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US 2020/0399262 A1Published application
Compounds for inhibiting protein degradation and methods of use thereof in the treatment of cancer
AssigneePI Therapeutics Ltd
InventorsOri KALID, Irina GOTLIV, Einat LEVY-APTER, Danit FINKELSHTEIN BEKER, Parkash JAGTAP
Life of this patent
Estimating the term…
Abstract
The present invention relates to compounds for inhibiting protein degradation and/or the ubiquitin-proteasome system and/or for modulating autophagy, pharmaceutical composition and methods of use thereof in the treatment of cancer.
Claims33
A compound represented by the structure of Formula IV:
- wherein
- Q1 and Q2 are each independently, either CH or CH2,
- R100 is selected from:
- (i) phenyl, optionally substituted with 1-5 substituents (i.e., aryl) selected from the group consisting of:
- F, Cl, Br, I, OH, R13, OR13, SH, SR13, R15—OH, R15—SH, —R15—O—R13, CF3, OCF3, CD3, OCD3, CN, NO2, —R15—CN, NH2, NHR13, N(R13)2, NR13R14, R15—N(R13)(R14), R16-R15—N(R13)(R14), B(OH)2, —OC(O)CF3, —OCH2Ph, NHC(O)—R13, NR13C(O)R14, NR13C(O)OR14, NR13SO2R14, NHCO—N(R13)(R14), COOH, —C(O)Ph, C(O)O—R13, R15—C(O)—R13, C(O)H, C(O)—R13, C1-C5 linear or branched C(O)-haloalkyl, —C(O)NH2, C(O)NHR13, C(O)N(R13)(R14), SO2R13, S(O)R13, SO2N(R13)(R14), CH(CF3)(NH—R13), C1-C14 linear or branched haloalkyl, C1-C1 linear, branched or cyclic alkyl, C1-C14 linear, branched or cyclic alkoxy, optionally wherein at least one methylene group (CH2) in the alkoxy is replaced with an oxygen atom, C1-C5 linear or branched thioalkoxy, C1-C5 linear or branched haloalkoxy, C1-C5 linear or branched alkoxyalkyl;
- (ii) naphthyl, optionally substituted with 1-5 substituents selected from the consisting of F, Cl, Br, I, OH, R13, OR13, SH, SR13, R15—OH, R15—SH, —R15—O—R13, CF3, OCF3, CD3, OCD3, CN, NO2, —R15—CN, NH2, NHR13, N(R13)2, NR13R14, R15—N(R13)(R14), R16-R15—N(R13)(R14), B(OH)2, —OC(O)CF3, —OCH2Ph, NHC(O)—R13, NR13C(O)R14, NR13C(O)OR14, NR13SO2R14, NHCO—N(R13)(R14), COOH, —C(O)Ph, C(O)O—R13, R15—C(O)—R13, C(O)H, C(O)—R13, C1-C5 linear or branched C(O)-haloalkyl, —C(O)NH2, C(O)NHR13, C(O)N(R13)(R14), SO2R13, S(O)R13, SO2N(R13)(R14), CH(CF3)(NH—R13), C1-C14 linear or branched haloalkyl, C1-C14 linear, branched or cyclic alkyl, C1-C14 linear, branched or cyclic alkoxy, optionally wherein at least one methylene group (CH2) in the alkoxy is replaced with an oxygen atom, C1-C5 linear or branched thioalkoxy, C1-C5 linear or branched haloalkoxy, C1-C5 linear or branched alkoxyalkyl;
- (iii) a 5 or 6 membered monocyclic heteroaryl group, having 1-3 heteroatoms selected from the group consisting of O, N, and S, optionally substituted with 1-3 substituents selected from the group consisting of:
- F, Cl, Br, I, OH, R13, OR13, SH, SR13, R15—OH, R15—SH, —R15—O—R13, CF3, OCF3, CD3, OCD3, CN, NO2, —R15—CN, NH2, NHR13, N(R13)2, NR13R14, R15—N(R13)(R14), R16-R15—N(R13)(R14), B(OH)2, —OC(O)CF3, —OCH2Ph, NHC(O)—R13, NR13C(O)R14, NR13C(O)OR14, NR13SO2R14, NHCO—N(R13)(R14), COOH, —C(O)Ph, C(O)O—R13, R15—C(O)—R13, C(O)H, C(O)—R13, C1-C5 linear or branched C(O)-haloalkyl, —C(O)NH2, C(O)NHR13, C(O)N(R13)(R14), SO2R13, S(O)R13, SO2N(R13)(R14), CH(CF3)(NH—R13), C1-C14 linear or branched haloalkyl, C1-C14 linear, branched or cyclic alkyl, C1-C14 linear, branched or cyclic alkoxy, optionally wherein at least one methylene group (CH2) in the alkoxy is replaced with an oxygen atom, C1-C5 linear or branched thioalkoxy, C1-C5 linear or branched haloalkoxy, C1-C5 linear or branched alkoxyalkyl;
- (iv) an 8 to 10 membered bicyclic heteroaryl group containing 1-3 heteroatoms selected from the group consisting of O, N, and S;
- and the second ring is fused to the first ring using 3 to 4 carbon atoms, and the bicyclic heteroaryl group is optionally substituted with 1-3 substituents selected from the group consisting of F, Cl, Br, I, OH, R13, OR13, SH, SR13, R15—OH, R15—SH, —R15—O—R13, CF3, OCF3, CD3, OCD3, CN, NO2, —R15—CN, NH2, NHR13, N(R13)2, NR13R14, R15—N(R13)(R14), R16-R15—N(R13)(R14), B(OH)2, —OC(O)CF3, —OCH2Ph, NHC(O)—R13, NR13C(O)R14, NR13C(O)OR14, NR13SO2R14, NHCO—N(R13)(R14), COOH, —C(O)Ph, C(O)O—R13, R15—C(O)—R13, C(O)H, C(O)—R13, C1-C5 linear or branched C(O)-haloalkyl, —C(O)NH2, C(O)NHR13, C(O)N(R13)(R14), SO2R13, S(O)R13, SO2N(R13)(R14), CH(CF3)(NH—R13), C1-C14 linear or branched haloalkyl, C1-C14 linear, branched or cyclic alkyl, C1-C14 linear, branched or cyclic alkoxy, optionally wherein at least one methylene group (CH2) in the alkoxy is replaced with an oxygen atom, C1-C5 linear or branched thioalkoxy, C1-C5 linear or branched haloalkoxy, C1-C5 linear or branched alkoxyalkyl;
- and
- (v) a substituted or unsubstituted C1-C5 linear or branched alkyl or a substituted or unsubstituted C1-C5 linear or branched alkene wherein substitutions include at least one selected of:
- F, Cl, Br, I, C1-C5 linear or branched alkyl, C1-C14 linear or branched haloalkyl, C1-C14 linear or branched alkoxy, C1-C14 linear or branched alkenyl, aryl, phenyl, heteroaryl, OH, COOH, NH2, N(R13)(R14), N3, CF3, CN or NO2;
- R200 is amine (—NR13R14), OH, —OCOR13, OR13, substituted or unsubstituted linear or branched (C2-C14) alkyl, substituted or unsubstituted linear or branched (C1-C14) alkyl-NR13R14, substituted or unsubstituted linear or branched (C1-C14) alkyl-NHR13, substituted or unsubstituted linear or branched (C2-C14) alkenyl-NR13R14, substituted or unsubstituted linear or branched (C2-C14) alkenyl-NHR13, substituted or unsubstituted linear or branched (C1-C14) alkyl-OR13, substituted or unsubstituted (C3-C8) cycloalkyl, R15—N(R13)(R14), R15—O(R13), R15—Cl, R15—Br, R15—F, R15—I, R15—N3, R15—CH═CH2, and R15—C≡CH;
- wherein substitutions include at least one selected of:
- F, Cl, Br, I, C1-C5 linear or branched alkyl, C1-C14 linear or branched haloalkyl, C1-C14 linear or branched alkoxy, C1-C14 linear or branched alkenyl, C1-C14 linear or branched alkynyl, aryl, phenyl, heteroaryl, OH, COOH, NH2, N(R13)(R14), N3, CF3, CN or NO2;
- R13 and R14 are each independently selected from:
- H, Cl, Br, I, F, OH, substituted or unsubstituted C1-C14 linear or branched alkyl group, substituted or unsubstituted (C3-C8) cycloalkyl, substituted or unsubstituted (C3-C8) heterocyclic ring having one or more heteroatoms selected from N, O and S;
- substituted or unsubstituted aryl (e.g., phenyl), substituted or unsubstituted heteroaryl (e.g., pyridyl), —C(O)—C1-C14 substituted or unsubstituted linear or branched alkyl (e.g., C(O)—CH3), or —S(O)2—C1-C14 substituted or unsubstituted linear or branched alkyl, wherein substitutions are selected from C1-C14 linear or branched haloalkyl, C1-C14 linear or branched alkoxy, C1-C14 linear or branched alkenyl, C1-C14 linear or branched alkynyl (e.g. CH2—C≡CH), aryl, phenyl, heteroaryl, NO2, OH, COOH, NH2, C1-C14 alkylamino, C1-C14 dialkylamino, F, Cl, Br, I, N3, and CN;
- R15 is [CH2]p
- wherein p is between 1 and 10;
- and
- R16 is [CH]q, [C]q
- wherein q is between 2 and 10;
- or geometrical isomer, optical isomer, solvate, metabolite, pharmaceutically acceptable salt, pharmaceutical product, tautomer, hydrate, N-oxide, prodrug, isotopic variant, PROTAC, polymorph, or crystal thereof.
22 more elements
(canceled)
(canceled)
(canceled)
(canceled)
A compound represented by the structure of Formula III:
- wherein
- A ring is a single or fused aromatic or heteroaromatic ring system, or a single or fused C3-C10 cycloalkyl, or a single or fused C3-C10 heterocyclic ring;
- Q1 and Q2 are each independently, either CH or CH2;
- R5 and R6 are each, independently, selected from:
- H, F, Cl, Br, I, OH, R15—OH, COOH, CN, unsubstituted C1-C10 alkyl, OR13, N(R13)(R14), substituted or unsubstituted (C3—C8) cycloalkyl, substituted or unsubstituted (C3-C8) heterocyclic ring having one or more heteroatoms selected from N, O and S;
- or R5 and R6 are joint to form a substituted or unsubstituted (C3-C8) cycloalkyl or an unsubstituted (C3-C8) heterocyclic ring;
- wherein substitutions are selected from:
- C1-C14 linear or branched haloalkyl, C1-C14 linear or branched alkoxy, C1-C14 linear or branched alkenyl, NO2, OH, OR13, COOH, NH2, C1-C14 alkylamino, C1-C14 dialkylamino, NR13R14, F, Cl, Br, I, CN, —OCF3, —COR13, —COOR13, —OCOOR13, —OCONR13R14, —(C1-C8) alkylene-COOR13, —SH, —SR13, —(C1-C8) alkyl, —NR13R14, —CONR13R14, N3, S(O)R13, and S(O)2R13;
- R7 and R8 are each independently selected from:
- H, F, Cl, Br, I, substituted or unsubstituted linear or branched C1-C10 alkyl, substituted or unsubstituted linear or branched C1-C10 alkoxy, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, C(O)—R13, S(O)—R13, S(O)2—R13, R15-Ph, R15-aryl, R15-heteroaryl, R15-R13, R15R16-R13, —CH2—CH═CH—C1-C10 alkyl, —CH2—CH═CH2, substituted or unsubstituted (C3-C8) cycloalkyl, substituted or unsubstituted (C3-C8) heterocyclic ring having one or more heteroatoms selected from N, O and S;
- wherein substitutions are selected from:
- C1-C14 linear or branched haloalkyl, C1-C14 linear or branched alkoxy, C1-C14 linear or branched alkenyl, NO2, OH, OR13, COOH, NH2, C1-C14 alkylamino, C1-C14 dialkylamino, halogen, CN, —OCF3, —COR13, —COOR13, —OCOOR13, —OCONR13R14, —(C1-C8) alkylene-COOR13, —SH, —SR13, —(C1-C8) alkyl, —NR13R14, —CONR13R14, N3, and S(O)q1R13;
- R13 is selected from:
- H, Cl, Br, I, F, OH, substituted or unsubstituted C1-C14 linear or branched alkyl group, substituted or unsubstituted (C3-C8) cycloalkyl, substituted or unsubstituted (C3-C8) heterocyclic ring having one or more heteroatoms selected from N, O and S;
- substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, —C(O)—C1-C14 substituted or unsubstituted linear or branched alkyl, or —S(O)2—C1-C14 substituted or unsubstituted linear or branched alkyl, wherein substitutions are selected from C1-C14 linear or branched haloalkyl, C1-C14 linear or branched alkoxy, C1-C14 linear or branched alkenyl, C1-C14 linear or branched alkynyl, aryl, phenyl, heteroaryl, NO2, OH, COOH, NH2, C1-C14 alkylamino, C1-C14 dialkylamino, F, Cl, Br, I, N3, and CN;
- R14 is selected from:
- Cl, Br, I, F, OH, substituted or unsubstituted C1-C14 linear or branched alkyl group, substituted or unsubstituted (C3-C8) cycloalkyl, substituted or unsubstituted (C3-C8) heterocyclic ring having one or more heteroatoms selected from N, O and S;
- substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, —C(O)—C1-C14 substituted or unsubstituted linear or branched alkyl, or —S(O)2—C1-C14 substituted or unsubstituted linear or branched alkyl, wherein substitutions are selected from C1-C14 linear or branched haloalkyl, C1-C14 linear or branched alkoxy, C1-C14 linear or branched alkenyl, C1-C14 linear or branched alkynyl, aryl, phenyl, heteroaryl, NO2, OH, COOH, NH2, C1-C14 alkylamino, C1-C14 dialkylamino, F, Cl, Br, I, N3, and CN;
- R15 is [CH2]p
- wherein p is between 1 and 10;
- R16 is [CH]q, [C]q
- wherein q is between 2 and 10;
- n is an integer between 1 and 15;
- R17 and R17′ are each independently selected from H, OH, COOH, NH2, F, Cl, Br, I, CN, R13, OR13, NH2, NR13R14, S(O)R13, S(O)2R13, —SR13, SO2NR13R14, NR13SO2R14, C(O)R13, C(O)OR13, C(O)OOR13, C(O)NR13R14, NR13C(O)R14, NR13C(O)OR14, —OCONR13R14, CF3, —COCF3, OCF3, R15-R13, R16-R13, substituted or unsubstituted C1-C14 linear or branched alkyl group, R15—C00R13, substituted or unsubstituted aryl, wherein substitutions are selected from:
- C1-C14 linear or branched haloalkyl, C1-C14 linear or branched alkoxy, C1-C14 linear or branched alkenyl, NO2, OH, OR13, COOH, NH2, C1-C14 alkylamino, C1-C14 dialkylamino, NR13R14, F, Cl, Br, I, CN, —OCF3, —COR13, —COOR13, —OCOR13, —OCONR13R14, —(C1-C8) alkylene-COOR13, —SH, —SR13, —(C1-C8) alkyl, —NR13R14, —CONR13R14, N3, S(O)R13, and S(O)2R13;
- m and m′ are each independently an integer between 0 and 5;
- G is C, S or N;
- T is O, S, NH, N—OH, CH2, or CR13R14;
- or
- G=T is SO2
- Z is —NH—C(O)—R15—N(R7)(R8), F, Br, I, N(R13)(R14), OR13, —NH—C(O)—R15-R13, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted R15-aryl, substituted or unsubstituted R15-heteroaryl, or C(O)—NH—R13;
- or geometrical isomer, optical isomer, solvate, metabolite, pharmaceutically acceptable salt, pharmaceutical product, tautomer, hydrate, N-oxide, prodrug, isotopic variant, PROTAC, polymorph, or crystal thereof.
29 more elements
-16. (canceled)
A compound, represented by the structure of Formula II:
- wherein
- Q1 and Q2 are each independently, either CH or CH2;
- R1, R2, R3, R4R1 ′, R2′, R3′, and R4′ are each, independently, selected from:
- H, NO2, OH, COOH, NH2, F, Cl, Br, I, CN, R13, OR13, NH2, NR13R14, S(O)R13, S(O)2R13, —SR13, SO2NR13R14, NR13SO2R14, C(O)R13, C(O)OR13, C(O)OOR13, C(O)NR13R14, NR13C(O)R14, NR13C(O)OR14, —OCONR13R14, CF3, —COCF3, OCF3, R15-R13, R16-R13, substituted or unsubstituted C1-C14 linear or branched alkyl group (e.g., methyl), R15—COOR13, substituted or unsubstituted aryl, wherein substitutions are selected from:
- C1-C14 linear or branched haloalkyl, C1-C14 linear or branched alkoxy, C1-C14 linear or branched alkenyl, NO2, OH, OR13, COOH, NH2, C1-C14 alkylamino, C1-C14 dialkylamino, NR13R14, F, Cl, Br, I, CN, —OCF3, —COR13, —COOR13, —OCOOR13, —OCONR13R14, —(C1-C8) alkylene-COOR13, —SH, —SR13, —(C1-C8) alkyl, —NR13R14, —CONR13R14, N3, S(O)R13, and S(O)2R13;
- R5 and R6 are each, independently, selected from:
- H, F, Cl, Br, I, OH, R15—OH, COOH, CN, unsubstituted C1-C10 alkyl, OR13, N(R13)(R14), substituted or unsubstituted (C3-C8) cycloalkyl, substituted or unsubstituted (C3-C8) heterocyclic ring having one or more heteroatoms selected from N, O and S;
- or R5 and R6 are joined to form a substituted or unsubstituted (C3-C8) cycloalkyl or an unsubstituted (C3-C8) heterocyclic ring;
- wherein substitutions are selected from:
- C1-C14 linear or branched haloalkyl, C1-C14 linear or branched alkoxy, C1-C14 linear or branched alkenyl, NO2, OH, OR13, COOH, NH2, C1-C14 alkylamino, C1-C14 dialkylamino, NR13R14, F, Cl, Br, I, CN, —OCF3, —COR13, —COOR13, —OCOOR13, —OCONR13R14, —(C1-C8) alkylene-COOR13, —SH, —SR13, —(C1-C8) alkyl, —NR13R14, —CONR13R14, N3, S(O)R13, and S(O)2R13;
- R7 and R8 are each independently selected from:
- H, F, Cl, Br, I, substituted or unsubstituted linear or branched C1-C10 alkyl, substituted or unsubstituted linear or branched C1-C10 alkoxy, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, C(O)—R13, S(O)—R13, S(O)2—R13, R15-Ph, R15-aryl, R15-heteroaryl, R15-R13, R15-R16-R13, —CH2—CH═CH—C1-C10 alkyl, —CH2—CH═CH2, substituted or unsubstituted (C3-C8) cycloalkyl, substituted or unsubstituted (C3-C8) heterocyclic ring having one or more heteroatoms selected from N, O and S;
- wherein substitutions are selected from:
- C1-C14 linear or branched haloalkyl, C1-C14 linear or branched alkoxy, C1-C14 linear or branched alkenyl, NO2, OH, OR13, COOH, NH2, C1-C14 alkylamino, C1-C14 dialkylamino, halogen, CN, —OCF3, —COR13, —COOR13, —OCOOR13, —OCONR13R14, —(C1-C8) alkylene-COOR13, —SH, —SR13, —(C1-C8) alkyl, —NR13R14, —CONR13R14, N3, and S(O)q1R13;
- R13 is selected from:
- H, Cl, Br, I, F, OH, substituted or unsubstituted C1-C14 linear or branched alkyl group, substituted or unsubstituted (C3-C8) cycloalkyl, substituted or unsubstituted (C3-C8) heterocyclic ring having one or more heteroatoms selected from N, O and S;
- substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, —C(O)—C1-C14 substituted or unsubstituted linear or branched alkyl, or —S(O)2—C1-C14 substituted or unsubstituted linear or branched alkyl, wherein substitutions are selected from C1-C14 linear or branched haloalkyl, C1-C14 linear or branched alkoxy, C1-C14 linear or branched alkenyl, C1-C14 linear or branched alkynyl, aryl, phenyl, heteroaryl, NO2, OH, COOH, NH2, C1-C14 alkylamino, C1-C14 dialkylamino, F, Cl, Br, I, N3, and CN;
- R14 is selected from:
- Cl, Br, I, F, OH, substituted or unsubstituted C1-C14 linear or branched alkyl group, substituted or unsubstituted (C3-C8) cycloalkyl, substituted or unsubstituted (C3-C8) heterocyclic ring having one or more heteroatoms selected from N, O and S;
- substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, —C(O)—C1-C14 substituted or unsubstituted linear or branched alkyl, or —S(O)2—C1-C14 substituted or unsubstituted linear or branched alkyl, wherein substitutions are selected from C1-C14 linear or branched haloalkyl, C1-C14 linear or branched alkoxy, C1-C14 linear or branched alkenyl, C1-C14 linear or branched alkynyl, aryl, phenyl, heteroaryl, NO2, OH, COOH, NH2, C1-C14 alkylamino, C1-C14 dialkylamino, F, Cl, Br, I, N3, and CN;
- R15 is [CH2]p
- wherein p is between 1 and 10;
- R16 is [CH]q, [C]q
- wherein q is between 2 and 10;
- n is an integer between 1 and 15;
- R17 and R17′ are each independently selected from H, OH, COOH, NH2, F, Cl, Br, I, CN, R13, OR13, NH2, NR13R14, S(O)R13, S(O)2R13, —SR13, SO2NR13R14, NR13SO2R14, C(O)R13, C(O)OR13, C(O)OOR13, C(O)NR13R14, NR13C(O)R14, NR13C(O)OR14, —OCONR13R14, CF3, —COCF3, OCF3, R15-R13, R16-R13, substituted or unsubstituted C1-C14 linear or branched alkyl group, R15—COOR13, substituted or unsubstituted aryl, wherein substitutions are selected from:
- C1-C14 linear or branched haloalkyl, C1-C14 linear or branched alkoxy, C1-C14 linear or branched alkenyl, NO2, OH, OR13, COOH, NH2, C1-C14 alkylamino, C1-C14 dialkylamino, NR13R14, F, Cl, Br, I, CN, —OCF3, —COR13, —COOR13, —OCOR13, —OCONR13R14, —(C1-C8) alkylene-COOR13, —SH, —SR13, —(C1-C8) alkyl, —NR13R14, —CONR13R14, N3, S(O)R13, and S(O)2R13;
- G is C, S or N;
- T is O, S, NH, N—OH, CH2, CR13R14;
- or
- G=T is SO2;
- and
- Z is —NH—C(O)—R15—N(R7)(R8), F, Cl, Br, I, N(R13)(R14), OR13, —NH—C(O)—R5-R13, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted R15-aryl, substituted or unsubstituted R15-heteroaryl, C(O)—NH—R13;
- or geometrical isomer, optical isomer, solvate, metabolite, pharmaceutically acceptable salt, pharmaceutical product, tautomer, hydrate, N-oxide, prodrug, isotopic variant, PROTAC, polymorph, or crystal thereof.
31 more elements
-22. (canceled)
A compound represented by the structure of Formula I:
- wherein
- Q1 and Q2 are each independently, either CH or CH2;
- R1, R2, R3, R4 R1′, R2′, R3′, and R4′ are each, independently, selected from:
- H, NO2, OH, COOH, NH2, F, Cl, Br, I, CN, R13, OR13, NH2, NR13R14, S(O)R13, S(O)2R13, —SR13, SO2NR13R14, NR13SO2R14, C(O)R13, C(O)OR13, C(O)OOR13, C(O)NR13R14, NR13C(O)R14, NR13C(O)OR14, —OCONR13R14, CF3, —COCF3, OCF3, R15-R13, R16-R13, substituted or unsubstituted C1-C14 linear or branched alkyl group, R15—COOR13, substituted or unsubstituted aryl, wherein substitutions are selected from:
- C1-C14 linear or branched haloalkyl, C1-C14 linear or branched alkoxy, C1-C14 linear or branched alkenyl, NO2, OH, OR13, COOH, NH2, C1-C14 alkylamino, C1-C14 dialkylamino, NR13R14, F, Cl, Br, I, CN, —OCF3, —COR13, —COOR13, —OCOOR13, —OCONR13R14, —(C1-C8) alkylene-COOR13, —SH, —SR13, —(C1-C8) alkyl, —NR13R14, —CONR13R14, N3, S(O)R13, and S(O)2R13;
- R5, R6, R5′ and R6′ are each, independently, selected from:
- H, F, Cl, Br, I, OH, R15—OH, COOH, CN, C1-C10 alkyl, OR13, NH2, N(R13)(R14), substituted or unsubstituted (C3-C8) cycloalkyl, substituted or unsubstituted (C3-C8) heterocyclic ring having one or more heteroatoms selected from N, O and S;
- or R5 and R6 are joint to form a substituted or unsubstituted (C3-C8) cycloalkyl or a substituted or unsubstituted (C3-C8) heterocyclic ring;
- or R5′ and R6′ are joint to form a substituted or unsubstituted (C3-C8) cycloalkyl or a substituted or unsubstituted (C3-C8) heterocyclic ring;
- wherein substitutions are selected from:
- C1-C14 linear or branched haloalkyl, C1-C14 linear or branched alkoxy, C1-C14 linear or branched alkenyl, NO2, OH, OR13, COOH, NH2, C1-C14 alkylamino, C1-C14 dialkylamino, NR13R14, F, Cl, Br, I, CN, —OCF3, —COR13, —COOR13, —OCOOR13, —OCONR13R14, —(C1-C8) alkylene-COOR13, —SH, —SR13, —(C1-C8) alkyl, —NR13R14, —CONR13R14, N3, S(O)R13, and S(O)2R13;
- R13 and R14 are each independently selected from:
- H, F, Cl, Br, I, substituted or unsubstituted linear or branched C1-C10 alkyl, substituted or unsubstituted linear or branched C1-C10 alkoxy, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, C(O)—R13, S(O)—R13, S(O)2—R13, R15-Ph, R15-aryl, R15-heteroaryl, R15-R13, R15-R16-R13, —CH2—CH═CH—C1-C10 alkyl, —CH2—CH═CH2, substituted or unsubstituted (C3-C8) cycloalkyl, substituted or unsubstituted (C3-C8) heterocyclic ring having one or more heteroatoms selected from N, O and S;
- wherein substitutions are selected from:
- C1-C14 linear or branched haloalkyl, C1-C14 linear or branched alkoxy, C1-C14 linear or branched alkenyl, NO2, OH, OR13, COOH, NH2, C1-C14 alkylamino, C1-C14 dialkylamino, halogen, CN, —OCF3, —COR13, —COOR13, —OCOOR13, —OCONR13R14, —(C1-C8) alkylene-COOR13, —SH, —SR13, —(C1-C8) alkyl, —NR13R14, —CONR13R14, N3, and S(O)q1R13;
- R13 and R14 are each independently selected from:
- H, Cl, Br, I, F, OH, substituted or unsubstituted C1-C14 linear or branched alkyl group, substituted or unsubstituted (C3-C8) cycloalkyl, substituted or unsubstituted (C3-C8) heterocyclic ring having one or more heteroatoms selected from N, O and S;
- substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, —C(O)—C1-C14 substituted or unsubstituted linear or branched alkyl, or —S(O)2—C1-C14 substituted or unsubstituted linear or branched alkyl, wherein substitutions are selected from C1-C14 linear or branched haloalkyl, C1-C14 linear or branched alkoxy, C1-C14 linear or branched alkenyl, C1-C14 linear or branched alkynyl, aryl, phenyl, heteroaryl, NO2, OH, COOH, NH2, C1-C14 alkylamino, C1-C14 dialkylamino, F, Cl, Br, I, N3, and CN;
- R15 is [CH2]p
- wherein p is between 1 and 10;
- R16 is [CH]q, [C]q
- wherein q is between 2 and 10;
- and
- n and n′ are each independently an integer between 1 and 15;
- or geometrical isomer, optical isomer, solvate, metabolite, pharmaceutically acceptable salt, pharmaceutical product, tautomer, hydrate, N-oxide, prodrug, isotopic variant, PROTAC, polymorph, or crystal thereof.
22 more elements
-29. (canceled)
The compound of any one of the preceding claims, wherein the compound is a protein degradation inhibitor, a UPS inhibitor, an autophagy modulator, a UPR inducer, wherein the compound induces proteotoxic stress and UPR by modulating protein degradation pathways and disrupting protein homeostasis, the compound induces accumulation of poly-ubiquitinated proteins in cells treated therewith, the compound disrupts autophagosomal flux in cells treated therewith, the compound induces the unfolded protein response (UPR) in cells treated therewith, or any combination thereof.
(canceled)
(canceled)
(canceled)
-53. (canceled)
A compound represented by any one of the following structures:
Dependencies are inferred from the claim text.