Inhibitors of N-linked glycosylation and methods using same

Patent metadata

Field	Value
Publication number	US-11219625-B2
Application number	US-201615746043-A
Country	US
Kind code	B2
Filing date	Jul 22, 2016
Priority date	Jul 24, 2015
Publication date	Jan 11, 2022
Grant date	Jan 11, 2022

Abstract

The present invention includes novel compounds and methods for preventing or treating diseases associated with N-linked glycosylation in a subject in need thereof. The methods comprise administering to the subject an effective amount of at least one compound of the invention.

First claim

What is claimed is:

1. A method of inhibiting or disrupting N-linked glycosylation in a cell, the method comprising contacting the cell with an effective amount of a compound of formula (I):

wherein:
R 1 is selected from the group consisting of

m=1 or 2;
R 2 is selected from the group consisting of

and —N(R 4 ) 2 ;
R 3 is selected from the group consisting of

each occurrence of R 4 is independently selected from the group consisting of H, -(C 1 -C 6 )alkyl, -(C 3 -C 6 )cycloalkyl, -(C 1 -C 6 )haloalkyl, -(C 1 -C 6 )alkoxy, -(C 3 -C 10 )heterocyclyl, -(C 1 -C 6 )heteroalkyl, —F, —Cl, —Br, —I, —CN, —NO 2 , —OR 5 , —SR 5 , —S(═O)R 5 , —S(═O) 2 R 5 , —C(═O)R 5 , —OC(═O)R 5 , —C(═O)OR 5 , aryl, —CH 2 -aryl, and -(C 5 -C 10 )heteroaryl, wherein the alkyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl group is optionally substituted; and,
each occurrence of R 5 is independently selected from the group consisting of H, -(C 1 -C 6 ) alkyl, -(C 1 -C 6 ) heteroalkyl, -(C 3 -C 6 ) cycloalkyl, -(C 3 -C 10 ) heterocyclyl, aryl, and -(C 5 -C 10 ) heteroaryl, wherein the alkyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl group is optionally substituted;

or a salt or N-oxide thereof.

2. The method of claim 1 , wherein the cell is a receptor tyrosine kinase-dependent cancer cell.

3. The method of claim 2 , wherein the receptor tyrosine kinase-dependent cancer is selected from the group consisting of non-small cell lung cancer, small cell lung cancer, head and neck squamous cell carcinoma, breast cancer, gastric cancer, cervical cancer, bladder cancer, ovarian cancer, colon cancer, rectal cancer, colorectal cancer, glioblastoma, and glioma.

4. The method of claim 1 , wherein the cell is in vivo in a mammal and wherein the compound is administered to the mammal.

5. A method of treating or ameliorating a receptor tyrosine kinase-dependent cancer in a subject in need thereof,
wherein the receptor tyrosine kinase-dependent cancer comprises non-small cell lung cancer, small cell lung cancer, head and neck squamous cell carcinoma, breast cancer, gastric cancer, cervical cancer, bladder cancer, ovarian cancer, colon cancer, rectal cancer, colorectal cancer, glioblastoma, or glioma,
the method comprising administering to the subject a therapeutically effective amount of a compound of formula (I):

wherein:
R 1 is selected from the group consisting of

m=1 or 2;
R 2 is selected from the group consisting of

R 3 is selected from the group consisting of

each occurrence of R 4 is independently selected from the group consisting of H, -(C 1 -C 6 )alkyl, -(C 3 -C 6 )cycloalkyl, -(C 1 -C 6 )haloalkyl, -(C 1 -C 6 )alkoxy, -(C 3 -C 10 )heterocyclyl, -(C 1 -C 6 )heteroalkyl, —F, —Cl, —Br, —I, —CN, —NO 2 , —OR 5 , —SR 5 , —S(═O)R 5 , —S(═O) 2 R 5 , —C(═O)R 5 , —OC(═O)R 5 , —C(═O)OR 5 , aryl, —CH 2 -aryl, and -(C 5 -C 10 )heteroaryl, wherein the alkyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl group is optionally substituted; and,
each occurrence of R 5 is independently selected from the group consisting of H, -(C 1 -C 6 ) alkyl, -(C 1 -C 6 ) heteroalkyl, -(C 3 -C 6 ) cycloalkyl, -(C 3 -C 10 ) heterocyclyl, aryl, and -(C 5 -C 10 ) heteroaryl, wherein the alkyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl group is optionally substituted;

or a salt or N-oxide thereof.

6. A method of treating or ameliorating a receptor tyrosine kinase-dependent cancer in a subject in need thereof,
wherein the receptor tyrosine kinase-dependent cancer comprises non-small cell lung cancer, small cell lung cancer, head and neck squamous cell carcinoma, breast cancer, gastric cancer, cervical cancer, bladder cancer, ovarian cancer, colon cancer, rectal cancer, colorectal cancer, glioblastoma, or glioma,
the method comprising administering to the subject a therapeutically effective amount of at least one compound selected from the group consisting of: 5-(N,N-Dimethylsulfamoyl)-N-(5-methyl-1,3-thiazol-2-yl)-2-(pyrrolidin-1-yl)benzamide, 5-(dimethylsulfamoyl)-N-(4-methyl-1,3-thiazol-2-yl)-2-pyrrolidin-1-ylbenzamide, 5-(dimethylsulfamoyl)-2-pyrrolidin-1-yl-N-(1,3-thiazol-2-yl)benzamide, 5-(dimethylsulfamoyl)-N-(5-methyl-1,3,4-thiadiazol-2-yl)-2-pyrrolidin-1-ylbenzamide, 5-(dimethylsulfamoyl)-N-(5-methyl-1H-1,2,4-triazol-3-yl)-2-pyrrolidin-1-ylbenzamide, N-(1,3-benzothiazol-2-yl)-5-(dimethylsulfamoyl)-2-pyrrolidin-1-ylbenzamide, 5-(dimethylsulfamoyl)-N-(4-methoxy-1,3-benzothiazol-2-yl)-2-pyrrolidin-1-ylbenzamide, 5-(dimethylsulfamoyl)-N-(5-methoxy-1,3-benzothiazol-2-yl)-2-pyrrolidin-1-ylbenzamide, 5-(dimethylsulfamoyl)-N-(6-methoxy-1,3-benzothiazol-2-yl)-2-pyrrolidin-1-ylbenzamide, 5-(dimethylsulfamoyl)-N-pyridin-3-yl-2-pyrrolidin-1-ylbenzamide, 5-(dimethylsulfamoyl)-N-pyridin-4-yl-2-pyrrolidin-1-ylbenzamide, 5-(dimethylsulfamoyl)-N-phenyl-2-pyrrolidin-1-ylbenzamide, 5-(dimethylsulfamoyl)-N-(2-methylphenyl)-2-pyrrolidin-1-ylbenzamide, 5-(dimethylsulfamoyl)-N-(4-methylphenyl)-2-pyrrolidin-1-ylbenzamide, 5-(dimethylsulfamoyl)-N-(2-methoxyphenyl)-2-pyrrolidin-1-ylbenzamide, 5-(dimethylsulfamoyl)-N-(4-methoxyphenyl)-2-pyrrolidin-1-ylbenzamide, 5-(dimethylsulfamoyl)-N-(2-fluorophenyl)-2-pyrrolidin-1-ylbenzamide, 5-(dimethylsulfamoyl)-N-(3-fluorophenyl)-2-pyrrolidin-1-ylbenzamide, 5-(dimethylsulfamoyl)-N-(2-chlorophenyl)-2-pyrrolidin-1-ylbenzamide, 5-(dimethylsulfamoyl)-N-(4-bromophenyl)-2-pyrrolidin-1-ylbenzamide, 5-(dimethylsulfamoyl)-N-(5-methyl-1,3-thiazol-2-yl)-2-pyrrolidin-1-ylbenzamide, 5-(diethylsulfamoyl)-N-(5-methyl-1,3-thiazol-2-yl)-2-pyrrolidin-1-ylbenzamide, N-(5-methyl-1,3-thiazol-2-yl)-2-pyrrolidin-1-yl-5-pyrrolidin-1-ylsulfonyl benzamide, N-(5-methyl-1,3-thiazol-2-yl)-5-piperidin-1-ylsulfonyl-2-pyrrolidin-1-ylbenzamide, N-(5-methyl-1,3-thiazol-2-yl)-5-morpholin-4-ylsulfonyl-2-pyrrolidin-1-ylbenzamide, N-(5-methyl-1,3-thiazol-2-yl)-5-piperazin-1-ylsulfonyl-2-pyrrolidin-1-ylbenzamide, 5-[methyl(phenyl)sulfamoyl]-N-(5-methyl-1,3-thiazol-2-yl)-2-pyrrolidin-1-ylbenzamide, 5-(benzylsulfamoyl)-N-(5-methyl-1,3-thiazol-2-yl)-2-pyrrolidin-1-ylbenzamide, 5-(dimethylsulfamoyl)-N-(5-methyl-1,3-thiazol-2-yl)-2-piperidin-1-ylbenzamide, 5-(dimethylsulfamoyl)-N-(5-methyl-1,3-thiazol-2-yl)-2-piperazin-1-ylbenzamide, 2-(dimethylamino)-5-(dimethylsulfamoyl)-N-(5-methyl-1,3-thiazol-2-yl)benzamide, 2-(diethylamino)-5-(dimethylsulfamoyl)-N-(5-methyl-1,3-thiazol-2-yl)benzamide, 2-cyclopentyl-5-(dimethylsulfamoyl)-N-(5-methyl-1,3-thiazol-2-yl)benzamide, and 3-(dimethylsulfamoyl)-N-(5-methyl-1,3-thiazol-2-yl)benzamide;

or a salt or N-oxide thereof.

7. The method of claim 6 , wherein the compound blocks or inhibits cell surface expression of the receptor tyrosine kinase in a cell from the cancer.

8. The method of claim 5 , further comprising administering to the subject at least one additional therapeutic agent that treats or ameliorates th

Assignees

• Univ Yale
• Univ Kansas

Inventors

• Contessa Joseph N
• Golden Jennifer E
• Flaherty Daniel P

Classifications

• C07D213/75

  Amino or imino radicals, acylated by carboxylic or carbonic acids, or by sulfur or nitrogen analogues thereof, e.g. carbamates · CPC title

• C07D277/46

  by carboxylic acids, or sulfur or nitrogen analogues thereof · CPC title

• C07D295/155

  with the ring nitrogen atoms and the carbon atoms with three bonds to hetero atoms separated by carbocyclic rings or by carbon chains interrupted by carbocyclic rings · CPC title

• A61K45/06

  Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca · CPC title

• C07D295/192

  from aromatic carboxylic acids · CPC title