Isoindolinone and pyrrolopyridinone derivatives as Akt inhibitors

A compound of Formula I:

• or a pharmaceutically acceptable salt thereof, wherein:
• X is N or CR4;
• Y is N or CR5;
• Z is N or CR6, provided at least one of X, Y, and Z comprises a carbon atom;
• A is C6-10 aryl, 5-10 membered heteroaryl, or C3-7 cycloalkyl, wherein said C6-10 aryl, 5-10 membered heteroaryl, and C3-7 cycloalkyl are each optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from Q;
• R1 is H, F, Cl, Br, CN, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-6 cycloalkyl, C6-10 aryl, 4-6 membered heterocycloalkyl, or 5-10 membered heteroaryl, wherein said C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-6 cycloalkyl, C6-10 aryl, 4-6 membered heterocycloalkyl, and 5-10 membered heteroaryl are each optionally substituted with 1, 2, or 3 substituents independently selected from Cy, halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, CN, ORa, SRa, C(O)Rb, C(O)NRcRd, C(O)ORa, OC(O)Rb, OC(O)NRcRd, NRcRd, NRc(O)Rb, NRcC(O)NRcRd, NRcC(O)ORa, C(═NRg)NRcRd, NRcC(═NRg)NRcRd, S(O)Rb, S(O)NRcRd, S(O)2Rb, NRcS(O)2Rb, and S(O)2NRcRd, wherein no more than one of said 1, 2, or 3 substituents is Cy;
• R2 is H, C1-6 alkyl, C3-6 cycloalkyl, or 4-6 membered heterocycloalkyl, wherein said 4-6 membered heterocycloalkyl is optionally substituted by 1, 2, or 3 substituents independently selected from RA;
• R3 is H or C1-3 alkyl;
• or R2 and R3 together with the nitrogen atom to which they are both attached form a 4-6 membered heterocycloalkyl group optionally substituted by 1 or 2 substituents independently selected from RA;
• R4 is H, F, Cl, CN, or C1-3 alkyl;
• R5 is H, F, Cl, CN, or C1-3 alkyl;
• R6 is H, F, Cl, CN, or C1-3 alkyl;
• R7 is C1-3 alkyl;
• Q is independently selected from Cy1, -L-Cy1, halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, CN, NO2, ORa1, SRa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, OC(O)Rb1, OC(O)NRc1Rd1, NRc1Rd1, NRc1C(O)Rb1, NRc1C(O)NRc1Rd1, NRc1C(O)ORa1, C(═NRg)NRc1Rd1, NRc1C(═NRg)NRc1Rd1, S(O)Rb1, S(O)NRc1Rd1, S(O)2Rb1, NRc1S(O)2Rb1, and S(O)2NRc1Rd1;
• wherein no more than two Q are independently selected from Cy1 and -L-Cy1, and wherein said C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, and C1-6 haloalkyl, are each optionally substituted by 1, 2, 3, 4 or 5 substituents independently selected from halo, CN, NO2, ORa1, SRa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, OC(O)Rb1, OC(O)NRc1Rd1, NRc1Rd1, NRc1C(O)Rb1, NRc1C(O)NRc1Rd1, NRc1C(O)ORa1, C(═NRg)NRc1Rd1, NRc1C(═NRg)NRc1Rd1, S(O)Rb1, S(O)NRc1Rd1, S(O)2Rb1, NRc1S(O)2Rb1, and S(O)2NRc1Rd1;
• L is C1-3 alkylene, (C1-3 alkylene)pO(C1-3 alkylene)q, (C1-3 alkylene)pS(C1-3 alkylene)q, (C1-3 alkylene)pC(O)(C1-3 alkylene)q, (C1-3 alkylene)pC(O)NRe(C1-3 alkylene)q, (C1-3 alkylene)pC(O)O(C1-3 alkylene)q, (C1-3 alkylene)pOC(O)(C1-3 alkylene)q, (C1-3 alkylene)pOC(O)NRe(C1-3 alkylene)q, (C1-3 alkylene)pNRe(C1-3 alkylene)q, (C1-3 alkylene)pNReC(O)NRf(C1-3 alkylene)q, (C1-3 alkylene)pS(O)(C1-3 alkylene)q, (C1-3 alkylene)pS(O)NRe(C1-3 alkylene)q, (C1-3 alkylene)pS(O)2(C1-3 alkylene)q, or (C1-3 alkylene)pS(O)2NRe(C1-3 alkylene)q, wherein said C1-3 alkylene occurring in any of the options for L is optionally substituted with 1, 2, or 3 substituents independently selected from F, Cl, CN, NH2, NH(C1-3 alkyl) and N(C1-3 alkyl)2;
• Cy is C3-6 cycloalkyl, C6-10 aryl, 4-6 membered heterocycloalkyl, or 5-10 membered heteroaryl, wherein said C3-6 cycloalkyl, C6-10 aryl, 4-6 membered heterocycloalkyl, and 5-10 membered heteroaryl are each optionally substituted by 1, 2, or 3 substituents independently selected from Cy2 and RB, wherein no more than one of said 1, 2, or 3 substituents is Cy2;
• Cy1 is C3-6 cycloalkyl, C6-10 aryl, 4-6 membered heterocycloalkyl, or 5-6 membered heteroaryl, wherein said C3-6 cycloalkyl, C6-10 aryl, 4-6 membered heterocycloalkyl, and 5-6 membered heteroaryl are each optionally substituted with 1, 2, or 3 substituents independently selected from RC;
• Cy2 is C3-6 cycloalkyl, C6-10 aryl, 4-6 membered heterocycloalkyl, or 5-6 membered heteroaryl, wherein said C3-6 cycloalkyl, C6-10 aryl, 4-6 membered heterocycloalkyl, and 5-6 membered heteroaryl are each optionally substituted with 1, 2, or 3 substituents independently selected from RD;
• RA, RB, RC, and RD are each independently selected from halo, CN, C1-3 alkyl, C1-3 haloalkyl, NO2, ORa2, C(O)Rb2, C(O)NRc2Rd2, C(O)ORa2, OC(O)Rb2, NRc1Rdl, NRc2C(O)Rb2, NRc2C(O)NRc2Rd2, NRc2C(O)ORa2, S(O)2Rb2, NRc2S(O)2Rb2, and S(O)2NRc2Rd2;
• Ra, Rb, Rc, Rd, Ra1, Rb1, Rc1, and Rd1 are each independently selected from H, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C3-7 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-3 alkyl, 5-10 membered heteroaryl-C1-3 alkyl, C3-7 cycloalkyl-C1-3 alkyl, and 4-10 membered heterocycloalkyl-C1-3 alkyl, wherein said C6-10 aryl-C1-3 alkyl, 5-10 membered heteroaryl-C1-3 alkyl, C3-7 cycloalkyl-C1-3 alkyl, and 4-10 membered heterocycloalkyl-C1-3 alkyl are each optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from C1-6 alkyl, halo, CN, ORa3, SRa3, C(O)Rb3, C(O)NRc3Rd3, C(O)ORa3, OC(O)Rb3, OC(O)NRc3Rd3, NRc3Rd3, NRc3C(O)Rb3, NRc3C(O)NRc3Rd3, NRc3C(O)ORa3, C(═NRg)NRc3Rd3, NRc3C(═NRg)NRc3Rd3, S(O)Rb3, S(O)NRc3Rd3, S(O)2Rb3, NRc3S(O)2Rb3, and S(O)2NRc3Rd3;
• or Rc and Rd together with the N atom to which they are attached form a 4-, 5-, 6- or 7-membered heterocycloalkyl group or 5-membered heteroaryl group, each optionally substituted with 1, 2, or 3 substituents independently selected from C1-6 alkyl, halo, CN, ORa3, SRa3, C(O)Rb3, C(O)NRc3Rd3, C(O)ORa3, OC(O)Rb3, OC(O)NRc3Rd3, NRc3Rd3, NRc3C(O)Rb3, NRc3C(O)NRc3Rd3, NRc3C(O)ORa3, C(═NRg)NRc3Rd3, NRc3C(═NRg)NRc3Rd3, S(O)Rb3, S(O)NRc3Rd3, S(O)2Rb3, NRc3S(O)2Rb3, and S(O)2NRc3Rd3;
• or Rc1 and Rd1 together with the N atom to which they are attached form a 4-, 5-, 6- or 7-membered heterocycloalkyl group or 5-membered heteroaryl group, each optionally substituted with 1, 2, or 3 substituents independently selected from C1-6 alkyl, halo, CN, ORa3, SRa3, C(O)Rb3, C(O)NRc3Rd3, C(O)ORa3, OC(O)Rb3, OC(O)NRc3Rd3, NRc3Rd3, NRc3C(O)Rb3, NRc3C(O)NRc3Rd3, NRc3C(O)ORa3, C(═NRg)NRc3Rd3, NRc3C(═NRg)NRc3Rd3, S(O)Rb3, S(O)NRc3Rd3, S(O)2Rb3, NRc3S(O)2Rb3, and S(O)2NRc3Rd3;
• Ra2, Rb2, Rc2, and Rd2 are each independently selected from H, C1-3 alkyl, and C3-6 cycloalkyl;
• or Rc2 and Rd2 together with the N atom to which they are attached form a 4-, 5-, or 6-membered heterocycloalkyl group or 5-membered heteroaryl group;
• Ra3, Rb3, Rc3, and Rd3 are each independently selected from H, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, aryl, C6-10 aryl-C1-3 alkyl, 5-10 membered heteroaryl-C1-3 alkyl, C3-7 cycloalkyl-C1-3 alkyl, and 4-10 membered heterocycloalkyl-C1-3 alkyl, wherein said C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl C6-10 aryl-C1-3 alkyl, 5-10 membered heteroaryl-C1-3 alkyl, C3-7 cycloalkyl-C1-3 alkyl, and 4-10 membered heterocycloalkyl-C1-3 alkyl are each optionally substituted with 1, 2, or 3 substituents independently selected from OH, CN, amino, halo, C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl, and C1-6 haloalkoxy;
• or Rc3 and Rd3 together with the N atom to which they are attached form a 4-, 5-, 6- or 7-membered heterocycloalkyl group or 5-membered heteroaryl group, each optionally substituted with 1, 2, or 3 substituents independently selected from OH, CN, amino, halo, C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl, and C1-6 haloalkoxy;
• Re and Rf are each independently selected from H and C1-4 alkyl;
• Rg is H, CN, or NO2;
• n is 0 or 1;
• p is 0 or 1;
• and
• q is 0 or 1.