Piperidine-2,6-dione derivatives that bind to cereblon and methods of use thereof

Abstract

The present invention provides novel compounds that bind to cereblon and methods of using the same, which are represented by the following formulas (Ia), (Ib), (IIa), and (IIb): [Formula 1] JPEG2023504143000208.jpg162146JPEG2023504143000209.jpg55146

Description

[Technical Field]

[0001] The present invention relates to a method for the detection of cereblon-binding proteins, which bind to the CUL4-DDB1-RBX1-CRBN ubiquitin ligase complex (CRL4) CRBN Cereblon is a novel compound that modulates the substrate specificity of CRL4. CRBN Chemical modulation of cereblon can induce the assembly of novel substrate proteins, followed by their ubiquitination and degradation. [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). These proteins together form a ubiquitin ligase complex, which belongs to the Cullin RING ligase (CRL) protein family. 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 regulates 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 adverse side effects. This has resulted in the creation of 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 in a number of malignant hematological diseases such as multiple myeloma, myelodysplastic syndrome lymphoma, and leukemia has been demonstrated (see Le Roy A et al.: Immunomodulatory Drugs Exert Anti-leukemia Effects in Acute Myeloid Leukemia by Direct and Immunostimulatory Activities. Front Immunol. 2018; 9: 977).

[0005] The antitumor activity of cereblon modulators 1) Inhibition of cancer cell proliferation and induction of apoptosis, 2) disruption 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)) and achieve a desirable safety profile. Thus, there is a continuing need to provide novel cereblon-binding compounds with pharmaceutically important properties.

[0007] Chemically modified thalidomide derivatives, such as pomalidomide and lenalidomide, induce the degradation of various neosubstrates, such as IKZF1, IKZF3, and / or CK1α. Degradation of IKZF1 and IKZF3 may be beneficial in the treatment of certain cancer types (e.g., multiple myeloma), but may also contribute to the dose-limiting toxicity of these compounds. Side effects resulting from lenalidomide activity include neutropenia, thrombocytopenia, and bleeding disorders (see Sun X et al. PROTACs: great opportunities for academia and industry. Signal Transduct Target Ther. 2019 Dec 24;4:64 and Stahl M, Zeidan AM: Lenalidomide Use in Myelodysplastic Syndromes: Insights Into the Biologic Mechanisms and Clinical Applications. Cancer. 2017 May 15;123(10):1703-1713). On the other hand, CK1α degradation contributes to the therapeutic effect of lenalidomide in myelodysplastic syndromes (Kronke J et al.: Lenalidomide induces ubiquitination and degradation of CK1α in del(5q) MDS. Nature. 2015 July 9; 523(7559): 183-188. doi:10.1038 / nature14610). Therefore, new chemically modified thalidomide derivatives capable of degrading CK1α and with more selective profiles may be particularly useful for cancer treatment. [Prior art documents] [Patent documents]

[0008] [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] International Publication No. 2017197051 Brochure [Patent Document 6] U.S. Patent No. 8,518,972 [Patent Document 7] European Patent No. 2057143 [Patent Document 8] International Publication No. 2019014100 Brochure [Patent Document 9] International Publication No. 2004103274 Brochure [Non-patent literature]

[0009] [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) [Non-Patent Document 5] Sun X et al. PROTACs: great opportunities for academia and industry. Signal Transduct Target Ther. 2019 Dec 24;4:64 [Non-patent document 6] Stahl M, Zeidan AM: Lenalidomide Use in Myelodysplastic Syndromes: Insights Into the Biologic Mechanisms and Clinical Applications. Cancer. 2017 May 15;123(10):1703-1713 [Non-Patent Document 7] Kronke J et al.: Lenalidomide induces ubiquitination and degradation of CK1α in del(5q) MDS. Nature. 2015 July 9; 523(7559): 183-188. doi:10.1038 / nature14610 Summary of the Invention [Means for solving the problem]

[0010] According to a first aspect of the present invention, there is provided a compound of formula (Ia) or (Ib):

[0011] [ka]

[0012] or a pharmaceutically acceptable salt or tautomer thereof, During the ceremony, Each of X1 and X2 is independently O or S; Z is O, S or NR 2 and; T is C=O or SO; Each of Y1, Y2, Y3, and Y4 is independently N or CR; At least one of Y1, Y2 and Y3 in formula (Ia) is CR, and at least one of Y1, Y2 and Y4 in formula (Ib) is CR; n is 0, 1 or 2; L is hydrogen, alkyl, alkenyl, aryl, heteroaryl, benzyl, haloalkyl, haloalkenyl, —C(O)R″, —CHC(O)OR″, —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, cycloalkyl, heterocycloalkyl, alkenyl, cycloalkenyl, alkynyl, aryl, heteroaryl, benzyl, haloalkyl, haloalkenyl, -NH2, -NHR'', -NR''2, -CH2NR''2, -NR''C(O)R'', -NR''C(O)CH2NR''2, -NR''C(O)CH2-heterocycloalkyl, -NR''C(O)CH(OH)R'', -CH2NR''C(O)OR'', -NR'' C(O)OR'', -NR''S02R'', -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, -NHC(S)NHR'', SR'', or -S(O)2R'', -S(O)2OR'', -S(O)2NH2, -S(O)2NHR'', or -S(O)2NR''2; each R″ is independently hydrogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, aryl, heteroaryl, or benzyl; R 2is hydrogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, aryl, heteroaryl, benzyl, haloalkyl, haloalkenyl, -NH2, -NHR'', -NR''2, -NR''C(O)R'', -N[C(O)R'']2, -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'', or -S(O)2R'', -S(O)2OR'', -S(O)2NH2, -S(O)2NHR'', or -S(O)2NR''2; R 1 is hydrogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, aryl, heteroaryl, or benzyl; When Z is O, Y2 is CR'; When the compound is of formula (Ia): (i) when each of Y1, Y2, and Y3 is CR, at least one of R is not H; (ii) Z is NR 2 then Y2 and Y3 are CR; (iii) if Z is S, then Y1 is not C-OMe and Y2 is not C-OMe; (iv) when Z is S and Y1 is C-NHCOMe, Y3 is not C-CH2NR''C(O)OR''; (v) when Z is S and Y1 is N, then Y2 is not CH, C-aryl or CC(O)OR''; (vi) When Z is S and Y2 is N, Y3 is C—NH2, C—NHR″, C—NR″2, C—NR″C(O)OR″, C—CH2NR″C(O)OR″, C-haloalkyl, C— t butyl, C—OR″, C—COOR″ or C—SR″; when Y3 is C—NH2, C—NHR″ or C—NR″2, Y1 is CH; When the compound is of formula (Ib): (vii) when each of Y1, Y2, and Y4 is CR, at least one of R is not H; (viii) when Z is S, Y1 is not C—COOH or C—NHC(O)Me and Y4 is not C—Br; (ix) When Z is S and Y2 is C-Br, Y4 is C-OR″; (x) When Z is S, Y1 is N, and Y2 is CH or C—NH2, then Y4 is not CH; (xi) when Z is S and Y is N, then Y is not C-halogen, C-alkyl, C-cycloalkyl, C-aryl, C-heteroaryl, C-CHNH, C-COOalkyl, or C-NHC(O)alkyl; (xii) When Z is NR2, Y1, Y2 and Y4 are CR.

[0013] In certain embodiments, the compound has the structure:

[0014] [ka]

[0015] In other embodiments, the compound has the structure:

[0016] [ka]

[0017] In some embodiments, T is C=O. In other embodiments, T is SO2.

[0018] In some embodiments, each R is independently hydrogen, halogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, aryl, heteroaryl, benzyl, haloalkyl, haloalkenyl, —NH, —NHR, —NR, —NRC(O)R, —NRC(O)CH(OH)R, —NRC(O)OR, —NRSO, —NO, —C N, -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'', or -S(O)2R'', -S(O)2OR'', -S(O)2NH2, -S(O)2NHR'', or -S(O)2NR''2.

[0019] In some embodiments, Z is S or NR 2 In some embodiments, Z is NR 2 In other embodiments, Z is S.

[0020] In some embodiments, L is hydrogen, alkyl, alkenyl, haloalkyl, haloalkenyl, —C(O)R″, —CHC(O)OR″, —C(O)OR″, —C(O)NH, —C(O)NHR″, —C(O)NR″2, —OR″, —NR″2, or —S(O)R″. In some embodiments, L is hydrogen, alkyl, alkenyl, —CHC(O)OR″, —OR″, —NR″2, or —S(O)R″; L can be hydrogen, alkyl, or alkenyl. In some embodiments, L is hydrogen, alkyl, —CHC(O)OR″, or —OR″.

[0021] In some embodiments, L is hydrogen, alkyl, alkenyl, aryl, heteroaryl, benzyl, haloalkyl, haloalkenyl, -OR", -NR"2, or -S(O)R". In other embodiments, 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, L is hydrogen, alkyl, alkenyl, aryl, heteroaryl, benzyl, haloalkyl, haloalkenyl, -OR", -NR"2, or -S(O)R". In some embodiments, L is hydrogen, alkyl, alkenyl, aryl, heteroaryl, benzyl, haloalkyl, or haloalkenyl. In other embodiments, L is -OR", -NR"2, or -S(O)R". In some embodiments, L is hydrogen, alkyl, alkenyl, aryl, heteroaryl, or benzyl. In some embodiments, L is hydrogen, alkyl, alkenyl, or aryl. In some embodiments, L is hydrogen, alkyl, or alkenyl. In some embodiments, L is hydrogen or alkyl. In some embodiments, L is hydrogen.

[0022] In some embodiments, R 2 is hydrogen, alkyl, cycloalkyl, aryl, heteroaryl, benzyl, haloalkyl, haloalkenyl, —NR″2, —NR″C(O)R″, —N[C(O)R″]2, —NR″C(O)OR″, —C(O)R″, —C(O)OR″, —OR″, —OC(O)R″, —OC(O)OR″, —OC(O)NH2, —OC(O)NHR″, or —OC(O)NR″2. In some such embodiments, R 2 is alkyl, benzyl, or —N[C(O)R″]2.

[0023] In some embodiments, the compound is of Formula (Ia), and one of Y1, Y2, and Y3 is N, and the remaining two of Y1, Y2, and Y3 are each CR. In some such embodiments, Y1 is N, and Y2 and Y3 are CR. In other such embodiments, Y2 is N; Y1 and Y3 are CR; and Z is S. In other such embodiments, Y3 is N; Y1 and Y2 are CR; and Z is S.

[0024] In some embodiments, the compound is of Formula (Ia), wherein one of Y1, Y2, and Y3 is CR; the remaining two of Y1, Y2, and Y3 are each N; and Z is S. In some such embodiments, Y1 is CR; Y2 and Y3 are N. In other such embodiments, Y2 is CR; and Y1 and Y3 are N. In other such embodiments, Y3 is CR; and Y1 and Y2 are N.

[0025] In some embodiments, the compound is of Formula (Ia), and Y, Y, and Y are each CR. In some such embodiments, Y is —C—NHC(O)R″, Y is CH, and Y is CH or CCl. In some such embodiments, L is hydrogen; Z is S; and R 1 is H; T is C=O; Y1 is -C-NHC(O)R''; Y2 is CH; and Y3 is CH.

[0026] In some embodiments, the compound is of Formula (Ib), one of Y1, Y2, and Y4 is N, the remaining two of Y1, Y2, and Y4 are each CR, and Z is S. In some such embodiments, Y1 is N and Y2 and Y4 are CR. In other such embodiments, Y2 is N and Y1 and Y4 are CR. In other such embodiments, Y4 is N and Y1 and Y2 are CR.

[0027] In some embodiments, the compound is of Formula (Ib), one of Y1, Y2, and Y4 is CR, the remaining two of Y1, Y2, and Y4 are each N, and Z is S. In some such embodiments, Y1 is CR, and Y2 and Y4 are N. In other such embodiments, Y2 is CR, and Y1 and Y4 are N. In other such embodiments, Y4 is CR, and Y1 and Y2 are N.

[0028] In some embodiments, the compound is of Formula (Ib), and Y, Y, and Y are each CR. In some such embodiments, each R is independently hydrogen, halogen, alkyl, cycloalkyl, haloalkyl, heteroaryl, -OR", -N[C(O)R"], -NR"C(O)R", -NHC(O)OR", -NHR", -NH, or -NHSOR"CN. In some such embodiments, each R" is independently alkyl, cycloalkyl, aryl, or benzyl. In some such embodiments, L is hydrogen; Z is S; R 1 is H; T is C=O; Y1 is CH, C-OR'', CCl, C-CN, or C-NHC(O)R''; Y2 is CH, CCl, C-alkyl, C-cycloalkyl, or C-haloalkyl; Y4 is CH, C-OR'', C-NHC(O)R'', C-NHC(O)OR'', C-NHR'', C-NH2, or C-NHSO2R''; When Y1 is CCl, Y2 is CH, C-alkyl, C-cycloalkyl, or C-haloalkyl.

[0029] In some such embodiments, each R" is independently alkyl, cycloalkyl, aryl, or benzyl. In some such embodiments, Y1 is CH; Y2 is CH or CCl; and Y4 is C-OR" or C-NH2, and may be C-OMe or C-NH2.

[0030] In some embodiments of a compound of Formula (Ia) or Formula (Ib), each R is independently hydrogen, halogen, alkyl, cycloalkyl, haloalkyl, heteroaryl, —NR″C(O)R″, NR″C(O)OR″, —NR″C(O)CH(OH)R″, —NHR″, —NH, —OR″, —CN, —C(O)NR″2, or —NR″S0R″. In some such embodiments, each R is independently hydrogen, halogen, alkyl, cycloalkyl, haloalkyl, —OR″, —CN, —NHC(O)R″, —NHC(O)OR″, —NHR″, —NH, or —NHS0R″. In some embodiments, each R″ is independently alkyl, cycloalkyl, aryl, or benzyl.

[0031] In some embodiments of compounds of Formula (Ia) or (Ib), 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.

[0032] In some embodiments of a compound of Formula (Ia) or (Ib), n is 0. In other embodiments of a compound of Formula (Ia) or (Ib), n is 1 or 2. In some embodiments, n is 1. In other embodiments, n is 2.

[0033] In some embodiments, the compound is of Formula (Ia), wherein: X1 and X2 are O; T is C=O, n is 1, R 1 is hydrogen, L is hydrogen; Z is S, When Y1 and Y3 are CR, (a) Y2 is CH, Y3 is CH, and Y1 is C-NHC(O)R''; (b) Y1 is CH, Y3 is CH, and Y2 is C—OH or C—CH2NHC(O)OR″; or (c) Y1 is CH, Y2 is CH, and Y3 is C-CH2NHC(O)OR''; When Y2 is N, Y3 is C-NHC(O)OR'' or C-NH2.

[0034] In some embodiments, the compound has Formula (Ib), wherein: X1 and X2 are O; T is C=O, n is 1, R 1 is hydrogen, L is hydrogen; Z is S, Y2 and Y4 are CR; When Y1 is N, Y2 is CH, C-NH2 or C-CH2NHC(O)OR'' and Y4 is CH or C-OR'' and at least one of Y2 and Y4 is not CH; When Y1, Y2 and Y4 are each CR, Y1 is CH, C-alkyl, C-Cl or C-OR″; Y2 is CH, C-halogen, C-cycloalkyl, C-haloalkyl, C-aryl, C-CONH(R"), or C-CN; Y4 is CH, C-NH2, C-NHR'', C-NR''C(O)R'', C-NR''S02R'', or C-OR''; at least one of Y1, Y2 and Y4 is CH or C—Cl; (a) when Y1 and Y2 are CH, Y4 is C-NHCOR'', C-NHSO2R'', C-OR'', or C-NH2; (b) when Y4 is C-NHCOR'' and Y1 is C-Cl, then Y2 is C-cycloalkyl; (c) When Y1 and Y2 are CH and Y4 is C-OMe, the compound is Compound 20 or Compound 21.

[0035] According to a second aspect of the present invention, there is provided a compound of formula (IIa) or (IIb):

[0036] [ka]

[0037] or a pharmaceutically acceptable salt or tautomer thereof, During the ceremony, Each of X1 and X2 is independently O or S; Z is O, S or NR 2 and; T is C=O or SO; Y3 is N or CR; Y4 is N or CR;

[0038] [ka] indicates a single or double bond, and each

[0039] [ka] is a double bond, each of W1, W2, W3 and W4 is independently N or CR', at least one of W1, W2, W3 and W4 is N, and each of

[0040] [ka] is a single bond, W1, W2, W3 and W4 are each CR'2 and Y4 is 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, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, aryl, heteroaryl, benzyl, haloalkyl, haloalkenyl, -NH2, -NHR'', -NR''2, -NR''C(O)R'', -NR''C(O)CH2R'', -NR''C(O)CH(OH)R'', -NR''C(O)OR'', -NR''S02R'', -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'', or -S(O)2R'', -S(O)2OR'', -S(O)2NH2, -S(O)2NHR'', or -S(O)2NR''2; Each R' is independently hydrogen, halogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, aryl, heteroaryl, benzyl, haloalkyl, haloalkenyl, -NH2, -NHR'', -NR''2, -NR''C(O)R'', -NR''C(O)CH(OH)R'', -NR''C(O)OR'', -NR''S02R'', -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'', or -S(O)2R'', -S(O)2OR'', -S(O)2NH2, -S(O)2NHR'', or -S(O)2NR''2; each R″ is independently hydrogen, alkyl, cycloalkyl, heterocycloalkyl, alkenyl, cycloalkenyl, aryl, heteroaryl, or benzyl; R 2is hydrogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, aryl, heteroaryl, benzyl, haloalkyl, haloalkenyl, -NH2, -NHR'', -NR''2, -NR''C(O)R'', -N[C(O)R'']2, -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'', or -S(O)2R'', -S(O)2OR'', -S(O)2NH2, -S(O)2NHR'', or -S(O)2NR''2; R 1 is hydrogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, aryl, heteroaryl, or benzyl; Each

[0041] [ka] is a double bond and Z is NR 2 and R 2 is hydrogen and each R' is hydrogen, then W4 is CR'.

[0042] In some embodiments, the compound is of Formula (IIa).

[0043] In some embodiments, the compound is of Formula (IIb).

[0044] In some embodiments, the compound of Formula (IIa) or (IIb) has the structure:

[0045] [ka]

[0046] In other embodiments, the compound of Formula (IIa) or (IIb) has the structure:

[0047] [ka]

[0048] In some embodiments, each

[0049] [ka] is a double bond and Z is NR 2 and R 2 is hydrogen, Y3 and Y4 are CR, one of W1, W2, W3 and W4 is N, and the remaining three of W1, W2, W3 and W4 are each CR', then at least one R' is not hydrogen.

[0050] In some embodiments of compounds of Formula (IIa) or (IIb), Z is O. In other embodiments, Z is S. In other embodiments, Z is NR 2 is.

[0051] In some embodiments of the compound of Formula (IIa) or (IIb), T is C=O. In other embodiments, T is SO2.

[0052] In some embodiments, L is hydrogen, alkyl, alkenyl, aryl, heteroaryl, benzyl, haloalkyl, haloalkenyl, -C(O)R", -C(O)OR", -C(O)NH, -C(O)NHR, -C(O)NR, -NR, or -S(O)R; L may be hydrogen, alkyl, alkenyl, aryl, heteroaryl, benzyl, -NR, or -S(O)R.

[0053] In some embodiments of a compound of Formula (IIa) or (IIb), L is hydrogen, alkyl, alkenyl, aryl, heteroaryl, benzyl, haloalkyl, haloalkenyl, -OR", -NR"2, or -S(O)R". In other embodiments of a compound of Formula (IIa) or (IIb), 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 a compound of Formula (IIa) or (IIb), L is hydrogen, alkyl, alkenyl, aryl, heteroaryl, benzyl, haloalkyl, haloalkenyl, -OR", -NR"2, or -S(O)R". In some embodiments of a compound of Formula (IIa) or (IIb), L is hydrogen, alkyl, alkenyl, aryl, heteroaryl, benzyl, haloalkyl, or haloalkenyl. In other embodiments of a compound of Formula (IIa) or (IIb), L is -OR", -NR"2, or -S(O)2R". In some embodiments of a compound of Formula (IIa) or (IIb), L is hydrogen, alkyl, alkenyl, aryl, heteroaryl, or benzyl. In some embodiments of a compound of Formula (IIa) or (IIb), L is hydrogen, alkyl, alkenyl, or aryl. In some embodiments of a compound of Formula (IIa) or (IIb), L is hydrogen, alkyl, or alkenyl. In some embodiments of a compound of Formula (IIa) or (IIb), L is hydrogen or alkyl. In some embodiments of a compound of Formula (IIa) or (IIb), L is hydrogen.

[0054] In some embodiments of the compound of Formula (IIa), Y3 is N. In other embodiments, Y3 is CR.

[0055] In some embodiments of the compound of Formula (IIb), Y4 is N. In other embodiments, Y4 is CR.

[0056] In some embodiments,

[0057] [ka] represents a single bond between W1 and W2, and W1 and W2 are each CR'2. In another embodiment,

[0058] [ka] represents a double bond between W1 and W2, and W1 and W2 are each independently N or CR'. In either of the above two embodiments,

[0059] [ka] represents a single bond between W3 and W4, and W3 and W4 are each CR'2; or

[0060] [ka] represents a double bond between W3 and W4, and W3 and W4 are each independently N or CR'.

[0061] In some embodiments of the compound of Formula (IIa) or (IIb), each

[0062] [ka] is a double bond or each

[0063] [ka] is a single bond.

[0064] In some embodiments, each

[0065] [ka] is a double bond. In some such 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, one of W1, W2, and W3 is N, and W4 is CR'. In some such embodiments, W1 is N, and W2, W3, and W4 are each CR'. In other such embodiments, W2 is N, and W1, W3, and W4 are each CR'. In other such embodiments, W3 is N, and W1, W2, and W4 are each CR'. In other such embodiments, W4 is N, and W1, W2, and W3 are each CR'. Each of

[0066] [ka] In other embodiments where W1 is a double bond, 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, 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'.

[0067] In other embodiments, each

[0068] [ka] is a double bond, one of W1, W2, W3, and W4 is CR' and the remaining three of W1, W2, W3, and W4 are each N. In some such embodiments, W1 is CR' and W2, W3, and W4 are each N. In other such embodiments, W2 is CR' and W1, W3, and W4 are each N. In other such embodiments, W3 is CR' and W1, W2, and W4 are each N. In other such embodiments, W4 is CR' and W1, W2, and W3 are each N.

[0069] In some embodiments, at least one R' is not hydrogen.

[0070] In some embodiments of the compound of Formula (IIa) or (IIb), each

[0071] [ka] is a single bond.

[0072] In some embodiments of compounds of Formula (IIa) or (IIb), each R is independently hydrogen, halogen, or —NR″C(O)R″.

[0073] In some embodiments of the compounds of Formula (IIa) or (IIb), each R' is hydrogen.

[0074] In some embodiments of compounds of Formula (IIa) or (IIb), 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.

[0075] In some embodiments of a compound of Formula (IIa) or (IIb), n is 0. In other embodiments of a compound of Formula (IIa) or (IIb), n is 1 or 2. In some embodiments, n is 1. In other embodiments, n is 2.

[0076] In some embodiments, the compound is of Formula (IIa), wherein: X1 and X2 are O; T is C=O, n is 1, R 1 is hydrogen, L is hydrogen; Z is S, Each

[0077] [ka] is a double bond, W1 is N, W2, W3 and W4 are each independently CH or C—Cl; Y3 is CH or C-halogen.

[0078] In some embodiments, the compound has Formula (IIb), wherein: X1 and X2 are O; T is C=O, n is 1, R 1 is hydrogen, L is hydrogen; Z is NH; Each

[0079] [ka] is a double bond, W4 is N, W3 is CH, one of W1 and W2 is C—Cl and the other of W1 and W2 is CH; Y4 is CH.

[0080] According to a third aspect, the present invention provides a method for producing a cellular membrane comprising:

[0081] [Table 1] JPEG0007760167000025.jpg241158JPEG0007760167000026.jpg242158JPEG0007760167000027.jpg242158 JPEG0007760167000028.jpg249158JPEG0007760167000029.jpg243158JPEG0007760167000030.jpg168158

[0082] The present invention provides a compound of formula (Ia), formula (Ib), formula (IIa) or formula (IIb) selected from:

[0083] According to a fourth aspect of the invention there is provided a pharmaceutical composition comprising a compound according to any of the above aspects of the invention.

[0084] The present invention also provides a compound according to any of the above aspects of the invention for use as a cereblon-binding agent.

[0085] The present invention also relates to a compound or composition according to any of the above aspects of the invention, or

[0086] [ka] Also provided is a compound selected from:

[0087] The present invention also relates to a compound or composition according to any of the above aspects of the invention for use in immuno-oncology, or

[0088] [ka] Also provided is a compound selected from:

[0089] The present invention also relates to a compound or composition according to any of the above aspects of the invention for use in 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;

[0090] [ka] Also provided is a compound selected from:

[0091] In some embodiments, the compound is a compound according to any one of the first to third aspects of the invention; or

[0092] [ka] The compound is selected from

[0093] In some embodiments, the compound is a compound according to any one of the first to third aspects of the invention.

[0094] The invention also provides a method for 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; the method comprising administering to a subject a compound or composition according to any of the above aspects of the invention, or

[0095] [ka] The method includes administering to a patient in need thereof an effective amount of a compound selected from

[0096] 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 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.

[0097] In some embodiments, an effective amount of a compound or composition according to any of the above aspects of the invention is administered to a patient.

[0098] The present invention also relates to a compound according to any one of the first to third aspects of the present invention, or

[0099] [ka] Also provided are combination preparations of a compound selected from and at least one additional active agent for simultaneous, separate or sequential therapeutic use.

[0100] The present invention also provides a combination preparation of a compound according to any one of the first to third aspects of the present invention and at least one additional active agent for simultaneous, separate or sequential therapeutic use.

[0101] In some embodiments of the combination, 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. In some embodiments, the treatment is treatment of cancer, an autoimmune disease, 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.

[0102] 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", -NH, -NHR, -NR, -SOR, -C(O)R, -CN, or -NO. In some embodiments, an alkyl group is an unsubstituted alkyl group. In some embodiments, an alkyl group is a C-C 12 Alkyl, C1-C 10 alkyl, C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl group.

[0103] 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", -NH, -NHR, -NR, -SOR, -C(O)R, -CN, or -NO. In some embodiments, an alkenyl group is an unsubstituted alkenyl group. In some embodiments, an alkenyl group is a C-C 12 Alkenyl, C2-C 10 alkenyl, C2-C8 alkenyl, C2-C6 alkenyl, or C2-C4 alkenyl group.

[0104] 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, -NH, -NHR, -NR, -SOR, -C(O)R, -CN, or -NO. In some embodiments, an alkynyl group is an unsubstituted alkynyl group. In some embodiments, an alkynyl group is a C-C 12 Alkynyl, C2-C 10 alkynyl, C2-C8 alkynyl, C2-C6 alkynyl, or C2-C4 alkynyl group.

[0105] As used herein, the term "aryl" is intended to include both unsubstituted aryl groups and aryl groups substituted with one or more additional groups, such as -OH, -OR", halogen, -NH, -NHR, -NR, -SOR, -C(O)R, -CN, or -NO. In some embodiments, an aryl group is an unsubstituted aryl group. In some embodiments, an aryl group is a C-C 10 aryl, C6-C8 aryl, or C6 aryl.

[0106] 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, -NH, -NHR, -NR, -SOR, -C(O)R, -CN, or -NO. In some embodiments, a heteroaryl group is an unsubstituted heteroaryl group. In some embodiments, a heteroaryl group is a C-C 10 heteroaryl, C6-C9 heteroaryl, C6-C8 heteroaryl, or C6 heteroaryl.

[0107] As used herein, the term "benzyl" is intended to include both an unsubstituted benzyl group and a benzyl group substituted with one or more additional groups, such as -OH, -OR", halogen, -NH, -NHR, -NR, -SOR, -C(O)R, -CN, or -NO. In some embodiments, the benzyl group is an unsubstituted benzyl group.

[0108] In some embodiments, all alkyl, cycloalkyl, heterocycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, and benzyl groups are unsubstituted. [Brief explanation of the drawings]

[0109] [Figure 1] FIG. 1 shows an assay showing the effect of various compounds of the invention and various reference compounds on CK1α degradation in the Kelly cell line. [Figure 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. [Figure 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. DETAILED DESCRIPTION OF THE INVENTION

[0110] As mentioned above, the present invention provides compounds of formula (Ia), (Ib), (IIa) and (IIb):

[0111] [ka] JPEG0007760167000038.jpg97120 wherein L, X1, X2, Y1, Y2, Y3, Y4, W1, W2, W3, W4, R1 and Z are as defined above.

[0112] The binding of the above compounds to cereblon is related to CRL4 CRBN It can alter the specificity of the complex, inducing 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.

[0113] These compounds uniquely regulate cereblon and inhibit CRL4 CRBN This may enable the ubiquitin ligase complex to recognize different substrates and target them for degradation than they would otherwise recognize. As a result, the compounds of the present invention are expected to extend / modify the growth-suppressive activity of CRBN, thus expanding the range of cancer types susceptible to treatment with CMA.

[0114] The compounds of the present invention are advantageous in terms of their ease of synthesis. The synthesis of the compounds can be summarized in the following general procedures (carried out under synthesis conditions A or B below).

[0115] [ka]

[0116] Synthesis condition A A suitable acid (R in the above reaction scheme) x COOH) (1.1 equiv.), DMAP (0.04 equiv.), and EDC (1.2 equiv.) were added to a solution of 3-aminopiperidine-2,6-dione (1 equiv.) and N-hydroxybenzotriazole (1.2 equiv.) in DMF (0.5 M). The reaction mixture was stirred overnight at room temperature (20-25 °C). Water (2 × DMF volume) was added, and the resulting solution was extracted with dichloromethane (3 × DMF volume). The combined organic layers were washed with water, dried over Na2SO4, and concentrated under reduced pressure. The crude product was purified by preparative HPLC or column chromatography.

[0117] Synthesis condition B In the above reaction scheme, the appropriate acid R xCOOH (1 equivalent) and EDC (1.2 equivalents) were added to a solution of 3-aminopiperidine-2,6-dione (hydrochloride, 1.1 equivalents), triethylamine (1.2 equivalents), and N-hydroxybenzotriazole (1.2 equivalents) in DMA (0.5 M). The reaction mixture was stirred overnight at room temperature. Water (2×DMA volumes) was added, and the resulting mixture was extracted with dichloromethane (3×DMA volumes). The combined organic layers were washed with water, dried over Na2SO4, and concentrated under reduced pressure. The crude product was isolated by preparative HPLC or column chromatography.

[0118] Example method 1: R x COOH (or its ester R x COOR y ) chlorinated R x Formation of the base NCS (1.1 equiv.) was added to a solution of the appropriate starting material (1 equiv.) in DMF (0.5 M), and the reaction mixture was stirred for 2 h at room temperature (20-25 °C). The reaction mixture was poured into water (2 × DMF volume), and the resulting precipitate was filtered. The solid was washed with water and dried in vacuo to give the acid ROOH.

[0119] Exemplary Method 2: The corresponding ester R x COOR y From R x Synthesis of COOH LiOH (1.1 equiv.) was added to a solution of the appropriate ester (1 equiv.) in a THF:water mixture (3:1 or 5:1, 85 mM), and the mixture was stirred overnight at room temperature (20-25 °C). The mixture was concentrated under reduced pressure, diluted with water, and acidified to pH = 2-3 with concentrated HCl. The precipitate was filtered, washed with water, and dried in vacuo to give the target carboxylic acid.

[0120] Example Method 3: R x COOR y Acetylated R x Formation of the base A mixture of the appropriate amine (1 equiv.), AcO (3 equiv.), and DMAP (0.2 equiv.) in dioxane (0.2 M) was heated to 80°C for 2 h. After completion, the mixture was cooled to room temperature (20-25°C) and concentrated under reduced pressure. The residue was diluted with water (1 x dioxane volume) and extracted with EtOAc (3 x dioxane volumes). The organic layer was washed with water, brine, dried over NaSO, and evaporated to dryness to give the acetylated product, which was typically used without further purification.

[0121] Some examples of compounds of the present invention are shown below.

[0122] [Table 2] JPEG0007760167000041.jpg214170JPEG0007760167000042.jpg204170JPEG0007760167000043.jpg204170JPEG0007760167000044.jpg207170 JPEG0007760167000045.jpg207170JPEG0007760167000046.jpg161170JPEG0007760167000047.jpg212170JPEG0007760167000048.jpg154170

[0123] As also discussed in the Examples section, the inventors have found that the compounds of the present invention exhibit similar cereblon-binding abilities as the known CMA CC-122. Despite the pharmacological activity of known CMAs such as CC-122, patients often develop resistance to these compounds. The use of novel compounds, such as the compounds of the present invention described above, may help overcome this clinical obstacle.

[0124] One of the significant 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 induce the degradation of CRL4 only in the presence of CMA. CRBNIt induces degradation of several proteins (including SALL4) that bind to the ligase. SALL4 degradation observed with treatment with CMA is (at least in part) responsible for the teratogenicity of CMA. Compounds with reduced ability to induce SALL4 degradation may exhibit improved safety profiles.

[0125] The compounds of the present invention may also possess advantageous pharmaceutically properties such as increased stability and improved ADMET (absorption, distribution, metabolism, excretion, and / or toxicity) properties.

[0126] 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, cancers of the skin, including melanoma; lymph nodes; breast; cervix; uterus; gastrointestinal tract; lung; ovary; prostate; colon; rectum; oral cavity; brain; head and neck; throat; testicle; kidney; pancreas; bone; spleen; liver; bladder; larynx; nasal cavity; and AIDS-related cancers and hematological malignancies. a) Hematological malignancies include leukemia, lymphoma, multiple myeloma, or smoldering myeloma. Leukemias are: acute leukemia, acute lymphoblastic leukemia (ALL), chronic lymphocytic leukemia (CLL), acute myeloid leukemia, acute myeloid leukemia (AML), adult acute basophilic leukemia, adult acute eosinophilic leukemia, adult acute megakaryoblastic leukemia, adult acute minimally differentiated myeloid leukemia, adult acute monoblastic leukemia, adult acute monocytic leukemia, adult acute myeloblastic leukemia with maturation, adult acute myeloblastic leukemia without maturation, and adult acute myeloid leukemia with abnormalities. The present invention can be selected from the group consisting of leukemia, adult acute myelomonocytic leukemia, adult erythroleukemia, adult pure erythroleukemia, 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's lymphoma, extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue, hepatosplenic T-cell lymphoma, intraocular lymphoma, lymphoma involving noncutaneous extranodal sites, mature T-cell and K-cell non-Hodgkin's lymphoma, nodal marginal zone lymphoma, and post-transplant lymphoproliferative Disorders, recurrent adult Burkitt lymphoma, recurrent adult diffuse large cell lymphoma, recurrent adult diffuse mixed cell lymphoma, recurrent adult diffuse small divided cell 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 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, Waldenstrom's Macroglobulinemia, Adult T-Cell Leukemia-Lymphoma, Peripheral T-Cell Lymphoma, B-Cell Lymphoma, Hodgkin's The cutaneous large B-cell lymphoma may be selected from the group consisting of cutaneous T-cell lymphoma, diffuse large B-cell lymphoma, MALT lymphoma, mantle cell lymphoma, non-Hodgkin's lymphoma, refractory primary cutaneous large B-cell lymphoma (leg type), refractory anemia, refractory anemia with excessive blasts, refractory anemia with ringed sideroblasts, refractory cytopenia with multilineage dysplasia, secondary myelodysplastic syndrome, myelodysplastic syndrome, and myeloproliferative disorder. 2) Autoimmune diseases, such as: acute disseminated encephalomyelitis, acute motor axonal neuropathy, Addison's disease, adiposity dolorosa, adult-onset Still's disease, alopecia areata, ankylosing spondylitis, anti-glomerular basement membrane nephritis, antineutrophil cytoplasmic antibody-associated vasculitis, anti-N-methyl-D-aspartate receptor encephalitis, antiphospholipid syndrome, antisynthetase syndrome, aplastic 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 steroid ... Infectious pancreatitis, autoimmune polyendocrine syndrome, autoimmune polyendocrine syndrome type 2, autoimmune polyendocrine syndrome type 3, autoimmune progestational dermatitis, autoimmune retinopathy, autoimmune thrombocytopenic 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 gestationis, giant cell arteritis, Goodpasture syndrome, Graves' disease, Graves' ophthalmopathy, Guillain-Barré syndrome, Hashimoto's encephalopathy, Hashimoto's thyroiditis, Henoch-Schönlein purpura, hidradenitis suppurativa, idiopathic inflammatory demyelinating disease, IgG4-related systemic disease, inclusion body myositis, inflammatory bowel disease (IBD) BD), intermediate uveitis, interstitial cystitis, juvenile arthritis, Kawasaki disease, Lambert-Eaton myasthenic syndrome, leukocytoclastic vasculitis, lichen planus, lichen sclerosus, lignified conjunctivitis, 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, acute pityriasis lichenoides, multiple sclerosis, myasthenia gravis, myocarditis, myositis, neuromyelitis optica, neuromyotonia, opsoclonus-myoclonus syndrome, optic neuritis, Ord's thyroiditis, relapsing rheumatoid arthritis,Paraneoplastic cerebellar degeneration, Parry-Romberg syndrome, Parsonage-Turner syndrome, Streptococcus-associated pediatric autoimmune neuropsychiatric disorders, Pemphigus vulgaris, Pernicious anemia, Acute pityriasis lichenoides, POEMS syndrome, Polyarteritis nodosa, Polymyalgia rheumatica, Polymyositis, Post-myocardial infarction syndrome, Post-pericardiotomy syndrome, Primary biliary cirrhosis, Primary immunodeficiency, Primary sclerosing cholangitis, Progressive inflammatory neuropathy, Psoriasis, Psoriatic arthritis, Pure red cell aplasia, Pyoderma gangrenosum, Raynaud's phenomenon, Reactive arthritis Relapsing polychondritis, restless legs syndrome, retroperitoneal fibrosis, rheumatic fever, rheumatoid arthritis, rheumatoid vasculitis, sarcoidosis, Schnitzler's syndrome, scleroderma, Sjögren's syndrome, stiff-person syndrome, subacute bacterial endocarditis, Susac's syndrome, Sydenham's chorea, sympathetic ophthalmia, systemic lupus erythematosus, systemic cutaneous sclerosis, thrombocytopenia, Tolosa-Hunt syndrome, transverse myelitis, ulcerative colitis, undifferentiated connective tissue disease, urticaria, urticarial vasculitis, vasculitis and vitiligo; 3) Diseases and disorders associated with 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, Zudek's 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 neurological 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 atrophy of the retinal pigment epithelium (RPE); 5) Skin disorders, such as: keratosis and related conditions, skin diseases or disorders characterized by epithelial overgrowth, acne, and wrinkles. Examples of skin diseases or disorders characterized by epithelial overgrowth include, but are not limited to, any condition, disease, or disorder characterized by the presence of epithelial overgrowth, such as, but not limited to, infections associated with papillomavirus, arsenic keratosis, Lezer-Toller sign, dyskeratosis verruciformis (WD), tractular keratosis microspinosa (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, pulmonary venous obstructive disease, and collagen disease. If you have pulmonary hypertension associated with, related to, or secondary to 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, sleep-disordered breathing, alveolar hypoventilation, chronic exposure to high altitude, neonatal lung disease, alveolar-capillary dysplasia, sickle cell disease, other coagulation disorders, chronic thromboembolism, connective tissue disease, systemic and cutaneous lupus including lupus, schistosomiasis, sarcoidosis, or pulmonary capillary hemangiomatosis; 7) Asbestos-related disorders, such as: mesothelioma, asbestosis, malignant pleural effusion, benign exudative effusion, pleural plaque, pleural calcification, diffuse pleural thickening, rounded atelectasis, fibrous mass, and lung cancer; 8) Human intracellular parasites, for example, 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, 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 levels, ataxia-telangiectasia, incomplete lymphocyte syndrome, common variable immunodeficiency, Ig deficiency with high IgM levels, Ig heavy chain deficiency, IgA deficiency, immunodeficiency associated with thymoma, reticular 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 disorders associated with CD34+ cell differentiation; 12) TNFα-related disorders, such as: endotoxemia or toxic shock syndrome; cachexia; adult respiratory distress syndrome; bone resorption diseases, such as 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 sepsis syndrome, post-ischemic reperfusion injury, malaria, mycobacterial infection, meningitis, psoriasis, congestive heart failure, fibrotic diseases, 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.

[0127] 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.

[0128] 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]

[0129] The compounds of the present invention are advantageous in terms of their synthetic feasibility, the synthesis of which can be summarized in the following general procedures (performed under synthetic conditions A or synthetic conditions B), as presented below:

[0130] [ka]

[0131] Synthesis condition A The appropriate acid (RCOOH in the reaction scheme above) (1.1 equiv.), DMAP (0.04 equiv.), and EDC (1.2 equiv.) were added to a solution of 3-aminopiperidine-2,6-dione (1 equiv.) and N-hydroxybenzotriazole (1.2 equiv.) in DMF (0.5 M). The reaction mixture was stirred overnight at room temperature (20-25 °C). Water (2 × DMF volume) was added, and the resulting solution was extracted with dichloromethane (3 × DMF volume). The combined organic layers were washed with water, dried over NaSO, and concentrated under reduced pressure. The crude product was purified by preparative HPLC or by column chromatography.

[0132] Synthesis condition B The appropriate acid (RCOOH in the above reaction scheme) (1 equivalent) and EDC (1.2 equivalents) were added to a solution of 3-aminopiperidine-2,6-dione (hydrochloride, 1.1 equivalents), triethylamine (1.2 equivalents), and N-hydroxybenzotriazole (1.2 equivalents) in DMA (0.5 M). The reaction mixture was stirred overnight at room temperature. Water (2×DMA volumes) was added, and the resulting mixture was extracted with dichloromethane (3×DMA volumes). The combined organic layers were washed with water, dried over NaSO, and concentrated under reduced pressure. The crude product was isolated by preparative HPLC or by column chromatography.

[0133] Synthesis condition C To a solution of the appropriate acid (RCOOH in the above reaction scheme) (1 equivalent) and HATU (1.5 equivalents) in dry DMF was added 3-aminopiperidine-2,6-dione (hydrochloride, 1.2 equivalents) and DIPEA (3 equivalents). The reaction mixture was stirred overnight at room temperature. The crude product was purified by preparative HPLC or / and preparative TLC.

[0134] Synthesis condition D To a solution of the appropriate acid (RCOOH in the above reaction scheme) (1 equivalent), 3-aminopiperidine-2,6-dione (hydrochloride, 1.2 equivalents), and DMAP (0.1 equivalents) in dry DMF under an inert atmosphere was added DIPEA (2.2 equivalents) and HATU (1.5 equivalents) in dry DMF. The reaction mixture was stirred overnight at room temperature. The crude product was purified by preparative HPLC or / and preparative TLC.

[0135] Exemplary Method 1: Formation of Chlorinated R Groups of RCOOH (or Their Esters RCOOR') N-Chlorosuccinimide (1.1 equiv.) was added to a solution of the appropriate starting material (1 equiv.) in DMF (0.5 M), and the reaction mixture was stirred for 2 h at room temperature (20-25 °C). The reaction mixture was poured into water (2 x DMF volume), and the resulting precipitate was filtered. The solid was washed with water and dried in vacuo to give the acid, ROOH.

[0136] Exemplary Method 2: Synthesis of RCOOH from the corresponding ester (RCOOR') LiOH (1.1 equiv.) was added to a solution of the appropriate ester (1 equiv.) in a THF:water mixture (3:1 or 5:1, 85 mM), and the resulting mixture was stirred overnight at room temperature (20-25 °C). The mixture was concentrated under reduced pressure, diluted with water, and acidified to pH = 2-3 with concentrated HCl. The precipitate was filtered, washed with water, and dried in vacuo to give the target carboxylic acid.

[0137] Exemplary Method 3: Formation of Acetylated R Groups of RCOOR' A mixture of the appropriate amine (1 equiv.), AcO (3 equiv.), and DMAP (0.2 equiv.) in dioxane (0.2 M) was heated to 80°C for 2 h. Upon completion, the mixture was cooled to room temperature (20-25°C) and concentrated under reduced pressure. The residue was diluted with water (1 x dioxane volume) and extracted with EtOAc (3 x dioxane volumes). The organic layer was washed with water, brine, dried over NaSO, and evaporated to dryness to give the acylated product, which was typically used without further purification. [Example]

[0138] Synthesis of tert-butyl (3-((2,6-dioxopiperidin-3-yl)carbamoyl)thiophen-2-yl)carbamate (1)

[0139] [ka]

[0140] This compound was synthesized using the general procedure shown in Reaction Scheme 1 and synthesis condition C, above (52% yield), using 2-((tert-butoxycarbonyl)amino)thiophene-3-carboxylic acid (43 mg) as the starting material. 1 H NMR(500MHz,DMSO)δ11.09(s,1H), 10.88(s,1H), 8.63(d,J=8.2Hz,1H), 7.38(d,J=5.9Hz,1H), 6.97(dd,J=5.8,0.8Hz,1H), 4.68(ddd,J=13.0,8.2, 5.3Hz,1H), 2.78(ddd,J=17.3,13.5,5.5Hz,1H), 2.59~2.54(m,1H), 2.15 (qd,J=13.0,4.5Hz,1H), 1.96(ddt,J=10.2,5.3,2.7Hz,1H), 1.48(s,9H). LCMS (m / z [M+H] - ):352.0 [Example]

[0141] Synthesis of N-(2,6-dioxopiperidin-3-yl)-2-(N-methylacetamido)thiophene-3-carboxamide (2)

[0142] [ka]

[0143] Step A: 3-Aminopiperidine-2,6-dione (3.3 g, 25.8 mmol) and triethylamine (2.45 g, 24.2 mmol) were added to a solution of 1-methyl-1H,2H,4H-thieno[2,3-d][1,3]oxazine-2,4-dione (3.7 g, 20.2 mmol) in ethanol (20 mL). The reaction mixture was refluxed for 16 hours and filtered. The precipitate was washed with water to give N-(2,6-dioxopiperidin-3-yl)-2-(methylamino)thiophene-3-carboxamide (19% yield).

[0144] Step B: Acetic anhydride (0.265 g, 2.60 mmol) and DMAP (0.026 g, 0.213 mmol) were added to a solution of N-(2,6-dioxopiperidin-3-yl)-2-(methylamino)thiophene-3-carboxamide (0.579 g, 2.17 mmol) and triethylamine (0.263 g, 2.60 mmol) in dioxane (10 mL). The reaction mixture was stirred at 60° C. for 16 hours, washed with water, extracted with EtOAc (3×10 mL), dried over NaSO, concentrated under reduced pressure, and purified by HPLC to give N-(2,6-dioxopiperidin-3-yl)-2-(N-methylacetamido)thiophene-3-carboxamide (11% yield). 1H NMR(500MHz,DMSO)δ10.86(s,1H), 8.53(d,J=8.0Hz,1H), 7.56(d,J=5.7Hz,1H), 7.34(d,J=5.7Hz,1H), 4.72~4.6 2(m,1H), 3.09(s,3H), 2.83~2.71(m,1H), 2.58~2.53(m,1H), 2.19~2.02(m,1H), 1.99~1.90(m,1H), 1.81(s,3H). LCMS (m / z [M+H] + ):310.2 [Example]

[0145] Synthesis of 5-chloro-N-(2,6-dioxopiperidin-3-yl)-2-pentanamidothiophene-3-carboxamide (3)

[0146] [ka]

[0147] Step A: Using exemplary method 1, described above (65% yield), methyl 5-chloro-2-pentanamidothiophene-3-carboxylate was synthesized using methyl 2-pentanamidothiophene-3-carboxylate as the starting material.

[0148] Step B: Using exemplary method 2, above (69% yield), 5-chloro-2-pentanamidothiophene-3-carboxylic acid was synthesized using methyl 5-chloro-2-pentanamidothiophene-3-carboxylate as the starting material.

[0149] Step C: 5-chloro-N-(2,6-dioxopiperidin-3-yl)-2-pentanamidothiophene-3-carboxamide was synthesized using the general procedure shown in Reaction Scheme 1 and Synthesis Condition A, as described above (40% yield), and 5-chloro-2-pentanamidothiophene-3-carboxylic acid as the starting material. 1H NMR(400MHz,DMSO)δ11.94(s,1H), 10.92(s,1H), 8.72~8.59(m,1H), 7.52(s,1H), 4.84~4.71(m,1H), 2.96~2.59(m,4H) ), 2.61~2.53(m,1H), 2.23~2.06(m,1H), 2.04~1.91(m,2H), 1.68~1.51(m,2H), 1.42~1.26(m,2H), 1.02~0.81(m,3H). LCMS (m / z [M+H] + ):372.2 [Example]

[0150] Synthesis of N-(2,6-dioxopiperidin-3-yl)-2-acetamidothiophene-3-carboxamide (4)

[0151] [ka]

[0152] This compound was synthesized using the general procedure shown in Reaction Scheme 1 and Synthesis Condition B, supra, (32% yield) with 2-acetamidothiophene-3-carboxylic acid as the starting material. 1 H NMR(400MHz,DMSO)δ11.84(s,1H), 10.90(s,1H), 8.67(d,J=8.1Hz,1H), 7.42(d,J=5.8Hz,1H), 7.00(d,J=5.7Hz, 1H), 4.79~4.67(m,1H), 2.85~2.72(m,1H), 2.61~2.54(m,1H), 2.20(s,3H), 2.17~2.11(m,1H), 1.96~1.84(m,1H). LCMS (m / z [M+H] + ):296.06 [Example]

[0153] Synthesis of N-(2,6-dioxopiperidin-3-yl)-2-acetamido-N-methylthiophene-3-carboxamide (5)

[0154] [ka]

[0155] Triethylamine (0.236 g, 2.328 mmol), N-hydroxybenzotriazole (0.314 g, 2.3 mmol), 2-acetamidothiophene-3-carboxylic acid (0.359 g, 1.94 mmol), and EDC (0.361 g, 2.328 mmol) were added sequentially to a solution of 3-(methylamino)piperidine-2,6-dione (0.381 g, 2.134 mmol, hydrochloride salt) in DMA (30 mL), and the reaction mixture was stirred overnight at room temperature. Water (10 mL) was added, and the resulting solution was extracted with DCM, dried over NaSO, and concentrated under reduced pressure. The product was purified by HPLC to give N-(2,6-dioxopiperidin-3-yl)-2-acetamido-N-methylthiophene-3-carboxamide (25% yield). 1 H NMR (400MHz, DMSO) δ10.99(s,1H), 10.54(s,1H), 7.13~7.02(m,1H), 7.01~6.89(m,1H), 5.13~4 .87(m,1H), 2.87(s,3H), 2.83~2.71(m,1H), 2.61~2.52(m,2H), 2.15(s,3H), 2.07~1.95(m,1H). LCMS (m / z [M+H] + ):310.0 [Example]

[0156] Synthesis of 5-chloro-2-cyclopropanamido-N-(2,6-dioxopiperidin-3-yl)thiophene-3-carboxamide (6)

[0157] [ka]

[0158] Step A: Using exemplary method 1, described above (80% yield), methyl 5-chloro-2-cyclopropanamidothiophene-3-carboxylate was synthesized using methyl 2-cyclopropanamidothiophene-3-carboxylate as the starting material.

[0159] Step B: Using exemplary method 2, above (86% yield), 5-chloro-2-cyclopropanamidothiophene-3-carboxylic acid was synthesized using methyl 5-chloro-2-cyclopropanamidothiophene-3-carboxylate as the starting material.

[0160] Step C: Using the general procedure shown in Reaction Scheme 1 and synthesis condition B, above (30% yield), 5-chloro-2-cyclopropanamido-N-(2,6-dioxopiperidin-3-yl)thiophene-3-carboxamide was synthesized using 5-chloro-2-cyclopropanamidothiophene-3-carboxylic acid as the starting material. 1 H NMR(500MHz,DMSO)δ12.11(s,1H), 10.88(s,1H), 8.69~8.60(m,1H), 7.50(s,1H), 4.79~4.69(m,1H) ), 2.84~2.72(m,1H), 2.61~2.53(m,1H), 2.21~2.08(m,1H), 2.04~1.92(m,2H), 0.98~0.84(m,4H). LCMS (m / z [M+H] + ):356.2 [Example]

[0161] Synthesis of N-(2,6-dioxopiperidin-3-yl)-3-acetamidothiophene-2-carboxamide (7)

[0162] [ka]

[0163] This compound was synthesized using the general procedure shown in Reaction Scheme 1 and Synthesis Condition B, as described above (15% yield), and N-(2,6-dioxopiperidin-3-yl)-3-acetamidothiophene-2-carboxamide as the starting material. 1 H NMR(400MHz,DMSO)δ10.89(s,2H), 8.55(d,J=8.1Hz,1H), 7.94(d,J=5.3Hz,1H), 7.75(d,J=5.4Hz,1H), 4. 76~4.66(m,1H), 2.85~2.69(m,1H), 2.59~2.52(m,1H), 2.25~2.12(m,1H), 2.09(s,3H), 2.01~1.89(m,1H). LCMS (m / z [M+H] + ):295.8 [Example]

[0164] Synthesis of N-(2,6-dioxopiperidin-3-yl)-2-acetamido-4-methoxythiophene-3-carboxamide (8)

[0165] [ka]

[0166] Step A: H2SO4 (1 mL) was added dropwise to a stirred suspension of methyl 2-({[(9H-fluoren-9-yl)methoxy]carbonyl}amino)-4-oxo-4,5-dihydrothiophene-3-carboxylate (9.65 g, 24.4 mmol) in MeOH (200 mL). The reaction mixture was refluxed for 16 h, cooled to room temperature, and filtered to give 2-({[(9H-fluoren-9-yl)methoxy]carbonyl}amino)-4-methoxythiophene-3-carboxylate (63% yield).

[0167] Step B: Morpholine (13.5 g, 155 mmol) was added to a solution of methyl 2-({[(9H-fluoren-9-yl)methoxy]carbonyl}amino)-4-methoxythiophene-3-carboxylate (6.3 g, 15.4 mmol) in dichloromethane (100 mL), and the reaction mixture was stirred overnight at room temperature, concentrated under reduced pressure, diluted with MTBE, filtered, and rinsed with a small amount of MTBE. The filtrate was evaporated in vacuo to give crude methyl 2-amino-4-methoxythiophene-3-carboxylate, which was used in the next step without further purification.

[0168] Step C: Using Exemplary Method 3, above, with methyl 2-amino-4-methoxythiophene-3-carboxylate as the starting material, methyl 2-acetamido-4-methoxythiophene-3-carboxylate was obtained in 73% yield.

[0169] Step D: Using exemplary method 2, above, with methyl 2-acetamido-4-methoxythiophene-3-carboxylate as the starting material, 2-acetamido-4-methoxythiophene-3-carboxylic acid was obtained in 20% yield.

[0170] Step E: N-(2,6-dioxopiperidin-3-yl)-2-acetamido-4-methoxythiophene-3-carboxamide was synthesized using the general procedure shown in Reaction Scheme 1 and synthesis condition B, as described above (47% yield), and 2-acetamido-4-methoxythiophene-3-carboxylic acid as the starting material. 1 H NMR(500MHz,DMSO)δ12.05(s,1H), 10.92(s,1H), 8.30(d,J=7.1Hz,1H), 6.14(s,1H), 4.76~4. 66(m,1H), 3.83(s,3H), 2.82~2.70(m,1H), 2.58~2.52(m,1H), 2.19(s,3H), 2.16~2.06(m,2H) LCMS (m / z [M+H] + ):326.2 [Example]

[0171] Synthesis of 5-cyano-N-(2,6-dioxopiperidin-3-yl)-2-acetamidothiophene-3-carboxamide (9)

[0172] [ka]

[0173] Step A: Ethyl 2-acetamidothiophene-3-carboxylate (11 g, 51.6 mmol) was dissolved in AcOH (110 mL), and a solution of bromine (3.2 mL, 61.9 mmol) in AcOH (55 mL) was added dropwise over 15 minutes at room temperature. The reaction mixture was stirred at room temperature for 18 hours, concentrated under reduced pressure, and diluted with water. The precipitate was filtered, washed with water, and dried to give ethyl 5-bromo-2-acetamidothiophene-3-carboxylate (93% yield).

[0174] Step B: Zn(CN) (8.45 g, 72 mmol) and Pd(dppf)Cl·DCM (3.92 g, 4.8 mmol) were added to a solution of ethyl 5-bromo-2-acetamidothiophene-3-carboxylate (14 g, 48 mmol) in DMF (120 mL). Argon was bubbled through the reaction mixture for 10 min, and then the reaction mixture was stirred at 150 °C for 16 h, cooled to room temperature, filtered, and washed with EtOAc. The organic layer was dried over NaSO, concentrated under reduced pressure, and purified by flash column chromatography to give 5-cyano-2-acetamidothiophene-3-carboxylate (83% yield).

[0175] Step C: Ethyl 5-cyano-2-acetamidothiophene-3-carboxylate (9.45 g, 39.7 mmol) was dissolved in an EtOH:THF solution (120 mL:360 mL). The solution was cooled to +5 °C, and lithium hydroxide monohydrate (11.7 g, 278 mmol) in HO (120 mL) was added dropwise over 20 min. The reaction mixture was stirred at room temperature for 18 h, concentrated under reduced pressure, and acidified with 15% citric acid. The product was extracted with EtOAc, dried over NaSO, and evaporated under reduced pressure to give 5-cyano-2-acetamidothiophene-3-carboxylic acid (57% yield).

[0176] Step D: 5-cyano-N-(2,6-dioxopiperidin-3-yl)-2-acetamidothiophene-3-carboxamide was synthesized using the general procedure shown in Reaction Scheme 1 and Synthesis Condition A, as described above (35% yield), and 5-cyano-2-acetamidothiophene-3-carboxylic acid as the starting material. 1 H NMR(400MHz,DMSO)δ12.08(s,1H), 10.94(s,1H), 8.89(d,J=7.9Hz,1H), 8.27(s,1H), 4.82~4.65 (m,1H), 2.87~2.72(m,1H), 2.62~2.53(m,1H), 2.30(s,3H), 2.24~2.08(m,1H), 2.06~1.93(m,1H) LCMS (m / z [M+H] + ):321.0 [Example]

[0177] Synthesis of 4-cyclopropyl-N-(2,6-dioxopiperidin-3-yl)-2-acetamidothiophene-3-carboxamide (10)

[0178] [ka]

[0179] This compound was synthesized using the general procedure shown in Reaction Scheme 1 and Synthesis Condition B, as described above (23% yield), and 4-chloro-N-(2,6-dioxopiperidin-3-yl)-2-acetamidothiophene-3-carboxamide as the starting material. 1 H NMR:(400MHz,DMSO-d6)δ11.21(s,1H), 11.05(s,1H), 8.30(d,J=7.7Hz,1H), 6.57(s,1H), 4.94~4.79(m,1H), 2.88~2.74(m,1H) , 2.63~2.52(m,1H), 2.16(s,3H), 2.13~2.04(m,2H), 2.03~1.95(m,2H), 0.98~0.83(m,2H), 0.72~0.64(m,1H), 0.64~0.55(m,1H) LCMS (m / z [M+H] + ):336.3 [Example]

[0180] Synthesis of 4,5-dichloro-N-(2,6-dioxopiperidin-3-yl)-2-acetamidothiophene-3-carboxamide (11)

[0181] [ka]

[0182] Step A: Using Exemplary Method 1, above, with methyl 4-chloro-2-acetamidothiophene-3-carboxylate as the starting material, methyl 4,5-dichloro-2-acetamidothiophene-3-carboxylate was prepared in 90% yield.

[0183] Step B: Using Exemplary Method 2, above, with methyl 4,5-chloro-2-acetamidothiophene-3-carboxylate as the starting material, 4,5-dichloro-2-acetamidothiophene-3-carboxylic acid was prepared in 70% yield.

[0184] Step C: Using the general procedure shown in Reaction Scheme 1 and Synthesis Condition A, as described above, and 4,5-dichloro-2-acetamidothiophene-3-carboxylic acid as the starting material, 4,5-dichloro-N-(2,6-dioxopiperidin-3-yl)-2-acetamidothiophene-3-carboxamide was synthesized in 40% yield. 1 H NMR:(500MHz,DMSO)d 11.20(s,1H), 11.09(s,1H), 8.74~8.67(m,1H), 4.93~4.80(m,1H), 2.88~2.75(m,1H), 2.62~2.52(m,1H), 2.19(s,3H), 2.14~2.02(m,2H). LCMS (m / z [M−H] - ):362.1 [Example]

[0185] Synthesis of 5-chloro-N-(2,6-dioxopiperidin-3-yl)-2-acetamidothiophene-3-carboxamide (12)

[0186] [ka]

[0187] This compound was synthesized using the general procedure shown in Reaction Scheme 1 and Synthesis Condition B, above (22% yield), with 5-chloro-2-acetamidothiophene-3-carboxylic acid as the starting material. 1 H NMR(500MHz,DMSO)δ11.84(s,1H), 10.91(s,1H), 8.67(d,J=8.0Hz 1H), 7.50(s,1H), 4.77~4.65(m,1H), 2.84~2.73(m,1H), 2.61~2.54(m,1H), 2.22(s,3H), 2.19~2.07(m,1H), 2.02~1.91(m,1H) LCMS(m / z[M+H]+):329.8 [Example]

[0188] Synthesis of N-(2,6-dioxopiperidin-3-yl)-2-methanesulfonamidothiophene-3-carboxamide (13)

[0189] [ka]

[0190] This compound was synthesized using the general procedure shown in Reaction Scheme 1 and Synthesis Condition B, above (26% yield), with 2-(methylsulfonamido)thiophene-3-carboxylic acid as the starting material. 1 H NMR(400MHz,DMSO)δ11.12(s,1H), 10.92(s,1H), 8.80~8.65(m,1H), 7.46~7.36(m,1H), 7.17~7.06(m,1H), 4.82~4.69(m,1H), 3.17(s,3H), 2.85~2.72(m,1H), 2.60~2.53(m,1H), 2.20~2.04(m,1H), 2.02~1.92(m,1H) LCMS (m / z [M+H] + ):332.2 [Example]

[0191] 5-Acetamido-N 4 -(2,6-dioxopiperidin-3-yl)-5-acetamide-N 2 Synthesis of 14-methylthiophene-2,4-dicarboxamide

[0192] [ka]

[0193] Step A: 4-tert-butyl 2-ethyl 5-aminothiophene-2,4-dicarboxylate (3.71 g, 13.7 mmol) was added to a 20% solution of methylamine in methanol (20 mL), and the reaction mixture was stirred at 70 °C for 5 days, concentrated under reduced pressure, and triturated with isopropyl alcohol:hexane (1:1). The precipitate was filtered to give tert-butyl 2-amino-5-(methylcarbamoyl)thiophene-3-carboxylate (93% yield).

[0194] Step B: Triethylamine (3.3 g, 32.6 mmol), DMAP (0.13 g, 1.06 mmol), and acetic acid (1.67 g, 27.8 mmol) were added to a solution of tert-butyl 2-amino-5-(methylcarbamoyl)thiophene-3-carboxylate (2.8 g, 10.9 mmol) in dry MeCN (30 mL). The reaction mixture was stirred overnight at 50 °C, cooled to room temperature, diluted with water, extracted with DCM, dried over Na SO , and concentrated under reduced pressure to give tert-butyl 2-acetamido-5-(methylcarbamoyl)thiophene-3-carboxylate (95% yield).

[0195] Step C: 10% HCl in dioxane (20 mL) was added to a solution of tert-butyl 2-acetamido-5-(methylcarbamoyl)thiophene-3-carboxylate (3.1 g, 10.4 mmol) in DCM (20 mL), and the reaction mixture was stirred at room temperature for 3 days. The precipitate was filtered, washed with DCM, and dried to give 2-acetamido-5-(methylcarbamoyl)thiophene-3-carboxylic acid (60% yield).

[0196] Step D: Using the general procedure shown in Reaction Scheme 1 and synthesis conditions B, as described above (44% yield), and 2-acetamido-5-(methylcarbamoyl)thiophene-3-carboxylic acid as starting material, N 4 -(2,6-dioxopiperidin-3-yl)-5-acetamide-N 2 -Methylthiophene-2,4-dicarboxamide was synthesized. 1 H NMR(400MHz,DMSO)δ11.84(s,1H), 10.92(s,1H), 8.78(d,J=8.1Hz,1H), 8.35~8.25(m,1H), 7.96(s,1H), 4.81~4.68(m ,1H), 2.85~2.74(m,1H), 2.73(d,J=4.4Hz,3H), 2.62~2.52(m,1H), 2.24(s,3H), 2.20~2.07(m,1H), 2.04~1.93(m,1H) LCMS (m / z [M+H] + ):352.9 [Example]

[0197] Synthesis of N-(2,6-dioxopiperidin-3-yl)-2-oxo-2,3-dihydrothiazole-4-carboxamide (15)

[0198] [ka]

[0199] This compound was synthesized using the general procedure shown in Reaction Scheme 1 and Synthesis Condition C, above (24% yield) using 2-oxo-2,3-dihydrothiazole-4-carboxylic acid (20 mg) as the starting material. 1 H NMR(500MHz,DMSO)δ11.62(s,1H), 10.89(s,1H), 8.69(d,J=8.3Hz,1H), 7.17(s,1H), 4.68(ddd,J=12.5,8.3,5.4Hz, 1H), 2.78(ddd,J=17.3,13.2,5.7Hz,1H), 2.60~2.52(m,1H), 2.11~2.00(m,1H), 1.96(dtd,J=12.7,5.5,2.8Hz,1H). LCMS (m / z [M+H] + ):256.2 [Example]

[0200] Synthesis of 5-chloro-N-(2,6-dioxopiperidin-3-yl)-2-(methylamino)thiophene-3-carboxamide (16)

[0201] [ka]

[0202] Step A: N-Chlorosuccinimide (0.884 g, 6.62 mmol) was added to a solution of 1-methyl-1H,2H,4H-thieno[2,3-d][1,3]oxazine-2,4-dione (1 g, 5.46 mmol) in a mixture of toluene (4 mL) and acetic acid (4 mL). The reaction mixture was stirred at 70 °C for 2 h, concentrated under reduced pressure, diluted with water, and filtered. The solid was washed with water and dried to give 6-chloro-1-methyl-1H,2H,4H-thieno[2,3-d][1,3]oxazine-2,4-dione (72% yield).

[0203] Step B: 3-Aminopiperidine-2,6-dione hydrochloride (0.655 g, 3.98 mmol) and triethylamine (0.483 g, 4.77 mmol) were added to a solution of 6-chloro-1-methyl-1H,2H,4H-thieno[2,3-d][1,3]oxazine-2,4-dione (0.865 g, 3.97 mmol) in ethanol (20 mL), and the reaction mixture was refluxed for 18 h, concentrated under reduced pressure, and diluted with water. The precipitate was filtered, washed with water and isopropyl alcohol, and dried to give 5-chloro-N-(2,6-dioxopiperidin-3-yl)-2-(methylamino)thiophene-3-carboxamide (44% yield). 1 H NMR (400MHz, DMSO) δ10.79(s,1H), 8.18~8.04(m,1H), 8.03~7.91(m,1H), 7.26(s,1H), 4.68~4.52 (m,1H), 2.85(s,3H), 2.79~2.67(m,1H), 2.60~2.53(m,1H), 2.16~2.01(m,1H), 1.99~1.85(m,1H). LCMS (m / z [M+H]+ ):302.2 [Example]

[0204] Synthesis of 5-chloro-N-(2,6-dioxopiperidin-3-yl)-2-[(2S)-2-hydroxypropanamido]thiophene-3-carboxamide (17)

[0205] [ka]

[0206] Step A: Oxalyl chloride (9.24 g, 72.8 mmol) and one drop of DMF were added to a solution of (2S)-2-[(tert-butyldimethylsilyl)oxy]propanoic acid (11.9 g, 58.2 mmol) in dry DCM (150 mL). The resulting mixture was stirred at room temperature for 2 hours, concentrated under reduced pressure, dissolved in DCM (50 mL), and added dropwise to a cooled solution of methyl 2-aminothiophene-3-carboxylate (4.58 g, 29.1 mmol) and DIPEA (11.3 g, 87.4 mmol) in DCM (150 mL). The reaction mixture was stirred at room temperature for 2 hours, washed with water, dried over NaSO, concentrated under reduced pressure, and purified by flash column chromatography to give methyl 2-[(2S)-2-[(tert-butyldimethylsilyl)oxy]propanamido]thiophene-3-carboxylate (24% yield).

[0207] Step B: N-Chlorosuccinimide (1.03 g, 7.71 mmol) was added to a solution of methyl 2-[(2S)-2-[(tert-butyldimethylsilyl)oxy]propanamido]thiophene-3-carboxylate (2.4 g, 6.99 mmol) in DMF (30 mL), and the mixture was stirred at room temperature for 18 h. The reaction mixture was poured into water, extracted with EtOAc, dried over NaSO, and concentrated under reduced pressure to give methyl 2-[(2S)-2-[(tert-butyldimethylsilyl)oxy]propanamido]-5-chlorothiophene-3-carboxylate (91% yield).

[0208] Step C: A 10% aqueous solution of LiOH (6 mL) was added to a solution of crude methyl 2-[(2S)-2-[(tert-butyldimethylsilyl)oxy]propanamido]-5-chlorothiophene-3-carboxylate (2.42 g, 6.40 mmol) in THF (12 mL), and the mixture was stirred at room temperature for 3 days. The reaction mixture was concentrated under reduced pressure, diluted with water, and acidified with 10% HCl. The product was extracted into DCM, dried over Na2SO4, concentrated under reduced pressure, and crystallized to give (S)-5-chloro-2-(2-hydroxypropanamido)thiophene-3-carboxylic acid (25% yield).

[0209] Step D: 3-Aminopiperidine-2,6-dione (0.421 g, 2.56 mmol, hydrochloride), 3H-[1,2,3]triazolo[4,5-b]pyridin-3-ol (0.191 g, 1.41 mmol), triethylamine (0.330 g, 3.27 mmol), and EDC (0.397 g, 2.56 mmol) were added sequentially to a solution of (S)-5-chloro-2-(2-hydroxypropanamido)thiophene-3-carboxylic acid (0.319 g, 1.28 mmol) in DMA (2.5 mL). The reaction mixture was stirred at room temperature for 18 hours, concentrated under reduced pressure, and purified by HPLC to give 5-chloro-N-(2,6-dioxopiperidin-3-yl)-2-[(2S)-2-hydroxypropanamido]thiophene-3-carboxamide (29% yield). 1H NMR(400MHz,DMSO)δ12.59(s,1H), 10.91(s,1H), 8.65(d,J=8.3Hz,1H), 7.54(s,1H), 6.25(d,J=4.8Hz,1H), 4.82~4.7 1(m,1H), 4.34~4.23(m,1H), 2.85~2.71(m,1H), 2.61~2.53(m,1H), 2.20~2.04(m,1H), 2.01~1.90(m,1H), 1.32(d,3H) LCMS (m / z [M+H] + ):359.9 [Example]

[0210] Synthesis of 5-chloro-N-(2,6-dioxopiperidin-3-yl)-3-acetamidothiophene-2-carboxamide (18)

[0211] [ka]

[0212] Step A: Using exemplary method 2, above, with methyl 5-chloro-3-acetamidothiophene-2-carboxylate as the starting material, 5-chloro-3-acetamidothiophene-2-carboxylic acid was obtained in 72% yield.

[0213] Step B: 5-chloro-N-(2,6-dioxopiperidin-3-yl)-3-acetamidothiophene-2-carboxamide was synthesized using the general procedure shown in Reaction Scheme 1 and Synthesis Condition A, as described above (40% yield), and 5-chloro-3-acetamidothiophene-2-carboxylic acid as the starting material. 1 H NMR(400MHz,DMSO)δ10.91(s,1H), 10.87(s,1H), 8.61(d,J=8.2Hz,1H), 7.90(s,1H), 4 .75~4.64(m,1H), 2.85~2.70(m,1H), 2.60~2.52(m,2H), 2.11(s,3H), 2.00~1.91(m,1H) LCMS (m / z [M+H]+ ):330.2 [Example]

[0214] Synthesis of 4-chloro-5-cyclopropyl-N-(2,6-dioxopiperidin-3-yl)-2-acetamidothiophene-3-carboxamide (19)

[0215] [ka]

[0216] Step A: SO2Cl2 (0.207 g, 1.53 mmol) was added to a solution of methyl 5-cyclopropyl-2-acetamidothiophene-3-carboxylate (0.306 g, 1.28 mmol) in CHCl3 (15 mL). The reaction mixture was refluxed for 2 h, concentrated under reduced pressure, and diluted with water. The product was extracted with EtOAc, dried over Na2SO4, and concentrated under reduced pressure to give methyl 4-chloro-5-cyclopropyl-2-acetamidothiophene-3-carboxylate (81% yield).

[0217] Step B: Using exemplary method 2, above, with methyl 4-chloro-5-cyclopropyl-2-acetamidothiophene-3-carboxylate as the starting material, 4-chloro-5-cyclopropyl-2-acetamidothiophene-3-carboxylic acid was obtained in 78% yield.

[0218] Step C: HATU (0.370 g, 0.973 mmol) was added to a solution of 4-chloro-5-cyclopropyl-2-acetamidothiophene-3-carboxylic acid (0.211 g, 0.812 mmol), 3-aminopiperidine-2,6-dione (0.134 g, 1.05 mmol), and N-methylmorpholine (0.205 g, 2.03 mmol) in DMF (5 mL) at 0° C. The reaction mixture was stirred overnight at room temperature, diluted with water, extracted with AcOEt, dried over NaSO, concentrated under reduced pressure, and purified by HPLC to give 4-chloro-5-cyclopropyl-N-(2,6-dioxopiperidin-3-yl)-2-acetamidothiophene-3-carboxamide (41% yield). 1 H NMR (400MHz, DMSO) δ11.07(s,1H), 11.04(s,1H), 8.54(d,J=8.2Hz,1H), 4.90~4.78(m,1H), 2.89~2. 72(m,1H), 2.65~2.52(m,2H), 2.16(s,3H), 2.12~1.98(m,2H), 1.08~0.98(m,2H), 0.71~0.58(m,2H). LCMS (m / z [M+H] + ):369.8 [Example]

[0219] Synthesis of N-(2,6-dioxopiperidin-3-yl)-2-methoxythiophene-3-carboxamide (20)

[0220] [ka]

[0221] This compound was synthesized using the general procedure shown in Reaction Scheme 1 and Synthesis Condition B, above (17% yield), using 2-methoxythiophene-3-carboxylic acid as the starting material. 1H NMR(400MHz,DMSO)δ10.86(s,1H), 7.81(d,J=7.5Hz,1H), 7.10(d,J=5.9Hz,1H), 6.82(d,J=5.9H) z,1H), 4.74~4.63(m,1H), 4.09(s,3H), 2.83~2.69(m,1H), 2.57~2.51(m,1H), 2.18~1.99(m,2H) LCMS (m / z [M+H] + ):269.0 [Example]

[0222] Synthesis of (S)-N-(2,6-dioxopiperidin-3-yl)-2-methoxythiophene-3-carboxamide (21)

[0223] [ka]

[0224] This compound was synthesized using the general procedure shown in Reaction Scheme 1 and synthesis condition D, supra (54% yield), using 2-methoxythiophene-3-carboxylic acid (20 mg) and (S)-3-aminopiperidine-2,6-dione as starting materials. 1 H NMR(500MHz,DMSO)δ10.86(s,1H), 7.81(d,J=7.5Hz,1H), 7.11(d,J=5.9Hz,1H), 6.83(d,J=5.9Hz,1H), 4. 76~4.61(m,1H), 4.05(s,3H), 2.77(ddd,J=17.4,13.3,6.0Hz,1H), 2.48~2.44(m,1H), 2.17~2.01(m,2H). LCMS (m / z [M+H] + ):268.9 [Example]

[0225] Synthesis of (R)-N-(2,6-dioxopiperidin-3-yl)-2-methoxythiophene-3-carboxamide (22)

[0226] [ka]

[0227] This compound was synthesized using the general procedure shown in Reaction Scheme 1 and synthesis condition D, supra (49.5% yield) using 2-methoxythiophene-3-carboxylic acid (20 mg) and (R)-3-aminopiperidine-2,6-dione as starting materials. 1 H NMR(500MHz,DMSO)δ10.86(s,1H), 7.81(d,J=7.5Hz,1H), 7.11(d,J=5.9Hz,1H), 6.83(d,J=5.9Hz,1H), 4. 78~4.52(m,1H), 4.05(s,3H), 2.77(ddd,J=17.4,13.3,6.0Hz,1H), 2.48~2.45(m,1H), 2.17~1.99(m,2H). LCMS (m / z [M+H] + ):268.9 [Example]

[0228] Synthesis of 2-methoxy-N-(1-methyl-2,6-dioxopiperidin-3-yl)thiophene-3-carboxamide (23)

[0229] [ka]

[0230] This compound was synthesized using the general procedure shown in Reaction Scheme 1 and synthesis condition C, above (61% yield), using 2-methoxythiophene-3-carboxylic acid (20 mg) and 3-amino-1-methylpiperidine-2,6-dione trifluoroacetate (1.2 equivalents) as starting materials. 1H NMR(500MHz,DMSO)δ7.86(d,J=7.5Hz,1H), 7.11(d,J=5.9Hz,1H), 6.82(d,J=5.9Hz,1H), 4.76(ddd,J=12.2,7.4,5.7Hz,1 H), 4.05(s,3H), 3.01(s,3H), 2.85(ddd,J=17.4,13.1,6.1Hz,1H), 2.67(ddd,J=17.3,4.5,2.9Hz,1H), 2.17~2.01(m,2H). LCMS (m / z [M+H] + ):283.1 [Example]

[0231] Synthesis of methyl 2-(3-(2-methoxythiophene-3-carboxamido)-2,6-dioxopiperidin-1-yl)acetate (25)

[0232] [ka]

[0233] This compound was synthesized using the general procedure shown in Reaction Scheme 1 and synthesis condition C, above (44% yield), using 2-methoxythiophene-3-carboxylic acid (25.5 mg, 1.1 equivalents) and methyl 2-(3-amino-2,6-dioxopiperidin-1-yl)acetate (trifluoroacetate salt, 1.0 equivalents) as starting materials. 1 H NMR(500MHz,DMSO)δ7.88(d,J=7.6Hz,1H), 7.11(d,J=6.0Hz,1H), 6.83(d,J=5.9Hz,1H), 4.84(ddd,J=12.8,7.6,5.4Hz,1H), 4.50~4 .34(m,2H), 4.05(s,3H), 3.66(s,3H), 3.03~2.91(m,1H), 2.76(ddd,J=17.6,4.3,2.5Hz,1H), 2.24~2.13(m,1H), 2.13~2.05(m,1H). LCMS (m / z [M+H] + ):341.2 [Example]

[0234] Synthesis of N-(2,6-dioxopiperidin-3-yl)-2-methoxythiophene-3-sulfonamide (27)

[0235] [ka]

[0236] To a mixture of 3-aminopiperidine-2,6-dione hydrochloride (1.5 equiv.) and triethylamine (5 equiv.) in DCM (1.5 mL) cooled to 0° C. was added 2-methoxythiophene-3-sulfonyl chloride (20 mg). The reaction was stirred at room temperature for 18 h, concentrated under reduced pressure, and purified by flash column chromatography to give N-(2,6-dioxopiperidin-3-yl)-2-methoxythiophene-3-sulfonamide (66% yield). 1 H NMR(500MHz,DMSO)δ10.77(s,1H), 7.79(d,J=8.0Hz,1H), 6.98(d,J=6.0Hz,1H), 6.86(d,J=6.0Hz,1H), 4.15(dtd ,J=11.9,9.3,8.7,5.8Hz,1H), 3.99(s,3H), 2.68(td,J=12.1,6.1Hz,1H), 2.48~2.44(m,1H), 1.92~1.78(m,2H). LCMS (m / z [M+H] + ):305.1 [Example]

[0237] Synthesis of N-(2,6-dioxopiperidin-3-yl)-2-ethoxythiophene-3-carboxamide (28)

[0238] [ka]

[0239] This compound was synthesized using the general procedure shown in Reaction Scheme 1 and synthesis condition D, supra (78% yield) using 2-ethoxythiophene-3-carboxylic acid (15 mg) as the starting material. 1 H NMR(500MHz,DMSO)δ10.90(s,1H), 7.86(d,J=6.7Hz,1H), 7.09(d,J=5.9Hz,1 H), 6.83(d,J=5.9Hz,1H), 4.67(ddd,J=12.3,6.7,5.3Hz,1H), 4.28(q,J=7.0 Hz,2H), 2.77(ddd,J=16.8,13.3,5.2Hz,1H), 2.57~2.52(m,1H), 2.18(dtd,J =12.9,5.4,2.4Hz,1H), 2.01(qd,J=12.8,4.5Hz,1H), 1.45(t,J=7.0Hz,3H). LCMS (m / z [M+H] + ):283.1; [Example]

[0240] Synthesis of N-(2,6-dioxopiperidin-3-yl)-2-methoxy-4-methylthiophene-3-carboxamide (29)

[0241] [ka]

[0242] This compound was synthesized using the general procedure shown in Reaction Scheme 1 and Synthesis Condition C, above (21% yield) using 2-methoxy-4-methylthiophene-3-carboxylic acid (10 mg) as the starting material. 1H NMR(500MHz,DMSO)δ10.83(s,1H), 7.97(d,J=7.6Hz,1H), 6.47(q,J=1.2Hz,1H), 4.66(ddd,J=11.5,7.6,6.1Hz,1H), 3. 98(s,3H), 2.75(ddd,J=17.3,12.5,6.5Hz,1H), 2.52(dd,J=8.0,4.2Hz,1H), 2.23(d,J=1.1Hz,3H), 2.12~1.99(m,2H). LCMS (m / z [M−H] - ):281.1 [Example]

[0243] Synthesis of N-(2,6-dioxopiperidin-3-yl)-2-methoxy-5-methylthiophene-3-carboxamide (30)

[0244] [ka]

[0245] This compound was synthesized using the general procedure shown in Reaction Scheme 1 and Synthesis Condition C, above (76% yield) using 2-methoxy-5-methylthiophene-3-carboxylic acid (20 mg) as the starting material. 1 H NMR(500MHz,DMSO)δ10.85(s,1H), 7.74(d,J=7.5Hz,1H), 6.80(q,J=1.2Hz,1H), 4.68(ddd,J=11.9,7.5,6.0Hz,1H) , 4.00(s,3H), 2.77(ddd,J=17.3,12.9,6.3Hz,1H), 2.53(q,J=1.5Hz,1H), 2.33(d,J=1.3Hz,3H), 2.15~2.00(m,2H). LCMS (m / z [M+H] + ):283.05 [Example]

[0246] Synthesis of 5-(aminomethyl)-N-(2,6-dioxopiperidin-3-yl)-2-methoxythiophene-3-carboxamide (31)

[0247] [ka]

[0248] Step A: Using the general procedure shown in Reaction Scheme 1 and synthesis condition C, described above (47% yield), and 5-(((tert-butoxycarbonyl)amino)methyl)-2-methoxythiophene-3-carboxylic acid (20 mg) as the starting material, tert-butyl N-({4-[(2,6-dioxopiperidin-3-yl)carbamoyl]-5-methoxythiophen-2-yl}methyl)carbamate) was synthesized.

[0249] Step B: To a solution of tert-butyl N-({4-[(2,6-dioxopiperidin-3-yl)carbamoyl]-5-methoxythiophen-2-yl}methyl)carbamate) (8.7 mg, 0.022 mmol, 1 equiv.) in dioxane (2 mL) was added 36% HCl (0.2 mL). The reaction was stirred at room temperature for 3 hours and concentrated under reduced pressure to give 5-(aminomethyl)-N-(2,6-dioxopiperidin-3-yl)-2-methoxythiophene-3-carboxamide hydrochloride (100% yield). 1 H NMR(500MHz,DMSO)δ10.86(s,1H), 8.15(s,3H), 7.78(d,J=7.6Hz,1H), 7.28(s,1H), 4.69(ddd,J=12.7,7.6,5.5Hz,1H), 4.06(s,3H), 3 .39(s,2H), 2.77(ddd,J=17.2,13.5,5.7Hz,1H), 2.59~2.52(m,1H), 2.11(qd,J=12.9,4.4Hz,1H), 2.03(ddt,J=10.2,5.7,2.9Hz,1H). LCMS (m / z [M+H] + ):298.1 [Example]

[0250] Synthesis of 5-cyclopropyl-N-(2,6-dioxopiperidin-3-yl)-2-methoxythiophene-3-carboxamide (32)

[0251] [ka]

[0252] Step A: To a stirred solution of 3,5-dibromo-2-methoxythiophene (500.0 mg, 1.845 mmol) in toluene (9 mL) was added cyclopropylboronic acid (206 mg, 2.399 mmol) and KPO (784 mg, 3.69 mmol) in water (3 mL). The reaction mixture was purged with argon for 15 minutes, and then Pd(PPh) (320 mg, 0.277 mmol) was added. The reaction was stirred at 90 °C for 20 hours, filtered through a bed of Celite, concentrated under reduced pressure, and purified by flash column chromatography to give 3-bromo-5-cyclopropyl-2-methoxythiophene (34% yield).

[0253] Step B: To a stirred solution of 3-bromo-5-cyclopropyl-2-methoxythiophene (700 mg, 3 mmol) in THF (20 mL) was added n-BuLi (1.8 M in THF) (3.4 mL, 6.005 mmol) dropwise at −78° C. The reaction mixture was stirred at −78° C. for 1 h, and benzyl chloroformate (0.86 mL, 6 mmol) was added dropwise. The reaction was continued for 1 h, quenched with water, extracted with ethyl acetate, and concentrated under reduced pressure. The product was purified by flash column chromatography to give benzyl 5-cyclopropyl-2-methoxythiophene-3-carboxylate (23% yield).

[0254] Step C: To a stirred solution of benzyl 5-cyclopropyl-2-methoxythiophene-3-carboxylate (350 mg, 1.215 mmol) in THF (6 mL) and methanol (6 mL) at 5-10 °C was added 50% aqueous NaOH (12 mL). The reaction mixture was stirred at room temperature for 16 h and acidified with 6 M HCl. The solid was filtered, washed with pentane, and dried to give 5-cyclopropyl-2-methoxythiophene-3-carboxylic acid (76% yield).

[0255] Step D: Using the general procedure shown in Reaction Scheme 1 and synthesis condition C, above, 5-cyclopropyl-N-(2,6-dioxopiperidin-3-yl)-2-methoxythiophene-3-carboxamide was synthesized (76% yield) using 5-cyclopropyl-2-methoxythiophene-3-carboxylic acid (20 mg) as the starting material. 1 H NMR(500MHz,DMSO)δ10.85(s,1H), 7.74(d,J=7.5Hz,1H), 6.78(d,J=1.0Hz,1H), 4.67(ddd,J=12.1,7.5,5.8Hz,1H), 4.00 (s,3H), 2.77(ddd,J=17.3,13.1,6.1Hz,1H), 2.60~2.51(m,1H), 2.15~1.95(m,3H), 0.95~0.88(m,2H), 0.65~0.59(m,2H). LCMS (m / z [M+H] + ):309.0 [Example]

[0256] Synthesis of N-(2,6-dioxopiperidin-3-yl)-2-methoxy-5-phenylthiophene-3-carboxamide (33)

[0257] [ka]

[0258] Step A: To 3,5-dibromo-2-methoxythiophene (4.0 g, 14.71 mmol) in dry THF (30 mL) was added 2.5 M n-BuLi hexane solution (6.47 mL, 16.2 mmol) at −78 °C under an argon atmosphere, and the solution was stirred for 1 h. Tri-n-butylborate (8.35 mL, 29.42 mmol) was added to the reaction mixture, and the mixture was stirred for 1.5 h and allowed to warm to room temperature. 20% Na2CO3 (33.6 mL), iodobenzene (1.65 mL, 14.71 mmol), and Pd(PPh3)4 (0.85 g, 0.73 mmol) were added, and the reaction mixture was refluxed for 16 h. The reaction mixture was extracted with ether, dried over MgSO4, concentrated under reduced pressure, and purified by flash column chromatography to give 3-bromo-2-methoxy-5-phenylthiophene (50% yield).

[0259] Step B: 3-Bromo-2-methoxy-5-phenylthiophene (900 mg, 3.34 mmol) was dissolved in THF (15 mL) and cooled to −78° C. 1.8 M n-BuLi in hexane (3.7 mL, 6.68 mmol) was added dropwise at −78° C. The reaction mixture was stirred at −78° C. for 1 h, and benzyl chloroformate (0.95 mL, 6.68 mmol) was added dropwise. The reaction was continued for 1 h, quenched with water, extracted with ethyl acetate, and concentrated under reduced pressure. The product was purified by flash column chromatography to give benzyl 2-methoxy-5-phenylthiophene-3-carboxylate (23% yield).

[0260] Step C: Benzyl 2-methoxy-5-phenylthiophene-3-carboxylate (230 mg, 0.71 mmol) was dissolved in THF (5 mL). MeOH (5 mL) and 50% NaOH solution (10 mL) were added, and the reaction mixture was stirred at room temperature for 16 h and acidified with 6 M HCl. The solid was filtered, washed with pentane, and dried to give 2-methoxy-5-phenylthiophene-3-carboxylic acid (130 mg, 78%) as an off-white solid.

[0261] Step D: Using the general procedure shown in Reaction Scheme 1 and synthesis condition C, above, (71% yield), N-(2,6-dioxopiperidin-3-yl)-2-methoxy-5-phenylthiophene-3-carboxamide was synthesized using 2-methoxy-5-phenylthiophene-3-carboxylic acid (20 mg) as the starting material. 1 H NMR(500MHz,DMSO)δ10.88(s,1H), 7.87(d,J=7.6Hz,1H), 7.63~7.57(m,2H), 7.51(s,1H), 7.48~7.38(m,2H), 7.33~7.27(m,1H) ), 4.73(ddd,J=12.7,7.6,5.6Hz,1H), 4.12(s,3H), 2.79(ddd,J=17.3,13.4,5.8Hz,1H), 2.57~2.52(m,1H), 2.19~2.03(m,2H). LCMS (m / z [M+H] + ):345.2 [Example]

[0262] Synthesis of 5-bromo-N-(2,6-dioxopiperidin-3-yl)-2-methoxythiophene-3-carboxamide (34)

[0263] [ka]

[0264] This compound was synthesized using the general procedure shown in Reaction Scheme 1 and synthesis condition D, supra (21% yield) using 5-bromo-2-methoxythiophene-3-carboxylic acid (20 mg) as the starting material. 1H NMR(500MHz,DMSO)δ10.85(s,1H), 7.82(d,J=7.7Hz,1H), 7.19(s,1H), 4.77~4.61(m,1H), 4.04(s,3H), 2.76( ddd,J=17.4,13.5,5.7Hz,1H), 2.56(d,J=18.3Hz,1H), 2.14~2.04(m,1H), 2.01(dtd,J=8.2,5.6,2.6Hz,1H). LCMS (m / z [M+H] + ):346.8 35 [Example]

[0265] Synthesis of 5-(tert-butyl)-N-(2,6-dioxopiperidin-3-yl)-2-methoxythiophene-3-carboxamide (35)

[0266] [ka]

[0267] Step A: To a stirred solution of AlCl (2.1 g, 15.544 mmol) in DCM (20 mL) at −78 °C, tert-butyl bromide (1.9 g, 13.472 mmol) in DCM (10 mL) was added dropwise at −78 °C and stirred for 20 min. 3-Bromo-2-methoxythiophene (2 g, 10.363 mmol) in DCM (10 mL) was added dropwise and stirred for 2 h. The reaction mixture was warmed to room temperature and stirred for an additional 16 h. The reaction mixture was quenched with water, extracted with DCM, concentrated under reduced pressure, and purified by flash column chromatography to give 3-bromo-5-(tert-butyl)-2-methoxythiophene (31% yield).

[0268] Step B: To a stirred solution of 3-bromo-5-(tert-butyl)-2-methoxythiophene (900 mg, 3.614 mmol) in THF (22 mL) was added n-BuLi (1.8 M in THF) (4 mL, 7.229 mmol) dropwise at −78° C. The reaction mixture was stirred at −78° C. for 1 h, and benzyl chloroformate (1.03 mL, 7.229 mmol) was added dropwise. The reaction was continued for 1 h, quenched with water, extracted with ethyl acetate, and concentrated under reduced pressure. The product was purified by flash column chromatography to afford benzyl 5-(tert-butyl)-2-methoxythiophene-3-carboxylate (220 mg, 20% yield) as a pale yellow oil.

[0269] Step C: To a stirred solution of benzyl 5-(tert-butyl)-2-methoxythiophene-3-carboxylate (450 mg, 1.47 mmol) in THF (8 mL) and methanol (8 mL) at 5° C. was added 50% aqueous NaOH (16 mL). The reaction mixture was stirred at room temperature for 16 h and acidified with 6 M HCl. The solid was filtered, washed with pentane, and dried to give 5-(tert-butyl)-2-methoxythiophene-3-carboxylic acid (69% yield).

[0270] Step D: Using the general procedure shown in Reaction Scheme 1 and synthesis condition C, above (75% yield), 5-(tert-butyl)-N-(2,6-dioxopiperidin-3-yl)-2-methoxythiophene-3-carboxamide was synthesized using 5-(tert-butyl)-2-methoxythiophene-3-carboxylic acid (20 mg) as the starting material. 1 H NMR(500MHz,DMSO)δ10.85(s,1H), 7.75(d,J=7.5Hz,1H), 6.83(s,1H), 4.68(ddd,J=12.2,7.5,5.7Hz,1H ), 4.02(s,3H), 2.77(ddd,J=17.3,13.3,6.0Hz,1H), 2.57~2.52(m,1H), 2.17~1.99(m,2H), 1.31(s,9H). LCMS (m / z [M+H]+ ):325.2 [Example]

[0271] Synthesis of 2-amino-N-(2,6-dioxopiperidin-3-yl)thiophene-3-carboxamide (36)

[0272] [ka]

[0273] tert-Butyl (3-((2,6-dioxopiperidin-3-yl)carbamoyl)thiophen-2-yl)carbamate (1.0 g, 2.8 mmol) was dissolved in dichloromethane (10 mL) and a 10% solution of HCl in dioxane (3 mL) was added dropwise. The reaction mixture was stirred at room temperature for 48 hours. The mixture was concentrated under reduced pressure and purified by preparative HPLC to give 2-amino-N-(2,6-dioxopiperidin-3-yl)thiophene-3-carboxamide (4% yield). 1 H NMR(500MHz,DMSO)δ10.78(s,1H), 7.96(d,J=8.3Hz,1H), 7.22(s,2H), 7.07(d,J=5.8Hz,1H), 6.28(d,J=8 .3Hz,1H), 4.69~4.61(m,1H), 2.82~2.68(m,1H), 2.57~2.52(m,1H), 2.15~2.04(m,1H), 1.96~1.84(m,1H). LCMS (m / z [M+H] + ):254.0 [Example]

[0274] Synthesis of 5-chloro-N-(2,6-dioxopiperidin-3-yl)-2-methoxythiophene-3-carboxamide (37)

[0275] [ka]

[0276] This compound was synthesized using the general procedure shown in Reaction Scheme 1 and Synthesis Condition A, above (24% yield), with 5-chloro-2-methoxythiophene-3-carboxylic acid as the starting material. 1 H NMR(400MHz,DMSO)δ10.87(s,1H), 7.83(d,J=7.6Hz,1H), 7.08(s,1H), 4.74~4. 60(m,1H), 4.04(s,3H), 2.85~2.68(m,1H), 2.58~2.51(m,1H), 2.18~1.93(m,2H) LCMS (m / z [M+H] + ):303.0 [Example]

[0277] Synthesis of N-{5-chloro-3-[(2,6-dioxopiperidin-3-yl)sulfamoyl]thiophen-2-yl}acetamide (38)

[0278] [ka]

[0279] Step 1: Synthesis of N-(2,6-dioxopiperidin-3-yl)-2-nitrothiophene-3-sulfonamide 2-Nitrothiophene-3-sulfonyl chloride (3.4 g, 15 mmol) was added to a solution of 3-aminopiperidine-2,6-dione (2.06 g, 12.5 mmol, hydrochloride salt) in pyridine (20 mL) cooled to −10° C. The resulting mixture was stirred at room temperature for 16 hours. The mixture was concentrated under reduced pressure, diluted with water, acidified to pH=3, and extracted with EtOAc (3×20 mL). The combined organic layers were washed with water, dried over NaSO, and concentrated under reduced pressure. The crude product was purified by preparative HPLC to give 0.895 g of N-(2,6-dioxopiperidin-3-yl)-2-nitrothiophene-3-sulfonamide (22% yield).

[0280] Step 2: Synthesis of N-{3-[(2,6-dioxopiperidin-3-yl)sulfamoyl]thiophen-2-yl}acetamide Fe (0.47 g, 8.42 mmol) was added to a solution of N-(2,6-dioxopiperidin-3-yl)-2-nitrothiophene-3-sulfonamide (0.895 g, 2.80 mmol) in acetic acid (6 mL). The reaction mixture was stirred at 50° C. for 3 hours. Acetic anhydride (0.315 g, 3.09 mmol) was added at room temperature, and the resulting mixture was stirred at 50° C. for 16 hours. The mixture was concentrated under reduced pressure, and the residue was purified by preparative HPLC to give 0.362 g of N-{3-[(2,6-dioxopiperidin-3-yl)sulfamoyl]thiophen-2-yl}acetamide (45% yield).

[0281] Step 3: Synthesis of P N-{5-chloro-3-[(2,6-dioxopiperidin-3-yl)sulfamoyl]thiophen-2-yl}acetamide NCS (0.161 g, 1.21 mmol) was added to a solution of N-{3-[(2,6-dioxopiperidin-3-yl)sulfamoyl]thiophen-2-yl}acetamide (0.362 g, 1.09 mmol) in DMF (2 mL). The reaction mixture was stirred at room temperature for 16 hours, then it was diluted with water and extracted with EtOAc (3 × 10 mL). The organic extract was dried over NaSO, concentrated, and purified by preparative HPLC to give 0.146 g of N-{5-chloro-3-[(2,6-dioxopiperidin-3-yl)sulfamoyl]thiophen-2-yl}acetamide (37% yield). 1 H NMR:(400MHz,DMSO-d6)δ10.90(s,1H), 10.33(s,1H), 8.37(d,J=8.0Hz,1H), 7.10(s,1H) , 4.41~4.24(m,1H), 2.75~2.63(m,1H), 2.59~2.52(m,1H), 2.26(s,3H), 2.00~1.86(m,2H) LCMS (m / z [M+H] - ):365.8 [Example]

[0282] Synthesis of N-(2,6-dioxopiperidin-3-yl)-2-(1H-pyrazol-1-yl)thiophene-3-carboxamide (39)

[0283] [ka]

[0284] This compound was synthesized using the general procedure shown in Reaction Scheme 1 and Synthesis Condition B, as described above (32% yield), and 2-(1H-pyrazol-1-yl)thiophene-3-carboxylic acid as the starting material. 1 H NMR(500MHz,DMSO)δ10.87(s,1H), 8.80(d,J=8.3Hz,1H), 8.39~8.36(m,1H), 7.75~7.70(m,1H), 7.41(d,J=5.5Hz,1H), 7.19(d, J=5.5Hz,1H)6.52~6.46(m,1H), 4.73~4.64(m,1H), 2.83~2.71(m,1H), 2.57~2.51(m,1H), 2.13~2.02(m,1H), 2.01~1.93(m,1H). LCMS (m / z [M+H] + ):305.1 [Example]

[0285] Synthesis of 2-amino-5-chloro-N-(2,6-dioxopiperidin-3-yl)thiophene-3-carboxamide (40)

[0286] [ka]

[0287] Step A: N-chlorosuccinimide (2.2 g, 16.5 mmol) was added to a solution of 2-((tert-butoxycarbonyl)amino)thiophene-3-carboxylic acid (3.3 g, 13.6 mmol) in DMF (20 mL), and the reaction mixture was stirred at room temperature for 2 hours. The mixture was diluted with water and filtered. The solid was washed with water and dried to give 2-{[(tert-butoxy)carbonyl]amino}-5-chlorothiophene-3-carboxylic acid (84% yield).

[0288] Step B: Using the general procedure shown in Reaction Scheme 1 and synthesis condition A, as described above (81% yield), and 2-{[(tert-butoxy)carbonyl]amino}-5-chlorothiophene-3-carboxylic acid as the starting material, tert-butyl N-{5-chloro-3-[(2,6-dioxopiperidin-3-yl)carbamoyl]thiophen-2-yl}carbamate was synthesized.

[0289] Step C: 10% HCl in dioxane (2 mL) was added dropwise to a solution of tert-butyl N-{5-chloro-3-[(2,6-dioxopiperidin-3-yl)carbamoyl]thiophen-2-yl}carbamate (2.0 g, 5.16 mmol) in dichloromethane (15 mL), and the mixture was stirred in an ultrasonic bath for 8 hours, concentrated under reduced pressure, and purified by HPLC to give 2-amino-5-chloro-N-(2,6-dioxopiperidin-3-yl)thiophene-3-carboxamide (15% yield). 1 H NMR(400MHz,DMSO)δ10.81(s,1H), 7.97(d,J=8.3Hz,1H), 7.41(brs,2H), 7.13(s,1H), 4.6 6~4.56(m,1H), 2.83~2.68(m,1H), 2.59~2.52(m,1H), 2.13~1.99(m,1H), 1.97~1.82(m,1H) LCMS (m / z [M+H] + ):288.1 [Example]

[0290] Synthesis of N-(2,6-dioxopiperidin-3-yl)-2-(1H-pyrrol-1-yl)thiophene-3-carboxamide (41)

[0291] [ka]

[0292] This compound was synthesized using the general procedure shown in Reaction Scheme 1 and Synthesis Condition B, as described above (55% yield), and 2-(1H-pyrrol-1-yl)thiophene-3-carboxylic acid as the starting material. 1 H NMR(400MHz,DMSO)δ10.84(s,1H), 8.47(d,J=8.3Hz,1H), 7.40(d,J=5.7Hz,1H), 7.19(d,J=5.7Hz,1H)7.11~ 7.01(m,2H), 6.28~6.12(m,2H), 4.70~4.59(m,1H), 2.84~2.65(m,1H), 2.58~2.52(m,1H), 2.09~1.85(m,2H). LCMS (m / z [M+H] + ):304.1 [Example]

[0293] Synthesis of N-(2,6-dioxopiperidin-3-yl)-2-acetamido-5-(trifluoromethyl)thiophene-3-carboxamide (42)

[0294] [ka]

[0295] Step A: Triethylamine (0.397 g, 3.92 mmol) and acetic anhydride (0.400 g, 3.92 mmol) were added to a solution of ethyl 2-amino-5-(trifluoromethyl)thiophene-3-carboxylate (0.852 g, 3.56 mmol) in MeCN (15 mL). The reaction mixture was stirred overnight at 50 °C, cooled to room temperature, concentrated under reduced pressure, extracted with DCM, dried over Na SO , and concentrated to give ethyl 2-acetamido-5-(trifluoromethyl)thiophene-3-carboxylate (91% yield).

[0296] Step B: A 10% solution of LiOH (0.081 g, 3.4 mmol) was added to a solution of ethyl 2-acetamido-5-(trifluoromethyl)thiophene-3-carboxylate (0.911 g, 3.24 mmol) in THF (15 mL), and the resulting mixture was stirred at room temperature for 5 days. The solvent was evaporated under reduced pressure, and the residue was diluted with water and washed with MTBE. The aqueous layer was acidified with citric acid, and the precipitate was filtered, washed with water, and dried to give 2-acetamido-5-(trifluoromethyl)thiophene-3-carboxylic acid (28% yield).

[0297] Step C: N-(2,6-dioxopiperidin-3-yl)-2-acetamido-5-(trifluoromethyl)thiophene-3-carboxamide was synthesized using the general procedure shown in Reaction Scheme 1 and synthesis condition A, as described above (26% yield), and 2-acetamido-5-(trifluoromethyl)thiophene-3-carboxylic acid as the starting material. 1 H NMR(400MHz,DMSO)δ11.98(s,1H), 10.93(s,1H), 9.00~8.81(m,1H), 8.13(s,1H), 4.8 7~4.62(m,1H), 2.98~2.65(m,2H), 2.28(s,3H), 2.20~2.08(m,1H), 2.07~1.88(m,1H). LCMS (m / z [M+H] + ):364.2 [Example]

[0298] Synthesis of 4-chloro-N-(2,6-dioxopiperidin-3-yl)-2-acetamidothiophene-3-carboxamide (43)

[0299] [ka]

[0300] Step A: A solution of methyl 4-chloroacetoacetate (13.3 g, 88.3 mmol) in THF (30 mL) was added dropwise to a suspension of 60% NaH (4.45 g, 111 mmol) in THF (150 mL) at 0 °C. After the addition was complete, the reaction mixture was warmed to room temperature and stirred for 20 min. The reaction mixture was then cooled to 0 °C, and a solution of acetyl isothiocyanate (8.92 g, 88.2 mmol) in THF (30 mL) was added dropwise. After the addition was complete, the reaction mixture was quenched with NH4Cl solution at 0 °C, concentrated under reduced pressure, and diluted with water and ethyl acetate. The mixture was filtered, and the solid was dried to give methyl 2-acetamido-4-oxo-4,5-dihydrothiophene-3-carboxylate (4% yield).

[0301] Step B: POCl (1.05 g, 6.85 mmol) was added to a suspension of methyl 2-acetamido-4-oxo-4,5-dihydrothiophene-3-carboxylate (0.74 g, 3.44 mmol) in dioxane (10 mL) and refluxed for 2 h. The reaction mixture was cooled and poured into ice-cold water, and the product was extracted with EtOAc, dried over NaSO, and concentrated under reduced pressure to give methyl 4-chloro-2-acetamidothiophene-3-carboxylate (26% yield).

[0302] Step C: 4-chloro-2-acetamidothiophene-3-carboxylic acid was synthesized using Exemplary Method 2, above, with methyl 4-chloro-2-acetamidothiophene-3-carboxylate as the starting material.

[0303] Step D: 4-chloro-N-(2,6-dioxopiperidin-3-yl)-2-acetamidothiophene-3-carboxamide was synthesized using the general procedure shown in Reaction Scheme 1 and synthesis condition B, as described above (17% yield), and 4-chloro-2-acetamidothiophene-3-carboxylic acid as the starting material. 1 H NMR(400MHz,DMSO)δ11.13(s,1H), 11.07(s,1H), 8.54(d,J=8.2Hz 1H), 7.09(s,1H), 4.93~4.79(m,1H), 2.89~2.74(m,1H), 2.62~2.52(m,1H), 2.19(s,3H), 2.15~2.01(m,2H). LCMS (m / z [M+H] + ):330.0 [Example]

[0304] Synthesis of 5-cyclopropyl-N-(2,6-dioxopiperidin-3-yl)-2-acetamidothiophene-3-carboxamide (44)

[0305] [ka]

[0306] Step A: Using exemplary method 3, above, methyl 5-cyclopropyl-2-acetamidothiophene-3-carboxylate was synthesized in 69% yield using 2-amino-5-cyclopropylthiophene-3-carboxylate as the starting material.

[0307] Step B: Using exemplary method 2, above, and methyl 5-cyclopropyl-2-acetamidothiophene-3-carboxylate as the starting material, 5-cyclopropyl-2-acetamidothiophene-3-carboxylic acid was synthesized in 57% yield.

[0308] Step C: 5-cyclopropyl-N-(2,6-dioxopiperidin-3-yl)-2-acetamidothiophene-3-carboxamide was synthesized using the general procedure shown in Reaction Scheme 1 and synthesis condition B, as described above (56% yield), and 5-cyclopropyl-2-acetamidothiophene-3-carboxylic acid as the starting material. 1 H NMR(400MHz,DMSO)δ11.73(s,1H), 10.89(s,1H), 8.52(d,J=8.5Hz,1H), 7.09(s,1H), 4.76~4.64(m,1H), 2.85 ~2.71(m,1H), 2.62~2.53(m,1H), 2.22~2.04(m,4H), 2.04~1.89(m,2H), 1.00~0.87(m,2H), 0.68~0.57(m,2H) LCMS (m / z [M+H] + ):336.2 [Example]

[0309] Synthesis of 2-benzamido-5-chloro-N-(2,6-dioxopiperidin-3-yl)thiophene-3-carboxamide (45)

[0310] [ka]

[0311] Step A: Using exemplary method 1, described above (69% yield), methyl 2-benzamido-5-chlorothiophene-3-carboxylate was synthesized using methyl 2-benzamidothiophene-3-carboxylate as the starting material.

[0312] Step B: Using exemplary method 2, above (70% yield), 2-benzamido-5-chlorothiophene-3-carboxylic acid was synthesized using methyl 2-benzamido-5-chlorothiophene-3-carboxylate as the starting material.

[0313] Step C: 2-benzamido-5-chloro-N-(2,6-dioxopiperidin-3-yl)thiophene-3-carboxamide was synthesized using the general procedure shown in Reaction Scheme 1 and synthesis condition A, as described above (50% yield), and 2-benzamido-5-chlorothiophene-3-carboxylic acid as the starting material. 1 H NMR(500MHz,DMSO)δ13.20(s,1H), 10.92(s,1H), 8.86~8.73(m,1H), 8.00~7.84(m,2H), 7.72~7.50(m ,4H), 4.95~4.81(m,1H), 2.89~2.74(m,1H), 2.67~2.56(m,1H), 2.22~2.08(m,1H), 2.06~1.93(m,1H) LCMS (m / z [M+H] + ):392.2 [Example]

[0314] Synthesis of 5-chloro-N-(2,6-dioxopiperidin-3-yl)-2-(2-phenylacetamido)thiophene-3-carboxamide (46)

[0315] [ka]

[0316] Step A: Using exemplary method 1, described above (75% yield), methyl 5-chloro-2-(2-phenylacetamido)thiophene-3-carboxylate was synthesized using methyl 2-(2-phenylacetamido)thiophene-3-carboxylate as the starting material.

[0317] Step B: Using exemplary method 2, above (82% yield), 5-chloro-2-(2-phenylacetamido)thiophene-3-carboxylic acid was synthesized using methyl 5-chloro-2-(2-phenylacetamido)thiophene-3-carboxylate as the starting material.

[0318] Step C: 5-chloro-N-(2,6-dioxopiperidin-3-yl)-2-(2-phenylacetamido)thiophene-3-carboxamide was synthesized using the general procedure shown in Reaction Scheme 1 and synthesis condition A, above (15% yield), with 5-chloro-2-(2-phenylacetamido)thiophene-3-carboxylic acid as the starting material. 1 H NMR (400MHz, DMSO) δ11.94(s,1H), 10.91(s,1H), 8.72~8.54(m,1H), 7.66~7.45(m,2H), 7.43~7.21(m,4H), 4.82~4.64(m,1H), 3.90(s,2H), 2.89~2.71(m,1H), 2.61~2.53(m,1H), 2.17~2.02(m,1H), 2.01~1.88(m,1H) LCMS (m / z [M+H] + ):406.2 [Example]

[0319] Synthesis of 2-cyclopropyl-N-(2,6-dioxopiperidin-3-yl)furan-3-carboxamide (47)

[0320] [ka]

[0321] This compound was synthesized using the general procedure shown in Reaction Scheme 1 and Synthesis Condition C, above (53% yield), using 2-cyclopropylfuran-3-carboxylic acid (20 mg) as the starting material. 1H NMR(500MHz,DMSO)δ10.83(s,1H), 8.24(d,J=8.5Hz,1H), 7.42(d,J=2.0Hz,1H ), 6.83(d,J=2.1Hz,1H), 4.70(ddd,J=12.4,8.3,5.3Hz,1H), 2.87(tt,J=8.5, 5.2Hz,1H), 2.78(ddd,J=17.4,13.4,5.6Hz,1H), 2.60~2.51(m,1H), 2.10(qd, J=13.0,4.4Hz,1H), 1.98~1.92(m,1H), 1.00~0.95(m,2H), 0.91~0.87(m,2H). LCMS (m / z [M+H] + ):263.2 [Example]

[0322] Synthesis of tert-butyl (3-((2,6-dioxopiperidin-3-yl)carbamoyl)furan-2-yl)(methyl)carbamate (48)

[0323] [ka]

[0324] Step A: To a solution of tert-butyl (3-bromofuran-2-yl)carbamate (2 g, 7.6 mmol) in DMF (40 ml) was added sodium hydride (0.28 g, 11.5 mmol) at 0° C. under nitrogen, and the reaction mixture was stirred at room temperature for 1 h. It was then recooled to 0° C., methyl iodide (1.42 ml, 23 mmol) was added, and the reaction mixture was stirred at room temperature for an additional 1 h. The reaction mixture was diluted with ethyl acetate, washed with water and brine, dried over NaSO, concentrated under reduced pressure, and purified by flash column chromatography to give 1.27 g (60% yield) of tert-butyl (3-bromofuran-2-yl)(methyl)carbamate.

[0325] Step B: n-Butyllithium (3.37 ml, 5.43 mmol, 1.6 M in hexane) was slowly added to a solution of tert-butyl (3-bromofuran-2-yl)(methyl)carbamate (1.5 g, 5.43 mmol) in THF (30 ml) at −78° C. under nitrogen. After 15 min of stirring, a stream of dry CO was bubbled through the solution for 30 min. The reaction was quenched with 1 M HCl (10 ml), extracted with DCM, dried over NaSO, and concentrated under reduced pressure to give 500 mg (38% yield) of 2-((tert-butoxycarbonyl)(methyl)amino)furan-3-carboxylic acid.

[0326] Step C: Using the general procedure shown in Reaction Scheme 1 and synthesis condition B, above (59% yield), tert-butyl (3-((2,6-dioxopiperidin-3-yl)carbamoyl)furan-2-yl)(methyl)carbamate was synthesized using 2-((tert-butoxycarbonyl)(methyl)amino)furan-3-carboxylic acid (20 mg) as the starting material. 1 H NMR(500MHz,DMSO)δ10.84(s,1H), 8.28(d,J=8.3Hz,1H), 7.52(d,J=2.3Hz,1H), 6.89(d,J=2.3Hz,1H), 4.70(ddd,J=12.2,8.2,5.3Hz,1H), 3.03(s ,3H), 2.78(ddd,J=17.3,13.3,5.5Hz,1H), 2.54(dd,J=4.5,2.9Hz,1H),2 .13~2.00(m,1H), 1.94(dtd,J=10.2,5.5,2.9Hz,1H), 1.45~1.19(m,9H). LCMS (m / z [M−H] - ):350.3 [Example]

[0327] Synthesis of tert-butyl ((5-((2,6-dioxopiperidin-3-yl)carbamoyl)thiophen-2-yl)methyl)carbamate (49)

[0328] [ka]

[0329] This compound was synthesized using the general procedure shown in Reaction Scheme 1 and synthesis condition C, above (24% yield), using 5-[(tert-butoxycarbonylamino)methyl]thiophene-2-carboxylic acid (23 mg) as the starting material. 1 H NMR(500MHz,DMSO)δ10.85(s,1H), 8.68(d,J=8.4Hz,1H), 7.59(d,J=3.7Hz,1H), 6.94(d,J=3.7Hz,1H), 4.70(ddd,J=12.7,8.4,5.3Hz, 1H), 4.27(d,J=6.0Hz,2H), 2.78(ddd,J=17.4,13.3,5.5Hz,1H), 2.52~2.51(m,2H), 2.15~2.04(m,1H), 2.00~1.92(m,1H), 1.40(s,9H). LCMS (m / z [M−H] - ):366.1 [Example]

[0330] Synthesis of 5-(aminomethyl)-N-(2,6-dioxopiperidin-3-yl)thiophene-2-carboxamide (50)

[0331] [ka]

[0332] To a suspension of tert-butyl ((5-((2,6-dioxopiperidin-3-yl)carbamoyl)thiophen-2-yl)methyl)carbamate (5 mg, 0.014 mmol, 1 equiv.) in DCM (0.1 mL) was added TFA (20 μL) and the mixture was stirred at room temperature for 2 days. The reaction mixture was evaporated under reduced pressure, suspended in ACN, and then 4 N HCl in 1,4-dioxane was added (50 μL). Concentration under reduced pressure gave 5-(aminomethyl)-N-(2,6-dioxopiperidin-3-yl)thiophene-2-carboxamide hydrochloride (92% yield). 1 H NMR(500MHz,DMSO)δ10.88(s,1H), 8.86(d,J=8.4Hz,1H), 8.29(s,3H), 7.71(d,J=3.8Hz,1H), 7.25(d,J=3.8Hz,1H), 4.77~4.65(m,1H), 4. 27(s,2H), 2.79(ddd,J=17.4,13.4,5.5Hz,1H), 2.52~2.51(m,1H), 2.12(qd,J=13.2,4.7Hz,1H), 1.97(dddd,J=10.9,8.2,5.4,2.8Hz,1H). LCMS (m / z [M+H] + ):268.0 [Example]

[0333] tert-Butyl ((5-((2,6-dioxopiperidin-3-yl)carbamoyl)thiophen-3-yl)methyl)carbamate (51)

[0334] [ka]

[0335] This compound was synthesized using the general procedure shown in Reaction Scheme 1 and Synthesis Condition C, above (31% yield) using 4-((tert-butoxycarbonyl)aminomethyl)thiophene-2-carboxylic acid (37.8 mg) as the starting material. 1H NMR(500MHz,DMSO)δ10.85(s,1H), 8.77(d,J=8.4Hz,1H), 7.65(d,J=1.3Hz,1H), 7.47(d,J=1.2Hz,1H), 4.71(ddd,J=12.6,8.4,5.3Hz,1H), 4.09(d ,J=5.9Hz,2H), 2.78(ddd,J=17.4,13.3,5.5Hz,1H), 2.52~2.51(m,2H), 2 .16~2.04(m,1H), 1.96(dddd,J=10.9,8.2,5.4,2.9Hz,1H), 1.39(s,9H). LCMS (m / z [M−H] - ):366.2 [Example]

[0336] 4-(aminomethyl)-N-(2,6-dioxopiperidin-3-yl)thiophene-2-carboxamide (52)

[0337] [ka]

[0338] To a suspension of tert-butyl ((5-((2,6-dioxopiperidin-3-yl)carbamoyl)thiophen-3-yl)methyl)carbamate (15.8 mg, 0.043 mmol) in DCM (0.5 mL) was added TFA (0.1 mL) and the mixture was stirred at room temperature for 2 days. The mixture was evaporated and purified by HPLC to give 4-(aminomethyl)-N-(2,6-dioxopiperidin-3-yl)thiophene-2-carboxamidoformate (63% yield). 1 H NMR(500MHz,DMSO)δ10.85(s,1H), 8.78(d,J=8.4Hz,1H), 7.78(d,J=1.2Hz,1 H), 7.71(s,1H), 4.73(ddd,J=12.6,8.4,5.4Hz,1H), 3.93(s,2H), 2.79(ddd,J =17.4,13.3,5.5Hz,1H), 2.56(dd,J=4.4,3.0Hz,1H), 2.52(dd,J=4.3,2.5Hz ,1H), 2.11(qd,J=12.9,4.5Hz,1H), 1.96(dddd,J=10.9,8.2,5.4,2.9Hz,1H). LCMS (m / z [M+H] + ):268.1 [Example]

[0339] Synthesis of N-(2,6-dioxopiperidin-3-yl)-4-hydroxythiophene-2-carboxamide (53)

[0340] [ka]

[0341] This compound was synthesized using the general procedure shown in Reaction Scheme 1 and synthesis condition D, supra (20% yield) using 4-hydroxythiophene-2-carboxylic acid (20 mg) as the starting material. 1 H NMR(500MHz,DMSO)δ10.86(s,1H), 9.75(s,1H), 8.67(d,J=8.4Hz,1H), 7.35(d,J=1.7Hz,1H), 6.55(d,J=1.7Hz,1H), 4.7 1(ddd,J=12.5,8.4,5.4Hz,1H), 2.85~2.73(m,1H), 2.58~2.52(m,1H), 2.10(qd,J=13.0,4.5Hz,1H), 2.02~1.92(m,1H). LCMS (m / z [M−H] - ):253.1 [Example]

[0342] Synthesis of N-(2,6-dioxopiperidin-3-yl)-4-methoxythiophene-3-carboxamide (54)

[0343] [ka]

[0344] This compound was synthesized using the general procedure shown in Reaction Scheme 1 and synthesis condition D, supra (32% yield) using 4-methoxythiophene-3-carboxylic acid (20 mg) as the starting material. 1 H NMR(500MHz,DMSO)δ10.89(s,1H), 8.12(d,J=7.4Hz,1H), 8.09(d,J=3.6Hz,1H), 6.81(d,J=3.6Hz,1H), 4.72(dt,J=10.3,7.5Hz,1H), 3.89(s,3H), 2.85~2.72(m,1H), 2.54(t,J=3.5Hz,1H), 2.15~2.05(m,2H). LCMS (m / z [M+H] + ):269.0 [Example]

[0345] Synthesis of 5-(aminomethyl)-N-(2,6-dioxopiperidin-3-yl)-4-methoxythiophene-3-carboxamide (55)

[0346] [ka]

[0347] Step A: (4-Bromo-3-methoxythiophen-2-yl)methanol (0.8 g, 3.58 mmol) was dissolved in DCM (10 mL). TBDMSCl (1.08 g, 7.17 mmol) and imidazole (0.6 g, 8.96 mmol) were added, and the reaction mixture was stirred at room temperature for 48 h, diluted, washed with water, dried over NaSO, concentrated under reduced pressure, and purified by flash column chromatography to give ((4-bromo-3-methoxythiophen-2-yl)methoxy)(tert-butyl)dimethylsilane (82% yield).

[0348] Step B: ((4-Bromo-3-methoxythiophen-2-yl)methoxy)(tert-butyl)dimethylsilane (1.5 g, 4.45 mmol) was dissolved in THF (20 mL) and cooled to −78 °C. n-BuLi (3.7 mL, 6.67 mmol) was added dropwise and the reaction mixture was stirred for 30 min. Methyl chloroformate (0.62 mL, 8.0 mmol) was added and stirring was continued for 2 h at −78 °C. Ammonium chloride solution was added and the product was extracted with ethyl acetate, dried over NaSO, concentrated under reduced pressure, and purified by flash column chromatography to give methyl 5-(((tert-butyldimethylsilyl)oxy)methyl)-4-methoxythiophene-3-carboxylate (51% yield).

[0349] Step C: Methyl 5-(((tert-butyldimethylsilyl)oxy)methyl)-4-methoxythiophene-3-carboxylate (0.8 g, 2.52 mmol) was dissolved in THF (10 mL) and TBAF (1 M solution in THF) (5.06 mL, 5.0 mmol) was added at 0° C. The reaction mixture was stirred at room temperature for 4 h, diluted with ethyl acetate, and washed with water. The organic phase was dried over NaSO and concentrated under reduced pressure to give methyl 5-(hydroxymethyl)-4-methoxythiophene-3-carboxylate (88% yield).

[0350] Step D: Methyl 5-(hydroxymethyl)-4-methoxythiophene-3-carboxylate (0.2 g, 1.0 mmol) was dissolved in toluene (3 mL) and cooled to 0 °C. DBU (0.19 mL, 1.3 mmol) and DPPA (0.26 mL, 1.2 mmol) were added, and the reaction mixture was stirred at room temperature for 16 h. The mixture was diluted with ethyl acetate, washed with water, dried over NaSO, concentrated under reduced pressure, and purified by flash column chromatography to give methyl 5-(azidomethyl)-4-methoxythiophene-3-carboxylate (78% yield).

[0351] Step E: Methyl 5-(azidomethyl)-4-methoxythiophene-3-carboxylate (40 mg, 0.176 mmol) was dissolved in MeOH (5 mL) and 10% Pd / C (20 mg) was added. The reaction mixture was stirred under an H atmosphere at room temperature for 3 h, filtered through a Celite bed, and concentrated under reduced pressure to give methyl 5-(aminomethyl)-4-methoxythiophene-3-carboxylate, which was used directly in the next step.

[0352] Step F: Methyl 5-(aminomethyl)-4-methoxythiophene-3-carboxylate (215 mg, 1.06 mmol) was dissolved in dioxane-water (1:1; 6 mL). Triethylamine (0.22 mL, 1.6 mmol) and BocO (0.29 mL, 1.28 mmol) were added, and the reaction mixture was stirred at room temperature for 18 h, diluted with ethyl acetate, washed with water, dried over NaSO, concentrated under reduced pressure, and purified by flash column chromatography to give methyl 5-(((tert-butoxycarbonyl)amino)methyl)-4-methoxythiophene-3-carboxylate (38% yield, two steps).

[0353] Step G: To 5-(((tert-butoxycarbonyl)amino)methyl)-4-methoxythiophene-3-carboxylate (200.0 mg, 0.66 mmol) in THF (1.0 mL) was added methanol (1.0 mL) and 50% aqueous NaOH (2 mL), and the reaction mixture was stirred at room temperature for 16 h, diluted with water, and acidified with citric acid. The product was extracted with ethyl acetate, concentrated, and triturated with diethyl ether to give 5-(((tert-butoxycarbonyl)amino)methyl)-4-methoxythiophene-3-carboxylic acid (83% yield).

[0354] Step H: Using the general procedure shown in Reaction Scheme 1 and synthesis condition B, described above (23% yield), and 5-(((tert-butoxycarbonyl)amino)methyl)-4-methoxythiophene-3-carboxylic acid (30 mg) as starting material, tert-butyl ((4-((2,6-dioxopiperidin-3-yl)carbamoyl)-3-methoxythiophen-2-yl)methyl)carbamate was synthesized. 1H NMR(500MHz,DMSO)δ10.86(s,1H), 8.67(d,J=8.4Hz,1H), 7.64(s,1H), 7.42(t,J=5.8Hz,1H), 4.79~4.63(m,1H), 4.15(d,J=6.0Hz,2H) ), 3.80(s,3H), 2.79(ddd,J=17.4,13.2,5.5Hz,1H), 2.60~2.52(m,1H), 2.08(qd,J=12.9,4.4Hz,1H), 2.03~1.90(m,1H), 1.39(s,9H). LCMS (m / z [M−H] - ):396.0

[0355] Step I: tert-Butyl ((4-((2,6-dioxopiperidin-3-yl)carbamoyl)-3-methoxythiophen-2-yl)methyl)carbamate (5 mg) was dissolved in 2 mL of TFA, and the solution was stirred at room temperature for 2 hours. Volatiles were removed under reduced pressure to give 5-(aminomethyl)-N-(2,6-dioxopiperidin-3-yl)-4-methoxythiophene-3-carboxamide trifluoroacetate (87% yield). 1 H NMR(500MHz,DMSO)δ10.88(s,1H), 8.88(d,J=8.3Hz,1H), 8.18(s,3H), 7.77(s,1H), 4.79~4.65(m,1H), 4.10(q,J=5.4 Hz,2H), 2.79(ddd,J=17.5,13.3,5.5Hz,1H), 2.54(ddd,J=9.0,6.1,2.2Hz,1H), 2.17~2.07(m,1H), 2.03~1.94(m,1H). [Example]

[0356] Synthesis of tert-butyl (3-((2,6-dioxopiperidin-3-yl)carbamoyl)thiophen-2-yl)(methyl)carbamate (56)

[0357] [ka]

[0358] Step A: Methyl 2-((tert-butoxycarbonyl)amino)thiophene-3-carboxylate (100 mg, 1 equiv.) was added to a stirred mixture of 60% NaH (1.2 equiv.) suspended in mineral oil in dry DMF under an inert atmosphere, followed by MeI (1.2 equiv.). The resulting mixture was stirred at room temperature for 18 hours, the solvent was removed under reduced pressure, and the residue was purified by flash column chromatography to give methyl 2-((tert-butoxycarbonyl)(methyl)amino)thiophene-3-carboxylate (49% yield).

[0359] Step B: 1M NaOH in HO (10 equiv.) was added to a solution of methyl 2-((tert-butoxycarbonyl)(methyl)amino)thiophene-3-carboxylate (52.0 mg, 1 equiv.) in methanol and stirred at room temperature for 18 h. When the reaction was complete, it was acidified with 1M HCl, concentrated under reduced pressure, and partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over NaSO, and evaporated. 2-((tert-butoxycarbonyl)(methyl)amino)thiophene-3-carboxylic acid (100%) was used in the next step without further purification.

[0360] Step C: Using the general procedure shown in Reaction Scheme 1 and synthesis condition C, above (57% yield), tert-butyl (3-((2,6-dioxopiperidin-3-yl)carbamoyl)thiophen-2-yl)(methyl)carbamate was synthesized using 2-((tert-butoxycarbonyl)(methyl)amino)thiophene-3-carboxylic acid (49.4 mg) as the starting material. 1H NMR(500MHz,DMSO)δ10.84(s,1H), 8.30(d,J=8.2Hz,1H), 7.38(d,J=5.8Hz,1H), 7.25(d,J=5.9Hz,1H), 4.70(ddd,J=13.0,8.1,5.3Hz,1H) , 3.10(s,3H), 2.78(ddd,J=17.3,13.3,5.6Hz,1H), 2.59~2.53(m,1H), 2.11~2.01(m,1H), 1.95(dtd,J=12.8,5.4,2.9Hz,1H), 1.32(s,9H). LCMS (m / z [M-Boc+H] + ):268.0 [Example]

[0361] Synthesis of N-(2,6-dioxopiperidin-3-yl)-5-phenylthiophene-3-carboxamide (57)

[0362] [ka]

[0363] This compound was synthesized using the general procedure shown in Reaction Scheme 1 and synthesis condition D, supra (50% yield) using 5-phenylthiophene-3-carboxylic acid (16.7 mg) as the starting material. 1 H NMR(500MHz,DMSO)δ10.87(s,1H), 8.64(d,J=8.4Hz,1H), 8.15(d,J=1.4Hz,1H), 7.89(d,J=1.4Hz,1H), 7.71~7.65(m,2H), 7.51~7.42(m,2H), 7.4 0~7.33(m,1H), 4.83~4.73(m,1H), 2.81(ddd,J=18.6,13.2,5.6Hz,1H), 2 .60~2.53(m,1H), 2.18~2.04(m,1H), 2.00(ddt,J=11.0,8.4,4.2Hz,1H). LCMS (m / z [M] + ):315.0 [Example]

[0364] Synthesis of 2-acetamido-N-(2,6-dioxopiperidin-3-yl)-5-phenylthiophene-3-carboxamide (58)

[0365] [ka]

[0366] This compound was synthesized using the general procedure shown in Reaction Scheme 1 and Synthesis Condition C, above (88% yield) using 2-acetamido-5-phenylthiophene-3-carboxylic acid (20 mg) as the starting material. 1 H NMR(500MHz,DMSO)δ11.84(s,1H), 10.92(s,1H), 8.72(d,J=8.2Hz,1H), 7.87 (s,1H), 7.62~7.55(m,2H), 7.48~7.39(m,2H), 7.35~7.26(m,1H), 4.83~4.70 (m,1H), 2.81(ddd,J=17.2,13.4,5.5Hz,1H), 2.58(dt,J=16.8,3.8Hz,1H),2 .24(s,3H), 2.17(qd,J=12.9,4.5Hz,1H), 2.01(dtd,J=12.9,5.4,2.8Hz,1H). LCMS (m / z [M+H] + ):372.3 [Example]

[0367] Synthesis of 2-benzamido-N-(2,6-dioxopiperidin-3-yl)-5-phenylthiophene-3-carboxamide (59)

[0368] [ka]

[0369] This compound was synthesized using the general procedure shown in Reaction Scheme 1 and Synthesis Condition C, above (83% yield) using 2-benzamido-5-phenylthiophene-3-carboxylic acid (20 mg) as the starting material. 1 H NMR(500MHz,DMSO)δ13.21(s,1H), 10.96(s,1H), 8.87(d,J=8.4Hz,1H), 7.9 9(s,1H), 7.97~7.91(m,2H), 7.74~7.68(m,1H), 7.68~7.61(m,4H), 7.51~7.4 3(m,2H), 7.38~7.29(m,1H), 4.94(ddd,J=13.0,8.3,5.3Hz,1H), 2.90~2.79 (m,1H), 2.60(dt,J=17.7,3.8Hz,1H), 2.23~2.12(m,1H), 2.07~2.02(m,1H). LCMS (m / z [M+H] + ):434.2 [Example]

[0370] Synthesis of N-(2,6-dioxopiperidin-3-yl)-5-phenyl-2-(2-(pyrrolidin-1-yl)acetamido)thiophene-3-carboxamide (60)

[0371] [ka]

[0372] Step A: To a solution of ethyl 5-phenyl-2-(2-(pyrrolidin-1-yl)acetamido)thiophene-3-carboxylate (20 mg, 0.056 mmol) in EtOH (0.6 mL) was added HO (0.1 mL), followed by NaOH (4 equiv.). The reaction was stirred at 50° C. for 3 h. The reaction mixture was acidified with 1 M HCl, concentrated under reduced pressure, and the crude 5-phenyl-2-(2-(pyrrolidin-1-yl)acetamido)thiophene-3-carboxylic acid was used directly in the next step (98% yield).

[0373] Step B: Using the general procedure shown in Reaction Scheme 1 and synthesis condition C, above (15% yield), N-(2,6-dioxopiperidin-3-yl)-5-phenyl-2-(2-(pyrrolidin-1-yl)acetamido)thiophene-3-carboxamide was synthesized using 5-phenyl-2-(2-(pyrrolidin-1-yl)acetamido)thiophene-3-carboxylic acid (18 mg) as the starting material. 1 H NMR(500MHz,DMSO)δ12.51(s,1H), 10.91(s,1H), 8.61(d,J=8.5Hz,1H), 8.14(s,1H), 7. 88(s,1H), 7.62~7.57(m,2H), 7.47~7.41(m,2H), 7.33~7.28(m,1H), 4.87(ddd,J=12.4, 8.5,5.5Hz,1H), 3.41(s,2H), 2.91~2.75(m,1H), 2.63(td,J=4.9,4.4,2.3Hz,4H), 2.57 (ddd,J=17.3,4.4,2.9Hz,1H), 2.16~2.06(m,1H), 2.06~1.98(m,1H), 1.82~1.74(m,4H). LCMS (m / z [M+H] + ):441.1 [Example]

[0374] Synthesis of tert-butyl ((3-((2,6-dioxopiperidin-3-yl)carbamoyl)thiophen-2-yl)methyl)carbamate (63)

[0375] [ka]

[0376] Step A: To a solution of methyl 2-(((tert-butoxycarbonyl)amino)methyl)thiophene-3-carboxylate (35 mg, 0.129 mmol, 1 equiv) in THF (1.0 mL) was added HO (0.3 mL) followed by NaOH (6 equiv). The reaction was stirred at room temperature for 18 h and at 50 °C for 4 h. The reaction mixture was acidified with 1 M HCl, extracted with EtOAc, dried over NaSO, and concentrated to give 2-(((tert-butoxycarbonyl)amino)methyl)thiophene-3-carboxylic acid (86% yield).

[0377] Step B: Using the general procedure shown in Reaction Scheme 1 and synthesis condition C, above (37% yield), tert-butyl ((3-((2,6-dioxopiperidin-3-yl)carbamoyl)thiophen-2-yl)methyl)carbamate was synthesized using 2-(((tert-butoxycarbonyl)amino)methyl)thiophene-3-carboxylic acid (30 mg) as the starting material. 1 H NMR(500MHz,DMSO)δ10.84(s,1H), 8.47(d,J=8.3Hz,1H), 7.39(s,2H), 4.78~4.67(m,1H), 4.57(d,J=6.7Hz,2H), 2. 78(ddd,J=17.4,13.3,5.5Hz,1H), 2.57~2.51(m,2H), 2.10(qd,J=13.0,4.5Hz,1H), 2.03~1.91(m,1H), 1.40(s,9H). LCMS (m / z [M−H] - ):366.0 [Example]

[0378] Synthesis of 2-(aminomethyl)-N-(2,6-dioxopiperidin-3-yl)thiophene-3-carboxamide (64)

[0379] [ka]

[0380] To a suspension of tert-butyl ((3-((2,6-dioxopiperidin-3-yl)carbamoyl)thiophen-2-yl)methyl)carbamate (12.7 mg, 0.035 mmol, 1 equiv.) in DCM (0.2 mL) was added TFA (50 μL) and the mixture was stirred at room temperature for 2 days. The reaction mixture was evaporated under reduced pressure, suspended in ACN, and then 4 N HCl in 1,4-dioxane was added (50 μL). Concentration under reduced pressure gave 2-(aminomethyl)-N-(2,6-dioxopiperidin-3-yl)thiophene-3-carboxamide hydrochloride (98% yield). 1 H NMR(500MHz,DMSO)δ10.91(s,1H), 8.90(d,J=8.3Hz,1H), 8.25(s,3H), 7.68(d,J=5.4Hz,1H), 7.59(d,J=5.4Hz,1H), 4.82~4.70(m,1 H), 2.80(ddd,J=17.4,13.4,5.5Hz,1H), 2.60~2.53(m,1H), 2.15(qd,J=13.0,4.5Hz,1H), 1.98(ddd,J=10.8,8.2,5.3,2.9Hz,1H). LCMS (m / z [M+H] + ):268.0 [Example]

[0381] Synthesis of N-(2,5-dioxopyrrolidin-3-yl)-2-methoxythiophene-3-carboxamide (65)

[0382] [ka]

[0383] To a mixture of 2-methoxythiophene-3-carboxylic acid (20.0 mg, 0.126 mmol, 1.000 equiv.) and CDI (30.8 mg, 0.189 mmol, 1.500 equiv.), DMF (1.0 mL) was added, and the reaction mixture was stirred at 50° C. for 1 h. After cooling to room temperature, 3-aminopyrrolidine-2,5-dione hydrochloride (22.8 mg, 0.151 mmol, 1.200 equiv.) was added, and the reaction mixture was stirred overnight. The solvent was removed under reduced pressure, and the residue was purified by preparative TLC (78% yield). 1H NMR(500MHz,DMSO)δ11.19(s,1H), 8.14(d,J=7.7Hz,1H), 7.08(d,J=5.9Hz,1H), 6.83(d,J=6.0Hz,1H), 4. 65(ddd,J=9.3,7.8,5.8Hz,1H), 4.05(s,3H), 2.89(dd,J=17.4,9.4Hz,1H), 2.60(dd,J=17.4,5.8Hz,1H). LCMS (m / z [M+H] + ):254.8 [Example]

[0384] Synthesis of 2-cyclopropyl-N-(2,6-dioxopiperidin-3-yl)thiophene-3-carboxamide (66)

[0385] [ka]

[0386] This compound was synthesized using the general procedure shown in Reaction Scheme 1 and synthesis condition D, supra (72% yield) using 2-(cyclopropyl)thiophene-3-carboxylic acid (20 mg) as the starting material. 1H NMR(500MHz,DMSO)δ10.83(s,1H), 8.32(d,J=8.3Hz,1H), 7.27(d,J=5.4Hz,1H), 7. 24(d,J=5.4Hz,1H), 4.76~4.68(m,1H), 2.96(tt,J=8.4,5.2Hz,1H), 2.78(ddd,J=17 .4,13.3,5.5Hz,1H), 2.57~2.51(m,1H), 2.11(qd,J=13.0,4.5Hz,1H), 1.98(dddd, J=11.0,8.3,5.4,2.9Hz,1H), 1.10(ddd,J=8.4,6.0,4.0Hz,2H), 0.68~0.63(m,2H). LCMS (m / z [M+H] + ):279.1 [Example]

[0387] Synthesis of N-(2,6-dioxopiperidin-3-yl)-5-methoxyoxazole-4-carboxamide (67)

[0388] [ka]

[0389] This compound was synthesized using the general procedure shown in Reaction Scheme 1 and Synthesis Condition C, supra (45% yield) using 5-methoxy-1,3-oxazole-4-carboxylic acid (7 mg) as the starting material. 1 H NMR(500MHz,DMSO)δ10.80(s,1H), 8.11(d,J=8.4Hz,1H), 8.01(s,1H), 4.67(ddd,J=12.5,8.4, 5.3Hz,1H), 4.12(s,3H), 2.81~2.73(m,1H), 2.58(s,1H), 2.20~2.09(m,1H), 1.97~1.89(m,1H). LCMS (m / z [M+H] + ):254.0 [Example]

[0390] Synthesis of N-(2,6-dioxopiperidin-3-yl)-5-ethoxy-2-methyloxazole-4-carboxamide (68)

[0391] [ka]

[0392] This compound was synthesized using the general procedure shown in Reaction Scheme 1 and synthesis condition D, supra (86% yield) using 5-ethoxy-2-methyloxazole-4-carboxylic acid (30 mg) as the starting material. 1H NMR(500MHz,DMSO)δ10.79(s,1H), 8.04(d,J=8.3Hz,1H), 4.69~4.60(m,1H), 4.44(q,J=7.1Hz,2H), 2.75(ddd,J=17.4,13.7,5.5Hz,1 H), 2.48(d,J=2.8Hz,1H), 2.33(s,3H), 2.13(qd,J=12.9,4.5Hz,1H), 1.93(dddd,J=10.8,7.9,5.4,2.5Hz,1H), 1.32(t,J=7.1Hz,3H). LCMS (m / z [M+H] + ):282.1 [Example]

[0393] Synthesis of N-(2,6-dioxopiperidin-3-yl)-5-methoxy-2-phenyloxazole-4-carboxamide (69)

[0394] [ka]

[0395] This compound was synthesized using the general procedure shown in Reaction Scheme 1 and Synthesis Condition C, described above (39% yield), and 5-methoxy-2-phenyloxazole-4-carboxylic acid (9.4 mg) as the starting material. 1H NMR(500MHz,DMSO)δ10.83(s,1H), 8.18(d,J=8.4Hz,1H), 7.97~7.92(m,2H), 7.58~7.50(m,3H), 4.73(ddd,J=12.5,8.4,5.3H z,1H), 4.23(s,3H), 2.84~2.73(m,1H), 2.59~2.52(m,1H), 2.18(qd,J=12.9,4.4Hz,1H), 1.97(dtd,J=12.9,5.4,2.6Hz,1H). LCMS (m / z [M+H] + ):330.0 [Example]

[0396] Synthesis of N-(2,6-dioxopiperidin-3-yl)-5-morpholino-2-phenyloxazole-4-carboxamide (70)

[0397] [ka]

[0398] This compound was synthesized using the general procedure shown in Reaction Scheme 1 and synthesis condition D, above (27% yield), using 5-(morpholin-4-yl)-2-phenyl-1,3-oxazole-4-carboxylic acid (8 mg) as the starting material. 1H NMR(500MHz,DMSO)δ10.82(s,1H), 8.15(d,J=8.2Hz,1H), 7.94~7.88(m,2H), 7.56~7.45(m,3H), 4.67(ddd,J=12.8,8.1,5.3Hz, 1H), 3.73(s,8H), 2.76(ddd,J=17.2,13.6,5.4Hz,1H), 2.58(d,J=4.9Hz,1H), 2.18(qd,J=12.9,4.4Hz,1H), 2.03~1.93(m,1H). LCMS (m / z [M+H] + ):385.1 [Example]

[0399] Synthesis of tert-butyl (5-((2,6-dioxopiperidin-3-yl)carbamoyl)thiazol-2-yl)carbamate (71)

[0400] [ka]

[0401] This compound was synthesized using the general procedure shown in Reaction Scheme 1 and Synthesis Condition C, above (31% yield) using 2-((tert-butoxycarbonyl)amino)thiazole-5-carboxylic acid (20 mg) as the starting material. 1H NMR(500MHz,DMSO)δ11.73(s,1H), 10.86(s,1H), 8.70(d,J=8.4Hz,1H), 8.00(s,1H), 4.78~4.66(m,1H), 2.78(ddd,J=17.5 ,13.2,5.6Hz,1H), 2.52~2.51(m,1H), 2.07(qd,J=12.9,4.5Hz,1H), 1.97(dddd,J=11.3,8.4,5.5,2.9Hz,1H), 1.50(s,9H). [Example]

[0402] Synthesis of N-(2,6-dioxopiperidin-3-yl)-2-(trifluoromethyl)thiazole-5-carboxamide (72)

[0403] [ka]

[0404] This compound was synthesized using the general procedure shown in Reaction Scheme 1 and synthesis condition C, above (29% yield), using 2-(trifluoromethyl)thiazole-5-carboxylic acid (20 mg) as the starting material. 1H NMR(500MHz,DMSO)δ10.87(s,1H), 7.89(d,J=7.4Hz,1H), 7.75(d,J=5.5Hz,1H), 7.14(d,J=5.5Hz,1H), 4.78~4. 63(m,1H), 3.98(s,3H), 3.31(s,3H), 2.77(ddd,J=17.4,13.1,6.3Hz,1H), 2.54~2.51(m,1H), 2.17~2.04(m,2H). LCMS (m / z [M−H] - ):305.8 [Example]

[0405] Synthesis of 2-(tert-butyl)-N-(2,6-dioxopiperidin-3-yl)thiazole-5-carboxamide (73)

[0406] [ka]

[0407] This compound was synthesized using the general procedure shown in Reaction Scheme 1 and synthesis condition C, described above (83% yield), using 2-(tert-butyl)thiazole-5-carboxylic acid (20 mg) as the starting material. 1 H NMR(500MHz,DMSO)δ10.88(s,1H), 8.88(d,J=8.4Hz,1H), 8.26(s,1H), 4.73(ddd,J=13.4,8.3,5.4Hz,1H), 2.79(dd d,J=17.5,13.3,5.6Hz,1H), 2.58~2.51(m,1H), 2.15~2.03(m,1H), 1.98(ddd,J=12.9,5.4,2.8Hz,1H), 1.39(s,9H). LCMS (m / z [M+H] + ):295.9 [Example]

[0408] Synthesis of benzyl ((5-((2,6-dioxopiperidin-3-yl)carbamoyl)thiazol-2-yl)methyl)carbamate (74)

[0409] [ka]

[0410] This compound was synthesized using the general procedure shown in Reaction Scheme 1 and synthesis condition C, described above (68% yield), using 2-((((benzyloxy)carbonyl)amino)methyl)thiazole-5-carboxylic acid (20 mg) as the starting material. 1 H NMR(500MHz,DMSO)δ10.88(s,1H), 8.91(d,J=8.3Hz,1H), 8.28(s,1H), 8.25(t,J =5.9Hz,1H), 7.38(d,J=4.1Hz,3H), 7.33(dd,J=8.8,4.5Hz,1H), 5.09(s,2H), 4.7 8~4.69(m,1H), 4.48(d,J=6.1Hz,2H), 2.79(ddd,J=18.6,13.3,5.6Hz,1H), 2.52( d,J=1.9Hz,1H), 2.09(qd,J=12.9,4.4Hz,1H), 1.99(tdd,J=8.2,5.4,2.8Hz,1H). LCMS (m / z [M+H] + ):403.1 [Example]

[0411] Synthesis of N-(2,6-dioxopiperidin-3-yl)-2-methoxythiazole-5-carboxamide (75)

[0412] [ka]

[0413] This compound was synthesized using the general procedure shown in Reaction Scheme 1 and Synthesis Condition C, above (16% yield), using 2-methoxythiazole-5-carboxylic acid (20 mg) as the starting material. 1H NMR(500MHz,DMSO)δ10.87(s,1H), 8.79(d,J=8.3Hz,1H), 7.87(s,1H), 4.71(ddd,J=12.6,8.3,5.4Hz,1H), 4.06(s,3H), 2.7 8(ddd,J=17.5,13.2,5.6Hz,1H), 2.53~2.51(m,1H), 2.07(qd,J=12.9,4.5Hz,1H), 1.97(ddd,J=11.0,8.3,5.5,2.8Hz,1H). LCMS (m / z [M+H] + ):269.9 [Example]

[0414] Synthesis of N-(2,6-dioxopiperidin-3-yl)-2-(methylthio)thiazole-5-carboxamide (76)

[0415] [ka]

[0416] This compound was synthesized using the general procedure shown in Reaction Scheme 1 and synthesis condition C, above (43% yield), using 2-(methylthio)thiazole-5-carboxylic acid (20 mg) as the starting material. 1 H NMR(500MHz,DMSO)δ10.88(s,1H), 8.90(d,J=8.3Hz,1H), 8.26(s,1H), 4.73(ddd,J=12.6,8.3,5.4Hz,1H), 2.79(ddd,J=17. 5,13.2,5.6Hz,1H), 2.72(s,3H), 2.52(dd,J=4.0,2.2Hz,1H), 2.13~2.03(m,1H), 1.99(dddd,J=11.1,8.3,5.5,2.8Hz,1H). LCMS (m / z [M+H] + ):285.9 [Example]

[0417] Synthesis of tert-butyl ((4-((2,6-dioxopiperidin-3-yl)carbamoyl)thiazol-2-yl)methyl)carbamate (77)

[0418] [ka]

[0419] This compound was synthesized using the general procedure shown in Reaction Scheme 1 and synthesis condition C, above (39% yield), using 2-(((tert-butoxycarbonyl)amino)methyl)thiazole-4-carboxylic acid (50 mg) as the starting material. 1 H NMR(500MHz,DMSO)δ10.83(s,1H), 8.59(d,J=8.5Hz,1H), 8.21(s,1H), 7.86(t,J=6.1Hz,1H), 4.76(ddd,J=12.6,8.5,5.3Hz,1H), 4.43(d,J=6.1 Hz,2H), 2.79(ddd,J=17.3,13.7,5.5Hz,1H), 2.59~2.53(m,1H), 2.19(qd,J=13.0,4.5Hz,1H), 1.97(dtd,J=12.9,5.4,2.6Hz,1H), 1.42(s,9H). LCMS (m / z [M-Boc+H] + ):268.9 [Example]

[0420] Synthesis of N-(2,6-dioxopiperidin-3-yl)-5-(methylamino)thiazole-4-carboxamide (78)

[0421] [ka]

[0422] To a solution of 5-(methylamino)thiazole-4-carboxylic acid (1 equivalent) in isopropanol and water was added 3-aminopiperidine-2,6-dione (hydrochloride, 3.0 equivalents), N-methylmorpholine (3 equivalents), and DMTMM (1.5 equivalents). The reaction mixture was stirred overnight at room temperature, concentrated under reduced pressure, and purified by HPLC to give N-(2,6-dioxopiperidin-3-yl)-5-(methylamino)thiazole-4-carboxamide (13% yield). 1 H NMR(500MHz,DMSO)δ10.78(s,1H), 8.11(d,J=0.9Hz,1H), 8.04(d,J=8.3Hz,1H), 7.60(q,J=5.0Hz,1H), 4.64(ddd,J=12.4,8.3,5.3Hz,1H ), 2.92(d,J=5.0Hz,3H), 2.76(ddd,J=17.2,13.7,5.5Hz,1H), 2.59~2.51(m,1H), 2.23~2.12(m,1H), 1.96(dtd,J=13.0,5.4,2.6Hz,1H). LCMS (m / z [M+H] + ):268.7 [Example]

[0423] Synthesis of N-(2,6-dioxopiperidin-3-yl)-5-methoxythiazole-4-carboxamide (79)

[0424] [ka]

[0425] Step A: To a stirred solution of ethyl 5-bromothiazole-4-carboxylate (2.0 g, 8.475 mmol, 1 equiv.) in methanol (24 mL) was added NaOMe (25% in MeOH) (3.8 mL, 16.95 mmol, 2 equiv.). The reaction mixture was refluxed for 2 h, cooled to room temperature, and quenched with saturated ammonium chloride solution (10 mL). The mixture was concentrated under reduced pressure and purified by flash column chromatography to give methyl 5-methoxythiazole-4-carboxylate (27% yield).

[0426] Step B: To a stirred solution of methyl 5-methoxythiazole-4-carboxylate (100 mg, 0.578 mmol, 1 equiv.) in THF, MeOH, HO (4:2:1) (7 mL) was added LiOH, HO (73 mg, 1.734 mmol, 3 equiv.). The reaction mixture was stirred at room temperature for 16 h, evaporated, redissolved in water, and washed with ethyl acetate. The aqueous layer was acidified with 0.5 M HCl, extracted with 10% MeOH in DCM, dried over NaSO, concentrated under reduced pressure, and purified by flash column chromatography to give 5-methoxythiazole-4-carboxylic acid (32% yield).

[0427] Step C: Using the general procedure shown in Reaction Scheme 1 and synthesis condition C, above (9% yield), N-(2,6-dioxopiperidin-3-yl)-5-methoxythiazole-4-carboxamide was synthesized using 5-methoxythiazole-4-carboxylic acid (20 mg) as the starting material. 1 H NMR(500MHz,DMSO)δ10.81(s,1H), 8.51(s,1H), 8.23(d,J=8.2Hz,1H), 4.67(ddd,J=12.5,8.2,5.3Hz,1H), 4.04 (s,3H), 2.83~2.73(m,1H), 2.52(dt,J=3.9,2.5Hz,1H), 2.19~2.09(m,1H), 1.97(dtd,J=12.7,5.5,2.6Hz,1H). LCMS (m / z [M+H] +):269.8 [Example]

[0428] Synthesis of 2-amino-N-(2,6-dioxopiperidin-3-yl)-5-methoxythiazole-4-carboxamide (80)

[0429] [ka]

[0430] Step A: To a stirred solution of methyl 2-amino-5-bromothiazole-4-carboxylate (1 g, 4.255 mmol, 1 equiv.) in methanol (30 mL) was added NaOMe (25% in MeOH) (2.3 mL, 10.638 mmol, 2.5 equiv.). The reaction mixture was refluxed for 1.5 h, cooled to room temperature, and quenched with saturated ammonium chloride solution (10 mL). The mixture was concentrated under reduced pressure and purified by flash column chromatography to give methyl 2-amino-5-methoxythiazole-4-carboxylate (50% yield).

[0431] Step B: Methyl 2-amino-5-methoxythiazole-4-carboxylate (400 mg, 2.128 mmol, 1 equiv.) was dissolved in DCM, followed by the addition of triethylamine (0.532 mmol, 2 equiv.) and BocO (0.532 mmol, 2 equiv.). The reaction mixture was stirred at room temperature for 18 h, diluted with DCM, washed successively with water and brine, dried over NaSO, concentrated under reduced pressure, and purified by flash column chromatography to give methyl 2-((tert-butoxycarbonyl)amino)-5-methoxythiazole-4-carboxylate (49% yield).

[0432] Step C: To a stirred solution of methyl 2-((tert-butoxycarbonyl)amino)-5-methoxythiazole-4-carboxylate (300 mg, 1.042 mmol, 1 equiv) in THF:MeOH:HO 3:2:1 (12 mL) was added LiOH·HO (131 mg, 3.125 mmol, 3 equiv). The reaction mixture was stirred at room temperature for 16 h, evaporated, redissolved in water, and washed with ethyl acetate. The aqueous layer was acidified with 0.5 M HCl, extracted with 10% MeOH in DCM, dried over NaSO, concentrated under reduced pressure, and triturated with ether and pentane to give 2-((tert-butoxycarbonyl)amino)-5-methoxythiazole-4-carboxylic acid (49% yield).

[0433] Step D: Using the general procedure shown in Reaction Scheme 1 and synthesis condition C, as described above (50% yield), and 2-((tert-butoxycarbonyl)amino)-5-methoxythiazole-4-carboxylic acid (20 mg) as starting material, tert-butyl (4-((2,6-dioxopiperidin-3-yl)carbamoyl)-5-methoxythiazol-2-yl)carbamate was synthesized.

[0434] Step E: To a solution of tert-butyl (4-((2,6-dioxopiperidin-3-yl)carbamoyl)-5-methoxythiazol-2-yl)carbamate (19.6 mg, 0.051 mmol, 1 equiv) in water (3 mL) and dioxane (3 mL) was added 36% HCl (1.5 mL). The reaction was stirred at room temperature for 3 hours and concentrated under reduced pressure to give 2-amino-N-(2,6-dioxopiperidin-3-yl)-5-methoxythiazole-4-carboxamide hydrochloride (100% yield). 1H NMR(500MHz,DMSO)δ10.84(s,1H), 7.75(d,J=7.8Hz,1H), 7.41~6.65(m,2H), 4.63(ddd,J=12.0,7.8, 5.8Hz,1H), 3.89(s,3H), 2.75(ddd,J=17.3,13.1,6.2Hz,1H), 2.60~2.52(m,1H), 2.11~1.98(m,2H). LCMS (m / z [M+H] + ):285.0 [Example]

[0435] Synthesis of 4-((2,6-dioxopiperidin-3-yl)carbamoyl)-5-methoxythiazole-2-carboxylic acid (81)

[0436] [ka]

[0437] Step A: To a stirred solution of ethyl 5-bromothiazole-4-carboxylate (2.0 g, 8.475 mmol) in methanol (24 mL) was added NaOMe (25% in MeOH) (3.8 ml, 16.95 mmol, 2 equiv.). The reaction mixture was then refluxed for 2 h, cooled to room temperature, and quenched with ammonium chloride solution. The product was extracted with ethyl acetate, dried over NaSO, concentrated under reduced pressure, and purified by flash column chromatography to give methyl 5-methoxythiazole-4-carboxylate (27% yield).

[0438] Step B: To a solution of methyl 5-methoxythiazole-4-carboxylate (70 mg, 0.405 mmol, 1 equiv.) in THF (5 mL) was added N-bromosuccinimide (288 mg, 1.618 mmol, 4 equiv.), and the reaction mixture was stirred at room temperature for 24 h. The reaction mixture was diluted with ethyl acetate, washed with water and brine, dried over NaSO, concentrated under reduced pressure, and purified by flash column chromatography to give methyl 2-bromo-5-methoxythiazole-4-carboxylate (73% yield).

[0439] Step C: To a solution of methyl 2-bromo-5-methoxythiazole-4-carboxylate (1.0 g, 3.968 mmol, 1 equiv.) in THF (30 mL) and water (15 mL), triethylamine (2.701 mL, 19.841 mmol, 5 equiv.) was added and the solution was purged with argon for 10 min. Xantphos (0.115 g, 0.198 mmol, 0.05 equiv.) and Pd(OAc) (44 mg, 0.198 mmol, 0.05 equiv.) were added, and the reaction mixture was stirred at 60 °C under CO (50 psi) for 16 h. The reaction mixture was cooled to room temperature, diluted with water, and washed with ethyl acetate. The aqueous layer was acidified with 2M HCl solution, extracted with 15% MeOH in DCM, dried over Na2SO4, and concentrated under reduced pressure to give 5-methoxy-4-(methoxycarbonyl)thiazole-2-carboxylic acid (30% yield).

[0440] Step D: To a solution of 5-methoxy-4-(methoxycarbonyl)thiazole-2-carboxylic acid (300 mg, 1.382 mmol, 1 equiv) in tert-butanol (15 mL) was added 2-tert-butyl-1,3-diisopropylisourea (829 mg, 4.147 mmol, 3 equiv), and the reaction mixture was stirred at room temperature for 16 h, diluted with ethyl acetate, washed with water, dried over Na2SO4, concentrated under reduced pressure, and purified by flash column chromatography to give 2-tert-butyl 4-methyl 5-methoxythiazole-2,4-dicarboxylate (31% yield).

[0441] Step E: To a solution of 2-tert-butyl 4-methyl-5-methoxythiazole-2,4-dicarboxylate (220 mg, 0.806 mmol, 1 equiv.) in DCE (5 mL) was added trimethyltin hydroxide (728 mg, 4.029 mmol, 5 equiv.). The reaction mixture was stirred at 90° C. for 6 h, filtered, and the filtrate was concentrated under reduced pressure and purified by HPLC to give 2-(tert-butoxycarbonyl)-5-methoxythiazole-4-carboxylic acid (11% yield).

[0442] Step F: Using the general procedure shown in Reaction Scheme 1 and synthesis condition C, above (39% yield), tert-butyl 4-((2,6-dioxopiperidin-3-yl)carbamoyl)-5-methoxythiazole-2-carboxylate was synthesized using 2-(tert-butoxycarbonyl)-5-methoxythiazole-4-carboxylic acid (16.5 mg) as the starting material. 1 H NMR(500MHz,DMSO)δ10.83(s,1H), 8.24(d,J=8.2Hz,1H), 4.77~4.65(m,1H), 4.14(s,3H), 2.77(ddd,J=17.2,13. 8,5.5Hz,1H), 2.60~2.53(m,0H), 2.17(qd,J=12.9,4.5Hz,1H), 1.96(dtd,J=12.9,5.5,2.6Hz,1H), 1.56(s,9H).

[0443] Step G: tert-Butyl 4-((2,6-dioxopiperidin-3-yl)carbamoyl)-5-methoxythiazole-2-carboxylate (6 mg, 0.016 mmol) was dissolved in DCM (0.5 mL) and trifluoroacetic acid (0.092 mL) was added. The reaction was stirred at room temperature for 2 hours and concentrated under reduced pressure to give 4-((2,6-dioxopiperidin-3-yl)carbamoyl)-5-methoxythiazole-2-carboxylic acid (71% yield). 1H NMR(500MHz,DMSO)δ14.03(s,1H), 10.82(s,1H), 8.27(d,J=8.3Hz,1H), 4.71(ddd,J=12.5,8.3,5.4Hz,1H), 4.14(s,3H) ), 2.77(ddd,J=17.1,13.7,5.5Hz,1H), 2.58(s,1H), 2.16(qd,J=12.9,4.5Hz,1H), 1.96(dtd,J=12.9,5.4,2.6Hz,1H). LCMS (m / z [M+H] + ):314.0 [Example]

[0444] Synthesis of 5-cyclopropyl-N-(2,6-dioxopiperidin-3-yl)thiazole-4-carboxamide (82)

[0445] [ka]

[0446] This compound was synthesized using the general procedure shown in Reaction Scheme 1 and Synthesis Condition C, above (67% yield) using 5-cyclopropyl-1,3-thiazole-4-carboxylic acid (20 mg) as the starting material. 1 H NMR(500MHz,DMSO)δ10.83(s,1H), 8.86(d,J=0.7Hz,1H), 8.59(d,J=8.3Hz,1H), 4.73(ddd,J=12.6,8.3,5.3Hz,1H), 3.35~3.31(m,1H), 2.7 8(ddd,J=17.4,13.7,5.6Hz,1H), 2.59~2.51(m,1H), 2.25~2.15(m,1H), 2.03~1.97(m,1H), 1.28~1.20(m,2H), 0.68(pd,J=4.4,1.9Hz,2H). LCMS (m / z [M+H] + ):280.1 [Example]

[0447] Synthesis of N-(2,6-dioxopiperidin-3-yl)-4,5-dimethyl-2-pivalamidothiophene-3-carboxamide (83)

[0448] [ka]

[0449] This compound was synthesized using the general procedure shown in Reaction Scheme 1 and Synthesis Condition C, described above (4% yield), and 4,5-dimethyl-2-pivalamidothiophene-3-carboxylic acid (22.5 mg) as the starting material. 1 H NMR(500MHz,DMSO)δ11.17(s,1H), 10.91(s,1H), 7.93(d,J=8.1Hz,1H), 4.80(ddd,J=13.0,8.1,5.4Hz,1H), 2.81(ddd,J=18.4 ,13.5,5.6Hz,1H), 2.59~2.51(m,1H), 2.24(s,3H), 2.22(s,3H), 2.14(qd,J=13.0,4.5Hz,1H), 2.07~2.01(m,1H), 1.21(s,9H). LCMS (m / z [M+H] + ):366.15 [Example]

[0450] Synthesis of 2-benzamido-N-(2,6-dioxopiperidin-3-yl)-4,5-dimethylthiophene-3-carboxamide (87)

[0451] [ka]

[0452] This compound was synthesized using the general procedure shown in Reaction Scheme 1 and Synthesis Condition C, above (27% yield) using 2-benzamido-4,5-dimethylthiophene-3-carboxylic acid (20 mg) as the starting material. 1H NMR(500MHz,DMSO)δ11.77(s,1H), 10.94(s,1H), 8.11(d,J=8.2Hz,1H), 7.90(dt,J=7.1,1.4Hz,2H), 7.68~7.61(m,1H), 7.58(dd,J=8.4, 6.9Hz,2H), 4.90~4.80(m,1H), 2.82(ddd,J=18.5,13.3,5.7Hz,1H), 2.58(d,J=3.5Hz,1H), 2.29(s,3H), 2.24(s,3H), 2.21~2.04(m,2H). LCMS (m / z [M+H] + ):386.0 [Example]

[0453] Synthesis of N-(2,6-dioxopiperidin-3-yl)-2-(4-methoxybenzamido)-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxamide (89)

[0454] [ka]

[0455] This compound was synthesized using the general procedure shown in Reaction Scheme 1 and Synthesis Condition C, above (3.9% yield), using 2-(4-methoxybenzamido)-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxylic acid (30 mg) as the starting material. 1 HNMR(500MHz,DMSO,300 K): δ12.28(s,1H), 10.92(s,1H), 7.85(d,J=8.8Hz,2H), 7.72(d,J=8.0Hz,1H), 7.14(d,J=8.6Hz,2H), 4.91~4.80(m,1H) , 3.85(s,3H), 2.87~2.79(m,1H), 2.77(d,J=5.5Hz,2H), 2.67(s,2H), 2.59~2.53(m,1H), 2.24~2.02(m,2H), 1.77(s,4H). LCMS (m / z [M+H] + ):441.9 [Example]

[0456] Synthesis of N-(2,6-dioxopiperidin-3-yl)-2-(2-morpholinoacetamido)-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxamide (90)

[0457] [ka]

[0458] This compound was synthesized using the general procedure shown in Reaction Scheme 1 and Synthesis Condition C, above (25% yield), using triethylamine instead of DIPEA and 2-(2-morpholinoacetamido)-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxylic acid (18 mg) as the starting material. 1 H NMR(500MHz,DMSO)δ11.84(s,1H), 10.86(s,1H), 7.69(d,J=8.2Hz,1H), 4.77(ddd,J= 13.0,8.1,5.4Hz,1H), 3.71~3.59(m,4H), 3.19(s,2H), 2.83(ddd,J=17.4,13.6,5.7Hz ,1H), 2.78~2.67(m,2H), 2.67~2.61(m,2H), 2.58~2.53(m,1H), 2.48(d,J=4.2Hz,2H) , 2.14(qd,J=12.9,4.4Hz,1H), 2.03(ddt,J=13.6,6.8,3.3Hz,1H), 1.82~1.67(m,4H). LCMS (m / z [M+H] + ):435.1 [Example]

[0459] Synthesis of N-(2,6-dioxopiperidin-3-yl)-2,4-dimethylthieno[3,4-b]pyridine-7-carboxamide (92)

[0460] [ka]

[0461] Step A: To a solution of methyl 2,4-dimethylthieno[3,4-b]pyridine-7-carboxylate (25.0 mg, 0.113 mmol, 1.000 equiv) in a mixture of HO (1.0 mL), THF (1.0 mL), and MeOH (1.0 mL) was added 1 M LiOH (2.0 mL, 2.000 mmol, 17.7 equiv), and the reaction was stirred at room temperature for 24 h and neutralized with 1 M HCl. After concentration under reduced pressure, 2,4-dimethylthieno[3,4-b]pyridine-7-carboxylic acid was used in the next step without further purification.

[0462] Step B: N-(2,6-dioxopiperidin-3-yl)-2,4-dimethylthieno[3,4-b]pyridine-7-carboxamide was synthesized using the general procedure shown in Reaction Scheme 1 and synthesis condition C, as described above (53% yield), and 2,4-dimethylthieno[3,4-b]pyridine-7-carboxylic acid (23.4 mg) as the starting material. 1 H NMR(500MHz,DMSO)δ10.95(s,1H), 10.08(d,J=6.8Hz,1H), 8.52(s,1H), 7.02(t,J=1.1Hz,1H), 4.84(ddd,J=12.3,6.8,5.3Hz,1H), 2. 82(ddd,J=17.4,13.6,5.5Hz,1H), 2.61(s,3H), 2.59~2.53(m,4H), 2.32(dtd,J=12.9,5.4,2.4Hz,1H), 2.12(qd,J=12.9,4.4Hz,1H). LCMS (m / z [M+H] + ):317.9 [Example]

[0463] Synthesis of 4-chloro-N-(2,6-dioxopiperidin-3-yl)-2-(trifluoromethyl)thieno[3,4-b]pyridine-7-carboxamide (93)

[0464] [ka]

[0465] 4-Chloro-2-(trifluoromethyl)thieno[3,4-b]pyridine-7-carboxylic acid (1 equivalent) and DMF (1 μL) were dissolved in DCM (3 mL), followed by the addition of oxalyl chloride (0.018 mL, 0.213 mmol, 3.000 equivalents). The reaction mixture was stirred at room temperature for 2 hours and concentrated under reduced pressure. The material was dissolved in DMF (2 mL), 3-aminopiperidine-2,6-dione hydrochloride (2 equivalents) and DIPEA (2 equivalents) were added, and the reaction mixture was stirred at room temperature for 72 hours. Purification by preparative HPLC afforded 4-chloro-N-(2,6-dioxopiperidin-3-yl)-2-(trifluoromethyl)thieno[3,4-b]pyridine-7-carboxamide (6% yield). 1 HNMR (500MHz, DMSO): δ11.03(s,1H), 9.30(d,J=6.4Hz,1H), 8.90(s,1H), 8.03(s,1H), 4.93~4.84(m,1H), 2. 82(ddd,J=18.8,13.6,5.5Hz,1H), 2.61~2.54(m,1H), 2.40(ddd,J=7.2,5.3,2.7Hz,1H), 2.11~2.02(m,1H). LCMS (m / z [M+H] + ):391.8 [Example]

[0466] Synthesis of N-(2,6-dioxopiperidin-3-yl)-4-hydroxy-2-(trifluoromethyl)thieno[3,4-b]pyridine-7-carboxamide (94)

[0467] [ka]

[0468] Step A: To a solution of methyl 4-hydroxy-2-(trifluoromethyl)thieno[3,4-b]pyridine-7-carboxylate (30.0 mg, 0.108 mmol, 1.000 equiv.) in MeOH (2.0 mL) was added NaOH (216 mg, 5.411 mmol, 50 equiv.). The reaction was stirred at room temperature for 24 h and neutralized with 1 M HCl. After concentration under reduced pressure, 4-hydroxy-2-(trifluoromethyl)thieno[3,4-b]pyridine-7-carboxylic acid was used in the next step without further purification.

[0469] Step B: N-(2,6-dioxopiperidin-3-yl)-4-hydroxy-2-(trifluoromethyl)thieno[3,4-b]pyridine-7-carboxamide was synthesized using the general procedure shown in Reaction Scheme 1 and synthesis condition C, as described above (24% yield), and 4-hydroxy-2-(trifluoromethyl)thieno[3,4-b]pyridine-7-carboxylic acid (28 mg) as starting material. 1 HNMR (500MHz, DMSO): δ12.98(s,1H), 10.98(s,1H), 9.53(d,J=6.6Hz,1H), 8.76(s,1H), 6.76(s,1H), 4.91~ 4.81(m,1H), 2.81(ddd,J=18.6,13.4,5.4Hz,1H), 2.60~2.54(m,1H), 2.38~2.33(m,1H), 2.08~1.99(m,1H). LCMS (m / z [M+H] + ):374.0 [Example]

[0470] Synthesis of 7-bromo-N-(2,6-dioxopiperidin-3-yl)thieno[3,4-b]pyridine-5-carboxamide (96)

[0471] [ka]

[0472] N-Bromosuccinimide (96.8 mg, 0.544 mmol, 1.1 equiv.) was added to a suspension of N-(2,6-dioxopiperidin-3-yl)thieno[3,4-b]pyridine-7-carboxamide (143.0 mg, 0.494 mmol, 1.000 equiv.) in DMF (4.9 mL) at ambient temperature. The reaction mixture was heated to 60° C. and stirred for 3 hours. The resulting crude compound was purified by HPLC to give 5-bromo-N-(2,6-dioxopiperidin-3-yl)thieno[3,4-b]pyridine-7-carboxamide (15% yield). 1 H NMR(500MHz,DMSO)δ10.97(s,1H), 9.53(d,J=7.4Hz,1H), 8.87(dd,J=4.0,1.5Hz,1H), 8.11(dd,J=8.9,1.5Hz,1H), 7.41(dd,J=8.9,4.0 Hz,1H), 4.91(ddd,J=12.8,7.3,5.6Hz,1H), 2.84(ddd,J=17.5,13.4,5.7Hz,1H), 2.57(ddd,J=17.4,4.3,2.3Hz,1H), 2.30~2.13(m,2H) LCMS (m / z [M+H] + ):368.37 [Example]

[0473] Synthesis of 4-chloro-N-(2,6-dioxopiperidin-3-yl)-1H-pyrrolo[2,3-b]pyridine-3-carboxamide (97)

[0474] [ka]

[0475] This compound was synthesized using the general procedure shown in Reaction Scheme 1 and Synthesis Condition C, above (15% yield) using 4-chloro-1H-pyrrolo[2,3-b]pyridine-3-carboxylic acid (20 mg) as the starting material. 1H NMR(500MHz,DMSO)δ12.40(s,1H), 10.82(s,1H), 8.38(d,J=8.3Hz,1H), 8.22(d,J=5.1Hz,1H), 7.96(s,1H), 7.2 5(d,J=5.1Hz,1H), 4.79~4.72(m,1H), 2.79(ddd,J=17.9,9.7,7.0Hz,1H), 2.59~2.52(m,1H), 2.12~2.01(m,2H). LCMS (m / z [M+H] + ):306.9 [Example]

[0476] Synthesis of N-(2,6-dioxopiperidin-3-yl)-1-methyl-1H-pyrrolo[2,3-b]pyridine-3-carboxamide (98)

[0477] [ka]

[0478] This compound was synthesized using the general procedure shown in Reaction Scheme 1 and synthesis condition C, above (61% yield), using 1-methyl-1H-pyrrolo[2,3-b]pyridine-3-carboxylic acid (20 mg) as the starting material. 1H NMR(500MHz,DMSO)δ10.84(s,1H), 8.44(dd,J=7.9,1.6Hz,1H), 8.34(dd,J=4.7,1 .6Hz,1H), 8.30(d,J=8.3Hz,1H), 8.21(s,1H), 7.23(dd,J=7.9,4.7Hz,1H), 4.78(d dd,J=12.2,8.3,5.3Hz,1H), 3.88(s,3H), 2.80(ddd,J=17.3,13.1,5.5Hz,1H), 2. 59~2.51(m,1H), 2.12(qd,J=12.8,4.5Hz,1H), 2.00(dtd,J=12.8,5.5,3.0Hz,1H). LCMS (m / z [M+H] + ):286.9 [Example]

[0479] Synthesis of 5-chloro-N-(2,6-dioxopiperidin-3-yl)-1H-pyrrolo[2,3-b]pyridine-3-carboxamide (99)

[0480] [ka]

[0481] This compound was synthesized using the general procedure shown in Reaction Scheme 1 and Synthesis Condition C, above (31% yield) using 5-chloro-1H-pyrrolo[2,3-b]pyridine-3-carboxylic acid (20 mg) as the starting material. 1 H NMR(500MHz,DMSO)δ12.40(s,1H), 10.85(s,1H), 8.44(d,J=2.5Hz,1H), 8.39(d,J=8.4Hz,1H), 8.30(d,J=2.4Hz,1H), 8.27(d,J=2.9Hz,1H), 4.79(dd d,J=12.2,8.3,5.3Hz,1H), 2.81(ddd,J=17.3,13.2,5.5Hz,1H), 2.59~2.5 2(m,1H), 2.11(qd,J=12.8,4.4Hz,1H), 2.01(dtd,J=13.0,5.4,2.9Hz,1H). LCMS (m / z [M+H] + ):307.2 [Example]

[0482] Synthesis of 4-chloro-N-(2,6-dioxopiperidin-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide (100)

[0483] [ka]

[0484] This compound was synthesized using the general procedure shown in Reaction Scheme 1 and Synthesis Condition C, described above (8% yield), and 4-chloro-7H-pyrrolo[2,3-d]pyrimidine-5-carboxylic acid (20.0 mg) as the starting material. 1 H NMR(500MHz,DMSO)δ10.82(s,1H), 8.55(s,1H), 8.49(s,1H), 8.36(s,1H), 8.06(s,1H), 4.76(q,J=8.5 Hz,1H), 2.78(ddd,J=18.0,10.3,8.4Hz,1H), 2.56(dt,J=17.2,3.8Hz,1H), 2.06(h,J=5.0,4.4Hz,2H). LCMS (m / z [M+H] + ):308.0 [Example]

[0485] Synthesis of N-(2,6-dioxopiperidin-3-yl)-1H-pyrazolo[4,3-b]pyridine-3-carboxamide (101)

[0486] [ka]

[0487] This compound was synthesized using the general procedure shown in Reaction Scheme 1 and Synthesis Condition C, above (40% yield) using 1H-pyrazolo[4,3-b]pyridine-3-carboxylic acid (20 mg) as the starting material. 1 HNMR (500MHz, DMSO): δ14.01(s,1H), 10.93(s,1H), 9.07(d,J=7.5Hz,1H), 8.69(dd,J=4.4,1.3Hz,1H), 8.19(dd,J=8.5,1.0Hz ,1H), 7.51(dd,J=8.5,4.4Hz,1H), 4.92(ddd,J=7.5,6.7,4.2Hz,1H), 2.90~2.78(m,1H), 2.60~2.54(m,1H), 2.25~2.11(m,2H). LCMS (m / z [M+H] + ):273.8 [Example]

[0488] Synthesis of N-(2,6-dioxopiperidin-3-yl)-2-acetamido-4,5,6,7-tetrahydro-1-benzothiophene-3-carboxamide (105)

[0489] [ka]

[0490] This compound was synthesized using the general procedure shown in Reaction Scheme 1 and Synthesis Condition B, above (19% yield), with 2-acetamido-4,5,6,7-tetrahydro-1-benzothiophene-3-carboxylic acid as the starting material. 1 H NMR (500MHz, DMSO) δ10.99(s,1H), 10.82(s,1H), 7.99(d,J=8.4Hz,1H), 4.91~4.76(m,1H), 2.82(dd d,J=17.5,13.1,6.1Hz,1H), 2.73~2.54(m,5H), 2.16(s,3H), 2.15~2.00(m,2H), 1.84~1.67(m,4H). LCMS (m / z [M−H] - ):347.8 [Example]

[0491] Synthesis of 5-chloro-N-(2,6-dioxopiperidin-3-yl)thieno[3,4-b]pyridine-7-carboxamide (106)

[0492] [ka]

[0493] N-chlorosuccinimide (0.059 g, 0.442 mmol, 1.1 equivalents) was added to a suspension of N-(2,6-dioxopiperidin-3-yl)thieno[3,4-b]pyridine-7-carboxamide (0.116 g, 0.401 mmol) in DMF (5 mL) at room temperature. The reaction mixture was heated to 60° C. and stirred for 3 hours. The resulting crude compound was purified by HPLC to give 5-chloro-N-(2,6-dioxopiperidin-3-yl)thieno[3,4-b]pyridine-7-carboxamide (43% yield). 1 H NMR(400MHz,DMSO)δ10.97(s,1H), 9.51(d,J=7.4Hz,1H), 8.91~8.83(m,1H), 8.19(d,J=8.8Hz,1H) ), 7.41~7.33(m,1H), 4.95~4.84(m,1H), 2.89~2.74(m,1H), 2.62~2.55(m,1H), 2.28~2.11(m,2H) LCMS (m / z [M+H] + ):323.8 [Example]

[0494] Synthesis of N-(2,6-dioxopiperidin-3-yl)thieno[3,4-b]pyridine-7-carboxamide (107)

[0495] [ka]

[0496] Step A: To an ice-cold solution of 2-bromo-3-(bromomethyl)pyridine 2 (10.5 g, 42.0 mmol) in THF (100 mL) was added methyl thioglycolate (4.089 g, 18.124 mmol) followed by EtN under stirring. The mixture was warmed to room temperature and stirred for an additional 30 min. The reaction mixture was diluted with water, extracted with DCM, dried over NaSO, concentrated under reduced pressure, and purified by flash column chromatography to give methyl 2-{[(2-bromopyridin-3-yl)methyl]sulfanyl}acetate (53% yield).

[0497] Step B: A solution of methyl 2-{[(2-bromopyridin-3-yl)methyl]sulfanyl}acetate (4.5 g, 16.295 mmol) in THF (25 mL) was slowly added to a suspension of KH (1.307 g, 32.591 mmol) and stirred for 20 min at room temperature. The reaction mixture was then cooled to −78° C., treated with saturated aqueous NH4Cl, warmed to room temperature, extracted with DCM, dried over Na2SO4, concentrated under reduced pressure, and purified by flash column chromatography to give methyl 5H,7H-thieno[3,4-b]pyridine-7-carboxylate (56% yield).

[0498] Step C: To a stirred solution of methyl 5H,7H-thieno[3,4-b]pyridine-7-carboxylate (3 g, 15.385 mmol) in CHCl (25 mL) was added activated MnO (13.375 g, 153.846 mmol), and the reaction mixture was stirred at room temperature for 16 h, filtered through a bed of Celite, concentrated under reduced pressure, and purified by flash column chromatography to give methyl thieno[3,4-b]pyridine-7-carboxylate (46% yield).

[0499] Step D: To a stirred solution of methyl thieno[3,4-b]pyridine-7-carboxylate (1.5 g, 7.772 mmol) in 4:2:1 THF:MeOH:HO (14 mL) was added LiOH·HO (1.304 g, 31.088 mmol) at 0 °C. The ice bath was then removed and the mixture was stirred at room temperature for 2.5 h. Saturated aqueous citric acid was added, and the product was extracted with 10% MeOH in DCM, dried over NaSO, concentrated under reduced pressure, and purified by HPLC to give thieno[3,4-b]pyridine-7-carboxylic acid (72 mg, 5%).

[0500] Step E: N-(2,6-dioxopiperidin-3-yl)thieno[3,4-b]pyridine-7-carboxamide was synthesized using the general procedure shown in Reaction Scheme 1 and synthesis condition C, as described above (69% yield), and thieno[3,4-b]pyridine-7-carboxylic acid (25.0 mg) as the starting material. 1 H NMR(500MHz,DMSO)δ10.95(s,1H), 9.71(d,J=7.4Hz,1H), 8.83(dd,J=4.0,1.6Hz,1H), 8.59(s,1H), 8.32(dd,J=8.8,1.6Hz,1 H), 7.29(dd,J=8.7,4.0Hz,1H), 4.92(ddd,J=12.7,7.4,5.4Hz,1H), 2.89~2.79(m,1H), 2.60~2.52(m,1H), 2.30~2.11(m,2H). LCMS (m / z [M+H] + ):290.0 [Example]

[0501] N-(2,6-dioxopiperidin-3-yl)-3-methoxythiophene-2-carboxamide (108)

[0502] [ka]

[0503] This compound was synthesized using the general procedure shown in Reaction Scheme 1 and Synthesis Condition C, above (50% yield) using 3-methoxythiophene-2-carboxylic acid (20 mg) as the starting material. 1 H NMR(500MHz,DMSO)δ10.87(s,1H), 7.89(d,J=7.4Hz,1H), 7.75(d,J=5.5Hz,1H), 7.14(d,J=5.5Hz,1H), 4.78~4. 63(m,1H), 3.98(s,3H), 3.31(s,3H), 2.77(ddd,J=17.4,13.1,6.3Hz,1H), 2.54~2.51(m,1H), 2.17~2.04(m,2H). LCMS (m / z [M+H] + ):268.9 [Example]

[0504] Synthesis of (S)-N-(2,6-dioxopiperidin-3-yl)-4-methoxythiophene-3-carboxamide (109)

[0505] [ka]

[0506] This compound was synthesized using the general procedure shown in Reaction Scheme 1 and synthesis condition D, supra (42% yield), using 4-methoxythiophene-3-carboxylic acid (20 mg) and (S)-3-aminopiperidine-2,6-dione as starting materials. 1 H NMR(500MHz,DMSO)δ10.89(s,1H), 8.12(d,J=7.4Hz,1H), 8.09(d,J=3.6Hz,1H), 6.81(d,J=3.6H) z,1H), 4.78~4.65(m,1H), 3.89(s,3H), 2.84~2.72(m,1H), 2.56~2.52(m,1H), 2.15~2.06(m,2H). LCMS (m / z [M+H] + ):268.9 [Example]

[0507] Synthesis of (R)-N-(2,6-dioxopiperidin-3-yl)-4-methoxythiophene-3-carboxamide (110)

[0508] [ka]

[0509] This compound was synthesized using the general procedure shown in Reaction Scheme 1 and synthesis condition D, above (40% yield), using 4-methoxythiophene-3-carboxylic acid (20 mg) and (R)-3-aminopiperidine-2,6-dione as starting materials. 1 H NMR(500MHz,DMSO)δ10.89(s,1H), 8.12(d,J=7.4Hz,1H), 8.09(d,J=3.6Hz,1H), 6.81(d,J=3.6H) z,1H), 4.76~4.68(m,1H), 3.89(s,3H), 2.84~2.72(m,1H), 2.55~2.52(m,1H), 2.14~2.06(m,2H). LCMS (m / z [M+H] + ):268.8 [Example]

[0510] Synthesis of N-(2,6-dioxopiperidin-3-yl)-2-(methoxymethyl)thiazole-5-carboxamide (111)

[0511] [ka]

[0512] This compound was synthesized using the general procedure shown in Reaction Scheme 1 and Synthesis Condition C, above (79% yield), using 2-(methoxymethyl)thiazole-5-carboxylic acid (20 mg) as the starting material. 1 H NMR(500MHz,DMSO)δ10.89(s,1H), 8.95(d,J=8.3Hz,1H), 8.34(s,1H), 4.77~4.70(m,3H), 4.72(s,2H), 3.40(d,J=17.0Hz,3H), 2.79 (ddd,J=17.5,13.3,5.6Hz,1H), 2.52(dd,J=5.7,3.8Hz,1H), 2.10(qd,J=13.0,4.5Hz,1H), 1.99(dddd,J=11.0,8.3,5.5,2.8Hz,1H). LCMS (m / z [M+H] +):283.9 [Example]

[0513] Synthesis of 2-amino-N-(2,6-dioxopiperidin-3-yl)thiazole-5-carboxamide (112)

[0514] [ka]

[0515] To a suspension of tert-butyl (5-((2,6-dioxopiperidin-3-yl)carbamoyl)thiazol-2-yl)carbamate (71, 30 mg, 0.085 mmol, 1 equiv) in DCM (1.5 mL) was added TFA (0.2 mL), and the mixture was stirred at room temperature for 18 h, concentrated under reduced pressure, and purified by HPLC to give 2-amino-N-(2,6-dioxopiperidin-3-yl)thiazole-5-carboxamide (37% yield). 1 H NMR(500MHz,DMSO)δ10.81(s,1H), 8.35(d,J=8.4Hz,1H), 7.64(s,1H), 7.49(s,2H), 4.64(ddd,J=12.5,8.4,5.4Hz,1H), 2.7 6(ddd,J=17.4,13.3,5.6Hz,1H), 2.53~2.51(m,2H), 2.05(qd,J=12.8,4.3Hz,1H), 1.93(ddd,J=10.7,8.1,5.3,2.9Hz,1H). LCMS (m / z [M+H] + ):255.2 [Example]

[0516] 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, and 2% v / v DMSO. The test solution was added to a 384-well assay plate.

[0517] The plate was spun down (1 min, 1000 rpm, 22 °C) and then shaken for 10 min at room temperature (20-25 °C) using a VibroTurbulator at level 3. The assay plate with protein and tracer was incubated for 60 min at room temperature (20-25 °C) before being read on a plate reader. Fluorescence polarization readings were performed on a Pherastar plate reader using a Cy5 FP filterset (590 nm / 675 nm).

[0518] K i To determine the values, FP experiments were performed with various concentrations of the test compound.

[0519] IC of the relationship between compound concentration and measured fluorescence polarization 50 values, K values ​​of Cy5-T and CRBN / DDB1 complex d Calculate the K of the competitive inhibitor using an equation based on the K value, as well as the concentrations of protein and tracer in the displacement assay. i Values ​​were calculated (as described by Z. Nikolovska-Coleska et al., Analytical Biochemistry 332 (2004) 261-273).

[0520] Fluorescence Polarization (FP) Assay - Results The compounds are categorized based on their affinity for CRBN, defined as K. As reported in Table 2 below, the compounds of the present invention interact with the CRBN-DDB1 protein within affinity ranges similar to those reported for the reference compounds.

[0521] [Table 3] JPEG0007760167000150.jpg200170JPEG0007760167000151.jpg205170JPEG0007760167 000152.jpg232170JPEG0007760167000153.jpg214170JPEG0007760167000154.jpg23217 0JPEG0007760167000155.jpg222170JPEG0007760167000156.jpg215170JPEG0007760167 000157.jpg233170JPEG0007760167000158.jpg222170JPEG0007760167000159.jpg73170

[0522] [Example]

[0523] CK1α degradation assay - Kelly cell line The following degradation assay protocol was used to study the effect of various compounds of the invention and various reference compounds on CK1α degradation in the Kelly cell line.

[0524] Kelly cells were maintained in RPMI-1640 medium supplemented with penicillin / streptomycin and 10% fetal bovine serum (FBS). Cells were seeded onto 6-well plates, and the 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% CO), the 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 Ab staining, the membranes were washed, and signals were developed. Densitometry analysis was performed to obtain values ​​that were subsequently used in the protein level evaluation process.

[0525] The compounds tested in this assay were: 54, 109, pomalidomide, CC-122, and lenalidomide at concentrations of 1 μM, 10 μM, and 20 μM. In addition, compounds 22, 21, 108, and 110 were tested at 20 μM. Treatment with all compounds was carried out for 24 hours.

[0526] Densitometry values ​​were normalized to a loading control (β-actin) and expressed as % of DMSO control using the following description: CK1α protein reduction of 0-25% ≤ 25%, CK1α protein reduction >25%, 26-74% ≥75% for 75-100% of CK1α protein reduction.

[0527] Representative results for compounds 54, 109, pomalidomide, CC-122, and lenalidomide are shown in Figure 1 and Table 3. The remaining compounds are presented in Table 4. As illustrated by the results, the compounds of the present invention induce CK1α degradation in the Kelly cell line. CK1α is also degraded by the known compound lenalidomide, and to a lesser extent, by treatment with pomalidomide. However, the lack of degradation by CC-122 illustrates that CK1α-directed activity is not evident for all chemically modified thalidomide-based derivatives, despite their high affinity for the CRBN protein.

[0528] [Table 4]

[0529] [Table 5]

[0530] [Example]

[0531] IKZF1 degradation assay - H929 cell line The following degradation assay protocol was used to examine the effect of various compounds of the present invention and various reference compounds on IKZF1 degradation in the H929 cell line.

[0532] 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 onto 6- or 12-well plates, and the compounds to be tested were added at the desired concentration range. The final DMSO concentration was 0.25%. After 6 or 24 hours of incubation (37°C, 5% CO), cells were harvested and washed, and cell lysates were prepared using RIPA lysis buffer. Protein quantity was determined via BCA assay, and appropriate aliquots were then loaded onto precast gels for protein separation. After primary and secondary Ab staining, the membrane was washed, and signals were developed. Densitometric analysis was performed to obtain values ​​that were subsequently used in the protein level evaluation process.

[0533] The compounds tested in this assay were compounds 109, 20, 108, 111, POM, CC-122, LEN, 106, and 107 at concentrations of 1 μM, 10 μM, and 20 μM. The remaining compounds listed in Table 6 were tested at 20 μM. Treatment with all compounds was carried out for 24 hours. Densitometry values ​​were normalized to the loading control (β-actin) and expressed as % of the DMSO control using the following description: ≤25% for 0-25% IKZF1 protein reduction, >25% for 26–74% of IKZF1 protein reductions; ≥75% for 75–100% of IKZF1 protein reduction.

[0534] Representative results for compounds 109, 20, 108, 111, POM, CC-122, LEN, 106, and 107 are shown in Figure 2 and Tables 5a and 5b. The remaining compounds are presented in Table 6. These results, taken together, illustrate that the compounds of the present invention demonstrate no or reduced IKZF1 decomposition capacity, in contrast to lenalidomide and the more effective pomalidomide and CC-122.

[0535] [Table 6] JPEG0007760167000163.jpg55170

[0536] [Table 7] JPEG0007760167000165.jpg108170

[0537] [Example]

[0538] IKZF3 degradation assay - H929 cell line The following degradation assay protocol was used to examine the effect of various compounds of the present invention and various reference compounds on IKZF3 degradation in the H929 cell line.

[0539] 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 onto 6- or 12-well plates, and the 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% CO), cells were harvested and washed, and cell lysates were prepared using RIPA lysis buffer. Protein quantity was determined via BCA assay, and appropriate aliquots were then loaded onto precast gels for protein separation. After primary and secondary Ab staining, the membrane was washed, and signals were developed. Densitometric analysis was performed to obtain values ​​that were subsequently used in the protein level evaluation process.

[0540] The compounds tested in this assay were: Compounds 109, 20, 108, 111, POM, CC-122, LEN, 106, 107 at concentrations of 1 μM, 10 μM and 20 μM. Treatment with all compounds was carried out for 24 hours. Densitometry values ​​were normalized to the loading control (β-actin) and expressed as % of the DMSO control using the following description: ≤25% for 0-25% IKZF3 protein reduction, >25% for 26-74% of IKZF3 protein reduction, ≥75% for 75–100% of IKZF3 protein reduction.

[0541] Representative results for compounds 109, 20, 108, 111, POM, CC-122, LEN, 106, and 107 are shown in Figure 3 and Tables 7a and 7b. As illustrated in this figure, the compounds of the present invention, in contrast to lenalidomide and the more potent pomalidomide and CC-122, do not exhibit any IKZF3 degradation efficiency.

[0542] [Table 8] JPEG0007760167000167.jpg54170

[0543] In summary, the compounds of the present invention are capable of potent degradation of CK1α, a disease-related protein kinase. In contrast, the results of the displayed neo-substrate IKZF1 and IKZF3 degradation assays for the compounds of the present invention show that the compounds induce no or low protein degradation, in contrast to the known CK1α degraders, lenalidomide and pomalidomide. This innovative profile makes the compounds of the present invention useful as more selective CK1α degraders.

[0544] Abbreviations and Definitions A list of abbreviations used in this application is provided in Table 8 below:

[0545] [Table 9] JPEG0007760167000169.jpg240163JPEG0007760167000170.jpg36163

[0546] As used herein, the term "room temperature" means a temperature between 20°C and 25°C.

[0547] As used herein, the term "small molecule" means an organic compound having a molecular weight of less than 900 Daltons. [Embodiments of the present invention]

[0548] 1. Compounds of formula (Ia) or (Ib):

[0549] [ka]

[0550] [In the formula, Each of X1 and X2 is independently O or S; Z is S or NR 2 and; T is C=O or SO; Each of Y1, Y2, Y3, and Y4 is independently N or CR; At least one of Y1, Y2 and Y3 in formula (Ia) is CR, and at least one of Y1, Y2 and Y4 in formula (Ib) is 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, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, aryl, heteroaryl, benzyl, haloalkyl, haloalkenyl, -NH2, -NHR'', -NR''2, -NR''C(O)R'', -NR''C(O)CH(OH)R'', -NR''C(O)OR'', -NR''S02R'', -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'', or -S(O)2R'', -S(O)2OR'', -S(O)2NH2, -S(O)2NHR'', or -S(O)2NR''2; each R″ is independently hydrogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, aryl, heteroaryl, or benzyl; R 2 is hydrogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, aryl, heteroaryl, benzyl, haloalkyl, haloalkenyl, -NH2, -NHR'', -NR''2, -NR''C(O)R'', -N[C(O)R'']2, -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'', or -S(O)2R'', -S(O)2OR'', -S(O)2NH2, -S(O)2NHR'', or -S(O)2NR''2; R 1 is hydrogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, aryl, heteroaryl, or benzyl; (i) when each of Y1, Y2 and Y3 in formula (Ia) is CR, or when each of Y1, Y2 and Y4 in formula (Ib) is CR, at least one of R is not H; (ii) when Z in formula (Ib) is S, Y1 is not C-COOH; (iii) In formula (Ib), when Z is NR2, Y1, Y2, and Y4 are CR; (iv) When Z in formula (Ia) is NR2, Y2 and Y3 are CR.

[0551] 2. The compound of embodiment 1, having the structure:

[0552] [ka]

[0553] 3. The compound of embodiment 1, having the structure:

[0554] [ka]

[0555] 4. A compound of any preceding embodiment, wherein T is C=O.

[0556] 5. The compound of any one of embodiments 1-3, wherein T is SO2.

[0557] 6. The compound of any preceding embodiment, wherein Z is NR 2 is.

[0558] 7. The compound of any preceding embodiment, wherein R 2 is alkyl, benzyl, or —N[C(O)R″]2.

[0559] 8. The compound of any one of embodiments 1-5, wherein Z is S.

[0560] 9. The compound of any one of embodiments 1-8, wherein L is hydrogen, alkyl, alkenyl, aryl, heteroaryl, benzyl, -OR", -NR"2, or -S(O)2R"; and L may be hydrogen, alkyl, alkenyl, aryl, heteroaryl, or benzyl.

[0561] 10. The compound of embodiment 9, wherein L is hydrogen.

[0562] 11. The compound of any preceding embodiment, wherein the compound is of Formula (Ia), wherein one of Y1, Y2, and Y3 is N, and the remaining two of Y1, Y2, and Y3 are each CR.

[0563] 12. The compound of embodiment 11, wherein Y1 is N, and Y2 and Y3 are CR.

[0564] 13. The compound of embodiment 11, wherein Y2 is N, Y1 and Y3 are CR; and Z is S.

[0565] 14. The compound of embodiment 11, wherein Y3 is N; Y1 and Y2 are CR; and Z is S.

[0566] 15. The compound of any one of embodiments 1-10, wherein the compound is of Formula (Ia), wherein one of Y1, Y2, and Y3 is CR, and the remaining two of Y1, Y2, and Y3 are each N; and Z is S.

[0567] 16. The compound of embodiment 15, wherein Y1 is CR; Y2 and Y3 are N.

[0568] 17. The compound of embodiment 15, wherein Y2 is CR; and Y1 and Y3 are N.

[0569] 18. The compound of embodiment 15, wherein Y3 is CR, and Y1 and Y2 are N.

[0570] 19. The compound of any one of embodiments 1-10, wherein the compound is of formula (Ia) and Y1, Y2, and Y3 are each CR.

[0571] 20. The compound of embodiment 19, Y1 is -C-NHC(O)R'', Y2 is CH; Y3 is CH or CCl.

[0572] 21. The compound of embodiment 20, wherein: L is hydrogen; Z is S; R 1 is H; T is C=O; Y1 is -C-NHC(O)R''; Y2 is CH; Y3 is CH.

[0573] 22. The compound of any one of embodiments 1-10, wherein the compound is of Formula (Ib), wherein one of Y1, Y2, and Y4 is N, the remaining two of Y1, Y2, and Y4 are each CR, and Z is S.

[0574] 23. The compound of embodiment 22, wherein Y1 is N, and Y2 and Y4 are CR.

[0575] 24. The compound of embodiment 22, wherein Y2 is N, and Y1 and Y4 are CR.

[0576] 25. The compound of embodiment 22, wherein Y4 is N, and Y1 and Y2 are CR.

[0577] 26. The compound of any one of embodiments 1-10, wherein the compound is of formula (Ib), wherein one of Y1, Y2, and Y4 is CR, the remaining two of Y1, Y2, and Y4 are each N, and Z is S.

[0578] 27. The compound of embodiment 26, wherein Y1 is CR, and Y2 and Y4 are N.

[0579] 28. The compound of embodiment 26, wherein Y2 is CR, and Y1 and Y4 are N.

[0580] 29. The compound of embodiment 26, wherein Y4 is CR and Y1 and Y2 are N.

[0581] 30. The compound of any one of embodiments 1-10, wherein the compound is of formula (Ib) and Y1, Y2, and Y4 are each CR.

[0582] 31. The compound of embodiment 30, wherein each R is independently hydrogen, halogen, alkyl, cycloalkyl, haloalkyl, heteroaryl, —OR″, —N[C(O)R″]2, —NR″C(O)R″, —NHC(O)OR″, —NHR″, —NH2, or —NHSO2R″CN; Each R'' may independently be alkyl, cycloalkyl, aryl, or benzyl.

[0583] 32. The compound of embodiment 31, wherein: L is hydrogen; Z is S; R 1 is H; T is C=O; Y1 is CH, C-OR'', CCl, C-CN, or C-NHC(O)R''; Y2 is CH, CCl, C-alkyl, C-cycloalkyl, or C-haloalkyl; Y4 is CH, C-OR'', C-NHC(O)R'', C-NHC(O)OR'', C-NHR'', C-NH2, or C-NHSO2R''; when Y1 is CCl, Y2 is CH, C-alkyl, C-cycloalkyl, or C-haloalkyl; Each R'' may independently be alkyl, cycloalkyl, aryl, or benzyl.

[0584] 33. The compound of embodiment 32, wherein: Y1 is CH; Y2 is CH or CCl; Y4 is C-OR'' or C-NH2, and may be C-OMe or C-NH2.

[0585] 34. The compound of any one of embodiments 1-31, wherein each R is independently hydrogen, halogen, alkyl, cycloalkyl, haloalkyl, heteroaryl, —NR″C(O)R″, NR″C(O)OR″, —NR″C(O)CH(OH)R″, —NHR″, —NH2, —OR″, —CN, —C(O)NR″2, or —NR″S02R″.

[0586] 35. The compound of embodiment 34, wherein each R is independently hydrogen, halogen, alkyl, cycloalkyl, haloalkyl, —OR″, —CN, —NHC(O)R″, —NHC(O)OR″, —NHR″, —NH2, or —NHSO2R″.

[0587] 36. A compound of embodiment 34 or 35, wherein each R″ is independently alkyl, cycloalkyl, aryl, or benzyl.

[0588] 37. Compounds of formula (IIa) or (IIb):

[0589] [ka]

[0590] [In the formula, Each of X1 and X2 is independently O or S; Z is O, S or NR 2 and; T is C=O or SO; Y3 is N or CR; Y4 is N or CR;

[0591] [ka] represents a single or double bond, Each

[0592] [ka] is a double bond, each of W1, W2, W3 and W4 is independently N or CR', and at least one of W1, W2, W3 and W4 is N; Each

[0593] [ka] is a single bond, W1, W2, W3 and W4 are each CR'2; 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, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, aryl, heteroaryl, benzyl, haloalkyl, haloalkenyl, -NH2, -NHR'', -NR''2, -NR''C(O)R'', -NR''C(O)CH(OH)R'', -NR''C(O)OR'', -NR''S02R'', -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'', or -S(O)2R'', -S(O)2OR'', -S(O)2NH2, -S(O)2NHR'', or -S(O)2NR''2; Each R' is independently hydrogen, halogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, aryl, heteroaryl, benzyl, haloalkyl, haloalkenyl, -NH2, -NHR'', -NR''2, -NR''C(O)R'', -NR''C(O)CH(OH)R'', -NR''C(O)OR'', -NR''S02R'', -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'', or -S(O)2R'', -S(O)2OR'', -S(O)2NH2, -S(O)2NHR'', or -S(O)2NR''2; each R″ is independently hydrogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, aryl, heteroaryl, or benzyl; R 2 is hydrogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, aryl, heteroaryl, benzyl, haloalkyl, haloalkenyl, -NH2, -NHR'', -NR''2, -NR''C(O)R'', -N[C(O)R'']2, -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'', or -S(O)2R'', -S(O)2OR'', -S(O)2NH2, -S(O)2NHR'', or -S(O)2NR''2; R 1 is hydrogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, aryl, heteroaryl, or benzyl.

[0594] 38. The compound of embodiment 37, having the structure:

[0595] [ka]

[0596] 39. The compound of embodiment 37, having the structure:

[0597] [ka]

[0598] 40. The compound of any one of embodiments 37-39, wherein Z is O.

[0599] 41. The compound of any one of embodiments 37-39, wherein Z is S.

[0600] 42. The compound of any one of embodiments 37-39, wherein Z is NR 2 . is.

[0601] 43. The compound of any one of embodiments 37-42, wherein T is C=O.

[0602] 44. The compound of any one of embodiments 37-42, wherein T is SO2.

[0603] 45. The compound of any one of embodiments 37-44, wherein L is hydrogen, alkyl, alkenyl, aryl, heteroaryl, benzyl, —OR″, —NR″2, or —S(O)2R″; and L may be hydrogen, alkyl, alkenyl, aryl, heteroaryl, or benzyl.

[0604] 46. ​​The compound of embodiment 45, wherein L is hydrogen.

[0605] 47. The compound of any one of embodiments 37-46, wherein Y3 is N.

[0606] 48. The compound of any one of embodiments 37-46, wherein Y3 is CR.

[0607] 49. The compound of any one of embodiments 37-46, wherein Y4 is N.

[0608] 50. The compound of any one of embodiments 37-46, wherein Y4 is CR.

[0609] 51. The compound of any one of embodiments 37 to 50, wherein each

[0610] [ka] is a double bond, or each

[0611] [ka] is a single bond.

[0612] 52. The compound of embodiment 51, wherein each

[0613] [ka] is a double bond.

[0614] 53. The compound of embodiment 52, wherein one of W1, W2, W3, and W4 is N, and the remaining three of W1, W2, W3, and W4 are each CR'.

[0615] 54. The compound of embodiment 52, wherein two of W1, W2, W3, and W4 are N, and the remaining two of W1, W2, W3, and W4 are each CR'.

[0616] 55. The compound of embodiment 52, wherein one of W1, W2, W3, and W4 is CR', and the remaining three of W1, W2, W3, and W4 are each N.

[0617] 56. The compound of embodiment 51, wherein each

[0618] [ka] is a single bond.

[0619] 57. The compound of any one of embodiments 37-56, wherein each R is independently hydrogen, halogen, or —NR″C(O)R″.

[0620] 58. The compound of any one of embodiments 37-57, wherein each R' is hydrogen.

[0621] 59. A compound of any preceding embodiment, wherein X1 and X2 are O.

[0622] 60. The compound of any one of embodiments 1-58, wherein X1 is O and X2 is S.

[0623] 61. The compound of any one of embodiments 1-58, wherein X1 is S and X2 is O.

[0624] 62. The compound of any one of embodiments 1-58, wherein X1 and X2 are S.

[0625] 63. The compound of any preceding embodiment, wherein n is 0.

[0626] 64. The compound of any one of embodiments 1-62, wherein n is 1.

[0627] 65. The compound of any one of embodiments 1-62, wherein n is 2.

[0628] 66. The compound of any one of the preceding embodiments for use as a cereblon-binding agent.

[0629] 67. A pharmaceutical composition comprising a compound of any one of embodiments 1-65.

[0630] 68. A compound according to any one of embodiments 1 to 65 or a composition according to embodiment 67 for use in the field of medicine.

[0631] 69. The compound of any one of embodiments 1 to 65, or the composition according to embodiment 67, for use in immuno-oncology.

[0632] 70. The compound of any one of embodiments 1-65, or the composition according to embodiment 67, for use in 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.

[0633] 71. 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 administering an effective amount of a compound according to any one of embodiments 1-65 or a composition according to embodiment 67 to a patient in need thereof.

[0634] 72. The method of embodiment 71, further comprising administering to the patient at least one additional active agent.

[0635] 73. A combination of a compound of any one of embodiments 1-65 and at least one additional active agent for simultaneous, separate or sequential use in therapy.

[0636] 74. The combination of embodiment 73 or the method of embodiment 72, wherein at least one additional active agent is an anti-cancer agent or an agent for treating an autoimmune disease.

[0637] 75. The combination of embodiment 73 or 74, or the method of embodiment 72 or 74, wherein at least one additional active agent is a small molecule, a peptide, an antibody, a corticosteroid, or a combination thereof.

[0638] 76. The combination or method of embodiment 75, wherein the at least one additional active agent is at least one of bortezomib, dexamethasone, and rituximab.

[0639] 77. The combination of any one of embodiments 73 to 76, wherein the treatment is 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.

Claims

1. Compounds of formula (Ia): 【Chemical 1】 (Ia) or a pharmaceutically acceptable salt or tautomer thereof [In the formula, X １ and X ２ is O; Z is S; T is C=O; Y １ , Y ２ , and Y ３ each is independently N or CR; n is 1; L is hydrogen; Each R is independently hydrogen, halogen, alkyl, cycloalkyl, heterocycloalkyl, alkenyl, cycloalkenyl, alkynyl, aryl, heteroaryl, benzyl, haloalkyl, haloalkenyl, -NH ２ , -NHR'', -NR'' ２ , -CH ２ NR'' ２ , -NR''C(O)R'', -NR''C(O)CH ２ NR'' ２ , -NR''C(O)CH ２ -heterocycloalkyl, -NR"C(O)CH(OH)R", -CH ２ NR''C(O)OR'', -NR''C(O)OR'', -NR''SO ２ R'', -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 , -NHC(S)NHR'', SR'', -S(O) ２ R″, —S(O) ２ OR'', -S(O) ２ NH ２ , -S(O) ２ NHR″, or —S(O) ２ NR'' ２ and each R″ is independently hydrogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, aryl, heteroaryl, or benzyl; and R １ is hydrogen; where: (i) Y ２ is CH and Y ３ is CH and Y １ is C-NHC(O)R″; (ii) Y ２ is C-OH or C-CH ２ NHC(O)OR″, and Y ３ is CH and Y １ is CH; (iii) Y ２ is CH and Y ３ is C-CH ２ NHC(O)OR″, and Y １ is CH; (iv) Y ２ is N and Y ３ is C-NHC(O)OR″, and Y １ is N or CR; or (v) Y ２ is N and Y ３ is C-NH ２ and Y １ is C—H; "Alkyl" refers to an unsubstituted alkyl group, as well as -OH, -OR", -NH ２ , -NHR'', -NR'' ２ , -SO ２ -R", -C(O)R", -CN, or -NO ２ "Alkenyl" includes both unsubstituted alkenyl groups and -OH, -OR", -NH ２ , -NHR'', -NR'' ２ , -SO ２ -R", -C(O)R", -CN, or -NO ２ and "alkynyl" includes both unsubstituted alkynyl groups and alkenyl groups substituted with one or more additional groups selected from -OH, -OR", halogen, -NH ２ , -NHR'', -NR'' ２ , -SO ２ -R", -C(O)R", -CN, and -NO ２ "aryl" includes unsubstituted aryl groups, as well as -OH, -OR", halogen, -NH ２ , -NHR'', -NR'' ２ , -SO ２ -R", -C(O)R", -CN, and -NO ２ "Heteroaryl" includes unsubstituted heteroaryl groups as well as -OH, -OR", halogen, -NH ２ , -NHR'', -NR'' ２ , -SO ２ -R", -C(O)R", -CN, and -NO ２ "Benzyl" refers to an unsubstituted benzyl group, as well as to -OH, -OR", halogen, -NH ２ , -NHR'', -NR'' ２ , -SO ２ -R", -C(O)R", -CN, and -NO ２ and a benzyl group substituted by one or more additional groups selected from:

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

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

4. Each R is independently hydrogen, halogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, aryl, heteroaryl, benzyl, haloalkyl, haloalkenyl, -NR'' ２ , -NR''C(O)R'', -NR''C(O)CH(OH)R'', -NR''C(O)OR'', -NR''SO ２ R'', -NO ２ , -CN, -C(O)R'', -C(O)OR'', -C(O)NR'' ２ , -OR'', -OC(O)R'', -OC(O)OR'', -OC(O)NR'' ２ , -SR'', -S(O) ２ R″, —S(O) ２ OR″, or —S(O) ２ NR'' ２ The compound according to any one of claims 1 to 3,

5. Each R is independently hydrogen, halogen, alkyl, cycloalkyl, haloalkyl, heteroaryl, —NR″C(O)R″, NR″C(O)OR″, —NR″C(O)CH(OH)R″, —NHR″, —NH ２ , -OR'', -CN, -C(O)NR'' ２ , or -NR''SO ２ The compound of claim 4, wherein R'' is

6. Each R is independently hydrogen, halogen, alkyl, cycloalkyl, haloalkyl, —OR″, —CN, —NHC(O)R″, —NHC(O)OR″, —NHR″, —NH ２ or -NHSO ２ The compound of claim 5 , wherein R″ is

7. 7. The compound of claim 5 or 6, wherein each R'' is independently alkyl, cycloalkyl, aryl, or benzyl. 【Request 8】 【Table 1】 2. The compound of claim 1 selected from:

9. A pharmaceutical composition comprising a compound according to any one of claims 1 to 8.

10. A compound according to any one of claims 1 to 8, or 【Chemistry 15】 A pharmaceutical comprising a compound selected from:

11. 10. A pharmaceutical composition for use in 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, or hemoglobinopathies and related disorders, said pharmaceutical composition comprising a compound according to any one of claims 1 to 8, or 【Chemistry 16】 A pharmaceutical composition for use comprising a compound selected from:

12. The pharmaceutical composition for use according to claim 11, wherein the cancer treatment is an immuno-oncology.

13. 13. A pharmaceutical composition for use according to claim 11 or 12, further comprising at least one additional active agent.

14. At least one additional active agent (a) an anti-cancer drug or a drug for the treatment of an autoimmune disease; and / or 14. The pharmaceutical composition for use according to claim 13, wherein (b) is a small molecule, a peptide, an antibody, a corticosteroid, or a combination thereof.

15. 15. The pharmaceutical composition for use according to claim 14, wherein the at least one additional active agent is at least one of bortezomib, dexamethasone, and rituximab.

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