Granted Patent B2

US 12,653,810 · App. 17/851,684 · Granted Jun 16, 2026

Inventors: Yaron R. Hadari (Harrison, NY); Luca Carta (Scarsdale, NY); Michael Schmertzler (St. Petersburg, FL); Theresa M. Williams (Harleysville, PA); Charles H. Reynolds (Austin, TX); Rebecca Hutcheson (Stamford, CT)

Assignee: Shy Therapeutics LLC

A61K31/4365A61K31/505A61P25/28A61P29/00A61P35/00C07D495/04C07K14/435C12N15/1037C12N15/1065

Abstract

Claims (68)

1 . A compound of Formula VIb1:

or a pharmaceutically acceptable salt thereof,

wherein:

R 1b1 is 2-pyridinyl;

R 8b1 is hydrogen or methyl;

R 9b1 is phenyl, thienyl, pyridinyl, quinolinyl, heterocyclyl, or C(O)NR 6 R 7 ; and

R 6 and R 7 are independently selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, cycloalkyl, or heterocycloalkyl, or R 6 and R 7 are combined to form a cyclic structure including the nitrogen atom to which they are both attached;

or

wherein:

R 1b1 is 2-pyridinyl;

R 8b1 is hydrogen, methyl, —COOH, or —COOCH 3 ;

R 9b1 is selected from the group consisting of cyclobutyl, —CO 2 CH 3 , piperidin-4-ylmethyl, piperidin-3-ylmethyl, 2-chlorophenyl,

or

wherein:

R 1b1 is pyridinyl;

R 8b1 is

 and

R 9b1 is hydrogen, methyl, —COOH, or —COOCH 3 ;

or

wherein:

R 1b1 is aryl, heteroaryl, or NR 6 R 7 ;

R 8b1 is C(O)R 4 ;

R 9b1 is alkyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, halo, pseudohalo, C(O)R 4 , or S(O) p R 4 ;

R 4 is hydrogen, hydroxy, alkyl, haloalkyl, alkenyl, alkynyl, aryl, alkylaryl, heterocyclyl, cycloalkyl, aralkyl, alkoxy, alkenyloxy, alkynyloxy, aryloxy, alkylaryloxy, heterocyclyloxy, cycloalkyloxy, aralkoxy, or —NR 6 R 7 ;

R 6 and R 7 are independently selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, cycloalkyl, alkylcarbonyl, cycloalkylcarbonyl, arylcarbonyl, heteroarylcarbonyl, arylsulfonyl, heteroarylsulfonyl, cycloalkylsulfonyl or alkylsulfonyl, or R 6 and R 7 are combined to form a cyclic structure including the nitrogen atom to which they are both attached;

p is 0-2;

or

wherein the compound is:

or a pharmaceutically acceptable salt thereof.

2 . The compound or pharmaceutically acceptable salt of claim 1 , wherein:

R 1b1 is 2-pyridinyl;

R 8b1 is hydrogen or methyl;

R 9b1 is phenyl, thienyl, pyridinyl, quinolinyl, heterocyclyl, or C(O)NR 6 R 7 , and

R 6 and R 7 are independently selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, cycloalkyl, or heterocycloalkyl, or R 6 and R 7 are combined to form a cyclic structure including the nitrogen atom to which they are both attached.

3 . The compound or pharmaceutically acceptable salt of claim 2 , wherein the compound is:

or a pharmaceutically acceptable salt thereof.

4 . The compound or pharmaceutically acceptable salt of claim 1 , wherein:

R 1b1 is 2-pyridinyl;

R 8b1 is hydrogen, methyl, —COOH, or —COOCH 3 ;

R 9b1 is selected from the group consisting of cyclobutyl, —CO 2 CH 3 , piperidin-4-ylmethyl, piperidin-3-ylmethyl, 2-chlorophenyl,

5 . The compound or pharmaceutically acceptable salt of claim 4 , wherein the compound is:

or a pharmaceutically acceptable salt thereof.

6 . The compound or pharmaceutically acceptable salt of claim 1 , wherein:

R 1b1 is pyridinyl;

R 8b1 is

 and

R 9b1 is hydrogen, methyl, —COOH, or —COOCH 3 .

7 . The compound or pharmaceutically acceptable salt of claim 6 , wherein the compound is

or a pharmaceutically acceptable salt thereof.

8 . The compound or pharmaceutically acceptable salt of claim 1 , wherein:

R 1b1 is aryl, heteroaryl, or NR 6 R 7 ;

R 8b1 is C(O)R 4 ;

R 9b1 is alkyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, halo, pseudohalo, C(O)R 4 , or S(O) p R 4 ;

R 4 is hydrogen, hydroxy, alkyl, haloalkyl, alkenyl, alkynyl, aryl, alkylaryl, heterocyclyl, cycloalkyl, aralkyl, alkoxy, alkenyloxy, alkynyloxy, aryloxy, alkylaryloxy, heterocyclyloxy, cycloalkyloxy, aralkoxy, or —NR 6 R 7 ;

R 6 and R 7 are independently selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, cycloalkyl, alkylcarbonyl, cycloalkylcarbonyl, arylcarbonyl, heteroarylcarbonyl, arylsulfonyl, heteroarylsulfonyl, cycloalkylsulfonyl or alkylsulfonyl, or R 6 and R 7 are combined to form a cyclic structure including the nitrogen atom to which they are both attached;

p is 0-2.

9 . The compound of claim 1 , wherein the compound is:

or a pharmaceutically acceptable salt thereof.

10 . A compound, wherein the compound is:

or a pharmaceutically acceptable salt thereof.

11 . A method of inhibiting the function of one or more members of the Ras superfamily in a subject in need thereof comprising administering to the subject the compound of claim 1 .

12 . The method of claim 11 , wherein the inhibiting the function of one or more members of the Ras superfamily is an amelioration of one or more symptoms of a Ras-mediated cancer, an inflammatory disease, rasopathy, or a fibrotic disease in the subject.

13 . The method of claim 12 , wherein:

the cancer is hepatocellular carcinoma, prostate cancer, pancreatic cancer, lung cancer, ovarian cancer, colon cancer, small intestine cancer, biliary tract cancer, endometrium cancer, skin cancer, cervix cancer, urinary tract cancer, or glioblastoma; or

the inflammatory disease is gastritis, schistosomiasis, cholangitis, chronic cholecystitis, pelvic inflammatory disease, chronic cervicitis, osteomyelitis, inflammatory bowel disease, reflux esophagitis, Barrett's esophagus, bladder inflammation, asbestosis, silicosis, gingivitis, lichen planus, pancreatitis, protease mutation, lichen sclerosis, slaladenitis, bronchitis, Sjogren syndrome or Hashimoto's thyroiditis; or

the rasopathy is neurofibromatosis type 1, Noonan's syndrome, or Costello syndrome.

14 . The method of claim 13 , wherein the skin cancer is melanoma.

15 . The method of claim 13 , wherein the bladder inflammation is cystitis.

Continuity (7)

References Cited (400)