides a sulfur-containing isoindoline derivative represented by general formula (I), a method for preparing the same, a pharmaceutical composition containing the derivative, and its use as a therapeutic agent, particularly in the field of treating multiple myeloma as a cereblon modulator. TIFF2026094330000156.tif3984

Claims

1. A compound represented by general formula (I) or its tautomers, meso compounds, racemic compounds, enantiomers, diastereomers, or mixtures thereof, or a pharmaceutically acceptable salt thereof, 【Chemistry 1】 Eventually, Ring A is an aryl group or a heteroaryl group, Ring B is a cycloalkyl group or a heterocyclyl group. Y is CH ２ or C(O), R １ These are homologous or homologous, and each is independently selected from a hydrogen atom, halogen, alkyl group, alkenyl group, alkynyl group, alkoxy group, haloalkyl group, haloalkoxy group, hydroxyalkyl group, cyano group, amino group, nitro group and hydroxyl group. R ２ This group is selected from hydrogen atoms, halogens, alkyl groups, alkenyl groups, alkynyl groups, alkoxy groups, haloalkyl groups, haloalkoxy groups, hydroxyalkyl groups, cyano groups, amino groups, nitro groups, hydroxyl groups, cycloalkyl groups, heterocyclyl groups, aryl groups, and heteroaryl groups, and each of these alkyl groups, alkenyl groups, alkynyl groups, alkoxy groups, cycloalkyl groups, heterocyclyl groups, aryl groups, and heteroaryl groups is independently and optionally substituted with one or more substituents selected from halogens, alkyl groups, alkenyl groups, alkynyl groups, alkoxy groups, haloalkyl groups, haloalkoxy groups, cyano groups, amino groups, nitro groups, hydroxyl groups, hydroxyalkyl groups, cycloalkyl groups, heterocyclyl groups, aryl groups, and heteroaryl groups. R ３ These are homologous or homologous, and each is independently selected from a hydrogen atom, halogen, alkyl group, alkenyl group, alkynyl group, alkoxy group, haloalkyl group, haloalkoxy group, hydroxyalkyl group, cyano group, amino group, nitro group and hydroxyl group. R ４ These groups are homologous or different, and each is independently selected from hydrogen atoms, halogens, alkyl groups, alkenyl groups, alkynyl groups, alkoxy groups, haloalkyl groups, haloalkoxy groups, cyano groups, amino groups, nitro groups, hydroxy groups, hydroxyalkyl groups, cycloalkyl groups, heterocyclyl groups, aryl groups, and heteroaryl groups, and each of these alkyl groups, alkenyl groups, alkynyl groups, alkoxy groups, cycloalkyl groups, heterocyclyl groups, aryl groups, and heteroaryl groups is independently and optionally substituted with one or more substituents selected from halogens, alkyl groups, alkenyl groups, alkynyl groups, alkoxy groups, haloalkyl groups, haloalkoxy groups, cyano groups, amino groups, nitro groups, hydroxy groups, hydroxyalkyl groups, cycloalkyl groups, heterocyclyl groups, aryl groups, and heteroaryl groups. R ５ and R ６ These are homologous or homologous, and each is independently selected from hydrogen atoms, halogens, alkyl groups, alkenyl groups, alkynyl groups, alkoxy groups, haloalkyl groups, haloalkoxy groups, hydroxyalkyl groups, cyano groups, amino groups, nitro groups, hydroxyl groups, cycloalkyl groups, heterocyclyl groups, aryl groups, and heteroaryl groups. n is 0, 1, 2, or 3. p is 0, 1, 2, 3 or 4, q is 0, 1, or 2, and t is 0, 1, 2, or 3. Compounds represented by general formula (I) or their tautomers, meso compounds, racemic compounds, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof.

2. The compound represented by general formula (II) or its tautomers, meso compounds, racemic compounds, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, 【Chemistry 2】 Eventually, Ring A, Ring B, Y, R １ ~R ４ , n, p and t are as defined in claim 1 A compound represented by general formula (I) as described in claim 1, or in the form of a tautomer, meso, racemic, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof.

3. A compound represented by general formula (II-1) or general formula (II-2), or its tautomers, meso compounds, racemic compounds, enantiomers, diastereomers, or mixtures thereof, or a pharmaceutically acceptable salt thereof. 【Transformation 3】 Eventually, Ring A, Ring B, Y, R １ ~R ４ n, p, and t are as defined in claim 1. A compound represented by general formula (I) as described in claim 1 or 2, or a tautomer, meso, racemic, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof.

4. Ring A is a phenyl group or a 5-6 membered heteroaryl group, preferably selected from a phenyl group, a pyridyl group, and a pyrimidinyl group. A compound represented by general formula (I) as described in any one of claims 1 to 3, or a tautomer, meso, racemic, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof.

5. structure 【Chemistry 4】 teeth 【Transformation 5】 Selected from, R ３ p is as defined in claim 1, A compound represented by general formula (I) as described in any one of claims 1 to 4, or in the form of a tautomer, meso, racemic, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof.

6. Ring B is a 3- to 8-membered heterocyclyl group, preferably selected from a piperidinyl group, a pyrrolidinyl group, and an azetidinyl group. A compound represented by general formula (I) as described in any one of claims 1 to 5, or a tautomer, meso, racemic, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof.

7. structure 【Transformation 6】 teeth 【Transformation 7】 And R ４ａ and R ４ｂ The atoms are homologous or homologous, and each is independently selected from a hydrogen atom, halogen, alkyl group, alkenyl group, alkynyl group, alkoxy group, haloalkyl group, haloalkoxy group, cyano group, amino group, nitro group, hydroxy group, hydroxyalkyl group, cycloalkyl group, heterocyclyl group, aryl group, and heteroaryl group, and each of the alkyl group, alkenyl group, alkynyl group, alkoxy group, cycloalkyl group, heterocyclyl group, aryl group, and heteroaryl group is independently and optionally substituted with one or more substituents selected from halogen, alkyl group, alkenyl group, alkynyl group, alkoxy group, haloalkyl group, haloalkoxy group, cyano group, amino group, nitro group, hydroxy group, hydroxyalkyl group, cycloalkyl group, heterocyclyl group, aryl group, and heteroaryl group, and r is 0, 1, or 2. A compound represented by general formula (I) as described in any one of claims 1 to 6, or a tautomer, meso, racemic, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof.

8. The compound represented by general formula (III) or its tautomers, meso compounds, racemic compounds, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, 【Transformation 8】 Eventually, R ４ａ and R ４ｂ These groups are homologous or different, and each is independently selected from hydrogen atoms, halogens, alkyl groups, alkenyl groups, alkynyl groups, alkoxy groups, haloalkyl groups, haloalkoxy groups, cyano groups, amino groups, nitro groups, hydroxy groups, hydroxyalkyl groups, cycloalkyl groups, heterocyclyl groups, aryl groups, and heteroaryl groups, and each of these alkyl groups, alkenyl groups, alkynyl groups, alkoxy groups, cycloalkyl groups, heterocyclyl groups, aryl groups, and heteroaryl groups is independently and optionally substituted with one or more substituents selected from halogens, alkyl groups, alkenyl groups, alkynyl groups, alkoxy groups, haloalkyl groups, haloalkoxy groups, cyano groups, amino groups, nitro groups, hydroxy groups, hydroxyalkyl groups, cycloalkyl groups, heterocyclyl groups, aryl groups, and heteroaryl groups. r is 0, 1, or 2. Y, R １ ~R ３ n and p are as defined in claim 1. A compound represented by general formula (I) as described in any one of claims 1 to 7, or in the form of a tautomer, meso, racemic, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof.

9. Y is CH ２ That is, A compound represented by general formula (I) as described in any one of claims 1 to 8, or in the form of a tautomer, meso, racemic, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof.

10. R ４ They are homologous or homologous, and each is independently a hydrogen atom, halogen, and C １－６ Selected from alkyl groups, 3-8 membered cycloalkyl groups, 3-8 membered heterocyclyl groups, 6-10 membered aryl groups, and 5-10 membered heteroaryl groups, of which the 3-8 membered cycloalkyl groups, 3-8 membered heterocyclyl groups, 6-10 membered aryl groups, and 5-10 membered heteroaryl groups are each independently and optionally selected from halogens and C １－６ alkyl group, C ２－６ Alkenyl group, C ２－６ Alkynyl group, C １－６ Alkoxy group, Halo C １－６ Alkyl, Halo C １－６ Alkoxy groups, cyano groups, amino groups, nitro groups, hydroxyl groups and C １－６ Substituted with one or more substituents selected from hydroxyalkyl groups, A compound represented by general formula (I) as described in any one of claims 1 to 6 and 9, or in the form of a tautomer, meso, racemic, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof.

11. R ４ａ The group is selected from a 3-8 member cycloalkyl group, a 3-8 member heterocyclyl group, a 6-10 member aryl group, and a 5-10 member heteroaryl group, of which the 3-8 member cycloalkyl group, the 3-8 member heterocyclyl group, the 6-10 member aryl group, and the 5-10 member heteroaryl group can each be independently and optionally selected from a halogen, C １－６ alkyl group, C ２－６ Alkenyl group, C ２－６ Alkynyl group, C １－６ Alkoxy group, Halo C １－６ Alkyl, Halo C １－６ Alkoxy groups, cyano groups, amino groups, nitro groups, hydroxyl groups and C １－６ Substituted with one or more substituents selected from hydroxyalkyl groups, R ４ｂ They are homologous or homologous, and each is independently a hydrogen atom, halogen, and C １－６ Selected from alkyl groups and 3- to 8-membered cycloalkyl groups, A compound represented by general formula (I) as described in claim 7 or 8, or a tautomer, meso, racemic, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof.

12. R １ These are homologous or homologous, and each is independently a hydrogen atom, a halogen, and C. １－６ Selected from alkyl groups, A compound represented by general formula (I) as described in any one of claims 1 to 11, or a tautomer, meso, racemic, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof.

13. R ２ C is a hydrogen atom. １－６ Selected from alkyl groups and 3- to 8-membered cycloalkyl groups, A compound represented by general formula (I) as described in any one of claims 1 to 12, or in the form of a tautomer, meso, racemic, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof.

14. R ３ These are homologous or homologous, and each is independently a hydrogen atom, a halogen, and C. １－６ Selected from alkyl groups, A compound represented by general formula (I) as described in any one of claims 1 to 13, or a tautomer, meso, racemic, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof.

15. the below described 【Chemistry 9】 【Chemistry 10】 【Chemistry 11】 【Chemistry 12】 【Chemistry 13】 Selected from the following compounds: A compound represented by general formula (I) as described in any one of claims 1 to 14, or in the form of a tautomer, meso, racemic, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof.

16. A compound represented by general formula (IA) or its tautomers, meso compounds, racemic compounds, enantiomers, diastereomers, or mixtures thereof, or a salt thereof, 【Chemistry 14】 Eventually, Ring A is selected from a phenyl group, a pyridyl group, and a pyrimidinyl group. Ring B is a heterocyclyl group, preferably a 3- to 8-membered heterocyclyl group, more preferably a piperidinyl group, a pyrrolidinyl group, or an azetidinyl group. R ２ ~R ６ p, q, and t are as defined in claim 1. A compound represented by general formula (IA), or its tautomers, meso compounds, racemic compounds, enantiomers, diastereomers, or mixtures thereof, or a salt thereof.

17. the below described 【Chemistry 15】 Selected from the following compounds: A compound represented by the general formula (IA) described in claim 16, or a tautomer, meso, racemic, enantiomer, diastereomer, or mixture thereof, or a salt thereof.

18. A compound represented by the general formula (IC) or its tautomers, meso compounds, racemic compounds, enantiomers, diastereomers, or mixtures thereof, or a salt thereof, 【Chemistry 16】 Eventually, R ｍ C １－６ It is an alkyl group, preferably a tert-butyl group, Ring A, Ring B, Y, R １ ~R ６ n, p, q, and t are as defined in claim 1. A compound represented by the general formula (IC) or its tautomers, meso compounds, racemic compounds, enantiomers, diastereomers, or mixtures thereof, or a salt thereof.

19. the below described 【Chemistry 17】 [Chemistry 18] Selected from the following compounds: The compound according to claim 18, or in the form of a tautomer, meso, racemic, enantiomer, diastereomer, or mixture thereof, or a salt thereof.

20. A method for preparing a compound represented by general formula (I) as described in claim 1, or a tautomer, meso, racemic, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, 【Chemistry 19】 This includes reacting a compound of general formula (IA) with a compound of general formula (IB) to obtain a compound of general formula (I), Eventually, Ring A, Ring B, Y, R １ ~R ６ n, p, q, and t are as defined in claim 1. method.

21. A method for preparing a compound represented by general formula (I) as described in claim 1, or a tautomer, meso, racemic, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, 【Chemistry 20】 This includes an intramolecular cyclization reaction of a compound of general formula (IC) to obtain a compound of general formula (I), Eventually, R ｍ C １－６ It is an alkyl group, preferably a tert-butyl group, Ring A, Ring B, Y, R １ ~R ６ n, p, q, and t are as defined in claim 1. method.

22. A pharmaceutical composition comprising a compound represented by general formula (I) as described in any one of claims 1 to 15, or a tautomer, meso, racemic, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable vectors, diluents, or excipients.

23. Uses of a compound represented by general formula (I) as described in any one of claims 1 to 15, or in the form of a tautomer, meso, racemic, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described in claim 22, in the preparation of a drug for treating and / or preventing diseases related to the CRBN protein.

24. Uses of a compound represented by general formula (I) as described in any one of claims 1 to 15, or a tautomer, meso, racemic, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described in claim 22, in the preparation of agents for the treatment and / or prevention of cancer, angiogenesis-related conditions, pain, macular degeneration or related syndromes, skin diseases, lung diseases, asbestos-related diseases, parasitic diseases, immunodeficiency, CNS diseases, CNS disorders, atherosclerosis or related conditions, sleep disorders or related conditions, infectious diseases, abnormal hemoglobin disorders or related conditions, or TNFα-related conditions, preferably in the preparation of agents for the treatment and / or prevention of cancer or CNS disorders.

25. The aforementioned cancers are selected from leukemia, myeloma, lymphoma, melanoma, skin cancer, liver cancer, kidney cancer, lung cancer, nasopharyngeal cancer, stomach cancer, esophageal cancer, colorectal cancer, gallbladder cancer, bile duct cancer, choriocarcinoma, pancreatic cancer, polycythemia vera, pediatric tumors, cervical cancer, ovarian cancer, breast cancer, bladder cancer, urothelial carcinoma, ureteral tumors, prostate cancer, seminomas, testicular tumors, head and neck tumors, head and neck squamous cell carcinoma, endometrial cancer, thyroid cancer, sarcoma, osteoma, neuroblastoma, neuroendocrine cancer, brain tumors, CNS cancer, astrocytoma, and glioma, preferably, the liver cancer is hepatocellular carcinoma, the colorectal cancer is colon cancer or rectal cancer, the sarcoma is osteosarcoma or soft tissue sarcoma, and the glioma is glioblastoma. The use described in claim 24.

26. The myelomas mentioned above are multiple myeloma (MM) and myelodysplastic syndrome (MDS), and preferably, the multiple myelomas are relapsed, refractory, or resistant. The use described in claim 25.

27. The aforementioned multiple myelomas are refractory or resistant to lenalidomide or pomalidomide. The use described in claim 26.

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