Pyrimidine compounds that inhibit anaplastic lymphoma kinase

A compound of Formula I:

• or a pharmaceutically acceptable salt thereof, a stereoisomer thereof, a pharmaceutically acceptable salt of the stereoisomer, or a mixture thereof,
• wherein:
• X is selected from —CH2—, —N(H)—, —O—, or —S—;
• V is absent or is selected from —CH2—, —O—, —S—, or —NH—;
• wherein if V is —O—, —S—, or —NH—, then r is 1 and q is 1;
• the subscript p is selected from 0, 1, 2, or 3, wherein X is CH2 if p is 0;
• the subscript q is selected from 0 or 1;
• the subscript r is selected from 0 or 1:
• the symbol indicates that the bond can be a single or double bond;
• Z is a C6-C10 aryl or a 5-10 membered heteroaryl comprising 1, 2, 3, or 4 heteroatoms independently selected from O, S, or N, wherein the C6-C10 aryl or the 5-10 membered heteroaryl are unsubstituted or are optionally substituted with 1, 2, 3, or 4 substituents independently selected from —Z′, —O—Z′, —S—Z′, —NH—Z′, —CH2Z′, —F, —Cl, —Br, —I, —C≡N, —NO2, —(C1-C6)alkyl, —(C2-C6)alkenyl, —(C2-C6)alkynyl, —(C1-C4)alkylene-OH, —NH2, —NH((C1-C4)alkyl), —N((C1-C4)alkyl)2, —C(═O)NH2, —C(═O)NH((C1-C4)alkyl), —C(═O)N((C1-C4)alkyl)2, —C(═O)NH—Z′, —SO2NH2, —SO2NH((C1-C4)alkyl), —SO2N((C1-C4)alkyl)2, —SO2NH—Z′, —NHSO2—(C1-C4)alkyl, —NHSO2—Z′, —NHC(═O)—(C1-C4)alkyl, —NHC(═O)—Z′, —SO2—(C1-C4)alkyl, —SO2—Z′, —SO—(C1-C4)alkyl, —(C1-C4)alkylene-NH—C(═O)—(C1-C4)alkyl, —CF3, —C(═O)—(C1-C4)alkyl, —CO2H, —C(═O)—Z′, —C(═O)—O—(C1-C4)alkyl, —C(═O)NH—(C1-C4)alkylene-NH2, —C(═O)NH—(C1-C4)alkylene-NH((C1-C4)alkyl), —C(═O)NH—(C1-C4)alkylene-N((C1-C4)alkyl)2, —(C1-C4)alkylene-C(═O)—(C1-C4)alkyl, —(C1-C4)alkylene-C(═O)—O—(C1-C4)alkyl, —(C1-C4)alkylene-C(═O)—OH, —OH, —O—(C1-C6)alkyl, —SH, —S—(C1-C6)alkyl, —OCF3, or —OCHF2;
• and two adjacent substituents on the C6-C10 aryl or the 5-10 membered heteroaryl may join to form a 5 or 6 membered ring comprising 0, 1, or 2 heteroatoms selected from O, N, or S;
• and further wherein the C6-C10 aryl and the 5-10 membered heteroaryl may be monocyclic or bicyclic and further wherein both rings of a bicyclic C6-C10 aryl or a bicyclic 5-10 membered heteroaryl may be aromatic or one of the rings may be partially saturated and the other ring may be aromatic and either the partially saturated ring or the aromatic ring may be bonded to V, if present, or to the C atom bearing Rb and Rb′ if V is not present, or to the C atom bearing Ra and Ra′ if V is not present and q is 0, or to the N atom bonded to the C(═O) if V is not present, q is 0, and r is 0;
• and further wherein, the partially saturated ring of a bicyclic C6-C10 aryl or a bicyclic 5-10 membered heteroaryl may include a —C(═O)— ring member;
• Z′ is a C6-C10 aryl, a 5-10 membered heteroaryl comprising 1, 2, 3, or 4 heteroatoms independently selected from O, S, or N, or a 5-7 membered heterocyclyl comprising 1, 2, or 3 heteroatoms selected from O, S, or N, wherein the C6-C10 aryl, the 5-10 membered heteroaryl, or the 5-7 membered heterocyclyl are unsubstituted or are optionally substituted with 1 or 2 substituents independently selected from —F, —Cl, —Br, —I, —C≡N, —NO2, —(C1-C6)alkyl, —(C2-C6)alkenyl, —(C2-C6)alkynyl, —(C1-C4)alkylene-OH, —NH2, —NH((C1-C4)alkyl), —N((C1-C4)alkyl)2, —C(═O)NH2, —C(═O)NH((C1-C4)alkyl), —C(═O)N((C1-C4)alkyl)2, —SO2NH2, —SO2NH((C1-C4)alkyl), —SO2N((C1-C4)alkyl)2, —NHSO2—(C1-C4)alkyl, —NHC(═O)—(C1-C4)alkyl, —SO2—(C1-C4)alkyl, —SO—(C1-C4)alkyl, —(C1-C4)alkylene-NH—C(═O)—(C1-C4)alkyl, —CF3, —C(═O)—(C1-C4)alkyl, —CO2H, —C(═O)—O—(C1-C4)alkyl, —C(═O)NH—(C1-C4)alkylene-NH2, —C(═O)NH—(C1-C4)alkylene-NH((C1-C4)alkyl), —C(═O)NH—(C1-C4)alkylene-N((C1-C4)alkyl)2, —(C1-C4)alkylene-C(═O)—(C1-C4)alkyl, —(C1-C4)alkylene-C(═O)—O—(C1-C4)alkyl, —(C1-C4)alkylene-C(═O)—OH, —OH, —O—(C1-C6)alkyl, —SH, —S—(C1-C6)alkyl, —OCF3, or —OCHF2;
• Ra and Ra′ are absent if r is 0 or are independently selected from —H, —(C1-C6)alkyl, —C≡N, —OH, or —CF3;
• or Ra and Ra′ may together represent a ═O;
• or Ra and Ra′ may join together with the carbon atom to which they are attached to form a cycloalkyl ring having from 3 to 6 members;
• Rb and Rb′ are absent if q is 0 or are independently selected from —H, —(C1-C6)alkyl, —C≡N, —OH, or —CF3;
• or Rb and Rb′ may together represent a ═O;
• or Rb and Rb′ may join together with the carbon atom to which they are attached to form a cycloalkyl ring having from 3 to 6 members;
• Rc is selected from —H, —(C1-C6)alkyl, —CF3, —F, —Cl, —Br, or —I;
• Rd is selected from —H, —(C1-C6)alkyl, —CF3, —F, —Cl, —Br, or —I;
• Re and Re′ are independently selected from —H or —(C1-C6)alkyl;
• W is a C6-C10 aryl, a 5-10 membered heteroaryl comprising 1, 2, 3 or 4 heteroatoms independently selected from O, S, or N, or a 5-7 membered heterocyclyl comprising 1, 2, or 3 heteroatoms selected from O, S, or N, wherein the C6-C10 aryl, the 5-10 membered heteroaryl, or the 5-7 membered heterocyclyl are unsubstituted or are optionally substituted with 1, 2, 3, or 4 substituents independently selected from —W′, —O—W′, —S—W′, —CH2—W′, —N(H)—W′, —O—CH2-W′, —C(═O)—W′, —C(═O)NH—W′, —SO2NH—W′, —NHSO2—W′, —NHC(═O)—W′, —SO2—W′, —F, —Cl, —Br, —I, —C≡N, —NO2, —(C1-C6)alkyl, —(C2-C6)alkenyl, —(C2-C6)alkynyl, —(C1-C4)alkylene-OH, —NH2, —NH((C1-C4)alkyl), —N((C1-C4)alkyl)2, —C(═O)NH2, —C(═O)NH((C1-C4)alkyl), —C(═O)N((C1-C4)alkyl)2, —SO2NH2, —SO2NH((C1-C4)alkyl), —SO2N((C1-C4)alkyl)2, —NHSO2—(C1-C4)alkyl, —NHC(═O)—(C1-C4)alkyl, —SO2—(C1-C4)alkyl, —SO—(C1-C4)alkyl, —(C1-C4)alkylene-NH—C(═O)—(C1-C4)alkyl, —CF3, —C(═O)—(C1-C4)alkyl, —CO2H, —C(═O)—O—(C1-C4)alkyl, —C(═O)NH—(C1-C4)alkylene-NH2, —C(═O)NH—(C1-C4)alkylene-NH((C1-C4)alkyl), —C(═O)NH—(C1-C4)alkylene-N((C1-C4)alkyl)2, —(C1-C4)alkylene-C(═O)—(C1-C4)alkyl, —(C1-C4)alkylene-C(═O)—O—(C1-C4)alkyl, —(C1-C4)alkylene-C(═O)—OH, —OH, —O—(C1-C6)alkyl, —SH, —S—(C1-C6)alkyl, —OCF3, or —OCHF2;
• and two adjacent substituents on the C6-C10 aryl or the 5-10 membered heteroaryl may join to form a 5 or 6 membered ring comprising 0, 1, or 2 heteroatoms selected from O, N, or S;
• and further wherein the C6-C10 aryl and the 5-10 membered heteroaryl may be monocyclic or bicyclic and further wherein both rings of a bicyclic C6-C10 aryl or a bicyclic 5-10 membered heteroaryl may be aromatic or one of the rings may be partially saturated and the other ring may be aromatic and either the partially saturated ring or the aromatic ring may be bonded to the N atom to which W is attached;
• and further wherein, the partially saturated ring of a bicyclic C6-C10 aryl or a bicyclic 5-10 membered heteroaryl may include a —C(═O)— ring member and the 5-7 membered heterocyclyl group may include a —C(═O)— ring member;
• and
• W′ is a C6-C10 aryl, a 5-10 membered heteroaryl comprising 1, 2, 3, or 4 heteroatoms independently selected from O, S, or N, or a 5-7 membered heterocyclyl comprising 1, 2, or 3 heteroatoms selected from O, S, or N, wherein the C6-C10 aryl, the 5-10 membered heteroaryl, or the 5-7 membered heterocyclyl are unsubstituted or are optionally substituted with 1 or 2 substituents independently selected from —F, —Cl, —Br, —I, —C≡N, —NO2, —(C1-C6)alkyl, —(C2-C6)alkenyl, —(C2-C6)alkynyl, —(C1-C4)alkylene-OH, —NH2, —NH((C1-C4)alkyl), —N((C1-C4)alkyl)2, —C(═O)NH2, —C(═O)NH((C1-C4)alkyl), —C(═O)N((C1-C4)alkyl)2, —SO2NH2, —SO2NH((C1-C4)alkyl), —SO2N((C1-C4)alkyl)2, —NHSO2—(C1-C4)alkyl, —NHC(═O)—(C1-C4)alkyl, —SO2—(C1-C4)alkyl, —SO—(C1-C4)alkyl, —(C1-C4)alkylene-NH—C(═O)—(C1-C4)alkyl, —CF3, —C(═O)—(C1-C4)alkyl, —CO2H, —C(═O)—O—(C1-C4)alkyl, —C(═O)NH—(C1-C4)alkylene-NH2, —C(═O)NH—(C1-C4)alkylene-NH((C1-C4)alkyl), —C(═O)NH—(C1-C4)alkylene-N((C1-C4)alkyl)2, —(C1-C4)alkylene-C(═O)—(C1-C4)alkyl, —(C1-C4)alkylene-C(═O)—O—(C1-C4)alkyl, —(C1-C4)alkylene-C(═O)—OH, —OH, —O—(C1-C6)alkyl, —SH, —S—(C1-C6)alkyl, —OCF3, or —OCHF2.