Enhancing CD8+ T cells for adoptive T cell therapy by inhibiting PTPN1 (PTP1B) and PTPN2 (TC-PTP)

An ex vivo method of stimulating an isolated memory T-cell, tumor-infiltrating lymphocyte (TIL), T cell receptor (TCR) engineered cell, and/or chimeric antigen receptor (CAR) engineered cell comprising:

• treating an isolated memory T-cell, tumor-infiltrating lymphocyte (TIL), T cell receptor (TCR) engineered cell, and/or chimeric antigen receptor (CAR) engineered cell with an effective amount of a compound of structural Formula I, or a pharmaceutically acceptable salts thereof, and stereoisomers thereof:
• wherein:
• X is selected from CH and N;
• R1 is selected from the group consisting of (a) C1-3 alkyl optionally substituted with 1-5 halogens and optionally with one group selected from —OH, —OC1-3 alkyl optionally substituted with 1-3 halogens, —SOxC1-3 alkyl, and —CN;
• (b) —(C═O)R4;
• (c) —CN;
• (d) —(C═O)OR4;
• (e) —(C═O)NHR4;
• (f) —(C═O)NR5R6;
• and (g) aryl or heteroaryl wherein the aryl and heteroaryl group itself may be optionally substituted with 1-3 substituents independently selected from (i) halogen, (ii) —(C═O)OC1-3 alkyl optionally substituted with 1-3 halogens, (iii) —COOH (iv) C1-3 alkyl optionally substituted with 1-3 halogens, (v) —OC1-3 alkyl optionally substituted with 1-3 halogens, (vi) —SOxMe, (vii) —CN, and (viii) —SO2NH2;
• R2 and R3 are independently selected from the group consisting of (a) halogen;
• (b) difluoromethylphosphonic acid;
• R4 is selected from the group consisting of (a) H;
• (b) C1-3 alkyl optionally substituted with 1-5 halogens and optionally with one group selected from —OH, —OC1-3 alkyl optionally substituted with 1-3 halogens, —SOxC1-3 alkyl, and —CN;
• (d) aryl or heteroaryl wherein the aryl or heteroaryl group itself may be optionally substituted by 1-3 halogens, C1-3 alkyl or C1-3haloalkyl;
• R5 and R6 are independently selected from the group consisting of (a) C1-3 alkyl optionally substituted with 1-5 halogens and optionally with one group selected from —OH, —OC1-3 alkyl optionally substituted with 1-3 halogens, —SOxC1-3 alkyl, and —CN;
• (b) aryl or heteroaryl wherein the aryl or heteroaryl group itself may be optionally substituted by 1-3 halogens, C1-3 alkyl or C1-3 haloalkyl;
• R5 and R6, together with the nitrogen atom to which they are attached may be joined to form a 5- to 7-membered ring, which may be substituted with 1-3 groups independently selected from (i) halogen, (ii) —(C═O)OC1-3 alkyl, (iii) —(C═O)OH (iv) C1-3 alkyl optionally substituted with 1-3 halogens, (v) —OC1-3 alkyl optionally substituted with 1-3 halogens, (vi) —OH, (vii) C1-3 hydroxyalkyl, (viii) aryl or heteroaryl wherein the aryl or heteroaryl group itself may be optionally substituted by 1-3 halogens, C1-3 alkyl or C1-3 haloalkyl;
• and
• x is an integer from 0 to 2.