RU2809680C1 - Isoindoline derivative, its pharmaceutical composition and use - Google Patents

Abstract

FIELD: organic chemistry.

SUBSTANCE: group of inventions includes an isoindoline derivative of general formula (I), its pharmaceutically acceptable salt, stereoisomer, a method of production of a pharmaceutical composition based on it and its use. In Formula (I), R₁ and R₂ are each independently selected from H and halogen, provided that R₁ and R₂ are not both H; X represents O; each of X₁, X₂ is independently selected from C or N; each of X₃, X₄ and X₅ represents C; each of R₄, R₅, R₆, R₇ and R₈ is independently absent or selected from H, halogen, unsubstituted (C₁-C₁₂)alkyl or substituted with 1–3 halogens, unsubstituted (C₁-C₁₂)alkoxy group or substituted with 1–3 substituents selected from D, halogen or (C₃-C₆)cycloalkyl, unsubstituted (C₃-C₆)cycloalkyl, -CH=CH₂, -C≡ CH, -CN, -OH, -NO₂, or where each of R₉ and R₁₀ is independently selected from H or unsubstituted (C₁-C₁₂ )alkyl, provided that at least one of R₄, R₅, R₆, R₇ and R₈ is selected from -CN, -NO₂, -CH=CH₂, -C≡ CH, (C₁-C₁₂)alkyl substituted with 1–3 halogens, (C₁-C₁₂)alkoxy group substituted with 1–3 halogens, or (C₁-C₁₂)alkoxy group substituted with 1–3 D.

EFFECT: obtaining isoindoline derivative of General formula (I), used for the treatment of multiple myeloma.

15 cl, 2 tbl, 29 ex

Description

Cross reference to related applications

[0001] The present application claims priority to Chinese Patent Application No. CN 202010067409.0, filed on January 20, 2020, and Chinese Patent Application No. CN 202010413162.3, filed on May 15, 2020. Both of these applications are incorporated by reference in their entirety herein.

Field of technology

[0002] The present invention relates to an isoindoline derivative, an intermediate thereof, a method for its preparation, a pharmaceutical composition thereof and its use.

Prerequisites for creating the invention

[0003] Cereblon is a protein that is encoded by the CRBN gene in humans. Cereblon forms an E3 ubiquitin ligase complex with damaged DNA binding protein 1 (DDB1), cullin-4A (CUL4A), and regulator of cullin 1 (ROC1). Many other proteins undergo ubiquitination through the formation of such a complex. Through a mechanism that is not fully understood, cereblon ubiquitination of target proteins leads to increased levels of fibroblast growth factor 8 (FGF8) and fibroblast growth factor 10 (FGF10), and FGF8, in turn, regulates multiple developmental processes.

[0004] Numerous studies indicate that lenalidomide-based immunomodulators can bind to the cereblon protein and alter the specificity of the complex, causing ubiquitination and degradation of Ikaros (IKZF1) and Aiolos (IKZF3). IKZF1 and IKZF3 are key transcription factors in multiple myeloma. A single amino acid substitution of IKZF3 confers resistance to degradation induced by lenalidomide-based immunomodulators and resistance to cell growth inhibition induced by lenalidomide-based immunomodulators. Similarly, we found that IL2 production induced by the immunomodulator lenalidomide in T cells was associated with decreased levels of IKZF1 and IKZF3. These results reveal a new therapeutic mechanism of action, that is, alteration of E3 ubiquitin ligase activity, which exposes certain targets to selective degradation (Jan Krönke et al., Lenalidomide Causes Selective Degradation of IKZF1 and IKZF3 in Multiple Myeloma Cells, Science, 2014, 343(6168) : 301-5).

[0005] There is a growing need in the art for effective treatment of tumors, as well as an urgent need to develop small molecule therapeutics that specifically target and regulate various tumor-associated proteins using the substrate specificity of cereblon.

The essence of the invention

[0006] The present invention provides an isoindoline derivative, a method for its preparation, a pharmaceutical composition based thereon and its use. The isoindoline derivatives of the present invention can specifically target and regulate various tumor-associated proteins by binding to Cereblon, thereby providing effective treatment for cancer and other related diseases.

[0007] The present invention relates to an isoindoline derivative represented by the general formula (I), a pharmaceutically acceptable salt, solvate, polymorph, metabolite, prodrug or stereoisomer thereof:

General formula (I)

wherein each of R ₁ and R ₂ is independently selected from H, halogen, -CN, substituted or unsubstituted (C ₁ -C ₁₂ )alkyl, substituted or unsubstituted (C ₁ -C ₁₂ )alkoxy group or -OH, provided that that: R ₁ and R ₂ do not simultaneously represent H;

X is selected from O or NH;

each of X ₁ , X ₂ , X ₃ , X ₄ and X ₅ is independently selected from C or N;

R ₄ , R ₅ , R ₆ , R ₇ and R ₈ are each independently absent or selected from H, halogen, substituted or unsubstituted (C ₁ -C ₁₂ )alkyl, substituted or unsubstituted (C ₁ -C ₁₂ )alkoxy group , substituted or unsubstituted (C ₃ -C ₆ )cycloalkyl, -CH=CH ₂ , , -OH, -CN, -NO ₂ , , or where each of R ₉ and R ₁₀ is independently selected from H, D or substituted or unsubstituted (C ₁ -C ₁₂ )alkyl, provided that: at least one of R ₄ , R ₅ , R ₆ , R ₇ and R ₈ selected from -CN, -NO ₂ , -CH=CH ₂ , , , , (C ₁ -C ₁₂ )alkyl substituted with one or more halogens, (C ₁ -C ₁₂ )alkoxy group substituted with one or more halogens, (C ₁ -C ₁₂ )alkyl substituted with one or more D, or ( C ₁ -C ₁₂ )alkoxy group substituted by one or more D;

the substituents on the substituted (C ₁ -C ₁₂ )alkyl and substituted (C ₁ -C ₁₂ )alkoxy group are selected from one or more D, one or more halogens or one or more (C ₃ -C ₆ )cycloalkyls;

the carbon marked * represents an asymmetric carbon atom.

[0008] Preferably, in general formula (I), at least one of R ₁ and R ₂ is selected from halogen, -CN, substituted or unsubstituted (C ₁ -C ₁₂ )alkyl, substituted or unsubstituted (C ₁ -C ₁₂ ) alkoxy groups or -OH.

[0009] Preferably, in the general formula (I), at least one of R ₁ and R ₂ is selected from F, Cl, Br, -CN, -CH ₃ , -OCH ₃ , -CF ₃ or -OCF ₃ .

[0010] More preferably, in the general formula (I), at least one of R ₁ and R ₂ is F.

[0011] It is preferable that X in the general formula (I) is O.

[0012] In one embodiment, X in general formula (I) is O, and X ₁ , X ₂ , X ₃ , X ₄ , and X ₅ are each independently C.

[0013] In one embodiment, X is O, and at least one of _X1 , _X2 , _X3 , _X4 , and _X5 is N.

[0014] It is preferable that X in the general formula (I) represents NH.

[0015] In one embodiment, X in general formula (I) is NH, and X ₁ , X ₂ , X ₃ , X ₄ , and X ₅ are each independently C.

[0016] In one embodiment, X is NH, and at least one of _X1 , _X2 , _X3 , _X4 , and _X5 is N.

[0017] In one embodiment, R ₄ in general formula (I) is selected from -CN, -NO ₂ , , , (C ₁ -C ₁₂ )alkyl substituted with one or more halogens, (C ₁ -C ₁₂ )alkoxy group substituted with one or more halogens, (C ₁ -C ₁₂ )alkyl substituted with one or more D, or ( a C ₁ -C ₁₂ )alkoxy group substituted by one or more D, wherein each of R ₉ and R ₁₀ is independently selected from H, D or substituted or unsubstituted (C ₁ -C ₁₂ )alkyl; and each of R ₅ , R ₆ , R ₇ and R ₈ is independently selected from H or halogen.

[0018] In one embodiment, R ₄ is selected from -CN, (C ₁ -C ₁₂ )alkyl substituted with one or more halogens, (C ₁ -C ₁₂ )alkoxy group substituted with one or more halogens, (C ₁ - A C ₁₂ )alkyl group substituted by one or more Ds, or a (C ₁ -C ₁₂ )alkoxy group substituted by one or more Ds, and each of R ₅ , R ₆ , R ₇ and R ₈ independently represents H.

[0019] In one embodiment, R ₅ in general formula (I) is selected from -CN, -NO ₂ , , , (C ₁ -C ₁₂ )alkyl substituted with one or more halogens, (C ₁ -C ₁₂ )alkoxy group substituted with one or more halogens, (C ₁ -C ₁₂ )alkyl substituted with one or more D, or ( a C ₁ -C ₁₂ )alkoxy group substituted by one or more D, wherein each of R ₉ and R ₁₀ is independently selected from H, D or substituted or unsubstituted (C ₁ -C ₁₂ )alkyl; and each of R ₄ , R ₆ , R ₇ and R ₈ is independently selected from H or halogen.

[0020] In one embodiment, R ₅ is selected from -CN, (C ₁ -C ₁₂ )alkyl substituted with one or more halogens, (C ₁ -C ₁₂ )alkoxy group substituted with one or more halogens, (C ₁ - A C ₁₂ )alkyl group substituted with one or more Ds, or a (C ₁ -C ₁₂ )alkoxy group substituted with one or more Ds, and each of R ₄ , R ₆ , R ₇ and R ₈ is more preferably independently selected from H.

[0021] In one embodiment, R ₆ in general formula (I) is selected from -CN, -NO ₂ , , , (C ₁ -C ₁₂ )alkyl substituted with one or more halogens, (C ₁ -C ₁₂ )alkoxy group substituted with one or more halogens, (C ₁ -C ₁₂ )alkyl substituted with one or more D, or ( a C ₁ -C ₁₂ )alkoxy group substituted by one or more D, wherein each of R ₉ and R ₁₀ is independently selected from H, D or substituted or unsubstituted (C ₁ -C ₁₂ )alkyl; and each of R ₄ , R ₅ , R ₇ and R ₈ is independently selected from H or halogen.

[0022] In one embodiment, R ₆ is selected from -CN, (C ₁ -C ₁₂ )alkyl substituted with one or more halogens, (C ₁ -C ₁₂ )alkoxy group substituted with one or more halogens, (C ₁ - A C ₁₂ )alkyl group substituted with one or more Ds, or a (C ₁ -C ₁₂ )alkoxy group substituted with one or more Ds, and each of R ₄ , R ₅ , R ₇ and R ₈ is more preferably independently selected from H.

[0023] In one embodiment, R ₇ in general formula (I) is selected from -CN, -NO ₂ , , , (C ₁ -C ₁₂ )alkyl substituted with one or more halogens, (C ₁ -C ₁₂ )alkoxy group substituted with one or more halogens, (C ₁ -C ₁₂ )alkyl substituted with one or more D, or ( a C ₁ -C ₁₂ )alkoxy group substituted by one or more D, wherein each of R ₉ and R ₁₀ is independently selected from H, D or substituted or unsubstituted (C ₁ -C ₁₂ )alkyl; and each of R ₄ , R ₅ , R ₆ and R ₈ is independently selected from H or halogen.

[0024] In one embodiment, R ₇ is selected from -CN, (C ₁ -C ₁₂ )alkyl substituted with one or more halogens, (C ₁ -C ₁₂ )alkoxy group substituted with one or more halogens, (C ₁ - A C ₁₂ )alkyl group substituted with one or more Ds, or a (C ₁ -C ₁₂ )alkoxy group substituted with one or more Ds, and each of R ₄ , R ₅ , R ₆ and R ₈ is more preferably independently selected from H.

[0025] In one embodiment, R ₈ in general formula (I) is selected from -CN, -NO ₂ , , , (C ₁ -C ₁₂ )alkyl substituted with one or more halogens, (C ₁ -C ₁₂ )alkoxy group substituted with one or more halogens, (C ₁ -C ₁₂ )alkyl substituted with one or more D, or ( a C ₁ -C ₁₂ )alkoxy group substituted by one or more D, wherein each of R ₉ and R ₁₀ is independently selected from H, D or substituted or unsubstituted (C ₁ -C ₁₂ )alkyl; and each of R ₄ , R ₅ , R ₆ and R ₇ is independently selected from H or halogen.

[0026] In one embodiment, R ₈ is selected from -CN, (C ₁ -C ₁₂ )alkyl substituted with one or more halogens, (C ₁ -C ₁₂ )alkoxy group substituted with one or more halogens, (C ₁ - A C ₁₂ )alkyl group substituted with one or more Ds, or a (C ₁ -C ₁₂ )alkoxy group substituted with one or more Ds, and R ₄ , R ₅ , R ₆ and R ₇ are more preferably each independently H.

[0027] Preferably, in the general formula (I), the asymmetric carbon atom refers to an achiral carbon, a carbon with a (S) configuration, a carbon with a predominant (S) configuration, a carbon with an (R) configuration, a carbon with a predominant (R) configuration )-configuration or racemate.

[0028] Preferably, in general formula (I), the halogen is F, Cl, Br or I.

[0029] Preferably, in the general formula (I), the substituted or unsubstituted (C ₁ -C ₁₂ )alkyl is selected from substituted or unsubstituted (C ₁ -C ₆ )alkyl, and more preferably from the substituted or unsubstituted (C ₁ - C ₄ )alkyl, wherein the substituted or unsubstituted (C ₁ -C ₄ )alkyl is most preferably selected from substituted or unsubstituted methyl, substituted or unsubstituted ethyl, substituted or unsubstituted n-propyl, substituted or unsubstituted isopropyl, substituted or unsubstituted n-butyl, substituted or unsubstituted isobutyl or substituted or unsubstituted tert-butyl; wherein the substituent described in the phrase "substituted or unsubstituted" is selected from one or more of D, halogen or (C ₃ -C ₆ )cycloalkyl, preferably selected from D, F, Cl, Br, I, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, more preferably from D, F, Cl, cyclopropyl or cyclobutyl, and most preferably from F.

[0030] In one embodiment, the substituted or unsubstituted (C ₁ -C ₁₂ )alkyl is preferably selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, -CD ₃ , -CD ₂ H, -CDH ₂ , -CF ₃ , -CH ₂ F, -CHF ₂ , , , or , more preferably from methyl, ethyl, n-propyl, isopropyl, -CD ₃ , -CF ₃ , -CH ₂ F, -CHF ₂ , or and most preferably from methyl, ethyl, -CD ₃ , -CF ₃ , -CH ₂ F or -CHF ₂ .

[0031] It is preferred that in the isoindoline derivative represented by the general formula (I), its pharmaceutically acceptable salt, solvate, polymorph, metabolite, prodrug or stereoisomer, the substituted or unsubstituted (C ₁ -C ₁₂ ) alkoxy group is selected from substituted or an unsubstituted (C ₁ -C ₆ )alkoxy group, and more preferably a substituted or unsubstituted (C ₁ -C ₄ )alkoxy group, wherein the substituted or unsubstituted (C ₁ -C ₄ )alkoxy group is most preferably selected from a substituted or unsubstituted methoxy group, substituted or unsubstituted ethoxy group, substituted or unsubstituted n-propoxy group, substituted or unsubstituted isopropoxy group, substituted or unsubstituted n-butoxy group, substituted or unsubstituted isobutoxy group or substituted or unsubstituted tert- butoxy groups; wherein the substituent described in the phrase "substituted or unsubstituted" is selected from one or more of D, halogen or (C ₃ -C ₆ )cycloalkyl, preferably selected from D, F, Cl, Br, I, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, more preferably from D, F, Cl, cyclopropyl or cyclobutyl, and most preferably from D or F.

[0032] In one embodiment, the substituted or unsubstituted (C ₁ -C ₁₂ )alkoxy group is preferably selected from methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy groups , -OCD ₃ , -OCD ₂ H, -OCDH ₂ , -OCF ₃ , -OCH ₂ F, -OCHF ₂ , , , or , more preferably from methoxy, ethoxy, n-propoxy, isopropoxy groups, -OCD ₃ , -OCF ₃ , -OCH ₂ F, -OCHF ₂ , or and most preferably from methoxy, ethoxy, -OCD ₃ , -OCF ₃ , -OCH ₂ F or -OCHF ₂ groups.

[0033] In one embodiment, the substituted or unsubstituted (C ₃ -C ₆ )cycloalkyl is selected from substituted or unsubstituted cyclopropyl, substituted or unsubstituted cyclobutyl, substituted or unsubstituted cyclopentyl, or substituted or unsubstituted cyclohexyl.

[0034] In one embodiment, R ₁ is selected from H, F, Cl, Br, -CN, methyl, methoxy or -OH; wherein it is preferable that R ₁ is selected from F, Cl, -CH ₃ , -CN or -OH, and more preferably, R ₁ is F.

[0035] In one embodiment, R ₂ is selected from H, F, Cl, Br, -CN, methyl, methoxy or -OH, with R ₂ preferably selected from F, Cl, -CH ₃ , -CN or -OH, and more preferably _R2 is F.

[0036] In one embodiment, R ₁ is selected from F, Cl, Br, -CN, -CH ₃ , -OCH ₃ , -CF ₃ , or -OCF ₃ and R ₂ is H.

[0037] In one embodiment, R ₂ is selected from F, Cl, Br, -CN, -CH ₃ , -OCH ₃ , -CF ₃ , or -OCF ₃ and R ₁ is H.

[0038] In one embodiment, R ₁ is F and R ₂ is H.

[0039] In one embodiment, R ₂ is selected from F and R ₁ is selected from H.

[0040] Preferably, in the general formula (I), one of R ₄ , R ₅ , R ₆ , R ₇ and R ₈ is selected from -CN, -NO ₂ , -CH=CH ₂ , , , , , -OCF ₃ , -OCH ₂ F, -OCHF ₂ , -CD ₃ , -OCD ₃ or -CF ₃ .

[0041] In one embodiment, R ₄ is selected from H, F, Cl, Br, -CH ₃ , -CH ₂ CH ₃ , -CF ₃ , -OCH ₃ , -OCH ₂ CH ₃ , -CH=CH ₂ , , -OCF ₃ , -OCH ₂ F, -OCHF ₂ , -CD ₃ , -OCD ₃ , -CN, -NO ₂ , , , , , , , or ; wherein it is preferable that R ₄ be selected from H, F, -CN, -OCH ₃ , -OCF ₃ , -OCD ₃ or -CD ₃ ; more preferably, R ₄ is selected from H or F; and most preferably _R4 is H.

[0042] In one embodiment, R ₅ is selected from H, F, Cl, Br, -CH ₃ , -CH ₂ CH ₃ , -CF ₃ , -OCH ₃ , -OCH ₂ CH ₃ , -CH=CH ₂ , , -OCF ₃ , -OCH ₂ F, -OCHF ₂ , -CD ₃ , -OCD ₃ , -CN, -NO ₂ , , , , , , , or ; wherein it is preferable that R ₅ be selected from H, F, -CN, -OCH ₃ , -OCF ₃ , -OCD ₃ or -CD ₃ ; more preferably, R ₅ is selected from H or F; and most preferably _R5 is H.

[0043] In one embodiment, R ₆ is selected from H, F, Cl, Br, -CH ₃ , -CH ₂ CH ₃ , -CF ₃ , -OCH ₃ , -OCH ₂ CH ₃ , -CH=CH ₂ , , -OCF ₃ , -OCH ₂ F, -OCHF ₂ , -CD ₃ , -OCD ₃ , -CN, -NO ₂ , , , , , , , or ; wherein it is preferable that R ₆ be selected from H, F, -CN, -OCH ₃ , -OCF ₃ , -OCD ₃ or -CD ₃ ; more preferably, R ₆ is selected from H or -CN; and most preferably, R ₆ is -CN.

[0044] In one embodiment, R ₇ is selected from H, F, Cl, Br, -CH ₃ , -CH ₂ CH ₃ , -CF ₃ , -OCH ₃ , -OCH ₂ CH ₃ , -CH=CH ₂ , , -OCF ₃ , -OCH ₂ F, -OCHF ₂ , -CD ₃ , -OCD ₃ , -CN, -NO ₂ , , , , , , , or ; wherein it is preferable that R ₇ be selected from H, F, -CN, -OCH ₃ , -OCF ₃ , -OCD ₃ or -CD ₃ ; more preferably, R ₇ is selected from H, F or -OCH ₃ ; and most preferably, R ₇ is -OCH ₃ .

[0045] In one embodiment, R ₈ is selected from H, F, Cl, Br, -CH ₃ , -CH ₂ CH ₃ , -CF ₃ , -OCH ₃ , -OCH ₂ CH ₃ , -CH=CH ₂ , , -OCF ₃ , -OCH ₂ F, -OCHF ₂ , -CD ₃ , -OCD ₃ , -CN, -NO ₂ , , , , , , , silt ; wherein it is preferable that R ₈ be selected from H, F, -CN, -OCH ₃ , -OCF ₃ , -OCD ₃ or -CD ₃ ; more preferably, R ₈ is selected from F or H; and most preferably _R8 is F.

[0046] It is preferable to select the isoindoline derivative represented by the general formula (I) from any of the following compounds:

[0047] Deuterium (D or ^2H ) is a stable, non-radioactive isotope of hydrogen with an atomic mass of 2.0144. Hydrogen in nature exists as a mixture of isotopes H (hydrogen or protium), D ( ^2H or deuterium) and T ( ^3H or tritium), with the deuterium content being 0.0156%. According to the generally accepted technical knowledge in the art, in all compounds whose structure contains natural hydrogen atoms, the hydrogen atom is actually a mixture of H, D and T. Therefore, if the compound contains deuterium, the content of which is higher than its natural content, i.e. greater than 0.0156% at any position, then these compounds should be considered unnatural or deuterium-enriched, and thus these compounds are novel compared to their unenriched counterparts.

[0048] In the present invention, "D", "deuterium" or "deuterium-enriched" compound refers to a compound of general formula (I) or this compound in the form of a pharmaceutically acceptable salt, solvate, polymorph, stereoisomer, metabolite or prodrug that contains deuterium in any corresponding position is greater than its natural content in that position. Therefore, in a “D”, “deuterium” or “deuterium-enriched” compound, the deuterium content at any of the respective positions is likely to range from greater than 0.0156% to 100%. The deuterium-enriched position is represented by the letter D, while the non-deuterium-enriched position is represented by the letter H. According to the generally accepted technical knowledge in the art, the symbol H may be omitted in the non-deuterium-enriched position. An example of a method for producing a deuterium-enriched compound is to replace hydrogen with deuterium or use deuterium-enriched starting material to synthesize the compound.

[0049] In the present invention, the percentage of deuterium in the deuterium-rich or deuterium content refers to the molar percentage.

[0050] In the present invention, the phrase “non-deuterium-enriched” refers to hydrogen in nature, namely hydrogen in the form of a mixture of the isotopes H (hydrogen or protium), D ( ^2H or deuterium), and T ( ^3H or tritium).

[0051] The present invention also relates to a method for producing an isoindoline derivative represented by the general formula (I), which can be synthesized from commercially available raw materials using methods generally used in the field of chemical synthesis, for example, reference is made to the synthetic methods disclosed in WO 2016065980 A1, WO 2019014100 A1, etc.

[0052] In one embodiment, a compound of general formula (I) can be prepared by reacting compound A-01,

where the values of X, X ₁ -X ₅ , *, R ₁ , R ₂ , R ₄ , R ₅ , R ₆ , R ₇ and R ₈ are as defined above, one of Ra and Rb corresponds , and the other corresponds , or , and R ^a' and R ^b' independently represent H.

[0053] The present invention also provides a pharmaceutical composition containing a therapeutically and/or prophylactically effective amount of the above isoindoline derivative represented by general formula (I), a pharmaceutically acceptable salt, solvate, polymorph, metabolite, prodrug or stereoisomer thereof.

[0054] In accordance with embodiments of the present invention, the pharmaceutical composition can be formulated in any form for administration, including injection (intravenous), mucosal administration, oral administration (solid and liquid preparations), inhalation, ocular administration, rectal administration, topical or parenteral administration (infusion, injection, implantation, subcutaneous, intravenous, intraarterial and intramuscular) administration. The pharmaceutical composition of the present invention may also be a controlled release or delayed release dosage form. Examples of solid oral preparations include, but are not limited to, powders, capsules, caplets, soft capsules and tablets. Examples of liquid preparations for oral or mucosal administration include, but are not limited to, suspensions, emulsions, elixirs and solutions. Examples of topical preparations include, but are not limited to, emulsions, gels, ointments, creams, patches, pastes, foams, lotions, drops or serum preparations. Examples of preparations for parenteral administration include, but are not limited to, injectable solutions, dry preparations that can be dissolved or suspended in a pharmaceutically acceptable carrier, injectable suspensions, and injectable emulsions. Examples of other suitable preparations of a compound of general formula (I), a pharmaceutically acceptable salt, solvate, polymorph, metabolite, prodrug or stereoisomer thereof include, but are not limited to, eye drops and other ophthalmic preparations; aerosol: for example, nasal sprays or inhalers; liquid dosage forms suitable for parenteral administration; suppositories and lozenges.

[0055] The pharmaceutical composition of the present invention may further contain a pharmaceutically acceptable excipient, such as those widely used in the field of drug production. The excipient is primarily used to produce a safe, stable and potent pharmaceutical formulation, it can also cause the active ingredients to dissolve at a desired rate after administration to a subject, or to promote effective absorption of active ingredients after the formulation is administered to a subject. The excipient may be an inert excipient or serve a specific function, such as stabilizing the overall pH of the formulation or preventing degradation of the active ingredients in the formulation.

[0056] In accordance with embodiments of the present invention, the pharmaceutically acceptable excipient may include one or more adhesives, suspending agents, emulsifiers, diluents, fillers, granulating agents, adhesives, disintegrants, lubricants, anti-tack agents, glidants, wetting agents agents, gelling agents, absorption retardants, dissolution retarders or structurants, adsorbents, buffers, chelating agents, preservatives, dyes, flavorings and sweeteners. The pharmaceutically acceptable carrier may be in various forms depending on the form of preparation desired for administration. For example, for a liquid oral preparation, suitable carriers and additives include water, glycols, oils, alcohols, flavor enhancers, preservatives, coloring agents, etc. As another illustrative example for a solid oral preparation, suitable carriers and additives include starch, sugar, diluents, granulating agents, lubricants, adhesives, disintegrants, etc. Pharmaceutically acceptable carriers or excipients will generally be non-toxic. The pharmaceutical composition of the present invention may contain one or more suitable carriers/excipients. The amount and type of forming agent will vary depending on specific requirements. Those skilled in the art can readily determine the suitable carrier(s)/excipient(s) to be included in the pharmaceutical composition of the present invention based on the present disclosure.

[0057] The pharmaceutical composition of the present invention, i.e. a composition containing a therapeutically or prophylactically effective amount of a compound of general formula (I), a pharmaceutically acceptable salt, solvate, polymorph, metabolite, prodrug or stereoisomer of the present invention may be prepared according to the disclosure by any method known to those skilled in the art. For example, the pharmaceutical composition of the present invention can be prepared by mixing a compound of general formula (I), a pharmaceutically acceptable salt, solvate, polymorph, stereoisomer, metabolite or prodrug with a pharmaceutically acceptable carrier in accordance with conventional drug mixing techniques, which include, but are not limited to them, the usual processes of mixing, dissolving, granulating, emulsifying, grinding, encapsulating, pouring or lyophilizing.

[0058] In accordance with embodiments of the present invention, in addition to one or more compounds of general formula (I), a pharmaceutically acceptable salt, solvate, polymorph, metabolite, prodrug or stereoisomer, the pharmaceutical composition may further contain one or more additional therapeutic agents. More detailed information about additional therapeutic agents that may be included in the pharmaceutical combination of the present invention will be disclosed below. The number and type of additional therapeutic agents will depend on the diseases, disorders or disease states to be treated or prevented; the severity of diseases, disorders or disease states; the particular circumstances of the subject to whom the composition is administered, such as age, weight and physical condition; method of administration, etc.

[0059] In some embodiments of the present invention, a therapeutic or prophylactic amount of a compound of general formula (I), a pharmaceutically acceptable salt, solvate, polymorph, metabolite, prodrug or stereoisomer thereof, or any pharmaceutical composition, preparation, etc., can be administered to a subject for a period of time (administration period), followed by a break in administration of the compound (non-administration period), by the method of the present invention. The administration period and the non-administration period can be repeated as many times as necessary. The desired duration and number of periods of administration or periods of non-administration will depend on the type and/or severity of the diseases, disorders or disease states being treated or prevented, as well as on gender, age, weight and other parameters (for example, biological, physical and physiological condition a separate subject, etc.) a separate subject. Given the content disclosed in the application, those skilled in the art are sufficiently qualified to determine the appropriate duration and number of administration periods and/or non-administration periods.

[0060] In accordance with embodiments of the present invention, the combined use of a compound represented by general formula (I), a pharmaceutically acceptable salt, solvate, polymorph, metabolite, prodrug or stereoisomer of the present invention with additional therapeutic agents may have a synergistic effect in the treatment or prevention of any a disease, disorder or disease state in accordance with the content disclosed in the present invention.

[0061] In accordance with embodiments of the present invention, additional therapeutic agents can be natural, semi-synthetic or synthetic compounds. In another embodiment, the additional therapeutic agents may be small molecules, such as synthetic organic or inorganic molecules; or larger molecules or biomolecules, such as proteins or nucleic acids, that have pharmacological effects. In another embodiment, the additional therapeutic agent may be an anti-angiogenic compound, an immunomodulatory compound, an immunotherapeutic compound, a chemotherapeutic compound, or a hormonal compound.

[0062] In one embodiment of the present invention, a formulation comprising a compound of general formula (I), a pharmaceutically acceptable salt, solvate, polymorph, metabolite, prodrug or stereoisomer thereof, and an additional therapeutic agent is simultaneously administered to a subject. In another embodiment, a compound of general formula (I), a pharmaceutically acceptable salt, solvate, polymorph, metabolite, prodrug or stereoisomer thereof, and an additional therapeutic agent are administered sequentially. In another embodiment, a compound of general formula (I), a pharmaceutically acceptable salt, solvate, polymorph, metabolite, prodrug or stereoisomer thereof, and the additional therapeutic agent are administered separately. The additional therapeutic agent may be administered before, sequentially with, or after administration of a compound of general formula (I), a pharmaceutically acceptable salt, solvate, polymorph, metabolite, prodrug, or stereoisomer thereof of the present invention.

[0063] One or more additional therapeutic agents that can be administered in combination with a compound of general formula (I) or a pharmaceutically acceptable salt, solvate, polymorph, metabolite, prodrug or stereoisomer of the present invention will depend on various circumstances, such as diseases, disorders or disease states that need to be prevented or treated. Those skilled in the art can readily identify suitable additional therapeutic agents for use in combination with the isoindoline derivative represented by general formula (I), a pharmaceutically acceptable salt, solvate, polymorph, metabolite, prodrug or stereoisomer thereof in accordance with the content disclosed in the present invention.

[0064] In accordance with one embodiment of the present invention, when a compound of general formula (I), a pharmaceutically acceptable salt, solvate, polymorph, metabolite, prodrug, or stereoisomer of the present invention is administered in combination with additional therapeutic agents, a therapeutically effective amount of the compound represented by of general formula (I), a pharmaceutically acceptable salt, solvate, polymorph, metabolite, prodrug or stereoisomer thereof will be less than a therapeutically effective amount of the same compound required when administered by a compound of general formula (I), a pharmaceutically acceptable salt, solvate, polymorph thereof , metabolite, prodrug or stereoisomer without additional therapeutic agents. In another embodiment, the therapeutically effective amount of the additional therapeutic agent will be less than its effective amount when the compound of general formula (I), a pharmaceutically acceptable salt, solvate, polymorph, metabolite, prodrug or stereoisomer thereof is not administered.

[0065] In accordance with embodiments of the present invention, when a compound of general formula (I), a pharmaceutically acceptable salt, solvate, polymorph, metabolite, prodrug or stereoisomer thereof and additional therapeutic agents thereof are administered to a subject for the treatment or prevention of diseases, disorders or disease states, that the compound of general formula (I), its pharmaceutically acceptable salt, solvate, polymorph, metabolite, prodrug or stereoisomer and additional therapeutic agents can be administered by the same route or by a different route. Additional therapeutic agents may be administered by any route described herein, including, but not limited to, oral administration, inhalation, injection, ocular administration, transmucosal administration, rectal administration, emulsion administration, liposome administration, long-acting implantation administration, or by uniform controlled release. The specific route of administration of the additional therapeutic agent will depend on the additional therapeutic agent and drug itself, as well as the diseases, disorders or disease states to be prevented or treated. Given the contents of this disclosure, the skill of one skilled in the art is sufficient to determine routes of administration of the additional therapeutic agent.

[0066] The compound of general formula (I), its pharmaceutically acceptable salt, solvate, polymorph, metabolite, prodrug or stereoisomer according to the present invention is suitable for various applications, which include, but are not limited to, use for the manufacture of a medicament for the treatment of corresponding diseases, disorders or disease states by inducing ubiquitination and degradation of target proteins in cells.

[0067] Thus, in another general aspect, the present invention relates to the use of a compound of general formula (I), a pharmaceutically acceptable salt, solvate, polymorph, metabolite, prodrug or stereoisomer thereof in the preparation of a drug. for the treatment or prevention of diseases, disorders or painful conditions. In another aspect, the present invention provides a method for treating or preventing related diseases, disorders or disease states by inducing ubiquitination and degradation of target proteins in cells, wherein the method comprises administering to the subject a therapeutically or prophylactically effective amount of an isoindoline derivative. represented by the general formula (I), a pharmaceutically acceptable salt, solvate, metabolite, prodrug or stereoisomer thereof. In accordance with the method of the present invention, examples of such diseases, disorders and painful conditions requiring treatment or prevention include, but are not limited to, cancer.

[0068] In a preferred embodiment, the diseases, disorders or disease states are cancer, preferably multiple myeloma.

[0069] Various publications, articles, and patents are cited or described throughout this document. The citation or description of these references or their complete inclusion herein or discussion thereof is intended to illustrate the background of the present invention, but does not imply that their contents constitute part of the prior art of the present invention.

[0070] Unless otherwise specified, all technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the art to which the present invention relates. Otherwise, certain terms used herein have the meanings set forth herein. All patents, published patent applications and publications cited herein are incorporated by reference as if set forth in their entirety herein. It should be noted that the singular forms used herein and in the appended claims include the plural unless the context clearly requires otherwise.

[0071] In this context, if a particular salt, composition, excipient, etc. are referred to as "pharmaceutically acceptable", meaning that the salt, composition, excipient, etc. generally non-toxic, safe and suitable for use by a subject, preferably a mammal, more preferably a human.

[0072] As used herein, the term "pharmaceutically acceptable salt" refers to a pharmaceutically acceptable organic or inorganic salt.

[0073] As used herein, the term "metabolite" refers to the active substance formed after the chemical structure of the drug molecule undergoes changes in vivo , and the active substance is usually a derivative of the above-mentioned drug molecule, and it can also be modified chemically way.

[0074] As used herein, the term "polymorph", and unless otherwise indicated, refers to one or more crystal structures in which the molecules are differently arranged in lattice space upon crystallization.

[0075] As used herein, the term “solvate” refers to a crystalline form of a compound of general formula (I), a pharmaceutically acceptable salt, polymorph, stereoisomer, metabolite or prodrug thereof, which further contains one or more solvent molecules included in the crystal structure. The solvate may include a stoichiometric amount or a non-stoichiometric amount of a solvent, and the solvent molecule in the solvent may be in an ordered or disordered position. A solvate containing a non-stoichiometric amount of solvent molecules can be prepared by removing at least one solvent molecule (but not all) from the solvate. In a specific embodiment, a solvate refers to a hydrate, which means that the crystalline form of the compound further contains water molecules as a solvent.

[0076] As used herein, the term “prodrug,” unless otherwise indicated, refers to a derivative of a compound containing a biologically reactive functional group such that the biologically reactive functional group can be cleaved from the compound or otherwise reacted to form the compound under biological conditions ( in vitro or in vivo ). Typically, a prodrug is inactive or at least has a lower activity than the activity of the compound itself, so that the compound becomes active until it is cleaved from the biologically reactive functional group. The biologically active functional group can be hydrolyzed or oxidized under biological conditions to provide the desired compound. For example, the prodrug may contain a biologically hydrolyzable group. Examples of a biologically hydrolyzable group include, but are not limited to: biologically hydrolysable phosphate, biologically hydrolysable ester, biologically hydrolysable amide, biologically hydrolysable carbonate, biologically hydrolysable carbamate and biologically hydrolysable ureide groups.

[0077] The compound of general formula (I), its pharmaceutically acceptable salt, solvate, polymorph, stereoisomer, metabolite or prodrug of the present invention may contain one or more asymmetric centers (“stereoisomers”). As used herein, the term "stereoisomer" refers to all stereoisomers, including enantiomers, diastereoisomers, epimers, endo-exoisomers, atropoisomers, regioisomers, cis- and trans-isomers, etc. “Stereoisomer” as used herein also includes “pure stereoisomer” and “predominant stereoisomer” or “racemate” of the various above-mentioned stereoisomers. These stereoisomers can be separated, purified and enriched using asymmetric synthesis methods or chiral resolution methods (including, but not limited to, thin layer chromatography, rotary chromatography, column chromatography, gas chromatography and high pressure liquid chromatography), and can also be obtained using chiral resolution due to the formation of bonds (chemical bonds, etc.) or the formation of salts (physical bonds) with other chiral compounds, etc. "Pure stereoisomer" in this context refers to a stereoisomer of the compound in question with a mass content of at least 95% relative to the other stereoisomers of the compound. "Predominant stereoisomer" in this context refers to a stereoisomer of the subject compound with a mass content of at least 50% relative to other stereoisomers of the compound. The term "racemate" as used herein refers to a stereoisomer of a compound whose weight content is equal to the weight content of the other stereoisomers of the compound.

[0078] As used herein, the term “subject” refers to any animal that will be or has been administered a compound or composition in accordance with embodiments of the present invention, and preferably refers to a mammal, and most preferably a human. As used herein, the term "mammals" includes any mammal. Examples of mammals include, but are not limited to, cattle, horse, sheep, pig, cat, dog, mouse, rat, rabbit, guinea pig, monkey, human, etc., most preferably human.

[0079] In one embodiment, “treat” or “be treated” refers to improving, preventing, or reversing a disease or disorder or at least one detectable symptom thereof, for example, treating cancer and unwanted angiogenesis-related disorders by reducing or stabilization of symptoms of cancer diseases or disorders. In another embodiment, the term “treat” or “be treated” refers to improving, preventing, or reversing at least one measurable body parameter of a disease or disorder being treated that may not yet be identified in mammals. However, in another embodiment, “treating” or “receiving treatment” refers to slowing the progression of a disease or disorder, either physically, such as by stabilizing a detectable symptom, or physiologically, such as by stabilizing a body score, or both. In another embodiment, “treating” or “receiving treatment” refers to delaying the onset of a disease or disorder.

[0080] In some embodiments, the compound of interest is administered as a precaution. As used herein, the term “prevent” or “be prevented” refers to reducing the risk of a given disease or disorder. In a preferred embodiment, the compound is administered as a precaution to a subject, such as a subject having a family history of cancer or a predisposition to developing cancer or autoimmune diseases.

[0081] As used herein, the term “therapeutically effective amount” refers to the amount of a compound or composition that can produce a biological or medical response (as sought by researchers, veterinarians, physicians, or other clinicians) in a tissue system, animal, or human, which may include alleviating the symptoms of the disease or disorder being treated. In a preferred embodiment, a therapeutically effective amount is an amount sufficient to effectively treat, improve the treatment of, or prevent cancer, disorders, or undesirable conditions associated with blood vessels.

[0082] The term “prophylactically effective amount” refers to an amount of an active compound or drug that can prevent the occurrence of a disorder (as desired by researchers, veterinarians, physicians, or other clinicians) in a subject. A prophylactically effective amount of a compound refers to an amount of a therapeutic agent, used alone or in combination with an additional therapeutically effective compound, that can provide a therapeutic effect in the treatment or prevention of diseases, disorders or disease states.

[0083] Unless otherwise indicated, the singular form of a term used herein also includes the plural form.

[0084] Unless otherwise indicated, the term “or” or “and” in this context refers to “and/or”.

[0085] Unless otherwise noted, " " or " " shown in certain groups in this context refers to the attachment position.

[0086] Without departing from the public knowledge in the art, the above-mentioned various preferred conditions can be optionally combined so as to obtain various preferred examples of the present invention.

[0087] All reagents and starting materials used in the present invention are commercially available.

[0088] The positive effect of the present invention is that: the isoindoline derivative represented by the general formula (I) in the present invention can induce ubiquitination and degradation of target proteins in cells, thereby providing effective treatment for cancer and other related diseases .

[0089] Experimental data show that the compound of the present application has a good inhibitory effect on multiple myeloma.

Detailed Description of Embodiments

[0090] Example 1

[0091] Connection I-1

[0092] Synthesis scheme:

[0093] Step A: 3-Hydroxy-2-methylbenzoic acid (CAS 603-80-5, 30.0 g, 197 mmol) was dissolved in anhydrous methanol (400 ml) under nitrogen and DMF was added dropwise at 0° C. (DMF) (2 ml) and thionyl chloride (70.3 g, 591 mmol). After completion of the dropwise addition, the reaction solution was heated to reflux and reacted overnight. The reaction solution was then cooled to room temperature (25°C) and concentrated to dryness under reduced pressure. The residue was dissolved in ethyl acetate (250 ml). The mixture was washed successively with saturated aqueous sodium bicarbonate (250 ml), water (250 ml) and saturated brine (250 ml), dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain methyl 3-hydroxy-2-methyl benzoate as gray solid (30.5 g, yield: 93%).

[0094] ¹ H NMR (CDCl ₃ , 300 MHz): δ 7.41 (dd, J = 8.1, 1.2 Hz, 1H), 7.10 (td, J = 7.8, 0.6 Hz, 1H), 6.94 (dd, J = 8.1, 1.2 Hz, 1H), 5.25 (s, 1H), 3.89 (s, 3H), 2.45 (s, 3H ).

[0095] Step B: Methyl 3-hydroxy-2-methyl benzoate (30.5 g, 184 mmol) and imidazole (31.2 g, 459 mmol) were dissolved in anhydrous DMF (200 mL) under nitrogen and the resulting solution was cooled to 0°C in an ice bath. TBDMSCl (tert-butyldimethylsilyl chloride, 33.2 g, 220 mmol) was added to the solution in portions. The resulting mixture was warmed to room temperature and stirred overnight. The reaction solution was concentrated under reduced pressure, ethyl acetate (250 ml) and water (250 ml) were added, and the organic phase was separated. The aqueous phase was again extracted with ethyl acetate (250 ml). The organic phases were combined, washed successively with water (250 ml) and saturated brine (250 ml), dried over anhydrous sodium sulfate and concentrated under reduced pressure to give methyl 3-((tert-butyldimethylsilyl)oxy)-2-methyl benzoate as yellow liquid (51.5 g, yield: 100%), which was immediately used in the next reaction.

[0096] ¹ H NMR (CDCl ₃ , 300 MHz): δ 7.42 (dd. J = 7.8, 1.2 Hz, 1H), 7.05-7.11 (m, 1H), 7. 42 (dd, J = 8.1, 1.2 Hz, 1H), 3.87 (s, 3H), 2.42 (s, 3H), 1.02 (s, 9H), 0.21 (s , 6H).

[0097] Step C: Compound methyl 3-((tert-butyldimethylsilyl)oxy)-2-methylbenzoate (51.5 g, 184 mmol), AIBN (1.49 g, 9.2 mmol) and NBS (N-bromosuccinimide) (39.3 g, 220 mmol) was added to carbon tetrachloride (600 ml). The reaction solution was refluxed and the reaction was carried out overnight. The reaction solution was concentrated under reduced pressure, and then the residue was subjected to column chromatography (petroleum ether/ethyl acetate = 20/1) to obtain methyl 2-bromomethyl-3-((tert-butyldimethylsilyl)oxy)benzoate as a light yellow liquid (63 .1 g, yield: 96%).

[0098] ¹ H NMR (CDCl ₃ , 300 MHz): δ 7.51 (dd, J = 7.5,1.2 Hz, 1H), 7.22 (t, J = 8.1 Hz, 1H) , 6.98 (dd. J = 8.4. 1.5 Hz, 1H), 5.02 (s, 2H), 3.92 (s, 3H), 1.06 (s, 9H), 0, 30 (s, 6H).

[0099] Step D: Compound methyl 2-bromomethyl-3-((tert-butyldimethylsilyl)oxy)benzoate (5.00 g, 13.9 mmol) and compound (CAS 108607-02-9, 3.65 g, 15.3 mmol) was dissolved in anhydrous acetonitrile (50 ml) and diisopropylethylamine (5.20 ml, 29.2 mmol) was added dropwise under a nitrogen atmosphere at room temperature (30 °C). The reaction solution was heated to 40°C and stirred overnight. The reaction solution was concentrated under reduced pressure. The residue was diluted with dichloromethane (100 ml), washed with water (50 ml x 2) and brine (30 ml), dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a light yellow oil. The resulting oil was dissolved in DMF (17.2 ml) and a solution of K ₂ CO ₃ (884 mg, 6.40 mmol) in water (1.89 ml) was added dropwise at 0°C. After completion of the dropwise addition, the reaction solution was warmed to room temperature (25°C) and stirred for 50 minutes. The reaction solution was neutralized by adding dropwise 1 N. dilute hydrochloric acid (11 ml) at 0°C, and concentrated under reduced pressure. The residue was then subjected to column chromatography (dichloromethane/methanol = 50/1) to obtain I-1 as a white foam (1.40 g, yield: 22%).

[0100] 1H NMR (CDCl ₃ , 300 MHz): δ 8.81 (br s, 1H), 7.20-7.31 (m, 2H), 6.95-6.98 (m, 2H), 6.09 (br s, 1H), 4.94-4.99 (m, 1H), 4.56 (d, J = 17.7 Hz, 1H), 4.43 (d, J = 17.4 Hz, 1H), 2.08-2.35 (m, 4H), 1.39 (s, 9H).

[0101] Example 2

[0102] Connection I-2

[0103] Synthesis scheme:

[0104] Step A: 2-fluoro-4-methylbenzoic acid (50 g, 324.4 mmol, CAS 7697-23-6) was dissolved in 400 ml DMF and K ₂ CO ₃ (67 g, 486 mmol) was added ). The reaction solution was stirred at room temperature for 0.5 hour, iodomethane (26.3 mL, 422 mmol) was added at 0° C., and the resulting mixture was reacted at room temperature for 16 hours. The reaction solution was poured into 1500 ml of water. The mixture was extracted using EtOAc (500 ml x 2), washed with brine (500 ml x 2), dried and concentrated under reduced pressure to give the product methyl 2-fluoro-4-methyl benzoate (51 g, yield: 94%) as a white solid, which was immediately used in the next step without purification.

[0105] Step B: Methyl 2-fluoro-4-methylbenzoate (48 g, 285 mmol) was dissolved in 400 ml CCl ₄ , NBS (N-bromosuccinimide, 55.9 g, 314 mmol) and BPO (benzoyl peroxide, 13, 8 g, 57.2 mmol), the reaction solution was heated to 80°C in an oil bath and reacted overnight. The reaction solution was cooled to room temperature, filtered and concentrated under reduced pressure, and the residue was dispersed in 500 ml EtOAc, then washed with saturated brine (500 ml x 2), dried and concentrated under reduced pressure to give the product methyl-4-(bromomethyl) -2-fluorobenzoate as a yellow solid (70 g). The above solid methyl 4-(bromomethyl)-2-fluorobenzoate (70 g) and N-Boc-piperazine (35 g, 0.188 mol, CAS 57260-71-6) were added to DMF (500 ml) and added K ₂ CO ₃ (65 g, 0.47 mol). The mixture was heated to 70°C in an oil bath and the reaction was carried out for 16 hours. The reaction solution was cooled to room temperature, then filtered and washed with EtOAc (200 ml) and extracted with EtOAc (500 ml x 3). The extract was washed with water and brine and dried, and the filtrate was concentrated to dryness under reduced pressure to give the product tert-butyl 4-(3-fluoro-4-(methoxycarbonyl)benzyl)piperazine-1-carboxylate as a yellow oil (80 g) . MS (ESI) mass/charge 353.4 [M+H] ⁺ .

[0106] Step C: Tert-Butyl 4-(3-fluoro-4-(methoxycarbonyl)benzyl)piperazine-1-carboxylate (80 g) was dissolved in EtOAc (500 mL) and HCl/EtOAc (5 N) was added. , 400 ml). The reaction solution was stirred for 16 hours at room temperature, the precipitated solid was filtered off, and the resulting solid was concentrated to dryness under reduced pressure to obtain hydrochloride I-2. MC (ESI) mass/charge 253.2[M+H] ⁺ .

[0107] Example 3

[0108] Connection CM-1

[0109] Synthesis scheme:

[0110] Step A: Compound CM-1 A (3,4-difluorobenzonitrile, 11.8 g, 84.83 mmol, CAS 64248-62-0) and N-Boc-piperazine (18.96 g, 101.8 mmol) was added to DMSO (100 ml) and K ₂ CO ₃ (17.56 g, 127.2 mmol) was added. The resulting mixture was heated to 100°C in an oil bath overnight, cooled to room temperature, and then poured into 600 ml of water. The mixture was stirred for 15 minutes, then filtered and washed with water, and the filter cake was concentrated to dryness under reduced pressure using an oil pump to obtain CM-1 C as a white solid (28 g). HCl/EA(ethyl acetate) (5 M, 300 ml) was then added, the resulting mixture was stirred at room temperature overnight and filtered, and the filter cake was concentrated to dryness under reduced pressure using an oil pump to give CM-1 D (3- fluoro-4-(piperazin-1-yl)benzonitrile hydrochloride, 23.0 g) as a white solid, MS: [M+H] ⁺ = 206.1.

[0111] Step B: CM-1E, namely 2-chloro-4-methylbenzoic acid (5 g, 29.3 mmol, CAS 7697-25-8) was dissolved in 40 ml DMF and K ₂ CO was added ₃ (6.1 g, 44 mmol). The resulting mixture was stirred at room temperature for 0.5 hour, iodomethane (5.4 g, 38.1 mmol) was added at 0°C, and the reaction solution was reacted at room temperature for 4 hours. The reaction solution was poured into 300 ml of water. The resulting mixture was extracted using EtOAc (200 mL x 2), then washed with brine (200 mL x 2), dried and concentrated under reduced pressure to give product CM-1F as a yellow oil (methyl-2-chloro-4- methyl benzoate, 5.2 g, yield: 96%), which was used immediately without purification in the next step.

[0112] Step C: CM-1F (5.0 g, 27.1 mmol, CAS 195318-63-9) was dissolved in 100 ml CCl ₄ , NBS (N-bromosuccinimide, 5.7 g, 32.5 mmol) was added ) and BPO (benzoyl peroxide, 354 mg, 1.46 mmol), the reaction solution was heated to 80°C in an oil bath and reacted overnight. The reaction solution was cooled to room temperature and filtered. The filtrate was washed with saturated brine (100 ml × 2), dried and concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (PE/EtOAc = 100:1-80:1), obtaining CM-1 G as a yellow liquid ( methyl 4-(bromomethyl)-2-chlorobenzoate, 4.4 g, yield: 61%).

[0113] ¹ H NMR (400 MHz, CDC1 ₃ ) δ 7.83-7.81 (m, 1H), 7.69 (s, 1H), 7.54-7.52 (m, 1H), 4 .74 (s, 2H), 3.86 (s, 3H).

[0114] Step D: Compound CM-1 G (4.0 g, 15 mmol) and CM-1 D (3.62 g, 15 mmol) were added to CH ₃ CN (80 ml), and then K ₂ CO was added ₃ (2.34 g, 38 mmol). The resulting mixture was heated to 80°C in an oil bath for 16 hours, cooled to room temperature, then filtered, washed using EtOAc, and extracted using EtOAc (50 ml x 2). The extract was washed with water and brine and dried, and the filtrate was evaporated to dryness under reduced pressure to give CM- 1H (methyl-2-chloro-4-((4-(4-cyano-2-fluorophenyl)piperazin-1-yl) methyl benzoate, 4.5 g, 11.6 mmol, 77%) as a yellow solid. MS: [M+H] ⁺ = 388.1.

[0115] Step E: Using the synthesis procedure given in Steps BD in Example 7 (compound CM-3), compound CM-1L - tert-butyl-( S )-5-amino-4-(4-(( 2-chloro-4-((4-(4-cyano-2-fluorophenyl)piperazin-1-yl)methyl)benzyl)oxy)-1-oxoisoindolin-2-yl)-5-oxopentanoate, replacing CM-3C with CM-1H.

MS: [M+H] ⁺ = 676.2.

[0116] Step F Using the synthesis procedure given in Steps EF in Example 9 (compound CM-6), compound CM-1 can be synthesized by replacing CM-6G, i.e. tert-butyl-( S )-5-amino-4-(4-((4-((4-(4-cyano-3-(trifluoromethyl)phenyl)piperazin-1-yl)methyl)-2-fluorobenzyl) oxy)-1-oxoisoindolin-2-yl)-5-oxopentanoate, on CM-1L.

[0117] ^1H NMR (400 MHz, DMSO- d6 ) δ 10.96 (s, 1H), 7.70-7.57 (m, 2H) _, 7.49-7.48 (m, 3H) , 7.38-7.34 (m, 3H), 7.14-7.09 (m, 1H), 5.29 (s, 2H), 5.13-5.09 (m, 1H), 4 .41 (d, J = 17.6 Hz, 1H), 4.26 (d, J = 17.6 Hz, 1H), 3.57 (s, 2H), 3.20-3.18 (m, 4H), 2.95-2.86 (m, 1H), 2.59-2.39 (m, 6H), 2.00-1.95 (m, 1H).

[0118] MS: [M+H]+ = 602.2.

[0119] her = 99.8%

[0120] Example 4

[0121] CM-2 connection

[0122] Synthesis circuit

[0123] To acetonitrile (30 ml) was added 1,2-difluoro-4-nitrobenzene (1.50 g, 9.43 mmol), I-2 (2.72 g, 9.43 mmol) and N,N, -diisopropylethylamine (4.26 g, 33.00 mmol) and the resulting mixture was heated at 80°C in an oil bath and stirred for 16 hours. The reaction solution was concentrated under reduced pressure and the residue was purified by preparative high performance liquid chromatography to obtain the product CM-2 C as a brown solid (methyl-2-fluoro-4-((4-(2-fluoro-4-nitrophenyl)piperazine- 1-yl)methyl)benzoate, 1.72 g, yield: 47%).

[0124] ^1H NMR (400 MHz, DMSO- d6 ) δ 8.02-7.98 (m, 2H) _, 7.89-7.85 (m, 1H), 7.32-7.30 ( m, 2H), 7.18-7.14 (m, 1H), 3.85 (s, 3H), 3.62 (s, 2H), 3.36-3.27 (m, 4H), 2 .57-2.50 (m, 4H). MC (ESI) mass/charge 392.4 [M+H] ⁺ .

[0125] Using the synthesis procedure for compound CM-6 given in Example 9, compound CM-2 (i.e., ( S )-3-(4-((2-fluoro-4-((4-(2 -fluoro-4-nitrophenyl)piperazin-1-yl)methyl)benzyl)oxy)-1-oxoisoindolin-2-yl)piperidin-2,6-dione), replacing compound CM-6C (i.e. methyl-4 -((4-(4-cyano-3-(trifluoromethyl)phenyl)piperazin-1-yl)methyl)-2-fluorobenzoate) with the corresponding starting compound CM-2C.

[0126] ^1H NMR (400 MHz, DMSO- d6 ) δ _10.95 (s, 1H), 8.06-7.96 (m, 2H), 7.61-7.48 (m, 2H) , 7.42-7.31 (m, 2H), 7.28-7.11 (m, 3H), 5.27 (s, 2H), 5.13-5.08 (m, 1H), 4 .38 (d, J = 17.6 Hz, 1H), 4.22 (d, J = 17.6 Hz, 1H), 3.58 (s, 2H), 3.23-3.14 (m, 4H), 2.96-2.83 (m, 1H), 2.60-2.52 (m, 5H), 2.48-2.37 (m, 1H), 1.99-1.96 ( m, 1H).

[0127] MC (ESI) mass/charge 606.2 [M+H] ⁺ . ee = 99.4%

[0128] Example 5

[0129] CM-5 connection

[0130] Using the synthesis procedure for compound CM-2 given in Example 4, compound CM-5 (i.e., ( S )-4-(4-(4-(((2-(2,6-dioxopiperidine) -3-yl)-1-oxoisoindolin-4-yl)oxy)methyl)-3-fluorobenzyl)piperazin-1-yl)-2-fluorobenzonitrile), replacing the original compound CM-2A with the compound (CAS 3939-09-1).

[0131] ^1H NMR (400 MHz, DMSO- d6 ) δ _10.95 (s, 1H), 7.61-7.49 (m, 3H), 7.40-7.34 (m, 2H) , 7.24-7.20 (m, 2H), 6.95-6.83 (m, 2H), 5.27 (s, 2H), 5.13-5.08 (m, 1H), 4 .38 (d, J = 17.6 Hz, 1H), 4.22 (d, J = 17.6 Hz, 1H), 3.56 (s, 2H), 3.45-3.36 (m, 4H), 2.96-2.83 (m, 1H), 2.61-2.53 (m, 1H), 2.48-2.40 (m, 5H), 1.99-1.96 ( m, 1H).

[0132] MC (ESI) mass/charge 586.2 [M+H] ⁺ .

[0133] Example 6

[0134] CM-7 connection

[0135] Using the synthesis procedure for compound CM-2 shown in Example 4, compound CM-7 (i.e., ( S )-4-(4-(4-(((2-(2,6-dioxopiperidine) -3-yl)-1-oxoisoindolin-4-yl)oxy)methyl)-3-fluorobenzyl)piperazin-1-yl)-2-methoxybenzonitrile), replacing the original compound CM-2A with the compound (CAS191014-55-8).

[0136] ^1H NMR (400 MHz, DMSO- d6 ) δ _10.95 (s, 1H), 7.58-7.49 (m, 2H), 7.43-7.34 (m, 3H) , 7.24-7.21 (m, 2H), 6.60-6.52 (m, 2H), 5.28 (s, 2H), 5.13-5.08 (m, 1H), 4 .38 (d, J = 17.6 Hz, 1H), 4.22 (d, J = 17.6 Hz, 1H), 3.86 (s, 3H), 3.37 (s, 2H), 3 .40-3.34 (m, 4H), 2.96-2.85 (m, 1H), 2.60-2.51 (m, 5H), 2.47-2.37 (m, 1H) , 1.99-1.96(m, 1H).

[0137] MC (ESI) mass/charge 598.3 [M+H] ⁺ .

[0138] Example 7

[0139] Connection CM-3

[0140] Synthesis scheme:

[0141] Step A: Compound I-2 (methyl 2-fluoro-4-(piperazin-1-ylmethyl)benzoate hydrochloride, 2.70 g, 9.35 mmol), CM-1A (3,4-difluorobenzonitrile, 1.18 g, 8.50 mmol) and DIEA (3.29 g, 25.5 mmol) were added to DMSO (15 ml) and the resulting mixture was heated to 100°C in an oil bath and stirred in within 3 hours. The reaction solution was poured into ice water and extracted using EtOAc (60 mL x 3), the organic phase was washed with brine, dried and concentrated, and the residue was subjected to preparative reverse phase chromatography to give product CM-3 C as a yellow solid colors (methyl 4-((4-(4-cyano-2-fluorophenyl)piperazin-1-yl)methyl)-2-fluorobenzoate, 2.50 g, 6.74 mmol, yield: 79%). MS: [M+H] ⁺ = 372.1.

[0142] Step B: Compound CM-3C (2.50 g, 6.74 mmol) was dissolved in THF/MeOH (30 ml/10 ml), LiBH ₄ (0.51 g) was added in portions at 0° C. , 23.55 mmol) and the resulting mixture was stirred under nitrogen atmosphere at room temperature for 16 hours. The reaction solution was poured into ice water and the mixture was extracted using EtOAc (50 ml x 3). The organic phase was washed with brine, dried and concentrated, and the residue was subjected to preparative reverse phase chromatography to give product CM-3 D as an off-white solid (3-fluoro-4-(4-(3-fluoro-4- (hydroxymethyl)benzyl)piperazin-1-yl)benzonitrile, 1.20 g, yield: 52%).

[0143] ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.39-7.34 (m, 2H), 7.28-7.24 (m, 1H), 7.13-7.08 (m, 2H), 6.92-6.88 (m, 1H), 4.75 (s, 2H), 3.56 (s, 2H), 3.49 (s, 1H), 3.24-3.22 (m, 4H), 2.63-2.60 (m, 4H). MC [M+H] ⁺ = 344.4.

[0144] Step C: To a solution of compound CM-3 D (1.20 g, 3.50 mmol) in DCM (15 ml) at 0°C, SOCl ₂ (1.25 g, 10.50 mmol) and the resulting mixture was stirred at room temperature for 3 hours. The reaction solution was concentrated to give crude product CM-3 E (4-(4-(4-(chloromethyl)-3-fluorobenzyl)piperazin-1-yl)-3-fluorobenzonitrile hydrochloride, 1.4 g) as a white solid .

[0145] MC [M+H] ⁺ = 362.1.

[0146] Step D: Compound I-1 (611 mg, 1.83 mmol), CM-3 E (800 mg, 2.01 mmol) and Cs ₂ CO ₃ (1.49 g, 4.57 mmol) were added to DMSO (15 ml) and the resulting mixture was stirred at room temperature for 2 hours. The reaction solution was filtered, the filter cake was washed using EtOAc, and the filtrate was poured into ice water. The mixture was extracted using EtOAc (50 mL x 3), the organic phase was washed with brine (100 mL x 3), dried and concentrated, and the resulting crude product was subjected to preparative reverse phase chromatography to give product CM-3 G (tert-butyl -(S)-5-amino-4-(4-((4-((4-(4-cyano-2-fluorophenyl)piperazin-1-yl)methyl)-2-fluorobenzyl)oxy)-1-oxoisoindoline -2-yl)-5-oxopentanoate, 600 mg, 0.91 mmol, yield: 50%) as an off-white solid.

[0147] ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.48-7.35 (m, 4H), 7.29-7.25 (m, 1H), 7.18-7.12 (m, 3H), 6.93-6.89 (m, 1H), 6.32 (m, 1H), 5.32 (m, 1H), 5.19 (s, 2H), 4.93-4.85 (m, 1H), 4.55-4.36 (m, 2H), 3.59 (s, 2H), 3.28-3.22 (m, 4H), 2.70-2.58 (m , 4H), 2.42-2.08 (m, 4H), 1.42 (s, 9H). MS [M+H] ⁺ = 660.2.

[0148] Step E: A solution of compound CM-3 G (600 mg, 0.91 mmol) and p-toluenesulfonic acid (469 mg, 2.73 mmol) in CH ₃ CN (15 ml) was stirred at 90°C for 4 hours. The reaction solution was concentrated and then diluted with EtOAc/THF(THF) (30 ml/30 ml) and aqueous NaHCO ₃ solution was added at 0°C-5°C until pH>7. The organic phase was washed with brine (80 mL), dried and concentrated, and the resulting crude product was purified by preparative HPLC to give product CM-3 (( S )-4-(4-(4-(((2-(2.6 -dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)oxy)methyl)-3-fluorobenzyl)piperazin-1-yl)-3-fluorobenzonitrile, 170 mg, 0.29 mmol, yield: 32%) in as an off-white solid.

[0149] ^l H NMR (400 MHz, DMSO- d6 ) δ 10.95 (s, 1H) _, 7.71-7.65 (m, 1H), 7.60-7.47 (m, 3H) , 7.42-7.31 (m, 2H), 7.25-7.08 (m, 3H), 5.27 (s, 2H), 5.15-5.05 (m, 1H), 4 .38 (d, J = 17.6 Hz, 1H), 4.22 (d, J = 17.6 Hz, 1H), 3.57 (s, 2H), 3.23-3.14 (m, 4H), 2.96-2.83 (m, 1H), 2.60-2.52 (m, 5H), 2.48-2.37 (m, 1H), 2.02-1.92 ( m, 1H).

[0150] MC (ESI) mass/charge 586.2 [M+H] ⁺ .

[0151] Example 8

[0152] CM-4 connection

[0153] Step A. Methyl 3-fluoro-4-methyl benzoate (5 g, 29.8 mmol, CAS: 87808-48-8), NBS (N-bromosuccinimide, 5.56 g, 31.25 mmol) and BPO (benzoyl peroxide, 1.44 g, 5.95 mmol) was added to CCl ₄ (60 ml) and the resulting mixture was heated at 80° C. in an oil bath, reacting overnight. The reaction solution was filtered, the filtrate was concentrated under reduced pressure and the residue was purified by silica gel column chromatography (PE/EtOAc = 100/1-30/1) to obtain compounds CM-4 D (methyl 4-(bromomethyl)-3-fluorobenzoate, 7 d, crude) as a yellow oil.

[0154] Step B. Compound CM-4 D (2.23 g, 9.04 mmol), CM-1D (2.40 g, 9.94 mmol) and K ₂ CO ₃ (3.12 g, 22. 6 mmol) was added to DMF (25 ml) and the resulting mixture was stirred at 70°C for 16 hours. The reaction solution was filtered, the filtrate was concentrated under reduced pressure and the residue was purified by preparative high performance liquid chromatography to obtain the product CM-4 E (methyl-4-((4-(4-cyano-2-fluorophenyl)piperazin-1-yl)methyl)- 3-fluorobenzoate, 2.4 g, yield: 71%) as an off-white solid. MS (ESI) mass/charge 372.4 [M+H] ⁺ .

[0155] Step C: Compound CM-4 E (2.40 g, 6.47 mmol) was dissolved in THF/MeOH (20 ml/20 ml) and LiBH ₄ (0.35 g, 16.17 mmol). The resulting mixture was stirred at room temperature for 16 hours. The reaction solution was poured into ice water and the mixture was extracted using EtOAc (50 ml x 3). The organic phase was washed with brine, dried and concentrated, and the residue was purified by preparative high performance liquid chromatography to give the product CM-4F (3-fluoro-4-(4-(2-fluoro-4-(hydroxymethyl)benzyl)piperazine-1- yl)benzonitrile, 1.3 g, yield: 58%) as a white solid.

[0156] ^1H NMR (400 MHz, DMSO- d6 ) δ 7.70-7.66 (m, 1H) _, 7.57-7.54 (m, 1H), 7.38-7.34 ( m, 1H), 7.13-7.08 (m, 3H), 5.27 (t, J = 6.4 Hz, 1H), 4.49 (d, J = 6.4 Hz, 2H), 3.57 (s, 2H), 3.18-3.16 (m, 4H), 2.54-2.49 (m, 4H). MC (ESI) mass/charge 344.1 [M+H] ⁺ .

[0157] Step D: To a solution of CM-4 F (1.3 g, 3.79 mmol) in DCM (30 mL) at 0°C, SOCl ₂ (1.35 g, 11.37 mmol) and the resulting mixture was stirred at room temperature for 3 hours. The reaction solution was concentrated under reduced pressure to obtain the product CM-4 G (4-(4-(4-(chloromethyl)-2-fluorobenzyl)piperazin-1-yl)-3-fluorobenzonitrile hydrochloride, 1.4 g) as crude -white solid.

[0158] MC (ESI) mass/charge 362.1, 364.1 [M+H] ⁺ .

[0159] Step E: Mixed solution of Compound CM-4 G (1.50 g, 3.77 mmol), Compound I-1 (1.15 g, 3.44 mmol) and K ₂ CO ₃ (1.18 g , 8.57 mmol) in NMP (N-methylpyrrolidine, 15 ml) was stirred at 50°C for 16 hours. The reaction solution was filtered, and the filtrate was poured into ice water. The mixture was extracted using EtOAc (50 ml x 3), the organic phase was washed with brine (100 ml), dried and concentrated under reduced pressure. The residue was purified by preparative high performance liquid chromatography to give the product CM-4 H (tert-butyl( S )-5-amino-4-(4-((4-((4-(4-cyano-2-fluorophenyl)piperazine-1 -yl)methyl)-3-fluorobenzyl)oxy)-1-oxoisoindolin-2-yl)-5-oxopentanoate, 1.80 g, yield: 79%) as an off-white solid.

[0160] ^1H NMR (400 MHz, DMSO- d6 ) δ 7.70-7.66 (m, 1H) _, 7.57-7.44 (m, 4H), 7.34-7.27 ( m, 4H), 7.17-7.08 (m, 2H), 5.26 (s, 2H), 4.76-4.70 (m, 1H), 4.58-4.42 (m, 2H), 3.60 (s, 2H), 3.22-3.10 (m, 4H), 2.60-2.52 (m, 4H), 2.19-2.00 (m, 4H) , 1.32 (s, 9H). MC (ESI) mass/charge 660.2 [M+H] ⁺ .

[0161] Step F: A solution of compound CM-4 H (0.90 g, 1.36 mmol) and p-toluenesulfonic acid (0.705 g, 4.10 mmol) in CH ₃ CN (20 ml) was heated to 90°C at oil bath and stirred for 4 hours. The reaction solution was concentrated under reduced pressure and then diluted with EtOAc/THF(THF) (30 ml/30 ml) and an aqueous NaHCO ₃ solution was added at 0°C-5°C until pH>7. The organic phase was washed with brine (100 ml), dried and concentrated under reduced pressure, and the residue was purified by preparative high performance liquid chromatography to give the product CM-4 (( S )-4-(4-(4-(((2 -(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)oxy)methyl)-2-fluorobenzyl)piperazin-1-yl)-3-fluorobenzonitrile, 415 mg, yield: 52%) in as a white solid.

[0162] ^1H NMR (400 MHz, DMSO- d6 ) δ 10.97 (s, 1H), _7.70-7.66 (m, 1H), 7.7-7.44 (m, 3H) , 7.35-7.31 (m, 4H), 7.13-7.08 (m, 1H), 5.26 (s, 2H), 5.14-5.09 (m, 1H), 4 .45 (d, J= 17.2 Hz, 1H), 4.29 (d, J = 17.2 Hz, 1H), 3.60 (s, 2H), 3.24-3.11 (m, 4H), 2.98-2.84 (m, 1H), 2.64-2.52 (m, 5H), 2.49-2.37 (m, 1H), 2.05-1.93 ( m, 1H).

[0163] MC (ESI) mass/charge 586.2 [M+H] ⁺ .

[0164] Example 9

[0165] Connection CM-6

[0166] Step A: Compound CM-6 A (4-fluoro-2-(trifluoromethyl)benzonitrile, 1.5 g, 7.93 mmol, CAS 194853-86-6), I-2 (methyl-2-fluoro -4-(piperazin-1-ylmethyl)benzoate hydrochloride, 2.29 g, 7.93 mmol) and K ₂ CO ₃ (2.74 g, 19.83 mmol) were added to DMSO (20 ml) and the resulting mixture was heated to 90°C in an oil bath and the reaction was carried out for 7 hours. The reaction solution was cooled to room temperature, then filtered and washed using EtOAc. The filtrate was concentrated to dryness under reduced pressure and the residue was purified by silica gel column chromatography (PE: EtOAc = 5: m) to give the product CM-6 C (methyl-4-((4-(4-cyano-3-(trifluoromethyl)phenyl) piperazin-1-yl)methyl)-2-fluorobenzoate, 3.0 g, 90% yield) as a yellow solid. MC (ESI) mass/charge 422.3 [M+H] ⁺ .

[0167] Step B: Compound CM- 6C (3.0 g, 7.12 mmol) was dissolved in THF(THF)/MeOH (50 mL, 5 mL) and LiBH ₄ (0. 93 g, 42.8 mmol). The resulting mixture was stirred at room temperature for 16 hours. The reaction was quenched in an ice bath by adding water. The reaction mixture was extracted using EtOAc (100 ml x 2), then washed with brine (100 ml), dried and concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (PE: EtOAc = 5:1, 1:1, EtOAc ), yielding the product CM-6 D (4-(4-(3-fluoro-4-(hydroxymethyl)benzyl)piperazin-1-yl)-2-(trifluoromethyl)benzonitrile, 2.5 g, yield: 90%) as a white solid.

[0168] ^1H NMR (400 MHz, DMSO- d6 ) δ 7.82 (d, J = 8.8 Hz _, 1H), 7.42-7.30 (m, 1H), 7.29-7 .08 (m, 3H), 5.21 (t, J = 5.6 Hz, 1H), 4.53 (d, J = 5.6 Hz, 2H), 3.53 (s, 2H), 3 .47-3.44 (m, 4H), 2.51-2.47 (m, 4H).

[0169] Step C: Compound CM-6 D (2.40 g, 6.10 mmol) was dissolved in CH ₃ CN (15 mL) and SOCl ₂ (2.18 g, 18.3 mmol) and the resulting mixture was stirred at room temperature for 2 hours. The reaction solution was concentrated to dryness under reduced pressure and the residue was suspended in EtOAc, then filtered and concentrated under reduced pressure to give the product CM-6 E (4-(4-(4 -(chloromethyl)-3-fluorobenzyl)piperazin-1-yl)-2-(trifluoromethyl)benzonitrile hydrochloride, 2.4 g, yield: 88%) as an off-white solid.

[0170] ^1H NMR (400 MHz, DMSO- d6 ) δ 11.96 (s, 1H) _, 7.92 (d, J = 8.8 Hz, 1H), 7.67-7.62 (m , 2H), 7.49-7.40 (m, 2H), 7.31-7.28 (m, 1H), 4.82 (s, 2H), 4.39 (s, 2H), 4, 23-4.20 (m, 2H), 3.55-3.49 (m, 2H), 3.36-3.33(m, 2H), 3.12-3.10 (m, 2H).

[0171] Step D: Compound CM-6E (1.70 g, 3.79 mmol) was dissolved in DMSO (10 mL) and Cs ₂ CO ₃ (3.1 g, 9.5 mmol) and compound were added I-1 (1.27 g, 3.80 mmol) at room temperature. The resulting mixture was stirred at 25°C for 2 hours. The reaction solution was filtered through diatomaceous earth and then washed using EtOAc. The filtrate was poured into ice water and the mixture was extracted using EtOAc (50 ml x 3). The organic phase was washed with brine (100 ml x 3), dried and concentrated under reduced pressure, and the resulting crude product was purified by preparative high performance liquid chromatography to give the product CM-6 G (tert-butyl-(S)-5-amino -4-(4-((4-((4-(4-cyano-3-(trifluoromethyl)phenyl)piperazin-1-yl)methyl)-2-fluorobenzyl)oxy)-1-oxoisoindolin-2-yl) -5-oxopentanoate, 2.0 g, yield: 74%) as a yellow solid. MS (ESI) mass/charge 710.3 [M+H] ⁺ .

[0172] Step E: Compound CM-6 G (1.05 g, 1.48 mmol) was dissolved in DMF (3 mL) and 4 N was added. HCl in dioxane (30 ml). The reaction solution was stirred at room temperature for 16 hours and concentrated under reduced pressure to obtain CM- 6H (( S )-5-amino-4-(4-((4-((4-(4-cyano-3- (trifluoromethyl)phenyl)piperazin-1-yl)methyl)-2-fluorobenzyl)oxy)-1-oxoisoindolin-2-yl)-5-oxopentanoic acid, 1.0 g) as a yellow oil. MS (ESI) mass/charge 654.6 [M+H] ⁺ .

[0173] Step F Compound CM-6 H (1.2 g, crude) was dissolved in DMF/DCM (8 ml/25 ml) and the resulting mixture was cooled to -40°C. SOCl ₂ (881 mg, 7.40 mmol) was added dropwise and after the resulting mixture was reacted over 1.5 hours, pyridine (1.17 g, 14.8 mmol) was added. After stirring the mixture at -40°C for 1 hour, Et ₃ N (747 mg, 7.40 mmol) was slowly added dropwise and the resulting mixture was stirred for 1 hour. The reaction was quenched by slowly adding 10 ml of water and maintaining the temperature below -40°C. The reaction mixture was adjusted to pH=8 with aqueous NaHCO ₃ at -20°C, then extracted using EtOAc/THF (60/30 ml, x 3), dried over Na ₂ SO ₄ and concentrated to dryness under reduced pressure, the residue was purified by preparative HPLC to give the product CM-6 (( S )-4-(4-(4-(((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)oxy) methyl)-3-fluorobenzyl)piperazin-1-yl)-2-(trifluoromethyl)benzonitrile, 202 mg, two-step yield: 21%) as a white solid.

[0174] ^1H NMR (400 MHz, DMSO- d6 ) δ _10.95 (s, 1H), 7.84-7.82 (m, 1H), 7.57-7.51 (m, 2H) , 7.40-7.20 (m, 6H), 5.28 (s, 2H), 5.13-5.08 (m, 1H), 4.39 (d, J = 17.6 Hz, 1H ), 4.23 (d, J = 17.6 Hz, 1H), 3.57-3.45 (m, 6H), 2.95-2.86 (m, 1H), 2.59-2, 42 (m, 6H), 1.99-1.95 (m, 1H).

[0175] MC (ESI) mass/charge 636.3 [M+H] ⁺ .

[0176] Example 10

[0177] Using the procedure for the synthesis of compound CM-6, given in example 9, and using the appropriate reagents, compounds CM-8, CM-9, CM-11, CM-27, CM-28, CM-29, CM-30 were obtained , SM-31 and SM-35.

[0178] CM-8 connection

[0179] ^1H NMR (400 MHz, DMSO- d6 ) δ 10.95 (s, 1H), _8.16 (d, J = 2.0 Hz, 1H), 8.07-8.05 (m , 1H), 7.58-7.49 (m, 3H), 7.40-7.34 (m, 2H), 7.24-7.20 (m, 2H), 5.27 (s, 2H ), 5.12-5.08 (m, 1H), 4.38 (d, J = 17.6 Hz, 1H), 4.22 (d, J = 17.6 Hz, 1H), 3.57 (s, 2H), 3.09-2.97 (m, 4H), 2.96-2.83 (m, 1H), 2.61-2.42 (m, 6H), 2.04-1 .90 (m, 1H).

[0180] MC (ESI) mass/charge 636.2 [M+H] ⁺ .

[0181] CM-9 connection

[0182] ^1H NMR (400 MHz, DMSO- d6 ) δ _10.95 (s, 1H), 7.98-7.93 (m, 1H), 7.76-7.73 (m, 1H) , 7.58-7.49 (m, 2H), 7.40-7.34 (m, 2H), 7.25-7.20 (m, 3H), 5.27 (s, 2H), 5 .13-5.08 (m, 1H), 4.38 (d, J = 17.6 Hz, 1H), 4.23 (d, J = 17.6 Hz, 1H), 3.59 (s, 2H), 3.12 (br s, 4H), 2.95-2.86 (m, 1H), 2.56-2.38 (m, 6H), 2.00-1.95 (m, 1H ).

[0183] MC (ESI) mass/charge 602.2 [M+H] ⁺ .

[0184] Connection CM-11

[0185] ^1H NMR (400 MHz, DMSO- d6 ) δ _10.95 (s, 1H), 7.58-7.48 (m, 3H), 7.40-7.34 (m, 2H) , 7.24-7.20 (m, 2H), 6.92 (s, 1H), 6.84-6.82 (m, 1H), 5.27 (s, 2H), 5.13-5 .08 (m, 1H), 4.38 (d, J = 18.0 Hz, 1H), 4.23 (d, J = 18.0 Hz, 1H), 3.56 (s, 2H), 3 .34-3.29 (m, 4H), 2.90-2.87 (m, 1H), 2.59-2.54 (m, 1H), 2.51-2.42 (m, 5H) , 2.07 (s, 3H), 2.01-1.95 (m, 1H).

[0186] MC (ESI) mass/charge 582.3 [M+H] ⁺ .

[0187] Connection CM-27

[0188] ^1H NMR (400 MHz, DMSO- d6 ) δ 10.96 (s, 1H) _, 7.59-7.48 (m, 2H), 7.42-7.31 (m, 4H) , 7.24-7.19 (m, 2H), 6.96 (d, J = 8.0 Hz, 1H), 5.27 (s, 2H), 5.14-5.07 (m, 1H ), 4.38 (d, J = 17.6 Hz, 1H), 4.22 (d, J = 17.6 Hz, 1H), 3.82 (s, 3H), 3.56 (s, 2H ), 3.18-3.01 (m, 4H), 2.96-2.82 (m, 1H), 2.61-2.52 (m, 5H), 2.47-2.38 (m , 1H), 2.02-1.90 (m, 1H).

[0189] MC (ESI) mass/charge 598.2 [M+H] ⁺ .

[0190] Connection CM-28

[0191] ^1H NMR (400 MHz, DMSO- d6 ) δ 10.96 (s, 1H) _, 8.41 (d, J = 2.4 Hz, 1H), 7.75 (d, J = 8 .8 Hz, 1H), 7.60-7.48 (m, 2H), 7.42-7.32 (m, 3H), 7.26-7.19 (m, 2H), 5.27 ( s, 2H), 5.14-5.07 (m, 1H), 4.38 (d, J = 17.6 Hz, 1H), 4.22 (d, J = 17.2 Hz, 1H), 3.57 (s, 2H), 3.46-3.37 (m, 4H), 2.97-2.83 (m, 1H), 2.61-2.53 (m, 1H), 2. 49-2.37 (m,5H), 2.02-1.91 (m,1H).

[0192] MC (ESI) mass/charge 569.2 [M+H] ⁺ .

[0193] Connection CM-29

[0194] ^1H NMR (400 MHz, DMSO- d6 ) δ 10.97 (s, 1H) _, 8.47 (s, 1H), 7.86-7.83 (m, 1H), 7.58 -7.50 (m, 2H), 7.41-7.34 (m, 2H), 7.24-7.20 (m, 2H), 6.93-6.91(m, 1H), 5 .27 (s, 2H), 5.13-5.08 (m, 1H), 4.41 (d, J = 17.6 Hz, 1H), 4.25 (d, J = 17.6 Hz, 1H), 3.68-3.66 (m, 4H), 3.55 (s, 2H), 3.12 (m, 4H), 2.95-2.86 (m, 1H), 2.59 -2.51 (m, 1H), 2.50-2.42 (m, 5H), 2.00-1.95 (m, 1H).

[0195] MC (ESI) mass/charge 569.2 [M+H] ⁺ .

[0196] Connection CM-30

[0197] ¹ H NMR(400 MHz, DMSO- d6 ) δ 10.96 (s, 1H) _, 8.25 (s, 1H), 7.97-7.91 (m, 1H), 7.60 -7.48 (m, 2H), 7.42-7.32 (m, 2H), 7.26-7.20 (m, 3H), 5.27 (s, 2H), 5.15-5 .06 (m, 1H), 4.38 (d, J = 17.6 Hz, 1H), 4.22 (d, J = 17.6 Hz, 1H), 3.59 (s, 2H), 3 .43-3.36 (m, 4H), 2.96-2.83 (m, 1H), 2.61-2.52 (m, 5H), 2.47-2.36 (m, 1H) , 2.00-1.91 (m, 1H).

[0198] MC (ESI) mass/charge 593.2 [M+H] ⁺ .

[0199] Connection CM-31

[0200] ¹ H NMR(400 MHz, DMSO- d6 ) δ _10.97 (s, 1H), 7.60-7.50 (m, 4H), 7.41-7.34(m, 2H) , 7.24-7.21 (m, 2H), 7.11-7.08 (m, 1H), 5.27 (s, 2H), 5.13-5.09 (m, 1H), 4 .41 (d, J = 17.6 Hz, 1H), 4.25 (d, J = 17.6 Hz, 1H), 3.58 (s, 2H), 2.95-2.86 (m, 5H), 2.58-2.54 (m, 5H), 2.46-2.42 (m, 1H), 2.25 (s, 3H), 1.99-1.95 (m, 1H) .

[0201] MC (ESI) mass/charge 582.2 [M+H] ⁺ .

[0202] CM-35 connection

[0203] 1H NMR (400 MHz, DMSO- d6 ) δ 10.97 (s, 1H) _, 7.64-7.50 (m, 4H), 7.41-7.15 (m, 5H), 5.27 (s, 2H), 5.28 (s, 2H), 5.13-5.09 (m, 1H), 4.41 (d, J = 17.6 Hz, 1H), 4.20 (d, J = 17.6 Hz, 1H), 3.58 (s, 2H), 2.92 (m, 5H), 2.55-2.50 (m, 8H), 1.98-1, 96 (m, 1H), 1.22 (t, J = 7.2 Hz, 3H).

[0204] MC (ESI) mass/charge 596.2 [M+H] ⁺ .

[0205] Example 11

[0206] CM-12 connection

[0207] Step A: Iodethane (2.56 g, 16.41 mmol) was added to a stirred solution of CM-12 A (2-hydroxy-4-fluorobenzonitrile, 1.50 g, 10.94 mmol) and K ₂ CO ₃ (3.02 g, 21.88 mmol) in DMF (20 ml) and the resulting mixture was reacted at room temperature for 16 hours. Water (100 ml) was added and the mixture was extracted with ethyl acetate (100 ml x 2). The organic phase was washed with brine, then dried over anhydrous sodium sulfate and concentrated to give CM-12 B (2-ethoxy-4-fluorobenzonitrile, 1.60 g, 88% yield) as an off-white solid.

[0208] Step B: K ₂ CO ₃ (2.67 g, 19.38 mmol) was added to a solution of compound CM-12 B (2-ethoxy-4-fluorobenzonitrile, 1.60 g, 9.69 mmol) and I -2 (methyl-2-fluoro-4-(piperazin-1-ylmethyl)benzoate hydrochloride, 3.15 g, 10.43 mmol) in DMSO (20 ml) and the mixed solution was stirred at 90°C for 16 hours. The reaction solution was poured into water (60 ml) and the mixture was extracted using EtOAc (50 ml x 2). The organic phase was washed with brine (60 ml x 3), then dried over anhydrous Na ₂ SO ₄ , filtered and concentrated. The residue was subjected to preparative reverse phase chromatography to give CM-12 D (methyl 4-((4-(4-cyano-3-ethoxyphenyl)piperazin-1-yl)methyl)-2-fluorobenzoate, 1.90 g, yield: 49%) as a yellow solid.

[0209] Step C: Compound CM-12 D (1.90 g, 4.78 mmol) was dissolved in a mixed solution of THF (40 ml), MeOH (10 ml) and LiBH ₄ (0.32 g, 14 .36 mmol) was added in portions at 0°C. The reaction solution was stirred at room temperature for 16 hours. The reaction solution was slowly poured into ice-cold ammonium chloride aqueous solution, and the mixture was extracted with ethyl acetate (40 ml×3). The organic phase was washed with saturated brine (80 ml) and then extracted. The resulting organic phase was washed with brine (80 ml), then dried over anhydrous Na ₂ SO ₄ , filtered and concentrated to give the crude product, which was subjected to preparative reverse phase chromatography to give the product CM-12 E (2-ethoxy-4- (4-(3-fluoro-4-(hydroxymethyl)benzyl)piperazin-1-yl)benzonitrile, 1.20 g, yield: 68%) as a white solid.

[0210] Step D: To a solution of compound CM-12 E (1.20 g, 3.25 mmol) in DCM (30 ml) at 0°C, SOCl ₂ (1.46 g, 12.24 mmol) and the resulting mixture was stirred at room temperature for 16 hours. The reaction solution was concentrated to give a brown solid (1.38 g, crude). The above brown solid (1.38 g, 3.25 mmol), I-1 (tert-butyl-( S )-5-amino-4-(4-hydroxy-1-oxoisoindolin-2-yl)-5 -oxopentanoate, 1.08 g, 3.25 mmol) and Cs ₂ CO ₃ (3.18 g, 9.75 mmol) were added to DMSO (20 ml) at room temperature and the resulting mixture was stirred at room temperature in within 2 hours. The reaction solution was poured into ice water, and the mixture was extracted with ethyl acetate (50 ml×2). The organic phase was washed with brine (80 ml x 3), then dried over anhydrous Na ₂ SO ₄ and filtered, and the filtrate was concentrated. The residue was subjected to preparative reverse phase chromatography to give the product CM-12 G (tert-butyl-( S )-5-amino-4-(4-((4-((4-(4-cyano-3-ethoxyphenyl)piperazine -1-yl)methyl)-2-fluorobenzyl)oxy)-1-oxoisoindolin-2-yl)-5-oxopentanoate, 1.50 g, yield: 67%) as a yellow solid.

[0211] ^1H NMR (400 MHz, DMSO- d6 ) δ 7.57-7.31 (m, 6H) _, 7.25-7.16 (m, 3H), 6.57-6.54 ( m, 2H), 5.27 (s, 2H), 4.72-4.69 (m, 1H), 4.51 (d, J = 17.6 Hz, 1H), 4.37 (d, J = 17.6 Hz, 1H), 4.18-4.10 (m, 2H), 3.57 (s, 2H), 3.40-3.32(m, 4H), 2.49-2, 43 (m, 4H), 2.19-2.00 (m, 4H), 1.31 (s, 9H).

[0212] MC (ESI) mass/charge 686.2 [M+H] ⁺ .

[0213] Step F: A solution of HCl in dioxane (4 N, 30 ml) was added to a solution of CM-12 G (1.50 g, 2.19 mmol) in dioxane (20 ml) at room temperature. The reaction solution was stirred at 30°C for 2 hours. The reaction solution was concentrated to obtain the intermediate. R SOCl ₂ (1.30 g, 10.94 mmol) was added to a solution of the above intermediate in DCM/DMF (70 ml/10 ml) at -45° C. under nitrogen atmosphere. The reaction mixture was stirred at -45°C for 1 hour. Pyridine (1.73 g, 21.90 mmol) was added slowly and the reagents were stirred at -45°C for 1 hour. Triethylamine (1.10 g, 10.94 mmol) was slowly added to the reaction solution at -45°C, and the reagents were stirred at -45°C for 1 hour. The reaction solution was quenched with water (10 ml) and then adjusted to pH>7 by adding aqueous NaHCO ₃ solution and the organic phase was separated. The aqueous phase was extracted with EA/THF (30 ml x 3, v/v = 1/1). The organic phases were combined and washed with saturated NaCl solution, then dried and concentrated to give the crude product, which was subjected to preparative HPLC to give CM-12 as an off-white solid (383 mg, yield: 29%).

[0214] ^1H NMR (400 MHz, DMSO- d6 ) δ 10.97 (s, 1H), 7.59-7.50 (m, 2H) _, 7.43-7.34 (m, 3H) , 7.25-7.20 (m, 2H), 6.56-6.54 (m, 2H), 5.27 (s, 2H), 5.13-5.09 (m, 1H), 4 .38 (d, J = 17.6 Hz, 1H), 4.24-4.11 (m, 3H), 3.56 (s, 2H), 3.35-3.33 (m, 4H), 2.90-2.87 (m, 1H), 2.58-2.53 (m, 1H), 2.49-2.42 (m, 5H), 2.99-1.96 (m, 1H ), 1.34 (t. J = 7.2 Hz, 3H).

[0215] MC (ESI) mass/charge 612.3 [M+H] ⁺ .

[0216] Example 12

[0217] Using the synthesis procedure for compound CM-12 given in Example 11 and using appropriate reagents, CM-10, CM-24, CM-33, CM-34 and CM-39 were synthesized.

[0218] Connection CM-10

[0219] ^1H NMR (400 MHz, DMSO- d6 ) δ 10.96 (s, 1H), 7.58-7.50 (m, 4H) _, 7.40-7.34 (m, 2H) , 7.24-7.20 (m, 2H), 7.01-6.99 (m, 2H), 5.27 (s, 2H), 5.13-5.08 (m, 1H), 4 .41 (d, J = 17.6 Hz, 1H), 4.25 (d, J = 17.6 Hz, 1H), 3.56 (s, 2H), 3.35-3.33 (m, 4H), 2.95-2.86 (m, 1H), 2.59-2.51 (m, 1H), 2.50-2.38 (m, 5H), 2.00-1.96 ( m, 1H).

[0220] MC (ESI) mass/charge 568.3 [M+H] ⁺ .

[0221] CM-24 connection

[0222] ¹ H NMR(400 MHz, DMSO- d6 ) δ 10.96 (s, 1H) _, 7.86 (s, 1H), 7.65-7.41 (m, 4H), 7.34 -7.21 (m, 5H), 7.06-7.02 (m, 1H), 5.27 (s, 2H), 5.13-5.08 (m, 1H), 4.39 (d , J = 17.6 Hz, 1H), 4.22 (d, J = 17.6 Hz, 1H), 3.57 (s, 2H), 3.16-3.02 (m, 4H), 2 .95-2.86 (m, 1H), 2.64-2.52 (m, 5H), 2.48-2.39 (m, 1H), 1.99-1.95 (m, 1H) .

[0223] MC (ESI) mass/charge 604.3 [M+H] ⁺ .

[0224] SM-33

[0225] ¹ H NMR(400 MHz, DMSO-d ₆ ) δ 10.96 (s, 1H), 7.90 (s, 1H), 7.78-7.70 (m, 2H), 7.66 -7.46 (m, 3H), 7.44-7.32 (m, 2H), 7.27-7.09 (m, 3H), 5.26 (s, 2H), 5.15-5 .06 (m, 1H), 4.38 (d, J = 17.6 Hz, 1H), 4.22 (d, J = 17.6 Hz, 1H), 3.56 (s, 2H), 3 .17-3.05 (m, 4H), 2.97-2.84 (m, 1H), 2.62-2.54 (m, 1H), 2.48-2.37 (m, 5H) , 2.00-1.91 (m, 1H).

[0226] MC (ESI) mass/charge 611.2 [M+H] ⁺ .

[0227] SM-34

[0228] ^1H NMR (400 MHz, DMSO- d6 ) δ 10.96 (s, 1H) _, 8.39-8.34 (m, 1H), 7.78-7.66 (m, 2H) , 7.60-7.47 (m, 2H), 7.43-7.31 (m, 2H), 7.27-7.09 (m, 3H), 5.27 (s, 2H), 5 .16-5.05 (m, 1H), 4.38 (d, J = 17.6 Hz, 1H), 4.22 (d, J = 17.6 Hz, 1H), 3.56 (s, 2H), 3.16-3.00 (m, 4H), 2.97-2.83 (m, 1H), 2.80-2.70 (m, 3H), 2.60-2.53 ( m, 1H), 2.49-2.37 (m, 5H), 2.02-1.91 (m, 1H).

[0229] MC (ESI) mass/charge 625.2 [M+H] ⁺ .

[0230] Connection CM-39

[0231] ^1H NMR (400 MHz, DMSO- d6 ) δ 10.96 (s, 1H) _, 7.66-7.59 (m, 3H), 7.58-7.50 (m, 2H) , 7.40-7.14 (m, 3H), 6.98-6.96 (m, 1H), 5.28 (s, 2H), 5.13-5.08 (m, 1H), 4 .41 (d, J = 17.6 Hz, 1H), 4.25 (d, J = 17.6 Hz, 1H), 3.56 (s, 2H), 3.39- 3.32 (m, 4H), 2.95-2.86 (m, 1H), 2.59-2.54 (m, 1H), 2.50-2.42 (m, 5H), 1.99-1.96 ( m, 1H).

[0232] MC (ESI) mass/charge 602.2 [M+H] ⁺ .

[0233] Example 13

[0234] CM-18 connection

[0235] Step A: Using the synthesis conditions for compound CM-12 given in Example 11, CM-18 C (i.e., methyl-4-((4-(4-cyano-3-fluorophenyl)piperazine-1- yl)methyl)-2-fluorobenzoate) as a yellow solid (3.0 g, yield: 45%) from SM-1 A (3,4-difluorobenzonitrile, 2.5 g, 18.0 mmol, CAS3939 -09-1). MS (ESI) mass/charge 372.2 [M+H] ⁺ .

[0236] Step B: Compound CM-18 C (3.0 g, 8.08 mmol) was added to the reaction flask and dissolved in DMSO/EtOH (60 ml/160 ml), and then an aqueous NaOH solution was added ( 1 N., 100 ml, 100.0 mmol) and 30% H ₂ O ₂ (30 ml) and stirred at 35°C for 16 hours. The reaction solution was poured into water (500 ml) and the mixture was acidified to pH=1 with concentrated hydrochloric acid, then stood to precipitate a white solid, which was filtered. The filter cake was concentrated to dryness under reduced pressure using an oil pump to give the product CM-18D (4-((4-(4-carbamoyl-3-fluorophenyl)piperazin-1-yl)methyl)-2-fluorobenzoic acid, 3. 0 g) as a white solid. MC (ESI) mass/charge 376.2 [M+H] ⁺ .

[0237] Step C: Compound CM-18D (3.0 g, crude) was added to the reaction flask and dissolved in DMF (40 ml), K ₂ CO ₃ (2.21 g, 16.0 mmol) was added and MeI (1.13 g, 8.00 mmol) and the mixture was stirred at room temperature overnight. Water (300 ml) was added and the resulting mixture was extracted using EtOAc (150 ml x 2). The organic phases were combined, then washed with brine (300 ml), dried over Na ₂ SO ₄ , filtered and concentrated to give the product CM-18 E (methyl-4-((4-(4-carbamoyl-3-fluorophenyl)piperazine- 1-yl)methyl)-2-fluorobenzoate, 1.80 g, yield in two stages: 57%). MC (ESI) mass/charge 390.2 [M+H] ⁺ .

[0238] Step D: Using the synthesis procedure described in Example 11, compound CM-18 (i.e., (S)-4-(4-(4-(((2-(2,6-dioxopiperidine-3 -yl)-1-oxoisoindolin-4-yl)oxy)methyl)-3-fluorobenzyl)piperazin-1-yl)-2-fluorobenzamide from compound CM-18 E.

[0239] ^1H NMR (400 MHz, DMSO- d6 ) δ 10.95 (s, 1H) _, 7.63-7.50 (m, 3H), 7.41-7.31 (m, 3H) , 7.24-7.18 (m, 3H), 6.79-6.69 (m, 2H), 5.27 (s, 2H), 5.13-5.08 (m, 1H), 4 .39 (d, J = 17.6 Hz, 1H), 4.23 (d, J = 17.6 Hz, 1H), 3.56 (s, 2H), 3.30-3.28 (m, 4H), 2.95-2.86 (m, 1H), 2.54-2.32 (m, 6H), 1.99-1.95 (m, 1H).

[0240] MC (ESI) mass/charge 603.8 [M+H] ⁺ .

[0241] Example 14

[0242] Connection CM-19

[0243] Step A: SOCl ₂ (27.2 g) was added to CM-19A (2-fluoro-4-bromobenzoic acid, 10.0 g, 45.70 mmol, CAS 112704-79-7) at 0°C , 16.5 ml, 0.228 mol) and the mixture was refluxed at 85°C for 2 hours. Excess SOCl ₂ was evaporated to give the compounds as a brown solid. The compound was then dissolved in DCM (50 ml) and a mixture of MeNH ₂ HCl (9.25 g, 0.14 mol) and Et ₃ N/DCM (25 ml/100 ml) was added at 0°C. . The resulting mixture was allowed to react at room temperature for 2 hours, water (100 ml) was added, solids and liquids were separated, and the aqueous phase was extracted using DCM (100 ml), then washed with brine (200 ml), dried over Na ₂ SO ₄ , filtered and concentrated to give the product CM-19 B (4-bromo-2-fluoro-N-methylbenzamide, 10.0 g, yield: 94%). MC (ESI) mass/charge 233.9 [M+1] ⁺ .

[0244] Step B: Compounds CM-19 B (6.00 g, 25.86 mmol) and I-2 (methyl 2-fluoro-4-(piperazin-1-ylmethyl)benzoate hydrochloride, 6.51 g, 25.80 mmol), Pd(OAc) ₂ (580 mg, 2.59 mmol), Xantphos (3.00 g, 5.18 mmol, CAS 161265-03-8) and Cs ₂ CO ₃ (16.8 g , 51.80 mmol) was added to dioxane (100 ml), the mixture was heated to 110°C in an oil bath and the reaction was carried out for 16 hours in an N ₂ atmosphere. The reaction mixture was poured into water (100 ml) and then the resulting mixture was extracted using EtOAc (100 ml x 2). The organic phase was washed with brine (200 ml), then dried over Na ₂ SO ₄ , filtered and concentrated to dryness under reduced pressure, and the residue was purified by silica gel column chromatography (EA/PE 10%-50%), yielding product CM-19 C (methyl-2-fluoro-4-((4-(3-fluoro-4-(methylcarbamoyl)phenyl)piperazin-1-yl)methyl)benzoate, 3.70 g, yield: 35%) as light yellow solid. MC (ESI) mass/charge 404.1 [M+1] ⁺ .

[0245] As for the remaining stages of obtaining compound CM-19, it can be obtained by applying the synthesis conditions given in example 11 and using the appropriate reagents.

[0246] ^1H NMR (400 MHz, DMSO- d6 ) δ 10.96 (s, 1H) _, 7.76-7.74 (m, 1H), 7.58-7.50 (m, 3H) , 7.41-7.34 (m, 2H), 7.24-7.20 (m, 2H), 6.78-6.71 (m, 2H), 5.27 (s, 2H), 5 .13-5.09 (m, 1H), 4.39 (d, J = 17.6 Hz, 1H), 4.23 (d, J = 17.6 Hz, 1H), 3.56 (s, 2H), 3.32-3.28 (m, 4H), 2.95-2.86 (m, 1H), 2.75-2.74 (m, 3H), 2.58-2.50 ( m, 1H), 2.50-2.42 (m, 5H), 1.98-1.95 (m, 1H).

[0247] MC (ESI) mass/charge 618.3 [M+H] ⁺ .

[0248] Example 15

[0249] Connection CM-17

[0250] Step A: Starting Materials CM-17 A (2-fluoro-5-bromobenzonitrile, 5.00 g, 25.00 mmol), N -Boc-piperazine (3.88 g, 20.80 mmol), Pd ₂ (dba) ₃ (0.95 g, 1.04 mmol), BINAP (2,2'-bis(diphenylphosphino)-1,1'-binaphthyl, 1.30 g, 2.08 mmol) and Cs ₂ CO ₃ (10.17 g, 31.20 mmol) was added to toluene (50 ml) and the resulting mixture was reacted at 80°C for 16 hours under a nitrogen atmosphere. The reaction mixture was cooled to room temperature, filtered through diatomaceous earth and then washed with ethyl acetate, the filtrate was concentrated and the residue was subjected to column chromatography (PE/EA (petroleum ether/ethyl acetate) = 10/1 to 5/1) to give the product CM-17 C (tert -butyl-4-(3-cyano-4-fluorophenyl)piperazine-1-carboxylate, 2.50 g, yield: 39%) as an off-white solid.

[0251] Step B: CM-17C (2.50 g, 8.19 mmol) was dissolved in ethyl acetate (20 mL), a solution of hydrogen chloride in ethyl acetate (4 M, 30 mL) was added slowly and the mixture was stirred at room temperature for 3 hours and then concentrated to give the intermediate (1.98 g, crude). Intermediate (1.98 g, 8.16 mmol), CM-17D (methyl 4-(bromomethyl)-2-fluorobenzoate, 2.62 g, 10.61 mmol) and K ₂ CO ₃ (3.37 g, 24.48 mmol) was added to DMF (20 ml) and the mixture was stirred at 55°C for 5 hours. The reaction solution was washed with ethyl acetate, the filtrate was concentrated and the residue was subjected to preparative reverse phase chromatography to give the product CM-17E (methyl-4-((4-(3-cyano-4-fluorophenyl)pipcrazin)-1-yl)methyl)-2 -fluorobenzoate, 1.90 g, yield: 62%) as a yellow solid. MC (ESI) mass/charge 372.1 [M+H] ⁺ .

[0252] As for the remaining stages of obtaining compound CM-17, it can be obtained by applying the synthesis conditions given in example 11 and using the appropriate reagents.

[0253] ^1H NMR (400 MHz, DMSO- d6 ) δ _10.95 (s, 1H), 7.58-7.49 (m, 2H), 7.40-7.33 (m, 5H) , 7.24-7.20 (m, 2H), 5.27 (s, 2H), 5.13-5.08 (m, 1H), 4.38 (d, J = 17.6 Hz, 1H ), 4.22 (d, J = 17.6 Hz, 1H), 3.56 (s, 2H), 3.22-3.11 (m, 4H), 2.98-2.83 (m, 1H), 2.61-2.52 (m, 5H), 2.48-2.37 (m, 1H), 2.03-1.92 (m, 1H).

[0254] MC (ESI) mass/charge 586.2 [M+H] ⁺ .

[0255] Example 16

[0256] CM-14 connection

[0257] Step A: Sodium difluorochloroacetate (7.70 g, 50.50 mmol, CAS: 1895-39-2) was added to a mixed solution of compound CM-14 A (4-bromo-2-hydroxybenzonitrile, 5.00 g, 25.25 mmol) and K ₂ CO ₃ (4.18 g, 30.30 mmol) in DMF/H ₂ O (50 ml/5 ml), and the mixture was reacted at 100°C for 3 hours. Water (100 ml) was added and the resulting mixture was extracted using EtOAc (80 ml x 2). The organic phase was washed with brine, then dried over anhydrous sodium sulfate and concentrated to give the crude product, which was purified by silica gel column chromatography (PE/EtOAc = 100/1-20/1) to give the product CM-14 B (4-bromo -2-difluoromethoxybenzonitrile, 4.60 g, yield: 73%) as a light yellow solid.

[0258] Step B: Compounds CM-14 B (4-bromo-2-difluoromethoxybenzonitrile, 2.00 g, 8.06 mmol), I-2 (methyl-2-fluoro-4-(piperazin-1-ylmethyl) benzoate hydrochloride, 2.21 g, 8.77 mmol), xphos Pd G2 (0.32 g, 0.41 mmol) and CS ₂ CO ₃ (3.91 g, 12.00 mmol) were added to dioxane (25 ml ) and carried out the reaction in a nitrogen atmosphere at 100°C for 16 hours. The reaction solution was filtered through diatomaceous earth, the filter cake was washed using EtOAc, the filtrate was rotary evaporated and concentrated to dryness under reduced pressure using a water pump. The residue was purified by silica gel column chromatography (PE/EtOAc = 10/1-4/1) to give the product CM-14 D (methyl-4-((4-(4-cyano-3-(difluoromethoxy)phenyl)piperazine-1 -yl)methyl)-2-fluorobenzoate, 2.00 g, 4.77 mmol, yield: 59%) as a yellow solid. MC (ESI) mass/charge 420.4 [M+H] ⁺ .

[0259] As for the remaining stages of obtaining compound CM-14, the synthesis conditions can be found in example 9.

[0260] ^1H NMR (400 MHz, DMSO- d6 ) δ 10.95 (s, 1H) _, 7.61-7.34 (m, 6H), 7.24-7.20 (m, 2H) , 6.88-6.80 (m, 2H), 5.28 (s, 2H), 5.13-5.08 (m, 1H), 4.38 (d, J = 17.6 Hz, 1H ), 4.22 (d, J = 17.6 Hz, 1H), 3.57 (s, 2H), 3.40-3.38 (m, 4H), 2.95-2.84 (m, 1H), 2.59-2.53 (m, 1H), 2.50-2.40 (m, 5H), 1.99-1.96 (m, 1H).

[0261] MC (ESI) mass/charge 634.2 [M+H] ⁺ .

[0262] Example 17

[0263] Connection CM-13

[0264] Using the synthesis conditions given for Step A in Example 11, we obtained , replacing iodoethane with iodomethylcyclopropane (CAS 33574-02-6);

as for the remaining stages, compound CM-13 can be obtained by following the procedure given in example 9.

[0265] ^1H NMR (400 MHz, DMSO- d6 ) δ _10.98 (s, 1H), 7.58-7.50 (m, 2H), 7.42-7.34 (m, 3H) , 7.24-7.20 (m, 2H), 6.56-6.52 (m, 2H), 5.27 (s, 2H), 5.13-5.09 (m, 1H), 4 .38 (d, J = 17.6 Hz, 1H), 4.22 (d, J = 17.6 Hz, 1H), 3.94 (d, J = 6.8 Hz, 2H), 3.56 (s, 2H), 3.34-3.32 (m, 4H), 2.95-2.86 (m, 1H), 2.61-2.53 (m, 1H), 2.50-2 .42 (m, 5H), 1.98-1.95 (m, 1H), 1.25-1.18 (m, 1H), 0.60-0.56 (m, 2H), 0.35 -0.29 (m, 2H).

[0266] MC (ESI) mass/charge 638.3 [M+H] ⁺ .

[0267] Example 18

[0268] CM-16 connection

[0269] Step A: Starting Materials CM-16A (methyl 2-fluoro-4-(piperazin-1-ylmethyl)benzoate, 2.20 g, 8.73 mmol), CM-16B (4-bromo-2- fluoro-1-(trifluoromethyl)benzene, 2.12 g, 8.73 mmol), Pd ₂ (dba) ₃ (0.80 g, 0.87 mmol), BINAP (2,2'-bis(diphenylphosphino)- 1,1'-binaphthyl, 1.08 g, 1.74 mmol) and Cs ₂ CO ₃ (4.27 g, 13.90 mmol) were added to 1,4-dioxane (50 ml) and reacted under nitrogen atmosphere at 85°C for 16 hours. The reaction mixture was cooled to room temperature, filtered through diatomaceous earth and washed with ethyl acetate, the filtrate was concentrated and the residue was subjected to column chromatography (PE/EA = 10/1 to 5/1) to give the product CM-16C (methyl-2-fluoro-4-( (4-(3-fluoro-4-(trifluoromethyl)phenyl)piperazin-1-yl)methyl)benzoate, 2.00 g, yield: 53.5%) as a yellow solid. MC (ESI) mass/charge 415.4 [M+H] ⁺ .

[0270] As for the remaining stages of obtaining compound CM-16, you can apply the synthesis procedure given in example 11 using the appropriate reagents.

[0271] ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.97 (s, 1H), 7.60-7.33 (m, 5H), 7.26-7.19 (m, 2H) , 6.97-6.90 (m, 1H), 6.86-6.81 (m, 1H), 5.27 (s, 2H), 5.15-5.07 (m, 1H), 4 .38 (d, J = 17.6 Hz, 1H), 4.22 (d, J = 17.6 Hz, 1H), 3.56 (s, 2H), 3.32-3.28 (m, 4H), 2.96-2.84 (m, 1H), 2.61-2.52 (m, 1H), 2.49-2.37 (m, 5H), 2.01-1.91 ( m, 1H).

[0272] MC (ESI) mass/charge 629.2 [M+H] ⁺ .

[0273] Example 19

[0274] CM-25 connection

[0275] Using the synthesis procedure described in Example 11 and using appropriate reagents, compound CM-25 was obtained.

[0276] ^1H NMR (400 MHz, DMSO- d6 ) δ 10.99 (s, 1H), 8.60 (d, J = 2.4 Hz _, 1H), 7.60 (d, J = 2 .4 Hz, 1H), 7.51-7.45 (m, 2H), 7.35-7.30 (m, 4H), 5.27 (s, 2H), 5.15-5.10 ( m, 1H), 4.35 (d, J = 17.6 Hz, 1H), 4.28 (d, J = 17.6 Hz, 1H), 3.61-3.54 (m, 6H), 2.99-2.85 (m, 1H), 2.61-2.52 (m, 5H), 2.48-2.37 (m, 1H), 2.01-1.98 (m, 1H ).

[0277] MC (ESI) mass/charge 637.3 [M+H] ⁺ .

[0278] Example 20

[0279] Connection CM-22

[0280] Step A: K ₂ CO ₃ (45.54 g, 0.13 mol) was added to a solution of compound CM-22A (methyl 4-(bromomethyl)-3-fluorobenzoate, 32.00 g, 0.13 mol ) and N-Boc-piperazine (24.21 g, 0.13 mol) in acetonitrile (250 ml) and the mixture was stirred at 70°C for 16 hours. The reaction solution was filtered, the filtrate was concentrated and the residue was purified by column chromatography to give the product CM-22 B (tert-butyl 4-(2-fluoro-4-(methoxycarbonyl)benzyl)piperazine-1-carboxylate, 36.00 g, yield: 78%) as a light yellow solid. MC (ESI) mass/charge 353.4 [M+H] ⁺ .

[0281] Stage B: 4 n. HCl/EA(ethyl acetate) (200 ml) was slowly added to a solution of compound CM-22B (36.00 g, 0.10 mol) in ethyl acetate (100 ml) and reacted at room temperature for 24 hours. The reaction solution was concentrated to a volume of approximately 100 ml, then filtered and the filter cake was dried to obtain the product CM-22C (methyl 3-fluoro-4-(piperazin-1-ylmethyl)benzoate dihydrochloride, 29.00 g, yield: 89% ) as an off-white solid. MC (ESI) mass/charge 253.2 [M+H] ⁺ .

[0282] Step C: Based on Example 22 and using appropriate reagents, compound CM-22D (ie, 4-fluoro-2-(methoxy _-d3 ) benzonitrile) was prepared. K ₂ CO ₃ (2.22 g, 16.12 mmol) at 25°C was added to a solution of compound CM-22 C (methyl-3-fluoro-4-(piperazin-1-ylmethyl)benzoate dihydrochloride, 2.62 g , 8.06 mmol) and CM-22 D (1.25 g, 8.06 mmol) in DMSO (20 ml) and the mixture was stirred at 90°C for 16 hours. The reaction solution was poured into water (60 ml) and the mixture was extracted using EtOAc (50 ml x 2). The organic phase was washed with brine (60 ml x 3), then dried over anhydrous Na ₂ SO ₄ , filtered and concentrated. The residue was subjected to preparative reverse phase chromatography to give the product CM-22 E (methyl 4-((4-(4-cyano-3-(methoxy- d ₃ )phenyl)piperazin-1-yl)methyl)-3-fluorobenzoate, 1.60 g, 4.15 mmol, yield: 51%) as a yellow solid. MC (ESI) mass/charge 387.1 [M+H] ⁺ .

[0283] As for the remaining stages of obtaining compound CM-22, it can be obtained by applying the synthesis conditions given in example 11 and using the appropriate reagents.

[0284] ¹ H NMR(400 MHz, DMSO- d6 ) δ 10.98 (s, 1H) _, 7.53-7.28 (m, 7H), 6.58-6.51 (m, 2H) , 5.26 (s, 2H), 5.16-5.08 (m, 1H), 4.44 (d, J = 17.6 Hz, 1H), 4.29 (d, J = 17.2 Hz, 1H), 3.59 (s, 2H), 3.40-3.32 (m, 4H), 2.96-2.86 (m, 1H), 2.59-2.53 (m, 1H), 2.49-2.40 (m, 5H), 2.01-1.97 (m, 1H).

[0285] MC (ESI) mass/charge 601.3 [M+H] ⁺ .

[0286] Example 21

[0287] Connection CM-40

[0288] Step A: At 0°C-5°C, chloromethyl methyl ether (4.05 g, 50.32 mmol, CAS: 107-30-2) was slowly added to a stirred solution of compound CM-40 A (3-hydroxy -4-fluorobenzonitrile, 4.60 g, 33.55 mmol, CAS: 186590-04-5) and DIEA (8.66 g, 67.10 mmol) in DCM (50 ml) and carried out reaction at room temperature for 16 hours. Water (60 ml) was added and the resulting mixture was extracted with ethyl acetate (50 ml x 2). The organic phase was washed with brine, then dried over anhydrous sodium sulfate and concentrated to give CM-40 B (4-fluoro-3-(methoxymethoxy)benzonitrile, 7.00 g, crude) as a light yellow liquid, which was immediately used in the next reaction.

[0289] Step B: Cs ₂ CO ₃ (30.97 g, 95.00 mmol) was added to a solution of CM-40 B (7.00 g, 38.67 mmol) and piperazine (16.63 g, 193. 37 mmol) in DMSO (100 ml) and the mixture was stirred at 100°C for 16 hours. The reaction solution was poured into water (200 ml) and the mixture was extracted using EtOAc (150 ml x 2). The organic phase was washed with brine (300 ml x 3), then dried over anhydrous Na ₂ SO ₄ , filtered and concentrated to give the product CM-40C (3-(methoxymethoxy)-4-(piperazin-1-yl)benzonitrile, 6 .60 g, 56% yield) as a yellow solid, which was immediately used in the next reaction.

[0290] Step C: To a solution of compound CM-40 C (6.60 g, 26.69 mmol) and CM-40 D (methyl 4-(bromomethyl)-2-fluorobenzoate, 6.60 g, 26.69 mmol) in DMF (80 ml) was added DIEA (6.89 g, 53.44 mmol) and the mixed solution was stirred at 100°C for 2 hours. The reaction solution was concentrated and the residue was subjected to column chromatography (PE/EtOAc = 4/1), obtaining the product CM-40 E (methyl-4-((4-(4-cyano-2-(methoxymethoxy)phenyl)piperazin-1-yl )methyl)-2-fluorobenzoate, 8.00 g, yield: 72%) as a yellow solid;

As for the remaining stages of obtaining the compound CM-40, the synthesis given in example 11 can be used using the appropriate reagents.

[0291] ^1H NMR (400 MHz, DMSO- d6 ) δ 10.96 (s, 1H) _, 10.02 (s, 1H), 7.60-7.47 (m, 2H), 7.44 -7.30 (m, 2H), 7.26-7.15 (m, 3H), 7.06-7.01 (m, 1H), 6.94-6.87 (m, 1H), 5 .27 (s, 2H), 5.14-5.06 (m, 1H), 4.38 (d, J = 17.6 Hz, 1H), 4.22 (d, J = 17.6 Hz, 1H), 3.56 (s, 2H), 3.17-3.05 (m, 4H), 2.94-2.85 (m, 1H), 2.60-2.51 (m, 5H) , 2.48-2.40 (m, 1H), 2.01-1.92 (m, 1H).

[0292] MC (ESI) mass/charge 584.3 [M+H] ⁺ .

[0293] Example 22

[0294] CM-32 connection

[0295] Step A: To a mixed solution of compound CM-32 A (3-hydroxy-4-fluorobenzonitrile, 1.50 g, 10.95 mmol) and K ₂ CO ₃ (3.02 g, 21.88 mmol) in DMF (20 ml), deuterated iodomethane (2.06 g, 14.23 mmol) was added and the mixture was reacted at room temperature for 16 hours. Water (60 ml) was added and the resulting mixture was extracted with ethyl acetate (30 ml x 2). The organic phase was washed with brine, then dried over anhydrous sodium sulfate and concentrated to give CM-32 B (4-fluoro-3-(methoxy _- d3 )benzonitrile, 1.50 g, yield: 89%) as a solid. a gray substance, which was immediately used in the next reaction.

[0296] Step B: Cs ₂ CO was added to a solution of compound CM-32 B (1.30 g, 8.44 mmol) and piperazine (3.63 g, 42.2 mmol) in DMSO (15 ml) ₃ (5.50 g, 16.08 mmol) and the mixed solution was stirred at 100°C for 16 hours. The reaction solution was poured into water (60 ml) and the mixture was extracted using EtOAc (50 ml x 2). The organic phase was washed with brine (60 ml x 3), then dried over anhydrous Na ₂ SO ₄ , filtered and concentrated to give the product CM-32 D (3-(methoxy -d ₃ )-4-(piperazin-1-yl )benzonitrile, 1.80 g, yield: 97%) as a light yellow solid, which was immediately used in the next reaction.

[0297] Step C: To a solution of compound CM-32 D (1.70 g, 7.72 mmol) and CM-40D (methyl 4-(bromomethyl)-2-fluorobenzoate, 2.38 g, 9.66 mmol ) in DMSO (15 ml) was added DIEA (2.99 g, 23.16 mmol) and the mixed solution was stirred at 90°C for 8 hours. The reaction solution was concentrated and the residue was subjected to column chromatography to obtain the product CM-32F (methyl 4-((4-(4-cyano-2-(methoxy- d ₃ )phenyl)piperazin-1-yl)methyl)-2-fluorobenzoate , 1.80 g, yield: 60%) as a yellow solid, MC (ESI) wt/charge 387.5 [M+H] ⁺ .

[0298] As for the remaining stages of obtaining compound CM-32, the synthesis procedure described in example 11 can be used using the appropriate reagents.

[0299] ^1H NMR (400 MHz, DMSO- d6 ) δ 10.96 (s, 1H), 7.58-7.50 (m, 2H) _, 7.41-7.20 (m, 6H) , 6.97-6.95 (m, 1H), 5.27 (s, 2H), 5.13-5.08 (m, 1H), 4.38 (d, J = 17.6 Hz, 1H ), 4.22 (d, J = 17.6 Hz, 1H), 3.56 (s, 2H), 3.18-3.01 (m, 4H), 2.94-2.83 (m, 1H), 2.58-2.51 (m, 1H), 2.49-2.38 (m, 5H), 1.98-1.95 (m, 1H).

[0300] MC (ESI) mass/charge 601.2 [M+H] ⁺ .

[0301] Using the synthesis procedure for compound CM-32 and using appropriate reagents, compounds CM-15 and CM-36 were obtained.

[0302] CM-15 connection

[0303] ^1H NMR (400 MHz, DMSO- d6 ) δ _10.95 (s, 1H), 7.58-7.49 (m, 2H), 7.43-7.34 (m, 3H) , 7.24-7.21 (m, 2H), 6.57-6.54 (m, 2H), 5.28 (s, 2H), 5.13-5.08 (m, 1H), 4 .38 (d, J = 17.6 Hz, 1H), 4.22 (d, J = 17.6 Hz, 1H), 3.57 (s, 2H), 3.38-3.32 (m, 4H), 2.93-2.85 (m, 1H), 2.60-2.53 (m, 1H), 2.49-2.40 (m, 5H), 1.99-1.95 ( m, 1H).

[0304] MC (ESI) mass/charge 601.3 [M+H] ⁺ .

[0305] CM-36 connection

[0306] ^1H NMR (400 MHz, DMSO- d6 ) δ 10.97 (s, 1H), 7.57-7.50 (m, 2H) _, 7.41-7.22 (m, 6H) , 6.96-6.94 (m, 1H), 5.27 (s, 2H), 5.13-5.09 (m, 1H), 4.41 (d, J = 17.6 Hz, 1H ), 4.25 (d, J = 17.6 Hz, 1H), 4.09-4.04 (m, 2H), 3.56 (s, 2H), 3.12 (m, 4H), 2 .95-2.86 (m, 1H), 2.58-2.50 (m, 5H), 2.46-2.40 (m, 1H), 1.99-1.96 (m, 1H) , 1.34 (t, J = 6.8 Hz, 3H).

[0307] MC (ESI) mass/charge 612.2 [M+H] ⁺ .

[0308] Example 23

[0309] Connection CM-41

[0310] CM-41 C (methyl 4-((4-(3-bromo-4-cyanophenyl)piperazin-1-yl)methyl)-2-fluorobenzoate, 3.50 g, 8.10 mmol), ethylboronic acid (1.20 g, 16.20 mmol), Pd ₂ (dppf)Cl ₂ (0.18 g, 0.24 mmol) and potassium carbonate (1.72 g, 16.20 mmol) were added to the dioxane/ water (30 ml/7 ml) and the mixture was reacted under nitrogen atmosphere at 90°C for 16 hours. The reaction mixture was cooled to room temperature, filtered through diatomite and then washed with ethyl acetate. The filtrate was concentrated to give the crude product, which was subjected to preparative reverse phase chromatography to give product CM-41 D (methyl-4-((4-(4-cyano-3-ethylphenyl)piperazin-1-yl)methyl)-2- fluorobenzoate, 1.00 g, 2.62 mmol, yield: 32%) as a white solid. MC (ESI) mass/charge 382.5 [M+H] ⁺ .

[0311] As for the remaining stages of obtaining compound CM-41, you can apply the synthesis procedure given in example 11 using the appropriate reagents.

[0312] ^1H NMR (400 MHz, DMSO- d6 ) δ 10.96 (s, 1H), 7.60-7.47 (m, 3H) _, 7.42-7.32 (m, 2H) , 7.26-7.18 (m, 2H), 6.93-6.81 (m, 2H), 5.27 (s, 2H), 5.15-5.06 (m, 1H), 4 .38 (d, J = 17.6 Hz, 1H), 4.22 (d, J = 17.6 Hz, 1H), 3.56 (s, 2H), 3.34-3.31 (m, 4H), 2.96-2.84 (m, 1H), 2.68 (q, J = 7.2 Hz, 2H), 2.58-2.52 (m, 1H), 2.49-2 .37 (m, 5H), 2.01-1.93 (m, 1H), 1.19 (t, 7.2 Hz, 3H).

[0313] MC (ESI) mass/charge 596.2 [M+H] ⁺ .

[0314] Using the synthesis procedure for compound CM-41, compound CM-37 was prepared by replacing ethyl boronic acid with cyclopropyl boronic acid.

[0315] Connection CM-37

^1H NMR (400 MHz, DMSO- d6 ) δ 10.96 (s, 1H) _. 7.60-7.32 (m, 5H), 7.25-7.18 (m, 2H), 6.83-6.78 (m, 1H), 6.42(d, J = 2.0 Hz, 1H).5.27(s, 2H), 5.15-5.06 (m, 1H), 4.38 (d, J = 17.6 Hz, 1H), 4.22 (d, J = 17.6 Hz,1H), 3.55 (s, 2H), 3.32-3.29 (m, 4H), 2.97-2.83 (m, 1H), 2.59-2, 52 (m, 1H), 2.49-2.37 (m, 5H), 2.10-1.91 (m, 2H), 1.05-0.98 (m, 2H), 0.85- 0.78 (m, 2H).

[0316] MC (ESI) mass/charge 608.2 [M+H] ⁺ .

[0317] Example 24

[0318] Connection CM-43

[0319] Using the synthesis procedure described in Example 11 and using appropriate reagents, compound CM-43G was prepared.

[0320] Compounds CM-43 G (200 mg, 0.31 mmol) and CM-43 H (trimethyl((4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)ethynyl) silane, 210 mg, 0.93 mmol, CAS 159087-46-4) was dissolved in 8 ml dioxane/water (6 ml/2 ml) and Pd(dppf) ₂ Cl ₂ (91.5 mg, 0.125 mmol) and Et ₃ N (126 mg, 1.25 mmol). The reaction system was purged with nitrogen 3 times and then heated at 80°C for 2.5 hours under a nitrogen atmosphere until the reaction was complete. The reaction solution was filtered through diatomaceous earth, then washed with EtOAc (10 ml) and concentrated under reduced pressure, and the residue was purified by preparative reverse phase chromatography (10%-80% ACN (acetonitrile)), giving CM-43 I (( S )-3 -(4-((2-fluoro-4-((4-(2-fluoro-4-((trimethylsilyl)ethynyl)phenyl)piperazin-1-yl)methyl)benzyl)oxy)-1-oxoisoindoline-2- yl)piperidine-2,6-dione, 100 mg, yield: 42%).

[0321] A solution of n-Bu ₄ NF/THF (1 M, 1 mmol, 1 ml) was added to a solution of CM-43 I (100 mg, 0.15 mmol) in THF (5 ml), the mixed solution was stirred at room temperature for 1 hour until the reaction was complete. The reaction solution was extracted using EtOAc (10 ml), then washed with water (10 ml x 6) and concentrated, and the residue was subjected to preparative reverse phase medium pressure chromatography and then purified by preparative HPLC (TFA) to obtain the product salt and TFA (15 mg). The salt was dissolved in DMF and the resulting mixture was slowly added dropwise to aq. NaHCO ₃ (20 ml) to precipitate a white solid. The solid was filtered and dried in vacuo using an oil pump to give compounds CM-43 (7.8 mg, yield: 9%).

[0322] ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 10.97 (s, 1H), 7.58-7.50 (m, 2H). 7.41-7.21 (m, 6H), 7.01-6.97 (m, 1H), 5.27 (s, 2H), 5.13-5.08 (m, 1H), 4. 41-4.13 (m, 3H), 3.57 (s, 2H), 3.07-2.95 (m, 4H), 2.95-2.86 (m, 1H), 2.58- 2.51 (m, 4H), 2.46-2.32 (m, 2H), 1.98-1.94 (m, 1H).

[0323] MC (ESI) mass/charge [M+H]+ = 585.3.

[0324] Using the synthesis procedure for compound CM-43, CM-38 was prepared by replacing CM-43H with (CAS 608534-34-5).

[0325] CM-38 connection

[0326] ^1H NMR (400 MHz, DMSO- d6 ) δ 10.96 (s, 1H), 7.58-7.50 (m, 2H) _, 7.41-7.16 (m, 6H) , 7.00-6.95 (m, 1H), 6.67-6.60 (m, 1H), 5.73 (d, J = 17.6 Hz, 1H), 5.27 (s, 2H ), 5.19-5.08 (m, 2H), 4.38 (d, J = 17.6 Hz, 1H), 4.22 (d, J = 17.6 Hz, 1H), 3.57 (s, 2H), 3.04-2.95 (m, 4H), 2.95-2.86 (m, 1H), 2.58-2.51 (m, 5H), 2.46-2 .39 (m, 1H), 1.99-1.95 (m, 1H).

[0327] MC (ESI) mass/charge [M+H] ⁺ = 587.2.

[0328] Example 25

[0329] CM-42 connection

[0330] Using the procedure described in Example 11, compound CM-42F was synthesized. SM-42 F (tert-butyl-(S)-5-amino-4-(4-((4-((4-(3-bromo-4-cyanophenyl)piperazin-1-yl)methyl)-2- fluorobenzyl)oxy)-1-oxoisoindolin-2-yl)-5-oxopentanoate, 1.00 g, 1.46 mmol), Zn(CN) ₂ (1.00 g, 256.23 mmol), Pd ₂ (dba ) ₃ (0.12 g, 0.13 mmol) and dppf (0.14 g, 0.26 mmol) were added to DMF (10 ml) and the mixture was reacted under nitrogen at 100°C for 5 hours. The reaction mixture was cooled to room temperature, water (50 ml) was added and the resulting mixture was extracted with ethyl acetate (30 ml x 2). The organic phases were combined and then washed with saturated brine (50 ml x 3). The organic phase was dried over anhydrous sodium sulfate, then filtered and concentrated to give the crude product, which was subjected to preparative reverse phase chromatography to give the product CM-42 G (tert-butyl(S)-5-amino-4-(4-(( 4-((4-(3,4-dicyanophenyl)piperazin-1-yl)methyl)-2-fluorobenzyl)oxy)-1-oxoisoindolin-2-yl)-5-oxopentanoate, 700 mg, yield: 72%) as a white solid.

[0331] As for the remaining steps for preparing compound CM-42, it can be prepared by following Example 11 and using the appropriate reagents.

[0332] ^1H NMR (400 MHz, DMSO- d6 ) δ 10.95 (s, 1H) _, 7.80 (d, J = 9.2 Hz, 1H), 7.60-7.48 (m , 3H), 7.42-7.18 (m, 5H), 5.27 (s, 2H), 5.15-5.06 (m, 1H), 4.38 (d, J = 17.6 Hz,1H), 4.22 (d, J = 17.6 Hz, 1H), 3.56 (s, 2H), 3.48-3.42 (m, 4H), 2.96-2.84 (m, 1H), 2.58-2.52 (m, 1H), 2.49-2.37 (m, 5H), 2.01-1.93 (m, 1H).

[0333] MC (EST) mass/charge 593.2 [M+H] ⁺ .

[0334] Example 26

[0335] CM-44 connection

[0336] Step A: To a solution of compound CM-44 A (methyl 4-((4-(4-cyano-2-(methoxymethoxy)phenyl)pipcrazin-1-yl)methyl)-2-fluorobenzoate, 3.00 g , 7.26 mmol) in DCM (20 ml) at 0°C-5°C was added TFA (20 ml) and the mixed solution was stirred at room temperature for 1.5 hours. The reaction solution was concentrated and then diluted with EtOAc and an aqueous solution of NaHCO ₃ was added, bringing the mixture to pH = 8-9. The resulting mixture was extracted using EtOAc (30 ml x 3). The organic phases were combined, then washed with saturated brine (50 ml), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated to give the product CM-44 B (methyl-4-((4-(4-cyano-2-hydroxyphenyl) piperazin-1-yl)methyl)-2-fluorobenzoate, 1.70 g, yield: 91%) as a yellow solid. MC (ESI) mass/charge 370.1 [M+H] ⁺

[0337] Step B: Compound CM-44 B (800 mg, 2.17 mmol) was dissolved in THF (8 ml) and the mixture was cooled to -15°C. Sodium hydride (104 mg, 4.34 mmol) was added in portions and the temperature was maintained below -5°C. After 30 minutes, water (78 mg, 4.34 mmol) was added dropwise. After 10 minutes, CM-44C (diethyl(bromodifluoromethyl)phosphonate, 1.16 g, 4.34 mmol) was added in portions and the mixture was stirred at room temperature for 1 hour. The reaction solution was poured into water, and the resulting mixture was extracted with ethyl acetate (30 ml×3). The organic phase was washed with brine (80 ml), then dried over anhydrous Na ₂ SO ₄ , filtered and concentrated, and the residue was subjected to preparative reverse phase chromatography to give the product CM-44 D (methyl-4-((4-(4 -cyano-2-(difluoromethoxy)phenyl)piperazin-1-yl)methyl)-2-fluorobenzoate, 0.35 g, 0.83 mmol, yield: 38%) as a white solid.

[0338] As for the remaining stages of obtaining CM-44, it can be obtained by following example 11 and using the appropriate reagents.

[0339] ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.95 (s, 1H), 7.68-7.48 (m, 4H), 7.42-6.95 (m, 6H) , 5.27 (s, 2H), 5.14-5.06 (m, 1H), 4.38(d, J = 17.6 Hz, 1H), 4.22 (d, J = 17.6 Hz, 1H), 3.56 (s, 2H), 3.20-3.06 (m, 4H), 2.97-2.82 (m, 1H). 2.62-2.52 (m, 5H), 2.48-2.40 (m, 1H), 2.01-1.92 (m, 1H).

[0340] MC (ESI) mass/charge 634.2 [M+H] ⁺ .

[0341] Example 27

[0342] Step A: Compound CM-48A (CAS 115843-99-7, 15.00 g, 66.82 mmol), 1,1'-bis(diphenylphosphino)ferrocene (dppf) (3.70 g, 6. 68 mmol), Pd ₂ (dba) ₃ (3.06 g, 3.34 mmol) and Zn(CN) ₂ (10.16 g, 86.84 mmol) were added to DMF (150 ml), heated to 100°C in a nitrogen atmosphere and the reaction was carried out for 16 hours. The reaction solution was cooled and filtered, and the filter cake was washed using EtOAc (80 ml). The filtrate was concentrated and the residue was subjected to silica gel column chromatography (PE/EA = 2/1) to give product CM-48B (9.00 g, 52.76 mmol, yield: 79%) as an off-white solid.

[0343] Step B: CuI (20.34 g, 106.49 mmol) and isoamyl nitrite (12.48 g, 106.49 mmol) were added to MeCN (90 mL). The reaction solution was heated to 65°C and a solution of CM-48 B (9.00 g, 52.79 mmol) in acetonitrile (90 ml) was added dropwise. The dropwise addition was completed in 30 minutes and the reaction continued for 5 hours. The reaction solution was concentrated and the residue was subjected to column chromatography (PE/EA = 20/1) to obtain the product CM-48 C (5.00 g, 17.77 mmol, yield: 33%) as an off-white solid. MC (ESI) mass/charge 281.9 [M+H] ⁺ .

[0344] Step C: Compounds CM-16A (2.70 g, 10.71 mmol) and CM-48C (3.00 g, 10.71 mmol), xphos Pd G2 (0.86 g, 1.07 mmol ) and Cs ₂ CO ₃ (5.24 g, 16.06 mmol) were added to 1,4-dioxane (30 ml) and reacted under nitrogen at 110°C for 16 hours. The reaction mixture was cooled to room temperature, filtered through diatomite and then washed with ethyl acetate. The filtrate was concentrated and the residue was subjected to column chromatography (PE/EA = 10/1-5/1) to give CM-48E as a yellow solid (2.07 g, 5.10 mmol, yield: 47.6%) .

[0345] As for the remaining stages of obtaining compound CM-48, the synthesis given in example 11 can be used using the appropriate reagents.

[0346] ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.96 (s, 1H), 7.68 (d, J = 8.8 Hz, 1H), 7.59-7.49 (m , 2H), 7.41-7.33 (m, 2H), 7.24-7.19 (m, 2H), 7.13-7.07(m, 1H), 5.27 (s, 2H ), 5.14-5.07 (m, 1H), 4.38 (d, J = 17.6 Hz, 1H), 4.22 (d, J = 17.6 Hz, 1H), 3.57 (s, 2H), 3.30-3.27 (m, 4H), 2.96-2.85 (m, 1H), 2.60-2.52 (m, 5H), 2.49-2 .39 (m, 1H), 2.00-1.94 (m, 1H).

[0347] MC (ESI) mass/charge 620.2 [M+H] ⁺ .

[0348] Using the synthesis procedure for compound CM-48 and using appropriate reagents, compounds CM-47 and CM-49 were prepared.

[0349] ^1H NMR (400 MHz, DMSO- d6 ) δ 10.96 (s, 1H), _7.80 (d, J = 8.8 Hz, 1H), 7.59-7.34 (m , 5H), 7.24-7.20 (m, 1H), 5.27 (s, 2H), 5.13-5.08 (m, 1H), 4.36 (d, J = 17.2 Hz, 1H), 4.21 (d, J = 17.6 Hz, 1H), 3.57 (s, 2H), 3.32-3.27 (m, 4H), 2.95-2.86 (m, 1H), 2.59-2.54 (m, 5H), 2.50-2.38 (m, 1H), 1.99-1.96 (m, 1H).

[0350] MC (ESI) mass/charge 654.3 [M+H] ⁺ .

[0351] ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.97 (s, 1H), 7.59-7.34 (m, 5H), 7.25-7.19 (m, 2H) , 6.85-6.79 (m, 1H), 5.27 (s, 2H), 5.14-5.07 (m, 1H), 4.38 (d, J = 17.6 Hz, 1H ), 4.22 (d, J = 17.2 Hz, 1H), 3.99 (d, J = 1.2 Hz, 1H), 3.57 (s, 2H), 3.22-3.15 (m, 4H), 2.92-2.85 (m, 1H), 2.60-2.52 (m, 5H), 2.49-2.39 (m, 1H), 2.00-1 .94 (m, 1H).

[0352] MC (ESI) mass/charge 616.3 [M+H] ⁺ .

[0353] Example 28

[0354] Using the synthesis conditions for compound CM-12 given in Example 11 and using appropriate reagents, compound CM-46 was synthesized.

[0355] ¹ H NMR (400 MHz, DMSO) δ 10.97 (s, 1H), 7.51-7.30 (m, 7H), 6.55-6.53 (m, 2H), 5, 27 (s, 2H), 5.14-5.09 (m, 1H), 4.43 (d, J = 17.2 Hz, 1H), 4.27 (d, J = 17.6 Hz, 1H ), 4.16-4.11 (m, 2H), 3.59 (s, 2H), 3.33 (m, 4H), 2.96-2.87 (m, 1H), 2.61- 2.50 (m, 5H), 2.43-2.40 (m, 1H), 2.01-1.98 (m, 1H), 1.33 (t, J = 6.8 Hz, 3H) .

[0356] MC (ESI) mass/charge 612.3 [M+H] ⁺ .

[0357] Using the procedure for the synthesis of compound CM-46 given in Example 28 and using the appropriate reagents, CM-20, CM-21, CM-23, CM-26 and CM-45 were synthesized.

[0358] CM-20 connection

[0359] ^1H NMR (400 MHz, DMSO- d6 ) δ 10.97 (s, 1H), _7.61-7.44 (m, 3H), 7.35-7.31 (m, 4H) , 6.95-6.91 (m, 1H), 6.85-6.82 (m, 1H), 5.26 (s, 2H), 5.14-5.09 (m, 1H), 4 .45 (d, J = 17.6 Hz, 1H), 4.29 (d, J = 17.6 Hz, 1H), 3.59 (s, 2H), 3.38-3.32 (m, 4H), 2.91-2.87 (m, 1H), 2.60-2.55 (m, 1H), 2.49-2.40 (m, 5H), 2.01-1.98 ( m, 1H).

[0360] MC (ESI) mass/charge 586.2 [M+H] ⁺ .

[0361] Connection CM-21

[0362] ^1H NMR (400 MHz, DMSO- d6 ) δ 10.99 (s, 1H) _, 7.49-7.30 (m, 7H), 6.56-6.54 (m, 2H) , 5.26 (s, 2H), 5.14-5.10 (m, 1H), 4.47 (d, J = 17.2 Hz, 1H), 4.31 (d, J = 17.2 Hz, 1H), 3.86 (s, 2H), 3.35-3.33 (m, 4H), 2.96-2.87 (m, 1H), 2.60-2.50 (m, 5H), 2.50-2.40 (m, 1H), 2.01-1.97 (m, 1H).

[0363] MC (ESI) mass/charge 598.2 [M+H] ⁺ .

[0364] Connection CM-23

[0365] ^1H NMR (400 MHz, DMSO- d6 ) δ 10.98 (s, 1H) _, 7.86 (s, 1H), 7.67-7.58 (m, 2H), 7.52 -7.43 (m, 2H),7.36-7.27 (m, 5H), 7.06-6.99 (m, 1H), 5.26 (s, 2H), 5.15-5 .08(m, 1H), 4.45 (d, J = 17.6 Hz, 1H), 4.29 (d, J = 17.6 Hz, 1H), 3.60 (s, 2H), 3 .15-3.00 (m, 4H), 2.98-2.83 (m, 1H), 2.64-2.52 (m, 5H), 2.48-2.39 (m, 1H) , 2.04-1.93 (m, 1H).

[0366] MC (ESI) mass/charge 604.2 [M+H] ⁺ .

[0367] Connection CM-26

[0368] ^1H NMR (400 MHz, DMSO- d6 ) δ _10.97 (s, 1H), 7.51-7.44 (m, 2H), 7.35-7.31 (m, 4H) , 7.17-7.15 (m, 1H), 6.18-6.16 (m, 1H), 5.26 (s, 2H), 5.14-5.09 (m, 1H), 4 .45 (d, J = 17.6 Hz, 1H), 4.31-4.22 (m, 3H), 3.65 (s, 3H), 3.57 (s, 2H), 3.32- 3.30 (m, 4H), 2.96-2.87 (m, 1H), 2.67-2.56 (m, 1H), 2.51-2.49 (m, 5H), 2. 00-1.96 (m, 1H), 1.28 (t, J =6.8 Hz, 3H).

[0369] MC (ESI) mass/charge 618.2 [M+H] ⁺ .

[0370] CM-45 connection

[0371] ¹ H NMR (400 MHz, DMSO-d6) δ 10.97 (s, 1H), 7.76-7.72 (m, 1H), 7.59-7.43 (m, 3H), 7.36-7.30 (m, 4H), 6.79-6.69 (m, 2H), 5.26 (s, 2H), 5.15-5.07 (m, 1H), 4, 45 (d. J = 17.6 Hz, 1H), 4.29 (d, J = 17.2 Hz, 1H), 3.58 (s, 2H), 3.30-3.24 (m, 4H ), 2.93-2.87 (m, 1H), 2.74 (d, J = 4.4 Hz, 3H), 2.62-2.52 (m, 5H), 2.49-2, 41 (m, 1H), 2.02-1.97 (m, 1H).

[0372] MC (ESI) mass/charge 618.2 [M+H]+.

[0373] Examples of effectiveness

[0374] Experimental method for studying the inhibition of cell proliferation using the MTS assay:

[0375] Proliferating MM.1S myeloma cells (ATCC, cat. no. CRL-2974) were suspended in RPMI-640 medium (Gibco, cat. no. A10491-01) and counted using an automatic cell counter. The cell suspension was diluted to the required density and 100 μl (15,000 cells) of the cell suspension per well was seeded into a 96-well plate. The plate was cultured in an incubator at 37°C and 5% CO ₂ for 24 hours. On the day of administration, each compound was prepared as a 20 mM stock solution with DMSO (Sigma, cat. no. D2650), diluted with the medium to the required concentration, and then added to the appropriate wells for cell proliferation inhibition assay with the drug at a 4-fold serial dilution 10 once. The final DMSO concentration was 0.5%. After drug application, the 96-well plate was cultured in an incubator at 37°C and 5% CO ₂ for 72 hours. Then 20 µl of MTS (Promega, cat. no. G3581) was added to each well and the plate was cultured for 2 hours in an incubator at 37°C and 5% CO ₂ , and then the absorbance was recorded at 490 nm in each well using the Ensight instrument . Data read from cells on day 0 was used as a negative control, and data read on day 3 from cells with 0.5% DMSO was used as a positive control. The cell proliferation inhibition curve was plotted using GraphPad Prism 5 software and the IC50 value was calculated. The results of the experiment are shown in Table 1.

Control 1

Table 1. Results of suppression of MM.1S cell proliferation

Connections MM.1S IC ₅₀ (nM) Control 1 23.0691 SM-1 0.1025 SM-2 0.0139 SM-3 0.0064 SM-4 0.0153 SM-5 0.0063 SM-6 0.0409 SM-7 0.0054 SM-8 0.0211 SM-9 0.0136 SM-10 0.0105 SM-11 0.0091 SM-12 0.0067 SM-13 0.0271 SM-14 0.0148 SM-15 0.0062 SM-16 0.1886 SM-17 0.0139 SM-18 0.0188 SM-19 0.0338 SM-20 0.0132 SM-21 0.0111 SM-22 0.0136 SM-23 0.0581 SM-24 0.0388 SM-25 0.0291 SM-26 0.4648 SM-27 0.1339 SM-28 0.1020 SM-29 0.2006 SM-30 0.1092 SM-31 0.1657 SM-32 0.0706 SM-33 0.0781 SM-34 0.0766 SM-35 0.0962 SM-36 0.1479 SM-37 0.1193 SM-38 1.2090 SM-39 0.0631 SM-40 0.3778 SM-41 0.1158 SM-42 0.1143 SM-43 0.5762 SM-44 0.1265

[0376] Experimental method for studying the inhibition of cell proliferation using a CTG assay:

[0377] The proliferation inhibitory activity of the compounds in the MM.1S myeloma cell model was determined using the CellTiter-Glo (CTG) Luminescent Cell Viability Assay (Promega). MM.1S cells (ATCC, cat. no. CRL-2974) in exponential phase were resuspended in RPMI-1640 medium (Gibco, cat. no. 11875-093), 10% FBS, 1% penicillin/streptomycin, 2 mM Glutamax, and were counted using an automatic cell counter (ViCellXR). According to the optimized cell seeding density in the preliminary experiments, 40 μL of cell suspension with a density of 100,000 cells/mL was seeded into the corresponding wells of a 384-well plate (4000 cells/well), which allowed the cells in the control group to be in the linear growth phase during five-day experiment. The seeded 384-well plate was cultured in an incubator at 37°C and 5% CO ₂ for 24 hours. On the day of administration, each compound was prepared as a 10 mM stock solution with DMSO (Sigma, part no. 276855-1L) and the stock solution was further diluted using DMSO to obtain 20 μM and 20 nM working solutions. Treatment of MM.1S cells with the drug began at a concentration of up to 100 nM, and the drug was serially diluted fourfold, 10 times in triplicate. Nanoliter volumes of compound solutions were added to the corresponding wells of a 384-well plate according to the required concentration by non-contact spraying using an HPD300 automatic microdispenser (Tecan). The final concentration of DMSO (DMSO) was 0.5%. After drug application, the 384-well plate was cultured in an incubator at 37°C and 5% CO ₂ for 120 hours. After five days of drug treatment, 25 μl of CTG reagent (Promega, cat. no. G7573) was added to each well and the plate was shaken on a plate shaker for 10 minutes to ensure complete cell lysis, and then stood for 10 minutes at room temperature to The CTG has sufficiently reacted with the substrate to produce a stable luminescent signal. The signal is proportional to the amount of ATP in the cell lysate, i.e. number of metabolically active cells. Chemiluminescence of cells in the plate was recorded using an EnSpire device. Data read from cells on day 0 were used as a control for cells at the initial growth point, and data read on day 5 from cells with 0.5% DMSO were used as a control for cells in the growth stage. The cell proliferation inhibition curve was generated using XLFit software and the IC50 value was calculated. The results of the experiment are shown in Table 2.

Table 2. Results of suppression of MM.1S cell proliferation

Connections MM.1S IC ₅₀ (nM) Control 1 119.0859 SM-45 0.0938 SM-46 0.0687 SM-47 0.1351 SM-48 0.0365 SM-49 0.0606

Claims (47)

1. An isoindoline derivative represented by the general formula (I), a pharmaceutically acceptable salt or stereoisomer thereof: wherein each of R ₁ and R ₂ is independently selected from H and halogen, with the proviso that R ₁ and R ₂ are not both H; X represents O; each of X ₁ , X ₂ is independently selected from C or N; each of X ₃ , X ₄ and X ₅ represents C; each of R ₄ , R ₅ , R ₆ , R ₇ and R ₈ is independently absent or selected from H, halogen, unsubstituted (C ₁ -C ₁₂ )alkyl or substituted with 1-3 halogens, unsubstituted (C ₁ -C ₁₂ )alkoxy group or substituted with 1-3 substituents selected from D, halogen or (C ₃ -C ₆ )cycloalkyl, unsubstituted (C ₃ -C ₆ )cycloalkyl, -CH=CH ₂ , -C≡CH, -CN, -OH, - NO ₂ or where each of R ₉ and R ₁₀ is independently selected from H or unsubstituted (C ₁ -C ₁₂ )alkyl, provided that at least one of R ₄ , R ₅ , R ₆ , R ₇ and R ₈ is selected from -CN , -NO ₂ , -CH=CH ₂ , -C≡CH, (C ₁ -C ₁₂ )alkyl substituted with 1-3 halogens, (C ₁ -C ₁₂ )alkoxy group substituted with 1-3 halogens, or (C ₁ -C ₁₂ )alkoxy group , substituted with 1-3 D; the carbon atom marked * represents an asymmetric carbon atom and the asymmetric carbon atom refers to achiral carbon, carbon with (S) configuration, carbon with predominant (S) configuration, carbon with (R) configuration, carbon with predominant (R) configuration )-configuration or racemate. 2. An isoindoline derivative represented by the general formula (I), a pharmaceutically acceptable salt or stereoisomer thereof according to claim 1, wherein in the general formula (I) at least one of R ₁ and R ₂ is selected from F, Cl or Br. 3. An isoindoline derivative represented by the general formula (I), a pharmaceutically acceptable salt or stereoisomer thereof according to claim 1, wherein in the general formula (I) at least one of R ₁ and R ₂ represents F. 4. An isoindoline derivative represented by the general formula (I), its pharmaceutically acceptable salt or stereoisomer according to claim 1, where in the general formula (I) R ₄ is selected from -CN, -NO ₂ , (C ₁ -C ₁₂ )alkyl substituted with 1-3 halogens, (C ₁ -C ₁₂ )alkoxy group substituted with 1-3 halogens, or (C ₁ -C ₁₂ )alkoxy group substituted with 1-3 D; R ₅ , R ₆ , R ₇ and R ₈ are each independently selected from H or halogen; or in the general formula (I) R ₅ is selected from -CN, -NO ₂ , (C ₁ -C ₁₂ )alkyl substituted with 1-3 halogens, (C ₁ -C ₁₂ )alkoxy group substituted with 1-3 halogens, or (C ₁ -C ₁₂ )alkoxy group substituted with 1-3 D; R ₄ , R ₆ , R ₇ and R ₈ are each independently selected from H or halogen; or in the general formula (I) R ₆ is selected from -CN, -NO ₂ , (C ₁ -C ₁₂ )alkyl substituted with 1-3 halogens, (C ₁ -C ₁₂ )alkoxy group substituted with 1-3 halogens, or (C ₁ -C ₁₂ )alkoxy group substituted with 1-3 D; R ₄ , R ₅ , R ₇ and R ₈ are each independently selected from H or halogen; or in the general formula (I) R ₇ is selected from -CN, -NO ₂ , (C ₁ -C ₁₂ )alkyl substituted with 1-3 halogens, (C ₁ -C ₁₂ )alkoxy group substituted with 1-3 halogens, or (C ₁ -C ₁₂ )alkoxy group substituted with 1-3 D; R ₄ , R ₅ , R ₆ and R ₈ are each independently selected from H or halogen; or in the general formula (I) R ₈ is selected from -CN, -NO ₂ , (C ₁ -C ₁₂ )alkyl substituted with 1-3 halogens, (C ₁ -C ₁₂ )alkoxy group substituted with 1-3 halogens, or (C ₁ -C ₁₂ )alkoxy group substituted with 1-3 D; more preferably, R ₄ , R ₅ , R ₆ and R ₇ are each independently selected from H or halogen. 5. An isoindoline derivative represented by the general formula (I), its pharmaceutically acceptable salt or stereoisomer according to claim 1, where R ₁ is selected from F, Cl and Br, and R ₂ represents H; or R ₂ is selected from F, Cl and Br and R ₁ is H. 6. An isoindoline derivative represented by the general formula (I), its pharmaceutically acceptable salt or stereoisomer according to claim 1, where R ₁ represents F and R ₂ represents H; or R ₂ is F and R ₁ is H. 7. An isoindoline derivative represented by the general formula (I), its pharmaceutically acceptable salt or stereoisomer according to claim 1, where R ₄ is selected from H, F, Cl, Br, -CH ₃ , -CH ₂ CH ₃ , -CF ₃ , -OCH ₃ , -OCH ₂ CH ₃ , -CH=CH ₂ , -C≡CH, -OCF ₃ , -OCH ₂ F, -OCHF ₂ , -OCD ₃ , -CN, -NO ₂ , R ₅ is selected from H, F, Cl, Br, -CH ₃ , -CH ₂ CH ₃ , -CF ₃ , -OCH ₃ , -OCH ₂ CH ₃ , -CH=CH ₂ , -C≡CH, -OCF ₃ , -OCH ₂ F, -OCHF ₂ , -OCD ₃ , -CN, -NO ₂ , R ₆ is selected from H, F, Cl, Br, -CH ₃ , -CH ₂ CH ₃ , -CF ₃ , -OCH ₃ , -OCH ₂ CH ₃ , -CH=CH ₂ , -C≡CH, -OCF ₃ , -OCH ₂ F, -OCHF ₂ , -OCD ₃ , -CN, -NO ₂ , R ₇ is selected from H, F, Cl, Br, -CH ₃ , -CH ₂ CH ₃ , -CF ₃ , -OCH ₃ , -OCH ₂ CH ₃ , -CH=CH ₂ , -C≡CH, -OCF ₃ , -OCH ₂ F, -OCHF ₂ , -OCD ₃ , -CN, -NO ₂ , and R ₈ is selected from H, F, Cl, Br, -CH ₃ , -CH ₂ CH ₃ , -CF ₃ , -OCH ₃ , -OCH ₂ CH ₃ , -CH=CH ₂ , -C≡CH, -OCF ₃ , -OCH ₂ F, -OCHF ₂ , -OCD ₃ , -CN, -NO ₂ , 8. An isoindoline derivative represented by the general formula (I), its pharmaceutically acceptable salt or stereoisomer according to claim 1, where R ₄ is selected from H, F, CN, -OCH ₃ , -OCF ₃ or -OCD ₃ ; R ₅ is selected from H, F, -CN, -OCH ₃ , -OCF ₃ or -OCD ₃ ; R ₆ is selected from H, F, -CN, -OCH ₃ , -OCF ₃ or -OCD ₃ ; R ₇ is selected from H, F, -CN, -OCH ₃ , -OCF ₃ or -OCD ₃ ; and R ₈ is selected from H, F, -CN, -OCH ₃ , -OCF ₃ or -OCD ₃ . 9. An isoindoline derivative represented by the general formula (I), its pharmaceutically acceptable salt or stereoisomer according to claim 1, where R ₄ is selected from H or F; R ₅ is selected from H or F; R ₆ is selected from F or -CN; R ₇ is selected from H, F or -OCH ₃ ; and R ₈ is selected from F or H. 10. The isoindoline derivative represented by the general formula (I), its pharmaceutically acceptable salt or stereoisomer according to claim 1, where each X ₁ , X ₂ , X ₃ , X ₄ and X ₅ independently represents C. 11. An isoindoline derivative represented by the general formula (I), its pharmaceutically acceptable salt or stereoisomer according to any one of paragraphs. 1-10, where the halogen is F, Cl, Br or I. 12. An isoindoline derivative represented by the general formula (I), its pharmaceutically acceptable salt or stereoisomer according to any one of paragraphs. 1-10, where the compound of general formula (I) is any of the following compounds: 13. A method for producing an isoindoline derivative represented by the general formula (I), according to any one of paragraphs. 1-12, including the following stage: obtaining a compound of general formula (I) from compound A-01 by reaction , where X, X ₁ -X ₅ , *, R ₁ , R ₂ , R ₄ , R ₅ , R ₆ , R ₇ and R ₈ take the same values as described in any of paragraphs. 1-12, one of Ra and Rb is and the other - or and R ^a' and R ^b' independently represent H. 14. A pharmaceutical composition for the treatment of multiple myeloma, containing a therapeutically effective amount of an isoindoline derivative represented by the general formula (I), its pharmaceutically acceptable salt or stereoisomer according to any one of paragraphs. 1-12 and a pharmaceutically acceptable excipient. 15. The use of an isoindoline derivative represented by the general formula (I), its pharmaceutically acceptable salt or stereoisomer according to any one of paragraphs. 1-12 for the preparation of a medicament for the treatment of multiple myeloma.