Cyclohexanedicarboximide derivatives substituted with fused heterocyclic groups, process for their preparation and their use in medicine

Abstract

This disclosure relates to fused heterocyclic substituted cyclohexamethylene imide derivatives, their preparation methods, and their pharmaceutical applications. Specifically, this disclosure relates to a fused heterocyclic substituted cyclohexamethylene imide derivative of general formula (I), its preparation method, pharmaceutical compositions containing the derivative, and its use as a therapeutic agent, particularly as a Cerebrolysin modulator in the treatment of multiple myeloma.

Description

Technical Field

[0001] This disclosure pertains to the pharmaceutical field and relates to a fused heterocyclic substituted cyclohexamethylene imide derivative, its preparation method, and its pharmaceutical application. In particular, this disclosure relates to a fused heterocyclic substituted cyclohexamethylene imide derivative of general formula (I), its preparation method, pharmaceutical compositions containing the derivative, and its use as a Cereblon modulator in the treatment of multiple myeloma. Background Technology

[0002] Multiple myeloma (MM) is a malignant tumor with main symptoms including hypercalcemia, kidney damage, anemia, and bone disease. MM is the second most common hematologic malignancy after non-Hodgkin's lymphoma, affecting 4-6 people per 100,000 globally each year, and approximately 1.6 people per 100,000 in China annually. Current treatment methods primarily involve drug therapy and autologous stem cell transplantation. Currently, widely used drugs fall into four main categories: lenalidomide immunomodulators, proteasome inhibitors, hormones, and monoclonal antibodies. Drugs in clinical research stages include bispecific antibodies, antibody-drug conjugates (ADCs), and CAR-T therapy. These drugs have different mechanisms of action, and combination therapy often achieves better efficacy. Clinically, dual, triple, or even quadruple therapy is commonly used, typically combining immunomodulators, proteasome inhibitors, and hormones, sometimes with the addition of antibodies. Lenalidomide is the most commonly used immunomodulator, used in first-line treatment, maintenance therapy after stem cell transplantation, and second- and third-line treatment after relapse. The drug generated $9.7 billion in sales in 2018 / 2019. Furthermore, the overall MM market is substantial and growing rapidly, thanks to continuous improvements in MM diagnosis and treatment, leading to longer patient survival and extended treatment durations. The MM market is projected to reach $33 billion by 2022, with immunomodulatory agents, represented by lenalidomide, still accounting for the largest share.

[0003] The mechanism of action of immunomodulators (IMiDs) in treating multiple myeloma (MM) is primarily based on their binding to the Cerebrolysin No. 1 (CRBN) protein. This binding activates the E3 ligase activity of CRBN, leading to selective binding with transcription factors Ikaros (IKZF1) and Aiolos (IKZF3). This results in the rapid ubiquitination and degradation of Ikaros and Aiolos. Downregulation of Ikaros / Aiolos leads to downregulation of c-Myc, followed by IRF4, ultimately inhibiting myeloma cell growth and inducing apoptosis. Furthermore, IKZF3 can inhibit the transcription of IL-2 and TNF cytokines in T / NK cells. IKZF3 degradation relieves this inhibition, promoting the release of these cytokines and thus exerting an immunomodulatory effect. Clinical trials have also shown a correlation between the clinical benefits of IMiDs and the level of CRBN expression. Knocking down CRBN in lenalidomide-sensitive cell lines (OPM2 and KMS18) revealed the loss of lenalidomide's inhibitory activity on cell growth, leading to drug resistance. The level of CRBN knockdown was correlated with the degree of drug resistance. In cell proliferation experiments, reducing the expression level of CRBN in cells (U266-CRBN60 and U266-CRBN75) reduced the inhibitory activity of both lenalidomide and pomalidomide on cell growth.

[0004] Currently approved IMiDs include thalidomide, lenalidomide, and pomalidomide, all from Celgene (now merged with BMS). The binding affinity of these three compounds to CRBN increases sequentially, hence the clinical dosage decreases accordingly. The primary indication for these three compounds is multidisciplinary disease (MM). Thalidomide and lenalidomide can also treat other indications, especially lenalidomide, which can be used to treat myelodysplastic syndromes (MDS). Regarding side effects, lenalidomide and pomalidomide exhibit similar effects, with significant myelosuppression, a target-related toxicity. Thalidomide also has some other side effects, such as sedation, constipation, and neurological side effects.

[0005] The adipicimide moiety of all IMiDs binds to a hydrophobic bag defined by three tryptophan residues in CRBN (called the "thalidomide binding bag"). Conversely, the phthalimide / isoindolone ring is exposed to the solvent and alters the molecular surface of CRBN, thereby modulating substrate recognition; different IMiDs lead to significant modifications of the CRBN molecular surface and different substrate recognition preferences. Therefore, modifications to IMiDs may lead to the degradation of other transcription factors, causing unwanted toxic side effects. This mode of action of IMiDs is also known as molecular glue, vividly describing the binding effect of these small molecules on two protein substrates.

[0006] Because the median survival for multiple myeloma is currently over five years, this prolonged survival has led to a high rate of resistance in many patients to currently marketed drugs such as lenalidomide and pomalidomide, severely reducing the effectiveness of these drugs. Therefore, the inventors envisioned developing drug molecules with better activity to overcome the problem of drug resistance while minimizing the toxic side effects of these compounds.

[0007] Published patent applications for Cereblon modifiers include WO2008115516A2, WO2011100380A1, WO2019226770A1, WO2019014100A1 and WO2020064002A1, etc. Summary of the Invention

[0008] The purpose of this disclosure is to provide a compound of general formula (I) or a pharmaceutically acceptable salt thereof:

[0009]

[0010] in:

[0011] G 1 G 2 and G 3 Whether the two are the same or different, and each is an independent CR 8 Or nitrogen atoms;

[0012] Z is CR a R b Or oxygen atoms;

[0013] R a and R b They may be the same or different, and each is independently selected from hydrogen atoms, halogens, alkyl groups and haloalkyl groups;

[0014] X is CH2 or C(O);

[0015] Y represents an oxygen atom or NH;

[0016] Ring A is aryl or heteroaryl;

[0017] R 1 Selected from hydrogen atom, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, hydroxyalkyl, cyano, amino and hydroxyl;

[0018] R 2Each of the following groups may be the same or different in each occurrence and is independently selected from hydrogen, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, hydroxyalkyl, cyano, amino, nitro, hydroxy, cycloalkyl, heterocyclic, aryl and heteroaryl, wherein the alkyl, alkoxy, cycloalkyl, heterocyclic, aryl and heteroaryl groups are each independently optionally substituted by one or more substituents selected from halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclic, aryl and heteroaryl groups;

[0019] R 3 and R 4 They may be the same or different, and each is independently selected from hydrogen atoms, halogens, and alkyl groups;

[0020] R 5 Each occurrence may be the same or different, and each is independently selected from hydrogen atom, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, oxo, cyano, amino, nitro, hydroxy, hydroxyalkyl, -C(O)OR 9 -CONR 10 R 11 Cycloalkyl and heterocyclic groups, wherein each of the alkyl, alkoxy, cycloalkyl and heterocyclic groups is independently and optionally substituted by one or more substituents selected from halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclic, aryl and heteroaryl groups;

[0021] R 6 Each of the following groups may be the same or different in each occurrence and is independently selected from hydrogen, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclic, aryl, and heteroaryl, wherein the alkyl, alkoxy, cycloalkyl, heterocyclic, aryl, and heteroaryl groups are each independently optionally substituted by one or more substituents selected from halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups;

[0022] R 7 Selected from cyano, -S(O)2R 9 and -S(O)2NR 10 R 11 ;

[0023] R 8 They may be the same or different each time they appear, and each is independently selected from hydrogen, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, hydroxyalkyl, cyano, amino, nitro, hydroxy, cycloalkyl and heterocyclic groups;

[0024] R 9They may be the same or different each time they appear, and each is independently selected from hydrogen atoms, alkyl, haloalkyl, hydroxyalkyl, cycloalkyl and heterocyclic groups;

[0025] R 10 and R 11 They may be the same or different each time they appear, and each is independently selected from hydrogen atoms, alkyl, haloalkyl, hydroxyalkyl, cycloalkyl and heterocyclic groups;

[0026] n is 1, 2, or 3;

[0027] m can be 0, 1, 2, or 3;

[0028] p is 0, 1, 2, 3, or 4; and

[0029] q can be 0, 1, 2, 3 or 4.

[0030] In some embodiments of this disclosure, the compound represented by general formula (I) or a pharmaceutically acceptable salt thereof is the compound represented by general formula (I-1) or a pharmaceutically acceptable salt thereof:

[0031]

[0032] in:

[0033] Rings A, X, Y, Z, G 1 G 2 G 3 R 1 To R 7 m, n, p and q are as defined in general formula (I).

[0034] In some embodiments of this disclosure, the compounds represented by general formula (I) and general formula (I-1), or their pharmaceutically acceptable salts, are compounds represented by general formula (I-1-1) or their pharmaceutically acceptable salts:

[0035]

[0036] in:

[0037] Rings A, X, Y, Z, G 1 G 2 G 3 R 1 To R 7 m, n, p and q are as defined in general formula (I).

[0038] In some embodiments of this disclosure, the compounds represented by general formula (I) and general formula (I-1) or their pharmaceutically acceptable salts are compounds represented by general formula (I-1-2) or their pharmaceutically acceptable salts:

[0039]

[0040] in:

[0041] Rings A, X, Y, Z, G 1 G 2 G 3 R 1 To R 7 m, n, p and q are as defined in general formula (I).

[0042] In some embodiments of this disclosure, the compounds represented by general formulas (I), (I-1), (I-1-1), and (I-1-2) or their pharmaceutically usable salts are used, wherein Y is an oxygen atom.

[0043] In some embodiments of this disclosure, the compounds represented by general formulas (I), (I-1), (I-1-1), and (I-1-2), or their pharmaceutically acceptable salts, wherein R 3 and R 4 All are hydrogen atoms.

[0044] In some embodiments of this disclosure, the compound represented by general formula (I) or a pharmaceutically acceptable salt thereof is a compound represented by general formula (II) or a pharmaceutically acceptable salt thereof:

[0045]

[0046] in:

[0047] Rings A, X, Z, G 1 G 2 G 3 R 1 R 2 R 5 To R 7 m, n, p and q are as defined in general formula (I).

[0048] In some embodiments of this disclosure, the compounds represented by general formula (I), general formula (I-1), and general formula (II), or their pharmaceutically acceptable salts, are compounds represented by general formula (II-1) or their pharmaceutically acceptable salts:

[0049]

[0050] in:

[0051] Rings A, X, Z, G 1 G 2 G 3 R 1 R 2 R 5 To R 7 m, n, p and q are as defined in general formula (I).

[0052] In some embodiments of this disclosure, the compounds represented by general formula (I), general formula (I-1), general formula (I-1-1), general formula (II), and general formula (II-1), or their pharmaceutically acceptable salts, are compounds represented by general formula (II-1-1) or their pharmaceutically acceptable salts:

[0053]

[0054] in:

[0055] Rings A, X, Z, G 1 G 2 G 3 R 1 R 2 R 5 To R 7 m, n, p and q are as defined in general formula (I).

[0056] In some embodiments of this disclosure, the compounds represented by general formula (I), general formula (I-1), general formula (I-1-2), general formula (II), and general formula (II-1), or their pharmaceutically acceptable salts, are compounds represented by general formula (II-1-2) or their pharmaceutically acceptable salts.

[0057]

[0058] in:

[0059] Rings A, X, Z, G 1 G 2 G 3 R 1 R 2 R 5 To R 7 m, n, p and q are as defined in general formula (I).

[0060] In some embodiments of this disclosure, the compounds represented by general formulas (I), (I-1), (I-1-1), (I-1-2), (II), (II-1), (II-1-1), and (II-1-2), or their pharmaceutically usable salts, wherein X is CH2.

[0061] In some embodiments of this disclosure, the compounds represented by general formulas (I), (I-1), (I-1-1), (I-1-2), (II), (II-1), (II-1-1), and (II-1-2), or their pharmaceutically acceptable salts, wherein Z is CR a R b ;R a and Rb They are identical, and each is independently a hydrogen atom or a halogen; preferably, R a and R b They are identical, and each is independently either a hydrogen atom or a fluorine atom.

[0062] In some embodiments of this disclosure, the compounds represented by general formula (I) and general formula (II) or their pharmaceutically acceptable salts are compounds represented by general formula (III) or their pharmaceutically acceptable salts:

[0063]

[0064] in:

[0065] Rings A and G 1 G 2 G 3 R 1 R 2 R 5 To R 7 m, n, p and q are as defined in general formula (I).

[0066] In some embodiments of this disclosure, the compounds represented by general formula (I), general formula (I-1), general formula (II), general formula (II-1), and general formula (III), or their pharmaceutically acceptable salts, are compounds represented by general formula (III-1) or their pharmaceutically acceptable salts:

[0067]

[0068] in:

[0069] Rings A and G 1 G 2 G 3 R 1 R 2 R 5 To R 7 m, n, p and q are as defined in general formula (I).

[0070] In some embodiments of this disclosure, the compounds or pharmaceutically acceptable salts of general formulas (I), (I-1), (I-1-1), (II), (II-1), (II-1-1), (III), and (III-1) are compounds or pharmaceutically acceptable salts of general formula (III-1-1).

[0071]

[0072] in:

[0073] Rings A and G 1 G 2 G3 R 1 R 2 R 5 To R 7 m, n, p and q are as defined in general formula (I).

[0074] In some embodiments of this disclosure, the compounds or pharmaceutically acceptable salts of general formulas (I), (I-1), (I-1-2), (II), (II-1), (II-1-2), (III), and (III-1) are compounds or pharmaceutically acceptable salts of general formula (III-1-2).

[0075]

[0076] in:

[0077] Rings A and G 1 G 2 G 3 R 1 R 2 R 5 To R 7 m, n, p and q are as defined in general formula (I).

[0078] In some embodiments of this disclosure, the compounds or pharmaceutically acceptable salts of the general formulas (I), (I-1), (I-1-1), (I-1-2), (II), (II-1), (II-1-1), (II-1-2), (III), (III-1), (III-1-1), and (III-1-2) are described, wherein G 1 G 2 and G 3 All are CR 8 ;R 8 It is a hydrogen atom.

[0079] In some embodiments of this disclosure, the compounds represented by general formulas (I), (I-1), (I-1-1), (I-1-2), (II), (II-1), (II-1-1), (II-1-2), (III), (III-1), (III-1-1), and (III-1-2), or pharmaceutically acceptable salts thereof, wherein ring A is a 6- to 10-membered aryl or a 5- to 10-membered heteroaryl; preferably, ring A is a phenyl.

[0080] In some embodiments of this disclosure, the compounds or pharmaceutically acceptable salts of the general formulas (I), (I-1), (I-1-1), (I-1-2), (II), (II-1), (II-1-1), (II-1-2), (III), (III-1), (III-1-1), and (III-1-2) are described, wherein R 1 It is a hydrogen atom.

[0081] In some embodiments of this disclosure, the compounds or pharmaceutically acceptable salts of the general formulas (I), (I-1), (I-1-1), (I-1-2), (II), (II-1), (II-1-1), (II-1-2), (III), (III-1), (III-1-1), and (III-1-2) are described, wherein R 2 It is a hydrogen atom.

[0082] In some embodiments of this disclosure, the compounds or pharmaceutically acceptable salts of the general formulas (I), (I-1), (I-1-1), (I-1-2), (II), (II-1), (II-1-1), (II-1-2), (III), (III-1), (III-1-1), and (III-1-2) are used, wherein p is 0, 1, or 2; preferably p is 0.

[0083] In some embodiments of this disclosure, the compounds or pharmaceutically acceptable salts of the general formulas (I), (I-1), (I-1-1), (I-1-2), (II), (II-1), (II-1-1), (II-1-2), (III), (III-1), (III-1-1), and (III-1-2) are described, wherein R 5 They may be the same or different each time they appear, and each is independently a hydrogen atom or a carbon atom. 1-6 Alkyl; preferably, R 5 It is a hydrogen atom.

[0084] In some embodiments of this disclosure, the compounds represented by general formulas (I), (I-1), (I-1-1), (I-1-2), (II), (II-1), (II-1-1), (II-1-2), (III), (III-1), (III-1-1), and (III-1-2), or pharmaceutically acceptable salts thereof, wherein q is 0, 1, or 2; preferably, q is 1.

[0085] In some embodiments of this disclosure, the compounds or pharmaceutically acceptable salts of the general formulas (I), (I-1), (I-1-1), (I-1-2), (II), (II-1), (II-1-1), (II-1-2), (III), (III-1), (III-1-1), and (III-1-2) are used, wherein R 6 They may be the same or different each time they appear, and each is independently selected from hydrogen atoms, halogens, and carbon atoms. 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl groups and C 1-6 Halogenated alkoxy group; preferably, R 6 Halogen; more preferably, R 6 It is a fluorine atom.

[0086] In some embodiments of this disclosure, the compounds or pharmaceutically acceptable salts of the general formulas (I), (I-1), (I-1-1), (I-1-2), (II), (II-1), (II-1-1), (II-1-2), (III), (III-1), (III-1-1), and (III-1-2) are used, wherein R 7 Selected from cyano, -S(O)2R 9 and -S(O)2NR 10 R 11 , where R 9 C 1-6 Alkyl, R 10 and R 11 All are hydrogen atoms; preferably, R 7 It is a cyano group.

[0087] In some embodiments of this disclosure, the compounds represented by general formulas (I), (I-1), (I-1-1), (I-1-2), (II), (II-1), (II-1-1), (II-1-2), (III), (III-1), (III-1-1), and (III-1-2), or pharmaceutically acceptable salts thereof, wherein n is 1 or 2.

[0088] In some embodiments of this disclosure, the compound represented by general formula (I), general formula (I-1), general formula (II), general formula (II-1), general formula (III) or general formula (III-1), or a pharmaceutically usable salt thereof, wherein n is 2.

[0089] In some embodiments of this disclosure, the compounds represented by general formulas (I), (I-1), (I-1-1), (I-1-2), (II), (II-1), (II-1-1), (II-1-2), (III), (III-1), (III-1-1), and (III-1-2), or pharmaceutically acceptable salts thereof, are used, wherein m is 0.

[0090] In some embodiments of this disclosure, the compounds represented by general formulas (I), (I-1), (II), and (II-1), or pharmaceutically acceptable salts thereof, wherein... for

[0091] In some embodiments of this disclosure, the compounds of general formula (I-1-1) and general formula (II-1-1) or their pharmaceutically acceptable salts, wherein for

[0092] In some embodiments of this disclosure, the compounds of general formula (I-1-2) and general formula (II-1-2) or their pharmaceutically acceptable salts, wherein for

[0093] In some embodiments of this disclosure, the compounds represented by general formulas (I), (I-1), (II), and (II-1), or pharmaceutically acceptable salts thereof, wherein... for

[0094] In some embodiments of this disclosure, the compounds represented by general formula (III), general formula (III-1), or pharmaceutically acceptable salts thereof, wherein for

[0095] In some embodiments of this disclosure, the compound represented by general formula (III-1-1) or a pharmaceutically acceptable salt thereof, wherein for

[0096] In some embodiments of this disclosure, the compound represented by general formula (III-1-2) or a pharmaceutically acceptable salt thereof, wherein for

[0097] In some embodiments of this disclosure, the compounds represented by general formula (III), general formula (III-1), or pharmaceutically acceptable salts thereof, wherein for

[0098] In some embodiments of this disclosure, the compounds or pharmaceutically acceptable salts of the general formulas (I), (I-1), (I-1-1), (I-1-2), (II), (II-1), (II-1-1), (II-1-2), (III), (III-1), (III-1-1), and (III-1-2) are wherein... for R 6 It is a halogen; R 7 It is cyano; preferably, for

[0099] In some embodiments of this disclosure, the compounds represented by general formulas (I), (I-1), (I-1-1), and (I-1-2), or their pharmaceutically acceptable salts, wherein G 1 G 2 and G 3 All are CR 8 ;R 8 Z represents a hydrogen atom; C represents a CR atom. a R b ;R a and R b The same, and each independently is a hydrogen atom or a halogen; X is CH2; Y is an oxygen atom; ring A is a 6- to 10-membered aryl or a 5- to 10-membered heteroaryl; R 1 For hydrogen atoms; R 2 For hydrogen atoms; R 3 and R 4 All are hydrogen atoms; R 5 They may be the same or different each time they appear, and each is independently a hydrogen atom or a carbon atom. 1-6 Alkyl; R 6 They may be the same or different each time they appear, and each is independently selected from hydrogen atoms, halogens, and carbon atoms. 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl and C 1-6 Haloalkoxy; R 7 Selected from cyano, -S(O)2R 9 and -S(O)2NR 10 R 11 , where R 9 C 1-6 Alkyl, R 10 and R 11 All are hydrogen atoms; p is 0, 1, or 2; q is 0, 1, or 2; n is 1 or 2; m is 0.

[0100] In some embodiments of this disclosure, the compounds represented by general formula (I), general formula (I-1), or pharmaceutically acceptable salts thereof, wherein G 1 G 2 and G 3 All are CR 8 ;R 8 Z represents a hydrogen atom; C represents a CR atom. a R b ;R a and R b The same, and each independently is a hydrogen atom or a halogen; X is CH2; Y is an oxygen atom; ring A is a 6- to 10-membered aryl or a 5- to 10-membered heteroaryl; R 1 For hydrogen atoms; R 2 For hydrogen atoms; R 3 and R 4 All are hydrogen atoms; R 5 They may be the same or different each time they appear, and each is independently a hydrogen atom or a carbon atom. 1-6 Alkyl; R 6 They may be the same or different each time they appear, and each is independently selected from hydrogen atoms, halogens, and carbon atoms. 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl and C 1-6 Haloalkoxy; R 7 Selected from cyano, -S(O)2R 9 and -S(O)2NR 10 R 11 , where R 9 C 1-6 Alkyl, R 10 and R 11 All are hydrogen atoms; p is 0, 1, or 2; q is 0, 1, or 2; n is 2; m is 0.

[0101] In some embodiments of this disclosure, the compounds represented by general formulas (II), (II-1), (II-1-1), and (II-1-2), or their pharmaceutically acceptable salts, wherein G 1 G 2 and G 3 All are CR 8 ;R 8 Z represents a hydrogen atom; C represents a CR atom. a R b ;R a and R b They are identical, and each is independently a hydrogen atom or a fluorine atom; X is CH2; ring A is phenyl; R 1 For hydrogen atoms; R 2 For hydrogen atoms; R 5 They may be the same or different each time they appear, and each is independently a hydrogen atom or a carbon atom. 1-6Alkyl; R 6 They may be the same or different each time they appear, and each is independently selected from hydrogen atoms, halogens, and carbon atoms. 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl groups and C 1-6 Haloalkoxy; R 7 It is a cyano group; p is 0, 1 or 2; q is 0, 1 or 2; n is 1 or 2; m is 0.

[0102] In some embodiments of this disclosure, the compounds represented by general formula (II), general formula (II-1), or pharmaceutically acceptable salts thereof, wherein G 1 G 2 and G 3 All are CR 8 ;R 8 Z represents a hydrogen atom; C represents a CR atom. a R b ;R a and R b They are identical, and each is independently a hydrogen atom or a fluorine atom; X is CH2; ring A is phenyl; R 1 For hydrogen atoms; R 2 For hydrogen atoms; R 5 They may be the same or different each time they appear, and each is independently a hydrogen atom or a carbon atom. 1-6 Alkyl; R 6 They may be the same or different each time they appear, and each is independently selected from hydrogen atoms, halogens, and carbon atoms. 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl groups and C 1-6 Haloalkoxy; R 7 It is a cyano group; p is 0, 1 or 2; q is 0, 1 or 2; n is 2; m is 0.

[0103] In some embodiments of this disclosure, the compounds represented by general formulas (III), (III-1), (III-1-1), and (III-1-2), or their pharmaceutically acceptable salts, wherein G 1 G 2 and G 3 All are CR 8 ;R 8 It is a hydrogen atom; ring A is a phenyl group; R 1 For hydrogen atoms; R 2 For hydrogen atoms; R 5 They may be the same or different each time they appear, and each is independently a hydrogen atom or a carbon atom. 1-6 Alkyl; R 6 They may be the same or different each time they appear, and each is independently selected from hydrogen atoms, halogens, and carbon atoms. 1-6 Alkyl, C1-6 Alkoxy, C 1-6 Halogenated alkyl and C 1-6 Haloalkoxy; R 7 It is a cyano group; p is 0, 1 or 2; q is 0, 1 or 2; n is 1 or 2; m is 0.

[0104] In some embodiments of this disclosure, the compounds represented by general formula (III), general formula (III-1), or pharmaceutically acceptable salts thereof, wherein G 1 G 2 and G 3 All are CR 8 ;R 8 It is a hydrogen atom; ring A is a phenyl group; R 1 For hydrogen atoms; R 2 For hydrogen atoms; R 5 They may be the same or different each time they appear, and each is independently a hydrogen atom or a carbon atom. 1-6 Alkyl; R 6 They may be the same or different each time they appear, and each is independently selected from hydrogen atoms, halogens, and carbon atoms. 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl and C 1-6 Haloalkoxy; R 7 It is a cyano group; p is 0, 1 or 2; q is 0, 1 or 2; n is 2; m is 0.

[0105] In some embodiments of this disclosure, the compounds represented by general formulas (III), (III-1), (III-1-1), and (III-1-2), or their pharmaceutically acceptable salts, wherein G 1 G 2 and G 3 All are CR 8 ;R 8 It is a hydrogen atom; ring A is a phenyl group; R 1 For hydrogen atoms; R 5 They may be the same or different each time they appear, and each is independently a hydrogen atom or a carbon atom. 1-6 Alkyl; R 6 They may be the same or different each time they appear, and each is independently selected from hydrogen atoms, halogens, and carbon atoms. 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl and C 1-6 Haloalkoxy; R 7 It is a cyano group; p is 0, 1 or 2; q is 0, 1 or 2; n is 1 or 2; m is 0.

[0106] In some embodiments of this disclosure, the compounds represented by general formulas (III), (III-1), (III-1-1), and (III-1-2), or their pharmaceutically acceptable salts, wherein G 1 G 2 and G 3 All are CR 8 ;R 8 It is a hydrogen atom; for R 1 For hydrogen atoms; R 6 It is a halogen; R 7 It is a cyano group; p is 0; q is 1; n is 1 or 2; m is 0.

[0107] Table A lists typical compounds disclosed herein, including but not limited to:

[0108]

[0109]

[0110]

[0111]

[0112]

[0113] Another aspect of this disclosure relates to compounds of general formula (IA) or salts thereof.

[0114]

[0115] in:

[0116] R m C 1-6 Alkyl; preferably, R m For tert-butyl;

[0117] Rings A, X, Y, Z, G 1 G 2 G 3 R 1 To R 7 m, n, p and q are as defined in compounds of general formula (I).

[0118] Another aspect of this disclosure relates to compounds of general formula (IA-1) or salts thereof.

[0119]

[0120] in:

[0121] R m C 1-6Alkyl; preferably, R m For tert-butyl;

[0122] Rings A, X, Y, Z, G 1 G 2 G 3 R 1 To R 7 m, n, p and q are as defined for compounds of general formula (I-1).

[0123] Another aspect of this disclosure relates to compounds of general formula (IA-1-1) or salts thereof.

[0124]

[0125] in:

[0126] R m C 1-6 Alkyl; preferably, R m For tert-butyl;

[0127] Rings A, X, Y, Z, G 1 G 2 G 3 R 1 To R 7 m, n, p and q are as defined for compounds of general formula (I-1-1).

[0128] Another aspect of this disclosure relates to compounds of general formula (IA-1-2) or salts thereof.

[0129]

[0130] in:

[0131] R m C 1-6 Alkyl; preferably, R m For tert-butyl;

[0132] Rings A, X, Y, Z, G 1 G 2 G 3 R 1 To R 7 m, n, p and q are as defined for compounds of general formula (I-1-2).

[0133] Another aspect of this disclosure relates to compounds of general formula (IIA) or salts thereof:

[0134]

[0135] in:

[0136] R m C1-6 Alkyl; preferably, R m For tert-butyl;

[0137] Rings A, X, Z, G 1 G 2 G 3 R 1 R 2 R 5 To R 7 m, n, p and q are as defined for compounds of general formula (II).

[0138] Another aspect of this disclosure relates to compounds of general formula (IIA-1) or salts thereof:

[0139]

[0140] in:

[0141] R m C 1-6 Alkyl; preferably, R m For tert-butyl;

[0142] Rings A, X, Z, G 1 G 2 G 3 R 1 R 2 R 5 To R 7 m, n, p and q are as defined for compounds of general formula (II-1).

[0143] Another aspect of this disclosure relates to compounds of general formula (IIA-1-1) or salts thereof:

[0144]

[0145] in:

[0146] R m C 1-6 Alkyl; preferably, R m For tert-butyl;

[0147] Rings A, X, Z, G 1 G 2 G 3 R 1 R 2 R 5 To R 7 m, n, p and q are as defined for compounds of general formula (II-1-1).

[0148] Another aspect of this disclosure relates to compounds of general formula (IIA-1-2) or salts thereof:

[0149]

[0150] in:

[0151] R m C 1-6 Alkyl; preferably, R m For tert-butyl;

[0152] Rings A, X, Z, G 1 G 2 G 3 R 1 R 2 R 5 To R 7 m, n, p and q are as defined in compounds of general formula (II-1-2).

[0153] Another aspect of this disclosure relates to compounds of general formula (IIIA) or salts thereof:

[0154]

[0155] in:

[0156] R m C 1-6 Alkyl; preferably, R m For tert-butyl;

[0157] Rings A and G 1 G 2 G 3 R 1 R 2 R 5 To R 7 m, n, p and q are as defined for compounds of general formula (III).

[0158] Another aspect of this disclosure relates to compounds of general formula (IIIA-1) or salts thereof:

[0159]

[0160] in:

[0161] R m C 1-6 Alkyl; preferably, R m For tert-butyl;

[0162] Rings A and G 1 G 2 G 3 R 1 R 2 R 5 To R 7m, n, p and q are as defined for compounds of general formula (III-1).

[0163] Another aspect of this disclosure relates to compounds of general formula (IIIA-1-1) or salts thereof:

[0164]

[0165] in:

[0166] R m C 1-6 Alkyl; preferably, R m For tert-butyl;

[0167] Rings A and G 1 G 2 G 3 R 1 R 2 R 5 To R 7 m, n, p and q are as defined for compounds of general formula (III-1-1).

[0168] Another aspect of this disclosure relates to compounds of general formula (IIIA-1-2) or salts thereof:

[0169]

[0170] in:

[0171] R m C 1-6 Alkyl; preferably, R m For tert-butyl;

[0172] Rings A and G 1 G 2 G 3 R 1 R 2 R 5 To R 7 m, n, p and q are as defined in compounds of general formula (III-1-2).

[0173] Table B lists typical intermediate compounds disclosed herein, including but not limited to:

[0174]

[0175]

[0176]

[0177]

[0178]

[0179] Another aspect of this disclosure relates to a method for preparing a compound of general formula (I) or a pharmaceutically acceptable salt thereof, the method comprising:

[0180]

[0181] The compound represented by general formula (IA) or its salt undergoes an intramolecular cyclization reaction to yield the compound represented by general formula (I) or its pharmaceutically usable salt.

[0182] in:

[0183] R m C 1-6 Alkyl; preferably, R m For tert-butyl;

[0184] Rings A, X, Y, Z, G 1 G 2 G 3 R 1 To R 7 m, n, p and q are as defined in general formula (I).

[0185] Another aspect of this disclosure relates to a method for preparing a compound of general formula (I-1) or a pharmaceutically acceptable salt thereof, the method comprising:

[0186]

[0187] Compounds of general formula (IA-1) or their salts undergo intramolecular cyclization reactions to yield compounds of general formula (I-1) or their pharmaceutically usable salts.

[0188] in:

[0189] R m C 1-6 Alkyl; preferably, R m For tert-butyl;

[0190] Rings A, X, Y, Z, G 1 G 2 G 3 R 1 To R 7 , m, n, p and q are as defined in general formula (I-1).

[0191] Another aspect of this disclosure relates to a method for preparing a compound of general formula (I-1-1) or a pharmaceutically acceptable salt thereof, the method comprising:

[0192]

[0193] Compounds of general formula (IA-1-1) or their salts undergo intramolecular cyclization reactions to yield compounds of general formula (I-1-1) or their pharmaceutically acceptable salts.

[0194] in:

[0195] R m C 1-6 Alkyl; preferably, R m For tert-butyl;

[0196] Rings A, X, Y, Z, G 1 G 2 G 3 R 1 To R 7 , m, n, p and q are defined as in general formula (I-1-1).

[0197] Another aspect of this disclosure relates to a method for preparing a compound of general formula (I-1-2) or a pharmaceutically acceptable salt thereof, the method comprising:

[0198]

[0199] Compounds of general formula (IA-1-2) or their salts undergo intramolecular cyclization reactions to yield compounds of general formula (I-1-2) or their pharmaceutically acceptable salts.

[0200] in:

[0201] R m C 1-6 Alkyl; preferably, R m For tert-butyl;

[0202] Rings A, X, Y, Z, G 1 G 2 G 3 R 1 To R 7 m, n, p and q are defined as in general formula (I-1-2).

[0203] Another aspect of this disclosure relates to a method for preparing a compound of general formula (II), or a pharmaceutically usable salt thereof, the method comprising:

[0204]

[0205] Compounds of general formula (IIA) or their salts undergo intramolecular cyclization reactions to yield compounds of general formula (II) or their pharmaceutically usable salts.

[0206] in:

[0207] R m C 1-6Alkyl; preferably, R m For tert-butyl;

[0208] Rings A, X, Z, G 1 G 2 G 3 R 1 R 2 R 5 To R 7 m, n, p and q are as defined for compounds of general formula (II).

[0209] Another aspect of this disclosure relates to a method for preparing a compound of general formula (II-1) or a pharmaceutically acceptable salt thereof, the method comprising:

[0210]

[0211] The compound represented by general formula (IIA-1) or its salt undergoes an intramolecular cyclization reaction to give the compound represented by general formula (II-1) or its pharmaceutically usable salt.

[0212] in:

[0213] R m C 1-6 Alkyl; preferably, R m For tert-butyl;

[0214] Rings A, X, Z, G 1 G 2 G 3 R 1 R 2 R 5 To R 7 m, n, p and q are as defined for compounds of general formula (II-1).

[0215] Another aspect of this disclosure relates to a method for preparing a compound of general formula (II-1-1) or a pharmaceutically acceptable salt thereof, the method comprising:

[0216]

[0217] The compound represented by general formula (IIA-1-1) or its salt undergoes an intramolecular cyclization reaction to give the compound represented by general formula (II-1-1) or its pharmaceutically usable salt.

[0218] in:

[0219] R m C 1-6 Alkyl; preferably, R m For tert-butyl;

[0220] Rings A, X, Z, G 1 G2 G 3 R 1 R 2 R 5 To R 7 m, n, p and q are as defined for compounds of general formula (II-1-1).

[0221] Another aspect of this disclosure relates to a method for preparing a compound of general formula (II-1-2) or a pharmaceutically acceptable salt thereof, the method comprising:

[0222]

[0223] The compound represented by general formula (IIA-1-2) or its salt undergoes an intramolecular cyclization reaction to give the compound represented by general formula (II-1-2) or its pharmaceutically usable salt.

[0224] in:

[0225] R m C 1-6 Alkyl; preferably, R m For tert-butyl;

[0226] Rings A, X, Z, G 1 G 2 G 3 R 1 R 2 R 5 To R 7 m, n, p and q are as defined in compounds of general formula (II-1-2).

[0227] Another aspect of this disclosure relates to a method for preparing a compound of general formula (III) or a pharmaceutically acceptable salt thereof, the method comprising:

[0228]

[0229] Compounds of general formula (IIIA) or their salts undergo intramolecular cyclization reactions to yield compounds of general formula (III) or their pharmaceutically usable salts.

[0230] in:

[0231] R m C 1-6 Alkyl; preferably, R m For tert-butyl;

[0232] Rings A and G 1 G 2 G 3 R 1 R 2 R 5 To R7 m, n, p and q are as defined for compounds of general formula (III).

[0233] Another aspect of this disclosure relates to a method for preparing a compound of general formula (III-1) or a pharmaceutically acceptable salt thereof, the method comprising:

[0234]

[0235] Compounds of general formula (IIIA-1) or their salts undergo intramolecular cyclization reactions to yield compounds of general formula (III-1) or their pharmaceutically usable salts.

[0236] in:

[0237] R m C 1-6 Alkyl; preferably, R m For tert-butyl;

[0238] Rings A and G 1 G 2 G 3 R 1 R 2 R 5 To R 7 m, n, p and q are as defined for compounds of general formula (III-1).

[0239] Another aspect of this disclosure relates to a method for preparing a compound of general formula (III-1-1) or a pharmaceutically acceptable salt thereof, the method comprising:

[0240]

[0241] Compounds of general formula (IIIA-1-1) or their salts undergo intramolecular cyclization reactions to yield compounds of general formula (III-1-1) or their pharmaceutically usable salts.

[0242] in:

[0243] R m C 1-6 Alkyl; preferably, R m For tert-butyl;

[0244] Rings A and G 1 G 2 G 3 R 1 R 2 R 5 To R 7 m, n, p and q are as defined for compounds of general formula (III-1-1).

[0245] Another aspect of this disclosure relates to a method for preparing a compound of general formula (III-1-2) or a pharmaceutically acceptable salt thereof, the method comprising:

[0246]

[0247] Compounds of general formula (IIIA-1-2) or their salts undergo intramolecular cyclization reactions to yield compounds of general formula (III-1-2) or their pharmaceutically acceptable salts.

[0248] in:

[0249] R m C 1-6 Alkyl; preferably, R m For tert-butyl;

[0250] Rings A and G 1 G 2 G 3 R 1 R 2 R 5 To R 7 m, n, p and q are as defined in compounds of general formula (III-1-2).

[0251] Another aspect of this disclosure relates to a pharmaceutical composition comprising a compound represented by general formula (I), general formula (I-1), general formula (I-1-1), general formula (I-1-2), general formula (II), general formula (II-1), general formula (II-1-1), general formula (II-1-2), general formula (III), general formula (III-1), general formula (III-1-1), general formula (III-1-2) and the compound shown in Table A, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, diluents or excipients.

[0252] This disclosure further relates to the use of compounds of general formula (I), general formula (I-1), general formula (I-1-1), general formula (I-1-2), general formula (II), general formula (II-1), general formula (II-1-1), general formula (II-1-2), general formula (III), general formula (III-1), general formula (III-1-1), general formula (III-1-2) and the compounds shown in Table A, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions comprising thereof, in the preparation of medicaments for the treatment and / or prevention of diseases related to CRBN protein.

[0253] This disclosure further relates to the use of compounds of general formulas (I), (I-1), (I-1-1), (I-1-2), (II), (II-1), (II-1-1), (II-1-2), (III), (III-1), (III-1-1), (III-1-2), and (III-1-2) as well as the compounds shown in Table A, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions comprising thereof, in the preparation of medicaments for the treatment and / or prevention of cancer, angiogenesis-related conditions, pain, macular degeneration or related syndromes, skin diseases, lung diseases, asbestos-related diseases, parasitic diseases, immunodeficiency diseases, central nervous system (CNS) diseases, CNS damage, atherosclerosis or related conditions, sleep disorders or related conditions, infectious diseases, hemoglobinopathies or related conditions, or TNFα-related conditions; preferably, in the preparation of medicaments for the treatment and / or prevention of cancer or CNS damage.

[0254] This disclosure also relates to a method of treating and / or preventing diseases associated with CRBN protein, comprising administering to a desired patient a therapeutically effective amount of a compound of formula (I), formula (I-1), formula (I-1-1), formula (I-1-2), formula (II), formula (II-1), formula (II-1-1), formula (II-1-2), formula (III), formula (III-1), formula (III-1-1), formula (III-1-2), and the compound shown in Table A, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the thereof.

[0255] This disclosure also relates to a method for treating and / or preventing cancer, angiogenesis-related conditions, pain, macular degeneration or related syndromes, skin diseases, lung diseases, asbestos-related diseases, parasitic diseases, immunodeficiency diseases, CNS diseases, CNS damage, atherosclerosis or related conditions, sleep disorders or related conditions, infectious diseases, hemoglobinopathies or related conditions, or TNFα-related conditions, preferably a method for treating and / or preventing cancer or CNS damage, comprising administering to a desired patient a therapeutically effective amount of the compounds shown in general formula (I), general formula (I-1), general formula (I-1-1), general formula (I-1-2), general formula (II), general formula (II-1), general formula (II-1-1), general formula (II-1-2), general formula (III), general formula (III-1), general formula (III-1-1), general formula (III-1-2), and the compounds shown in Table A, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions comprising them.

[0256] This disclosure further relates to a compound of general formula (I), general formula (I-1), general formula (I-1-1), general formula (I-1-2), general formula (II), general formula (II-1), general formula (II-1-1), general formula (II-1-2), general formula (III), general formula (III-1), general formula (III-1-1), general formula (III-1-2), and the compound shown in Table A, or a pharmaceutically acceptable salt thereof or a pharmaceutical composition comprising the thereof, which is used as a medicine.

[0257] This disclosure further relates to compounds of general formulas (I), (I-1), (I-1-1), (I-1-2), (II), (II-1), (II-1-1), (II-1-2), (III), (III-1), (III-1-1), (III-1-2), and (III-1-2), as well as the compounds shown in Table A, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions comprising thereof, for the treatment and / or prevention of diseases associated with CRBN protein.

[0258] This disclosure further relates to compounds of general formulas (I), (I-1), (I-1-1), (I-1-2), (II), (II-1), (II-1-1), (II-1-2), (III), (III-1), (III-1-1), (III-1-2), and (III-1-2), as well as compounds shown in Table A, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions comprising thereof, for the treatment and / or prevention of cancer, angiogenesis-related conditions, pain, macular degeneration or related syndromes, skin diseases, lung diseases, asbestos-related diseases, parasitic diseases, immunodeficiency diseases, CNS diseases, CNS damage, atherosclerosis or related conditions, sleep disorders or related conditions, infectious diseases, hemoglobinopathies or related conditions, or TNFα-related conditions; preferably for the treatment and / or prevention of cancer or CNS damage.

[0259] The CRBN protein-related diseases described in this disclosure are selected from cancer, angiogenesis-related diseases, pain, macular degeneration or related syndromes, skin diseases, lung diseases, asbestos-related diseases, parasitic diseases, immunodeficiency diseases, CNS diseases, CNS damage, atherosclerosis or related diseases, sleep disorders or related diseases, infectious diseases, hemoglobinopathies or related diseases, or TNFα-related diseases; preferably cancer or CNS damage.

[0260] The cancers described in this disclosure are selected from leukemia, myeloma, lymphoma, melanoma, skin cancer, liver cancer (such as hepatocellular carcinoma), kidney cancer, lung cancer (such as non-small cell lung cancer and small cell lung cancer), nasopharyngeal carcinoma, gastric cancer, esophageal cancer (also known as esophageal cancer), colorectal cancer (such as colon cancer and rectal cancer), gallbladder cancer, bile duct cancer, choriocarcinoma, pancreatic cancer, polycythemia vera, pediatric tumors, cervical cancer, ovarian cancer, breast cancer, bladder cancer, urothelial carcinoma, ureteral tumors, prostate cancer, seminoma, testicular tumors, head and neck cancer, and head and neck squamous cell carcinoma. Cellular cancer, endometrial cancer, thyroid cancer, sarcoma (such as osteosarcoma and soft tissue sarcoma), osteoma, neuroblastoma (i.e., neuroblastoma), neuroendocrine carcinoma, brain tumor, CNS cancer, astrocytoma, and glioma (such as glioblastoma); preferably, the myeloma is preferably multiple myeloma (MM) and myelodysplastic syndrome (MDS); more preferably, the multiple myeloma is relapsed, refractory, or resistant; most preferably, the multiple myeloma is refractory or resistant to lenalidomide or pomalidomide.

[0261] The leukemia is preferably chronic lymphocytic leukemia, acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), chronic myeloid leukemia (CML), and hairy cell leukemia. The lymphoma is preferably small lymphocytic lymphoma, marginal zone lymphoma, follicular lymphoma, mantle cell lymphoma, non-Hodgkin lymphoma (NHL), lymphoplasmacytic lymphoma, extranodal marginal zone lymphoma, T-cell lymphoma, B-cell lymphoma, and diffuse large B-cell lymphoma.

[0262] The cancers described in this disclosure include primary or metastatic cancers. The cancers described in this disclosure also include those that are refractory to treatment or resistant to chemotherapy or radiotherapy.

[0263] Examples of CNS diseases include, but are not limited to, the diseases described in U.S. Publication No. 2005 / 0143344, published June 30, 2005, the contents of which are incorporated herein by reference. Specific examples include, but are not limited to, amyotrophic lateral sclerosis (ALS), Alzheimer's disease, Parkinson's disease, Huntington's disease, multiple sclerosis, and other neuroimmunological diseases such as Tourette syndrome, delusions, or disturbances of consciousness occurring in a short period of time, and amnesia, or diffuse memory impairment occurring in the absence of other central nervous system damage.

[0264] Examples of CNS injury and related syndromes include, but are not limited to, the diseases described in U.S. Publication No. 2006 / 0122228, published June 8, 2006, the contents of which are incorporated herein by reference. Specific examples include, but are not limited to, CNS injury / damage and related syndromes including, but not limited to, primary brain injury, secondary brain injury, traumatic brain injury, focal brain injury, diffuse axonal injury, craniocerebral injury, concussion, post-concussion syndrome, cerebral contusion, subdural hematoma, epidermal hematoma, post-traumatic epilepsy, chronic vegetative state, complete spinal cord injury (SCI), incomplete SCI, acute SCI, subacute SCI, chronic SCI, central spinal cord syndrome, spinal cord hemisection syndrome, anterior column syndrome, conus medullaris syndrome, cauda equina syndrome, neurogenic shock, spinal shock, altered level of consciousness, headache, nausea, vomiting, memory loss, dizziness, diplopia, blurred vision, mood instability, sleep disturbances, irritability, inability to concentrate, neuroticism, behavioral disorders, cognitive deficits, and epilepsy.

[0265] Diseases related to angiogenesis include, but are not limited to, inflammatory diseases, autoimmune diseases, viral diseases, genetic diseases, allergic diseases, bacterial diseases, ocular neovascularization, choroidal neovascularization, retinal neovascularization, and iridochromia (angiosynostosis). Preferably, these include, but are not limited to, arthritis, endometriosis, Crohn's disease, heart failure, severe heart failure, kidney injury, endotoxemia, toxic shock syndrome, osteoarthritis, retroviral replication, wasting diseases, meningitis, silica-induced fibrosis, asbestos-induced fibrosis, veterinary diseases, malignant tumor-related hypercalcemia, stroke, circulatory shock, periodontitis, gingivitis, megaloblastic anemia, refractory anemia, and 5q deletion syndrome.

[0266] The active compounds can be formulated into forms suitable for administration via any appropriate route, using one or more pharmaceutically acceptable carriers through conventional methods. Therefore, the active compounds of this disclosure can be formulated into various dosage forms for oral administration, injection (e.g., intravenous, intramuscular, or subcutaneous), inhalation, or blow-through administration. The compounds of this disclosure can also be formulated into sustained-release dosage forms, such as tablets, hard or soft capsules, aqueous or oily suspensions, emulsions, injections, dispersible powders or granules, suppositories, lozenges, or syrups.

[0267] As a general guideline, the active compound is preferably expressed in a unit dose manner, or in a manner that allows the patient to self-administer a single dose. The unit dose of the disclosed compound or composition may be expressed as a tablet, capsule, sachet, bottled liquid, powder, granule, lozenge, suppository, regenerated powder, or liquid formulation. Suitable unit doses may range from 0.1 to 1000 mg.

[0268] In addition to the active compound, the pharmaceutical compositions disclosed herein may contain one or more excipients selected from the following: fillers (diluents), binders, wetting agents, disintegrants, or excipients. Depending on the method of administration, the composition may contain 0.1 to 99% by weight of the active compound.

[0269] Tablets contain an active ingredient and non-toxic, pharmaceutically acceptable excipients suitable for tablet preparation, used for mixing. These excipients may be inert excipients, granulating agents, disintegrants, binders, and lubricants. These tablets may be uncoated or coated using known techniques that mask the taste of the drug or delay disintegration and absorption in the gastrointestinal tract, thus providing sustained release over a longer period.

[0270] Oral formulations can also be provided using soft gelatin capsules in which the active ingredient is mixed with an inert solid diluent or in which the active ingredient is mixed with a water-soluble carrier or an oil solvent.

[0271] Aqueous suspensions contain active substances and excipients suitable for preparing aqueous suspensions, used for mixing. These excipients are suspending agents, dispersing agents, or wetting agents. Aqueous suspensions may also contain one or more preservatives, one or more coloring agents, one or more flavoring agents, and one or more sweeteners.

[0272] Oil suspensions are prepared by suspending the active ingredient in vegetable or mineral oil. Oil suspensions may contain thickeners. Sweeteners and flavoring agents mentioned above may be added to provide palatable formulations. These compositions may be preserved by adding antioxidants.

[0273] The pharmaceutical compositions disclosed herein may also be in the form of an oil-in-water emulsion. The oil phase may be a vegetable oil, a mineral oil, or a mixture thereof. Suitable emulsifiers may be naturally occurring phospholipids, and the emulsion may also contain sweeteners, flavoring agents, preservatives, and antioxidants. Such formulations may also contain modifiers, preservatives, colorants, and antioxidants.

[0274] The pharmaceutical compositions disclosed herein may be in the form of sterile injectable aqueous solutions. Acceptable solvents or media that can be used include water, Ringer's solution, and isotonic sodium chloride solution. The sterile injectable formulation may be a sterile injectable oil-in-water microemulsion in which the active ingredient is dissolved in the oil phase, which can be injected into the patient's bloodstream via local large-volume injection. Alternatively, the solution and microemulsion are preferably administered in a manner that maintains a constant circulating concentration of the compounds disclosed herein. To maintain such a constant concentration, a continuous intravenous delivery device can be used. An example of such a device is the Deltec CADD-PLUS™ 5400 intravenous infusion pump.

[0275] The pharmaceutical compositions disclosed herein may be in the form of sterile injectable aqueous or oil suspensions for intramuscular and subcutaneous administration. These suspensions may be formulated using suitable dispersants or wetting agents and suspending agents as described above, according to known techniques. The sterile injectable formulations may also be sterile injectable solutions or suspensions prepared in parenteral-acceptable, non-toxic diluents or solvents. Furthermore, sterile fixative oils may be conveniently used as solvents or suspension media. For this purpose, any blended fixative oil may be used. Additionally, fatty acids may also be used to prepare injectable formulations.

[0276] The disclosed compounds can be administered in suppository form for rectal administration. These pharmaceutical compositions can be prepared by mixing the drug with a suitable, non-irritating excipient that is solid at normal temperatures but liquid in the rectum, and thus dissolves in the rectum to release the drug.

[0277] The compounds disclosed herein can be administered by adding water to prepare water-soluble dispersible powders and granules. These pharmaceutical compositions can be prepared by mixing the active ingredient with a dispersant or wetting agent, a suspending agent, or one or more preservatives.

[0278] As is well known to those skilled in the art, the dosage of a drug depends on a variety of factors, including but not limited to: the activity of the specific compound used, the patient's age, the patient's weight, the patient's health status, the patient's behavior, the patient's diet, the timing of administration, the route of administration, the rate of excretion, the combination of drugs, the severity of the disease, etc.; in addition, the optimal treatment mode, such as the treatment pattern, the daily dosage of the compound, or the type of medicinal salt can be validated based on conventional treatment protocols.

[0279] Terminology Explanation

[0280] Unless otherwise stated, the terms used in the specification and claims have the following meanings.

[0281] The term "alkyl" refers to a saturated straight-chain or branched aliphatic hydrocarbon group having 1 to 20 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20) carbon atoms (i.e., C2). 1-20 Alkyl group). The alkyl group is preferably an alkyl group having 1 to 12 carbon atoms (i.e., C12). 1-12 Alkyl groups, more preferably alkyl groups having 1 to 6 carbon atoms (i.e., C14-C6 ... 1-6Alkyl groups). Non-limiting examples include: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, n-heptyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 2, 3-Dimethylpentyl, 2,4-Dimethylpentyl, 2,2-Dimethylpentyl, 3,3-Dimethylpentyl, 2-Ethylpentyl, 3-Ethylpentyl, n-Octyl, 2,3-Dimethylhexyl, 2,4-Dimethylhexyl, 2,5-Dimethylhexyl, 2,2-Dimethylhexyl, 3,3-Dimethylhexyl, 4,4-Dimethylhexyl, 2-Ethylhexyl, 3-Ethylhexyl, 4-Ethylhexyl, 2-Methyl-2-Ethylpentyl, 2-Methyl-3-Ethylpentyl, n-Nonyl, 2-Methyl-2-Ethylhexyl, 2-Methyl-3-Ethylhexyl, 2,2-Diethylpentyl, n-Decyl, 3,3-Diethylhexyl, 2,2-Diethylhexyl, and their various branched isomers, etc. The most preferred alkyl group is a lower alkyl group having 1 to 6 carbon atoms. Non-limiting examples include: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, etc. Alkyl groups can be substituted or unsubstituted. When substituted, they can be substituted at any usable connection point. The substituents are preferably selected from one or more of the following: D atom, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclic oxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclic, aryl, and heteroaryl.

[0282] The term "alkylene" refers to a divalent alkyl group, wherein the alkyl group, as defined above, has 1 to 20 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20) carbon atoms (i.e., C2). 1-20 Alkylenes). The alkylene group is preferably an alkylene group having 1 to 12 carbon atoms (i.e., C12). 1-12Alkylenes, more preferably alkylenes having 1 to 6 carbon atoms (i.e., C16-164 ... 1-6 Alkylenes. Non-limiting examples of alkylenes include, but are not limited to: methylene (-CH2-), 1,1-ethylene (-CH(CH3)-), 1,2-ethylene (-CH2CH2)-, 1,1-propylene (-CH(CH2CH3)-), 1,2-propylene (-CH2CH(CH3)-), 1,3-propylene (-CH2CH2CH2-), 1,4-butylene (-CH2CH2CH2CH2-), etc. Alkylenes can be substituted or unsubstituted, and when substituted, they can be substituted at any usable linking point. Substituents are preferably selected from one or more of alkyl, alkenyl, alkynyl, alkoxy, haloalkoxy, cycloalkyloxy, heterocyclic alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocyclic, aryl, heteroaryl, cycloalkoxy, heterocyclic alkoxy, cycloalkylthio, heterocyclic alkylthio, and oxo.

[0283] The term "alkenyl" refers to an alkyl compound containing at least one carbon-carbon double bond in its molecule, wherein the alkyl group is defined as described above and has 2 to 12 (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12) carbon atoms (i.e., C atoms). 2-12 Alkenyl). The alkenyl group is preferably an alkenyl group having 2 to 6 carbon atoms (i.e., C). 2-6 Alkenyl). Non-limiting examples include vinyl, propenyl, butenyl, pentenyl, hexenyl, etc. Alkenyl groups can be substituted or unsubstituted, and when substituted, the substituent is preferably selected from one or more of alkyl, alkoxy, halogen, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclic oxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclic, aryl, and heteroaryl.

[0284] The term "alkynyl" refers to an alkyl compound containing at least one carbon-carbon triple bond in its molecule, wherein the alkyl group is defined as described above and has 2 to 12 (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12) carbon atoms. 2-12 The alkynyl group is preferably an alkynyl group having 2 to 6 carbon atoms (i.e., C64). 2-6 (Alynyl). Non-limiting examples include: ethynyl, propynyl, butynyl, pentyynyl, hexynyl, etc. The alkynyl group can be substituted or unsubstituted, and when substituted, the substituent is preferably selected from one or more of alkyl, alkoxy, halogen, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclic oxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclic, aryl, and heteroaryl.

[0285] The term "alkoxy" refers to -O-(alkyl), where alkyl is defined as described above. Non-limiting examples of alkoxy groups include: methoxy, ethoxy, propoxy, and butoxy. Alkoxy groups can be optionally substituted or unsubstituted, and when substituted, the substituent is preferably selected from one or more of the following: D atom, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclic oxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclic, aryl, and heteroaryl.

[0286] The term "cycloalkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent having 3 to 20 (e.g., 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20) carbon atoms (i.e., 3 to 20-membered cycloalkyl), preferably having 3 to 12 carbon atoms (i.e., 3 to 12-membered cycloalkyl), more preferably having 3 to 8 carbon atoms (i.e., 3 to 8-membered cycloalkyl), and most preferably having 3 to 6 carbon atoms (i.e., 3 to 6-membered cycloalkyl). Non-limiting examples of monocyclic cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cyclohepttrienyl, cyclooctyl, etc.; polycyclic cycloalkyl includes spirocycloalkyl, fused cycloalkyl, and bridged cycloalkyl.

[0287] The term "spirocycloalkyl" refers to a polycyclic group consisting of 5 to 20 quintile rings sharing a single carbon atom (called a spiro atom), and may contain one or more double bonds. Preferably, it is 6 to 14 quintiles, more preferably 7 to 10 quintiles (e.g., 7, 8, 9, or 10 quintiles). Spirocycloalkyl groups are classified as monospirocycloalkyl or polyspirocycloalkyl (such as bispirocycloalkyl) based on the number of shared spiro atoms between rings, with monospirocycloalkyl or bispirocycloalkyl being preferred. More preferably, they are 3 / 5 quintile, 3 / 6 quintile, 4 / 4 quintile, 4 / 5 quintile, 4 / 6 quintile, 5 / 5 quintile, 5 / 6 quintile, 6 / 4 quintile, 6 / 5 quintile, or 6 / 6 quintile monospirocycloalkyl groups. Non-limiting examples of spirocycloalkyl groups include:

[0288]

[0289] The term "fused cycloalkyl" refers to a fully carbon polycyclic group consisting of 5 to 20-membered rings sharing an adjacent pair of carbon atoms, wherein one or more rings may contain one or more double bonds. Preferably, they are 6 to 14-membered, more preferably 7 to 10-membered (e.g., 7, 8, 9, or 10-membered). Depending on the number of rings, they can be classified as bicyclic, tricyclic, tetracyclic, etc., with bicyclic or tricyclic fused cycloalkyl being preferred, and more preferably 3 / 4-membered, 3 / 5-membered, 3 / 6-membered, 4 / 4-membered, 4 / 5-membered, 4 / 6-membered, 5 / 4-membered, 5 / 5-membered, 5 / 6-membered, 6 / 3-membered, 6 / 4-membered, 6 / 5-membered, and 6 / 6-membered bicyclic fused cycloalkyl. Non-limiting examples of fused cycloalkyl groups include:

[0290]

[0291] The term "bridged cycloalkyl" refers to a fully carbon polycyclic group consisting of any two non-directly connected carbon atoms sharing a common ring, ranging from 5 to 20 members, and may contain one or more double bonds. Preferably, it consists of 6 to 14 members, more preferably 7 to 10 members (e.g., 7, 8, 9, or 10 members). Depending on the number of rings, it can be classified as bicyclic, tricyclic, tetracyclic, etc., with bicyclic, tricyclic, or tetracyclic bridged cycloalkyl being preferred, and bicyclic or tricyclic bridged cycloalkyl being more preferred. Non-limiting examples of bridged cycloalkyl groups include:

[0292]

[0293] The cycloalkyl ring comprises a cycloalkyl group (including monocyclic, spirocyclic, fused, and bridged rings) fused to an aryl, heteroaryl, or heterocyclic alkyl ring as described above, wherein the ring attached to the parent structure is a cycloalkyl group. Non-limiting examples include... etc.; preferred

[0294] The cycloalkyl group can be substituted or unsubstituted. When substituted, it can be substituted at any usable connection point. The substituent is preferably selected from one or more of halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclic oxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclic, aryl, and heteroaryl.

[0295] The term "heterocyclic group" refers to a saturated or partially unsaturated monocyclic or polycyclic substituent having 3 to 20 (e.g., 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20) ring atoms, wherein one or more ring atoms are heteroatoms selected from nitrogen, oxygen, and sulfur, wherein the sulfur may optionally be oxidized (i.e., forming sulfoxides or sulfones), but does not include the -OO-, -OS-, or -SS- ring moiety, and the remaining ring atoms are carbon. Preferably, the ring group has 3 to 12 ring atoms, of which 1 to 4 (e.g., 1, 2, 3, and 4) are heteroatoms (i.e., 3 to 12-membered heterocyclic groups); more preferably, it has 3 to 8 ring atoms, of which 1 to 3 are heteroatoms (e.g., 1, 2, and 3) (i.e., 3 to 8-membered heterocyclic groups); even more preferably, it has 3 to 6 ring atoms, of which 1 to 3 are heteroatoms (i.e., 3 to 6-membered heterocyclic groups); most preferably, it contains 5 or 6 ring atoms, of which 1 to 3 are heteroatoms (i.e., 5 or 6-membered heterocyclic groups). Non-limiting examples of monocyclic heterocyclic groups include: pyrrolidinyl, tetrahydropyranyl, 1,2,3,6-tetrahydropyridyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, etc. Polycyclic heterocyclic groups include spirocyclic, fused heterocyclic, and bridged heterocyclic groups.

[0296] The term "spiroheterocyclic group" refers to a polycyclic heterocyclic group consisting of 5 to 20 rings sharing a single atom (called a spiro atom), wherein one or more ring atoms are heteroatoms selected from nitrogen, oxygen, and sulfur, wherein the sulfur may optionally be oxidized (i.e., forming a sulfoxide or sulfone), and the remaining ring atoms are carbon. It may contain one or more double bonds. Preferably, it is 6 to 14 rings, more preferably 7 to 10 rings (e.g., 7, 8, 9, or 10 rings). Spiroheterocyclic groups are classified into monospirocyclic groups or polyspirocyclic groups (such as bispirocyclic groups) according to the number of shared spiro atoms between rings, with monospirocyclic and bispirocyclic groups being preferred. More preferably, 4-ring / 4-ring, 4-ring / 5-ring, 4-ring / 6-ring, 5-ring / 5-ring, 5-ring / 6-ring, or 6-ring / 6-ring monospirocyclic groups are preferred. Non-limiting examples of spirocyclic groups include:

[0297]

[0298] The term "fused heterocyclic group" refers to a polycyclic heterocyclic group in which 5 to 20 rings share an adjacent pair of atoms. One or more rings may contain one or more double bonds, wherein one or more ring atoms are heteroatoms selected from nitrogen, oxygen, and sulfur, wherein the sulfur may optionally be oxidized (i.e., forming sulfoxide or sulfone), and the remaining ring atoms are carbon. Preferably, the group consists of 6 to 14 rings, more preferably 7 to 10 rings (e.g., 7, 8, 9, or 10 rings). Based on the number of constituent rings, fused heterocyclic groups can be classified into bicyclic, tricyclic, and tetracyclic groups, among others. Bicyclic or tricyclic fused heterocyclic groups are preferred, and 3-membered / 4-membered, 3-membered / 5-membered, 3-membered / 6-membered, 4-membered / 4-membered, 4-membered / 5-membered, 4-membered / 6-membered, 5-membered / 3-membered, 5-membered / 4-membered, 5-membered / 5-membered, 5-membered / 6-membered, 5-membered / 7-membered, 6-membered / 3-membered, 6-membered / 4-membered, 6-membered / 5-membered, 6-membered / 6-membered, 6-membered / 7-membered, 7-membered / 5-membered, or 7-membered / 6-membered bicyclic fused heterocyclic groups are more preferred. Non-limiting examples of fused heterocyclic groups include:

[0299]

[0300] The term "bridged heterocyclic group" refers to a polycyclic heterocyclic group consisting of any two rings sharing two non-directly connected atoms, ranging from 5 to 14 members. It may contain one or more double bonds, wherein one or more ring atoms are selected from nitrogen, oxygen, and sulfur, and the sulfur may optionally be oxidized (i.e., forming sulfoxide or sulfone), with the remaining ring atoms being carbon. Preferably, it consists of 6 to 14 members, more preferably 7 to 10 members (e.g., 7, 8, 9, or 10 members). Based on the number of constituent rings, it can be classified into bicyclic, tricyclic, and tetracyclic polycyclic bridged heterocyclic groups, with bicyclic, tricyclic, or tetracyclic bridged heterocyclic groups being preferred, and bicyclic or tricyclic bridged heterocyclic groups being more preferred. Non-limiting examples of bridged heterocyclic groups include:

[0301]

[0302] The heterocyclic ring comprises a heterocyclic group (including monocyclic, spirocyclic, fused heterocyclic, and bridged heterocyclic rings) fused to an aryl, heteroaryl, or cycloalkyl ring as described above, wherein the ring connected to the parent structure is a heterocyclic group, and non-limiting examples include:

[0303] wait.

[0304] The heterocyclic group can be substituted or unsubstituted. When substituted, it can be substituted at any usable connection point. The substituent is preferably selected from one or more of halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclic oxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclic, aryl, and heteroaryl.

[0305] The term "aryl" refers to a 6- to 14-membered all-carbon monocyclic or fused polycyclic (fused polycyclic) group having a conjugated π-electron system, preferably 6- to 10-membered, such as phenyl and naphthyl. The aryl ring comprises an aryl ring fused to a heteroaryl, heterocyclic, or cycloalkyl ring as described above, wherein the ring attached to the parent structure is an aryl ring, and non-limiting examples include:

[0306]

[0307] The aryl group can be substituted or unsubstituted. When substituted, it can be substituted at any usable connection point. The substituent is preferably selected from one or more of halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclic oxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclic, aryl, and heteroaryl.

[0308] The term "heteroaryl" refers to a heteroaryl system comprising 1 to 4 heteroatoms (e.g., 1, 2, 3, and 4) and 5 to 14 ring atoms, wherein the heteroatoms are selected from oxygen, sulfur, and nitrogen. The heteroaryl group is preferably 5 to 10-membered (e.g., 5, 6, 7, 8, 9, or 10-membered), more preferably 5- or 6-membered, such as furanyl, thiophene, pyridinyl, pyrroleyl, N-alkylpyrroleyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, etc. The heteroaryl ring comprises a heteroaryl group fused to an aryl, heterocyclic, or cycloalkyl ring as described above, wherein the ring connected to the parent structure is a heteroaryl ring, and non-limiting examples include:

[0309]

[0310] The heteroaryl group can be substituted or unsubstituted. When substituted, it can be substituted at any usable connection point. The substituent is preferably selected from one or more of halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclic oxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclic, aryl, and heteroaryl.

[0311] The aforementioned cycloalkyl, heterocyclic, aryl, and heteroaryl groups include residues derived from removing one hydrogen atom from a parent ring atom, or residues derived from removing two hydrogen atoms from the same ring atom or two different ring atoms of the parent, namely "cycloalkylene", "heterocyclicene", "arylene", and "heteroarylene".

[0312] The term "amino protecting group" refers to a group that is easily removed from the amino group, introduced onto the amino group to ensure that the amino group remains unchanged during reactions at other sites of the molecule. Non-limiting examples include: (trimethylsilyl)ethoxymethyl, tetrahydropyranyl, tert-butoxycarbonyl (Boc), acetyl, p-toluenesulfonyl (Ts), benzyl, allyl, and p-methoxybenzyl. These groups may optionally be replaced by 1-3 substituents selected from halogens, alkoxy groups, or nitro groups.

[0313] The term "hydroxyl protecting group" refers to a group introduced onto a hydroxyl group that is easily removed, typically used to block or protect the hydroxyl group so that reactions can proceed on other functional groups of the compound. Non-limiting examples include: triethylsilyl, triisopropylsilyl, tert-butyldimethylsilyl (TBS), tert-butyldiphenylsilyl, tert-butyl, C 1-6 alkoxy-substituted C 1-6 alkyl or phenyl substituted C 1-6 Alkyl groups (such as methoxymethyl (MOM) and ethoxyethyl), (C 1-10 Alkyl or aromatic group) acyl group (e.g., formyl, acetyl, benzoyl, p-nitrobenzoyl, etc.), (C 1-6 alkyl or 6 to 10 aryl) sulfonyl, (C 1-6 Alkyl or 6 to 10 aryloxy groups, carbonyl, allyl, 2-tetrahydropyranyl (THP), etc.

[0314] The term “cycloalkyloxy” refers to cycloalkyl-O-, where the cycloalkyl group is as defined above.

[0315] The term “heterocyclic oxy group” refers to the heterocyclic group -O-, where the heterocyclic group is as defined above.

[0316] The term "alkylthio" refers to alkyl-S-, where the alkyl group is as defined above.

[0317] The term "haloalkyl" refers to an alkyl group that has been substituted with one or more halogens, wherein the alkyl group is as defined above.

[0318] The term "haloalkoxy" refers to an alkoxy group that is substituted by one or more halogens, wherein the alkoxy group is as defined above.

[0319] The term “deuterated alkyl” refers to an alkyl group that is replaced by one or more deuterium atoms, wherein the alkyl group is as defined above.

[0320] The term "hydroxyalkyl" refers to an alkyl group that is replaced by one or more hydroxyl groups, wherein the alkyl group is as defined above.

[0321] The term "halogen" refers to fluorine, chlorine, bromine, or iodine.

[0322] The term "hydroxyl group" refers to -OH.

[0323] The term "thiol" refers to -SH.

[0324] The term "amino" refers to -NH2.

[0325] The term "cyano" refers to -CN.

[0326] The term "nitro" refers to -NO2.

[0327] The term "oxo" or "oxo group" refers to "=O".

[0328] The term "carbonyl" refers to C=O.

[0329] The term "carboxyl group" refers to -C(O)OH.

[0330] The term "carboxylic acid ester group" refers to -C(O)O(alkyl), -C(O)O(cycloalkyl), (alkyl)C(O)O- or (cycloalkyl)C(O)O-, where alkyl and cycloalkyl are as defined above.

[0331] The compounds disclosed herein can exist in specific stereoisomer forms. The term "stereoisomer" refers to isomers with the same structure but different spatial arrangements of atoms. These include cis and trans (or Z and E) isomers, (-)- and (+)- isomers, (R)- and (S)- enantiomers, diastereomers, (D)- and (L)- isomers, tautomers, blocked isomers, conformational isomers, and mixtures thereof (such as racemic mixtures and mixtures of diastereomers). Substituents in the compounds disclosed herein may contain additional asymmetric atoms. All such stereoisomers and mixtures thereof are included within the scope of this disclosure. Optically active (-)- and (+)- isomers, (R)- and (S)- enantiomers, and (D)- and (L)- isomers can be prepared by chiral synthesis, chiral reagents, or other conventional techniques. This disclosure discloses an isomer of a compound, which can be prepared by asymmetric synthesis or with chiral auxiliaries, or, when the molecule contains a basic functional group (such as an amino group) or an acidic functional group (such as a carboxyl group), by forming a salt of the diastereomer with a suitable optically active acid or base, followed by diastereomer resolution using conventional methods known in the art to obtain the pure isomer. Furthermore, the separation of enantiomers and diastereomers is typically performed by chromatography.

[0332] In the chemical structure of the compounds described in this disclosure, the bonds... This indicates that the configuration is not specified; that is, if chiral isomers exist in the chemical structure, the bond... It can be or Or simultaneously include and Two configurations.

[0333] The compounds disclosed herein may exist in various tautomer forms, and all such forms are included within the scope of this disclosure. The terms "tautomer" or "tautomer form" refer to a structural isomer that exists in equilibrium and readily transforms from one isomer to another. This includes all possible tautomers, i.e., existing as a single isomer or as a mixture of said tautomers in any proportion. Non-limiting examples include: keto-enols, imine-enamines, lactam-lactamimides, etc. Examples of lactam-lactamimide equilibrium are shown below:

[0334]

[0335] When referring to the pyrazolyl group, it should be understood to include any one or a mixture of two tautomers of the following two structures:

[0336]

[0337] All tautomers are within the scope of this disclosure, and the naming of compounds does not exclude any tautomers.

[0338] The compounds disclosed herein include all suitable isotopic derivatives thereof. The term "isotopic derivative" refers to a compound in which at least one atom is replaced by an atom having the same atomic number but a different atomic mass. Examples of isotopes that may be introduced into the compounds of this disclosure include stable and radioactive isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, bromine, and iodine, for example, […]. 2 H (deuterium, D) 3 H (tritium, T) 11 C 13 C 14 C 15 N、 17 O、 18 O、 32 p、 33 p、 33 S, 34 S, 35 S, 36 S, 18 F, 36 Cl、 82 Br、 123 I, 124 I, 125 I, 129 I and 131 Grade I, with deuterium as the preferred grade.

[0339] Compared to undeuterated drugs, deuterated drugs offer advantages such as reduced toxicity, increased drug stability, enhanced efficacy, and prolonged biological half-life. All isotopic variations of the compounds disclosed herein, regardless of radioactivity, are included within the scope of this disclosure. Each available hydrogen atom bonded to a carbon atom can be independently replaced by a deuterium atom, wherein the deuterium substitution can be partial or complete; partial deuterium substitution refers to the replacement of at least one hydrogen atom with at least one deuterium atom.

[0340] In the compounds disclosed herein, when a position is specifically designated as "deuterium" or "D", that position should be understood to indicate that the abundance of deuterium is at least 1000 times greater than the native abundance of deuterium (which is 0.015%) (i.e., at least 15% deuterium doping). In some embodiments, the abundance of deuterium per designated deuterium atom is at least 1000 times greater than the native abundance of deuterium (i.e., at least 15% deuterium doping). In some embodiments, the abundance of deuterium per designated deuterium atom is at least 2000 times greater than the native abundance of deuterium (i.e., at least 30% deuterium doping). In some embodiments, the abundance of deuterium per designated deuterium atom is at least 3000 times greater than the native abundance of deuterium (i.e., at least 45% deuterium doping). In some embodiments, the deuterium abundance of each designated deuterium atom is at least 3340 times greater than the natural deuterium abundance (i.e., at least 50.1% deuterium doping). In some embodiments, the deuterium abundance of each designated deuterium atom is at least 3500 times greater than the natural deuterium abundance (i.e., at least 52.5% deuterium doping). In some embodiments, the deuterium abundance of each designated deuterium atom is at least 4000 times greater than the natural deuterium abundance (i.e., at least 60% deuterium doping). In some embodiments, the deuterium abundance of each designated deuterium atom is at least 4500 times greater than the natural deuterium abundance (i.e., at least 67.5% deuterium doping). In some embodiments, the deuterium abundance of each designated deuterium atom is at least 5000 times greater than the natural deuterium abundance (i.e., at least 75% deuterium doping). In some embodiments, the deuterium abundance of each designated deuterium atom is at least 5500 times greater than the natural deuterium abundance (i.e., at least 82.5% deuterium doping). In some embodiments, the deuterium abundance of each designated deuterium atom is at least 6000 times greater than the natural deuterium abundance (i.e., at least 90% deuterium doping). In some embodiments, the deuterium abundance of each designated deuterium atom is at least 6333.3 times greater than the natural deuterium abundance (i.e., at least 95% deuterium doping). In some embodiments, the deuterium abundance of each designated deuterium atom is at least 6466.7 times greater than the natural deuterium abundance (i.e., at least 97% deuterium doping). In some embodiments, the deuterium abundance of each designated deuterium atom is at least 6600 times greater than the natural deuterium abundance (i.e., at least 99% deuterium doping). In some implementations, the abundance of deuterium in each designated deuterium atom is at least 6633.3 times greater than the natural abundance of deuterium (i.e., at least 99.5% deuterium doping).

[0341] The compounds represented by general formulas (I), (I-1), (I-1-1), (I-1-2), (II), (II-1), (II-1-1), (II-1-2), (III), (III-1), (III-1-1), and (III-1-2), as well as the compounds shown in Table A, or pharmaceutically acceptable salts thereof, including their tautomers, racemates, enantiomers, diastereomers, cis-trans isomers, or mixtures thereof.

[0342] "Optional" or "optional" means that the event or situation subsequently described may, but does not have to, occur; the description includes the possibility or possibility that the event or situation may or may not occur. For example, "optionally (optionally) C substituted with halogen or cyano groups..." 1-6 "Alkyl" means that halogens or cyano groups may or may not be present. This description includes cases where alkyl groups are substituted by halogens or cyano groups and cases where alkyl groups are not substituted by halogens or cyano groups.

[0343] "Substitution" or "substituted" refers to one or more hydrogen atoms in a group, preferably 1 to 6, more preferably 1 to 3 hydrogen atoms, which are independently substituted by the corresponding number of substituents. Those skilled in the art can determine possible or impossible substitutions without much effort (through experimentation or theory). For example, an amino or hydroxyl group with free hydrogen may be unstable when combined with a carbon atom having an unsaturated bond (such as an alkene).

[0344] "Pharmaceutical composition" means a mixture containing one or more of the compounds described herein or their pharmaceutically acceptable salts, along with other chemical components, such as pharmaceutically acceptable carriers and excipients. The purpose of a pharmaceutical composition is to facilitate administration to a living organism, thereby promoting the absorption of the active ingredient and its biological activity.

[0345] "Pharmacologically acceptable salt" refers to the salt of the compounds disclosed herein, which may be selected from inorganic or organic salts. Such salts are safe and effective when used in mammals and possess the expected biological activity. The salt can be prepared separately during the final isolation and purification of the compound, or by reacting a suitable group with a suitable base or acid. Bases commonly used to form pharmaceutically acceptable salts include inorganic bases, such as sodium hydroxide and potassium hydroxide, and organic bases, such as ammonia. Acids commonly used to form pharmaceutically acceptable salts include both inorganic and organic acids.

[0346] For the purposes of pharmaceuticals or pharmacologically active agents, the term "therapeutic effective amount" refers to the amount of a drug or agent sufficient to achieve or at least partially achieve the intended effect. The determination of the therapeutic effective amount varies from person to person, depending on the recipient's age and general condition, as well as the specific active substance. The appropriate therapeutic effective amount in a given case can be determined by a person skilled in the art based on routine testing.

[0347] As used herein, the term "pharmaceutically acceptable" means that these compounds, materials, compositions, and / or dosage forms are suitable for contact with patient tissues without excessive toxicity, irritation, allergic reactions, or other problems or complications, within reasonable medical judgment, have a reasonable benefit / risk ratio, and are effective for their intended use.

[0348] As used herein, the singular forms of “a,” “an,” and “the” include plural references, and vice versa, unless the context clearly indicates otherwise.

[0349] When the term "about" is applied to parameters such as pH, concentration, and temperature, it indicates that the parameter can vary by ±10%, and sometimes more preferably within ±5%. As those skilled in the art will understand, when a parameter is not critical, figures are usually given for illustrative purposes only, not as limitations.

[0350] The method for synthesizing the compounds disclosed herein

[0351] In order to achieve the purpose of this disclosure, the following technical solution is adopted:

[0352] Option 1

[0353] Another aspect of this disclosure relates to a method for preparing a compound of general formula (I) or a pharmaceutically acceptable salt thereof, the method comprising:

[0354]

[0355] Compounds of general formula (IA) or their salts undergo intramolecular cyclization reactions under acidic conditions to yield compounds of general formula (I) or their pharmaceutically usable salts.

[0356] in:

[0357] R m C 1-6 Alkyl; preferably, R m For tert-butyl;

[0358] Rings A, X, Y, Z, G 1 G 2 G 3 R 1 To R 7 m, n, p and q are as defined in general formula (I).

[0359] Option 2

[0360] Another aspect of this disclosure relates to a method for preparing a compound of general formula (I-1) or a pharmaceutically acceptable salt thereof, the method comprising:

[0361]

[0362] Compounds of general formula (IA-1) or their salts undergo intramolecular cyclization reactions under acidic conditions to yield compounds of general formula (I-1) or their pharmaceutically usable salts.

[0363] in:

[0364] R m C 1-6 Alkyl; preferably, R m For tert-butyl;

[0365] Rings A, X, Y, Z, G 1 G 2 G 3 R 1 To R 7 , m, n, p and q are as defined in general formula (I-1).

[0366] Option 3

[0367] Another aspect of this disclosure relates to a method for preparing a compound of general formula (II) or a pharmaceutically acceptable salt thereof, the method comprising:

[0368]

[0369] Compounds of general formula (IIA) or their salts undergo intramolecular cyclization reactions under acidic conditions to yield compounds of general formula (II) or their pharmaceutically usable salts.

[0370] in:

[0371] R m C 1-6 Alkyl; preferably, R m For tert-butyl;

[0372] Rings A, X, Z, G 1 G 2 G 3 R 1 R 2 R 5 To R 7 m, n, p and q are as defined for compounds of general formula (II).

[0373] Option 4

[0374] Another aspect of this disclosure relates to a method for preparing a compound of general formula (II-1) or a pharmaceutically acceptable salt thereof, the method comprising:

[0375]

[0376] Compounds of general formula (IIA-1) or their salts undergo intramolecular cyclization reactions under acidic conditions to yield compounds of general formula (II-1) or their pharmaceutically usable salts.

[0377] in:

[0378] R m C 1-6 Alkyl; preferably, R m For tert-butyl;

[0379] Rings A, X, Z, G 1 G 2 G 3 R 1 R 2 R 5 To R 7 m, n, p and q are as defined for compounds of general formula (II-1).

[0380] Option 5

[0381] Another aspect of this disclosure relates to a method for preparing a compound of general formula (III), or a pharmaceutically usable salt thereof, the method comprising:

[0382]

[0383] Compounds of general formula (IIIA) or their salts undergo intramolecular cyclization reactions under acidic conditions to yield compounds of general formula (III) or their pharmaceutically usable salts.

[0384] in:

[0385] R m C 1-6 Alkyl; preferably, R m For tert-butyl;

[0386] Rings A and G 1 G 2 G 3 R 1 R 2 R 5 To R 7 m, n, p and q are as defined for compounds of general formula (III).

[0387] Option Six

[0388] Another aspect of this disclosure relates to a method for preparing a compound of general formula (III-1) or a pharmaceutically acceptable salt thereof, the method comprising:

[0389]

[0390] Compounds of general formula (IIIA-1) or their salts undergo intramolecular cyclization reactions under acidic conditions to yield compounds of general formula (III-1) or their pharmaceutically usable salts.

[0391] in:

[0392] R m C 1-6 Alkyl; preferably, R m For tert-butyl;

[0393] Rings A and G 1 G 2 G 3 R 1 R 2 R 5 To R 7 m, n, p and q are as defined for compounds of general formula (III-1).

[0394] Option 7

[0395] Another aspect of this disclosure relates to a method for preparing a compound of general formula (I-1-1) or a pharmaceutically acceptable salt thereof, the method comprising:

[0396]

[0397] Compounds of general formula (IA-1-1) or their salts undergo intramolecular cyclization reactions under acidic conditions to yield compounds of general formula (I-1-1) or their pharmaceutically usable salts.

[0398] in:

[0399] R m C 1-6 Alkyl; preferably, R m For tert-butyl;

[0400] Rings A, X, Y, Z, G 1 G 2 G 3 R 1 To R 7 , m, n, p and q are defined as in general formula (I-1-1).

[0401] Option 8

[0402] Another aspect of this disclosure relates to a method for preparing a compound of general formula (I-1-2) or a pharmaceutically acceptable salt thereof, the method comprising:

[0403]

[0404] Compounds of general formula (IA-1-2) or their salts undergo intramolecular cyclization reactions under acidic conditions to yield compounds of general formula (I-1-2) or their pharmaceutically usable salts.

[0405] in:

[0406] R m C 1-6 Alkyl; preferably, R m For tert-butyl;

[0407] Rings A, X, Y, Z, G 1 G 2 G 3 R 1 To R 7 m, n, p and q are defined as in general formula (I-1-2).

[0408] Option Nine

[0409] Another aspect of this disclosure relates to a method for preparing a compound of general formula (II-1-1) or a pharmaceutically acceptable salt thereof, the method comprising:

[0410]

[0411] Compounds of general formula (IIA-1-1) or their salts undergo intramolecular cyclization reactions under acidic conditions to yield compounds of general formula (II-1-1) or their pharmaceutically usable salts.

[0412] in:

[0413] R m C 1-6 Alkyl; preferably, R m For tert-butyl;

[0414] Rings A, X, Z, G 1 G 2 G 3 R 1 R 2 R 5 To R 7 m, n, p and q are as defined for compounds of general formula (II-1-1).

[0415] Option 10

[0416] Another aspect of this disclosure relates to a method for preparing a compound of general formula (II-1-2) or a pharmaceutically acceptable salt thereof, the method comprising:

[0417]

[0418] Compounds of general formula (IIA-1-2) or their salts undergo intramolecular cyclization reactions under acidic conditions to yield compounds of general formula (II-1-2) or their pharmaceutically usable salts.

[0419] in:

[0420] R m C 1-6 Alkyl; preferably, R m For tert-butyl;

[0421] Rings A, X, Z, G 1 G 2 G 3 R 1 R 2 R 5 To R 7 m, n, p and q are as defined in compounds of general formula (II-1-2).

[0422] Option 11

[0423] Another aspect of this disclosure relates to a method for preparing a compound of general formula (III-1-1) or a pharmaceutically acceptable salt thereof, the method comprising:

[0424]

[0425] Compounds of general formula (IIIA-1-1) or their salts undergo intramolecular cyclization reactions under acidic conditions to yield compounds of general formula (III-1-1) or their pharmaceutically usable salts.

[0426] in:

[0427] R m C 1-6 Alkyl; preferably, R m For tert-butyl;

[0428] Rings A and G 1 G 2 G 3 R 1 R 2 R 5 To R 7 m, n, p and q are as defined for compounds of general formula (III-1-1).

[0429] Option Twelve

[0430] Another aspect of this disclosure relates to a method for preparing a compound of general formula (III-1-2) or a pharmaceutically acceptable salt thereof, the method comprising:

[0431]

[0432] Compounds of general formula (IIIA-1-2) or their salts undergo intramolecular cyclization reactions under acidic conditions to yield compounds of general formula (III-1-2) or their pharmaceutically usable salts.

[0433] in:

[0434] R m C 1-6 Alkyl; preferably, R m For tert-butyl;

[0435] Rings A and G 1 G 2 G 3 R 1 R 2 R 5 To R 7 m, n, p and q are as defined in compounds of general formula (III-1-2).

[0436] The reagents providing acidic conditions in the above synthesis schemes include, but are not limited to, p-toluenesulfonic acid, p-toluenesulfonic acid monohydrate, benzenesulfonic acid, methanesulfonic acid, trifluoromethanesulfonic acid, sulfuric acid, hydrochloric acid, nitric acid, and trifluoroacetic acid; benzenesulfonic acid is preferred.

[0437] The above reaction is preferably carried out in a solvent, including but not limited to: ethylene glycol dimethyl ether, acetic acid, methanol, ethanol, acetonitrile, n-butanol, toluene, tetrahydrofuran, dichloromethane, petroleum ether, ethyl acetate, n-hexane, dimethyl sulfoxide, 1,4-dioxane, water, N,N-dimethylformamide, N,N-dimethylacetamide, and mixtures thereof. Attached Figure Description

[0438] Figure 1 This document presents efficacy data for compounds from Example 2-1 and CC-92480 against NCI-H929 xenografts in CB-17SCID mice.

[0439] Figure 2 This shows the effect of the compounds in Example 2-1 and CC-92480 on the body weight of CB-17SCID mice. Detailed Implementation

[0440] The following embodiments are used to further describe this disclosure, but these embodiments are not intended to limit the scope of this disclosure.

[0441] Example

[0442] The structure of the compound was determined by nuclear magnetic resonance (NMR) and / or mass spectrometry (MS). NMR shifts (δ) were expressed in 10⁻¹⁰. -6The unit (ppm) is given. NMR determination was performed using a Bruker AVANCE-400 NMR spectrometer or a Bruker AVANCE NEO 500M. The solvents used were deuterated dimethyl sulfoxide (DMSO-d6), deuterated chloroform (CDCl3), and deuterated methanol (CD3OD). The internal standard was tetramethylsilane (TMS).

[0443] MS measurements were performed using an Agilent 1200 / 1290DAD-6110 / 6120 Quadrupole MS LC-MS system (manufacturer: Agilent, MS model: 6110 / 6120 Quadrupole MS), a waters ACQuity UPLC-QD / SQD system (manufacturer: waters, MS model: waters ACQuity Qda Detector / waters SQ Detector), or a THERMO Ultimate3000-Q Exactive system (manufacturer: THERMO, MS model: THERMO Q Exactive).

[0444] High-performance liquid chromatography (HPLC) analysis was performed using an Agilent HPLC 1200DAD, an Agilent HPLC 1200VWD, and a Waters HPLC e2695-2489 HPLC system.

[0445] Chiral HPLC analysis was performed using an Agilent 1260 DAD high-performance liquid chromatograph.

[0446] High performance liquid chromatography (HPLC) was performed using Waters 2545-2767, Waters 2767-SQ Detecor2, Shimadzu LC-20AP, and Gilson GX-281 preparative chromatographs.

[0447] Chiral preparation was performed using a Shimadzu LC-20AP preparative chromatograph.

[0448] The CombiFlash rapid preparation system uses a CombiFlash Rf200 (TELEDYNE ISCO).

[0449] Thin-layer chromatography silica gel plates are Yantai Huanghai HSGF254 or Qingdao GF254. The silica gel plates used in thin-layer chromatography (TLC) have a diameter of 0.15 mm to 0.2 mm, and the diameter of the silica gel plates used for thin-layer chromatography separation and purification products is 0.4 mm to 0.5 mm.

[0450] Silica gel column chromatography typically uses Yantai Huanghai silica gel with a mesh size of 200 to 300 as the carrier.

[0451] Mean inhibition rate of kinases and IC 50 The values ​​were determined using a NovoStar microplate reader (BMG GmbH, Germany).

[0452] The known starting materials disclosed herein can be synthesized using or in accordance with methods known in the art, or can be purchased from companies such as ABCR GmbH & Co.KG, Acros Organics, Aldrich Chemical Company, J&K, Accela ChemBio Inc, Shanghai Bid Pharmaceutical, and Darui Chemicals.

[0453] Unless otherwise specified in the examples, all reactions can be carried out under an argon or nitrogen atmosphere.

[0454] Argon or nitrogen atmosphere refers to a reaction flask connected to an argon or nitrogen gas balloon with a volume of approximately 1L.

[0455] A hydrogen atmosphere refers to a reaction flask connected to a hydrogen balloon with a volume of approximately 1L.

[0456] The pressurized hydrogenation reaction was performed using a Parr 3916EKX hydrogenator and a Qinglan QL-500 hydrogen generator or an HC2-SS hydrogenator.

[0457] The hydrogenation reaction is usually carried out under vacuum, filled with hydrogen gas, and repeated 3 times.

[0458] The microwave reaction was performed using a CEM Discover-S 908860 microwave reactor.

[0459] Unless otherwise specified in the examples, "solution" refers to an aqueous solution.

[0460] Unless otherwise specified in the examples, the reaction temperature is room temperature, ranging from 20°C to 30°C.

[0461] The reaction process in the examples was monitored using thin-layer chromatography (TLC). The developing solvent used in the reaction, the eluent system for column chromatography used to purify the compounds, and the developing solvent system for TLC included: A: dichloromethane / methanol system; B: n-hexane / ethyl acetate system. The volume ratio of the solvent was adjusted according to the polarity of the compounds, and small amounts of basic or acidic reagents such as triethylamine and acetic acid could also be added for adjustment.

[0462] Example 1

[0463] 4-(4-(6-(((2-((S)-2,6-dioxopiperidin-3-yl)-1-oxoisoindoline-4-yl)oxy)methyl)-1,2,3,4-tetrahydronaphthyl-1-yl)piperazin-1-yl)-3-fluorobenzonitrile 1

[0464]

[0465] first step

[0466] 5-O-5,6,7,8-Tetrahydronaphthalene-2-carboxylic acid methyl ester 1b

[0467] 5-O-5,6,7,8-tetrahydronaphthalene-2-carboxylic acid 1a (1.0 g, 5.26 mmol, Shanghai Bide Pharmaceutical) was dissolved in 100 mL of methanol. Concentrated sulfuric acid (0.6 mL, 11.0 mmol) was added dropwise under ice bath conditions. After the addition was complete, the reaction mixture was heated to 60 °C and stirred overnight. The mixture was concentrated under reduced pressure to remove most of the methanol, diluted with water (200 mL), and then extracted with ethyl acetate (100 mL × 3). The combined organic phases were washed with saturated sodium chloride solution (100 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure and dried to give crude title compound 1b (1.0 g, yield: 96%).

[0468] MS m / z(ESI):205.2[M+1].

[0469] Step 2

[0470] 5-Hydroxy-5,6,7,8-Tetrahydronaphthalene-2-carboxylic acid methyl ester 1c

[0471] Compound 1b (1.0 g, 4.90 mmol) was dissolved in anhydrous ethanol (20 mL), and potassium borohydride (530 mg, 9.82 mmol) was added in portions under ice bath conditions. The reaction mixture was allowed to rise naturally to room temperature and stirred for 4 hours. The reaction mixture was concentrated, diluted with water (100 mL), and extracted with ethyl acetate (100 mL × 3). The combined organic phases were washed with saturated sodium chloride solution (100 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography using eluent system B to give the title compound 1c (1.0 g, yield: 99%).

[0472] MS m / z(ESI):207.2[M+1].

[0473] Step 3

[0474] 5-Chloro-5,6,7,8-Tetrahydronaphthalene-2-carboxylic acid methyl ester 1d

[0475] Compound 1c (1.0 g, 4.85 mmol) was dissolved in dichloromethane (10 mL), and thionyl chloride (0.6 mL, 8.27 mmol) was added dropwise under ice bath conditions. The reaction was continued to be stirred under ice bath conditions for 2 hours. The reaction was quenched dropwise with ice water (100 mL), and then extracted with dichloromethane (100 mL × 3). The organic phases were combined, washed with saturated sodium chloride solution (100 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography using eluent system B to give the title compound 1d (540 mg, yield: 50%).

[0476] Step 4

[0477] 5-(4-(4-cyano-2-fluorophenyl)piperazin-1-yl)-5,6,7,8-tetrahydronaphthalene-2-carboxylic acid methyl ester 1e

[0478] Compound 1d (520 mg, 2.31 mmol), 3-fluoro-4-(piperazin-1-yl)benzonitrile (720 mg, 3.51 mmol, Shanghai Bide Pharmaceutical) was dissolved in N,N-dimethylformamide (5 mL), and N,N-diisopropylethylamine (2 mL, 12.1 mmol) and tetrabutylammonium bromide (746 mg, 2.31 mmol) were added. The reaction mixture was heated to 50 °C and stirred for 48 hours. The reaction solution was cooled to room temperature, diluted with water (100 mL), and extracted with ethyl acetate (50 mL × 3). The organic phases were combined, washed with saturated sodium chloride solution (100 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography using eluent system B to give the title compound 1e (820 mg, yield: 90%).

[0479] MS m / z(ESI): 394.2 [M+1].

[0480] Step 5

[0481] 3-Fluoro-4-(4-(6-(hydroxymethyl)-1,2,3,4-tetrahydronaphth-1-yl)piperazin-1-yl)benzonitrile 1f

[0482] Compound 1e (500 mg, 1.27 mmol) was dissolved in 22 mL of a mixture of tetrahydrofuran and methanol (V / V = 10:1). Lithium borohydride (275 mg, 12.62 mmol) was added under ice bath conditions, and the reaction was stirred overnight at room temperature. The reaction mixture was quenched with water (50 mL) and then extracted with ethyl acetate (50 mL × 2). The combined organic phases were washed with saturated sodium chloride solution (50 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography using eluent system B to give the title compound 1f (340 mg, yield: 73%).

[0483] MS m / z(ESI): 366.2 [M+1].

[0484] Step 6

[0485] 4-(4-(6-(chloromethyl)-1,2,3,4-tetrahydronaphth-1-yl)piperazin-1-yl)-3-fluorobenzonitrile 1g

[0486] Compound 1f (50 mg, 0.137 mmol) was dissolved in dichloromethane (2 mL), and thionyl chloride (0.1 mL, 1.38 mmol) was added dropwise under ice bath conditions. The reaction was slowly brought to room temperature and stirred for 2 hours. The reaction was quenched with ice water (20 mL), and extracted with dichloromethane (20 mL × 3). The organic phases were combined, washed with saturated sodium chloride solution (20 mL), dried, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography using eluent system A to give 1 g (50 mg, yield: 95%) of the title compound.

[0487] MS m / z(ESI): 384.2 [M+1].

[0488] Step 7

[0489] (4S)-5-amino-4-(4-((5-(4-(4-cyano-2-fluorophenyl)piperazin-1-yl)-5,6,7,8-tetrahydronaphthyl-2-yl)methoxy)-1-oxoisoindolin-2-yl)-5-oxopentanoic acid tert-butyl ester 1i

[0490] 1 g (50 mg, 0.130 mmol) of compound tert-butyl (S)-5-amino-4-(4-hydroxy-1-oxoisoindoline-2-yl)-5-oxovalerate 1 h (46 mg, 0.137 mmol, prepared by the method disclosed in "Journal of Medicinal Chemistry, 2020, 63(13), 6648-6676") was dissolved in N,N-dimethylformamide (2 mL), and anhydrous potassium carbonate (72 mg, 0.521 mmol) and tetrabutylammonium bromide (42 mg, 0.130 mmol) were added. The reaction mixture was heated to 60 °C and stirred for 4 hours. The reaction solution was diluted with water (20 mL) and extracted with ethyl acetate (20 mL × 3). The organic phases were combined, washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography using eluent system A to give the title compound 1i (85 mg, yield: 95%).

[0491] MS m / z(ESI): 682.3 [M+1].

[0492] Step 8

[0493] 4-(4-(6-(((2-((S)-2,6-dioxopiperidin-3-yl)-1-oxoisoindoline-4-yl)oxy)methyl)-1,2,3,4-tetrahydronaphthyl-1-yl)piperazin-1-yl)-3-fluorobenzonitrile 1

[0494] Compound 1i (90 mg, 0.132 mmol) was dissolved in acetonitrile (12 mL), and benzenesulfonic acid (63 mg, 0.396 mmol) was added. The reaction mixture was heated to 85 °C and stirred overnight. The reaction solution was concentrated under reduced pressure, and the residue was prepared by high performance liquid chromatography (Gilson GX-281, mobile phase: 10 mmol / L ammonium bicarbonate aqueous solution and acetonitrile, acetonitrile gradient: 45%-55%, flow rate: 30 mL / min) to give title compound 1 (45 mg, yield: 56%).

[0495] MS m / z(ESI): 608.2 [M+1].

[0496] 1 H NMR(500MHz,DMSO-d6)δ11.0(s,1H),7.70(dd,1H),7.86(d,1H),7.58(dd,1H),7.50 (t,1H),7.39-7.31(m,2H),7.28(d,1H),7.19(s,1H),7.13(t,1H),5.18(s,2H),5.12 (dd,1H),4.41(d,1H),4.25(d,1H),3.93-3.80(m,1H),3.38-3.10(m,4H),2.99-2.85 (m,1H),2.81-2.54(m,7H),2.48-2.40(m,1H),2.03-1.87(m,3H),1.74-1.57(m,2H).

[0497] Example 2-1

[0498] 4-(4-((S)-6-(((2-((S)-2,6-dioxopiperidin-3-yl)-1-oxoisoindoline-4-yl)oxy)methyl)-1,2,3,4-tetrahydronaphth-1-yl)piperazin-1-yl)-3-fluorobenzonitrile 2-1

[0499]

[0500] first step

[0501] (S)-3-fluoro-4-(4-(6-(hydroxymethyl)-1,2,3,4-tetrahydronaphth-1-yl)piperazin-1-yl)benzonitrile 1f-1

[0502] (R)-3-fluoro-4-(4-(6-(hydroxymethyl)-1,2,3,4-tetrahydronaphth-1-yl)piperazin-1-yl)benzonitrile 1f-2

[0503] Compound 1f (2.0 g) was chirally resolved (separation conditions: Shimadzu LC-20AP, column: CHIRALPAKAY (20×250 mM), mobile phase: n-hexane / 10 mmol / L ammonia (NH3) in ethanol = 70 / 30 (v / v)), flow rate 20 mL / min) to give title compounds 1f-1 (730 mg) and 1f-2 (830 mg).

[0504] Compound 1f-2:

[0505] MS m / z(ESI): 366.2 [M+1].

[0506] Chiral HPLC analysis method: retention time 4.27 min (Agilent 1260DAD, column: CHIRALPAK AY (4.6×150 mM), 5 μm; mobile phase: n-hexane / ethanol (containing 0.1% diethylamine) = 70 / 30 (v / v)), flow rate 1 mL / min).

[0507] Compound 1f-1:

[0508] MS m / z(ESI): 366.2 [M+1].

[0509] Chiral HPLC analysis method: retention time 5.43 min (Agilent 1260DAD, column: CHIRALPAK AY (4.6×150 mM), 5 μm; mobile phase: n-hexane / ethanol (containing 0.1% diethylamine) = 70 / 30 (v / v)), flow rate 1 mL / min).

[0510] Step 2

[0511] (S)-4-(4-(6-(chloromethyl)-1,2,3,4-tetrahydronaphth-1-yl)piperazin-1-yl)-3-fluorobenzonitrile 1g-1

[0512] Compound 1f-1 (730 mg, 2.0 mmol) was dissolved in dichloromethane (10 mL), and thionyl chloride (1.31 g, 11.03 mmol) was added dropwise under ice bath conditions. The reaction was slowly raised to room temperature and stirred for 4 hours. The reaction was quenched with ice water (20 mL), and extracted with dichloromethane (50 mL × 3). The organic phases were combined, washed with saturated sodium chloride solution (30 mL × 2), dried, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography using eluent system A to give the title compound 1g-1 (760 mg, yield: 99%).

[0513] MS m / z(ESI): 384.2 [M+1].

[0514] Step 3

[0515] (S)-5-amino-4-(4-(((S)-5-(4-(4-cyano-2-fluorophenyl)piperazin-1-yl)-5,6,7,8-tetrahydronaphthyl-2-yl)methoxy)-1-oxoisoindolin-2-yl)-5-oxovalerate tert-butyl ester 1i-1

[0516] Compound 1g-1 (730 mg, 1.90 mmol) and compound 1h (640 mg, 1.91 mmol) were dissolved in N,N-dimethylformamide (10 mL), and anhydrous potassium carbonate (790 mg, 5.72 mmol) and tetrabutylammonium bromide (620 mg, 1.92 mmol) were added. The reaction mixture was heated to 40 °C and stirred for 6 hours. The reaction mixture was diluted with water (20 mL) and extracted with ethyl acetate (50 mL × 3). The organic phases were combined, washed with saturated sodium chloride solution (30 mL × 2), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography using eluent system A to give the title compound 1i-1 (930 mg, yield: 72%).

[0517] MS m / z(ESI): 682.3 [M+1].

[0518] Step 4

[0519] 4-(4-((S)-6-(((2-((S)-2,6-dioxopiperidin-3-yl)-1-oxoisoindoline-4-yl)oxy)methyl)-1,2,3,4-tetrahydronaphth-1-yl)piperazin-1-yl)-3-fluorobenzonitrile 2-1

[0520] Compound 1i-1 (930 mg, 1.36 mmol) was dissolved in acetonitrile (15 mL), and benzenesulfonic acid (650 mg, 4.11 mmol) was added. The reaction mixture was heated to 85 °C and stirred overnight. The reaction solution was concentrated under reduced pressure, and the residue was subjected to high performance liquid chromatography (Gilson GX-281, mobile phase: 10 mmol / L ammonium bicarbonate aqueous solution and acetonitrile, acetonitrile gradient: 45%-55%, flow rate: 30 mL / min) to give title compound 2-1 (510 mg, yield: 62%).

[0521] MS m / z(ESI): 608.2 [M+1].

[0522] 1H NMR(500MHz,DMSO-d6)δ10.98(s,1H),7.69(dd,1H),7.66(d,1H),7.57(dd,1H),7.50 (t,1H),7.39-7.31(m,2H),7.29(d,1H),7.20(s,1H),7.14(t,1H),5.18(s,2H),5.12 (dd,1H),4.42(d,1H),4.26(d,1H),3.93-3.80(m,1H),3.28-3.12(m,4H),2.99-2.85 (m,1H),2.82-2.54(m,7H),2.48-2.40(m,1H),2.05-1.87(m,3H),1.78-1.58(m,2H).

[0523] Example 2-2

[0524] 4-(4-((R)-6-(((2-((S)-2,6-dioxopiperidin-3-yl)-1-oxoisoindoline-4-yl)oxy)methyl)-1,2,3,4-tetrahydronaphth-1-yl)piperazin-1-yl)-3-fluorobenzonitrile 2-2

[0525]

[0526] Following the synthetic route of Example 2-1, compound 1f-1 was replaced with compound 1f-2 (830 mg) to obtain title compound 2-2 (640 mg).

[0527] MS m / z(ESI): 608.2 [M+1].

[0528] 1 H NMR(500MHz,DMSO-d6)δ10.98(s,1H),7.69(dd,1H),7.66(d,1H),7.57(dd,1H),7.50 (t,1H),7.39-7.31(m,2H),7.28(d,1H),7.19(s,1H),7.14(t,1H),5.18(s,2H),5.12 (dd,1H),4.42(d,1H),4.26(d,1H),3.93-3.80(m,1H),3.28-3.12(m,4H),2.99-2.85 (m,1H),2.81-2.54(m,7H),2.48-2.40(m,1H),2.05-1.87(m,3H),1.75-1.57(m,2H).

[0529] Example 3

[0530] 4-(4-(5-(((2-((S)-2,6-dioxopiperidin-3-yl)-1-oxoisoindoline-4-yl)oxy)methyl)-2,3-dihydro-1H-indene-1-yl)piperazin-1-yl)-3-fluorobenzonitrile 3

[0531]

[0532] first step

[0533] 1-Oxo-2,3-dihydro-1H-indene-5-carboxylic acid methyl ester 3b

[0534] Compound 1-oxo-2,3-dihydro-1H-indene-5-carboxylic acid 3a (1.0 g, 5.68 mmol, Shanghai Haohong Biomedical Technology Co., Ltd.) was dissolved in 100 mL of methanol. Concentrated sulfuric acid (0.7 mL, 12.9 mmol, 98% by mass) was added dropwise under ice bath conditions. After the addition was complete, the reaction was heated to 60 °C and stirred overnight. Most of the methanol was removed by vacuum concentration, diluted with water (200 mL), and then extracted with ethyl acetate (100 mL × 3). The combined organic phases were washed with saturated sodium chloride solution (100 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under vacuum and dried under vacuum to give the crude title compound 3b (1.05 g, yield: 97%).

[0535] MS m / z(ESI):191.1[M+1].

[0536] Step 2

[0537] 1-Hydroxy-2,3-dihydro-1H-indene-5-carboxylic acid methyl ester 3c

[0538] Compound 3b (1.05 g, 5.5 mmol) was dissolved in methanol (20 mL), and potassium borohydride (800 mg, 14.3 mmol) was added in portions under ice bath conditions. The mixture was allowed to rise naturally to room temperature and reacted for 4 hours. The reaction solution was concentrated, diluted with water (100 mL), and extracted with ethyl acetate (100 mL × 3). The organic phases were combined, washed with saturated sodium chloride solution (100 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography using eluent system B to give the title compound 3c (1.0 g, yield: 99%).

[0539] MS m / z(ESI):193.1[M+1].

[0540] Step 3

[0541] 1-Chloro-2,3-dihydro-1H-inden-5-carboxylic acid methyl ester 3d

[0542] Compound 3c (2.0 g, 10.4 mmol) was dissolved in dichloromethane (10 mL), and thionyl chloride (1.5 mL, 20.7 mmol) was added dropwise under ice bath conditions. The reaction mixture was reacted under ice bath conditions for 2 hours. The reaction solution was quenched dropwise with ice water (100 mL), and then extracted with dichloromethane (100 mL × 3). The organic phases were combined, washed with saturated sodium chloride solution (100 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography using eluent system B to give the title compound 3d (1.0 g, yield: 46%).

[0543] Step 4

[0544] 1-(4-(4-cyano-2-fluorophenyl)piperazin-1-yl)-2,3-dihydro-1H-indene-5-carboxylic acid methyl ester 3e

[0545] Compound 3d (1.0 g, 4.7 mmol) and 3-fluoro-4-piperazinylbenzonitrile (1.02 g, 4.9 mmol) were dissolved in N,N-dimethylformamide (5 mL), and N,N-diisopropylethylamine (4 mL, 24.2 mmol) and tetrabutylammonium bromide (155 mg, 0.48 mmol) were added. The mixture was heated to 50 °C and reacted for 3 hours. After cooling to room temperature, the reaction mixture was diluted with water (100 mL) and extracted with ethyl acetate (50 mL × 3). The organic phases were combined, washed with saturated sodium chloride solution (100 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography using eluent system B to give the title compound 3e (500 mg, yield: 28%).

[0546] MS m / z(ESI): 380.1 [M+1].

[0547] Step 5

[0548] 3-Fluoro-4-(4-(5-(hydroxymethyl)-2,3-dihydro-1H-inden-1-yl)piperazin-1-yl)benzonitrile 3f

[0549] Compound 3e (500 mg, 1.32 mmol) was dissolved in 11 mL of a mixture of tetrahydrofuran and methanol (V / V = 10 / 1). Lithium borohydride (140 mg, 6.4 mmol) was added under ice bath conditions, and the reaction was stirred at room temperature for 12 hours. The reaction mixture was quenched with water (50 mL) and then extracted with ethyl acetate (50 mL × 2). The organic phases were combined, washed with saturated sodium chloride solution (50 mL), and dried over anhydrous sodium sulfate. The mixture was filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography using eluent system B to give the title compound 3f (210 mg, yield: 43%).

[0550] MS m / z(ESI): 352.2 [M+1].

[0551] Step 6

[0552] 4-(4-(5-(chloromethyl)-2,3-dihydro-1H-inden-1-yl)piperazin-1-yl)-3-fluorobenzonitrile 3g

[0553] Compound 3f (80 mg, 0.228 mmol) was dissolved in dichloromethane (2 mL), and thionyl chloride (0.1 mL, 1.38 mmol) was added dropwise under ice bath conditions. The mixture was slowly brought to room temperature and reacted for 2 hours. The reaction solution was quenched with ice water (20 mL) and then extracted with dichloromethane (20 mL × 2). The organic phases were combined, washed with saturated sodium chloride solution (20 mL), dried, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography using eluent system A to give the title compound 3 g (76 mg, yield: 90%).

[0554] MS m / z(ESI): 370.1 [M+1].

[0555] Step 7

[0556] (4S)-5-amino-4-(4-((1-(4-(4-cyano-2-fluorophenyl)piperazin-1-yl)-2,3-dihydro-1H-inden-5-yl)methoxy)-1-oxoisoindolin-2-yl)-5-oxovalerate tert-butyl ester 3h

[0557] Compound 3 g (76 mg, 0.205 mmol) and compound 1 h (70 mg, 0.209 mmol) were dissolved in N,N-dimethylformamide (1 mL), and anhydrous potassium carbonate (57 mg, 0.412 mmol) and tetrabutylammonium bromide (66 mg, 0.205 mmol) were added. The mixture was heated to 60 °C and reacted for 4 hours. The reaction solution was diluted with water (20 mL) and extracted with ethyl acetate (20 mL × 2). The organic phases were combined, washed with saturated sodium chloride solution (20 mL), dried, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography using eluent system A to give the title compound 3 h (102 mg, yield: 74%).

[0558] MS m / z(ESI): 668.3 [M+1].

[0559] Step 8

[0560] 4-(4-(5-(((2-((S)-2,6-dioxopiperidin-3-yl)-1-oxoisoindoline-4-yl)oxy)methyl)-2,3-dihydro-1H-indene-1-yl)piperazin-1-yl)-3-fluorobenzonitrile 3

[0561] Compound 3h (100 mg, 0.150 mmol) was dissolved in acetonitrile (10 mL), and benzenesulfonic acid (72 mg, 0.455 mmol) was added. The mixture was heated to 85 °C and reacted overnight. The reaction solution was concentrated under reduced pressure, and the residue was prepared by high performance liquid chromatography (Gilson GX-281, mobile phase: 10 mmol / L ammonium bicarbonate aqueous solution and acetonitrile, acetonitrile gradient: 45%-63%, flow rate: 30 mL / min) to give title compound 3 (67 mg, yield: 75%).

[0562] MS m / z(ESI): 594.2 [M+1].

[0563] 1 H NMR(500MHz,DMSO-d6)δ10.99(s,1H),7.69(dd,1H),7.57(dd,1H),7.50(t,1H),7.39-7.30(m,5H),7.12(t,1H),5.23(s,2H),5.12(dd,1H),4.42(d ,1H),4.35(t,1H),4.26(d,1H),3.25-3.10(m,4H),3.00-2.86(m,2H),2. 84-2.73(m,1H),2.70-2.53(m,4H),2.48-2.38(m,1H),2.15-1.92(m,4H).

[0564] Examples 4-1, 4-2

[0565] 4-(4-((S)-5-(((2-((S)-2,6-dioxopiperidin-3-yl)-1-oxoisoindoline-4-yl)oxy)methyl)-2,3-dihydro-1H-indene-1-yl)piperazin-1-yl)-3-fluorobenzonitrile 4-1

[0566] 4-(4-((R)-5-(((2-((S)-2,6-dioxopiperidin-3-yl)-1-oxoisoindoline-4-yl)oxy)methyl)-2,3-dihydro-1H-indene-1-yl)piperazin-1-yl)-3-fluorobenzonitrile 4-2

[0567]

[0568] Split:

[0569] Compound 3f (180 mg) was chirally separated (separation conditions: Shimadzu LC-20AP, column: CHIRALPAK OJ (20×250 mM), mobile phase: n-hexane / 10 mmol / L ammonia (NH3) in ethanol = 70 / 30 (v / v)), flow rate 20 mL / min) to obtain compound 3f-1 (70 mg) and compound 3f-2 (80 mg).

[0570] Compound 3f-1:

[0571] MS m / z(ESI): 352.2 [M+1].

[0572] Chiral HPLC analysis method: retention time 3.90 min (Agilent 1260DAD, column: CHIRALPAK OJ (4.6×150 mM), 5 μm; mobile phase: n-hexane / ethanol (containing 0.1% diethylamine) = 60 / 40 (v / v)), flow rate 1 mL / min).

[0573] Compound 3f-2:

[0574] MS m / z(ESI): 352.2 [M+1].

[0575] Chiral HPLC analysis method: retention time 4.68 min (Agilent 1260DAD, column: CHIRALPAK OJ (4.6×150 mM), 5 μm; mobile phase: n-hexane / ethanol (containing 0.1% diethylamine) = 60 / 40 (v / v)), flow rate 1 mL / min).

[0576] Following the synthetic route of compound 3, 3f was replaced with compound 3f-1 (70 mg) to obtain compound 4-1 (59 mg).

[0577] Following the synthetic route of compound 3, 3f was replaced with compound 3f-2 (80 mg) to obtain compound 4-2 (63 mg).

[0578] Compound 4-1 (59 mg):

[0579] MS m / z(ESI): 594.2 [M+1].

[0580] 1H NMR(500MHz,DMSO-d6)δ10.99(s,1H),7.69(dd,1H),7.57(dd,1H),7.50(t,1H),7.42-7.27(m,5H),7.12(t,1H),5.23(s,2H),5.12(dd,1H),4.42(d ,1H),4.35(t,1H),4.26(d,1H),3.25-3.10(m,4H),3.00-2.85(m,2H),2. 84-2.75(m,1H),2.72-2.53(m,4H),2.48-2.38(m,1H),2.15-1.90(m,4H).

[0581] Compound 4-2 (63 mg):

[0582] MS m / z(ESI): 594.2 [M+1].

[0583] 1 H NMR(500MHz,DMSO-d6)δ10.98(s,1H),7.69(dd,1H),7.57(dd,1H),7.50(t,1H),7.40-7.30(m,5H),7.12(t,1H),5.23(s,2H),5.12(dd,1H),4.42(d ,1H),4.35(t,1H),4.26(d,1H),3.25-3.10(m,4H),2.98-2.86(m,2H),2. 84-2.73(m,1H),2.70-2.53(m,4H),2.48-2.38(m,1H),2.13-1.92(m,4H).

[0584] Biological evaluation

[0585] The following test examples further describe and explain this disclosure, but these test examples are not intended to limit the scope of this disclosure.

[0586] Test Example 1: Biological Evaluation of NCI-H929 Proliferation Experiment

[0587] The following method was used to determine the inhibitory activity of the disclosed compound on the proliferation of NCI-H929 cells. The experimental method is briefly described below:

[0588] NCI-H929 cells (ATCC, CRL-9068) were cultured in complete medium (RPMI 1640 medium (Hyclone, SH30809.01) containing 10% fetal bovine serum (Corning, 35-076-CV) and 0.05 mM 2-mercaptoethanol (Sigma, M3148)). On the first day of the experiment, H929 cells were seeded at a density of 6000 cells / well in 96-well plates using complete medium, with 100 μL of cell suspension per well. Simultaneously, 10 μL of serially diluted test compounds prepared in complete medium were added to each well. The compounds were first dissolved in DMSO at an initial concentration of 10 mM, and then serially diluted 5-fold to a total of 9 concentration points. The blank control was 100% DMSO. Then, 5 μL of the DMSO-dissolved compound was added to 95 μL of complete medium, resulting in a 20-fold dilution of the compound in complete medium. Finally, 10 μL of the compound diluted in complete culture medium was added to each well of the cell suspension, resulting in nine concentration points representing a five-fold serial dilution starting from 50 μM. A blank control containing 0.5% DMSO was included. The cells were incubated at 37°C in a 5% CO2 cell culture incubator for 5 days. On the sixth day, 50 μL of the compound was added to each well of the 96-well cell culture plate. The luminescent cell activity assay reagent (Promega, G7573) was incubated at room temperature for 10 minutes. The luminescence signal values ​​were then read using a multi-functional microplate reader (PerkinElmer, EnVision2015). The IC50 of the compound's inhibitory activity was calculated using Graphpad Prism software. 50 The values ​​are shown in Table 1.

[0589] Table 1 shows the inhibitory activity of the disclosed compounds on the proliferation of NCI-H929 cells.

[0590] compound <![CDATA[IC 50 (nM) <!-- 68 -->]]> Example 1 0.3 Example 2-1 0.17 Example 2-2 1.48 Example 3 0.07 Example 4-1 0.02 Example 4-2 0.31

[0591] Conclusion: The compound disclosed herein exhibits excellent activity in inhibiting the proliferation of NCI-H929 cells.

[0592] Test Example 2: Efficacy Test

[0593] 1. Experimental Objective

[0594] Evaluation of the inhibitory effects of compound 2-1 and CC-92480 on the growth of human multiple myeloma cell NCI-H929 (lenalidomide-resistant strain) xenografts in CB-17SCID mice.

[0595] 2 Experimental drugs

[0596] Compound of Example 2-1;

[0597] CC-92480: (Synthesized according to the method of Example 2 of WO2019014100A1);

[0598] Both were prepared with 5% DMSO + 20% PEG400 + 70% (10% TPGS) + 5% (1% HPMC K100LV).

[0599] 3 Experimental methods and materials

[0600] 3.1 Experimental animals and feeding conditions

[0601] Experimental animals: CB-17 SCID female mice, purchased from Beijing Vital River Laboratory Animal Technology Co., Ltd. (Certificate number: 20170011006049, SCXK (Shanghai) 2017-0011), with a body weight of about 19 g when purchased.

[0602] Feeding conditions: Raised at 5 animals per cage, with a 12 / 12-hour light / dark cycle adjustment, a constant temperature of 23 ± 1 °C, a humidity of 50 to 60%, and free access to food and water.

[0603] 3.2 Animal grouping

[0604] After the CB-17 SCID mice were adaptively raised, the grouping was as follows:

[0605]

[0606] Note: qd means administered once a day; i.g. means administered by gavage.

[0607] 3.3 Experimental method:

[0608] 5×10 6 Cells / mouse / 100 μL (containing 50 μL of Matrigel) were inoculated subcutaneously into the right rib of female CB-17 SCID mice. After 11 days, when the tumor volume of the tumor-bearing mice reached about 130 mm 3 , the mice were randomly divided into 6 groups according to tumor volume and body weight: vehicle control group, CC-92480-0.1 mpk, CC-92480-1 mpk, Example 2-1-0.1 mpk, Example 2-1-0.3 mpk, and Example 2-1-1 mpk, with 8 mice in each group. The day of grouping was set as D0, and gavage administration was started once a day for a total of 14 days. The 14th day after administration was set as D14 (Table 2). The tumor volume of the tumor-bearing mice was measured twice a week with a vernier caliper and the body weight was measured with a balance and the data were recorded. When the tumor volume reached 2000 mm 3 or most tumors showed ulceration or the body weight decreased by 20%, the tumor-bearing animals were euthanized as the experimental endpoint.

[0609] 3.4 Data statistics

[0610] All data were plotted and statistically analyzed using Excel and GraphPad Prism 5 software.

[0611] The formula for calculating tumor volume (V) is: V = 1 / 2 × a × b 2 Where a and b represent length and width, respectively.

[0612] The relative tumor proliferation rate T / C (%) = (T-T0) / (C-C0) × 100 (%), where T and C are the tumor volumes of the treatment group and the control group at the end of the experiment; T0 and C0 are the tumor volumes at the beginning of the experiment.

[0613] Tumor inhibition rate TGI (%) = 1 - T / C (%). When TGI (%) exceeds 100%, the specific value will not be displayed, but only >100% will be used.

[0614] Tumor regression (%) = [(T0-T) / T0] × 100 (%).

[0615] 4 Results

[0616] Example 2-1: Efficacy data of compounds and CC-92480 against NCI-H929 xenografts in CB-17 SCID mice are shown in Table 2 and... Figure 1 .

[0617] The effects of compound 2-1 and CC-92480 on body weight of CB-17 SCID mice are shown in Example 2-1. Figure 2 .

[0618] Table 2. Efficacy of the disclosed compounds against NCI-H929 xenografts in CB-17 SCID mice.

[0619]

[0620] Note: qd means once a day; d means day; ig means gavage; SEM means standard error.

[0621] 5. Conclusion

[0622] In Example 2-1, the compound was administered once daily, starting 11 days after tumor cell transplantation. After 14 days of administration, the tumor inhibition rate was 74% in the low-dose (0.1 mpk) group, 91% in the medium-dose (0.3 mpk) group, and 5% in the high-dose (1 mpk) group, with no effect on mouse body weight. Under the same conditions, the tumor inhibition rate of CC-92480 was 37% in the low-dose (0.1 mpk) group and 91% in the high-dose (1 mpk) group, with no tumor regression.

[0623] Test Example 3: Pharmacokinetic Evaluation

[0624] 1 Overview

[0625] Using beagle dogs as test animals, the plasma drug concentrations at different time points after gavage administration of the compound of Example 2-1 and CC-92480 were determined by LC / MS / MS. The pharmacokinetic behavior of the disclosed compound in beagle dogs was investigated to evaluate its pharmacokinetic characteristics.

[0626] 2. Test Plan

[0627] 2.1 Test Drugs

[0628] Example 2-1: Compound and CC-92480.

[0629] 2.2 Experimental Animals

[0630] Example 2-1: Four beagle dogs (half male and half female) were used for the compound and divided into two groups. Three male beagle dogs were used for CC-92480. All were provided by Shanghai Medicilon Biopharmaceutical Co., Ltd.

[0631] 2.3 Drug Preparation

[0632] Weigh the compound from Example 2-1, add 5% DMSO, 30% PG and 30% PEG400 to dissolve it, and then add 35% physiological saline to prepare the solution.

[0633] Weigh CC-92480, add 5% DMSO, 30% PG and 30% PEG400 to dissolve it, and then add 35% physiological saline to prepare the solution.

[0634] 2.4 Administration

[0635] After fasting overnight, the drug was administered by gavage. The dosage of both compound 2-1 and CC-92480 was 2 mg / kg, and the administration volume was 5 mL / kg.

[0636] 3 Operations

[0637] For the administration of compound 2-1 and CC-92480 via gavage, 1 mL of blood was collected before administration and at 0.25 h, 0.5 h, 1 h, 2 h, 4 h, 6 h, 8 h, 12 h, and 24 h after administration. The blood samples were placed in EDTA-K2 anticoagulant tubes, centrifuged at 10000 rpm for 5 minutes (4 °C), and plasma was separated within 1 hour and stored at -80 °C. Food was consumed 3 hours after administration. The blood collection and centrifugation process was performed under ice bath conditions.

[0638] The content of the analyte compound in beagle dog plasma after administration of different drug concentrations was determined: 20 μL of beagle dog plasma was collected at each time point after drug administration, and internal standard solution (100 ng / mL tolbutamide for the compound in Example 2-1, and 100 ng / mL camptothecin for CC-92480) and 400 μL of methanol were added. The mixture was vortexed for 1 min and centrifuged for 10 min (18000 g). 200 μL of the supernatant was transferred to a 96-well plate. 1 μL of the supernatant from the plasma sample was analyzed by LC / MS / MS.

[0639] 4. Pharmacokinetic Parameter Results

[0640] The pharmacokinetic parameters of the compounds disclosed herein are shown in Table 3 below.

[0641] Table 3 Pharmacokinetic parameters of the compounds disclosed herein

[0642]

[0643] Conclusion: The compound of Example 2-1 of this disclosure has better pharmacokinetic absorption than CC-92480 and has pharmacokinetic advantages.

Claims

1. A compound of general formula (I) or a pharmaceutically acceptable salt thereof: in: G 1 G 2 and G 3 Whether the same or different, and each independently constitutes a CR 8 ; Z is CR a R b ; R a and R b They may be the same or different, and each is independently selected from hydrogen atoms, halogens, and carbon atoms. 1-6 Alkyl and C 1-6 Halogenated alkyl groups; X is CH2 or C(O); Y represents an oxygen atom or NH; Ring A is a 6- to 10-membered aryl or a 5- to 10-membered heteroaryl; R 1 Selected from hydrogen atoms, halogens and C 1-6 alkyl; R 2 They may be the same or different each time they appear, and each is independently selected from hydrogen atoms, halogens, and carbon atoms. 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups, C 1-6 Hydroxyl and cyano groups; R 3 and R 4 They may be the same or different, and each is independently selected from hydrogen atoms, halogens, and carbon atoms. 1-6 alkyl; R 5 They may be the same or different each time they appear, and each is independently selected from hydrogen atoms, halogens, and carbon atoms. 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Haloalkoxy, oxo, and cyano groups; R 6 They may be the same or different each time they appear, and each is independently selected from hydrogen atoms, halogens, and carbon atoms. 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy and cyano groups; R 7 It is cyano; R 8 They may be the same or different each time they appear, and each is independently selected from hydrogen atoms, halogens, and carbon atoms. 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl groups and C 1-6 Halogenated alkoxy groups; n is 1, 2, or 3; m can be 0, 1, 2, or 3; p is 0, 1, 2, 3, or 4; and q can be 0, 1, 2, 3 or 4.

2. The compound of formula (I) according to claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound is of formula (I-1), formula (I-1-1), or formula (I-1-2), or a pharmaceutically acceptable salt thereof: in: Rings A, X, Y, Z, G 1 G 2 G 3 R 1 To R 7 m, n, p and q are as defined in claim 1.

3. The compound of formula (I) according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein Y is an oxygen atom.

4. The compound of general formula (I) according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein R 3 and R 4 All are hydrogen atoms.

5. The compound of general formula (I) according to claim 1 or 2, wherein the compound is of general formula (II), general formula (II-1), general formula (II-1-1) or general formula (II-1-2), or a pharmaceutically acceptable salt thereof: in: Rings A, X, Z, G 1 G 2 G 3 R 1 R 2 R 5 To R 7 m, n, p and q are as defined in claim 1.

6. The compound of general formula (I) according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein X is CH2.

7. The compound of general formula (I) according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein R a and R b They are identical, and each is independently a hydrogen atom or a halogen.

8. The compound of general formula (I) according to claim 1 or 2, wherein the compound is of general formula (III), general formula (III-1), general formula (III-1-1) or general formula (III-1-2) or a pharmaceutically acceptable salt thereof: in: Rings A and G 1 G 2 G 3 R 1 R 2 R 5 To R 7 m, n, p and q are as defined in claim 1.

9. The compound of general formula (I) according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein G 1 G 2 and G 3 All are CR 8 ;R 8 It is a hydrogen atom.

10. The compound of general formula (I) according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein ring A is a 6- to 10-membered aryl group.

11. The compound of general formula (I) according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein ring A is phenyl.

12. The compound of general formula (I) according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein R 1 It is a hydrogen atom.

13. The compound of formula (I) according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein R 2 It is a hydrogen atom.

14. The compound of general formula (I) according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein R 5 They may be the same or different each time they appear, and each is independently a hydrogen atom or a carbon atom. 1-6 alkyl.

15. The compound of general formula (I) according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein R 5 It is a hydrogen atom.

16. The compound of general formula (I) according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein R 6 They may be the same or different each time they appear, and each is independently selected from hydrogen atoms, halogens, and carbon atoms. 1-6 Alkyl and C 1-6 Halogenated alkyl groups.

17. The compound of formula (I) according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein R 6 It is a halogen.

18. The compound of general formula (I) according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein R 6 It is a fluorine atom.

19. The compound of formula (I) according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein q is 0, 1 or 2.

20. The compound of formula (I) according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein q is 1.

21. The compound of formula (I) according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein n is 1 or 2.

22. The compound of formula (I) according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein n is 2.

23. The compound of general formula (I) according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, selected from the following compounds:

24. A compound of general formula (IA) or a salt thereof, in: R m C 1-6 alkyl; Rings A, X, Y, Z, G 1 G 2 G 3 R 1 To R 7 m, n, p and q are as defined in claim 1.

25. The compound or a salt thereof according to claim 24, wherein R m It is tert-butyl.

26. The compound or a salt thereof according to claim 24, wherein the compound is selected from the group consisting of:

27. A method for preparing a compound of general formula (I) or a pharmaceutically acceptable salt thereof, the method comprising: The compound represented by general formula (IA) or its salt undergoes an intramolecular cyclization reaction to yield the compound represented by general formula (I) or its pharmaceutically usable salt. in: R m C 1-6 alkyl; Rings A, X, Y, Z, G 1 G 2 G 3 R 1 To R 7 m, n, p and q are as defined in claim 1.

28. The method of claim 27, wherein R m It is tert-butyl.

29. A pharmaceutical composition comprising a compound of formula (I) according to any one of claims 1 to 23 or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, diluents or excipients.

30. Use of the compound of general formula (I) according to any one of claims 1 to 23, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 29, in the preparation of a medicament for treating and / or preventing cancer, wherein the cancer is myeloma.

31. The use according to claim 30, wherein the myeloma is multiple myeloma and myelodysplastic syndrome.

32. The use according to claim 30, wherein the multiple myeloma is relapsed, refractory, or resistant.

33. The use according to claim 30, wherein the multiple myeloma is lenalidomide or pomalidomide refractory or resistant.

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