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1. A method for treating an ALK-driven cancer in a subject comprising the steps of:
a) providing a subject having an ALK-driven cancer characterized by the presence of a mutation in anaplastic lymphoma kinase (ALK), wherein said mutation is selected from mutations corresponding to the amino acid positions in SEQ ID NO: 2 for: (i) a substitution for isoleucine to threonine at amino acid position 1171; (ii) a substitution for phenylalanine to cysteine at amino acid position 1174; (iii) a substitution for leucine to methionine at amino acid position 1196; (iv) a substitution for serine with arginine at amino acid position 1206; (v) a substitution for glutamic acid to lysine at amino acid position 1210; (vi) a substitution for phenylalanine to cysteine at amino acid position 1245; (vii) a substitution for glycine to serine at amino acid position 1269; and (viii) a substitution for valine to leucine at amino acid position 1180; and b) administering to said subject a therapeutically effective amount of compound of formula (I), or a pharmaceutically acceptable salt thereof: wherein Rd is H, C1-4 alkyl, or halo; and Re is H; or Rd and Re, together with the pyrimidine ring atoms to which they are attached, form a 5- or 6-membered ring containing one, two or three heteroatoms, independently selected from N, S and O, wherein the 5- or 6-membered ring is substituted by Rh; Rh is H, C1-4 alkyl, or halo; Ra2 is H, C1-6 alkoxy, C3-6 alkenyloxy, or C3-6 cycloalkyloxy; Rg is —P(O)(R3A)(R3B); each of R3A and R3B is, independently, selected from H, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, and heteroalkyl, or R3A and R3B, together with the atoms to which they are attached, combine to form a 5- or 6-membered heterocyclic ring which is unsubstituted or substituted;
Rg2 is H, halo, CN, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, heteroalkyl, or, Rg2 and Rg together with the atoms to which they are attached form a 5- to 7-member heterocyclic ring comprising 1-3 hetero atoms independently selected from P, N, O and S, the heterocyclic ring being unsubstituted or substituted;Rg1 is H, F, or a 5 or 6 member heterocyclic ring comprising 1 or 2 N atoms, the heterocyclic ring being unsubstituted or substituted;Rb2 is H, F, or is a 5 or 6 member heterocyclic ring containing 1, 2 or 3 N or O atoms, the heterocyclic ring being unsubstituted or substituted;Rb4 is H, halo, CN, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, heteroalkyl, C1-6 alkoxy, C3-6 alkenyloxy, or C3-6 cycloalkyloxy, —OC(O)N(R5A)(R5B), —NR5CC(O)OR5D; a 5 or 6 member heterocyclic ring comprising 1, 2 or 3 N or O atoms, the heterocyclic ring being unsubstituted or substituted, or, Rb4 and Ra1 together with the atoms to which they are attached form a 6 member heterocyclic ring comprising 1, 2 or 3 N or O atoms which is unsubstituted or substituted;
each of R5A, R5B, R5C, and R5D is, independently, selected from H, alkyl, alkenyl, alkynyl, and heteroalkyl, or R5A and R5B, together with the atoms to which they are attached, combine to form a 5- or 6-membered heterocyclic ring which is unsubstituted or substituted;Ra1 combines with Rb4 to form a 6 member heterocyclic ring, or is H, halo, —CN, —NO2, —R1, —OR2, —O—NR1R2, —NR1R2, —NR1—NR1R2, —NR1—OR2, —C(O)YR2, —OC(O)YR2, —NR1C(O)YR2, —SC(O)YR2, —NR1C(═S)YR2, —OC(═S)YR2, —C(═S)YR2, —YC(═NR1)YR2, —YC(═N—OR1)YR2, —YC(═N—NR1R2)YR2, —YP(═O)(YR1)(YR2), —NR1SO2R2, —S(O)rR2,—SO2NR1R2, —NR1SO2NR1R2, or each Y is, independently, a bond, —O—, —S— or —NR1—; each occurrence of R1 and R2 is, independently, selected from H, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroalkyl, heterocyclic and heteroaryl; each of X1 and X2 is, independently, selected from CH and N; and R4 is selected from alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroalkyl, heterocyclic and heteroaryl. |
