# US 2020/0399262 A1 · Compounds for inhibiting protein degradation and methods of use thereof in the treatment of cancer

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- Number: US 2020/0399262 A1
- Document ID: US20200399262A1
- Status: Published application
- Kind: A1
- Application number: 16/978,697
- Filed: 2019-03-07
- Published: 2020-12-24
- Earliest claimed: 2018-03-08
- Assignees: PI Therapeutics Ltd
- Applicants: PI Therapeutics Ltd
- Inventors: Ori KALID; Irina GOTLIV; Einat LEVY-APTER; Danit FINKELSHTEIN BEKER; Parkash JAGTAP
- Web page: https://patentgrep.com/patent/US20200399262A1

## CPC

- A61K 45/06: Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
- C07D 413/14: containing three or more hetero rings
- A61P 35/00: Antineoplastic agents
- C07D 211/86: Oxygen atoms
- C07D 213/68: attached in position 4
- C07D 213/89: with hetero atoms directly attached to the ring nitrogen atom
- C07D 401/06: linked by a carbon chain containing only aliphatic carbon atoms
- C07D 413/06: linked by a carbon chain containing only aliphatic carbon atoms
- A61N 2005/1098: {Enhancing the effect of the particle by an injected agent or implanted device}
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61N: ELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY (measurement of bioelectric currents A61B; surgical instruments, devices or methods for transferring non-mechanical forms of energy to or from the body A61B18/00; anaesthetic apparatus in general A61M; incandescent lamps H01K; infrared radiators for heating H05B)

## 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.

## Claims

### Claim 1

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.

### Claim 2 (depends on 1)

The compound of claim 1, wherein R200 is R15—N(R13)(R14), R15—O(R13), R15—Cl, or R15—Br;
R15 is (CH2)2 or (CH2)3;
R13 is CH3;
R14 is CH3 or a C1-C14 linear alkyl group substituted with C1-C14 linear or branched alkynyl or N3;
R100 is substituted phenyl or a substituted 5 or 6 membered monocylclic heteroaryl, preferably wherein R100 is substituted with at least one selected from: CH3, F, Cl, NO2, CF3 or CN; or
R100 is an aryl represented by the structure of formula V:
wherein
R1, R2, R3, R4 and R17 are each independently selected from: H, NO2, OH, COOK 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, —N(R13)(R14), —CON(R13)(R14), N3, S(O)R13, and S(O)2R13;
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.

### Claim 3

(canceled)

### Claim 4

(canceled)

### Claim 5 (depends on 2)

The compound of claim 2, wherein R17 is CN, Cl or F and R2 is Cl, CF3 or H.

### Claim 6

(canceled)

### Claim 7

(canceled)

### Claim 8 (depends on 1)

The compound of claim 1 represented by the structure of the following compounds:
Com-
pound
name
Structure
D1
AA
CA
E1
BA
F1
A2
BA-2
A3
CA-2
F1-5
E1-2
AA-8
or geometrical isomer, optical isomer, solvate, metabolite, pharmaceutically acceptable salt, pharmaceutical product, tautomer, hydrate, N-oxide, prodrug, isotopic variant, PROTAC, polymorph, or crystal thereof.

### Claim 9

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.

### Claim 10 (depends on 9)

The compound of claim 9, wherein A is a phenyl or an isoxazole; m and m′ are each independently 1 or 2, and R17 and R17′ are each independently H, F, Cl, Br, I, CN, CH3 or CF3; O1 is CH; O2 is CH or CH2; R5 and R6 are each independently H, OH, R15—OH, CH2—OH, COOH, C1-C10 alkyl, iPr, OR13, OMe, NH2, N(R13)(R14), N(CH3)2, or R and R6 are joined to form a substituted or unsubstituted (C3-C8) cycloalkyl, a cyclopropyl, a substituted or unsubstituted (C3-C8) heterocyclic ring, or a morpholine; G is C, T is O, or G=T is SO2, R13 is H, OH, methyl, methoxyethyl, phenyl, pyridyl, or C(O)—CH3; R4 is H, or methyl; R7 is a methyl, C3 alkyl substituted with N3, a propyl-azide or CH2—C≡CH; R8 is a methyl; or any combination thereof.

### Claim at position 11

-16. (canceled)

### Claim 17 (depends on 9)

The compound of claim 9, represented by the following structures:
Compound name
Structure
B9
B10
B11
B12
B13
B14
B15
B16
B17
B23
B24
B25
B26
B27
B28
B29
B30
B32
D1
B6
B7
B1
B8
AA
E1
BA
B3
B2
C1
F1
H1
B1-11
C1-7
C1-8
B2-7
or geometrical isomer, optical isomer, solvate, metabolite, pharmaceutically acceptable salt, pharmaceutical product, tautomer, hydrate, N-oxide, prodrug, isotopic variant, PROTAC, polymorph, or crystal thereof.

### Claim 18

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.

### Claim 19 (depends on 18)

The compound of claim 18, wherein R17 and R17′ are each independently Cl, CN, H, F; R2 and R2′ are each independently H, CF3, CN, Cl, NO2; R4 and R4′ are each independently H or Cl; G is C, T is O, or G=T is SO2; R13 is H, OH, methyl, methoxyethyl, phenyl, pyridyl, or C(O)—CH3; R14 is methyl; R7 is a methyl, C3 alkyl substituted with N3, propyl-azide or CH2—C≡CH; R8 is a methyl; or any combination thereof.

### Claim at position 15

-22. (canceled)

### Claim 23 (depends on 18)

The compound of claim 18, represented by the following structures:
Compound name Structure
Compound name
Structure
B9
B10
B11
B12
B13
B14
B15
B16
B17
B23
B24
B25
B26
B27
B28
B29
B30
B4
B32
D1
B5
B6
B7
B1
B8
AA
CA
BA
B3
B2
C1
F1
B1-11
C1-7
C1-8
B2-7
or geometrical isomer, optical isomer, solvate, metabolite, pharmaceutically acceptable salt, pharmaceutical product, tautomer, hydrate, N-oxide, prodrug, isotopic variant, PROTAC, polymorph, or crystal thereof.

### Claim 24

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.

### Claim 25 (depends on 24)

The compound of claim 24, wherein R7 and R8 are each independently substituted or unsubstituted linear or branched C1-C10 alkyl, a methyl, a propyl azide or a propynyl; R1, R2, R3, R1′, R2′, R3′, and R4′ are H; R1, R2, R3, R1′, R2′, R3′, and R4′ are H; Q1 is CH; O2 is CH or CH2; R7 is a methyl, C3 alkyl substituted with N3 or CH2—C≡CH; R8 is a methyl; or any combination thereof.

### Claim at position 19

-29. (canceled)

### Claim 30 (depends on 24)

The compound of claim 24, represented by the following structures:
Compound name
Structure
B1
B3
B2
C1
G1
H1
or geometrical isomer, optical isomer, solvate, metabolite, pharmaceutically acceptable salt, pharmaceutical product, tautomer, hydrate, N-oxide, prodrug, isotopic variant, PROTAC, polymorph, or crystal thereof.

### Claim 31

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.

### Claim 32

(canceled)

### Claim 33 (depends on 1)

A pharmaceutical composition comprising the compound of claim 1 and a pharmaceutically acceptable carrier.

### Claim 34 (depends on 1)

A method of treating, suppressing, reducing the severity, reducing the risk of developing or inhibiting in a subject a disease or condition selected from:
a. cancer;
b. a plasma cell disorder;
c. a non-plasma-cell hematologic malignancy;
d. a hematologic condition;
e. a SMARCB1-deficient malignancy;
f. a Post-transplant lymphoproliferative disease (PTLD);
g. a multiple myeloma;
comprising administering a compound according to claim 1 to a subject suffering from said disease or condition, under conditions effective to treat, suppress, reduce the severity, reduce the risk of developing, or inhibit said disease or condition.

### Claim 35 (depends on 34)

The method of claim 34, wherein the cancer is selected from the list of:
multiple myeloma, leukemia, Alveolar rhabdomyosarcoma, Melanoma, lymphoma, Astrocytoma, Biphasic synovial sarcoma, Bladder carcinoma, Bone cancer, Breast Cancer, Cecum adenocarcinoma, Cervical cancer, CNS cancer, Colon cancer, Colorectal cancer, Duodenal adenocarcinoma, Embryonal rhabdomyosarcoma, Endometrial cancer, Epithelioid sarcoma, Fibrosarcoma, Gastric cancer, Signet ring cell gastric adenocarcinoma, Gestational choriocarcinoma, Glioblastoma, Hereditary thyroid gland medullary carcinoma, Hypopharyngeal squamous cell carcinoma, Invasive ductal carcinoma, Liposarcoma, Lung cancer, Neuroblastoma, Osteosarcoma, Ovarian cancer, Uterine cancer, Pancreatic cancer, Papillary renal cell carcinoma, Prostate cancer, Rectal adenocarcinoma, Medulloblastoma, Renal cancer, Testicular embryonal carcinoma and Tongue squamous cell carcinoma;
wherein the plasma cell disorder is Monoclonal Gammopathy of Undetermined Significance (MGUS), smoldering multiple myeloma (SMM), Asymptomatic Plasma Cell Myeloma, Multiple myeloma (MM), Waldenstrom's macroglobulinemia (WM), immunoglobulin light chain (AL) amyloidosis, POEMS syndrome, plasma cell (PC) leukemia, or Plasmacytoma;
wherein the plasma cell disorder is malignant;
wherein the Non-plasma-cell hematologic malignancy is B-cell non-Hodgkin's lymphoma (NHL) such as Mantle cell lymphoma (MCL);
wherein the hematologic conditions is AL Amyloidosis, post-transplant lymphoproliferative disease (PTLD) or combination thereof; or
wherein the PTLD is polymorphic PTLD or monomorphic PTLD or classical Hodgkin-lymphoma-type PTLD.

### Claim 36 (depends on 34)

The method of claim 34, wherein the cancer is early cancer, advanced cancer, invasive cancer, metastatic cancer, drug resistant cancer or any combination thereof; wherein the subject has been previously treated with chemotherapy, immunotherapy, radiotherapy, biological therapy, surgical intervention, or any combination thereof; wherein the compound is administered in combination with an anti-cancer therapy; or any combination thereof.

### Claim 37

(canceled)

### Claim 38

(canceled)

### Claim 39 (depends on 38)

The method of claim 38, wherein the anti-cancer therapy is chemotherapy, immunotherapy, radiotherapy, biological therapy, surgical intervention, or any combination thereof.

### Claim 40 (depends on 1)

A method of suppressing, reducing or inhibiting tumor growth in a subject, comprising administering a compound according to claim 1, to a subject suffering from cancer under conditions effective to suppress, reduce or inhibit said tumor growth in said subject.

### Claim 41 (depends on 40)

The method of claim 40, wherein the tumor is a solid tumor and/or a SMARCB1-deficient tumor.

### Claim at position 32

-53. (canceled)

### Claim 54

A compound represented by any one of the following structures: