IP Library Granted Patent US 11,220,486
Granted Patent B2
US 11,220,486 · App. 16/794,076 · Granted Jan 11, 2022

Inhibitors of low molecular weight protein tyrosine phosphatase and uses thereof

Inventors: Nunzio Bottini (La Jolla, CA); Jiwen Zou (La Jolla, CA); Santhi R. Ganji (La Jolla, CA); Stephanie Stanford (La Jolla, CA); Anthony Pinkerton (La Jolla, CA); Thomas D. Y. Chung (La Jolla, CA); Michael Hedrick (La Jolla, CA); Robert Ardecky (La Jolla, CA)
Assignees: LA JOLLA INSTITUTE OF ALLERGY & IMMUNOLOGY; SANFORD BURNHAM PREBYS MEDICAL DISCOVERY INSTITUTE
C07D239/94C07D215/42C07D215/46C07D401/04C07D401/12C07D403/12C07D405/04C07D405/12C07D409/04
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Quick Facts
Patent No.
US 11,220,486
App. No.
16/794,076
Granted
Jan 11, 2022
Kind
B2
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).

Claims (35)

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.

Assignments (3)
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Feb 27, 2020
From: BOTTINI, NUNZIO; STANFORD, STEPHANIE
To: LA JOLLA INSTITUTE OF ALLERGY & IMMUNOLOGY
Reel/Frame 051954/0384 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Feb 27, 2020
From: ZOU, JIWEN; GANJI, SANTHI R.; PINKERTON, ANTHONY; CHUNG, THOMAS D. Y.; HEDRICK, MICHAEL; ARDECKY, ROBERT
To: SANFORD BURNHAM MEDICAL RESEARCH INSTITUTE
Reel/Frame 051954/0625 →
CHANGE OF NAME Recorded Feb 27, 2020
From: SANFORD-BURNHAM MEDICAL RESEARCH INSTITUTE
To: SANFORD BURNHAM PREBYS MEDICAL DISCOVERY INSTITUTE
Reel/Frame 052045/0862 →
Continuity (3)
Division 15518331
Provisional Application 62063937 · Oct 14, 2014
Related Publication 20200290977A1 · Sep 17, 2020