Novel compounds that bind to cereblon and methods of use thereof

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] The present invention relates to a method for the identification of cereblon-binding proteins that bind to the CUL4-DDB1-RBX1-CRBN ubiquitin ligase complex (CRL4 CRBN Cereblon is a novel compound that regulates the substrate specificity of CRL4. CRBN Cereblon is the substrate recognition component of cereblon. Chemical modulation of cereblon can induce the association of novel substrate proteins, followed by ubiquitination and degradation of the substrate proteins. [Background technology]

[0002] Cereblon (CRBN) is a protein that associates with DDB1 (Damaged DNA-binding protein 1), CUL4 (Cullin-4), and RBX1 (RING-Box protein 1). Together, these proteins form a ubiquitin ligase complex, which belongs to the Cullin RING ligase (CRL) protein family and is involved in the ubiquitin ligase activity of CRL4. CRBN Cereblon became of particular interest to the scientific community after it was identified as the direct protein target of thalidomide, which mediates the biological activity of cereblon. Thalidomide, a drug approved in the late 1990s for the treatment of multiple myeloma, binds to cereblon and inhibits CRL4. CRBN It modulates the substrate specificity of ubiquitin ligase complexes, a mechanism that 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 treating cancer has stimulated efforts to develop analogs with greater efficacy and fewer side effects. This has resulted in a variety of drug candidates, including lenalidomide, pomalidomide, CC-220, CC-122, CC-885, and TD-106. These compounds are collectively known as cereblon modulators (CMAs). For a discussion of these compounds, see, e.g., U.S. Pat. No. 5,635,517, WO 2008039489, WO 2017197055, WO 2018237026, WO 2017197051, U.S. Pat. No. 8,518,972, EP 2057143, WO 2019014100, WO 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 a number of malignant hematological diseases such as 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] Antitumor activity of cereblon modulators 1) Inhibition of cancer cell proliferation and induction of apoptosis, 2) the breakdown of trophic support from the tumor stroma; 3) Stimulation of immune cells to promote T cell proliferation, cytokine production, and activation of NK (natural killer) cells (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 inhibit CRL4 CRBN It has been shown that the substrate specificity of ubiquitin ligases can be significantly altered. Thus, CMA-bound CRL4 CRBN It is desirable to advance the development of cereblon-modulating agents to achieve the desired substrate specificity in the ubiquitin ligase complex (see Sievers QL et al.: Defining the human C2H2zinc finger degrome targeted by thalidomide analogues through CRBN. Science. 2018 Nov 2; 362(6414)) to reach a desired safety profile, as well as to achieve stable drugs without loss of their potency due to chemical degradation. Thus, there is a continuing need to provide novel cereblon-binding compounds with pharma- ceutical relevant properties while ensuring their high drug stability with improved resistance to hydrolytic degradation. [Prior art documents] [Patent documents]

[0007] [Patent Document 1] U.S. Patent No. 5,635,517 [Patent Document 2] International Publication No. 2008039489 Brochure [Patent Document 3] International Publication No. 2017197055 Brochure [Patent Document 4] International Publication No. 2018237026 Brochure [Patent Document 5] Pamphlet of International Publication No. WO2017 / 197051 [Patent Document 6] Specification of US Patent No. 8,518,972 [Patent Document 7] Specification of European Patent No. EP2057143 [Patent Document 8] Pamphlet of International Publication No. WO2019 / 014100 [Patent Document 9] Pamphlet of International Publication No. WO2004 / 103274 [Non-Patent Document]

[0008] [Non-Patent 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-Patent 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-Patent 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-Patent 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) Summary of the Invention [Means for solving the problem]

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

[0010] [ka]

[0011] or a pharma- ceutically 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 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, -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 certain embodiments, the compound of formula (I) has the structure:

[0013] [ka]

[0014] In other embodiments, the compound of formula (I) has the 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, aryl is substituted with one or more groups selected from halogen, alkyl, and O-haloalkyl. In some embodiments, halogen is Cl, alkyl is methyl, and 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 yet 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)NH2, CC(O)NH3, CC(O)NH4, CC(O)NH5, CC(O)NH6, CC(O)NH7, CC(O)NH8, CC(O)NH9, CC(O)NH10, CC(O)NH2, CC(O)NH2, CC(O)NH11, CC(O)NH2, CC(O)NH12, CC(O)NH2, CC(O)NH3, CC(O)NH4, CC(O)NH ...2, CC(O)NH3, CC(O)NH4, CC(O)NH2, CC(O)NH2, CC(O)NH2, CC(O)NH3, CC(O)NH2, CC(O)NH2, CC(O)NH2, CC(O)NH3, CC(O)NH2 )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''. In some such embodiments, W2 is C-NH2 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'. In other such embodiments, W3 and W4 are each N and W1 and W2 are each CR'.

[0030] In still 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, C1-C4 alkyl is methyl, ethyl, n-propyl or n-butyl. In some embodiments, 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 compounds 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 compounds of Formula (I), L is -OR", -NR"2, or -S(O)2R". In some embodiments of the compounds of Formula (I), L is hydrogen, alkyl, alkenyl, aryl, heteroaryl, or benzyl. In some embodiments of the compounds of Formula (I), L is hydrogen, alkyl, alkenyl, or aryl. In some embodiments of the compounds of Formula (I), L is hydrogen, alkyl, or alkenyl. In some embodiments of the compounds of Formula (I), L is hydrogen or alkyl. In some embodiments of the compounds of Formula (I), L is hydrogen.

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

[0037] [ka]

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

[0039] [ka]

[0040] In another embodiment, the compound of formula (I) is:

[0041] [ka]

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

[0043] [ka]

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

[0045] [Table 1] JPEG2024501537000010.jpg192116JPEG2024501537000011.jpg253152

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

[0047] [Table 2] JPEG2024501537000013.jpg191134JPEG2024501537000014.jpg102131

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

[0049] [Table 3] JPEG2024501537000016.jpg67130

[0050] In one embodiment, the compound of formula (I) is:

[0051] [ka]

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

[0053] [ka]

[0054] During the ceremony: 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)NR b 2; Each R a 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)NR b 2; Each R b is independently hydrogen, alkyl, alkenyl, aryl, heteroaryl, or benzyl.

[0055] In some embodiments, the compound of Formula (IIa), (IIb), or (IIc) has the structure:

[0056] [ka]

[0057] In other embodiments, the compound of Formula (IIa), (IIb), or (IIc) has the 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 compound 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 of W1, W2, and W3 is CH.

[0061] In some embodiments of the compound of Formula (IIa), (IIb), or (IIc), W1, W2, and W3 are each CR a It is.

[0062] In some embodiments of the compound of Formula (IIa) or (IIc), W1 is C-NH2, C-NHR b or C-NR b 2. In some such embodiments, W1 is C—NH2.

[0063] In some embodiments of the compound of Formula (IIa), (IIb), or (IIc), W 1 , W 2 , and W 3 are each N.

[0064] In some embodiments, the compound has 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 compound of Formula (IIa), (IIb) or (IIc), Z is O. In other embodiments of the compound of Formula (IIa), (IIb) or (IIc), Z is S. In other embodiments of the compound of Formula (IIa), (IIb) or (IIc), Z is NH. In other embodiments of the compound of Formula (IIa), (IIb) or (IIc), Z is N-alkyl. In some such embodiments, Z is N-Me.

[0068] In some embodiments of the compound of Formula (IIa), (IIb) or (IIc), Q1 is N and Q2 is CR. In some embodiments of the compound 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), Q 1 is N and Q 2 is N.

[0070] In some embodiments of the compound 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, C1-C4 alkyl is methyl, ethyl, n-propyl or n-butyl. In some embodiments, C1-C4 alkyl is methyl or ethyl. In some embodiments, each R is independently hydrogen or methyl.

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

[0072] In some embodiments of the compound 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 a compound 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 compound 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 In some embodiments of the compound 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 compound of Formula (IIa), (IIb) or (IIc), L is hydrogen, alkyl, alkenyl, aryl, heteroaryl, benzyl, haloalkyl, or haloalkenyl. In other embodiments of the compound of Formula (IIa), (IIb) or (IIc), L is -OR b , -NR b 2, or -S(O)2R b In some embodiments of the compound of Formula (IIa), (IIb) or (IIc), L is hydrogen, alkyl, alkenyl, aryl, heteroaryl, or benzyl. In some embodiments of the compound of Formula (IIa), (IIb) or (IIc), L is hydrogen, alkyl, alkenyl, or aryl. In some embodiments of the compound of Formula (IIa), (IIb) or (IIc), L is hydrogen, alkyl, or alkenyl. In some embodiments of the compound of Formula (IIa), (IIb) or (IIc), L is hydrogen or alkyl. In some embodiments of the compound of Formula (IIa), (IIb) or (IIc), L is hydrogen.

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

[0076] [Table 4]

[0077] In some embodiments, the compound is:

[0078] [ka]

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

[0080] [ka]

[0081] A compound of the formula: During the ceremony, 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 and; 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 , -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)NR 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 structure:

[0083] [ka]

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

[0085] [ka]

[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.

[0087] In some embodiments of a 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 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, there is provided a compound of formula (IV):

[0090] [ka]

[0091] A compound of the formula: During the ceremony, Each of X1 and X2 is independently O or S; 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 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 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 , -S(O)2OR b , -S(O)2NH2, -S(O)2NHR b or -S(O)NR b 2; Each R bis independently hydrogen, alkyl, alkenyl, aryl, heteroaryl, or benzyl.

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

[0093] [ka]

[0094] In some embodiments, the compound of formula (IV) has the 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, -NH, -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 -NH. In some embodiments, each R is hydrogen.

[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 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 invention there is provided a pharmaceutical composition comprising a compound according to any of the above aspects of the invention.

[0103] The present invention also provides a compound according to any of the above aspects of the invention for use as a cereblon binding agent.

[0104] The present invention also provides a compound or composition according to any of the above aspects of the invention for use in medicine.

[0105] The present invention also provides a compound or composition according to any of the above aspects of the invention for use in immuno-oncology.

[0106] The present invention also provides a method for treating cancer, autoimmune diseases, macular degeneration (MD) and related disorders, There is also provided a compound or composition according to any of the above aspects of the invention for use in the treatment of diseases and disorders involving unwanted angiogenesis, skin diseases, pulmonary disorders, asbestos-related disorders, parasitic diseases and disorders, immunodeficiency disorders, atherosclerosis and related conditions, hemoglobinopathies and related disorders, or TNFα-related disorders.

[0107] The present invention also provides a method for the treatment of cancer, autoimmune diseases, macular degeneration (MD) and related disorders, diseases and disorders involving unwanted angiogenesis, skin diseases, pulmonary disorders, asbestos-related disorders, parasitic diseases and disorders, immunodeficiency disorders, atherosclerosis and related conditions, hemoglobinopathies and related disorders, or TNFα-related disorders; the method comprises the step of administering to a patient in need thereof an effective amount of a compound or composition according to any of the above aspects of the invention.

[0108] In some embodiments of the method, the method further comprises administering at least one additional active agent to the patient. In some embodiments, the at least one additional active agent is an anti-cancer agent or an agent for treating 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 a combination of a compound according to any one of the first to fourth aspects of the present invention and at least one additional active agent, for simultaneous, separate or sequential use in therapy.

[0110] In some embodiments of the combination, at least one additional active agent is an anti-cancer agent or an agent for treating an autoimmune disease. In some embodiments, at least one additional active agent is a peptide, an antibody, a corticosteroid, or a combination thereof. In some embodiments, at least one additional active agent is at least one of bortezomib, dexamethasone, and rituximab. In some embodiments, the treatment is the treatment of cancer, autoimmune disease, macular degeneration (MD) and related disorders, diseases and disorders involving undesired angiogenesis, skin diseases, lung disorders, asbestos-related disorders, parasitic diseases and disorders, immunodeficiency disorders, atherosclerosis and related conditions, hemoglobinopathies and related disorders, or TNFα-related disorders.

[0111] The present invention also relates to a compound having the following structure: CLM-[Link]-PTM or a pharma- ceutically acceptable salt, enantiomer, stereoisomer, solvate, polymorph, or prodrug thereof, CLM is cereblon E3 ubiquitin ligase binding moiety; PTM is a protein targeting moiety; [Link] is selected from a bond and a chemical linking moiety that covalently links the CLM and the PTM; CLM is a compound according to any of the above embodiments, and R, R′, R a , R b At least one of R1, R2 and R3 contains or is modified to contain a group capable of covalently bonding to [Link] or a PTM.

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

[0113] [ka]

[0114] is selected from

[0115] [ka]

[0116] indicates binding to PTM,

[0117] [ka]

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

[0119] In some embodiments, [Link] is

[0120] [ka]

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

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

[0123] [ka]

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

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

[0126] In some embodiments, the PTM is

[0127] [ka]

[0128] and

[0129] [ka]

[0130] indicates a connection 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 or 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, -S02R", -C(O)R", -CN, or -NO2. In some embodiments, an alkyl group is an unsubstituted alkyl group. In some embodiments, an alkyl group is a C1-C2 12 Alkyl, C1-C 10 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, for example, -OH, -OR", -NH2, -NHR", -NR"2, -S02R", -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, -S02R", -C(O)R", -CN, or -NO2. In some embodiments, an alkenyl group is an unsubstituted alkenyl group. In some embodiments, an alkenyl group is a C2-C6 alkyl group. 12 Alkenyl, C2-C 10 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, -S02R", -C(O)R", -CN, or -NO2. In some embodiments, an alkynyl group is an unsubstituted alkynyl group. In some embodiments, an alkynyl group is a C2-C 12 Alkynyl, C2-C 10 alkynyl, C2-C8 alkynyl, C2-C6 alkynyl, or C2-C4 alkynyl group.

[0138] The term "aryl" as used herein 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, -S02R", -C(O)R", -CN, or -NO2. In some embodiments, an aryl group is substituted with one or more additional groups selected from -R", -O-haloalkyl, alkyl, halogen, -NR"2, -S02R", -C(O)R", -CN, or -NO2. In some embodiments, an aryl group is substituted with one or more additional groups selected from halogen, alkyl, and O-haloalkyl. In some embodiments, an aryl group is substituted with one or more additional groups selected from Cl, methyl, and O-CF3. In some embodiments, an aryl group is an unsubstituted aryl group. In some embodiments, an aryl group is a C6-C 10 aryl, C6-C8 aryl, or C6 aryl. As used herein, the term "heteroaryl" is intended to include both unsubstituted heteroaryl groups and heteroaryl groups substituted with one or more additional groups, such as -OH, -OR", halogen, -NH2, -NHR", -NR"2, -S02R", -C(O)R", -CN, or -NO2. In some embodiments, the heteroaryl group is an unsubstituted heteroaryl group. In some embodiments, the heteroaryl group is a C6-C 10 heteroaryl, C6-C9 heteroaryl, C6-C8 heteroaryl, or C6 heteroaryl.

[0139] As used herein, the term "benzyl" is intended to include both unsubstituted benzyl groups and benzyl groups substituted with one or more additional groups, such as -OH, -OR", halogen, -NH2, -NHR", -NR"2, -S02R", -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] FIG. 1 shows an assay showing the effect of various compounds of the invention and various reference compounds on SALL4 degradation in the Kelly cell line. [Diagram 2] FIG. 1 shows an assay showing the effect of various compounds of the invention and various reference compounds on IKZF1 degradation in H929 cell line. [Diagram 3] FIG. 1 shows an assay showing the effect of various compounds of the invention and various reference compounds on IKZF3 degradation in H929 cell line. [Figure 4] FIG. 1 shows the stability of various compounds of the present invention when incubated at 37° C. in phosphate-buffered saline (PBS) / 10% fetal bovine serum (FBS) over a 48 hour period as analyzed by liquid chromatography-mass spectrometry (LC-MS). DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

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

[0142] [ka] JPEG2024501537000038.jpg99121

[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 compounds to cereblon was confirmed by CRL4 CRBNIt may alter the specificity of the complex and induce the association of novel substrate proteins, followed by ubiquitination and degradation of the substrate proteins. Examples of such proteins include, but are not limited to, IKZF1 and IKZF3.

[0145] These compounds uniquely regulate cereblon and inhibit CRL4 CRBN This may enable the ubiquitin ligase complex to recognize substrates different from those it would otherwise recognize and target them for degradation. As a result, the compounds of the present invention are expected to expand / modify the growth inhibitory activity of CRBN, thus expanding the range of cancer types susceptible to treatment with 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] [ka]

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

[0149] [ka]

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

[0151] [ka]

[0152] where step 1 involves reaction with m-CPBA and phosphoryl bromide; step 2 involves 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; step 3 involves reaction with H2 gas in the presence of Pd on activated carbon. Full experimental details for the synthesis of 3-(5-amino-2-methylquinolin-3-yl)piperidine-2,6-dione are provided in the "Examples" section below.

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

[0154] [Table 5] JPEG2024501537000043.jpg247152JPEG2024501537000044.jpg248152JPEG2024501537000045.jpg93148

[0155] In some embodiments, the compound is:

[0156] [ka]

[0157] As further discussed in the Examples section, the inventors have found that various compounds of the present invention exhibit cereblon-binding abilities similar to or improved from those of the known CMA, CC-122. Despite the pharmaceutical activity of known CMAs, such as CC-122, patients often become resistant to these compounds. The use of novel compounds, such as the compounds of the present invention described above, may help overcome this clinical obstacle.

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

[0159] Compounds of the invention may also possess advantageous pharma- ceutical 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 in the treatment of a variety of 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 cancer include, but are not limited to, skin cancer, such as melanoma; lymph node cancer; breast cancer; cervical cancer; uterine cancer; gastrointestinal cancer; lung cancer; ovarian cancer; prostate cancer; colon cancer; rectal cancer; oral cancer; brain cancer; 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 cancer and malignant hematological diseases. a) Malignant hematological diseases include leukemia, lymphoma, multiple myeloma or smoldering myeloma. Leukemias are: 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, adult acute myeloblastic leukemia with maturation, adult acute myeloblastic leukemia without maturation, adult acute myelogenous leukemia with abnormalities, adult acute myelomonocytic leukemia, adult erythroleukemia, adult pure erythroid ... erythroleukemia, adult pure erythroid leukemia, adult erythroleukemia, adult erythroleukemia, adult erythroleukemia, adult eryth 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, relapsed or refractory chronic lymphocytic leukemia. Lymphomas include: adult grade III lymphomatoid granulomatosis, adult nasal-type extranodal NK / T-cell lymphoma, anaplastic large cell lymphoma, angioimmunoblastic T-cell lymphoma, cutaneous B-cell non-Hodgkin lymphoma, extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue, hepatosplenic T-cell lymphoma, intraocular lymphoma, lymphomatous involvement of non-cutaneous extranodal site, mature T-cell and K-cell non-Hodgkin lymphoma, nodal marginal zone lymphoma, post-transplant lymphoproliferative disorder, recurrent adult Burkitt lymphoma, recurrent adult diffuse large cell lymphoma, recurrent adult diffuse mixed cell lymphoma, recurrent adult diffuse small cleaved cell lymphoma. lymphoma, recurrent adult grade III lymphomatoid granulomatosis, recurrent adult immunoblastic lymphoma, recurrent adult lymphoblastic lymphoma, recurrent adult T-cell leukemia / lymphoma, recurrent cutaneous T-cell non-Hodgkin's lymphoma, recurrent grade 1 follicular lymphoma, recurrent grade 2 follicular lymphoma, recurrent grade 3 follicular lymphoma, recurrent mantle cell lymphoma, recurrent marginal zone lymphoma, recurrent mycosis fungoides and Sézary syndrome, recurrent small lymphocytic lymphoma, Richter's syndrome, small intestinal lymphoma, splenic marginal zone lymphoma, testicular lymphoma, Waldenström's 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's lymphoma, central nervous system lymphoma, refractory primary cutaneous large B-cell lymphoma (lower limb type), refractory anemia, refractory anemia with excess blasts, refractory anemia with ringed sideroblasts, refractory cytopenia with multilineage dysplasia, secondary myelodysplastic syndromeThe myelodysplastic syndromes, myeloproliferative disorders, and myeloproliferative disorders may be selected from the group consisting of: 2) Autoimmune diseases, such as: acute disseminated encephalomyelitis, acute motor axonal neuropathy, Addison's disease, adiposis dolorosa, adult-onset Still's disease, alopecia areata, ankylosing spondylitis, antiglomerular basement membrane nephritis, antineutrophil cytoplasmic antibody-associated vasculitis, anti-N-methyl-D-aspartate receptor encephalitis, antiphospholipid syndrome, antisynthetase syndrome, aplastic anemia anemia), autoimmune angioedema, autoimmune encephalitis, autoimmune enteropathy, 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 Hypoplastic purpura, autoimmune thyroiditis, autoimmune urticaria, autoimmune uveitis, Baroconcentric sclerosis, Behçet's disease, Bickerstaff encephalitis, bullous pemphigoid, celiac disease, chronic fatigue syndrome, chronic inflammatory demyelinating polyneuropathy, Churg-Strauss syndrome, cicatricial pemphigoid, Cogan's syndrome, cold agglutinin disease, complex regional pain syndrome, CREST syndrome, Crohn's disease, dermatitis herpetiformis, dermatomyositis, type 1 diabetes, discoid lupus erythematosus, endometriosis, enthesitis, enthesitis-associated arthritis, eosinophilic esophagitis, eosinophilic fasciitis, epidermolysis bullosa acquisita, erythema nodosum, essential mixed cryoglobulinemia, Evans syndrome, Felty syndrome, fibromyalgia, gastritis, herpes of pregnancy pemphigoid), giant cell arteritis, Goodpasture's syndrome, Graves' disease, Graves' ophthalmopathy, Guillain-Barré syndrome, Hashimoto's encephalopathy, Hashimoto's thyroiditis, Henoch-Schönlein purpura, sweat gland abscess, idiopathic inflammatory demyelinating disease, iG4-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 sclerosus, lignified 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, morphea, Mucha-Habermann's disease, disease), multiple sclerosis, myasthenia gravis, myocarditis, myositis, neuromyelitis optica, neuromyotonia, opsoclonus-myoclonus syndrome, optic neuritis, Ord's thyroiditis, relapsing rheumatism, paraneoplastic cerebellar degeneration, Parry-Romberg syndrome, Parsonage-Turner syndrome, streptococcal-associated pediatric autoimmune neuropsychiatric disorder, 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 inflammatory neuropathy, psoriasis, psoriatic arthritis, pure red cell aplasia, pyoderma gangrenosum, Raynaud's phenomenon, reactive arthritis, relapsing polychondritis, restless legs syndrome, retroperitoneal fibrosis, rheumatic fever, rheumatoid arthritis, rheumatic vasculitis, sarcoidosis, Schnitzler's syndrome, scleroderma, Sjögren's syndrome, stiff-body syndrome, subacute bacterial endocarditis, Susac's syndrome, Sydenham's chorea, sympathetic ophthalmia, systemic lupus erythematosus, systemic dermatosclerosis, thrombocytopenia, Trosa-Hunt syndrome, transverse myelitis, ulcerative colitis, undifferentiated connective tissue disease, urticaria, urticarial vasculitis, vasculitis and vitiligo; 3) Diseases and disorders involving or characterized by unwanted angiogenesis, such as inflammatory diseases, autoimmune diseases, pain, viral diseases, genetic diseases, allergic diseases, bacterial diseases, ocular neovascular diseases, choroidal neovascular diseases, retinal neovascular diseases, and rubeosis (corneal neovascularization). Specific examples of diseases and disorders associated with or characterized by unwanted angiogenesis include, but are not limited to: arthritis, endometriosis, Crohn's disease, heart failure, advanced heart failure, renal dysfunction, endotoxemia, toxic shock syndrome, osteoarthritis, retroviral replication, wasting, 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 bruises, osteoarthritis, rheumatoid arthritis, tendonitis, and myofascial pain. Examples of neuropathic pain include, but are not limited to, CRPSI, CRPS II, reflex sympathetic dystrophy (RSD), reflex neurovascular dystrophy, reflex dystrophy, sympathetically maintained pain syndrome, causalgia, Sudeck atrophy of bone, argon dystrophy, shoulder-hand syndrome, post-traumatic dystrophy, trigeminal neuralgia, post-herpetic 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 neuropathic conditions such as those induced by drugs such as vincristine and Velcade; 4) Macular degeneration ("MD") and related syndromes, such as: nutritional (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 disorders, such as: keratosis and related conditions, diseases or disorders of the skin characterized by epithelial hyperproliferation, acne, and wrinkles. Examples of skin diseases or disorders characterized by epithelial hyperproliferation include, but are not limited to, any condition, disease or disorder characterized by the presence of epithelial hyperproliferation, such as, but not limited to, infections associated with papillomavirus, arsenic keratosis, Laser-Toleler sign, dyskeratosis verruciformis (WD), fasciculosis tularensis (TS), erythrokeratoderma variabilis (EKV), Harlequin fetus (Harlequin ichthyosis), knuckle pads, cutaneous melanomatosis, porokeratosis, psoriasis, squamous cell carcinoma, confluent reticular papillomatosis (CRP), acrochordons, cutaneous horns, Cowden's disease (multiple hamartoma syndrome), dermatosis papularis nigricans (DPN), epidermal nevus syndrome (ENS), ichthyosis vulgaris, molluscum contagiosum, prurigo nodularis, and acanthosis nigricans (AN); 6) Pulmonary 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 arteriopathy (TPA); multifactorial pulmonary arteriopathy; functional class I-IV pulmonary hypertension; and left ventricular dysfunction, mitral valve disease, constrictive endocarditis, aortic stenosis, cardiomyopathy, mediastinal fibrosis, anomalous pulmonary venous return, obstructive pulmonary venous disease, have pulmonary hypertension secondary to, associated with, or secondary to collagen vascular disease, congenital heart disease, HIV viral infection, drugs and toxins such as fenfluramine, congenital heart disease, elevated pulmonary venous pressure, chronic obstructive pulmonary disease, interstitial lung disease, impaired alveolar hypoventilation, chronic exposure to high altitude, neonatal pulmonary disease, alveolar-capillary dysplasia, sickle cell disease, other coagulation disorders, chronic thromboembolism, connective tissue diseases, systemic and cutaneous lupus including lupus, schistosomiasis, sarcoidosis or pulmonary capillary hemangiomatosis; 7) Asbestos-related disorders, such as: mesothelioma, asbestosis, malignant pleural effusion, benign exudative effusion, pleural plaque, pleural calcification, diffuse pleural thickening, round atelectasis, fibrous mass, and lung cancer; 8) Human intracellular parasites, including but not limited to P. falcifarium, P. ovale, P. vivax, P. 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. cayetanensis, C. Parasitic diseases and disorders caused by E. cayetanensis, E. histolytica, I. belli, S. monsonii, S. haemolobium, Trypanosoma ssp., Toxoplasma ssp., and O. volvulus. Also included are 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, Eimeria ssp., Hammondia ssp., and Theileria ssp.Specific examples include, but are not limited to, malaria, babesiosis, trypanosomiasis, leishmaniasis, toxoplasmosis, meningoencephalitis, keratitis, amebiasis, giardiasis, cryptosporidiosis, isosporiasis, cyclosporiasis, microsporidiosis, ascariasis, trichuriasis, duodenal worm disease, fecal nematode disease, toxocariasis, trichinosis, lymphatic filariasis, onchocerciasis, filariasis, schistosomiasis, and dermatitis caused by animal blood flukes; 9) Immunodeficiency disorders including but not limited to adenosine deaminase deficiency, antibody deficiency with normal or elevated Ig, ataxia telangiectasia, insufficient lymphocyte syndrome, common variable immunodeficiency, Ig deficiency with hyper-IgM, Ig heavy chain deficiency, IgA deficiency, immunodeficiency with thymoma, reticulum dysplasia, Nezerov syndrome, selective IgG subclass deficiency, transient infantile hypogammaglobulinemia, Wiskott-Aldrich syndrome, X-linked agammaglobulinemia, and X-linked severe combined immunodeficiency; 10) Atherosclerosis and related conditions, including: any form of condition involving atherosclerosis, including restenosis after vascular interventions such as angioplasty, stenting, atherectomy and grafting; 11) Hemoglobinopathies and related disorders, such as sickle cell anemia, and any other disorder associated with CD34+ cell differentiation; 12) TNFα-related disorders, such as: 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 pulmonary inflammatory disease; reperfusion injury; myocardial infarction; stroke; circulatory shock; rheumatoid arthritis; Crohn's disease; HIV infection and AIDS; other disorders, such as rheumatoid arthritis, rheumatoid spondylitis, osteoarthritis, psoriatic arthritis and other arthritic conditions, septic shock, sepsis, endotoxic shock, graft-versus-host disease, wasting, Crohn's disease, ulcerative colitis. , multiple sclerosis, systemic lupus erythematosus, ENL in leprosy, HIV, AIDS, and opportunistic infections in AIDS; disorders such as septic shock, sepsis, endotoxic shock, hemodynamic shock and septic syndrome, post-ischemic reperfusion injury, malaria, mycobacterial infections, meningitis, psoriasis, congestive heart failure, fibrotic disease, cachexia, transplant rejection, neoplastic or cancerous conditions, asthma, autoimmune diseases, radiation injury, and hyperoxic alveolar damage; viral infections such as those caused by herpes viruses; viral conjunctivitis; or atopic dermatitis.

[0161] The compounds of the invention may also be useful in preventing, treating, or reducing the risk of developing graft-versus-host disease (GVHD) or transplant rejection.

[0162] The compounds of the present invention can also inhibit the production of certain cytokines, including but not limited to TNF-α, IL-1β, IL-12, IL-18, GM-CSF, IL-10, TGF-β, and / or IL-6. The compounds can stimulate the production of certain cytokines and function as costimulatory signals for T cell activation, resulting in increased production of cytokines such as but not limited to IL-12, IL-2, IL-10, TGF-β, and / or IFN-γ. In addition, the compounds provided herein can enhance the efficacy of NK cells and antibody-mediated cytotoxicity (ADCC). Furthermore, the compounds provided herein can be immunomodulatory and / or cytotoxic, and therefore useful as chemotherapeutic agents. [Example]

[0163] General method A:

[0164] [ka]

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

[0166] General method B:

[0167] [ka]

[0168] To a solution of DCC (1.1 eq.) in DCM was added DMAP (0.8 eq.) and the appropriate 2-(quinolin-3-yl)acetic acid (1 eq.) at 0° C. Tert-butanol (3 eq.) was added and the reaction mixture was warmed to room temperature and stirred for 12 h. 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 the appropriate tert-butyl 2-(quinolin-3-yl)acetate (1 eq.) in DMF was added K2CO3 (1 eq.), benzyltriethylammonium chloride (1 eq.) and acrylonitrile (1 eq.) and the reaction mixture was stirred at room temperature for 16 h. 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 the appropriate tert-butyl 4-cyano-2-(quinolin-3-yl)butanoate (1 eq.) in DMSO was added H2O2 (5 eq.) and K2CO3 (0.1 eq.). The reaction mixture was warmed to room temperature and stirred for 16 h. The reaction mixture was diluted with water and the product was extracted with ethyl acetate. The combined organic phases were dried over Na2SO4, concentrated under reduced pressure, and purified by flash column chromatography.

[0175] General method E:

[0176] [ka]

[0177] Into a vial was placed the appropriate tert-butyl 5-amino-2-(2-methylquinolin-3-yl)-5-oxopentanoate (1 equiv.), p-toluenesulfonic acid (5-10 equiv.) and ACN, and the reaction mixture was stirred for 2-48 h at 80° C. The mixture was concentrated under reduced pressure and purified by flash column chromatography or preparative HPLC.

[0178] General method F:

[0179] [ka]

[0180] In a vial was placed the appropriate nitro compound, 10% Pd / C, and ethanol, 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, pyridine (0.01-0.1 M) was added followed by the appropriate sulfonyl chloride, and 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 bromoarene (1 equiv.) in dioxane, KOAc (2 equiv.), ((1-(tert-butoxy)vinyl)oxy)(tert-butyl)dimethylsilane (4 equiv.) and Pd[P(o-Tol)3]2Cl2 (0.2 equiv.) were added under inert gas and the reaction mixture was stirred at 130° C. for 48 h. The reaction mixture was filtered through Celite, concentrated under reduced pressure and purified by flash column chromatography to give the appropriate tert-butyl aryl acetate. [Example 1]

[0187] Synthesis of 3-(5-amino-2-methylquinolin-3-yl)piperidine-2,6-dione (Compound 1) and 3-(2-methyl-5-nitroquinolin-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 equiv.) in DCM (25 mL) was added m-CPBA (2.3 g, 13.67 mmol, 1.1 equiv.). The reaction mixture was warmed to room temperature and stirred for 16 h. The mixture was filtered and the filtrate was washed with 1M KOH solution, dried over Na2SO4, and concentrated under reduced pressure to give 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 equiv.) in DCM (5 mL) was added POBr3 (1.4 g, 4.9 mmol, 2 equiv.) in DCM (5 mL). The reaction mixture was warmed to room temperature and stirred for 48 h. Ice water was added and 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 give 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 equiv.) to give tert-butyl 2-(2-methyl-5-nitroquinolin-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-nitroquinolin-3-yl)acetate (200 mg, 0.662 mmol) to give tert-butyl 4-cyano-2-(2-methyl-5-nitroquinolin-3-yl)butanoate (40% yield).

[0193] Step E: The reaction was carried out according to general procedure D using tert-butyl 4-cyano-2-(2-methyl-5-nitroquinolin-3-yl)butanoate (120.0 mg, 0.338 mmol) to give tert-butyl 5-amino-2-(2-methyl-5-nitroquinolin-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-nitroquinolin-3-yl)-5-oxopentanoate (250 mg, 0.670 mmol) to give 3-(2-methyl-5-nitroquinolin-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-nitroquinolin-3-yl)piperidine-2,6-dione (139 mg, 0.464 mmol) to give 3-(5-amino-2-methylquinolin-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-methylquinolin-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 added thereto in portions and the reaction mixture was stirred at room temperature (20-25 °C) for 12 h. The mixture was washed with 2 M NaOH solution (2 × 150 mL), dried over anhydrous sodium sulfate, and evaporated under vacuum to give 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) in CHCl3 (300 mL) was added dropwise to the reaction mixture. The mixture was stirred at room temperature (20-25 °C) for 12 h, poured into cold water, basified with solid potassium carbonate to pH = 12, and extracted with CHCl3 (3 x 100 mL). The combined extracts were dried over anhydrous sodium sulfate and evaporated under vacuum. The crude product was purified by flash column chromatography (eluent hexane-MTBE 0-100%) to give 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)pyridin-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 added sequentially 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 at 100° C. for 12 h under argon atmosphere. The solvent was removed under vacuum and the residue was diluted with EtOAc (100 mL) and filtered through a pad of silica gel. The filtrate was evaporated in vacuo and recrystallized from EtOAc to give 2.05 g of 3-[2,6-bis(benzyloxy)pyridin-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-methylquinolin-3-yl)piperidine-2,6-dione Pd on activated carbon (1.2 g) was added to a solution of 3-[2,6-bis(benzyloxy)pyridin-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 H2 atmosphere for 96 h. 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 give 0.05 g of the target compound 3-(5-amino-2-methylquinolin-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-methylquinolin-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 give 2-(5-fluoro-2-methylquinolin-3-yl)acetic acid (38% yield).

[0204] Step B: The reaction was carried out according to general procedure B using 2-(5-fluoro-2-methylquinolin-3-yl)acetic acid (1.0 g, 4.56 mmol) to give tert-butyl 2-(5-fluoro-2-methylquinolin-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-methylquinolin-3-yl)acetate (500 mg, 1.81 mmol) to give tert-butyl 4-cyano-2-(5-fluoro-2-methylquinolin-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-methylquinolin-3-yl)butanoate (500 mg, 1.52 mmol) to give tert-butyl 5-amino-2-(5-fluoro-2-methylquinolin-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-methylquinolin-3-yl)-5-oxopentanoate (5.0 mg, 14 μmol) to give 3-(5-fluoro-2-methylquinolin-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-nitroquinolin-3-yl)piperidine-2,6-dione (compound 12) and 3-(5-aminoquinolin-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 equiv) in AcOH (140 mL) was added N-bromosuccinimide (5.11, 43 mmol, 1.5 equiv) in small portions and the reaction mixture was refluxed for 16 h. Volatiles were removed under reduced pressure and the residue was neutralized with 6M NaOH. The product was extracted with DCM, washed with water and brine, concentrated under reduced pressure and purified by flash column chromatography to give 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 equiv) to give tert-butyl 2-(5-nitroquinolin-3-yl)acetate (69% yield).

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

[0213] Step D: The reaction was carried out according to general procedure D using tert-butyl 4-cyano-2-(5-nitroquinolin-3-yl)butanoate (430 mg, 1.257 mmol) to give tert-butyl 5-amino-2-(5-nitroquinolin-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-nitroquinolin-3-yl)-5-oxopentanoate (30 mg, 0.083 mmol) to give 3-(5-nitroquinolin-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-nitroquinolin-3-yl)piperidine-2,6-dione (13.7 mg, 0.048 mmol) to give 3-(5-aminoquinolin-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-nitroquinolin-3-yl)piperidine-2,6-dione (Compound 5) and 3-(6-amino-2-methylquinolin-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 give 2-(2-methyl-6-nitroquinolin-3-yl)acetic acid (67% yield).

[0219] Step B: The reaction was carried out according to general procedure B using 2-(2-methyl-6-nitroquinolin-3-yl)acetic acid (1.0 g, 4.06 mmol) to give tert-butyl 2-(2-methyl-6-nitroquinolin-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-nitroquinolin-3-yl)acetate (290 mg, 0.96 mmol) to give tert-butyl 4-cyano-2-(2-methyl-6-nitroquinolin-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-nitroquinolin-3-yl)butanoate (150 mg, 0.423 mmol) to give tert-butyl 5-amino-2-(2-methyl-6-nitroquinolin-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-nitroquinolin-3-yl)butanoate (30 mg, 0.080 mmol) to give 3-(2-methyl-6-nitroquinolin-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-nitroquinolin-3-yl)piperidine-2,6-dione (16 mg, 0.053 mmol) to give 3-(6-amino-2-methylquinolin-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-nitroquinolin-3-yl)piperidine-2,6-dione (Compound 6) and 3-(7-amino-2-methylquinolin-3-yl)piperidine-2,6-dione (Compound 8)

[0225] [ka]

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

[0227] Step B: The reaction was carried out according to general procedure B using 2-(2-methyl-7-nitroquinolin-3-yl)acetic acid (830 mg, 3.36 mmol) to give tert-butyl 2-(2-methyl-7-nitroquinolin-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-nitroquinolin-3-yl)acetate (460 mg, 1.52 mmol) to give tert-butyl 4-cyano-2-(2-methyl-7-nitroquinolin-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-nitroquinolin-3-yl)butanoate (255 mg, 0.718 mmol) to give tert-butyl 5-amino-2-(2-methyl-7-nitroquinolin-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-nitroquinolin-3-yl)butanoate (30 mg, 0.080 mmol) to give 3-(2-methyl-7-nitroquinolin-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-nitroquinolin-3-yl)piperidine-2,6-dione (18 mg, 0.063 mmol) to give 3-(7-amino-2-methylquinolin-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-nitroquinolin-3-yl)piperidine-2,6-dione (Compound 7) and 3-(8-amino-2-methylquinolin-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 give 2-(2-methyl-8-nitroquinolin-3-yl)acetic acid (40% yield).

[0235] Step B: The reaction was carried out according to general procedure B using 2-(2-methyl-8-nitroquinolin-3-yl)acetic acid (3.0 g, 13.36 mmol) to give tert-butyl 2-(2-methyl-8-nitroquinolin-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-nitroquinolin-3-yl)acetate (1.20 g, 3.97 mmol) to give tert-butyl 4-cyano-2-(2-methyl-8-nitroquinolin-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-nitroquinolin-3-yl)butanoate (310 mg, 0.871 mmol) to give tert-butyl 5-amino-2-(2-methyl-8-nitroquinolin-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-nitroquinolin-3-yl)butanoate (30 mg, 0.080 mmol) to give 3-(2-methyl-8-nitroquinolin-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-nitroquinolin-3-yl)piperidine-2,6-dione (16 mg, 0.053 mmol) to give 3-(8-amino-2-methylquinolin-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-methylquinolin-3-yl)piperidine-2,6-dione (compound 21)

[0241] [ka]

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

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

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

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

[0246] Step E: The reaction was carried out according to general procedure E using tert-butyl 5-amino-2-(8-chloro-2-methylquinolin-3-yl)-5-oxopentanoate to give 3-(8-chloro-2-methylquinolin-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-dimethylquinolin-3-yl)piperidine-2,6-dione (compound 22)

[0248] [ka]

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

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

[0251] Step C: The reaction was carried out according to general procedure C using tert-butyl 2-(2,8-dimethylquinolin-3-yl)acetate (500 mg, 1.84 mmol) to give tert-butyl 4-cyano-2-(2,8-dimethylquinolin-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-dimethylquinolin-3-yl)butanoate (200 mg, 0.616 mmol) to give tert-butyl 5-amino-2-(2,8-dimethylquinolin-3-yl)-5-oxopentanoate.

[0253] Step E: The reaction was carried out according to general procedure E using tert-butyl 5-amino-2-(2,8-dimethylquinolin-3-yl)-5-oxopentanoate to give 3-(2,8-dimethylquinolin-3-yl)piperidine-2,6-dione (30% yield, two 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-methylquinolin-3-yl)piperidine-2,6-dione (compound 13)

[0255] [ka]

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

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

[0258] Step C: The reaction was carried out according to general procedure C using tert-butyl 2-(2-methylquinolin-3-yl)acetate (800 mg, 3.11 mmol) to give tert-butyl 4-cyano-2-(2-methylquinolin-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-methylquinolin-3-yl)butanoate (700 mg, 2.25 mmol) to give tert-butyl 5-amino-2-(2-methylquinolin-3-yl)-5-oxopentanoate (67% yield).

[0260] Step E: The reaction was carried out according to general procedure E using 5-amino-2-(2-methylquinolin-3-yl)-5-oxopentanoate (100 mg, 0.304 mmol) to give 3-(2-methylquinolin-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-dioxopiperidin-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 give 2-(7-bromo-2-methylquinolin-3-yl)acetic acid (45% yield).

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

[0265] Step C: In a pressure Schlenk tube was placed molybdenum hexacarbonyl (196.3 mg, 0.744 mmol, 1 equiv.) and benzyltriethylammonium chloride (169.4 mg, 0.744 mmol, 1 equiv.). Dioxane (10 mL) was added and the mixture was heated at 140° C. for 1 h. (S)-1-Cyclohexylethylamine (189.2 mg, 1.487 mmol, 2 equiv.) and tert-butyl 2-(7-bromo-2-methylquinolin-3-yl)acetate (250.0 mg, 0.744 mmol, 1 equiv.) were added and the reaction was continued at 150° C. for 16 h. The volatiles were removed under reduced pressure and the residue was purified by flash column chromatography to give tert-butyl (S)-2-(7-((1-cyclohexylethyl)carbamoyl)-2-methylquinolin-3-yl)acetate (199.0 mg, 65% yield).

[0266] Step D: The reaction was carried out according to general procedure C using tert-butyl (S)-2-(7-((1-cyclohexylethyl)carbamoyl)-2-methylquinolin-3-yl)acetate (150 mg, 0.365 mmol) to give tert-butyl 4-cyano-2-(7-(((S)-1-cyclohexylethyl)carbamoyl)-2-methylquinolin-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-methylquinolin-3-yl)butanoate (130 mg, 0.280 mmol) to give tert-butyl 5-amino-2-(7-(((S)-1-cyclohexylethyl)carbamoyl)-2-methylquinolin-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-methylquinolin-3-yl)-5-oxopentanoate (75 mg, 0.156 mmol) to give N-((S)-1-cyclohexylethyl)-3-(2,6-dioxopiperidin-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-dioxopiperidin-3-yl)-2-methylquinolin-7-yl]methyl}urea (Compound 15)

[0270] [ka]

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

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

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

[0274] Step D: A flask was charged with 3-(7-bromo-2-methylquinolin-3-yl)piperidine-2,6-dione (80.0 mg, 0.24 mmol, 1 equiv.), zinc cyanide (84.6 mg, 0.72 mmol, 3 equiv.) and Pd(PPh3)4 (27.7 mg, 24 μmol, 0.1 equiv.). DMF (2.0 mL) was added and the reaction mixture was stirred at 130° C. for 18 h. The volatiles were removed under reduced pressure and the residue was purified by flash column chromatography to give 3-(2,6-dioxopiperidin-3-yl)-2-methylquinoline-7-carbonitrile (55 mg, 82% yield).

[0275] Step E: In a flask was placed 3-(2,6-dioxopiperidin-3-yl)-2-methylquinoline-7-carbonitrile (30.0 mg, 0.107 mmol, 1 equiv), DMF (1.0 mL), and THF (2.0 mL). Raney Nickel (37.8 mg, 0.644 mmol, 6 equiv) was added followed by Boc2O (46.9 mg, 0.215 mmol, 2 equiv) and the reaction mixture was stirred at room temperature under hydrogen atmosphere (balloon) for 18 h. 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 give tert-butyl ((3-(2,6-dioxopiperidin-3-yl)-2-methylquinolin-7-yl)methyl)carbamate (29 mg, 70% yield).

[0276] Step F: Into a vial was placed tert-butyl ((3-(2,6-dioxopiperidin-3-yl)-2-methylquinolin-7-yl)methyl)carbamate (5.5 mg, 14 μmol, 1 equiv). Dioxane (0.5 mL) was added followed by 12 M HCl (0.1 mL) and the reaction mixture was stirred at room temperature for 2 h. Volatiles were removed under reduced pressure and the residue was redissolved in DMF (1 mL). DIPEA (0.012 mL, 71 μmol, 5 equiv) was added followed by 3-chloro-4-methylphenylisocyanate (2.9 mg, 17 μmol, 1.2 equiv) and the reaction mixture was stirred at room temperature for 18 h. The volatiles were removed under reduced pressure and the crude product was purified by preparative HPLC to give 1-(3-chloro-4-methylphenyl)-3-{[3-(2,6-dioxopiperidin-3-yl)-2-methylquinolin-7-yl]methyl}urea (4.8 mg, 74% yield). 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-dioxopiperidin-3-yl)-2-methylquinolin-7-yl]methyl}-2,2-difluoroacetamide (Compound 16)

[0278] [ka]

[0279] Into a vial was placed tert-butyl ((3-(2,6-dioxopiperidin-3-yl)-2-methylquinolin-7-yl)methyl)carbamate (5.5 mg, 14 μmol, 1 equiv). Dioxane (0.5 mL) was added followed by 12 M HCl (0.1 mL) and the reaction mixture was stirred at room temperature for 2 h. Volatiles 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 equiv) and DIPEA (12 μL, 72 μmol, 5 equiv) were added followed by HATU (8.2 mg, 21 μmol, 1.5 equiv) and the reaction mixture was stirred at room temperature for 18 h. The volatiles were removed under reduced pressure and the crude product was purified by preparative TLC to give 2-(4-chlorophenyl)-N-{[3-(2,6-dioxopiperidin-3-yl)-2-methylquinolin-7-yl]methyl}-2,2-difluoroacetamide (2.9 mg, 42% yield). 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-dioxopiperidin-3-yl)-2-methylquinolin-5-yl)-2-(trifluoromethoxy)benzenesulfonamide (Compound 17)

[0281] [ka]

[0282] The reaction was carried out according to general procedure G using 3-(5-amino-2-methylquinolin-3-yl)piperidine-2,6-dione (5.1 mg, 18.9 μmol) to give N-(3-(2,6-dioxopiperidin-3-yl)-2-methylquinolin-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-dioxopiperidin-3-yl)-2-methylquinolin-6-yl)-2-(trifluoromethoxy)benzenesulfonamide (Compound 18)

[0284] [ka]

[0285] The reaction was carried out according to general procedure G using 3-(6-amino-2-methylquinolin-3-yl)piperidine-2,6-dione (6.5 mg, 24.1 μmol) to give N-(3-(2,6-dioxopiperidin-3-yl)-2-methylquinolin-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-dioxopiperidin-3-yl)-2-methylquinolin-7-yl)-2-(trifluoromethoxy)benzenesulfonamide (Compound 19)

[0287] [ka]

[0288] The reaction was carried out according to general procedure G using 3-(7-amino-2-methylquinolin-3-yl)piperidine-2,6-dione (5.3 mg, 19.6 μmol) to give N-(3-(2,6-dioxopiperidin-3-yl)-2-methylquinolin-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-dioxopiperidin-3-yl)-2-methylquinolin-8-yl)-2-(trifluoromethoxy)benzenesulfonamide (Compound 20)

[0290] [ka]

[0291] The reaction was carried out according to general procedure G using 3-(8-amino-2-methylquinolin-3-yl)piperidine-2,6-dione (5.3 mg, 20 μmol) to give N-(3-(2,6-dioxopiperidin-3-yl)-2-methylquinolin-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]pyridin-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 equiv) to give tert-butyl 2-(1,6-dimethyl-1H-pyrazolo[3,4-b]pyridin-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]pyridin-5-yl)acetate (1.80 g, 6.90 mmol) to give tert-butyl 4-cyano-2-(1,6-dimethyl-1H-pyrazolo[3,4-b]pyridin-5-yl)butanoate (64% yield).

[0296] Step C: The reaction was carried out according to general procedure D using tert-butyl 4-cyano-2-(1,6-dimethyl-1H-pyrazolo[3,4-b]pyridin-5-yl)butanoate (700 mg, 2.23 mmol) to give tert-butyl 5-amino-2-(1,6-dimethyl-1H-pyrazolo[3,4-b]pyridin-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]pyridin-5-yl)-5-oxopentanoate (40.0 mg, 0.12 mmol) to give 3-(1,6-dimethyl-1H-pyrazolo[3,4-b]pyridin-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]pyridin-5-yl)piperidine-2,6-dione (compound 23)

[0299] [ka]

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

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

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

[0303] Step D: The reaction was carried out according to general procedure E using tert-butyl 5-amino-5-oxo-2-(thieno[2,3-b]pyridin-5-yl)pentanoate to give 3-(thieno[2,3-b]pyridin-5-yl)piperidine-2,6-dione (20% yield, two 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-methylquinolin-3-yl)piperidine-2,6-dione (compound 24)

[0305] [ka]

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

[0307] Step B: The reaction was carried out according to general procedure B using 2-(7-methoxy-2-methylquinolin-3-yl)acetic acid (400 mg, 1.72 mmol) to give tert-butyl 2-(7-methoxy-2-methylquinolin-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-methylquinolin-3-yl)acetate (130 mg, 0.452 mmol) to give tert-butyl 4-cyano-2-(7-methoxy-2-methylquinolin-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-methylquinolin-3-yl)butanoate (100 mg, 0.293 mmol) to give tert-butyl 5-amino-2-(7-methoxy-2-methylquinolin-3-yl)-5-oxopentanoate.

[0310] Step E: The reaction was carried out according to general procedure E using 5-amino-2-(7-methoxy-2-methylquinolin-3-yl)-5-oxopentanoate to give 3-(7-methoxy-2-methylquinolin-3-yl)piperidine-2,6-dione (28% yield, two 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-methylquinolin-3-yl)pyrrolidine-2,5-dione (compound 25)

[0312] [ka]

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

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

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

[0316] Step D: The reaction was carried out according to general procedure F using 3-(2-methyl-8-nitroquinolin-3-yl)pyrrolidine-2,5-dione (25 mg, 0.087 mmol) to give 3-(8-amino-2-methylquinolin-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]diazepin-6-yl)-N-(8-(2-((3-(2,6-dioxopiperidin-3-yl)-2-methylquinolin-7-yl)amino)acetamide)octyl)acetamide (compound 26)

[0318] [ka]

[0319] Step A: A flask was charged with 3-(7-amino-2-methylquinolin-3-yl)piperidine-2,6-dione (71 mg, 0.265 mmol), tetrabutylammonium iodide (97.9 mg, 0.265 mmol, 1 equiv.) and DMF (15 mL). DIPEA (185 μL, 1.02 mmol, 4 equiv.) was added followed by tert-butyl bromoacetate (51.7 mg, 0.265 mmol, 1 equiv.) and the reaction mixture was stirred at 60° C. for 4 h. The reaction mixture was concentrated under reduced pressure and the residue was purified by flash column chromatography to give tert-butyl (3-(2,6-dioxopiperidin-3-yl)-2-methylquinolin-7-yl)glycinate (14% yield).

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

[0321] Step C: Into a vial was placed (3-(2,6-dioxopiperidin-3-yl)-2-methylquinolin-7-yl)glycine (6.2 mg, 0.0.19 mmol), (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]diazepin-6-yl)acetamide (12.0 mg, 0.023 mmol, 1.2 equiv). DMF (1 mL) was added followed by DIPEA (26 μL, 0.152 mmol, 8 equiv) and HATU (8.7 mg, 0.023 mmol, 1.2 equiv) and the reaction mixture was stirred at room temperature for 2 h. The volatiles were removed under reduced pressure and the residue was purified by preparative HPLC to give 2-((S)-4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)-N-(8-(2-((3-(2,6-dioxopiperidin-3-yl)-2-methylquinolin-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]diazepin-6-yl)-N-(8-(2-((3-(2,6-dioxopiperidin-3-yl)-2-methylquinolin-6-yl)amino)acetamide)octyl)acetamide (compound 27)

[0323] [ka]

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

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

[0326] Step C: In a vial was placed (3-(2,6-dioxopiperidin-3-yl)-2-methylquinolin-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]diazepin-6-yl)acetamide (18.1 mg, 0.032 mmol, 1 equiv.). DMF (3 mL) was added followed by DIPEA (56 μL, 0.320 mmol, 10 equiv.) and HATU (14.6 mg, 0.038 mmol, 1.2 equiv.) and the reaction mixture was stirred at room temperature for 6 h. The volatiles were removed under reduced pressure and the residue was purified by preparative HPLC to give 2-((S)-4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)-N-(8-(2-((3-(2,6-dioxopiperidin-3-yl)-2-methylquinolin-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 to be tested ("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, 2% v / v DMSO. The test solution was added to a 384-well assay plate.

[0328] The plate was spun down (1 min, 1000 rpm, 22°C) and then shaken using a VibroTurbulator for 10 min at room temperature (20-25°C) with the frequency set to level 3. The assay plate with protein and tracer was incubated for 60 min at room temperature (20-25°C) and then read on a plate reader. The readout (fluorescence polarization) was performed with a Pherastar plate reader using a Cy5 FP Filterset (590nm / 675nm).

[0329] K i To determine this value, FP experiments were performed with various concentrations of test compounds.

[0330] IC of the relationship between compound concentration and measured fluorescence polarization 50 values, K of Cy5-T and CRBN / DDB1 complex d The K of competitive inhibitors was calculated using an equation based on the protein and tracer concentrations in the displacement assay (as described by Z. Nikolovska-Coleska et al., Analytical Biochemistry 332 (2004) 261-273) and the K i values ​​were calculated.

[0331] Fluorescence Polarization (FP) Assay - Results The compounds are categorized based on their activity towards CRBN, defined as Ki. As reported in Table 1 below, the compounds of the present invention interact with the CRBN-DDB1 protein within a similar affinity range as reported for the reference compounds.

[0332] [Table 6] JPEG2024501537000079.jpg189134JPEG2024501537000080.jpg190134JPEG2024501537000081.jpg103132

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

[0334] SALL4 Degradation Assay-Kelly Cell Line The following degradation assay protocol was used to investigate the effect of various compounds of the invention and various reference compounds on SALL4 degradation in the Kelly cell line.

[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 compounds to be tested were added at the desired concentration range. The final DMSO concentration was 0.25%. After 24 hours of incubation (37°C, 5% CO2), cells were washed and cell lysates were prepared using RIPA lysis buffer. Protein amounts were determined via BCA assay and appropriate aliquots were then loaded onto precast gels for protein separation. After primary and secondary antibody staining, membranes were washed and signals were developed. Densitometric analysis was performed to obtain values ​​that were later used in the protein level evaluation process.

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

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

[0338] [Table 7] [Example 25]

[0339] IKZF1 Degradation Assay-H929 Cell Line The following degradation assay protocol was used to investigate the effect of various compounds of the invention and various reference compounds on IKZF1 degradation in H929 cell line.

[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 compounds to be tested were added at 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 lysates were prepared using RIPA lysis buffer. Protein amount was determined via BCA assay and appropriate aliquots were then loaded onto precast gels for protein separation. After primary and secondary Ab staining, membranes were washed and signals were developed. Densitometric analysis was performed to obtain values ​​that were used later in the protein level evaluation process.

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

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

[0343] [Table 8] [Example 26]

[0344] IKZF3 Degradation Assay-H929 Cell Line The effect of various compounds of the invention and various reference compounds on IKZF3 degradation in H929 cell line was investigated using the degradation assay protocol described below.

[0345] H929 cells were maintained in RPMI-1640 medium supplemented with penicillin / streptomycin and 10% fetal bovine serum (FBS) and 0.05 mM 2-mercaptoethanol. Cells were seeded on 6-well or 12-well plates and compounds to be tested were added at 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 lysates were prepared using RIPA lysis buffer. Protein amount was determined via BCA assay and appropriate aliquots were then loaded onto precast gels for protein separation. After primary and secondary Ab staining, membranes were washed and signals were developed. Densitometric analysis was performed to obtain values ​​that were used later in the protein level evaluation process.

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

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

[0348] [Table 9]

[0349] [Table 10] [Example 27]

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

[0351] 3000 cells in 50 μL of culture medium were plated in 384-well plates and incubated with 50 μM, 13 μM and 2 μM of each compound for 72 hours. The ATP content in the remaining cells after treatment was quantified with CellTiter-Glo Luminescent Viability Assay Kit (Promega). The activity of the compound at each concentration was shown as percentage viability; 100% viability was the ATP content in cells incubated with DMSO, the carrier of the compound. The results are presented 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 invention over a 48 hour incubation period in phosphate-buffered saline (PBS) / 10% fetal bovine serum (FBS) at 37° C. was analyzed by liquid chromatography-mass spectrometry (LC-MS), and the results are shown in FIG.

[0355] Compounds tested:

[0356] [Table 12]

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

[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 additionally diluted twice with water before analysis.

[0359] LC-MS Instrument Methods Compound 4, Compound 15, Compound 18, and Lenalidomide Kinetex XB-C18 2.6 μm, 50 × 2.1 mm column maintained at 40 °C. LC-MS grade mobile phase of 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 3 μm, 150×3 mm column maintained at 40° C. LC-MS grade mobile phase of water + 0.1% formic acid (A) and acetonitrile + 0.1% formic acid (B). Elution gradient (flow 0.5 mL / 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), Compound 1 (271 ± 4 nm).

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

[0363] The effect of bifunctional compounds of the invention on BRD4 degradation in H929 cell lines 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 (1x10^6 cells / condition) and compounds to be tested were added at the desired concentration range. Final DMSO concentration was 0.25%. After 6 hours of incubation (37°C, 5% CO2), cells were harvested and washed. Cell lysates were then prepared using RIPA lysis buffer. Protein amounts were determined via BCA assay and appropriate aliquots were then loaded into pre-filled microplates. Analysis was performed using SIMPLE WESTERN™ technology (from Protein Simple), an automated capillary-based immunoassay. Software dedicated to Simple Western analysis was used to count values ​​for further protein level evaluation process. Protein normalization was based on Protein Normalization Reagent from Protein Simple. Values ​​are expressed as % of DMSO control using the following labels: ≤25% if BRD4 protein reduction is 0–25%; >25% if BRD4 protein reduction was 26–74%; ≥75% for 75–100% reduction in BRD4 protein.

[0365] The bifunctional compounds of the present invention induce the degradation of the BRD4 protein.

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

[0367] [Table 13] JPEG2024501537000089.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 following numbering clauses: Clause 1. A compound of formula (I):

[0371] [ka]

[0372] During the ceremony: 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, 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. A compound according to clause 1, having the structure:

[0374] [ka]

[0375] Clause 3. The compound of clause 1, having the 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 of clause 4, wherein W1 is N and W2, W3 and W4 are CR'.

[0379] Clause 6. The compound of clause 4, wherein W2 is N and W1, W3 and W4 are CR'.

[0380] Clause 7. The compound of clause 4, wherein W3 is N and W1, W2 and W4 are CR'.

[0381] Clause 8. The compound of clause 4, wherein W4 is N and W1, W2 and W3 are CR'.

[0382] Clause 9. The compound according to any one of clauses 1 to 3, wherein W1, W2, W3 and W4 are each CR'.

[0383] Clause 10. The compound of clause 9, wherein W2, W3 and W4 are each CH.

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

[0385] Clause 12. A compound according to any one of clauses 1 to 3, wherein 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. A compound according to any one of clauses 1 to 3, wherein three of W1, W2, W3 and W4 are N, and the remaining one of W1, W2, W3 and W4 is CR'.

[0387] Clause 14. The 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. A compound according to any one of clauses 1 to 3, wherein the compound is:

[0389] [ka]

[0390] Clause 16. A compound according to any one of clauses 1 to 3, wherein the compound is:

[0391] [ka]

[0392] Clause 17. A compound according to clause 16, wherein the compound is:

[0393] [ka]

[0394] Clause 18. A compound of formula (IIa), (IIb), or (IIc):

[0395] [ka]

[0396] During the ceremony: 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'; 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] Clause 19. A compound according to clause 18, having the structure:

[0398] [ka]

[0399] Clause 20. A compound according to clause 18, having the structure:

[0400] [ka]

[0401] Clause 21. The compound according to any one of clauses 18 to 20, wherein W1 is N.

[0402] Clause 22. The compound according to any one of clauses 18 to 21, wherein W2 is N.

[0403] Clause 23. The compound according to any one of clauses 18 to 22, wherein W3 is N.

[0404] Clause 24. A compound according to any one of clauses 18 to 23, wherein one of W1, W2 and W3 is N, and the other W1, W2 and W3 are CR'.

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

[0406] Clause 26: The compound according to any one of clauses 18 to 25, wherein W1, W2 and W3 are each CR'.

[0407] Clause 27. The compound of any one of clauses 18 to 25, wherein W1 is C-NH2, C-NHR'' or C-NR''2; optionally, C-NH2.

[0408] Clause 28: The compound according to any one of clauses 18 to 23, wherein W1, W2 and W3 are each N.

[0409] Clause 29. The compound according to any one of clauses 18 to 28, wherein Z is O.

[0410] Clause 30. The compound according to any one of clauses 18 to 28, wherein Z is S.

[0411] Clause 31. The compound according to any one of clauses 18 to 28, wherein Z is NH.

[0412] Clause 32. A compound according to any preceding clause, wherein Q1 is N and Q2 is CR.

[0413] Clause 33. A compound according to any one of clauses 1 to 31, wherein Q1 is CR and Q2 is N.

[0414] Clause 34. A compound according to any one of clauses 1 to 31, wherein 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, 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, wherein each R' is independently hydrogen, -NH2, -NHR'' or -NR''2; optionally, hydrogen or -NH2.

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

[0418] [ka]

[0419] During the ceremony, 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'', -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] Clause 38. A compound according to clause 37, having the following structure:

[0421] [ka]

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

[0423] [ka]

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

[0425] Clause 41. A compound according to any one of clauses 1 to 39, wherein X1 is O and X2 is S.

[0426] Clause 42. A compound according to any one of clauses 1 to 39, wherein X1 is S and X2 is O.

[0427] Clause 43. The compound according to any one of clauses 1 to 39, wherein X1 and X2 are S.

[0428] Clause 44. A compound according to any preceding clause, wherein n is 0.

[0429] Clause 45. A compound according to any one of clauses 1 to 43, wherein n is 1 or 2.

[0430] Clause 46: A compound according to any one of clauses 1 to 43, wherein n is 1.

[0431] Clause 47. A compound according to any one of clauses 1 to 43, wherein n is 2.

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

[0433] [ka]

[0434] During the ceremony, Each of X1 and X2 is independently 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] Clause 49. A compound according to clause 48, having the following structure:

[0436] [ka]

[0437] Article 50. A compound according to Article 48, having the following structure:

[0438] [ka]

[0439] Clause 51. The compound according to any one of clauses 48 to 50, wherein X1 and X2 are O.

[0440] Clause 52. A compound according to any one of clauses 48 to 50, wherein X1 is O and X2 is S.

[0441] Clause 53. The compound according to any one of clauses 48 to 50, wherein X1 is S and X2 is O.

[0442] Clause 54. The compound according to any one of clauses 48 to 50, wherein X1 and X2 are S.

[0443] Clause 55. The compound according to any one of clauses 48 to 54, wherein 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] Clause 56. The compound according to clause 55, wherein Q1 is N.

[0445] Clause 57. The compound according to clause 55, wherein Q2 is N.

[0446] Clause 58. The compound according to clause 55, wherein Q3 is N.

[0447] Clause 59. The compound according to any one of clauses 48 to 54, wherein 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] Clause 60. The compound of clause 59, wherein Q1 and Q2 are N, and Q3, Q4 and Q5 are each CR.

[0449] Clause 61. The compound of clause 59, wherein Q2 and Q3 are N, and Q1, Q4 and Q5 are each CR.

[0450] Clause 62. The compound of clause 59, wherein Q1 and Q3 are N, and Q2, Q4 and Q5 are each CR.

[0451] Clause 63. The compound of clause 59, wherein Q2 and Q4 are N, and Q1, Q3 and Q5 are each CR.

[0452] Clause 64. The compound of clause 59, wherein Q1 and Q4 are N, and Q2, Q3 and Q5 are each CR.

[0453] Clause 65. The compound according to any one of clauses 48 to 54, wherein 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. The compound of any one of clauses 48 to 65, wherein 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 further optionally, each R is hydrogen.

[0455] Clause 67. The compound of any one of clauses 18 to 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] Clause 68. The compound of clause 67, wherein L is hydrogen.

[0457] Clause 69. A compound according to any one of the preceding clauses for use as a cereblon binding agent.

[0458] Clause 70. A pharmaceutical composition comprising a compound according to any one of clauses 1 to 68.

[0459] Clause 71. A compound according to any one of clauses 1 to 68 or a composition according to clause 70 for use in the field of medicine.

[0460] Clause 72. A compound according to any one of clauses 1 to 68 or a composition according to clause 70 for use in immuno-oncology.

[0461] Clause 73. A compound according to any one of clauses 1 to 68 or a composition according to clause 70 for use in the treatment of cancer, an autoimmune disease, macular degeneration (MD) and related disorders, diseases and disorders involving unwanted angiogenesis, skin diseases, lung disorders, asbestos-related disorders, parasitic diseases and disorders, immunodeficiency disorders, atherosclerosis and related conditions, hemoglobinopathies and related disorders, or TNFα-related disorders.

[0462] Clause 74. A method for the treatment of cancer, autoimmune diseases, macular degeneration (MD) and related disorders, diseases and disorders involving unwanted angiogenesis, skin diseases, lung disorders, asbestos-related disorders, parasitic diseases and disorders, immunodeficiency disorders, atherosclerosis and related conditions, hemoglobinopathies and related disorders, or TNFα-related disorders; The method comprises the step of administering to a patient in need thereof an effective amount of a compound according to any one of clauses 1-68 or a composition according to clause 70.

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

[0464] Article 76. A combination of a compound according to any one of articles 1 to 68 and at least one additional active agent for simultaneous, separate or sequential use in therapy.

[0465] Clause 77. The combination of clause 76 or the method of clause 75, wherein at least one additional active agent is an anti-cancer agent or an agent for treating an autoimmune disease.

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

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

[0468] Article 80. A combination of any one of articles 76 to 79, wherein the treatment is for the treatment of cancer, an autoimmune disease, macular degeneration (MD) and related disorders, diseases and disorders involving undesired angiogenesis, skin diseases, lung disorders, asbestos-related disorders, parasitic diseases and disorders, immunodeficiency disorders, atherosclerosis and related conditions, hemoglobinopathies and related disorders, or TNFα-related disorders.

Claims

1. Compounds of formula (I): 【Chemistry 1】 or a pharma- ceutically acceptable salt, ester, optically active isomer, racemate, solvate, amino acid conjugate, or prodrug thereof. [In the formula, X １ and X ２ each is independently O or S; Q １ and Q. ２ Each of is independently N or CR; １ and Q. ２ at least one of is N; W １ , W ２ , W ３ and W ４ each 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)NH ２ , -C(O)NHR'', -C(O)NR'' ２ , -OR'', -NR'' ２ or -S(O) ２ R″; Each R is independently hydrogen, halogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, benzyl, haloalkyl, haloalkenyl, -NH ２ , -NHR'', -NR'' ２ , -NR''C(O)R'', -NR''C(O)OR'', -NO ２ , -CN, -C(O)R'', -C(O)OR'', -C(O)NH ２ , -C(O)NHR'', -C(O)NR'' ２ , -OR'', -OC(O)R'', -OC(O)OR'', -OC(O)NH ２ , -OC(O)NHR'', -OC(O)NR'' ２ , -SR'', -S(O) ２ R″, —S(O) ２ OR'', -S(O) ２ N.H. ２ , -S(O) ２ NHR″, or —S(O) ２ N.R. ２ and Each R' is independently hydrogen, halogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, benzyl, haloalkyl, haloalkenyl, -NH ２ , -NHR'', -NR'' ２ , -NR''C(O)R'', -NR''C(O)OR'', -NO ２ , -CN, -C(O)R'', -C(O)OR'', -C(O)NH ２ , -C(O)NHR'', -C(O)NR'' ２ , -C(O)NHCHHR'' ２ , -CHR''NHC(O)NHR'', -CHR''NHC(O)C(halogen) ２ R'', -OR'', -OC(O)R'', -OC(O)OR'', -OC(O)NH ２ , -OC(O)NHR'', -OC(O)NR'' ２ , -SR'', -S(O) ２ R″, —S(O) ２ OR'', -S(O) ２ N.H. ２ , -S(O) ２ NHR″, -S(O) ２ N.R. ２ or -NHS(O) ２ R″, Each R'' is independently hydrogen, alkyl, cycloalkyl, alkenyl, aryl, heteroaryl, or benzyl.

2. structure: 【Chemistry 2】 or 【Chemistry 3】 2. The compound of claim 1 having the formula:

3. The compound of claim 1 or 2, wherein each R' is independently hydrogen, halogen, -NH 2 , -NO 2 , -C(O)NHCHR'' 2 , -CHR''NHC(O)NHR'', -CHR''NHC(O)C(halogen) 2 R'' or -NHS(O) 2 R''.

4. The compound of any one of claims 1 to 3, wherein each R'' is independently hydrogen, alkyl, cycloalkyl, or aryl, optionally wherein the aryl is substituted with one or more groups selected from halogen, alkyl, and O-haloalkyl, and optionally wherein the halogen is Cl, the alkyl is methyl, and the O-haloalkyl is O-CF3.

5. One of W 1 , W 2 , W 3 and W 4 is N, and the remaining three of W 1 , W 2 , W 3 and W 4 are each CR'; Optionally, (a) W 1 is N, and W 2 , W 3 and W 4 are CR′; (b) W 2 is N and W 1 , W 3 and W 4 are CR′; (c) W 3 is N and W 1 , W 2 and W 4 are CR′; or (d) W 4 is N, and W 1 , W 2 and W 3 are CR′; The compound according to any one of claims 1 to 4.

6. The compound of claim 1, wherein W 1 , W 2 , W 3 and W 4 are each CR'; and optionally, W 1 , W 2 , W 3 and W 4 are each CH.

7. Three of W 1 , W 2 , W 3 and W 4 are CH, and one of W 1 , W 2 , W 3 and W 4 is C-halogen, C-alkyl, C-alkenyl, C-alkynyl, C-aryl, C-heteroaryl, C-benzyl, C-haloalkyl, C-haloalkenyl, C-NH 2 , C-NHR'', C-NR'' 2 , C-NR''C(O)R'', C-NR''C(O)OR'', C-NO 2 , C-CN, C-C(O)R'', C-C(O)OR'', C-C(O)NH 2 , C-C(O)NHR'', C-C(O)NR'' 2 , C-C(O)NHCHR'' 2 , C-CHR″NHC(O)NHR″, C-CHR″NHC(O)C(halogen) 2 R″, C-OR″, C-OC(O)R″, C-OC(O)OR″, C-OC(O)NH 2 , C-OC(O)NHR″, C-OC(O)NR″ 2 , C-SR″, C-S(O) 2 R″, C-S(O) 2 OR″, C-S(O) 2 NH 2 , C-S(O) 2 NHR″, C-S(O) 2 NR″ 2 , or C-NHS(O) 2 R″; optionally one of W 1 , W 2 , W 3 and W 4 is C-halogen, C—NH 2 , C—NO 2 , C—NHR″, C—NR″ 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″; Further optionally, one of W 1 , W 2 , W 3 and W 4 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″; Further optionally, one of W 1 , W 2 , W 3 and W 4 is C-halogen, C—NH 2 , C—NO 2 , C—C(O)NHCHR″ 2 , C—CH 2 NHC(O)NHR″, C—CH 2 NHC(O)CF 2 R″ or C—NHS(O) 2 R″; The compound according to any one of claims 1 to 4.

8. (a) W 2 , W 3 and W 4 are each CH; optionally, W 1 is C-halogen, C-NH 2 , C-NO 2 or C-NHS(O) 2 R″; further optionally, W 1 is C-NH 2 or C-NHS(O) 2 R″; or (b) W 1 , W 2 and W 3 are each CH; optionally, W 4 is C-halogen, C-NH 2 , C-NO 2 or C-NHS(O) 2 R″; further optionally, W 4 is C-NH 2 ; or (c) W 1 , W 2 and W 4 are each CH; optionally, W 2 is C—NH 2 , C—NO 2 or C—NHS(O) 2 R″; further optionally, W 2 is C—NH 2 or C—NHS(O) 2 R″; or (d) W 1 , W 3 and W 4 are each CH; optionally W 3 is C—NH 2 , C—NO 2 , C—C(O)NHCHR″ 2 , C—CH 2 NHC(O)NHR″, C—CH 2 NHC(O)CF 2 R″ or C—NHS(O) 2 R″; further optionally W 3 is C—NH 2 , C—C(O)NHCHR″ 2 , C—CH 2 NHC(O)NHR″, C—CH 2 NHC(O)CF 2 R″ or C—NHS(O) 2 R″; further optionally W 3 is C—NH 2 , C—CH 2 NHC(O)NHR″, C—CH 2 NHC(O)CF 2R″ or C—NHS(O) 2R″; The compound according to claim 7.

9. (a) Q 1 is N and Q 2 is CR; (b) Q 1 is N and Q 2 is N; or (c) Q 1 is CR and Q 2 is N; optionally, Q 1 is C—H or C-alkyl; further optionally, Q 1 is C—H; or Q 1 is C-methyl; The compound according to any one of claims 1 to 8.

10. The compound according to claim 1, wherein two of W 1 , W 2 , W 3 and W 4 are N, and the remaining two of W 1 , W 2 , W 3 and W 4 are each CR'.

11. A compound according to any one of claims 1 to 4, wherein three of W 1 , W 2 , W 3 and W 4 are N, and the remaining one of W 1 , W 2 , W 3 and W 4 is CR'.

12. The compound of any one of claims 1 to 11, wherein L is hydrogen, alkyl, alkenyl, aryl, heteroaryl, benzyl, haloalkyl, haloalkenyl, -OR'', -NR'' 2 , or -S(O) 2 R''; optionally, L is hydrogen, alkyl, alkenyl, aryl, heteroaryl, or benzyl; further optionally, L is hydrogen.

13. 【Chemical 4】 or 【Chemistry 5】 The compound according to any one of claims 1 to 12,

14. 【Table 1】 14. The compound of any one of claims 1 to 13, optionally selected from compounds 1, 2, 3, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20 and 21; and further optionally selected from compounds 8, 10, 11, 14, 15, 16, 17, 18 and 19.

15. 【Chemical 6】 15. The compound of claim 14, wherein

16. A compound of formula (IIa), (IIb), or (IIc): 【Chemistry 7】 [In the formula, Each of X 1 and X 2 is independently O or S; Each of Q 1 and Q 2 is independently N or CR, and at least one of Q 1 and Q 2 is N; Each of W 1 , W 2 and W 3 is independently N or CR a ; Z is O, S, or NR b ; n is 0, 1 or 2; L is hydrogen, alkyl, alkenyl, aryl, heteroaryl, benzyl, haloalkyl, haloalkenyl, -C(O)Rb, -C(O)ORb, -C(O)NH2, -C(O)NHRb, -C(O)NRb2, -ORb, -NRb2, or -S(O)2Rb; Each R is independently hydrogen, halogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, benzyl, haloalkyl, haloalkenyl, -NH 2 , -NHR b , -NR b 2 , -NR b C(O)R b , -NR b C(O)OR b , -NO 2 , -CN, -C(O)R b , -C(O)OR b , -C(O)NH 2 , -C(O)NHR b , -C(O)NR b 2 , -OR b , -OC(O)R b , -OC(O)OR b , -OC(O)NH 2 , -OC(O)NHR b , -OC(O)NR b 2 , -SR b , -S(O) 2 R b , —S(O) 2 OR b , —S(O) 2 NH 2 , —S(O) 2 NHR b , or —S(O) 2 NR b 2 ; each R a is independently hydrogen, halogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, benzyl, haloalkyl, haloalkenyl, —NH 2 , —NHR b , —NR b 2 , —NR b C(O)R b , —NR b C(O)OR b , —NO 2 , —CN, —C(O)R b , —C(O)OR b , —C(O)NH 2 , —C(O)NHR b , —C(O)NR b 2 , —OR b , —OC(O)R b , -OC(O)OR b , -OC(O)NH 2 , -OC(O)NHR b , -OC(O)NR b 2 , -SR b , -S(O) 2 R b , -S(O) 2 OR b , -S(O) 2 NH 2 , -S(O) 2 NHR b , or -S(O) 2 NR b 2 ; Each R b is independently hydrogen, alkyl, alkenyl, aryl, heteroaryl, or benzyl.

17. Structure: 【Chemistry 8】 or structure: 【Chemistry 9】 17. The compound of claim 16 having the formula:

18. The compound according to claim 16 or 17, wherein W 1 is N.

19. The compound according to claim 16, wherein W 2 is N.

20. The compound according to claim 16, wherein W 3 is N.

21. A compound described in any of claims 16 to 20, wherein one of W 1, W 2 and W 3 is N and the other W 1, W 2 and W 3 are CR a ; and optionally, one of W 1, W 2 and W 3 is N and the other W 1, W 2 and W 3 are CH.

22. The compound of claim 16 or 17, wherein W 1 , W 2 and W 3 are each CR a .

23. The compound according to any one of claims 16 to 17 and 19 to 22, wherein W 1 is C-NH 2 , C-NHR b or C-NR b 2 ; optionally, C-NH 2 .

24. The compound according to any one of claims 16 to 20, wherein W 1 , W 2 and W 3 are each N.

25. A compound according to claim 25, wherein (a) is of formula (IIc): (b) of formula (IIb); or (c) of formula (IIa), The compound according to any one of claims 16 to 24.

26. The compound according to claim 16, wherein Z is O or S.

27. The compound of any one of claims 16 to 25, wherein Z is NH or N-alkyl, and optionally, Z is N-Me. (a) Q 1 is N and Q 2 is CR; (b) Q 1 is N and Q 2 is N; or (c) Q 1 is CR and Q 2 is N; optionally, Q 1 is C-H or C-alkyl; further optionally, Q 1 is C-methyl or C-H; The compound according to any one of claims 16 to 27.

29. 【Table 2】 17. The compound of claim 16, which is optionally compound 4.

30. The compound of any of claims 16-29, wherein each R 3 is independently hydrogen, -NH 2 , -NHR b , or -NR b 2 ; optionally, hydrogen or -NH 2 .

31. The compound of any one of claims 1 to 30, wherein each R is independently hydrogen or alkyl; optionally, hydrogen or C 1 -C 4 alkyl; further optionally, said C 1 -C 4 alkyl is methyl or ethyl; further optionally, each R is independently hydrogen or methyl.

32. A compound of formula (III): 【Chemistry 10】 [In the formula, Each of X 1 and X 2 is independently O or S; n is 0, 1 or 2; L is hydrogen, alkyl, alkenyl, aryl, heteroaryl, benzyl, haloalkyl, haloalkenyl, -C(O)Rb, -C(O)ORb, -C(O)NH2, -C(O)NHRb, -C(O)NRb2, -ORb, -NRb2, or -S(O)2Rb; Each of R 1 , R 2 and R 3 is independently hydrogen, halogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, benzyl, haloalkyl, haloalkenyl, -NH 2 , -NHR b , -NR b 2 , -NR b C(O)R b , -NR b C(O)OR b , -NO 2 , -CN, -C(O)R b , -C(O)OR b , -C(O)NH 2 , -C(O)NHR b , -C(O)NR b 2 , -OR b , -OC(O)R b , -OC(O)OR b , -OC(O)NH 2 , -OC(O)NHR b , -OC(O)NR b 2 . , -SR b , S(O) 2 R b , -S(O) 2 OR b , -S(O) 2 NH 2 , -S(O) 2 NHR b , or -S(O) 2 NR b 2 ; Each R b is independently hydrogen, alkyl, alkenyl, aryl, heteroaryl, or benzyl.

33. Structure: 【Chemistry 11】 or 【Chemistry 12】 33. The compound of claim 32, having the formula:

34. (a) n is 0; (b) n is 1; or (c) n is 2; A compound according to any one of claims 1 to 33.

35. A compound of formula (IV): 【Chemistry 13】 [In the formula, Each of X 1 and X 2 is independently O or S; L is hydrogen, alkyl, alkenyl, aryl, heteroaryl, benzyl, haloalkyl, haloalkenyl, -C(O)Rb, -C(O)ORb, -C(O)NH2, -C(O)NHRb, -C(O)NRb2, -ORb, -NRb2, or -S(O)2Rb; Each of Q 1 , Q 2 , Q 3 , Q 4 and Q 5 is independently N or CR, and at least one of Q 1 , Q 2 , Q 3 , Q 4 and Q 5 is N; Each R is independently hydrogen, halogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, benzyl, haloalkyl, haloalkenyl, -NH 2 , -NHR b , -NR b 2 , -NR b C(O)R b , -NR b C(O)OR b , -NO 2 , -CN, -C(O)R b , -C(O)OR b , -C(O)NH 2 , -C(O)NHR b , -C(O)NR b 2 , -OR b , -OC(O)R b , -OC(O)OR b , -OC(O)NH 2 , -OC(O)NHR b , -OC(O)NR b 2 , -SR b , -S(O) 2 R b , —S(O) 2 OR b , —S(O) 2 NH 2 , —S(O) 2 NHR b , or —S(O) 2 NR b 2 ; each R b is independently hydrogen, alkyl, alkenyl, aryl, heteroaryl, or benzyl.

36. Structure: 【Chemistry 14】 or 【Chemistry 15】 36. The compound of claim 35 having the formula:

37. One of Q1, Q2, Q3, Q4, and Q5 is N, and the remaining four of Q1, Q2, Q3, Q4, and Q5 are each CR; Optionally, (a) Q 1 is N; (b) Q 2 is N; or (c) Q 3 is N; 37. A compound according to claim 35 or 36.

38. Two of Q1, Q2, Q3, Q4, and Q5 are N, and the remaining three of Q1, Q2, Q3, Q4, and Q5 are each CR; Optionally, (a) Q 1 and Q 2 are N, and Q 3 , Q 4 and Q 5 are each CR; (b) Q 2 and Q 3 are N and Q 1 , Q 4 and Q 5 are each CR; (c) Q 1 and Q 3 are N and Q 2 , Q 4 and Q 5 are each CR; (d) Q 2 and Q 4 are N and Q 1 , Q 3 and Q 5 are each CR; or (e) Q 1 and Q 4 are N, and Q 2 , Q 3 and Q 5 are each CR; 37. A compound according to claim 35 or 36.

39. The compound of claim 35 or 36, wherein three of Q 1 , Q 2 , Q 3 , Q 4 and Q 5 are N, and the remaining two of Q 1 , Q 2 , Q 3 , Q 4 and Q 5 are each CR.

40. Each R is independently hydrogen, halogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, benzyl, haloalkyl, haloalkenyl, -NH2, -NHRb, -NRb2, -NRbC(O)Rb, -NRbC(O)ORb, -NO2, -CN, -C(O)Rb, -C(O)ORb, -C(O)NH2, -C(O)NHRb, -C(O)NRb2, -ORb, -OC(O)Rb, -OC(O)ORb, -OC(O)NH2, -OC(O)NHRb, -OC(O)NRb2, -SRb, S(O) 2 R b ; optionally, each R is hydrogen or alkyl, and further optionally, each R is hydrogen.

41. The compound of any of claims 16-40, wherein L is hydrogen, an alkyl, an alkenyl, an aryl, a heteroaryl, a benzyl, a haloalkyl, a haloalkenyl, -OR b , -NR b 2 , or -S(O) 2 R b ; optionally, L is hydrogen, an alkyl, an alkenyl, an aryl, a heteroaryl, or a benzyl; and optionally, L is hydrogen. (a) X 1 and X 2 are O; (b) X 1 is O and X 2 is S; (c) X 1 is S and X 2 is O; or (d) X 1 and X 2 are S; 42. The compound according to any one of claims 1 to 41.

43. A compound described in any one of claims 1 to 42 for use as a cereblon binding agent.

44. A pharmaceutical composition comprising a compound according to any one of claims 1 to 43.

45. A compound according to any one of claims 1 to 43, or a composition according to claim 44, for use in medicine, optionally for use in immuno-oncology.

46. A compound according to any one of claims 1 to 43, or a composition according to claim 44, for use in the treatment of cancer, an autoimmune disease, macular degeneration (MD) and related disorders, diseases and disorders associated with unwanted angiogenesis, skin diseases, pulmonary disorders, asbestos-related disorders, parasitic diseases and disorders, immunodeficiency disorders, atherosclerosis and related conditions, or hemoglobinopathies and related disorders.

47. A combination of a compound according to any one of claims 1 to 43 and at least one additional active agent for simultaneous, separate or sequential use in therapy, optionally wherein the treatment is treatment of cancer, an autoimmune disease, macular degeneration (MD) and related disorders, diseases and disorders associated with unwanted angiogenesis, skin diseases, pulmonary disorders, asbestos-related disorders, parasitic diseases and disorders, immunodeficiency disorders, atherosclerosis and related conditions, or hemoglobinopathies and related disorders.

48. The combination of claim 47, wherein at least one additional active agent is an anti-cancer 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.

49. Structure: CLM-[Link]-PTM or a pharma- ceutically acceptable salt, enantiomer, stereoisomer, solvate, polymorph, or prodrug thereof, having the formula: CLM is cereblon E3 ubiquitin ligase binding moiety; PTM is a protein targeting moiety, optionally a BRD4 targeting moiety; [Link] is selected from a bond and a chemical linking moiety that covalently links the CLM and the PTM; The CLM is a compound according to any one of claims 1 to 102, wherein at least one of R, R', R a , R b , R 1 , R 2 and R 3 contains or is modified to contain a [Link] or a group capable of covalently bonding to the PTM, optionally a carboxylic acid or ester group; Optionally, [Link] 【Chemistry 16】 is selected from 【Chemistry 17】 indicates binding to the PTM, 【Chemistry 18】 indicates binding to the CLM, p is an integer from 3 to 12, 4 to 11, 5 to 10, 6 to 9, or 7 to 8; The bifunctional compound, wherein s is an integer of 1 to 6.

50. PTM 【Chemistry 19】 and 【Chemistry 20】 indicates a bond to [Link], Optionally, the compound 【Chemistry 21】 50. The bifunctional compound of claim 49, selected from:

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