Protein-targeting compounds and pharmaceutical compositions thereof, and their therapeutic applications
The present disclosure provides compounds, for example, a compound of Formula (I), that modulate a protein function and/or restore protein homeostasis. The disclosure provides a method of modulating a protein-mediated disease, disorder, condition, or response. Compositions, including in combination with other therapeutic agents, are provided.
1. A compound of Formula (III):
or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof; wherein:
R 1 is selected from the group consisting of
each X is independently CH 2 or C(═O);
R Z is —NR 7a R 8a or ring A; and ring A is C 6 -C 10 aryl, 5 to 10 membered heteroaryl, C 3 -C 8 carbocyclyl, or 3 to 10 membered heterocyclyl, each optionally substituted with one or more R A ;
R 2 is H, deuterium, optionally substituted C 1 -C 6 alkyl, optionally substituted C 3 -C 8 carbocyclyl, optionally substituted C 6 -C 10 aryl, optionally substituted 3 to 10 membered heterocyclyl, or optionally substituted 5 to 10 membered heteroaryl;
R 3a , R 3b , R 3c , R 3d , R 3e , and R 3f are each independently H, deuterium, hydroxyl, halogen, cyano, nitro, optionally substituted C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, —(CH 2 ) t —NR 7a R 8a , —O(CH 2 ) t —NR 7a R 8a , —C(O)NR 7b R 8b , —S(O) 2 NR 7c R 8c , —OR 9 , —SR 10a , —C(O)OR 10b , —C(O)R 11a , —NR 7d C(O)R 11b , —S(O) 2 R 11c , —NR 7e S(O) 2 R 11d , (C 1 -C 6 alkoxy)C 1 -C 6 alkyl, —O(C 1 -C 6 alkoxy)C 1 -C 6 alkyl, optionally substituted C 3 -C 8 carbocyclyl, optionally substituted C 6 -C 10 aryl, optionally substituted 3 to 10 membered heterocyclyl, or optionally substituted 5 to 10 membered heteroaryl;
each R 3g is independently deuterium, hydroxyl, halogen, cyano, nitro, optionally substituted C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, —(CH 2 ) t —NR 7a R 8a , —O(CH 2 ) t —NR 7a R 8a , —C(O)NR 7b R 8b , —S(O) 2 NR 7c R 8c , —OR 9 , —SR 10a , —C(O)OR 10b , —C(O)R 11a , —NR 7d C(O)R 11b , —S(O) 2 R 11c , —NR 7e S(O) 2 R 11d , (C 1 -C 6 alkoxy)C 1 -C 6 alkyl, —O(C 1 -C 6 alkoxy)C 1 -C 6 alkyl, optionally substituted C 3 -C 8 carbocyclyl, optionally substituted C 6 -C 10 aryl, optionally substituted 3 to 10 membered heterocyclyl, or optionally substituted 5 to 10 membered heteroaryl;
each R 4 is independently H, deuterium, halogen, or optionally substituted C 1 -C 6 alkyl;
each R 5 is independently H, deuterium, C 1 -C 6 alkyl,
each R 6a , R 6b , R 14 , and R 15 is independently H, substituted or unsubstituted amino, halogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, or C 3 -C 8 carbocyclyl; or R 6a and R 6b together with the carbon atom to which they are attached form a C 3 -C 8 carbocyclyl; wherein each C 3 -C 8 carbocyclyl is optionally substituted with one or more R B ;
each R 7a , R 7b , R 7c , R 7d , R 7e , R 8a , R 8b , R 8c , R 16 , and R 17 is independently H, optionally substituted C 1 -C 6 alkyl, optionally substituted C 6 -C 10 aryl, optionally substituted C 7 -C 14 aralkyl, or optionally substituted C 3 -C 8 carbocyclyl; or R 7a and R 8a together with the nitrogen atom to which they are attached form optionally substituted 3 to 7 membered heterocyclyl; or R 7b and R 8b together with the nitrogen atom to which they are attached form optionally substituted 3 to 7 membered heterocyclyl; or R 7c and R 8c together with the nitrogen atom to which they are attached form optionally substituted 3 to 7 membered heterocyclyl; or R 16 and R 17 together with the nitrogen atom to which they are attached form optionally substituted 3 to 7 membered heterocyclyl; wherein each of C 6 -C 10 aryl, C 7 -C 14 aralkyl, C 3 -C 8 carbocyclyl, and 3 to 7 membered heterocyclyl is optionally substituted with one or more R B ;
each R 9 is independently optionally substituted C 1 -C 6 alkyl, optionally substituted C 2 -C 6 alkenyl, optionally substituted C 2 -C 6 alkynyl, optionally substituted C 6 -C 10 aryl, optionally substituted 5 to 10 membered heteroaryl, optionally substituted C 7 -C 14 aralkyl, optionally substituted 3 to 10 membered heterocyclyl, or optionally substituted C 3 -C 8 carbocyclyl;
each of R 10a , R 11b , R 12 , and R 13 is independently H, optionally substituted C 1 -C 6 alkyl, optionally substituted C 2 -C 6 alkenyl, optionally substituted C 2 -C 6 alkynyl, optionally substituted C 6 -C 10 aryl, optionally substituted 5 to 10 membered heteroaryl, optionally substituted C 7 -C 14 aralkyl, optionally substituted 3 to 10 membered heterocyclyl, or optionally substituted C 3 -C 8 carbocyclyl;
each R 11a , R 11b , R 11c , and R 11d is independently optionally substituted C 1 -C 6 alkyl, optionally substituted C 2 -C 6 alkenyl, optionally substituted C 2 -C 6 alkynyl, optionally substituted C 6 -C 10 aryl, optionally substituted 5 to 10 membered heteroaryl, optionally substituted C 7 -C 14 aralkyl, optionally substituted 3 to 10 membered heterocyclyl, or optionally substituted C 3 -C 8 carbocyclyl;
each R A is independently halogen, cyano, nitro, hydroxyl, optionally substituted C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, —(CH 2 ) t —NR 7a R 8a , —O(CH 2 ) t —NR 7a R 8a , —C(O)NR 7b R 8b , —S(O) 2 NR 7c R 8c , —OR 9 , —SR 10a , —C(O)OR 10b , —C(O)R 11a , —NR 7d C(O)R 11b , —S(O) 2 R 11c , —NR 7e S(O) 2 R 11d , (C 1 -C 6 alkoxy)C 1 -C 6 alkyl, —O(C 1 -C 6 alkoxy)C 1 -C 6 alkyl, phenyl, 5 to 10 membered heteroaryl, C 3 -C 8 carbocyclyl, or 3 to 10 membered heterocyclyl, wherein each of phenyl, 5 to 10 membered heteroaryl, C 3 -C 8 carbocyclyl, and 3 to 10 membered heterocyclyl is optionally substituted with one or more R B ;
each R B is independently C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, (C 1 -C 6 alkoxy)C 1 -C 6 alkyl, —O(C 1 -C 6 alkoxy)C 1 -C 6 alkyl, halogen, or cyano; or two geminal R B form oxo;
m is an integer of 0, 1, 2, 3, 4, or 5;
n1 is an integer of 0, 1, 2, or 3;
each p is independently an integer of 0, 1, or 2; and
each t is independently an integer of 0, 1, 2, 3, 4, 5, 6, 7, or 8.
2. The compound of claim 1 , being a compound of Formula (IIIa):
or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate, thereof.
3. The compound of claim 1 , being a compound of Formula (IIIb):
or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof.
4. The compound of claim 1 , being a compound of Formula (IIIc):
or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof.
5. The compound of claim 1 , being a compound of Formula (IIId):
or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate, thereof.
6. The compound of claim 1 , being a compound of Formula (IIIe):
or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate, thereof.
7. The compound of claim 1 , being a compound of Formula (IIIf):
or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof.
8. The compound of claim 1 , being a compound of Formula (IIIg):
or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate, thereof.
9. The compound of claim 1 , being a compound of Formula (IIIh):
or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate, thereof.
10. The compound of claim 1 , being a compound of Formula (IIIi):
or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate, thereof.
11. The compound of claim 1 , wherein R Z is ring A.
12. The compound of claim 1 , wherein X is CH 2 .
13. The compound of claim 1 , wherein X is C(═O).
14. The compound of claim 1 , wherein p is 1.
15. The compound of claim 1 , wherein R 3g is halo, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl.
16. The compound of claim 15 , wherein R 3g is fluoro or methyl.
17. The compound of claim 1 , wherein R 4 is H.
18. The compound of claim 1 , wherein R 5 is H.
19. The compound of claim 1 , wherein R 2 is H.
20. The compound of claim 11 , wherein ring A is C 6 -C 10 aryl, 5 to 10 membered heteroaryl, C 3 -C 8 carbocyclyl, or 3 to 10 membered heterocyclyl, each of which is optionally substituted with one, two, or three substituents R A .
21. The compound of claim 11 , wherein ring A is C 6 -C 10 aryl, optionally substituted with one, two, or three substituents R A .
22. The compound of claim 11 , wherein ring A is phenyl, optionally substituted with one, two, or three substituents R A .
23. The compound of claim 11 , wherein ring A is selected from the group consisting of pyridyl, thienyl, furyl, pyrimidinyl, pyrazolyl, imidazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, and thiadiazolyl, each optionally substituted with one, two, or three R A .
24. The compound of claim 11 , wherein ring A is phenyl, 4-cyanophenyl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 3-chlorophenyl, 4-chlorophenyl, 4-bromophenyl, 4-methylphenyl, 4-(1-trifluoromethylethyl)-phenyl, 4-trifluoro-methylphenyl, 4-dimethylaminomethylphenyl, 4-morpholin-4-ylmethylphenyl, 4-isopropyl-phenyl, 4-sec-butylphenyl, 3-tert-butylphenyl, 4-tert-butylphenyl, 4-(hydroxyl-tert-butyl)phenyl, 4-cyclopropylphenyl, 4-(1-methyl-cyclopropyl)phenyl, 4-(1-trifluoromethylcyclopropyl)phenyl, 4-phenylphenyl, 4-(1-methylpiperidin-4-yl)phenyl, 4-hydroxylphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 4-dimethylaminophenyl, 4-acetamidophenyl, 3,4-difluorophenyl, 3,4-dichloro-phenyl, 3-chloro-4-methylphenyl, 3-methyl-4-tert-butylphenyl, 3,5-dimethylphenyl, 2,4,6-trimethylphenyl, 2,4,6-trimethoxyphenyl, 2,6-dimethyl-4-tert-butylphenyl, 3-dimethylamino-4-methylphenyl, 2-naphthyl, thien-2-yl, 5-isopropylthien-2-yl, 4-pyridyl, 4-tert-butylcyclohexyl, piperdin-4-yl, or 4-tert-butylpiperidin-1-yl.
25. The compound of claim 11 , wherein ring A is phenyl, 4-cyanophenyl, 2-fluorophenyl, 3-fluorophenyl, 3-chlorophenyl, 4-trifluoromethyl-phenyl, 3-tert-butylphenyl, 4-tert-butylphenyl, 4-(1-trifluoromethylcyclopropyl)-phenyl, 3-methoxyphenyl, 4-methoxyphenyl, 3,4-difluorophenyl, 3,4-dichlorophenyl, 3-chloro-4-methyl-phenyl, 3-methyl-4-tert-butylphenyl, 3,5-dimethylphenyl, 2,4,6-trimethylphenyl, 2,4,6-trimethoxyphenyl, 2,6-dimethyl-4-tert-butylphenyl, 2-naphthyl, 5-isopropylthien-2-yl, 4-pyridyl, 4-tert-butylcyclohexyl, or 4-tert-butylpiperidin-1-yl.
26. The compound of claim 11 , wherein:
X is CH 2 or C(═O);
ring A is phenyl, 4-cyanophenyl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 3-chlorophenyl, 4-chlorophenyl, 4-bromophenyl, 4-methylphenyl, 4-(1-trifluoromethyl-ethyl)-phenyl, 4-trifluoromethylphenyl, 4-dimethylaminomethylphenyl, 4-morpholin-4-ylmethylphenyl, 4-isopropylphenyl, 4-sec-butylphenyl, 3-tert-butylphenyl, 4-tert-butyl-phenyl, 4-(hydroxyl-tert-butyl)phenyl, 4-cyclopropylphenyl, 4-(1-methylcyclopropyl)-phenyl, 4-(1-trifluoromethylcyclopropyl)phenyl, 4-phenylphenyl, 4-(1-methylpiperidin-4-yl)phenyl, 4-hydroxylphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 4-dimethylamino-phenyl, 4-acetamidophenyl, 3,4-difluorophenyl, 3,4-dichlorophenyl, 3-chloro-4-methyl-phenyl, 3-methyl-4-tert-butylphenyl, 3,5-dimethylphenyl, 2,4,6-trimethylphenyl, 2,4,6-trimethoxyphenyl, 2,6-dimethyl-4-tert-butylphenyl, 3-dimethylamino-4-methylphenyl, 2-naphthyl, thien-2-yl, 5-isopropylthien-2-yl, 4-pyridyl, 4-tert-butylcyclohexyl, piperdin-4-yl, or 4-tert-butylpiperidin-1-yl;
R 2 is H or methyl;
R 4 is H;
R 5 is H or D-valyloxymethyl;
R 3g is fluoro or methyl;
p is an integer of 1 or 2; and
m is an integer of 0, 1, or 2.
27. A compound of:
2-(4-(tert-butyl)phenyl)-N-((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methyl)-2-oxoacetamide I-1;
N-((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)-methyl)-2-oxo-2-(4-(1-(trifluoromethyl)cyclopropyl)phenyl)acetamide I-3;
N-((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)-methyl)-2-(5-isopropylthiophen-2-yl)-2-oxoacetamide I-4;
2-(3-chloro-4-methylphenyl)-N-((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methyl)-2-oxoacetamide I-6;
2-(4-dimethylaminophenyl)-N-((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methyl)-2-oxoacetamide I-7;
2-phenyl-N-((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methyl)-2-oxoacetamide I-8;
N-((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)-methyl)-2-(thiophen-2-yl)-2-oxoacetamide I-9;
2-(4-methoxyphenyl)-N-((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methyl)-2-oxoacetamide I-11;
2-(4-cyclopropylphenyl)-N-((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methyl)-2-oxoacetamide I-12;
2-(4-(tert-butyl)phenyl)-N-((5-(2,6-dioxopiperidin-3-yl)-4,6-dioxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methyl)-2-oxoacetamide I-13;
2-(4-isopropylphenyl)-N-((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methyl)-2-oxoacetamide I-14;
2-(4-(sec-butyl)phenyl)-N-((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methyl)-2-oxoacetamide I-15;
2-(4-hydroxyphenyl)-N-((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methyl)-2-oxoacetamide I-16;
2-(4-methylphenyl)-N-((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methyl)-2-oxoacetamide I-17;
2-(4-chlorophenyl)-N-((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methyl)-2-oxoacetamide I-18;
2-(3-tert-butylphenyl)-N-((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methyl)-2-oxoacetamide I-19;
2-(4-acetamidophenyl)-N-((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methyl)-2-oxoacetamide I-20;
2-([1,1′-biphenyl]-4-yl)-N-((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methyl)-2-oxoacetamide I-21;
2-(4-fluorophenyl)-N-((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methyl)-2-oxoacetamide I-22;
2-(4-trifluoromethylphenyl)-N-((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methyl)-2-oxoacetamide I-23;
2-(3,4-dichlorophenyl)-N-((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methyl)-2-oxoacetamide I-24;
2-(4-((dimethylamino)methyl)phenyl)-N-((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methyl)-2-oxoacetamide I-25;
2-(4-(morpholinomethyl)phenyl)-N-((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methyl)-2-oxoacetamide I-26;
2-(3-methyl-4-(tert-butyl)phenyl)-N-((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methyl)-2-oxoacetamide I-27;
N-((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)-methyl)-2-(4-(1-methylpiperidin-4-yl)phenyl)-2-oxoacetamide I-31;
N-((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)-methyl)-2-oxo-2-(4-(1,1,1-trifluoropropan-2-yl)phenyl)acetamide I-36;
2-(4-(tert-butyl)phenyl)-N-((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methyl)-2-oxoacetamide I-40;
2-(4-(tert-butyl)phenyl)-N-(2-(5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)ethyl)-2-oxoacetamide I-41;
N-((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)-methyl)-2-(4-(1-methylcyclopropyl)phenyl)-2-oxoacetamide I-42;
N-((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)-methyl)-2-(4-(1-hydroxy-2-methylpropan-2-yl)phenyl)-2-oxoacetamide I-43;
2-(3-(dimethylamino)-4-methylphenyl)-N-((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methyl)-2-oxoacetamide I-44;
N 1 -((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)-methyl)-N 2 ,N 2 -dimethyloxalamide I-70;
2-(4-(tert-butyl)phenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2-oxoacetamide I-2;
N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2-oxo-2-(4-(1-(trifluoro-methyl)cyclopropyl)phenyl)acetamide I-5;
(S)-2-(4-(tert-butyl)phenyl)-N-((2-(2,7-dioxoazepan-3-yl)-1-oxoisoindolin-5-yl)-methyl)-2-oxoacetamide I-10;
2-(4-(tert-butyl)phenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)-methyl)-2-oxoacetamide I-32;
2-(3-(tert-butyl)phenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2-oxoacetamide I-33;
2-(4-(tert-butyl)phenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-N-methyl-2-oxoacetamide I-34;
N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2-(5-isopropylthiophen-2-yl)-2-oxoacetamide I-37;
N-(2-(2-(2,6-dioxopiperidin-3-yl)-1-oxoiso-indolin-5-yl)ethyl)-2-oxo-2-(4-(1-(trifluoro-methyl)cyclopropyl)phenyl)-acetamide I-52;
2-(3-chloro-4-methylphenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)-methyl)-2-oxoacetamide I-53;
2-(3-methyl-4-(tert-butyl)phenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2-oxoacetamide I-55;
N-((2-(2,6-dioxopiperidin-3-yl)-4-methyl-1-oxoisoindolin-5-yl)methyl)-2-oxo-2-(4-(1-(trifluoromethyl)cyclopropyl)phenyl)acetamide I-60;
2-(4-(tert-butyl)piperidin-1-yl)-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)-methyl)-2-oxoacetamide I-62;
N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2-oxo-3-(4-(1-(trifluoro-methyl)cyclopropyl)phenyl)propanamide I-63;
2-(4-(tert-butyl)cyclohexyl)-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)-methyl)-2-oxoacetamide I-68;
N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2-oxo-2-phenylacetamide I-83;
N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2-oxo-2-(2,4,6-trimethoxyphenyl)acetamide I-84;
N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2-oxo-2-(2,4,6-trimethyl-phenyl)acetamide I-85;
N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2-oxo-2-(2-fluoro-phenyl)acetamide I-86;
N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2-oxo-2-(4-trifluoro-methylphenyl)acetamide I-87;
N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2-(4-methoxyphenyl)-2-oxoacetamide I-89;
2-(4-cyanophenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2-oxoacetamide I-90;
2-(3-chlorophenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2-oxoacetamide I-91;
2-(3,4-difluorophenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2-oxoacetamide I-93;
N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2-(3-methoxyphenyl)-2-oxoacetamide I-95;
N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2-(naphthalen-2-yl)-2-oxoacetamide I-97;
2-(3,5-dimethylphenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2-oxoacetamide I-99;
N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2-(3-fluorophenyl)-2-oxoacetamide I-100;
2-(3,4-dichlorophenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2-oxoacetamide I-102;
N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2-oxo-2-(pyridin-4-yl)-acetamide I-103;
2-(4-(tert-butyl)-2,6-dimethylphenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2-oxoacetamide I-104;
2-(4-(tert-butyl)phenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)methyl)-2-oxoacetamide I-28;
2-(4-(tert-butyl)phenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1-oxoisoindolin-4-yl)methyl)-2-oxoacetamide I-29;
N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)methyl)-2-oxo-2-(4-(1-(trifluoro-methyl)cyclopropyl)phenyl)acetamide I-30;
2-(3-(tert-butyl)phenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)methyl)-2-oxoacetamide I-46;
2-(4-(tert-butyl)phenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)methyl)-N-methyl-2-oxoacetamide I-47;
2-(4-(tert-butyl)phenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)-methyl)-2-oxoacetamide I-48;
(2R)-(3-(4-((2-(4-(tert-butyl)phenyl)-2-oxoacetamido)methyl)-1-oxoisoindolin-2-yl)-2,6-dioxopiperidin-1-yl)methyl 2-amino-3-methylbutanoate I-49;
2-(4-(tert-butyl)phenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-5-fluoro-1-oxoisoindolin-4-yl)methyl)-2-oxoacetamide I-50;
2-(4-(tert-butyl)phenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-5,6-difluoro-1-oxoisoindolin-4-yl)methyl)-2-oxoacetamide I-51;
2-(3-methyl-4-(tert-butyl)phenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)methyl)-2-oxoacetamide I-54;
2-(4-(tert-butyl)phenyl)-N-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)-2-oxoacetamide I-56;
N-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)-2-oxo-2-(4-(1-(trifluoromethyl)-cyclopropyl)phenyl)acetamide I-57;
N-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)methyl)-2-oxo-2-(4-(1-(trifluoromethyl)cyclopropyl)phenyl)acetamide I-58;
N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)methyl)-2-(5-isopropylthiophen-2-yl)-2-oxoacetamide I-59;
2-(4-(tert-butyl)piperidin-1-yl)-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)-methyl)-2-oxoacetamide I-61;
(2,6-dioxo-3-(1-oxo-4-((2-oxo-2-(4-(1-(trifluoromethyl)cyclopropyl)-phenyl)-acetamido)methyl)isoindolin-2-yl)piperidin-1-yl)methyl D-valinate I-64;
N-(2-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)ethyl)-2-oxo-2-(4-(1-(trifluoro-methyl)cyclopropyl)phenyl)acetamide I-65;
N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)methyl)-2-oxo-2-(4-(piperidin-4-yl)phenyl)acetamide I-66;
2-(4-(tert-butyl)cyclohexyl)-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)-methyl)-2-oxoacetamide I-67;
N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)methyl)-2-oxo-2-(p-tolyl)-acetamide I-72;
2-(3,4-difluorophenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)methyl)-2-oxoacetamide I-73;
N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)methyl)-2-oxo-2-phenylacetamide I-74;
N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)methyl)-2-oxo-2-(4-(trifluoro-methyl)phenyl)acetamide I-75;
2-(4-cyanophenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)methyl)-2-oxoacetamide I-76;
2-(4-chlorophenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)methyl)-2-oxoacetamide I-77;
2-(4-methoxyphenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)methyl)-2-oxoacetamide I-78;
2-(2,4,6-trimethoxyphenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)-methyl)-2-oxoacetamide I-79;
2-(2,4,6-trimethylphenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)-methyl)-2-oxoacetamide I-80;
2-(4-fluorophenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)methyl)-2-oxoacetamide I-81;
2-(2-fluorophenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)methyl)-2-oxoacetamide I-82;
2-(3-chlorophenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)methyl)-2-oxoacetamide I-88;
2-(3-fluorophenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)methyl)-2-oxoacetamide I-92;
2-(3-methoxyphenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)methyl)-2-oxoacetamide I-94;
N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)methyl)-2-(naphthalen-2-yl)-2-oxoacetamide I-96;
2-(3,5-dimethylphenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)methyl)-2-oxoacetamide I-98;
2-(3,4-dichlorophenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)methyl)-2-oxoacetamide I-101;
2-(4-(tert-butyl)-2,6-dimethylphenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)methyl)-2-oxoacetamide I-105;
2-(4-bromophenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)methyl)-2-oxoacetamide I-106;
2-(4-(tert-butyl)phenyl)-N-((5-(2,6-dioxopiperidin-3-yl)-6-oxo-5,6-dihydro-4H-thieno[2,3-c]pyrrol-2-yl)methyl)-2-oxoacetamide I-35;
2-(4-(tert-butyl)phenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindolin-4-yl)methyl)-2-oxoacetamide I-38;
2-(4-(tert-butyl)phenyl)-N-((5-(2,6-dioxopiperidin-3-yl)-6-oxo-5,6-dihydro-4H-thieno[2,3-c]pyrrol-3-yl)methyl)-2-oxoacetamide I-39;
2-(4-(tert-butyl)phenyl)-N-((5-(2,6-dioxopiperidin-3-yl)-6-oxo-5,6-dihydro-4H-thieno[2,3-c]pyrrol-2-yl)methyl)-2-oxoacetamide I-45;
N-((5-(2,6-dioxopiperidin-3-yl)-6-oxo-5,6-dihydro-4H-thieno[2,3-c]pyrrol-2-yl)-methyl)-2-oxo-4-phenylbutanamide I-69; or
N 1 -((5-(2,6-dioxopiperidin-3-yl)-6-oxo-5,6-dihydro-4H-thieno[2,3-c]pyrrol-2-yl)-methyl)-N 2 ,N 2 -dimethyloxalamide I-71;
or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof.
28. A pharmaceutical composition comprising a compound of claim 1 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.
29. The compound of claim 1 , wherein R 1 is
30. The compound of claim 1 , wherein R 1 is
optionally substituted with one R 3g .
31. The compound of claim 1 , wherein R 1 is
optionally substituted with one R 3g .
32. The compound of claim 1 , wherein the compound is 2-(4-(tert-butyl)phenyl)-N-((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methyl)-2-oxoacetamide I-1, or a pharmaceutically acceptable salt thereof.
33. The compound of claim 1 , wherein the compound is 2-(4-(tert-butyl)-phenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2-oxoacetamide I-2, or a pharmaceutically acceptable salt thereof.
34. The compound of claim 1 , wherein the compound is N-((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methyl)-2-oxo-2-(4-(1-(trifluoromethyl)cyclopropyl)phenyl)acetamide I-3, or a pharmaceutically acceptable salt thereof.
35. The compound of claim 1 , wherein the compound is N-((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methyl)-2-(5-isopropyl-thiophen-2-yl)-2-oxoacetamide I-4, or a pharmaceutically acceptable salt thereof.
36. The compound of claim 1 , wherein the compound is N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2-oxo-2-(4-(1-(trifluoromethyl)cyclopropyl)-phenyl)acetamide I-5, or a pharmaceutically acceptable salt thereof.
37. The compound of claim 1 , wherein the compound is 2-(3-chloro-4-methylphenyl)-N-((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methyl)-2-oxoacetamide I-6, or a pharmaceutically acceptable salt thereof.
38. The compound of claim 1 , wherein the compound is 2-(4-dimethyl-aminophenyl)-N-((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methyl)-2-oxoacetamide I-7, or a pharmaceutically acceptable salt thereof.
39. The compound of claim 1 , wherein the compound is 2-phenyl-N-((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methyl)-2-oxo-acetamide I-8, or a pharmaceutically acceptable salt thereof.
40. The compound of claim 1 , wherein the compound is N-((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methyl)-2-(thiophen-2-yl)-2-oxoacetamide I-9, or a pharmaceutically acceptable salt thereof.
41. The compound of claim 1 , wherein the compound is (S)-2-(4-(tert-butyl)phenyl)-N-((2-(2,7-dioxoazepan-3-yl)-1-oxoisoindolin-5-yl)methyl)-2-oxoacetamide I-10, or a pharmaceutically acceptable salt thereof.
42. The compound of claim 1 , wherein the compound is 2-(4-methoxy-phenyl)-N-((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methyl)-2-oxoacetamide I-11, or a pharmaceutically acceptable salt thereof.
43. The compound of claim 1 , wherein the compound is 2-(4-cyclopropyl-phenyl)-N-((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methyl)-2-oxoacetamide I-12, or a pharmaceutically acceptable salt thereof.
44. The compound of claim 1 , wherein the compound is 2-(4-(tert-butyl)-phenyl)-N-((5-(2,6-dioxopiperidin-3-yl)-4,6-dioxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methyl)-2-oxoacetamide I-13, or a pharmaceutically acceptable salt thereof.
45. The compound of claim 1 , wherein the compound is 2-(4-isopropyl-phenyl)-N-((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methyl)-2-oxoacetamide I-14, or a pharmaceutically acceptable salt thereof.
46. The compound of claim 1 , wherein the compound is 2-(4-(sec-butyl)-phenyl)-N-((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methyl)-2-oxoacetamide I-15, or a pharmaceutically acceptable salt thereof.
47. The compound of claim 1 , wherein the compound is 2-(4-hydroxy-phenyl)-N-((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methyl)-2-oxoacetamide I-16, or a pharmaceutically acceptable salt thereof.
48. The compound of claim 1 , wherein the compound is 2-(4-methyl-phenyl)-N-((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methyl)-2-oxoacetamide I-17, or a pharmaceutically acceptable salt thereof.
49. The compound of claim 1 , wherein the compound is 2-(4-chloro-phenyl)-N-((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methyl)-2-oxoacetamide I-18, or a pharmaceutically acceptable salt thereof.
50. The compound of claim 1 , wherein the compound is 2-(3-tert-butyl-phenyl)-N-((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methyl)-2-oxoacetamide I-19, or a pharmaceutically acceptable salt thereof.
51. The compound of claim 1 , wherein the compound is 2-(4-acetamido-phenyl)-N-((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methyl)-2-oxoacetamide I-20, or a pharmaceutically acceptable salt thereof.