US 12,152,015 B2
Inhibitors of ectonucleotide pyrophosphatase/phosphodiesterase 1 (ENPP1) and methods of use thereof
Srinivas Rao Kasibhatla, San Diego, CA (US); Raman Kumar Kalakuntla, Telangana (IN); Alexis Weston, Phoenix, AZ (US); Trason Thode, Phoenix, AZ (US); Sunil Sharma, Phoenix, AZ (US); and Mohan R. Kaadige, Scottsdale, AZ (US)
Assigned to STINGRAY THERAPEUTICS, INC., Houston, TX (US)
Filed by Stingray Therapeutics, Inc., Houston, TX (US)
Filed on Feb. 14, 2023, as Appl. No. 18/109,705.
Application 18/109,705 is a continuation of application No. 17/168,109, filed on Feb. 4, 2021, granted, now 11,591,313.
Claims priority of provisional application 62/970,138, filed on Feb. 4, 2020.
Prior Publication US 2023/0183212 A1, Jun. 15, 2023
Int. Cl. C07D 403/04 (2006.01); A61P 35/00 (2006.01); C07D 215/54 (2006.01); C07D 239/74 (2006.01); C07D 239/88 (2006.01); C07D 239/94 (2006.01); C07D 401/04 (2006.01); C07D 401/14 (2006.01); C07D 403/14 (2006.01); C07D 487/08 (2006.01)
CPC C07D 403/04 (2013.01) [A61P 35/00 (2018.01); C07D 215/54 (2013.01); C07D 239/74 (2013.01); C07D 239/88 (2013.01); C07D 239/94 (2013.01); C07D 401/04 (2013.01); C07D 401/14 (2013.01); C07D 403/14 (2013.01); C07D 487/08 (2013.01)] 32 Claims
 
1. A method for the treatment of cancer selected from the group consisting of breast cancer, prostate cancer, colon cancer, squamous cell cancer, small-cell lung cancer, non-small cell lung cancer, gastrointestinal cancer, pancreatic cancer, cervical cancer, ovarian cancer, peritoneal cancer, liver cancer, bladder cancer, rectal cancer, endometrial carcinoma, kidney cancer, thyroid cancer, basal cell carcinoma, biliary tract cancer, bone cancer; brain cancer, central nervous system (CNS) cancer, choriocarcinoma, connective tissue cancer, esophageal cancer, eye cancer, cancer of the head and neck, intra-epithelial neoplasm; larynx cancer; lymphoma, melanoma, myeloma, neuroblastoma, oral cavity cancer, retinoblastoma, rhabdomyosarcoma, cancer of the respiratory system, sarcoma, skin cancer, stomach cancer, testicular cancer, uterine cancer, and cancer of the urinary system in a mammal, the method comprising the step of administering to the mammal in need thereof a therapeutically effective amount of a compound of Formula II:

OG Complex Work Unit Chemistry
wherein
X is N or CR11;
Z is C or N;
W is selected from the group consisting of an C1-C5 alkyl, —C(═O)—(CH2)n—, —(C1-C5 alkyl)-N—; NH, and a direct bond as follows:

OG Complex Work Unit Chemistry
each R1, R2 and R3 are independently selected from the group consisting of hydrogen, halogen, CN, ORa, —C(═O)NRbRc, —NRbRc, —C(═O)Rd, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl;
each Ra is independently selected from the group consisting of hydrogen, lower alkyl, and —(CH2)n—C(═O)NRbRc, aralkyl, aryl, heteroaryl, heterocycloalkyl, cycloalkyl;
wherein n is an integer between 1 and 3;
each Rb and Rc is independently selected from the group consisting of hydrogen, a lower alkyl, and lower aryl, heterocycloalkyl, or cycloalkyl;
each Rd is independently selected from the group consisting of —ORe and lower alkyl;
each Re is independently selected from the group consisting of hydrogen, a lower alkyl, and a lower aryl;
R11 is independently selected from the group consisting of hydrogen, halogen, COOEt, COOH, and CN;
R7, R8 and R9 are independently selected from the group consisting of H, halogen and lower alkyl; and R8 and R9 can also form a bridge across the 7-membered ring with 1 or 2 atoms, as follows:

OG Complex Work Unit Chemistry
R10 is independently selected from the group consisting of hydrogen and CF3;
or an isomer, hydrate, solvate, polymorph, tautomer or a pharmaceutically acceptable salt thereof.