Phosphatase inhibitors as nk cells modulators for the treatment of cancer

An ex vivo method of stimulating an isolated natural killer (NK) cell comprising:

• treating said isolated natural killer (NK) cell with an effective amount of a compound of structural Formula I, of structural Formula II, or pharmaceutically acceptable salts thereof, and stereoisomers thereof, or combinations 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) —ON, 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 C1-3 haloalkyl;
• 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) C3 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;
• wherein X′ is selected from CH and N;
• R1′ is selected from the group consisting of (a) C1-3alkyl optionally substituted with 1-3 halogens and optionally with one group selected from —OH, —OC1-3alkyl optionally substituted with 1-3 halogens, —SOxC1-3alkyl, and —CN, (b) —C(═O)H, (c) —C(═O)C1-3alkyl optionally substituted with 1-3 halogens, (d) —CN, (e) —HC═NOH, (f) —(CH3)C═NOH, (g) —HC═NOC1-3alkyl optionally substituted with 1-3 halogens, (h) —(CH3)C═NOC1-3alkyl optionally substituted with 1-3 halogens (i) —C(═O)OC1-3alkyl optionally substituted with 1-3 halogens, (j) —C(═O)NHR6′, (k) —CH═CH-Phenyl wherein —CH═CH— is optionally substituted with 1-2 substituents independently selected from halogen and C1-2alkyl optionally substituted with 1-3 F, (l) —CH2CH2-Phenyl wherein —CH2CH2— is optionally substituted with 1-4 substituents independently selected from halogen and C1-2alkyl optionally substituted with 1-3 F, (m) Phenyl, (n) -HET-Phenyl, wherein HET is a 5- or 6-membered heteroaromatic ring containing 1-3 heteroatoms selected from O, N and S, (o) —C≡C-Phenyl, and (p) —CH2-Phenyl, wherein the —CH2— group of —CH2-Phenyl is optionally substituted with 1-2 substituents independently selected from halogen and C1-2alkyl optionally substituted with 1-3 F, wherein Phenyl and HET in all occurrences are optionally substituted with 1-3 substituents independently selected from (i) halogen, (ii) —C(═O)OC1-3alkyl optionally substituted with 1-3 halogens, (iii) —C(═O)OH (iv) C1-3alkyl optionally substituted with 1-3 halogens, (v) —OC1-3alkyl optionally substituted with 1-3 halogens, (vi) —SOxMe, and (vii) —SO2NH2;
• R6′ is selected from the group consisting of H, C1-3alkyl optionally substituted with 1-3 halogens, Phenyl, and —CH2-Phenyl, wherein Phenyl in both occurrences is optionally substituted with 1-3 substituents independently selected from (i) halogen, (ii) —C(═O)OC1-3alkyl optionally substituted with 1-3 halogens, (iii) —C(═O)OH (iv) C1-3alkyl optionally substituted with 1-3 halogens, and (v) —OC1-3alkyl optionally substituted with 1-3 halogens;
• R2′ and R4′ are independently selected from H, halogen, —CH3, —CF3, —OCH3, and —OCF3;
• R3′ is halogen, wherein said halogen is bonded to the fused aromatic ring of Formula II at a position ortho to the —CF2PO(OR5′)2 group,
• each R5′ group is independently selected from the group consisting of H and C1-3alkyl optionally substituted with 1-3 halogens, and
• x is 0, 1, or 2,
• to obtain a stimulated isolated NK cell.