TW202241872A - Cyclohexadiimide derivatives substituted by fused heterocyclyl, preparation method and medical use thereof - Google Patents

Abstract

The present disclosure relates to cyclohexadiimide derivatives substituted by fused heterocyclyl, preparation methods and medical use thereof. Specifically, the present disclosure relates to a cyclohexadiimide derivative substituted by fused heterocyclyl represented by general formula (I), a preparation method thereof, a pharmaceutical composition containing the derivative, and its use as a therapeutic agent, in particular as a Cereblon modulator in the treatment of multiple myeloma.

Description

Cyclohexanediimide derivative substituted by fused heterocyclic group, its preparation method and its application in medicine

The disclosure belongs to the field of medicine, and relates to a cycloadipamide derivative substituted by a condensed heterocyclic group, its preparation method and its application in medicine. In particular, the present disclosure relates to condensed heterocyclic group substituted cycloadipamide derivatives represented by general formula (I), their preparation methods and pharmaceutical compositions containing the derivatives, and their use as Cereblon regulators in Use in the field of treating multiple myeloma.

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 next to non-Hodgkin's lymphoma, with 4 to 6 cases per 100,000 people globally and 1.6 cases per 100,000 people in China each year. The current treatment methods are mainly drug therapy and autologous stem cell transplantation. At present, there are four main categories of drugs that are widely used clinically, namely immunomodulators of the amine class, proteasome inhibitors, Hormones and monoclonal antibodies; drugs in the clinical research stage include double antibodies, ADC, CAR-T, etc. These drugs have different mechanisms of action, and combined use can often achieve better curative effect. Clinically, dual, triple, or even quadruple drugs are generally used, usually in combination with immunomodulators, proteasome inhibitors and hormones, sometimes Antibodies will be added. Among them, lenalidomide is the most commonly used immunomodulator. Lenalidomide will be used in first-line treatment, maintenance treatment after stem cell transplantation, and second- and third-line treatment after relapse. Sales of the drug reached $9.7 billion in 2018/2019. In addition, the entire MM market is also considerable and growing rapidly. This is due to the continuous improvement and perfection of the diagnosis and treatment of MM, the longer survival period of patients, and the corresponding extension of medication time. It is estimated that the MM market will reach a scale of 33 billion US dollars in 2022, of which the largest proportion is still the immunomodulator represented by lenalidomide.

The mechanism of action of immunomodulators (IMiDs for short) in the treatment of MM is that after the IMiDs drug binds to the Cereblon (CRBN) protein, it will activate the E3 ligase activity of CRBN, and then selectively bind to the transcription factors Ikaros (IKZF1) and Aiolos (IKZF3 ) binding; resulting in rapid ubiquitination and degradation of Ikaros and Aiolos. Downregulation of Ikaros/Aiolos leads to downregulation of c-Myc, followed by downregulation of IRF4, which finally leads to growth inhibition and apoptosis of myeloma cells. In addition, IKZF3 can also inhibit the transcription of IL2 and TNF cytokines in T/NK cells. After IKZF3 is degraded, this inhibition can be released to promote the release of these cytokines and play a role in immune regulation. Clinical trials have also shown that the clinical benefits of IMiDs drugs are also correlated with the level of CRBN expression. After knocking down CRBN in lenalidomide-sensitive cell lines (OPM2 and KMS18), it was found that the activity of lenalidomide to inhibit cell growth disappeared, resulting in drug resistance, and the level of CRBN knockdown was related to the degree of drug resistance; in cell proliferation experiment Among them, reducing the expression level of CRBN in cells (U266-CRBN60 and U266-CRBN75), the inhibitory activity of lenalidomide and pomalidomide on cell growth was reduced.

The currently approved IMiDs drugs include thalidomide, lenalidomide and pomalidomide, all of which come from Celgene (currently merged by BMS). The binding force between these three compounds and CRBN is enhanced sequentially, so the clinical dosage is decreased sequentially. The main indication of these three compounds is MM, and thalidomide and lenalidomide can also treat other indications, especially lenalidomide, which can be used to treat myelodysplastic syndrome (MDS). In terms of side effects, lenalidomide and pomalidomide have similar performance and have obvious bone marrow suppression, which is a toxicity related to the target; thalidomide has some other side effects, such as sedation, constipation, and neurological side effects Wait.

The adipimide moiety of all IMiDs binds to a hydrophobic pocket defined by three tryptophan residues (termed the "thalidomide-binding pocket") in the CRBN. On the contrary, the phthalimide/isoindolinone ring is exposed to the solvent and changes the molecular surface of CRBN, thereby regulating the substrate recognition; different IMiDs lead to obvious modification of the molecular surface of CRBN, and the preference of substrate recognition also changes. different. Therefore, the modification of IMiDs may lead to the degradation of other transcription factors, causing unnecessary toxic side effects. This mode of action of IMiDs is also called molecular glue, which vividly expresses the binding effect of this small molecule on two protein substrates.

Since the current median survival period of multiple myeloma is more than five years, the prolongation of survival period makes most patients have a high proportion of drug resistance to currently marketed drugs such as lenalidomide and pomalidomide, making this type of drug The therapeutic effect is severely reduced. Therefore, the inventors envisage developing drug molecules with better activity to overcome the problem of drug resistance, while minimizing the toxic and side effects of such compounds.

Published patent applications for Cereblon regulators include WO2008115516A2, WO2011100380A1, WO2019226770A1, WO2019014100A1 and WO2020064002A1, among others.

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

in,

G ¹ , G ² and G ³ are the same or different, and are each independently CR ⁸ or a nitrogen atom;

Z is CR ^a R ^b or an oxygen atom;

R ^a and R ^b are the same or different, and are each independently selected from a hydrogen atom, halogen, alkyl and haloalkyl;

X is CH ₂ or C(O);

Y is an oxygen atom or NH;

Ring A is aryl or heteroaryl;

R ^is selected from hydrogen atom, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, hydroxyalkyl, cyano, amino and hydroxyl;

R ² are the same or different at each occurrence, and each independently selected from a hydrogen atom, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, hydroxyalkyl, cyano, amino, nitro , hydroxy, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein the alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently selected from halogen , alkyl, alkoxy, haloalkyl, haloalkoxy, cyano, amine, nitro, hydroxyl, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl or Replaced by multiple substituents;

R ³ and R ⁴ are the same or different, and are each independently selected from a hydrogen atom, a halogen and an alkyl group;

R ⁵ are the same or different at each occurrence, and are each independently selected from a hydrogen atom, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, pendant oxy, cyano, amine, nitro , hydroxyl, hydroxyalkyl, -C(O)OR ⁹ , -CONR ¹⁰ R ¹¹ , cycloalkyl and heterocyclyl, wherein the alkyl, alkoxy, cycloalkyl and heterocyclyl are each independently optional is selected from the group consisting of halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cyano, amine, nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl Replaced by one or more substituents in;

R ⁶ are the same or different at each occurrence, and are each independently selected from hydrogen atom, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cyano, amine, nitro, hydroxy, hydroxy Alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein the alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently selected from halogen , alkyl, alkoxy, haloalkyl, haloalkoxy, cyano, amine, nitro, hydroxyl, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl or Replaced by multiple substituents;

R ⁷ is selected from cyano, -S(O) ₂ R ⁹ and -S(O) ₂ NR ¹⁰ R ¹¹ ;

R ⁸ are the same or different at each occurrence, and each independently selected from a hydrogen atom, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, hydroxyalkyl, cyano, amino, nitro , hydroxyl, cycloalkyl and heterocyclyl;

^R9 are the same or different at each occurrence, and are each independently selected from a hydrogen atom, an alkyl group, a haloalkyl group, a hydroxyalkyl group, a cycloalkyl group and a heterocyclyl group;

R ¹⁰ and R ¹¹ are the same or different at each occurrence, and are each independently selected from a hydrogen atom, an alkyl group, a haloalkyl group, a hydroxyalkyl group, a cycloalkyl group and a heterocyclyl group;

n is 1, 2 or 3;

m is 0, 1, 2 or 3;

p is 0, 1, 2, 3 or 4; and

q is 0, 1, 2, 3 or 4.

In some embodiments of the present disclosure, the compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof is a compound represented by the general formula (I-1) 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 the general formula (I).

In some embodiments of the present disclosure, the compound represented by the general formula (I), the general formula (I-1) or a pharmaceutically acceptable salt thereof is a compound represented by the general formula (I-1-1) or its pharmaceutically acceptable salt Medicinal salts:

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 the general formula (I).

In some embodiments of the present disclosure, the compound represented by the general formula (I), the general formula (I-1) or a pharmaceutically acceptable salt thereof is a compound represented by the general formula (I-1-2) or its pharmaceutically acceptable salt Medicinal salts:

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 the general formula (I).

In some embodiments of the present disclosure, the compound represented by the general formula (I), the general formula (I-1), the general formula (I-1-1), the general formula (I-1-2) or its alternative A pharmaceutically acceptable salt, wherein Y is an oxygen atom.

In some embodiments of the present disclosure, the compound represented by the general formula (I), the general formula (I-1), the general formula (I-1-1), the general formula (I-1-2) or its alternative A pharmaceutically acceptable salt, wherein R ³ and R ⁴ are both hydrogen atoms.

In some embodiments of the present disclosure, the compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof is a compound represented by the general formula (II) 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 the general formula (I).

In some embodiments of the present disclosure, the compound represented by general formula (I), general formula (I-1), general formula (II) or a pharmaceutically acceptable salt thereof is represented by general formula (II-1) A compound 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 the general formula (I).

In some embodiments of the present disclosure, the general formula (I), general formula (I-1), general formula (I-1-1), general formula (II), general formula (II-1) shown The compound or its pharmaceutically acceptable salt is the compound or its pharmaceutically acceptable salt shown in general formula (II-1-1):

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 the general formula (I).

In some embodiments of the present disclosure, the general formula (I), general formula (I-1), general formula (I-1-2), general formula (II), general formula (II-1) shown The compound or its pharmaceutically acceptable salt is the compound or its pharmaceutically acceptable salt shown in general formula (II-1-2):

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 the general formula (I).

In some embodiments of the present disclosure, the general formula (I), general formula (I-1), general formula (I-1-1), general formula (I-1-2), general formula (II), general formula A compound represented by formula (II-1), general formula (II-1-1), general formula (II-1-2) or a pharmaceutically acceptable salt thereof, wherein X is CH ₂ .

In some embodiments of the present disclosure, the general formula (I), general formula (I-1), general formula (I-1-1), general formula (I-1-2), general formula (II), general formula A compound represented by formula (II-1), general formula (II-1-1), general formula (II-1-2) or a pharmaceutically acceptable salt thereof, wherein Z is CR ^a R ^b ; R ^a and R ^b are the same, and each independently is a hydrogen atom or a halogen; preferably, R ^a and R ^b are the same, and each independently is a hydrogen atom or a fluorine atom.

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

in,

Ring A, G ¹ , G ² , G ³ , R ¹ , R ² , R ⁵ to R ⁷ , m, n, p and q are as defined in the general formula (I).

In some embodiments of the present disclosure, the compound represented by the general formula (I), general formula (I-1), general formula (II), general formula (II-1), general formula (III) or its druggable The salt used is a compound shown in general formula (III-1) or a pharmaceutically acceptable salt thereof:

in,

Ring A, G ¹ , G ² , G ³ , R ¹ , R ² , R ⁵ to R ⁷ , m, n, p and q are as defined in the general formula (I).

In some embodiments of the present disclosure, the general formula (I), general formula (I-1), general formula (I-1-1), general formula (II), general formula (II-1), general formula ( II-1-1), general formula (III), the compound shown in general formula (III-1) or its pharmaceutically acceptable salt is the compound shown in general formula (III-1-1) or its pharmaceutically acceptable the salt:

in,

Ring A, G ¹ , G ² , G ³ , R ¹ , R ² , R ⁵ to R ⁷ , m, n, p and q are as defined in the general formula (I).

In some embodiments of the present disclosure, the general formula (I), general formula (I-1), general formula (I-1-2), general formula (II), general formula (II-1), general formula ( II-1-2), general formula (III), the compound shown in general formula (III-1) or its pharmaceutically acceptable salt is the compound shown in general formula (III-1-2) or its pharmaceutically acceptable the salt:

in,

Ring A, G ¹ , G ² , G ³ , R ¹ , R ² , R ⁵ to R ⁷ , m, n, p and q are as defined in the general formula (I).

In some embodiments of the present disclosure, the general formula (I), general formula (I-1), general formula (I-1-1), general formula (I-1-2), general formula (II), general formula 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) . A compound represented by general formula (III-1-2) or a pharmaceutically acceptable salt thereof, wherein G ¹ , G ² and G ³ are all CR ⁸ ; R ⁸ is a hydrogen atom.

In some embodiments of the present disclosure, the general formula (I), general formula (I-1), general formula (I-1-1), general formula (I-1-2), general formula (II), general formula 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) 1. A compound represented by general formula (III-1-2) or a pharmaceutically acceptable salt thereof, wherein ring A is 6 to 10 membered aryl or 5 to 10 membered heteroaryl; preferably, ring A is phenyl .

In some embodiments of the present disclosure, the general formula (I), general formula (I-1), general formula (I-1-1), general formula (I-1-2), general formula (II), general formula 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) . A compound represented by general formula (III-1-2) or a pharmaceutically acceptable salt thereof, wherein R ¹ is a hydrogen atom.

In some embodiments of the present disclosure, the general formula (I), general formula (I-1), general formula (I-1-1), general formula (I-1-2), general formula (II), general formula 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) . A compound represented by general formula (III-1-2) or a pharmaceutically acceptable salt thereof, wherein R ² is a hydrogen atom.

In some embodiments of the present disclosure, the general formula (I), general formula (I-1), general formula (I-1-1), general formula (I-1-2), general formula (II), general formula 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) . A compound represented by general formula (III-1-2) or a pharmaceutically acceptable salt thereof, wherein p is 0, 1 or 2; preferably p is 0.

In some embodiments of the present disclosure, the general formula (I), general formula (I-1), general formula (I-1-1), general formula (I-1-2), general formula (II), general formula 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) , a compound represented by the general formula (III-1-2) or a pharmaceutically acceptable salt thereof, wherein R ⁵ are the same or different at each occurrence, and are each independently a hydrogen atom or a C _1-6 alkyl group; Preferably, R ⁵ is a hydrogen atom.

In some embodiments of the present disclosure, the 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 ), a compound represented by general formula (III-1-2) or a pharmaceutically acceptable salt thereof, wherein q is 0, 1 or 2; preferably, q is 1.

In some embodiments of the present disclosure, the 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 ), a compound represented by general formula (III-1-2) or a pharmaceutically acceptable salt thereof, wherein R ⁶ is the same or different at each occurrence, and each independently selected from hydrogen atom, halogen, C _1-6 Alkyl, C _1-6 alkoxy, C _1-6 haloalkyl and C _1-6 haloalkoxy; preferably, R ⁶ is halogen; more preferably, R ⁶ is fluorine atom.

In some embodiments of the present disclosure, the 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 ), a compound represented by general formula (III-1-2) or a pharmaceutically acceptable salt thereof, wherein R ⁷ is selected from cyano, -S(O) ₂ R ⁹ and -S(O) ₂ NR ¹⁰ R ¹¹ , wherein R ⁹ is a C _1-6 alkyl group, R ¹⁰ and R ¹¹ are both hydrogen atoms; preferably, R ⁷ is a cyano group.

In some embodiments of the present disclosure, the general formula (I), general formula (I-1), general formula (I-1-1), general formula (I-1-2), general formula (II), general formula 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) . A compound represented by general formula (III-1-2), wherein n is 1 or 2, or a pharmaceutically acceptable salt thereof.

In some embodiments of the present disclosure, the general formula (I), general formula (I-1), general formula (II), general formula (II-1), general formula (III) or general formula (III-1) The compound shown, or a pharmaceutically acceptable salt thereof, wherein n is 2.

In some embodiments of the present disclosure, the general formula (I), general formula (I-1), general formula (I-1-1), general formula (I-1-2), general formula (II), general formula 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) . A compound represented by the general formula (III-1-2), wherein m is 0, or a pharmaceutically acceptable salt thereof.

為

或 In some embodiments of the present disclosure, the compound represented by general formula (I), general formula (I-1), general formula (II), general formula (II-1) or a pharmaceutically acceptable salt thereof, wherein

for

or

為

或

。 In some embodiments of the present disclosure, the compound represented by general formula (I-1-1), general formula (II-1-1) or a pharmaceutically acceptable salt thereof, wherein

for

or

.

為

或

。 In some embodiments of the present disclosure, the compound represented by general formula (I-1-2), general formula (II-1-2) or a pharmaceutically acceptable salt thereof, wherein

for

or

.

為

。 In some embodiments of the present disclosure, the compound represented by general formula (I), general formula (I-1), general formula (II), general formula (II-1) or a pharmaceutically acceptable salt thereof, wherein

for

.

為

或

。 In some embodiments of the present disclosure, the compound represented by general formula (III), general formula (III-1) or a pharmaceutically acceptable salt thereof, wherein

for

or

.

為

或

。 In some embodiments of the present disclosure, the compound represented by the general formula (III-1-1) or a pharmaceutically acceptable salt thereof, wherein

for

or

.

為

或

。 In some embodiments of the present disclosure, the compound represented by the general formula (III-1-2) or a pharmaceutically acceptable salt thereof, wherein

for

or

.

為

。 In some embodiments of the present disclosure, the compound represented by general formula (III), general formula (III-1) or a pharmaceutically acceptable salt thereof, wherein

for

.

為

，R⁶為鹵素；R⁷為氰基； 較佳地，

為

。 In some embodiments of the present disclosure, the general formula (I), general formula (I-1), general formula (I-1-1), general formula (I-1-2), general formula (II), general formula 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) , a compound represented by general formula (III-1-2) or a pharmaceutically acceptable salt thereof, wherein

for

, R ⁶ is halogen; R ⁷ is cyano; Preferably,

for

.

In some embodiments of the present disclosure, the compound represented by the general formula (I), the general formula (I-1), the general formula (I-1-1), the general formula (I-1-2) or its alternative A pharmaceutically acceptable salt, wherein G ¹ , G ² and G ³ are all CR ⁸ ; R ⁸ is a hydrogen atom; Z is CR ^a R ^b ; R ^a and R ^b are the same, and each independently is a hydrogen atom or a halogen; X is CH ₂ ; Y is an oxygen atom; Ring A is a 6 to 10 membered aryl group or a 5 to 10 membered heteroaryl group; R ¹ is a hydrogen atom; R ² is a hydrogen atom; R ³ and R ⁴ are both hydrogen atoms; R ⁵ are the same or different at each occurrence, and are each independently a hydrogen atom or a C _1-6 alkyl group; R ⁶ are the same or different at each occurrence, and are each independently selected from a hydrogen atom, halogen, C _{1-6 6} alkyl, C _1-6 alkoxy, C _1-6 haloalkyl and C _1-6 haloalkoxy; R ⁷ is selected from cyano, -S(O) ₂ R ⁹ and -S(O) ₂ NR ¹⁰ R ¹¹ , wherein R ⁹ is C _1-6 alkyl, R ¹⁰ and R ¹¹ are both hydrogen atoms; p is 0, 1 or 2; q is 0, 1 or 2; n is 1 or 2; m is 0.

In some embodiments of the present disclosure, the compound represented by general formula (I), general formula (I-1) or a pharmaceutically acceptable salt thereof, wherein G ¹ , G ² and G ³ are all CR ⁸ ; R ⁸ is a hydrogen atom; Z is CR ^a R ^b ; R ^a and R ^b are the same, and each independently is a hydrogen atom or a halogen; X is CH ₂ ; Y is an oxygen atom; to 10-membered heteroaryl; R ¹ is a hydrogen atom; R ² is a hydrogen atom; R ³ and R ⁴ are both hydrogen atoms; R ⁵ is the same or different at each occurrence, and each independently is a hydrogen atom or C _{1 -6} alkyl; R ⁶ is the same or different at each occurrence, and each independently selected from hydrogen atom, halogen, C _1-6 alkyl, C _1-6 alkoxy, C _1-6 haloalkyl and C _1-6 haloalkoxy; R ⁷ is selected from cyano, -S(O) ₂ R ⁹ and -S(O) ₂ NR ¹⁰ R ¹¹ , wherein R ⁹ is C _1-6 alkyl, R ¹⁰ and R ¹¹ are all hydrogen atoms; p is 0, 1 or 2; q is 0, 1 or 2; n is 2; m is 0.

In some embodiments of the present disclosure, the compound represented by general formula (II), general formula (II-1), general formula (II-1-1), general formula (II-1-2) or its A pharmaceutically acceptable salt, wherein G ¹ , G ² and G ³ are all CR ⁸ ; R ⁸ is a hydrogen atom; Z is CR ^a R ^b ; R ^a and R ^b are the same, and each independently is a hydrogen atom or a fluorine atom; X is CH ₂ ; Ring A is phenyl; R ¹ is a hydrogen atom; R ² is a hydrogen atom; R ⁵ is the same or different at each occurrence, and each independently is a hydrogen atom or a C _1-6 alkyl group; R ⁶ are the same or different at each occurrence, and are each independently selected from hydrogen atom, halogen, C _1-6 alkyl, C _1-6 alkoxy, C _1-6 haloalkyl and C _1-6 haloalkane Oxygen; R ⁷ is cyano; p is 0, 1 or 2; q is 0, 1 or 2; n is 1 or 2; m is 0.

In some embodiments of the present disclosure, the compound represented by general formula (II), general formula (II-1) or a pharmaceutically acceptable salt thereof, wherein G ¹ , G ² and G ³ are all CR ⁸ ; R ⁸ is a hydrogen atom; Z is CR ^a R ^b ; R ^a and R ^b are the same, and each independently is a hydrogen atom or a fluorine atom; X is CH ₂ ; Ring A is a phenyl group; R ¹ is a hydrogen atom; R ² is Hydrogen atom; R ⁵ is the same or different at each occurrence, and each independently is a hydrogen atom or C _1-6 alkyl; R ⁶ is the same or different at each occurrence, and each independently selected from a hydrogen atom, a halogen , C _1-6 alkyl, C _1-6 alkoxy, C _1-6 haloalkyl and C _1-6 haloalkoxy; R ⁷ is cyano; p is 0, 1 or 2; q is 0 , 1 or 2; n is 2; m is 0.

In some embodiments of the present disclosure, the compound represented by the general formula (III), general formula (III-1), general formula (III-1-1), general formula (III-1-2) or its A pharmaceutically acceptable salt, wherein G ¹ , G ² and G ³ are all CR ⁸ ; R ⁸ is a hydrogen atom; ring A is a phenyl group; R ¹ is a hydrogen atom; R ² is a hydrogen atom ^; The same or different, and each independently is a hydrogen atom or C _1-6 alkyl; R ⁶ is the same or different at each occurrence, and each independently selected from a hydrogen atom, halogen, C _1-6 alkyl, C _{1 -6} alkoxy, C _1-6 haloalkyl and C _1-6 haloalkoxy; R ⁷ is cyano; p is 0, 1 or 2; q is 0, 1 or 2; n is 1 or 2 ;m is 0.

In some embodiments of the present disclosure, the compound represented by general formula (III), general formula (III-1) or a pharmaceutically acceptable salt thereof, wherein G ¹ , G ² and G ³ are all CR ⁸ ; R ⁸ is a hydrogen atom; ring A is a phenyl group; R ¹ is a hydrogen atom; R ² is a hydrogen atom; R ⁵ is the same or different at each occurrence, and each independently is a hydrogen atom or a C _1-6 alkyl group; ⁶ are the same or different at each occurrence, and are each independently selected from hydrogen atom, halogen, C _1-6 alkyl, C _1-6 alkoxy, C _1-6 haloalkyl and C _1-6 haloalkane Oxygen; R ⁷ is cyano; p is 0, 1 or 2; q is 0, 1 or 2; n is 2; m is 0.

In some embodiments of the present disclosure, the compound represented by the general formula (III), general formula (III-1), general formula (III-1-1), general formula (III-1-2) or its A pharmaceutically acceptable salt, wherein G ¹ , G ² and G ³ are all CR ⁸ ; R ⁸ is a hydrogen atom; ring A is a phenyl group; R ¹ is a hydrogen atom; R ⁵ is the same or different at each occurrence, and each independently hydrogen atom or C _1-6 alkyl; R ⁶ is the same or different at each occurrence, and each independently selected from hydrogen atom, halogen, C _1-6 alkyl, C _1-6 alkoxy, C _1-6 haloalkyl and C _1-6 haloalkoxy; R ⁷ is cyano; p is 0, 1 or 2; q is 0, 1 or 2; n is 1 or 2; m is 0.

為

；R¹為氫原子；R⁶為鹵素；R⁷為氰基；p為0；q為1；n為1或2；m為0。 In some embodiments of the present disclosure, the compound represented by the general formula (III), general formula (III-1), general formula (III-1-1), general formula (III-1-2) or its A pharmaceutically acceptable salt, wherein G ¹ , G ² and G ³ are all CR ⁸ ; R ⁸ is a hydrogen atom;

for

; R ¹ is a hydrogen atom; R ⁶ is a halogen; R ⁷ is a cyano group; p is 0; q is 1; n is 1 or 2; m is 0.

Table A Typical compounds of the present disclosure include, but are not limited to:

Another aspect of the present disclosure relates to a compound represented by general formula (IA) or a salt thereof,

in,

R ^m is C _1-6 alkyl; preferably, R ^m is tertiary butyl;

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 the compound of general formula (I).

Another aspect of the present disclosure relates to a compound represented by general formula (IA-1) or a salt thereof,

in,

R ^m is C _1-6 alkyl; preferably, R ^m is tertiary butyl;

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 the compound of general formula (I-1).

Another aspect of the present disclosure relates to a compound represented by general formula (IA-1-1) or a salt thereof,

in,

R ^m is C _1-6 alkyl; preferably, R ^m is tertiary butyl;

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 the compound of general formula (I-1-1).

Another aspect of the present disclosure relates to a compound represented by general formula (IA-1-2) or a salt thereof,

in,

R ^m is C _1-6 alkyl; preferably, R ^m is tertiary butyl;

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 the compound of general formula (I-1-2).

Another aspect of the present disclosure relates to compounds or salts thereof represented by general formula (IIA):

in,

R ^m is C _1-6 alkyl; preferably, R ^m is tertiary butyl;

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 the compound of general formula (II).

Another aspect of the present disclosure relates to compounds or salts thereof represented by general formula (IIA-1):

in,

R ^m is C _1-6 alkyl; preferably, R ^m is tertiary butyl;

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 the compound of general formula (II-1).

Another aspect of the present disclosure relates to compounds or salts thereof represented by general formula (IIA-1-1):

in,

R ^m is C _1-6 alkyl; preferably, R ^m is tertiary butyl;

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 the compound of general formula (II-1-1).

Another aspect of the present disclosure relates to compounds or salts thereof represented by general formula (IIA-1-2):

in,

R ^m is C _1-6 alkyl; preferably, R ^m is tertiary butyl;

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 the compound of general formula (II-1-2).

Another aspect of the present disclosure relates to compounds or salts thereof represented by general formula (IIIA):

in,

R ^m is C _1-6 alkyl; preferably, R ^m is tertiary butyl;

Rings A, G ¹ , G ² , G ³ , R ¹ , R ² , R ⁵ to R ⁷ , m, n, p and q are as defined for the compound of general formula (III).

Another aspect of the present disclosure relates to compounds or salts thereof represented by general formula (IIIA-1):

in,

R ^m is C _1-6 alkyl; preferably, R ^m is tertiary butyl;

Ring A, G ¹ , G ² , G ³ , R ¹ , R ² , R ⁵ to R ⁷ , m, n, p and q are as defined for the compound of general formula (III-1).

Another aspect of the present disclosure relates to compounds or salts thereof represented by general formula (IIIA-1-1):

in,

R ^m is C _1-6 alkyl; preferably, R ^m is tertiary butyl;

Ring A, G ¹ , G ² , G ³ , R ¹ , R ² , R ⁵ to R ⁷ , m, n, p and q are as defined for the compound of general formula (III-1-1).

Another aspect of the present disclosure relates to compounds or salts thereof represented by general formula (IIIA-1-2):

in,

R ^m is C _1-6 alkyl; preferably, R ^m is tertiary butyl;

Ring A, G ¹ , G ² , G ³ , R ¹ , R ² , R ⁵ to R ⁷ , m, n, p and q are as defined for the compound of general formula (III-1-2).

Table B Typical intermediate compounds of the present disclosure include, but are not limited to:

Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (I) or a pharmaceutically acceptable salt thereof, the method comprising:

The compound represented by the general formula (IA) or its salt undergoes an intramolecular ring-closing reaction to obtain the compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof,

in,

R ^m is C _1-6 alkyl; preferably, R ^m is tertiary butyl;

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 the general formula (I).

Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (I-1) or a pharmaceutically acceptable salt thereof, the method comprising:

Compounds represented by general formula (IA-1) or salts thereof undergo intramolecular ring closure reactions to obtain compounds represented by general formulas (I-1) or pharmaceutically acceptable salts thereof,

in,

R ^m is C _1-6 alkyl; preferably, R ^m is tertiary butyl;

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 the general formula (I-1).

Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (I-1-1) or a pharmaceutically acceptable salt thereof, the method comprising:

Compounds represented by general formula (IA-1-1) or salts thereof undergo intramolecular ring closure reactions to obtain compounds represented by general formulas (I-1-1) or pharmaceutically acceptable salts thereof,

in,

R ^m is C _1-6 alkyl; preferably, R ^m is tertiary butyl;

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 the general formula (I-1-1).

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

The compound represented by the general formula (IA-1-2) or its salt undergoes an intramolecular ring-closing reaction to obtain the compound represented by the general formula (I-1-2) or a pharmaceutically acceptable salt thereof,

in,

R ^m is C _1-6 alkyl; preferably, R ^m is tertiary butyl;

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 the general formula (I-1-2).

Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (II), or a pharmaceutically acceptable salt thereof, the method comprising:

The compound represented by the general formula (IIA) or its salt undergoes an intramolecular ring-closing reaction to obtain the compound represented by the general formula (II) or a pharmaceutically acceptable salt thereof,

in,

R ^m is C _1-6 alkyl; preferably, R ^m is tertiary butyl;

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 the compound of general formula (II).

Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (II-1) or a pharmaceutically acceptable salt thereof, the method comprising:

The compound represented by the general formula (IIA-1) or its salt undergoes an intramolecular ring-closing reaction to obtain the compound represented by the general formula (II-1) or a pharmaceutically acceptable salt thereof,

in,

R ^m is C _1-6 alkyl; preferably, R ^m is tertiary butyl;

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 the compound of general formula (II-1).

Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (II-1-1) or a pharmaceutically acceptable salt thereof, the method comprising:

The compound represented by the general formula (IIA-1-1) or its salt undergoes an intramolecular ring-closing reaction to obtain the compound represented by the general formula (II-1-1) or a pharmaceutically acceptable salt thereof,

in,

R ^m is C _1-6 alkyl; preferably, R ^m is tertiary butyl;

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 the compound of general formula (II-1-1).

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

Compounds represented by general formula (IIA-1-2) or salts thereof undergo intramolecular ring closure reactions to obtain compounds represented by general formulas (II-1-2) or pharmaceutically acceptable salts thereof,

in,

R ^m is C _1-6 alkyl; preferably, R ^m is tertiary butyl;

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 the compound of general formula (II-1-2).

Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (III) or a pharmaceutically acceptable salt thereof, the method comprising:

The compound represented by the general formula (IIIA) or its salt undergoes an intramolecular ring-closing reaction to obtain the compound represented by the general formula (III) or a pharmaceutically acceptable salt thereof,

in,

R ^m is C _1-6 alkyl; preferably, R ^m is tertiary butyl;

Rings A, G ¹ , G ² , G ³ , R ¹ , R ² , R ⁵ to R ⁷ , m, n, p and q are as defined for the compound of general formula (III).

Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (III-1) or a pharmaceutically acceptable salt thereof, the method comprising:

The compound represented by the general formula (IIIA-1) or its salt undergoes an intramolecular ring-closing reaction to obtain the compound represented by the general formula (III-1) or a pharmaceutically acceptable salt thereof,

in,

R ^m is C _1-6 alkyl; preferably, R ^m is tertiary butyl;

Ring A, G ¹ , G ² , G ³ , R ¹ , R ² , R ⁵ to R ⁷ , m, n, p and q are as defined for the compound of general formula (III-1).

Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (III-1-1) or a pharmaceutically acceptable salt thereof, the method comprising:

The compound represented by the general formula (IIIA-1-1) or its salt undergoes an intramolecular ring-closing reaction to obtain the compound represented by the general formula (III-1-1) or a pharmaceutically acceptable salt thereof,

in,

R ^m is C _1-6 alkyl; preferably, R ^m is tertiary butyl;

Ring A, G ¹ , G ² , G ³ , R ¹ , R ² , R ⁵ to R ⁷ , m, n, p and q are as defined for the compound of general formula (III-1-1).

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

The compound represented by the general formula (IIIA-1-2) or its salt undergoes an intramolecular ring-closing reaction to obtain the compound represented by the general formula (III-1-2) or a pharmaceutically acceptable salt thereof,

in,

R ^m is C _1-6 alkyl; preferably, R ^m is tertiary butyl;

Ring A, G ¹ , G ² , G ³ , R ¹ , R ² , R ⁵ to R ⁷ , m, n, p and q are as defined for the compound of general formula (III-1-2).

Another aspect of the present disclosure relates to a pharmaceutical composition, which contains the general formula (I), general formula (I-1), general formula (I-1-1), general formula (I-1) of the present disclosure -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 ), the compound shown in the general formula (III-1-1), the compound shown in the general formula (III-1-2) and the compound shown in Table A or its pharmaceutically acceptable salt, and one or more pharmaceutically acceptable carriers, diluent or excipient.

The present disclosure is further related to 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 ( The compound shown in III-1-2) and Use of a compound shown in Table A or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising it in the preparation of a medicament for treating and/or preventing diseases related to CRBN protein.

The present disclosure is further related to 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 ( The compounds shown in III-1-2) and the compounds shown in Table A or pharmaceutically acceptable salts thereof, or the pharmaceutical compositions containing them are used in the preparation for the treatment and/or prevention of cancer, diseases related to angiogenesis, 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 Use in medicine for diseases, infectious diseases, hemoglobinopathies or related diseases or TNFα-related diseases; preferably, use in the preparation of medicines for treating and/or preventing cancer or CNS damage.

The present disclosure also relates to a method for treating and/or preventing diseases related to CRBN protein, which comprises administering a therapeutically effective dose 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 ), the compound shown in the general formula (III-1), the general formula (III-1-1), the general formula (III-1-2) and the compound shown in Table A or its pharmaceutically acceptable salt, or comprising its pharmaceutical composition.

The present disclosure also relates to a method for treating and/or preventing cancer, disorders related to angiogenesis, pain, macular degeneration or related syndromes, skin diseases, lung diseases, asbestos related diseases, parasitic diseases, immunodeficiency diseases, CNS diseases, A method for CNS damage, atherosclerosis or related disorders, sleep disorders or related disorders, infectious diseases, hemoglobinopathies or related disorders or TNFα-related disorders, preferably a method for treating and/or preventing cancer or CNS damage, comprising 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), The compound shown in general formula (III-1), general formula (III-1-1), general formula (III-1-2) and the compound shown in Table A or its pharmaceutically acceptable salt, or the medicine containing it Composition.

The present disclosure is further related to a 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 A compound shown in (III-1-2) and a compound shown in Table A or a pharmaceutically acceptable salt thereof or a pharmaceutical composition containing the same for use as a medicament.

The present disclosure is further related to 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 ( The compounds shown in III-1-2) and the compounds shown in Table A or pharmaceutically acceptable salts thereof, or pharmaceutical compositions containing them, are used for treating and/or preventing diseases related to CRBN protein.

The present disclosure is further related to 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 ( The compound shown in III-1-2) and the compound shown in Table A or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing it, which is used for the treatment and/or prevention of cancer, diseases related to angiogenesis, and pain , macular degeneration or related syndrome, skin disease, lung disease, asbestos related disease, parasitic disease, immunodeficiency disease, CNS disease, CNS injury, atherosclerosis or related disease, sleep disorder or related disease, infectious disease , hemoglobinopathies or related disorders or TNFα-related disorders; preferably for the treatment and/or prevention of cancer or CNS damage.

The diseases related to CRBN protein described in the present disclosure are selected from cancer, disorders related to angiogenesis, pain, macular degeneration or related syndromes, skin diseases, lung diseases, asbestos related diseases, parasitic diseases, immunodeficiency diseases , CNS disease, CNS injury, atherosclerosis Hemoglobinopathies or related disorders, sleep disorders or related disorders, infectious diseases, hemoglobinopathies or related disorders or TNFα related disorders; preferably cancer or CNS injury.

The cancer described in this disclosure is 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 cancer cancer, gastric cancer, esophageal cancer (also known as esophageal cancer), colorectal cancer (such as colon and rectal cancer), gallbladder cancer, bile duct cancer, choriocarcinoma, pancreatic cancer, polycythemia vera, pediatric tumors, cervical cancer, Ovarian cancer, breast cancer, bladder cancer, urothelial cancer, ureteral tumors, prostate cancer, seminoma, testicular tumors, head and neck cancer, head and neck squamous cell carcinoma, endometrial cancer, thyroid cancer, sarcomas (such as osteosarcoma and soft tissue sarcomas), osteomas, neuroblastomas (i.e., neuroblastoma), neuroendocrine carcinomas, brain tumors, CNS carcinomas, astrocytomas, and gliomas (e.g., 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 Myeloma is refractory or resistant to lenalidomide or pomalidomide.

Preferably the leukemia is chronic lymphocytic leukemia, acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), chronic myeloid leukemia (CML) and hairy cell leukemia, and the lymphoma is preferably small lymphocytic leukemia cell 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.

Cancers described in this disclosure include primary or metastatic cancers. Cancers described in the present disclosure also include refractory or resistant to chemotherapy or radiotherapy.

Examples of CNS diseases include, but are not limited to, those described in US 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, Alzheimer's disease, Parkinson's disease, Huntington's disease, multiple sclerosis, and other neuroimmune disorders such as Tourette syndrome, delusions, Or disturbance of consciousness that occurs over a short period of time, and amnesia, or diffuse memory impairment that occurs in the absence of other central nervous system impairments.

Examples of CNS injuries and associated syndromes include, but are not limited to, the disorders described in US 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/impairment 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, brain contusion, subdural hematoma, epidermal hematoma, post-traumatic epilepsy, chronic autonomic state, complete spinal cord injury (SCI), incomplete SCI, acute SCI, subacute SCI, chronic SCI, central cord syndrome, hemisected cord syndrome, anterior cord syndrome, conus medullaris, cauda equina syndrome, neurogenic shock, spinal cord shock, altered level of consciousness, headache, nausea, vomiting, memory loss , dizziness, double vision, blurred vision, mood swings, sleep disturbances, irritability, inability to concentrate, nervousness, behavioral disturbances, cognitive deficits, and seizures.

Diseases related to angiogenesis include but are not limited to inflammatory diseases, autoimmune diseases, viral diseases, genetic diseases, allergic diseases, bacterial diseases, ocular neovascular diseases, choroidal neovascular diseases, retinal neovascularization disease, and iris redness (angle neovascularization). Preferably include but not limited to arthritis, endometriosis, Crohn's disease, heart failure, severe heart failure, kidney injury, endotoxemia, toxic shock syndrome syndrome, osteoarthritis, retroviral replication, wasting disease, meningitis, silica-induced fibrosis, asbestos-induced fibrosis, veterinary disease, malignancy-associated hypercalcemia, stroke, circulatory shock, Periodontitis, gingivitis, megaloblastic anemia, refractory anemia, and 5q deletion syndrome.

The active compounds may be prepared in a form suitable for administration by any suitable route, and the compositions of the present disclosure may be formulated by conventional methods using one or more pharmaceutically acceptable carriers. Accordingly, the active compounds of the present disclosure may be formulated in various dosage forms for oral administration, injection (eg, intravenous, intramuscular or subcutaneous), administration by inhalation or insufflation. The disclosed compounds can also be formulated in 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.

As a general guide, the active compound is preferably presented in unit dosage form, or in such a form that the patient can self-administer as a single dose. The unit dosage form of a compound or composition of the present disclosure may be expressed as a tablet, capsule, cachet, bottled solution, powder, granule, lozenge, suppository, reconstitution powder or liquid preparation. A suitable unit dose may be 0.1 to 1000 mg.

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

Tablets contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients suitable for the manufacture of tablets. These excipients may be inert excipients, granulating agents, disintegrants, binders and lubricants. These tablets may be uncoated or coated by known techniques to mask the taste of the drug or to delay disintegration and absorption in the gastrointestinal tract, thus providing sustained release over a longer period of time.

Oral formulations can also be provided in soft gelatin capsules, wherein the active ingredient is mixed with an inert solid diluent, or where the active ingredient is mixed with a water-soluble carrier or an oil vehicle.

Aqueous suspensions contain the active materials in admixture with excipients suitable for the manufacture of aqueous suspensions. Such excipients are suspending, dispersing 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 sweetening agents.

Oily suspensions can be formulated by suspending the active ingredient in a vegetable or mineral oil. The oily suspensions may contain a thickening agent. Sweetening and flavoring agents as mentioned above may be added to provide a palatable preparation. These compositions can be preserved by adding antioxidants.

The pharmaceutical compositions of the present disclosure may also be in the form of oil-in-water emulsions. The oily phase may be vegetable oil, or mineral oil or mixtures thereof. Suitable emulsifiers may be naturally occurring phospholipids, and the emulsions may also contain sweetening agents, flavoring agents, preservatives and antioxidants. Such formulations may also contain a demulcent, a preservative, coloring agents and antioxidants.

The pharmaceutical compositions of the present disclosure may be in the form of sterile injectable aqueous solutions. Among the acceptable vehicles or solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution. The sterile injectable preparation can be a sterile injectable oil-in-water microemulsion in which the active ingredient is dissolved in an oily phase. The injection or microemulsion can be injected into the patient's bloodstream by local bolus injection. Alternatively, solutions and microemulsions are preferably administered in a manner that maintains a constant circulating concentration of the disclosed compounds. To maintain this constant concentration, a continuous intravenous delivery device can be used. An example of such a device is the Deltec CADD-PLUS.TM. Model 5400 IV pump.

The pharmaceutical compositions of the present disclosure may be in the form of sterile injectable aqueous or oily suspensions for intramuscular and subcutaneous administration. This suspension may be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents which have been mentioned above. The sterile injectable preparation may also be a sterile injectable solution or suspension prepared in a parenterally acceptable non-toxic diluent or solvent. In addition, it can be conveniently fixed with sterile Oil acts as a solvent or suspending medium. For this purpose, any blended and fixed oil may be used. In addition, fatty acids are also used in the preparation of injectables.

The disclosed compounds may be administered in the form of suppositories for rectal administration. These pharmaceutical compositions can be prepared by mixing the drug with a suitable non-irritating excipient which is solid at ordinary temperatures but liquid in the rectum and will therefore melt in the rectum to release the drug.

Aqueous suspensions of dispersible powders and granules can be prepared by the addition of water to administer the disclosed compounds. These pharmaceutical compositions can be prepared by mixing the active ingredient with a dispersing or wetting agent, suspending agent or one or more preservatives.

As is well known to those of ordinary skill in the art, the dosage of a drug to be administered depends on a variety of factors including, but not limited to, the activity of the particular compound used, the age of the patient, the weight of the patient, the state of the patient's health, the patient's behavior, patient’s diet, administration time, administration method, excretion rate, drug combination, disease severity, etc.; in addition, the optimal treatment method such as the mode of treatment, the daily dosage of the compound or the pharmaceutically acceptable The type of salt can be verified according to the traditional treatment plan.

Glossary

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

The term "alkyl" refers to a saturated linear 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 (ie C _1-20 alkyl). The alkyl group is preferably an alkyl group having 1 to 12 carbon atoms (ie, a C _1-12 alkyl group), more preferably an alkyl group having 1 to 6 carbon atoms (ie, a C _1-6 alkyl group). Non-limiting examples include: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, second-butyl, n-pentyl, 1,1-dimethylpropane base, 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 base, 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-dimethyl Hexyl, 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 various branched chain isomers, etc. Preferably lower alkyl having 1 to 6 carbon atoms, non-limiting examples include: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, second 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-di Methylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methyl Pentyl, 2,3-dimethylbutyl, etc. Alkyl may be substituted or unsubstituted, and when substituted, it may be substituted at any available point of attachment, substituents are preferably selected from D atoms, halogen, alkyl, alkoxy, haloalkyl One of , haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amine, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl or more.

The term "(alkylene)" refers to a divalent alkyl group, wherein the alkyl group is as defined above, which has 1 to 20 (eg 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20) carbon atoms (ie C _1-20 alkylene). The (alkylene) alkylene is preferably an (alkylene) alkylene having 1 to 12 carbon atoms (i.e. C _1-12 (alkylene) alkylene), more preferably an alkylene (alkylene) having 1 to 6 carbon atoms. ) alkyl (i.e. C _1-6 (alkylene)). Non-limiting examples of alkylene include, but are not limited to: methylene (-CH ₂ -), 1,1-ethylene (-CH(CH ₃ )-), 1,2-ethylene (-CH ₂ CH ₂ )-, 1,1-propylene (-CH(CH ₂ CH ₃ )-), 1,2-propylidene (-CH ₂ CH(CH ₃ )-), 1,3 -Propylene (-CH ₂ CH ₂ CH ₂ -), 1,4-butylene (-CH ₂ CH ₂ CH ₂ CH ₂ -), etc. Alkylene may be substituted or unsubstituted, and when substituted, it may be substituted at any available point of attachment, the substituents are preferably selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy radical, haloalkoxy, cycloalkyloxy, heterocyclyloxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocyclyl, aromatic One or more of radical, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio and pendant oxy.

The term "alkenyl" refers to an alkyl compound containing at least one carbon-carbon double bond in the molecule, wherein the definition of the alkyl group is as described above, and it has 2 to 12 (such as 2, 3, 4, 5, 6, 7, 8 , 9, 10, 11 or 12) carbon atoms (ie C _2-12 alkenyl). The alkenyl group is preferably an alkenyl group having 2 to 6 carbon atoms (ie, a C _2-6 alkenyl group). Non-limiting examples include: vinyl, propenyl, butenyl, pentenyl, hexenyl, and the like. Alkenyl may be substituted or unsubstituted, and when substituted, the substituent is preferably selected from alkyl, alkoxy, halogen, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy One or more of hydroxy, hydroxyalkyl, cyano, amine, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl.

The term "alkynyl" refers to an alkyl compound containing at least one carbon-carbon triple bond in the molecule, wherein the definition of the alkyl group is as described above, and it has 2 to 12 (such as 2, 3, 4, 5, 6, 7, 8 , 9, 10, 11 or 12) carbon atoms alkynyl (ie C _2-12 alkynyl). The alkynyl group is preferably an alkynyl group having 2 to 6 carbon atoms (ie, a C _2-6 alkynyl group). Non-limiting examples include: ethynyl, propynyl, butynyl, pentynyl, hexynyl, and the like. Alkynyl may be substituted or unsubstituted, and when substituted, the substituent is preferably selected from alkyl, alkoxy, halogen, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy One or more of hydroxy, hydroxyalkyl, cyano, amine, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl.

The term "alkoxy" refers to -O-(alkyl), wherein alkyl is as defined above. Non-limiting examples of alkoxy include: methoxy, ethoxy, propoxy, butoxy. Alkoxy may be optionally substituted or unsubstituted, and when substituted, the substituent is preferably selected from D atom, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy One or more of radical, heterocyclyloxy, hydroxyl, hydroxyalkyl, cyano, amine, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl.

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 (ie 3 to 20 membered cycloalkyl), preferably 3 to 12 carbon atoms (ie 3 to 12 membered Cycloalkyl), more preferably has 3 to 8 carbon atoms (ie 3 to 8 membered cycloalkyl), most preferably has 3 to 6 carbon atoms (ie 3 to 6 membered cycloalkyl). Non-limiting examples of monocyclic cycloalkyls include: cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptyl Alkenyl, cyclooctyl, etc.; polycyclic cycloalkyl includes spirocycloalkyl, fused cycloalkyl and bridged cycloalkyl.

The term "spirocycloalkyl" refers to a polycyclic group with 5 to 20 membered monocyclic rings sharing one carbon atom (called a spiro atom), which may contain one or more double bonds. Preferably 6 to 14 members, more preferably 7 to 10 members (eg 7, 8, 9 or 10 members). According to the number of spiro atoms shared between the ring and the ring, spirocycloalkyl is divided into single spirocycloalkyl or polyspirocycloalkyl (such as double spirocycloalkyl), preferably single spirocycloalkyl or double spirocycloalkyl. Better 3/5, 3/6, 4/4, 4/5, 4/6, 5/5, 5/6, 6/4, 6-membered/5-membered or 6-membered/6-membered single spirocycloalkyl. Non-limiting examples of spirocycloalkyl groups include:

The term "fused cycloalkyl" refers to an all-carbon polycyclic group having 5 to 20 membered rings sharing adjacent pairs of carbon atoms, wherein one or more rings may contain one or more double bonds. Preferably 6 to 14 members, more preferably 7 to 10 members (eg 7, 8, 9 or 10 members). According to the number of rings, it can be divided into bicyclic, tricyclic, tetracyclic and other polycyclic fused cycloalkyl groups, preferably bicyclic or tricyclic fused cycloalkyl groups, more preferably 3-membered/4-membered, 3-membered/5-membered, 3-membered/ 6 people, 4 people/4 people, 4 people/5 people, 4 people/6 people, 5 people/4 people, 5 people/5 people, 5 people/6 people, 6 people/3 people, 6 people/4 people , 6-membered/5-membered and 6-membered/6-membered bicyclic fused cycloalkyl groups. Non-limiting examples of fused cycloalkyl groups include:

The term "bridged cycloalkyl" refers to an all-carbon polycyclic group in which any two rings of 5 to 20 members share two non-directly connected carbon atoms, which may contain one or more double bonds. Preferably 6 to 14 members, more preferably 7 to 10 members (eg 7, 8, 9 or 10 members). According to the number of rings, it can be divided into bicyclic, tricyclic, tetracyclic and other polycyclic bridged cycloalkyl groups, preferably bicyclic, tricyclic or tetracyclic bridged cycloalkyl groups, more preferably bicyclic or tricyclic bridged cycloalkyl groups. Non-limiting examples of bridged cycloalkyl groups include:

、

和

等；較佳

和

。 The cycloalkyl ring includes a cycloalkyl group as described above (including monocyclic, spiro, fused and bridged rings) fused to an aryl, heteroaryl or heterocycloalkyl ring wherein the bond to the parent structure is at The rings together are cycloalkyl, non-limiting examples include

,

with

etc; better

with

.

Cycloalkyl may be substituted or unsubstituted, and when substituted, it may be substituted at any available point of attachment, the substituents are preferably selected from halogen, alkyl, alkoxy, haloalkyl, halo One or more of alkoxy, cycloalkyloxy, heterocyclyloxy, hydroxyl, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl indivual.

The term "heterocyclyl" refers to a saturated or partially unsaturated monocyclic or polycyclic ring 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, the sulfur optionally being oxidized (i.e. forming or 碸), but excluding the ring portion of -O-O-, -O-S- or -S-S-, the remaining ring atoms are carbon. preferably have 3 to 12 ring atoms, of which 1 to 4 (eg 1, 2, 3 and 4) are heteroatoms (ie 3 to 12 membered heterocyclyl); more preferably have 3 to 8 ring atoms, wherein 1 to 3 are heteroatoms (eg 1, 2 and 3) (ie 3 to 8 membered heterocyclyl); more preferably have 3 to 6 ring atoms, of which 1 to 3 are heteroatoms (ie 3 to 6 membered heterocyclyl); optimally contain 5 or 6 ring atoms, of which 1 to 3 are heteroatoms (ie 5 or 6 membered heterocyclyl). Non-limiting examples of monocyclic heterocyclyl groups include: pyrrolidinyl, tetrahydropyranyl, 1,2,3,6-tetrahydropyridyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholine base, homopiperazinyl, etc. Polycyclic heterocyclyls include spiroheterocyclyls, fused heterocyclyls and bridged heterocyclyls.

The term "spiroheterocyclyl" refers to a polycyclic heterocyclic group that shares one atom (called spiro atom) between 5 to 20-membered monocyclic rings, wherein one or more ring atoms are heterocyclic groups selected from nitrogen, oxygen and sulfur atoms, the sulfur can be oxidized (ie to form argon or sulfur) if desired, and the remaining ring atoms are carbon. It may contain one or more double bonds. Preferably 6 to 14 members, more preferably 7 to 10 members (eg 7, 8, 9 or 10 members). According to the number of shared spiro atoms between the ring and the ring, the spiro heterocyclic group is divided into a single spiro heterocyclic group or a polyspiro heterocyclic group (such as a double spiro heterocyclic group), preferably a single spiro heterocyclic group and a double spiro heterocyclic group base. More preferably 4-membered/4-membered, 4-membered/5-membered, 4-membered/6-membered, 5-membered/5-membered, 5-membered/6-membered or 6-membered/6-membered monospiro heterocyclic group. Non-limiting examples of spiroheterocyclyls include:

The term "fused heterocyclic group" refers to a polycyclic heterocyclic group that shares an adjacent pair of atoms between rings of 5 to 20 members, one or more rings may contain one or more double bonds, and one or more rings The atoms are heteroatoms selected from nitrogen, oxygen and sulfur, the sulfur optionally being oxidized (ie to form argon or thionium), and the remaining ring atoms are carbon. Preferably 6 to 14 members, more preferably 7 to 10 members (eg 7, 8, 9 or 10 members). According to the number of rings, it can be divided into bicyclic, tricyclic, tetracyclic and other polycyclic fused heterocyclic groups, preferably bicyclic or tricyclic fused heterocyclic groups, more preferably 3-membered/4-membered, 3-membered/5-membered, and 3-membered /6 people, 4 people/4 people, 4 people/5 people, 4 people/6 people, 5 people/3 people, 5 people/4 people, 5 people/5 people, 5 people/6 people, 5 people/7 people member, 6 member/3 member, 6 member/4 member, 6 member/5 member, 6 member/6 member, 6 member/7 member, 7 member/5 member or 7 member/6 member bicyclic fused heterocyclyl. Non-limiting examples of fused heterocyclic groups include:

The term "bridged heterocyclyl" refers to a polycyclic heterocyclic group in which any two rings of 5 to 14 members share two atoms not directly connected, which may contain one or more double bonds, in which one or more ring atoms To be selected from nitrogen, oxygen and sulfur, the sulfur optionally being oxidized (ie to form argon or sulfur), the remaining ring atoms are carbon. Preferably 6 to 14 members, more preferably 7 to 10 members (eg 7, 8, 9 or 10 members). According to the number of rings, it can be divided into bicyclic, tricyclic, tetracyclic and other polycyclic bridged heterocyclic groups, preferably bicyclic, tricyclic or tetracyclic bridged heterocyclic groups, more preferably bicyclic or tricyclic bridged heterocyclic groups. Non-limiting examples of bridged heterocyclyl groups include:

The heterocyclyl ring includes a heterocyclyl as described above (including monocyclic, spiroheterocycle, fused heterocycle and bridged heterocycle) fused to an aryl, heteroaryl or cycloalkyl ring wherein the parent structure The rings joined together are heterocyclyl, non-limiting examples of which include:

等。

Wait.

The heterocyclyl group may be substituted or unsubstituted, and when substituted, it may be substituted at any available point of attachment, the substituents are preferably selected from halogen, alkyl, alkoxy, haloalkyl, halo One or more of alkoxy, cycloalkyloxy, heterocyclyloxy, hydroxyl, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl indivual.

The term "aryl" refers to a 6 to 14 membered full carbon monocyclic or fused polycyclic (a fused polycyclic is a ring sharing adjacent pairs of carbon atoms) group with a conjugated π electron system, preferably 6 to 10 members such as phenyl and naphthyl. The aryl ring includes an aryl ring as described above fused to a heteroaryl, heterocyclyl or cycloalkyl ring wherein the ring bonded to the parent structure is an aryl ring, non-limiting examples of which include:

Aryl may be substituted or unsubstituted, and when substituted, it may be substituted at any available point of attachment, the substituents are preferably selected from halogen, alkyl, alkoxy, haloalkyl, haloalkane One or more of oxy, cycloalkyloxy, heterocyclyloxy, hydroxyl, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl .

The term "heteroaryl" refers to a heteroaromatic system comprising 1 to 4 heteroatoms (eg 1, 2, 3 and 4), 5 to 14 ring atoms, wherein the heteroatoms are selected from oxygen, sulfur and nitrogen. Heteroaryl is preferably 5 to 10 members (for example 5, 6, 7, 8, 9 or 10 members), more preferably 5 or 6 members, for example furyl, thienyl, pyridyl, pyrrolyl, N-alkyl Pyrrolyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, etc. The heteroaryl ring includes a heteroaryl as described above fused to an aryl, heterocyclyl or cycloalkyl ring wherein the ring bonded to the parent structure is a heteroaryl ring, non-limiting examples of which include:

Heteroaryl may be substituted or unsubstituted, and when substituted, it may be substituted at any available point of attachment, the substituents are preferably selected from halogen, alkyl, alkoxy, haloalkyl, halo One or more of alkoxy, cycloalkyloxy, heterocyclyloxy, hydroxyl, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl indivual.

The above cycloalkyl, heterocyclyl, aryl and heteroaryl groups include residues derived by removing one hydrogen atom from a parent ring atom, or by removing two hydrogen atoms from the same ring atom or two different ring atoms of the parent The residue derived from the atom is "(extended) cycloalkylene", "(extended) heterocyclyl", "(extended) arylene", "(extended) heteroarylylene".

The term "amino-protecting group" refers to an easy-to-remove group introduced on the amine group in order to keep the amine group unchanged when other parts of the molecule are reacted. Non-limiting examples include: (trimethylsilyl)ethoxymethyl, tetrahydropyranyl, tert-butoxycarbonyl (Boc), acetyl, p-toluenesulfonyl (Ts), benzyl, alkenyl Propyl and p-methoxybenzyl, etc. These groups may be optionally substituted with 1 to 3 substituents selected from halogen, alkoxy or nitro.

The term "hydroxyl protecting group" refers to an easy-to-remove group introduced on the hydroxyl group, which is usually used to block or protect the hydroxyl group to react 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 (such as methoxymethyl (MOM) and ethoxyethyl etc.), (C _1-10 alkyl or Aryl) acyl (such as formyl, acetyl, benzoyl, p-nitrobenzoyl, etc.), (C _1-6 alkyl or 6 to 10 membered aryl) sulfonyl, (C _1-6 alkoxy or 6 to 10 membered aryloxy)carbonyl, allyl, 2-tetrahydropyranyl (THP) and the like.

The term "cycloalkyloxy" refers to cycloalkyl-O-, wherein cycloalkyl is as defined above.

The term "heterocyclyloxy" refers to heterocyclyl-O-, wherein heterocyclyl is as defined above.

The term "alkylthio" refers to alkyl-S-, wherein alkyl is as defined above.

The term "haloalkyl" refers to an alkyl group substituted with one or more halogens, wherein alkyl is as defined above.

The term "haloalkoxy" refers to an alkoxy group substituted with one or more halogens, wherein alkoxy group is as defined above.

The term "deuteroalkyl" refers to an alkyl group substituted with one or more deuterium atoms, wherein alkyl is as defined above.

The term "hydroxyalkyl" refers to an alkyl group substituted with one or more hydroxy groups, wherein alkyl is as defined above.

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

The term "hydroxyl" refers to -OH.

The term "mercapto" refers to -SH.

The term "amino" refers to _-NH2 .

The term "cyano" refers to -CN.

The term "nitro" refers to _-NO2 .

The term "side oxygen" or "side oxy" refers to "=0".

The term "carbonyl" refers to C=O.

The term "carboxy" refers to -C(O)OH.

The term "carboxylate" refers to -C(O)O(alkyl), -C(O)O(cycloalkyl), (alkyl)C(O)O- or (cycloalkyl)C(O )O-, wherein alkyl and cycloalkyl are as defined above.

Compounds of the present disclosure may exist in particular stereoisomeric forms. The term "stereoisomer" refers to isomers that are identical in structure but differ in the arrangement of the atoms in space. It includes cis and trans (or Z and E ) isomers, (-)- and (+)-isomers, ( R )- and ( S )-enantiomers, diastereomers isomers, (D )- and ( L )-isomers, tautomers, atropisomers, conformers and mixtures thereof (eg racemates, mixtures of diastereomers). Substituents in compounds of the present disclosure may be present with additional asymmetric atoms. All such stereoisomers, as well as mixtures thereof, are included within the scope of the present disclosure. Optically active (-)- and (+)-isomers, ( R )- and ( S )-enantiomers and (D )- and ( L )-isomers. An isomer of a certain compound in the present disclosure can be prepared by asymmetric synthesis or chiral auxiliary agents, or, when the molecule contains a basic functional group (such as an amine group) or an acidic functional group (such as a carboxyl group), it can be prepared with an appropriate Optically active acids or bases form diastereomeric salts, which are then resolved by conventional methods well known in the art to obtain the pure isomers. Furthermore, separation of enantiomers and diastereomers is usually accomplished by chromatography.

”表示未指定構型，即如果化學結構中存在手性異構體，鍵“

”可以為“

”或“

”，或者同時包含“

”和“

”兩種構型。 In the chemical structures of the compounds described in this disclosure, the bond "

"indicates that no configuration is specified, i.e. if chiral isomers exist in the chemical structure, the bond"

"can be"

"or"

, or both "

"with"

"Two configurations.

The compounds of the present disclosure may exist in different tautomeric forms and all such forms are included within the scope of the present disclosure. The term "tautomer" or "tautomeric form" refers to structural isomers that exist in equilibrium and are readily converted from one isomeric form to the other. It includes all possible tautomers, ie present as single isomers or as mixtures of such tautomers in any ratio. Non-limiting examples include: keto-enol, imine-enamine, lactam-lactimine, and the like. An example of a lactam-lactimine equilibrium is shown below:

For example, when referring to pyrazolyl, it should be understood to include any one of the following two structures or a mixture of two tautomers:

All tautomeric forms are within the scope of the present disclosure, and the naming of compounds does not exclude any tautomers.

Compounds of the present disclosure include all suitable isotopic derivatives of their compounds. 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 incorporated into compounds of the present disclosure include stable and radioactive isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, bromine, and iodine, etc., such as ² H (deuterium, D), respectively, 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 I, etc., preferably deuterium.

Compared with non-deuterated drugs, deuterated drugs have the advantages of reducing toxic and side effects, increasing drug stability, enhancing curative effect, and prolonging the biological half-life of drugs. All compounds of the present disclosure Changes in isotopic composition, whether radioactive or not, are included within the scope of this disclosure. Each available hydrogen atom attached to a carbon atom may be independently replaced by a deuterium atom, wherein the replacement of deuterium may be partial or complete, and partial deuterium replacement means that at least one hydrogen is replaced by at least one deuterium.

In a compound of the present disclosure, when a position is specifically designated as "deuterium" or "D", this position is understood to mean that the abundance of deuterium is at least 1000 times greater than the natural abundance of deuterium (which is 0.015%) (i.e. at least 15% deuterium incorporation). In some embodiments, the abundance of deuterium per designated deuterium atom is at least 1000 times greater than the natural abundance of deuterium (ie, at least 15% deuterium incorporation). In some embodiments, the abundance of deuterium per designated deuterium atom is at least 2000 times greater than the natural abundance of deuterium (ie, at least 30% deuterium incorporation). In some embodiments, the abundance of deuterium per designated deuterium atom is at least 3000 times greater than the natural abundance of deuterium (ie, at least 45% deuterium incorporation). In some embodiments, the abundance of deuterium per designated deuterium atom is at least 3340 times greater than the natural abundance of deuterium (ie, at least 50.1% deuterium incorporation). In some embodiments, the abundance of deuterium per designated deuterium atom is at least 3500 times greater than the natural abundance of deuterium (ie, at least 52.5% deuterium incorporation). In some embodiments, the abundance of deuterium per designated deuterium atom is at least 4000 times greater than the natural abundance of deuterium (ie, at least 60% deuterium incorporation). In some embodiments, the abundance of deuterium per designated deuterium atom is at least 4500 times greater than the natural abundance of deuterium (ie, at least 67.5% deuterium incorporation). In some embodiments, the abundance of deuterium per designated deuterium atom is at least 5000 times greater than the natural abundance of deuterium (ie, at least 75% deuterium incorporation). In some embodiments, the abundance of deuterium per designated deuterium atom is at least 5500 times greater than the natural abundance of deuterium (ie, at least 82.5% deuterium incorporation). In some embodiments, the abundance of deuterium per designated deuterium atom is at least 6000 times greater than the natural abundance of deuterium (ie, at least 90% deuterium incorporation). In some embodiments, the abundance of deuterium per designated deuterium atom is at least 6333.3 times greater than the natural abundance of deuterium (ie, at least 95% deuterium incorporation). In some embodiments, the abundance of deuterium per designated deuterium atom is at least 6466.7 times greater than the natural abundance of deuterium (ie, at least 97% deuterium incorporation). In some embodiments, the abundance of deuterium per designated deuterium atom is at least 6600 times greater than the natural abundance of deuterium (ie, at least 99% deuterium incorporation). In some embodiments, the abundance of deuterium per designated deuterium atom is at least 6633.3 times greater than the natural abundance of deuterium (ie, at least 99.5% deuterium incorporation).

The present disclosure 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) the compound shown in and the compound shown in Table A or its pharmaceutically acceptable salt, including its tautomers, racemates, enantiomers, diastereoisomers, cis-trans isomers body or a mixture thereof.

"Optionally" or "optionally" means that the subsequently described event or circumstance can but need not occur, and that the description includes instances where the event or circumstance occurs or does not occur. For example, "C _1-6 alkyl optionally (optionally) substituted by halogen or cyano" means that halogen or cyano may but not necessarily exist, and this description includes the case where the alkyl is substituted by halogen or cyano and the alkyl The case where the group is not substituted by halogen and cyano.

"Substituted" or "substituted" means that one or more hydrogen atoms in a group, preferably 1 to 6, more preferably 1 to 3 hydrogen atoms, are independently substituted by the corresponding number of substituents. Those skilled in the art are able to determine possible or impossible substitutions (by experiment or theory) without undue effort. For example, an amine or hydroxyl group with free hydrogen may be unstable when bonded to a carbon atom with an unsaturated (eg, ethylenic) bond.

"Pharmaceutical composition" means a mixture containing one or more compounds described herein, or a pharmaceutically acceptable salt thereof, and other chemical components, and other components such as a pharmaceutically acceptable carrier and excipients. The purpose of the pharmaceutical composition is to promote the administration to the living body, facilitate the absorption of the active ingredient and thus exert the biological activity.

"Pharmaceutically acceptable salt" refers to a salt of a compound of the present disclosure, which may be selected from inorganic or organic salts. Such salts are safe and effective when used in mammals, and have proper biological activity. Salts can be prepared separately during the final isolation and purification of the compounds, or by reacting the appropriate 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 amines. Acids commonly used to form pharmaceutically acceptable salts include inorganic acids as well as organic acids.

With respect to a drug or pharmacologically active agent, the term "therapeutically effective amount" refers to an amount of the drug or agent sufficient to achieve, or at least partially achieve, the desired effect. The determination of the therapeutically effective dose varies from person to person, depending on the age and general condition of the subject, and also depends on the specific active substance. The appropriate therapeutically effective dose in individual cases can be determined by those skilled in the art according to routine experiments.

As used herein, the term "pharmaceutically acceptable" refers to those compounds, materials, compositions and/or dosage forms, which are suitable for use in contact with patient tissues without undue toxicity, irritation, allergic reaction or Other problems or complications that have a reasonable benefit/risk ratio and are valid for the intended use.

As used herein, the singular forms "a", "an" and "the" include plural references and vice versa unless the context clearly dictates otherwise.

When the term "about" is applied to a parameter such as pH, concentration, temperature, etc., it means that the parameter may vary by ±10%, and sometimes preferably within ±5%. If the technical field has a general Those of ordinary skill will understand that when a parameter is not critical, the numbers are generally given for illustrative purposes only, not limitations.

Synthetic Methods of the Disclosed Compounds

In order to accomplish the purpose of this disclosure, this disclosure adopts the following technical solutions:

Option One

Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (I) or a pharmaceutically acceptable salt thereof, the method comprising:

Compounds represented by general formula (IA) or salts thereof undergo intramolecular ring closure reactions under acidic conditions to obtain compounds represented by general formula (I) or pharmaceutically acceptable salts thereof,

in,

R ^m is C _1-6 alkyl; preferably, R ^m is tertiary butyl;

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 the general formula (I).

Option II

Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (I-1) or a pharmaceutically acceptable salt thereof, the method comprising:

Compounds represented by general formula (IA-1) or salts thereof undergo intramolecular ring closure reactions under acidic conditions to obtain compounds represented by general formulas (I-1) or pharmaceutically acceptable salts thereof,

in,

R ^m is C _1-6 alkyl; preferably, R ^m is tertiary butyl;

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 the general formula (I-1).

third solution

Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (II) or a pharmaceutically acceptable salt thereof, the method comprising:

The compound represented by the general formula (IIA) or its salt undergoes an intramolecular ring-closure reaction under acidic conditions to obtain the compound represented by the general formula (II) or a pharmaceutically acceptable salt thereof,

in,

R ^m is C _1-6 alkyl; preferably, R ^m is tertiary butyl;

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 the compound of general formula (II).

Option four

Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (II-1) or a pharmaceutically acceptable salt thereof, the method comprising:

The compound represented by the general formula (IIA-1) or its salt undergoes an intramolecular ring closure reaction under acidic conditions to obtain the compound represented by the general formula (II-1) or a pharmaceutically acceptable salt thereof,

in,

R ^m is C _1-6 alkyl; preferably, R ^m is tertiary butyl;

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 the compound of general formula (II-1).

Option five

Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (III), or a pharmaceutically acceptable salt thereof, the method comprising:

The compound represented by the general formula (IIIA) or its salt undergoes an intramolecular ring-closing reaction under acidic conditions to obtain the compound represented by the general formula (III) or a pharmaceutically acceptable salt thereof,

in,

R ^m is C _1-6 alkyl; preferably, R ^m is tertiary butyl;

Rings A, G ¹ , G ² , G ³ , R ¹ , R ² , R ⁵ to R ⁷ , m, n, p and q are as defined for the compound of general formula (III).

Option six

Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (III-1) or a pharmaceutically acceptable salt thereof, the method comprising:

The compound represented by the general formula (IIIA-1) or its salt undergoes an intramolecular ring closure reaction under acidic conditions to obtain the compound represented by the general formula (III-1) or a pharmaceutically acceptable salt thereof,

in,

R ^m is C _1-6 alkyl; preferably, R ^m is tertiary butyl;

Ring A, G ¹ , G ² , G ³ , R ¹ , R ² , R ⁵ to R ⁷ , m, n, p and q are as defined for the compound of general formula (III-1).

Option seven

Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (I-1-1) or a pharmaceutically acceptable salt thereof, the method comprising:

The compound represented by the general formula (IA-1-1) or its salt undergoes an intramolecular ring closure reaction under acidic conditions to obtain the compound represented by the general formula (I-1-1) or a pharmaceutically acceptable salt thereof,

in,

R ^m is C _1-6 alkyl; preferably, R ^m is tertiary butyl;

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 the general formula (I-1-1).

Option eight

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

The compound represented by the general formula (IA-1-2) or its salt undergoes an intramolecular ring closure reaction under acidic conditions to obtain the compound represented by the general formula (I-1-2) or its pharmaceutically acceptable salt,

in,

R ^m is C _1-6 alkyl; preferably, R ^m is tertiary butyl;

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 the general formula (I-1-2).

Option nine

Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (II-1-1) or a pharmaceutically acceptable salt thereof, the method comprising:

The compound represented by the general formula (IIA-1-1) or its salt undergoes an intramolecular ring closure reaction under acidic conditions to obtain the compound represented by the general formula (II-1-1) or a pharmaceutically acceptable salt thereof,

in,

R ^m is C _1-6 alkyl; preferably, R ^m is tertiary butyl;

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 the compound of general formula (II-1-1).

Plan ten

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

Compounds represented by general formula (IIA-1-2) or salts thereof undergo intramolecular ring closure reactions under acidic conditions to obtain compounds represented by general formulas (II-1-2) or pharmaceutically acceptable salts thereof,

in,

R ^m is C _1-6 alkyl; preferably, R ^m is tertiary butyl;

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 the compound of general formula (II-1-2).

Plan Eleven

Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (III-1-1) or a pharmaceutically acceptable salt thereof, the method comprising:

The compound represented by the general formula (IIIA-1-1) or its salt undergoes an intramolecular ring closure reaction under acidic conditions to obtain the compound represented by the general formula (III-1-1) or a pharmaceutically acceptable salt thereof,

in,

R ^m is C _1-6 alkyl; preferably, R ^m is tertiary butyl;

Ring A, G ¹ , G ² , G ³ , R ¹ , R ² , R ⁵ to R ⁷ , m, n, p and q are as defined for the compound of general formula (III-1-1).

Plan twelve

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

The compound represented by the general formula (IIIA-1-2) or its salt undergoes an intramolecular ring closure reaction under acidic conditions to obtain the compound represented by the general formula (III-1-2) or a pharmaceutically acceptable salt thereof,

in,

R ^m is C _1-6 alkyl; preferably, R ^m is tertiary butyl;

Ring A, G ¹ , G ² , G ³ , R ¹ , R ² , R ⁵ to R ⁷ , m, n, p and q are as defined for the compound of general formula (III-1-2).

Reagents providing acidic conditions in the above synthesis scheme 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; Preferred is benzenesulfonic acid.

The above-mentioned reaction is preferably carried out in a solvent, and the solvent used includes but is not limited to: ethylene glycol dimethyl ether, acetic acid, methanol, ethanol, acetonitrile, n-butanol, toluene, tetrahydrofuran, dichloromethane, petroleum ether, ethyl acetate, n-Hexane, Dimethylsulfide, 1,4-Dioxane, Water, N,N-Dimethylformamide, N,N-Dimethylacetamide and mixtures thereof.

Figure 1 shows the curative effect data of the compound of Example 2-1 and CC-92480 on NCI-H929 transplanted tumors in CB-17 SCID mice.

Figure 2 shows the effect of the compound of Example 2-1 and CC-92480 on body weight of CB-17 SCID mice.

The following examples are used to further describe the present disclosure, but these examples do not limit the scope of the present disclosure.

Example

Compound structures were determined by nuclear magnetic resonance (NMR) or/and mass spectroscopy (MS). NMR shifts (δ) are given in units of 10 ^-6 (ppm). The determination of NMR is to use Bruker AVANCE-400 nuclear magnetic apparatus or Bruker AVANCE NEO 500M, and the determination solvent is deuterated dimethyl sulfide (DMSO- d ₆ ), deuterated chloroform (CDCl ₃ ), deuterated methanol (CD ₃ OD) , the internal standard is tetramethylsilane (TMS).

The determination of MS uses Agilent 1200/1290 DAD-6110/6120 Quadrupole MS liquid mass spectrometer (manufacturer: Agilent, MS model: 6110/6120 Quadrupole MS), waters ACQuity UPLC-QD/SQD (manufacturer: waters, MS Model: waters ACQuity Qda Detector/waters SQ Detector), THERMO Ultimate 3000-Q Exactive (manufacturer: THERMO, MS model: THERMO Q Exactive).

High-performance liquid chromatography (HPLC) was analyzed using Agilent HPLC 1200DAD, Agilent HPLC 1200VWD and Waters HPLC e2695-2489 high-performance liquid chromatography.

Chiral HPLC analysis and determination using Agilent 1260 DAD high performance liquid chromatography.

Waters 2545-2767, Waters 2767-SQ Detecor2, Shimadzu LC-20AP and Gilson GX-281 preparative chromatographs were used for HPLC preparation.

Chiral preparation A Shimadzu LC-20AP preparative chromatograph was used.

The CombiFlash rapid preparation instrument uses Combiflash Rf200 (TELEDYNE ISCO).

The thin-layer chromatography silica gel plate uses Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plate. The specification of the silica gel plate used in thin-layer chromatography (TLC) is 0.15mm to 0.2mm, and the specification of thin-layer chromatography separation and purification products is 0.4mm. to 0.5mm.

Silica gel column chromatography generally uses Yantai Huanghai silica gel 200 to 300 mesh silica gel as the carrier.

Kinase average inhibition rate and IC ₅₀ value were measured with NovoStar microplate reader (BMG Company, Germany).

The known starting materials of the present disclosure can be adopted or synthesized according to methods known in the art, or can be purchased from ABCR GmbH & Co.KG, Acros Organics, Aldrich Chemical Company, J&K, Shaoyuan Chemical Technology (Accela ChemBio Inc ), Shanghai Biide Pharmaceuticals, Darui Chemicals and other companies.

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

The argon atmosphere or nitrogen atmosphere means that the reaction bottle is connected to an argon or nitrogen balloon with a volume of about 1 L.

The hydrogen atmosphere means that the reaction bottle is connected to a hydrogen balloon with a capacity of about 1L.

The pressurized hydrogenation reaction uses a Parr 3916EKX hydrogenator and Qinglan QL-500 hydrogen generator or HC2-SS hydrogenator.

The hydrogenation reaction is usually evacuated and filled with hydrogen, and the operation is repeated 3 times.

For the microwave reaction, a CEM Discover-S 908860 microwave reactor was used.

Unless otherwise specified in the examples, the solution refers to an aqueous solution.

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

The monitoring of the reaction process in the embodiment adopts thin-layer chromatography (TLC), the developing agent used in the reaction, the system of the eluting agent of the column chromatography adopted by the purified compound and the developing agent system of the thin-layer chromatography include: A : dichloromethane/methanol system; B: n-hexane/ethyl acetate system. The volume ratio of the solvent is adjusted according to the polarity of the compound, and it can also be adjusted by adding a small amount of basic or acidic reagents such as triethylamine and acetic acid.

Example 1

4-(4-(6-(((2-(( S )-2,6-dioxopiperidin-3-yl)-1-oxoisoindoline-4-yl)oxy)methyl Base)-1,2,3,4-tetrahydronaphthalen-1-yl)piperazin-1-yl)-3-fluorobenzonitrile 1

first step

Methyl 5-oxo-5,6,7,8-tetrahydronaphthalene-2-carboxylate 1b

Dissolve 5-oxo-5,6,7,8-tetrahydronaphthalene-2-carboxylic acid 1a (1.0g, 5.26mmol, Shanghai Bi De Pharmaceutical) in 100mL of methanol, add concentrated sulfuric acid (0.6 mL, 11.0 mmol), after the addition, the reaction solution was heated to 60°C and stirred overnight. Concentrate under reduced pressure to remove most of methanol, add water (200 mL) to dilute, then extract with ethyl acetate (100 mL×3), combine organic phases, wash with saturated sodium chloride solution (100 mL), dry over anhydrous sodium sulfate, and filter. The filtrate was concentrated under reduced pressure and sucked to dryness to obtain the crude title compound 1b (1.0 g, yield: 96%).

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

second step

Methyl 5-hydroxy-5,6,7,8-tetrahydronaphthalene-2-carboxylate 1c

Compound 1b (1.0 g, 4.90 mmol) was dissolved in absolute ethanol (20 mL), and potassium borohydride (530 mg, 9.82 mmol) was added in batches under ice-cooling, and the reaction was naturally warmed to room temperature and stirred for 4 hours. The reaction solution was concentrated, diluted with water (100 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 the residue was purified by column chromatography with eluent system B to obtain the title compound 1c (1.0 g, yield: 99%).

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

third step

Methyl 5-chloro-5,6,7,8-tetrahydronaphthalene-2-carboxylate 1d

Compound 1c (1.0g, 4.85mmol) was dissolved in dichloromethane (10mL), and phosphine chloride (0.6mL, 8.27mmol) was added dropwise under ice-cooling, and the reaction was stirred for 2 hours under ice-cooling. Add ice water (100 mL) dropwise to quench the reaction, then extract with dichloromethane (100 mL×3), combine the organic phases, wash with saturated sodium chloride solution (100 mL), dry over anhydrous sodium sulfate, and filter. The filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography with eluent system B to obtain the title compound 1d (540 mg, yield: 50%).

the fourth step

Methyl 5-(4-(4-cyano-2-fluorophenyl)piperazin-1-yl)-5,6,7,8-tetrahydronaphthalene-2-carboxylate 1e

Compound 1d (520mg, 2.31mmol), 3-fluoro-4-(piperazin-1-yl)benzonitrile (720mg, 3.51mmol, Shanghai Bid Pharmaceutical) was dissolved in N , N -dimethylformamide ( 5 mL), N , N -diisopropylethylamine (2 mL, 12.1 mmol), tetrabutylammonium bromide (746 mg, 2.31 mmol) were added, and the reaction was heated to 50°C and stirred for 48 hours. The reaction solution was cooled to room temperature, diluted with water (100 mL), and then extracted with ethyl acetate (50 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 with eluent system B to obtain the title compound 1e (820 mg, yield: 90%).

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

the fifth step

3-fluoro-4-(4-(6-(hydroxymethyl)-1,2,3,4-tetrahydronaphthalen-1-yl)piperazin-1-yl)benzonitrile 1f

Compound 1e (500mg, 1.27mmol) was dissolved in 22mL of a mixed solution of tetrahydrofuran and methanol (V/V=10:1), lithium borohydride (275mg, 12.62mmol) was added under ice-cooling, and the reaction was raised to room temperature and stirred overnight . The reaction solution was quenched with water (50 mL), then extracted with ethyl acetate (50 mL×2), the organic phases were combined, 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 with eluent system B to obtain the title compound 1f (340 mg, yield: 73%).

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

step six

4-(4-(6-(Chloromethyl)-1,2,3,4-tetrahydronaphthalen-1-yl)piperazin-1-yl)-3-fluorobenzonitrile 1g

Compound 1f (50mg, 0.137mmol) was dissolved in dichloromethane (2mL), and argon chloride (0.1mL, 1.38mmol) was added dropwise under ice-cooling. The reaction was slowly raised to room temperature and stirred for 2 hours. The reaction was quenched by adding ice water (20 mL), and extracted with dichloromethane (20 mL×3). The combined organic phases were 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 with eluent system A to obtain 1 g of the title compound (50 mg, yield: 95%).

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

step seven

(4 S )-5-amino-4-(4-((5-(4-(4-cyano-2-fluorophenyl)piperazin-1-yl)-5,6,7,8- Tetrahydronaphthalene-2-yl)methoxy)-1-oxoisoindoline-2-yl)-5-oxo-pentanoic acid tertiary butyl ester 1i

Compound 1g (50mg, 0.130mmol), ( S )-5-amino-4-(4-hydroxyl-1-oxoisoindoline-2-yl)-5-oxovaleric acid tertiary butyl ester 1h (46mg, 0.137mmol, prepared by the method disclosed in "Journal of Medicinal Chemistry, 2020, 63(13), 6648-6676") was dissolved in N , N -dimethylformamide (2mL), added to anhydrous Potassium carbonate (72mg, 0.521mmol), tetrabutylammonium bromide (42mg, 0.130mmol), and the reaction 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 with eluent system A to obtain the title compound 1i (85 mg, yield: 95%).

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

eighth step

4-(4-(6-(((2-(( S )-2,6-dioxopiperidin-3-yl)-1-oxoisoindoline-4-yl)oxy)methyl Base)-1,2,3,4-tetrahydronaphthalen-1-yl)piperazin-1-yl)-3-fluorobenzonitrile 1

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

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

¹ H NMR (500MHz,DMSO- d ₆ )δ 11.0(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).

Example 2-1

4-(4-(( S )-6-(((2-(( S )-2,6-dioxopiperidin-3-yl)-1-oxoisoindoline-4-yl)oxy Base) methyl)-1,2,3,4-tetrahydronaphthalen-1-yl)piperazin-1-yl)-3-fluorobenzonitrile 2-1

first step

( S )-3-fluoro-4-(4-(6-(hydroxymethyl)-1,2,3,4-tetrahydronaphthalen-1-yl)piperazin-1-yl)benzonitrile 1f-1

( R )-3-fluoro-4-(4-(6-(hydroxymethyl)-1,2,3,4-tetrahydronaphthalen-1-yl)piperazin-1-yl)benzonitrile 1f-2

Compound 1f (2.0g) was subjected to chiral resolution (separation condition: Shimadzu LC-20AP, chromatographic column: CHIRALPAK AY (20×250mM), mobile phase: ethanol solution of n-hexane/10mmol/L ammonia (NH ₃ )= 70/30 (v/v)), flow rate 20mL/min) to obtain the title compounds 1f-1 (730mg) and 1f-2 (830mg).

Compound 1f-2 :

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

Chiral HPLC analysis method: retention time 4.27 minutes (Agilent1260 DAD, chromatographic column: CHIRALPAK AY (4.6×150mM), 5μm; mobile phase: n-hexane/ethanol (containing 0.1% diethylamine)=70/30(v/ v)) at a flow rate of 1 mL/min).

Compound 1f-1 :

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

Chiral HPLC analysis method: retention time 5.43 minutes (Agilent1260 DAD, chromatographic column: CHIRALPAK AY (4.6×150mM), 5μm; mobile phase: n-hexane/ethanol (containing 0.1% diethylamine)=70/30(v/ v)) at a flow rate of 1 mL/min).

second step

( S )-4-(4-(6-(Chloromethyl)-1,2,3,4-tetrahydronaphthalen-1-yl)piperazin-1-yl)-3-fluorobenzonitrile 1g-1

Compound 1f-1 (730mg, 2.0mmol) was dissolved in dichloromethane (10mL), and phosphine chloride (1.31g, 11.03mmol) was added dropwise under ice-cooling, and the reaction was slowly raised to room temperature, and stirred for 4 hours. The reaction was quenched by adding ice water (20 mL), and extracted with dichloromethane (50 mL×3). The combined organic phases were 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 with eluent system A to obtain the title compound 1g-1 (760 mg, yield: 99%).

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

third step

( S )-5-amino-4-(4-((( S )-5-(4-(4-cyano-2-fluorophenyl)piperazin-1-yl)-5,6,7 ,8-tetrahydronaphthalen-2-yl)methoxy)-1-oxoisoindolin-2-yl)-5-oxo-pentanoic acid tertiary butyl ester 1i-1

Dissolve compound 1g-1 (730mg, 1.90mmol), compound 1h (640mg, 1.91mmol) in N , N -dimethylformamide (10mL), add anhydrous potassium carbonate (790mg, 5.72mmol), tetrabutyl Ammonium bromide (620mg, 1.92mmol), the reaction was heated to 40°C and stirred for 6 hours. The reaction solution 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 with eluent system A to obtain the title compound 1i-1 (930 mg, yield: 72%).

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

the fourth step

4-(4-(( S )-6-(((2-(( S )-2,6-dioxopiperidin-3-yl)-1-oxoisoindoline-4-yl)oxy Base) methyl)-1,2,3,4-tetrahydronaphthalen-1-yl)piperazin-1-yl)-3-fluorobenzonitrile 2-1

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

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

¹ H NMR (500MHz,DMSO- d ₆ )δ 10.98(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).

Example 2-2

4-(4-(( R )-6-(((2-(( S )-2,6-dioxopiperidin-3-yl)-1-oxoisoindoline-4-yl)oxy Base) methyl)-1,2,3,4-tetrahydronaphthalen-1-yl)piperazin-1-yl)-3-fluorobenzonitrile 2-2

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

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

¹ H NMR (500MHz,DMSO- d ₆ )δ 10.98(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).

Example 3

4-(4-(5-(((2-(( S )-2,6-dioxopiperidin-3-yl)-1-oxoisoindoline-4-yl)oxy)methyl Base)-2,3-dihydro- 1H -inden-1-yl)piperazin-1-yl)-3-fluorobenzonitrile 3

first step

Methyl 1-oxo-2,3-dihydro-1 H -indene-5-carboxylate 3b

The compound 1-oxo-2,3-dihydro-1 H -indene-5-carboxylic acid 3a (1.0g, 5.68mmol, Shanghai Haohong Biomedical Technology Co., Ltd.) was dissolved in 100mL of methanol, and dropped in an ice bath Concentrated sulfuric acid (0.7 mL, 12.9 mmol, 98% by mass) was added, and the addition was completed, and the reaction was heated to 60 °C and stirred overnight. Concentrate under reduced pressure to remove most of the methanol, add water (200mL) to dilute, then extract with ethyl acetate (100mL×3), combine the organic phases, wash with saturated sodium chloride solution (100mL), dry over anhydrous sodium sulfate, filter, and the filtrate Concentrate under reduced pressure and dry in vacuo to obtain the crude title compound 3b (1.05 g, yield: 97%).

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

second step

Methyl 1-hydroxy-2,3-dihydro-1 H -indene-5-carboxylate 3c

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

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

third step

Methyl 1-chloro-2,3-dihydro-1 H -indene-5-carboxylate 3d

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

the fourth step

Methyl 1-(4-(4-cyano-2-fluorophenyl)piperazin-1-yl)-2,3-dihydro-1 H -indene-5-carboxylate 3e

Compound 3d (1.0g, 4.7mmol), 3-fluoro-4-piperazinylbenzonitrile (1.02g, 4.9mmol) was dissolved in N , N -dimethylformamide (5mL), and N , N - Diisopropylethylamine (4mL, 24.2mmol) and tetrabutylammonium bromide (155mg, 0.48mmol) were heated to 50°C for 3 hours. After cooling down to room temperature, the reaction solution was diluted with water (100 mL), then 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 with eluent system B to obtain the title compound 3e (500 mg, yield: 28%).

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

the fifth step

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

Compound 3e (500mg, 1.32mmol) was dissolved in 11mL of a mixed solution of tetrahydrofuran and methanol (V/V=10/1), lithium borohydride (140mg, 6.4mmol) was added under ice-cooling, and the reaction was raised to room temperature and stirred for 12 Hour. The reaction solution 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. After filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography with eluent system B to obtain the title compound 3f (210 mg, yield: 43%).

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

step six

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

Compound 3f (80mg, 0.228mmol) was dissolved in dichloromethane (2mL), and phosphine chloride (0.1mL, 1.38mmol) was added dropwise under ice-cooling, slowly warmed 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 (20mL), dried, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography with eluent system A to obtain the title compound 3g (76mg, yield: 90% ).

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

step seven

(4 S )-5-amino-4-(4-((1-(4-(4-cyano-2-fluorophenyl)piperazin-1-yl)-2,3-dihydro-1 H -inden-5-yl)methoxy)-1-oxoisoindoline-2-yl)-tert-butyl 5-oxovalerate 3h

Dissolve compound 3g (76mg, 0.205mmol), compound 1h (70mg, 0.209mmol) in N , N -dimethylformamide (1mL), add anhydrous potassium carbonate (57mg, 0.412mmol), tetrabutyl bromide Ammonium (66mg, 0.205mmol), heated to 60°C 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 with eluent system A to obtain the title compound 3h (102 mg, yield: 74% ).

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

eighth step

4-(4-(5-(((2-(( S )-2,6-dioxopiperidin-3-yl)-1-oxoisoindoline-4-yl)oxy)methyl Base)-2,3-dihydro- 1H -inden-1-yl)piperazin-1-yl)-3-fluorobenzonitrile 3

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

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

¹ H NMR (500MHz,DMSO- d ₆ )δ 10.99(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).

Embodiment 4-1, 4-2

4-(4-(( S )-5-(((2-(( S )-2,6-dioxopiperidin-3-yl)-1-oxoisoindoline-4-yl)oxy Base) methyl)-2,3-dihydro- 1H -inden-1-yl)piperazin-1-yl)-3-fluorobenzonitrile 4-1

4-(4-(( R )-5-(((2-(( S )-2,6-dioxopiperidin-3-yl)-1-oxoisoindoline-4-yl)oxy Base) methyl)-2,3-dihydro- 1H -inden-1-yl)piperazin-1-yl)-3-fluorobenzonitrile 4-2

Split:

Compound 3f (180mg) was resolved chiralally (separation condition: Shimadzu LC-20AP, chromatographic column: CHIRALPAK OJ (20×250mM), mobile phase: ethanol solution of n-hexane/10mmol/L ammonia (NH ₃ )=70 /30 (v/v)), flow rate 20mL/min) to obtain compound 3f-1 (70mg) and compound 3f-2 (80mg).

Compound 3f-1 :

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

Chiral HPLC analysis method: retention time 3.90 minutes (Agilent1260 DAD, chromatographic column: CHIRALPAK OJ (4.6×150mM), 5μm; mobile phase: n-hexane/ethanol (containing 0.1% diethylamine)=60/40(v/ v)) at a flow rate of 1 mL/min).

Compound 3f-2 :

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

Chiral HPLC analysis method: retention time 4.68 minutes (Agilent1260 DAD, chromatographic column: CHIRALPAK OJ (4.6×150mM), 5μm; mobile phase: n-hexane/ethanol (containing 0.1% diethylamine)=60/40(v/ v)) at a flow rate of 1 mL/min).

Subsequently, according to the synthetic route of compound 3 , 3f was replaced by compound 3f-1 (70 mg) to obtain compound 4-1 (59 mg).

Subsequently, according to the synthetic route of compound 3 , 3f was replaced by compound 3f-2 (80 mg) to obtain compound 4-2 (63 mg).

Compound 4-1 (59mg):

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

¹ H NMR (500MHz,DMSO- d ₆ )δ 10.99(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).

Compound 4-2 (63mg) :

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

¹ H NMR (500MHz,DMSO- d ₆ )δ 10.98(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).

biological evaluation

The following further describes and explains the present disclosure in combination with test examples, but these test examples are not meant to limit the scope of the present disclosure.

Test Example 1 Biological Evaluation of NCI-H929 Proliferation Experiment

The following method was used to determine the inhibitory activity of the disclosed compounds on the proliferation of NCI-H929 cells. The experimental method is briefly described as follows:

NCI-H929 cells (ATCC, CRL-9068) were treated with complete medium (i.e. RPMI1640 medium (Hyclone containing 10% fetal bovine serum (Corning, 35-076-CV) and 0.05mM 2-methyl alcohol (Sigma, M3148) , SH30809.01)) for cultivation. On the first day of the experiment, H929 cells were seeded in a 96-well plate at a density of 6,000 cells/well using complete medium, and 100 μL of cell suspension was added to each well. Firstly, it was dissolved in DMSO with an initial concentration of 10 mM, followed by 5-fold concentration gradient serial dilution, with a total of 9 concentration points, and the blank control was 100% DMSO. Then 5 μL of the compound dissolved in DMSO was added to 95 μL of complete medium, that is, the compound was diluted 20 times with the complete medium. Finally, 10 μL of each well of the compound diluted in complete medium was added to the cell suspension, that is, the final concentration of the compound was 9 concentration points of 5-fold serial dilution starting from 50 μM, and a blank control containing 0.5% DMSO was set, and placed Incubate for 5 days at 37°C in a 5% CO ₂ cell incubator. On the sixth day, the 96-well cell culture plate was taken out, and 50 μL CellTiter-Glo ^® luminescent cell viability detection reagent (Promega, G7573) was added to each well. ) to read the luminescent signal value, and use Graphpad Prism software to calculate the _IC50 value of the inhibitory activity of the compound, as shown in Table 1.

Table 1 The compounds of the present disclosure inhibit the proliferation of NCI-H929 cells.

Conclusion: The disclosed compound has good activity of inhibiting the proliferation of NCI-H929 cells.

Test example 2 Drug efficacy test

1 Experiment purpose

Evaluation of the effect of the compound of Example 2-1 and CC-92480 on inhibiting the growth of transplanted tumors of human multiple myeloma cells NCI-H929 (lenalidomide-resistant strain) on CB-17 SCID mice.

2 experimental drugs

Embodiment 2-1 compound;

CC-92480:

(Synthesized according to the method of Example 2 of WO2019014100A1);

Both are formulated with 5%DMSO+20%PEG400+70%(10%TPGS)+5%(1%HPMC K100LV).

3 Experimental methods and experimental materials

3.1 Experimental animals and feeding conditions

Experimental animals: CB-17 SCID female mice, purchased from Beijing Weitong Lihua Experimental Animal Co., Ltd. (certificate number: 20170011006049, SCXK (Shanghai) 2017-0011), weighing about 19 g when purchased.

Breeding conditions: 5 birds/cage, 12/12 hours light/dark cycle adjustment, constant temperature at 23±1°C, humidity 50 to 60%, free access to food and water.

3.2 Animal grouping

After adaptive feeding of CB-17 SCID mice, they were grouped as follows:

Note: qd means administration once a day; i.g means intragastric administration.

3.3 Experimental method:

Inoculate 5×10 ⁶ cells/mouse/100 μL (containing 50 μL matrigel) of NCI-H929 cells in the logarithmic growth phase subcutaneously in the right flank of female CB-17 SCID mice. After 11 days, the tumor volume of the tumor-bearing mice When reaching about 130mm ³ , the mice were randomly divided into 6 groups according to tumor volume and body weight: vehicle control group, CC-92480-0.1mpk, CC-92480-1mpk, Example 2-1-0.1mpk, Example 2- 1-0.3mpk and embodiment 2-1-1mpk, 8 in each group. The day of grouping was set as D0, and intragastric administration was started once a day for a total of 14 days, and 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 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 ruptured or the body weight decreased by 20%, the tumor-bearing animals were euthanized as the end point of the experiment.

3.4 Statistics

All data were drawn and statistically analyzed using Excel and GraphPad Prism 5 software.

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

Relative tumor proliferation rate T/C(%)=(TT ₀ )/(CC ₀ )×100(%), where T and C are the tumor volumes of the treatment group and the control group at the end of the experiment; T ₀ and C ₀ are the experimental Tumor volume at start.

Tumor inhibition rate TGI(%)=1-T/C(%), when TGI(%) exceeds 100%, the specific value will not be displayed, and only >100% will be indicated.

Tumor regression (%)=[(T ₀ -T)/T ₀ ]×100(%).

4 results

The curative effect data of the compound of Example 2-1 and CC-92480 on NCI-H929 transplanted tumor in CB-17 SCID mice are shown in Table 2 and Figure 1 .

The effect of the compound of Example 2-1 and CC-92480 on the body weight of CB-17 SCID mice is shown in Fig. 2 .

Table 2 The curative effect of the disclosed compound on NCI-H929 transplanted tumor in CB-17 SCID mice

Note: qd means administration once a day; d means day; i.g means intragastric administration; SEM means standard error.

5 Conclusion

The compound of Example 2-1 began to be administered 11 days after tumor cell transplantation, once a day. After 14 days of administration, the tumor inhibition rate of the low-dose 0.1mpk group was 74%, and the tumor inhibition rate of the middle-dose 0.3mpk group was 91%. In the high-dose 1mpk group, the tumor volume disappeared, and the regression rate was 5%, and the administration was effective for small Mouse body weight was not affected. Under the same conditions, the tumor inhibition rate of the low dose 0.1mpk group of CC-92480 was 37%, and the tumor inhibition rate of the high dose 1mpk group was 91%, and the tumor did not subside.

Test Example 3 Pharmacokinetic Evaluation

1 Overview

Taking Beagle dogs as test animals, LC/MS/MS method was used to determine the drug concentration in blood plasma of Beagle dogs at different times after intragastric administration of the compound of Example 2-1 and CC-92480. To study the pharmacokinetic behavior of the disclosed compound in Beagle dogs, and evaluate its pharmacokinetic characteristics.

2 test plan

2.1 Test drugs

Compound of Example 2-1 and CC-92480.

2.2 Test animals

Example 2-1 4 Beagle dogs, half male and half male, were equally divided into 2 groups for the compound of Example 2-1, and 3 male Beagle dogs were used for CC-92480, all provided by Shanghai Medicilon Biopharmaceutical Co., Ltd.

2.3 Drug preparation

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

Weigh CC-92480, add 5% DMSO, 30% PG and 30% PEG400 to dissolve it, then add 35% normal saline to prepare.

2.4 Administration

After fasting overnight, they were intragastrically administered. Both the compound of Example 2-1 and CC-92480 were administered at a dose of 2 mg/kg, and the administration volume was 5 mL/kg.

3 operation

The compound of Example 2-1 and CC-92480 were intragastrically administered, and 1 mL of blood was collected before administration and at 0.25h, 0.5h, 1h, 2h, 4h, 6h, 8h, 12h, and 24h after administration, and EDTA-K2 anti- Centrifuge at 10,000 rpm for 5 minutes (4°C) in the coagulation test tube, separate the plasma within 1 hour, and store at -80°C. Eat 3 hours after administration. The process from blood collection to centrifugation was operated under ice bath conditions.

Measure the content of the compound to be tested in the Beagle dog plasma after the drug administration of different concentrations: get 20 μ L of the Beagle dog plasma at each moment after the administration, add internal standard solution (the internal standard solution of the compound of embodiment 2-1 is toluene sulfonate Butylurea 100ng/mL, the internal standard solution of CC-92480 is camptothecin 100ng/mL) and methanol 400μL, vortexed for 1min, centrifuged for 10min (18000g). Transfer 200 µL of the supernatant to a 96-well plate. From the plasma samples, 1 μL of the supernatant was taken for LC/MS/MS analysis.

4 Results of Pharmacokinetic Parameters

The pharmacokinetic parameters of the disclosed compounds are shown in Table 3 below.

Table 3 Pharmacokinetic parameters of the disclosed compounds

Conclusion: The compound of Example 2-1 of the present disclosure has better drug metabolism and absorption than CC-92480, and has pharmacokinetic advantages.

Claims (22)

A compound represented by general formula (I) or a pharmaceutically acceptable salt thereof,

in, G ¹ , G ² and G ³ are the same or different, and are each independently CR ⁸ or a nitrogen atom; Z is CR ^a R ^b or an oxygen atom; R ^a and R ^b are the same or different, and are each independently selected from a hydrogen atom, halogen, alkyl and haloalkyl; X is CH ₂ or C(O); Y is an oxygen atom or NH; Ring A is aryl or heteroaryl; R ^is selected from hydrogen atom, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, hydroxyalkyl, cyano, amino and hydroxyl; R ² are the same or different at each occurrence, and each independently selected from a hydrogen atom, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, hydroxyalkyl, cyano, amino, nitro , hydroxy, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein the alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently selected from halogen , alkyl, alkoxy, haloalkyl, haloalkoxy, cyano, amine, nitro, hydroxyl, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl or Replaced by multiple substituents; R ³ and R ⁴ are the same or different, and are each independently selected from a hydrogen atom, a halogen and an alkyl group; R ⁵ are the same or different at each occurrence, and are each independently selected from a hydrogen atom, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, pendant oxy, cyano, amine, nitro , hydroxyl, hydroxyalkyl, -C(O)OR ⁹ , -CONR ¹⁰ R ¹¹ , cycloalkyl and heterocyclyl, wherein the alkyl, alkoxy, cycloalkyl and heterocyclyl are each independently optional is selected from the group consisting of halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cyano, amine, nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl Replaced by one or more substituents in; R ⁶ are the same or different at each occurrence, and are each independently selected from hydrogen atom, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cyano, amine, nitro, hydroxy, hydroxy Alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein the alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently selected from halogen , alkyl, alkoxy, haloalkyl, haloalkoxy, cyano, amine, nitro, hydroxyl, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl or Replaced by multiple substituents; R ⁷ is selected from cyano, -S(O) ₂ R ⁹ and -S(O) ₂ NR ¹⁰ R ¹¹ ; R ⁸ are the same or different at each occurrence, and each independently selected from a hydrogen atom, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, hydroxyalkyl, cyano, amino, nitro , hydroxyl, cycloalkyl and heterocyclyl; ^R9 are the same or different at each occurrence, and are each independently selected from a hydrogen atom, an alkyl group, a haloalkyl group, a hydroxyalkyl group, a cycloalkyl group and a heterocyclyl group; R ¹⁰ and R ¹¹ are the same or different at each occurrence, and are each independently selected from a hydrogen atom, an alkyl group, a haloalkyl group, a hydroxyalkyl group, a cycloalkyl group and a heterocyclyl group; n is 1, 2 or 3; m is 0, 1, 2 or 3; p is 0, 1, 2, 3 or 4; and q is 0, 1, 2, 3 or 4. The compound represented by general formula (I) or its pharmaceutically acceptable salt as described in claim item 1, it is general formula (I-1), general formula (I-1-1) or general formula (I-1 -2) the indicated compound or its pharmaceutically acceptable salt:

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. The compound represented by general formula (I) or a pharmaceutically acceptable salt thereof as claimed in item 1 or 2, wherein Y is an oxygen atom. The compound represented by general formula (I) or a pharmaceutically acceptable salt thereof as described in any one of claims 1 to 3, wherein R ³ and R ⁴ are both hydrogen atoms. The compound represented by general formula (I) or its pharmaceutically acceptable salt as described in any one of claims 1 to 4, which is general formula (II), general formula (II-1), general formula (II -1-1) or a compound represented by 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. The compound represented by general formula (I) or a pharmaceutically acceptable salt thereof as described in any one of claims 1 to 5, wherein X is CH ₂ . A compound represented by general formula (I) or a pharmaceutically acceptable salt thereof as described in any one of claim items 1 to 6, wherein Z is CR ^a R ^b ; R ^a and R ^b are the same, and are each independently hydrogen atom or halogen. The compound represented by general formula (I) or its pharmaceutically acceptable salt as described in any one of claims 1 to 7, which is general formula (III), general formula (III-1), general formula (III -1-1) or a compound represented by general formula (III-1-2) or a pharmaceutically acceptable salt thereof:

in, Ring A, 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. The compound represented by general formula (I) or a pharmaceutically acceptable salt thereof as described in any one of claims 1 to 8, wherein G ¹ , G ² and G ³ are all CR ⁸ ; R ⁸ is a hydrogen atom. A compound represented by general formula (I) or a pharmaceutically acceptable salt thereof as described in any one of claims 1 to 9, wherein ring A is 6 to 10 membered aryl or 5 to 10 membered heteroaryl; Preferably, ring A is phenyl. The compound represented by general formula (I) or a pharmaceutically acceptable salt thereof as described in any one of claims 1 to 10, wherein R ¹ is a hydrogen atom. The compound represented by general formula (I) or a pharmaceutically acceptable salt thereof as described in any one of claims 1 to 11, wherein R ² is a hydrogen atom. The compound represented by general formula (I) or a pharmaceutically acceptable salt thereof as described in any one of claims 1 to 12, wherein R ⁵ is the same or different at each occurrence, and each independently represents a hydrogen atom or C _1-6 alkyl; preferably, R ⁵ is a hydrogen atom. The compound represented by general formula (I) or a pharmaceutically acceptable salt thereof as described in any one of claims 1 to 13, wherein R ⁶ is the same or different at each occurrence, and each independently selected from a hydrogen atom , halogen, C _1-6 alkyl, C _1-6 alkoxy, C _1-6 haloalkyl and C _1-6 haloalkoxy; preferably, R ⁶ is halogen; more preferably, R ⁶ is a fluorine atom. A compound represented by general formula (I) or a pharmaceutically acceptable salt thereof as described in any one of claims 1 to 14, wherein R ⁷ is selected from cyano, -S(O) ₂ R ⁹ and -S( O) ₂ NR ¹⁰ R ¹¹ , wherein R ⁹ is C _1-6 alkyl, R ¹⁰ and R ¹¹ are both hydrogen atoms; preferably, R ⁷ is cyano. A compound represented by general formula (I) or a pharmaceutically acceptable salt thereof as described in any one of claims 1 to 15, which is selected from the following compounds:

with

. A compound represented by general formula (IA) or a salt thereof,

in, R ^m is C _1-6 alkyl; preferably, R ^m is tertiary butyl; 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. The compound or salt thereof as described in claim item 17, which is selected from the following compounds:

with

. A method for preparing a compound represented by general formula (I) or a pharmaceutically acceptable salt thereof, the method comprising:

The compound represented by the general formula (IA) or its salt undergoes an intramolecular ring-closing reaction to obtain the compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof, in, R ^m is C _1-6 alkyl; preferably tertiary butyl; 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. A pharmaceutical composition, which contains a compound represented by general formula (I) or a pharmaceutically acceptable salt thereof as described in any one of claim items 1 to 16, and one or more pharmaceutically acceptable carriers , diluent or excipient. A compound represented by general formula (I) as described in any one of claim items 1 to 16 or a pharmaceutically acceptable salt thereof or a pharmaceutical composition as described in claim item 20 is used for treatment and/or prevention Cancer, conditions related to angiogenesis, pain, macular degeneration or related syndromes, skin disease, pulmonary disease, asbestos-related disease, parasitic disease, immunodeficiency disease, central nervous system disease, central nervous system injury, atherosclerosis Sclerosis or related diseases, sleep disorders or related diseases, infectious diseases, hemoglobinopathies or related diseases, or medicines for TNFα-related diseases; preferably, in the preparation of drugs for treating and/or preventing cancer or central nervous system damage use in medicines. Use as described in claim 21, wherein the cancer is selected from leukemia, myeloma, lymphoma, melanoma, skin cancer, liver cancer, kidney cancer, lung cancer, nasopharyngeal cancer, gastric cancer, esophageal cancer, colorectal cancer, gallbladder cancer , cholangiocarcinoma, choriocarcinoma, pancreatic cancer, polycythemia vera, pediatric cancer, cervical cancer, ovarian cancer, breast cancer, bladder cancer, urothelial cancer, ureteral cancer, prostate cancer, seminoma, testicular tumor , head and neck cancer, head and neck squamous cell carcinoma, endometrial cancer, thyroid cancer, sarcoma, osteoma, neuroblastoma, neuroendocrine cancer, brain tumor, central nervous system cancer, astrocytoma, and glioma; preferred Preferably, wherein the myeloma is multiple myeloma and myelodysplastic syndrome; more preferably, the multiple myeloma is relapsed, refractory or resistant; most preferably, wherein the multiple myeloma Are refractory or resistant to lenalidomide or pomalidomide.

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