Inhibitors of RPN11

Patent metadata

Field	Value
Publication number	US-10005735-B2
Application number	US-201615239795-A
Country	US
Kind code	B2
Filing date	Aug 17, 2016
Priority date	Aug 17, 2015
Publication date	Jun 26, 2018
Grant date	Jun 26, 2018

Abstract

Candidate compounds for specific inhibition of Rpn11 are represented by Formula 1 a

where each of R 2 , R 3 , R 4 , R 5 , R 6 , and R 7 is independently selected from hydrogen (H), substituted and unsubstituted alkyl groups, carboxyl groups, or substituted and unsubstituted carboxyamides.

First claim

What is claimed is:

1. A compound represented by Formula 1a:

where each of R 2 , R 3 , R 4 , R 5 , R 6 , and R 7 is independently selected from hydrogen (H), substituted and unsubstituted alkyl groups, carboxyl groups, or substituted and unsubstituted carboxyamido groups;
where at least one of R 2 , R 3 , R 4 , R 5 , R 6 , and/or R 7 of Formula 1 a is a group represented by Formula 1 b

wherein in Formula 1 b:
n is 0, 1, 2, 3, or 4;
* represents a binding site to Formula 1 a;
each of R 8 and R 9 are independently selected from hydrogen or methyl groups; and
R 10 is represented by one of Formulae 2, 2a and 4-6 where * in Formulae 2 and 4-6 represents a binding site to Formula 1 b,

wherein in Formulae 2, 2a and 4-6:
each of X 1 , X 2 , X 3 , X 4 , X 5 , and X 6 is independently selected from S, C, N, or O;
R 11 and R 12 are each independently selected from:
H,
unsubstituted alkyl groups,
fluorine (F),
trifluoromethyl groups,
carboxyl groups,
CO2CH2CH3 groups,
OCH3 groups,
phenyl groups,
morpholino groups, or
alkyl groups substituted with one or more substituents, at least one of which substituents is selected from the group consisting of amino groups, amido groups, carboxyl groups, and thiol groups;

a is 0 or 1, wherein when a is 1, X 5 and X 6 form a pi bond; and
R 13 and R 14 are each independently selected from H, substituted or unsubstituted alkyl groups, fluorine (F), trifluoromethyl groups, carboxyl groups, CO2CH2CH3 groups, OCH3 groups, phenyl groups, or morpholino groups;
where when R 10 is represented by Formula 4, R 3 is represented by Formula 1 b;
where when R 10 is represented by Formula 4 and each of X 3 , X 4 , X 5 , and X 6 are C, then a is 1 and at least one of R 11 and R 12 is fluorine (F), a trifluoromethyl group, a carboxyl group, a CO2CH2CH3 group, a OCH3 group, a phenyl group, or a morpholino group.

2. The compound of claim 1 , wherein each of R 2 , R 3 , R 4 , R 5 , R 6 , and R 7 is independently selected from H, substituted and unsubstituted C1-C12 alkyl groups, carboxyl groups, or substituted and unsubstituted carboxyamido groups.

3. The compound of claim 1 , wherein the substituted alkyl groups are selected from the group consisting of alkyl groups having at least one substituent selected from the group consisting of amino groups, amido groups, carboxyl groups, and thiol groups.

4. The compound of claim 1 , wherein the substituted carboxyamides are selected from the group consisting of carboxyamides having at least one substituent selected from the group consisting of substituted and unsubstituted C1-C12 alkyl groups, acetyl groups, oxazolyl groups, thiazolyl groups, tetrahydrofuranyl groups, furanyl groups, thiophenyl groups, pyridinyl groups, phenyl groups, fluorophenyl groups, trifluorophenyl groups, methoxyphenyl groups, dioxolylmethylphenyl groups, morphilino groups, and morpholinophenyl groups.

5. The compound of claim 4 , wherein the substituted carboxyamides are selected from the group consisting of carboxyamides having at least one substituent selected from the group consisting of substituted C1-C12 alkyl groups is having at least one substituent selected from acetyl groups, oxazolyl groups, thiazolyl groups, tetrahydrofuranyl groups, furanyl groups, thiophenyl groups, pyridinyl groups, phenyl groups, fluorophenyl groups, trifluorophenyl groups, methoxyphenyl groups, dioxolylmethylphenyl groups, morphilino groups, or morpholinophenyl groups.

6. The compound of claim 1 , wherein the substituted alkyl groups of R 13 and R 14 of Formula 2a have at least one substituent selected from the group consisting of amino groups, amido groups, carboxyl groups, and thiol groups.

7. The compound of claim 1 , wherein:
at least one of R 3 , R 4 , R 5 , and/or R 6 is represented by Formula 1 b,
each of R 2 and R 7 is hydrogen (H), and
R 10 of Formula 1b is represented by Formula 2a.

8. The compound of claim 1 , wherein:
at least one of R 3 or R 4 is represented by Formula 1 b,
each of R 2 and R 7 is hydrogen (H), and
R 10 of Formula 1b is represented by Formula 2a.

9. The compound of claim 1 , wherein:
at least one of R 5 or R 6 is represented by Formula 1 b,
each of R 2 and R 7 is hydrogen (H), and
R 10 of Formula 1b is represented by Formula 2a.

10. A compound represented by one of Compounds 5, 8, 9, 11, 12, 15, 17, 18, 19, 20, 21, 24, 27, 28, 31, or 32:

11. A compound represented by Formula 1a:

where each of R 2 , R 3 , R 4 , R 5 , R 6 , and R 7 is independently selected from hydrogen (H), substituted and unsubstituted alkyl groups, carboxyl groups, or substituted and unsubstituted carboxyamido groups;
where at least one of R 2 , R 3 , R 4 , R 5 , R 6 , and/or R 7 of Formula 1 a is a group represented by Formula 1 b

wherein in Formula 1 b:
n is 0, 1, 2, 3, or 4;
*represents a binding site to Formula 1 a;
each of R 8 and R 9 are independently selected from hydrogen or methyl groups; and
R 10 is represented by one of Formulae 2, 2a, 5, or 6 where * in Formulae 2, 2a, 5, and 6 represents a binding site to Formula 1 b,

wherein in Formulae 2, 2a, and 6:
X 1 , is independently selected from S, C, N, or O;
R 13 and R 14 are each independently selected from:
H,
unsubstituted alkyl groups,
fluorine (F),
trifluoromethyl groups,
carboxyl groups,
CO2CH2CH3 groups,
OCH3 groups,
phenyl groups,
morpholino groups, and
alkyl groups substituted with one or more substituents, at least one of which substituents is selected from the group consisting of amino groups, amido groups, carboxyl groups, and thiol groups.

12. A method of inhibiting Rpn11 in a cell, a cell culture, or a cell in a human or animal subject, comprising:
administering the compound of claim 1 to the cell, the cell culture, or to the cell in the human or animal subject.

13. A method of inhibiting Rpn11 in a cell, a cell culture, or a cell in a human or animal subject, the method comprising:
administering the compound of claim 10 to the cell, the cell culture, or to the cell in the human or animal subject.

14. The compound of claim 11 , wherein:
at least one of R 3 or R 4 is represented by Formula 1 b,
each of R 2 and R 7 is hydrogen (H), and
R 10 of Formula 1b is represented by Formula 2a.

15. The compound of claim 11 , wherein:
at least one of R 5 or R 6 is represented by Formula 1 b,
each of R 2 and R 7 is hydrogen (H), and
R 10 of Formula 1b is represented by Formula 2a.

16. The compound of claim 11 , wherein each of R 2 , R

Assignees

• California Inst Of Techn
• Univ California

Inventors

• Deshaies Raymond J
• Li Jing
• Cohen Seth
• Perez Christian
• Ma Yuyong

Classifications

• C07D413/12

  linked by a chain containing hetero atoms as chain links · CPC title

• C07D409/12

  linked by a chain containing hetero atoms as chain links · CPC title

• C07D215/54 Primary

  attached in position 3 · CPC title

• C07D401/12

  linked by a chain containing hetero atoms as chain links · CPC title

• C07D417/12

  linked by a chain containing hetero atoms as chain links · CPC title