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WO2022255889A1 - Compounds which bind to cereblon, and use thereof - Google Patents

Compounds which bind to cereblon, and use thereof Download PDF

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Publication number
WO2022255889A1
WO2022255889A1 PCT/PL2021/000033 PL2021000033W WO2022255889A1 WO 2022255889 A1 WO2022255889 A1 WO 2022255889A1 PL 2021000033 W PL2021000033 W PL 2021000033W WO 2022255889 A1 WO2022255889 A1 WO 2022255889A1
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Prior art keywords
compound
hydrogen
nhr
alkyl
aryl
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PCT/PL2021/000033
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French (fr)
Inventor
Sylvain Cottens
Katarzyna Kaczanowska
Roman PLUTA
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Captor Therapeutics S.A.
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Priority to PCT/PL2021/000033 priority Critical patent/WO2022255889A1/en
Publication of WO2022255889A1 publication Critical patent/WO2022255889A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D498/10—Spiro-condensed systems

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  • Leukemia can be selected from: acute leukemia, acute lymphoblastic leukemia (ALL), chronic lymphocytic leukemia (CLL), acute myelogenous leukemia, acute myeloid leukemia (AML), adult acute basophilic leukemia, adult acute eosinophilic leukemia, adult acute megakaryoblastic leukemia, adult acute minimally differentiated myeloid leukemia, adult acute monoblastic leukemia, adult acute monocytic leukemia, adult acute myeloblastic leukemia with maturation, adult acute myeloblastic leukemia without maturation, adult acute myeloid leukemia with abnormalities, adult acute myelomonocytic leukemia, adult erythroleukemia, adult pure erythroid leukemia, secondary acute myeloid leukemia, untreated adult acute myeloid leukemia, adult acute myeloid leukemia in remission, adult acute promyelocytic leukemia with PML- RARA, alkylating agent-
  • reaction mixture was acidified with 2M HCI and the precipitate was filtered to give 6-((tert-butoxycarbonyl)amino)-2-(trifluoromethyl)-1H-benzo[d]imidazole-7-carboxylic acid 300 mg (52% yield).
  • the FP experiment was carried out with various concentrations of the test compounds in order to measure K, values.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

The present invention provides novel compounds which bind to cereblon, and methods of use thereof. The compounds are represented by Formulas (I), (II), (III), (IV), (V) and (VI):

Description

COMPOUNDS WHICH BIND TO CEREBLON, AND USE THEREOF
FIELD OF THE INVENTION
The present invention relates to novel compounds which bind to the protein cereblon and modulate the substrate specificity of CUL4-DDB1-RBX1-CRBN ubiquitin ligase complex (CRL4CRBN). Cereblon is a substrate recognition component of CRL4CRBN. Chemical modulation of cereblon may induce association of novel substrate proteins, followed by their ubiquitination and degradation.
BACKGROUND
Cereblon (CRBN) is a protein which associates with DDB1 (damaged DNA binding protein 1), CUL4 (Cullin- 4), and RBX1 (RING-Box Protein 1). Collectively, the proteins form a ubiquitin ligase complex, which belongs to Cullin RING Ligase (CRL) protein family and is referred to as CRL4CRBN. Cereblon became of particular interest to the scientific community after it was confirmed to be a direct protein target of thalidomide, which mediates the biological activity of cereblon. Thalidomide, a drug approved for treatment of multiple myeloma in the late 1990s, binds to cereblon and modulates the substrate specificity of the CRL4CRBN ubiquitin ligase complex. This mechanism underlies the pleiotropic effect of thalidomide on both immune cells 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).
Thalidomide's success in cancer therapy stimulated efforts towards development of analogues with higher potency and fewer detrimental side effects. As a result, various drug candidates were produced: lenalidomide, pomalidomide, CC-220, CC-122, CC-885, and TD-106. These compounds are collectively called Cereblon Modulating Agents (CMAs). For discussions of these compounds, see - for example - US 5635517(B2), W02008039489 (A2), WO2017197055 (Al), WO2018237026 (Al), W02017197051 (A1), US 8518972 (B2), EP 2057143 (B1), W02019014100 (Al), W02004103274 (A2), and Kim SA et al.: A novel cereblon modulator for targeted protein degradation. Eur J Med Chem. 2019 Mar 15; 166: 65-74. The clinical applicability of CMAs in numerous hematologic malignancies, such as multiple myeloma, myelodysplastic syndromes lymphomas 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).
The antitumor activity of cereblon modulators is mediated by:
1) inhibition of cancer cell proliferation and induction of apoptosis,
2) disruption of trophic support from tumor stroma,
3) stimulation of immune cells, resulting in proliferation of T-cells, cytokine production and activation of NK (natural killer) cells (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) .
It has been demonstrated that chemically-modified thalidomide-based derivatives can significantly modify the substrate specificity of CRL4CRBN ubiquitin ligase. Thus, it is desired to progress development of cereblon modulating agents in order to achieve desired substrate specificity in the CMA-bound CRL4CRBN ubiquitin ligase complex ( see Sievers QL et al.: Defining the human C H zinc finger degrome targeted by thalidomide analogues through CRBN. Science. 2018 Nov 2; 362(6414)) combined with a favorable physicochemical properties. There is thus a continuing need to provide novel cereblon-binding compounds which have pharmaceutically relevant properties.
SUMMARY OF INVENTION
In accordance with a first aspect of the invention, there is provided a compound of Formula (I), (II) or (III):
Figure imgf000003_0001
Figure imgf000004_0002
wherein: each of X1 and X2 is independently O or S;
T is C= O or SO2;
R1 is hydrogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, aryl, heteroaryl, or benzyl; n is 0, 1 or 2;
L is hydrogen, alkyl, alkenyl, benzyl, aryl, heteroaryl, haloalkyl, haloalkenyl, -CH2OC(O)lBu, -
C(O)H, -C(O)R" -C(O)OH, -C(O)OR", -CH2C(O)OR", -C(O)NH2, -C(O)NHR", -C(O)NR"2; -OH, -OR", -NH2, - NHR", -NR"2, -S(O)2H, -S(O)2R" or P(O)(OR")(OR");
Rx is selected from
Figure imgf000004_0001
Z is O, S or NR4;
V is CR2, NR4 or S; each of W1, W2) W3 and W4 is independently N or CR2, each of Y1 and Y2 is independently N or CR, each R is independently hydrogen, halogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, aryl, fused aryl-cycloalkyl, fused aryl-heterocycloalkyl, heteroaryl, heteroaryl substituted with at least one aryl group, benzyl, haloalkyl, haloalkenyl, -NH2, -NHR", -NR"2, -NHC(O)R", -NR"C(O)R",
NHC(O)CH(OH)R", -NR"C(O)CH(OH)R", -NHC(O)OR", -NR"C(O)OR", -NHSO2R", -NR"SO2R", -NO2, -CN, - C(O)H, C(O)R", -C(O)OH, -C(O)OR", -C(O)NH2, -C(O)NHR", -C(O)NR"2,-OH, -OR", -OC(O)H, -OC(O)R", - OC(O)OH,-OC(O)OR", -OC(O)NH2, -OC(O)NHR", -OC(O)NR"2, -SH, -SR", -S(O)2H, -S(O)2R", -S(O)2OH, - S(O)2OR", -S(O)2NH2, -S(O)2NHR", or -S(O)2NR"2; or when Y4 and Y2 are CR then each R, together with the carbon atom to which it is attached, forms a 5- or 6- membered ring; each R2 is independently hydrogen, halogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, aryl, aryl substituted with at least one -OR", heteroaryl, benzyl, haloalkyl, haloalkenyl, -IMH2, -NHR", -NR"2, - CH2NH2, -NHC(O)R", -NR"C(O)R", NHC(O)CH(OH)R", -NR"C(O)CH(OH)R", -NHC(O)OR", -NR"C(O)OR", - NHSOzR", -NR"SO2R", -NO2, -CN, -C(O)H, C(O)R", -C(O)OR", -C(O)NH2, -C(O)NHR", -C(O)NR"2,-OH, -OR", -OC(O)H, -OC(O)R", -OC(O)OH,-OC(O)OR", -OC(O)NH2, -OC(O)NHR", -OC(O)NR"2, -SH, -SR", -S(O)2H, - S(O)2R", -S(O)2OH, -S(O)2OR", -S(O)2NH2, -S(O)2NHR", -S(O)2NR"2, or -CH2NHR8; each R4 is independently hydrogen, halogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, aryl, heteroaryl, benzyl, haloalkyl, haloalkenyl, -C(O)H, C(O)R", -C(O)OH, -C(O)OR", -C(O)NH2, -C(O)NHR", - C(O)NR"2, -OH, -OR", -NH2, -NHR", -NR"2, -S(O)2H, -S(O)2R", fluorenylmethoxycarbonyl, benzyloxycarbonyl, phthalimide, benzylideneamine, or toluenesulfonyl;
R5 is hydrogen, deuterium or alkyl; each R6 is independently deuterium or hydrogen;
R7 is hydrogen, deuterium or alkyl; each R" is independently alkyl, cycloalkyl, alkenyl, cycloalkenyl, aryl, heteroaryl, or benzyl;
R8 is a protecting group selected from alkyl, benzyl, -C(O)Me, -C(O)CF3, -C(O)*Bu, -C(O)OMe, - C(O)O*Bu, -C(PH)3, fluorenylmethoxycarbonyl, benzyloxycarbonyl, phthalimide, benzylideneamine, and toluenesulfonyl; wherein, when n = 2, each R2 is hydrogen, and each of W1, W2, W3 and W4 is CR2, then C=X1 may be replaced by CH. In some embodiments:
(i) when Rx is and Z is NH, then L is hydrogen, -CH2C(O)OR", or -OR";
Figure imgf000006_0002
(ii) when Rx is
Figure imgf000006_0003
, Z is NR4, Y1 is CR, and Y2 is N, then R4 is not alkyl and at least one of R2 and R is not H;
(iii) when Rx is
Figure imgf000006_0004
, Z is NR4, and Y1 and Y2 are CR, then at least one of W1, W2 and W3 is N; (iv) when Z is NR4, and Y1 and Y2 are CR, then Rx is not
Figure imgf000006_0001
(v) when Rx is
, Z is MR4, and Y1
Figure imgf000007_0001
or Y2 is N, then R4 is not alkyl; (vi) when Rx is
Figure imgf000007_0002
, then n = 1 or 2; and
(vii) when Rx is
, then Z = O or S
Figure imgf000007_0003
In some embodiments, the compound is of Formula (I). In some such embodiments, the compound has the structure:
Figure imgf000008_0002
In other embodiments, the compound has the structure:
Figure imgf000008_0001
In some embodiments, T is C=O. In other embodiments, T is SO2.
In some embodiments, Z is NR4. In other embodiments, Z is O. In other embodiments, Z is S.
In some embodiments, V is CR2. In other embodiments, V is NR4. In other embodiments, V is S.
In some embodiments, L is alkyl, benzyl, -C(O)Me, or -C(O)tBun other embodiments, L is hydrogen.
In some embodiments, each R6 is deuterium. In other embodiments, each R6 is hydrogen.
In some embodiments, R7 is deuterium. In other embodiments, R7 is hydrogen.
In some embodiments, R5 is deuterium. In other embodiments, R5 is hydrogen.
In some embodiments, R1 is hydrogen. In some embodiments, Ya is N, and Y2 is CR. In other embodiments, Y2 is N, and Ya is CR. In other embodiments, both of Y1 and Y2 are N. In other embodiments, Y1 and Y2 are CR.
In some embodiments, Rx is selected from
Figure imgf000009_0001
In some embodiments, Rx is selected from
Figure imgf000009_0002
In some embodiments, Rx is selected from
Figure imgf000010_0001
In some embodiments, Rx is
Figure imgf000010_0002
In some embodiments, Rx is selected from
Figure imgf000010_0003
In some embodiments, Rx is selected from
Figure imgf000011_0001
In some embodiments, Rx is selected from
Figure imgf000011_0003
Figure imgf000011_0004
In some embodiments, Rx is selected from
Figure imgf000011_0002
In some embodiments, Rx is
Figure imgf000012_0001
In some embodiments, one of W1, W2 and W3 is N, and the remaining two of W1, W2 and W3 are each CR2. In other embodiments, two of W1, W2 and W3 are N, and the remaining one of W1; W2 and W3 is CR2. In other embodiments, each of W1, W2 and W3 is N. In other embodiments, each of W1, W2 and W3 is CR2.
In some embodiments, Rx is
Figure imgf000012_0002
In some embodiments, one of W1, W2 and W4 is N, and the remaining two of Wa, W2 and W3 are each CR2. In other embodiments, two of W1, W2 and W4 are N, and the remaining one of W1, W2 and W3 is CR2. In other embodiments, each of W1, W2 and W4 is N. In other embodiments, each of W1, W2 and W4 is CR2.
In some embodiments, T is C=O; R1 is hydrogen, L is hydrogen, Z is NR4; each of W1, W2 and W4 is CR2, Y1 is N, and Y2 is CR, wherein R is not hydrogen.
In some embodiments, R* is
Figure imgf000013_0001
In some embodiments, Rx is
Figure imgf000013_0002
In some embodiments, Rx is
Figure imgf000013_0003
In some embodiments, Rx is
Figure imgf000013_0004
In some embodiments, Rx is
Figure imgf000014_0001
In some embodiments, Rx is
Figure imgf000014_0002
In some embodiments, Rx is
Figure imgf000014_0003
In some embodiments, Rx is
Figure imgf000015_0001
In some embodiments, R4 is hydrogen, halogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, aryl, heteroaryl, benzyl, haloalkyl, haloalkenyl, -OH, -OR", -NH2, -NHR", -NR"2, -S(O)2H or -S(O)2R"; optionally wherein R4 is hydrogen, halogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, aryl, heteroaryl, benzyl, haloalkyl, or haloalkenyl. In some embodiments, R4 is hydrogen or alkyl.
In some embodiments, V is CH2.
In some embodiments, each R2 is independently hydrogen, halogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, aryl, aryl substituted with at least one -OR", benzyl, haloalkyl, haloalkenyl, -NH2, - NHR", -NR"2, -CH2NHZ, -NHC(O)R", -NR"C(O)R", NHC(O)CH(OH)R", -NR"C(O)CH(OH)R", -NHC(O)OR", - NR"C(O)OR", -NHSOzR", -NR"SO2R", -NO2, -CN, -OH, -OR", -OC(O)H, -OC(O)R", -OC(O)OH,-OC(O)OR", - OC(O)NH2, -OC(O)NHR", -OC(O)NR"2, -SH, -SR", -S(O)2H, -S(O)2R", -S(O)2OH, -S(O)2OR", -S(O)2NH2, - S(O)2NHR", or -S(O)2NR"2. In some embodiments, wherein each R2 is independently hydrogen, halogen, aryl, aryl substituted with at least one -OR", -NH2, -CH2NH2, -NHC(O)R", -NO2, or -OR". In other embodiments, each R2 is independently hydrogen, halogen, alkyl, heteroaryl, -NH2, -NHR", -NHC(O)R", - NHSOzR", -CN, -C(O)NH2, -C(O)NHR", -C(O)NR"2,-OH, -OR", -S(O)2NH2, -S(O)2NHR", or -S(O)2NR"2. In some embodiments, each R2 is hydrogen.
In some embodiments, when n = 2 and C=Xa is replaced by CH, then Rx is
Figure imgf000016_0001
In some embodiments, each R is independently independently hydrogen, halogen, alkyl, haloalkyl, fused aryl-cycloalkyl, fused aryl-heterocycloalkyl, heteroaryl, heteroaryl substituted with at least one aryl group, -NH2, -NHR", -NHC(O)R", -NHSO2R", -CN, -C(O)NH2, -C(O)NHR", -C(O)NR"2,-OH, -OR", -S(O)2NH2, - S(O)2NHR", or -S(O)2NR"2; or when Y1 and Y2 are CR then each R, together with the carbon atom to which it is attached, forms a 5- or 6- membered ring.
In some embodiments, each R is independently hydrogen, halogen, alkyl, haloalkyl, fused aryl-cycloalkyl, fused aryl-heterocycloalkyl, heteroaryl, heteroaryl substituted with at least one aryl group, -NH2 or -CN; or when Y1 and Y2 are CR then each R, together with the carbon atom to which it is attached, forms a 5- or 6- membered ring.
In some embodiments, each R is hydrogen.
In some embodiments, R1 is hydrogen or alkyl. In some embodiments, R1 is hydrogen or methyl. In some embodiments, R1 is hydrogen.
In some embodiments, R4 is hydrogen or alkyl. In some embodiments, R4 is hydrogen or methyl. In some embodiments, R4 is hydrogen.
Figure imgf000016_0002
In accordance with a second aspect of the invention, there is provided a compound of Formula (IV), (V) or (VI):
Figure imgf000017_0001
wherein: each of X1 and X2 is independently O or S;
T is C=O or SO2;
R1 is hydrogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, aryl, heteroaryl, or benzyl;
R5 is hydrogen, deuterium or alkyl; each R6 is independently deuterium or hydrogen;
R7 is hydrogen, deuterium or alkyl; n is 0, 1 or 2; L is hydrogen, alkyl, alkenyl, benzyl, aryl, heteroaryl, haloalkyl, haloalkenyl, -CH2OC(O)*Bu, - C(O)H, -C(O)OH, -C(O)R", -C(O)OR", -C(O)NH2, -C(O)NHR", -C(O)NR"2, -OH, -OR", -NH2, -NHfc", -NR"2, - S(O)2H, -S(O)2R", or P(O)(OR")(OR");
Rv is selected from
Figure imgf000018_0001
wherein
Figure imgf000018_0002
indicates attachment to T,
Z is O, S or NR3;
U is O, S, NR3 or CR2 2; each of Y1, Y2 and Y3 is independently N or CR; each R is independently hydrogen, halogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, aryl, heteroaryl, benzyl, haloalkyl, haloalkenyl, -NH2, -NHR", -NR"2, -NHC(O)R", -NR"C(O)R", NHC(O)CH(OH)R", -NR"C(O)CH(OH)R", -NHC(O)OR", -NR"C(O)OR", -NHSO2R", -NR"SO2R", -NO2, -CN, - C(O)H, C(O)R", -C(O)OH, -C(O)OR", -C(O)NH2, -C(O)NHR", -C(O)NR"2,-OH, -OR", -OC(O)H, -OC(O)R", - OC(O)OH,-OC(O)OR", -OC(O)NH2, -OC(O)NHR", -OC(O)NR"2, -SH, -SR", -S(O)2H, -S(O)2R", -S(O)2OH, - S(O)2OR", -S(O)2NH2, -S(O)2NHR", or -S(O)2NR"2; each R2 is independently hydrogen, halogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, aryl, heteroaryl, benzyl, haloalkyl, haloalkenyl, -NH2, -NHR", -NR"2, -NHC(O)R", -NR"C(O)R", NHC(O)CH(OH)R", -NR"C(O)CH(OH)R", -NHC(O)OR", -NR"C(O)OR", -NHSO2R", -NR"SO2R", -NO2, -CN, - C(O)H, C(O)R", -C(O)OH, -C(O)OR", -C(O)NH2, -C(O)NHR", -C(O)NR"2,-OH, -OR", -OC(O)H, -OC(O)R", - OC(O)OH,-OC(O)OR", -OC(O)NH2, -OC(O)NHR", -OC(O)NR"2, -SH, -SR", -S(O)2H, -S(O)2R", -S(O)2OH, - S(O)2OR", -S(O)2NH2, -S(O)2NHR", or -S(O)2NR"2; each R3 is independently hydrogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, aryl, heteroaryl, benzyl, haloalkyl, haloalkenyl, -NH2, -NHR", -NR"2, -NHC(O)R", -NR"C(O)R", NHC(O)CH(OH)R", -NR"C(O)CH(OH)R", -NHC(O)OR", -NR"C(O)OR", -NHSO2R", -NR"SO2R", -NO2, -CN, - C(O)H, C(O)R", -C(O)OH, -C(O)OR", -C(O)NH2, -C(O)NHR", -C(O)NR"2,-OH, -OR", -OC(O)H, -OC(O)R", - OC(O)OH,-OC(O)OR", -OC(O)NH2, -OC(O)NHR", -OC(O)NR"2, -SH, -SR", -S(O)2H, -S(O)2R", -S(O)2OH, - S(O)2OR", -S(O)2NH2, -S(O)2NHR", -S(O)2NR"2I fluorenylmethoxycarbonyl, benzyloxycarboiryl, phthalimide, benzylideneamine, or toluenesulfonyl; each R" is independently alkyl, cycloalkyl, alkenyl, cycloalkenyl, aryl, heteroaryl, or benzyl.
In some embodiments,
Figure imgf000019_0003
Figure imgf000019_0002
Figure imgf000019_0004
In some embodiments, the compound is of Formula (IV).
In some embodiments, the compound has the structure:
Figure imgf000019_0001
In some embodiments, the compound has the structure:
Figure imgf000020_0001
In some embodiments, T is C-O. In other embodiments, T is SO2.
In some embodiments, Z is NR3. In other embodiments, Z is O. In other embodiments, Z is S.
In some embodiments, Y1 is N, and Y2 is CR. In other embodiments, Y2 is N, and Y1 is CR. In other embodiments, both of Y1 and Y2 are N. In other embodiments, both of Y1 and Y2 are CR.
In some embodiments, L is alkyl, benzyl, -C(O)Me, or -CiOfBu. In other embodiments, L is hydrogen.
In some embodiments, each R6 is deuterium. In other embodiments, each R6 is hydrogen.
In some embodiments, R7 is deuterium.
In some embodiments, R5 is deuterium. In other embodiments, R5 is hydrogen.
In some embodiments, R1 is hydrogen.
In some embodiments, Rv is
Figure imgf000020_0002
In some embodiments, Ry is
Figure imgf000021_0001
In some embodiments, Rv is
Figure imgf000021_0002
In some embodiments, Rv is
Figure imgf000021_0003
In some embodiments, Rv is
Figure imgf000022_0001
In some embodiments, RY is
Figure imgf000022_0002
In some embodiments, RY is
Figure imgf000022_0003
In some embodiments, RY is
Figure imgf000023_0001
In some embodiments, each R2 is independently hydrogen, halogen, alkyl, heteroaryl, -NH2, -IMHR", - NHC(O)R", -NHSO2R", -CN, -C(O)NHz, -C(O)NHR", -C(O)NR"2,-OH, -OR", -S(O)2NH2, -S(O)2NHR", or - S(O)2NR"2.. In some embodiments, In some embodiments, each R2 is hydrogen.
In some embodiments, each R is independently hydrogen, halogen, alkyl, heteroaryl, -NH2, -NHR", - NHC(O)R", -NHSO2R", -CN, -C(O)NH2, -C(O)NHR", -C(O)NR"2,-OH, -OR", -S(O)2NH2, -S(O)2NHR", or - S(O)2NR"2. in some embodiments, each R is hydrogen.
In some embodiments, each R3 is independently hydrogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, aryl, heteroaryl, benzyl, haloalkyl, haloalkenyl, or C(O)R". In some embodiments, each R3 is hydrogen
In some embodiments, R7 is hydrogen. In some embodiments, when R7 is hydrogen, at least one R6 is deuterium.
In some embodiments of any of the above aspects, X1 is 0. In other embodiments, X1 is S.
In some embodiments of any of the above aspects, X2 is 0. In other embodiments, X2 is S.
In some embodiments of any of the above aspects, n is 0. In other embodiments, n is 1. In other embodiments, n is 2.
In some embodiments of any of the above aspects, the alkyl, alkenyl, alkynyl, aryl, heteroaryl and benzyl groups are all unsubstituted. Also provided is a pharmaceutical composition comprising a compound according to any of t he above aspects of the present invention.
Also provided is a compound according to any of the above aspects of the present invention for use as a cereblon binder.
The invention also provides a compound or composition according to any of the above aspects of the present invention, for use in medicine.
The invention also provides a compound or composition according to any of the above aspects of the present invention, for use in immune-oncology.
The invention also provides a compound or composition according to any of the above aspects of the present invention, for use in the treatment of cancer, autoimmune diseases, macular degeneration (MD) and related disorders, diseases and disorders associated with undesired angiogenesis, skin diseases, pulmonary disorders, asbestos-related disorders, parasitic diseases and disorders, immunodeficiency disorders, atherosclerosis and related conditions, hemoglobinopathy and related disorders, orTNFa related disorders.
The present invention also provides a method for the treatment of cancer, autoimmune diseases, macular degeneration (MD) and related disorders, diseases and disorders associated with undesired angiogenesis, skin diseases, pulmonary disorders, asbestos-related disorders, parasitic diseases and disorders, immunodeficiency disorders, atherosclerosis and related conditions, hemoglobinopathy and related disorders, or TNFa related disorders; wherein the method comprises administering to a patient in need thereof an effective amount of a compound or composition according to any of the above aspects of the present invention.
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 the treatment of an autoimmune disease. In some embodiments, the at least one additional active agent is a small molecule, a peptide, an antibody, a corticosteroid, or a combination thereof. In some embodiments, the at least one additional active agent is at lea st one of bortezomib, dexamethasone, and rituximab.
The present invention also provides a combined preparation of a compound of any one of the first to second aspects of the present invention and at least one additional active agent, for simultaneous, separate or sequential use in therapy.
In some embodiments of the combined preparation, the at least one additional active agent is an anticancer agent or an agent for the treatment of an autoimmune disease. In some embodiments, the at least one additional active agent is a small molecule, a peptide, an antibody, a corticosteroid, or a combination thereof. In some embodiments, the at least one additional active agent is at least one of bortezomib, dexamethasone, and rituximab. In some embodiments, the therapy is the treatment of cancer, autoimmune diseases, macular degeneration (MD) and related disorders, diseases and disorders associated with undesired angiogenesis, skin diseases, pulmonary disorders, asbestos-related disorders, parasitic diseases and disorders, immunodeficiency disorders, atherosclerosis and related conditions, hemoglobinopathy and related disorders, or TNFa related disorders.
As used herein the term "alkyl" is intended to include both unsubstituted alkyl groups, and alkyl groups which are substituted by one or more additional groups. In some embodiments, the alkyl group is an unsubstituted alkyl group. In some embodiments, the alkyl group is substituted by one or more groups selected from -OH, -ORw, -NH¾ -NHRW, -NRW 2, -SO2RW, -C(O)Rw, -CN, and -NO2, wherein each Rw is unsubstituted and is independently alkyl, cycloalkyl, alkenyl, cycloalkenyl, aryl, heteroaryl, or benzyl. In some embodiments, the alkyl group is a Ci-Ci2 alkyl, a Ci-Cio alkyl, a Ci-C8 alkyl, a Ci-C6 alkyl, or a CrC4 alkyl group. In some embodiments the alkyl group is a linear alkyl group. In some embodiments the alkyl group is an unsubstituted linear alkyl group. In some embodiments the alkyl group is a linear alkyl group which is substituted by one or more groups selected from -OH, -ORw, -NH2, -NHRW, -NRW 2, -SO2Rw, - C(O)Rw, -CN, and -NO2, wherein each Rw is unsubstituted and is independently alkyl, cycloalkyl, alkenyl, cycloalkenyl, aryl, heteroaryl, or benzyl. In some embodiments the alkyl group is a branched alkyl group. In some embodiments the alkyl group is an unsubstituted branched alkyl group. In some embodiments the alkyl group is a branched alkyl group which is substituted by one or more groups selected from -OH, - ORw, -NH2, -NHRw, -NRw 2, -SO2Rw, -C(O)Rw, -CN, and -NO2, wherein each Rw is unsubstituted and is independently alkyl, cycloalkyl, alkenyl, cycloalkenyl, aryl, heteroaryl, or benzyl.
As used herein the term "alkenyl" is intended to include both unsubstituted alkenyl groups, and alkenyl groups which are substituted by one or more additional groups. In some embodiments, the a Ikenyl group is an unsubstituted alkenyl group. In some embodiments, the alkenyl group is substituted by one or more groups selected from -OH, -ORw, -NH2, -NHRW, -NRW 2, -SO2Rw, -C(O)Rw, -CN, and -NO2, wherein each Rw is unsubstituted and is independently alkyl, cycloalkyl, alkenyl, cycloalkenyl, aryl, heteroaryl, or benzyl. In some embodiments, the alkenyl group is a C2-Ci2 alkenyl, a C2-Ci0 alkenyl, a C2-C8 alkenyl, a C2-C6 alkenyl, or a C2-C4 alkenyl group. In some embodiments the alkenyl group is a linear alkenyl group. In some embodiments the alkenyl group is an unsubstituted linear alkenyl group. In some embodiments the alkenyl group is a linear alkenyl group which is substituted by one or more groups selected from -OH, - ORw, -NH2, -NHRw, -NRw 2, -SO2Rw, -C(O)Rw, -CN, and -NO2, wherein each Rw is unsubstituted and is independently alkyl, cycloalkyl, alkenyl, cycloalkenyl, aryl, heteroaryl, or benzyl. In some embodiments the alkenyl group is a branched alkenyl group. In some embodiments the alkenyl group is an unsubstituted branched alkenyl group. In some embodiments the alkenyl group is a branched alkenyl group which is substituted by one or more groups selected from -OH, -ORw, -NH2, -NHRW, -NRW 2, -SO2Rw, -C(O)Rw, -CN, and -NO2, wherein each Rw is unsubstituted and is independently alkyl, cycloalkyl, alkenyl, cycloalkenyl, aryl, heteroaryl, or benzyl.
As used herein the term "alkynyl" is intended to include both unsubstituted alkynyl groups, and alkynyl groups which are substituted by one or more additional groups. In some embodiments, the alkynyl group is an unsubstituted alkynyl group. In some embodiments, the alkynyl group is substituted by one or more groups selected from -OH, -ORw, -NH2, -NHRW, -NRW 2, -SO2Rw, -C(O)Rw, -CN, and -NO2, wherein each Rw is unsubstituted and is independently alkyl, cycloalkyl, alkenyl, cycloalkenyl, aryl, heteroaryl, or benzyl. In some embodiments, the alkynyl group is a C2-C12 alkynyl, a C -C alkynyl, a C2-C8 alkynyl, a C2-C6 alkynyl, or a C2-C4 alkynyl group. In some embodiments the alkynyl group is a linear alkynyl group. In some embodiments the alkynyl group is an unsubstituted linear alkynyl group. In some embodiments the alkynyl group is a linear alkynyl group which is substituted by one or more groups selected from -OH, -ORw, -NH2, -NHRW, -NRW , -SO2Rw, -C(O)Rw, -CN, and -NO2, wherein each Rw is unsubstituted and is independently alkyl, cycloalkyl, alkenyl, cycloalkenyl, aryl, heteroaryl, or benzyl. In some embodiments the alkynyl group is a branched alkynyl group. In some embodiments the alkynyl group is an unsubstituted branched alkynyl group. In some embodiments the alkynyl group is a branched alkynyl group which is substituted by one or more groups selected from -OH; -ORw, -NH2, -NHRW, -NRW 2, -SO2Rw, -C(O)Rw ; -CN, and -MO2, wherein each Rw is unsubstituted and is independently alkyl, cycloalkyl, alkenyl, cycloalkenyl, aryl, heteroaryl, or benzyl.
As used herein the term "aryl" is intended to include both unsubstituted aryl groups, and aryl groups which are substituted by one or more additional groups. In some embodiments, the aryl group is an unsubstituted aryl group. In some embodiments, the aryl group is substituted by one or more groups selected from -OH, -ORw, -NH2, -NHRW, -NRW 2, -SO2Rw, -C(O)Rw, -CN, and -NO2, wherein each Rw is unsubstituted and is independently alkyl, cycloalkyl, alkenyl, cycloalkenyl, aryl, heteroaryl, or benzyl. In some embodiments, the aryl group is a C6-Cio aryl, a C6-C8 aryl, or a C6 aryl.
As used herein the term "heteroaryl" is intended to include both unsubstituted heteroaryl groups, and heteroaryl groups which are substituted by one or more additional groups. In some embodiments, the heteroaryl group is an unsubstituted heteroaryl group. In some embodiments, the heteroaryl group is substituted by one or more groups selected from -OH, -ORw, -NH2, -NHRW, -NRW 2, -SO2Rw, -C(O)Rw, -CN, and -NO2, wherein each Rw is unsubstituted and is independently alkyl, cycloalkyl, alkenyl, cycloalkenyl, aryl, heteroaryl, or benzyl. In some embodiments, the heteroaryl group is a C6-Ci0 heteroaryl, a C6-C9 heteroaryl, a C6-C8 heteroaryl, or a C6 heteroaryl.
As used herein the term "benzyl" is intended to include both unsubstituted benzyl groups, and benzyl groups which are substituted by one or more additional groups. In some embodiments, the benzyl group is an unsubstituted benzyl group. In some embodiments, the benzyl group is substituted by one or more groups selected from -OH, -ORw, -NH2, -NHRW, -NRW 2, -SO2Rw, -C(0)Rw, -CN, and -N02, wherein each Rw is unsubstituted and is independently alkyl, cycloalkyl, alkenyl, cycloalkenyl, aryl, heteroaryl, or benzyl.
In some embodiments of any of the above aspects of the invention, all alkyl, alkenyl, alkynyl, aryl, heteroaryl and benzyl groups in the compounds are unsubstituted.
DETAILED DESCRIPTION OF THE INVENTION
As discussed above, the present invention provides compounds of Formulas (I), (II), (III), (IV), (V), and (VI)
Figure imgf000028_0001
wherein L, X1, X2, Rx, Rv, R1, R5 ; R6, R7 and n are as defined above.
Biotransformation of thalidomide-based drugs in humans includes chiral inversion, hydroxylation, and slow non-enzymatic hydrolysis (see Chen N et al.: Clinical Pharmacokinetics and Pharmacodynamics of Lenalidomide. Clin Pharmacokinet 2017; 56(139)).
Disclosed cereblon ligands contain structural modifications of the glutarimide that are designed to alleviate the ligand's chemical and biochemical instability resulting in improved in vitro and in vivo stability. These modifications include for example application of compatible protecting groups, deuteration, or incorporation of an oxetane ring as a bioisostere of a carbonyl group . Most chiral drugs are developed as single enantiomers to limit the undesired enantiomer's impact on the drug development processes. Unfortunately, some chirally pure drug molecules, such as thalidomide, are hampered by rapid in vivo racemization. In such cases, replacement of the exchangeable hydrogen at the chiral center with deuterium allows the enantiomer stabilization. (See Jacques V et al.: Differentiation of antiinflammatory and antitumorigenic properties of stabilized enantiomers of thalidomide analogs. Proc Natl Acad Sci 2015 Mar 24;112(12):E1471-9)
Figure imgf000029_0002
The compounds of the present invention are advantageous in terms of their synthetic feasibility. The synthesis of the compounds can be summarized in the following general procedures:
Figure imgf000029_0001
Reaction Scheme la: General procedure
Figure imgf000030_0001
Reaction Scheme lb: General procedure wherein:
C=O corresponds to T in Formulas (I) - (VI) above,
R1, Rx and RY are as defined in Formulas (I) - (VI) above, R2 is
Figure imgf000030_0002
(For compounds where T is -SO2-, RXSO2CI may be used in place of RxCOOH, and RVSO2CI may be used in place of RvCOOH)
Examples of commercially-available carboxylic acids RxCOOH and RvCOOH which may be used in Reaction Schemes la and lb, above, include:
Figure imgf000030_0003
Figure imgf000031_0001
Figure imgf000032_0001
Figure imgf000033_0001
Figure imgf000034_0001
Figure imgf000035_0001
Figure imgf000036_0001
Figure imgf000037_0001
Figure imgf000038_0001
Binding of the compounds of the present invention to cereblon may alter the specificity of the CRL4CRBN complexes, and induce association of novel substrate proteins, followed by their ubiquitination and degradation. Examples of such proteins include, but are not limited to, IKZF1 and IKZF3.
The compounds of the present invention may modulate cereblon in a unique way allowing CRL4CRBN ubiquitin ligase complex to recognise different substrates to those which it would otherwise recognise, and target them for degradation. Consequently, the compounds of the present invention are expected to broaden/modify CRBN's antiproliferative activity, thus extending the range of cancer types sensitive to treatment with CMAs.
As discussed in the Examples section, the present inventors have found that the above compounds exhibit similar cereblon binding capabilities to that of the known CMA, thalidomide. Despite the pharmaceutical activity of the known CMAs such as thalidomide, patients often develop resistance to these compounds. The use of novel compounds - such as those of the present invention, as described above - may help to overcome this clinical obstacle.
The compounds of the present invention may possess pharmaceutically advantageous properties, such as increased stability and improved ADMET (absorption, distribution, metabolism, excretion, and/or toxicity) properties. The compounds of the present invention may be useful in the treatment of various diseases and disorders, including (but not limited to):
1) Cancer. The compounds provided herein can be used for treating, preventing or managing either primary or metastatic tumors. Specific examples of cancer include, but are not limited to, cancers of the skin, such as melanoma; lymph node; breast; cervix; uterus; gastrointestinal tract; lung; ovary; prostate; colon; rectum; mouth; brain; head and neck; throat; testes; kidney; pancreas; bone; spleen; liver; bladder; larynx; nasal passages, and AIDS-related cancers and hematological malignancies. a) Hematological malignancies include leukemia, lymphoma, multiple myeloma or smoldering myeloma.
• Leukemia can be selected from: acute leukemia, acute lymphoblastic leukemia (ALL), chronic lymphocytic leukemia (CLL), acute myelogenous leukemia, acute myeloid leukemia (AML), adult acute basophilic leukemia, adult acute eosinophilic leukemia, adult acute megakaryoblastic leukemia, adult acute minimally differentiated myeloid leukemia, adult acute monoblastic leukemia, adult acute monocytic leukemia, adult acute myeloblastic leukemia with maturation, adult acute myeloblastic leukemia without maturation, adult acute myeloid leukemia with abnormalities, adult acute myelomonocytic leukemia, adult erythroleukemia, adult pure erythroid leukemia, secondary acute myeloid leukemia, untreated adult acute myeloid leukemia, adult acute myeloid leukemia in remission, adult acute promyelocytic leukemia with PML- RARA, alkylating agent-related 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.
• Lymphoma can be selected from the group consisting of: adult grade III lymphomatoid granulomatosis, adult nasal type extranodal NK/T-cell lymphoma, anaplastic large cell lymphoma, angioimmunoblastic T-cell lymphoma, cutaneous B- Cell non- Hodgkin lymphoma, extranodal marginal zone lymphoma of mucosa- associated lymphoid tissue, hepatosplenic T-cell lymphoma, intraocular lymphoma, lymphomatous involvement of non- cutaneous extranodal site, mature T-cell and K- cell non-Hodgkin lymphoma, nodal marginal zone lymphoma, post-transplant lymphoproliferative disorder, recurrent adult Burkitt lymphoma, recurrent adult diffuse large cell lymphoma, recurrent adult diffuse mixed cell lymphoma, recurrent adult diffuse small cleaved cell lymphoma, 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 Sezary syndrome, recurrent small lymphocytic lymphoma, Richter syndrome, small intestinal lymphoma, splenic marginal zone lymphoma, testicular lymphoma, Waldenstrom macroglobulinemia, adult T-cell leukemia- lymphoma, peripheral T-cell lymphoma, B-cell lymphoma, Hodgkin's disease, cutaneous T-cell lymphoma, diffuse large B-cell lymphoma, MALT lymphoma, mantle cell lymphoma, non-Hodgkins lymphoma, central nervous system lymphoma, refractory primary- cutaneous large B-cell lymphoma (Leg-type), refractory anemia, refractory anemia with excess blasts, refractory anemia with ringed sideroblasts, refractory cytopenia with multilineage dysplasia, secondary myelodysplastic syndromes, myelodysplastic syndrome, and myeloproliferative disease. ) Autoimmune diseases, such as: Acute disseminated encephalomyelitis, acute motor axonal neuropathy, Addison's disease, adiposis dolorosa, adult-onset Still's disease, alopecia areata, ankylosing spondylitis, anti-glomerular basement membrane nephritis, anti-neutrophil 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 pancreatitis, autoimmune polyendocrine syndrome, autoimmune polyendocrine syndrome type 2, autoimmune polyendocrine syndrome type 3, autoimmune progesterone dermatitis, autoimmune retinopathy, autoimmune thrombocytopenic purpura, autoimmune thyroiditis, autoimmune urticaria, autoimmune uveitis, balo concentric sclerosis, Behget's disease, Bickerstaff's encephalitis, bullous pemphigoid, celiac disease, chronic fatigue syndrome, chronic inflammatory demyelinating polyneuropathy, churg-Strauss syndrome, cicatricial pemphigoid, cogan syndrome, cold agglutinin disease, complex regional pain syndrome, CREST syndrome, Croh n's disease, dermatitis herpetiformis, dermatomyositis, diabetes mellitus type 1, discoid lupus erythematosus, endometriosis, enthesitis, enthesitis-related arthritis, eosinophilic esophagitis, eosinophilic fasciitis, epidermolysis bullosa acquisita, erythema nodosum, essential mixed cryoglobulinemia, evans syndrome, felty syndrome, fibromyalgia, gastritis, gestational pemphigoid, giant cell arteritis, goodpasture syndrome, Graves' disease, graves ophthalmopathy, Guillain— Barre syndrome, hashimoto's encephalopathy, hashimoto thyroiditis, Henoch-Schonlein purpura, hidradenitis suppurativa, idiopathic inflammatory demyelinating diseases, igG4-related systemic disease, inclusion body myositis, inflamatory bowel disease (IBD), intermediate uveitis, interstitial cystitis, juvenile arthritis, kawasaki's disease, Lambert-Eaton myasthenic syndrome, leukocytoclastic vasculitis, Lichen planus, Lichen sclerosus, ligneous 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, Mucha-Habermann disease, multiple sclerosis, myasthenia gravis, myocarditis, myositis, neuromyelitis optica, neuromyotonia, opsoclonus myoclonus syndrome, optic neuritis, Ord's thyroiditis, palindromic rheumatism, paraneoplastic cerebellar degeneration, Parry Romberg syndrome, Parsonage-Turner syndrome, pediatric autoimmune neuropsychiatric disorder associated with streptococcus, pemphigus vulgaris, pernicious anemia, pityriasis lichenoides et varioliformis acuta, POEMS syndrome, polyarteritis nodosa, polymyalgia rheumatica, polymyositis, postmyocardial infarction syndrome, postpericardiotomy 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 leg syndrome, retroperitoneal fibrosis, rheumatic fever, rheumatoid arthritis, rheumatoid vasculitis, sarcoidosis, Schnitzler syndrome, scleroderma, Sjogren's syndrome, stiff person syndrome, subacute bacterial endocarditis, Susac's syndrome, Sydenham chorea, sympathetic ophthalmia, systemic lupus erythematosus, systemic scleroderma, thrombocytopenia, Tolosa-Hunt syndrome, transverse myelitis, ulcerative colitis, undifferentiated connective tissue disease, urticaria, urticarial vasculitis, vasculitis and vitiligo; ) Diseases and disorders associated with, or characterized by, undesired angiogenesis, including inflammatory diseases, autoimmune diseases, pain, viral diseases, genetic diseases, allergic diseases, bacterial diseases, ocular neovascular diseases, choroidal neovascular diseases, retina neovascular diseases, and rubeosis (neovascularization of the angle). Specific examples of the diseases and disorders associated with, or characterized by, undesired angiogenesis include, but are not limited to: arthritis, endometriosis, Crohn's disease, heart failure, advanced heart failure, renal impairment, endotoxemia, toxic shock syndrome, osteoarthritis, retrovirus replication, wasting, meningitis, silica-induced fibrosis, asbestos- induced fibrosis, veterinary disorder, malignancy-associated hypercalcemia, stroke, circulatory shock, periodontitis, gingivitis, macrocytic anemia, refractory anemia, and 5q- deletion syndrome, nociceptive pain, neuropathic pain, mixed pain of 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 bums, cuts of the skin, contusions of the skin, osteoarthritis, rheumatoid arthritis, tendonitis, and myofascial pain. Examples of neuropathic pain include, but are not limited to, CRPS type I, CRPS type II, reflex sympathetic dystrophy (RSD), reflex neurovascular dystrophy, reflex dystrophy, sympathetically maintained pain syndrome, causalgia, Sudeck atrophy of bone, algoneurodystrophy, shoulder hand syndrome, post-traumatic dystrophy, trigeminal neuralgia, post herpetic neuralgia, cancer related pain, phantom limb pain, fibromyalgia, chronic fatigue syndrome, spinal cord injury pain, central post-stroke pain, radiculopathy, diabetic neuropathy, post-stroke pain, luetic neuropathy, and other painful neuropathic conditions such as those induced by drugs such as vincristine and velcade; ) Macular Degeneration ("MD") and related syndromes, such as: atrophic (dry) MD, exudative (wet) MD, age-related maculopathy (ARM), choroidal neovascularisation (CNVM), retinal pigment epithelium detachment (PED), and atrophy of retinal pigment epithelium (RPE);) Skin diseases such as: keratoses and related symptoms, skin diseases or disorders characterized with overgrowths of the epidermis, acne, and wrinkles. Examples of skin diseases or disorders characterized with overgrowths of the epidermis include, but are not limited to, any conditions, diseases or disorders marked by the presence of overgrowths of the epidermis, including but not limited to, infections associated with papi lloma virus, arsenical keratoses, sign of Leser-Trelat, warty dyskeratoma (WD), trichostasis spinulosa (TS), erythrokeratodermia variabilis (EKV), ichthyosis fetalis (harlequin ichthyosis), knuckle pads, cutaneous melanoacanthoma, porokeratosis, psoriasis, squamous cell carcinoma, confluent and reticulated papillomatosis (CRP), acrochordons, cutaneous horn, cowden disease (multiple hamartoma syndrome), dermatosis papulosa nigra (DPN), epidermal nevus syndrome (ENS), ichthyosis vulgaris, molluscum contagiosum, prurigo nodularis, and acanthosis nigricans (AN); ) 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 artery hypertension; idiopathic pulmonary hypertension; thrombotic pulmonary arteriopathy (TPA); plexogenic pulmonary arteriopathy; functional classes I to IV pulmonary hypertension; and pulmonary hypertension associated with, related to, or secondary to, left ventricular dysfunction, mitral valvular disease, constrictive pericarditis, aortic stenosis, cardiomyopathy, mediastinal fibrosis, anomalous pulmonary venous drainage, pulmonary venoocclusive disease, collagen vasular disease, congenital heart disease, HIV virus infection, drugs and toxins such as fenfluramines, congenital heart disease, pulmonary venous hypertension, chronic obstructive pulmonary disease, interstitial lung disease, sleep- disordered breathing, alveolar hypoventilation disorder, chronic exposure to high altitude, neonatal lung disease, alveolar-capillary dysplasia, sickle cell disease, other coagulation disorder, chronic thromboemboli, connective tissue disease, lupus including systemic and cutaneous lupus, schistosomiasis, sarcoidosis or pulmonary capillary hemangiomatosis;) Asbestos-related disorders, such as: mesothelioma, asbestosis, malignant pleural effusion, benign exudative effusion, pleural plaques, pleural calcification, diffuse pleural thickening, rounded atelectasis, fibrotic masses, and lung cancer; ) Parasitic diseases and disorders caused by human intracellular parasites such as, 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 braziiiensis, T. Gondii, B. microti, B. divergens, B. coli, C. parvum, C. cayetanensis, E. histolytica, I. belli, S. monsonii, S. haemolobium, Trypanosoma ssp., Toxoplasma ssp.,andO. volvulus. 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.,andTheileria ssp., are also encompassed. Specific examples include, but are not limited to, malaria, babesiosis, trypanosomiasis, leishmaniasis, toxoplasmosis, meningoencephalitis, keratitis, amebiasis, giardiasis, cryptosporidiosis, isosporiasis, cyclosporiasis, microsporidiosis, ascariasis, trichuriasis, ancylostomiasis, strongyloidiasis, toxocariasis, trichinosis, lymphatic filariasis, onchocerciasis, filariasis, schistosomiasis, and dermatitis caused by animal schistosomes; ) Immunodeficiency disorders, which include, but are not limited to, adenosine deaminase deficiency, antibody deficiency with normal or elevated Igs, ataxia-tenlangiectasia, bare lymphocyte syndrome, common variable immunodeficiency, Ig deficiency with hyper-lgM, Ig heavy chain deletions, IgA deficiency, immunodeficiency with thymoma, reticular dysgenesis, Nezelof syndrome, selective IgG subclass deficiency, transient hypogammaglobulinemia of infancy, Wistcott-Aldrich syndrome, X-linked agammaglobulinemia, X-linked severe combined immunodeficiency; 0) Atherosclerosis and related conditions, such as: all forms of conditions involving atherosclerosis, including restenosis after vascular intervention such as angioplasty, stenting, atherectomy and grafting; 1) Hemoglobinopathy and related disorders, such as sickle cell anemia, and any other disorders related to the differentiation of CD34+ cells; 2) TNFa 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 diseases; 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, septis, endotoxic shock, graft versus host disease, wasting, Crohn's disease, ulcerative colitis, multiple sclerosis, systemic lupus erythromatosis, ENL in leprosy, HIV, AIDS, and opportunistic infections in AIDS; disorders such as septic s hock, sepsis, endotoxic shock, hemodynamic shock and sepsis syndrome, post ischemic reperfusion injury, malaria, mycobacterial infection, meningitis, psoriasis, congestive heart failure, fibrotic disease, cachexia, graft rejection, oncogenic or cancerous conditions, asthma, autoimmune disease, radiation damages, and hyperoxic alveolar injury; viral infections, such as those caused by the herpes viruses; viral conjunctivitis; or atopic dermatitis.
The compounds of the present invention may also be useful in preventing, treating, or reducing the risk of developing graft versus host disease (GVHD) or transplant rejection.
The compounds of the present invention may also inhibit the production of certain cytokines including, but not limited to, TNF-a, IL-Ib, IL-12, 1L-18, GM-CSF, IL-10, TGF-b and/or IL-6. The present compounds may stimulate the production of certain cytokines, and also act as a costimulatory signal for T cell activation, resulting in increased production of cytokines such as, but not limited to, IL-12, IL-2, IL-10, TGF- b and/or IFN-y. In addition, compounds provided herein can enhance the effects of NK cells and antibody- mediated cellular cytotoxicity (ADCC). Further, compounds provided herein may be immunomodulatory and/or cytotoxic, and thus may be useful as chemotherapeutic agents.
EXAMPLES
The compounds of the present invention may be synthesized by the method shown in Reaction Schemes la and lb, below:
Figure imgf000046_0001
Reaction Scheme la: General procedure
Figure imgf000046_0002
Reaction Scheme lb: General procedure wherein OO corresponds to T in Formulas (I) - (VI) above, and wherein R1, Rx, Ry and Rz are as defined above.
Synthetic Conditions
DIPEA (2-3 eq) was added to a solution of an appropriate acid (RxCOOH or RyCOOH in the above reaction schemes), DMAP (0-0.1 eq), HATU (1.0-1.5 eq) and amine (free base or salt - R1RZNH in the above reaction schemes) (1.2-3.0 eq) in DMF (0.1-0.5 M). The reaction mixture was stirred overnight at room temperature (20-25°C). After removal of the solvent under reduced pressure, the crude product was purified by preparative HPLC, flash column chromatography or preparative TLC.
Example 1: Synthesis of fert-butyl ((4-((2.6-dioxopiperidin-3-yl-3.5.5-d3)carbamoyl)-2-methyl-1H- benzofd1imidazol-6-yl)methyl)carbamate (Compound 1)
Figure imgf000046_0003
This compound was synthesized using the general procedure shown in Reaction Scheme la, above, (22% yield) using 6-(((tert-butoxycarbonyl)amino)methyl)-2-methyl-1H-benzo[d]imidazole-4- carboxylic acid (26.5 mg) and 3-aminopiperidine-2,6-dione-3,5,5-d3 (1.0 eq.) as starting materials.
XH NMR: (500MHz, DMSO) d 12.39 (s, 1H), 10.56 (s, 1H), 10.19 (s, 1H), 7.80 (d, J = 1.3 Hz, 1H), 7.56 - 7.49 (m, 1H), 7.05 (s, 1H), 4.29 (d, J = 6.2 Hz, 2H), 2.59 (s, 3H), 2.30 (d, J = 12.8 Hz, 1H), 2.11 (d, J = 12.8 Hz, 1H), 1.43 (s, 9H).
LCMS (m/z [M+H]+): 419.1
Example 2: Synthesis of fert-butyl ((2-methyl-4-((6-oxo-2-oxa-5-azaspiro[3.5]nonan-9- yl)carbamoyl)-1H-benzo[d]imidazol-6-yl)methyl)carbamate (Compound 2)
Figure imgf000047_0001
This compound was synthesized using the general procedure shown in Reaction Scheme la, above, (22% yield) using 6-(((tert-butoxycarbonyl)amino)methyl)-2-methyl-l/7-benzo[d]imidazole-4- carboxylic acid (11.7 mg) and 9-amino-2-oxa-5-azaspiro[3.5]nonan-6-one (1.0 eq.) as starting materials.
1H NMR: (500MHz, DMSO) d 12.42 (s, 1H), 10.35 (d, J = 8.6 Hz, 1H), 8.19 (s, 1H), 7.81 (s, 1H), 7.51 (s, 1H), 7.06 (s, 1H), 4.83 (tt, J = 6.1, 2.8 Hz, 1H), 4.63 (d, J = 6.4 Hz, 1H), 4.61 - 4.55 (m, 2H), 4.54 (d, J = 6.3 Hz, 1H), 4.29 (d, J = 6.3 Hz, 2H), 2.55 (s, 3H), 2.52 - 2.41 (m, 1H), 2.33 (ddd, J = 18.2, 6.6, 4.7 Hz, 1H), 2.01 (dddt, J = 16.4, 9.5, 6.8, 3.2 Hz, 1H), 1.96 - 1.86 (m, 1H), 1.43 (s, 9H).
LCMS (m/z [M+H]+): 444.2 Example syntheses of R*OOH and RyOOH
Example 3: 5-hexanamido-1-methvl-1H-benzo[d]imidazole-7-carboxvlic acid
Figure imgf000048_0001
Step A: 5-amino-1-methyl-1H-benzo[d]imidazole-7-carboxylic acid dihydrochloride (20 mg, 0.076 mmol) and hexanoyl chloride (l.leq.) were dissolved in 4 mL of dry DCM and cooled in water/ice bath. TEA (4 eq.) was slowly injected into the reaction mixture. The ice bath was removed and the reaction was allowed to warm up to ambient temperature. The reaction was completed i n two hours, monitored by LCMS. The solution was diluted with DCM (lOmL) and washed with 7mL 3% HCI water soln. The aqueous phase was then evaporated to yield off-white crystals of 5- hexanamido-1-methyl-1H-benzo[d]imidazole-7-carboxylic acid.
Example 4: 6-((tert-butoxycarbonvl)amino)-2-(trifluoromethvl)-1H-benzo[d]imidazole-7-carboxvlicc acid
Figure imgf000048_0002
F F
Step D Step E
OH
Boc
Figure imgf000049_0001
Figure imgf000049_0002
Step A: To a stirred solution of methyl 2-amino-6-fluoro-3-nitrobenzoate (2 g, 9.339 mmol) in DMSO (20 mL) was added K2CO3 (2.58 g, 18.67 mmol) followed by addition of (4-methoxyphenyl) methanamine (1.59 mL, 12.14 mmol). Then the reaction mixture was stirred at RT for 16 h. After completion of the reaction, quenched with ice water and precipitate was filtered and dried to give methyl 2-amino-6-((4-methoxybenzyl)amino)-3-nitrobenzoate 2.0 g (64% yield).
Step B: To a stirred solution of methyl 2-amino-6-((4-methoxybenzyl)amino)-3-nitrobenzoate (550 mg, 1.66 mmol) in THF (16 ml) was added Zn (1.5 g, 21.6 mmol) followed by addition of NH4CI (1.15 g, 21.6 mmol) in water (3 ml) at 0 °C and stirred at RT for lh. After completion of the reaction, reaction mixture was filtered through celite, washed with ethyl acetate. Organic layer was washed with water, brine, dried over sodium sulphate and concentrated under reduced pressure to give methyl 2,3-diamino-6- ((4-methoxybenzyl)amino)benzoate (250 mg, crude) as brownish solid.
Step C: Methyl 2,3-diamino-6-((4-methoxybenzyl)amino)benzoate (2 g, 6.645 mmol) in TFA (20 mL) was stirred at rt for 16 h . After completion of the reaction, TFA was removed and quenched with aqueous NaHCO3 and extracted with ethyl acetate. Organic layer washed with brine and dried over Na2SO4 and concentrated and purified by flash column chromatography to give methyl 6-amino-2- (trifluoromethyl)-lW-benzo[d]imidazole-7-carboxylate 200 mg (13% yield).
Step D: To a stirred solution of methyl 6-amino-2-(trifluoromethyl)-1H-benzo[d]imidazole-7- carboxylate (600 mg, 2.317 mmol) in dioxane (5 mL) was added aq NaOH (IN) (15 mL) followed by addition of B0C2O (3.2 mL , 13.9 mmol) at 0 °C and stirred at RT for 72h. After completion of the reaction quenched with ice water and extracted with ethyl acetate, dried over sodium sulphate and concentrated. The crude product was purified by flash column chromatography to give methyl 6- ((tert-butoxycarbonyl)amino)-2-(trifluoromethyl)-1H-benzo[d]imidazole-7-carboxylate 600 mg (72% yield). Step E: Solution of methyl 6-((tert-butoxycarbonyl)amino)-2-(trifluoromethyl)-1H- benzo[d]imidazole-7-carboxylate in 50% aq NaOH (13 mL) was stirred at 80 °C for 4 h. After completion of reaction, reaction mixture was acidified with 2M HCI and the precipitate was filtered to give 6-((tert-butoxycarbonyl)amino)-2-(trifluoromethyl)-1H-benzo[d]imidazole-7-carboxylic acid 300 mg (52% yield).
Example 5: 5-((tert-butoxycarbonvl)amino)-2-(trifluoromethvl)-1H-benzo[d]imidazole-7-carboxylic acid
Figure imgf000050_0001
Step A: TFA (2 mL) and 4(N) HCI (5 mL) were added to 2,3-diamino-5-nitrobenzoic acid (500 mg , 2.54 mmol). Then the resulting reaction mixture was allowed to reflux for 12 h. After completion of reaction, the reaction mixture was cooled to 0 °C and then carefully neutralized with 10M NaOH solution. Aqueous part was extracted by DCM (100 mL x 3). Organic layer was washed with brine and dried over Na2SO4 and concentrated to get the crude. Finally the crude was triturated with pentane and ether to get crude compound of 5-nitro-2-(trifluoromethyl)-1H-benzo[d]imidazole-7- carboxylic acid (500 mg) as dark brown solid. Compound was used in next step without further purification
Step B: To a stirred solution of 5-nitro-2-(trifluoromethyl)-1H-benzo[d]imidazole-7-carboxylic acid (500.0 mg, 1.82 mmol) in MeOH (10 mL) was added 10% Pd/C (193 mg). The reaction mixture was allowed to stir at rt for 4 h under hydrogen atmosphere. After completion of the reaction, the reaction mixture was filtered through celite and concentrated under reduced pressure to get methyl 5-amino-2-(trifluoromethyl)-l1H-benzo[d]imidazole-7-carboxylic acid (500 mg) as crude which was used in next step without further purification.
Step C: To an ice cooled solution of methyl 5-amino-2-(trifluoromethyl)-1H-benzo[d]imidazole-7- carboxylic acid (1.0 g, 4.1 mmol) in dioxane (5.0 mL) and H2O (5.0 mL) was added TEA (0.85 mL, 6.1 mmol). The reaction mixture was allowed to stir at ice cool condition for 2-3 min. B0C2O (1.0 mL, 4.49 mmol) was added and the reaction mixture was stirred at RT for 6h. After completion of reaction, solvent was evaporated and the crude product was purified by preparative HPLC to give 5- ((tert-butoxycarbonyl)amino)-2-(trifluoromethyl)-lW-benzo[d]imidazole-7-carboxylic acid (50 mg) as white solid (2.8% yield over 3 steps).
Example 6: 7-((tert-butoxycarbonvl)amino)-2-(trifluoromethvl)-1H-benzo[cflimidazole-4-carboxylic acid
Figure imgf000051_0001
NHBoc
Step A: To ethyl 3-acetamido-4-chlorobenzoate (20.0 g, 82.97 mmol) was dropwise added 40.0 mL of 100% HNO3 at -15 °C and the resultant reaction mixture was stirred and warmed up slowly to 10°C during 2 h and then stirred at RT for 12 h, poured into crashed ice, the solids were filtered, dried under reduced pressure and the mixture of nitro compounds (16 g) was used directly in the next step. To a stirred solution of nitro compounds in 160 mL of ethanol was added 7.5 mL of cone. H2SO4. The reaction mixture was refluxed for 16 h, concentrated under reduced pressure and ice- cold water was added. The product was extracted into DCM, the combined organic layers were washed with brine, dried over Na2SO4 and concentrated. The crude product was purified by flash column chromatography to give ethyl 3-amino-4-chloro-2-nitrobenzoate (6.3 g, 30%).
Step B: To a stirred solution of ethyl 3-amino-4-chloro-2-nitrobenzoate (6.3 g, 25.753 mmol) in ethanol (60.0 mL) and water (30.0 mL) was added Fe powder (10.78 g) followed by NH4CI (1.791 g). The reaction mixture was refluxed for 12 h, concentrated under reduced pressure, diluted with DCM, filtered through celite bed and concentrated under reduced pressure. The crude product was purified by flash column chromatography to give ethyl 2,3-diamino-4-chlorobenzoate (5 g, 90.45%).
Step C: To ethyl 2,3-diamino-4-chlorobenzoate (2.0 g , 9.317 mmol , 1.0 eq) was added 15 ml of TFA and the reaction mixture was refluxed for 12 h and concentrated under reduced pressure. To the residue was added NaHCO3 solution and the product was extracted with ethyl acetate, washed with brine, dried over Na2SO4 and concentrated. The crude product was purified by flash column chromatography to give ethyl 7-chloro-2-(trifluoromethyl)-1H-benzo[d]imidazole-4-carboxylate (2.4 g, 88% yield).
Step D: A solution of ethyl 7-chloro-2-(trifluoromethyl)-1H-benzo[d]imidazole-4-carboxylate (1.0 g, 3.417 mmol) in dioxane (12 mL) was degassed under argon atmosphere for 10-15 min. CS2CO3 (2.22 g, 6.834 mmol), NH2Boc (1.60 g, 13.669 mmol), X-phos (326 mg, 0.683 mmol) and X-phosPdG3 (0.289 g, 0.342 mmol) were added and reaction mixture was stirred at 85°C for 16 h. Reaction mixture was filtered through celite bed, concentrated and purified by flash column chromatography to give ethyl 7-((tert-butoxycarbonyl)amino)-2-(trifluoromethyl)-1H-benzo[d]imidazole-4- carboxylate (800mg, 62% yield).
Step E: A stirred solution of ethyl 7-((tert-butoxycarbonyl)amino)-2-(trifluoromethyl)-1H- benzo[d]imidazole-4-carboxylate (500.0 mg, 1.339 mmol) in MeOH (3.0 mL) and THF (3.0mL) was added slowly 50% aqueous NaOH solution (6.0 mL) at ice cool condition. Then the resultant reaction mixture was allowed to stir at rt for 16 h. Reaction mixture was concentrated under reduced pressure and then it was diluted with water and washed with ethyl acetate. After that the aqueous part was gently neutralized with saturated aqueous citric acid solution in ice cool condition and then it was extracted with ethyl acetate. Then the combined organic layer was washed with brine and then dried over Na2SO4, filtered and concentrated to get the crude which was triturated with pentane and ether to get 7-((tert-butoxycarbonyl)amino)-2-(trifluoromethyl)-1H- benzo[d]imidazole-4-carboxylic acid (250mg, 54.06% yield) as white solid.
Example 7: 6-(((tert-butoxycarbonvl)amino)methvl)-2-methvl-1H-benzofdlimidazole-4-carboxylic acid
Figure imgf000053_0001
Step A: To a degassed solution of ethyl 6-bromo-2-methyl-1H-benzo[d]imidazole-4-carboxylate (500mg, 1.76 mmol) in DMF (12 mL) were added ZN(CN>2 (518 mg, 4.41 mmol) and Pd(PPh3)4 (408 mg, 0.35 mmol) and the reaction mixture was at 120 °C for 16h, quenched with ice water, extracted with ethyl acetate, dried over aa2SO4, concentrated under reduced pressure and purified by flash column chromatography to give ethyl 6-cyano-2-methyl-1H-benzo[d]imidazole-4-carboxylate (27% yield).
Step B: To a solution of ethyl 6-cyano-2-methyl-1H-benzo[d]imidazole-4-carboxylate (400 mg, 1.747 mmol) in ethanol (13 ml) were added Raney-nickel and B0C2O (2.1 ml, 8.734 mmol) and the reaction mixture was stirred under hydrogen (15 psi) for 16h, filtered through celite bed, filtrates were concentrated under reduced pressure and purified by flash column chromatography to give l-(fert- butyl) 4-ethyl 6-(((tert-butoxycarbonyl)amino)methyl)-2-methyl-1H-benzo[d]imidazole-l,4- dicarboxylate (47% yield).
Step C: To a solution of l-(tert-butyl) 4-ethyl 6-(((tert-butoxycarbonyl)amino)methyl)-2-methyl-1H- benzo[d]imidazole-l,4-dicarboxylate (430 mg, 0.993 mmol) in THF:MeOH 1:1 (10 mL) was added 50% aqueous NaOH (4 mL) and the reaction mixture was stirred at RT for 16h, neutralized with 1M HCI, and filtered. The solids were dried to give 6-(((tert-butoxycarbonyl)amino)methyl)-2-methyl- 1H-benzo[d]imidazole-4-carboxylic acid (62% yield). Example 8: 7-(((tert-butoxycarbonvl)amino)methvl)-2-methyl-1H-benzo[d]imidazole-4-carboxvlic acid
Figure imgf000054_0001
Step A: To a stirred solution of ethyl 2,3-diamino-4-chlorobenzoate (1.5 g, 6.99 mmol) in toluene (20.0 mL) was added respectively triethyl orthoacetate (5.1 mL, 27.95 mmol) and PTSA (0.337 g, 1.957 mmol) and the reaction mixture was refluxed for 16 h, concentrated under reduced pressure and the crude product was purified by flash column chromatography to give ethyl 7-chloro-2- methyl-1H-benzo[d]imidazole-4-carboxylate 1.2 g (71% yield).
Step B: A solution of ethyl 7-chloro-2-methyl-1H-benzo[d]imidazole-4-carboxylate (400 mg, 1.676 mmol) in DMF (10 mL) was degassed under argon atmosphere for 10-15 minutes. Zn(CN)2 (492 mg, 4.19 mmol), X-phos (159.792 mg, 0.335 mmol) and X-phosPdG3 (0141.86 mg, 0.168 mmol) were added and the reaction mixture was heated to 110°C for 16 h. The mixture was filtered through celite bed, diluted with water, the product was extracted with ethyl acetate, washed with brine, dried over Na2SO4 and concentrated under reduced pressure. The crude product was purified by flash column chromatography to give ethyl 7-cyano-2-methyl-1H-benzo[d]imidazole-4-carboxylate 251 mg (65% yield).
Step C: The a stirred solution of ethyl 7-cyano-2-methyl-1H-benzo[d]imidazole-4-carboxvlate (3) (375 mg, 1.636 mmol) in ethanol (10 mL) was added Boc2O (0.564 mL, 2.454 mmol) and Raney- nickel (200 mg) and reaction mixture was stirred at RT under hydrogen atmosphere for 16 h, filtered through celite bed and concentrated under reduced pressure. The crude product was purified by flash column chromatography to give ethyl 7-(((tert-butoxycarbonyl)amino)methyl)-2- methyl-1H-benzo[d]imidazole-4-carboxylate 230 mg (42% yield).
Step D: To a solution of ethyl 7-(((tert-butoxycarbonyl)amino)methyl)-2-methyl-1H- benzo[d]imidazole-4-carboxylate (200.0 mg, 0.6 mmol) in MeOH (1 mL) and THF (1 mL) w/as added 50% NaOH solution (2 mL) at 0 °C. The reaction mixture was stirred at RT for 16 h, concentrated under reduced pressure, diluted with water and washed with DCM. The aqueous phase was gently acidified by citric acid solution and the product was extracted with ethyl acetate, washed with brine, dried over Na2SO4 and concentrated under reduced pressure. The crude product was triturated with diethyl ether to give 7-(((tert-butoxycarbonyl)amino)methyl)-2-methyl-1H- benzo[d]imidazole-4-carboxylic acid 60 mg (32%).
Example 9: 2-methvl-1H-thieno[2,3-d]imidazole-6-carboxvlic acid
Figure imgf000055_0001
Step A: A mixture of methyl 4,5-diaminothiophene-3-carboxylate (400 mg, 2.04 mmol) in dioxane (3 mL ), triethyl orthoacetate (3 mL) and PTSA (102 mg, 0.40 mmol) was heated to reflux for 16 h, the reaction mixture was concentrated under reduced pressure and the crude material was purified by flash column chromatography to give methyl 2-methyl-1H-thieno[2,3-d]imidazole-6-carboxylate 200 mg (50% yield).
Step B: To a stirred solution of methyl 2-methyl-1H-thieno[2,3-d]imidazole-6-carboxylate (0.13 g, 1.02 mmol) in methanol (0.5 mL) and THF (2 mL) was added NaOH (27 mg, 0.68 mmol) in water (0.5 mL) and the resulting solution was stirred at RT for 16 h. The reaction mixture was diluted with water and washed with ethyl acetate. The aqueous part was acidified with 6N HCI to pH~5 and the resulting precipitate was filtered, washed with water and purified by HPLC to give 2-methyl-lW- thieno[2,3-d]imidazole-6-carboxylic acid 7O mg (37%).
Example 1O: 1H-thieno[2.3-d] imidazole-6-carboxvlic acid
Figure imgf000056_0001
Step A: A Solution of methyl 4-acetamidothiophene-3-carboxylate (3 g, 12.3 mmol) in acetic anhydride (40 mL) was cooled at -15 °C. To it a precooled solution (at -15 °C) of concentrated nitric acid (6 mL) in 30 mL acetic anhydride was added drop wise very slowly with stirring. After 30 min the reaction mixture was poured into crushed ice and the resulting light yellow coloured solid was filtered. The solid was thoroughly washed with water and diethyl ether to give 2.4 g (81%) of methyl 4-acetamido-5-nitrothiophene-3-carboxylate.
Step B: To a stirred solution of methyl 4-acetamido-5-nitrothiophene-3-carboxylate (2g, 8.19 mmol) in 4N HCI-dioxane (20 mL), methanol (10 mL) was added and the resulting solution was heated at 100 °C for 16 h. After cooling, dioxane was removed under reduced pressure. The residue was diluted with water and extracted with ethyl acetate. The organic layer was washed with saturated sodium bicarbonate and brine and dried over Na2SO4. After concentration under reduced pressure, the crude methyl 4-amino-5-nitrothiophene-3-carboxylate 850 mg (51%) was used in the next step without further purification.
Step C: To a stirred solution of methyl 4-amino-5-nitrothiophene-3-carboxylate (1 g, 4.95 mmol) in a mixture of dioxane-HCI (10 mL) and methanol (10 mL), SnCl2 was added and the resulting solution was stirred at RT for 2h. The reaction mixture was then poured on to a precooled solution of ammonium hydroxide and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, filtered and dried under reduced pressure. The crude methyl 4,5-diamino- thiophene-3-carboxylate 700 mg (82%) was used in the next step without further purification.
Step D: To a stirred solution of methyl 4,5-diaminothiophene-3-carboxylate (650 mg, 3.78 mmol) in a mixture of trimethyl orthoformate (2.5 mL) and toluene (2.5 mL), a catalytic amount of PTSA (189 mg, 0.75 mmol) was added and the resulting solution was heated at 110 °C for 2h. After that the volatiles were removed under reduced pressure, the crude material was purified by flash column chromatography to give 350 mg (50%) of methyl 1H-thieno[2,3-d]imidazole-6-carboxylate.
Step E: To a stirred solution of methyl 1H-thieno[2,3-d]imidazole-6-carboxylate (400 mg, 2.2 mmol mmol) in methanol (3 mL) and THF (3 mL), NaOH (439 mg, 10.9 mmol) dissolved in water (1 mL) was added and the resulting solution was stirred for 16 h. The reaction mixture was diluted with water and washed with ethyl acetate. The aqueous part was acidified with 6N HCI to pH~5 and the resulting brown coloured precipitate was filtered, washed with water and diethyl ether to obtain 1H-thieno[2,3-d] imidazole-6-carboxylic acid 230 mg (62%).
Example 11: 2,5.6-trimethyl-4H-thieno[3.2-b]-pyrrole-3-carboxvlic acid
Figure imgf000057_0001
Step A: To a solution of ethyl 2,5,6-trimethyl-4H-thieno[3,2-b]-pyrrole-3-carboxylate (10.0 mg,
0.042 mmol, 1.000 eq) in a mixture of H2O (1.0 mL), THF (1.0 mL) and MeOH (1.0 mL) was added 1M LiOH (2.0 mL, 2.000 mmol, 17.702 eq). The reaction was stirred for 24h at rt. After this time, to a mixture was added 1M HCI (2.0 mL, 2.000 mmol, 17.702 eq) to neutralize pH. The crude was concentrated in vacuo. Example 12: Fluorescence Polarization (FP) Assays
CRBN-DDB1 protein complex was mixed with Cy5-labelled thalidomide and a compound to be tested (the "test compound"). The test solution contained 50 mM Tris pH=7.0, 200 mM NaCI, 0.02 % v/v Tween-20, 2 mM DTT, 5 nM Cy5-labelled thalidomide (the tracer), 25 nM CRBN-DDB1 protein, 2% v/v DMSO. The test solution was added to a 384-well assay plate.
The plate was spun-down (1 min, 1000 rpm, 22°C) and then shaken using a VibroTurbulator for 10 min at room temperature (20-25°C), with the frequency set to level 3. The assay plate with protein and the tracer was incubated for 60 min at room temperature (20-25°C) prior to read-out with a plate reader. Read-out (fluorescence polarization) was performed by a Pherastar plate reader, using a Cy5 FP Filterset (590nm/675nm).
The FP experiment was carried out with various concentrations of the test compounds in order to measure K, values.
The K, values of competitive inhibitors were calculated using the equation based on the IC50 values of relationship between compound concentration and measured fluorescence polarization, the Kd value of the Cy5-T and CRBN/DDB1 complex, and the concentrations of the protein and the tracer in the displacement assay (as described by Z. Nikolovska-Coleska et al., Analytical Biochemistry 332 (2004) 261-273).
Fluorescence Polarization (FP) Assay - Results
Compounds are categorized based on their affinity to CRBN defined as Ki. As reported in Table 1 below, the compounds of the present invention interact with CRBN-DDB1 protein within similar affinity range as reported for reference compounds.
Table 1: FP assay results for compounds of the present invention, and control compound Thalidomide CRBN binding Ki [mM] is indicated as follows:
A < 0.5 mM
0.5 mM < B < 20 mM
Figure imgf000059_0001
ABBREVIATIONS AND DEFINITIONS
A list of the abbreviations used in the present application is shown in Table 2, below:
Table 2: Abbreviations
Figure imgf000060_0001
As used herein, the term "room temperature" means a temperature of between 20°C and 25°C.
As used herein, the term "small molecule" means an organic compound with a molecular weight of less than 900 Daltons.

Claims

1. A compound of Formula (I), (li) or (III):
Figure imgf000062_0001
wherein: each of X1 and X2 is independently O or S;
T is C=O or SO2;
R1 is hydrogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, aryl, heteroaryl, or benzyl; n is 0, 1 or 2; L is hydrogen, alkyl, alkenyl, benzyl, aryl, heteroaryl, haloalkyl, haloalkenyl, -CH2OC(O)*Bu, - C(O)H, -C(O)R" -C(O)OH, -C(O)OR", -CH2C(O)OR", -C(O)NH2, -C(O)NHR", -C(O)NR"2, -OH, -OR", -NH2, - NHR", -NR"2, -S(O)2H, -S(O)2R" or P(O)(OR")(OR");
Rx is selected from
Figure imgf000063_0001
wherein indicates attachment to T,
Z is O, S or NR4;
V is CR2, NR4 or S; each of W1, W2, W3 and W4 is independently N or CR2, each of Y1 and Y2 is independently N or CR, each R is independently hydrogen, halogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, aryl, fused aryl-cycloalkyl, fused aryl-heterocycloalkyl, heteroaryl, heteroaryl substituted with at least one aryl group, benzyl, haloalkyl, haloalkenyl, -NH2, -NHR", -NR"2, -NHC(O)R", -NR"C(O)R",
NHC(O)CH(OH)R", -NR"C(O)CH(OH)R", -NHC(O)OR", -NR"C(O)OR", -NHSO2R", -NR"SO2R", -NO2, -CN, - C(O)H, C(O)R", -C(O)OH, -C(O)OR", -C(O)NH2, -C(O)NHR", -C(O)NR"2,-OH, -OR", -OC(O)H, -OC(O)R", - OC(O)OH,-OC(O)OR", -OC(O)NH2, -OC(O)NHR", -OC(O)NR"2, -SH, -SR", -S(O)2H, -S(O)2R", -S(O)2OH, -
S(O)2OR", -S(O)2NH2, -S(O)2NHR", or -S(O)2NR"2; or when Y1 and Y2 are CR then each R, together with the carbon atom to which it is attached, forms a 5- or 6- membered ring; each R2 is independently hydrogen, halogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, aryl, aryl substituted with at least one -OR", heteroaryl, benzyl, haloalkyl, haloalkenyl, -NH2, -NHR", -NR"2, - CH2NH2, -NHC(O)R", -NR"C(O)R", NHC(O)CH(OH)R", -NR"C(O)CH(OH)R", -NHC(O)OR", -NR"C(O)OR", - NHSOzR", -NR"SO2R", -NO2, -CN, -C(O)H, C(O)R", -C(O)OR", -C(O)NH2, -C(O)NHR", -C(O)NR"2,-OH, -OR", -OC(O)H, -OC(O)R", -OC(O)OH,-OC(O)OR", -OC(O)NH2, -OC(O)NHR", -OC(O)NR"2, -SH, -SR", -S(O)2H, - S(O)2R", -S(O)2OH, -S(O)2OR", -S(O)2NH2, -S(O)2NHR", -S(O)2NR"2, or -CH2NHR8; each R4 is independently hydrogen, halogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, aryl, heteroaryl, benzyl, haloalkyl, haloalkenyl, -C(O)H, C(O)R", -C(O)OH, -C(O)OR", -C(O)NH2, -C(O )NHR”, - C(O)NR"2, -OH, -OR”, -NH2, -NHR", -NR”2, -S(O)2H, -S(O)2R", fluorenylmethoxycarbonyl, benzyloxycarbonyl, phthalimide, benzylideneamine, or toluenesulfonyl;
R5 is hydrogen, deuterium or alkyl; each R6 is independently deuterium or hydrogen;
R7 is hydrogen, deuterium or alkyl; each R” is independently alkyl, cycloalkyl, alkenyl, cycloalkenyl, aryl, heteroaryl, or benzyl;
R8 is a protecting group selected from alkyl, benzyl, -C(O)Me, -C(O)CF3, -C(O)*Bu, -C(O)OMe, - C(O)0*Bu, -C(PH)3, fluorenylmethoxycarbonyl. benzyloxycarbonyl, phthalimide, benzylideneamine, and toluenesulfonyl; wherein, when n = 2, each R2 is hydrogen, and each of W1, W2, W3 and W4 is CR2, then OX1 may be replaced by CH.
2. The compound of claim 1, wherein:
(i) when Rx is
Figure imgf000064_0001
(ii) when Rx is
Figure imgf000064_0002
Z is NR4, Y1 is CR, and Y2 is N, then R4 is not alkyl and at least one of R2 and R is not H;
(iii) when Rx is
Figure imgf000065_0002
, Z is NR4, and Y1 and Y2 are CR, then at least one of W1, W2 and W3 is N;
(iv) when Z is NR4, and Y1 and Y2 are CR, then Rx is not
Figure imgf000065_0003
(v) when Rx is
, Z is NR4, and Y
Figure imgf000065_0004
1 or Y2 is N, then R4 is not alkyl;
(vi) when Rx is
Figure imgf000065_0001
then n = 1 or 2; and
(vii) when Rx is
Figure imgf000066_0001
then Z = O or S
3. The compound of claim 1 or 2, wherein the compound is of Formula (I).
4. The compound of claim 3, having the structure:
Figure imgf000066_0002
5. The compound of claim 3, having the structure:
Figure imgf000066_0003
6. The compound of any preceding claim, wherein T is OO.
7. The compound of any one of claims 1-5, wherein T is SO2.
8. The compound of any preceding claim, wherein Z is NR4.
9. The compound of any one of claims 1-7, wherein Z is O.
10. The compound of any one of claims 1-7, wherein Z is S.
11. The compound of any preceding claim, wherein V is CR2.
12. The compound of any one of claims 1-10, wherein V is NR4.
13. The compound of any one of claims 1-10, wherein V is S.
14. The compound of any preceding claim, wherein L is alkyl, benzyl, -C(O)Me, or -C(O)‘Bu.
15. The compound of any one of claims 1-13, wherein L is hydrogen.
16. The compound of any preceding claim, wherein each R6 is deuterium.
17. The compound of any one of claims 1-15, wherein each R6 is hydrogen.
18. The compound of any preceding claim, wherein R7 is deuterium.
19. The compound of any one of claims 1-17, wherein R7 is hydrogen.
20. The compound of any preceding claim, wherein R5 is deuterium.
21. The compound of any one of claims 1-19, wherein R5 is hydrogen.
22. The compound of any preceding claim, wherein R1 is hydrogen.
23. The compound of any preceding claim, wherein Y1 is N, and Y2 is CR.
24. The compound of any one of claims 1-22, wherein Y2 is N, and Y1 is CR.
25. The compound of any one of claims 1-22, wherein both of Y1 and Y2 are N.
26. The compound of any one of claims 1-22, wherein both of Y1 and Y2 are CR.
27. The compound of any preceding claim, wherein Rx is selected from
Figure imgf000068_0001
28. The compound of any one of claims 1-26, wherein Rx is selected from
Figure imgf000068_0002
29. The compound of any one of claims 1-26, wherein Rx is selected from
Figure imgf000069_0001
30. The compound of any one of claims 1-26, wherein Rx is
Figure imgf000069_0002
31. The compound of any one of claims 1-26, wherein Rx is selected from
32. The compound of any one of claims 1-26, wherein Rx is selected from
Figure imgf000070_0003
Figure imgf000070_0004
34. The compound of any one of claims 1-26, wherein Rx is
Figure imgf000070_0001
35. The compound of any one of claims 1-26, wherein Rx is selected from
Figure imgf000070_0002
36. The compound of any one of claims 1-26, wherein Rx is
Figure imgf000071_0001
37. The compound of any one of claims 1-26, wherein one of W1, W2 and W3 is N, and the remaining two of W1, W2 and W3 are each CR2.
38. The compound of any one of claims 1-26, wherein two of W1, W2 and W3 are N, and the remaining one of W1, W2 and W3 is CR2.
39. The compound of any one of claims 1-26, wherein each of W1, W2 and W3 is N.
40. The compound of any one of claims 1-26, wherein each of W1, W2 and W3 is CR2.
Figure imgf000071_0002
42. The compound of any one of claims 1-41, wherein one of W1, W2 and W4 is N, and the remaining two of W1, W2 and W3 are each CR2.
43. The compound of any one of claims 1-41, wherein two of W1, W2 and W4 are N, and the remaining one of W1, W2 and W3 is CR2.
44. The compound of any one of claims 1-41, wherein each of W1, W2 and W4 is N.
45. The compound of any one of claims 1-41, wherein each of W1, W2 and W4 is CR2.
46. The compound of claim 41, wherein:
T is C=O;
R1 is hydrogen,
L is hydrogen,
Z is NR4; each of W1, W2 and W4 is CR2, Y1 is N, and
Y2 is CR, wherein R is not hydrogen.
47. The compound of any one of claims 1-26, wherein Rx is
Figure imgf000072_0001
48. The compound of any one of claims 1-26, wherein Rx is
Figure imgf000072_0002
49. The compound of any one of claims 1-26, wherein Rx is
Figure imgf000073_0001
50. The compound of any one of claims 1-26, wherein Rx is
Figure imgf000073_0002
51. The compound of any one of claims 1-26, wherein Rx is
Figure imgf000073_0003
52. The compound of any one of claims 1-26, wherein Rx is
Figure imgf000074_0001
53. The compound of any one of claims 1-26, wherein Rx is
Figure imgf000074_0002
54. The compound of any one of claims 1-26, wherein Rx is
Figure imgf000074_0003
55. The compound of any one of claims 47-54, wherein R4 is hydrogen, halogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, aryl, heteroaryl, benzyl, haloalkyl, haloalkenyl, -OH, -OR", -NH2, -NHR", - NR"2, -S(O)2H or -S(O)2R"; optionally wherein R4 is hydrogen, halogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, aryl, heteroaryl, benzyl, haloalkyl, or haloalkenyl.
56. The compound of claim 55, wherein R4 is hydrogen or alkyl.
57. The compound of any one of claims 47-56, wherein V is CH2.
58. The compound of any preceding claim, wherein each R2 is independently hydrogen, halogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, aryl, aryl substituted with at least one -OR", benzyl, haloalkyl, haloalkenyl, -NH2, -NHR", -NR"2, -CH2NH2, -NHC(O)R", -NR"C(O)R", NHC(O)CH(OH) R", - NR"C(O)CH(OH)R", -NHC(O)OR", -NR"C(O)OR", -NHSO2R", -NR"SO2R", -NO2, -CN, -OH, -OR", -OC(O)H, - OC(O)R", -OC(O)OH,-OC(O)OR", -OC(O)NH2, -OC(O)NHR", -OC(O)NR"2, -SH, -SR", -S(O)2H, -S(O)2R", - S(O)2OH, -S(O)2OR", -S(O)2NH2, -S(O)2NHR", or -S(O)2NR"2.
6O. The compound of claim 58, wherein each R2 is independently hydrogen, halogen, aryl, aryl substituted with at least one -OR", -NH2, -CH2NH2, -NHC(O)R", -NO2, or -OR".
61. The compound of claim 58, wherein each R2 is independently hydrogen, halogen, alkyl, heteroaryl, -NH2, -NHR", -NHC(O)R", -NHSO2R", -CN, -C(O)NH2, -C(O)NHR", -C(O)NR"2,-OH, -OR", - S(O)2NH2, -S(O)2NHR", or -S(O)2NR"2.
62. The compound of any preceding claim, wherein each R2 is hydrogen.
63. The compound of any one of claims 1-28, wherein when n = 2 and C=X1 is replaced by CH, then Rx is
Figure imgf000075_0001
64. The compound of any preceding claim, wherein each R is independently independently hydrogen, halogen, alkyl, haloalkyl, fused aryl-cycloalkyl, fused aryl-heterocycloalkyl, heteroaryl, heteroaryl substituted with at least one aryl group, -NH2, -NHR", -NHC(O)R", -NHSO2R", -CN, -C(O)NH2, - C(O)NHR", -C(O)NR'VOH, -OR”, -S(O)2NH2, -S(O)2NHR", or -S(O)2NR"2; or when Y1 and Y2 are CR then each R, together with the carbon atom to which it is attached, forms a 5- or 6- membered ring.
65. The compound of any preceding claim, wherein each R is independently hydrogen, halogen, alkyl, haloalkyl, fused aryl-cycloalkyl, fused aryl-heterocycloalkyl, heteroaryl, heteroaryl substituted with at least one aryl group, -NH2 or -CN; or when Y1 and Y2 are CR then each R, together with the carbon atom to which it is attached, forms a 5- or 6- membered ring.
66. The compound of any preceding claim, wherein each R is hydrogen.
67. The compound of any preceding claim, wherein R1 is hydrogen or alkyl; optionally hydrogen or methyl; further optionally wherein R1 is hydrogen.
68. The compound of any preceding claim, wherein R4 is hydrogen or alkyl; optionally hydrogen or methyl; further optionally wherein R4 is hydrogen.
69. The compound of claim 1, selected from
Figure imgf000076_0001
70. A compound of Formula (IV), (V) or (VI):
Figure imgf000076_0002
Figure imgf000077_0001
wherein: each of X1 and X2 is independently O or S;
T is C=O or SO2;
R1 is hydrogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, aryl, heteroaryl, or benzyl;
R5 is hydrogen, deuterium or alkyl; each R6 is independently deuterium or hydrogen;
R7 is hydrogen, deuterium or alkyl; n is 0, 1 or 2;
L is hydrogen, alkyl, alkenyl, benzyl, aryl, heteroaryl, haloalkyl, haloalkenyl, -CH2OC(O)lBu, -
C(O)H, -C(O)OH, -C(O)R", -C(O)OR", -C(O)NH2, -C(O)NHR", -C(O)NR"2, -OH, -OR", -NH2, -NHR", -NR"2, - S(O)2H, -S(O)2R", or P(O)(OR")(OR");
Ry is selected from
Figure imgf000077_0002
wherein
Figure imgf000078_0001
indicates attachment to T,
Z is O, S or NR3;
U is O, S, NR3 or CR¾ each of Y1, Y2 and Y3 is independently N or CR; each R is independently hydrogen, halogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, aryl, heteroaryl, benzyl, haloalkyl, haloalkenyl, -NH2, -NHR", -NR"2, -NHC(O)R", -NR"C(O)R", NHC(O)CH(OH)R", -NR"C(O)CH(OH)R", -NHC(O)OR", -NR"C(O)OR", -NHSO2R", -NR"SO2R", -NO2, -CN, - C(O)H, C(O)R", -C(O)OH, -C(O)OR", -C(O)NH2, -C(O)NHR", -C(O)NR"2,-OH, -OR", -OC(O)H, -OC(O)R", - OC(O)OH,-OC(O)OR", -OC(O)NH2, -OC(O)NHR", -OC(O)NR"z, -SH, -SR", -S(O)2H, -S(O)2R", -S(O)2OH, - S(O)2OR", -S(O)2NH2, -S(O)2NHR", or-S(O)2NR"2; each R2 is independently hydrogen, halogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, aryl, heteroaryl, benzyl, haloalkyl, haloalkenyl, -NH2, -NHR", -NR"2, -NHC(O)R", -NR"C(O)R", NHC(O)CH(OH)R", -NR"C(O)CH(OH)R", -NHC(O)OR", -NR"C(O)OR", -NHSO2R", -NR"SO2R", -NO2, -CN, - C(O)H, C(O)R", -C(O)OH, -C(O)OR", -C(O)NH2, -C(O)NHR", -C(O)NR"2,-OH, -OR", -OC(O)H, -OC(O)R", - OC(O)OH,-OC(O)OR", -OC(O)NH2, -OC(O)NHR", -OC(O)NR"2, -SH, -SR", -S(O)2H, -S(O)2R", -S(O)2OH, - S(O)2OR", -S(O)2NH2, -S(O)2NHR", or -S(O)2NR"2; each R3 is independently hydrogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, aryl, heteroaryl, benzyl, haloalkyl, haloalkenyl, -NH2, -NHR", -NR"2, -NHC(O)R", -NR"C(O)R", NHC(O)CH(OH)R", -NR"C(O)CH(OH)R", -NHC(O)OR", -NR"C(O)OR", -NHSO2R", -NR"SO2R", -NO2, -CN, - C(O)H, C(O)R", -C(O)OH, -C(O)OR", -C(O)NH2, -C(O)NHR", -C(O)NR"2,-OH, -OR", -OC(O)H, -OC(O)R", - OC(O)OH,-OC(O)OR", -OC(O)NH2, -OC(O)NHR", -OC(O)NR"2, -SH, -SR", -S(O)2H, -S(O)2R", -S(O)2OH, - S(O)2OR", -S(O)2NH2, -S(O)2NHR", -S(0)2NR"2, fluorenylmethoxycarbonyl, benzyloxycarbonyl, phthalimide, benzylideneamine, or toluenesulfonyl. each R" is independently alkyl, cycloalkyl, alkenyl, cycloalkenyl, aryl, heteroaryl, or benzyl.
71. The compound of claim 70, wherein,
Figure imgf000079_0003
Figure imgf000079_0004
72. The compound of claim 70 or 71, wherein the compound is of Formula (IV).
73. The compound of claim 72, having the structure:
Figure imgf000079_0001
74. The compound of claim 72, having the structure:
Figure imgf000079_0002
75. The compound of any one of claims 70-74, wherein T is C=O.
76. The compound of any one of claims 70-74, wherein T is SO2.
77. The compound of any one of claims 70-76, wherein Z is NR3.
78. The compound of any one of claims 70-76, wherein Z is O.
79. The compound of any one of claims 70-76, wherein Z is S.
80. The compound of any one of claims 70-79, wherein Ya is N, and Y2 is CR.
81. The compound of any one of claims 70-79, wherein Y2 is N, and Y1 is CR.
82. The compound of any one of claims 70-79, wherein both of Y1 and Y2 are N.
83. The compound of any one of claims 70-79, wherein both of Y1 and Y2 are CR.
84. The compound of any one of claims 70-83, wherein L is alkyl, benzyl, -C(O)Me, or -CiOfBu.
85. The compound of any one of claims 70-83, wherein L is hydrogen.
86. The compound of any one of claims 70-85, wherein each R6 is deuterium.
87. The compound of any one of claims 70-85, wherein each R6 is hydrogen.
88. The compound of any one of claims 70-87, wherein R7 is deuterium.
89. The compound of any one of claims 70-89, wherein R5 is deuterium.
90. The compound of any one of claims 70-89, wherein R5 is hydrogen.
91. The compound of any one of claims 70-90, wherein R1 is hydrogen.
92. The compound of any one of claims 70-91, wherein Rv is
Figure imgf000081_0001
93. The compound of any one of claims 70-91, wherein Rv is
Figure imgf000081_0002
94. The compound of any one of claims 70-91, wherein Ry is
Figure imgf000081_0003
95. The compound of any one of claims 70-91, wherein Rv is
Figure imgf000082_0001
96. The compound of any one of claims 70-91, wherein Rv is
Figure imgf000082_0002
97. The compound of any one of claims 70-91, wherein Rv is
Figure imgf000082_0003
98. The compound of any one of claims 70-91, wherein Rv is
Figure imgf000083_0001
99. The compound of any one of claims 70-91, wherein Ry is
Figure imgf000083_0002
100. The compound of any one of claims 70-99, wherein each R2 is independently hydrogen, halogen, alkyl, heteroaryl, -NH2, -NHR", -NHC(O)R", -NHSO2R", -CN, -C(O)NH2, -C(O)NHR", -C(O)NR"2,-OH, -OR", - S(O)2NH2, -S(O)2NHR", or -S(O)2NR"2.
101. The compound of any one of claims 70-100, wherein each R2 is hydrogen.
102. The compound of any one of claims 70-101, wherein each R is independently hydrogen, halogen, alkyl, heteroaryl, -NH2, -NHR", -NHC(O)R", -NHSO2R", -CN, -C(O)NH2, -C(O)NHR", -C(O)NR"2/- OH, -OR", -S(O)2NH2, -S(O)2NHR", or -S(O)2NR"2.
103. The compound of any one of claims 70-102, wherein each R is hydrogen.
104. The compound of any one of claims 70-103, wherein each R3 is independently hydrogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, aryl, heteroaryl, benzyl, haloalkyl, haloalkenyl, or C(O)R".
105. The compound of any one of claims 70-104, wherein each R3 is hydrogen
106. The compound of any preceding claim, wherein R7 is hydrogen.
107. The compound of any preceding claim, wherein when R7 is hydrogen, at least one R6 is deuterium.
108. The compound of any preceding claim, wherein X1 is O.
109. The compound of any one of claims 1-107, wherein X1 is S.
110. The compound of any one of claims 1-109, wherein X2 is O.
111. The compound of any one of claims 1-109, wherein X2 are S.
112. The compound of any preceding claim, wherein n is 0.
113. The compound of any one of claims 1-111, wherein n is 1.
114. The compound of any one of claims 1-111, wherein n is 2.
115. The compound of any preceding claim, wherein the alkyl, alkenyl, alkynyl, aryl, heteroaryl and benzyl groups are all unsubstituted.
116. A compound of any one of the preceding claims, for use as a cereblon binder.
117. A pharmaceutical composition comprising a compound of any one of claims 1-115.
118. A compound of any one of claims 1-116, or a composition according to claim 117, for use in medicine.
119. A compound of any one of claims 1-116, or a composition according to claim 117, for use in immune-oncology.
120. A compound of any one of claims 1-116, or a composition according to claim 117, for use in the treatment of cancer, autoimmune diseases, macular degeneration (MD) and related disorders, diseases and disorders associated with undesired angiogenesis, skin diseases, pulmonary disorders, asbestos- related disorders, parasitic diseases and disorders, immunodeficiency disorders, atherosclerosis and related conditions, hemoglobinopathy and related disorders, orTNFot related disorders.
121. A method for the treatment of cancer, autoimmune diseases, macular degeneration (MD) and related disorders, diseases and disorders associated with undesired angiogenesis, skin diseases, pulmonary disorders, asbestos-related disorders, parasitic diseases and disorders, immunodeficiency disorders, atherosclerosis and related conditions, hemoglobinopathy and related disorders, or TNFa related disorders; wherein the method comprises administering to a patient in need thereof an effective amount of a compound of any one of claims 1-116, or a composition according to claim 117.
122. The method of claim 121, further comprising administering at least one additional active agent to the patient.
123. A combined preparation of a compound of any one of claims 1-116 and at least one additional active agent, for simultaneous, separate or sequential use in therapy.
124. The combined preparation of claim 123, or the method of claim 122, wherein the at least one additional active agent is an anti-cancer agent or an agent for the treatment of an autoimmune disease.
125. The combined preparation of claim 123-124, or the method of claim 122 or 124, wherein the at least one additional active agent is a small molecule, a peptide, an antibody, a corticosteroid, or a combination thereof.
126. The combined preparation or method of claim 125, wherein the at least one additional active agent is at least one of bortezomib, dexamethasone, and rituximab.
127. The combined preparation of any one of claims 123-126, the therapy is the treatment of cancer, autoimmune diseases, macular degeneration (MD) and related disorders, diseases and disorders associated with undesired angiogenesis, skin diseases, pulmonary disorders, asbestos-related disorders, parasitic diseases and disorders, immunodeficiency disorders, atherosclerosis and related conditions, hemoglobinopathy and related disorders, orTNFα related disorders.
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