Novel compounds that bind to cereblon, and methods for using the same.

Abstract

The present invention discloses novel compounds that bind to cereblon, and methods of using the same. The compounds are represented by the following formulas (I), (IIa)-(IIc), (III) and (IV): [Formula 1] JPEG2024501537000138.jpg73121JPEG2024501537000139.jpg87121

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 those substrate proteins. [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 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 the tumor stroma from nutrient support, 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 and a desirable safety profile 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 to achieve stable drugs without loss of efficacy due to chemical degradation, it is desirable to develop cereblon modifiers. Therefore, there is a constant need to provide novel cereblon-binding compounds that possess pharmaceutically relevant properties while ensuring high drug stability along with improved resistance to hydrolytic degradation. [Prior art documents] [Patent Documents]

[0007] [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 パンフレット [License 6] U.S. Patent No. 8518972 [License 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]

[0008] [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) [Overview of the project] [Means for solving the problem]

[0009] According to a first aspect of the present invention, formula (I):

[0010] [ka]

[0011] A compound, or a pharmaceutically acceptable salt, ester, optically active isomer, racemate, solvate, amino acid conjugate, or prodrug thereof is provided. During the ceremony: Each of X1 and X2 is independently either O or S; Each of Q1 and Q2 is independently N or CR, and at least one of Q1 and Q2 is N; Each of W1, W2, W3, and W4 is independently N or CR'; n is 0, 1, or 2; L is hydrogen, alkyl, alkenyl, aryl, heteroaryl, benzyl, haloalkyl, haloalkenyl, -C(O)R'', -C(O)OR'', -C(O)NH2, -C(O)NHR'', -C(O)NR''2, -OR'', -NR''2, or -S(O)2R''; Each R is independently hydrogen, halogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, benzyl, haloalkyl, haloalkenyl, -NH2, -NHR'', -NR''2, -NR''C(O)R'', -NR''C(O)OR'', -NO2, -CN, -C(O)R'', -C(O)OR'', -C(O)NH2, -C(O)NHR'', -C(O)NR''2, -OR'', -OC(O)R'', -OC(O)OR'', -OC(O)NH2, -OC(O)NHR'', -OC(O)NR''2, -SR'', -S(O)2R'', -S(O)2OR'', -S(O)2NH2, -S(O)2NHR'', or -S(O)2NR''2; Each R' independently represents hydrogen, halogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, benzyl, haloalkyl, haloalkenyl, -NH2, -NHR'', -NR''2, -NR''C(O)R'', -NR''C(O)OR'', -NO2, -CN, -C(O)R'', -C(O)OR'', -C(O)NH2, -C(O)NHR'', -C(O)NR''2, -C(O)NHCHR ''2, -CHR''NHC(O)NHR'', -CHR''NHC(O)C(halogen)2R'', -OR'', -OC(O)R'', -OC(O)OR'', -OC(O)NH2, -OC(O)NHR'', -OC(O)NR''2, -SR'', -S(O)2R'', -S(O)2OR'', -S(O)2NH2, -S(O)2NHR'', -S(O)2NR''2, or -NHS(O)2R''; Each R'' is independently hydrogen, alkyl, cycloalkyl, alkenyl, aryl, heteroaryl, or benzyl.

[0012] In a particular embodiment, 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, each R' is independently hydrogen, halogen, -NH2, -NO2, -C(O)NHCHR''2, -CHR''NHC(O)NHR'', -CHR''NHC(O)C(halogen)2R'', or -NHS(O)2R''.

[0017] In some embodiments, each R'' is independently hydrogen, alkyl, cycloalkyl, or aryl. In some such embodiments, the aryl is substituted with one or more groups selected from halogen, alkyl, and O-haloalkyl. In some embodiments, the halogen is Cl, the alkyl is methyl, and the O-haloalkyl is O-CF3.

[0018] In some embodiments, one of W1, W2, W3, and W4 is N, and the remaining three of W1, W2, W3, and W4 are each CR'. In some such embodiments, W1 is N, and W2, W3, and W4 are CR'. In other embodiments, W2 is N, and W1, W3, and W4 are CR'. In other embodiments, W3 is N, and W1, W2, and W4 are CR'. In other embodiments, W4 is N, and W1, W2, and W3 are CR'.

[0019] In some embodiments, W1, W2, W3, and W4 are each CR'.

[0020] In some embodiments, W1, W2, W3, and W4 are each CH.

[0021] In other embodiments, three of W1, W2, W3, and W4 are CH, and one of W1, W2, W3, and W4 is C-halogen, C-alkyl, C-alkenyl, C-alkynyl, C-aryl, C-heteroaryl, C-benzyl, C-haloalkyl, C-haloalkenyl, C-NH2, C-NHR'', C-NR''2, C-NR''C(O)R'', C-NR''C(O)OR'', C-NO2, C-CN, CC(O)R'', CC(O)OR'', CC(O)NH2, CC(O )NHR'', CC(O)NR''2, CC(O)NHCHR''2, C-CHR''NHC(O)NHR'', C-CHR''NHC(O)C(halogen)2R'', C-OR'', C-OC(O)R'', C-OC(O)OR'', C-OC( O)NH2, C-OC(O)NHR'', C-OC(O)NR''2, C-SR'', CS(O)2R'', CS(O)2OR'', CS(O)2NH2, CS(O)2NHR'', CS(O)2NR''2, or C-NHS(O)2R''. In some such embodiments, one of W1, W2, W3, and W4 is C-halogen, C-NH2, C-NO2, C-NHR'', C-NR''2, CC(O)NHCHR''2, C-CHR''NHC(O)NHR'', C-CHR''NHC(O)C(halogen)2R'', or C-NHS(O)2R''. In some such embodiments, one of W1, W2, W3, and W4 is C-halogen, C-NH2, C-NO2, CC(O)NHCHR''2, C-CHR''NHC(O)NHR'', C-CHR''NHC(O)C(halogen)2R'', or C-NHS(O)2R''. In some such embodiments, one of W1, W2, W3, and W4 is C-halogen, C-NH2, C-NO2, CC(O)NHCHR''2, C-CH2NHC(O)NHR'', C-CH2NHC(O)CF2R'', or C-NHS(O)2R''.

[0022] In some embodiments, W2, W3, and W4 are each CH. In some such embodiments, W1 is C-halogen, C-NH2, C-NO2, or C-NHS(O)2R''. In some such embodiments, W1 is C-NH2 or C-NHS(O)2R''.

[0023] In other embodiments, W1, W2, and W3 are each CH. In some such embodiments, W4 is C-halogen, C-NH2, C-NO2, or C-NHS(O)2R''. In some such embodiments, W4 is C-NH2.

[0024] In other embodiments, W1, W2, and W4 are each CH. In some such embodiments, W2 is C-NH2, C-NO2, or C-NHS(O)2R''.

[0025] In other embodiments, W1, W3, and W4 are each CH. In some such embodiments, W3 is C-NH2, C-NO2, CC(O)NHCHR''2, C-CH2NHC(O)NHR'', C-CH2NHC(O)CF2R'', or C-NHS(O)2R''. In some such embodiments, W3 is C-NH2, CC(O)NHCHR''2, C-CH2NHC(O)NHR'', C-CH2NHC(O)CF2R'', or C-NHS(O)2R''. In some such embodiments, W3 is C-NH2, C-CH2NHC(O)NHR'', C-CH2NHC(O)CF2R'', or C-NHS(O)2R''.

[0026] In some embodiments, Q1 is N and Q2 is CR.

[0027] In other embodiments, Q1 is N and Q2 is N.

[0028] In other embodiments, Q1 is CR and Q2 is N. In some such embodiments, Q1 is CH or C-alkyl. In some such embodiments, Q1 is CH. In other embodiments, Q1 is C-methyl.

[0029] In other embodiments, two of W1, W2, W3, and W4 are N, and the remaining two of W1, W2, W3, and W4 are each CR'. In some such embodiments, W1 and W2 are each N, and W3 and W4 are each CR'. In other such embodiments, W1 and W3 are each N, and W2 and W4 are each CR'. In other such embodiments, W1 and W4 are each N, and W2 and W3 are each CR'. In other such embodiments, W2 and W3 are each N, and W1 and W4 are each CR'. In other such embodiments, W2 and W4 are each N, and W1 and W3 are each CR'. In other such embodiments, W3 and W4 are each N, and W1 and W2 are each CR'.

[0030] In other embodiments, three of W1, W2, W3, and W4 are N, and the remaining one of W1, W2, W3, and W4 is CR'. In some such embodiments, W1, W2, and W3 are N, and W4 is CR'. In other such embodiments, W1, W2, and W4 are N, and W3 is CR'. In other such embodiments, W1, W3, and W4 are N, and W2 is CR'. In other such embodiments, W2, W3, and W4 are N, and W1 is CR'.

[0031] In some embodiments of the compound of formula (I), Q1 is N and Q2 is CR. In some embodiments of the compound of formula (I), Q1 is CR and Q2 is N. In some embodiments of the compound of formula (I), Q1 is N and Q2 is N.

[0032] In some embodiments of the compound of formula (I), each R is independently hydrogen or alkyl. In some such embodiments, each R is independently hydrogen or C1-C4 alkyl. In some embodiments, the C1-C4 alkyl is methyl, ethyl, n-propyl, or n-butyl. In some embodiments, the C1-C4 alkyl is methyl or ethyl. In some embodiments, each R is independently hydrogen or methyl.

[0033] In some embodiments of the compound of formula (I), 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.

[0034] In some embodiments of the compound of formula (I), n is 0. In other embodiments, n is 1 or 2. In some embodiments, n is 1. In other embodiments, n is 2.

[0035] In some embodiments of the compound of formula (I), L is hydrogen, alkyl, alkenyl, aryl, heteroaryl, benzyl, haloalkyl, haloalkenyl, -OR'', -NR''2, or -S(O)2R''. In other embodiments of the compound of formula (I), 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 (I), L is hydrogen, alkyl, alkenyl, aryl, heteroaryl, benzyl, haloalkyl, haloalkenyl, -OR'', -NR''2, or -S(O)2R''. In some embodiments of the compound of formula (I), L is hydrogen, alkyl, alkenyl, aryl, heteroaryl, benzyl, haloalkyl, or haloalkenyl. In other embodiments of the compound of formula (I), L is -OR'', -NR''2, or -S(O)2R''. In some embodiments of the compound of formula (I), L is hydrogen, alkyl, alkenyl, aryl, heteroaryl, or benzyl. In some embodiments of the compound of formula (I), L is hydrogen, alkyl, alkenyl, or aryl. In some embodiments of the compound of formula (I), L is hydrogen, alkyl, or alkenyl. In some embodiments of the compound of formula (I), L is hydrogen or alkyl. In some embodiments of the compound of formula (I), L is hydrogen.

[0036] In some embodiments, the compound of formula (I) is as follows:

[0037] [ka]

[0038] In some such embodiments, the compound of formula (I) is as follows:

[0039] [ka]

[0040] In other embodiments, the compound of formula (I) is as follows:

[0041] [ka]

[0042] In some such embodiments, the compound of formula (I) is as follows:

[0043] [ka]

[0044] In some embodiments, the compound of formula (I) is selected from the following:

[0045] [Table 1] JPEG0007853713000009.jpg192116JPEG0007853713000010.jpg253152

[0046] In some embodiments, the compound of formula (I) is selected from the following:

[0047] [Table 2] JPEG0007853713000012.jpg191134JPEG0007853713000013.jpg102131

[0048] In some embodiments, the compound of formula (I) is selected from the following:

[0049] [Table 3] JPEG0007853713000015.jpg67130

[0050] In one embodiment, the compound of formula (I) is as follows.

[0051]

Chemical formula

[0052] According to a second aspect of the present invention, compounds of formula (IIa), (IIb), or (IIc) are provided:

[0053]

Chemical formula

[0054] Where: Each of X1 and X2 is independently O or S; Each of Q1 and Q2 is independently N or CR, and at least one of Q1 and Q2 is N; Each of W1, W2, and W3 is independently N or CR a and; Z is O, S, or NR b and; n is 0, 1, or 2; L is hydrogen, alkyl, alkenyl, aryl, heteroaryl, benzyl, haloalkyl, haloalkenyl, -C(O)R b -C(O)OR b -C(O)NH2, -C(O)NHR b -C(O)NR b 2, -OR b -NR b 2, or -S(O)2R b and; Each R is independently hydrogen, halogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, benzyl, haloalkyl, haloalkenyl, -NH2, -NHR b -NR b 2, -NR b C(O)R b -NR b C(O)OR b -NO2, -CN, -C(O)R b -C(O)ORb -C(O)NH2, -C(O)NHR b -C(O)NR b 2, -OR b -OC(O)R b -OC(O)OR b -OC(O)NH2, -OC(O)NHR b -OC(O)NR b 2, -SR b -S(O)2R b -S(O)2OR b -S(O)2NH2, -S(O)2NHR b , or -S(O)2NR b It is 2; Each R a These are independently hydrogen, halogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, benzyl, haloalkyl, haloalkenyl, -NH2, -NHR b , -NR b 2. -NR b C(O)R b , -NR b C(O)OR b -NO2, -CN, -C(O)R b , -C(O)OR b -C(O)NH2, -C(O)NHR b -C(O)NR b 2, -OR b -OC(O)R b -OC(O)OR b -OC(O)NH2, -OC(O)NHR b -OC(O)NR b 2, -SR b -S(O)2R b -S(O)2OR b -S(O)2NH2, -S(O)2NHR b , or -S(O)2NR b It is 2; Each R b These are independently hydrogen, alkyl, alkenyl, aryl, heteroaryl, or benzyl.

[0055] In some embodiments, compounds of formula (IIa), (IIb), or (IIc) have the following structure.

[0056] [ka]

[0057] In other embodiments, the compound of formula (IIa), (IIb), or (IIc) has the following structure.

[0058] [ka]

[0059] In some embodiments of the compound of formula (IIa) or (IIc), W1 is N. In some embodiments of the compound of formula (IIa) or (IIb), W2 is N. In some embodiments of the compound of formula (IIb) or (IIc), W3 is N.

[0060] In some embodiments of the compounds of formula (IIa), (IIb), or (IIc), one of W1, W2, and W3 is N, and the other W1, W2, and W3 is CR. a In some such embodiments, one of W1, W2, and W3 is N, and the other W1, W2, and W3 are CH.

[0061] In some embodiments of the compounds of formula (IIa), (IIb), or (IIc), W1, W2, and W3 are each CR a That is the case.

[0062] In some embodiments of the compounds of formula (IIa) or (IIc), W1 is C-NH2, C-NHR b or C-NR b The answer is 2. In some such embodiments, W1 is C-NH2.

[0063] In some embodiments of the compounds of formula (IIa), (IIb), or (IIc), W1, W2, and W3 are each N.

[0064] In some embodiments, the compound is represented by formula (IIc).

[0065] In other embodiments, the compound is of formula (IIb).

[0066] In other embodiments, the compound is of formula (IIa).

[0067] In some embodiments of the compounds of formula (IIa), (IIb), or (IIc), Z is O. In other embodiments of the compounds of formula (IIa), (IIb), or (IIc), Z is S. In other embodiments of the compounds of formula (IIa), (IIb), or (IIc), Z is NH. In other embodiments of the compounds of formula (IIa), (IIb), or (IIc), Z is N-alkyl. In some such embodiments, Z is N-Me.

[0068] In some embodiments of the compounds of formula (IIa), (IIb), or (IIc), Q1 is N and Q2 is CR. In some embodiments of the compounds of formula (IIa), (IIb), or (IIc), Q1 is CR and Q2 is N. In some embodiments, Q1 is CH or C-alkyl. In some such embodiments, Q1 is C-methyl. In other embodiments, Q1 is CH.

[0069] In other embodiments of the compounds of formula (IIa), (IIb), or (IIc), Q1 is N and Q2 is N.

[0070] In some embodiments of the compounds of formula (IIa), (IIb), or (IIc), each R is independently hydrogen or alkyl. In some such embodiments, each R is independently hydrogen or C1-C4 alkyl. In some embodiments, the C1-C4 alkyl is methyl, ethyl, n-propyl, or n-butyl. In some embodiments, the C1-C4 alkyl is methyl or ethyl. In some embodiments, each R is independently hydrogen or methyl.

[0071] In some embodiments of the compounds of formula (IIa), (IIb), or (IIc), each R' is independently hydrogen, -NH2, or -NHR b or -NR b 2. In some such embodiments, each R a R is independently hydrogen or -NH2. In some such embodiments, each R a It is hydrogen.

[0072] In some embodiments of the compounds of formula (IIa), (IIb), or (IIc), 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.

[0073] In some embodiments of the compounds of formula (IIa), (IIb), or (IIc), n is 0. In other embodiments, n is 1 or 2. In some embodiments, n is 1. In other embodiments, n is 2.

[0074] In some embodiments of the compounds of formula (IIa), (IIb), or (IIc), L is hydrogen, alkyl, alkenyl, aryl, heteroaryl, benzyl, haloalkyl, haloalkenyl, -OR b , -NR b 2, or -S(O)2R bIn other embodiments of the compounds of formula (IIa), (IIb), or (IIc), L is hydrogen, alkyl, alkenyl, aryl, heteroaryl, benzyl, haloalkyl, haloalkenyl, -C(O)R b , -C(O)OR b -C(O)NH2, -C(O)NHR b , or -C(O)NR b 2. In some embodiments of the compounds of formula (IIa), (IIb), or (IIc), L is hydrogen, alkyl, alkenyl, aryl, heteroaryl, benzyl, haloalkyl, haloalkenyl, -OR b , -NR b 2, or -S(O)2R b In some embodiments of the compounds of formula (IIa), (IIb), or (IIc), L is hydrogen, alkyl, alkenyl, aryl, heteroaryl, benzyl, haloalkyl, or haloalkenyl. In other embodiments of the compounds of formula (IIa), (IIb), or (IIc), L is -OR b , -NR b 2, or -S(O)2R b In some embodiments of the compounds of formula (IIa), (IIb), or (IIc), L is hydrogen, alkyl, alkenyl, aryl, heteroaryl, or benzyl. In some embodiments of the compounds of formula (IIa), (IIb), or (IIc), L is hydrogen, alkyl, alkenyl, or aryl. In some embodiments of the compounds of formula (IIa), (IIb), or (IIc), L is hydrogen, alkyl, or alkenyl. In some embodiments of the compounds of formula (IIa), (IIb), or (IIc), L is hydrogen or alkyl. In some embodiments of the compounds of formula (IIa), (IIb), or (IIc), L is hydrogen.

[0075] In some embodiments, the compound of formula (IIa), (IIb), or (IIc) is selected from the following:

[0076] [Table 4]

[0077] In some embodiments, the compound is as follows.

[0078] [Chemical formula]

[0079] According to a third aspect of the present invention, formula (III):

[0080] [Chemical formula]

[0081] the compound of is provided, wherein each of X1 and X2 is independently O or S; n is 0, 1 or 2; L is hydrogen, alkyl, alkenyl, aryl, heteroaryl, benzyl, haloalkyl, haloalkenyl, -C(O)R b , -C(O)OR b , -C(O)NH2, -C(O)NHR b , -C(O)NR b 2, -OR b , -NR b 2, or -S(O)2R b ; each of R1, R2 and R3 is independently hydrogen, halogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, benzyl, haloalkyl, haloalkenyl, -NH2, -NHR b , -NR b 2, -NR b C(O)R b , -NR b C(O)OR b , -NO2, -CN, -C(O)R b , -C(O)OR b , -C(O)NH2, -C(O)NHR b , -C(O)NR b 2, -OR b [[ID=7�]], -OC(O)Rb 、 -OC(O)OR b 、 -OC(O)NH2, -OC(O)NHR b 、 -OC(O)NR b 2, -SR b 、 S(O)2R b 、 -S(O)2OR b 、 -S(O)2NH2, -S(O)2NHR b 、 or -S(O)2NR b 2; each R b is independently hydrogen, alkyl, alkenyl, aryl, heteroaryl, or benzyl.

[0082] In some embodiments, the compound of formula (III) has the following structure.

[0083] [[ID=3O]]

Chemical formula

[0084] In other embodiments, the compound of formula (III) has the following structure.

[0085]

Chemical formula

[0086] In some embodiments of the compound of formula (III), 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. <00OO654>

[0087] In some embodiments of the compound of formula (III), n is 0. In other embodiments, n is 1 or 2. In some embodiments, n is 1. In other embodiments, n is 2.

[0088] In some embodiments of the compound of formula (III), L is hydrogen, alkyl, alkenyl, aryl, heteroaryl, benzyl, haloalkyl, haloalkenyl, -OR b , -NR b 2, or -S(O)2R b In other embodiments of the compound of formula (III), L is hydrogen, alkyl, alkenyl, aryl, heteroaryl, benzyl, haloalkyl, haloalkenyl, -C(O)R b '', -C(O)OR b -C(O)NH2, -C(O)NHR b , or -C(O)NR b 2. In some embodiments of the compound of formula (III), L is hydrogen, alkyl, alkenyl, aryl, heteroaryl, benzyl, haloalkyl, haloalkenyl, -OR b , -NR b 2, or -S(O)2R b In some embodiments of the compound of formula (III), L is hydrogen, alkyl, alkenyl, aryl, heteroaryl, benzyl, haloalkyl, or haloalkenyl. In other embodiments of the compound of formula (III), L is -OR b , -NR b 2, or -S(O)2R b In some embodiments of the compound of formula (III), L is hydrogen, alkyl, alkenyl, aryl, heteroaryl, or benzyl. In some embodiments of the compound of formula (III), L is hydrogen, alkyl, alkenyl, or aryl. In some embodiments of the compound of formula (III), L is hydrogen, alkyl, or alkenyl. In some embodiments of the compound of formula (III), L is hydrogen or alkyl. In some embodiments of the compound of formula (III), L is hydrogen.

[0089] According to a fourth aspect of the present invention, formula (IV):

[0090] [ka]

[0091] The compound is provided, During the ceremony, Each of X1 and X2 is independently either O or S; L stands for hydrogen, alkyl, alkenyl, aryl, heteroaryl, benzyl, haloalkyl, haloalkenyl, -C(O)R b , -C(O)OR b -C(O)NH2, -C(O)NHR b -C(O)NR b 2, -OR b , -NR b 2, or -S(O)2R b and; Each of Q1, Q2, Q3, Q4, and Q5 is independently N or CR, where at least one of Q1, Q2, Q3, Q4, and Q5 is N; Each R independently represents hydrogen, halogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, benzyl, haloalkyl, haloalkenyl, -NH2, or -NHR. b , -NR b 2. -NR b C(O)R b , -NR b C(O)OR b -NO2, -CN, -C(O)R b , -C(O)OR b -C(O)NH2, -C(O)NHR b -C(O)NR b 2, -OR b -OC(O)R b -OC(O)OR b -OC(O)NH2, -OC(O)NHR b -OC(O)NR b 2, -SR b -S(O)2R b -S(O)2OR b -S(O)2NH2, -S(O)2NHR b , or -S(O)2NR b It is 2; Each R bThese are independently hydrogen, alkyl, alkenyl, aryl, heteroaryl, or benzyl.

[0092] In some embodiments, the compound of formula (IV) has the following structure.

[0093] [ka]

[0094] In some embodiments, the compound of formula (IV) has the following structure.

[0095] [ka]

[0096] In some embodiments of the compound of formula (IV), 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.

[0097] In some embodiments of the compound of formula (IV), one of Q1, Q2, Q3, Q4, and Q5 is N, and the remaining four of Q1, Q2, Q3, Q4, and Q5 are each CR. In some such embodiments, Q1 is N. In other such embodiments, Q2 is N. In other such embodiments, Q3 is N. In other such embodiments, Q4 is N. In other such embodiments, Q5 is N.

[0098] In some embodiments of the compound of formula (IV), two of Q1, Q2, Q3, Q4, and Q5 are N, and the remaining three of Q1, Q2, Q3, Q4, and Q5 are each CR. In some such embodiments, Q1 and Q2 are N, and Q3, Q4, and Q5 are each CR. In other such embodiments, Q2 and Q3 are N, and Q1, Q4, and Q5 are each CR. In other such embodiments, Q1 and Q3 are N, and Q2, Q4, and Q5 are each CR. In other such embodiments, Q2 and Q4 are N, and Q1, Q3, and Q5 are each CR. In other such embodiments, Q1 and Q4 are N, and Q2, Q3, and Q5 are each CR.

[0099] In some embodiments of the compound of formula (IV), three of Q1, Q2, Q3, Q4, and Q5 are N, and the remaining two of Q1, Q2, Q3, Q4, and Q5 are each CR.

[0100] In some embodiments of the compound of formula (IV), each R is independently hydrogen, halogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, benzyl, haloalkyl, haloalkenyl, -NH2, -NHR b , -NR b 2. -NR b C(O)R b , -NR b C(O)OR b -NO2, -CN, -C(O)R b , -C(O)OR b -C(O)NH2, -C(O)NHR b -C(O)NR b 2, -OR b -OC(O)R b -OC(O)OR b -OC(O)NH2, -OC(O)NHR b -OC(O)NR b 2, -SR b S(O)2R b In some embodiments, each R is independently hydrogen or -NH2.

[0101] In some embodiments of the compound of formula (IV), L is hydrogen, alkyl, alkenyl, aryl, heteroaryl, benzyl, haloalkyl, haloalkenyl, -OR b , -NR b 2, or -S(O)2R b In other embodiments of the compound of formula (IV), L is hydrogen, alkyl, alkenyl, aryl, heteroaryl, benzyl, haloalkyl, haloalkenyl, -C(O)R b , -C(O)OR b -C(O)NH2, -C(O)NHR b , or -C(O)NR b 2. In some embodiments of the compound of formula (IV), L is hydrogen, alkyl, alkenyl, aryl, heteroaryl, benzyl, haloalkyl, haloalkenyl, -OR b , -NR b 2, or -S(O)2R b In some embodiments of the compound of formula (IV), L is hydrogen, alkyl, alkenyl, aryl, heteroaryl, benzyl, haloalkyl, or haloalkenyl. In other embodiments of the compound of formula (IV), L is -OR b , -NR b 2, or -S(O)2R b In some embodiments of the compound of formula (IV), L is hydrogen, alkyl, alkenyl, aryl, heteroaryl, or benzyl. In some embodiments of the compound of formula (IV), L is hydrogen, alkyl, alkenyl, or aryl. In some embodiments of the compound of formula (IV), L is hydrogen, alkyl, or alkenyl. In some embodiments of the compound of formula (IV), L is hydrogen or alkyl. In some embodiments of the compound of formula (IV), L is hydrogen.

[0102] According to a fifth aspect of the present invention, a pharmaceutical composition comprising a compound according to any of the above aspects of the present invention is provided.

[0103] The present invention also provides compounds according to any of the above embodiments of the present invention that are used as cereblon binders.

[0104] 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.

[0105] The present invention also provides compounds or compositions according to any of the above embodiments of the present invention for use in immuno-oncology.

[0106] 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.

[0107] 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.

[0108] In some embodiments of the 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.

[0109] 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.

[0110] In some embodiments of the combination formulation, at least one additional active agent is an anticancer agent or an agent for the treatment of an autoimmune disease. In some embodiments, at least one additional active agent is a peptide, antibody, 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.

[0111] The present invention also has the following structure: CLM-[Link]-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; [Link] is selected from the bonds, as well as the chemical bonds that covalently bond CLM and PTM; CLM is a compound of any of the embodiments described above, and R, R', R a , R b At least one of R1, R2, and R3 contains a group that can be covalently bonded to [Link] or PTM, or is modified to contain such a group.

[0112] In some embodiments, [Link] is:

[0113] [ka]

[0114] Selected from,

[0115] [ka]

[0116] This indicates binding to PTM,

[0117] [ka]

[0118] indicates a connection to the CLM; p is an integer between 3 and 12; and s is an integer between 1 and 6.

[0119] In some embodiments, [Link] is

[0120] [ka]

[0121] In some embodiments, p is an integer between 4 and 11, 5 and 10, 6 and 9, or 7 and 8.

[0122] In some embodiments, [Link] is as follows:

[0123] [ka]

[0124] In some embodiments, [Link] is a link.

[0125] In some embodiments, the PTM targets BRD4.

[0126] In some embodiments, PTM is

[0127] [ka]

[0128] And,

[0129] [ka]

[0130] This indicates a link to [Link].

[0131] In some embodiments, R, R', R a , R b At least one of R1, R2, and R3 is modified to include a carboxylic acid group or an ester group.

[0132] In some embodiments, the bifunctional compound is selected from the following:

[0133] [ka]

[0134] 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.

[0135] As used herein, the term "cycloalkyl" is intended to include both unsubstituted cycloalkyl groups and cycloalkyl 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 cycloalkyl group is an unsubstituted alkyl group. In some embodiments, the cycloalkyl group is a cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl group. In some embodiments, the cycloalkyl group is a cyclopentyl or cyclohexyl group. In some embodiments, the cycloalkyl group is a cyclohexyl group.

[0136] 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.

[0137] 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.

[0138] 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''-O-haloalkyl, alkyl, halogen, -NH2, -NHR'', -NR''2, -SO2R'', -C(O)R'', -CN, or -NO2. In some embodiments, the aryl group is substituted with one or more additional groups selected from -R'', -O-haloalkyl, alkyl, halogen, -NR''2, -SO2R'', -C(O)R'', -CN, or -NO2. In some embodiments, the aryl group is substituted with one or more additional groups selected from halogen, alkyl, and O-haloalkyl. In some embodiments, the aryl group is substituted with one or more additional groups selected from Cl, methyl, and O-CF3. In some embodiments, the aryl group is an unsubstituted aryl group. In some embodiments, the aryl group is C6-C 10 The group is an aryl, C6-C8 aryl, or C6 aryl. As used herein, the term "heteroaryl" is intended to include both an unsubstituted heteroaryl group and a heteroaryl 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 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.

[0139] 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 Description of the Drawings

[0140] [Figure 1] It is a figure showing assays showing the effects of various compounds of the present invention and various reference compounds on SALL4 degradation in the Kelly cell line. [Figure 2] It is a figure showing assays showing the effects of various compounds of the present invention and various reference compounds on IKZF1 degradation in the H929 cell line. [Figure 3] It is a figure showing assays showing the effects of various compounds of the present invention and various reference compounds on IKZF3 degradation in the H929 cell line. [Figure 4] It is a figure showing the stability of various compounds of the present invention when analyzed by liquid chromatography - mass spectrometry (LC - MS) over a 48 - hour period when incubated at 37°C in phosphate - buffered saline (PBS) / 10% fetal bovine serum (FBS).

Modes for Carrying Out the Invention

[0141] As described above, the present invention provides compounds of the following formulas (I), (IIa) - (IIc), (III) and (IV):

[0142]

Chemical formula

[0143] In the formula, L, X1, X2, Q1, Q2, Q3, Q4, Q5, W1, W2, W3, W4, R, R1, R2, R3 and Z are as defined above.

[0144] The binding of the above - mentioned compounds to cereblon is CRL4 CRBNThe specificity of the complex can be changed, inducing the association of a novel substrate protein, followed by ubiquitination and degradation of the substrate protein. Examples of such proteins include, but are not limited to, IKZF1 and IKZF3.

[0145] The above compounds regulate cereblon in a unique way, enabling the CRL4 CRBN ubiquitin ligase complex to recognize substrates different from those recognized in other cases and target them for degradation. As a result, the compounds of the present invention are expected to expand / alter the growth inhibitory activity of CRBN, and thus expand the range of cancer types sensitive to treatment by CMA.

[0146] The compounds of the present invention are advantageous in terms of their synthetic feasibility. The synthesis of the compounds can be summarized as follows:

[0147]

Chemical formula

[0148] One example of the compounds of the present invention is 3-(5-amino-2-methylquinolin-3-yl)piperidine-2,6-dione (Compound 1):

[0149]

Chemical formula

[0150] 3-(5-amino-2-methylquinolin-3-yl)piperidine-2,6-dione (Compound 1) can be synthesized as follows:

[0151]

Chemical formula

[0152] In the formula, step 1 involves the reaction with m-CPBA and phosphoryl bromide; step 2 involves the reaction with 2,6-bis(benzyloxy)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine, tripotassium phosphate and Pd(dppf)Cl2CH2Cl2; and step 3 involves the reaction with H2 gas in the presence of Pd on activated carbon. Complete experimental details of the synthesis of 3-(5-amino-2-methylquinoline-3-yl)piperidine-2,6-dione are shown in the "Examples" section below.

[0153] Other examples of the compounds of the present invention are shown below:

[0154] [Table 5] JPEG0007853713000042.jpg247152JPEG0007853713000043.jpg248152JPEG0007853713000044.jpg93148

[0155] In some embodiments, the compound is as follows:

[0156] [ka]

[0157] As discussed above in the Examples section, the inventors have found that various compounds of the present invention exhibit cereblon-binding ability similar to or improved to that of known CMAs, such as CC-122. Despite the pharmaceutically active properties of known CMAs such as CC-122, patients often develop tolerance to these compounds. The use of novel compounds such as those of the present invention described above may help overcome this clinical limitation.

[0158] One of the significant disadvantages of currently available CMAs is their safety profiles. For example, the teratogenicity of CMAs depends on the extent to which CMAs induce the degradation of the SALL4 transcription factor. Known CMAs induce the degradation of several proteins (including SALL4) that bind to the CRL4 CRBN ligase only in the presence of CMA. The SALL4 degradation observed with CMA treatment is (at least in part) responsible for the teratogenicity of CMA. Compounds with a reduced ability to induce SALL4 degradation may exhibit an improved safety profile.

[0159] 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.

[0160] The compounds of the present invention may be useful for the treatment of various diseases and disorders including, but not limited to: 1) Cancer. The compounds provided herein can be used to treat, prevent or manage primary or metastatic tumors. Specific examples of cancers include, but are not limited to, skin cancer such as melanoma; lymph node cancer; breast cancer; cervical cancer; endometrial cancer; gastrointestinal cancer; lung cancer; ovarian cancer; prostate cancer; colon cancer; rectal cancer; oral cancer; brain tumors; head and neck cancer; pharyngeal cancer; testicular cancer; kidney cancer; pancreatic cancer; bone cancer; spleen cancer; liver cancer; bladder cancer; laryngeal cancer; nasal cancer, and AIDS-related cancers as well as hematological malignancies. a) Hematological malignancies include leukemia, lymphoma, multiple myeloma or smoldering myeloma. Leukemia includes: acute leukemia, acute lymphoblastic leukemia (ALL), chronic lymphocytic leukemia (CLL), acute myelogenous 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, mature adult acute myeloid leukemia, immature adult acute myeloid leukemia, abnormal adult acute myeloid leukemia, adult acute myelomonocytic leukemia, adult erythroleukemia, and adult pure erythroid leukemia. The following can be selected: leukemia, secondary acute myeloid leukemia, untreated adult acute myeloid leukemia, adult acute myeloid leukemia in remission, adult acute promyelocytic leukemia with PML-RARA, alkylating agent-associated acute myeloid 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 lymphomatoid 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 of non-cutaneous extranodal site, mature T cell and K cell non-Hodgkin lymphoma, nodal marginal zone lymphoma, post-transplant lymphoproliferative disorder, relapsed adult Burkitt lymphoma, relapsed adult diffuse large cell lymphoma, relapsed adult diffuse mixed cell lymphoma, and relapsed adult diffuse small cleaved cell lymphoma. 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 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, diffuse large B-cell lymphoma 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 excess blasts, refractory anemia with ringed sideroblasts, refractory cytopenia with multilineage dysplasia, secondary myelodysplastic syndromeThe following can be selected from the group consisting of myelodysplastic syndromes and myeloproliferative disorders. 2) Autoimmune diseases, e.g.: acute disseminated encephalomyelitis, acute motor axonal neuropathy, Addison's disease, adiposis dolorosa, 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 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 pancreatitis, autoimmune polyendocrine syndrome, autoimmune polyendocrine syndrome type 2, autoimmune polyendocrine syndrome type 3, autoimmune progesterone dermatitis, autoimmune retinopathy, autoimmune thrombocytopenia Purpura minor, 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 syndrome, cold agglutinin disease, complex regional pain syndrome, Crest syndrome, Crohn's disease, herpetiform dermatitis, dermatomyositis, type 1 diabetes, discoid lupus erythematosus, endometriosis, enthesitis, enthesitis-associated arthritis, eosinophilic esophagitis, eosinophilic fasciitis, acquired epidermolysis bullosa, erythema nodosum, essential mixed cryoglobulinemia, Evans syndrome, Felty syndrome, fibromyalgia, gastritis, gestational herpes Pemphigoid, 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 (IBD), intermediate uveitis, interstitial cystitis, juvenile arthritis, Kawasaki disease, Lambert-Eaton myasthenic syndrome, leukocytoclastic vasculitis, lichen planus, lichen sclerosing, ligneous conjunctivitisConjunctivitis, linear IgA disease, lupus nephritis, lupus vasculitis, Lyme disease (chronic), Meniere's disease, microscopic colitis, microscopic polyangiitis, mixed connective tissue disease, Mooren's ulcer, focal scleroderma (morphea), acute pityriasis lichenoides (Mucha-Habermann Diseases, 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 inflammation Symptomatic 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, neovascular diseases of the eye, choroidal neovascular diseases, retinal neovascular diseases, and rubeosis (neovascularization of the cornea). 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 diseases. Collagen disease-related vascular disorders, 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, alveolar hypoventilation impairment, 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 hemangiomatosis, associated with, or secondary to; 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.

[0161] 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.

[0162] 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 of NK cells and antibody-mediated cytotoxicity (ADCC). Furthermore, the compounds provided herein may be immunomodulatory and / or cytotoxic and therefore may be useful as chemotherapeutic agents. [Examples]

[0163] General method A:

[0164] [ka]

[0165] To a solution of suitable 2-aminobenzaldehyde (1 equivalent) in MeOH (0.5-1 M), 4-oxopentanoic acid (1 equivalent), followed by 2 M NaOH (1.2 equivalents), was added. The reaction mixture was refluxed for 18 hours, concentrated under reduced pressure, neutralized with acetic acid, the solid was filtered, and washed with water, diethyl ether, and pentane to obtain the substitute 2-(2-methylquinoline-3-yl)acetic acid.

[0166] General method B:

[0167] [ka]

[0168] To a solution of DCC (1.1 equivalents) in DCM, DMAP (0.8 equivalents) and appropriate 2-(quinoline-3-yl)acetic acid (1 equivalent) were added at 0°C. Tert-butanol (3 equivalents) was added, and the reaction mixture was warmed to room temperature and stirred for 12 hours. The reaction mixture was diluted with water, extracted with ethyl acetate, dried over Na2SO4, concentrated under reduced pressure, and purified by flash column chromatography.

[0169] General method C:

[0170] [ka]

[0171] To a solution of appropriate tert-butyl 2-(quinoline-3-yl)acetate (1 equivalent) in DMF, K2CO3 (1 equivalent), benzyltriethylammonium chloride (1 equivalent), and acrylonitrile (1 equivalent) were added, and the reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was diluted with water, and the product was extracted with ethyl acetate. The combined organic phase was dried over Na2SO4, concentrated under reduced pressure, and purified by flash column chromatography.

[0172] General method D:

[0173] [ka]

[0174] To an ice-cold solution of appropriate tert-butyl 4-cyano-2-(quinoline-3-yl)butanoate (1 equivalent) in DMSO, H2O2 (5 equivalents) and K2CO3 (0.1 equivalent) were added. The reaction mixture was heated to room temperature and stirred for 16 hours. The reaction mixture was diluted with water, and the product was extracted with ethyl acetate. The combined organic phase was dried over Na2SO4, concentrated under reduced pressure, and purified by flash column chromatography.

[0175] General method E:

[0176] [ka]

[0177] In a vial, appropriate amounts of tert-butyl 5-amino-2-(2-methylquinoline-3-yl)-5-oxopentanoate (1 equivalent), p-toluenesulfonic acid (5-10 equivalents), and ACN were added, and the reaction mixture was stirred at 80°C for 2-48 hours. The mixture was concentrated under reduced pressure and purified by flash column chromatography or preparative HPLC.

[0178] General method F:

[0179] [ka]

[0180] The appropriate nitro compound, 10% Pd / C, and ethanol were placed in a vial, and the reaction mixture was stirred at room temperature under a hydrogen atmosphere (1 bar) until complete conversion was achieved. The mixture was filtered through Celite and concentrated under reduced pressure.

[0181] General method G:

[0182] [ka]

[0183] The appropriate amino compound was placed in a vial, followed by pyridine (0.01-0.1 M), and then the appropriate sulfonyl chloride. The reaction mixture was stirred at room temperature until complete conversion was achieved. The mixture was concentrated under reduced pressure and purified by flash column chromatography or preparative HPLC.

[0184] General method H:

[0185] [ka]

[0186] To a solution of bromoalene (1 equivalent) in dioxane, KOAc (2 equivalents), ((1-(tert-butoxy)vinyl)oxy)(tert-butyl)dimethylsilane (4 equivalents), and Pd[P(o-Tol)3]2Cl2 (0.2 equivalents) were added with inert gas, and the reaction mixture was stirred at 130°C for 48 hours. The reaction mixture was filtered through Celite, concentrated under reduced pressure, and purified by flash column chromatography to obtain the appropriate tert-butylaryl acetate. [Example 1]

[0187] Synthesis of 3-(5-amino-2-methylquinoline-3-yl)piperidine-2,6-dione (compound 1) and 3-(2-methyl-5-nitroquinoline-3-yl)piperidine-2,6-dione (compound 2)

[0188] [ka]

[0189] Step A: To an ice-cold solution of 5-nitro-2-methylquinoline (2.30 g, 12.22 mmol, 1 equivalent) in DCM (25 mL), m-CPBA (2.3 g, 13.67 mmol, 1.1 equivalents) was added. The reaction mixture was warmed to room temperature and stirred for 16 hours. The mixture was filtered, the filtrate was washed with 1 M KOH solution, dried over Na2SO4, and concentrated under reduced pressure to obtain 2-methyl-5-nitroquinoline 1-oxide (88% yield).

[0190] Step B: To an ice-cold solution of 2-methyl-5-nitroquinoline 1-oxide (500.0 mg, 2.44 mmol, 1 equivalent) in DCM (5 mL), POBr3 (1.4 g, 4.9 mmol, 2 equivalents) in DCM (5 mL) was added. The reaction mixture was warmed to room temperature and stirred for 48 hours. Ice water was added, the solution was neutralized with 10% NH3 solution, extracted with DCM, dried over Na2SO4, concentrated under reduced pressure, and purified by flash column chromatography to obtain 2-methyl-3-bromo-5-nitroquinoline (14% yield).

[0191] Step C: The reaction was carried out according to general procedure H using 2-methyl-3-bromo-5-nitroquinoline (600 mg, 2.24 mmol, 1 equivalent) to obtain tert-butyl 2-(2-methyl-5-nitroquinoline-3-yl)acetate (58% yield).

[0192] Step D: The reaction was carried out according to general procedure C using tert-butyl 2-(2-methyl-5-nitroquinoline-3-yl) acetate (200 mg, 0.662 mmol) to obtain tert-butyl 4-cyano-2-(2-methyl-5-nitroquinoline-3-yl)butanoate (40% yield).

[0193] Step E: The reaction was carried out using tert-butyl 4-cyano-2-(2-methyl-5-nitroquinoline-3-yl)butanoate (120.0 mg, 0.338 mmol) according to general procedure D to obtain tert-butyl 5-amino-2-(2-methyl-5-nitroquinoline-3-yl)-5-oxopentanoate (51% yield).

[0194] Step F: The reaction was carried out according to general procedure E using tert-butyl 5-amino-2-(2-methyl-5-nitroquinoline-3-yl)-5-oxopentanoate (250 mg, 0.670 mmol) to obtain 3-(2-methyl-5-nitroquinoline-3-yl)piperidine-2,6-dione (69% yield). 1 H NMR(500MHz,DMSO)δ10.98(s,1H), 8.60(s,1H), 8.40~8.30(m,2H), 7.89(dd,J=8.5,7.7Hz,1H), 4.42(dd,J=12.5,4.7Hz,1H), 2.82 (ddd,J=17.8,12.8,5.3Hz,1H), 2.71(s,3H), 2.66~2.61(m,1H), 2.44(dd,J=12.8,4.3Hz,1H), 2.14(ddt,J=10.0,7.8,3.9Hz,1H). LCMS(m / z [M+H] + ):299.9

[0195] Step G: The reaction was carried out according to general procedure F using 3-(2-methyl-5-nitroquinoline-3-yl)piperidine-2,6-dione (139 mg, 0.464 mmol) to obtain 3-(5-amino-2-methylquinoline-3-yl)piperidine-2,6-dione (99% yield). 1 H NMR(500MHz,DMSO)δ10.91(s,1H), 8.26(s,1H), 7.42~7.27(m,1H), 7.08(d,J =8.3Hz,1H), 6.62(dd,J=7.6,0.8Hz,1H), 5.85(s,2H), 4.22(dd,J=12.6,4.8 Hz,1H), 2.85(ddd,J=18.1,13.2,5.3Hz,1H), 2.65(dt,J=17.0,3.4Hz,1H),2 .60(s,3H), 2.46(dq,J=13.0,4.1Hz,1H), 2.11(dtd,J=13.0,5.1,2.9Hz,1H). LCMS(m / z [M+H] + ) 270.0 [Example 1a]

[0196] Alternative synthesis of 3-(5-amino-2-methylquinoline-3-yl)piperidine-2,6-dione (compound 1)

[0197] [ka]

[0198] Step 1: Synthesis of 3-bromo-2-methyl-5-nitro-8,8a-dihydroquinoline 2-Methyl-5-nitro-8,8a-dihydroquinoline (19.8 g, 105.3 mmol) was dissolved in dichloromethane (250 mL) and cooled to 5°C in an ice bath. m-CPBA (32.9 g, 133.4 mmol, 70%) was gradually added thereto, and the reaction mixture was stirred at room temperature (20-25°C) for 12 hours. The mixture was washed with 2 M NaOH solution (2 × 150 mL), dried on anhydrous sodium sulfate, and evaporated under vacuum to obtain a yellow solid (22 g). The solid was dissolved in CHCl3 (200 mL), the resulting solution was cooled to 5°C in an ice bath, and phosphoryl bromide (62.6 g, 218.3 mmol) from CHCl3 (300 mL) was added dropwise to the reaction mixture. The mixture was stirred at room temperature (20-25°C) for 12 hours, poured into cold water, basicized to pH=12 with solid potassium carbonate, and extracted with CHCl3 (3 × 100 mL). The combined extract was dried on anhydrous sodium sulfate and evaporated under vacuum. The crude product was purified by flash column chromatography (eluent hexane-MTBE 0-100%) to obtain 2.9 g of 3-bromo-2-methyl-5-nitro-8,8a-dihydroquinoline (10% yield) as a brown solid.

[0199] Step 2: Synthesis of 3-[2,6-bis(benzyloxy)pyridine-3-yl]-2-methyl-5-nitro-8,8a-dihydroquinoline 2,6-Bis(benzyloxy)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (4.55 g, 10.9 mmol), tripotassium phosphate (4.8 g, 22.6 mmol), and Pd(dppf)Cl2CH2Cl2 (0.86 g, 1 mmol) were successively added to a solution of 3-bromo-2-methyl-5-nitro-8,8a-dihydroquinoline (2.9 g, 10.86 mmol) in 1,4-dioxane (50 mL) and water (5 mL). The resulting mixture was stirred under an argon atmosphere at 100 °C for 12 hours. The solvent was removed under vacuum, and the residue was diluted with ELISA (100 mL) and filtered through a silica gel pad. The filtrate was evaporated under vacuum and recrystallized from siRNA to obtain 2.05 g of 3-[2,6-bis(benzyloxy)pyridine-3-yl]-2-methyl-5-nitro-8,8a-dihydroquinoline (4.3 mmol, 39% yield) as a pale yellow solid.

[0200] Step 3: Synthesis of 3-(5-amino-2-methylquinoline-3-yl)piperidine-2,6-dione Pd on activated carbon (1.2 g) was added to a solution of 3-[2,6-bis(benzyloxy)pyridine-3-yl]-2-methyl-5-nitro-8,8a-dihydroquinoline (2.05 g, 4.29 mmol) in THF / methanol (5:1, 300 mL). The reaction mixture was stirred under an H2 atmosphere for 96 hours. The catalyst was removed by filtration, and the filtrate was evaporated under vacuum. The resulting crude product was purified by HPLC (eluent water-acetonitrile) to obtain 0.05 g of the target compound 3-(5-amino-2-methylquinoline-3-yl)piperidine-2,6-dione (4% yield) as a white solid. 1H NMR:(500MHz,DMSO-d6)δ10.92(s,1H), 8.25(s,1H), 7.33(t,J= 7.9Hz,1H) 7.07(d,J=8.2Hz,1H), 6.61(d,J=7.5Hz,1H), 5.86(brs,2H), 4.25~4.17(m,1H), 2.8 9~2.79(m,1H), 2.69~2.61(m,1H), 2.59(s,3H), 2.46~2.36(m,1H), 2.15~2.08(m,1H) LCMS(m / z [M+H] + ):270.2 [Example 2]

[0201] Synthesis of 3-(5-fluoro-2-methylquinoline-3-yl)piperidine-2,6-dione (compound 3)

[0202] [ka]

[0203] Step A: The reaction was carried out according to general procedure A using 2-amino-6-fluorobenzaldehyde (1.0 g, 7.19 mmol) to obtain 2-(5-fluoro-2-methylquinoline-3-yl)acetic acid (38% yield).

[0204] Step B: The reaction was carried out according to general procedure B using 2-(5-fluoro-2-methylquinoline-3-yl)acetic acid (1.0 g, 4.56 mmol) to obtain tert-butyl 2-(5-fluoro-2-methylquinoline-3-yl)acetate (35% yield).

[0205] Step C: The reaction was carried out according to general procedure C using tert-butyl 2-(5-fluoro-2-methylquinoline-3-yl) acetate (500 mg, 1.81 mmol) to obtain tert-butyl 4-cyano-2-(5-fluoro-2-methylquinoline-3-yl)butanoate (50% yield).

[0206] Step D: The reaction was carried out according to general procedure D using tert-butyl 4-cyano-2-(5-fluoro-2-methylquinoline-3-yl)butanoate (500 mg, 1.52 mmol) to obtain tert-butyl 5-amino-2-(5-fluoro-2-methylquinoline-3-yl)-5-oxopentanoate (45% yield).

[0207] Step E: The reaction was carried out according to general procedure E using 5-amino-2-(5-fluoro-2-methylquinoline-3-yl)-5-oxopentanoate (5.0 mg, 14 μmol) to obtain 3-(5-fluoro-2-methylquinoline-3-yl)piperidine-2,6-dione (84% yield). 1 H NMR(500MHz,DMSO)δ10.94(s,1H), 8.24(s,1H), 7.79(d,J=8.5Hz,1H), 7.70(td,J=8.2,6.2Hz,1H), 7.37(dd,J=10.0,7.6Hz,1H), 4.36(dd,J=12.7, 4.7Hz,1H), 2.82(ddd,J=17.8,13.2,5.4Hz,1H), 2.68(s,3H), 2.61(dd,J =17.4,3.5Hz,1H), 2.57~2.51(m,1H), 2.12(dtd,J=12.8,5.1,2.6Hz,1H). LCMS(m / z [M+H] + ):272.9 [Example 3]

[0208] Synthesis of 3-(5-nitroquinoline-3-yl)piperidine-2,6-dione (compound 12) and 3-(5-aminoquinoline-3-yl)piperidine-2,6-dione (compound 14)

[0209] [ka]

[0210] Step A: To a solution of 5-nitroquinoline (5.00 g, 28.7 mmol, 1 equivalent) in AcOH (140 mL), N-bromosuccinimide (5.11 g, 43 mmol, 1.5 equivalents) was added in small increments, and the reaction mixture was refluxed for 16 hours. Volatile substances were removed under reduced pressure, and the residue was neutralized with 6 M NaOH. The product was extracted by DCM, washed with water and brine, concentrated under reduced pressure, and purified by flash column chromatography to obtain 3-bromo-5-nitroquinoline (3.80 g, 52% yield).

[0211] Step B: The reaction was carried out according to general procedure H using 3-bromo-5-nitroquinoline (1.00 g, 3.98 mmol, 1 equivalent) to obtain tert-butyl 2-(5-nitroquinoline-3-yl) acetate (69% yield).

[0212] Step C: The reaction was carried out according to general procedure C using tert-butyl 2-(5-nitroquinoline-3-yl) acetate (800 mg, 2.78 mmol) to obtain tert-butyl 4-cyano-2-(5-nitroquinoline-3-yl)butanoate (45% yield).

[0213] Step D: The reaction was carried out using tert-butyl 4-cyano-2-(5-nitroquinoline-3-yl)butanoate (430 mg, 1.257 mmol) according to general procedure D to obtain tert-butyl 5-amino-2-(5-nitroquinoline-3-yl)-5-oxopentanoate (23% yield).

[0214] Step E: The reaction was carried out according to general procedure E using tert-butyl 5-amino-2-(5-nitroquinoline-3-yl)-5-oxopentanoate (30 mg, 0.083 mmol) to obtain 3-(5-nitroquinoline-3-yl)piperidine-2,6-dione (68% yield). 1H NMR(500MHz,DMSO)δ11.01(s,1H), 9.01(d,J=2.1Hz,1H), 8.72~8.67(m,1H), 8.50~8.40(m,2H), 7.95(dd,J=8.4,7.7Hz,1H), 4.32(dd ,J=12.7,4.8Hz,1H), 2.77(ddd,J=17.4,12.9,5.4Hz,1H), 2.64~2.59(m,1H), 2.48~2.42(m,1H), 2.15(dtd,J=13.0,5.2,2.9Hz,1H). LCMS(m / z [M+H] + ) 286.0

[0215] Step F: The reaction was carried out according to general procedure F using 3-(5-nitroquinoline-3-yl)piperidine-2,6-dione (13.7 mg, 0.048 mmol) to obtain 3-(5-aminoquinoline-3-yl)piperidine-2,6-dione (27% yield). 1 H NMR(500MHz,DMSO)δ10.94(s,1H), 8.66(d,J=2.1Hz,1H), 8.39(s,1H), 7.40(t,J=8.0Hz,1H), 7.18(d,J=8.2Hz,1H), 6.71(dd,J=7.6,1.1Hz,1H), 5.94 (s,2H), 4.05(dd,J=12.6,4.9Hz,1H), 2.79(ddd,J=17.7,12.8,5.3Hz,1H) , 2.66~2.60(m,1H), 2.42~2.35(m,1H), 2.14(dtd,J=13.3,5.2,3.1Hz,1H). LCMS(m / z [M+H] + ) 256.0 [Example 4]

[0216] Synthesis of 3-(2-methyl-6-nitroquinoline-3-yl)piperidine-2,6-dione (compound 5) and 3-(6-amino-2-methylquinoline-3-yl)piperidine-2,6-dione (compound 11)

[0217] [ka]

[0218] Step A: The reaction was carried out according to general procedure A using 2-amino-5-nitrobenzaldehyde (2.0 g, 12.05 mmol) to obtain 2-(2-methyl-6-nitroquinoline-3-yl)acetic acid (67% yield).

[0219] Step B: The reaction was carried out according to general procedure B using 2-(2-methyl-6-nitroquinoline-3-yl)acetic acid (1.0 g, 4.06 mmol) to obtain tert-butyl 2-(2-methyl-6-nitroquinoline-3-yl)acetate (40% yield).

[0220] Step C: The reaction was carried out according to general procedure C using tert-butyl 2-(2-methyl-6-nitroquinoline-3-yl) acetate (290 mg, 0.96 mmol) to obtain tert-butyl 4-cyano-2-(2-methyl-6-nitroquinoline-3-yl)butanoate (44% yield).

[0221] Step D: The reaction was carried out according to general procedure D using tert-butyl 4-cyano-2-(2-methyl-6-nitroquinoline-3-yl)butanoate (150 mg, 0.423 mmol) to obtain tert-butyl 5-amino-2-(2-methyl-6-nitroquinoline-3-yl)-5-oxopentanoate (28% yield).

[0222] Step E: The reaction was carried out according to general procedure E using tert-butyl 4-cyano-2-(2-methyl-6-nitroquinoline-3-yl)butanoate (30 mg, 0.080 mmol) to obtain 3-(2-methyl-6-nitroquinoline-3-yl)piperidine-2,6-dione (67% yield). 1H NMR(500MHz,DMSO)δ11.00(s,1H), 8.96(d,J=2.6Hz,1H), 8.50(s,1H), 8.44~8.38(m,1H), 8.12(d,J=9.1Hz,1H), 4.39(dd,J=12.5,4. 7Hz,1H), 2.84(ddd,J=17.6,12.8,5.2Hz,1H), 2.74(s,3H), 2.68~2.62(m,1H), 2.44~2.38(m,1H), 2.17(dtd,J=13.1,5.1,2.9Hz,1H). LCMS(m / z [M+H] + ):300.0

[0223] Step F: The reaction was carried out according to general procedure F using 3-(2-methyl-6-nitroquinoline-3-yl)piperidine-2,6-dione (16 mg, 0.053 mmol) to obtain 3-(6-amino-2-methylquinoline-3-yl)piperidine-2,6-dione (58% yield). 1 H NMR(500MHz,DMSO)δ10.88(s,1H), 7.73(s,1H), 7.61(d,J=8.9Hz,1H), 7.17 ~7.01(m,1H), 6.73(d,J=2.5Hz,1H), 5.49(s,2H), 4.17(dd,J=12.4,4.8Hz, 1H), 2.79(ddd,J=17.7,12.8,5.3Hz,1H), 2.59(dt,J=17.1,3.7Hz,1H), 2.5 4(s,3H), 2.40(dd,J=12.9,4.3Hz,1H), 2.07(dtd,J=13.2,5.2,3.1Hz,1H). LCMS(m / z [M+H] + ):270.05 [Example 5]

[0224] Synthesis of 3-(2-methyl-7-nitroquinoline-3-yl)piperidine-2,6-dione (compound 6) and 3-(7-amino-2-methylquinoline-3-yl)piperidine-2,6-dione (compound 8)

[0225] [ka]

[0226] Step A: The reaction was carried out using 2-amino-4-nitrobenzaldehyde (560 mg, 3.37 mmol) according to general procedure A to obtain 2-(2-methyl-7-nitroquinoline-3-yl)acetic acid (quantitative).

[0227] Step B: The reaction was carried out using 2-(2-methyl-7-nitroquinoline-3-yl)acetic acid (830 mg, 3.36 mmol) according to general procedure B to obtain tert-butyl 2-(2-methyl-7-nitroquinoline-3-yl)acetate (45% yield).

[0228] Step C: The reaction was carried out according to general procedure C using tert-butyl 2-(2-methyl-7-nitroquinoline-3-yl) acetate (460 mg, 1.52 mmol) to obtain tert-butyl 4-cyano-2-(2-methyl-7-nitroquinoline-3-yl)butanoate (47% yield).

[0229] Step D: The reaction was carried out according to general procedure D using tert-butyl 4-cyano-2-(2-methyl-7-nitroquinoline-3-yl)butanoate (255 mg, 0.718 mmol) to obtain tert-butyl 5-amino-2-(2-methyl-7-nitroquinoline-3-yl)-5-oxopentanoate (35% yield).

[0230] Step E: The reaction was carried out according to general procedure E using tert-butyl 4-cyano-2-(2-methyl-7-nitroquinoline-3-yl)butanoate (30 mg, 0.080 mmol) to obtain 3-(2-methyl-7-nitroquinoline-3-yl)piperidine-2,6-dione (84% yield). 1H NMR(500MHz,DMSO)δ10.99(s,1H), 8.72(d,J=2.4Hz,1H), 8.37(s,1H), 8.28(dd,J=8.9,2.3Hz,1H), 8.17(d,J=8.9Hz,1H), 4.40(dd,J=12.7,4.7 Hz,1H), 2.84(ddd,J=18.0,13.0,5.3Hz,1H), 2.74(s,3H), 2.68~2.62(m,1H), 2.45(td,J=12.9,4.4Hz,1H), 2.16(dtd,J=13.0,5.2,2.8Hz,1H). LCMS(m / z [M+H] + ):300.05

[0231] Step F: The reaction was carried out according to general procedure F using 3-(2-methyl-7-nitroquinoline-3-yl)piperidine-2,6-dione (18 mg, 0.063 mmol) to obtain 3-(7-amino-2-methylquinoline-3-yl)piperidine-2,6-dione (95% yield). 1 H NMR(500MHz,DMSO)δ10.85(s,1H), 7.75(s,1H), 7.50(d,J=8.7Hz,1H), 6.90(dd,J=8.7,2.2Hz,1H), 6.84(d,J=2.2Hz,1H), 5.63(s,2H), 4.12(dd ,J=12.3,4.8Hz,1H), 2.79(ddd,J=17.5,12.7,5.2Hz,1H), 2.60~2.55(m,1H), 2.30(td,J=12.8,4.2Hz,1H), 2.06(dtd,J=13.2,5.2,3.2Hz,1H). LCMS(m / z [M+H] + ):270.0 [Example 6]

[0232] Synthesis of 3-(2-methyl-8-nitroquinoline-3-yl)piperidine-2,6-dione (compound 7) and 3-(8-amino-2-methylquinoline-3-yl)piperidine-2,6-dione (compound 10)

[0233] [ka]

[0234] Step A: The reaction was carried out according to general procedure A using 2-amino-3-nitrobenzaldehyde (5.0 g, 30.04 mmol) to obtain 2-(2-methyl-8-nitroquinoline-3-yl)acetic acid (40% yield).

[0235] Step B: The reaction was carried out according to general procedure B using 2-(2-methyl-8-nitroquinoline-3-yl)acetic acid (3.0 g, 13.36 mmol) to obtain tert-butyl 2-(2-methyl-8-nitroquinoline-3-yl)acetate (35% yield).

[0236] Step C: The reaction was carried out according to general procedure C using tert-butyl 2-(2-methyl-8-nitroquinoline-3-yl) acetate (1.20 g, 3.97 mmol) to obtain tert-butyl 4-cyano-2-(2-methyl-8-nitroquinoline-3-yl)butanoate (22% yield).

[0237] Step D: The reaction was carried out according to general procedure D using tert-butyl 4-cyano-2-(2-methyl-8-nitroquinoline-3-yl)butanoate (310 mg, 0.871 mmol) to obtain tert-butyl 5-amino-2-(2-methyl-8-nitroquinoline-3-yl)-5-oxopentanoate (46% yield).

[0238] Step E: The reaction was carried out according to general procedure E using tert-butyl 4-cyano-2-(2-methyl-8-nitroquinoline-3-yl)butanoate (30 mg, 0.080 mmol) to obtain 3-(2-methyl-8-nitroquinoline-3-yl)piperidine-2,6-dione (65% yield). 1H NMR(500MHz,DMSO)δ10.98(s,1H), 8.36(s,1H), 8.22~8.13(m,2H), 7.72~7.64(m,1H), 4.38(dd,J=12.7,4.7Hz,1H), 2.84(ddd,J=1 7.4,13.1,5.3Hz,1H), 2.68(s,3H), 2.64(dd,J=16.9,3.7Hz,1H), 2.44(td,J=12.9,4.2Hz,1H), 2.16(dtd,J=12.8,5.1,2.8Hz,1H). LCMS(m / z [M+H] + ):299.95

[0239] Step F: The reaction was carried out according to general procedure F using 3-(2-methyl-8-nitroquinoline-3-yl)piperidine-2,6-dione (16 mg, 0.053 mmol) to obtain 3-(8-amino-2-methylquinoline-3-yl)piperidine-2,6-dione (91% yield). 1 H NMR(500MHz,DMSO)δ10.90(s,1H), 7.92(s,1H), 7.20(t,J=7.7Hz,1H), 6.97(dd,J=8.2,1.4Hz,1H), 6.80(dd,J=7.5,1.3Hz,1H), 5.78(s,2H), 4.24( dd,J=12.4,4.8Hz,1H), 2.81(ddd,J=17.8,12.9,5.3Hz,1H), 2.64(s,3H), 2.62~2.57(m,1H), 2.44~2.37(m,1H), 2.11(dtd,J=13.1,5.2,3.0Hz,1H). LCMS(m / z [M+H] + ):270.0 [Example 7]

[0240] Synthesis of 3-(8-chloro-2-methylquinoline-3-yl)piperidine-2,6-dione (compound 21)

[0241] [ka]

[0242] Step A: The reaction was carried out using 2-amino-3-chlorobenzaldehyde (1.0 g, 6.42 mmol) according to general procedure A to obtain 2-(8-chloro-2-methylquinoline-3-yl)acetic acid.

[0243] Step B: The reaction was carried out using 2-(8-chloro-2-methylquinoline-3-yl)acetic acid according to general procedure B to obtain tert-butyl 2-(8-chloro-2-methylquinoline-3-yl)acetate (38% yield, 2 steps).

[0244] Step C: The reaction was carried out according to general procedure C using tert-butyl 2-(8-chloro-2-methylquinoline-3-yl) acetate (400 mg, 1.47 mmol) to obtain tert-butyl 4-cyano-2-(8-chloro-2-methylquinoline-3-yl)butanoate.

[0245] Step D: The reaction was carried out using tert-butyl 4-cyano-2-(8-chloro-2-methylquinoline-3-yl)butanoate according to general procedure D to obtain tert-butyl 5-amino-2-(8-chloro-2-methylquinoline-3-yl)-5-oxopentanoate.

[0246] Step E: The reaction was carried out using tert-butyl 5-amino-2-(8-chloro-2-methylquinoline-3-yl)-5-oxopentanoate according to general procedure E to obtain 3-(8-chloro-2-methylquinoline-3-yl)piperidine-2,6-dione (9% yield, 3 steps). 1 H NMR(400MHz,DMSO) 10.96(s,1H), 8.22(s,1H), 7.91~7.84(m,2H), 7.50(t,J=7.8Hz,1H), 4.34(dd,J=12.5,4.6Hz, 1H), 2.88~2.77(m,1H), 2.71(s,3H), 2.66~2.57(m,1H), 2.48~2.38(m,1H), 2.18~2.12(m,1H). LCMS(m / z [M+H]+ ):289.2 [Example 8]

[0247] Synthesis of 3-(2,8-dimethylquinoline-3-yl)piperidine-2,6-dione (compound 22)

[0248] [ka]

[0249] Step A: The reaction was carried out using 2-amino-3-methylbenzaldehyde (1.0 g, 7.39 mmol) according to general procedure A to obtain 2-(2,8-dimethylquinoline-3-yl)acetic acid.

[0250] Step B: The reaction was carried out using 2-(2,8-dimethylquinoline-3-yl)acetic acid according to general procedure B to obtain tert-butyl 2-(2,8-dimethylquinoline-3-yl)acetate (39% yield, 2 steps).

[0251] Step C: The reaction was carried out according to general procedure C using tert-butyl 2-(2,8-dimethylquinoline-3-yl) acetate (500 mg, 1.84 mmol) to obtain tert-butyl 4-cyano-2-(2,8-dimethylquinoline-3-yl)butanoate (35% yield).

[0252] Step D: The reaction was carried out according to general procedure D using tert-butyl 4-cyano-2-(2,8-dimethylquinoline-3-yl)butanoate (200 mg, 0.616 mmol) to obtain tert-butyl 5-amino-2-(2,8-dimethylquinoline-3-yl)-5-oxopentanoate.

[0253] Step E: The reaction was carried out using tert-butyl 5-amino-2-(2,8-dimethylquinoline-3-yl)-5-oxopentanoate according to general procedure E to obtain 3-(2,8-dimethylquinoline-3-yl)piperidine-2,6-dione (30% yield, 2 steps). 1 H NMR(400MHz,DMSO) 10.92(s,1H), 8.07(s,1H), 7.70(d,J=8.1Hz,1H), 7.54(d,J=6.8Hz,1H), 7.40(dd,J=8.1,6.8Hz,1H), 4.29(dd,J=12. 4,4.5Hz,1H), 2.80~2.65(m,1H), 2.69(s,3H), 2.67(s,3H), 2.65~2.53(m,1H), 2.50~2.35(m,1H), 2.17~2.08(m,1H). LCMS(m / z [M+H] + ):269.3 [Example 9]

[0254] Synthesis of 3-(2-methylquinoline-3-yl)piperidine-2,6-dione (compound 13)

[0255] [ka]

[0256] Step A: The reaction was carried out using 2-aminobenzaldehyde (5.0 g, 41.3 mmol) according to general procedure A to obtain 2-(2-methylquinoline-3-yl)acetic acid (17% yield).

[0257] Step B: The reaction was carried out according to general procedure B using 2-(2-methylquinoline-3-yl)acetic acid (1.40 g, 6.96 mmol) to obtain tert-butyl 2-(2-methylquinoline-3-yl)acetate (44% yield).

[0258] Step C: The reaction was carried out according to general procedure C using tert-butyl 2-(2-methylquinoline-3-yl) acetate (800 mg, 3.11 mmol) to obtain tert-butyl 4-cyano-2-(2-methylquinoline-3-yl)butanoate (72% yield).

[0259] Step D: The reaction was carried out according to general procedure D using tert-butyl 4-cyano-2-(2-methylquinoline-3-yl)butanoate (700 mg, 2.25 mmol) to obtain tert-butyl 5-amino-2-(2-methylquinoline-3-yl)-5-oxopentanoate (67% yield).

[0260] Step E: The reaction was carried out according to general procedure E using 5-amino-2-(2-methylquinoline-3-yl)-5-oxopentanoate (100 mg, 0.304 mmol) to obtain 3-(2-methylquinoline-3-yl)piperidine-2,6-dione (76% yield). 1 H NMR(500MHz,DMSO)δ10.93(s,1H), 8.12(s,1H), 7.94~7.90(m,1H), 7.90~7.85(m ,1H), 7.69(ddd,J=8.4,6.9,1.5Hz,1H), 7.52(ddd,J=8.1,6.9,1.2Hz,1H), 4.29 (dd,J=12.5,4.8Hz,1H), 2.83(ddd,J=17.2,12.9,5.3Hz,1H), 2.66(s,3H), 2.65 ~2.56(m,1H), 2.42(qd,J=12.9,4.3Hz,1H), 2.13(dtd,J=13.0,5.1,3.0Hz,1H). LCMS(m / z [M+H] + ) 255.0 [Example 10]

[0261] Synthesis of N-((S)-1-cyclohexylethyl)-3-(2,6-dioxopiperidine-3-yl)-2-methylquinoline-7-carboxamide (compound 9)

[0262] [ka]

[0263] Step A: The reaction was carried out according to general procedure A using 2-amino-4-bromobenzaldehyde (3.00 g, 15.0 mmol) to obtain 2-(7-bromo-2-methylquinoline-3-yl)acetic acid (45% yield).

[0264] Step B: The reaction was carried out using 2-(7-bromo-2-methylquinoline-3-yl)acetic acid (500 mg, 1.78 mmol) according to general procedure B to obtain tert-butyl 2-(7-bromo-2-methylquinoline-3-yl)acetate (31% yield).

[0265] Step C: Molybdenum hexacarbonyl (196.3 mg, 0.744 mmol, 1 equivalent) and benzyltriethylammonium chloride (169.4 mg, 0.744 mmol, 1 equivalent) were placed in a pressure Schlenk tube. Dioxane (10 mL) was added, and the mixture was heated at 140°C for 1 hour. (S)-1-cyclohexylethylamine (189.2 mg, 1.487 mmol, 2 equivalents) and tert-butyl 2-(7-bromo-2-methylquinoline-3-yl) acetate (250.0 mg, 0.744 mmol, 1 equivalent) were added, and the reaction was continued at 150°C for 16 hours. By removing volatile substances under reduced pressure and purifying the residue by flash column chromatography, tert-butyl(S)-2-(7-((1-cyclohexylethyl)carbamoyl)-2-methylquinoline-3-yl)acetate (199.0 mg, 65% yield) was obtained.

[0266] Step D: The reaction was carried out according to general procedure C using tert-butyl(S)-2-(7-((1-cyclohexylethyl)carbamoyl)-2-methylquinoline-3-yl) acetate (150 mg, 0.365 mmol) to obtain tert-butyl4-cyano-2-(7-(((S)-1-cyclohexylethyl)carbamoyl)-2-methylquinoline-3-yl)butanoate (77% yield).

[0267] Step E: The reaction was carried out according to general procedure D using tert-butyl 4-cyano-2-(7-(((S)-1-cyclohexylethyl)carbamoyl)-2-methylquinoline-3-yl)butanoate (130 mg, 0.280 mmol) to obtain tert-butyl 5-amino-2-(7-(((S)-1-cyclohexylethyl)carbamoyl)-2-methylquinoline-3-yl)-5-oxopentanoate (59% yield).

[0268] Step F: The reaction was carried out according to general procedure E using tert-butyl 5-amino-2-(7-(((S)-1-cyclohexylethyl)carbamoyl)-2-methylquinoline-3-yl)-5-oxopentanoate (75 mg, 0.156 mmol) to obtain N-((S)-1-cyclohexylethyl)-3-(2,6-dioxopiperidine-3-yl)-2-methylquinoline-7-carboxamide (60% yield). 1H NMR(500MHz,DMSO)δ10.97(s,1H), 8.49(s,1H), 8.41(d,J=8.6Hz,1H), 8.20(s,1H), 7.99~7.92(m,2H), 4.34(d d,J=12.5,4.7Hz,1H), 3.92(h,J=6.9Hz,1H), 2.85(ddd,J=17.7,12.9,5.3Hz,1H), 2.71(s,3H), 2.65(dt,J=17 .2,3.4Hz,1H), 2.46(qd,J=13.0,4.3Hz,1H), 2.21~2.12(m,1H), 1.81(d,J=12.6Hz,2H), 1.74(d,J=11.2Hz,2H) ), 1.64(d,J=11.4Hz,1H), 1.49(tdt,J=11.1,7.0,3.3Hz,1H), 1.31~1.08(m,6H), 1.01(qd,J=12.5,3.1Hz,2H). LCMS(m / z [M+H] + ) 408.1 [Example 11]

[0269] Synthesis of 1-(3-chloro-4-methylphenyl)-3-{[3-(2,6-dioxopiperidine-3-yl)-2-methylquinoline-7-yl]methyl}urea (compound 15)

[0270] [ka]

[0271] Step A: The reaction was carried out using tert-butyl 2-(7-bromo-2-methylquinoline-3-yl) acetate (600 mg, 1.78 mmol) according to general procedure C to obtain tert-butyl 2-(7-bromo-2-methylquinoline-3-yl)-4-cyanobutanoate (31% yield).

[0272] Step B: The reaction was carried out using tert-butyl 2-(7-bromo-2-methylquinoline-3-yl)-4-cyanobutanoate (350 mg, 0.899 mmol) according to general procedure D to obtain tert-butyl 5-amino-2-(7-bromo-2-methylquinoline-3-yl)-5-oxopentanoate.

[0273] Step C: The reaction was carried out using tert-butyl 5-amino-2-(7-bromo-2-methylquinoline-3-yl)-5-oxopentanoate according to general procedure E to obtain 3-(7-bromo-2-methylquinoline-3-yl)piperidine-2,6-dione (67% yield, 2 steps).

[0274] Step D: 3-(7-bromo-2-methylquinoline-3-yl)piperidine-2,6-dione (80.0 mg, 0.24 mmol, 1 equivalent), zinc cyanide (84.6 mg, 0.72 mmol, 3 equivalents), and Pd(PPh3)4 (27.7 mg, 24 μmol, 0.1 equivalent) were placed in a flask. DMF (2.0 mL) was added, and the reaction mixture was stirred at 130°C for 18 hours. Volatile substances were removed under reduced pressure, and the residue was purified by flash column chromatography to obtain 3-(2,6-dioxopiperidine-3-yl)-2-methylquinoline-7-carbonitrile (55 mg, 82% yield).

[0275] Step E: 3-(2,6-dioxopiperidine-3-yl)-2-methylquinoline-7-carbonitrile (30.0 mg, 0.107 mmol, 1 equivalent), DMF (1.0 mL), and THF (2.0 mL) were added to a flask. Raney nickel (37.8 mg, 0.644 mmol, 6 equivalents), followed by Boc2O (46.9 mg, 0.215 mmol, 2 equivalents), was added, and the reaction mixture was stirred at room temperature under a hydrogen atmosphere (balloon) for 18 hours. The reaction mixture was filtered through Celite, the solid was washed with EtOH, and the filtrate was concentrated under reduced pressure. The crude product was purified by flash column chromatography to obtain tert-butyl((3-(2,6-dioxopiperidine-3-yl)-2-methylquinoline-7-yl)methyl)carbamate (29 mg, 70% yield).

[0276] Step F: Add tert-butyl((3-(2,6-dioxopiperidine-3-yl)-2-methylquinoline-7-yl)methyl)carbamate (5.5 mg, 14 μmol, 1 equivalent) to the vial. Add dioxane (0.5 mL), followed by 12 M HCl (0.1 mL), and stir the reaction mixture at room temperature for 2 hours. Remove volatile substances under reduced pressure, and redissolve the residue in DMF (1 mL). Add DIPEA (0.012 mL, 71 μmol, 5 equivalents), followed by 3-chloro-4-methylphenyl isocyanate (2.9 mg, 17 μmol, 1.2 equivalents), and stir the reaction mixture at room temperature for 18 hours. After removing volatile substances under reduced pressure and purifying the crude product by preparative HPLC, 1-(3-chloro-4-methylphenyl)-3-{[3-(2,6-dioxopiperidine-3-yl)-2-methylquinoline-7-yl]methyl}urea (4.8 mg, 74% yield) was obtained. 1H NMR(500MHz,DMSO)δ10.94(s,1H), 8.78(s,1H), 8.10(s,1H), 7.86(d,J=8.4Hz,1H), 7.81(s,1H), 7.70 (d,J=2.1Hz,1H), 7.48(dd,J=8.4,1.6Hz,1H), 7.21(d,J=8.4Hz,1H), 7.17(dd,J=8.3,2.1Hz,1H), 6.8 5(t,J=6.0Hz,1H), 4.51(d,J=5.9Hz,2H), 4.29(dd,J=12.4,4.7Hz,1H), 2.84(ddd,J=17.7,12.9,5.3H z,1H), 2.66(s,3H), 2.65~2.59(m,1H), 2.43(qd,J=13.0,4.4Hz,1H), 2.26(s,3H), 2.18~2.10(m,1H). LCMS(m / z [M+H] + ) 451.0 [Example 12]

[0277] Synthesis of 2-(4-chlorophenyl)-N-{[3-(2,6-dioxopiperidine-3-yl)-2-methylquinoline-7-yl]methyl}-2,2-difluoroacetamide (compound 16)

[0278] [ka]

[0279] tert-butyl((3-(2,6-dioxopiperidine-3-yl)-2-methylquinoline-7-yl)methyl)carbamate (5.5 mg, 14 μmol, 1 equivalent) was placed in a vial. Dioxane (0.5 mL), followed by 12 M HCl (0.1 mL), was added, and the reaction mixture was stirred at room temperature for 2 hours. Volatile substances were removed under reduced pressure, and the residue was redissolved in DMF (1 mL). 2-(4-chlorophenyl)-2,2-difluoroacetic acid (4.4 mg, 21.5 μmol, 1.5 equivalents) and DIPEA (12 μL, 72 μmol, 5 equivalents), followed by HATU (8.2 mg, 21 μmol, 1.5 equivalents), was added, and the reaction mixture was stirred at room temperature for 18 hours. By removing volatile substances under reduced pressure and purifying the crude product by preparative TLC, 2-(4-chlorophenyl)-N-{[3-(2,6-dioxopiperidine-3-yl)-2-methylquinoline-7-yl]methyl}-2,2-difluoroacetamide (2.9 mg, 42% yield) was obtained. 1 H NMR(500MHz,DMSO)δ10.94(s,1H), 9.73(t,J=6.1Hz,1H), 8.10(s,1H), 7.84(d,J=8. 4Hz,1H), 7.70(s,1H), 7.69~7.61(m,4H), 7.39(dd,J=8.4,1.6Hz,1H), 4.56(d,J=6. 1Hz,2H), 4.29(dd,J=12.5,4.7Hz,1H), 2.84(ddd,J=17.7,12.9,5.3Hz,1H), 2.66(s ,3H), 2.63(dt,J=17.2,3.9Hz,1H), 2.42(qd,J=12.7,4.0Hz,1H), 2.17~2.09(m,1H). LCMS(m / z [M+H] + ) 472.0 [Example 13]

[0280] Synthesis of N-(3-(2,6-dioxopiperidine-3-yl)-2-methylquinoline-5-yl)-2-(trifluoromethoxy)benzenesulfonamide (compound 17)

[0281] [ka]

[0282] The reaction was carried out using 3-(5-amino-2-methylquinoline-3-yl)piperidine-2,6-dione (5.1 mg, 18.9 μmol) according to general procedure G to obtain N-(3-(2,6-dioxopiperidine-3-yl)-2-methylquinoline-5-yl)-2-(trifluoromethoxy)benzenesulfonamide (58% yield). 1 H NMR(500MHz,DMSO)δ10.95(s,1H), 10.68(s,1H), 8.17(s,1H), 7.82(dd,J=8.1,1.7Hz,1 H), 7.74(s,1H), 7.71~7.63(m,1H), 7.58(s,1H), 7.49~7.39(m,2H), 7.29(d,J=6.3Hz,1H ), 4.26(dd,J=12.4,4.7Hz,1H), 2.84(ddd,J=17.7,12.8,5.2Hz,1H), 2.67(dt,J=16.9, 3.6Hz,1H), 2.63(s,3H), 2.24(qd,J=13.0,4.3Hz,1H), 2.04(dq,J=8.1,4.1,3.1Hz,1H). LCMS(m / z [M+H] + ) 494.2 [Example 14]

[0283] Synthesis of N-(3-(2,6-dioxopiperidine-3-yl)-2-methylquinoline-6-yl)-2-(trifluoromethoxy)benzenesulfonamide (compound 18)

[0284] [ka]

[0285] The reaction was carried out using 3-(6-amino-2-methylquinoline-3-yl)piperidine-2,6-dione (6.5 mg, 24.1 μmol) according to general procedure G to obtain N-(3-(2,6-dioxopiperidine-3-yl)-2-methylquinoline-6-yl)-2-(trifluoromethoxy)benzenesulfonamide (65% yield). 1 H NMR(500MHz,DMSO)δ10.93(s,2H), 8.09(s,1H), 8.05(dd,J=7.9,1.6Hz,1H), 7.88~7.81(m,1H), 7.75(ddd,J=8.4,7.6,1.7Hz,1H), 7.58~7.47( m,4H), 4.27(dd,J=12.6,4.6Hz,1H), 2.82(ddd,J=17.7,13.1,5.3Hz,1H), 2.68~2.58(m,4H), 2.43(qd,J=13.0,4.2Hz,1H), 2.14~2.06(m,1H). LCMS(m / z [M+H] + ) 494.05 [Example 15]

[0286] Synthesis of N-(3-(2,6-dioxopiperidine-3-yl)-2-methylquinoline-7-yl)-2-(trifluoromethoxy)benzenesulfonamide (compound 19)

[0287] [ka]

[0288] The reaction was carried out using 3-(7-amino-2-methylquinoline-3-yl)piperidine-2,6-dione (5.3 mg, 19.6 μmol) according to general procedure G to obtain N-(3-(2,6-dioxopiperidine-3-yl)-2-methylquinoline-7-yl)-2-(trifluoromethoxy)benzenesulfonamide (60% yield). 1H NMR(500MHz,DMSO)δ10.89(s,1H), 8.14(s,1H), 8.04(dd,J=8.1,1.7Hz,1H), 7.96(s,1H) ), 7.77~7.68(m,2H), 7.53(dd,J=8.9,6.4Hz,2H), 7.49(d,J=2.2Hz,1H), 7.30(dd,J=8.8 ,2.3Hz,1H), 4.21(dd,J=12.5,4.7Hz,1H), 2.79(ddd,J=17.7,12.8,5.3Hz,1H), 2.60(dd ,J=8.2,4.5Hz,1H), 2.57(s,3H), 2.39~2.29(m,1H), 2.06(dtd,J=13.0,5.1,3.0Hz,1H). LCMS(m / z[M+H] + ) 493.7 [Example 16]

[0289] Synthesis of N-(3-(2,6-dioxopiperidine-3-yl)-2-methylquinoline-8-yl)-2-(trifluoromethoxy)benzenesulfonamide (compound 20)

[0290] [ka]

[0291] The reaction was carried out using 3-(8-amino-2-methylquinoline-3-yl)piperidine-2,6-dione (5.3 mg, 20 μmol) according to general procedure G to obtain N-(3-(2,6-dioxopiperidine-3-yl)-2-methylquinoline-8-yl)-2-(trifluoromethoxy)benzenesulfonamide (63% yield). 1H NMR(500MHz,DMSO)δ10.93(s,1H), 9.76(s,1H), 8.13(s,1H), 8.06(dd,J=7.9,1.7Hz ,1H), 7.69(td,J=7.9,1.7Hz,1H), 7.58(t,J=9.0Hz,2H), 7.52~7.44(m,2H), 7.41(t, J=7.9Hz,1H), 4.30(dd,J=12.6,4.7Hz,1H), 2.81(ddd,J=17.2,13.0,5.3Hz,1H), 2. 65(s,3H), 2.64~2.57(m,1H), 2.45~2.34(m,1H), 2.10(dtd,J=12.6,5.0,2.7Hz,1H). LCMS(m / z[M+H] + ) 493.8 [Example 17]

[0292] Synthesis of 3-(1,6-dimethyl-1H-pyrazolo[3,4-b]pyridine-5-yl)piperidine-2,6-dione (compound 4)

[0293] [ka]

[0294] Step A: The reaction was carried out according to general procedure H using 5-bromo-1,6-dimethyl-1H-pyrazolo[3,4-b]pyridine (2.00 g, 8.85 mmol, 1 equivalent) to obtain tert-butyl 2-(1,6-dimethyl-1H-pyrazolo[3,4-b]pyridine-5-yl) acetate (77% yield).

[0295] Step B: The reaction was carried out according to general procedure C using tert-butyl 2-(1,6-dimethyl-1H-pyrazolo[3,4-b]pyridine-5-yl) acetate (1.80 g, 6.90 mmol) to obtain tert-butyl 4-cyano-2-(1,6-dimethyl-1H-pyrazolo[3,4-b]pyridine-5-yl)butanoate (64% yield).

[0296] Step C: The reaction was carried out using tert-butyl 4-cyano-2-(1,6-dimethyl-1H-pyrazolo[3,4-b]pyridine-5-yl)butanoate (700 mg, 2.23 mmol) according to general procedure D to obtain tert-butyl 5-amino-2-(1,6-dimethyl-1H-pyrazolo[3,4-b]pyridine-5-yl)-5-oxopentanoate (48% yield).

[0297] Step D: The reaction was carried out according to general procedure E using tert-butyl 5-amino-2-(1,6-dimethyl-1H-pyrazolo[3,4-b]pyridine-5-yl)-5-oxopentanoate (40.0 mg, 0.12 mmol) to obtain 3-(1,6-dimethyl-1H-pyrazolo[3,4-b]pyridine-5-yl)piperidine-2,6-dione (33% yield). 1 H NMR(500MHz,DMSO)δ10.88(s,1H), 8.01(s,1H), 7.98(s,1H), 4.22(dd,J=12.4,4.8Hz,1H), 4.01(s,3H), 2.81(ddd ,J=17.3,12.9,5.3Hz,1H), 2.60(s,3H), 2.59~2.55(m,1H), 2.41~2.30(m,1H), 2.06(dtd,J=13.1,5.2,3.0Hz,1H). LCMS(m / z[M+H] + ):259.1 [Example 18]

[0298] Synthesis of 3-(thieno[2,3-b]pyridine-5-yl)piperidine-2,6-dione (compound 23)

[0299] [ka]

[0300] Step A: The reaction was carried out using 5-bromothieno[2,3-b]pyridine (1.00 g, 4.67 mmol) according to general procedure H to obtain tert-butyl 2-(thieno[2,3-b]pyridine-5-yl)acetate (51% yield).

[0301] Step B: The reaction was carried out using tert-butyl 2-(thieno[2,3-b]pyridine-5-yl) acetate (500 mg, 2.00 mmol) according to general procedure C to obtain tert-butyl 4-cyano-2-(thieno[2,3-b]pyridine-5-yl)butanoate (41% yield).

[0302] Step C: The reaction was carried out using tert-butyl 4-cyano-2-(thieno[2,3-b]pyridine-5-yl)butanoate (200 mg, 0.632 mmol) according to general procedure D to obtain tert-butyl 5-amino-5-oxo-2-(thieno[2,3-b]pyridine-5-yl)pentanoate.

[0303] Step D: The reaction was carried out using tert-butyl 5-amino-5-oxo-2-(thieno[2,3-b]pyridine-5-yl)pentanoate according to general procedure E to obtain 3-(thieno[2,3-b]pyridine-5-yl)piperidine-2,6-dione (20% yield, 2 steps). 1 H NMR(400MHz,DMSO)δ10.90(s,1H), 8.46(d,J=2.0Hz,1H), 8.15(d,J=2.0Hz,1H), 7.88(d,J=5.9Hz,1H), 7.43(d,J=5. 9Hz,1H), 4.09(dd,J=12.4,4.8Hz,1H), 2.80~2.70(m,1H), 2.63~2.52(m,1H), 2.41~2.31(m,1H), 2.15~2.06(m,1H). LCMS(m / z[M+H] + ) 247.2 [Example 19]

[0304] Synthesis of 3-(7-methoxy-2-methylquinoline-3-yl)piperidine-2,6-dione (compound 24)

[0305] [ka]

[0306] Step A: The reaction was carried out using 2-amino-4-methoxybenzaldehyde (600 mg, 3.96 mmol) according to general procedure A to obtain 2-(7-methoxy-2-methylquinoline-3-yl)acetic acid (43% yield).

[0307] Step B: The reaction was carried out according to general procedure B using 2-(7-methoxy-2-methylquinoline-3-yl)acetic acid (400 mg, 1.72 mmol) to obtain tert-butyl 2-(7-methoxy-2-methylquinoline-3-yl)acetate (26% yield).

[0308] Step C: The reaction was carried out according to general procedure C using tert-butyl 2-(7-methoxy-2-methylquinoline-3-yl) acetate (130 mg, 0.452 mmol) to obtain tert-butyl 4-cyano-2-(7-methoxy-2-methylquinoline-3-yl)butanoate (75% yield).

[0309] Step D: The reaction was carried out according to general procedure D using tert-butyl 4-cyano-2-(7-methoxy-2-methylquinoline-3-yl)butanoate (100 mg, 0.293 mmol) to obtain tert-butyl 5-amino-2-(7-methoxy-2-methylquinoline-3-yl)-5-oxopentanoate.

[0310] Step E: The reaction was carried out using 5-amino-2-(7-methoxy-2-methylquinoline-3-yl)-5-oxopentanoate according to general procedure E to obtain 3-(7-methoxy-2-methylquinoline-3-yl)piperidine-2,6-dione (28% yield, 2 steps). 1 H NMR(400MHz,DMSO)δ10.90(s,1H), 8.01(s,1H), 7.77(d,J=8.9Hz,1H), 7.31(d,J=2.1Hz,1H), 7.16(dd,J=8.9,2.2Hz, 1H), 4.24(dd,J=12.4,4.8Hz,1H), 3.90(s,3H), 2.87~2.75(m,1H), 2.62(s,3H),2.43~2.31(m,1H), 2.17~2.05(m,1H). LCMS(m / z[M+H] + ) 284.8 [Example 20]

[0311] Synthesis of 3-(8-amino-2-methylquinoline-3-yl)pyrrolidine-2,5-dione (compound 25)

[0312] [ka]

[0313] Step A: To a solution of tert-butyl 2-(2-methyl-8-nitroquinoline-3-yl)acetate (1.00 g, 3.30 mmol) in THF (20 mL), LDA (1 M in THF, 7.26 mL, 7.26 mmol, 2.2 equivalents) was added at -78°C. The solution was stirred for 30 minutes, and bromoacetonitrile (0.920 mL, 13.2 mmol, 4 equivalents) was added dropwise. The solution was warmed to room temperature and stirred for 12 hours. The reaction mixture was quenched with 1 M HCl, and the product was extracted with ethyl acetate. The combined organic phase was dried over Na2SO4, concentrated under reduced pressure, and purified by flash column chromatography to obtain tert-butyl 3-cyano-2-(2-methyl-8-nitroquinoline-3-yl)propanoate (20% yield).

[0314] Step B: The reaction was carried out using tert-butyl 3-cyano-2-(2-methyl-8-nitroquinoline-3-yl)propanoate (200 mg, 0.585 mmol) according to general procedure D to obtain tert-butyl 4-amino-2-(2-methyl-8-nitroquinoline-3-yl)-4-oxobutanoate.

[0315] Step C: The reaction was carried out using tert-butyl 4-amino-2-(2-methyl-8-nitroquinoline-3-yl)-4-oxobutanoate according to general procedure E to obtain 3-(2-methyl-8-nitroquinoline-3-yl)pyrrolidine-2,5-dione (20% yield, 2 steps).

[0316] Step D: The reaction was carried out using 3-(2-methyl-8-nitroquinoline-3-yl)pyrrolidine-2,5-dione (25 mg, 0.087 mmol) according to general procedure F to obtain 3-(8-amino-2-methylquinoline-3-yl)pyrrolidine-2,5-dione (84% yield). 1 H NMR(400MHz,DMSO)δ11.44(s,1H), 7.97(s,1H), 7.21(dd,J=8.0,7.5Hz,1H), 6.98(d,J=8.0Hz,1H), 6.80(d,J=7.5Hz,1 H), 5.78(s,1H), 4.54(dd,J=9.6,6.0Hz,1H), 3.21(dd,J=18.0,9.6Hz,1H), 2.81(dd,J=18.0,6.0Hz,1H), 2.67(s,3H). LCMS(m / z[M+H] + ):256.1 [Example 21]

[0317] Synthesis of 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)-N-(8-(2-((3-(2,6-dioxopiperidine-3-yl)-2-methylquinoline-7-yl)amino)acetamide)octyl)acetamide (compound 26)

[0318] [ka]

[0319] Step A: 3-(7-amino-2-methylquinoline-3-yl)piperidine-2,6-dione (71 mg, 0.265 mmol), tetrabutylammonium iodide (97.9 mg, 0.265 mmol, 1 equivalent), and DMF (15 mL) were placed in a flask. DIPEA (185 μL, 1.02 mmol, 4 equivalents) was added, followed by tert-butylbromoacetate (51.7 mg, 0.265 mmol, 1 equivalent), and the reaction mixture was stirred at 60°C for 4 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by flash column chromatography to obtain tert-butyl(3-(2,6-dioxopiperidine-3-yl)-2-methylquinoline-7-yl)glycinate (14% yield).

[0320] Step B: tert-butyl(3-(2,6-dioxopiperidine-3-yl)-2-methylquinoline-7-yl)glycinate (14.0 mg, 0.037 mmol) was placed in a vial. Dioxane (1 mL) was added, followed by 12 M HCl (2 mL). The reaction mixture was stirred at room temperature for 1 hour and then concentrated under reduced pressure to obtain (3-(2,6-dioxopiperidine-3-yl)-2-methylquinoline-7-yl)glycine (quantitative).

[0321] Step C: (3-(2,6-dioxopiperidine-3-yl)-2-methylquinoline-7-yl)glycine (6.2 mg, 0.019 mmol) 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 (12.0 mg, 0.023 mmol, 1.2 equivalents) were added to the vial. DMF (1 mL), followed by DIPEA (26 μL, 0.152 mmol, 8 equivalents) and HATU (8.7 mg, 0.023 mmol, 1.2 equivalents) were added, and the reaction mixture was stirred at room temperature for 2 hours. By removing volatile substances under reduced pressure and purifying the residue by preparative HPLC, 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)-N-(8-(2-((3-(2,6-dioxopiperidine-3-yl)-2-methylquinoline-7-yl)amino)acetamide)octyl)acetamide (35% yield). 1 H NMR(500MHz,DMSO)δ10.85(s,1H), 8.12(t,J=5.7Hz,1H), 7.94(t,J=5.7Hz,1H), 7.78(s,1H), 7.54(d,J=8.8Hz,1H), 7.47(d,2H), 7 .42(d,2H), 7.01(dd,J=8.9,2.3Hz,1H), 6.65(d,J=2.2Hz,1H), 6.48(t,J=5.9Hz,1H), 4.50(dd,J=8.0,6.1Hz,1H), 4.14(dd,J=12. 2,4.8Hz,1H), 3.73(d,J=5.8Hz,2H), 3.30~3.13(m,2H), 3.12~3.03(m,4H), 2.78(ddd,J=17.5,12.7,5.3Hz,1H), 2.59(s,3H), 2.57 ~2.54(m,1H), 2.53(s,3H), 2.40(s,3H), 2.37~2.25(m,1H), 2.10~2.01(m,1H), 1.62(s,3H), 1.44~1.34(m,4H), 1.32~1.14(m,8H). LCMS(m / z[M+H] +):836.3 [Example 22]

[0322] Synthesis of 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)-N-(8-(2-((3-(2,6-dioxopiperidine-3-yl)-2-methylquinoline-6-yl)amino)acetamide)octyl)acetamide (compound 27)

[0323] [ka]

[0324] Step A: 3-(6-amino-2-methylquinoline-3-yl)piperidine-2,6-dione (18.0 mg, 0.067 mmol), tetrabutylammonium iodide (24.7 mg, 0.067 mmol, 1 equivalent), and DMF (1 mL) were placed in a flask. DIPEA (47 μL, 0.268 mmol, 4 equivalents) was added, followed by tert-butylbromoacetate (13.1 mg, 0.067 mmol, 1 equivalent), and the reaction mixture was stirred at 60°C for 3 hours. The second portion of tert-butylbromoacetate (13.1 mg, 0.067 mmol, 1 equivalent) was added, and heating was continued for another 3 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by flash column chromatography to obtain tert-butyl(3-(2,6-dioxopiperidine-3-yl)-2-methylquinoline-6-yl)glycinate (47% yield).

[0325] Step B: tert-butyl(3-(2,6-dioxopiperidine-3-yl)-2-methylquinoline-6-yl)glycinate (12.3 mg, 0.032 mmol) was placed in a vial. Dioxane (2 mL) was added, followed by 12 M HCl (3 mL). The reaction mixture was stirred at room temperature for 1 hour and then concentrated under reduced pressure to obtain (3-(2,6-dioxopiperidine-3-yl)-2-methylquinoline-6-yl)glycine (quantitative).

[0326] Step C: (3-(2,6-dioxopiperidine-3-yl)-2-methylquinoline-6-yl)glycine (10.5 mg, 0.032 mmol) 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 (18.1 mg, 0.032 mmol, 1 equivalent) were added to the vial. DMF (3 mL), followed by DIPEA (56 μL, 0.320 mmol, 10 equivalents) and HATU (14.6 mg, 0.038 mmol, 1.2 equivalents) were added, and the reaction mixture was stirred at room temperature for 6 hours. By removing volatile substances under reduced pressure and purifying the residue by preparative HPLC, 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)-N-(8-(2-((3-(2,6-dioxopiperidine-3-yl)-2-methylquinoline-6-yl)amino)acetamide)octyl)acetamide (40% yield). 1 H NMR(500MHz,DMSO)δ10.88(s,1H), 8.14(t,J=5.7Hz,1H), 7.92(t,J=5.8Hz,1H), 7.71(s,1H), 7.63(d,J=9.0Hz,1H), 7.47(d,J=8.7 Hz,2H), 7.42(d,J=8.7Hz,2H), 7.19(dd,J=9.0,2.5Hz,1H), 6.52(d,J=2.5Hz,1H), 6.35(t,J=5.8Hz,1H), 4.50(dd,J=8.1,6.0Hz,1 H), 4.17(dd,J=12.3,4.8Hz,1H), 3.70(d,J=5.7Hz,2H), 3.29~3.13(m,2H), 3.12~3.00(m,4H), 2.84~2.70(m,1H), 2.58(s,3H), 2.5 7~2.54(m,1H), 2.53(s,3H), 2.40(s,3H), 2.38~2.30(m,1H), 2.11~2.02(m,1H), 1.61(s,3H), 1.43~1.26(m,4H), 1.28~1.12(m,8H). LCMS(m / z[M+H] + ):836.4 [Example 23]

[0327] 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.

[0328] 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).

[0329] K i To measure the values, FP experiments were performed with test compounds at various concentrations.

[0330] 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 (as described by Z. Nikolovska-Coleska et al., Analytical Biochemistry 332 (2004) 261-273), the K of competitive inhibitors i The value was calculated.

[0331] Fluorescence polarization (FP) assay - results The compounds are categorized based on their activity toward 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 similar affinity ranges to those reported for the reference compounds.

[0332] [Table 6] JPEG0007853713000078.jpg189134JPEG0007853713000079.jpg190134JPEG0007853713000080.jpg103132

[0333] As can be seen from Table 1 above, the compounds of the present invention exhibit the same CRBN binding affinity (Ki in the same concentration range) as the reference compound. [Example 24]

[0334] 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.

[0335] 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 antibody staining, the membranes were washed, and signals were obtained. Densitometry analysis was performed to obtain numerical values ​​to be used later in the protein level assessment process.

[0336] The compounds tested in this assay were thalidomide, CC-122, and compound 1 of the present invention at concentrations of 1–20 μM over 24 hours. The results are shown in Figure 1. Densitometry values ​​were normalized to the loading control (β-actin) and are expressed as a percentage relative to the DMSO control in Table 2 below, using the following labels: If the reduction in SALL4 protein is 0-25%, then ≤25%. If the reduction in SALL4 protein is 26-74%, then >25% If the reduction in SALL4 protein is 75-100%, then it is ≥75%.

[0337] As illustrated in Figure 1, the compounds of the present invention induce degradation of the SALL4 protein in Kelly (neuroblastoma) cell lines with lower potency than the reference compound CC-122 and thalidomide. Therefore, the compounds of the present invention may be more useful in situations where SALL4 protein degradation is undesirable.

[0338] [Table 7] [Example 25]

[0339] 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.

[0340] 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-hour 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.

[0341] The compounds tested in this assay were thalidomide and compound 1 of the present invention, at concentrations of 1–20 μM over 24 hours. The results are shown in Figure 2. Densitometry values ​​were normalized to the loading control (β-actin) and are expressed as a percentage relative to the DMSO control in Table 3 below, using the following labels: If the reduction in IKZF1 protein is 0-25%, then ≤25%. If the reduction in IKZF1 protein is 26-74%, then >25% If the reduction in IKZF1 protein is 75-100%, then ≥75%.

[0342] As illustrated in Figure 2, the compounds of the present invention induce degradation of the IKZF1 protein in the H929 cell line with higher potency than the reference compound thalidomide. Therefore, the compounds of the present invention may be useful as anticancer compounds.

[0343] [Table 8] [Example 26]

[0344] 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.

[0345] 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.

[0346] The compounds tested in this assay were thalidomide and compound 1 of the present invention at concentrations of 1–20 μM over 24 hours. The results are shown in Figure 3. Densitometry values ​​were normalized to the loading control (β-actin) and are expressed as % relative to the DMSO control in Tables 4A and 4B below, using the following labels: If the reduction of IKZF3 protein is 0-25%, then ≤25%. If the reduction in IKZF3 protein is 26-74%, then >25% If the reduction in IKZF3 protein is 75-100%, then ≥75%.

[0347] As illustrated in Figure 3, the compounds of the present invention induce degradation of the IKZF3 protein in the H929 cell line with higher potency than the reference compound thalidomide. Therefore, the compounds of the present invention may be useful as anticancer compounds.

[0348] [Table 9]

[0349] [Table 10] [Example 27]

[0350] Viability-CTG assay The effect of compound 1 of the present invention on the viability of H929 (myeloma) was investigated using the following CTG assay protocol.

[0351] 3000 cells in 50 μL of culture medium were cultured in a 384-well plate and incubated with 50 μM, 13 μM, and 2 μM of each compound for 72 hours. ATP content in the remaining cells after treatment was quantified using the CellTiter-Glo Luminescent Viability Assay Kit (Promega). The activity of each compound at each concentration is expressed as percentage viability; 100% viability was the ATP content in cells incubated with DMSO and the compound carrier. The results are shown in Table 5.

[0352] As can be seen from Table 5, the compounds of the present invention may be useful in the treatment of cancer.

[0353] [Table 11] [Example 28]

[0354] chemical stability studies The stability of various compounds of the present invention was analyzed by liquid chromatography-mass spectroscopy (LC-MS) over a 48-hour incubation period at 37°C in phosphate-buffered saline (PBS) / 10% fetal bovine serum (FBS). The results are shown in Figure 4.

[0355] Compounds tested:

[0356] [Table 12]

[0357] Aliquots of the compound in DMSO (20 mM) were diluted in phosphate-buffered saline (PBS) containing 10% fetal bovine serum (FBS) to obtain a concentration of 0.5 mM. The samples were incubated at 37°C. Samples for LC-MS analysis were collected at the beginning of incubation (0 hours) and at 2, 4, 6, 8, 10, 24, 34, and 48 hours.

[0358] For LC-MS analysis, 30 μL of sample was taken, thoroughly mixed with 30 μL of acetonitrile, and vortexed. The sample was then centrifuged (10°C, 10 min, 15000 × g). The supernatant was transferred to an HPLC vial. For compounds 1, 15, and 18, the supernatant was further diluted twice with water before analysis.

[0359] Methods for using LC-MS instruments Regarding Compound 4, Compound 15, Compound 18, and Lenalidomide Kinetex XB-C18 2.6 μm, 50 × 2.1 mm column held at 40°C. LC-MS grade mobile phases: water + 0.1% formic acid (A) and acetonitrile + 0.1% formic acid (B). Elution gradient (flow 0.5 mL / min): 0 min 5% B, 4 min 95% B, 5 min 95% B, 5.2 min 5% B, 7 min 5% B.

[0360] Regarding Compound 1 Shim-pack Scepter C18-120 3μm, 150×3mm column held at 40℃. LC-MS grade mobile phases: water + 0.1% formic acid (A) and acetonitrile + 0.1% formic acid (B). Elution gradient (flow 0.5mL / min): 0 min 5%B, 15 min 95%B, 18 min 95%B, 19 min 5%B, 25 min 5%B.

[0361] LC-MS processing The chromatograms were integrated and the areas of the observed peaks were calculated. Different wavelengths were used for the quantification of the following compounds: compound 4 (306±4 nm), compound 15 (244±4 nm), compound 18 (252±4 nm), lenalidomide (220±4 nm), CC-122 (235±4 nm), and compound 1 (271±4 nm).

[0362] As illustrated in Figure 4, the compounds of the present invention have better chemical stability compared to the reference compound lenalidomide. [Example 29]

[0363] The effect of the bifunctional compound of the present invention on BRD4 degradation in the H929 cell line can be investigated using the following degradation assay protocol.

[0364] 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 and washed. Cell solubilates were then prepared using RIPA lysis buffer. Protein levels were determined via BCA assay, and appropriate amounts were then loaded onto pre-filled microplates. Analysis was performed using SIMPLE WESTERN® scientific technology (from Protein Simple), an automated capillary-based immunoassay. 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 relative to the DMSO control using the following labels: If the reduction in BRD4 protein is 0-25%, then ≤25%. If the reduction in BRD4 protein is 26-74%, then >25% If the reduction in BRD4 protein is 75-100%, then ≥75%.

[0365] The bifunctional compound of the present invention induces the degradation of the BRD4 protein.

[0366] Abbreviations and Definitions A list of abbreviations used in this application is shown in Table 6 below:

[0367] [Table 13] JPEG0007853713000088.jpg66162

[0368] As used herein, the term "room temperature" means a temperature between 20°C and 25°C.

[0369] As used herein, the term "small molecule" means an organic compound having a molecular weight of less than 900 daltons.

[0370] Further embodiments are described below with reference to the numbered clauses below: Clause 1. Compounds of formula (I):

[0371] [ka]

[0372] During the ceremony: Each of X1 and X2 is independently either O or S; Each of Q1 and Q2 is independently N or CR, and at least one of Q1 and Q2 is N; Each of W1, W2, W3, and W4 is independently N or CR'; n is 0, 1, or 2; L is hydrogen, alkyl, alkenyl, aryl, heteroaryl, benzyl, haloalkyl, haloalkenyl, -C(O)R'', -C(O)OR'', -C(O)NH2, -C(O)NHR'', -C(O)NR''2, -OR'', -NR''2, or -S(O)2R''; Each R is independently hydrogen, halogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, benzyl, haloalkyl, haloalkenyl, -NH2, -NHR'', -NR''2, -NR''C(O)R'', -NR''C(O)OR'', -NO2, -CN, -C(O)R'', -C(O)OR'', -C(O)NH2, -C(O)NHR'', -C(O)NR''2, -OR'', -OC(O)R'', -OC(O)OR'', -OC(O)NH2, -OC(O)NHR'', -OC(O)NR''2, -SR'', -S(O)2R'', -S(O)2OR'', -S(O)2NH2, -S(O)2NHR'', or -S(O)2NR''2; Each R' is independently hydrogen, halogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, benzyl, haloalkyl, haloalkenyl, -NH2, -NHR'', -NR''2, -NR''C(O)R'', -NR''C(O)OR'', -NO2, -CN, -C(O)R'', -C(O)OR'', -C(O)NH2, -C(O)NHR'', -C(O)NR''2, -OR'', -OC(O)R'', -OC(O)OR'', -OC(O)NH2, -OC(O)NHR'', -OC(O)NR''2, -SR'', -S(O)2R'', -S(O)2OR'', -S(O)2NH2, -S(O)2NHR'', or -S(O)2NR''2; Each R'' is independently hydrogen, alkyl, alkenyl, aryl, heteroaryl, or benzyl.

[0373] Clause 2. The compound is as described in Clause 1 and has the following structure.

[0374] [ka]

[0375] Clause 3. The compound is as described in Clause 1 and has the following structure.

[0376] [ka]

[0377] Clause 4. A compound of any preceding clause, wherein one of W1, W2, W3, and W4 is N, and the remaining three of W1, W2, W3, and W4 are each CR'.

[0378] Clause 5. The compound is as described in Clause 4, where W1 is N and W2, W3 and W4 are CR'.

[0379] Clause 6. The compound is as described in Clause 4, where W2 is N and W1, W3 and W4 are CR'.

[0380] Clause 7. The compound is as described in Clause 4, where W3 is N and W1, W2 and W4 are CR'.

[0381] Clause 8. The compound is as described in Clause 4, where W4 is N and W1, W2 and W3 are CR'.

[0382] Clause 9. One of the compounds from Clauses 1 to 3, where W1, W2, W3, and W4 are each CR'.

[0383] Clause 10. The compound is as described in Clause 9, and W2, W3, and W4 are each CH.

[0384] Clause 11. A compound of Clause 9 or Clause 10, wherein W1 is C-NH2, C-NHR'' or C-NR''2; optionally, C-NH2.

[0385] Clause 12. One of the compounds from Clauses 1 to 3, where two of W1, W2, W3, and W4 are N, and the remaining two of W1, W2, W3, and W4 are each CR'.

[0386] Clause 13. One of the compounds from Clauses 1 to 3, where three of W1, W2, W3, and W4 are N, and the remaining one of W1, W2, W3, and W4 is CR'.

[0387] Clause 14. A compound of any preceding clause, wherein L is hydrogen, alkyl, alkenyl, aryl, heteroaryl, benzyl, haloalkyl, haloalkenyl, -OR'', -NR''2, or -S(O)2R''; optionally, L is hydrogen, alkyl, alkenyl, aryl, heteroaryl, or benzyl; further optionally, L is hydrogen.

[0388] Clause 15. One of the compounds from Clauses 1 to 3, the compound being:

[0389] [ka]

[0390] Clause 16. One of the compounds from Clauses 1 to 3, the compound being:

[0391] [ka]

[0392] Article 17. The compound in Article 16 is as follows:

[0393] [ka]

[0394] Article 18. Compounds of formula (IIa), (IIb), or (IIc):

[0395] [ka]

[0396] During the ceremony: Each of X1 and X2 is independently either O or S; Each of Q1 and Q2 is independently N or CR, and at least one of Q1 and Q2 is N; Each of W1, W2, and W3 is independently N or CR'; Z is O, S, or NH; n is 0, 1, or 2; L is hydrogen, alkyl, alkenyl, aryl, heteroaryl, benzyl, haloalkyl, haloalkenyl, -C(O)R'', -C(O)OR'', -C(O)NH2, -C(O)NHR'', -C(O)NR''2, -OR'', -NR''2, or -S(O)2R''; Each R is independently hydrogen, halogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, benzyl, haloalkyl, haloalkenyl, -NH2, -NHR'', -NR''2, -NR''C(O)R'', -NR''C(O)OR'', -NO2, -CN, -C(O)R'', -C(O)OR'', -C(O)NH2, -C(O)NHR'', -C(O)NR''2, -OR'', -OC(O)R'', -OC(O)OR'', -OC(O)NH2, -OC(O)NHR'', -OC(O)NR''2, -SR'', -S(O)2R'', -S(O)2OR'', -S(O)2NH2, -S(O)2NHR'', or -S(O)2NR''2; Each R' is independently hydrogen, halogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, benzyl, haloalkyl, haloalkenyl, -NH2, -NHR'', -NR''2, -NR''C(O)R'', -NR''C(O)OR'', -NO2, -CN, -C(O)R'', -C(O)OR'', -C(O)NH2, -C(O)NHR'', -C(O)NR''2, -OR'', -OC(O)R'', -OC(O)OR'', -OC(O)NH2, -OC(O)NHR'', -OC(O)NR''2, -SR'', -S(O)2R'', -S(O)2OR'', -S(O)2NH2, -S(O)2NHR'', or -S(O)2NR''2; Each R'' is independently hydrogen, alkyl, alkenyl, aryl, heteroaryl, or benzyl.

[0397] Article 19. The compound of Article 18, having the following structure:

[0398] [ka]

[0399] Article 20. The compound of Article 18, having the following structure:

[0400] [ka]

[0401] Clause 21. One of the compounds from Clauses 18-20, where W1 is N.

[0402] Clause 22. The compound is one of the compounds specified in Clauses 18-21, and W2 is N.

[0403] Clause 23. One of the compounds specified in Clauses 18-22, where W3 is N.

[0404] Clause 24. One of the compounds from Clauses 18-23, where one of W1, W2, and W3 is N and the other W1, W2, and W3 are CR'.

[0405] Clause 25. A compound according to Clause 24, wherein one of W1, W2, and W3 is N, and the other W1, W2, and W3 are CH.

[0406] Clause 26. One of the compounds specified in Clauses 18-25, where W1, W2, and W3 are each CR'.

[0407] Clause 27. One of the compounds from Clauses 18-25, where W1 is C-NH2, C-NHR'' or C-NR''2; optionally, C-NH2.

[0408] Clause 28. One of the compounds specified in Clauses 18-23, where W1, W2, and W3 are each N.

[0409] Clause 29. One of the compounds from Clauses 18-28, where Z is O.

[0410] Clause 30. One of the compounds from Clauses 18-28, where Z is S.

[0411] Clause 31. One of the compounds from Clauses 18-28, where Z is NH.

[0412] Clause 32. A compound of any of the preceding clauses, where Q1 is N and Q2 is CR.

[0413] Clause 33. One of the compounds from Clauses 1 to 31, where Q1 is CR and Q2 is N.

[0414] Clause 34. One of the compounds from Clauses 1 to 31, where Q1 is N and Q2 is N.

[0415] Clause 35. A compound of any preceding clause, wherein each R is independently hydrogen or alkyl; optionally hydrogen or C1-C4 alkyl; further optionally the C1-C4 alkyl is methyl or ethyl; further optionally each R is independently hydrogen or methyl.

[0416] Clause 36. A compound of any preceding clause, where each R' is independently hydrogen, -NH2, -NHR'' or -NR''2; optionally, hydrogen or -NH2.

[0417] Article 37. Compounds of formula (III):

[0418] [ka]

[0419] During the ceremony, Each of X1 and X2 is independently either O or S; n is 0, 1, or 2; L is hydrogen, alkyl, alkenyl, aryl, heteroaryl, benzyl, haloalkyl, haloalkenyl, -C(O)R'', -C(O)OR'', -C(O)NH2, -C(O)NHR'', -C(O)NR''2, -OR'', -NR''2, or -S(O)2R''; Each of R1, R2, and R3 is independently hydrogen, halogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, benzyl, haloalkyl, haloalkenyl, -NH2, -NHR'', -NR''2, -NR''C(O)R'', -NR''C(O)OR'', -NO2, -CN, -C(O)R'', -C(O)OR'', -C(O)NH2, -C(O)NHR'', -C(O)NR''2, -OR'', -OC(O)R'', -OC(O)OR'', -OC(O)NH2, -OC(O)NHR'', -OC(O)NR''2, -SR'', S(O)2R'', -S(O)2OR'', -S(O)2NH2, -S(O)2NHR'', or -S(O)2NR''2; Each R'' is independently hydrogen, alkyl, alkenyl, aryl, heteroaryl, or benzyl.

[0420] Article 38. The compound of Article 37, having the following structure:

[0421] [ka]

[0422] Article 39. The compound of Article 37, having the following structure:

[0423] [ka]

[0424] Clause 40. A compound of any preceding clause, wherein X1 and X2 are O.

[0425] Clause 41. A compound from any of Clauses 1 to 39, where X1 is O and X2 is S.

[0426] Clause 42. One of the compounds from Clauses 1 to 39, where X1 is S and X2 is O.

[0427] Clause 43. One of the compounds from Clauses 1 to 39, where X1 and X2 are S.

[0428] Clause 44. A compound of any preceding clause, where n is 0.

[0429] Clause 45. One of the compounds from Clauses 1 to 43, where n is 1 or 2.

[0430] Clause 46. One of the compounds from Clauses 1 to 43, where n is 1.

[0431] Clause 47. One of the compounds from Clauses 1 to 43, where n is 2.

[0432] Article 48. Compounds of formula (IV):

[0433] [ka]

[0434] During the ceremony, Each of X1 and X2 is independently either O or S; L is hydrogen, alkyl, alkenyl, aryl, heteroaryl, benzyl, haloalkyl, haloalkenyl, -C(O)R'', -C(O)OR'', -C(O)NH2, -C(O)NHR'', -C(O)NR''2, -OR'', -NR''2, or -S(O)2R''; Each of Q1, Q2, Q3, Q4, and Q5 is independently N or CR, and at least one of Q1, Q2, Q3, Q4, and Q5 is N; Each R is independently hydrogen, halogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, benzyl, haloalkyl, haloalkenyl, -NH2, -NHR'', -NR''2, -NR''C(O)R'', -NR''C(O)OR'', -NO2, -CN, -C(O)R'', -C(O)OR'', -C(O)NH2, -C(O)NHR'', -C(O)NR''2, -OR'', -OC(O)R'', -OC(O)OR'', -OC(O)NH2, -OC(O)NHR'', -OC(O)NR''2, -SR'', -S(O)2R'', -S(O)2OR'', -S(O)2NH2, -S(O)2NHR'', or -S(O)2NR''2; Each R'' is independently hydrogen, alkyl, alkenyl, aryl, heteroaryl, or benzyl.

[0435] Article 49. A compound of Article 48, having the following structure:

[0436] [ka]

[0437] Article 50. The compound of Article 48, having the following structure:

[0438] [ka]

[0439] Clause 51. One of the compounds from Clauses 48-50, where X1 and X2 are O.

[0440] Clause 52. One of the compounds specified in Clauses 48-50, where X1 is O and X2 is S.

[0441] Clause 53. One of the compounds specified in Clauses 48-50, where X1 is sulfur and X2 is oxygen.

[0442] Clause 54. One of the compounds specified in Clauses 48-50, where X1 and X2 are S.

[0443] Clause 55. One of the compounds specified in Clauses 48-54, where one of Q1, Q2, Q3, Q4, and Q5 is N, and the remaining four of Q1, Q2, Q3, Q4, and Q5 are each CR.

[0444] Article 56. The compound is as described in Article 55, and Q1 is N.

[0445] Article 57. It is a compound of Article 55, and Q2 is N.

[0446] Article 58. It is a compound of Article 55, and Q3 is N.

[0447] Clause 59. One of the compounds specified in Clauses 48-54, where two of Q1, Q2, Q3, Q4, and Q5 are N, and the remaining three of Q1, Q2, Q3, Q4, and Q5 are each CR.

[0448] The compound is as described in Clause 60. Clause 59, where Q1 and Q2 are N, and Q3, Q4, and Q5 are each CR.

[0449] The compound is as described in Clause 61. Clause 59, where Q2 and Q3 are N, and Q1, Q4 and Q5 are CR, respectively.

[0450] The compound is as described in Clause 62. Clause 59, where Q1 and Q3 are N, and Q2, Q4, and Q5 are each CR.

[0451] Article 63. The compound is as described in Article 59, where Q2 and Q4 are N, and Q1, Q3, and Q5 are each CR.

[0452] The compound is as described in Clause 64, Clause 59, where Q1 and Q4 are N, and Q2, Q3, and Q5 are each CR.

[0453] Clause 65. One of the compounds specified in Clauses 48-54, where three of Q1, Q2, Q3, Q4, and Q5 are N, and the remaining two of Q1, Q2, Q3, Q4, and Q5 are each CR.

[0454] Clause 66. A compound from any of Clauses 48-65, where each R is independently hydrogen, halogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, benzyl, haloalkyl, haloalkenyl, -NH2, -NHR'', -NR''2, -NR''C(O)R'', -NR''C(O)OR'', -NO2, -CN, -C(O)R'', -C(O)OR'', -C(O)NH2, -C(O)NHR'', -C(O)NR''2, -OR'', -OC(O)R'', -OC(O)OR'', -OC(O)NH2, -OC(O)NHR'', -OC(O)NR''2, -SR'', S(O)2R''; optionally, each R is hydrogen or alkyl, and optionally, each R is hydrogen.

[0455] Clause 67. One of the compounds from Clauses 18-66, wherein L is hydrogen, alkyl, alkenyl, aryl, heteroaryl, benzyl, haloalkyl, haloalkenyl, -OR'', -NR''2, or -S(O)2R''; optionally, L is hydrogen, alkyl, alkenyl, aryl, heteroaryl, or benzyl.

[0456] Article 68. A compound of Article 67, where L is hydrogen.

[0457] Clause 69. Any one of the compounds in the preceding clauses for use as a cereblon binder.

[0458] Clause 70. A pharmaceutical composition comprising any one compound from Clauses 1 to 68.

[0459] Clause 71. Any one compound from Clauses 1 to 68, or a composition according to Clause 70, used in the field of pharmaceuticals.

[0460] Clause 72. Any one compound from Clauses 1 to 68, or a composition according to Clause 70, used in immuno-oncology.

[0461] Clause 73. Any one compound from Clauses 1 to 68, or a composition according to Clause 70, used for the treatment of 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.

[0462] Article 74. 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 one compound from any of clauses 1 to 68 or a composition according to clause 70 to a patient who needs it.

[0463] Clause 75. The method of Clause 74, further comprising the step of administering at least one additional active agent to the patient.

[0464] Clause 76. A combination of any one compound from Clauses 1 to 68 and at least one additional active agent, used simultaneously, separately, or in succession for therapeutic purposes.

[0465] Clause 77. A combination of the preparations of Clause 76, or the method of Clause 75, wherein at least one additional active agent is an anticancer agent or an agent for the treatment of an autoimmune disease.

[0466] Clause 78. A combination of Clause 76 or 77, or a method of Clause 75 or 77, wherein at least one additional active agent is a small molecule, peptide, antibody, corticosteroid, or a combination thereof.

[0467] Clause 79. A combination of the preparations or methods of Clause 78, wherein at least one additional active agent is at least one of bortezomib, dexamethasone, and rituximab.

[0468] Clause 80. A combination of any one of Clauses 76-79, the treatment of 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】 or its pharmaceutically acceptable salts, optically active isomers, racemates, or solvates. [In the formula, X １ and X ２ Each of them is O; Q １ Q2 is C-H or C-alkyl, and Q2 is N; n is 1; L is hydrogen, alkyl, alkenyl, aryl, heteroaryl, or benzyl; R is either hydrogen or alkyl; W1, W2, W3, and W4 are each CH; or three of W1, W2, W3, and W4 are CH, and one of W1, W2, W3, and W4 is C-halogen, C-NH2, C-NO2, C-NHR'', C-NR''2, C-C(O)NHCHR''2, C-CHR''NHC(O)NHR'', C-CHR''NHC(O)C(halogen)2R'' or C-NHS(O)2R''; and Each R'' is independently hydrogen, alkyl, cycloalkyl, alkenyl, aryl, heteroaryl, or benzyl.

2. structure: 【Chemistry 2】 【Transformation 3】 The compound according to claim 1, having the following characteristics.

3. Each R'' is independently hydrogen, alkyl, cycloalkyl, or aryl, and optionally the aryl is substituted with one or more groups selected from halogen, alkyl, and O-haloalkyl, and optionally the halogen is Cl, the alkyl is methyl, and the O-haloalkyl is O-CF ３ The compound according to claim 1 or 2.

4. W １ , W ２ , W ３ and W ４ The compound according to any one of claims 1 to 3, wherein each of them is CH.

5. W １ 、W ２ 、W ３ and W ４ among which three are CH, and W １ 、W ２ 、W ３ and W ４ among which one is C-halogen, C-NH ２ 、C-NO ２ 、C-C(O)NHCHR’’ ２ 、C-CHR’’NHC(O)NHR’’, C-CHR’’NHC(O)C(halogen) ２ R’’ or C-NHS(O) ２ R’’; Optional, W １ , W ２ , W ３ and W ４ One of them is C-halogen, C-NH ２ , C-NO ２ , C-C(O)NHCHHR'' ２ C-CH ２ NHC(O)NHR'', C-CH ２ NHC(O)CF ２ R'' or C-NHS(O) ２ R'' is The compound according to any one of claims 1 to 3.

6. (a) W ２ , W ３ and W ４ Each of them is CH; optionally, W １ C-halogen, C-NH ２ , C-NO ２ or C-NHS(O) ２ R'' is; furthermore, W １ C-NH ２ or C-NHS(O) ２ It is R''; Or, (b) W １ , W ２ and W ３ Each of them is CH; optionally, W ４ C-halogen, C-NH ２ , C-NO ２ or C-NHS(O) ２ R'' is; furthermore, W ４ C-NH ２ is; or (c) W １ , W3 and W ４ Each of them is CH; optionally, W ２ However, C-NH ２ , C-NO ２ or C-NHS(O) ２ R'' is; furthermore, W ２ C-NH ２ or C-NHS(O) ２ It is R''; or (d) W １ , W2 and W ４ Each of them is CH; optionally, W ３ C-NH ２ , C-NO ２ , C-C(O)NHCHHR'' ２ C-CH ２ NHC(O)NHR'', C-CH ２ NHC(O)CF ２ R'' or C-NHS(O) ２ R'' is; furthermore, W ３ C-NH ２ , C-C(O)NHCHHR'' ２ C-CH ２ NHC(O)NHR'', C-CH ２ NHC(O)CF ２ R'' or C-NHS(O) ２ R'' is; furthermore, W ３ C-NH ２ C-CH ２ NHC(O)NHR'', C-CH ２ NHC(O)CF ２ R'' or C-NHS(O) ２ R'' is The compound according to claim 5.

7. Q １ is C-H or C-methyl, The compound according to any one of claims 1 to 6.

8. The compound according to any one of claims 1 to 7, wherein L is hydrogen. 【Request Item 9】 【Table 1】 A compound according to any one of claims 1 to 8, selected from, optionally, selected from compounds 1, 2, 3, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20 and 21; further optionally, selected from compounds 8, 10, 11, 14, 15, 16, 17, 18 and 19. 【Request Item 10】 【Chemistry 4】 The compound according to claim 9.

11. A pharmaceutical composition comprising the compound described in any one of claims 1 to 10.

12. A compound according to any one of claims 1 to 10, or a composition according to claim 11, which is used in pharmaceuticals, and optionally, the compound or composition is used in immuno-oncology.

13. A compound according to any one of claims 1 to 10, or a composition according to claim 11, used for the treatment of cancer, autoimmune diseases, macular degeneration (MD) and related disorders, diseases and disorders associated with undesirable angiogenesis, skin diseases, lung disorders, asbestos-related disorders, parasitic diseases and disorders, immunodeficiency disorders, atherosclerosis and related conditions, or hemoglobin disorders and related disorders.

14. A combination of a compound according to any one of claims 1 to 10 and at least one additional active agent for use simultaneously, separately, or consecutively in a treatment, wherein the treatment is optionally the treatment of cancer, autoimmune diseases, macular degeneration (MD) and related disorders, diseases and disorders associated with undesirable angiogenesis, skin diseases, lung disorders, asbestos-related disorders, parasitic diseases and disorders, immunodeficiency disorders, atherosclerosis and related conditions, or hemoglobin disorders and related disorders.

15. The combination according to claim 14, wherein at least one additional active agent is an anticancer agent or an agent for the treatment of an autoimmune disease; optionally, the at least one additional active agent is a small molecule, a peptide, an antibody, a corticosteroid, or a combination thereof; and further optionally, the at least one additional active agent is at least one of bortezomib, dexamethasone, and rituximab.

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