Inhibitors of low molecular weight protein tyrosine phosphatase and uses thereof

Patent metadata

Field	Value
Publication number	US-11220486-B2
Application number	US-202016794076-A
Country	US
Kind code	B2
Filing date	Feb 18, 2020
Priority date	Oct 14, 2014
Publication date	Jan 11, 2022
Grant date	Jan 11, 2022

Abstract

Herein are provided, inter alia, compounds capable of modulating the level of activity of low molecular weight protein tyrosine phosphatase (LMPTP) and methods of using the same. In embodiments, the compound has a structure according to Formula (I-A).

First claim

What is claimed is:

1. A compound having the formula:

or a pharmaceutically acceptable salt thereof, wherein
L 1 is substituted or unsubstituted C 2 -C 6 alkylene, and R 2 is substituted or unsubstituted heterocycloalkyl, where said heterocycloalkyl is not unsubstituted morpholine;
R 1 is phenyl comprising a substituent group R 1A ;
R 1A is —C(O)NR 1C R 1D ;
R 1C is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;
R 1D is substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;
or R 1C and R 1D and the nitrogen atom they are attached to may optionally combine to form a substituted or unsubstituted heterocycloalkyl;
R 3 is hydrogen, halogen, —CX 3 3 , —CHX 3 2 , —CH 2 X 3 , —OCX 3 3 , —OCHX 3 2 , —OCH 2 X 3 , —CN, —SO n3 R 16 , —SO v3 NR 13 R 14 , —NHC(O)NR 13 R 14 , —N(O) m3 , —NR 13 R 14 , —C(O)R 15 , —C(O)—OR 15 , —C(O)NR 13 R 14 , —OR 16 , —NR 13 SO 2 R 16 , —NR 13 C(O)R 15 , —NR 13 C(O)OR 15 , —NR 13 OR 15 , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;
R 4 is hydrogen, halogen, —CX 4 3 , —CHX 4 2 , —CH 2 X 4 , —OCX 4 3 , —OCHX 4 2 , —OCH 2 X 4 , —CN, —SO n4 R 20 , —SO v4 NR 17 R 18 , —NHC(O)NR 17 R 18 , —N(O) m4 , —NR 17 R 18 , —C(O)R 19 , —C(O)—OR 19 , —C(O)NR 17 R 18 , —OR 20 , —NR 17 SO 2 R 20 , —NR 17 C(O)R 19 , —NR 17 C(O)OR 19 , —NR 17 OR 19 , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;
R 5 is hydrogen, halogen, —CN, —SO n5 R 24 , —SO v5 NR 21 R 22 , —NHC(O)NR 21 R 22 , —N(O) m5 , —NR 21 R 22 , —NR 21 SO 2 R 24 , —NR 21 C(O)R 23 , —NR 21 C(O)OR 23 , —NR 21 OR 23 , substituted or unsubstituted heteroalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;
R 6 is hydrogen, halogen, —CX 6 3 , —CHX 6 2 , —CH 2 X 6 , —OCX 6 3 , —OCHX 6 2 , —OCH 2 X 6 , —CN, —SO n6 R 28 , —SO v6 NR 25 R 26 , —NHC(O)NR 25 R 26 , —N(O) m6 , —NR 25 R 26 , —C(O)R 27 , —C(O)—OR 27 , —C(O) NR 25 R 26 , —OR 28 , —NR 25 SO 2 R 28 , —NR 25 C(O)R 27 , —NR 25 C(O)OR 27 , —NR 25 OR 27 substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;
each R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , R 19 , R 20 , R 21 , R 22 , R 23 , R 24 , R 25 , R 26 , R 27 and R 28 is independently hydrogen, —CX 3 , —CN, —COOH, —CONH 2 ,
—CHX 2 , —CH 2 X, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;
each X is independently —F, —Cl, —Br, or —I;
each X 3 , X 4 , and X 6 is independently —F, —Cl, —Br, or —I;
each m3, m4, m5, and m6 is independently 1 or 2;
each n3, n4, n5, and n6 is independently an integer from 0 to 3; and
each v3, v4, v5, and v6 is independently 1 or 2.

2. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein:
L 1 is substituted or unsubstituted C 2 -C 6 alkylene, and
R 2 is unsubstituted heterocycloalkyl.

3. The compound of claim 1 , or a pharmaceutically acceptable salt, wherein: R 1A is para to the carbon attached to the quinazoline moiety.

4. The compound of claim 1 , or a pharmaceutically acceptable salt, wherein:
R 1C is hydrogen or substituted or unsubstituted alkyl; and
R 1D is substituted or unsubstituted alkyl.

5. The compound of claim 1 , or a pharmaceutically acceptable salt, wherein: R 1C and R 1D attached to the same nitrogen atom optionally combine to form a substituted or unsubstituted heterocycloalkyl.

6. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein: each of R 3 , R 4 , R 5 , and R 6 is hydrogen.

7. A pharmaceutical composition comprising the compound of claim 1 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

8. A method of treating a disease or condition, said method comprising administering to a subject in need thereof an effective amount of a compound of claim 1 , or a pharmaceutically acceptable salt thereof, and
wherein said disease or condition is diabetes, heart disease, coronary artery disease, hyperlipidemia, lipodystrophy, insulin resistance, rheumatic disease, atherosclerosis, myocardial infarction, stroke, high blood pressure (hypertension), obesity, elevated fasting plasma glucose, high serum triglycerides, elevated blood cholesterol, cardiac hypertrophy, heart failure or metabolic syndrome.

9. The method of claim 8 , wherein said disease or condition is heart failure.

10. The method of claim 9 , wherein said heart failure is hypertrophy-induced heart failure.

11. The method of claim 8 , wherein said disease or condition is diabetes or hyperlipidemia.

12. The method of claim 8 , wherein said disease or condition is metabolic syndrome.

Assignees

• La Jolla Inst Of Allergy & Immunology
• Sanford Burnham Prebys Medical Discovery Inst

Inventors

• Bottini Nunzio
• Zou Jiwen
• Ganji Santhi R
• Stanford Stephanie
• Pinkerton Anthony
• Chung Thomas D Y
• Hedrick Michael
• Ardecky Robert

Classifications

• C07D409/04

  directly linked by a ring-member-to-ring-member bond · CPC title

• C07D403/12

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

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title

• A61P9/00

  Drugs for disorders of the cardiovascular system · CPC title

• C07D401/04

  directly linked by a ring-member-to-ring-member bond · CPC title