Benzo(hetero)cycloalkyl compounds for androgen receptor-dependent disorders

Abstract

This disclosure relates to benzo(hetero)cycloalkyl compounds or pharmaceutically acceptable salts thereof for the treatment or prevention of androgen receptor-dependent disorders. Specifically, this disclosure relates to compounds of formula (I), pharmaceutical compositions comprising these compounds, and the use of these compounds in the prevention or treatment of diseases, particularly androgen receptor-dependent disorders. JPEG2026518325000079.jpg41121

Description

[Technical Field]

[0001] Cross-reference of related applications This application claims priority to patent application CN202310646204.1, filed on 1 June 2023, the disclosures of which are incorporated herein by reference.

[0002] Technical field This disclosure relates to benzo(hetero)cycloalkyl compounds, or pharmaceutically acceptable salts thereof, for the treatment or prevention of androgen receptor (AR)-dependent disorders. This disclosure also relates to pharmaceutical compositions comprising these compounds, and to the use of these compounds in the treatment or prevention of diseases, particularly androgen receptor-dependent disorders. [Background technology]

[0003] Prostate cancer is one of the most common tumors and the deadliest tumor in men. Currently, the main treatment options for prostate cancer include surgery, radiation therapy, chemotherapy, castration, androgen-targeted therapy, PARP inhibitors, and PD-1 immune checkpoint antibodies. Since most prostate cancer cells require androgens for growth, castration and androgen-targeted therapy are common clinical treatments. Androgen-targeted therapy involves inhibiting androgen synthesis and inhibiting androgen receptors. Bicalutamide, abiraterone, and enzalutamide are common clinical drugs that can effectively extend patient survival. However, many prostate cancer patients eventually develop resistance to castration and androgen-targeted drugs. Known mechanisms of resistance acquisition include 1) androgen receptor reactivation, 2) activation of the glucocorticoid receptor pathway, and 3) neuroendocrine prostate cancer (Nat Rev Cancer. 2015 Dec;15(12):701-11). Of these, androgen receptor reactivation accounts for more than 60% of patients who acquire resistance.

[0004] Conventional androgen-targeted therapies are approved for prostate cancer, and there is also strong evidence that anti-androgen drugs are useful for a variety of other cancers, both hormone-dependent and hormone-independent. For example, antiandrogen drugs have been tested in the following cancers: breast cancer (enzalutamide, Breast Cancer Res. (2014) 16(1): R7; darolutamide (ClinicalTrials.gov Identifier: NCT03004534), non-small cell lung cancer (shRNAi AR), renal cell carcinoma (ASC-J9), partial androgen insensitivity syndrome (PAIS)-associated malignancies (e.g., gonadal tumors and seminomas), advanced pancreatic cancer (World J. Gastroenterology 20(29), 9229), ovarian cancer, fallopian tube cancer, or peritoneal cancer, and salivary gland cancer (Head and Neck (2016) 38, 724-731; androgen deprivation therapy (ADT) has been tested in AR-expressing recurrent / metastatic salivary gland cancer and has been shown to be beneficial in progression-free survival and overall survival endpoints), bladder cancer (Oncotarget 6(30),29860-29876;Int J.Endocrinol(2015),ID 384860).

[0005] The androgen receptor is a transcription factor activated by androgens. In prostate cancer, androgens can activate the androgen receptor via its ligand-binding domain, allowing it to enter the cell nucleus from the cell membrane and form a bimolecular complex that activates the transcription and expression of downstream genes. The androgen receptor is divided into three main structural domains: The N-terminus is a relatively loosely structured region (NTD), primarily responsible for binding to other transcription factors and forming complexes. The middle is the DNA-binding region (DBD), which helps the androgen receptor bind to the DNA of downstream genes. The C-terminus is the ligand-binding region (LBD), through which androgen binding occurs. Existing androgen receptor-targeted therapies primarily act on androgen synthesis and the ligand-binding region of the androgen receptor, antagonizing androgenic activation of the receptor. Mutations in prostate cancer that show resistance to androgen receptor-targeted therapy mainly occur in the LBD-binding region. This includes a) point mutations in amino acid sites such as F877L and T878A, which neutralize the antagonistic effect of androgen receptor antagonists and even induce agonist effects, and b) splicing mutations of the androgen receptor such as AR-Vs, which cause the androgen receptor to lose its complete ligand-binding domain, leaving only the N-terminus and DNA-binding domain. Due to the deletion or mutation of the LBD-binding domain, existing androgen receptor antagonists cannot effectively inhibit the function of the androgen receptor and are no longer effective in treating prostate cancer patients who have acquired drug resistance. Due to the resistance mechanisms caused by the above-mentioned mutations and deletions of the androgen receptor's LBD-binding domain, it is necessary to develop next-generation androgen receptor-targeted drugs with different mechanisms of action to provide new treatments for drug-resistant patients. PROTAC molecules based on androgen ligand binding can degrade the androgen receptor and completely block the androgen receptor pathway.Arvinas' ARV-110 has shown preliminary efficacy in clinical practice in prostate cancer patients with androgen receptor mutations such as T878A, but it cannot bind to mutations such as AR-Vs that lack an LBD binding region, and is therefore ineffective in patients expressing androgen receptor splicing mutations. ESSA's EPI-7386, an inhibitor targeting the N-terminus of the androgen receptor, is also in early clinical trials and has shown good tolerability in clinical studies, but its efficacy has not yet been verified.

[0006] Therefore, there remains a significant medical need for the development of androgen receptor-targeted drugs based on novel mechanisms of action, which could potentially be effective treatments for prostate cancer. Despite the numerous treatment options available to cancer patients, there is still a need for effective and safe therapies, as well as favorable use in combination therapies. [Overview of the Initiative]

[0007] The compounds disclosed herein are androgen receptor inhibitors and / or degradants that can treat various diseases and disorders as disclosed herein, and are used in particular to modulate and / or degrade androgen receptors having mutations or deletions in the full-length AR (AR-FL), AR splicing variant (AR-SV), and / or LBD domain, which are selected from androgen receptor-dependent diseases including, but not limited to, prostate cancer, other prostate diseases, breast cancer, non-small cell lung cancer, renal cell carcinoma, gonadal tumors, seminoma, pancreatic cancer, ovarian cancer, fallopian tube cancer, peritoneal cancer, salivary gland cancer, bladder cancer, acne, hirsutism, hidradenitis suppurativa, male pattern baldness, undescended testicles, androgen insensitivity syndrome, and Kennedy syndrome.

[0008] Specifically, this disclosure provides androgen receptor inhibitors and / or degradants represented by formula (I), or stereoisomers, solvates, hydrates, or pharmaceutically acceptable salts thereof.

[0009] [ka] (Hereinafter, each variable is as defined herein. These may be used to treat or prevent androgen receptor-dependent diseases or disorders, particularly cancer.)

[0010] The compound of formula (I), or its stereoisomers, solvates, hydrates, or pharmaceutically acceptable salts, and specific compounds disclosed in the context of this disclosure and falling within the scope of the above-mentioned compounds are collectively referred to as the "Compounds of the Disclosure."

[0011] This disclosure also provides methods for preparing the compounds of this disclosure, uses in the preparation of intermediates of the compounds of this disclosure, and methods for preparing said intermediates.

[0012] This disclosure also provides compositions comprising at least one compound of the disclosure.

[0013] The Disclosure also provides a pharmaceutical composition comprising a therapeutically effective amount of the Compound of the Disclosure and one or more pharmaceutically acceptable excipients.

[0014] The compounds of this disclosure are androgen receptor inhibitors and / or degradants capable of inhibiting and / or degrading androgen receptors (including androgen receptors with mutations or deletions of the AR-FL, AR-SV, and LBD domains) in vivo, and can therefore be used for androgen receptor-dependent diseases or disorders, particularly AR-SV-positive diseases or disorders, AR-V7-positive diseases or disorders, or diseases or disorders involving mutations or deletions of the LBD domain, such as cancer. Accordingly, this disclosure can provide methods or uses for inhibiting the transcriptional activation function of androgen receptors. For example, the compounds of this disclosure can be used to inhibit androgen-mediated responses in organisms, and the compounds of this disclosure can be used to modulate immune responses in organisms.

[0015] This disclosure provides compounds of the disclosure that are used as pharmaceuticals.

[0016] This disclosure provides compounds used to inhibit and / or degrade androgen receptors, including androgen receptors containing mutations or deletions of the AR-FL, AR-SV, and LBD domains.

[0017] This disclosure provides compounds of the disclosure that can be used to treat or prevent androgen receptor-dependent diseases or disorders of individuals, particularly AR-SV-positive diseases or disorders, AR-V7-positive diseases or disorders, or diseases or disorders involving mutations or deficiencies in the LBD domain, such as cancer.

[0018] This disclosure provides the use of the compounds of this disclosure in the preparation of a drug, which is used to treat or prevent androgen receptor-dependent diseases or disorders, particularly AR-SV-positive diseases or disorders, AR-V7-positive diseases or disorders, or diseases or disorders involving mutations or deficiencies of the LBD domain, such as cancer.

[0019] This disclosure provides a method for inhibiting and / or degrading androgen receptors (including androgen receptors with mutations or deletions in the AR-FL, AR-SV, and LBD domains) in vivo or in vitro, the method comprising contacting an androgen receptor inhibitor and / or degradation agent, such as a compound of this disclosure, with an androgen receptor.

[0020] This disclosure provides a method for inhibiting and / or degrading androgen receptors (including androgen receptors with mutations or deletions in the AR-FL, AR-SV, and LBD domains) in an individual, comprising administering an effective amount of an androgen receptor inhibitor and / or degradant, such as a compound of this disclosure, to an individual in need.

[0021] This disclosure provides a method for treating or preventing a disease or disorder in an individual, comprising administering an effective amount of the compound of this disclosure to an individual in need thereof, wherein the disease or disorder is an androgen receptor-dependent disease or disorder, particularly an AR-SV-positive disease or disorder, an AR-V7-positive disease or disorder, or a disease or disorder involving mutations or deletions of the LBD domain, such as cancer.

[0022] This disclosure provides a method for treating or preventing a disease or disorder, comprising administering an effective amount of a first therapeutic agent and an optional second therapeutic agent to an individual in need thereof, wherein the first therapeutic agent is a compound of this disclosure, and the second therapeutic agent is one or more other therapeutic agents, and the disease or disorder is an androgen receptor-dependent disease or disorder, particularly an AR-SV-positive disease or disorder, an AR-V7-positive disease or disorder, or a disease or disorder involving mutations or deficiencies in the LBD domain, such as cancer.

[0023] Furthermore, the Disclosure also provides combinations (combination products) or cartridges, which provide the compounds (or pharmaceutical compositions thereof) of the Disclosure as defined above, and one or more other therapeutic agents (or pharmaceutical compositions thereof). These are used simultaneously, separately, or sequentially in the treatment of androgen receptor-dependent disorders or conditions.

[0024] Embodiment

[0025] Embodiment 1. A compound of formula (I), or its stereoisomer, solvate, hydrate, or pharmaceutically acceptable salt.

[0026] [ka] (Here, n is 0 or 1, X is N, CCH3, or CH. Y is NR4 or CH2, where R4 is H, acetyl, or C 1~3 It is alkyl, Z is C(O) or CH2, R1 and R2 are each independently H, halogen, CN, C 1~4 alkyl, C 1~4 alkoxy, and halo C 1~4 alkyl, selected from L1 is a single bond, O, S, or NH, R3 is C optionally substituted by halogen or CN 1~6 alkyl, C 3~6 cycloalkyl, or C 3~6 cycloalkyl-C 1~4 alkyl, L0 is a single bond, O, S, NH, -C(O)-NH-, -NH-C(O)-, -NH-(CH2)-, or -NH-(CH2)2-, W is C 6~12 aryl, 5- to 12-membered heteroaryl, or 4- to 12-membered heterocyclyl, each of which is optionally substituted by one, two, or three substituents independently selected from halogen, CN, oxo, NH2, NR7R8, OH, OR8, R8, -C(O)-NHR7, -OC(O)-NHR8, -SO2R8, -SO2NHR7, -NR7SO2R8, -NR7SO2NHR8, and -NHC(O)-R8, where R7 is each independently H, C 1~4 alkyl, and acetyl, and R8 is C optionally substituted by one or more halogens, hydroxy, or NH2 1~4 alkyl, L2 is a single bond, -NH-C 1~6 alkyl-, -NH-C 2~6 alkenyl-, -NH-C 1~4 alkyl-O-C 1~4 alkyl-, -O-C 1~6 alkyl-, -O-C 2~6 alkenyl-, -O-C 1~4 alkyl-O-C 1~4 alkyl-, -C 1~8 alkyl-, -C 2~6 alkenyl-, -C 1~4 alkyl-O-C 1~4Alkyl-, -C 1~4 Alkyl-NH-C 1~4 Alkyl-, -C 3~6 Cycloalkyl, -OC 3~6 Cycloalkyl, -NH-C 3~6 They are cycloalkyl, phenyl, 3-10 member heterocycloalkyl, or 5-10 member heteroaryl. L3 is -C 1~6 Alkyl-O-, -C 2~6 Alkenyl-O-,-C 1~4 Alkyl-OC 1~4 Alkyl-O-, -C 1~6 Alkyl-NH-,-C 2~6 Alkenyl-NH-,-C 1~4 Alkyl-OC 1~4 Alkyl-NH-,-C 1~8 Alkyl-, -C 2~6 Alkenyl-, -C 1~4 Alkyl-OC 1~4 Alkyl-, -C 1~4 Alkyl-NH-C 1~4 Alkyl-, -C 3~6 Cycloalkyl, -C 3~6 Cycloalkyl-O-,-C 3~6 It is a cycloalkyl-NH-, phenyl, 3-10 member heterocycloalkyl, or 5-10 member heteroaryl, and The alkyl, heteroaryl, and heterocycloalkyl in L2 and L3 are, respectively, halogen, OH, NH2, CN, and C(O)C. 1~6 Alkyl, C(O)NH2, C 1~6 Alkyl, C 3~6 Cycloalkyl, C 1~6 Alkoxy, -NHC 1~6 Alkyl and -N(C) 1~6 It is optionally substituted with one or more substituents independently selected from alkyl)2, V is CH2, O, S, or NH. Here, each of the heteroaryl, heterocyclyl, and heterocycloalkyl compounds independently contains 1, 2, 3, or 4 heteroatoms independently selected from N, O, and S.

[0027] Embodiment 2. According to the compound described in Embodiment 1, its stereoisomer, solvate, hydrate, or pharmaceutically acceptable salt,

[0028] structural fragment

[0029] [ka] teeth,

[0030] [ka] or

[0031] [ka] That is the case.

[0032] Embodiment 3. A structural fragment according to any one of the embodiments described above, its stereoisomer, solvate, hydrate, or pharmaceutically acceptable salt thereof.

[0033] [ka] teeth,

[0034] [ka] or

[0035] [ka] That is the case.

[0036] Embodiment 4. A compound described in any one of the embodiments described above, or a stereoisomer, solvate, hydrate, or pharmaceutically acceptable salt thereof. (Here, n is 0 or 1, X is CH, Y is NR4 or CH2, where R4 is H, acetyl, or C1~3 It is alkyl, Z is C(O) or CH2, R1 and R2 are, independently, halogen, CN, and C. 1~4 Alkyl, C 1~4 Alkoxy and Halo C 1~4 Selected from alkyl groups, L1 is a single bond, O, S, or NH. R3 is C, optionally replaced by halogen or CN. 1~6 It is alkyl, L0 is a single bond, O, S, NH, -C(O)-NH-, -NH-C(O)-, -NH-(CH2)-, or -NH-(CH2)2-. W is C 6~12 The aryl, heteroaryl, and heterocyclyl are, respectively, halogen, CN, OH, NH2, oxo, C(O)NH2, and C 1~4 Alkyl and C 1~4 It is optionally substituted with one, two, or three substituents independently selected from the alkoxy, L2 is a single bond, -NH-C 1~6 Alkyl-,-NH-C 2~6 Alkenyl-,-NH-C 1~4 Alkyl-OC 1~4 Alkyl-, -OC 1~6 Alkyl-, -OC 2~6 Alkenyl-, -OC 1~4 Alkyl-OC 1~4 Alkyl-, -C 1~8 Alkyl-, -C 2~6 Alkenyl-, -C 1~4 Alkyl-OC 1~4 Alkyl-, -C 1~4 Alkyl-NH-C 1~4 Alkyl-, -C 3~6 Cycloalkyl, -OC 3~6 Cycloalkyl, -NH-C 3~6 They are cycloalkyl, phenyl, 3-10 member heterocycloalkyl, or 5-10 member heteroaryl. L3 is -C 1~6Alkyl-O-, -C 2~6 Alkenyl-O-, -C 1~4 Alkyl-O-C 1~4 Alkyl-O-, -C 1~6 Alkyl-NH-, -C 2~6 Alkenyl-NH-, -C 1~4 Alkyl-O-C 1~4 Alkyl-NH-, -C 1~8 Alkyl-, -C 2~6 Alkenyl-, -C 1~4 Alkyl-O-C 1~4 Alkyl-, -C 1~4 Alkyl-NH-C 1~4 Alkyl-, -C 3~6 Cycloalkyl, -C 3~6 Cycloalkyl-O-, -C 3~6 Cycloalkyl-NH-, phenyl, 3- to 10-membered heterocycloalkyl, or 5- to 10-membered heteroaryl, and the heteroaryl and heterocycloalkyl in L2 and L3 are each optionally substituted with one or more substituents independently selected from halogen, OH, CN, C(O)C 1~6 alkyl, C 1~4 alkyl and C 1~4 are optionally substituted by one or more substituents independently selected from alkoxy, V is CH2, O, S, or NH, wherein the heteroaryl, heterocyclyl, and heterocycloalkyl each independently contain 1, 2, 3, or 4 heteroatoms independently selected from N, O, and S.)

[0037] Embodiment 5. A compound according to any one of the foregoing embodiments, or a stereoisomer, solvate, hydrate, or pharmaceutically acceptable salt thereof. (where n is 0 or 1, X is CH, Y is CH2, Z is C(O) or CH2, R1 and R2 are each independently halogen, CN, C 1~4 alkyl, C 1~4 alkoxy, and haloC 1~4Selected from alkyl groups, L1 is a single bond, O, S, or NH. R3 is C, optionally replaced by halogen or CN. 1~6 It is alkyl, L0 is a single bond, O, S, or NH. W is C 6~12 The aryl, heteroaryl, and heterocyclyl are, respectively, halogen, OH, NH2, CN, oxo, C(O)NH2, and C 1~4 Alkyl and C 1~4 It is optionally substituted with one, two, or three substituents independently selected from the alkoxy, L2 is a single bond, -NH-C 1~6 Alkyl-,-NH-C 2~6 Alkenyl-,-NH-C 1~4 Alkyl-OC 1~4 Alkyl-, -OC 1~6 Alkyl-, -OC 2~6 Alkenyl-, -OC 1~4 Alkyl-OC 1~4 Alkyl-, -C 1~8 Alkyl-, -C 2~6 Alkenyl-, -C 1~4 Alkyl-OC 1~4 Alkyl-, -C 1~4 Alkyl-NH-C 1~4 Alkyl-, -C 3~6 Cycloalkyl, -OC 3~6 Cycloalkyl, -NH-C 3~6 They are cycloalkyl, phenyl, 3-10 member heterocycloalkyl, or 5-10 member heteroaryl. L3 is -C 1~6 Alkyl-O-, -C 2~6 Alkenyl-O-,-C 1~4 Alkyl-OC 1~4 Alkyl-O-, -C 1~6 Alkyl-NH-,-C 2~6 Alkenyl-NH-,-C 1~4 Alkyl-OC 1~4 Alkyl-NH-,-C 1~8Alkyl-, -C 2~6 Alkenyl-, -C 1~4 Alkyl-OC 1~4 Alkyl-, -C 1~4 Alkyl-NH-C 1~4 Alkyl-, -C 3~6 Cycloalkyl, -C 3~6 Cycloalkyl-O-,-C 3~6 It is a cycloalkyl-NH-, phenyl, 3-10 member heterocycloalkyl, or 5-10 member heteroaryl, and In L2 and L3, the heteroaryl and heterocycloalkyl elements are, respectively, halogen, OH, CN, and C(O)C. 1~6 Alkyl, C 1~4 Alkyl and C 1~4 It is optionally substituted with one or more substituents independently selected from the alkoxy, V is CH2, O, S, or NH. Here, each of the heteroaryl, heterocyclyl, and heterocycloalkyl compounds independently contains 1, 2, 3, or 4 heteroatoms independently selected from N, O, and S.

[0038] Embodiment 6. According to any of the compounds described in any of the embodiments above, their stereoisomers, solvates, hydrates, or pharmaceutically acceptable salts, W is C 6~12 The heteroaryl is an aryl or a 5- to 10-membered heteroaryl, wherein the heteroaryl comprises one, two, three, or four heteroatoms independently selected from N, O, and S, for example, the heteroaryl comprises one N heteroatom and optionally further comprises one, two, or three more heteroatoms independently selected from N, O, and S.

[0039] Embodiment 7. A compound described in any one of the embodiments described above, or a stereoisomer, solvate, hydrate, or pharmaceutically acceptable salt thereof. (Here, n is 0 or 1, X is CH, Y is CH2, Z is C(O) or CH2, R1 and R2 are, independently, halogen, CN, and C. 1~4 Alkyl, C 1~4 Alkoxy and Halo C 1~4 Selected from alkyl groups, L1 is a single bond, O, S, or NH. R3 is C, optionally replaced by halogen or CN. 1~6 It is alkyl, L0 is a single bond, O, S, or NH. W is C 6~12 The aryl or 5-10 membered heteroaryl is, and the aryl and heteroaryl are, respectively, halogen, CN, OH, NH2, oxo, C(O)NH2, C 1~4 Alkyl and C 1~4 It is optionally substituted with one, two, or three substituents independently selected from the alkoxy, L2 is a single bond, -NH-C 1~6 Alkyl-,-NH-C 2~6 Alkenyl-,-NH-C 1~4 Alkyl-OC 1~4 Alkyl-, -OC 1~6 Alkyl-, -OC 2~6 Alkenyl-, -OC 1~4 Alkyl-OC 1~4 Alkyl-, -C 1~6 Alkyl-, -C 1~4 Alkyl-OC 1~4 Alkyl-, -C 1~4 Alkyl-NH-C 1~4 Alkyl-, -OC 3~6 Cycloalkyl, -NH-C 3~6 They are cycloalkyl, 3-10 member heterocycloalkyl, or 5-10 member heteroaryl. L3 is -C 1~6 Alkyl-O-, -C 2~6 Alkenyl-O-,-C 1~4 Alkyl-OC 1~4 Alkyl-O-, -C 1~6 Alkyl-NH-,-C 2~6 Alkenyl-NH-,-C 1~4 Alkyl-OC 1~4 Alkyl-NH-,-C1~6 Alkyl-, -C 1~4 Alkyl-OC 1~4 Alkyl-, -C 1~4 Alkyl-NH-C 1~4 Alkyl-, -C 3~6 Cycloalkyl-O-,-C 3~6 It is a cycloalkyl-NH-, a 3-10 member heterocycloalkyl, or a 5-10 member heteroaryl, and V is CH2, O, S, or NH. Here, each heterocycloalkyl or heteroaryl independently comprises one, two, three, or four heteroatoms independently selected from N, O, and S. For example, each heterocycloalkyl or heteroaryl independently comprises one N heteroatom and optionally further comprises one, two, or three heteroatoms independently selected from N, O, and S.

[0040] Embodiment 8. According to any one of the embodiments described above, the compound has the structure of formula (II).

[0041] [ka]

[0042] Embodiment 9. According to any of the compounds described in any of the embodiments above, their stereoisomers, solvates, hydrates, or pharmaceutically acceptable salts, W is C 6~12 An aryl or a 5-10 membered heteroaryl, wherein the heteroaryl contains one N heteroatom and optionally further contains one, two, or three heteroatoms independently selected from N, O, and S, each optionally substituted by one, two, or three substituents independently selected from halogens and CN.

[0043] Embodiment 10. According to any of the compounds, stereoisomers, solvates, hydrates, or pharmaceutically acceptable salts described in any of the embodiments described above, W is a 5-10 membered heteroaryl, the heteroaryl comprising one N heteroatom and optionally further comprising one, two, or three heteroatoms independently selected from N, O, and S, and optionally substituted with one, two, or three substituents independently selected from halogens and CN.

[0044] Embodiment 11. According to any one of the compounds described in Embodiments 1 to 9 above, its stereoisomer, solvate, hydrate, or pharmaceutically acceptable salt, W is C 6~10 These are aryls (e.g., benzene rings) or 5- to 10-membered heteroaryls containing 1, 2, or 3 N heteroatoms, each optionally substituted with 1, 2, or 3 substituents independently selected from halogens and CN.

[0045] Embodiment 12. According to any of the compounds, stereoisomers, solvates, hydrates, or pharmaceutically acceptable salts described in any of the embodiments described above, W is a 5-10 membered heteroaryl, the heteroaryl comprising one N heteroatom and one or two heteroatoms independently selected from N, O, and S (e.g., one, two, or three N heteroatoms) (e.g., pyridyl, indazolyl, azindazolyl, or pyrimidinyl), and optionally substituted with one, two, or three substituents independently selected from halogens and CN.

[0046] Embodiment 13. According to any of the compounds, stereoisomers, solvates, hydrates, or pharmaceutically acceptable salts described in any of the embodiments described above, W is a 5-6 membered heteroaryl or an 8-10 membered heteroaryl, wherein the heteroaryl comprises one N heteroatom and optionally further comprises one or two heteroatoms independently selected from N, O, and S, each optionally substituted by one, two, or three substituents independently selected from halogens and CN.

[0047] Embodiment 14. According to any of the embodiments described above, the compound, stereoisomer, solvate, hydrate, or pharmaceutically acceptable salt thereof, where W is a 5-6 membered heteroaryl (e.g., a 6-membered heteroaryl), the heteroaryl comprising one N heteroatom and optionally further comprising one or two heteroatoms independently selected from N, O, or S (e.g., one, two, or three N heteroatoms) (e.g., pyridyl or pyrimidinyl), and optionally substituted with one, two, or three substituents independently selected from halogens and CN.

[0048] Embodiment 15. According to any of the compounds described in the preceding embodiments, or their stereoisomers, solvates, hydrates, or pharmaceutically acceptable salts, W is a six-membered heteroaryl (e.g., pyridyl or pyrimidinyl) containing one, two, or three N heteroatoms, and is optionally substituted with one or two CN atoms.

[0049] Embodiment 16. According to any of the compounds, stereoisomers, solvates, hydrates, or pharmaceutically acceptable salts described in any of the embodiments described above, W is an 8-10 membered heteroaryl, the heteroaryl comprising one N heteroatom and optionally further comprising one or two heteroatoms independently selected from N, O, and S (e.g., comprising one, two, or three N heteroatoms) (e.g., indazolyl or azindazolyl), and optionally substituted with one or two CN atoms.

[0050] Embodiment 17. According to any one of the compounds described in Embodiments 1 to 5 above, its stereoisomer, solvate, hydrate, or pharmaceutically acceptable salt, L2 is a single bond, -NH-C 1~6 Alkyl-,-NH-C 2~6 Alkenyl-,-NH-C 1~4 Alkyl-OC 1~4 Alkyl-, -OC 1~6 Alkyl-, -OC 2~6 Alkenyl-, -OC 1~4 Alkyl-OC 1~4 Alkyl-, -C 1~6Alkyl-, -C 1~4 Alkyl-OC 1~4 Alkyl-, -C 1~4 Alkyl-NH-C 1~4 Alkyl-, -OC 3~6 Cycloalkyl, -NH-C 3~6 A cycloalkyl or a 3- to 10-membered heterocycloalkyl, wherein the heterocycloalkyl comprises one N heteroatom and optionally further comprises one, two, or three heteroatoms independently selected from N, O, and S, and the heterocycloalkyl is a halogen, OH, CN, C(O)C 1~4 Alkyl, C 1~4 Alkyl, or C 1~4 It is arbitrarily substituted with alkoxy compounds.

[0051] Embodiment 18. According to any of the compounds described in the preceding embodiments, their stereoisomers, solvates, hydrates, or pharmaceutically acceptable salts, L2 is a single bond, -NH-C 1~6 Alkyl-,-NH-C 2~6 Alkenyl-,-NH-C 1~4 Alkyl-OC 1~4 Alkyl-, -OC 1~6 Alkyl-, -OC 2~6 Alkenyl-, -OC 1~4 Alkyl-OC 1~4 Alkyl-, -C 1~6 Alkyl-, -C 1~4 Alkyl-OC 1~4 Alkyl-, -C 1~4 Alkyl-NH-C 1~4 Alkyl-, -OC 3~6 Cycloalkyl, -NH-C 3~6 A cycloalkyl or a 3- to 10-membered heterocycloalkyl, wherein the heterocycloalkyl comprises one N heteroatom and optionally further comprises one, two, or three heteroatoms independently selected from N, O, and S.

[0052] Embodiment 19. According to any of the compounds described in the preceding embodiments, their stereoisomers, solvates, hydrates, or pharmaceutically acceptable salts, L2 is a single bond, -NH-C 1~6 Alkyl-, -OC 1~6 Alkyl-, -C 1~6 Alkyl-, -OC 3~6 The cycloalkyl or 4-8 membered heterocycloalkyl, wherein the 4-8 membered heterocycloalkyl contains one N heteroatom and optionally further contains one or two heteroatoms independently selected from N, O, and S.

[0053] Embodiment 20. According to any of the compounds described in the preceding embodiments, their stereoisomers, solvates, hydrates, or pharmaceutically acceptable salts, L2 is a single bond, -NH-C 1~4 Alkyl-, -OC 1~4 Alkyl-, -C 1~4 Alkyl-, -OC 3~6 The cycloalkyl or 4-6 membered heterocycloalkyl, wherein the 4-6 membered heterocycloalkyl contains one N heteroatom and optionally further contains one or two heteroatoms independently selected from N, O, and S.

[0054] Embodiment 21. According to any of the compounds described in the preceding embodiments, their stereoisomers, solvates, hydrates, or pharmaceutically acceptable salts, L2 is a single bond, -NH-C 1~4 Alkyl-, -OC 1~4 Alkyl-, -C 1~4 Alkyl-, -OC 3~6 The L2 is a cycloalkyl or a 4-6 member heterocycloalkyl, wherein the 4-6 member heterocycloalkyl contains one N heteroatom, where L2 is a single bond or -C 1~4 If it is not alkyl-, it is linked to W via a heteroatom.

[0055] Embodiment 22. According to any of the compounds described in the preceding embodiments, their stereoisomers, solvates, hydrates, or pharmaceutically acceptable salts, L2 is a single bond, -NH-C 1~4 Alkyl-, -OC1~4 Alkyl-, -OC 5~6 The cycloalkyl or 4-6 membered heterocycloalkyl is a 4-6 membered heterocycloalkyl, wherein the 4-6 membered heterocycloalkyl contains one N heteroatom, where L2 is linked to W via a heteroatom if it is not a single bond.

[0056] Embodiment 23. According to any one of the compounds described in Embodiments 1 to 17, its stereoisomers, solvates, hydrates, or pharmaceutically acceptable salts, L2 is -NH-C 1~4 Alkyl-, -OC 1~4 Alkyl-, -OC 3~6 Cycloalkyl and halogens, OH, -C(O)C 1~4 Alkyl, C 1~4 Alkyl, or C 1~4 Optionally substituted with alkoxy

[0057] [ka] Selected from, where L2 is linked to W via a heteroatom.

[0058] Embodiment 24. According to any of the compounds described in the preceding embodiments, their stereoisomers, solvates, hydrates, or pharmaceutically acceptable salts, L2 is a single bond, -NH-C 1~3 Alkyl-, -OC 1~3 Alkyl, -OC 5~6 Cycloalkyl,

[0059] [ka] Selected from, where L2 is linked to W via a heteroatom if it is not a single bond.

[0060] Embodiment 25. According to any of the compounds described in any of the embodiments above, their stereoisomers, solvates, hydrates, or pharmaceutically acceptable salts, L3 is -C 1~6 Alkyl-O-, -C 2~6 Alkenyl-O-,-C 1~4Alkyl-OC 1~4 Alkyl-O-, -C 1~6 Alkyl-NH-,-C 2~6 Alkenyl-NH-,-C 1~4 Alkyl-OC 1~4 Alkyl-NH-,-C 1~6 Alkyl-, -C 1~4 Alkyl-OC 1~4 Alkyl-, -C 1~4 Alkyl-NH-C 1~4 Alkyl-, -C 3~6 Cycloalkyl-O-,-C 3~6 A cycloalkyl-NH- or 3- to 10-membered heterocycloalkyl, where the heterocycloalkyl comprises one N heteroatom and optionally further comprises one, two, or three heteroatoms independently selected from N, O, and S, and the heterocycloalkyl is a halogen, OH, CN, C(O)C 1~4 Alkyl, C 1~4 Alkyl, or C 1~4 It is arbitrarily substituted with alkoxy compounds.

[0061] Embodiment 26. According to any of the compounds described in any of the embodiments above, their stereoisomers, solvates, hydrates, or pharmaceutically acceptable salts, L3 is -C 1~6 Alkyl-O-, -C 2~6 Alkenyl-O-,-C 1~4 Alkyl-OC 1~4 Alkyl-O-, -C 1~6 Alkyl-NH-,-C 2~6 Alkenyl-NH-,-C 1~4 Alkyl-OC 1~4 Alkyl-NH-,-C 1~6 Alkyl-, -C 1~4 Alkyl-OC 1~4 Alkyl-, -C 1~4 Alkyl-NH-C 1~4 Alkyl-, -C 3~6 Cycloalkyl-O-,-C 3~6A cycloalkyl-NH- or 3- to 10-membered heterocycloalkyl, wherein the heterocycloalkyl comprises one N heteroatom and optionally further comprises one, two, or three heteroatoms independently selected from N, O, and S.

[0062] Embodiment 27. According to any of the compounds described in any of the embodiments above, their stereoisomers, solvates, hydrates, or pharmaceutically acceptable salts, L3 is -C 1~4 Alkyl-O-, -C 1~4 Alkyl-NH-,-C 3~6 Cycloalkyl-O-,-C 3~6 The cycloalkyl-NH- or 4- to 8-membered heterocycloalkyl group, wherein the 4- to 8-membered heterocycloalkyl group contains one N heteroatom and optionally further contains one or two heteroatoms independently selected from N, O, and S.

[0063] Embodiment 28. According to any of the compounds described in any of the embodiments above, their stereoisomers, solvates, hydrates, or pharmaceutically acceptable salts, L3 is -C 1~4 Alkyl-O-, -C 1~4 Alkyl-NH-,-C 3~6 The molecule is a cycloalkyl-O- or a 4- to 6-membered heterocycloalkyl, wherein the 4- to 6-membered heterocycloalkyl contains one N heteroatom, where L3 is linked to the benzene ring in the general formula via the heteroatom.

[0064] Embodiment 29. According to any of the compounds described in any of the embodiments above, their stereoisomers, solvates, hydrates, or pharmaceutically acceptable salts, L3 is -C 1~3 Alkyl-O-, -C 1~3 Alkyl-NH-,-C 5~6 The molecule is a cycloalkyl-O- or a 4- to 6-membered heterocycloalkyl, wherein the 4- to 6-membered heterocycloalkyl contains one N heteroatom, where L3 is linked to the benzene ring in the general formula via the heteroatom.

[0065] Embodiment 30. According to the compound described in Embodiment 25, its stereoisomer, solvate, hydrate, or pharmaceutically acceptable salt, L3 is -C 1~6 Alkyl-O-, -C 1~6 alkyl-NH-, and halogens, OH, -C(O)C 1~4 Alkyl, C 1~4 Alkyl, or C 1~4 Optionally substituted with alkoxy

[0066] [ka] Selected from the above, and L3 is linked to the benzene ring in the general formula via a heteroatom.

[0067] Embodiment 31. According to any of the compounds described in the preceding embodiments, their stereoisomers, solvates, hydrates, or pharmaceutically acceptable salts, L3 is -C 1~3 Alkyl-O-, -C 1~3 Alkyl-NH-, and

[0068] [ka] and

[0069] [ka] Selected from the above, and L3 is linked to the benzene ring in the general formula via a heteroatom.

[0070] Embodiment 32. According to any one of the embodiments described above, the compound, stereoisomer thereof, solvate, hydrate, or pharmaceutically acceptable salt thereof, the structure

[0071] [ka] or

[0072] [ka] The following options are available:

[0073] [ka]

[0074] Embodiment 33. According to the compound, stereoisomer, solvate, hydrate, or pharmaceutically acceptable salt described in any one of the embodiments, V is CH2, O, or NH.

[0075] Embodiment 34. According to any of the compounds, stereoisomers, solvates, hydrates, or pharmaceutically acceptable salts described in any of the embodiments described above, V is CH2 or O.

[0076] Embodiment 35. According to any of the compounds described in the preceding embodiments, their stereoisomers, solvates, hydrates, or pharmaceutically acceptable salts, n is 1.

[0077] Embodiment 36. According to any of the compounds, stereoisomers, solvates, hydrates, or pharmaceutically acceptable salts described in any of the embodiments described above, R1 and R2 are each independently a halogen, CN, or halo C 1~4 It is alkyl.

[0078] Embodiment 37. According to any of the compounds, stereoisomers, solvates, hydrates, or pharmaceutically acceptable salts described in any of the embodiments described above, R1 and R2 are each independently a halogen, CN, or CF3, for example Cl or CN.

[0079] Embodiment 38. According to the compound described in any one of the embodiments above, or its stereoisomer, solvate, hydrate, or pharmaceutically acceptable salt, R1 and R2 are each independently a halogen or CN, for example Cl or CN.

[0080] Embodiment 39. According to any of the compounds, stereoisomers, solvates, hydrates, or pharmaceutically acceptable salts described in any of the embodiments described above, L1 is O, or S, for example, O.

[0081] Embodiment 40. According to any of the compounds, stereoisomers, solvates, hydrates, or pharmaceutically acceptable salts described in any of the embodiments described above, L1 is O.

[0082] Embodiment 41. According to any of the compounds, stereoisomers, solvates, hydrates, or pharmaceutically acceptable salts described in any of the embodiments above, R3 is a C optionally substituted with a halogen. 1~4 Alkyl compounds, such as C1-C4 alkyl groups optionally substituted with Cl, such as ethyl or chloroethyl.

[0083] Embodiment 42. According to any of the compounds, stereoisomers, solvates, hydrates, or pharmaceutically acceptable salts described in any of the embodiments described above, L0 is a single bond or NH.

[0084] Embodiment 43. A compound described in any one of the embodiments described above, or a stereoisomer, solvate, hydrate, or pharmaceutically acceptable salt thereof. (Here, n is 0 or 1, X is CH, Y is CH2, Z is C(O), R1 and R2 are independently selected from halogen and CN. L1 is O, R3 is ethyl, optionally substituted with a halogen. L0 is a single bond or NH, W is C 6~12 These are aryls, or 5-10 membered heteroaryls containing 1, 2, or 3 N heteroatoms, each optionally substituted with 1, 2, or 3 substituents independently selected from halogens and CN. L2 is a single bond, -C 1~4Alkyl-,-NH-C 1~4 Alkyl-, -OC 1~4 Alkyl-, -OC 3~6 Cycloalkyl, -NH-C 3~6 Cycloalkyl, and F, Cl, OH, C(O)C 1~6 Alkyl, or C 1~4 Arbitrarily substituted with alkyl

[0085] [ka] Selected from, and L2 is a single bond or -C 1~4 If it is not alkyl-, it is linked to W via a heteroatom, L3 is -C 1~4 Alkyl-O-, -C 1~4 Alkyl-NH-,-C 3~6 Cycloalkyl-O-,-C 3~6 Cycloalkyl-NH-, and F,Cl,OH,C(O)C 1~4 Alkyl, or C 1~4 Arbitrarily substituted with alkyl

[0086] [ka] Selected from, and L3 is linked to the benzene ring in the general formula via a heteroatom, V is either CH2 or O.

[0087] Embodiment 44. According to any of the compounds described in the preceding embodiments, or their stereoisomers, solvates, hydrates, or pharmaceutically acceptable salts, W is a 5- to 10-membered heteroaryl compound containing 1, 2, or 3 N heteroatoms, and is optionally substituted with 1, 2, or 3 substituents independently selected from halogens and CN.

[0088] Embodiment 45. According to the compound described in any one of the foregoing embodiments, or its stereoisomer, solvate, hydrate, or pharmaceutically acceptable salt, W is pyrazolyl, phenyl, pyridyl, pyrimidinyl, indolyl, indazolyl, or azaindazolyl (e.g., 7-azaindazolyl, 6-azaindazolyl, 5-azaindazolyl, 4-azaindazolyl) optionally substituted by 1, 2, or 3 substituents independently selected from halogen and CN, for example

[0089]

Chemical Formula

[0090] Embodiment 46. The compound described in any one of the foregoing embodiments, or its stereoisomer, solvate, hydrate, or pharmaceutically acceptable salt. (Here, n is 1, X is CH, Y is CH2, Z is C(O), R1 is halogen, R2 is CN, L1 is O, R3 is ethyl optionally substituted by halogen, L0 is a single bond or NH, W is a 5- to 10-membered heteroaryl containing 1, 2, or 3 N heteroatoms (e.g., pyridyl, pyrimidinyl, azaindazolyl, or indazolyl), optionally substituted by 1 or 2 substituents independently selected from halogen and CN, L2 is a single bond, -NH-CH2-, -NH-CH2-CH2-, -O-CH2-, -O-CH2-CH2-, -C 1~3 alkyl-, -O-C 3~6 cycloalkyl, or

[0091]

Chemical Formula

[0092] [ka] Here, p is independently selected from 0 and 1, for example, p is 0, and L3 is linked to the benzene ring in the general formula via a heteroatom, V is either CH2 or O.

[0093] Embodiment 47. According to any of the compounds, stereoisomers, solvates, hydrates, or pharmaceutically acceptable salts described in any of the embodiments described above, L0 is a single bond.

[0094] Embodiment 48. According to any one of the embodiments described above, the compound, stereoisomer thereof, solvate, hydrate, or pharmaceutically acceptable salt thereof, where L0 is NH.

[0095] Embodiment 49. According to any of the compounds, stereoisomers, solvates, hydrates, or pharmaceutically acceptable salts described in any of the embodiments described above, V is O.

[0096] Embodiment 50. According to any of the compounds, stereoisomers, solvates, hydrates, or pharmaceutically acceptable salts described in any of the embodiments described above, V is CH2.

[0097] Embodiment 51. According to the compound described in any one of the embodiments above, or its stereoisomer, solvate, hydrate, or pharmaceutically acceptable salt, R1 is a halogen, such as Cl, and R2 is CN.

[0098] Compound according to any one of the foregoing embodiments, or a stereoisomer, solvate, hydrate, or pharmaceutically acceptable salt thereof. (where n is 1, X is CH, Y is CH2, Z is -C(O)-, R1 is halogen, R2 is halogen or CN, L1 is O, R3 is C 1~3 alkyl optionally substituted by halogen, L0 is a single bond, W is a 5- to 10-membered heteroaryl containing 1, 2, or 3 N heteroatoms, optionally substituted by 1 or 2 CN, L2 is a single bond, -NH-C 1~4 alkyl-, -O-C 1~4 alkyl, -O-C 5~6 cycloalkyl,

[0099]

Chemical formula

[0100]

Chemical formula

[0101] According to the compound according to any one of the foregoing embodiments, or a stereoisomer, solvate, hydrate, or pharmaceutically acceptable salt thereof, R1 is Cl.

[0102] Embodiment 54. According to the compound described in any one of the embodiments above, or its stereoisomer, solvate, hydrate, or pharmaceutically acceptable salt, R2 is CN.

[0103] Embodiment 55. According to the compound described in any one of the embodiments above, or its stereoisomer, solvate, hydrate, or pharmaceutically acceptable salt, R3 is ethyl or chloroethyl.

[0104] Embodiment 56. According to any of the compounds described in any of the embodiments above, or their solvates, hydrates, or pharmaceutically acceptable salts, W is pyridyl, pyrimidinyl, azindazolyl, or indazolyl (for example,

[0105] [ka] or

[0106] [ka] ) and is optionally replaced by 1 or 2 CNs.

[0107] Embodiment 57. According to any of the compounds described in the preceding embodiments, their stereoisomers, solvates, hydrates, or pharmaceutically acceptable salts, L2 is linked to W via its heteroatom.

[0108] Embodiment 58. According to any of the compounds described in the preceding embodiments, their stereoisomers, solvates, hydrates, or pharmaceutically acceptable salts, L3 is linked to the benzene ring of the general formula via its heteroatom.

[0109] Embodiment 59. According to any of the compounds described in any of the embodiments above, or their solvates, hydrates, or pharmaceutically acceptable salts, the compound is a racemate.

[0110] Embodiment 60. According to any one of the embodiments described above, or its stereoisomers, solvates, hydrates, or pharmaceutically acceptable salts, the compound is selected from the following: [Table 1-1] [Table 1-2]

[0111] Embodiment 61. A pharmaceutical composition comprising a compound described in any one of Embodiments 1 to 60, a stereoisomer thereof, a solvate, a hydrate, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

[0112] Embodiment 62. The compound described in any one of Embodiments 1 to 60, its stereoisomer, solvate, hydrate, or pharmaceutically acceptable salt is used as a drug.

[0113] Embodiment 63. A compound, stereoisomer, solvate, hydrate, or pharmaceutically acceptable salt thereof described in any one of Embodiments 1 to 60 can be used to treat or prevent an androgen receptor-dependent disorder or disorder in an individual, particularly an AR-SV positive disorder or disorder, or an AR-V7 positive disorder or disorder, the disorder or disorder being, for example, cancer, such as prostate cancer, castration-resistant prostate cancer (CRPC), primary / focal prostate cancer, locally advanced prostate cancer, recurrent prostate cancer, non-metastatic castration-resistant prostate cancer (nmCRPC), metastatic castration-resistant prostate cancer, metastatic prostate cancer (mCRPC), hormone The following conditions are selected from susceptible prostate cancer, other prostate diseases such as prostatic hyperplasia, prostatitis, breast cancer, non-small cell lung cancer, renal cell carcinoma, gonadal tumors, seminoma, pancreatic cancer, ovarian cancer, fallopian tube cancer, peritoneal cancer, salivary gland cancer, bladder cancer, acne, hirsutism, hidradenitis suppurativa, male pattern baldness, undescended testicles, androgen insensitivity syndrome, and Kennedy syndrome, among which breast cancer includes, but is not limited to, Luminal A type (ER+ / PR+, HER-2-), Luminal B type (ER+ / PR+, HER-2+), HER-2+ type (ER- / PR- / HER-2+), and Basal-like type (ER- / PR- / HER-2-) breast cancer.

[0114] Embodiment 64. According to the compound used in claim 63, its stereoisomers, solvates, hydrates, or pharmaceutically acceptable salts, the androgen receptor-dependent disease or disorder is characterized by the presence of abnormal androgen receptor activity, which, for example, is caused by an androgen receptor including an AR splicing mutation or a mutation or deletion of the LBD domain.

[0115] Embodiment 65. Use of a compound, stereoisomer, solvate, hydrate, or pharmaceutically acceptable salt thereof described in any one of Embodiments 1 to 60 in the preparation of a drug for treating or preventing a disease or disorder of an individual, wherein the disorder or disease is an androgen receptor-dependent disorder or disorder, particularly an AR-SV positive disorder or disorder, or an AR-V7 positive disorder or disorder, and the disorder or disease is, for example, prostate cancer, for example castration-resistant prostate cancer, primary / focal prostate cancer, locally advanced prostate cancer, recurrent prostate cancer, non-metastatic castration-resistant prostate cancer, metastatic castration-resistant prostate cancer, metastatic prostate cancer, etc. The following conditions are selected from Lumont-sensitive prostate cancer, other prostate diseases such as prostatic hyperplasia, prostatitis, breast cancer, non-small cell lung cancer, renal cell carcinoma, gonadal tumors, seminoma, pancreatic cancer, ovarian cancer, fallopian tube cancer, peritoneal cancer, salivary gland cancer, bladder cancer, acne, hirsutism, hidradenitis suppurativa, male pattern baldness, undescended testicles, androgen insensitivity syndrome, and Kennedy syndrome, among which breast cancer includes, but is not limited to, Luminal A type (ER+ / PR+, HER-2-), Luminal B type (ER+ / PR+, HER-2+), HER-2+ type (ER- / PR- / HER-2+), and Basal-like type (ER- / PR- / HER-2-) breast cancer.

[0116] Embodiment 66. According to the use described in claim 65, the androgen receptor-dependent disease or disorder is characterized by the presence of abnormal androgen activity, which, for example, is caused by an androgen receptor including an AR splicing mutation or a mutation or deletion of the LBD domain.

[0117] Embodiment 67. A method for treating or preventing a disease or disorder in an individual, comprising administering an effective amount of a compound, stereoisomer thereof, solvate, hydrate, or pharmaceutically acceptable salt described in any one of Embodiments 1 to 60 to an individual in need thereof, wherein the disorder or disease is an androgen receptor-dependent disease or disorder, particularly an AR-SV positive disease or disorder, or an AR-V7 positive disease or disorder, and the disorder or disease is, for example, prostate cancer, such as castration-resistant prostate cancer, primary / localized prostate cancer, locally advanced prostate cancer, recurrent prostate cancer, non-metastatic castration-resistant prostate cancer, metastatic castration-resistant prostate cancer, metastatic The selection includes metastatic prostate cancer, hormone-sensitive prostate cancer, other prostate diseases such as prostatic hyperplasia, prostatitis, breast cancer, non-small cell lung cancer, renal cell carcinoma, gonadal tumors, seminoma, pancreatic cancer, ovarian cancer, fallopian tube cancer, peritoneal cancer, salivary gland cancer, bladder cancer, acne, hirsutism, hidradenitis suppurativa, male pattern baldness, undescended testicles, androgen insensitivity syndrome, and Kennedy syndrome, among which breast cancer includes, but is not limited to, Luminal A type (ER+ / PR+, HER-2-), Luminal B type (ER+ / PR+, HER-2+), HER-2+ type (ER- / PR- / HER-2+), and Basal-like type (ER- / PR- / HER-2-) breast cancer.

[0118] Embodiment 68. The method according to claim 67, wherein the androgen receptor-dependent disease or disorder is caused by an androgen receptor including an AR splicing mutation or a mutation or deletion of the LBD domain.

[0119] Embodiment 69. A method for inhibiting and / or degrading androgen receptors, particularly androgen receptors including full-length AR (AR-FL), AR splicing variant (AR-SV), and / or LBD domain mutations or deletions, in vivo or in vitro, comprising contacting the androgen receptor with an effective amount of a compound described in any one of Embodiments 1 to 60, its stereoisomer, solvate, hydrate, or pharmaceutically acceptable salt thereof.

[0120] Embodiment 70. A drug combination comprising a compound described in any one of Embodiments 1 to 60, a stereoisomer thereof, a solvate, a hydrate, or a pharmaceutically acceptable salt thereof, and one or more other therapeutic agents.

[0121] Each embodiment described in this disclosure (including the following embodiments) and the features of each embodiment should be understood to be able to be combined in any way, and each aspect resulting from such combinations is within the scope of this disclosure as if it were specifically and individually listed herein, unless the context clearly indicates otherwise.

[0122] Beneficial effects

[0123] The compounds disclosed herein are N-terminal inhibitors of the androgen receptor, exhibiting high selectivity for the AR receptor and showing good growth inhibitory activity in cells expressing AR splicing variants (AR-SV) lacking the ligand-binding domain (LBD) of the androgen receptor, particularly in cells expressing androgen receptor splicing mutations of AR-SV that are resistant to second-generation AR antagonists.

[0124] In some embodiments, the compounds of the present disclosure are bifunctional compounds that inhibit and degrade androgen receptors, particularly androgen receptors including full-length AR (AR-FL), AR splicing variant (AR-SV), and LBD domain mutations or deletions, such as AR-V7.

[0125] In specific embodiments, in experiments on AR inhibitory activity and degradation activity, the compounds disclosed herein exhibit IC50 or less. 50 IC with a value of preferably 1.5 μM or less 50 The value, more preferably 1 μM or less, is for ICs. 50 The IC value, more preferably 0.5 μM or less. 50 The IC value is most preferably 0.2 μM or less. 50 It has a value.

[0126] definition

[0127] Unless otherwise specified in this disclosure, terms used in this disclosure have the meanings defined below. Terms not expressly defined in this disclosure have the general meanings commonly understood by those skilled in the art.

[0128] As used herein, the singular forms "the" and "the foregoing" shall also include the plural forms unless the context clearly indicates otherwise.

[0129] A dash ("-") between two letters or symbols indicates that the substituent is attached to the rest of the molecule. A divalent group with "-" is attached to the other two variables in the same direction as the attachment of the corresponding variables shown in the general formula. For example, "L2" is a divalent group attached to W and V in the general formula in the form W-L2-V, respectively. For example, L2 is -NH-C 1~6 If it is alkyl-, it is linked to W via the N atom on the left and to V on the opposite side.

[0130] As used herein, the "---" on a group indicates a bond, thereby linking the group to the rest of the molecule, and unless otherwise specified, the direction of the bond is arbitrary. For example, a divalent group having two "---"s is linked to the rest of the molecule, and the direction of the bond is arbitrary. For example, W is linked to groups L0 and L2 respectively, and W is,

[0131] [ka] If L0 is NH and L2 is -O-CH2-, then W is L0 and L2 in order from left to right.

[0132] [ka] Alternatively, you may configure it as follows: L0 and L2 in order from right to left.

[0133] [ka] The following configuration may be formed. It is preferable that the two groups containing "---" are linked from left to right. The combination of the linking groups, substituents, and / or variants thereof is acceptable only if such a combination results in a stable compound.

[0134] As used herein, “heteroatom” means a nitrogen (N), oxygen (O), or sulfur (S) atom, particularly nitrogen or oxygen, which may be substituted or unsubstituted, and may also be in oxidized forms. Examples of heteroatoms include, but are not limited to, -O-, -N=, -NR-, -S-, -S(O)-, and -S(O)2-, where R is hydrogen, a C1-C4 alkyl group, or a nitrogen protecting group.

[0135] As used herein, "halogen" or "halo" refers to fluorine, chlorine, bromine, and iodine. The halogen substituents are preferably fluorine and chlorine, and particularly chlorine.

[0136] As used herein, "alkyl" refers to a fully saturated linear or branched hydrocarbon group. The alkyl group preferably consists of 1 to 20 carbon atoms (C 1~20 ), more preferably 1 to 10 carbon atoms (C 1~10 ), 1 to 8 carbon atoms (C 1~8 ), 1 to 6 carbon atoms (C 1~6 ), 1 to 4 carbon atoms (C 1~4 ), 1 to 3 carbon atoms (C 1~3 ), or 2-3 carbon atoms (C 2~3 ) includes. For example, "C 1~6 "Alkyl" refers to an alkyl group that has 1 to 6 carbon atoms. 1~4"Alkyl" refers to alkyl groups having 1, 2, 3, or 4 carbon atoms. Typical examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, 3-methylhexyl, 2,2-dimethylpentyl, and 2,3-dimethylpentyl.

[0137] As used herein, "alkenyl" refers to a linear or branched hydrocarbon group containing one or more carbon-carbon double bonds (C=C), for example, one, two, or three carbon-carbon double bonds (C=C). Alkenyls preferably contain 2 to 20 carbon atoms (C=C). 2~20 ), more preferably 2 to 10 carbon atoms (C 2~10 ), 2 to 6 carbon atoms (C 2~6 ), 2-4 carbon atoms (C 2~4 ), 2-3 carbon atoms (C 2~3 ), or 2-3 carbon atoms (C 2~3 ) includes. For example, "C 2~6 An "alkenyl" refers to an alkenyl having 2 to 6 carbon atoms.

[0138] As used herein, “alkoxy” means alkyl-O-, where alkyl is as defined above. 1~6 "Alkoxy" refers to an alkoxy molecule that has 1 to 6 carbon atoms.

[0139] When used herein, "halogen-substituted C 1~6 Alkyl" (for example, "halogen-substituted C") 1~4 "Alkyl" refers to the C as defined above, substituted with one or more (e.g., 1, 2, 3, or 4) halogens. 1~6 Alkyl (for example, C 1~4 This refers to alkyl groups, such as fluoromethyl, difluoromethyl, trifluoromethyl, difluoroethyl, trifluoroethyl, chloromethyl, dichloromethyl, trichloromethyl, chloroethyl, dichloroethyl, and trichloroethyl.

[0140] As used herein, "cycloalkyl" refers to a saturated or unsaturated monocyclic, bicyclic, or tricyclic hydrocarbon group having 3 to 12 carbon atoms. Cycloalkyls preferably contain 3 to 8 ring carbon atoms, for example, 3 to 8, 3 to 7, 3 to 6, 4 to 7, or 5 to 6 ring carbon atoms. Exemplary monocyclic hydrocarbon groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, and cyclohexenyl. Exemplary bicyclic hydrocarbon groups include bornyl, decahydronaphthyl, bicyclo[2.1.1]hexyl, bicyclo[2.2.1]heptyl, bicyclo[2.2.1]heptenyl, 6,6-dimethylbicyclo[3.1.1]heptyl, 2,6,6-trimethylbicyclo[3.1.1]heptyl, and bicyclo[2.2.2]octyl.

[0141] As used herein, "aryl" refers to a carbocyclic hydrocarbon group having 6 to 12 carbon atoms, consisting of one ring or multiple rings such as two fused rings, where at least one ring is an aromatic ring. Examples of aryls include, but are not limited to, phenyl, naphthyl, and 1,2,3,4-tetrahydronaphthyl, with phenyl being preferred.

[0142] As used herein, “heteroaryl” means a monocyclic or bicyclic ring system having 5 to 14 (5 to 14 membered), 5 to 10 (5 to 10 membered), e.g., 5 to 9 (5 to 9 membered), e.g., 5 to 6 (5 to 6 membered), or 6 (6 membered) ring atoms, comprising 1, 2, 3, or 4 heteroatoms independently selected from N, O, and S, the remaining ring atoms being carbon atoms, and at least one ring being an aromatic ring containing heteroatoms. For example, a heteroaryl may contain one N heteroatom and optionally further comprise 1, 2, or 3 more heteroatoms independently selected from N, O, and S. If the total number of S and O atoms in a heteroaryl is greater than 1, these S and O heteroatoms are not adjacent to each other. For example, the heteroaryls include, but are not limited to, the following:

[0143] A 5-6 membered monocyclic heteroaryl, i.e., a monocyclic aromatic hydrocarbon group having 5 or 6 ring atoms: comprising 1, 2, or 3 heteroatoms independently selected from N, O, and S, with the remaining ring atoms being carbon atoms. For example, comprising 1 N heteroatom and optionally further comprising 1 or 2 more heteroatoms independently selected from N, O, and S, for example, comprising 1, 2, and 3 N heteroatoms, with the remaining ring atoms being carbon atoms. The heteroaryl is, for example, pyrrolyl, pyrazolyl, pyrazinyl, pyridadinyl, pyridinyl, or pyrimidinyl.

[0144] 8-10 membered bicyclic heteroaryls, i.e., bicyclic aromatic hydrocarbon groups having 8, 9, or 10 ring atoms: comprising 1, 2, 3, or 4 heteroatoms independently selected from N, O, and S, the remaining ring atoms being carbon atoms, and at least one ring being an aromatic ring containing heteroatoms. For example, comprising one N heteroatom and optionally further comprising 1, 2, 3, or 4 heteroatoms independently selected from N, O, and S, for example 1, 2, or 3 heteroatoms, the remaining ring atoms being carbon atoms. The heteroaryls are, for example, 8-9 membered bicyclic heteroaryls, such as benzimidazolyl, indazolyl, azindazolyl, benzotriazolyl, or indolyl.

[0145] For example, the heteroaryls mentioned above include, but are not limited to, pyrrolyl, furanil, thienyl, pyrazolyl, imidazolyl, thiazolyl, isothiazolyl, indolyl, benzotriazolyl, benzimidazolyl, benzofuranil, quinolyl, isoquinolyl, sinnolinyl, quinazolinyl, quinoxalinyl, tetrahydroquinolyl, oxazolopyridinyl, 7-azaindryl, 6-azaindryl, 5-azaindryl, 4-azaindryl, indazolyl (e.g., 1H-indazolyl), 7-azaindryl, 6-azaindryl, 5-azaindryl, 4-azaindryl, pyridinyl, pyrimidinyl, pyridadinyl, pyrazinyl, or imidazo[1,2-a]pyridinyl. Preferably, pyridinyl, pyrimidinyl, or indazolyl (e.g., 1H-indazolyl) are included.

[0146] Examples of heteroaryls include the following:

[0147] [ka]

[0148] As used herein, “heterocyclic” and “heterocyclyl” are used interchangeably and refer to fully saturated or partially saturated non-aromatic monocyclic, bicyclic, or tricyclic cyclic groups having 3 to 15 ring atoms (e.g., 4 to 12 ring atoms, 3 to 10 ring atoms, 5 to 10 ring atoms, 4 to 7 ring atoms, 5 to 6 ring atoms, 7 to 12 ring atoms, 10 to 15 ring atoms), for example, a 4- to 7-membered monocyclic, 7- to 12-membered bicyclic, or 10- to 15-membered tricyclic ring system, for example, containing 1, 2, 3, or 4 heteroatoms independently selected from N, O, and S, and optionally further containing 1, 2, or 3 more heteroatoms independently selected from N, O, and S, with the remaining ring atoms being carbon atoms. Here, the nitrogen heteroatom and sulfur heteroatom may be optionally oxidized, for example, the sulfur heteroatom may form a -S(O)- or -S(O)2- structure. The heterocyclil may be a monocyclic group, a bicyclic group, a fused cyclic group, a spirocyclic group, or a bridging cyclic group. A "5-6 membered heterocyclil" refers to a heterocyclil having 5 or 6 ring atoms and containing 1, 2, 3, or 4 heteroatoms independently selected from N, O, and S, for example, 1, 2, or 3 N heteroatoms, which is a monocyclic group.

[0149] As used herein, “heterocycloalkyl” means a fully saturated heterocyclyl as defined herein. For example, a “3- to 10-membered heterocycloalkyl” is a saturated heterocycle having 3 to 10 ring atoms, containing 1, 2, 3, or 4 heteroatoms independently selected from N, O, and S. A “4- to 6-membered heterocycloalkyl” is a saturated heterocycle having 4 to 6 ring atoms, containing 1, 2, 3, or 4 heteroatoms independently selected from N, O, and S, for example, one N heteroatom.

[0150] Examples of monocyclic heterocycles include fully saturated or partially saturated pyrrolidines, oxetanes, oxolanes, amylene oxides, pyrazolines, imidazolines, imidazolidines, thiazolidins, isothiazolidines, tetrahydrofurans, piperidines, piperazines, 2-oxopiperazines, 2-oxopiperidines, 2-oxopyrrolidines, 4-piperidones, imidazolidinones, tetrahydropyrans, morpholines, thiomorpholines, thiomorpholine sulfoxides, thiomorpholine sulfones, 1,3-dioxolanes, and tetrahydro-1,1-dioxothiophene, and 1,1,4-trioxo-1,2,5-thiadiazolidine-2-yl.

[0151] Examples of bicyclic heterocycles include fully saturated or partially saturated indolines, isoindolines, dihydroindole, hexahydroindole, octahydropyrrole, dihydrobenzofuran, tetrahydroquinoline, and tetrahydroisoquinoline.

[0152] Exemplary heterocyclyls include oxyranil, azilidinil, oxetanil, azetidinil, pyrrolidinil, tetrahydrofuranil, tetrahydropyranil, pyrazolidinil, imidazolidinil, piperidinil, piperazinil, morpholinil, thiomorpholinil, 2-oxopiperazinil, hexahydropyrimidinil, hexahydroindolyl, imidazolidinonil, octahydropyrrolyl,

[0153] [ka] It includes.

[0154] Examples of heterocycloalkyls include oxyranil, oxetanil, tetrahydrofuranil, pyrazolidinil, imidazolidinil,

[0155] [ka] It includes.

[0156] As used herein, "C(O)" refers to -C(=O)-, i.e., a carbonyl group. "Oxo" refers to -(=O)-yl.

[0157] As used herein, “optional,” “any,” or “optionally” means that the substitution patterns, events, or situations described below may or may not occur, and such descriptions include both cases in which such substitution patterns occur and cases in which they do not occur. For example, “optionally substituted alkyl groups” include “unsubstituted alkyl groups” and “substituted alkyl groups” as defined herein. Those skilled in the art will understand that for any group containing one or more substituents, there are no substitution patterns that are sterically impractical, chemically inaccurate, unsynthetic, and / or inherently unstable.

[0158] As used herein, “substituted” or “substituted by” means that one or more (e.g., 1, 2, 3, or 4) hydrogen atoms on a given atom or group are substituted by one or more (e.g., 1, 2, 3, or 4) substituents selected from a given group of substituents, provided that the substituents do not exceed the normal valence of the given atom, and the substituents may be identical or different from each other. A combination of substituents and / or variables is permissible only if such a combination results in a chemically correct and stable compound. A chemically correct and stable compound means one that can be isolated from the reaction mixture and is stable enough that its chemical structure can be determined. In this specification, groups such as alkyl, alkenyl, alkoxy, cycloalkyl, heteroaryl, heterocyclyl, heterocycloalkyl, carbonyl, sulfonyl, and sulfinyl may be substituted with substituents, and such substituents include, but are not limited to, OH, Boc, halogen, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, NRR', C(O)R, C(O)NRR', or C(O)OR, and each R and b' is independently selected from H and substituted or unsubstituted alkyl.

[0159] As used herein, “pharmaceutically acceptable salt” includes both acid addition salts and base addition salts. pharmaceutically acceptable salts are those obtained by reacting an active compound acting as a base with an inorganic or organic acid to form a salt, such as hydrochlorides, hydrobroms, sulfates, nitrates, phosphates, methanesulfons, oxalates, maleates, succinates, citrates, formates, benzoates, fumarates, tartrates, salicylates, mandelates, and carbonates. Acid addition salts are prepared by any of many known methods, as will be understood by those skilled in the art, by reacting the compound with a suitable inorganic or organic acid.

[0160] As used herein, “pharmaceutically acceptable excipients” include solvents, dispersions, coatings, surfactants, antioxidants, preservatives (e.g., antimicrobials, antifungals), isotonic agents, absorption retarders, salts, preservatives, drugs, drug stabilizers, binders, excipients, disintegrants, lubricants, sweeteners, flavorings, dyes, analogues, and combinations thereof, which are well known to those skilled in the art.

[0161] The compounds of this disclosure, or pharmaceutically acceptable salts thereof, may contain one or more chiral centers, and thus enantiomers, diastereomers, and other stereoisomers may arise, the form of which such stereoisomers may be defined as (R)- or (S)- based on absolute stereochemistry. This specification includes all such possible isomers, whether or not they are specifically described herein, as well as their racemic and optically pure forms. Optically active (+)- and (-)-, or (R)- and (S)- isomers can be prepared by chiral synthesis or using chiral reagents, or resolved using conventional techniques such as chromatography and fractional crystallization. Conventional techniques for preparing / isolating individual enantiomers include chiral synthesis from suitable optically pure precursors, or resolution of racemics (or racemics of salts or derivatives) using, for example, chiral high-pressure liquid chromatography (HPLC).

[0162] A "stereoisomer" refers to a compound composed of the same atoms bonded together by the same bonds, but possessing different, incompatible three-dimensional structures. This disclosure includes various stereoisomers and mixtures thereof, and also includes "enantiomers," which refer to two stereoisomers having mirror-image molecules that cannot be superimposed on each other.

[0163] As used herein, “effective amount” means the amount of the compound of this disclosure that can induce a biological or medical response in an individual, improve symptoms, slow the progression of a disease, or prevent a disease.

[0164] As used herein, “individual” or “patient” refers to an animal. Preferably, the animal is a mammal such as a primate (e.g., human), cattle, sheep, goats, horses, dogs, cats, rabbits, rats, mice, fish, or birds. In a preferred embodiment, the individual is a human.

[0165] As used herein, “to treat a disease or disorder” means administering one or more medicinal substances, in particular the compounds of this disclosure, or pharmaceutically acceptable salts thereof, to an individual suffering from or exhibiting symptoms of such disease or disorder, thereby curing, merging, alleviating, reducing, altering, treating, improving, relieving, or influencing the disease or disorder or its symptoms. In some embodiments, the disease or disorder is an androgen receptor-dependent disease or disorder, in particular an AR-SV-positive disease or disorder, or an AR-V7-positive disease or disorder. The aforementioned disorders or diseases include, for example, prostate cancer, such as castration-resistant prostate cancer (CRPC), primary / localized prostate cancer, locally advanced prostate cancer, recurrent prostate cancer, non-metastatic castration-resistant prostate cancer (nmCRPC), metastatic castration-resistant prostate cancer, metastatic prostate cancer (mCRPC), hormone-sensitive prostate cancer, other prostate diseases such as prostatic hyperplasia, prostatitis, breast cancer, non-small cell lung cancer, renal cell carcinoma, gonadal tumors, seminoma, pancreatic cancer, ovarian cancer, fallopian tube cancer, peritoneal cancer, The selection includes salivary gland cancer, bladder cancer, acne, hirsutism, hidradenitis suppurativa, male pattern baldness, undescended testicles, androgen insensitivity syndrome, and Kennedy syndrome, among which breast cancer includes, but is not limited to, Luminal A type (ER+ / PR+, HER-2-), Luminal B type (ER+ / PR+, HER-2+), HER-2+ type (ER- / PR- / HER-2+), and Basal-like type (ER- / PR- / HER-2-) breast cancer.

[0166] As used herein, “preventing” a disease means administering one or more medicinal substances, in particular the compounds of this disclosure, to an individual who is susceptible to or at risk of developing a disease or disorder, thereby preventing or delaying the onset of the disease or disorder in said individual.

[0167] As used herein, “androgen receptor-dependent disorder or condition” refers to a medical condition that is partially or completely dependent on, or sensitive to, in vivo androgen activity or activation of the AR axis. Such androgen receptor-dependent disorders or conditions include androgen receptor-positive disorders. Androgen receptors include full-length AR (AR-FL), AR splicing variants (AR-SV), and / or androgen receptors with mutations or deletions of the LBD domain. AR-V7 is a splicing variant of AR lacking the LBD.

[0168] All numerical ranges in this specification should be understood to disclose all values ​​and any subsets of values ​​within that range, whether otherwise specifically disclosed. For example, when referring to a numerical range, it should be interpreted as referring to all values ​​within that range, such as all integers within that range. This disclosure includes all values ​​contained within these ranges, all smaller ranges, and the upper or lower limits of such ranges.

[0169] Pharmaceutical composition and administration

[0170] The compounds of this disclosure (for example, any of the compounds described in the examples herein) can be formulated into pharmaceutical compositions, either alone or in combination with one or more other therapeutic agents. A pharmaceutical composition may comprise (a) the compounds of this disclosure, (b) pharmaceutically acceptable excipients, and optionally (c) at least one other therapeutic agent.

[0171] A pharmaceutically acceptable excipient is a carrier or auxiliary material that is compatible with the active ingredient in the composition (and in some embodiments, stabilizes the active ingredient) and is not harmful to the patient being treated. Suitable pharmaceutically acceptable carriers are listed in standard references in the art (e.g., Remington's Pharmaceutical Sciences, Remington: The Science and Practice of Pharmacy).

[0172] The compounds of this disclosure can be administered by a variety of known methods, including orally, parenterally, by inhalation, or by implantation. As used herein, the term "parenterally" includes injection or infusion into the subcutaneous, intradermal, intravenous, intramuscular, intra-articular, intra-arterial, intra-synovial, intrasternal, intra-spinal, intra-lesional, and intracranial regions.

[0173] The compounds of this disclosure can be administered in any convenient formulation, such as tablets, powders, capsules, solutions, dispersants, suspensions, syrups, sprays, suppositories, gels, emulsions, and patches.

[0174] In one embodiment, the effective dose of the compound disclosed is 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, when administered parenterally, where the typical initial dose of the compound used is in the range of 0.3 to 15 mg / kg / day. In another embodiment, an oral unit dosage form, such as a tablet or capsule, contains about 0.1 to about 1000 mg of the compound disclosed.

[0175] Indications and treatment methods

[0176] The compounds disclosed herein are AR inhibitors that exhibit high selectivity for AR receptors, particularly androgen receptors including full-length AR (AR-FL), AR splicing variants (AR-SV), and mutations or deletions of the LBD domain. The compounds disclosed herein are bifunctional compounds that inhibit and degrade androgen receptors, particularly androgen receptors including full-length AR (AR-FL), AR splicing variants (AR-SV), and mutations or deletions of the LBD domain such as AR-V7.

[0177] The present invention relates to a method for treating or preventing androgen receptor-dependent diseases or disorders, particularly AR-SV-positive diseases or disorders, AR-V7-positive diseases or disorders, or diseases or disorders involving mutations or deletions of the LBD domain, the method comprising administering an effective amount of the compound of the present disclosure to an individual in need thereof.

[0178] This disclosure relates to a method for treating or preventing a disease or disorder, the method comprising administering an effective amount of the compound of this disclosure to an individual in need thereof, the disease or disorder being prostate cancer, e.g., castration-resistant prostate cancer (CRPC), primary / localized prostate cancer, locally advanced prostate cancer, recurrent prostate cancer, non-metastatic castration-resistant prostate cancer (nmCRPC), metastatic castration-resistant prostate cancer, metastatic prostate cancer (mCRPC), hormone-sensitive prostate cancer, other prostate diseases, e.g., prostatic hyperplasia, prostatitis, breast cancer, non-small cell lung cancer, The selection includes renal cell carcinoma, gonadal tumors, seminoma, pancreatic cancer, ovarian cancer, fallopian tube cancer, peritoneal cancer, salivary gland cancer, bladder cancer, acne, hirsutism, hidradenitis suppurativa, male pattern baldness, undescended testicles, androgen insensitivity syndrome, and Kennedy syndrome, among which breast cancer includes, but is not limited to, Luminal A type (ER+ / PR+, HER-2-), Luminal B type (ER+ / PR+, HER-2+), HER-2+ type (ER- / PR- / HER-2+), and Basal-like type (ER- / PR- / HER-2-) breast cancer.

[0179] In one embodiment, the compounds of the present disclosure are used to treat or prevent androgen receptor-dependent diseases or disorders, particularly AR-SV-positive diseases or disorders, AR-V7-positive diseases or disorders, or diseases or disorders involving mutations or deletions of the LBD domain.

[0180] In one embodiment, the compounds of the present disclosure are used to treat prostate cancer, e.g., castration-resistant prostate cancer (CRPC), primary / localized prostate cancer, locally advanced prostate cancer, recurrent prostate cancer, non-metastatic castration-resistant prostate cancer (nmCRPC), metastatic castration-resistant prostate cancer, metastatic prostate cancer (mCRPC), hormone-sensitive prostate cancer, other prostate diseases, e.g., prostatic hyperplasia, prostatitis, breast cancer, non-small cell lung cancer, renal cell carcinoma, gonadal tumors, seminoma, pancreatic cancer, ovarian cancer, fallopian tube cancer, peritoneal cancer, salivary gland cancer, It is used to treat or prevent bladder cancer, acne, hirsutism, hidradenitis suppurativa, male pattern baldness, undescended testicles, androgen insensitivity syndrome, and Kennedy syndrome, among which breast cancer includes, but is not limited to, Luminal A (ER+ / PR+, HER-2-), Luminal B (ER+ / PR+, HER-2+), HER-2+ (ER- / PR- / HER-2+), and Basal-like (ER- / PR- / HER-2-) breast cancer.

[0181] Drug combinations

[0182] The compounds of this disclosure can be combined with other therapeutic agents for the treatment of androgen receptor-dependent disorders, particularly AR-SV-positive disorders, AR-V7-positive disorders, or disorders involving mutations or deficiencies in the LBD domain. The other therapeutic agents may be administered separately from the compounds of this disclosure, or together with them, they may be included in the pharmaceutical compositions relating to this disclosure, such as fixed combination products. In some embodiments, the other therapeutic agents are known or proven effective in treating androgen receptor-dependent disorders, or compounds that antagonize another target associated with a particular disease. This combination may be used to enhance the efficacy of the compounds of this disclosure, reduce one or more side effects, or decrease the required dose.

[0183] 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, chemotherapeutic agents, immunotherapy agents, and targeted therapies.

[0184] Common synthesis routes

[0185] In one embodiment, the compounds of the present disclosure can be synthesized by the following general synthesis scheme, where the variables are as defined herein and the specific reaction conditions are the same as in the examples.

[0186] Starting with 6-hydroxy-1-tetralone, halogenation, coupling, and alkylation reactions are carried out to obtain 5,7-disubstituted alkoxynaphthalenone. This is then converted to the important common intermediate INT-2 / 4 by reaction with Tf2O. This intermediate can be hydrogenated and reduced by the Suzuki reaction with various boronic acids or boron esters. After removing the Boc protecting group from the product, it is reacted with fluorothalidomide to obtain the first target product TM1 (flow 1). Alternatively, starting with alkoxynaphthalenone, the carbonyl group is reduced to an alcohol, which is then reacted with PBr3 to obtain the important common intermediate INT-1 / 3. INT-1 / 3 is reacted with aqueous ammonia to convert Br to an amino acid. The resulting benzylamine can be coupled with bromoaryl / heteroaryl via Buchwald coupling. After removing the Boc protecting group from the product, it is reacted with fluorothalidomide to obtain the first target product TM2. Alternatively, starting from INT-1 / 3, a direct substitution reaction with an aminoaryl / heteroaryl compound is carried out, followed by a similar deprotection and substitution reaction to obtain product TM2 (flow 2).

[0187] [ka]

[0188] Flow 1

[0189] [ka]

[0190] Flow 2 [Modes for carrying out the invention]

[0191] In this application, if the chemical name and structural formula do not match, the structural formula shall take precedence unless the context suggests that the chemical name is correct rather than the structural formula.

[0192] This disclosure is described in more detail in conjunction with specific embodiments. It should be understood that these embodiments are used solely to illustrate this disclosure and do not limit its scope. Experimental methods in the following embodiments where specific conditions are not specified generally follow conventional conditions or conditions recommended by the manufacturer. Unless otherwise specified, percentages and parts are weight percentages and parts by weight.

[0193] Unless otherwise noted, the experimental materials and reagents used in the following examples are available from commercially available suppliers.

[0194] Each embodiment describes the experimental apparatus (for example, 1 ¹H NMR is recorded using a Varian Mercury-300 or Varian Mercury-400 nuclear magnetic resonance spectrometer. 13 ¹³C NMR was recorded using a Varian Mercury-400, Varian Mercury-500, or Varian Mercury-600 nuclear magnetic resonance spectrometer, with chemical shifts expressed in δ (ppm). Mass spectra were recorded using Finnigan / MAT-95 (EI), Finnigan LCQ / DECA, and Micromass Ultra Q-TOF (ESI) mass spectrometers. Silica gel used for reverse-phase preparative HPLC separation was 200-300 mesh. SFC purification method (column: Chiralpak IG 250mm*4.6mm 5μm, mobile phase: Hex-EtOH, 30℃).

[0195] Here, the Chinese names for reagents represented by chemical formulas or English abbreviations are as follows:

[0196] DCM: Dichloromethane; DCE: 1,2-Dichloroethane; THF: Tetrahydrofuran; DMF: N,N-Dimethylformamide; Tol: Toluene; TFA: Trifluoroacetic acid; PE: Petroleum ether; EA: Ethyl acetate; TEA: Triethylamine; DIEA: N,N-Diisopropylethylamine; Tf2O: Trifluoromethanesulfonic anhydride; DBAD: Dibenzyl azodicarboxylate; KOAc: Potassium acetate; NMP: N-Methylpyrrolidone; NIS: N-Iodosuccinimide; Pd(dppf)Cl2: [1,1'-Bis(diphenylphosphino)ferrocene]palladium dichloride; 9-BBN: 9-Borabicyclo[3.3.1]nonane; RT: Retention time; LCMS: Liquid chromatography-mass spectrometry.

[0197] Synthesis of key intermediates

[0198] Intermediate INT-1

[0199] [ka]

[0200] Step 1: Synthesis of 5-chloro-6-hydroxy-3,4-dihydronaphthalene-1(2H)-one

[0201] Compound S1 (20 g, 125 mmol) was added to chloroform (300 mL), and S2 (12 g, 110 mmol) was added at 0°C. The mixture was stirred overnight at room temperature and then concentrated to obtain solid INT-1-1 (18 g, yield: 75%). LC-MS (ESI): m / z = 197.0 [M + H] + .

[0202] Step 2: Synthesis of 5-chloro-6-hydroxy-7-iodo-3,4-dihydronaphthalene-1(2H)-one

[0203] Compound INT-1-1 (18 g, 91.8 mmol) and NIS (26 g, 115 mmol) were dissolved in DCE (300 mL) and reacted at 60°C for 4 hours. After cooling, the reaction mixture was filtered and concentrated under reduced pressure to obtain the brown solid INT-1-2 (20 g, yield: 77%). LCMS (ESI): m / z = 322.9 [M + H] + .

[0204] Step 3: Synthesis of 5-chloro-6-ethoxy-7-iodo-3,4-dihydronaphthalene-1(2H)-one

[0205] INT-1-2 (1 g, 3.1 mmol), S3 (960 mg, 6.2 mmol), and DMF (15 mL) were added sequentially to a dry flask. Next, potassium carbonate (1.3 g, 9.3 mmol) was added, and the mixture was reacted at 60°C for 6 hours. After cooling, the reaction mixture was injected into an EA, washed with saturated brine, and the organic phase was collected and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain a yellow solid INT-1-3 (370 mg, yield: 34%). LC-MS (ESI): m / z = 351.0 [M + H] + .

[0206] Step 4: Synthesis of 4-chloro-3-ethoxy-8-oxo-5,6,7,8-tetrahydronaphthalene-2-carbonitrile

[0207] INT-1-3 (320 mg, 0.91 mmol) and CuCN (410 mg, 4.6 mmol) were sequentially added to a dry sealed tube, dissolved in NMP (15 mL), and stirred at 160°C for 5 hours. After cooling, the mixture was quenched with aqueous ammonia, the reaction mixture was injected into an EA, washed with aqueous ammonium chloride solution, the organic phase was collected and concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to obtain a yellow solid INT-1-4 (140 mg, yield: 54%). LCMS (ESI): m / z = 250.1 [M + H] + .

[0208] Step 5: Synthesis of 4-chloro-3-ethoxy-8-hydroxy-5,6,7,8-tetrahydronaphthalene-2-carbonitrile

[0209] INT-1-4 (140 mg, 0.56 mmol) was added to a dry flask, dissolved in MeOH (10 mL), and NaBH4 (85 mg, 2.2 mmol) was added under ice bath. The mixture was reacted overnight at room temperature. Quetzing with water, the mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to obtain a white solid INT-1-5 (110 mg, yield: 78%). LC-MS (ESI): m / z = 251.1 [M + H] + .

[0210] Step 6: Synthesis of 8-bromo-4-chloro-3-ethoxy-5,6,7,8-tetrahydronaphthalene-2-carbonitrile

[0211] INT-1-5 (110 mg, 0.44 mmol) was added to a dry flask, dissolved in DMF (10 mL), and PBr3 (590 mg, 2.2 mmol) was added at 0°C. The mixture was stirred at room temperature for 6 hours. Quetzing was performed with NH4Cl aqueous solution, extraction was performed with EA, the organic phase was washed with saturated saline solution, dried, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain a white solid INT-1 (80 mg, yield: 51%). LCMS (ESI): m / z = 314.0 [M + H] + ; 1 H NMR(400MHz,CDCl3)δ7.53(s,1H),5.46(brs,1H),4.25(q,J=6.9Hz,2H),3.16-3.08(m,1H),2.7 9-2.70(m,1H),2.40-2.35(m,1H),2.26-2.21(m,1H),2.10-1.99(m,2H),1.49(t,J=6.9Hz,2H).

[0212] Intermediate INT-2

[0213] [ka]

[0214] Step 1: Synthesis of 5-chloro-6-(2-chloroethoxy)-7-iodo-3,4-dihydronaphthalene-1(2H)-one

[0215] INT-1-2 (20g, 62mmol), S4 (15g, 186mmol), DBAD (14g, 61mmol), and PPh3 (16g, 61mmol) were dissolved in 300mL of water and reacted at 110°C for 8 hours under nitrogen protection. After cooling, the reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to obtain a white solid INT-2-1 (15g, yield: 85%). LCMS (ESI): m / z = 384.9 [M + H] + .

[0216] Step 2: Synthesis of 4-chloro-3-(2-chloroethoxy)-8-oxo-5,6,7,8-tetrahydronaphthalene-2-carbonitrile

[0217] INT-2-1 (5g, 13 mmol) and CuCN (2.4g, 26 mmol) were dissolved in a sealed tube containing NMP (80 mL) and reacted at 120°C for 8 hours under nitrogen protection. After cooling, the reaction mixture was extracted with EA, the organic phase was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to obtain a white solid INT-2-2 (3.2g, yield: 86%). LC-MS (ESI): m / z = 284.0 [M + H] + .

[0218] Step 3: Synthesis of 5-chloro-6-(2-chloroethoxy)-7-cyano-3,4-dihydronaphthalene-1-yltrifluoromethanesulfonate

[0219] INT-2-2 (3.2g, 11.3 mmol), TEA (3.4g, 33.9 mmol), and DCM (100 mL) were added to a three-necked flask. Under nitrogen protection, Tf2O (16g, 56.5 mmol) was added at 0°C, and the mixture was reacted overnight at room temperature. The reaction mixture was extracted with DCM, the organic phase was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to obtain yellow solid INT-2 (3.5g, yield: 66%). LC-MS (ESI): m / z = 416.0 [M + H] + ; 1H NMR(400MHz,CDCl3)δ7.46(s,1H),6.15(t,J=4.8Hz,1H),4.48(t,J=6.0Hz,2H),3.90(t,J=6.0Hz,2H),3.08(t,J=8.3Hz,2H),2.66-2.56(m,2H).

[0220] Intermediate INT-3

[0221] [ka]

[0222] Step 1: Synthesis of 4-chloro-3-(2-chloroethoxy)-8-hydroxy-5,6,7,8-tetrahydronaphthalene-2-carbonitrile

[0223] INT-2-2 (800 mg, 2.8 mmol) was added to methanol (10 mL), and NaBH4 (430 mg, 11.3 mmol) was added at 0°C. The mixture was stirred at room temperature for 3 hours. The reaction solution was concentrated, the residue was extracted with EA, and the organic phase was dried and concentrated to obtain solid INT-3-1 (700 mg, yield: 87%). LCMS (ESI): m / z = 286.0 [M + H] + .

[0224] Step 2: Synthesis of 8-bromo-4-chloro-3-(2-chloroethoxy)-5,6,7,8-tetrahydronaphthalene-2-carbonitrile

[0225] INT-3-1 (700 mg, 2.4 mmol) was added to DCM (10 mL), and PBr3 (1.3 g, 4.8 mmol) was added at 0°C. The mixture was stirred at room temperature for 5 hours. The reaction mixture was extracted using DCM, the organic phase was dried and concentrated, and the residue was purified by silica gel column chromatography to obtain solid INT-3 (500 mg, yield: 59%). LCMS (ESI): m / z = 347.9 [M + H] + ; 1H NMR(400MHz,CDCl3)δ7.55(s,1H),5.45(t,J=3.7Hz,1H),4.42(td,J=6.1,1.7Hz,2H),3.88(t,J=6.1H z,2H),3.18-3.05(m,1H),2.82-2.65(m,1H),2.43-2.32(m,1H),2.29-2.18(m,1H),2.12-1.96(m,2H).

[0226] Intermediate INT-4

[0227] [ka]

[0228] The synthesis method was the same as for INT-2. 1 H NMR(400MHz,CD3OD)δ7.47(s,1H),6.27(t,J=4.8Hz,1H),4.30(q,J=7.2Hz,2H ),3.09(t,J=8.4Hz,2H),2.61(td,J=8.4Hz,4.8Hz,2H),1.48(t,J=7.2Hz,3H).

[0229] intermediate INT-5

[0230] [ka]

[0231] Step 1: Synthesis of 4-chloro-3-ethoxy-8-(2-fluoropyrimidine-5-yl)-5,6-dihydronaphthalene-2-carbonitrile

[0232] INT-5-1 (500 mg) was dissolved in 16 mL of 1,4-dioxane. Then, 1.6 mL of water, INT-4 (500 mg, 1.20 mmol), Pd(dppf)Cl2 (88.2 mg, 0.12 mmol), and sodium carbonate (383 mg, 3.61 mmol) were added, and the mixture was reacted at 90°C for 3 hours under nitrogen protection. After cooling, the organic phase was filtered and placed in a saturated ammonium chloride aqueous solution, extracted with EA, washed with saturated brine, dried over sodium sulfate, concentrated under reduced pressure, and the residue was purified by silica gel column (PE:EA = 2:1) to obtain compound INT-5-2 (337 mg, white solid) in yield: 85%. LCMS (ESI): m / z = 330.1 [M + H] + .

[0233] Step 2: Synthesis of 4-chloro-3-ethoxy-8-(2-fluoropyrimidine-5-yl)-5,6,7,8-tetrahydronaphthalene-2-carbonitrile

[0234] Compound INT-5-2 (330 mg, 1.0 mmol) was dissolved in 33 mL of methanol and 15 mL of EA, then Pd(OH)2 / C (33 mg) was added, and the mixture was reacted overnight at room temperature in a hydrogen environment. The mixture was filtered and concentrated to obtain crude product INT-5 (white oily) in 100% yield. LC-MS (ESI): m / z = 330.0 [MH] + .

[0235] Intermediate INT-6

[0236] [ka]

[0237] Step 1: Synthesis of 2-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidine

[0238] S1 (1 g, 5.7 mmol), S2 (2 g, 7.8 mmol), Pd(dppf)Cl2 (300 mg, 0.4 mmol), potassium acetate (1.5 g, 15.3 mmol), and dioxane (30 mL) were added sequentially to a dry flask and reacted at 90°C for 6 hours under nitrogen protection. After cooling, the mixture was concentrated under reduced pressure to obtain the crude product INT-6-1, which was then directly used in the next reaction. LCMS(ESI): m / z = 225.2 [M + H] + .

[0239] Step 2: Synthesis of 4-chloro-3-(2-chloroethoxy)-8-(2-fluoropyrimidine-5-yl)-5,6-dihydronaphthalene-2-carbonitrile

[0240] INT-6-1 (800 mg, 3.6 mmol), INT-2 (1 g, 2.4 mmol), Pd(PPh3)4 (138 mg, 0.12 mmol), and sodium carbonate (760 mg, 7.2 mmol) were sequentially added to a dry flask, dissolved in dioxane / water (30 / 6 mL), and stirred at 90°C under nitrogen protection for 6 hours. After cooling, the reaction mixture was injected into saturated saline solution, extracted with EA, and the organic phase was collected and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain a yellow oily substance, INT-6-2 (400 mg, yield: 46%). LCMS (ESI): m / z = 364.1 [M + H] + .

[0241] Step 3: Synthesis of 4-chloro-3-(2-chloroethoxy)-8-(2-fluoropyrimidine-5-yl)-5,6,7,8-tetrahydronaphthalene-2-carbonitrile

[0242] INT-6-2 (mg, 1.0 mmol) was dissolved in 33 mL of methanol and 15 mL of EA, and Pd(OH)2 / C (33 mg) was added. The mixture was reacted overnight at room temperature in a hydrogen environment. The mixture was filtered and concentrated to obtain crude INT-6 (yellow oily) in 100% yield. LCMS (ESI): m / z = 364.0 [MH] - ; 1H NMR(400MHz,DMSO-d6)δ8.56(s,2H),7.36(s,1H),4.39(t,J=6.4Hz,2H),3.97(t,J=6.4Hz,2H),2.87(brs,1H),2.07-1.99(m,1H),1.86-1.79(m,3H).

[0243] Example 1

[0244] [ka]

[0245] Step 1: Synthesis of tert-butyl(3-((5-(5-chloro-7-cyano-6-ethoxy-1,2,3,4-tetrahydronaphthalene-1-yl)amino)pyridine-2-yl)oxy)propyl)carbamate

[0246] INT-1 (100 mg, 0.32 mmol), S2 (128 mg, 0.47 mmol), and DIEA (205 mg, 1.60 mmol) were dissolved in DMF (10 mL) solution and reacted at 60°C for 8 hours under nitrogen protection. After cooling, the reaction mixture was quenched with NH4Cl, extracted with EA, and the organic phases were dried over anhydrous sodium sulfate. The mixture was filtered and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to obtain compound HT312-1 (150 mg, yellow oily, yield: 94%). LCMS (ESI): m / z = 501.2 [M + H] + .

[0247] Step 2: Synthesis of 8-(6-(3-aminopropoxy)pyridine-3-yl)amino)-4-chloro-3-ethoxy-5,6,7,8-tetrahydronaphthalene-2-carbonitrile

[0248] HT312-1 (150 mg, 0.30 mmol) was dissolved in DCM (5 mL) solution, TFA (0.5 mL) was added, and the mixture was reacted at room temperature for 2 hours. The reaction mixture was quenched with NH4Cl, extracted with EA, and the organic phase was dried over anhydrous sodium sulfate. After filtration, the mixture was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography to obtain compound HT312-2 (100 mg, yellow oily, 83% yield). LCMS (ESI): m / z = 401.2 [M + H] + .

[0249] Step 3: Synthesis of 4-chloro-8-(6-(3-((2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindorin-5-yl)amino)propoxy)pyridine-3-amino)-3-ethoxy-5,6,7,8-tetrahydronaphthalene-2-carbonitrile

[0250] HT312-2 (100 mg, 0.25 mmol) and S3 (173 mg, 0.63 mmol) were dissolved in DMSO (10 mL) solution, TEA (125 mg, 1.25 mmol) was added, and the mixture was reacted overnight at 90°C. The reaction mixture was injected into a saturated NH4Cl aqueous solution, EA was added for extraction, the organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography to obtain compound HANT-312 (16.3 mg, white solid, yield: 4%). LCMS (ESI): m / z = 657.2 [M + H] + ; 1H NMR(400MHz,DMSO-d6)δ11.04(s,1H),7.71(s,1H),7.61(d,J=3.0Hz,1H),7.56(d,J=8.4Hz,1H),7.15-7.20( m,2H),6.98-6.99(m,1H),6.87(dd,J=8.5,2.1Hz,1H),6.66(d,J=8.8Hz,1H),5.62(d,J=9.0Hz,1H),5.03(dd, J=12.9,5.4Hz,1H),4.61-4.50(m,1H),4.25-4.20(m,2H),4.17(t,J=7.0Hz,2H),3.30-3.31(m,1H),2.94-2. 79(m,2H),2.76-2.66(m,1H),2.63-2.52(m,2H),2.11-1.89(m,4H),1.88-1.71(m,4H),1.39(t,J=7.0Hz,3H).

[0251] Example 2

[0252] [ka]

[0253] Step 1: Synthesis of tert-butyl(3-((5-bromopyrimidine-2-yl)amino)propyl)carbamate

[0254] S1 (1 g, 5.65 mmol), S2 (1.08 g, 6.22 mmol), potassium carbonate (2.34 g, 16.9 mmol), and DMF (20 mL) were added sequentially to a dry flask and stirred at 50°C for 3 hours. After cooling, EA was injected, washed with saturated saline, and the organic phase was collected and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain a white solid HT314-1 (1.72 g, yield: 93%). LCMS: m / z = 331.2 [M + H] + .

[0255] Step 2: Synthesis of tert-butyl(3-(5-(4,4,5,5-tetramethyl-1,3,2-dioxybenzaldehyde-2-yl)pyrimidine-2-yl)aminopropyl)carbamate

[0256] HT314-1 (1.7g, 5.15 mmol), S3 (1.96g, 7.72 mmol), Pd(dppf)Cl2 (1.13g, 1.54 mmol), potassium acetate (1.52g, 15.5 mmol), and dioxane (15 mL) were added sequentially to a dry flask and stirred overnight at 90°C under nitrogen protection. After cooling, the mixture was filtered to remove the solvent, and EA was injected into the residue. The organic phase was washed with aqueous sodium chloride solution, and the mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain a white solid HT314-2 (1.56g, yield: 80%). LCMS: m / z = 379.2 [M + H] + .

[0257] Step 3: Synthesis of tert-butyl(3-(5-(5-chloro-6-(2-chloroethoxy)-7-cyano-3,4-dihydronaphthalene-1-yl)pyrimidine-2-yl)amino)propyl)carbamate

[0258] HT314-2 (272 mg, 0.72 mmol), INT-2 (200 mg, 0.48 mmol), Pd(dppf)Cl2 (71 mg, 0.097 mmol), sodium carbonate (153 mg, 1.4 mmol), and dioxane / H2O (10 / 2 mL) were added sequentially to a dry flask and stirred at 90°C under nitrogen protection for 3 hours. After cooling, the mixture was filtered, the reaction solution was injected into saturated saline, extracted with EA, the organic phase was collected and concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to obtain a yellow oily substance, HT314-3 (220 mg, yield: 80%). LCMS: m / z = 520.0 [M + H] + .

[0259] Step 4: Synthesis of tert-butyl(3-(5-(5-chloro-6-(2-chloroethoxy)-7-cyano-1,2,3,4-tetrahydronaphthalene-1-yl)pyrimidine-2-yl)amino)propyl)carbamate

[0260] HT314-3 (220 mg, 0.42 mmol) was added to a dry flask and dissolved in methanol (10 mL). Then, palladium hydroxide / carbon (22 mg, 10% wt) was added. The reaction was carried out at room temperature under a hydrogen atmosphere for 24 hours. The mixture was filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to obtain a colorless oily substance, HT314-4 (160 mg, yield: 72%). LCMS: m / z = 522.0 [M + H] + .

[0261] Step 5: Synthesis of 8-(2-(3-aminopropyl)amino)pyrimidine-5-yl)-4-chloro-3-(2-chloroethoxy)-5,6,7,8-tetrahydronaphthalene-2-carbonitrile

[0262] HT314-4 (160 mg, 0.308 mmol), DCM (5 mL), and TFA (1 mL) were added to a dry flask and stirred at room temperature for 1 hour. The mixture was filtered, the filtrate was collected and concentrated under reduced pressure, EA and water were added, the pH was adjusted to 8-10 with aqueous ammonia, and the mixture was extracted and concentrated under reduced pressure to obtain a yellow oily substance, HT314-5 (85 mg, yield: 65.8%). LCMS: m / z = 420.3 [M + H] + .

[0263] Step 6: Synthesis of 4-chloro-3-(2-chloroethoxy)-8-(2-(3-(2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindorin-5-yl)amino)propyl)amino)pyrimidine-5-yl)-5,6,7,8-tetrahydronaphthalene-2-carbonitrile

[0264] HT314-5 (85 mg, 0.202 mmol), DMF (1 mL), S5 (140 mg, 0.507 mmol), and DIEA (130 mg, 1.01 mmol) were added sequentially to a dry flask and reacted overnight at 100°C. After cooling, EA was injected, washed with saturated saline, and the organic phase was collected and concentrated under reduced pressure. Purification was performed using reverse phase preparative separation to obtain yellow solid HANT-314 (15.4 mg, yield: 11.3%). LCMS: m / z = 676.1 [M + H] + ; 1H NMR(400MHz,DMSO-d6)δ11.04(s,1H),8.00(s,2H),7.55(d,J=8.4Hz,1H),7.29(s,1H),7.19(t ,J=5.6Hz,1H),7.11(t,J=5.3Hz,1H),6.95(s,1H),6.84(dd,J=8.4,1.9Hz,1H),5.02(dd,J=12 .9,5.4Hz,1H),4.47-4.31(m,2H),3.99(dt,J=19.4,5.0Hz,3H),3.41-3.32(m,2H),3.23(dd,J =12.5,6.5Hz,2H),2.95-2.75(m,3H),2.62-2.51(m,2H),2.02-1.91(m,2H),1.87-1.70(m,5H).

[0265] Example 3

[0266] [ka]

[0267] Step 1: Synthesis of 2-(2-((5-bromopyrimidine-2-yl)amino)ethoxy)ethane-1-ol

[0268] S1 (500 mg, 2.8 mmol), S2 (330 mg, 3.1 mmol), DMF (15 mL), and potassium carbonate (1.2 g, 8.5 mmol) were added sequentially to a dry flask, and the mixture was reacted at 50°C for 8 hours. After cooling, the reaction mixture was injected into an EA, washed with saturated brine, and the organic phase was collected and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain a colorless oily substance HT315-1 (650 mg, yield: 89%). LC-MS (ESI): m / z = 262.0 [M + H] + .

[0269] Step 2: Synthesis of 2-(2-((5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidine-2-yl)amino)ethoxy)ethane-1-ol

[0270] HT315-1 (1.4g, 5.4 mmol), S3 (2g, 7.8 mmol), Pd(dppf)Cl2 (300 mg, 0.4 mmol), potassium acetate (1.5g, 15.3 mmol), and dioxane (50 mL) were added sequentially to a dry flask and stirred overnight at 90°C under nitrogen protection. After cooling, the mixture was concentrated under reduced pressure to obtain the crude product HT315-2, which was then directly used in the next reaction. LCMS(ESI): m / z = 310.2 [M + H] + .

[0271] Step 3: Synthesis of 4-chloro-3-(2-chloroethoxy)-8-(2-((2-(2-hydroxyethoxyethyl)amino)pyrimidine-5-yl)-5,6-dihydronaphthalene-2-carbonitrile

[0272] HT315-2 (220 mg, 0.72 mmol), INT-2 (200 mg, 0.48 mmol), Pd(PPh3)4 (110 mg, 0.09 mmol), sodium carbonate (150 mg, 1.4 mmol), and dioxane / water (15 / 3 mL) were added sequentially to a dry flask and stirred at 90°C under nitrogen protection for 6 hours. After cooling, the reaction mixture was injected into saturated saline solution and extracted with EA. The organic phase was collected and concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to obtain a yellow oily substance, HT315-3 (200 mg, yield: 95%). LCMS (ESI): m / z = 449.1 [M + H] + .

[0273] Step 4: Synthesis of 4-chloro-3-(2-chloroethoxy)-8-(2-((2-(2-hydroxyethoxyethyl)amino)pyrimidine-5-yl)-5,6,7,8-tetrahydronaphthalene-2-carbonitrile

[0274] HT315-3 (200 mg, 0.45 mmol), methanol (10 mL), and Pd(OH)2 / C (20 mg, 10% wt) were added to a dry flask. The mixture was reacted under a hydrogen atmosphere at room temperature for 48 hours. After filtration, the filtrate was concentrated under reduced pressure to obtain a white solid HT315-4 (200 mg, yield: 100%), which was directly used in the next reaction. LCMS(ESI): m / z = 451.1 [M + H] +.

[0275] Step 5: Synthesis of 4-toluenesulfonic acid 2-(2-((5-(5-chloro-6-(2-chloroethoxy)-7-cyano-1,2,3,4-tetrahydronaphthalene-1-yl)pyrimidine-2-yl)amino)ethoxyethyl ester

[0276] HT315-4 (110 mg, 0.24 mmol), p-toluenesulfonyl chloride (93 mg, 0.49 mmol), DCM (8 mL), TEA (73 mg, 0.72 mmol), and DMAP (6 mg, 0.05 mmol) were added sequentially to a dry flask. The reaction was allowed to proceed at room temperature for 48 hours. The reaction mixture was poured into saturated saline solution, extracted with EA, and the organic phase was collected. The mixture was dried, concentrated under reduced pressure, and purified by preparative thin-layer chromatography to obtain a colorless oily substance, HT315-5 (60 mg, yield: 43%). LCMS (ESI): m / z = 605.1 [M + H] + .

[0277] Step 6: Synthesis of 4-chloro-3-(2-chloroethoxy)-8-(2-(2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindorin-5-yl)oxy)ethoxy-amino)pyrimidine-5-yl-5,6,7,8-tetrahydronaphthalene-2-carbonitrile

[0278] HT315-5 (60 mg, 0.1 mmol), S5 (40 mg, 0.15 mmol), DMF (5 mL), and potassium carbonate (28 mg, 0.2 mmol) were added to a dry flask. The reaction was carried out at 60°C for 6 hours. After cooling, the reaction mixture was injected into an aqueous solution (EA), washed with saturated brine, and the organic phase was collected. The organic phase was dried, concentrated under reduced pressure, and purified by neutral reverse phase fractionation to obtain a white solid HANT-315 (9.5 mg, yield: 13.5%). LC-MS (ESI): m / z = 707.0 [M + H] + ; 1H NMR(400MHz,DMSO-d6)δ11.10(s,1H),8.00(s,2H),7.82(d,J=8.3Hz,1H),7.45(d,J=2.3Hz,1H),7.36(dd,J =8.3,2.3Hz,1H),7.29(s,1H),7.04(t,J=5.8Hz,1H),5.11(dd,J=12.9,5.4Hz,1H),4.43-4.35(m,2H),4.34- 4.28(m,2H),4.02(t,J=5.6Hz,1H),3.99-3.93(m,2H),3.79(dd,J=5.6,3.4Hz,2H),3.59(t,J=6.1Hz,2H),3 .44(q,J=6.0Hz,2H),2.86(dd,J=11.1,7.0Hz,3H),2.64-2.53(m,2H),2.09-1.90(m,2H),1.83-1.62(m,3H).

[0279] Examples 4 and 5

[0280] [ka]

[0281] Step 1: Preparation of HT315-P1-4 and HT315-P2-4

[0282] The brown oily substance HT315-4 (1.3 g, crude product) was subjected to chiral separation (SFC purification method (Column: ChiralpakIJ 250 mm * 4.6 mm 5 μm, Hex-EtOH-50-50-15 MIN), 30°C) to obtain a pair of enantiomers HT315-P1-4 (RT1 = 6.105 min, 600 mg) and HT315-P2-4 (RT2 = 8.309 min, 550 mg). LCMS: m / z = 451.1 [M + H] + .

[0283] Step 2: Preparation of HT315-P1-5 and HT315-P2-5

[0284] HT315-P1-4 (600 mg, 1.33 mmol) and DCM (50 mL) were added to a dry flask. TosCl (512 mg, 2.69 mmol), TEA (408 mg, 4.04 mmol), and DMAP (33 mg, 0.27 mmol) were added at 0°C, and the mixture was stirred at room temperature for 24 hours. The reaction mixture was poured into saturated saline solution, extracted with DCM, and the organic phase was collected and concentrated under reduced pressure. Then, reverse-phase purification was performed to obtain a light brown oily substance, HT315-P1-5 (530 mg, yield: 62.3%). LCMS: m / z = 605.1 [M + H] + .

[0285] A colorless oily substance, HT315-P2-5 (270 mg, yield: 36%), was obtained by a similar method. LC-MS: m / z = 605.1 [M + H] + .

[0286] Step 3: Synthesis of HANT315-P1 and HANT315-P2

[0287] HT315-P1-5 (530 mg, 0.877 mmol), DMF (30 mL), S5 (340 mg, 1.24 mmol), and potassium carbonate (230 mg, 1.67 mmol) were added sequentially to a dry flask, and the mixture was reacted at 60°C for 6 hours. After cooling, EA was injected, washed with saturated saline, and the organic phase was collected and concentrated under reduced pressure. Purification was performed using reverse phase preparative chromatography to obtain a white solid HANT-315-P1 (163.8 mg, yield: 28.0%). LCMS: m / z = 707.0 [M + H] + ; 1H NMR(400MHz,DMSO-d6)δ11.10(s,1H),8.00(s,2H),7.82(d,J=8.3Hz,1H),7.45(d,J=1.9Hz,1H),7.36(dd,J= 8.3,2.1Hz,1H),7.29(s,1H),7.04(t,J=5.6Hz,1H),5.11(dd,J=12.9,5.3Hz,1H),4.44-4.35(m,2H),4.35-4. 25(m,2H),4.02(t,J=5.6Hz,1H),3.99-3.91(m,2H),3.86-3.71(m,2H),3.60(t,J=6.0Hz,2H),3.44(dd,J=11. 6,5.8Hz,2H),2.96-2.74(m,3H),2.64-2.52(m,2H),2.10-2.00(m,1H),1.99-1.89(m,1H),1.85-1.67(m,3H).

[0288] HT315-P2-5 (250 mg, 0.40 mmol), DMF (10 mL), S1 (170 mg, 0.60 mmol), and potassium carbonate (110 mg, 0.80 mmol) were added sequentially to a dry flask and stirred at 60°C for 6 hours. After cooling, the mixture was diluted with water, extracted with EA, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and then purified using reverse phase preparative (formic acid) to obtain a white solid HANT-315-P2 (57.5 mg, yield: 19%). LCMS: m / z = 707.0 [M + H] + ; 1H NMR(400MHz,DMSO-d6)δ11.10(s,1H),8.01(s,2H),7.82(d,J=8.3Hz,1H),7.45(d,J=2.1Hz,1H),7.36(d d,J=8.3,2.2Hz,1H),7.29(s,1H),7.04(t,J=5.7Hz,1H),5.11(dd,J=12.9,5.4Hz,1H),4.43-4.24(m,4H) ,4.02(t,J=5.6Hz,1H),3.99-3.93(m,2H),3.84-3.74(m,2H),3.60(t,J=6.1Hz,2H),3.44(dd,J=11.9,6. 0Hz,2H),2.97-2.75(m,3H),2.64-2.52(m,2H),2.11-2.00(m,1H),1.99-1.89(m,1H),1.85-1.67(m,3H).

[0289] Example 6

[0290] [ka]

[0291] Step 1: Synthesis of tert-butyl(4-((5-nitropyridine-2-yl)oxy)butyl)carbamate

[0292] In a dry flask, S1 (500 mg, 3.52 mmol) and THF (5 mL) were added. NaH (215 mg, 5.4 mmol, 60%) was added at 0°C and stirred for 0.5 hours. Then, S2 (732 mg, 3.87 mmol) was added and stirred overnight at room temperature. Water was added and quenched at 0°C, EA was injected, and the mixture was washed with saturated brine. The organic phase was collected and concentrated under reduced pressure. Purification was then performed using silica gel column chromatography to obtain a white solid HT331-1 (980 mg, yield: 89.5%). LCMS: m / z = 312.3 [M + H] + .

[0293] Step 2: Synthesis of tert-butyl(4-((5-aminopyridine-2-yl)oxy)carboxylate

[0294] HT331-1 (170 mg, 0.55 mmol), methanol (10 mL), and palladium-carbon (17 mg, 10% wt) were added to a dry flask. The mixture was reacted overnight at room temperature under a hydrogen atmosphere. After filtration, the filtrate was collected and concentrated under reduced pressure. It was then purified using silica gel column chromatography to obtain a yellow oily substance, HT331-2 (138 mg, yield: 90%). LCMS: m / z = 282.4 [M + H] + .

[0295] Step 3: Synthesis of tert-butyl(4-((5-((5-chloro-6-(2-chloroethoxy)-7-cyano-1,2,3,4-tetrahydronaphthalene-1-yl)amino)pyridine-2-yl)oxy)butyl)carbamate

[0296] HT331-2 (136 mg, 0.483 mmol), INT-3 (112 mg, 0.323 mmol), DIEA (208 mg, 1.61 mmol), and DMF (5 mL) were added sequentially to a dry flask and stirred overnight at 60°C under nitrogen protection. After cooling, the reaction mixture was injected into saturated saline solution, extracted with EA, and the organic phase was collected and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain a yellow oily substance, HT331-3 (160 mg, yield: 90%). LCMS: m / z = 549.4 [M + H] + .

[0297] Step 4: Synthesis of 8-((6-(4-aminobutoxy)pyridine-3-yl)amino)-4-chloro-3-(2-chloroethoxy)-5,6,7,8-tetrahydronaphthalene-2-carbonitrile

[0298] HT331-3 (160 mg, 0.29 mmol), DCM (5 mL), and TFA (1 mL) were added to a dry flask and stirred at room temperature for 2 hours. The filtrate was collected and concentrated under reduced pressure, EA was added, the pH was adjusted to 8-10 with aqueous ammonia, and the mixture was extracted. The organic phase was collected and concentrated under reduced pressure to obtain a yellow oily substance, HT331-4 (130 mg, crude product, yield: 99%), which was then directly subjected to the next step. LCMS: m / z = 449.2 [M + H] + .

[0299] Step 5: Synthesis of 4-chloro-3-(2-chloroethoxy)-8-((6-(4-(2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindorin-5-yl)amino)butoxy)pyridine-3-amino)-5,6,7,8-tetrahydronaphthalene-2-carbonitrile

[0300] HT331-4 (76 mg, 0.17 mmol), DMF (1 mL), S4 (117 mg, 0.424 mmol), and DIEA (109 mg, 0.845 mmol) were added sequentially to a dry flask and reacted at 100°C for 8 hours. After cooling, EA was injected, washed with saturated saline, and the organic phase was collected and concentrated under reduced pressure. Purification was performed using reverse phase preparative separation to obtain yellow solid HANT-331 (9.0 mg, yield: 7.5%). LCMS: m / z = 705.0 [M + H] + ; 1 H NMR(300MHz,DMSO-d6)δ11.05(s,1H),7.73(s,1H),7.60(d,J=2.8Hz,1H),7.56(d,J=8.4Hz,1H),7.18-7.12(m,2H),6.9 6(d,J=1.7Hz,1H),6.85(dd,J=8.4,1.9Hz,1H),6.63(d,J=8.8Hz,1H),5.62(d,J=9.1Hz,1H),5.03(dd,J=12.7,5.4Hz,1 H),4.60-4.53(m,1H),4.39(t,J=12Hz,2H)4.17(t,J=6.3Hz,2H),3.98,(t,J=9Hz,2H),3.26-3.19(m,2H),2.94-2.79(m ,2H),2.78-2.66(m,1H),2.60-2.53(m,1H),2.02-1.96(m,1H),1.95-1.85(m,1H),1.85-1.72(m,6H),1.72-1.65(m,2H).

[0301] Example 7

[0302] [ka]

[0303] The synthesis method was the same as for compound HANT-315 in Example 3, but the starting material S2 in Example 3 was replaced with 5-aminopentan-1-ol. Purification using reverse-phase preparative fractionation yielded white solid HANT-336 (11.5 mg, yield: 12.3%). LC-MS: m / z = 706.0 [M + H] + ; 1 H NMR(400MHz,DMSO-d6)δ11.10(s,1H),7.98(s,2H),7.82(d,J=8.3Hz,1H),7.42(d,J=2.1Hz,1H),7.34( dd,J=8.3,2.2Hz,1H),7.29(s,1H),7.12(t,J=5.7Hz,1H),5.11(dd,J=12.9,5.3Hz,1H),4.41-4.36(m, 2H),4.17(t,J=6.4Hz,2H),4.01(t,J=5.7Hz,1H),3.98-3.94(m,2H),3.26(d,J=6.2Hz,2H),2.93-2.79 (m,3H),2.62-2.53(m,1H),2.09-1.88(m,3H),1.81-1.73(m,5H),1.61-1.54(m,2H),1.50-1.42(m,2H).

[0304] Example 8

[0305] [ka]

[0306] Step 1: Synthesis of 2-(4-benzyloxy)butoxy)-5-bromopyridine

[0307] S1 (6.0 g, 36.1 mmol) was dissolved in DMF (100 mL), and NaH (2.77 g, 72 mmol) was added at 0°C and the mixture was stirred for 0.5 hours. Next, S2 (7.5 mg, 43.3 mmol) was added and the reaction was allowed to proceed at room temperature for 2 hours. The reaction mixture was extracted using EA, the organic phase was collected and dried, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain a white solid HT338-1 (8.0 g, yield: 66.7%). LCMS (ESI): m / z = 336.1 [M + H] + .

[0308] Step 2: Synthesis of 2-(4-(benzyloxy)butoxy)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine

[0309] HT338-1 (500 mg, 1.5 mmol), S3 (455 mg, 1.8 mmol), Pd(dppf)Cl2 (328 mg, 0.45 mmol), and KOAc (439 mg, 4.5 mmol) were dissolved in 1,4-dioxane (10 mL), stirred overnight at 90°C under nitrogen protection, cooled, and the reaction mixture was extracted with EA. The organic phase was dried and concentrated, and the residue was purified by silica gel column chromatography to obtain crude product HT338-2 (600 mg). LCMS (ESI): m / z = 383.2 [M + H] + .

[0310] Step 3: Synthesis of 8-(6-(4-(benzyloxy)butoxy)pyridine-3-yl)-4-chloro-3-(2-chloroethoxy)-5,6-dihydronaphthalene-2-carbonitrile

[0311] HT338-3 (600 mg, 1.57 mmol), INT-2 (782 mg, 1.88 mmol), Pd(dppf)Cl2 (229 mg, 0.31 mmol), and Na2CO3 (332 mg, 3.1 mmol) were dissolved in 1,4-dioxane / water (10 mL / 2 mL), stirred at 90°C for 4 hours, cooled, and the reaction mixture was extracted by EA. The organic phase was dried and concentrated, and the residue was purified by silica gel column chromatography to obtain solid HT338-4 (550 mg, yield: 67%). LCMS (ESI): m / z = 523.1 [M + H] + .

[0312] Step 4: Synthesis of 4-chloro-3-(2-chloroethoxy)-8-(6-(4-hydroxybutoxy)pyridine-3-yl)-5,6,7,8-tetrahydronaphthalene-2-carbonitrile

[0313] HT338-4 (550 mg, 1.05 mmol) and Pd / C (300 mg) were dissolved in MeOH (5 mL), stirred at room temperature for 2 hours, filtered, and the organic phase was concentrated to obtain solid HT338-5 (200 mg, yield: 44%). LC-MS (ESI): m / z = 435.1 [M + H] + .

[0314] Step 5: Synthesis of 4-toluenesulfonic acid 4-((5-(5-chloro-6-(2-chloroethoxy)-7-cyano-1,2,3,4-tetrahydronaphthalene-1-yl)pyridine-2-yl)oxy)butyl ester

[0315] HT338-5 (200 mg, 0.46 mmol), TosCl (130 mg, 0.69 mmol), TEA (70 mg, 0.69 mmol), and DMAP (11 mg, 0.09 mmol) were dissolved in DCM (5 mL), stirred at room temperature for 1 hour, and the reaction mixture was extracted with DCM. The organic phase was dried and concentrated, and the residue was purified by silica gel column chromatography to obtain solid HT338-6 (120 mg, yield: 44%). LCMS (ESI): m / z = 589.1 [M + H] + .

[0316] Step 6: Synthesis of 4-chloro-3-(2-chloroethoxy)-8-(6-(4-((2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindorin-5-yl)oxy)butoxy)pyridine-3-yl)-5,6,7,8-tetrahydronaphthalene-2-carbonitrile

[0317] HT338-6 (120 mg, 0.2 mmol), S4 (84 mg, 0.31 mmol), and K2CO3 (84 mg, 0.6 mmol) were dissolved in DMF (5 mL), stirred at 60°C for 8 hours, cooled, and the reaction mixture was extracted with EA. The organic phase was dried and concentrated, and the residue was purified by prep-HPLC to obtain solid HANT-338 (120 mg, yield: 44%). LCMS (ESI): m / z = 691.2 [M + H] + ; 1H NMR(400MHz,DMSO-d6)δ11.10(s,1H),7.89(d,J=2.5Hz,1H),7.83(d,J=8.3Hz,1H),7.43(d, J=2.3Hz,1H),7.37(ddd,J=15.5,8.5,2.4Hz,2H),7.19(s,1H),6.75(d,J=8.5Hz,1H),5.11(d d,J=12.9,5.4Hz,1H),4.43-4.37(m,2H),4.34-4.13(m,5H),3.97(dd,J=6.0,4.3Hz,2H),2. 94-2.83(m,3H),2.63-2.52(m,2H),2.08-1.97(m,2H),1.93-1.86(m,4H),1.85-1.74(m,3H).

[0318] Example 9

[0319] [ka]

[0320] The synthesis method was the same as that for compound HANT-314 in Example 2, but the intermediate HT314-1 from Example 2 was replaced with compound tert-butyl(3-((5-bromopyridine-2-yl)oxy)propyl)carbamate (synthesis is described in WO2021155006). Purification by reverse-phase fractionation yielded the yellow solid HANT-339 (34.9 mg, yield: 21.7%). LCMS: m / z = 676.1 [M + H] + ; 1H NMR (400MHz, DMSO-d6) δ11.04(s,1H),7.90(d,J=2.3Hz,1H),7.56(d,J=8.3Hz,1H),7.40(dd,J=8.5, 2.3Hz,1H),7.27-7.10(m,2H),6.97(s,1H),6.87(dd,J=8.4,2.0Hz,1H),6.79(d,J=8.6Hz,1H),5.02( dd,J=12.8,5.4Hz,1H),4.43-4.37(m,2H),4.34(t,J=6.2Hz,2H),4.22-4.12(m,1H),3.99-3.92(m,2H) ),3.34(d,J=6.3Hz,1H),2.93-2.80(m,3H),2.62-2.52(m,2H),2.07-1.90(m,5H),1.83-1.72(m,3H).

[0321] Example 10

[0322] [ka]

[0323] Step 1: Synthesis of tert-butyl 4-(2-ethoxy-2-oxoethoxy)piperidine-1-carboxylate

[0324] S1 (10 g, 49.75 mmol) was added to a dry flask, dissolved in THF (100 mL), and slowly added to NaH (3 g, 74.63 mmol) under an ice bath. The mixture was then stirred in an ice bath for 30 minutes, and then S3 (10 g, 59.70 mmol) was added. The reaction was allowed to proceed overnight at room temperature. The reaction mixture was poured into ice-cold saline solution, extracted with EA, and the organic phase was collected and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain a colorless oily substance HT342-1 (7.8 g, yield: 55%). LCMS (ESI): m / z = 288.2 [M + H] + .

[0325] Step 2: Synthesis of tert-butyl 4-(2-hydroxyethoxy)piperidine-1-carboxylate

[0326] HT342-1 (5g, 27.3 mmol) was added to a dry flask and dissolved in THF (100 mL). LiAlH4 solution (54.6 mL, 54.6 mmol, 1 M) was slowly added dropwise at -70°C and the mixture was stirred for 2 hours. The reaction was quenched with methanol, and EA (200 mL) and saturated potassium sodium tartrate aqueous solution (20 mL) were added. The mixture was stirred for 2 hours, then dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a yellow oily substance, HT342-2 (4.5 g, yield: 100%). LCMS (ESI): m / z = 246.2 [M + H] + .

[0327] Step 3: Synthesis of 2-(piperidine-4-yloxy)ethane-1-ol

[0328] HT342-2 (2g, 18.3 mmol) and dioxane (100 mL) were added sequentially to a dry flask, followed by the addition of HCl / dioxane (20 mL, 80 mmol, 4 M). The mixture was reacted at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure to obtain crude HT342-3 hydrochloride as a yellow oily substance, which was then directly used in the next reaction. LCMS(ESI): m / z = 146.2 [M + H] + .

[0329] Step 4: Synthesis of 4-chloro-3-(2-chloroethoxy)-8-(2-(4-(2-hydroxymethoxy)piperidine-1-yl)pyrimidine-5-yl)-5,6-dihydronaphthalene-2-carbonitrile

[0330] INT-6-2 (358 mg, 0.98 mmol), HT342-3 (120 mg, 0.82 mmol), DMSO (10 mL), and potassium carbonate (400 mg, 2.9 mmol) were added sequentially to a dry flask, and the mixture was reacted at 50°C for 3 hours. After cooling, the reaction mixture was injected into an EA, washed with saturated brine, and the organic phase was collected and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain a yellow oily substance, HT342-4 (230 mg, yield: 58%). LCMS (ESI): m / z = 489.2 [M + H] + .

[0331] Step 5: Synthesis of 4-chloro-3-(2-chloroethoxy)-8-(2-(4-(2-hydroxymethoxy)piperidine-1-yl)pyrimidine-5-yl)-5,6,7,8-tetrahydronaphthalene-2-carbonitrile

[0332] HT342-4 (230 mg, 0.47 mmol), methanol (10 mL), and Pd(OH)2 / C (23 mg, 10% wt) were added to a dry flask and reacted overnight at room temperature under a hydrogen atmosphere. After filtration, the filtrate was concentrated under reduced pressure to obtain a white solid HT342-5 (230 mg, yield: 100%), which was directly used in the next reaction. LCMS(ESI): m / z = 491.2 [M + H] + .

[0333] Step 6: Synthesis of 2-((1-(5-(5-chloro-6-(2-chloroethoxy)-7-cyano-1,2,3,4-tetrahydronaphthalene-1-yl)pyrimidine-2-yl)piperidine-4-yl)oxy)ethyl-4-methylbenzenesulfonic acid ester

[0334] HT342-5 (230 mg, 0.51 mmol) and p-toluenesulfonyl chloride (200 mg, 1.02 mmol) were added to a dry flask and dissolved in DCM (10 mL). Then, TEA (154 mg, 1.53 mmol) and DMAP (20 mg, 0.15 mmol) were added. The mixture was reacted at room temperature for 1 hour. The reaction mixture was poured into saturated saline solution, extracted with EA, and the organic phase was collected. The organic phase was dried and concentrated under reduced pressure. The solution was then purified by preparative thin-layer chromatography to obtain a colorless oily substance, HT342-6 (140 mg, yield: 43%). LCMS (ESI): m / z = 645.2 [M + H] + .

[0335] Step 7: Synthesis of 4-chloro-3-(2-chloroethoxy)-8-(2-(4-(2-((2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindole-5-yl)oxy)ethoxy)piperidine-1-yl)pyrimidine-5-yl)-5,6,7,8-tetrahydronaphthalene-2-carbonitrile

[0336] HT342-6 (130 mg, 0.2 mmol) and S6 (82 mg, 0.3 mmol) were added to a dry flask and dissolved in DMF (6 mL). Then, potassium carbonate (55 mg, 0.4 mmol) was added. The reaction was carried out at 60°C for 6 hours. The reaction mixture was injected into EA, washed with saturated brine, and the organic phase was collected. The organic phase was dried, concentrated under reduced pressure, and purified by neutral reverse phase preparative fractionation to obtain a white solid HANT-342 (36.3 mg, yield: 25%). LCMS(ESI): m / z = 747.2 [M + H] + ; 1 H NMR(400MHz,DMSO-d6)δ11.10(s,1H),8.08(s,2H),7.83(d,J=8.3Hz,1H),7.47(d,J=2.3Hz,1H),7.38(dd, J=8.3,2.3Hz,1H),7.30(s,1H),5.11(dd,J=12.9,5.4Hz,1H),4.44-4.36(m,2H),4.33(t,J=4.6Hz,2H),4.1 7(dt,J=13.4,4.9Hz,2H),4.04(d,J=6.5Hz,1H),4.00-3.92(m,2H),3.84(t,J=4.6Hz,2H),3.66(dt,J=8.6, 4.6Hz,1H),3.35-3.32(m,2H),2.93-2.80(m,3H),2.62-2.54(m,1H),2.12-1.69(m,8H),1.49-1.34(m,2H).

[0337] Example 11

[0338] [ka]

[0339] The synthesis method was the same as for compound HANT-315 in Example 3, but 5-bromo-2-fluoropyridine was used as the starting material instead of S1 as in Example 3. Purification by silica gel column chromatography yielded compound HANT-346 (8.3 mg, white solid, yield: 8%). LC-MS (ESI): m / z = 706.0 [M + H] + ; 1H NMR(400MHz,DMSO-d6)δ11.08(s,1H),7.83(d,J=8.3Hz,1H),7.70(d,J=2.4Hz,1H),7.46(d,J=2.4Hz,1H), 7.37(dd,J=8.3,2.3Hz,1H),7.18(s,1H),7.06(dd,J=8.6,2.5Hz,1H),6.50-6.43(m,2H),5.14-5.11(m,1H) ),4.42-4.37(m,2H),4.34-4.32(m,2H),4.00-3.96(m,3H),3.85-3.77(m,2H),3.62-3.59(m,2H),3.44-3. 34(m,2H),2.90-2.84(m,3H),2.65-2.54(m,2H),2.08-2.03(m,1H),1.98-1.90(m,1H),1.77-1.71(m,3H).

[0340] Example 12

[0341] [ka]

[0342] Step 1: Synthesis of 4-chloro-3-ethoxy-8-(2-(2-hydroxyethoxy)ethyl)amino)pyrimidine-5-yl)-5,6,7,8-tetrahydronaphthalene-2-carbonitrile

[0343] INT-5 (100 mg, 0.303 mmol) was dissolved in 5 mL of dimethyl sulfoxide, then S3 (64 mg, 0.606 mmol) and potassium carbonate (84 mg, 0.606 mmol) were added, and the mixture was reacted under nitrogen at 90°C for 2 hours. After cooling, the organic phase was filtered and injected into water, extracted with EA, washed with saturated brine, dried over sodium sulfate, and purified by column chromatography (DCM:MeOH = 10:1) to obtain HT354-1 (90 mg, white oily) in 74% yield. LCMS (ESI): m / z = 417.3 [M + H] + .

[0344] Step 2: Synthesis of 2-(2-(5-(5-chloro-7-cyano-6-ethoxy-1,2,3,4-tetrahydronaphthalene-1-yl)pyrimidine-2-yl)amino)ethoxy)ethyl-4-toluenesulfonate

[0345] HT354-1 (90 mg, 0.216 mmol) was dissolved in 10 mL of DCM, and TEA (66 mg, 0.647 mmol) and DMAP (8 mg, 0.065 mmol) were added. The mixture was stirred at room temperature for 5 minutes, and then p-toluenesulfonyl chloride (82 mg, 0.432 mmol) was added. The mixture was reacted overnight at 40°C under nitrogen. The organic phase was filtered and injected into water, extracted with DCM, washed with saturated brine, dried over sodium sulfate, and purified by column chromatography (DCM:MeOH = 10:1) to obtain HT354-2 (80 mg, yellow oily) in yield: 61%. LCMS (ESI): m / z = 571.1 [M + H] + .

[0346] Step 3: Synthesis of 4-chloro-8-(2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindorin-5-yl)oxy)ethoxy)ethyl)amino)pyrimidine-5-yl-3-ethoxy-5,6,7,8-tetrahydronaphthalene-2-carbonitrile

[0347] HT354-2 (90 mg, 0.158 mmol) was dissolved in 10 mL of DMF, and S3 (65 mg, 0.236 mmol) and potassium carbonate (40 mg, 0.315 mmol) were added. The mixture was reacted under nitrogen at 60°C for 3 hours. After cooling, the organic phase was filtered and injected into water, extracted with EA, washed with saturated brine, dried over sodium sulfate, and compound HANT-354 (8.9 mg, white solid) was obtained in 13% yield by reverse phase fractionation. LCMS (ESI): m / z = 673.1 [M + H] + ; 1H NMR(400MHz,DMSO-d6)δ11.10(s,1H),7.82(d,J=8.3Hz,1H),7.45(d,J=2.3Hz,1H),7.36(dd,J=8.3,2.3 Hz,1H),7.26(s,1H),7.04(t,J=5.9Hz,1H),5.11(dd,J=12.9,5.4Hz,1H),4.31(dd,J=5.7,3.3Hz,2H),4. 17(q,J=7.0Hz,2H),4.01(d,J=6.3Hz,1H),3.82-3.76(m,2H),3.60(t,J=6.1Hz,2H),3.44(q,J=6.0Hz,2H ),2.99-2.76(m,3H),2.69-2.53(m,2H),2.12-1.89(m,2H),1.76(d,J=8.4Hz,3H),1.38(t,J=7.0Hz,3H).

[0348] Example 13

[0349] [ka]

[0350] Step 1: Synthesis of tert-butyl 4-(allyloxy)piperidine-1-carboxylate

[0351] S1 (2 g, 10.0 mmol) was added to a dry flask and dissolved in THF (15 mL). NaH (0.8 g, 20.0 mmol) was added under ice bath conditions, and the mixture was stirred at 0°C for 0.5 hours. Next, S2 (1 mL, 12.0 mmol) was added, and the mixture was stirred at room temperature for 2 hours. The reaction was quenched with saturated ammonium chloride aqueous solution under ice bath conditions, the reaction mixture was injected into EA, washed with saturated brine, the organic phase was collected, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to obtain a colorless oily substance HT371-1 (2.5 g, yield: 100%). LCMS (ESI): m / z = 242.1 [M + H] + .

[0352] Step 2: Synthesis of tert-butyl 4-(3-hydroxypropoxy)piperidine-1-carboxylate

[0353] HT371-1 (1 g, 4.15 mmol) and THF (20 mL) were added to a dry flask, and 9-BBN (12.5 mL, 25 mmol, 0.5 Min THF) was added dropwise under ice bath. The mixture was stirred at room temperature for 4 hours. Next, 3 M NaOH (aq) (3 mL) and 30% H2O2 aqueous solution were added, and the mixture was stirred at room temperature for 2 hours. After that, the solution was injected into saturated sodium bicarbonate aqueous solution, extracted with EA, the organic phase was dried, and the mixture was concentrated under reduced pressure to obtain the crude product HT371-2, which was then directly used in the next reaction. LCMS (ESI): m / z = 260.2 [M + H] + .

[0354] Step 3: Synthesis of tert-butyl 4-(3-((2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindorin-5-yl)oxy)propoxy)piperidine-1-carboxylate

[0355] HT371-2 (100 mg, 0.39 mmol), S3 (100 mg, 0.36 mmol), and PPh3 (150 mg, 0.57 mmol) were added sequentially to a dry flask and dissolved in THF (5 mL). Under an ice bath, DIAD (110 mg, 0.55 mmol) was added dropwise, and the mixture was stirred at 60°C under nitrogen protection for 3 hours. After cooling, the reaction mixture was concentrated under reduced pressure, and the resulting crude product was purified by reverse-phase column chromatography to obtain a colorless oily substance, HT371-3 (50 mg, yield: 28%). LCMS (ESI): m / z = 516.2 [M + H] + .

[0356] Step 4: Synthesis of 2-(2,6-dioxopiperidine-3-yl)-5-(3-(piperidine-4-yloxy)propoxy)isoindole-1,3-dione

[0357] HT371-3 (200 mg, 0.39 mmol) was added to a dry flask and dissolved in DCM (10 mL), then TFA (2 mL) was added. The reaction was allowed to proceed at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure to obtain a colorless oily crude product HT371-4, which was then directly used in the next reaction. LCMS(ESI): m / z = 416.2 [M + H] + .

[0358] Step 5: Synthesis of 4-chloro-3-(2-chloroethoxy)-8-(2-(4-(3-((2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindole-5-yl)oxy)propoxy)piperidine-1-yl)pyrimidine-5-yl)-5,6,7,8-tetrahydronaphthalene-2-carbonitrile

[0359] HT371-4 (80 mg, 0.2 mmol) and INT-6 (73 mg, 0.2 mmol) were added to a dry flask and dissolved in DMSO (5 mL). Then, TEA (60 mg, 0.6 mmol) was added. The reaction was carried out at 80°C for 2 hours. After cooling, the reaction mixture was injected into EA, washed with saturated brine, and the organic phase was collected. The organic phase was dried and concentrated under reduced pressure, and then purified by neutral reverse phase preparative fractionation to obtain a white solid HANT-371 (57.9 mg, yield: 38%). LCMS(ESI): m / z = 761.2 [M + H] + ; 1 H NMR(400MHz,DMSO-d6)δ11.00(s,1H),8.07(s,2H),7.83(d,J=8.3Hz,1H),7.44(d,J=2.3Hz,1H),7.36(dd,J= 8.3,2.3Hz,1H),7.29(s,1H),5.11(dd,J=12.9,5.4Hz,1H),4.39(dd,J=5.8,4.6Hz,2H),4.26(t,J=6.3Hz,2H) ,4.18-4.09(m,2H),4.08-4.01(m,1H),3.99-3.90(m,2H),3.62(t,J=6.1Hz,2H),3.56(p,J=4.3Hz,1H),3.39 -3.32(m,2H),2.95-2.75(m,3H),2.64-2.52(m,2H),2.08-1.91(m,4H),1.90-1.68(m,5H),1.45-1.37(m,2H).

[0360] Example 14

[0361] [ka]

[0362] Step 1: Synthesis of tert-butyl 3-((1-(5-(5-chloro-6-(2-chloroethoxy)-7-cyano-1,2,3,4-tetrahydronaphthalene-1-yl)pyrimidine-2-yl)piperidine-4-yl)oxy)azetidine-1-carboxylate

[0363] INT-6 (100 mg, 0.274 mmol), S2 (80 mg, 0.313 mmol), TEA (140 mg, 1.39 mmol), and DMSO (5 mL) were added sequentially to a dry flask and stirred at 80°C for 2 hours. EA was injected, washed with saturated saline, and the organic phase was collected. The mixture was concentrated under reduced pressure and purified by silica gel column chromatography to obtain a brown oily substance, HT390-1 (140 mg, yield: 84.8%). LCMS: m / z = 602.2 [M + H] + .

[0364] Step 2: Synthesis of 8-(2-(4-(azetidine-3-yloxy)piperidine-1-yl)pyrimidine-5-yl)-4-chloro-3-(2-chloroethoxy)-5,6,7,8-tetrahydronaphthalene-2-carbonitrile

[0365] HT390-1 (140 mg, 0.232 mmol) was added to a dry flask, dissolved in DCM (2 mL), and TFA (1 mL) was added. The mixture was then stirred at room temperature for 2 hours. After filtration, the filtrate was collected and concentrated under reduced pressure. EA and saturated sodium bicarbonate aqueous solution were added for extraction, and the organic phase was collected and concentrated under reduced pressure to obtain crude product HT390-2 (100 mg). LCMS: m / z = 502.2 [M + H] + .

[0366] Step 3: Synthesis of 4-chloro-3-(2-chloroethoxy)-8-(2-(4-((1-(2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindole-5-yl)azetidine-3-yl)oxy)piperidine-1-yl)pyrimidine-5-yl)-5,6,7,8-tetrahydronaphthalene-2-carbonitrile

[0367] HT390-2 (100 mg, 0.199 mmol) and DMSO (2 mL) were added to a dry flask, then S3 (85 mg, 0.308 mmol) and TEA (100 mg, 0.990 mmol) were added, and the mixture was reacted at 100°C for 16 hours. After cooling, EA was injected, washed with saturated saline, and the organic phase was collected and concentrated under reduced pressure. Purification was performed using reverse phase preparative separation to obtain yellow solid HANT-390 (25.9 mg, yield: 17.2%). LCMS: m / z = 758.3 [M + H] + ; 1 H NMR(400MHz,DMSO-d6)δ11.07(s,1H),8.09(s,2H),7.65(d,J=8.3Hz,1H),7.30(s,1H),6.81(d,J=1.8Hz,1H),6. 66(dd,J=8.4,2.0Hz,1H),5.06(dd,J=12.9,5.4Hz,1H),4.71-4.59(m,1H),4.42-4.36(m,2H),4.34-4.22(m,4H) ,4.05(t,J=5.6Hz,1H),4.00-3.94(m,2H),3.85(dd,J=9.0,4.2Hz,2H),3.72-3.63(m,1H),3.28-3.16(m,2H),2. 94-2.78(m,3H),2.62-2.52(m,2H),2.05-1.94(m,2H),1.93-1.84(m,2H),1.83-1.69(m,3H),1.49-1.36(m,2H).

[0368] Example 15

[0369] [ka]

[0370] Step 1: Synthesis of tert-butyl 3-(2-((2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindorin-5-yl)amino)ethoxy)pyrrolidine-1-carboxylate

[0371] S1 (200 mg, 0.87 mmol) was added to a dry flask and dissolved in DMSO (2 mL). Then, S2 (360 mg, 1.30 mmol) and TEA (440 mg, 4.36 mmol) were added, and the mixture was reacted at 90°C for 7 hours. After cooling, EA was injected, washed with saturated saline, and the organic phase was collected and concentrated under reduced pressure. Then, reverse-phase purification was performed to obtain the yellow solid HT-393-1 (110 mg, yield: 26.1%). LCMS: m / z = 487.1 [M + H] + .

[0372] Step 2: Synthesis of 2-(2,6-dioxopiperidine-3-yl)-5-((2-(pyrrolidine-3-yloxy)ethyl)amino)isoindole-1,3-dione

[0373] HT393-1 (110 mg, 0.226 mmol), DCM (2 mL), and TFA (1 mL) were added to a dry flask and stirred at room temperature for 2 hours. The mixture was concentrated under reduced pressure, EA and saturated sodium bicarbonate aqueous solution were added, and the organic phase was collected and concentrated under reduced pressure to obtain compound HT393-2 (90 mg, crude product). LCMS: m / z = 387.3 [M + H] + .

[0374] Step 3: Synthesis of 4-chloro-3-(2-chloroethoxy)-8-(2-(3-(2-((2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindole-5-yl)amino)ethoxypyrrolidine-1-yl)pyrimidine-5-yl)-5,6,7,8-tetrahydronaphthalene-2-carbonitrile

[0375] HT393-2 (60 mg, 0.155 mmol), INT-6 (62 mg, 0.169 mmol), and TEA (78 mg, 0.772 mmol) were added sequentially to a dry flask, dissolved in DMSO (5 mL), and stirred at 80°C for 2 hours. After cooling, EA was injected, washed with saturated saline, and the organic phase was collected and concentrated under reduced pressure. Yellow solid HANT-393 (52 mg, yield: 45.8%) was obtained by reverse phase preparative fractionation. LCMS: m / z = 732.2 [M + H] + ; 1H NMR(400MHz,DMSO-d6)δ11.05(s,1H),8.06(s,2H),7.52(dd,J=8.4,2.5Hz,1H),7.27(d,J=5.1Hz,1 H),7.12(t,J=5.6Hz,1H),7.01(s,1H),6.88(d,J=8.4Hz,1H),5.02(dd,J=12.9,5.4Hz,1H),4.41-4. 34(m,2H),4.21(s,1H),4.03(t,J=5.6Hz,1H),3.98-3.91(m,2H),3.67-3.59(m,2H),3.58-3.48(m, 3H),3.48-3.37(m,3H),2.95-2.77(m,3H),2.63-2.52(m,2H),2.06-1.92(m,4H),1.85-1.70(m,3H).

[0376] Example 16

[0377] [ka]

[0378] Step 1: Synthesis of tert-butyl 3-(2-((5-(5-chloro-7-cyano-6-ethoxy-1,2,3,4-tetrahydronaphthalene-1-yl)pyrimidine-2-yl)amino)ethoxy)azetidine-1-carboxylate

[0379] INT-5 (100 mg, 0.3 mmol), S2 (98 mg, 0.45 mmol), and TEA (91 mg, 0.90 mmol) were added to 10 mL of DMF, stirred under nitrogen conditions at 90°C for 2 hours, cooled, and the reaction mixture was extracted with EA. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to obtain compound HT431-1 (110 mg, yellow oily, 70% yield). LCMS (ESI): m / z = 528.2 [M + H] + .

[0380] Step 2: Synthesis of 8-(2-((2-(azetidine-3-yloxy)ethyl)amino)pyrimidine-5-yl)-4-chloro-3-ethoxy-5,6,7,8-tetrahydronaphthalene-2-carbonitrile

[0381] HT431-1 (110 mg, 0.21 mmol) and TFA (1 mL) were added to 10 mL of DCM and stirred at room temperature for 2 hours. The reaction mixture was added dropwise to saturated sodium bicarbonate aqueous solution to neutralize the pH, the organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the resulting crude product was purified by silica gel column chromatography to obtain compound HT431-2 (80 mg, yellow oily substance, yield: 91%). LCMS (ESI): m / z = 428.2 [M + H] + .

[0382] Step 3: Synthesis of 4-chloro-8-(2-((2-(1-(2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindole-5-yl)azetidine-3-yl)oxy)ethyl)amino)pyrimidine-5-yl)-3-ethoxy-5,6,7,8-tetrahydronaphthalene-2-carbonitrile

[0383] HT431-2 (80 mg, 0.18 mmol), S3 (78 mg, 0.28 mmol), and TEA (91 mg, 0.90 mmol) were added to 10 mL of DMSO and stirred overnight at 120°C under nitrogen conditions. After cooling, the reaction mixture was extracted with EA, the organic phase was dried over anhydrous sodium sulfate, and then concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography to obtain compound HANT-431 (13.4 mg, white solid, yield 11%). LCMS (ESI): m / z = 684.2 [M + H] + ; 1H NMR(400MHz,DMSO-d6)δ11.05(s,1H),8.02(s,2H),7.64(d,J=8.3Hz,1H),7.27(s,1H),7.13(t,J=5.7Hz,1H), 6.80(d,J=2.1Hz,1H),6.66(dd,J=8.4,2.2Hz,1H),5.05(dd,J=12.9,5.4Hz,1H),4.53-4.48(m,1H),4.28-4.2 2(m,2H),4.20-4.17(m,2H),4.01(t,J=6.1Hz,1H),3.86(dd,J=9.6,3.9Hz,2H),3.57-3.54(m,2H),3.45(q,J= 5.9Hz,2H),2.88-2.83(m,3H),2.61-2.54(m,2H),2.05-1.95(m,2H),1.85-1.77(m,3H),1.38(t,J=7.0Hz,3H).

[0384] Example 17

[0385] [ka]

[0386] Step 1: Synthesis of tert-butyl(3-(5-nitro-1H-indazole-1-yl)propyl)carbamate

[0387] INT-5 (100 mg, 0.3 mmol), S2 (98 mg, 0.45 mmol), and TEA (91 mg, 0.90 mmol) were dissolved in 10 mL of DMF, stirred under nitrogen conditions at 90°C for 2 hours, cooled, and the reaction mixture was extracted with EA. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to obtain compound HT501-1 (110 mg, yellow oily, 70% yield). LCMS (ESI): m / z = 528.2 [M + H] + .

[0388] Step 2: Synthesis of 8-(2-((2-(azetidine-3-yloxy)ethyl)amino)pyrimidine-5-yl)-4-chloro-3-ethoxy-5,6,7,8-tetrahydronaphthalene-2-carbonitrile

[0389] HT501-1 (110 mg, 0.21 mmol) and TFA (1 mL) were dissolved in 10 mL of DCM and stirred at room temperature for 2 hours. The reaction mixture was adjusted to a neutral pH with saturated sodium bicarbonate aqueous solution, the organic phase was dried over anhydrous sodium sulfate, and after concentration under reduced pressure, the crude product was purified by silica gel column chromatography to obtain HT501-2 (80 mg, yellow oily substance, yield: 91%). LC-MS (ESI): m / z = 428.2 [M + H] + .

[0390] Step 3: Synthesis of tert-butyl(3-(5-((5-chloro-6-(2-chloroethoxy)-7-cyano-1,2,3,4-tetrahydronaphthalene-1-yl)amino)-1H-indazole-1-propyl)carbamate

[0391] HT501-2 (460 mg, 1.59 mmol) and INT-3 (826 mg, 2.4 mmol) were dissolved in 10 mL of DMSO, then DIEA (614 mg, 4.76 mmol) was added, and the mixture was reacted at 90°C for 3 hours. Water was added to the reaction mixture, and the mixture was extracted with DIEA. The organic phase was backwashed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain compound HT501-3 (300 mg, yield: 34%). LCMS (ESI): m / z = 558.2 [M + H] + .

[0392] Step 4: Synthesis of 8-(1-(3-aminopropyl)-1H-indazole-5-amino)-4-chloro-3-(2-chloroethoxy)-5,6,7,8-tetrahydronaphthalene-2-carbonitrile

[0393] HT501-3 (300 mg, 0.54 mmol) was dissolved in DCM (10 mL), TFA (3 mL) was added, and the mixture was reacted at room temperature for 2 hours. The reaction mixture was adjusted to pH=8 with aqueous sodium bicarbonate solution, then extracted with DCM, the organic phase was dried, filtered, and concentrated to obtain crude product HT501-4 (300 mg). LCMS (ESI): m / z = 458.1 [M + H]+ .

[0394] Step 5: Synthesis of 4-chloro-3-(2-chloroethoxy)-8-(1-(2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindorin-5-yl)amino)propyl)-1H-indazole-5-amino)-5,6,7,8-tetrahydronaphthalene-2-carbonitrile

[0395] HT501-4 (300 mg, 0.66 mmol) and S4 (270 mg, 0.98 mmol) were dissolved in 10 mL of DMSO, then DIEA (250 mg, 1.94 mmol) was added, and the mixture was reacted at 90°C for 3 hours. Extraction was performed with EA, and the organic phase was dried and concentrated. The residue was preparatively purified to obtain HANT-501 (75.2 mg, yield: 16%). LCMS (ESI): m / z = 714.2 [M + H] + . 1 H NMR(400MHz,DMSO)δ11.05(s,1H),7.79(s,1H),7.73(s,1H),7.55(d,J=8.3Hz,1H),7.45(d,J=8.9Hz,1H), 7.18(t,J=5.2Hz,1H),7.02-6.91(m,2H),6.86(s,1H),6.80(dd,J=8.3,0.7Hz,1H),5.73(d,J=8.8Hz,1H),5 .03(dd,J=12.8,5.4Hz,1H),4.63(s,1H),4.45-4.38(m,4H),4.04-3.93(m,2H),3.32-3.21(m,2H),2.94-2 .82(m,2H),2.81-2.66(m,1H),2.62-2.51(m,2H),2.16-2.05(m,2H),2.04-1.95(m,1H),1.90-1.72(m,4H).

[0396] Example 18

[0397] [ka]

[0398] The synthesis method was the same as that for compound HANT-501 in Example 17, but tert-butyl(4-bromobutyl)carbamate was used as the starting material instead of S2 as in Example 17. Purification by preparative fractionation yielded compound HANT-503 (40.7 mg, yield: 6%). LCMS(ESI): m / z = 728.2[M+H] + . 1 H NMR(400MHz,DMSO)δ11.06(s,1H),7.77(s,1H),7.73(s,1H),7.54(d,J=8.4Hz,1H),7.46(d,J=9.0Hz,1H),7.1 0(t,J=5.3Hz,1H),6.94(td,J=4.4,2.0Hz,2H),6.86-6.75(m,2H),5.73(d,J=8.8Hz,1H),5.03(dd,J=12.9,5.3 Hz,1H),4.63(d,J=6.1Hz,1H),4.43-4.31(m,4H),4.02-3.92(m,2H),3.19-3.14(m,2H),2.94-2.81(m,2H),2.8 0-2.65(m,1H),2.62-2.51(m,2H),2.03-1.95(m,1H),1.94-1.86(m,3H),1.86-1.75(m,3H),1.56-1.47(m,2H).

[0399] Example 19

[0400] [ka]

[0401] The synthesis method was the same as that for compound HANT-315 in Example 3, except that the starting materials S1 and S2 in Example 3 were replaced with 5-bromo-2-fluoropyridine and 3-(piperidine-4-yloxy)propan-1-ol, respectively. Purification by prep-HPLC yielded compound HANT-512 (18.0 mg, yellow solid) in 19.6% yield. LC-MS (ESI): m / z = 760.2 [M + H] + RT=2.318min(5.0min). 1H NMR(400MHz,DMSO)δ11.11(s,1H),7.97-7.65(m,2H),7.44(d,J=2.2Hz,1H),7.36(dd,J=8.3,2.2Hz,1H),7.18 (dd,J=8.6,2.6Hz,2H),6.77(d,J=8.8Hz,1H),5.11(dd,J=12.9,5.3Hz,1H),4.56-4.35(m,2H),4.25(t,J=6.3H) z,2H),4.04(t,J=5.7Hz,1H),4.00-3.78(m,4H),3.61(t,J=6.1Hz,2H),3.54-3.50(m,1H),3.11(t,J=10.2Hz, 2H),2.97-2.77(m,3H),2.72-2.56(m,2H),2.18-1.91(m,4H),1.93-1.68(m,5H),1.42(dd,J=18.1,8.8Hz,2H).

[0402] Example 20

[0403] [ka]

[0404] The synthesis method was the same as that for compound HANT-315 in Example 3, except that the starting materials S1 and S2 in Example 3 were replaced with 5-bromo-2-fluoropyridine and 2-(azetidine-3-yloxy)ethane-1-ol, respectively. Purification by prep-HPLC yielded compound HANT-513 (27.4 mg, yellow solid) in 23.6% yield. LCMS(ESI): m / z = 718.2 [M + H] + RT=2.172min(5.0min). 1H NMR(400MHz,DMSO-d6)δ11.10(s,1H),7.84(d,J=8.2Hz,2H),7.48(d,J=2.2Hz,1H),7.39(dd,J=8.3, 2.3Hz,1H),7.20(dd,J=8.6,2.4Hz,1H),7.15(s,1H),6.36(d,J=8.5Hz,1H),5.12(dd,J=12.9,5.4Hz ,1H),4.62-4.44(m,1H),4.48-4.24(m,4H),4.23-4.09(m,2H),4.05(t,J=5.6Hz,1H),4.00-3.88(m, 2H),3.88-3.61(m,4H),2.89-2.84(m,3H),2.70-2.53(m,2H),2.09-1.91(m,2H),1.87-1.61(m,3H).

[0405] Example 21

[0406] [ka]

[0407] The synthesis method was the same as that for compound HANT-315 in Example 3, but the starting materials S1 and S2 in Example 3 were changed to 5-bromo-2-fluoropyridine and 2-(piperidine-4-yloxy)ethane-1-ol, respectively. Purification by neutral reverse-phase fractionation yielded the white solid HANT-514 (35 mg, yield: 30.2%). LC-MS (ESI): m / z = 746.2 [M + H] + RT=1.343min(2.5min). 1H NMR(400MHz,DMSO-d6)δ11.10(s,1H),7.91-7.77(m,2H),7.47(d,J=2.2Hz,1H),7.37(dd,J=8.3,2.3Hz,1H ),7.25-7.13(m,2H),6.79(d,J=8.8Hz,1H),5.11(dd,J=12.9,5.4Hz,1H),4.45-4.37(m,2H),4.35-4.29(m, 2H),4.09-4.01(m,1H),3.99-3.88(m,4H),3.86-3.78(m,2H),3.68-3.56(m,1H),3.17-3.04(m,2H),2.96-2 .80(m,3H),2.64-2.52(m,2H),2.12-2.01(m,1H),2.00-1.86(m,3H),1.85-1.69(m,3H),1.51-1.35(m,2H).

[0408] Example 22

[0409] [ka]

[0410] The synthesis method was the same as that for compound HANT-518 in Example 23, but HT515-1 was used as the starting material instead of S1 in Example 23. The synthesis of intermediate HT515-1 is as follows.

[0411] [ka]

[0412] Compound HT515-0 (2.00 g, 10.1 mmol) was dissolved in DMF (50 mL), and 2-bromoethane-1-ol (1.50 g, 12.0 mmol) and potassium carbonate (4.10 g, 29.7 mmol) were added. The mixture was reacted at 50°C for 3 hours. After cooling, water (100 mL) was added, and the mixture was extracted with EA (100 mL). The organic phase was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography (EA:PE = 1:1) to obtain a white solid crude product HT515-1 (0.870 g, yield: 35.7%). LCMS (ESI): m / z = 242.0 [M + H] + RT=1.09min (1.80min).

[0413] The compound HANT-515 (40.6 mg, yellow solid) was purified by preparative HPLC in 35.2% yield. LC-MS (ESI): m / z = 731.2 [M + H] + RT=2.52min(5.00min). 1 H NMR(400MHz,DMSO-d6)δ11.11(s,1H),8.40(d,J=2.0Hz,1H),8.05(d,J=1.5Hz,1H),7.78(d,J=8.4H z,2H),7.35(s,1H),7.25(dd,J=8.3,2.2Hz,1H),7.23(s,1H),5.12(dd,J=12.9,5.4Hz,1H),4.62(t, J=8.0Hz,2H),4.41(s,1H),4.40(t,J=4.0Hz,2H),4.21(t,J=4.0Hz,2H),3.98(m,4H),3.77(t,J=4. 0Hz,2H),2.89(m,3H),2.66-2.54(m,2H),2.07(s,1H),2.06-2.01(m,1H),1.86(m,1H),1.78(m,2H).

[0414] Example 23

[0415] [ka]

[0416] The synthesis method was the same as that for compound HANT-315 in Example 3, but the starting materials S1 and S2 in Example 3 were changed to 5-bromo-2-fluoronicotinonitrile and 2-(azetidine-3-yloxy)ethane-1-ol, respectively. Separation by HPLC yielded HANT-516 (13 mg, yield: 11.1%). LC-MS (ESI): m / z = 743.1 [M + H] + RT=2.75min(5.00min); 1 H NMR(400MHz,DMSO-d6)δ11.11(s,1H),8.11(d,J=2.2Hz,1H),7.84(d,J=8.3Hz,1H),7.68(d,J=2.1Hz,1 H),7.48(d,J=2.1Hz,1H),7.39(dd,J=8.3,2.2Hz,1H),7.23(s,1H),5.12(dd,J=13.0,5.3Hz,1H),4.53 (s,1H),4.49-4.32(m,6H),4.12(s,1H),4.03(dd,J=9.5,3.8Hz,2H),4.01-3.91(m,2H),3.83(s,2H),2 .87(dd,J=13.4,5.5Hz,3H),2.63-2.52(m,2H),2.11-2.01(m,1H),1.95(s,1H),1.75(d,J=7.5Hz,3H).

[0417] Example 24

[0418] [ka]

[0419] The synthesis method was the same as that for compound HANT-315 in Example 3, except that the starting materials S1 and S2 in Example 3 were replaced with 5-bromo-2-fluoropyridine and cyclohexane-1,4-diol, respectively. Purification by preparative HPLC yielded compound HANT-517 (4.8 mg, yellow solid) in 5.6% yield. LC-MS (ESI): m / z = 717.2 [M + H] + RT=1.51min (1.80min). 1H NMR(400MHz,DMSO-d6)δ11.10(s,1H),7.88(d,J=2.4Hz,1H),7.85-7.81(m,1H),7.49(d,J= 2.2Hz,1H),7.43-7.36(m,2H),7.22(s,1H),6.75(d,J=8.6Hz,1H),5.11(dd,J=12.9,5.3Hz, 2H),4.84(s,1H),4.48-4.33(m,2H),4.16(d,J=6.7Hz,1H),4.03-3.89(m,2H),2.93-2.78( m,3H),2.71-2.56(m,2H),2.02(dd,J=15.2,7.9Hz,2H),1.87(s,8H),1.77(d,J=6.5Hz,3H).

[0420] Example 25

[0421] [ka]

[0422] Step 1: 5-Bromo-2-((4-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)cyclohexyl)oxy

[0423] S1 (2.00 g, 7.38 mmol) was dissolved in DMF (50 mL), protected with nitrogen under an ice bath, and sodium hydride (0.440 g, 18.3 mmol) was added. The mixture was reacted in an ice bath for 1 hour, then S2 (2.20 g, 10.5 mmol) was added, and the mixture was reacted at 60°C for 16 hours. After cooling, the reaction was quenched with water (100 mL), extracted with EA (100 mL), the organic phase was washed with saturated saline (50 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column (EA:PE = 1:3) to obtain a white solid HT518-1 (0.500 g, yield: 17.0%). LCMS (ESI): m / z = 422.0 [M + H] + RT=1.50min (1.80min).

[0424] Step 2: 2-((4-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)cyclohexyl)oxy)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine

[0425] HT518-1 (350 mg, 0.88 mmol), S3 (446 mg, 1.76 mmol), potassium acetate (258 mg, 2.63 mmol), Pd(dppf)Cl2 (64 mg, 0.087 mmol), and 1,4-dioxane (20 mL) were added sequentially to a dry flask, and the mixture was stirred at 90°C under nitrogen protection for 6 hours. The resulting reaction solution HT518-2 was used directly in the next step.

[0426] Step 3: 4-Chloro-3-(2-chloroethoxy)-8-(6-((4-(2-(tetrahydro-2H-pyran-2-yl)ethoxy]cyclohexyl)oxy)pyridine-3-yl)-5,6-dihydronaphthalene-2-nitrile

[0427] To the reaction solution HT518-2, water (4 mL), INT-2 (300 mg, 0.721 mmol), sodium carbonate (229 mg, 2.16 mmol), and Pd(dppf)Cl2 (53 mg, 0.073 mmol) were added, and the mixture was stirred at 90°C under nitrogen protection for 6 hours. After cooling, the mixture was extracted with EA, the organic phase was washed, dried, and concentrated. The solution was then purified by silica gel column chromatography (EA:PE = 1:2) to obtain a yellow solid HT518-3 (260 mg, colorless oily) in yield: 71.7%. LCMS (ESI): m / z = 587.3 [M + H] + RT = 1.660 min (2.50 min).

[0428] Step 4: 4-Chloro-3-(2-chloroethoxy)-8-(6-(4-(2-(tetrahydro-2H-pyran-2-yl)oxy)ethoxycyclohexyl)oxypyridine-3-yl)-5,6,7,8-tetrahydronaphthalene-2-carbonitrile

[0429] HT518-3 (260 mg, 0.517 mmol) was dissolved in methanol (5 mL), Pd(OH)2 / C (70 mg) was added, and the mixture was stirred under hydrogen conditions at room temperature for 10 hours. The mixture was filtered to remove the solvent and yielded crude product HT518-4 (220 mg, colorless oil) in 84.3% yield. LC-MS (ESI): m / z = 589 [M + H] + RT=3.036min(5.0min).

[0430] Step 5: 4-Chloro-3-(2-chloroethoxy)-8-(6-((4-(2-hydroxyethoxycyclohexyl)oxy)pyridine-3-yl)-5,6,7,8-tetrahydronaphthalene-2-carbonitrile

[0431] HT518-4 (260 mg, 0.442 mmol) was dissolved in DCM (4 mL), and 1,4-dioxane hydrochloride (1 mL, 4 M) was added. The reaction was allowed to proceed at room temperature for 2 hours. The reaction was quenched with water, and the pH was adjusted to 8 using saturated sodium bicarbonate aqueous solution under an ice bath. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The mixture was then purified by silica gel column chromatography (EA:PE = 3:2) to obtain compound HT518-6 (140 mg, white oily) in yield: 62.8%. LCMS (ESI): m / z = 505.2 [M + H] + RT=2.544min(5min).

[0432] Step 6: 2-((4-((5-(5-chloro-6-(2-chloroethoxy)-7-cyano-1,2,3,4-tetrahydronaphthalene-1-yl)pyridine-2-yl)oxy)cyclohexyl)oxy

[0433] HT518-5 (140 mg, 0.278 mmol) was dissolved in DCM (5 mL), and p-toluenesulfonyl chloride (105 mg, 0.553 mmol), TEA (84.0 mg, 0.832 mmol), and DMAP (3.40 mg, 0.0278 mmol) were added. The reaction was carried out at 40°C for 10 hours. Water (10 mL) was added to the reaction mixture, and the mixture was extracted with DCM (10 mL). The organic phase was washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column (EA:PE = 1:2) to obtain HT518-6 (160 mg, red oily) in yield: 87.5%. LCMS (ESI): m / z = 659.2 [M + H] + RT=1.61min (1.80min).

[0434] Step 7: 4-Chloro-3-(2-chloroethoxy)-8-(6-((4-(2-((2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindole-5-yl)oxy)ethoxycyclohexyl)oxypyridine-3-yl)-5,6,7,8-tetrahydronaphthalene-2-carbonitrile

[0435] HT518-6 (140 mg, 0.212 mmol) was dissolved in DMF (5 mL), and S5 (117 mg, 0.424 mmol) and potassium carbonate (88 mg, 0.637 mmol) were added. The mixture was reacted at 70°C for 7 hours. After extraction with EA, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and purified by HPLC (formic acid system) to obtain HANT-518 (47.3 mg, white solid) in yield: 29.2%. LCMS (ESI): m / z = 761.2 [M + H] + RT=3.081min(5.0min). 1H NMR(400MHz,DMSO-d6)δ11.12(s,1H),7.93-7.75(m,2H),7.52-7.44(m,1H),7.41-7.33(m,2H),7. 24-7.18(m,1H),6.73-6.66(m,1H),5.12(dd,J=12.9,5.3Hz,1H),5.06-4.90(m,1H),4.45-4.37(m ,2H),4.34-4.28(m,2H),4.20-4.12(m,1H),4.02-3.92(m,2H),3.84-3.75(m,2H),3.54-3.41(m,1 H),2.94-2.79(m,3H),2.65-2.52(m,2H),2.12-1.91(m,5H),1.88-1.59(m,5H),1.54-1.30(m,3H).

[0436] Example 26

[0437] [ka]

[0438] The synthesis method was the same as that for compound HANT-371 in Example 13, but HT371-2 in Example 13 was replaced with HT519-1. The synthesis of intermediate HT519-1 is as follows.

[0439] [ka]

[0440] Crude HT519-0 (200 mg, 0.920 mmol) and TosCl (351 mg, 1.84 mmol) were dissolved in 10 mL of DCM. Then, 4-DMAP (11 mg, 0.092 mmol) and TEA (372 mg, 3.68 mmol) were added, and the mixture was reacted under nitrogen at room temperature for 6 hours. Water was added to the reaction mixture, and the mixture was extracted with EA. The organic phase was backwashed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (PE:EA = 4:1) to obtain HT519-1 (300 mg, yellow oily substance) in yield: 88%. LCMS (ESI): m / z = 316.1 [M + H - 56] + RT=1.447min(2.5min).

[0441] The compound HANT-519 (22.3 mg, white solid) was purified by prep-HPLC in 14.4% yield. LC-MS (ESI): m / z = 719.2 [M + H] + RT=2.533min(5.0min). 1 H NMR(400MHz,DMSO-d6)δ11.13(s,1H),8.09(s,2H),7.85(d,J=9.6Hz,1H),7.48(s,1H) ,7.39(d,J=9.0Hz,1H),7.27(s,1H),5.13(d,J=11.9Hz,1H),4.52(s,1H),4.37(d,J=1 5.0Hz,4H),4.28-4.19(m,2H),4.06(s,1H),3.97(s,2H),3.85(d,J=17.9Hz,4H),2.86 (s,3H),2.65(d,J=19.5Hz,2H),2.03(dd,J=27.5,18.5Hz,2H),1.77(d,J=10.8Hz,3H).

[0442] Biological Tests

[0443] Experiments on androgen receptor reporter genes

[0444] Experimental reagents: 11-Ketodihydrotestosterone (11-KDHT) was purchased from MCE (catalog number HY-135794). Enzalutamide (MDV3100) was purchased from Selleck (catalog number S1250). The Bright-Lite luciferase assay system kit was purchased from Vazyme (catalog number DD1204-01).

[0445] Experimental method:

[0446] 1. The compound was dissolved in 100% DMSO to a final concentration of 10 mM. 100 nL each of the 400X test compound and 400X 11-KDHT (40 nM) were added to a 384-well detection plate using Echo. 20 μL of complete medium was added, the mixture was centrifuged at 1000 rpm for 1 minute, and shaken at room temperature for 20-30 minutes.

[0447] 2. 20 μL of AR+ARE / Luc HEK293T cells (10,000 cells / well) were inoculated into a detection plate containing the test compound and 11-KDHT, and the plate was centrifuged at 1000 rpm for 1 minute. The detection plate was then incubated in a 37°C CO2 incubator for 24 hours.

[0448] 3. Transfer 40 μL of Bright-Lite detection reagent to each well of the detection plate, centrifuge at 1000 rpm for 1 minute, and shake in the dark at room temperature for 2 minutes.

[0449] 4. The luminescence value (RLU) was measured using Envision. Based on the results, the IC of the compound was determined. 50 The value was calculated.

[0450] [Table 2]

[0451] AR disassembly experiment:

[0452] In this experiment, a HiBiT tag (Promega™) was incorporated into the C-terminus of the AR-V7 genome of 22RV1 cells (ATCC) using CRISPR / Cas9 technology to construct 22RV1 cells that stably express AR-V7-HiBiT. The test compound was started at 1000 nM and diluted 11-fold with a 3-fold gradient using DMSO. The cells were cultured in RMPI-1640 culture medium, and 5000 cells were inoculated per well into a 384-well plate. After incubation with the sample at 37°C for 24 hours, the luminescence signal of the HiBiT tag in the treated cells (the abundance of AR-V7 HiBiT protein is proportional to the luminescence signal value) was detected using the Nano-Glo HiBiT Lytic Detection System (Promega, N3040) according to the manufacturer's operating manual. Dose-response curves were plotted using GraphPad Prism, and the DC50 (compound concentration required for 50% degradation of the target protein) of the test compound was calculated.

[0453] [Table 3]

Claims

1. The compound of formula (I), or its stereoisomers, solvates, hydrates, or pharmaceutically acceptable salts. 【Chemistry 1】 (Here, n is 0 or 1, X is N, -CCH ３ , or CH, Y is NR ４ , or CH ２ And here, R ４ is H, acetyl, or C １～３ It is alkyl, Z is C(O) or CH ２ And, R １ and R ２ each independently is H, halogen, CN, C １～４ alkyl, C １～４ alkoxy, and halo C １～４ alkyl, and is selected from L １ It is a single bond, O, S, or NH, R ３ C is optionally substituted with halogen or CN. １～６ Alkyl, C ３～６ Cycloalkyl, or C ３～６ Cycloalkyl-C １～４ It is alkyl, L ０ is a single bond, O, S, NH, -C(O)-NH-, -NH-C(O)-, -NH-(CH ２ )-, or-NH-(CH ２ ) ２ - and W is C ６～１２ These are aryl, 5-12 membered heteroaryl, or 4-12 membered heterocyclyl, which are halogen, CN, oxo, and NH, respectively. ２ NR ７ R ８ OH, OR ８ , R ８ , -C(O)-NHR ７ , -OC(O)-NHR ８ , -SO ２ R ８ , -SO ２ NHR ７ , -NR ７ SO ２ R ８ , -NR ７ SO ２ NHR ８ and -NHC(O)-R ８ It is optionally substituted with one, two, or three substituents independently selected from the above, Here, R ７ These are H and C, which are independent of each other. １～４ Selected from alkyl and acetyl, R ８ is one or more halogens, hydroxyls, or NH ２ C arbitrarily substituted by １～４ It is alkyl, L ２ This is a single bond, -NH-C １～６ Alkyl-,-NH-C ２～６ Alkenyl-,-NH-C １～４ Alkyl-O-C １～４ Alkyl-, -O-C １～６ Alkyl-, -O-C ２～６ Alkenyl-,-O-C １～４ Alkyl-O-C １～４ Alkyl-, -C １～８ Alkyl-, -C ２～６ Alkenyl-, -C １～４ Alkyl-O-C １～４ Alkyl-, -C １～４ Alkyl-NH-C １～４ Alkyl-, -C ３～６ Cycloalkyl, -O-C ３～６ Cycloalkyl, -NH-C ３～６ The members are cycloalkyl, phenyl, 3-10 member heterocycloalkyl, or 5-10 member heteroaryl. L ３ is, -C １～６ Alkyl-O-,-C ２～６ Alkenyl-O-,-C １～４ Alkyl-O-C １～４ Alkyl-O-,-C １～６ Alkyl-NH-,-C ２～６ Alkenyl-NH-,-C １～４ Alkyl-O-C １～４ Alkyl-NH-,-C １～８ Alkyl-, -C ２～６ Alkenyl-, -C １～４ Alkyl-O-C １～４ Alkyl-, -C １～４ Alkyl-NH-C １～４ Alkyl-, -C ３～６ Cycloalkyl, -C ３～６ Cycloalkyl-O-,-C ３～６ The cycloalkyl-NH-, phenyl, 3-10 member heterocycloalkyl, or 5-10 member heteroaryl, and L ２ and L ３ The alkyl, heteroaryl, and heterocycloalkyl in L are each independently optionally substituted with one or more substituents selected from halogen, OH, NH ２ , CN, C(O)C １～６ alkyl, C(O)NH ２ , C １～６ alkyl, C ３～６ cycloalkyl, C １～６ alkoxy, -NHC １～６ alkyl and -N(C １～６ alkyl) ２ and are optionally substituted by one or more substituents independently selected from V is CH ２ , O, S, or NH, Here, each of the heteroaryl, heterocyclyl, and heterocycloalkyl compounds independently contains one, two, three, or four heteroatoms independently selected from N, O, and S.

2. n is either 0 or 1. X is CH, Y is CH ２ And, Z is C(O) or CH ２ And, R １ and R ２ each independently represents halogen, CN, C １～４ alkyl, C １～４ alkoxy, and halo C １～４ alkyl, and is selected from L １ It is a single bond, O, S, or NH, R ３ C is optionally substituted with halogen or CN. １～６ It is alkyl, L ０ It is a single bond, O, S, or NH, W is C ６～１２ The aryl or 5-10 membered heteroaryl is, and the aryl and heteroaryl are, respectively, halogen, CN, OH, and NH. ２ , oxo, C(O)NH ２ , C １～４ Alkyl and C １～４ It is optionally substituted with one, two, or three substituents independently selected from the alkoxy. L ２ This is a single bond, -NH-C １～６ Alkyl-,-NH-C ２～６ Alkenyl-,-NH-C １～４ Alkyl-O-C １～４ Alkyl-, -O-C １～６ Alkyl-, -O-C ２～６ Alkenyl-,-O-C １～４ Alkyl-O-C １～４ Alkyl-, -C １～６ Alkyl-, -C １～４ Alkyl-O-C １～４ Alkyl-, -C １～４ Alkyl-NH-C １～４ Alkyl-, -O-C ３～６ Cycloalkyl, -NH-C ３～６ They are cycloalkyl, 3-10 member heterocycloalkyl, or 5-10 member heteroaryl. L ３ is, -C １～６ Alkyl-O-,-C ２～６ Alkenyl-O-,-C １～４ Alkyl-O-C １～４ Alkyl-O-,-C １～６ Alkyl-NH-,-C ２～６ Alkenyl-NH-,-C １～４ Alkyl-O-C １～４ Alkyl-NH-,-C １～６ Alkyl-, -C １～４ Alkyl-O-C １～４ Alkyl-, -C １～４ Alkyl-NH-C １～４ Alkyl-, -C ３～６ Cycloalkyl-O-,-C ３～６ It is a cycloalkyl-NH-, 3-10 member heterocycloalkyl, or 5-10 member heteroaryl, and V is CH ２ , O, S, or NH, Herein, the heterocycloalkyl or heteroaryl each independently comprises one, two, three, or four heteroatoms independently selected from N, O, and S, for example, the heterocycloalkyl or heteroaryl each independently comprises one N heteroatom and optionally further comprises one, two, or three heteroatoms independently selected from N, O, and S, the compound according to claim 1, or a stereoisomer, solvate, hydrate, or pharmaceutically acceptable salt thereof.

3. A compound according to any one of the preceding claims, having the structure of formula (II). 【Chemistry 2】

4. W is a 5- to 10-membered heteroaryl, the heteroaryl comprising one N heteroatom and optionally further comprising one, two, or three heteroatoms independently selected from N, O, and S, and optionally substituted with one, two, or three substituents independently selected from halogens and CN, the compound according to any one of the preceding claims, a stereoisomer thereof, a solvate, a hydrate, or a pharmaceutically acceptable salt thereof.

5. L ２ This is a single bond, -NH-C １～６ Alkyl-,-NH-C ２～６ Alkenyl-,-NH-C １～４ Alkyl-O-C １～４ Alkyl-, -O-C １～６ Alkyl-, -O-C ２～６ Alkenyl-,-O-C １～４ Alkyl-O-C １～４ Alkyl-, -C １～６ Alkyl-, -C １～４ Alkyl-O-C １～４ Alkyl-, -C １～４ Alkyl-NH-C １～４ Alkyl-, -O-C ３～６ Cycloalkyl, -NH-C ３～６ A compound according to any one of the preceding claims, a stereoisomer thereof, a solvate, a hydrate, or a pharmaceutically acceptable salt thereof, which is a cycloalkyl or a 3- to 10-membered heterocycloalkyl, wherein the heterocycloalkyl comprises one N heteroatom and optionally further comprises one, two, or three heteroatoms independently selected from N, O, and S.

6. L ２ This is a single bond, -NH-C １～４ Alkyl-, -O-C １～４ Alkyl, -C １～４ Alkyl-, -O-C ３～６ The cycloalkyl or 4-6 membered heterocycloalkyl, wherein the 4-6 membered heterocycloalkyl contains one N heteroatom, where L ２ This is a single bond, or -C １～４ If not alkyl-, the compound according to any one of the preceding claims, a stereoisomer thereof, solvate, hydrate, or pharmaceutically acceptable salt thereof, linked to W via a heteroatom.

7. L ３ is, -C １～６ Alkyl-O-,-C ２～６ Alkenyl-O-,-C １～４ Alkyl-O-C １～４ Alkyl-O-,-C １～６ Alkyl-NH-,-C ２～６ Alkenyl-NH-,-C １～４ Alkyl-O-C １～４ Alkyl-NH-,-C １～６ Alkyl-, -C １～４ Alkyl-O-C １～４ Alkyl-, -C １～４ Alkyl-NH-C １～４ Alkyl-, -C ３～６ Cycloalkyl-O-,-C ３～６ A compound according to any one of the preceding claims, a stereoisomer thereof, a solvate, a hydrate, or a pharmaceutically acceptable salt thereof, which is a cycloalkyl-NH- or 3- to 10-membered heterocycloalkyl, wherein the heterocycloalkyl comprises one N heteroatom and optionally further comprises one, two, or three heteroatoms independently selected from N, O, and S.

8. L ３ is, -C １～４ Alkyl-O-,-C １～４ Alkyl-NH-,-C ３～６ It is a cycloalkyl-O- or a 4- to 6-membered heterocycloalkyl, wherein the 4- to 6-membered heterocycloalkyl contains one N heteroatom, where L ３ The compound, stereoisomer, solvate, hydrate, or pharmaceutically acceptable salt thereof, wherein the compound is linked to the benzene ring in the general formula via a heteroatom.

9. V is CH ２ A compound according to any one of the preceding claims, a stereoisomer thereof, a solvate, a hydrate, or a pharmaceutically acceptable salt thereof, wherein the compound is or is O.

10. n is 1, and the compound, stereoisomer, solvate, hydrate, or pharmaceutically acceptable salt thereof according to any one of the preceding claims.

11. L １ The compound, stereoisomer, solvate, hydrate, or pharmaceutically acceptable salt thereof, wherein is O.

12. L ０ The compound, stereoisomer, solvate, hydrate, or pharmaceutically acceptable salt thereof, wherein the compound is a single bond or NH.

13. n is 1, X is CH, Y is CH ２ And, Z is C(O), R １ It is a halogen, R ２ , is CN, L １ It is O, R ３ This is ethyl, optionally substituted with a halogen. L ０ It is a single bond or NH, W is a 5- to 10-membered heteroaryl compound containing 1, 2, or 3 N heteroatoms, and is optionally substituted with 1 or 2 substituents independently selected from halogens and CN. L ２ This is a single bond, -NH-CH ２ -, -NH-CH ２ -CH ２ -, -O-CH ２ -, -O-CH ２ -CH ２ -, -C １～３ Alkyl-, -O-C ３～６ Cycloalkyl, or 【Transformation 3】 Here, p is independently selected from 0 and 1, and L ２ This is a single bond, or -C １～３ If it is not alkyl-, it is linked to W via a heteroatom. L ３ is, -CH ２ -CH ２ -O-, -CH ２ -CH ２ -CH ２ -O-, -CH ２ -NH-, -C ３～６ Cycloalkyl-O-, or 【Chemistry 4】 Here, p is independently selected from 0 and 1, for example, p is 0 and L ３ It is linked to the benzene ring in the general formula via a heteroatom, and V is CH ２ A compound according to any one of the preceding claims, or a stereoisomer, solvate, hydrate, or pharmaceutically acceptable salt thereof.

14. The compound is selected from the following: the compound according to claim 1, its optical isomer, hydrate, and pharmaceutically acceptable salt thereof. 【Chemistry 5-1】 【Chemistry 5-2】

15. A pharmaceutical composition comprising a compound according to any one of claims 1 to 14, a stereoisomer thereof, a solvate, a hydrate, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

16. A compound, stereoisomer, solvate, hydrate, or pharmaceutically acceptable salt thereof, used as a drug, according to any one of claims 1 to 14.

17. A compound, stereoisomer, solvate, hydrate, or pharmaceutically acceptable salt thereof, used for treating or preventing an androgen receptor-dependent disorder or disorder of an individual, particularly an AR-SV-positive disorder or an AR-V7-positive disorder, wherein the disorder or disorder is selected from, for example, prostate cancer, other prostate diseases such as prostatic hyperplasia, prostatitis, breast cancer, non-small cell lung cancer, renal cell carcinoma, gonadal tumors, seminoma, pancreatic cancer, ovarian cancer, fallopian tube cancer, peritoneal cancer, salivary gland cancer, bladder cancer, acne, hirsutism, hidradenitis suppurativa, male pattern baldness, undescended testicles, androgen insensitivity syndrome.

18. Use of a compound, stereoisomer, solvate, hydrate, or pharmaceutically acceptable salt thereof according to any one of claims 1 to 14 in the preparation of a drug for treating or preventing a disease or disorder of an individual, wherein the disorder or disease is an androgen receptor-dependent disorder or disorder, particularly an AR-SV positive disorder or an AR-V7 positive disorder, and the disorder or disease is selected from, for example, prostate cancer, other prostate diseases such as prostatic hyperplasia, prostatitis, breast cancer, non-small cell lung cancer, renal cell carcinoma, gonadal tumors, seminoma, pancreatic cancer, ovarian cancer, fallopian tube cancer, peritoneal cancer, salivary gland cancer, bladder cancer, acne, hirsutism, hidradenitis suppurativa, male pattern baldness, undescended testicles, androgen insensitivity syndrome, and Kennedy syndrome.

19. A method for treating or preventing a disease or disorder of an individual, comprising administering an effective amount of a compound, stereoisomer, solvate, hydrate, or pharmaceutically acceptable salt thereof, described in any one of claims 1 to 14, to an individual in need thereof, wherein the disorder or disease is an androgen receptor-dependent disorder or disorder, particularly an AR-SV positive disorder or an AR-V7 positive disorder, and the disorder or disease is selected from, for example, prostate cancer, other prostate diseases such as prostatic hyperplasia, prostatitis, breast cancer, non-small cell lung cancer, renal cell carcinoma, gonadal tumors, seminoma, pancreatic cancer, ovarian cancer, fallopian tube cancer, peritoneal cancer, salivary gland cancer, bladder cancer, acne, hirsutism, hidradenitis suppurativa, male pattern baldness, undescended testicles, androgen insensitivity syndrome, and Kennedy syndrome.

20. A method for inhibiting and / or degrading an androgen receptor in vivo or in vitro, comprising contacting an effective amount of a compound, stereoisomer, solvate, hydrate, or pharmaceutically acceptable salt thereof, described in any one of claims 1 to 14, with an androgen receptor.

21. A drug combination comprising a compound according to any one of claims 1 to 14, a stereoisomer thereof, a solvate, a hydrate, or a pharmaceutically acceptable salt thereof, and one or more other therapeutic agents.

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