Piperidine-2,6-dione derivatives that bind to cereblon, and methods for using the same.

Abstract

The present invention provides novel compounds that bind to cereblon, and methods of using the same. The compounds have formulas (I) and (II): [Formula 1] Represented by JPEG2023504445000246.jpg166144. R x is selected from (Ia), (Ib), (Ic) and (Id), and R y is selected from (IIa), (IIb), (IIc) and (IId).

Description

[Technical Field]

[0001] This invention relates to a CUL4-DDB1-RBX1-CRBN ubiquitin ligase complex (CRL4) that binds to the protein cereblon. CRBN This relates to a novel compound that modulates the substrate specificity of cereblon. CRBN It is a substrate recognition component. Chemical regulation of cereblon can induce the association of novel substrate proteins, followed by ubiquitination and degradation of the substrate proteins. The present invention also provides a bifunctional compound comprising a ligand that binds to cereblon E3 ubiquitin ligase and a moiety that binds to the target protein so that the target protein is positioned in close proximity to the ubiquitin ligase and induces the degradation of that protein. [Background technology]

[0002] Cerebron (CRBN) is a protein that associates with DDB1 (damaged DNA binding protein 1), CUL4 (Cullin-4), and RBX1 (RING-Box protein 1). These proteins together form a ubiquitin ligase complex, which belongs to the Cullin RING ligase (CRL) protein family, and CRL4 CRBN It is said that cereblon became of particular interest to the scientific community after it was confirmed to be a direct protein target of thalidomide, which mediates cereblon's biological activity. Thalidomide, a drug approved in the late 1990s for the treatment of multiple myeloma, binds to cereblon and CRL4 CRBN It regulates the substrate specificity of ubiquitin ligase complexes. This mechanism underlies the pleiotropic effects of thalidomide on both immune and cancer cells (see Lu G et al.: The Myeloma Drug Lenalidomide Promotes the Cereblon-Dependent Destruction of Ikaros Proteins. Science. 2014 Jan 17; 343(6168): 305-9).

[0003] The success of thalidomide in cancer treatment stimulated efforts to develop analogues with higher efficacy and fewer harmful side effects. As a result, various drug candidates were developed, including lenalidomide, pomalidomide, CC-220, CC-122, CC-885, and TD-106. These compounds are collectively known as cereblon modifiers (CMAs). For further information on these compounds, please refer to, for example, U.S. Patent No. 5635517, International Publication No. 2008039489, International Publication No. 2017197055, International Publication No. 2018237026, International Publication No. 2017197051, U.S. Patent No. 8518972, European Patent No. 2057143, International Publication No. 2019014100, International Publication No. 2004103274, and Kim SA et al.: A novel cereblon modulator for targeted protein degradation. Eur J Med Chem. 2019 Mar 15; 166: 65-74.

[0004] The clinical applicability of CMA has been demonstrated in numerous malignant hematological disorders, including multiple myeloma, myelodysplastic syndrome lymphoma, and leukemia (see Le Roy A et al.: Immunomodulatory Drugs Exert Anti-leukemia Effects in Acute Myeloid Leukemia by Direct and Immunostimulatory Activities. Front Immunol. 2018; 9: 977).

[0005] The antitumor activity of cereblon modulator is 1) Inhibition of cancer cell proliferation and induction of apoptosis, 2) Disintegration of trophic support from the tumor stroma, 3) Stimulation of immune cells leads to T cell proliferation, cytokine production, and activation of NK (natural killer) cells. It is mediated by (see Le Roy A et al.: Immunomodulatory Drugs Exert Anti-Leukemia Effects in Acute Myeloid Leukemia by Direct and Immunostimulatory Activities. Front Immunol. 2018; 9: 977).

[0006] Chemically modified thalidomide derivatives are CRL4 CRBN It has been shown that the substrate specificity of ubiquitin ligases can be significantly altered. Therefore, CMA-binding CRL4 CRBN To achieve desirable substrate specificity in ubiquitin ligase conjugates (see Sievers QL et al.: Defining the human C2H2zinc finger degrome targeted by thalidomide analogues through CRBN. Science. 2018 Nov 2; 362(6414)) and attain a desirable safety profile, it is desirable to develop cereblon modulators. Thus, there is a constant need to provide novel cereblon-binding compounds with pharmaceutically important properties.

[0007] Alternatively, chemically modified thalidomide derivatives can link with target protein-binding ligands to form bifunctional compounds. Such compounds, when added to cells or administered to animals or humans, can be recruited to cereblon and subsequently ubiquitinated, thereby inducing proteasome-mediated degradation of selected proteins. This concept was first described in Sakamoto KM et al.: Chimeric molecules that target proteins to the Skp1-Cullin-F box complex for ubiquitination and degradation. Proc Natl Acad Sci US A. 2001 Jul 17;98(15):8554-9, and more recently reviewed in Burslem GM and Crews CM: Proteolysis-Targeting Chimeras as Therapeutics and Tools for Biological Discovery. Cell. 2020 Apr 2;181(1):102-114.

[0008] Thalidomide derivatives applied in the design of cereblon-mobilizing bifunctional compounds such as pomalidomide and lenalidomide induce the degradation of various neosubstrates such as IKZF1, IKZF3, SALL4, and / or CK1α. Therefore, treatment with bifunctional compounds constructed from these known CMAs may result in not only the degradation of the selected target protein but also further protein degradation induced by the CRBN ligand itself, potentially leading to a variety of side effects. Side effects caused by lenalidomide activity include neutropenia, thrombocytopenia, and hemorrhagic disorders (see Sun X et al. PROTACs: great opportunities for academia and industry. Signal Transduct Target Ther. 2019 Dec 24;4:64 and Stahl M, Zeidan AM: Lenalidomide Use in Myelodysplastic Syndromes: Insights Into the Biologic Mechanisms and Clinical Applications Cancer. 2017 May 15;123(10):1703-1713). [Prior art documents] [Patent Documents]

[0009] [Patent Document 1] U.S. Patent No. 5635517 [Patent Document 2] International Publication No. 2008039489 [Patent Document 3] International Publication No. 2017197055 Brochure [Patent Document 4] International Publication No. 2018237026 Brochure [Patent Document 5] International Publication No. 2017197051 brochure [Patent Document 6] U.S. Patent No. 8518972 [Patent Document 7] European Patent No. 2057143 [License 8] International Publication No. 2019014100 パンフレット [License 9] International Publication No. 2004103274 パンフレット [Non-licensed literature]

[0010] [Non-licensed Document 1] Lu G et al.: The Myeloma Drug lenalidomide Promotes the Cereblon-Dependent Destruction of Ikaros Proteins. Science. 2014 Jan 17; 343(6168): 305-9 [Non-licensed Document 2] Kim SA et al.: A novel cereblon modulator for targeted protein degradation. Eur J Med Chem. 2019 Mar 15; 166: 65-74 [Non-licensed Document 3] Le Roy A et al.: Immunomodulatory Drugs Exert Anti-leukemia Effects in Acute Myeloid Leukemia by Direct and Immunostimulatory Activities. Front Immunol. 2018; 9: 977 [Non-licensed Document 4] Sievers QL et al.: Defining the human C2H2 zinc finger degrome targeted by thalidomide analogues through CRBN. Science. 2018 Nov 2; 362(6414) [Non-licensed Document 5] Sakamoto KM et al.: Chimeric molecules that target proteins to the Skp1-Cullin-F box complex for ubiquitination and degradation. Proc Natl Acad Sci US A. 2001 Jul 17;98(15):8554-9 [Non-Patent Document 6] Burslem GM and Crews CM: Proteolysis-Targeting Chimeras as Therapeutics and Tools for Biological Discovery. Cell. 2020 Apr 2;181(1):102-114 [Non-Patent Document 7] Sun X et al. PROTACs: great opportunities for academia and industry. Signal Transduct Target Ther. 2019 Dec 24;4:64 [Non-Patent Document 8] Stahl M, Zeidan AM: Lenalidomide Use in Myelodysplastic Syndromes: Insights Into the Biologic Mechanisms and Clinical ApplicationsCancer. 2017 May 15;123(10):1703-1713 [Overview of the Initiative] [Means for solving the problem]

[0011] According to a first aspect of the present invention, formula (I): [ka] A compound is provided, in which, Each of X1 and X2 is independently either O or S; T is either C=O or SO2; R 1 is hydrogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, aryl, heteroaryl, or benzyl; n is 0, 1 or 2; L is hydrogen, alkenyl, aryl, heteroaryl, benzyl, haloalkyl, haloalkenyl, -C(O)H, -C(O)R'', -C(O)OH, -C(O)OR'', -CH2C(O)OR'', -C(O)NH2, -C(O)NHR'', -C(O)NR''2, -OH, -OR'', -NH2, -NHR'', -NR''2, -S(O)2H or -S(O)2R''; R x is

Chemical formula

[0012] In some embodiments, the compound of formula (I) has the following structure.

[0013] [ka]

[0014] In other embodiments, the compound of formula (I) has the following structure.

[0015] [ka]

[0016] In some embodiments of the compound of formula (I), T is C=O. In other embodiments, T is SO2.

[0017] In some embodiments of the compound of formula (I), Z is NR 4 In some embodiments of the compound of formula (I), Z is NH. In other embodiments, Z is O. In other embodiments, Z is S.

[0018] In some embodiments of the compound of formula (I), V is CR2. In other embodiments, V is NR 4 In other embodiments, V is S.

[0019] In some embodiments of the compound of formula (I), Y1 is N and Y2 is CR. In other embodiments, Y2 is N and Y1 is CR.

[0020] In some embodiments of the compound of formula (I), both Y1 and Y2 are N. In other embodiments, both Y1 and Y2 are CR.

[0021] In some embodiments of the compound of formula (I), L is hydrogen, alkenyl, aryl, heteroaryl, benzyl, haloalkyl, haloalkenyl, -OH, -OR'', -CH2C(O)OR'', -NH2, -NHR'', -NR''2, -S(O)2H, or -S(O)2R''. In other embodiments of the compound of formula (I), L is hydrogen, alkenyl, aryl, heteroaryl, benzyl, haloalkyl, haloalkenyl, -C(O)R'', -C(O)OR'', -CH2C(O)OR'', -C(O)NH2, -C(O)NHR'', or -C(O)NR''2. In some embodiments of the compound of formula (I), L is hydrogen, alkenyl, aryl, heteroaryl, benzyl, haloalkyl, haloalkenyl, -OH, -OR'', -CH2C(O)OR'', -NH2, -NHR'', -NR''2, -S(O)2H, or -S(O)2R''. In some embodiments of the compound of formula (I), L is hydrogen, alkenyl, aryl, heteroaryl, benzyl, haloalkyl, or haloalkenyl. In other embodiments of the compound of formula (I), L is -OH, -OR'', -CH2C(O)OR'', -NH2, -NHR'', -NR''2, -S(O)2H, or -S(O)2R''. In some embodiments of the compound of formula (I), L is hydrogen, alkenyl, aryl, heteroaryl, or benzyl. In some embodiments of the compound of formula (I), L is hydrogen, alkenyl, or aryl. In some embodiments of the compound of formula (I), L is hydrogen or an alkenyl. In some embodiments of the compound of formula (I), L is hydrogen, -CH2C(O)OR'' or -OR''. In some embodiments of the compound of formula (I), L is hydrogen.

[0022] In some embodiments of the compound of formula (I), R x The following can be selected.

[0023] [ka]

[0024] In some embodiments of the compound of formula (I), R x The following can be selected.

[0025] [ka]

[0026] In some embodiments of the compound of formula (I), R x The following can be selected.

[0027] [ka]

[0028] In some embodiments of the compound of formula (I), R x The following applies:

[0029] [ka]

[0030] In some embodiments of the compound of formula (I), R x The following can be selected.

[0031] [ka]

[0032] In some embodiments of the compound of formula (I), R x The following can be selected.

[0033] [ka]

[0034] In some embodiments of the compound of formula (I), R x The following can be selected.

[0035] [ka]

[0036] In some embodiments of the compound of formula (I), R x The following applies:

[0037] [ka]

[0038] In some embodiments of the compound of formula (I), R x The following can be selected.

[0039] [ka]

[0040] In some embodiments of the compound of formula (I), R x The following applies:

[0041] [ka]

[0042] In some such embodiments, one of W1, W2, and W3 is N, and the remaining two W1, W2, and W3 are CR, respectively. 2 In some embodiments, W1 is N, and W2 and W3 are CR, respectively. 2 In other embodiments, W2 is N, and W1 and W3 are CR, respectively. 2 In other embodiments, W3 is N, and W1 and W2 are CR, respectively. 2 That is the case.

[0043] In other such embodiments, two of W1, W2, and W3 are N, and the remaining one of W1, W2, and W3 is CR. 2 In some embodiments, W1 and W2 are N, and W3 is CR. 2In other embodiments, W1 and W3 are N, and W2 is CR. 2 In other embodiments, W2 and W3 are N, and W1 is CR. 2 That is the case.

[0044] In other embodiments, each of W1, W2, and W3 is N.

[0045] In other embodiments, each of W1, W2, and W3 is CR 2 That is the case.

[0046] In some such embodiments, each R 2 is hydrogen; Y1 is N; and Y2 is CH. In some such embodiments, the compound of formula (I) has the following structure:

[0047] [ka]

[0048] In other such embodiments, each R 2 is hydrogen; Y1 and Y2 are each CH.

[0049] In some embodiments of the compound of formula (I), R x The following applies:

[0050] [ka]

[0051] In some such embodiments, one of W1, W2, and W4 is N, and the remaining two of W1, W2, and W3 are CR, respectively. 2 In some embodiments, W1 is N, and W2 and W4 are CR, respectively. 2 In other embodiments, W2 is N, and W1 and W4 are CR, respectively. 2 In other embodiments, W4 is N, and W1 and W2 are CR, respectively. 2 That is the case.

[0052] In other such embodiments, two of W1, W2, and W4 are N, and the remaining one of W1, W2, and W3 is CR. 2 In some embodiments, W1 and W2 are N, and W4 is CR. 2 In other embodiments, W1 and W4 are N, and W2 is CR. 2 In other embodiments, W2 and W4 are N, and W1 is CR. 2 That is the case.

[0053] In other such embodiments, each of W1, W2, and W4 is N.

[0054] In other such embodiments, each of W1, W2, and W4 is CR 2 That is the case.

[0055] In some embodiments of the compound of formula (I), R x The following applies:

[0056] [ka]

[0057] In some such embodiments, R x The following applies:

[0058] [ka]

[0059] In other such embodiments, R x The following applies:

[0060] [ka]

[0061] In other such embodiments, R x The following applies:

[0062] [ka]

[0063] In other such embodiments, R x The following applies:

[0064] [ka]

[0065] In some embodiments of the compound of formula (I), R x The following applies:

[0066] [ka]

[0067] In some such embodiments, R x The following applies:

[0068] [ka]

[0069] In other such embodiments, R x The following applies:

[0070] [ka]

[0071] In other such embodiments, R x The following applies:

[0072] [ka]

[0073] In other such embodiments, Rx The following applies:

[0074] [ka]

[0075] In some embodiments, R 4 is hydrogen, halogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, aryl, heteroaryl, benzyl, haloalkyl, haloalkenyl, -OH, -OR'', -NH2, -NHR'', -NR''2, -S(O)2H or -S(O)2R''. In other embodiments, R 4 is hydrogen, halogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, aryl, heteroaryl, benzyl, haloalkyl, haloalkenyl, -C(O)H, C(O)R'', -C(O)OH, -C(O)OR'', -C(O)NH2, -C(O)NHR'', or -C(O)NR''2. ​​In some embodiments, R 4 R is hydrogen, halogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, aryl, heteroaryl, or benzyl. In other embodiments, R 4 is -OH, -OR'', -NH2, -NHR'', -NR''2, -S(O)2H, or -S(O)2R''. In some embodiments, R 4 R is hydrogen, alkyl, alkenyl, or aryl. In some embodiments, R 4 is hydrogen, alkyl, or alkenyl. In some embodiments, R 4 is hydrogen or alkyl. In some embodiments, R 4 It is hydrogen.

[0076] In some embodiments, V is CH2. In some embodiments, each R 2 is hydrogen, and Z is NH.

[0077] In some such embodiments, the compound has the following structure:

[0078] [ka]

[0079] In some embodiments of the compound of formula (I), each R 2 These are independently hydrogen, halogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, aryl, aryl substituted with at least one -OR'', benzyl, haloalkyl, haloalkenyl, -NH2, -NHR'', -NR''2, -CH2NH2, -NHC(O)R'', -NR''C(O)R'', NHC(O)CH(OH)R'', -NR''C(O)CH(OH)R'', -NHC(O)OR'', -NR''C(O)O R'', -NHSO2R'', -NR''SO2R'', -NO2, -CN, -OH, -OR'', -OC(O)H, -OC(O)R'', -OC(O)OH, -OC(O)OR'', -OC(O)NH2, -OC(O)NHR '', -OC(O)NR''2, -SH, -SR'', -S(O)2H, -S(O)2R'', -S(O)2OH, -S(O)2OR'', -S(O)2NH2, -S(O)2NHR'', or -S(O)2NR''2.

[0080] In some embodiments of the compound of formula (I), each R 2 These are independently hydrogen, halogen, alkyl, -NH2, -NHR'', -NHC(O)R'', -NHSO2R'', -CN, -OH, -OR'', -S(O)2NH2, -S(O)2NHR'', or -S(O)2NR''2.

[0081] In some embodiments of the compound of formula (I), each R 2 These are independently hydrogen, halogen, aryl, aryl substituted with at least one -OR'', -NH2, -CH2NH2, -NHC(O)R'', -NO2, or -OR''.

[0082] In some embodiments of the compound of formula (I), each R 2These are independently hydrogen, halogen, alkyl, heteroaryl, -NH2, -NHR'', -NHC(O)R'', -NHSO2R'', -CN, -C(O)NH2, -C(O)NHR'', -C(O)NR''2, -OH, -OR'', -S(O)2NH2, -S(O)2NHR'', or -S(O)2NR''2.

[0083] In some embodiments of the compound of formula (I), each R 2 It is hydrogen.

[0084] In some embodiments of the compound of formula (I), n=2 and C=X1 is replaced by CH, R x The following applies:

[0085] [ka]

[0086] In some embodiments of the compound of formula (I), each R is independently hydrogen, halogen, alkyl, haloalkyl, condensed aryl-cycloalkyl, condensed aryl-heterocycloalkyl, heteroaryl, heteroaryl substituted with at least one aryl group, -NH2, -NHR'', -NHC(O)R'', -NHSO2R'', -CN, -C(O)NH2, -C(O)NHR'', -C(O)NR''2, -OH, -OR'', -S(O)2NH2, -S(O)2NHR'', or -S(O)2NR''2; or, if Y1 and Y2 are CR, each R together with the carbon atom to which it is bonded forms a 5- or 6-membered ring.

[0087] In some embodiments of the compound of formula (I), each R is independently hydrogen, halogen, alkyl, haloalkyl, fused aryl-cycloalkyl, fused aryl-heterocycloalkyl, heteroaryl, heteroaryl substituted with at least one aryl group, -NH2 or -CN; or when Y1 and Y2 are CR, each R together with the carbon atom to which it is attached forms a 5- or 6-membered ring. In some embodiments, each R is hydrogen.

[0088] In some embodiments of the compound of formula (I), R 1 is hydrogen or alkyl. In some embodiments, R 1 is hydrogen or methyl. In some embodiments, R 1 is hydrogen.

[0089] In some embodiments of the compound of formula (I), R 4 is hydrogen or alkyl. In some embodiments, R 4 is hydrogen or methyl; and in further some embodiments, R 4 may be hydrogen.

[0090] According to a second aspect of the present invention, a compound of formula (II) is provided:

[0091]

Chemical formula

[0092] wherein each of X1 and X2 is independently O or S; T is C=O or SO2; R 1 is hydrogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, aryl, heteroaryl, or benzyl; n is 0, 1 or 2; L is hydrogen, alkyl, alkenyl, aryl, heteroaryl, benzyl, haloalkyl, haloalkenyl, -C(O)H, -C(O)R'', -C(O)OH, -C(O)OR'', -C(O)NH2, -C(O)NHR'', -C(O)NR''2, -OH, -OR'', -NH2, -NHR'', -NR''2, -S(O)2H or -S(O)2R''; R y is

Chem.

[0093] In some embodiments, the compound of formula (II) has the following structure.

[0094] [Chemical formula]

[0095] In other embodiments, the compound of formula (II) has the following structure.

[0096] [Chemical formula]

[0097] In some embodiments of the compound of formula (II), T is C=O. In other embodiments, T is SO2.

[0098] In some embodiments of the compound of formula (II). Z is NR 3 In other embodiments, Z is O. In other embodiments, Z is S.

[0099] In some embodiments of the compound of formula (II), Y1 is N and Y2 is CR. In other embodiments, Y2 is N and Y1 is CR.

[0100] In some embodiments of the compound of formula (II), both Y1 and Y2 are N.

[0101] In some embodiments of the compound of formula (II), both Y1 and Y2 are CR.

[0102] In some embodiments of the compound of formula (II), L is hydrogen, alkyl, alkenyl, aryl, heteroaryl, benzyl, haloalkyl, haloalkenyl, -OH, -OR'', -NH2, -NHR'', -NR''2, -S(O)2H or -S(O)2R''. In other embodiments of the compound of formula (II), L is hydrogen, alkyl, alkenyl, aryl, heteroaryl, benzyl, haloalkyl, haloalkenyl, -C(O)R'', -C(O)OR'', -C(O)NH2, -C(O)NHR'', or -C(O)NR''2. In some embodiments of the compound of formula (II), L is hydrogen, alkyl, alkenyl, aryl, heteroaryl, benzyl, haloalkyl, haloalkenyl, -OH, -OR'', -NH2, -NHR'', -NR''2, -S(O)2H or -S(O)2R''. In some embodiments of the compound of formula (II), L is hydrogen, alkyl, alkenyl, aryl, heteroaryl, or benzyl. In some embodiments of the compound of formula (II), L is hydrogen, alkyl, alkenyl, or aryl. In some embodiments of the compound of formula (II), L is hydrogen, alkyl, or alkenyl. In some embodiments of the compound of formula (II), L is hydrogen or alkyl. In some embodiments of the compound of formula (II), L is hydrogen.

[0103] In some embodiments of the compound of formula (II), R y is as follows.

[0104]

Chem.

[0105] In other embodiments of the compound of formula (II), R y is as follows.

[0106]

Chem.

[0107] In other embodiments of the compound of formula (II), R y is as follows.

[0108]

Chem.

[0109] In some embodiments of the compound of formula (II), R y is as follows.

[0110]

Chem.

[0111] In some embodiments of the compound of formula (II), R y is as follows.

[0112]

Chem.

[0113] In some embodiments of the compound of formula (II), R y is as follows.

[0114]

Chem.

[0115] In some embodiments of the compound of formula (II), R y The following applies:

[0116] [ka]

[0117] In some embodiments of the compound of formula (II), R y The following applies:

[0118] [ka]

[0119] In some embodiments of the compound of formula (II), each R 2 R is independently hydrogen, halogen, alkyl, heteroaryl, -NH2, -NHR'', -NHC(O)R'', -NHSO2R'', -CN, -C(O)NH2, -C(O)NHR'', -C(O)NR''2, -OH, -OR'', -S(O)2NH2, -S(O)2NHR'', or -S(O)2NR''2. ​​In some such embodiments, each R 2 It is hydrogen.

[0120] In some embodiments of the compound of formula (II), each R is independently hydrogen, halogen, alkyl, heteroaryl, -NH2, -NHR'', -NHC(O)R'', -NHSO2R'', -CN, -C(O)NH2, -C(O)NHR'', -C(O)NR''2, -OH, -OR'', -S(O)2NH2, -S(O)2NHR'', or -S(O)2NR''2. ​​In some such embodiments, each R is hydrogen.

[0121] In some embodiments of the compound of formula (II), each R 3 R is independently hydrogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, aryl, heteroaryl, benzyl, haloalkyl, haloalkenyl, or C(O)R''. In some such embodiments, each R3 It is hydrogen.

[0122] In some embodiments of the compound of formula (II), R 1 It is hydrogen.

[0123] In some embodiments of the compound of formula (II), X1 and X2 are O. In other embodiments, X1 is O and X2 is S. In other embodiments, X1 is S and X2 is O. In other embodiments, X1 and X2 are S.

[0124] In some embodiments of the compound of formula (II), n is 0. In other embodiments, n is 1 or 2. In some embodiments, n is 1. In other embodiments, n is 2.

[0125] According to a third aspect of the present invention, a pharmaceutical composition comprising a compound according to any of the above aspects of the present invention is provided.

[0126] The present invention also provides compounds according to any of the above embodiments of the present invention for use as cereblon binders.

[0127] The present invention also provides compounds or compositions according to any of the above embodiments of the present invention for use in the field of medicine.

[0128] The present invention also provides compounds or compositions according to any of the above embodiments of the present invention for use in immuno-oncology.

[0129] The present invention also addresses cancer, autoimmune diseases, macular degeneration (MD) and related disorders. The present invention also provides compounds or compositions according to any of the above embodiments for use in the treatment of diseases and disorders involving undesirable angiogenesis, skin diseases, lung disorders, asbestos-related disorders, parasitic diseases and disorders, immunodeficiency disorders, atherosclerosis and related conditions, abnormal hemoglobin disorders and related disorders, or TNFα-related disorders.

[0130] The present invention also provides methods for the treatment of cancer, autoimmune diseases, macular degeneration (MD) and related disorders, diseases and disorders involving undesirable angiogenesis, skin diseases, lung disorders, asbestos-related disorders, parasitic diseases and disorders, immunodeficiency disorders, atherosclerosis and related conditions, abnormal hemoglobin disorders and related disorders, or TNFα-related disorders; the method comprises the step of administering an effective amount of a compound or composition according to any of the above embodiments of the present invention to a patient in need.

[0131] In some embodiments of the above method, the method further includes the step of administering at least one additional active agent to the patient. In some embodiments, the at least one additional active agent is an anticancer agent or an agent for the treatment of an autoimmune disease. In some embodiments, the at least one additional active agent is a small molecule, a peptide, an antibody, a corticosteroid, or a combination thereof. In some embodiments, the at least one additional active agent is at least one of bortezomib, dexamethasone, and rituximab.

[0132] The present invention also provides combination formulations of any one compound of the first to fourth embodiments of the present invention and at least one additional active agent, which can be used simultaneously, separately, or sequentially for therapeutic purposes.

[0133] In some embodiments of the above combination, at least one additional active agent is an anticancer agent or an agent for the treatment of autoimmune diseases. In some embodiments, at least one additional active agent is a small molecule, a peptide, an antibody, a corticosteroid, or a combination thereof. In some embodiments, at least one additional active agent is at least one of bortezomib, dexamethasone, and rituximab. In some embodiments, the treatment is for cancer, autoimmune diseases, macular degeneration (MD) and related disorders, diseases and disorders with undesirable angiogenesis, skin diseases, lung disorders, asbestos-related disorders, parasitic diseases and disorders, immunodeficiency disorders, atherosclerosis and related conditions, abnormal hemoglobin disorders and related disorders, or TNFα-related disorders.

[0134] The present invention also has the following structure: CLM-L-PTM We also provide difunctional compounds having the same, or pharmaceutically acceptable salts, enantiomers, stereoisomers, solvates, polymorphs, or prodrugs thereof. CLM is the ubiquitin ligase binding site of cereblon E3; PTM is the protein target region; L is selected from the bonds and the chemical bonds that covalently bond CLM and PTM; CLM is a compound according to any one of claims 1 to 101, and R, R 2 , R 3 and R 4 At least one of these contains a group that can be covalently bonded to L or PTM, or is modified to contain such a group.

[0135] In some embodiments, L is: [ka] Selected from, Single merged image with the filename JPEG0007852923000053.jpg88 This indicates binding to PTM, Single merged image with the filename JPEG0007852923000054.jpg88 This indicates a connection to the CLM; p is an integer between 3 and 12; and s is an integer between 1 and 6.

[0136] In some embodiments, L is [ka] In some embodiments, p is an integer between 4 and 11, 5 and 10, 6 and 9, or 7 and 8.

[0137] In some embodiments, L is [ka] In some embodiments, s is an integer between 2 and 5, or between 3 and 4.

[0138] In some embodiments, L is as follows:

[0139] [ka]

[0140] In other embodiments, L is a bond.

[0141] In some embodiments, the PTM targets BRD4. In some embodiments, the PTM [ka] And, Single merged image with the filename JPEG0007852923000059.jpg79 This indicates a bond to L.

[0142] In some embodiments, R, R 2 , R 3 and R 4 At least one of them has been modified to include a carboxylic acid group or an ester group.

[0143] In some embodiments, the bifunctional compound is selected from the following:

[0144] [ka] JPEG0007852923000061.jpg57120

[0145] As used herein, the term "alkyl" is intended to include both unsubstituted alkyl groups and alkyl groups substituted with one or more additional groups, such as -OH, -OR'', -NH2, -NHR'', -NR''2, -SO2R'', -C(O)R'', -CN, or -NO2. In some embodiments, the alkyl group is an unsubstituted alkyl group. In some embodiments, the alkyl group is C1-C 12 Alkyl, C1-C 10 It is an alkyl, C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl group.

[0146] As used herein, the term "alkenyl" is intended to include both unsubstituted alkenyl groups and alkenyl groups substituted with one or more additional groups, such as -OH, -OR'', -NH2, -NHR'', -NR''2, -SO2R'', -C(O)R'', -CN, or -NO2. In some embodiments, the alkenyl group is an unsubstituted alkenyl group. In some embodiments, the alkenyl group is C2-C 12 Alkenyl, C2-C 10 It is an alkenyl, C2-C8 alkenyl, C2-C6 alkenyl, or C2-C4 alkenyl group.

[0147] As used herein, the term "alkynyl" is intended to include both unsubstituted alkynyl groups and alkynyl groups substituted with one or more additional groups, such as -OH, -OR'', halogen, -NH2, -NHR'', -NR''2, -SO2R'', -C(O)R'', -CN, or -NO2. In some embodiments, the alkynyl group is an unsubstituted alkynyl group. In some embodiments, the alkynyl group is C2-C 12 Alkinyl, C2-C 10 These are alkynyl, C2-C8 alkynyl, C2-C6 alkynyl, or C2-C4 alkynyl groups.

[0148] As used herein, the term "aryl" is intended to include both unsubstituted aryl groups and aryl groups substituted with one or more additional groups, such as -OH, -OR'', halogens, -NH2, -NHR'', -NR''2, -SO2R'', -C(O)R'', -CN, or -NO2. In some embodiments, the aryl group is an unsubstituted aryl group. In some embodiments, the aryl group is C6-C 10 It is an aryl, C6-C8 aryl, or C6 aryl.

[0149] As used herein, the term "heteroaryl" is intended to include both unsubstituted heteroaryl groups and heteroaryl groups substituted with one or more additional groups, such as -OH, -OR'', halogen, -NH2, -NHR'', -NR''2, -SO2R'', -C(O)R'', -CN, or -NO2. In some embodiments, the heteroaryl group is an unsubstituted heteroaryl group. In some embodiments, the heteroaryl group is C6-C 10 These are heteroaryl compounds, C6-C9 heteroaryl compounds, C6-C8 heteroaryl compounds, or C6 heteroaryl compounds.

[0150] As used herein, the term "benzyl" is intended to include both an unsubstituted benzyl group and a benzyl group substituted with one or more additional groups, such as -OH, -OR'', halogen, -NH2, -NHR'', -NR''2, -SO2R'', -C(O)R'', -CN, or -NO2. In some embodiments, the benzyl group is an unsubstituted benzyl group. [Brief explanation of the drawing]

[0151] [Figure 1] This figure shows assays demonstrating the effects of various compounds of the present invention and various reference compounds on SALL4 degradation in Kelly cell lines. [Figure 2]This figure shows assays demonstrating the effects of various compounds of the present invention and various reference compounds on CK1α degradation in Kelly cell lines. [Figure 3] This figure shows assays demonstrating the effects of various compounds of the present invention and various reference compounds on IKZF1 degradation in the H929 cell line. [Figure 4] This figure shows assays demonstrating the effects of various compounds of the present invention and various reference compounds on IKZF1 degradation in the H929 cell line. [Figure 5] This figure shows assays demonstrating the effects of various compounds of the present invention and various reference compounds on IKZF3 degradation in the H929 cell line. [Figure 6] This figure shows assays demonstrating the effects of various compounds of the present invention and various reference compounds on IKZF3 degradation in the H929 cell line. [Figure 7] This figure shows assays demonstrating the effects of various compounds of the present invention and various reference compounds on BRD4 degradation in the H929 cell line. [Figure 8] This figure shows the effect of the compound of the present invention on the formation of a ternary complex composed of BRD4-compound-CRBN / DDB1. [Figure 9] This figure shows the effect of the compound of the present invention on the formation of a ternary complex composed of IKZF1-compound-CRBN / DDB1. [Figure 10] This figure illustrates a schematic example of the general principle of targeted protein degradation in treatments using bifunctional compounds. [Modes for carrying out the invention]

[0152] As described above, the present invention provides compounds of the following formulas (I) and (II):

[0153] [ka] In the formula, R x The following can be selected: [ka]

[0154] [ka] In the formula, R y The following can be selected: [ka] In the formula, L, X1, X2, Y1, Y2, Y3, W1, W2, W3, W4, R 1 , R 2 T, U, V, and Z are as defined above.

[0155] The binding of the above compound to cereblon is via CRL4. CRBN The specificity of the complex can be altered, inducing the association of novel substrate proteins, which can then lead to ubiquitination and degradation of those substrate proteins. Examples of such proteins, but not limited to, include IKZF1 and IKZF3.

[0156] The above compound modulates cereblon in a unique way, and CRL4 CRBN The ubiquitin ligase complex may recognize substrates different from those it recognizes in other cases, allowing it to target them for degradation. As a result, the compounds of the present invention are expected to expand / modify the growth inhibitory activity of CRBN, and thus broaden the range of cancer types that are highly sensitive to CMA treatment.

[0157] The compounds of the present invention are advantageous in that they are easy to synthesize. The synthesis of the compounds can be summarized as follows:

[0158] [ka]

[0159] Examples of compounds from the present invention are shown below:

[0160] [Table 1] JPEG0007852923000068.jpg222170JPEG0007852923000069.jpg235170JPEG0007852923000070.jpg235170 JPEG0007852923000071.jpg235170JPEG0007852923000072.jpg235170JPEG0007852923000073.jpg204170

[0161] As described in the Examples section, the inventors found that the above compound exhibits cereblon-binding ability similar to that of the known CMA CC-122. Despite the drug activity of known CMAs such as CC-122, patients often develop tolerance to these compounds. The use of novel compounds such as the compounds of the present invention described above may help overcome this clinical limitation.

[0162] One of the significant drawbacks of currently available CMAs is their safety profile. For example, the teratogenicity of CMAs depends on the extent to which they induce degradation of the SALL4 transcription factor. Known CMAs have shown that CRL4 degradation occurs only in the presence of CMA. CRBN It induces the degradation of several proteins (including SALL4) that bind to ligases. The SALL4 degradation observed in CMA treatment is (at least partially) responsible for the teratogenicity of CMA. Compounds with reduced ability to induce SALL4 degradation may exhibit an improved safety profile.

[0163] The compounds of the present invention may also possess pharmaceutically advantageous properties such as increased stability and improved ADMET (absorption, distribution, metabolism, excretion, and / or toxicity) properties.

[0164] The compounds of the present invention may be useful in treating a variety of diseases and disorders, including, but are not limited to, the following: 1) Cancer. The compounds provided herein can be used to treat, prevent or control primary or metastatic tumors. Specific examples of cancer include, but are not limited to, cancers of the skin, e.g., melanoma; lymph nodes; chest; cervix; uterus; gastrointestinal tract; lung; ovaries; prostate; colon; rectum; oral cavity; brain; head and neck; throat; testicles; kidneys; pancreas; bone; spleen; liver; bladder; larynx; nasal cavity; and AIDS-related cancers as well as malignant hematological disorders. a) Malignant hematological disorders include leukemia, lymphoma, multiple myeloma, or smoldering myeloma. Leukemia includes: acute leukemia, acute lymphoblastic leukemia (ALL), chronic lymphocytic leukemia (CLL), acute myeloid leukemia, acute myeloid leukemia (AML), adult acute basophilic leukemia, adult acute eosinophilic leukemia, adult acute megakaryoblastic leukemia, adult acute minimally differentiated myeloid leukemia, adult acute monoblastic leukemia, adult acute monocytic leukemia, adult acute myeloid leukemia with maturation, adult acute myeloid leukemia without maturation, adult acute myeloid leukemia with abnormalities The following can be selected: hematological leukemia, adult acute myelomonocytic leukemia, adult erythroleukemia, adult pure erythroleukemia, secondary acute myelomonocytic leukemia, untreated adult acute myelomonocytic leukemia, adult acute myelomonocytic leukemia in remission, adult acute promyelocytic leukemia with PML-RARA, alkylating agent-associated acute myelomonocytic leukemia, prolymphocytic leukemia, and chronic myelomonocytic leukemia, refractory hairy cell leukemia, T-cell large granular lymphocyte leukemia, and relapsed or refractory chronic lymphocytic leukemia. Lymphomas include: adult grade III lymphomatous granulomatosis, adult nasal extranodular NK / T-cell lymphoma, anaplastic large cell lymphoma, angioimmunoblastic T-cell lymphoma, cutaneous B-cell non-Hodgkin lymphoma, extranodular marginal zone lymphoma of mucosa-associated lymphoid tissue, hepatosplenic T-cell lymphoma, intraocular lymphoma, lymphoma involvement in non-cutaneous extranodular sites, mature T-cell and K-cell non-Hodgkin lymphoma, nodular marginal zone lymphoma, and post-transplant lymphoproliferative disorders. Relapsed adult Burkitt lymphoma, relapsed adult diffuse large cell lymphoma, relapsed adult diffuse mixed cell lymphoma, relapsed adult diffuse small-cell lymphoma, relapsed adult grade III lymphomatoid granulomatosis, relapsed adult immunoblastic lymphoma, relapsed adult lymphoblastic lymphoma, relapsed adult T-cell leukemia / lymphoma, relapsed cutaneous T-cell non-Hodgkin lymphoma, relapsed grade 1 follicular lymphoma, relapsed grade Grade 2 follicular lymphoma, relapsed grade 3 follicular lymphoma, relapsed mantle cell lymphoma, relapsed marginal zone lymphoma, relapsed mycosis fungoides and Sézary syndrome, relapsed small lymphocytic lymphoma, Richter syndrome, intestinal lymphoma, splenic marginal zone lymphoma, testicular lymphoma, Valdenström macroglobulinemia, adult T-cell leukemia-lymphoma, peripheral T-cell lymphoma, B-cell lymphoma, Hodgkin's disease, cutaneous T-cell lymphoma The following conditions can be selected from the group consisting of lymphoma, diffuse large B-cell lymphoma, MALT lymphoma, mantle cell lymphoma, non-Hodgkin lymphoma, central nervous system lymphoma, refractory primary cutaneous large B-cell lymphoma (lower extremity type), refractory anemia, refractory anemia with excessive blasts, refractory anemia with ring sideroblasts, refractory cytopenia with polycytic dysplasia, secondary myelodysplastic syndrome, myelodysplastic syndrome, and myeloproliferative disorders. 2) Autoimmune diseases, e.g.: acute disseminated encephalomyelitis, acute motor axonal neuropathy, Addison's disease, painful steatosis, adult-onset Still's disease, alopecia areata, ankylosing spondylitis, anti-glomerular basement membrane nephritis, anti-neutrophil cytoplasmic antibody-associated vasculitis, anti-N-methyl-D-aspartate receptor encephalitis, antiphospholipid syndrome, anti-synthetic enzyme syndrome, aplastic anemia, autoimmune angioedema, autoimmune encephalitis, autoimmune bowel disease, autoimmune hemolytic anemia, autoimmune hepatitis, autoimmune inner ear disease, autoimmune lymphoproliferative syndrome, autoimmune neutropenia, autoimmune oophoritis, autoimmune orchitis, autoimmune Epidemic pancreatitis, autoimmune polyendocrine syndrome, autoimmune polyendocrine syndrome type 2, autoimmune polyendocrine syndrome type 3, autoimmune progesterone dermatitis, autoimmune retinopathy, autoimmune thrombocytopenic purpura, autoimmune thyroiditis, autoimmune urticaria, autoimmune uveitis, Baro concentric sclerosis, Behçet's disease, Vickerstaff's encephalitis, bullous pemphigoid, celiac disease, chronic fatigue syndrome, chronic inflammatory demyelinating polyneuropathy, Churg-Strauss syndrome, scarring pemphigoid, Cogan's syndrome, cold agglutinin disease, complex regional pain syndrome, CREST syndrome, Crohn's disease Herpetiform dermatitis, dermatomyositis, type 1 diabetes, lupus discoid, endometriosis, enthesitis, enthesitis-associated arthritis, eosinophilic esophagitis, eosinophilic fasciitis, acquired epidermolysis bullosa, erythema nodosum, essential mixed cryoglobulinemia, Evans syndrome, Felty syndrome, fibromyalgia, gastritis, herpes zoster of pregnancy, giant cell arteritis, Goodpasture syndrome, Graves' disease, Graves' ophthalmopathy, Guillain-Barré syndrome, Hashimoto's encephalopathy, Hashimoto's thyroiditis, Henoch-Schönlein purpura, sweat gland abscess, idiopathic inflammatory demyelinating disease, IgG4-related systemic disease, inclusion body myositis, inflammatory bowel disease (I BD), intermediate uveitis, interstitial cystitis, juvenile arthritis, Kawasaki disease, Lambert-Eaton myasthenic syndrome, leukocytoclastic vasculitis, lichen planus, lichen sclerosing, woody conjunctivitis, linear IgA disease, lupus nephritis, lupus vasculitis, Lyme disease (chronic), Meniere's disease, microscopic colitis, microscopic polyangiitis, mixed connective tissue disease, Mohren's ulcer, focal scleroderma, acute pityriasis lichenoides, multiple sclerosis, myasthenia gravis, myocarditis, myositis, neuromyelitis optica, neuromyotonia, opsoclonus-myoclonus syndrome, optic neuritis, Ord's thyroiditis, relapsing rheumatoid arthritis,Paraneoplastic cerebellar degeneration, Parry-Romberg syndrome, Personage-Turner syndrome, Streptococcal-associated childhood autoimmune neuropsychiatric disorders, pemphigus vulgaris, pernicious anemia, acute pityriasis lichenoides, POEMS syndrome, polyarteritis nodosa, polymyalgia rheumatica, polymyositis, post-myocardial infarction syndrome, post-pericardiotomy syndrome, primary biliary cirrhosis, primary immunodeficiency, primary sclerosing cholangitis, progressive inflammatory neuropathy, psoriasis, psoriatic arthritis, pure red cell aplasia, pyoderma gangrenosum, Raynaud's phenomenon, reactive arthritis, Relapsing polychondritis, restless legs syndrome, retroperitoneal fibrosis, rheumatic fever, rheumatoid arthritis, rheumatic vasculitis, sarcoidosis, Schnitzler syndrome, scleroderma, Sjögren's syndrome, generalized rigidity syndrome, subacute bacterial endocarditis, Suzak syndrome, Sydenham's chorea, sympathetic ophthalmitis, systemic lupus erythematosus, systemic sclerosis, thrombocytopenia, Trosa Hunt syndrome, transverse myelitis, ulcerative colitis, undifferentiated connective tissue disease, urticaria, urticarial vasculitis, vasculitis, and vitiligo; 3) Diseases and disorders that involve or are characterized by undesirable angiogenesis, such as inflammatory diseases, autoimmune diseases, pain, viral diseases, genetic diseases, allergic diseases, bacterial diseases, neovascularization of the eye, choroidal neovascularization, retinal neovascularization, and rubeosis (neovascularization of the horn). Specific examples of diseases and disorders that involve or are characterized by undesirable angiogenesis include, but are not limited to, arthritis, endometriosis, Crohn's disease, heart failure, progressive heart failure, renal dysfunction, endotoxemia, toxic shock syndrome, osteoarthritis, retroviral replication, debilitation, meningitis, silica-induced fibrosis, asbestos-induced fibrosis, veterinary disorders, paraneoplastic hypercalcemia, stroke, circulatory shock, periodontitis, gingivitis, macrocytic anemia, refractory anemia, and 5q-deletion syndrome, nociceptive pain, neuropathic pain, mixed nociceptive and neuropathic pain, visceral pain, migraine, headache, and postoperative pain. Examples of nociceptive pain include, but are not limited to, pain associated with chemical or thermal burns, skin wounds, skin contusions, osteoarthritis, rheumatoid arthritis, tendinitis, and myofascial pain. Examples of neuropathic pain include, but are not limited to, CRPSI type II, reflex sympathetic dystrophy (RSD), reflex neurovascular dystrophy, reflex dystrophy, sympathetic-maintained pain syndrome, burning pain, Sudek's atrophy of bone, argon nerve dystrophy, shoulder-hand syndrome, post-traumatic dystrophy, trigeminal neuralgia, postherpetic neuralgia, cancer pain, phantom limb pain, fibromyalgia, chronic fatigue syndrome, spinal cord injury pain, central post-stroke pain, radiculopathy, diabetic neuropathy, post-stroke pain, syphilitic neuropathy, and other painful neurological conditions such as those induced by drugs like vincristine and velcade; 4) Macular degeneration ("MD") and related syndromes, e.g.: nutritious (dry) MD, exudative (wet) MD, age-related macular degeneration (ARM), choroidal neovascularization (CNVM), retinal pigment epithelial detachment (PED), and retinal pigment epithelium (RPE) atrophy; 5) Skin diseases, e.g.: keratosis and related symptoms, skin diseases or disorders characterized by abnormal proliferation of the epithelium, acne, and wrinkles. Examples of skin diseases or disorders characterized by abnormal epithelial proliferation include, but are not limited to, any condition, disease, or disorder characterized by the presence of abnormal epithelial proliferation, such as, but are not limited to, infections associated with papillomavirus, arsenic keratosis, Laser-Treller sign, keratoma verruciformis (WD), trichosporine crustyloidia (TS), erythema keratoderma variant (EKV), harlekin fetus (harlekin's ichthyosis), knuckle pads, cutaneous melanocytic santhoma, porokeratosis, psoriasis, squamous cell carcinoma, confluent reticular papilloma (CRP), acrochordon, cutaneous horn, Cowden's disease (multiple hamartoma syndrome), ameliorative dermatosis (DPN), epidermal nevus syndrome (ENS), ichthyosis vulgaris, molluscum contagiosum, prurigo nodosa, and acanthosis nigricans (AN); 6) Lung disorders, such as pulmonary hypertension and related disorders. Examples of pulmonary hypertension and related disorders include, but are not limited to: primary pulmonary hypertension (PPH); secondary pulmonary hypertension (SPH); familial PPH; sporadic PPH; precapillary pulmonary hypertension; pulmonary arterial hypertension (PAH); pulmonary arterial hypertension; idiopathic pulmonary hypertension; thrombotic pulmonary arteropathy (TPA); multifactorial pulmonary arteropathy; functional class I-IV pulmonary hypertension; and left ventricular dysfunction, mitral valve disease, constrictive endocarditis, aortic stenosis, cardiomyopathy, mediastinal fibrosis, anomalous pulmonary venous return, pulmonary venous obstructive disease, collagen disease There is pulmonary hypertension associated with, related to, or secondary to, vascular disease, congenital heart disease, HIV virus infection, drugs and toxins such as fenfluramine, congenital heart disease, elevated pulmonary venous pressure, chronic obstructive pulmonary disease, interstitial lung disease, sleep-disordered breathing, impaired alveolar hypoventilation, chronic exposure to high altitude, neonatal lung disease, alveolar capillary dysplasia, sickle cell disease, other coagulation disorders, chronic thromboembolism, connective tissue disease, systemic and cutaneous lupus including lupus, schistosomiasis, sarcoidosis, or pulmonary capillary angiomatosis; 7) Asbestos-related disorders, e.g.: mesothelioma, asbestosis, malignant pleural effusion, benign exudative effusion, pleural plaques, pleural calcification, diffuse pleural thickening, round atelectasis, fibrous masses, and lung cancer; 8) Human intracellular parasites, for example, but not limited to, Plasmodium falcifarium, Plasmodium ovale, Plasmodium vivax, Plasmodium malariae, L. donovari, L. infanium, L. aethiopica, L. major, L. tropica, L. Mexicana, L. braziliensis, T. Gondii, B. microti, B. divergens, B. coli, C. parvum, C. kaietanensis (C. Parasitic diseases and disorders caused by *E. cayetanensis*, *E. histolytica*, *I. belli*, *S. monsonii*, *S. haemolobium*, species of the genus *Trypanosoma*, species of the genus *Toxoplasma*, and *O. volvulus*. This also includes other diseases and disorders caused by non-human intracellular parasites, such as, but not limited to, Babesia bovis, Babesia canis, Banesia Gibsoni, Besnoitia darlingi, Cytauxzoon felis, species of the genera Eimeria, Hammondia, and Theileria.Specific examples, though not limited to them, include malaria, babesiosis, trypanosomiasis, leishmaniasis, toxoplasmosis, meningoencephalitis, keratitis, amoebiasis, lambluvencorticoplasia, cryptosporidiosis, isosporiasis, cyclosporiasis, microsporidiasis, ascariasis, whipworm disease, duodenal worm disease, stercorticoplasia, toxocariasis, trichinellosis, lymphangiofilariasis, onchocerciasis, filariasis, schistosomiasis, and dermatitis caused by zoonotic schistosomiasis. 9) Immunodeficiency disorders, including but not limited to adenosine deaminase deficiency, normal or elevated Ig antibody deficiency, ataxia telangiectasia, lymphocytic syndrome, unclassifiable immunodeficiency, Ig deficiency with high IgM, Ig heavy chain deletion, IgA deficiency, immunodeficiency with thymoma, reticular dysplasia, Nezorov syndrome, selective IgG subclass deficiency, transient infantile hypogammaglobulinemia, Wiscott-Aldrich syndrome, X-linked agammaglobulinemia, and X-linked severe combined immunodeficiency; 10) Atherosclerosis and related conditions, e.g.: any form of condition associated with atherosclerosis, including restenosis after vascular interventions such as angioplasty, stent implantation, atherectomy and grafting; 11) Abnormal hemoglobin disorders and related disorders, such as sickle cell anemia, and any other disorders related to the differentiation of CD34+ cells; 12) TNFα-related disorders, e.g.: endotoxemia or toxic shock syndrome; cachexia; adult respiratory distress syndrome; bone resorption disorders, e.g., arthritis; hypercalcemia; graft-versus-host reaction; cerebral malaria; inflammation; tumor growth; chronic inflammatory pneumonia; reperfusion injury; myocardial infarction; stroke; circulatory shock; rheumatoid arthritis; Crohn's disease; HIV infection and AIDS; other disorders, e.g., rheumatoid arthritis, rheumatoid spondylitis, osteoarthritis, psoriatic arthritis and other arthritis conditions, septic shock, sepsis, endotoxin shock, graft-versus-host disease, debilitation, Crohn's disease, ulcerative colitis , multiple sclerosis, systemic lupus erythematosus, ENL in leprosy, HIV, AIDS, and opportunistic infections in AIDS; disorders, e.g., septic shock, sepsis, endotoxin shock, hemodynamic shock and septic syndrome, post-ischemic reperfusion injury, malaria, mycobacterial infection, meningitis, psoriasis, congestive heart failure, fibrosis, cachexia, graft rejection, neoplastic or malignant conditions, asthma, autoimmune diseases, radiation injury, and hyperxic alveolar injury; viral infections, e.g., those caused by herpesviruses; viral conjunctivitis; or atopic dermatitis.

[0165] The compounds of the present invention may also be useful in preventing, treating, or reducing the risk of graft-versus-host disease (GVHD) or graft rejection.

[0166] The compounds of the present invention may also inhibit the production of certain cytokines, including, but are not limited to, TNF-α, IL-1β, IL-12, IL-18, GM-CSF, IL-10, TGF-β, and / or IL-6. These compounds may stimulate the production of certain cytokines and, as a result of functioning as a co-stimulatory signal for T cell activation, may cause increased production of cytokines such as, but are not limited to, IL-12, IL-2, IL-10, TGF-β, and / or IFN-γ. In addition, the compounds provided herein may enhance the effects and antibody-mediated cytotoxicity (ADCC) of NK cells. Furthermore, the compounds provided herein may be immunomodulatory and / or cytotoxic and therefore may be useful as chemotherapeutic agents. [Examples]

[0167] [ka]

[0168] Synthesis condition A A suitable acid (R in reaction scheme 1 above) z COOH (1 equivalent), DMAP (0.04 equivalents), and EDC (1.2 equivalents) were added to a solution of 3-aminopiperidine-2,6-dione (1 equivalent) and N-hydroxybenzotriazole (1.2 equivalents) in DMF (0.5M). The reaction mixture was stirred overnight at room temperature (20-25°C). After removing the solvent under reduced pressure, the crude product was purified by preparative HPLC, flash column chromatography, or preparative TLC.

[0169] Synthesis condition B Add DIPEA (2-3 equivalents) to a suitable acid in DMF (0.1-0.5M) (R in reaction scheme 1 above). z The reaction mixture was added to a solution of COOH, DMAP (0-0.1 equivalents), HATU (1.0-1.5 equivalents), and 3-aminopiperidine-2,6-dione hydrochloride (1.2-3.0 equivalents). The reaction mixture was stirred overnight at room temperature (20-25°C). After removing the solvent under reduced pressure, the crude product was purified by preparative HPLC, flash column chromatography, or preparative TLC.

[0170] Synthesis condition C Add CDI (1.2-2 equivalents) to a suitable acid in DMF (0.1-0.5 M) (R in reaction scheme 1 above). z The mixture was added to a COOH solution and stirred at 50°C for 1 hour. After cooling to room temperature, 1.2 to 1.5 equivalents of 3-aminopiperidine-2,6-dione hydrochloride were added, and the reaction mixture was stirred overnight at room temperature (20 to 25°C). After removing the solvent under reduced pressure, the crude product was purified by preparative HPLC, flash column chromatography, or preparative TLC. [Examples]

[0171] Synthesis of N-(2,6-dioxopiperidine-3-yl)-2-oxoindoline-7-carboxamide (1)

[0172] [ka]

[0173] The compound was synthesized using the general procedure shown in Reaction Scheme 1 and Synthesis Condition A, as described above (32% yield), and with 2-oxoindoline-7-carboxylic acid (20 mg) as a starting material. 1 H NMR:(500MHz,DMSO)δ10.91(s,1H), 9.82(s,1H), 8.83(d,J=8.1Hz,1H)7.72~7.64(m,1H), 7.42~7.36(m,1H), 7.09~7. 02(m,1H), 4.86~4.75(m,1H), 3.55(s,2H), 2.88~2.74(m,1H), 2.62~2.53(m,1H), 2.22~2.08(m,1H), 2.04~1.97(m,1H) LCMS(m / z[M+H] + ):287.8 [Examples]

[0174] Synthesis of N-(2,6-dioxopiperidine-3-yl)-1H-1,3-benzodiazole-7-carboxamide (2) To a solution of 3-aminopiperidine-2,6-dione (0.96 g, 7.5 mmol) and N-hydroxybenzotriazole (1.22 g, 9.0 mmol) in DMF (15 mL), 1H-benzo[d]imidazole-7-carboxylic acid (8.25 g, 1.3 mmol), DMAP (37 mg, 0.30 mmol), and EDC (1.40 g, 9.0 mmol) were added. The reaction mixture was stirred overnight at room temperature. Water (30 mL) was added, and the resulting solution was extracted with dichloromethane (3 × 20 mL). The combined organic layers were washed with water, dried over Na₂SO₄, and concentrated under reduced pressure. The crude product was purified by preparative HPLC to obtain the target compound (0.41 g, 20% yield). 1 H NMR: (400MHz,DMSO-d6)δ10.49(s,1H), 9.67~9.52(m,1H), 9.45~9.28(m,1H), 8.12(d,J=7.4Hz,1H)8.01(d,J=8.1Hz,1H), 7.64 (t,J=8.0Hz,1H), 4.90~4.78(m,1H), 3.85(brs,1H), 2.92~2.77(m,1H), 2.65~2.54(m,1H), 2.36~2.16(m,1H), 2.15~2.02(m,1H) LCMS(m / z[M+H] + ):273.1 [Examples]

[0175] Synthesis of N-(2,6-dioxopiperidine-3-yl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-4-carboxamide (3)

[0176] [ka]

[0177] The compound was synthesized using the general procedure shown in Reaction Scheme 1 and Synthesis Condition B, the above (14% yield), and 2-oxo-2,3-dihydro-1H-benzo[d]imidazole-4-carboxylic acid (20 mg) as a starting material. 1H NMR(500MHz,DMSO)δ10.89(s,1H), 10.83(s,1H), 10.19(s,1H), 8.74(d,J=7.9 Hz,1H), 7.44(dd,J=8.1,1.0Hz,1H), 7.09(dd,J=7.6,0.9Hz,1H), 7.02(t,J=7. 8Hz,1H), 4.84~4.74(m,1H), 2.82(ddd,J=18.8,13.4,5.5Hz,1H), 2.60~2.54( m,1H), 2.16(qd,J=13.0,4.5Hz,1H), 2.00(dddd,J=10.9,8.2,5.4,2.9Hz,1H). LCMS(m / z[M+H] + ):288.7 [Examples]

[0178] Synthesis of N-(2,6-dioxopiperidine-3-yl)-1-methyl-1H-benzo[d]imidazole-4-carboxamide(4)

[0179] [ka]

[0180] The compound was synthesized using the general procedure shown in Reaction Scheme 1 and Synthesis Condition B, the above (25% yield), and 1-methyl-1H-benzo[d]imidazole-4-carboxylic acid (20 mg) as a starting material. 1 H NMR(500MHz,DMSO)δ10.93(s,1H), 10.19(d,J=7.3Hz,1H), 8.47(s,1H), 7.94(dd ,J=7.5,1.0Hz,1H), 7.85(dd,J=8.1,1.0Hz,1H), 7.44(t,J=7.8Hz,1H), 4.91(ddd ,J=12.6,7.2,5.3Hz,1H), 3.94(s,3H), 2.83(ddd,J=17.6,13.5,5.5Hz,1H), 2.6 1~2.53(m,1H), 2.26(dtd,J=12.8,5.4,2.4Hz,1H), 2.11(qd,J=12.9,4.5Hz,1H). LCMS(m / z[M+H] + ):286.4 [Examples]

[0181] Synthesis of N-(2,6-dioxopiperidine-3-yl)-1-methyl-1H-benzo[d]imidazole-7-carboxamide (5)

[0182] [ka]

[0183] The compound was synthesized using the general procedure shown in Reaction Scheme 1 and Synthesis Condition B, as described above (4% yield), and with 1-methyl-1H-benzo[d]imidazole-7-carboxylic acid (20 mg) as a starting material. 1 H NMR(500MHz,DMSO)δ10.87(s,1H), 8.94(d,J=8.4Hz,1H), 8.29(s,1H), 7.84~7.71( m,1H), 7.37(dt,J=7.4,3.7Hz,1H), 7.28(dd,J=8.0,7.5Hz,1H), 4.80(ddd,J=12.5, 8.4,5.5Hz,1H), 3.87(s,3H), 2.83(ddd,J=17.4,13.1,5.7Hz,1H), 2.56(ddd,J=9. 9,5.2,2.5Hz,1H), 2.15(qd,J=12.9,4.5Hz,1H), 2.07(tdd,J=8.5,5.6,2.8Hz,1H). LCMS(m / z[M+H] + ):286.7 [Examples]

[0184] Synthesis of N-(2,6-dioxopiperidine-3-yl)-5-hexaneamide-1-methyl-1H-benzo[d]imidazole-7-carboxamide(6)

[0185] [ka]

[0186] Step A: 5-amino-1-methyl-1H-benzo[d]imidazole-7-carboxylic acid dihydrochloride (20 mg, 0.076 mmol) and hexanoyl chloride (1.1 equivalents) were dissolved in 4 mL of dry DCM and cooled in a water / ice bath. TEA (4 equivalents) was slowly added to the reaction mixture. The ice bath was removed and the reaction mixture was allowed to warm to ambient temperature. The reaction was completed in 2 hours and monitored by LC-MS. The solution was diluted with DCM (10 mL) and washed with 7 mL of 3% aqueous HCl. Off-white crystals were obtained by evaporating the aqueous phase, and 5-hexaneamide-1-methyl-1H-benzo[d]imidazole-7-carboxylic acid was used directly in the next step.

[0187] Step B: This compound was synthesized using the general procedure shown in Reaction Scheme 1 and Synthesis Conditions B, as described above (29% yield), and 5-hexaneamido-1-methyl-1H-benzo[d]imidazole-7-carboxylic acid (20 mg) as a starting material. 1 H NMR(500MHz,DMSO)δ10.87(s,1H), 10.00(s,1H), 8.97(t,J=14.9Hz,1H), 8.21(s,1H), 8.16(d ,J=1.9Hz,1H), 7.51(d,J=1.9Hz,1H), 4.79(ddd,J=12.6,8.4,5.4Hz,1H), 3.82(s,3H), 2.82(d dd,J=17.4,13.1,5.6Hz,1H), 2.57(dt,J=16.6,3.2Hz,1H), 2.31(t,J=7.4Hz,2H), 2.20~2.09 (m,1H), 2.09~2.01(m,1H), 1.67~1.56(m,2H), 1.37~1.25(m,4H), 0.87(dt,J=7.1,5.0Hz,3H). LCMS(m / z[M+H] + ):400.2 [Examples]

[0188] Synthesis of N-(2,6-dioxopiperidine-3-yl)-5-fluoro-1H-benzo[d]imidazole-4-carboxamide (7)

[0189] [ka]

[0190] The compound was synthesized using the general procedure shown in Reaction Scheme 1 and Synthesis Condition C, as described above (35% yield), and with 5-fluoro-1H-benzo[d]imidazole-4-carboxylic acid (20 mg) as a starting material. 1 H NMR(500MHz,DMSO)δ12.66(s,1H), 10.90(s,1H), 8.30(s,1H), 7.79(s,1H), 7.17(dd,J=11.9,8. 8Hz,1H), 4.84(dd,J=17.6,7.8Hz,1H), 2.90~2.74(m,1H), 2.59~2.53(m,1H), 2.25~2.07(m,2H). LCMS(m / z[M+H] + ):291.3 [Examples]

[0191] Synthesis of N-(2,6-dioxopiperidine-3-yl)-6-fluoro-1H-benzo[d]imidazole-4-carboxamide (8)

[0192] [ka]

[0193] The compound was synthesized using the general procedure shown in Reaction Scheme 1 and Synthesis Condition B, the above (43% yield), and 6-fluoro-1H-benzo[d]imidazole-4-carboxylic acid (19.5 mg) as a starting material. 1H NMR(500MHz,DMSO)δ13.09(s,1H), 10.94(s,1H), 10.25(d,J=7.2Hz,1H), 8.51(s,1H), 7.64(s,1H), 7.62(d,J=2.8Hz,1H), 4.91(dt,J= 12.4,6.1Hz,1H), 2.83(ddd,J=17.6,13.5,5.5Hz,1H), 2.55(t,J=12.4Hz,1H), 2.31~2.19(m,1H), 2.11(ddd,J=15.3,12.0,5.3Hz,1H). LCMS(m / z[M+H] + ):290.9 [Examples]

[0194] Synthesis of N-(2,6-dioxopiperidine-3-yl)-3H-imidazo[4,5-b]pyridine-7-carboxamide (9)

[0195] [ka]

[0196] The compound was synthesized using the general procedure shown in reaction scheme 1 and synthesis conditions C, as described above (76% yield), and with 3H-imidazo[4,5-b]pyridine-7-carboxylic acid (20 mg) as a starting material. 1H NMR(500MHz,DMSO)δδ13.68(s,0.8H), 12.84(s,0.2H), 10.98(s,0.8H), 10.94(s,0.2H), 9.93(d,J=7.3Hz,0.8 H), 9.27(d,J=8.2Hz,0.2H), 8.72(s,0.8H), 8.56(d,J=5.1Hz,0.2HH), 8.54(d,J=5.0Hz,0.8H), 8.47(s,0.2H), 7.78(d,J=5.0Hz,0.8H), 7.71(d,J=5.0Hz,0.2H), 4.95(ddd,J=12.6,7.1,5.4Hz,0.8H), 4.89~4.80(m,0.2H), 2 .84(ddd,J=17.6,13.6,5.5Hz,1H), 2.62~2.55(m,1H), 2.32~2.23(m,1H), 2.14(ddd,J=26.3,13.0,4.6Hz,1H). LCMS(m / z[M+H] + ):274.1 [Examples]

[0197] Synthesis of N-(2,6-dioxopiperidine-3-yl)-3H-imidazo[4,5-c]pyridine-7-carboxamide (10)

[0198] [ka]

[0199] The compound was synthesized using the general procedure shown in Reaction Scheme 1 and Synthesis Condition C, the above (57% yield), and 3H-imidazo[4,5-c]pyridine-7-carboxylic acid (20 mg) as a starting material. 1H NMR(500MHz,DMSO,353K)δ12.90(s,1H), 10.51(s,1H), 9.38(s,1H), 8.97(s,1H), 8.80(s,1H), 8.41(s,1H), 4.83~4.73( m,1H), 2.73(ddd,J=18.5,13.0,5.6Hz,1H), 2.58~2.50(m,1H), 2.23~2.13(m,1H), 2.07(ddd,J=25.6,12.8,4.6Hz,1H). LCMS(m / z[M+H] + ):274.1 [Examples]

[0200] Synthesis of N-(2,6-dioxopiperidine-3-yl)-1H-imidazo[4,5-c]pyridine-4-carboxamide (11)

[0201] [ka]

[0202] The compound was synthesized using the general procedure shown in reaction scheme 1 and synthesis conditions C, as described above (75% yield), and with 1H-imidazo[4,5-c]pyridine-4-carboxylic acid (20 mg) as a starting material. 1 H NMR(500MHz,DMSO)δ12.93(s,1H), 10.80(s,1H), 9.14(d,J=6.2Hz,1H), 8.38(s,1H), 8.31(d,J=5.4Hz,1H), 7.83(d,J=5.0Hz) ,1H), 4.81~4.67(m,1H), 2.79~2.67(m,1H), 2.47(dd,J=17.3,2.4Hz,1H), 2.21(dd,J=22.4,12.1Hz,1H), 2.04~1.92(m,1H). LCMS(m / z[M+H] + ):273.9 [Examples]

[0203] Synthesis of 2-chloro-N-(2,6-dioxopiperidine-3-yl)-1H-benzo[d]imidazole-4-carboxamide (12)

[0204] [ka]

[0205] The compound was synthesized using the general procedure shown in Reaction Scheme 1 and Synthesis Condition B, as described above (13% yield), and 2-chloro-1H-benzo[d]imidazole-4-carboxylic acid (15 mg) as a starting material. 1 H NMR(500MHz,DMSO)δ13.85(s,1H), 10.92(s,2H), 9.66(s,2H), 7.86(s,2H), 7.70(d,J=6.9Hz ,3H), 7.36(t,J=7.5Hz,3H), 4.86(s,3H), 2.89~2.76(m,3H), 2.61~2.53(m,4H), 2.16(s,6H). LCMS(m / z[M+H] + ):307.0 [Examples]

[0206] Synthesis of N-(2,5-dioxopyrrolidine-3-yl)-2-methyl-1H-benzo[d]imidazole-4-carboxamide (14)

[0207] [ka]

[0208] The compound was synthesized using the general procedure shown in Reaction Scheme 1 and Synthesis Condition C, as described above (70% yield), with 2-methyl-1H-benzo[d]imidazole-4-carboxylic acid (36 mg) and 3-aminopyrrolidine-2,5-dione hydrochloride (20.5 mg) as starting materials. 1H NMR(500MHz,DMSO,353K)δ11.73(s,2H), 10.03(s,1H), 7.77(d,J=7.6Hz,1H), 7.65(d,J=7.8Hz,1H), 7.25(t ,J=7.8Hz,1H), 4.83~4.74(m,1H), 3.03(dd,J=17.5,9.2Hz,1H), 2.77(dd,J=17.5,5.7Hz,1H), 2.60(s,3H). LCMS(m / z[M+H] + ):272.85 [Examples]

[0209] Synthesis of N-(2,6-dioxopiperidine-3-yl)-2-methyl-1H-benzo[d]imidazole-4-carboxamide (15)

[0210] [ka]

[0211] The compound was synthesized using the general procedure shown in Reaction Scheme 1 and Synthesis Condition B, the above (20% yield), and 2-methyl-1H-benzo[d]imidazole-4-carboxylic acid (20 mg) as a starting material. 1 H NMR(500MHz,DMSO)δ12.73(s,1H), 10.90(s,1H), 10.29(d,J=7.3Hz,1H), 7.82(d,J=7.0Hz,1H), 7.63(s,1H), 7.32~7.23(m,1H), 4.87(ddd,J=12.6,7.1,5.4Hz,1H), 2.89~2.76(m,1H), 2.58(s,3H), 2.55(d,J=3.7Hz,1H), 2.28~2.19(m,1H), 2.18~2.07(m,1H). LCMS(m / z[M+H] + ):286.5 [Examples]

[0212] Synthesis of methyl 2-(3-(2-methyl-1H-benzo[d]imidazole-4-carboxamide)-2,6-dioxopiperidine-1-yl)acetate (17)

[0213] [ka]

[0214] The compound was synthesized using the general procedure shown in Reaction Scheme 1 and Synthesis Condition B, as described above (31% yield), with 2-methyl-1H-benzo[d]imidazole-4-carboxylic acid (40 mg) and methyl 2-(3-amino-2,6-dioxopiperidine-1-yl) acetate (trifluoroacetate, 1.0 equivalent) as starting materials. 1 H NMR(500MHz,DMSO)δ12.75(s,1H), 10.35(s,1H), 7.83(s,1H), 7.65(d,J=4.6Hz,1H), 7.28(d,J=5.7Hz,1H), 5.06(d,J=5.3Hz,1H), 4. 45(s,2H), 3.66(s,3H), 3.03(t,J=15.4Hz,1H), 2.81(d,J=16.9Hz,1H), 2.57(t,J=11.7Hz,3H), 2.30(s,1H), 2.16(d,J=12.9Hz,1H). LCMS(m / z[M+H] + ):359.0 [Examples]

[0215] Synthesis of 2-methyl-N-(2-oxoazepan-3-yl)-1H-1,3-benzodiazole-4-carboxamide (19)

[0216] [ka]

[0217] 2-methyl-1H-1,3-benzodiazole-4-carboxylic acid (60.0 mg, 0.341 mmol, 1.000 equivalents), 3-aminoazepan-2-one hydrochloride (67.3 mg, 0.409 mmol, 1.200 equivalents), and DMAP (4.2 mg, 0.034 mmol, 0.100 equivalents) were added to a vial and purged with argon for 15 minutes. DMF (10 mL) was added via syringe, followed by DIPEA (0.119 mL, 0.681 mmol, 2.000 equivalents) and HATU (155.4 mg, 0.409 mmol, 1.200 equivalents), and the reaction mixture was stirred overnight. The solvent was evaporated under reduced pressure, and the crude compound was purified by preparative TLC to yield 81 mg (82% yield) of the product. 1 H NMR(500MHz,DMSO)δ12.77(s,1H), 10.45(s,1H), 7.90~7.73(m,2H), 7.61(dd,J=7.8,0.7Hz,1H), 7.23(t,J=7.8Hz,1H), 4.73(ddd,J=10.9,6.6,1.3 Hz,1H), 3.30~3.21(m,1H), 3.18~3.06(m,1H), 2.58(s,3H), 2.03~1.90(m, 2H), 1.82~1.70(m,2H), 1.53(dd,J=24.4,11.9Hz,1H), 1.34~1.21(m,1H). LCMS(m / z[M+H] + ):286.9 [Examples]

[0218] Synthesis of N-(2,7-dioxoazepan-3-yl)-2-methyl-1H-benzo[d]imidazole-4-carboxamide (20)

[0219] [ka]

[0220] To a solution of 2-methyl-N-(2-oxoazepan-3-yl)-1H-1,3-benzodiazole-4-carboxamide (20.0 mg, 0.070 mmol, 1.000 equivalents) in MeCN (4.0 mL) / DMSO (0.085 mL) / water (0.010 mL), Dess-Martin perodinane (74.1 mg, 0.175 mmol, 2.500 equivalents) was added. The suspension was heated at 80°C for 1 hour. The solvent was evaporated under reduced pressure, and the crude product was purified by preparative TLC and HPLC to provide 16 mg (76%) of the product. 1 H NMR(500MHz,DMSO)δ12.73(s,1H), 10.67(s,1H), 10.38(d,J=6.5Hz,1H), 7.81(dd,J=7.6,1.0Hz,1H), 7.64(d,J=7.8Hz,1H), 7.27(t,J=7. 7Hz,1H), 5.19~5.06(m,1H), 3.08~2.95(m,1H), 2.65~2.61(m,1H), 2.60(s,3H), 2.35~2.22(m,1H), 2.08~1.94(m,1H), 1.89~1.69(m,2H). LCMS(m / z[M+H] + ):301.1 [Examples]

[0221] Synthesis of 2-cyano-N-(2,6-dioxopiperidine-3-yl)-1H-benzo[d]imidazole-4-carboxamide (22)

[0222] [ka]

[0223] The compound was synthesized using the general procedure shown in Reaction Scheme 1 and Synthesis Condition B, the above (59% yield), and 2-cyano-benzo[d]imidazole-4-carboxylic acid (20 mg) as a starting material. 1H NMR(500MHz,DMSO)δ14.23(s,1H), 10.59(s,1H), 9.32(s,1H), 8.06(d,J=7.4Hz,1H), 7.92(d,J=8.2Hz,1H), 7.56(t,J=7.7Hz,1H), 4 .86(dt,J=13.0,7.2Hz,1H), 2.82(ddd,J=18.5,12.8,5.9Hz,1H), 2.63(dt,J=17.4,3.7Hz,1H), 2.20(ddd,J=25.4,12.6,4.5Hz,2H). LCMS(m / z[M+H] + ):297.9 [Examples]

[0224] Synthesis of 2-(difluoromethyl)-N-(2,6-dioxopiperidine-3-yl)-1H-benzo[d]imidazole-7-carboxamide (23)

[0225] [ka]

[0226] The compound was synthesized using the general procedure shown in Reaction Scheme 1 and Synthesis Condition B, the above (86% yield), and 2-(difluoromethyl)-1H-benzo[d]imidazole-7-carboxylic acid (20 mg) as a starting material. 1 H NMR(500MHz,DMSO)δ13.89(s,1H), 10.93(s,1H), 9.89(s,1H), 7.97(d,J=6.6 Hz,1H), 7.83(d,J=23.7Hz,1H), 7.48(s,1H), 7.44~7.17(m,1H), 4.88(s,1H). LCMS(m / z[M+H] + ):323.3 [Examples]

[0227] Synthesis of N-(2,6-dioxopiperidine-3-yl)-2-isobutyl-1H-benzo[d]imidazole-7-carboxamide (24)

[0228] [ka]

[0229] The compound was synthesized using the general procedure shown in Reaction Scheme 1 and Synthesis Condition B, as described above (21% yield), and with 2-isobutyl-1H-benzo[d]imidazole-7-carboxylic acid (20 mg) as a starting material. 1 H NMR(500MHz,DMSO)δ12.80(s,1H), 10.91(s,1H), 10.44(s,1H), 7.81(d,J=6.1Hz,1H), 7.66(d,J=7.8Hz,1H), 7.37~7.12(m,1H), 4.81(d,J =43.5Hz,1H), 2.87~2.78(m,1H), 2.76(td,J=7.2,2.5Hz,3H), 2.61~2.54(m,1H), 2.33~2.18(m,1H), 2.17~2.03(m,1H), 1.02~0.90(m,6H). LCMS(m / z[M+H] + ):329.0 [Examples]

[0230] Synthesis of N-(2,6-dioxopiperidine-3-yl)-2-(trifluoromethyl)-1H-benzo[d]imidazole-7-carboxamide (25)

[0231] [ka]

[0232] The compound was synthesized using the general procedure shown in Reaction Scheme 1 and Synthesis Condition B, the above (74% yield), and 2-(trifluoromethyl)-1H-benzo[d]imidazole-7-carboxylic acid (21 mg) as a starting material. 1H NMR(500MHz,DMSO)δ14.58(s,1H), 10.94(s,1H), 9.74(s,1H), 8.03(s,1H), 7.90(d,J=6.9Hz,1H), 7 .58(s,1H), 4.88(s,1H), 2.89~2.76(m,1H), 2.57(d,J=17.5Hz,1H), 2.29(s,1H), 2.20~2.08(m,1H). LCMS(m / z[M+H] + ):340.9 [Examples]

[0233] Synthesis of 6-amino-N-(2,6-dioxopiperidine-3-yl)-2-(trifluoromethyl)-1H-1,3-benzodiazole-7-carboxamide (26)

[0234] [ka]

[0235] Step A: To a stirred solution of methyl 2-amino-6-fluoro-3-nitrobenzoate (2 g, 9.339 mmol) in DMSO (20 mL), K2CO3 (2.58 g, 18.67 mmol) was added, followed by (4-methoxyphenyl)methaneamine (1.59 mL, 12.14 mmol). The reaction mixture was then stirred at room temperature for 16 hours. After the reaction was complete, the mixture was stopped in ice water, the precipitate was filtered, and dried to obtain 2.0 g of methyl 2-amino-6-((4-methoxybenzyl)amino)-3-nitrobenzoate (64% yield).

[0236] Step B: To a stirred solution of methyl 2-amino-6-((4-methoxybenzyl)amino)-3-nitrobenzoate (550 mg, 1.66 mmol) in THF (16 ml), Zn (1.5 g, 21.6 mmol) was added, followed by the addition of NH4Cl (1.15 g, 21.6 mmol) in water (3 ml) at 0°C, and the mixture was stirred at room temperature for 1 hour. After the reaction was complete, the reaction mixture was filtered through Celite and washed with ethyl acetate. The organic layer was washed with water and brine, dried over sodium sulfate, and concentrated under reduced pressure to obtain methyl 2,3-diamino-6-((4-methoxybenzyl)amino)benzoate (250 mg, crude) as a brownish solid.

[0237] Step C: Methyl 2,3-diamino-6-((4-methoxybenzyl)amino)benzoate (2 g, 6.645 mmol) in TFA (20 mL) was stirred at room temperature for 16 hours. After the reaction was complete, the TFA was removed, stopped with aqueous NaHCO3, and extracted with ethyl acetate. The organic layer was washed with brine, dried over Na2SO4, concentrated, and purified by flash column chromatography to obtain 200 mg of methyl 6-amino-2-(trifluoromethyl)-1H-benzo[d]imidazole-7-carboxylate (13% yield).

[0238] Step D: To a stirred solution of methyl 6-amino-2-(trifluoromethyl)-1H-benzo[d]imidazole-7-carboxylate (600 mg, 2.317 mmol) in dioxane (5 mL), 15 mL of NaOH (1N) aqueous solution was added, followed by the addition of Boc2O (3.2 mL, 13.9 mmol) at 0°C, and the mixture was stirred at room temperature for 72 hours. After the reaction was complete, the mixture was stopped in ice water, extracted with ethyl acetate, dried over sodium sulfate, and concentrated. The crude product was purified by flash column chromatography to obtain 600 mg of methyl 6-((tert-butoxycarbonyl)amino)-2-(trifluoromethyl)-1H-benzo[d]imidazole-7-carboxylate (72% yield).

[0239] Step E: A solution of methyl 6-((tert-butoxycarbonyl)amino)-2-(trifluoromethyl)-1H-benzo[d]imidazole-7-carboxylate in 13 mL of 50% NaOH aqueous solution was stirred at 80°C for 4 hours. After the reaction was complete, the reaction mixture was acidified with 2 M HCl, and the precipitate was filtered to obtain 300 mg of 6-((tert-butoxycarbonyl)amino)-2-(trifluoromethyl)-1H-benzo[d]imidazole-7-carboxylic acid (52% yield).

[0240] Step F: Using the general procedure shown in Reaction Scheme 1 and Synthesis Conditions B, and the above (36% yield), tert-butyl N-{7-[(2,6-dioxopiperidine-3-yl)carbamoyl]-2-(trifluoromethyl)-1H-benzo[d]imidazole-4-carboxylic acid (30.0 mg) was used as a starting material to synthesize tert-butyl N-{7-[(2,6-dioxopiperidine-3-yl)carbamoyl]-2-(trifluoromethyl)-1H-1,3-benzodiazole-6-yl}carbamate.

[0241] Step G: Tert-butyl(4-((2,6-dioxopiperidine-3-yl)carbamoyl)-2-(trifluoromethyl)-1H-benzo[d]imidazole-5-yl)carbamate (10.0 mg, 0.022 mmol, 1.000 equivalents) was dissolved in THF (0.220 mL), and 4 M HCl in dioxane (0.038 mL, 1.098 mmol, 50.000 equivalents) was added. The mixture was stirred at room temperature for 4 hours. By evaporating the solvent under reduced pressure, 8.0 mg of 6-amino-N-(2,6-dioxopiperidine-3-yl)-2-(trifluoromethyl)-1H-1,3-benzodiazole-7-carboxamide hydrochloride (88.0% yield) was obtained. 1H NMR(500MHz,DMSO)δ14.15(s,1H), 10.91(s,1H), 10.19(s,1H), 7.54(d,J=9.0Hz,1H), 6.94(d,J=9.0Hz,1H) , 4.86~4.77(m,1H), 2.88~2.75(m,1H), 2.63~2.54(m,1H), 2.33~2.22(m,1H), 2.10(qd,J=12.9,4.4Hz,1H). LCMS(m / z[M+H] + ):356.3 [Examples]

[0242] Synthesis of 5-amino-N-(2,6-dioxopiperidine-3-yl)-2-(trifluoromethyl)-1H-benzo[d]imidazole-7-carboxamide (27)

[0243] [ka]

[0244] Step A: TFA (2 mL) and 4(N)HCl (5 mL) were added to 2,3-diamino-5-nitrobenzoic acid (500 mg, 2.54 mmol). The resulting reaction mixture was then refluxed for 12 hours. After the reaction was complete, the reaction mixture was cooled to 0°C and then carefully neutralized with 10 M NaOH solution. The aqueous portion was extracted by DCM (100 mL x 3). The organic layer was washed with brine, dried over Na2SO4, and concentrated to obtain the crude product. Finally, the crude product was triturated with pentane and ether to obtain the crude compound of 5-nitro-2-(trifluoromethyl)-1H-benzo[d]imidazole-7-carboxylic acid (500 mg) as a dark brown solid. The compound was used in the next step without further purification.

[0245] Step B: 10% Pd / C (193 mg) was added to a stirred solution of 5-nitro-2-(trifluoromethyl)-1H-benzo[d]imidazole-7-carboxylic acid (500.0 mg, 1.82 mmol) in MeOH (10 mL). The reaction mixture was stirred under a hydrogen atmosphere at room temperature for 4 hours. After the reaction was complete, the reaction mixture was filtered through Celite and concentrated under reduced pressure to obtain methyl 5-amino-2-(trifluoromethyl)-1H-benzo[d]imidazole-7-carboxylic acid (500 mg) as a crude product, which was used in the next step without further purification.

[0246] Step C: To an ice-cold solution of methyl 5-amino-2-(trifluoromethyl)-1H-benzo[d]imidazole-7-carboxylic acid (1.0 g, 4.1 mmol) in dioxane (5.0 mL) and H2O (5.0 mL), TEA (0.85 mL, 6.1 mmol) was added. The reaction mixture was stirred under ice-cold conditions for 2-3 minutes. Boc2O (1.0 mL, 4.49 mmol) was added, and the reaction mixture was stirred at room temperature for 6 hours. After the reaction was complete, the solvent was evaporated, and the crude product was purified by preparative HPLC to obtain 5-((tert-butoxycarbonyl)amino)-2-(trifluoromethyl)-1H-benzo[d]imidazole-7-carboxylic acid (50 mg) as a white solid (2.8% yield over 3 steps).

[0247] Step D: Using the general procedure shown in Reaction Scheme 1 and Synthesis Conditions B, and the above (37% yield), Tert-butyl(7-((2,6-dioxopiperidine-3-yl)carbamoyl)-2-(trifluoromethyl)-1H-benzo[d]imidazole-7-carboxylic acid (30.0 mg) was used as a starting material to synthesize Tert-butyl(7-((2,6-dioxopiperidine-3-yl)carbamoyl)-2-(trifluoromethyl)-1H-benzo[d]imidazole-5-yl)carbamate.

[0248] Step E: Tert-butyl(7-((2,6-dioxopiperidine-3-yl)carbamoyl)-2-(trifluoromethyl)-1H-benzo[d]imidazole-5-yl)carbamate (10.0 mg, 0.022 mmol, 1.000 equivalents) was dissolved in THF (0.220 mL), and 4 M HCl in dioxane (0.038 mL, 1.098 mmol, 50.000 equivalents) was added. The mixture was stirred at room temperature for 4 hours. By evaporating the solvent under reduced pressure, 5-amino-N-(2,6-dioxopiperidine-3-yl)-2-(trifluoromethyl)-1H-benzo[d]imidazole-7-carboxamide hydrochloride was obtained. 1 H NMR(500MHz,DMSO)δ13.67(s,1H), 10.91(s,1H), 9.71(s,1H), 7.48~7.34(m,1H), 6.86(d,J=2.1Hz,1H), 5.53(s,1H), 4.84( ddd,J=12.4,7.0,5.2Hz,2H), 2.80(ddd,J=17.3,13.5,5.5Hz,1H), 2.59~2.52(m,1H), 2.32~2.21(m,1H), 2.15~2.03(m,1H). LCMS(m / z[M+H] + ):355.9 [Examples]

[0249] Synthesis of 7-amino-N-(2,6-dioxopiperidine-3-yl)-2-(trifluoromethyl)-1H-benzo[d]imidazole-4-carboxamide (28)

[0250] [ka]

[0251] Step A: To ethyl 3-acetamido-4-chlorobenzoate (20.0 g, 82.97 mmol), 40.0 mL of 100% HNO3 was added dropwise at -15°C. The resulting reaction mixture was stirred and slowly warmed to 10°C over 2 hours, then stirred at room temperature for 12 hours, poured onto crushed ice, filtered the solid, dried under reduced pressure, and the mixture of nitro compounds (16 g) was used directly in the next step. To a stirred solution of nitro compounds in 160 mL of ethanol, 7.5 mL of concentrated H2SO4 was added. The reaction mixture was refluxed for 16 hours, concentrated under reduced pressure, and ice water was added. The product was extracted in DCM, the combined organic layers were washed with brine, dried over Na2SO4, and concentrated. The crude product was purified by flash column chromatography to obtain ethyl 3-amino-4-chloro-2-nitrobenzoate (6.3 g, 30%).

[0252] Step B: To a stirred solution of ethyl 3-amino-4-chloro-2-nitrobenzoate (6.3 g, 25.753 mmol) in ethanol (60.0 mL) and water (30.0 mL), Fe powder (10.78 g) was added, followed by NH4Cl (1.791 g). The reaction mixture was refluxed for 12 hours, concentrated under reduced pressure, diluted with DCM, filtered through a Celite bed, and concentrated under reduced pressure. The crude product was purified by flash column chromatography to obtain ethyl 2,3-diamino-4-chlorobenzoate (5 g, 90.45%).

[0253] Step C: 15 ml of TFA was added to ethyl 2,3-diamino-4-chlorobenzoate (2.0 g, 9.317 mmol, 1.0 equivalent), and the reaction mixture was refluxed for 12 hours and concentrated under reduced pressure. NaHCO3 solution was added to the residue, the product was extracted with ethyl acetate, washed with brine, dried over Na2SO4, and concentrated. The crude product was purified by flash column chromatography to obtain ethyl 7-chloro-2-(trifluoromethyl)-1H-benzo[d]imidazole-4-carboxylate (2.4 g, 88% yield).

[0254] Step D: A solution of ethyl 7-chloro-2-(trifluoromethyl)-1H-benzo[d]imidazole-4-carboxylate (1.0 g, 3.417 mmol) in dioxane (12 mL) was degassed under an argon atmosphere for 10-15 minutes. Cs2CO3 (2.22 g, 6.834 mmol), NH2Boc (1.60 g, 13.669 mmol), X-phos (326 mg, 0.683 mmol), and X-phosPdG3 (0.289 g, 0.342 mmol) were added, and the reaction mixture was stirred at 85°C for 16 hours. The reaction mixture was filtered through a Celite bed, concentrated, and purified by flash column chromatography to obtain ethyl 7-((tert-butoxycarbonyl)amino)-2-(trifluoromethyl)-1H-benzo[d]imidazole-4-carboxylate (800 mg, 62% yield).

[0255] Step E: A stirred solution of ethyl 7-((tert-butoxycarbonyl)amino)-2-(trifluoromethyl)-1H-benzo[d]imidazole-4-carboxylate (500.0 mg, 1.339 mmol) in MeOH (3.0 mL) and THF (3.0 mL) was slowly added to 50% NaOH aqueous solution (6.0 mL) under ice cooling conditions. The resulting reaction mixture was then stirred at room temperature for 16 hours. The reaction mixture was concentrated under reduced pressure, then diluted with water and washed with ethyl acetate. The aqueous portion was then gently neutralized with saturated citric acid aqueous solution under ice cooling conditions and extracted with ethyl acetate. Next, the combined organic layers were washed with brine, then dried over Na2SO4, filtered, and concentrated to obtain a crude product, which was crushed with pentane and ether to obtain 7-((tert-butoxycarbonyl)amino)-2-(trifluoromethyl)-1H-benzo[d]imidazole-4-carboxylic acid (250 mg, 54.06% yield) as a white solid.

[0256] Step F: Tert-butyl(4-((2,6-dioxopiperidine-3-yl)carbamoyl)-2-(trifluoromethyl)-1H-benzo[d]imidazole-4-yl)carbamate was synthesized using the general procedure shown in reaction scheme 1 and synthesis conditions B, the above (80% yield), and 7-((tert-butoxycarbonyl)amino)-2-(trifluoromethyl)-1H-benzo[d]imidazole-4-carboxylic acid (30 mg) as a starting material. 1H NMR(500MHz,DMSO)δ14.02(s,1H), 10.93(s,1H), 9.57(s,1H), 8.93(s,1H), 7.98(s,2H), 4.86(dt,J=12.3,5. 9Hz,1H), 2.88~2.79(m,1H), 2.57(s,1H), 2.29(d,J=12.4Hz,1H), 2.11(td,J=13.1,4.5Hz,1H), 1.53(s,9H). LCMS(m / z[M+H] + ):456.5

[0257] Step G: To a mixture of tert-butyl(4-((2,6-dioxopiperidine-3-yl)carbamoyl)-2-(trifluoromethyl)-1H-benzo[d]imidazole-7-yl)carbamate (8 mg, 0.018 mmol) in DCM (0.5 mL), TFA (0.1 mL) was added, and the reaction mixture was stirred at room temperature for 18 hours. The mixture was concentrated under reduced pressure and purified by HPLC to obtain 7-amino-N-(2,6-dioxopiperidine-3-yl)-2-(trifluoromethyl)-1H-1,3-benzodiazole-4-carboxamide trifluoroacetate (44% yield). 1 H NMR(500MHz,DMSO)δ10.51(s,1H), 7.75(d,J=8.3Hz,1H), 6.58(s,1H), 5.97(d,J=72.1Hz,2H), 4 .76(d,J=10.7Hz,1H), 2.81~2.73(m,1H), 2.60(dd,J=17.5,3.9Hz,1H), 2.12(d,J=26.4Hz,2H). LCMS(m / z[M+H] +):356.0 [Examples]

[0258] Synthesis of N-(2,6-dioxopiperidine-3-yl)-1,2-dimethyl-1H-benzo[d]imidazole-4-carboxamide (29)

[0259] [ka]

[0260] The compound was synthesized using the general procedure shown in Reaction Scheme 1 and Synthesis Condition B, the above (10% yield), and 1,2-dimethyl-1H-benzo[d]imidazole-4-carboxylic acid (8.9 mg) as a starting material. 1 H NMR(500MHz,DMSO)δ10.91(s,1H), 10.25(d,J=7.3Hz,1H), 7.85(dd,J=7.6,1.0Hz ,1H), 7.75(dd,J=8.0,1.0Hz,1H), 7.33(t,J=7.8Hz,1H), 4.87(ddd,J=12.6,7.2,5 .3Hz,1H), 3.81(s,3H), 2.82(ddd,J=17.5,13.5,5.5Hz,1H), 2.62(s,3H), 2.56(dd d,J=17.4,4.1,2.3Hz,1H), 2.24(dtd,J=12.9,5.4,2.4Hz,1H), 2.18~2.07(m,1H). LCMS(m / z[M+H] + ):301.0 [Examples]

[0261] Synthesis of N-(2,6-dioxopiperidine-3-yl)-6-methoxy-2-methyl-1H-benzo[d]imidazole-4-carboxamide (30)

[0262] [ka]

[0263] The compound was synthesized using the general procedure shown in Reaction Scheme 1 and Synthesis Condition B, the above (49% yield), and 6-methoxy-2-methyl-1H-benzo[d]imidazole-4-carboxylic acid (22 mg) as a starting material. 1 H NMR(500MHz,DMSO)δ12.52(s,1H), 10.90(s,1H), 10.26(d,J=7.3Hz,1H), 7.39(d,J=2.5Hz,1H), 7.16(d,J=2.5Hz,1H), 4.86(ddd,J=12 .6,7.3,5.4Hz,1H), 3.82(s,3H), 2.87~2.76(m,1H), 2.54(s,3H), 2.53~2.51(m,1H), 2.26~2.19(m,1H), 2.12(qd,J=12.9,4.5Hz,1H). LCMS(m / z[M+H] + ):317.5 [Examples]

[0264] Synthesis of 6-(aminomethyl)-N-(2,6-dioxopiperidine-3-yl)-2-methyl-1H-benzo[d]imidazole-4-carboxamide (31)

[0265] [ka]

[0266] Step A: To a degassed solution of ethyl 6-bromo-2-methyl-1H-benzo[d]imidazole-4-carboxylate (500 mg, 1.76 mmol) in DMF (12 mL), Zn(CN)2 (518 mg, 4.41 mmol) and Pd(PPh3)4 (408 mg, 0.35 mmol) were added. The reaction mixture was stirred at 120 °C for 16 hours, stopped with ice water, extracted with ethyl acetate, dried over Na2SO4, concentrated under reduced pressure, and purified by flash column chromatography to obtain ethyl 6-cyano-2-methyl-1H-benzo[d]imidazole-4-carboxylate (27% yield).

[0267] Step B: To a solution of ethyl 6-cyano-2-methyl-1H-benzo[d]imidazole-4-carboxylate (400 mg, 1.747 mmol) in ethanol (13 ml), Raney nickel and Boc2O (2.1 ml, 8.734 mmol) were added, and the reaction mixture was stirred under hydrogen (15 psi) for 16 hours. The mixture was filtered through a Celite bed, and the filtrate was concentrated under reduced pressure and purified by flash column chromatography to obtain 1-(tert-butyl)4-ethyl 6-(((tert-butoxycarbonyl)amino)methyl)-2-methyl-1H-benzo[d]imidazole-1,4-dicarboxylate (47% yield).

[0268] Step C: To a solution of 1-(tert-butyl)4-ethyl 6-(((tert-butoxycarbonyl)amino)methyl)-2-methyl-1H-benzo[d]imidazole-1,4-dicarboxylate (430 mg, 0.993 mmol) in THF:MeOH 1:1 (10 mL), 50% NaOH aqueous solution (4 mL) was added, and the reaction mixture was stirred at room temperature for 16 hours, neutralized with 1 M HCl, and filtered. By drying the solid, 6-(((tert-butoxycarbonyl)amino)methyl)-2-methyl-1H-benzo[d]imidazole-4-carboxylic acid (62% yield) was obtained.

[0269] Step D: Tert-butyl((4-((2,6-dioxopiperidine-3-yl)carbamoyl)-2-methyl-1H-benzo[d]imidazole-4-carboxylic acid (30 mg) was used as a starting material to synthesize Tert-butyl((4-((2,6-dioxopiperidine-3-yl)carbamoyl)-2-methyl-1H-benzo[d]imidazole-6-yl)methyl)carbamate. 1H NMR(500MHz,DMSO)δ12.64(s,1H), 10.89(s,1H), 10.24(d,J=7.3Hz,1H), 8.1 6(s,1H), 7.74(s,1H), 7.49(s,1H), 7.45(t,J=6.4Hz,1H), 4.88(dt,J=12.6, 6.4Hz,1H), 4.24(d,J=6.2Hz,2H), 2.82(ddd,J=17.3,13.3,5.5Hz,1H), 2.61 ~2.52(m,4H), 2.27~2.20(m,1H), 2.11(qd,J=12.9,4.3Hz,1H), 1.40(s,9H). LCMS(m / z[M+H]+):416.0

[0270] Step E: Tert-butyl((4-((2,6-dioxopiperidine-3-yl)carbamoyl)-2-methyl-1H-benzo[d]imidazole-6-yl)methyl)carbamate was suspended in DCM (0.5 mL). TFA (0.1 mL) was added to the mixture and stirred at room temperature for 2 hours. The crude product was concentrated under vacuum, dissolved in water, and freeze-dried to obtain 6-(aminomethyl)-N-(2,6-dioxopiperidine-3-yl)-2-methyl-1H-benzo[d]imidazole-4-carboxamide. 1 H NMR(500MHz,DMSO)δ10.93(s,1H), 10.12(s,1H), 8.14(s,3H), 7.97(d,J=1.6Hz,1H), 7.79(s,1H), 4.88(dt,J=13 .0,7.1Hz,1H), 4.20(q,J=5.8Hz,2H), 2.84(ddd,J=17.3,13.0,6.0Hz,1H), 2.67~2.53(m,4H), 2.25~2.09(m,2H). LCMS(m / z[M+H] + ):315.8 [Examples]

[0271] Synthesis of 7-(aminomethyl)-N-(2,6-dioxopiperidine-3-yl)-2-methyl-1H-benzo[d]imidazole-4-carboxamide (32)

[0272] [ka]

[0273] Step A: To a stirred solution of ethyl 2,3-diamino-4-chlorobenzoate (1.5 g, 6.99 mmol) in toluene (20.0 mL), triethyl orthoacetate (5.1 mL, 27.95 mmol) and PTSA (0.337 g, 1.957 mmol) were added, respectively. The reaction mixture was refluxed for 16 hours, concentrated under reduced pressure, and the crude product was purified by flash column chromatography to obtain 1.2 g of ethyl 7-chloro-2-methyl-1H-benzo[d]imidazole-4-carboxylate (71% yield).

[0274] Step B: A solution of ethyl 7-chloro-2-methyl-1H-benzo[d]imidazole-4-carboxylate (400 mg, 1.676 mmol) in DMF (10 mL) was degassed under an argon atmosphere for 10-15 minutes. Zn(CN)2 (492 mg, 4.19 mmol), X-phos (159.792 mg, 0.335 mmol), and X-phosPdG3 (0.141.86 mg, 0.168 mmol) were added, and the reaction mixture was heated at 110°C for 16 hours. The mixture was filtered through a Celite bed, diluted with water, the product extracted with ethyl acetate, washed with brine, dried over Na2SO4, and concentrated under reduced pressure. The crude product was purified by flash column chromatography to obtain 251 mg of ethyl 7-cyano-2-methyl-1H-benzo[d]imidazole-4-carboxylate (65% yield).

[0275] Step C: To a stirred solution of ethyl 7-cyano-2-methyl-1H-benzo[d]imidazole-4-carboxylate (3) (375 mg, 1.636 mmol) in ethanol (10 mL), Boc2O (0.564 mL, 2.454 mmol) and Raney nickel (200 mg) were added. The reaction mixture was stirred at room temperature under a hydrogen atmosphere for 16 hours, filtered through a Celite bed, and concentrated under reduced pressure. The crude product was purified by flash column chromatography to obtain 230 mg of ethyl 7-(((tert-butoxycarbonyl)amino)methyl)-2-methyl-1H-benzo[d]imidazole-4-carboxylate (42% yield).

[0276] Step D: To a solution of ethyl 7-(((tert-butoxycarbonyl)amino)methyl)-2-methyl-1H-benzo[d]imidazole-4-carboxylate (200.0 mg, 0.6 mmol) in MeOH (1 mL) and THF (1 mL), 50% NaOH solution (2 mL) was added at 0°C. The reaction mixture was stirred at room temperature for 16 hours, concentrated under reduced pressure, diluted with water, and washed with DCM. The aqueous phase was gently acidified with citric acid solution, the product was extracted with ethyl acetate, washed with brine, dried over Na2SO4, and concentrated under reduced pressure. The crude product was crushed with diethyl ether to obtain 60 mg (32%) of 7-(((tert-butoxycarbonyl)amino)methyl)-2-methyl-1H-benzo[d]imidazole-4-carboxylic acid.

[0277] Step E: Tert-butyl((4-((2,6-dioxopiperidine-3-yl)carbamoyl)-2-methyl-1H-benzo[d]imidazole-4-carboxylic acid (20 mg) was used as a starting material to synthesize Tert-butyl((4-((2,6-dioxopiperidine-3-yl)carbamoyl)-2-methyl-1H-benzo[d]imidazole-7-yl)methyl)carbamate. 1H NMR(500MHz,DMSO)δ12.66(s,1H), 10.89(s,1H), 10.24(d,J=7.3Hz,1H), 8.15(s ,1H), 7.79(d,J=7.8Hz,1H), 7.47(t,J=6.1Hz,1H), 7.13(d,J=7.9Hz,1H), 4.86( ddd,J=12.5,7.2,5.2Hz,1H), 4.42(d,J=6.1Hz,2H), 2.81(ddd,J=17.3,13.5,5. 5Hz,1H), 2.61~2.51(m,4H), 2.26~2.20(m,1H), 2.16~2.07(m,1H), 1.40(s,9H). LCMS(m / z[M+H]+):416.0

[0278] Step F: Tert-butyl((4-((2,6-dioxopiperidine-3-yl)carbamoyl)-2-methyl-1H-benzo[d]imidazole-7-yl)methyl)carbamate was suspended in DCM (0.5 mL). TFA (0.1 mL) was added to the mixture and stirred at room temperature for 2 hours. The crude product was concentrated under vacuum, dissolved in water, and freeze-dried to obtain 7-(aminomethyl)-N-(2,6-dioxopiperidine-3-yl)-2-methyl-1H-benzo[d]imidazole-4-carboxamide. 1 H NMR(500MHz,DMSO)δ10.91(s,1H), 10.12(s,1H), 9.20(s,1H), 8.30(s,3H), 7.85(d,J=7.8Hz,1H), 7.37(d,J=7.9Hz, 1H), 4.82(d,J=10.7Hz,1H), 4.39(d,J=5.7Hz,2H), 2.88~2.77(m,1H), 2.64(s,3H), 2.62~2.50(m,1H), 2.17(s,2H). LCMS(m / z[M+H] + ):316.1 [Examples]

[0279] Synthesis of 5-(2,4-dimethoxyphenyl)-N-(2,6-dioxopiperidine-3-yl)-2-methyl-3H-imidazo[4,5-b]pyridine-7-carboxamide (33)

[0280] [ka]

[0281] Step A: A suspension of 5-(2,4-dimethoxyphenyl)-2-methyl-1H-imidazo[4,5-b]pyridine-7-carboxylic acid (10.0 mg, 31.917 μmol, 1.000 equivalents) and HOSu (4.4 mg, 38.300 μmol, 1.200 equivalents) in DCM (1.0 mL) was to be mixed with a solution of DCC (7.9 mg, 38.300 μmol, 1.200 equivalents) in DCM (0.500 mL). The reaction mixture was stirred at room temperature for 18 hours. The reaction mixture was concentrated under reduced pressure and purified by preparative TLC to obtain 2,5-dioxopyrrolidine-1-yl 5-(2,4-dimethoxyphenyl)-2-methyl-1H-imidazo[4,5-b]pyridine-7-carboxylate (71% yield).

[0282] Step B: To a solution of 3-aminopiperidine-2,6-dione hydrochloride (8.4 mg, 51.171 μmol, 3.000 equivalents) and DIPEA (9 μL, 51.171 μmol, 3.000 equivalents) in DMF (2.0 mL), 2,5-dioxopyrrolidine-1-yl 5-(2,4-dimethoxyphenyl)-2-methyl-1H-imidazo[4,5-b]pyridine-7-carboxylate (7.0 mg, 17.057 μmol, 1.000 equivalents) was added in one go. The reaction mixture was stirred at room temperature for 18 hours. The solvent was evaporated under reduced pressure, and the residue was purified by preparative TLC to provide 4.1 mg (56%) of the product. 1H NMR(500MHz,DMSO)δ13.04(s,1H), 10.54(s,1H), 8.72(d,J=8.0Hz,1H), 7.7 6(d,J=8.5Hz,1H), 7.65(s,1H), 6.73(d,J=2.4Hz,1H), 6.70(dd,J=8.6,2.4H z,1H), 4.81(q,J=8.2Hz,1H), 3.87(s,3H), 3.87(s,3H), 2.81(dt,J=18.0,9 .5Hz,1H), 2.67~2.57(m,1H), 2.53(s,3H), 2.15(dq,J=9.1,5.2,4.1Hz,2H). LCMS(m / z[M+H] + ):423.9 [Examples]

[0283] Synthesis of N-(2,6-dioxopiperidine-3-yl)-2-methyl-3H-imidazo[4,5-c]pyridine-7-carboxamide (35)

[0284] [ka]

[0285] The compound was synthesized using the general procedure shown in reaction scheme 1 and synthesis conditions C, the above (60% yield), and 2-methyl-3H-imidazo[4,5-c]pyridine-7-carboxylic acid (20 mg) as a starting material. 1 H NMR(500MHz,DMSO,353K)δ12.65(s,1H), 10.58(s,1H), 9.50(s,1H), 8.89(s,1H), 8.82(s,1H), 8.14(s,0H), 4.85(dt,J= 12.6,6.9Hz,1H), 2.81(ddd,J=17.5,12.9,5.7Hz,1H), 2.63(s,2H), 2.62~2.57(m,0H), 2.25(s,1H), 2.22~2.11(m,1H). LCMS(m / z[M+H] + ):288.1 [Examples]

[0286] Synthesis of N-(2,6-dioxopiperidine-3-yl)-2-methyl-3H-imidazo[4,5-b]pyridine-7-carboxamide (36)

[0287] [ka]

[0288] The compound was synthesized using the general procedure shown in reaction scheme 1 and synthesis conditions C, as described above (29% yield), and with 2-methyl-3H-imidazo[4,5-b]pyridine-7-carboxylic acid (20 mg) as a starting material. 1 H NMR(500MHz,DMSO,353K)δ12.93(s,1H), 10.60(s,1H), 9.71(s,1H), 8.38(d,J=5.0Hz,1H), 7.66(d,J=5.0Hz,1H), 4.86(ddd,J=12.4,7. 3,5.3Hz,1H), 2.81(ddd,J=17.3,13.1,5.5Hz,1H), 2.65~2.57(m,4H), 2.29(dtd,J=10.7,5.2,2.7Hz,1H), 2.15(qd,J=12.8,4.7Hz,1H). LCMS(m / z[M+H] + ):287.6 [Examples]

[0289] Synthesis of N-(2,6-dioxopiperidine-3-yl)-1H-pyrrolo[3,2-b]pyridine-7-carboxamide (37)

[0290] [ka]

[0291] The compound was synthesized using the general procedure shown in reaction scheme 1 and synthesis conditions C, as described above (30% yield), and with 1H-pyrrolo[3,2-b]pyridine-7-carboxylic acid (20 mg) as a starting material. 1 H NMR(500MHz,DMSO)δ11.36(s,1H), 10.93(s,1H), 9.16(d,J=8.3Hz,1H), 8.47(d,J=4. 9Hz,1H), 7.68~7.61(m,1H), 7.56(d,J=5.0Hz,1H), 6.64(d,J=3.0Hz,1H), 4.84(ddd, J=12.6,8.2,5.4Hz,1H), 2.85(ddd,J=17.4,13.4,5.5Hz,1H), 2.60(ddd,J=17.3,4.3 ,2.9Hz,1H), 2.23(qd,J=13.0,4.5Hz,1H), 2.05(dddd,J=10.8,8.2,5.4,2.8Hz,1H). LCMS(m / z[M+H] + ):272.9 [Examples]

[0292] Synthesis of N-(2,6-dioxopiperidine-3-yl)-2-methyl-1H-pyrrolo[2,3-c]pyridine-7-carboxamide (38)

[0293] [ka]

[0294] The compound was synthesized using the general procedure shown in Reaction Scheme 1 and Synthesis Condition B, the above (39% yield), and 2-methyl-1H-pyrrolo[2,3-c]pyridine-7-carboxylic acid (10 mg) as a starting material. 1H NMR(500MHz,DMSO)δ11.43(s,1H), 10.89(s,1H), 9.13(d,J=8.2Hz,1H), 8.14( d,J=5.2Hz,1H), 7.65(d,J=5.2Hz,1H), 6.39~6.29(m,1H), 4.85~4.75(m,J=13. 4,8.1,5.5Hz,1H), 2.84(ddd,J=17.4,13.8,5.5Hz,1H), 2.61~2.56(m,J=17.8, 3.1Hz,1H), 2.51(s,3H), 2.37~2.27(m,J=13.1,4.5Hz,1H), 2.14~2.04(m,1H). LCMS(m / z[M+H] + ):287.1 [Examples]

[0295] Synthesis of N-(2,6-dioxopiperidine-3-yl)-2-methylbenzofuran-7-carboxamide (39)

[0296] [ka]

[0297] The compound was synthesized using the general procedure shown in Reaction Scheme 1 and Synthesis Condition B, the above (62% yield), and 2-methyl-1-benzofuran-7-carboxylic acid (20 mg) as a starting material. 1 H NMR(500MHz,DMSO)δ10.91(s,1H), 8.52(d,J=7.6Hz,1H), 7.72(dd,J=7.7,1.3Hz,1H), 7.67(dd,J=7.6,1.3Hz,1H), 7.30(t,J=7.6Hz,1H), 6.71(q,J=1. 1Hz,1H), 4.83(ddd,J=12.1,7.6,5.7Hz,1H), 2.82(ddd,J=17.3,13.1,5.9H z,1H), 2.56(ddd,J=17.3,4.4,2.8Hz,1H), 2.51(s,3H), 2.24~2.10(m,2H). LCMS(m / z[M+H] + ):287.1 [Examples]

[0298] Synthesis of N-(2,6-dioxopiperidine-3-yl)-6,7,8,9-tetrahydrodibenzo[b,d]furan-4-carboxamide (40)

[0299] [ka]

[0300] This compound was synthesized using the general procedure shown in Reaction Scheme 1 and Synthesis Condition B, with COMU instead of HATU (45.5% yield), and 6,7,8,9-tetrahydrodibenzo[b,d]furan-4-carboxylic acid (20 mg) as a starting material. NMR:1H NMR(500MHz,DMSO)δ10.90(s,1H), 8.50(d,J=7.6Hz,1H), 7.67(ddd,J=12.0,7.7,1.3Hz,2H), 7.32(t,J=7.6Hz,1H), 4.82(ddd,J=12.1,7.6,5 .6Hz,1H), 2.86~2.75(m,3H), 2.65~2.60(m,2H), 2.56(ddd,J=17.3,4. 3,2.7Hz,1H), 2.25~2.09(m,2H), 1.95~1.88(m,2H), 1.85~1.77(m,2H). LCMS(m / z[M+H] + ):327.2 [Examples]

[0301] Synthesis of N-(2,6-dioxopiperidine-3-yl)-2-methylbenzo[b]thiophene-7-carboxamide (41)

[0302] [ka]

[0303] The compound was synthesized using the general procedure shown in Reaction Scheme 1 and Synthesis Condition B, the above (31% yield), and 2-methylbenzo[b]thiophene-7-carboxylic acid (20 mg) as a starting material. 1 H NMR(500MHz,DMSO)δ10.54(s,1H), 8.68(d,J=7.7Hz,1H), 7.88(dd,J=7.7,1.3Hz,2H), 7.44(t,J=7.6Hz,1H), 7.20~7.12(m,1H), 4.82(ddd,J=11.9 ,8.1,5.5Hz,1H), 2.81(ddd,J=17.5,12.8,5.6Hz,1H), 2.66~2.59(m,1H) , 2.58(d,J=1.1Hz,3H), 2.20(qd,J=12.8,4.6Hz,1H), 2.15~2.07(m,1H). LCMS(m / z[M+H] + ):303.0 [Examples]

[0304] Synthesis of 3-bromo-N-(2,6-dioxopiperidine-3-yl)-1H-indazole-7-carboxamide (42)

[0305] [ka]

[0306] The compound was synthesized using the general procedure shown in Reaction Scheme 1 and Synthesis Condition B, the above (17% yield), and 3-bromo-1H-indazole-7-carboxylic acid (20 mg) as a starting material. 1H NMR (500MHz, DMSO): δ13.46(s,1H), 10.92(s,1H), 9.07(d,J=8.3Hz,1H), 8.05(d,J=7.3Hz,1H), 7.82(d,J=8.1Hz,1H), 7.36(t,J=7.7Hz,1H), 4.8 7~4.79(m,J=13.1,8.1,5.4Hz,1H), 2.90~2.77(m,J=18.6,13.4,5.5Hz, 1H), 2.63~2.56(m,1H), 2.22(qd,J=12.9,4.4Hz,1H), 2.08~2.02(m,1H). LCMS(m / z[M+H] + ):351.1 [Examples]

[0307] Synthesis of N-(2,6-dioxopiperidine-3-yl)-3-(thiophen-2-yl)-1H-indazole-7-carboxamide (43)

[0308] [ka]

[0309] The compound was synthesized using the general procedure shown in Reaction Scheme 1 and Synthesis Condition B, the above (32% yield), and 3-(thiophen-2-yl)-1H-indazole-7-carboxylic acid (7 mg) as a starting material. 1H NMR (500MHz, DMSO): δ13.22(s,1H), 10.91(s,1H), 9.05(d,J=7.1Hz,1H), 8.33(d,J=8.1Hz,1H ), 8.01(d,J=7.3Hz,1H), 7.79(d,J=3.1Hz,1H), 7.60(d,J=4.9Hz,1H), 7.35(t,J=7.7Hz,1H), 7 .22(dd,J=5.1,3.6Hz,1H), 4.84(ddd,J=13.2,7.9,5.5Hz,1H), 2.84(ddd,J=18.5,13.4,5.5Hz ,1H), 2.59(dd,J=13.7,3.3Hz,1H), 2.23(qd,J=12.9,4.4Hz,1H), 2.06(dd,J=9.4,4.6Hz,1H). LCMS(m / z[M+H] + ):355.1 [Examples]

[0310] Synthesis of N-(2,6-dioxopiperidine-3-yl)-3-(5,6,7,8-tetrahydronaphthalene-2-yl)-1H-indazole-7-carboxamide (45)

[0311] [ka]

[0312] The compound was synthesized using the general procedure shown in Reaction Scheme 1 and Synthesis Condition B, the above (76% yield), and 3-(5,6,7,8-tetrahydronaphthalene-2-yl)-1H-indazole-7-carboxylic acid (8 mg) as a starting material. 1H NMR(500MHz,DMSO)δ13.13(s,1H), 10.91(s,1H), 9.02(s,1H), 8.26(d,J=8 .1Hz,1H), 7.98(d,J=7.4Hz,1H), 7.71~7.62(m,2H), 7.30(t,J=7.7Hz,1H), 7.21(d,J=7.8Hz,1H), 4.90~4.79(m,1H), 2.87~2.76(m,5H), 2.62~2.56(m, 1H), 2.22(dt,J=13.3,6.5Hz,1H), 2.07(s,1H), 1.79(h,J=3.9,3.5Hz,4H). LCMS(m / z[M+H] + ):403.4 [Examples]

[0313] Synthesis of 3-(benzo[d][1,3]dioxol-5-yl)-N-(2,6-dioxopiperidine-3-yl)-1H-indazole-7-carboxamide (46)

[0314] [ka]

[0315] The compound was synthesized using the general procedure shown in Reaction Scheme 1 and Synthesis Condition B, the above (40% yield), and 3-(benzo[d][1,3]dioxol-5-yl)-1H-indazole-7-carboxylic acid (18 mg) as a starting material. 1 H NMR (500MHz, DMSO): δ13.13(s,1H), 10.91(s,1H), 9.02(s,1H), 8.24(d,J=8.1H z,1H), 7.99(d,J=7.3Hz,1H), 7.54~7.42(m,2H), 7.30(t,J=7.7Hz,1H), 7.08(d ,J=8.0Hz,1H), 6.10(s,2H), 4.91~4.79(m,1H), 2.84(ddd,J=18.5,13.4,5.5Hz ,1H), 2.59(dd,J=13.8,3.4Hz,1H), 2.22(td,J=12.9,8.9Hz,1H), 2.07(s,1H). LCMS(m / z[M+H] + ):393.1 [Examples]

[0316] Synthesis of 5-bromo-N-(2,6-dioxopiperidine-3-yl)-1H-indazole-7-carboxamide (47)

[0317] [ka]

[0318] The compound was synthesized using the general procedure shown in Reaction Scheme 1 and Synthesis Condition B, the above (14% yield), and 5-bromo-1H-indazole-7-carboxylic acid (30 mg) as a starting material. 1 H NMR(500MHz,DMSO)δ13.30(s,1H), 10.92(s,1H), 9.11(d,J=6.7Hz,1H), 8.24(d,J=1.5Hz,1H), 8.13(d,J=17.5Hz,2H), 4.89~4.79( m,1H), 2.88~2.78(m,J=18.5,13.3,5.5Hz,1H), 2.62~2.54(m,J=13.7,3.5Hz,1H), 2.18(qd,J=12.8,4.2Hz,1H), 2.09~1.94(m,1H). LCMS(m / z[M+H] + ):351.1 [Examples]

[0319] Synthesis of 6-amino-N-(2,6-dioxopiperidine-3-yl)-1H-indazole-7-carboxamide (48)

[0320] [ka]

[0321] The compound was synthesized using the general procedure shown in Reaction Scheme 1 and Synthesis Condition B, the above (20% yield), and 6-amino-1H-indazole-7-carboxylic acid (30 mg) as a starting material. 1 H NMR(500MHz,DMSO)δ13.57(s,1H), 10.88(s,1H), 10.00(d,J=6.9Hz,1H), 8.25(s,1H), 7.60(d,J=9.0Hz,1H), 6.64(d,J=9.0Hz, 1H), 4.90~4.78(m,J=12.5,6.3Hz,1H), 2.91~2.73(m,1H), 2.59(s,1H), 2.30~2.19(m,1H), 2.11~1.96(m,J=23.7,11.1Hz,1H). LCMS(m / z[M+H] + ):288.2 [Examples]

[0322] Synthesis of N-(2,6-dioxopiperidine-3-yl)benzo[d]isothiazol-7-carboxamide(50)

[0323] [ka]

[0324] The compound was synthesized using the general procedure shown in Reaction Scheme 1 and Synthesis Condition B, the above (48% yield), and benzo[d]isothiazole-7-carboxylic acid (20 mg) as a starting material. 1H NMR(500MHz,DMSO)δ10.93(s,1H), 9.32(d,J=8.3Hz,1H), 9.17(s,1H), 8.44(dd,J=7.8,0.9Hz,1H), 8.33(dd,J=7.5,0.9Hz,1H), 7.70(t,J=7.6Hz,1H), 4.89(ddd,J=13.3,8.2,5.4Hz,1H), 2.84(ddd,J=17.4,13.4,5.5Hz,1H),2. 59(dt,J=17.2,3.9Hz,1H), 2.21(qd,J=13.0,4.5Hz,1H), 2.09~2.00(m,1H). LCMS(m / z[M+H] + ):290.3 [Examples]

[0325] Synthesis of N-(2,6-dioxopiperidine-3-yl)-2-methylbenzo[d]oxazole-4-carboxamide (51)

[0326] [ka]

[0327] The compound was synthesized using the general procedure shown in Reaction Scheme 1 and Synthesis Condition B, the above (35% yield), and 2-methylbenzo[d]oxazole-4-carboxylic acid (20 mg) as a starting material. 1 H NMR(500MHz,DMSO)δ10.90(s,1H), 8.62(d,J=8.0Hz,1H), 7.84(dd,J=7.9,1.1Hz,1H), 7.74(dd,J=7.8,1.2Hz,1H), 7.44(t,J=7.8Hz,1H), 4.86~4. 79(m,1H), 2.82(ddd,J=17.3,13.4,5.6Hz,1H), 2.67(s,3H), 2.56(ddd,J =17.3,4.4,2.7Hz,1H), 2.19(qd,J=12.9,4.5Hz,1H), 2.12~2.04(m,1H). LCMS(m / z[M+H] + ):288.0 [Examples]

[0328] Synthesis of N-(2,6-dioxopiperidine-3-yl)-2-methylbenzo[d]oxazole-7-carboxamide (52)

[0329] [ka]

[0330] The compound was synthesized using the general procedure shown in Reaction Scheme 1 and Synthesis Condition B, the above (47% yield), and 2-methylbenzo[d]oxazole-7-carboxylic acid (20 mg) as a starting material. 1 H NMR(500MHz,DMSO)δ10.95(s,1H), 9.30(d,J=7.2Hz,1H), 7.94(ddd,J=16.3,7.9,1.0Hz,2H), 7.50(t,J=8.0Hz,1H), 4.89(ddd,J=12.6,7. 2,5.3Hz,1H), 2.87~2.77(m,1H), 2.72(s,3H), 2.56(ddd,J=17.6,4.5,2.5Hz,1H), 2.24(dtd,J=13.1,5.5,2.4Hz,1H), 2.18~2.08(m,1H). LCMS(m / z[M+H] + ):287.8 [Examples]

[0331] Synthesis of N-(2,6-dioxopiperidine-3-yl)-2-methylbenzo[d]thiazole-7-carboxamide (53)

[0332] [ka]

[0333] The compound was synthesized using the general procedure shown in Reaction Scheme 1 and Synthesis Condition B, the above (32% yield), and 2-methylbenzo[d]thiazole-7-carboxylic acid (20 mg) as a starting material. 1 H NMR(500MHz,DMSO)δ10.90(s,1H), 9.13(d,J=8.3Hz,1H), 8.10(dd,J=8.0,0.9Hz,1H), 8.06(dd,J=7.7,1.0Hz,1H), 7.63(t,J=7.8Hz,1H), 4.86(ddd ,J=12.5,8.2,5.4Hz,1H), 2.87~2.77(m,4H), 2.57(ddd,J=17.3,4.4,2.8 Hz,1H), 2.18(qd,J=13.0,4.5Hz,1H), 2.02(dtd,J=13.2,5.5,2.8Hz,1H). LCMS(m / z[M+H] + ):304.0 [Examples]

[0334] Synthesis of N-(2,6-dioxopiperidine-3-yl)thiazolo[5,4-b]pyridine-7-carboxamide (54)

[0335] [ka]

[0336] The compound was synthesized using the general procedure shown in Reaction Scheme 1 and Synthesis Condition B, the above (56% yield), and thiazolo[5,4-b]pyridine-7-carboxylic acid (20 mg) as a starting material. 1 H NMR(500MHz,DMSO)δ10.98(s,1H), 9.93(d,J=7.2Hz,1H), 9.86~9.80(m,1H), 8.89(d,J=4.8Hz,1H), 8.08(d,J=4.8Hz,1H), 4.93(ddd,J =12.6,7.2,5.4Hz,1H), 2.83(ddd,J=17.5,13.5,5.6Hz,1H), 2.53~2.51(m,1H), 2.25(dtd,J=13.1,5.5,2.4Hz,1H), 2.20~2.10(m,1H). LCMS(m / z[M+H] + ):290.9 [Examples]

[0337] Synthesis of N-(2,6-dioxopiperidine-3-yl)-1H-benzo[d][1,2,3]triazole-4-carboxamide(55) [ka]

[0338] The compound was synthesized using the general procedure shown in Reaction Scheme 1 and Synthesis Condition C, the above (76% yield), and 1H-benzo[d][1,2,3]triazole-4-carboxylic acid (20 mg) as a starting material. 1 H NMR(500MHz,DMSO,353K)δ15.65(s,1H), 10.61(s,1H), 9.26(s,1H), 8.18~8.00(m,2H), 7.58(t,J=7.7Hz,1H), 4.89(dt,J =12.8,6.6Hz,1H), 2.83(ddd,J=17.2,12.8,5.8Hz,1H), 2.63(dt,J=17.4,3.8Hz,1H), 2.21(qd,J=13.2,12.7,5.4Hz,2H). LCMS(m / z[M+H] + ):274.1 [Examples]

[0339] Synthesis of N-(2,6-dioxopiperidine-3-yl)-6-nitro-1H-benzo[d][1,2,3]triazole-4-carboxamide (57)

[0340] [ka]

[0341] The compound was synthesized using the general procedure shown in Reaction Scheme 1 and Synthesis Condition C, the above (48% yield), and 6-nitro-1H-benzo[d][1,2,3]triazole-4-carboxylic acid (5 mg) as a starting material. 1H NMR(500MHz,DMSO)δ10.93(s,1H), 9.32(d,J=7.2Hz,1H), 8.81(d,J=2.2Hz,1H), 8.48(d,J=2.2Hz,1H), 4. 78~4.67(m,J=12.6,7.0,5.5Hz,1H), 2.82(ddd,J=17.5,13.6,5.6Hz,1H), 2.53(s,1H), 2.26~2.08(m,2H). [Examples]

[0342] Synthesis of N-(2,6-dioxopiperidine-3-yl)benzo[d][1,2,3]thiadiazole-7-carboxamide (58)

[0343] [ka]

[0344] The compound was synthesized using the general procedure shown in Reaction Scheme 1 and Synthesis Condition B, the above (62% yield), and benzo[d][1,2,3]thiadiazole-7-carboxylic acid (10 mg) as a starting material. 1 H NMR(500MHz,DMSO)δ10.95(s,1H), 9.51(d,J=8.2Hz,1H), 9.01~8.89(m,1H), 8.53(dd,J=7.4,0.8Hz,1H), 7.97(dd,J=8.2,7.4Hz,1H), 4.96~4.84( m,1H), 2.84(ddd,J=17.4,13.4,5.5Hz,1H), 2.59(ddd,J=17.3,4.5,2.7Hz,1H), 2.21(qd,J=13.0,4.5Hz,1H), 2.05(dtd,J=13.0,5.3,2.7Hz,1H). LCMS(m / z[M+H] + ):291.1 [Examples]

[0345] Synthesis of N-(2,6-dioxopiperidine-3-yl)-2-methyl-1H-thieno[2,3-d]imidazole-6-carboxamide (59)

[0346] [ka]

[0347] Step A: A mixture of dioxane (3 mL), triethyl orthoacetate (3 mL), and methyl 4,5-diaminothiophene-3-carboxylate (400 mg, 2.04 mmol) in PTSA (102 mg, 0.40 mmol) was heated under reflux for 16 hours. The reaction mixture was concentrated under reduced pressure, and the crude material was purified by flash column chromatography to obtain 200 mg of methyl 2-methyl-1H-thieno[2,3-d]imidazole-6-carboxylate (50% yield).

[0348] Step B: To a stirred solution of methyl 2-methyl-1H-thieno[2,3-d]imidazole-6-carboxylate (0.13 g, 1.02 mmol) in methanol (0.5 mL) and THF (2 mL), NaOH (27 mg, 0.68 mmol) in water (0.5 mL) was added, and the resulting solution was stirred at room temperature for 16 hours. The reaction mixture was diluted with water and washed with ethyl acetate. The aqueous portion was acidified to approximately pH 5 with 6N HCl, and the resulting precipitate was filtered, washed with water, and purified by HPLC to obtain 70 mg (37%) of 2-methyl-1H-thieno[2,3-d]imidazole-6-carboxylic acid.

[0349] Step C: N-(2,6-dioxopiperidine-3-yl)-2-methyl-1H-thieno[2,3-d]imidazole-6-carboxyamide was synthesized using the general procedure shown in reaction scheme 1 and synthesis conditions B, the above (17% yield), and 2-methyl-3H-thieno[2,3-d]imidazole-6-carboxyamide (20 mg) as a starting material. 1H NMR (500MHz, DMSO): δ12.53(s,1H), 10.87(s,1H), 8.70(d,J=8.0Hz,1H), 7.82(s,1H), 4.78~4.67(m,1H), 2.81(ddd,J=1 7.4,13.3,5.5Hz,1H), 2.56(ddd,J=17.1,4.1,2.9Hz,1H), 2.43(s,3H), 2.16(qd,J=12.9,4.5Hz,1H), 2.04~1.96(m,1H). LCMS(m / z[M+H]+):293.0 [Examples]

[0350] Synthesis of N-(2,6-dioxopiperidine-3-yl)-1H-thieno[2,3-d]imidazole-6-carboxamide(60)

[0351] [ka]

[0352] Step A: A solution of methyl 4-acetamidothiophene-3-carboxylate (3 g, 12.3 mmol) in anhydrous acetic acid (40 mL) was cooled to -15°C. A pre-cooled solution of concentrated nitric acid (6 mL) in 30 mL of acetic anhydride (at -15°C) was added very slowly dropwise while stirring. After 30 minutes, the reaction mixture was poured onto crushed ice, and the resulting pale yellow solid was filtered. The solid was thoroughly washed with water and diethyl ether to obtain 2.4 g (81%) of methyl 4-acetamidothiophene-3-carboxylate.

[0353] Step B: Methanol (10 mL) was added to a stirred solution of methyl 4-acetamido-5-nitrothiophene-3-carboxylate (2 g, 8.19 mmol) in 4N HCl-dioxane (20 mL), and the resulting solution was heated at 100°C for 16 hours. After cooling, the dioxane was removed under reduced pressure. The residue was diluted with water and extracted with ethyl acetate. The organic layer was washed with saturated sodium bicarbonate and brine and dried over Na2SO4. After concentration under reduced pressure, 850 mg (51%) of crude methyl 4-amino-5-nitrothiophene-3-carboxylate was used in the next step without further purification.

[0354] Step C: SnCl2 was added to a stirred solution of methyl 4-amino-5-nitrothiophene-3-carboxylate (1 g, 4.95 mmol) in a mixture of dioxane-HCl (10 mL) and methanol (10 mL), and the resulting solution was stirred at room temperature for 2 hours. The reaction mixture was then poured over a pre-cooled solution of ammonium hydroxide and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, filtered, and dried under reduced pressure. 700 mg (82%) of crude methyl 4,5-diaminothiophene-3-carboxylate was used in the next step without further purification.

[0355] Step D: A stirring solution of methyl 4,5-diaminothiophene-3-carboxylate (650 mg, 3.78 mmol) in a mixture of trimethyl orthoformate (2.5 mL) and toluene (2.5 mL) was mixed with a catalytic amount of PTSA (189 mg, 0.75 mmol), and the resulting solution was heated at 110°C for 2 hours. After removing volatile substances under reduced pressure, the crude material was purified by flash column chromatography to obtain 350 mg (50%) of methyl 1H-thieno[2,3-d]imidazole-6-carboxylate.

[0356] Step E: To a stirred solution of methyl 1H-thieno[2,3-d]imidazole-6-carboxylate (400 mg, 2.2 mmol) in methanol (3 mL) and THF (3 mL), NaOH (439 mg, 10.9 mmol) dissolved in water (1 mL) was added, and the resulting solution was stirred for 16 hours. The reaction mixture was diluted with water and washed with ethyl acetate. The aqueous portion was acidified with 6N HCl to approximately pH 5, and the resulting brown precipitate was filtered and washed with water and diethyl ether to obtain 230 mg (62%) of 1H-thieno[2,3-d]imidazole-6-carboxylic acid.

[0357] Step F: N-(2,6-dioxopiperidine-3-yl)-1H-thieno[2,3-d]imidazole-6-carboxamide was synthesized using the general procedure shown in reaction scheme 1 and synthesis conditions B, the above (40% yield), and 1H-thieno[2,3-d]imidazole-6-carboxylic acid (20 mg) as a starting material. 1 H NMR(500MHz,DMSO)δ12.79(s,1H), 10.88(s,1H), 8.74(d,J=8.2Hz,1H), 7.99(d,J=1.3Hz,1H), 7.90(s,1H), 4.74(ddd,J=13.3,8.1,5.3Hz ,1H), 2.81(ddd,J=17.2,13.3,5.5Hz,1H), 2.57(dt,J=18.0,4.1Hz,1H), 2.16(qd,J=12.9,4.5Hz,1H), 2.01(dtd,J=13.1,5.4,2.8Hz,1H). LCMS(m / z[M+H] + ):279.0 [Examples]

[0358] Synthesis of N-(2,6-dioxopiperidine-3-yl)-2,5,6-trimethyl-4H-thieno[3,2-b]pyrrole-3-carboxamide (61)

[0359] [ka]

[0360] Step A: To a solution of ethyl 2,5,6-trimethyl-4H-thieno[3,2-b]-pyrrole-3-carboxylate (10.0 mg, 0.042 mmol, 1.000 equivalents) in a mixture of H2O (1.0 mL), THF (1.0 mL), and MeOH (1.0 mL), 1 M LiOH (2.0 mL, 2.000 mmol, 17.702 equivalents) was added. The reaction mixture was stirred at room temperature for 24 hours. After this time, the pH of the mixture was neutralized by adding 1 M HCl (2.0 mL, 2.000 mmol, 17.702 equivalents). The crude product was concentrated under vacuum and used in the next step without further purification.

[0361] Step B: N-(2,6-dioxopiperidine-3-yl)-2,5,6-trimethyl-4H-thieno[3,2-b]pyrrole-3-carboxyamide was synthesized using the general procedure shown in Reaction Scheme 1 and Synthesis Conditions B, the above (23% yield), and 2,5,6-trimethyl-4H-thieno[3,2-b]pyrrole-3-carboxyamide as a starting material (8.8 mg). 1H NMR(500MHz,DMSO)δ10.87(s,1H), 10.45(s,1H), 7.94(d,J=8.2Hz,1H), 4.76(ddd,J=12.3,8.2,5.4Hz,1H), 2.80(ddd,J=17.3,13. 4,5.6Hz,1H), 2.63(s,3H), 2.59~2.52(m,1H), 2.22(s,3H), 2.16(qd,J=13.0,4.5Hz,1H), 2.05(qd,J=4.8,2.3Hz,1H), 2.02(s,3H). LCMS(m / z[M+H] + ):319.8 [Examples]

[0362] Synthesis of N-(2,6-dioxopiperidine-3-yl)thieno[3,4-b]thiophene-2-carboxamide (62)

[0363] [ka]

[0364] The compound was synthesized using the general procedure shown in Reaction Scheme 1 and Synthesis Condition B, the above (50% yield), and thieno[3,4-b]thiophene-2-carboxylic acid (10 mg) as a starting material. 1 H NMR(500MHz,DMSO)δ10.89(s,1H), 8.94(d,J=8.3Hz,1H), 7.97(d,J=2.7Hz,1H), 7.76(s,1H), 7.71(dd,J=2.7,0.8Hz,1H), 4.78~4.71(m,1H), 2.85~2.76(m,1H), 2.59~2.52(m,1H), 2.12(qd,J=12.9,4.5Hz,1H), 2.00(dtd,J=12.9,5.4,2.8Hz,1H). LCMS(m / z[M+H] + ):294.5 [Examples]

[0365] Synthesis of 2-(3-((2-(2-(2-(4-(((S)-4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine-6-yl)acetamide)phenoxy)ethoxy)ethoxy)ethyl)amino)-3-oxopropyl)-N-(2,6-dioxopiperidine-3-yl)-1H-benzo[d]imidazole-7-carboxamide (63)

[0366] [ka]

[0367] Step A: A mixture of methyl 2,3-diaminobenzoate (2 g, 12.05 mmol) and succinic anhydride (1.2 g, 12.05 mmol) in acetic acid (70 mL) was heated at 80°C for 16 hours. After the reaction was complete, the acetic acid was removed under reduced pressure. The crude product was crushed with water (10 mL), filtered, the solid was washed with cold water (5 mL), and dried in vacuum to provide 2.5 g (83%) of 3-(7-(methoxycarbonyl)-1H-benzo[d]imidazole-2-yl)propanoic acid.

[0368] Step B: DIPEA (0.175 mL, 1.0 mmol, 4 equivalents) was added to a solution of 2-(2-(2-(4-nitrophenoxy)ethoxy)ethoxy)ethanamine (77 mg, 0.251 mmol, 1 equivalent), 3-(7-(methoxycarbonyl)-1H-benzo[d]imidazole-2-yl)propanoic acid (74.8 mg, 0.301 mmol, 1.2 equivalents), DMAP (3.1 mg, 0.025 mmol, 0.1 equivalent), and HATU (114.5 mg, 0.301 mmol, 1.2 equivalents) in DMF (13 mL). The reaction mixture was stirred at room temperature for 2 hours. After evaporation of the solvent, the crude product was purified by HPLC to provide 87 mg (69%) of methyl 2-(3-((2-(2-(2-(4-nitrophenoxy)ethoxy)ethoxy)ethyl)amino)-3-oxopropyl)-1H-benzo[d]imidazole-7-carboxylate.

[0369] Step C: Methyl 2-(3-((2-(2-(2-(4-nitrophenoxy)ethoxy)ethoxy)ethyl)amino)-3-oxopropyl)-1H-benzo[d]imidazole-7-carboxylate (85 mg, 0.170 mmol, 1 equivalent) was dissolved in 20 mL of EtOH and 10 mL of water. Then, NH4Cl (2.27 g, 250 equivalents) was added, followed by Fe powder (663 mg, 70 equivalents), and the flask was immediately closed with a septum. The slurry was stirred at 40°C for 3 hours. The mixture was diluted with water, filtered on Celite, and the solid residue was washed with DCM. The filtrate was extracted with DCM, dried over Na2SO4, and evaporated to obtain 77 mg (97%) of methyl 2-(3-((2-(2-(2-(4-aminophenoxy)ethoxy)ethoxy)ethyl)amino)-3-oxopropyl)-1H-benzo[d]imidazole-7-carboxylate.

[0370] Step D: Methyl 2-(3-((2-(2-(2-(4-aminophenoxy)ethoxy)ethoxy)ethyl)amino)-3-oxopropyl)-1H-benzo[d]imidazole-7-carboxylate (75 mg, 0.159 mmol, 1.04 equivalents), (S)-[4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][ To a solution of [1,2,4]triazolo[4,3-a][1,4]diazepine-6-yl]acetic acid (61.5 mg, 0.15 mmol, 1 equivalent), HATU (72.7 mg, 0.191 mmol, 1.2 equivalents), and DMAP (1.9 mg, 0.016 mmol, 0.1 equivalent), DIPEA (0.111 mL, 0.638 mmol, 4 equivalents) was added, and the reaction mixture was stirred at room temperature for 3 hours. DMF was removed under reduced pressure, and the residue was redissolved in methanol (8 mL). 1 M lithium hydroxide in water (8 mL) was added, and the reaction mixture was stirred at room temperature for 2 hours. The mixture was neutralized with 1M HCl, concentrated under reduced pressure, and purified by HPLC to obtain (S)-2-(3-((2-(2-(2-(4-(2-(4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine-6-yl)acetamide)phenoxy)ethoxy)ethoxy)ethyl)amino)-3-oxopropyl)-1H-benzo[d]imidazole-7-carboxylic acid (40 mg, 30%).

[0371] Step E: (S)-2-(3-((2-(2-(2-(4-(2-(4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine-6-yl)acetamide)phenoxy)ethoxy)ethoxy)ethyl)amino)-3-oxopropyl)-1H-benzo[d]imidazole-7-carboxylic acid (21.5 mg, 0.026 mmol, 1 equivalent), 3-aminopiperidine-2,6-dione hydrochloride (12.6 mg, 0.77 mmol, 3 equivalents), HATU (29.2 mg, 0.077 mmol, 3 equivalents), and DMAP (0.3 mg, 0.003 mmol, 0.1 equivalent) were dissolved in DMF (2 mL). DIPEA (0.036 mL, 0.205 mmol, 8 equivalents) was added, and the reaction mixture was stirred at room temperature for 2 hours. The solvent was removed under reduced pressure, and the residue was purified by preparative HPLC to obtain 2-(3-((2-(2-(2-(4-(((S)-4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine-6-yl)acetamide)phenoxy)ethoxy)ethoxy)ethyl)amino)-3-oxopropyl)-N-(2,6-dioxopiperidine-3-yl)-1H-benzo[d]imidazole-7-carboxamide (14.6 mg, 60%). 1H NMR(500MHz,DMSO)δ12.69(s,1H), 10.91(s,1H), 10.35(d,J=6.7Hz,1H), 10.15 (s,1H), 7.97(s,1H), 7.81(d,J=7.5Hz,1H), 7.64(d,J=7.7Hz,1H), 7.55~7.50(m ,2H), 7.48(d,J=8.8Hz,2H), 7.42(d,J=8.6Hz,2H), 7.27(t,J=7.7Hz,1H), 6.89( d,J=9.1Hz,2H), 4.86(d,J=6.7Hz,1H), 4.59(t,J=7.1Hz,1H), 4.07~4.00(m,2H) , 3.74~3.66(m,2H), 3.54(d,J=4.8Hz,2H), 3.49(d,J=4.8Hz,2H), 3.46(d,J=7.1 Hz,2H), 3.39(t,J=5.8Hz,2H), 3.20(dd,J=11.4,5.6Hz,2H), 3.11(t,J=7.4Hz,2 H), 2.88~2.77(m,1H), 2.71(t,J=7.3Hz,2H), 2.60(s,2H), 2.57(d,J=18.5Hz,1H ), 2.42(d,J=0.6Hz,3H), 2.24(s,1H), 2.20~2.09(m,1H), 1.63(d,J=0.6Hz,3H). LCMS(m / z[M+H] + ):949.9 [Examples]

[0372] Synthesis of 2-(3-((8-(2-((S)-4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine-6-yl)acetamide)octyl)amino)-3-oxopropyl)-N-(2,6-dioxopiperidine-3-yl)-1H-benzo[d]imidazole-7-carboxamide (64)

[0373] [ka]

[0374] Step A: DIPEA (0.110 mL, 0.630 mmol, 6 equivalents) was added to a solution of (S)-N-(8-aminooctyl)-2-(4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine-6-yl)acetamide (59.2 mg, 0.105 mmol, 1 equivalent), 3-(7-(methoxycarbonyl)-1H-benzo[d]imidazole-2-yl)propanoic acid (31.3 mg, 0.126 mmol, 1.2 equivalents), HATU (47.9 mg, 0.126 mmol, 1.2 equivalents), and DMAP (1.3 mg, 0.011 mmol, 0.1 equivalent) in DMF (5 mL). The reaction mixture was stirred at room temperature for 18 hours, the solvent was removed under reduced pressure, and the residue was purified by flash column chromatography to obtain 79.5 mg (over 99%) of methyl(S)-2-(3-((8-(2-(4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine-6-yl)acetamide)octyl)amino)3-oxopropyl)-1H-benzo[d]imidazole-7-carboxylate.

[0375] Step B: To a solution of methyl(S)-2-(3-((8-(2-(4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine-6-yl)acetamide)octyl)amino)-3-oxopropyl)-1H-benzo[d]imidazole-7-carboxylate (79.5 mg, 0.105 mmol, 1 equivalent) in THF (2.5 mL), methanol (0.5 mL), and water (0.9 mL), lithium hydroxide (80 mg, 3.34 mmol) was added, and the reaction mixture was stirred at room temperature for 18 hours. The solution was acidified with 1 M HCl and extracted with ethyl acetate. The organic phase was dried over Na2SO4 and concentrated under reduced pressure to obtain (S)-2-(3-((8-(2-(4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine-6-yl)acetamide)octyl)amino)-3-oxopropyl)-1H-benzo[d]imidazole-7-carboxylic acid (75 mg, 96%).

[0376] Step C: (S)-2-(3-((8-(2-(4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine-6-yl)acetamide)octyl)amino)-3-oxopropyl)-1H-benzo[d]imidazole-7-carboxylic acid (70 mg, 0.094 mmol, 1 equivalent), 3-aminopiperidine-2,6-dione hydrochloride (18.6 mg, 0.113 mmol, 1.2 equivalents), HATU (43 mg, 0.113 mmol, 1.2 equivalents), and DMAP (0.2 mg, 0.009 mmol, 0.1 equivalent) were dissolved in DMF (3.6 mL). DIPEA (0.049 mL, 0.283 mmol, 3 equivalents) was added, and the reaction mixture was stirred at room temperature for 18 hours. The solvent was removed under reduced pressure, and the residue was purified by preparative HPLC to obtain 31 mg (26%) of 2-(3-((8-(2-((S)-4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine-6-yl)acetamide)octyl)amino)-3-oxopropyl)-N-(2,6-dioxopiperidine-3-yl)-1H-benzo[d]imidazole-7-carboxamide. 1H NMR(500MHz,DMSO)δ12.70(s,1H), 10.93(s,1H), 10.37(s,1H), 8.14(t,J=5.6Hz,1H), 7.83(s,1H), 7.82(s,1H), 7.66(s,1H), 7.47(d,J=8 .8Hz,2H), 7.41(dd,J=10.2,8.4Hz,2H), 7.29(s,1H), 4.85(d,J=5.2Hz,1H), 4.55~4.46(m,1H), 3.28~3.15(m,2H), 3.15~3.05(m,4H), 3.05 ~2.95(m,2H), 2.83(ddd,J=17.5,13.3,5.6Hz,1H), 2.68(t,J=7.4Hz,2H), 2.59(s,3H), 2.55(dd,J=10.8,3.7Hz,1H), 2.40(d,J=0.5Hz,3H) ), 2.36(dt,J=14.1,6.1Hz,1H), 2.32~2.24(m,1H), 1.62(d,J=0.5Hz,3H), 1.45~1.36(m,2H), 1.36~1.28(m,2H), 1.23(s,3H), 1.16(s,5H). LCMS(m / z[M+H] + ):852.9 [Examples]

[0377] Synthesis of 1-(2-((8-(2-((S)-4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine-6-yl)acetamide)octyl)amino)-2-oxoethyl)-N-(2,6-dioxopiperidine-3-yl)-2-methyl-1H-benzo[d]imidazole-4-carboxamide (65)

[0378] [ka]

[0379] Step A: To a solution of methyl 3-fluoro-2-nitrobenzoate (150 mg, 0.753 mmol, 1 equivalent) and glycine tert-butyl hydrochloride (429 mg, 2.56 mmol, 3.4 equivalents) in acetonitrile (6 mL), DIPEA (0.656 mL, 3.75 mmol, 5 equivalents) was added, and the reaction mixture was stirred at 70 °C for 18 hours. The solvent was removed under reduced pressure, and the residue was purified by flash column chromatography to provide methyl 3-((2-(tert-butoxy)-2-oxoethyl)amino)-2-nitrobenzoate (149 mg, 63%).

[0380] Step B: Methyl 3-((2-(tert-butoxy)-2-oxoethyl)amino)-2-nitrobenzoate (70 mg, 0.226 mmol, 1 equivalent) was dissolved in ethanol (5 mL) and water (2 mL). Iron powder (882 mg, 70 equivalents), followed by ammonium chloride (3.02 g, 250 equivalents), was added, and the reaction mixture was stirred at 40°C for 18 hours. The reaction mixture was filtered, the solid was washed with DCM, and the filtrate was concentrated under reduced pressure. The crude product was purified by flash column chromatography to provide methyl 2-amino-3-((2-(tert-butoxy)-2-oxoethyl)amino)benzoate (36 mg, 56%).

[0381] Step C: Methyl 2-amino-3-((2-(tert-butoxy)-2-oxoethyl)amino)benzoate (110 mg, 0.393 mmol, 1 equivalent) was dissolved in hexafluoroisopropanol (4 mL). Ethyl orthoacetate (0.577 mL, 3.14 mmol, 8 equivalents) was added, and the reaction mixture was stirred at room temperature for 60 hours. After removing volatile substances under reduced pressure, the reaction mixture was purified by flash column chromatography to provide methyl 1-(2-(tert-butoxy)-2-oxoethyl)-2-methyl-1H-benzo[d]imidazole-4-carboxylate (89 mg, 74%).

[0382] Step D: Methyl 1-(2-(tert-butoxy)-2-oxoethyl)-2-methyl-1H-benzo[d]imidazole-4-carboxylate (30.4 mg, 0.100 mmol, 1 equivalent) was dissolved in trifluoroacetic acid (3 mL), and the reaction mixture was stirred at room temperature for 18 hours. Volatile substances were removed under reduced pressure, and the mixture was dried under high vacuum. HATU (48.8 mg, 1.28 mmol, 1.28 equivalents), DMAP (1.3 mg, 0.011 mmol, 0.11 equivalents), and (S)-N-(8-aminooctyl)-2-(4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine-6-yl)acetamide (50 mg, 0.11 mmol, 1.1 equivalents) were added, followed by DMF (12 mL) and DIPEA (0.225 mL, 1.28 mmol, 12 equivalents). The reaction mixture was stirred at room temperature for 6 hours, and the solvent was removed under reduced pressure. The solid was redissolved in methanol (4 mL) and water (1 mL), and lithium hydroxide (64 mg, 25 equivalents) was added. The mixture was stirred at room temperature for 72 hours. The mixture was acidified by adding 1M HCl, the solvent was evaporated, and the residue was purified by HPLC to provide (S)-1-(2-((8-(2-(4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine-6-yl)acetamide)octyl)amino)-2-oxoethyl)-2-methyl-1H-benzo[d]imidazole-4-carboxylic acid (69.4 mg, 87%).

[0383] Step E: (S)-1-(2-((8-(2-(4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine-6-yl)acetamide)octyl)amino)-2-oxoethyl)-2-methyl-1H-benzo[d]imidazole-4-carboxylic acid (14 mg, 0.019 mmol, 1 equivalent), 3-aminopiperidine-2,6-dione hydrochloride (18.6 mg, 0.113 mmol, 1.2 equivalents), HATU (43 mg, 0.113 mmol, 1.2 equivalents), and DMAP (0.5 mg, 0.004 mmol, 0.1 equivalent) were dissolved in NMP (2 mL). DIPEA (0.098 mL, 0.565 mmol, 30 equivalents) was added, and the reaction mixture was stirred at room temperature for 3 hours. Purification of the reaction mixture by HPLC provided 1-(2-((8-(2-((S)-4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine-6-yl)acetamide)octyl)amino)-2-oxoethyl)-N-(2,6-dioxopiperidine-3-yl)-2-methyl-1H-benzo[d]imidazole-4-carboxamide (6.4 mg, 39%). 1H NMR(500MHz,DMSO)δ10.91(s,1H), 10.23(d,J=7.3Hz,1H), 8.33(t,J=5.6Hz,1H), 8.15(q,J=5.4Hz,1H), 7.85(dd,J=7.6,1.0 Hz,1H), 7.64(dd,J=8.1,1.0Hz,1H), 7.48(dd,J=8.8,3.1Hz,3H), 7.42(dd,J=8.7,2.0Hz,3H), 7.31(t,J=7.8Hz,1H), 4.94(s ,2H), 4.89(ddd,J=12.6,9.0,5.3Hz,1H), 4.50(dd,J=8.1,6.1Hz,1H), 2.86~2.77(m,2H), 2.58(d,J=5.1Hz,3H), 2.56(d,J=4 .0Hz,3H), 2.40(d,J=0.5Hz,3H), 2.28~2.21(m,1H), 2.18~2.07(m,1H), 1.61(s,3H), 1.47~1.36(m,5H), 1.33~1.19(m,12H). LCMS(m / z[M+H] + ):853.9 [Examples]

[0384] Synthesis of 5-(2-((8-(2-((S)-4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine-6-yl)acetamide)octyl)amino)-2-oxoethoxy)-N-(2,6-dioxopiperidine-3-yl)-2-methyl-1H-benzo[d]imidazole-7-carboxamide (66)

[0385] [ka]

[0386] Step A: Methyl 3,5-difluoro-2-nitro-benzoate (10 g, 46.083 mmol) was dissolved in DMF and treated with ammonium carbonate (5.3 g, 55.3 mmol). The reaction mixture was heated at 60°C for 6 hours. The reaction mixture was diluted with ethyl acetate and washed sequentially with water and brine. The organic layer was dried over Na2SO4 and concentrated under reduced pressure to obtain the crude product, which was purified by flash column chromatography to obtain 7.6 g (77%) of methyl 3-amino-5-fluoro-2-nitro-benzoate.

[0387] Step B: Sodium hydride (706 mg, 17.674 mmol) was added to a solution of tert-butyl 2-hydroxyacetate (2.4 g, 18.6 mmol) in DMF (100 ml) under nitrogen at 0°C. The reaction mixture was stirred at 0°C for 30 minutes. Methyl 3-amino-5-fluoro-2-nitrobenzoate (2 g, 9.302 mmol) was added to the mixture at 0°C. The resulting mixture was stirred at room temperature for 1.5 hours. The reaction mixture was then cooled to 0°C and stopped by adding saturated ammonium chloride solution, diluted with ethyl acetate, and washed with water. The organic layer was dried over Na2SO4 and concentrated under reduced pressure to obtain the crude product, which was purified by flash column chromatography to obtain 1.5 g (49%) of methyl 3-amino-5-(2-(tert-butoxy)-2-oxoethoxy)-2-nitrobenzoate.

[0388] Step C: Methyl 3-amino-5-(2-(tert-butoxy)-2-oxoethoxy)-2-nitrobenzoate (1.5 g, 4.6 mmol) was dissolved in methanol (30 mL), the reaction mixture was deoxygenated using an argon balloon, and palladium (75 mg) on ​​charcoal was added. The reaction vessel was backfilled with hydrogen (1 bar), stirred at room temperature for 18 hours, and filtered on Celite. The filtrate was concentrated under reduced pressure, and the residue was purified by flash column chromatography to obtain 900 mg (66%) of methyl 2,3-diamino-5-(2-(tert-butoxy)-2-oxoethoxy)benzoate.

[0389] Step D: To an aqueous solution of sodium bisulfite (40% in water, 15 mL, and 4.561 mmol), methyl 2,3-diamino-5-(2-(tert-butoxy)-2-oxoethoxy)benzoate (900 mg, 3.041 mmol), followed by a solution of acetaldehyde (0.3 ml, 4.561 mmol) in ethanol (15 mL). The reaction mixture was heated under reflux for 4 hours. Volatile substances were removed under reduced pressure, the mixture was diluted with dichloromethane, and washed with water and brine. The organic layer extract was dried over Na2SO4 and concentrated under reduced pressure to obtain the crude product, which was purified by flash column chromatography to obtain methyl 6-(2-(tert-butoxy)-2-oxoethoxy)-2-methyl-1H-benzo[d]imidazole-4-carboxylate 400 mg (40%).

[0390] Step E: Methyl 6-(2-(tert-butoxy)-2-oxoethoxy)-2-methyl-1H-benzo[d]imidazole-4-carboxylate (400 mg, 1.25 mmol) was suspended in dioxane (5 mL) and cooled to 0°C. 4 M HCl was added dropwise to dioxane (4 mL), and the reaction mixture was stirred at room temperature for 16 hours. Volatile substances were removed under reduced pressure, and the product was crushed with ether and pentane to obtain 300 mg (91%) of 2-((4-(methoxycarbonyl)-2-methyl-1H-benzo[d]imidazole-6-yl)oxy)acetic acid.

[0391] Step F: In a solution of (S)-N-(8-aminooctyl)-2-(4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine-6-yl)acetamide (55 mg, 0.098 mmol, 1 equivalent), 2-((7-(methoxycarbonyl)-2-methyl-1H-benzo[d]imidazole-5-yl)oxy)acetic acid (31 mg, 0.117 mmol, 1.2 equivalents), and HATU (260 mg, 0.976 mmol, 7 equivalents), DIPEA (0.170 mL, 0.976 mmol, 10 equivalents) was added, and the reaction mixture was stirred at room temperature for 20 hours. The solvent was removed under reduced pressure, and the residue was purified by flash column chromatography to obtain methyl(S)-5-(2-((8-(2-(4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine-6-yl)acetamide)octyl)amino)-2-oxoethoxy)-2-methyl-1H-benzo[d]imidazole-7-carboxylate (35 mg, 46%).

[0392] Step G: To a solution of methyl(S)-5-(2-((8-(2-(4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine-6-yl)acetamide)octyl)amino)-2-oxoethoxy)-2-methyl-1H-benzo[d]imidazole-7-carboxylate (34 mg, 0.044 mmol, 1 equivalent) in methanol (2 mL), sodium hydroxide (2.3 ml, 1 M) was added, and the reaction mixture was stirred at room temperature for 20 hours. The base was neutralized by adding 1 M HCl, and the mixture was evaporated under reduced pressure. To the residue, 3-aminopiperidine-2,6-dione hydrochloride (37 mg, 0.224 mmol, 5 equivalents), HATU (34 mg, 0.090 mmol, 2 equivalents), and NMP (1 mL) were added. DIPEA (0.023 mL, 0.134 mmol, 3 equivalents) was added, and the reaction mixture was stirred at room temperature for 20 hours. Purification of the reaction mixture by HPLC yielded 26 mg (65%) of 5-(2-((8-(2-((S)-4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine-6-yl)acetamide)octyl)amino)-2-oxoethoxy)-N-(2,6-dioxopiperidine-3-yl)-2-methyl-1H-benzo[d]imidazole-7-carboxamide. 1H NMR(500MHz,DMSO)δ12.57(s,1H), 10.90(s,1H), 10.25(d,J=7.3Hz,1H), 8.12(dd,J=13.5,5.8Hz,2H), 7.52~7.40(m, 5H), 7.18(d,J=2.5Hz,1H), 4.87(ddd,J=12.6,7.2,5.4Hz,1H), 4.53~4.46(m,3H), 3.21(ddd,J=21.0,15.0,7.1Hz,3H ), 3.08(ddd,J=18.9,13.1,6.3Hz,4H), 2.82(ddd,J=18.5,15.9,8.7Hz,1H), 2.59(s,3H), 2.53(s,3H), 2.40(d,J=0.5 Hz,3H), 2.27~2.17(m,1H), 2.11(qd,J=12.9,3.8Hz,1H), 1.61(s,3H), 1.41(d,J=6.5Hz,4H), 1.22(d,J=14.5Hz,8H). LCMS(m / z[M+H] + ):869.9 [Examples]

[0393] Synthesis of 6-(2-((8-(2-((S)-4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine-6-yl)acetamide)octyl)amino)-2-oxoethoxy)-N-(2,6-dioxopiperidine-3-yl)-2-methyl-1H-benzo[d]imidazole-7-carboxamide (67)

[0394] [ka]

[0395] Step A: Methyl 2,6-difluoro-3-nitro-benzoate (10 g, 46.08 mmol) was dissolved in DMF and treated with ammonium carbonate (5.3 g, 55.3 mmol). The reaction mixture was heated at 60°C for 6 hours. The reaction mixture was diluted with ethyl acetate and washed sequentially with water and brine. The organic layer was dried over Na2SO4 and concentrated under reduced pressure to obtain the crude product, which was purified by flash column chromatography to obtain 5.1 g (51%) of methyl 2-amino-6-fluoro-3-nitro-benzoate.

[0396] Step B: Sodium hydride (896 mg, 22.43 mmol) was added to a solution of tert-butyl 2-hydroxyacetate (3.1 g, 23.3 mmol) in DMF (100 ml) under nitrogen at 0°C. The reaction mixture was stirred at 0°C for 30 minutes, and methyl 2-amino-6-fluoro-3-nitro-benzoate (2 g, 9.302 mmol) was added at 0°C. The resulting mixture was stirred at room temperature for 1.5 hours. The reaction mixture was then cooled to 0°C and stopped by adding saturated ammonium chloride solution, diluted with ethyl acetate, and washed with water. The organic layer was dried over Na2SO4 and concentrated under reduced pressure to obtain the crude product, which was purified by flash column chromatography to obtain 700 mg (23%) of methyl 2-amino-6-(2-(tert-butoxy)-2-oxoethoxy)-3-nitrobenzoate.

[0397] Step C: Methyl 2-amino-6-(2-(tert-butoxy)-2-oxoethoxy)-3-nitrobenzoate (700 mg, 2.14 mmol) was dissolved in methanol (30 mL). The reaction mixture was deoxygenated using an argon balloon, and palladium (70 mg) on ​​charcoal was added. The reaction vessel was backfilled with hydrogen (1 bar), stirred at room temperature for 18 hours, and filtered on Celite. The filtrate was concentrated under reduced pressure, and the residue was purified by flash column chromatography to obtain 600 mg (94%) of methyl 2,3-diamino-6-(2-(tert-butoxy)-2-oxoethoxy)-benzoate.

[0398] Step D: To an aqueous solution of sodium bisulfite (40% in water, 15 mL, and 3.041 mmol), methyl 2,3-diamino-6-(2-(tert-butoxy)-2-oxoethoxy)-benzoate (600 mg, 2.027 mmol), followed by a solution of acetaldehyde (0.2 ml, 3.041 mmol) in ethanol (15 mL). The reaction mixture was heated under reflux for 4 hours. Volatile substances were removed under reduced pressure, the mixture was diluted with dichloromethane, and washed with water and brine. The organic layer extract was dried over Na2SO4 and concentrated under reduced pressure to obtain the crude product, which was purified by flash column chromatography to obtain methyl 5-(2-(tert-butoxy)-2-oxoethoxy)-2-methyl-1H-benzo[d]imidazole-4-carboxylate 400 mg (61%).

[0399] Step E: Methyl 5-(2-(tert-butoxy)-2-oxoethoxy)-2-methyl-1H-benzo[d]imidazole-4-carboxylate (400 mg, 1.25 mmol, 1 equivalent) was suspended in dioxane (5 mL) and cooled to 0°C. 4M HCl in dioxane (4 mL) was added dropwise, and the reaction mixture was stirred at room temperature for 16 hours. Volatile substances were removed under reduced pressure, and the product was crushed with ether and pentane to obtain 280 mg (84%) of 2-((7-(methoxycarbonyl)-2-methyl-1H-benzo[d]imidazole-6-yl)oxy)acetic acid.

[0400] Step F: In a solution of (S)-N-(8-aminooctyl)-2-(4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine-6-yl)acetamide (55 mg, 0.098 mmol, 1 equivalent), 2-((7-(methoxycarbonyl)-2-methyl-1H-benzo[d]imidazole-6-yl)oxy)acetic acid (31 mg, 0.117 mmol, 1.2 equivalents), and HATU (260 mg, 0.976 mmol, 7 equivalents), DIPEA (0.170 mL, 0.976 mmol, 10 equivalents) was added, and the reaction mixture was stirred at room temperature for 20 hours. The solvent was removed under reduced pressure, and the residue was purified by flash column chromatography to obtain 36 mg (47%) of methyl(S)-6-(2-((8-(2-(4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine-6-yl)acetamide)octyl)amino)-2-oxoethoxy)-2-methyl-1H-benzo[d]imidazole-7-carboxylate.

[0401] Step G: To a solution of methyl(S)-6-(2-((8-(2-(4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine-6-yl)acetamide)octyl)amino)-2-oxoethoxy)-2-methyl-1H-benzo[d]imidazole-7-carboxylate (35 mg, 0.045 mmol, 1 equivalent) in methanol (2 mL), sodium hydroxide (2.3 ml, 1 M) was added, and the reaction mixture was stirred at room temperature for 20 hours. The base was neutralized by adding 1 M HCl, and the mixture was evaporated under reduced pressure. To the residue, 3-aminopiperidine-2,6-dione hydrochloride (37 mg, 0.224 mmol, 5 equivalents), HATU (34 mg, 0.090 mmol, 2 equivalents), and NMP (1 mL) were added. DIPEA (0.023 mL, 0.134 mmol, 3 equivalents) was added, and the reaction mixture was stirred at room temperature for 20 hours. Purification of the reaction mixture by HPLC yielded 24 mg (60%) of 6-(2-((8-(2-((S)-4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine-6-yl)acetamide)octyl)amino)-2-oxoethoxy)-N-(2,6-dioxopiperidine-3-yl)-2-methyl-1H-benzo[d]imidazole-7-carboxamide. 1H NMR(500MHz,DMSO)δ12.06(s,1H), 10.87(s,1H), 9.45(d,J=7.9Hz,1H), 8.24~8.06(m,2H), 7.60(d,J=8.7Hz,1H), 7.48 (d,J=8.8Hz,2H), 7.42(d,J=8.6Hz,2H), 6.86(d,J=8.8Hz,1H), 4.84~4.75(m,1H), 4.73~4.54(m,2H), 4.50(dd,J=8.1,6 .1Hz,1H), 3.21(ddd,J=21.0,15.0,7.1Hz,3H), 3.15~3.03(m,4H), 2.87~2.77(m,1H), 2.59(s,3H), 2.48(s,3H), 2.40(d ,J=0.5Hz,3H), 2.27(qd,J=13.0,4.4Hz,1H), 2.12~2.05(m,1H), 1.62(d,J=0.5Hz,3H), 1.48~1.35(m,4H), 1.23(s,8H). LCMS(m / z[M+H] + ):868.8 [Examples]

[0402] Fluorescence Polarization (FP) assay The CRBN-DDB1 protein complex was mixed with Cy5-labeled thalidomide and the compound under test ("test compound"). The test solution contained 50 mM Tris pH=7.0, 200 mM NaCl, 0.02% v / v Tween-20, 2 mM DTT, 5 nM Cy5-labeled thalidomide (tracer), 25 nM CRBN-DDB1 protein, and 2% v / v DMSO. The test solution was added to a 384-well assay plate.

[0403] The plates were spun down (1 minute, 1000 rpm, 22°C), and then shaken for 10 minutes at room temperature (20-25°C) using a VibroTurbulator with the frequency set to level 3. The assay plates containing the proteins and tracers were incubated at room temperature (20-25°C) for 60 minutes, and then read out with a plate reader. Readout (fluorescence polarization) was performed using a Pherastar plate reader with a Cy5 FP Filterset (590 nm / 675 nm).

[0404] K i To measure the values, FP experiments were performed with test compounds at various concentrations.

[0405] IC relationship between compound concentration and measured fluorescence polarization 50 Values, Cy5-T and CRBN / DDB1 complex K d Using the values ​​and equations based on the concentrations of protein and tracer in the substitution assay (described in Z. Nikolovska-Coleska et al., Analytical Biochemistry 332 (2004) 261-273), the K of competitive inhibitors i The value was calculated.

[0406] Fluorescence polarization (FP) assay - results The compounds are categorized based on their affinity for CRBN, which is defined as Ki. As reported in Table 1 below, the compounds of the present invention interact with the CRBN-DDB1 protein within the same affinity range as reported for the reference compound.

[0407] [Table 2] JPEG0007852923000134.jpg213170JPEG0007852923000135.jpg223170JPEG0007852923 000136.jpg235170JPEG0007852923000137.jpg235170JPEG0007852923000138.jpg65170 * CRBN binding Ki[μM]A≦1;1 <B≦10、10<C≦50 [Examples]

[0408] SALL 4-degradation assay - Kelly cell line The effects of various compounds of the present invention and various reference compounds on SALL4 degradation in Kelly cell lines were investigated using the degradation assay protocol described below.

[0409] Kelly cells were maintained in RPMI-1640 medium supplemented with penicillin / streptomycin and 10% fetal bovine serum (FBS). Cells were seeded on 6-well plates, and the compounds to be tested were added within the desired concentration range. The final DMSO concentration was 0.25%. After 24 hours of incubation (37°C, 5% CO2), the cells were washed, and cell solubilizes were prepared using RIPA lysis buffer. Protein levels were determined via BCA assay, and appropriate amounts were then loaded onto precast gels for protein separation. After primary and secondary Ab staining, the membranes were washed, and signals were detected. Densitometry analysis was performed to obtain numerical values ​​to be used later in the protein level assessment process.

[0410] The compounds tested in this assay were: lenalidomide, pomalidomide, 39, 35, and 50 at concentrations of 10 μM and 20 μM, and the group of compounds listed in Table 3 at a concentration of 20 μM; treatment with all compounds was carried out for 24 hours. Densitometry values ​​were normalized to the loaded control (β-actin) and expressed as a percentage of the DMSO control using the following notation: Regarding the reduction of SALL4 protein from 0-25%, less than 25%. Regarding the reduction of SALL4 protein, over 25% accounted for 26-74%. Regarding the reduction of SALL4 protein, it was over 75% for the 75-100% range.

[0411] Representative results for compounds lenalidomide, 39, 35, 50, and pomalidomide are shown in Figure 1 and Table 2. The remaining compounds are shown in Table 10. As illustrated in Figure 1 and Tables 2 and 10, the compounds of the present invention, unlike the reference compounds lenalidomide or pomalidomide, do not possess the ability to degrade SALL4.

[0412] [Table 3]

[0413] [Table 4] [Examples]

[0414] CK1α degradation assay - Kelly cell line The effects of various compounds of the present invention and various reference compounds on CK1α degradation in Kelly cell lines were investigated using the degradation assay protocol described below.

[0415] Kelly cells were maintained in RPMI-1640 medium supplemented with penicillin / streptomycin and 10% fetal bovine serum (FBS). Cells were seeded on 6-well plates, and the compounds to be tested were added within the desired concentration range. The final DMSO concentration was 0.25%. After 24 hours of incubation (37°C, 5% CO2), the cells were washed, and cell solubilizes were prepared using RIPA lysis buffer. Protein levels were determined via BCA assay, and appropriate amounts were then loaded onto precast gels for protein separation. After primary and secondary Ab staining, the membranes were washed, and signals were detected. Densitometry analysis was performed to obtain numerical values ​​to be used later in the protein level assessment process.

[0416] The compounds tested in this assay were: lenalidomide, pomalidomide, 39, 35, and 50 at concentrations of 10 μM and 20 μM, and the group of compounds listed in Table 3 at a concentration of 20 μM; treatment with all compounds was carried out for 24 hours. Densitometry values ​​were normalized to the loaded control (β-actin) and expressed as a percentage of the DMSO control using the following notation: Regarding the reduction of CK1α protein from 0-25%, 25% or less. Regarding the reduction of CK1α protein, which is 26-74%, over 25% Regarding the reduction of CK1α protein, the figure is 75% or higher, compared to 75-100%.

[0417] Representative results for compounds lenalidomide, 39, 35, 50, and pomalidomide are shown in Figure 2 and Table 4. The remaining compounds are shown in Table 10. As illustrated in Figure 2 and Tables 4 and 10, the compounds of the present invention do not induce CK1α degradation in the Kelly cell line, which is degraded by the reference compound lenalidomide, or to a lesser extent by pomalidomide.

[0418] [Table 5] [Examples]

[0419] IKZF1 degradation assay - H929 cell line The effects of various compounds of the present invention and various reference compounds on IKZF1 degradation in the H929 cell line were investigated using the degradation assay protocol described below.

[0420] H929 cells were maintained in RPMI-1640 medium supplemented with penicillin / streptomycin, 10% fetal bovine serum (FBS), and 0.05 mM 2-mercaptoethanol. Cells were seeded on 6-well or 12-well plates, and the compounds to be tested were added within the desired concentration range. The final DMSO concentration was 0.25%. After 6 or 24 hours of incubation (37°C, 5% CO2), cells were harvested, washed, and cell solubilizes were prepared using RIPA lysis buffer. Protein levels were determined via BCA assay, and appropriate amounts were then loaded onto precast gels for protein separation. After primary and secondary Ab staining, the membranes were washed, and signals were detected. Densitometry analysis was performed to obtain numerical values ​​to be used later in the protein level assessment process.

[0421] The compounds tested in this assay were: 39, 35, 50, lenalidomide and pomalidomide at concentrations of 10 μM and 20 μM, and the group of compounds listed in Table 5 at a concentration of 20 μM; treatment with all compounds was performed over a 24-hour period. Additionally, compounds 64, 66 and ARV-825 were tested in this assay at concentrations of 0.1 μM, 1 μM and 10 μM for a duration of 6 hours. Densitometry values ​​were normalized to the loaded control (β-actin) and expressed as a percentage of the DMSO control using the following notation: Regarding the reduction of IKZF1 protein from 0-25%, less than 25%. Regarding IKZF1 protein reduction, over 25% accounted for 26-74%. Regarding the reduction of IKZF1 protein, it was over 75% for 75-100% of cases.

[0422] Table 5 lists the compounds tested in the IKZF1 degradation assay at a concentration of 20 μM. [Table 6]

[0423] Representative results for compounds 64, 66, and ARV-825 are shown in Figure 3 and Table 6. As illustrated in Figure 3 and Table 6, the compounds of the present invention show no IKZF1 degradation potential at all, compared to the reference compound ARV-825, which can induce approximately 50% of IKZF1 degradation.

[0424] Representative results for compounds lenalidomide, 39, 35, 50, and pomalidomide are shown in Figure 4 and Table 7. The remaining compounds are shown in Table 10. As illustrated in Figure 4 and Tables 7 and 10, the compounds of the present invention exhibit no IKZF1 decomposing ability whatsoever, in contrast to lenalidomide and the more effective pomalidomide.

[0425] [Table 7]

[0426] [Table 8] [Examples]

[0427] IKZF3 degradation assay - H929 cell line The effects of various compounds of the present invention and various reference compounds on IKZF3 degradation in the H929 cell line were investigated using the degradation assay protocol described below.

[0428] H929 cells were maintained in RPMI-1640 medium supplemented with penicillin / streptomycin, 10% fetal bovine serum (FBS), and 0.05 mM 2-mercaptoethanol. Cells were seeded on 6-well or 12-well plates, and the compounds to be tested were added within the desired concentration range. The final DMSO concentration was 0.25%. After 24 hours of incubation (37°C, 5% CO2), cells were harvested, washed, and cell solubilizes were prepared using RIPA lysis buffer. Protein levels were determined via BCA assay, and appropriate amounts were then loaded onto precast gels for protein separation. After primary and secondary Ab staining, the membranes were washed, and signals were detected. Densitometry analysis was performed to obtain numerical values ​​to be used later in the protein level assessment process.

[0429] The compounds tested in this assay were: lenalidomide, pomalidomide, 15, 30, 39, 35, and 50 at concentrations of 10 μM and 20 μM. Treatment with all compounds was performed over a 24-hour period. In addition, compounds 64, 66, and ARV-825 were tested in this assay at concentrations of 0.1 μM, 1 μM, and 10 μM for a duration of 6 hours. Densitometry values ​​were normalized to the loaded control (β-actin) and expressed as a percentage of the DMSO control using the following notation: Regarding the reduction of IKZF3 protein from 0-25%, less than 25%. Regarding the reduction of IKZF3 protein, over 25% accounted for 26-74%. Regarding the reduction of IKZF3 protein, it was over 75% for 75-100% of cases.

[0430] Representative results for compounds 64, 66, and ARV-825 are shown in Figure 5 and Table 8. As illustrated in Figure 5 and Table 8, the compounds of the present invention exhibit little to no IKZF3 degradation potential compared to the reference compound ARV-825, which exhibits approximately 60% IKZF3 degradation.

[0431] Representative results for compounds lenalidomide, 39, 35, 50, 15, 30, 55, and pomalidomide are shown in Figure 6 and Table 9. As illustrated in Figure 6 and Table 9, the compounds of the present invention exhibit no IKZF3 degradation efficiency whatsoever, in contrast to lenalidomide and the more potent pomalidomide.

[0432] [Table 9]

[0433] [Table 10] JPEG0007852923000147.jpg59170

[0434] [Table 11] [Examples]

[0435] BRD4 degradation assay - H929 cell line The effects of various compounds of the present invention and various reference compounds on BRD4 degradation in the H929 cell line were investigated using the degradation assay protocol described below.

[0436] H929 cells were maintained in RPMI-1640 medium (modified ATCC, cat.: Gibco A1049101) supplemented with penicillin / streptomycin, 10% fetal bovine serum (FBS), and 0.05 mM 2-mercaptoethanol. Cells were seeded onto 6-well plates (1 × 10^6 cells / condition), and the compounds to be tested were added within the desired concentration range. The final DMSO concentration was 0.25%. After 6 hours of incubation (37°C, 5% CO2), cells were harvested, washed, and cell solubilizes were prepared using RIPA lysis buffer. Protein levels were determined via BCA assay, and appropriate amounts were then loaded into pre-filled microplates. Analysis was performed using the automated capillary-based immunoassay, SIMPLE WESTERN® technology (from Protein Simple). Numerical values ​​for further protein level assessment processes were counted using software specifically designed for Simple Western analysis. Protein normalization is based on Protein Simple's Protein Normalization Reagent. Values ​​are expressed as a percentage of the DMSO control, using the following description: Regarding BRD4 protein reduction of 0-25%, less than 25% Regarding BRD4 protein reduction, over 25% accounted for 26-74% of cases. Regarding the reduction of BRD4 protein, it was over 75% for 75-100% of cases.

[0437] The compounds tested in this assay were 64, 66, and ARV-825 at concentrations of 0.1 μM, 1 μM, and 10 μM over a period of 6 hours. In addition, ARV-825 was tested at 0.01 μM. The results are shown in Figure 7 and Table 11. As illustrated in this figure, the compounds of the present invention have BRD4 degradation ability.

[0438] [Table 12] [Examples]

[0439] BRD4 compound-CRBN / DDB1 ternary complex formation-AlphaLISA homogeneous assay The effect of the compound of the present invention on the formation of a ternary complex composed of BRD4-compound-CRBN / DDB1 was investigated.

[0440] Large aggregates were removed by centrifugation of the biotinylated BRD4 and His-CRBN / DDB1 complex preparations (18000 rcf, 4°C, 5 min). The supernatant was collected and the protein concentration was determined spectrophotometrically. AlphaLISA bead-protein mixtures were prepared: CRBN-acceptor beads (40 μg / ml anti-6xHis beads, 200 nM His-CRBN / DDB1 in pH 7.4 PBS supplemented with 0.1% Tween-20) and BRD4-donor beads (40 μg / ml streptavidin beads, 40 nM BRD4 in pH 7.4 PBS supplemented with 0.1% Tween-20 and 2 mM DTT). The bead mixes were incubated in the dark at room temperature for 30 minutes. The test compounds were dispensed into small volumes of AlphaPlate (Perkin Elmer) using an Echo555 liquid dispenser. The CRBN-acceptor bead mix and BRD4-donor bead mix were combined and dispensed into plates containing only the compound and DMSO (10 μl of master mix per well). Final sample composition: 20 μg / ml anti-6xHis beads, 20 μg / ml streptavidin beads, 100 nM His-CRBN / DDB1, 20 nM BRD4, 2% DMSO, 0.1% Tween-20, 1 mM DTT, + / - compound in PBS at pH 7.4. The plate was sealed and covered to protect it from light. The sample was mixed using a vibroturbulator. Subsequently, the solution in the plate was centrifuged and incubated in the dark at 25°C for 30 minutes. The plate seal was removed and sample luminescence was determined using a Perkin Elmer Enspire plate reader. Readouts were assigned to specific compound concentrations. The background response (mean) was determined using a compound-free solution and subsequently subtracted from the raw data recovered for the compound mixture. The results are expressed as TF50 values ​​(compound concentration mediating half of the maximum response observed for the ternary complex) and AUC (Area Under Curve, representing the overall compound potency).

[0441] The compounds tested in this assay were 66, 64, 65, and dBET1. Test compound concentrations were 1.63 nM, 4.11 nM, 10.3 nM, 25.3 nM, 64.3 nM, 160 nM, 392 nM, 980 nM, and 2500 nM. The results are shown in Figure 8 and Table 12. As illustrated by this figure, the bifunctional compounds of the present invention promote highly potent BRD4-compound-CRBN / DDB1 complex formation.

[0442] [Table 13] [Examples]

[0443] IKZF1 compound-CRBN / DDB1 ternary complex formation-AlphaLISA homogeneous assay The effect of the compound of the present invention on the formation of a ternary complex composed of IKZF1-compound-CRBN / DDB1 was investigated.

[0444] Large aggregates were removed by centrifugation of Strep-tagged Ikaros (IKZF1 ZF2) and His-CRBN / DDB1 complex preparations (18000 rcf, 4°C, 5 min). The supernatant was collected and the protein concentration was determined spectrophotometrically. AlphaLISA bead-protein mixtures were prepared: CRBN-acceptor beads (40 μg / ml anti-6x His beads, 200 nM His-CRBN / DDB1 in pH 7.4 PBS supplemented with 0.1% Tween-20) and Ikaros-donor bead mix (40 μg / ml Strep-Tactin beads, 800 nM IKZF1 in pH 7.4 PBS supplemented with 0.1% Tween-20 and 2 mM DTT). The bead mixes were incubated in the dark at room temperature for 30 minutes. Using an Echo555 liquid dispenser, the test compound was dispensed into small-volume AlphaPlates (Perkin Elmer). The CRBN-acceptor bead mix and Ikaros-donor bead mix were combined and dispensed into plates containing only the compound and DMSO (10 μl of master mix per well). Final sample composition: 20 μg / ml anti-6xHis beads, 20 μg / ml Strep-Tactin beads, 100 nM His-CRBN / DDB1, 400 nM IKZF1, 2% DMSO, 0.1% Tween-20, 1 mM DTT, + / - compound in PBS at pH 7.4. The plate was sealed and covered to protect it from light. The sample was mixed using a vibroturbulator. Subsequently, the solution in the plate was centrifuged and incubated in the dark at 25°C for 30 minutes. The plate seal was removed and sample luminescence was determined using a Perkin Elmer Enspire plate reader. Readouts were assigned to specific compound concentrations. Using a compound-free solution, the background response (mean) was determined and subsequently subtracted from the raw data recovered for the compound mixture. The mean and standard deviation (SD) were calculated for each compound concentration point. Finally, the luminescence values ​​were normalized and expressed as a percentage of the lenalidomide response at a given concentration (internal, positive control).

[0445] The compounds tested in this assay were 65 and lenalidomide. Test compound concentrations: 0.1 μM, 1 μM, and 10 μM. The results are shown in Figure 9 (AlphaLISA is attributed to Ikaros-CRBN / DDB1 TCF in the presence of 65, where the luminescence obtained for the mixture with 65 was normalized to the response mediated by lenalidomide). As illustrated by this figure, the bifunctional compounds of the present invention do not promote IKZF1-compound-CRBN / DDB1 complex formation.

[0446] summary In summary, the presented results of the neosubstrate SALL4, CK1α, IKZF1, and IKZF3 degradation tests for the compounds of the present invention indicate little to no degradation of proteins by the compounds. This profile gives the compounds the ability to act as warheads in a bifunctional degradation agent. Bifunctional compounds 64 and 66 degrade BRD4 and are more selective for substrate degradation.

[0447] Bifunctional compounds Figure 10 is a schematic example of the general principle of targeted protein degradation in treatments using bifunctional compounds.

[0448] The bifunctional compound comprises a protein-targeting moiety (PTM), a cereblon-targeting moiety (CTM), and optionally, a linker moiety (L) connecting the PTM to the CTM. The bifunctional compound binds to cereblon (CRBN) ubiquitin ligase at one end and to the target protein (protein) at the other end, bringing the target protein closer to cereblon (see the lower left of Figure 10). The polyubiquitinated protein (shown in the lower center of Figure 10) is then targeted for degradation by the cellular proteasome mechanism (see the lower right of Figure 10). Examples of linker moieties are as described in WO2019 / 199816 and WO2020 / 010227.

[0449] Abbreviations and Definitions A list of abbreviations used in this application is shown in Table 13 below:

[0450] [Table 14] JPEG0007852923000152.jpg200161

[0451] As used herein, the term "room temperature" means a temperature between 20°C and 25°C.

[0452] As used herein, the term "small molecule" means an organic compound having a molecular weight of less than 900 daltons. [Embodiments of the present invention]

[0453] 1. Compound of formula (I): [ka] During the ceremony, Each of X1 and X2 is independently either O or S; T is either C=O or SO2; R 1 is hydrogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, aryl, heteroaryl, or benzyl; n is 0, 1, or 2; L is hydrogen, alkyl, alkenyl, aryl, heteroaryl, benzyl, haloalkyl, haloalkenyl, -C(O)H, -C(O)R'', -C(O)OH, -C(O)OR'', -C(O)NH2, -C(O)NHR'', -C(O)NR''2, -OH, -OR'', -NH2, -NHR'', -NR''2, -S(O)2H or -S(O)2R''; R x teeth [ka] Selected from, Single merged image with the filename JPEG0007852923000155.jpg79 This indicates binding to T, Z is O, S, or NH; V is CR2, NR 4 or S; Each of W1, W2, and W3 is independently N or CR. 2 And, Each of Y1 and Y2 is independently N or CR. Each R independently represents hydrogen, halogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, aryl, heteroaryl, benzyl, haloalkyl, haloalkenyl, -NH2, -NHR'', -NR''2, -NHC(O)R'', -NR''C(O)R'', NHC(O)CH(OH)R'', -NR''C(O)CH(OH)R'', -NHC(O)OR'', -NR''C(O)OR'', -NHSO2R'', -NR''SO2R'', -NO2, -CN, -C(O)H , C(O)R'', -C(O)OH, -C(O)OR'', -C(O)NH2, -C(O)NHR'', -C(O)NR''2, -OH, -OR'', -OC(O)H, -OC(O)R'', -OC(O)OH, -OC(O)OR'', -OC(O)N H2, -OC(O)NHR'', -OC(O)NR''2, -SH, -SR'', -S(O)2H, -S(O)2R'', -S(O)2OH, -S(O)2OR'', -S(O)2NH2, -S(O)2NHR'', or -S(O)2NR''2; Each R 2These are independently hydrogen, halogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, aryl, heteroaryl, benzyl, haloalkyl, haloalkenyl, -NH2, -NHR'', -NR''2, -NHC(O)R'', -NR''C(O)R'', NHC(O)CH(OH)R'', -NR''C(O)CH(OH)R'', -NHC(O)OR'', -NR''C(O)OR'', -NHSO2R'', -NR''SO2R'', -NO2, -CN, -C(O )H, C(O)R'', -C(O)OR'', -C(O)NH2, -C(O)NHR'', -C(O)NR''2, -OH, -OR'', -OC(O)H, -OC(O)R'', -OC(O)OH, -OC(O)OR'', -OC(O)NH2, -OC(O)NHR'', -OC(O)NR''2, -SH, -SR'', -S(O)2H, -S(O)2R'', -S(O)2OH, -S(O)2OR'', -S(O)2NH2, -S(O)2NHR'', or -S(O)2NR''2; Each R 4 These are independently hydrogen, halogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, aryl, heteroaryl, benzyl, haloalkyl, haloalkenyl, -C(O)H, C(O)R'', -C(O)OH, -C(O)OR'', -C(O)NH2, -C(O)NHR'', -C(O)NR''2, -OH, -OR'', -NH2, -NHR'', -NR''2, -S(O)2H or -S(O)2R''; Each R'' is independently alkyl, cycloalkyl, alkenyl, cycloalkenyl, aryl, heteroaryl, or benzyl; R x but [ka] Therefore, if Z is NH, then n is either 1 or 2.

[0454] 2. The compound of Embodiment 1 has the following structure.

[0455] [ka]

[0456] 3. The compound of Embodiment 1 has the following structure.

[0457] [ka]

[0458] 4. A compound of any of the preceding embodiments, where T is C=O.

[0459] 5. A compound from any one of Embodiments 1 to 3, where T is SO2.

[0460] 6. A compound of any of the preceding embodiments, where Z is NH.

[0461] 7. A compound from any one of Embodiments 1 to 5, where Z is O.

[0462] 8. A compound from any one of Embodiments 1 to 5, where Z is S.

[0463] 9. A compound of any of the preceding embodiments, where V is CR2.

[0464] 10. A compound of any of the preceding embodiments, where V is NR 4 That is the case.

[0465] 11. A compound of any of the preceding embodiments, wherein V is S.

[0466] 12. A compound of any of the preceding embodiments, wherein Y1 is N and Y2 is CR.

[0467] 13. A compound from any one of Embodiments 1 to 11, where Y2 is N and Y1 is CR.

[0468] 14. A compound from any one of Embodiments 1 to 11, wherein both Y1 and Y2 are N.

[0469] 15. A compound from any one of Embodiments 1 to 11, wherein both Y1 and Y2 are CR.

[0470] 16. A compound of any of the preceding embodiments, wherein L is hydrogen, alkyl, alkenyl, aryl, heteroaryl, benzyl, -OH, -OR'', -NH2, -NHR'', -NR''2, -S(O)2H or -S(O)2R''; L may also be hydrogen, alkyl, alkenyl, aryl, heteroaryl, or benzyl.

[0471] 17. The compound of Embodiment 16, where L is hydrogen.

[0472] 18. A compound of any of the preceding embodiments, R x The following applies:

[0473] [ka]

[0474] 19. A compound of any of the preceding embodiments, R x The following applies:

[0475] [ka]

[0476] 20. The compound of Embodiment 19, R x The following applies:

[0477] [ka]

[0478] 21. The compound of Embodiment 20, in which one of W1, W2, and W3 is N, and the remaining two W1, W2, and W3 are each CR2 That is the case.

[0479] 22. The compound of Embodiment 20, in which two of W1, W2, and W3 are N, and the remaining one of W1, W2, and W3 is CR. 2 That is the case.

[0480] 23. The compound of Embodiment 20, wherein W1, W2, and W3 are all N.

[0481] 24. The compound of Embodiment 20, wherein each of W1, W2, and W3 is CR 2 That is the case.

[0482] 25. The compound of Embodiment 24: Each R 2 That is hydrogen, Y1 is N, Y2 is CH.

[0483] 26. The compound of Embodiment 25 has the following structure.

[0484] [ka]

[0485] 27. Compound of Embodiment 24: Each R 2 That is hydrogen, Y1 and Y2 are both CH.

[0486] 28. The compound of Embodiment 27 has the following structure.

[0487] [ka]

[0488] 29. The compound of Embodiment 19, R x The following applies:

[0489] [ka]

[0490] 30. The compound of Embodiment 29, R x The following applies:

[0491] [ka]

[0492] 31. The compound of Embodiment 29, R x The following applies:

[0493] [ka]

[0494] 32. The compound of Embodiment 29, R x The following applies:

[0495] [ka]

[0496] 33. The compound of Embodiment 29, R x The following applies:

[0497] [ka]

[0498] 34. One of the compounds from Embodiments 1 to 17, R x The following applies:

[0499] [ka]

[0500] 35. The compound of Embodiment 34, R x The following applies:

[0501] [ka]

[0502] 36. The compound of Embodiment 34, R x The following applies:

[0503] [ka]

[0504] 37. The compound of Embodiment 34, R x The following applies:

[0505] [ka]

[0506] 38. The compound of Embodiment 34, R x The following applies:

[0507] [ka]

[0508] 39. One of the compounds from Embodiments 34 to 38, R 4 R is hydrogen, halogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, aryl, heteroaryl, benzyl, haloalkyl, haloalkenyl, -OH, -OR'', -NH2, -NHR'', -NR''2, -S(O)2H or -S(O)2R''; 4 This may be hydrogen, halogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, aryl, heteroaryl, benzyl, haloalkyl, or haloalkenyl.

[0509] 40. The compound of Embodiment 39, R 4 It is hydrogen or alkyl.

[0510] 41. A compound from any one of embodiments 34 to 38, wherein V is CH2.

[0511] 42. One of the compounds from Embodiments 34 to 41: Each R 2 That is hydrogen, Z is NH.

[0512] 43. This is the compound of Embodiment 34, and has the following structure.

[0513] [ka]

[0514] 44. A compound of any of the preceding embodiments, each R 2 R is independently hydrogen, halogen, alkyl, heteroaryl, -NH2, -NHR'', -NHC(O)R'', -NHSO2R'', -CN, -C(O)NH2, -C(O)NHR'', -C(O)NR''2, -OH, -OR'', -S(O)2NH2, -S(O)2NHR'', or -S(O)2NR''2; each R 2 It may be hydrogen.

[0515] 45. A compound of any of the preceding embodiments, wherein each R is independently hydrogen, halogen, alkyl, heteroaryl, -NH2, -NHR'', -NHC(O)R'', -NHSO2R'', -CN, -C(O)NH2, -C(O)NHR'', -C(O)NR''2, -OH, -OR'', -S(O)2NH2, -S(O)2NHR'', or -S(O)2NR''2.

[0516] 46. ​​A compound of any of the preceding embodiments, where R is hydrogen.

[0517] 47. A compound of any of the preceding embodiments, R 1 That is hydrogen.

[0518] 48. Compounds of formula (II): [ka] During the ceremony, Each of X1 and X2 is independently either O or S; T is either C=O or SO2; R 1 is hydrogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, aryl, heteroaryl, or benzyl; N is 0, 1, or 2; L is hydrogen, alkyl, alkenyl, aryl, heteroaryl, benzyl, haloalkyl, haloalkenyl, -C(O)H, -C(O)R'', -C(O)OH, -C(O)OR'', -C(O)NH2, -C(O)NHR'', -C(O)NR''2, -OH, -OR'', -NH2, -NHR'', -NR''2, -S(O)2H or -S(O)2R''; R y teeth, [ka] Selected from, Z is O, S, or NR 3 and; U is O, S, NR 3 or CR 2 It is 2; Each of Y1 and Y2 is independently N or CR; Each R independently represents hydrogen, halogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, aryl, heteroaryl, benzyl, haloalkyl, haloalkenyl, -NH2, -NHR'', -NR''2, -NHC(O)R'', -NR''C(O)R'', NHC(O)CH(OH)R'', -NR''C(O)CH(OH)R'', -NHC(O)OR'', -NR''C(O)OR'', -NHSO2R'', -NR''SO2R'', -NO2, -CN, -C(O)H , C(O)R'', -C(O)OH, -C(O)OR'', -C(O)NH2, -C(O)NHR'', -C(O)NR''2, -OH, -OR'', -OC(O)H, -OC(O)R'', -OC(O)OH, -OC(O)OR'', -OC(O)N H2, -OC(O)NHR'', -OC(O)NR''2, -SH, -SR'', -S(O)2H, -S(O)2R'', -S(O)2OH, -S(O)2OR'', -S(O)2NH2, -S(O)2NHR'', or -S(O)2NR''2; Each R 2 These are independently hydrogen, halogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, aryl, heteroaryl, benzyl, haloalkyl, haloalkenyl, -NH2, -NHR'', -NR''2, -NHC(O)R'', -NR''C(O)R'', NHC(O)CH(OH)R'', -NR''C(O)CH(OH)R'', -NHC(O)OR'', -NR''C(O)OR'', -NHSO2R'', -NR''SO2R'', -NO2, -CN, -C(O)H, C (O)R'', -C(O)OH, -C(O)OR'', -C(O)NH2, -C(O)NHR'', -C(O)NR''2, -OH, -OR'', -OC(O)H, -OC(O)R'', -OC(O)OH, -OC(O)OR'', -OC(O)NH 2, -OC(O)NHR'', -OC(O)NR''2, -SH, -SR'', -S(O)2H, -S(O)2R'', -S(O)2OH, -S(O)2OR'', -S(O)2NH2, -S(O)2NHR'', or -S(O)2NR''2; Each R 3These are independently hydrogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, aryl, heteroaryl, benzyl, haloalkyl, haloalkenyl, -NH2, -NHR'', -NR''2, -NHC(O)R'', -NR''C(O)R'', NHC(O)CH(OH)R'', -NR''C(O)CH(OH)R'', -NHC(O)OR'', -NR''C(O)OR'', -NHSO2R'', -NR''SO2R'', -NO2, -CN, -C(O)H, C(O) R'', -C(O)OH, -C(O)OR'', -C(O)NH2, -C(O)NHR'', -C(O)NR''2, -OH, -OR'', -OC(O)H, -OC(O)R'', -OC(O)OH, -OC(O)OR'', -OC(O)NH2, -OC(O)NHR'', -OC(O)NR''2, -SH, -SR'', -S(O)2H, -S(O)2R'', -S(O)2OH, -S(O)2OR'', -S(O)2NH2, -S(O)2NHR'', or -S(O)2NR''2; Each R'' is independently alkyl, cycloalkyl, alkenyl, cycloalkenyl, aryl, heteroaryl, or benzyl.

[0519] 49. The compound of Embodiment 48 has the following structure.

[0520] [ka]

[0521] 50. This is the compound of Embodiment 48, and has the following structure. [ka]

[0522] 51. A compound from any one of embodiments 48 to 50, wherein T is C=O.

[0523] 52. A compound from any one of embodiments 48 to 50, wherein T is SO2.

[0524] 53. Any one of the compounds from Embodiments 48 to 52, where Z is NR 3 That is the case.

[0525] 54. A compound from any one of embodiments 48 to 52, wherein Z is O.

[0526] 55. A compound from any one of embodiments 48 to 52, wherein Z is S.

[0527] 56. A compound from any one of embodiments 48 to 55, where Y1 is N and Y2 is CR.

[0528] 57. A compound from any one of embodiments 48 to 55, where Y2 is N and Y1 is CR.

[0529] 58. A compound from any one of embodiments 48 to 55, wherein both Y1 and Y2 are N.

[0530] 59. A compound from any one of embodiments 48 to 55, wherein both Y1 and Y2 are CR.

[0531] 60. Any one of the compounds from Embodiments 48 to 59, wherein L is hydrogen, alkyl, alkenyl, aryl, heteroaryl, benzyl, -OH, -OR'', -NH2, -NHR'', -NR''2, -S(O)2H or -S(O)2R''; L may also be hydrogen, alkyl, alkenyl, aryl, heteroaryl, or benzyl.

[0532] 61. The compound of Embodiment 60, where L is hydrogen.

[0533] 62. One of the compounds from Embodiments 48 to 61, R y The following applies:

[0534] [ka]

[0535] 63. One of the compounds from Embodiments 48 to 61, R y The following applies:

[0536] [ka]

[0537] 64. One of the compounds from Embodiments 48 to 61, R y The following applies:

[0538] [ka]

[0539] 65. One of the compounds from Embodiments 48 to 61, R y The following applies:

[0540] [ka]

[0541] 66. One of the compounds from Embodiments 48 to 61, R y The following applies:

[0542] [ka]

[0543] 67. One of the compounds from Embodiments 48 to 61, R y The following applies:

[0544] [ka]

[0545] 68. One of the compounds from Embodiments 48 to 67, each with R 2These are independently hydrogen, halogen, alkyl, heteroaryl, -NH2, -NHR'', -NHC(O)R'', -NHSO2R'', -CN, -C(O)NH2, -C(O)NHR'', -C(O)NR''2, -OH, -OR'', -S(O)2NH2, -S(O)2NHR'', or -S(O)2NR''2.

[0546] 69. Any one of the compounds from Embodiments 48 to 68, each with R 2 That is hydrogen.

[0547] 70. One of the compounds from Embodiments 48 to 69, where each R is independently hydrogen, halogen, alkyl, heteroaryl, -NH2, -NHR'', -NHC(O)R'', -NHSO2R'', -CN, -C(O)NH2, -C(O)NHR'', -C(O)NR''2, -OH, -OR'', -S(O)2NH2, -S(O)2NHR'', or -S(O)2NR''2.

[0548] 71. A compound from any one of embodiments 48 to 70, where R is hydrogen in each case.

[0549] 72. Any one of the compounds from Embodiments 48 to 71, each with R 3 These are independently hydrogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, aryl, heteroaryl, benzyl, haloalkyl, haloalkenyl, or C(O)R''.

[0550] 73. One of the compounds from Embodiments 48 to 72, each with R 3 That is hydrogen.

[0551] 74. One of the compounds from Embodiments 48 to 74, R 1 That is hydrogen.

[0552] 75. A compound of any of the preceding embodiments, wherein X1 and X2 are O.

[0553] 76. A compound from any one of Embodiments 1 to 74, where X1 is O and X2 is S.

[0554] 77. A compound from any one of Embodiments 1 to 74, wherein X1 is S and X2 is O.

[0555] 78. A compound from any one of Embodiments 1 to 74, where X1 and X2 are S.

[0556] 79. A compound of any of the preceding embodiments, wherein n is 0.

[0557] 80. A compound from any one of Embodiments 1 to 78, wherein n is 1.

[0558] 81. A compound from any one of Embodiments 1 to 78, wherein n is 2.

[0559] 82. Any one of the compounds from the preceding embodiments for use as a cereblon binder.

[0560] 83. A pharmaceutical composition comprising any one compound from Embodiments 1 to 81.

[0561] 84. Any one compound from Embodiments 1 to 81, or a composition according to Embodiment 83, for use in the field of medicine.

[0562] 85. Any one compound from Embodiments 1 to 81, or a composition according to Embodiment 83, for use in immuno-oncology.

[0563] 86. Any one compound from Embodiments 1 to 81, or a composition according to Embodiment 83, for use in the treatment of cancer, autoimmune diseases, macular degeneration (MD) and related disorders, diseases and disorders involving undesirable angiogenesis, skin diseases, lung disorders, asbestos-related disorders, parasitic diseases and disorders, immunodeficiency disorders, atherosclerosis and related conditions, abnormal hemoglobin disorders and related disorders, or TNFα-related disorders.

[0564] 87. Methods for the treatment of cancer, autoimmune diseases, macular degeneration (MD) and related disorders, diseases and disorders with undesirable angiogenesis, skin diseases, lung diseases, asbestos-related disorders, parasitic diseases and disorders, immunodeficiency disorders, atherosclerosis and related conditions, abnormal hemoglobin disorders and related disorders, or TNFα-related disorders; The method includes the step of administering an effective amount of any one compound from Embodiments 1 to 81 or a composition according to Embodiment 83 to a patient who needs it.

[0565] 88. The method of Embodiment 87, further comprising the step of administering at least one additional active agent to the patient.

[0566] 89. A combination of any one compound from Embodiments 1 to 81 and at least one additional active agent for use in therapy, either simultaneously, separately, or in succession.

[0567] 90. The combination of Embodiment 89, or the method of Embodiment 88, wherein at least one additional active agent is an anticancer agent or an agent for the treatment of an autoimmune disease.

[0568] 91. The formulation of Embodiment 89 or 90, or the method of Embodiment 88 or 90, wherein at least one additional active agent is a small molecule, peptide, antibody, corticosteroid, or a combination thereof.

[0569] 92. The combination or method of Embodiment 91, wherein at least one additional active agent is at least one of bortezomib, dexamethasone, and rituximab.

[0570] 93. A combination of any one of Embodiments 89 to 92, wherein the treatment is for cancer, autoimmune diseases, macular degeneration (MD) and related disorders, diseases and disorders with undesirable angiogenesis, skin diseases, lung disorders, asbestos-related disorders, parasitic diseases and disorders, immunodeficiency disorders, atherosclerosis and related conditions, abnormal hemoglobin disorders and related disorders, or TNFα-related disorders.

Claims

1. Compound of formula (I): 【Chemistry 1】 [In the formula, X １ and X ２ Each of them is O; T is C = O; R １ is hydrogen; n is 1; L is hydrogen, alkenyl, aryl, heteroaryl, benzyl, haloalkyl, haloalkenyl, -C(O)H, -C(O)R'', -C(O)OH, -C(O)OR'', -CH ２ C(O)OR'', -C(O)NH ２ , -C(O)NHR'', -C(O)NR'' ２ , -OH, -OR'', -NH ２ , -NHR'', -NR'' ２ , -S(O) ２ H or -S(O) ２ R''; R ｘ teeth, (a) 【Chemistry 2】 Z is O, S, or NH. W １ , W ２ , and W ３ Each of these independently is N or CR ２ and Y １ and Y ２ Each of them is independently N or CR; (b) 【Transformation 3】 Z is either O or S, and Y １ and Y ２ Each of them is independently N or CR; (c) 【Chemistry 4】 R4 is H; Y １ is N and Y ２ is N or CR; (d) 【Transformation 5】 Z is O, S, or NH; and (e) 【Transformation 6】 Z is S or NH, Y １ is N or CR; and Y ２ is CR; and (A)W １ , W ２ and W ４ One of them is N, and W １ , W ２ and W ４ The remaining two are each CR ２ is, or (B)W １ , W ２ and W ４ These two are N, and W １ , W ２ and W ４ The remaining one is CR ２ is, or (C) W １ , W ２ and W ４ Assuming that each of them is N, W １ , W ２ , and W ４ Each of these independently is N or CR ２ It is; Selected from, 【change】 This indicates binding to T, Each R is independently hydrogen, halogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, aryl, condensed aryl-cycloalkyl, condensed aryl-heterocycloalkyl, heteroaryl, heteroaryl substituted with at least one aryl group, benzyl, haloalkyl, haloalkenyl, -NH ２ , -NHR'', -NR'' ２ , -NHC(O)R'', -NR''C(O)R'', NHC(O)CH(OH)R'', -NR''C(O)CH(OH)R'', -NHC(O)OR'', -NR''C(O)OR'', -NHSO ２ R'', -NR''SO ２ R'', -NO ２ , -CN, -C(O)H, C(O)R'', -C(O)OH, -C(O)OR'', -C(O)NH ２ , -C(O)NHR'', -C(O)NR'' ２ , -OH, -OR'', -OC(O)H, -OC(O)R'', -OC(O)OH, -OC(O)OR'', -OC(O)NH ２ , -OC(O)NHR'', -OC(O)NR'' ２ , -SH, -SR'', -S(O) ２ H, -S(O) ２ R'', -S(O) ２ OH, -S(O) ２ OR'', -S(O) ２ NH ２ , -S(O) ２ NHR'', or -S(O) ２ NR'' ２ is; or Y １ and Y ２ If it is CR, each R, together with the carbon atom it is bonded to, forms a 5- or 6-membered ring; Each R ２ These are independently hydrogen, halogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, aryl, aryl substituted with at least one -OR'', heteroaryl, benzyl, haloalkyl, haloalkenyl, -NH ２ , -NHR'', -NR'' ２ ien-CH ２ NH ２ , -NHC(O)R'', -NR''C(O)R'', NHC(O)CH(OH)R'', -NR''C(O)CH(OH)R'', -NHC(O)OR'', -NR''C(O)OR'', -NHSO ２ R'', -NR''SO ２ R'', -NO ２ , -CN, -C(O)H, C(O)R'', -C(O)OR'', -C(O)NH ２ , -C(O)NHR'', -C(O)NR'' ２ , -OH, -OR'', -OC(O)H, -OC(O)R'', -OC(O)OH, -OC(O)OR'', -OC(O)NH ２ , -OC(O)NHR'', -OC(O)NR'' ２ , -SH, -SR'', -S(O) ２ H, -S(O) ２ R'', -S(O) ２ OH, -S(O) ２ OR'', -S(O) ２ NH ２ , -S(O) ２ NHR'', or -S(O) ２ NR'' ２ and Each R'' is independently alkyl, cycloalkyl, alkenyl, cycloalkenyl, aryl, heteroaryl, or benzyl; (i) R ｘ but 【Transformation 7】 And if Z is NH, then L is hydrogen, -CH ２ C(O)OR'' or -OR''; (ii) R ｘ but 【Transformation 8】 where Z is NH and Y １ is CR and Y ２ is N, at least one of R2 and R is not H; (iii) R ｘ but 【Chemistry 9】 And Z is NH, Y １ and Y ２ If CR, W １ , W ２ and W ３ At least one of them is N; (iv) Z is NH, and Y １ and Y ２ is CR, R ｘ is 【Chemistry 10】 Rather; (v) R ｘ but 【Chemistry 11】 If so, then Z = O or S; and (vi) The compound is 【Chemistry 12】 isn't it].

2. structure: 【Chemistry 14】 or 【Chemistry 15】 The compound according to claim 1, having the following characteristics.

3. (a) Y １ N is Y ２ CR is; (b) Y ２ N is Y １ CR is; (c) Y １ and Y ２ Both of them are N; or (d) Y １ and Y ２ The compound according to any one of claims 1 to 2, wherein both of the compounds are CR.

4. L (a) Hydrogen, alkenyl, aryl, heteroaryl, benzyl, -OH, -CH ２ C(O)OR'', -OR'', -NH ２ , -NHR'', -NR'' ２ , -S(O) ２ H or -S(O) ２ R''; (b) Hydrogen, alkenyl, aryl, heteroaryl, or benzyl; (c) Hydrogen, -CH ２ C(O) OR'' or -OR''; or (d) Hydrogen The compound according to any one of claims 1 to 3.

5. (a) R ｘ but 【Chemistry 16】 Selected from; or (b) R ｘ but 【Chemistry 17】 Selected from; or (c) R ｘ but [Chemistry 18] Selected from; or (d) R ｘ but 【Chemistry 19】 Selected from; or (e) R ｘ but 【Chemistry 20】 That is, The compound according to any one of claims 1 to 4.

6. (a) W １ , W ２ and W ３ One of them is N, and W １ , W ２ and W ３ The remaining two are each CR ２ It is; (b) W １ , W ２ and W ３ These two are N, and W １ , W ２ and W ３ The remaining one is CR ２ It is; (c) W １ , W ２ and W ３ Each of them is N, and each R ２ is hydrogen and Y １ and Y ２ Each of them is CH; or (d) W １ , W ２ and W ３ Each of them is CR ２ And each R is optional ２ is hydrogen, Y １ If N and Y ２ CH is The compound according to any one of claims 1 to 5.

7. R ｘ but (a) 【Chemistry 21】 (b) 【Chemistry 22】 (c) 【Chemistry 23】 The compound according to any one of claims 1 to 4.

8. R ｘ but 【Chemistry 24】 The compound according to any one of claims 1 to 4.

9. R ｘ but 【Chemistry 25】 【Chemistry 26】 【Chemistry 27】 or 【Chemistry 28】 The compound according to claim 8.

10. Each R ２ That is hydrogen, The compound according to claim 8 or 9, wherein Z is NH.

11. structure: 【Chemistry 29】 The compound according to claim 8 or 9, having the following characteristics.

12. (a) Each R ２ These independently consist of hydrogen, halogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, aryl, aryl substituted with at least one -OR'', benzyl, haloalkyl, haloalkenyl, and -NH ２ , -NHR'', -NR'' ２ ien-CH ２ NH ２ , -NHC(O)R'', -NR''C(O)R'', NHC(O)CH(OH)R'', -NR''C(O)CH(OH)R'', -NHC(O)OR'', -NR''C(O)OR'', -NHSO ２ R'', -NR''SO ２ R'', -NO ２ , -CN, -OH, -OR'', -OC(O)H, -OC(O)R'', -OC(O)OH, -OC(O)OR'', -OC(O)NH ２ , -OC(O)NHR'', -OC(O)NR'' ２ , -SH, -SR'', -S(O) ２ H, -S(O) ２ R'', -S(O) ２ OH, -S(O) ２ OR'', -S(O) ２ NH ２ , -S(O) ２ NHR'', or -S(O) ２ NR'' ２ is; or (b) Each R ２ These independently produce hydrogen, halogen, alkyl, and -NH ２ , -NHR'', -NHC(O)R'', -NHSO ２ R'', -CN, -OH, -OR'', -S(O) ２ NH ２ , -S(O) ２ NHR'', or -S(O) ２ NR'' ２ is; or (c) Each R ２ Independently, hydrogen, halogen, aryl, aryl substituted with at least one -OR'', -NH ２ ien-CH ２ NH ２ , -NHC(O)R'', -NO ２ , or -OR''; or (d) Each R ２ These independently produce hydrogen, halogens, alkyls, heteroaryls, and -NH ２ , -NHR'', -NHC(O)R'', -NHSO ２ R'', -CN, -C(O)NH ２ , -C(O)NHR'', -C(O)NR'' ２ , -OH, -OR'', -S(O) ２ NH ２ , -S(O) ２ NHR'', or -S(O) ２ NR'' ２ is; or (e) Each R ２ The compound according to any one of claims 1 to 10, wherein is hydrogen.

13. (a) Each R is independently hydrogen, halogen, alkyl, haloalkyl, condensed aryl-cycloalkyl, condensed aryl-heterocycloalkyl, heteroaryl, heteroaryl substituted with at least one aryl group, -NH ２ , -NHR'', -NHC(O)R'', -NHSO ２ R'', -CN, -C(O)NH ２ , -C(O)NHR'', -C(O)NR'' ２ , -OH, -OR'', -S(O) ２ NH ２ , -S(O) ２ NHR'', or -S(O) ２ NR'' ２ is; or Y １ and Y ２ If it is CR, each R together with the carbon atom it is bonded to will form a 5- or 6-membered ring; or (b) Each R is independently hydrogen, halogen, alkyl, haloalkyl, condensed aryl-cycloalkyl, condensed aryl-heterocycloalkyl, heteroaryl, heteroaryl substituted with at least one aryl group, -NH ２ or -CN; or Y １ and Y ２ If it is CR, each R, together with the carbon atom to which it is bonded, forms a 5- or 6-membered ring; or (c) The compound according to any one of claims 1 to 10 and 12, wherein each R is hydrogen.

14. Compound of formula (II): 【Chemistry 31】 [In the formula, X １ and X ２ Each of them is O; T is C = O; R １ is hydrogen; n is 1; L represents hydrogen, alkyl, alkenyl, aryl, heteroaryl, benzyl, haloalkyl, haloalkenyl, -C(O)H, -C(O)R'', -C(O)OH, -C(O)OR'', -C(O)NH ２ , -C(O)NHR'', -C(O)NR'' ２ , -OH, -OR'', -NH ２ , -NHR'', -NR'' ２ , -S(O) ２ H or -S(O) ２ It is R''; R ｙ teeth, 【Chemistry 32】 Selected from, 【change】 This indicates binding to T, Z is O, S, or NR ３ And; U is S; Y １ , Y ２ and Y ３ Each of them is independently N or CR; Each R independently represents hydrogen, halogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, aryl, heteroaryl, benzyl, haloalkyl, haloalkenyl, or -NH ２ , -NHR'', -NR'' ２ , -NHC(O)R'', -NR''C(O)R'', NHC(O)CH(OH)R'', -NR''C(O)CH(OH)R'', -NHC(O)OR'', -NR''C(O)OR'', -NHSO ２ R'', -NR''SO ２ R'', -NO ２ , -CN, -C(O)H, C(O)R'', -C(O)OH, -C(O)OR'', -C(O)NH ２ , -C(O)NHR'', -C(O)NR'' ２ , -OH, -OR'', -OC(O)H, -OC(O)R'', -OC(O)OH, -OC(O)OR'', -OC(O)NH ２ , -OC(O)NHR'', -OC(O)NR'' ２ , -SH, -SR'', -S(O) ２ H, -S(O) ２ R'', -S(O) ２ OH, -S(O) ２ OR'', -S(O) ２ NH ２ , -S(O) ２ NHR'', or -S(O) ２ NR'' ２ And; Each R ２ These are independently hydrogen, halogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, aryl, heteroaryl, benzyl, haloalkyl, haloalkenyl, -NH ２ , -NHR'', -NR'' ２ , -NHC(O)R'', -NR''C(O)R'', NHC(O)CH(OH)R'', -NR''C(O)CH(OH)R'', -NHC(O)OR'', -NR''C(O)OR'', -NHSO ２ R'', -NR''SO ２ R'', -NO ２ , -CN, -C(O)H, C(O)R'', -C(O)OH, -C(O)OR'', -C(O)NH ２ , -C(O)NHR'', -C(O)NR'' ２ , -OH, -OR'', -OC(O)H, -OC(O)R'', -OC(O)OH, -OC(O)OR'', -OC(O)NH ２ , -OC(O)NHR'', -OC(O)NR'' ２ , -SH, -SR'', -S(O) ２ H, -S(O) ２ R'', -S(O) ２ OH, -S(O) ２ OR'', -S(O) ２ NH ２ , -S(O) ２ NHR'', or -S(O) ２ NR'' ２ And; Each R ３ These are independently hydrogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, aryl, heteroaryl, benzyl, haloalkyl, haloalkenyl, -NH ２ , -NHR'', -NR'' ２ , -NHC(O)R'', -NR''C(O)R'', NHC(O)CH(OH)R'', -NR''C(O)CH(OH)R'', -NHC(O)OR'', -NR''C(O)OR'', -NHSO ２ R'', -NR''SO ２ R'', -NO ２ , -CN, -C(O)H, C(O)R'', -C(O)OH, -C(O)OR'', -C(O)NH ２ , -C(O)NHR'', -C(O)NR'' ２ , -OH, -OR'', -OC(O)H, -OC(O)R'', -OC(O)OH, -OC(O)OR'', -OC(O)NH ２ , -OC(O)NHR'', -OC(O)NR'' ２ , -SH, -SR'', -S(O) ２ H, -S(O) ２ R'', -S(O) ２ OH, -S(O) ２ OR'', -S(O) ２ NH ２ , -S(O) ２ NHR'', or -S(O) ２ NR'' ２ And; Each R'' is independently alkyl, cycloalkyl, alkenyl, cycloalkenyl, aryl, heteroaryl, or benzyl; (i) R ｙ but 【Transformation 33】 If Y ２ is CR; (ii) R ｙ but 【Transformation 34】 If R ３ It is not hydrogen.

15. structure: 【Chemistry 35】 or 【Transformation 36】 The compound according to claim 14, having the following characteristics.

16. (a) Y １ N is Y ２ is CR; or (b) Y ２ N is Y １ is CR; or (c) Y １ and Y ２ Both of them are N; or (d) Y １ and Y ２ The compound according to claim 14 or 15, wherein both of the compounds are CR.

17. L, (a) Hydrogen, alkyl, alkenyl, aryl, heteroaryl, benzyl, -OH, -OR'', -NH ２ , -NHR'', -NR'' ２ , -S(O) ２ H or -S(O) ２ It is R''; (b) hydrogen, alkyl, alkenyl, aryl, heteroaryl, or benzyl; or (c) The compound according to any one of claims 14 to 16, wherein the compound is hydrogen.

18. R ｙ but 【Chemistry 37】 【Transformation 38】 【Chemistry 39】 【Chemistry 40】 【Chemistry 41】 【Chemistry 42】 【Chemistry 43】 or 【Chemistry 44】 The compound according to any one of claims 14 to 17.

19. (a) Each R ２ They became independent, (i) Hydrogen, halogen, alkyl, heteroaryl, -NH ２ , -NHR'', -NHC(O)R'', -NHSO ２ R'', -CN, -C(O)NH ２ , -C(O)NHR'', -C(O)NR'' ２ , -OH, -OR'', -S(O) ２ NH ２ , -S(O) ２ NHR'', or -S(O) ２ NR'' ２ is; or (ii) hydrogen; and / or (b) Each R is independent, (i) Hydrogen, halogen, alkyl, heteroaryl, -NH ２ , -NHR'', -NHC(O)R'', -NHSO ２ R'', -CN, -C(O)NH ２ , -C(O)NHR'', -C(O)NR'' ２ , -OH, -OR'', -S(O) ２ NH ２ , -S(O) ２ NHR'', or -S(O) ２ NR'' ２ is; or (ii) hydrogen; and / or (c) Each R ３ They became independent, (i) hydrogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, aryl, heteroaryl, benzyl, haloalkyl, haloalkenyl, or C(O)R''; or, (ii) The compound according to any one of claims 14 to 18, wherein the compound is hydrogen.

20. Z is NR ３ The compound according to any one of claims 14 to 19.

21. The compound according to any one of claims 1 to 13, wherein Z is NH.

22. (a) Z is S, or (b) Z is O, The compound according to any one of claims 1 to 19. 【Request Item 23】 【Table 1】 A compound according to claim 1 or 14, selected from the above.

24. A pharmaceutical composition comprising the compound described in any one of claims 1 to 23.

25. structure: CLM-L'-PTM A bifunctional compound having, or a pharmaceutically acceptable salt, enantiomer, stereoisomer, solvate, or polymorph thereof, CLM is the cereblon E3 ubiquitin ligase binding site; PTM is the protein target region; L' is selected from the bonds and the chemical bonding portions that covalently bond the CLM and the PTM; The CLM is a compound according to any one of claims 1 to 23, and R, R ２ , R ３ and R ４ The difunctional compound, or a pharmaceutically acceptable salt, enantiomer, stereoisomer, solvate, or polymorph thereof, wherein at least one of the compounds is modified to contain a carboxylic acid group or ester group that can thereby be covalently bonded to L' or the PTM.

26. L' is a bond, or L' is 【Chemistry 45】 Selected from, 【Chemistry 46】 This indicates binding to PTM, 【Chemistry 47】 This indicates a connection to CLM, p is an integer between 3 and 12. The bifunctional compound according to claim 25, wherein s is an integer from 1 to 6.

27. p is, (a) an integer between 4 and 11; (b) an integer between 5 and 10; (c) an integer between 6 and 9; or (d) The bifunctional compound according to claim 26, wherein the compound is an integer between 7 and 8.

28. s, (a) an integer between 2 and 5; or (b) The bifunctional compound according to claim 26 or 27, wherein the bifunctional compound is an integer between 3 and 4.

29. L' is 【Chemistry 48】 or 【Chemistry 49】 The bifunctional compound according to any one of claims 26 to 28.

30. PTM [Transformation 50] And, 【Chemistry 51】 A bifunctional compound according to any one of claims 25 to 29, wherein the compound exhibits bonding to L.

31. The compound 【Chemistry 52】 【change】 A bifunctional compound according to claim 30, selected from the above.

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