ATG7 inhibitors and the uses thereof

A chemical entity which is a compound or a pharmaceutically acceptable salt of formula (I):

• wherein:
• R1 is H and R2 is H;
• or R1 is H and R2 is —OH;
• or R1 is F and R2 is H;
• Ra is H, I, —CN, —CO2CH3, —C(O)CH3, —C(S)NH2, —C(O)NH2, —S(O)CH3, C1-3 fluoroaliphatic, —O—C1-3 fluoroaliphatic, —S—C1-3 fluoroaliphatic, -T1-Rb, Rbb, —O-T1-Rb, —O—Rdd, —S-T1-Rc, or —S—Ree;
• T1 is absent or C1-C3 alkylene optionally substituted with 1 or 2 independent occurrences of —CH3,
• Rb is 3-7 membered cycloaliphatic;
• 4-10-membered heterocyclyl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
• 6-10-membered aryl;
• or 5-10-membered heteroaryl having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
• wherein each Rb is substituted with 0-5 Rd;
• Rc is 3-7 membered cycloaliphatic;
• 4-10-membered heterocyclyl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
• 6-10-membered aryl;
• or 5-10-membered heteroaryl having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
• wherein each Rc is substituted with 0-5 Rf;
• each occurrence of Rd is independently halo, —OH, —CN, —NO2, C1-4 aliphatic, —O—C1-3 aliphatic, C1-3 fluoroaliphatic, —O—C1-3 fluoroaliphatic, —S—C1-3 aliphatic, —S—C1-3 fluoroaliphatic, —N(Re)2, —C(O)—N(Re)2, —SO2CH3, —S(O)CH3, or —O—CH2-phenyl wherein the phenyl ring is optionally substituted with 1 or 2 independent occurrences of halo, —CN, C1-3 aliphatic, or —O—C1-3 aliphatic;
• or two occurrences of Rd are taken together to form a 5 or 6 membered cycloaliphatic or heterocyclic ring, having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, which is further optionally substituted with one occurrence of ═O and optionally substituted with one occurrence of Rg;
• each occurrence of Rf is independently halo, —OH, —CN, —NO2, C1-4 aliphatic, —O—C1-3 aliphatic, C1-3 fluoroaliphatic, —O—C1-3 fluoroaliphatic, —S—C1-3 aliphatic, —S—C1-3 fluoroaliphatic, —N(Re)2, —C(O)—N(Re)2, —SO2CH3, —S(O)CH3, or —O—CH2-phenyl wherein the phenyl ring is optionally substituted with 1 or 2 independent occurrences of halo, —CN, C1-3 aliphatic, or —O—C1-3 aliphatic;
• or two occurrences of Rf are taken together to form a 5 or 6 membered cycloaliphatic or heterocyclic ring, having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, which is further optionally substituted with one occurrence of ═O and optionally substituted with one occurrence of Rg;
• Rbb is C1-3 aliphatic substituted with 0-5 Rbx;
• Rdd is C1-3 aliphatic substituted with 0-5 Rdx;
• Ree is C1-3 aliphatic substituted with 0-5 Rfx;
• each occurrence of Rbx is independently —OH, —CN, —NO2, C1-4 aliphatic, —O—C1-3 aliphatic, C1-3 fluoroaliphatic, —O—C1-3 fluoroaliphatic, —S—C1-3 aliphatic, —S—C1-3 fluoroaliphatic, —N(Re)2, —C(O)—N(Re)2, —SO2CH3, —S(O)CH3, or —O—CH2-phenyl wherein the phenyl ring is optionally substituted with 1 or 2 independent occurrences of halo, —CN, C1-3 aliphatic, or —O—C1-3 aliphatic;
• or two occurrences of Rbx are taken together to form a 5 or 6 membered cycloaliphatic or heterocyclic ring, having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, which is further optionally substituted with one occurrence of ═O and optionally substituted with one occurrence of R8;
• each occurrence of Rdx is independently —Cl, —OH, —CN, —NO2, C1-4 aliphatic, —O—C1-3 aliphatic, C1-3 fluoroaliphatic, —O—C1-3 fluoroaliphatic, —S—C1-3 aliphatic, —S—C1-3 fluoroaliphatic, —N(Re)2, —C(O)—N(Re)2, —SO2CH3, —S(O)CH3, or —O—CH2-phenyl wherein the phenyl ring is optionally substituted with 1 or 2 independent occurrences of halo, —CN, C1-3 aliphatic, or —O—C1-3 aliphatic;
• or two occurrences of Rdx are taken together to form a 5 or 6 membered cycloaliphatic or heterocyclic ring, having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, which is further optionally substituted with one occurrence of ═O and optionally substituted with one occurrence of R8;
• each occurrence of Rfx is independently —OH, —CN, —NO2, C1-4 aliphatic, —O—C1-3 aliphatic, C1-3 fluoroaliphatic, —O—C1-3 fluoroaliphatic, —S—C1-3 aliphatic, —S—C1-3 fluoroaliphatic, —N(Re)2, —C(O)—N(Re)2, —SO2CH3, —S(O)CH3, or —O—CH2-phenyl wherein the phenyl ring is optionally substituted with 1 or 2 independent occurrences of halo, —CN, C1-3 aliphatic, or —O—C1-3 aliphatic;
• or two occurrences of Rfx are taken together to form a 5 or 6 membered cycloaliphatic or heterocyclic ring, having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, which is further optionally substituted with one occurrence of ═O and optionally substituted with one occurrence of Rg;
• Rg is C1-3 aliphatic;
• and
• Re is hydrogen or C1-3 aliphatic.