Claims for Patent: 9,611,283

Summary for Patent: 9,611,283

Title:	Methods for inhibiting cell proliferation in ALK-driven cancers
Abstract:	The invention features a method for treating patients who have an ALK-driven cancer, which is, or has become, refractory to one or more of crizotinib, CH5424802 and ASP3026, or which bears an ALK mutation identified herein, by administering a compound of formula (I) to the patient. The invention also features methods, kits, and compositions for characterizing ALK-driven cancers to determine whether they express an ALK mutant.
Inventor(s):	Zhang; Sen (Newton, MA), Shakespeare; William C. (Southborough, MA), Rivera; Victor M. (Arlington, MA)
Assignee:	Ariad Pharmaceuticals, Inc. (Cambridge, MA)
Application Number:	14/249,483
Patent Claims:	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: ##STR00023## wherein R.sup.d is H, C.sub.1-4 alkyl, or halo; and R.sup.e is H; or R.sup.d and R.sup.e, 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 R.sup.h; R.sup.h is H, C.sub.1-4 alkyl, or halo; R.sup.a2 is H, C.sub.1-6 alkoxy, C.sub.3-6 alkenyloxy, or C.sub.3-6 cycloalkyloxy; R.sup.g is --P(O)(R.sup.3A)(R.sup.3B); each of R.sup.3A and R.sup.3B is, independently, selected from H, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, and heteroalkyl, or R.sup.3A and R.sup.3B, together with the atoms to which they are attached, combine to form a 5- or 6-membered heterocyclic ring which is unsubstituted or substituted; R.sup.g2 is H, halo, CN, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, heteroalkyl, or, R.sup.g2 and R.sup.g 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; R.sup.g1 is H, F, or a 5 or 6 member heterocyclic ring comprising 1 or 2 N atoms, the heterocyclic ring being unsubstituted or substituted; R.sup.b2 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; R.sup.b4 is H, halo, CN, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, heteroalkyl, C.sub.1-6 alkoxy, C.sub.3-6 alkenyloxy, or C.sub.3-6 cycloalkyloxy, --OC(O)N(R.sup.5A)(R.sup.5B), --NR.sup.5CC(O)OR.sup.5D; a 5 or 6 member heterocyclic ring comprising 1, 2 or 3 N or O atoms, the heterocyclic ring being unsubstituted or substituted, or, R.sup.b4 and R.sup.a1 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 R.sup.5A, R.sup.5B, R.sup.5C, and R.sup.5D is, independently, selected from H, alkyl, alkenyl, alkynyl, and heteroalkyl, or R.sup.5A and R.sup.5B, together with the atoms to which they are attached, combine to form a 5- or 6-membered heterocyclic ring which is unsubstituted or substituted; R.sup.a1 combines with R.sup.b4 to form a 6 member heterocyclic ring, or is H, halo, --CN, --NO.sub.2, --R.sup.1, --OR.sup.2, --O--NR.sup.1R.sup.2, --NR.sup.1R.sup.2, --NR.sup.1--NR.sup.1R.sup.2, --NR.sup.1--OR.sup.2, --C(O)YR.sup.2, --OC(O)YR.sup.2, --NR.sup.1C(O)YR.sup.2, --SC(O)YR.sup.2, --NR.sup.1C(.dbd.S)YR.sup.2, --OC(.dbd.S)YR.sup.2, --C(.dbd.S)YR.sup.2, --YC(.dbd.NR.sup.1)YR.sup.2, --YC(.dbd.N--OR.sup.1)YR.sup.2, --YC(.dbd.N--NR.sup.1R.sup.2)YR.sup.2, --YP(.dbd.O)(YR.sup.1)(YR.sup.2), --NR.sup.1SO.sub.2R.sup.2, --S(O).sub.rR.sup.2, --SO.sub.2NR.sup.1R.sup.2, --NR.sup.1SO.sub.2NR.sup.1R.sup.2, or ##STR00024## each Y is, independently, a bond, --O--, --S-- or --NR.sup.1--; each occurrence of R.sup.1 and R.sup.2 is, independently, selected from H, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroalkyl, heterocyclic and heteroaryl; each of X.sub.1 and X.sub.2 is, independently, selected from CH and N; and R.sup.4 is selected from alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroalkyl, heterocyclic and heteroaryl. 2. The method of claim 1, wherein said ALK is full-length ALK. 3. The method of claim 1, wherein said ALK is an ALK-fusion product. 4. A method for treating an ALK-driven cancer expressing an ALK-fusion protein in a subject comprising the steps of: a) providing a subject having an ALK-driven cancer characterized by the presence of a mutation in said ALK-fusion protein, wherein said mutation is selected from mutations corresponding to the amino acid positions in SEQ ID NO: 2 for: (i) a substitution for phenylalanine with valine at amino acid position 1174; and (ii) a substitution for tyrosine with serine at amino acid position 1278; and b) administering to said subject a therapeutically effective amount of compound of formula (I), or a pharmaceutically acceptable salt thereof: ##STR00025## wherein R.sup.d is H, C.sub.1-4 alkyl, or halo; and R.sup.e is H; or R.sup.d and R.sup.e, 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 R.sup.h; R.sup.h is H, C.sub.1-4 alkyl, or halo; R.sup.a2 is H, C.sub.1-6 alkoxy, C.sub.3-6 alkenyloxy, or C.sub.3-6 cycloalkyloxy; R.sup.g is --P(O)(R.sup.3A)(R.sup.3B); each of R.sup.3A and R.sup.3B, is, independently, selected from H, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, and heteroalkyl, or R.sup.3A and R.sup.3B, together with the atoms to which they are attached, combine to form a 5- or 6-membered heterocyclic ring which is unsubstituted or substituted; R.sup.g2 is H, halo, CN, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, heteroalkyl, or, R.sup.g2 and R.sup.g 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; R.sup.g1 is H, F, or a 5 or 6 member heterocyclic ring comprising 1 or 2 N atoms, the heterocyclic ring being unsubstituted or substituted; R.sup.b2 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; R.sup.b4 halo, CN, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, heteroalkyl, C.sub.1-6 alkoxy, C.sub.3-6 alkenyloxy, or C.sub.3-6 cycloalkyloxy, --OC(O)N(R.sup.5A)(R.sup.5B), --NR.sup.5CC(O)OR.sup.5D; a 5 or 6 member heterocyclic ring comprising 1, 2 or 3 N or O atoms, the heterocyclic ring being unsubstituted or substituted, or, R.sup.b4 and R.sup.a1 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 R.sup.5A, R.sup.5B, R.sup.5C, and R.sup.5D is, independently, selected from H, alkyl, alkenyl, alkynyl, and heteroalkyl, or R.sup.5A and R.sup.5B, together with the atoms to which they are attached, combine to form a 5- or 6-membered heterocyclic ring which is unsubstituted or substituted; R.sup.a1 combines with R.sup.b4 to form a 6 member heterocyclic ring, or is H, halo, --CN, --NO.sub.2, --R.sup.1, --OR.sup.2, --O--NR.sup.1R.sup.2, --NR.sup.1R.sup.2, --NR.sup.1--NR.sup.1R.sup.2, --NR.sup.1--OR.sup.2, --C(O)YR.sup.2, --OC(O)YR.sup.2, --NR.sup.1C(O)YR.sup.2, --SC(O)YR.sup.2, --NR.sup.1C(.dbd.S)YR.sup.2, --OC(.dbd.S)YR.sup.2, --C(.dbd.S)YR.sup.2, --YC(.dbd.NR.sup.1)YR.sup.2, --YC(.dbd.N--OR.sup.1)YR.sup.2, --YC(.dbd.N--NR.sup.1R.sup.2)YR.sup.2, --YP(.dbd.O)(YR.sup.1)(YR.sup.2), --NR.sup.1SO.sub.2R.sup.2, --S(O).sub.rR.sup.2, --SO.sub.2NR.sup.1R.sup.2, --NR.sup.1SO.sub.2NR.sup.1R.sup.2, or ##STR00026## each Y is, independently, a bond, --O--, --S-- or --NR.sup.1--; each occurrence of R.sup.1 and R.sup.2 is, independently, selected from H, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroalkyl, heterocyclic and heteroaryl; each of X.sub.1 and X.sub.2 is, independently, selected from CH and N; and R.sup.4 is selected from alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroalkyl, heterocyclic and heteroaryl. 5. A method of inhibiting the proliferation of a cell expressing an ALK mutant, wherein said ALK mutant is characterized by the presence of a mutation in anaplastic lymphoma kinase (ALK) selected from mutations corresponding to the amino acid positions in SEQ ID NO: 2 for: (i) a substitution for threonine to lysine at amino acid position 1151; (ii) a substitution for leucine to valine at amino acid position 1152; (iii) a substitution for cysteine to tyrosine at amino acid position 1156; (iv) a substitution for isoleucine with serine at amino acid position 1171; and (v) a substitution for glycine to cysteine, serine, or alanine at amino acid position 1269, said method comprising contacting said cell with a compound of formula (I), or a pharmaceutically acceptable salt thereof: ##STR00027## wherein R.sup.d is H, C.sub.1-4 alkyl, or halo; and R.sup.e is H; or R.sup.d and R.sup.e, together with the pyrimidine ring atoms to which they are attached, form a 5- or 6-membered ring containing one or two heteroatoms, independently selected from N, S and O, wherein the 5- or 6-membered ring is substituted by R.sup.h; R.sup.h is H, C.sub.1-4 alkyl, or halo; R.sup.a2 is H, C.sub.1-6 alkoxy, C.sub.3-6 alkenyloxy, or C.sub.3-6 cycloalkyloxy; R.sup.g is --P(O)(R.sup.3A)(R.sup.3B); each of R.sup.3A and R.sup.3B is, independently, selected from H, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, and heteroalkyl, or R.sup.3A and R.sup.3B, together with the atoms to which they are attached, combine to form a 5- or 6-membered heterocyclic ring which is unsubstituted or substituted; R.sup.g2 is H, halo, CN, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, heteroalkyl, or, R.sup.g2 and R.sup.g 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; R.sup.g1 is H, F, or a 5 or 6 member heterocyclic ring comprising 1 or 2 N atoms, the heterocyclic ring being unsubstituted or substituted; R.sup.b2 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; R.sup.b4 is H, halo, CN, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, heteroalkyl, C.sub.1-6 alkoxy, C.sub.3-6 alkenyloxy, or C.sub.3-6 cycloalkyloxy, --OC(O)N(R.sup.5A)(R.sup.5B), --NR.sup.5CC(O)OR.sup.5D; a 5 or 6 member heterocyclic ring comprising 1, 2 or 3 N or O atoms, the heterocyclic ring being unsubstituted or substituted, or, R.sup.b4 and R.sup.a1 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 R.sup.5A, R.sup.5B, R.sup.5C, and R.sup.5D is, independently, selected from H, alkyl, alkenyl, alkynyl, and heteroalkyl, or R.sup.5A and R.sup.5B, together with the atoms to which they are attached, combine to form a 5- or 6-membered heterocyclic ring which is unsubstituted or substituted; R.sup.a1 combines with R.sup.b4 to form a 6 member heterocyclic ring, or is H, halo, --CN, --NO.sub.2, --R.sup.1, --OR.sup.2, --O--NR.sup.1R.sup.2, --NR.sup.1R.sup.2, --NR.sup.1--NR.sup.1R.sup.2, --NR.sup.1--OR.sup.2, --C(O)YR.sup.2, --OC(O)YR.sup.2, --NR.sup.1C(O)YR.sup.2, --SC(O)YR.sup.2, --NR.sup.1C(.dbd.S)YR.sup.2, --OC(.dbd.S)YR.sup.2, --C(.dbd.S)YR.sup.2, --YC(.dbd.NR.sup.1)YR.sup.2, --YC(.dbd.N--OR.sup.1)YR.sup.2, --YC(.dbd.N--NR.sup.1R.sup.2)YR.sup.2, --YP(.dbd.O)(YR.sup.1)(YR.sup.2), --NR.sup.1SO.sub.2R.sup.2, --S(O).sub.rR.sup.2, --SO.sub.2NR.sup.1R.sup.2, --NR.sup.1SO.sub.2NR.sup.1R.sup.2, or ##STR00028## each Y is, independently, a bond, --O--, --S-- or --NR.sup.1--; each occurrence of R.sup.1 and R.sup.2 is, independently, selected from H, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroalkyl, heterocyclic and heteroaryl; each of X.sub.1 and X.sub.2 is, independently, selected from CH and N; and R.sup.4 is selected from alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroalkyl, heterocyclic and heteroaryl, in an amount sufficient to inhibit said proliferation. 6. A method of inhibiting the proliferation of a cell expressing a mutant ALK-fusion protein, wherein said mutant ALK-fusion protein is characterized by the presence of a mutation in said ALK-fusion protein selected from mutations corresponding to the amino acid positions in SEQ ID NO: 2 for: (i) a substitution for phenylalanine with valine at amino acid position 1174; and (ii) a substitution for tyrosine with serine at amino acid position 1278, said method comprising contacting said cell with a compound of formula (I), or a pharmaceutically acceptable salt thereof: ##STR00029## wherein R.sup.d is H, C.sub.1-4 alkyl, or halo; and R.sup.e is H; or R.sup.d and R.sup.e, 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 R.sup.h; R.sup.h is H, C.sub.1-4 alkyl, or halo; R.sup.a2 is H, C.sub.1-6 alkoxy, C.sub.3-6 alkenyloxy, or C.sub.3-6 cycloalkyloxy; R.sup.g is --P(O)(R.sup.3A)(R.sup.3B); each of R.sup.3A and R.sup.3B is, independently, selected from H, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, and heteroalkyl, or R.sup.3A and R.sup.3B, together with the atoms to which they are attached, combine to form a 5- or 6-membered heterocyclic ring which is unsubstituted or substituted; R.sup.g2 is H, halo, CN, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, heteroalkyl, or, R.sup.g2 and R.sup.g 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; R.sup.g1 is H, F, or a 5 or 6 member heterocyclic ring comprising 1 or 2 N atoms, the heterocyclic ring being unsubstituted or substituted; R.sup.b2 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; R.sup.b4 is H, halo, CN, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, heteroalkyl, C.sub.1-6 alkoxy, C.sub.3-6 alkenyloxy, or C.sub.3-6 cycloalkyloxy, --OC(O)N(R.sup.5A)(R.sup.5B), --NR.sup.5CC(O)OR.sup.5D; a 5 or 6 member heterocyclic ring comprising 1, 2 or 3 N or O atoms, the heterocyclic ring being unsubstituted or substituted, or, R.sup.b4 and R.sup.a1 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 R.sup.5A, R.sup.5B, R.sup.5C, and R.sup.5D is, independently, selected from H, alkyl, alkenyl, alkynyl, and heteroalkyl, or R.sup.5A and R.sup.5B, together with the atoms to which they are attached, combine to form a 5- or 6-membered heterocyclic ring which is unsubstituted or substituted; R.sup.a1 combines with R.sup.b4 to form a 6 member heterocyclic ring, or is H, halo, --CN, --NO.sub.2, --R.sup.1, --OR.sup.2, --O--NR.sup.1R.sup.2, --NR.sup.1R.sup.2, --NR.sup.1--NR.sup.1R.sup.2, --NR.sup.1--OR.sup.2, --C(O)YR.sup.2, --OC(O)YR.sup.2, --NR.sup.1C(O)YR.sup.2, --SC(O)YR.sup.2, --NR.sup.1C(.dbd.S)YR.sup.2, --OC(.dbd.S)YR.sup.2, --C(.dbd.S)YR.sup.2, --YC(.dbd.NR.sup.1)YR.sup.2, --YC(.dbd.N--OR.sup.1)YR.sup.2, --YC(.dbd.N--NR.sup.1R.sup.2)YR.sup.2, --YP(.dbd.O)(YR.sup.1)(YR.sup.2), --NR.sup.1SO.sub.2R.sup.2, --S(O).sub.rR.sup.2, --SO.sub.2NR.sup.1R.sup.2, --NR.sup.1SO.sub.2NR.sup.1R.sup.2, or ##STR00030## each Y is, independently, a bond, --O--, --S-- or --NR.sup.1--; each occurrence of R.sup.1 and R.sup.2 is, independently, selected from H, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroalkyl, heterocyclic and heteroaryl; each of X.sub.1 and X.sub.2 is, independently, selected from CH and N; and R.sup.4 is selected from alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroalkyl, heterocyclic and heteroaryl, in an amount sufficient to inhibit said proliferation. 7. A method of treating an ALK-driven cancer refractory to one or more of crizotinib, CH5424802 and ASP3026 in a subject, said method comprising administering to said subject a compound of formula I: ##STR00031## wherein R.sup.d is H, C.sub.1-4 alkyl, or halo; and R.sup.e is H; or R.sup.d and R.sup.e, 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 R.sup.h; R.sup.h is H, C.sub.1-4 alkyl, or halo; R.sup.a2 is H, C.sub.1-6 alkoxy, C.sub.3-6 alkenyloxy, or C.sub.3-6 cycloalkyloxy; R.sup.g is --P(O)(R.sup.3A)(R.sup.3B); each of R.sup.3A and R.sup.3B is, independently, selected from H, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, and heteroalkyl, or R.sup.3A and R.sup.3B, together with the atoms to which they are attached, combine to form a 5- or 6-membered heterocyclic ring which is unsubstituted or substituted; R.sup.g2 is H, halo, CN, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, heteroalkyl, or, R.sup.g2 and R.sup.g 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; R.sup.g1 is H, F, or a 5 or 6 member heterocyclic ring comprising 1 or 2 N atoms, the heterocyclic ring being unsubstituted or substituted; R.sup.b2 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; R.sup.b4 is H, halo, CN, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, heteroalkyl, C.sub.1-6 alkoxy, C.sub.3-6 alkenyloxy, or C.sub.3-6 cycloalkyloxy, --OC(O)N(R.sup.5A)(R.sup.5B), --NR.sup.5CC(O)OR.sup.5D; a 5 or 6 member heterocyclic ring comprising 1, 2 or 3 N or O atoms, the heterocyclic ring being unsubstituted or substituted, or, R.sup.b4 and R.sup.a1 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 R.sup.5A, R.sup.5B, R.sup.5C, and R.sup.5D is, independently, selected from H, alkyl, alkenyl, alkynyl, and heteroalkyl, or R.sup.5A and R.sup.5B, together with the atoms to which they are attached, combine to form a 5- or 6-membered heterocyclic ring which is unsubstituted or substituted; R.sup.a1 combines with R.sup.b4 to form a 6 member heterocyclic ring, or is H, halo, --CN, --NO.sub.2, --R.sup.1, --OR.sup.2, --O--NR.sup.1R.sup.2, --NR.sup.1R.sup.2, --NR.sup.1--NR.sup.1R.sup.2, --NR.sup.1--OR.sup.2, --C(O)YR.sup.2, --OC(O)YR.sup.2, --NR.sup.1C(O)YR.sup.2, --SC(O)YR.sup.2, --NR.sup.1C(.dbd.S)YR.sup.2, --OC(.dbd.S)YR.sup.2, --C(.dbd.S)YR.sup.2, --YC(.dbd.NR.sup.1)YR.sup.2, --YC(.dbd.N--OR.sup.1)YR.sup.2, --YC(.dbd.N--NR.sup.1R.sup.2)YR.sup.2, --YP(.dbd.O)(YR.sup.1)(YR.sup.2), --NR.sup.1SO.sub.2R.sup.2, --S(O).sub.rR.sup.2, --SO.sub.2NR.sup.1R.sup.2, --NR.sup.1SO.sub.2NR.sup.1R.sup.2, or ##STR00032## each Y is, independently, a bond, --O--, --S-- or --NR.sup.1--; each occurrence of R.sup.1 and R.sup.2 is, independently, selected from H, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroalkyl, heterocyclic and heteroaryl; each of X.sub.1 and X.sub.2 is, independently, selected from CH and N; and R.sup.4 is selected from alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroalkyl, heterocyclic and heteroaryl, or a pharmaceutically acceptable salt thereof, in an amount sufficient to treat said cancer, and wherein the term CH5424802 refers to the compound, ##STR00033## and the term ASP3026 refers to the compound, ##STR00034## 8. A method of treating an ALK-driven cancer in a subject intolerant to one or more of crizotinib, CH5424802 and ASP3026, said method comprising administering to said subject a compound of formula I: ##STR00035## wherein R.sup.d is H, C.sub.1-4 alkyl, or halo; and R.sup.e is H; or R.sup.d and R.sup.e, 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 R.sup.h; R.sup.h is H, C.sub.1-4 alkyl, or halo; R.sup.a2 is H, C.sub.1-6 alkoxy, C.sub.3-6 alkenyloxy, or C.sub.3-6 cycloalkyloxy; R.sup.g is --P(O)(R.sup.3A)(R.sup.3B); each of R.sup.3A and R.sup.3B is, independently, selected from H, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, and heteroalkyl, or R.sup.3A and R.sup.3B, together with the atoms to which they are attached, combine to form a 5- or 6-membered heterocyclic ring which is unsubstituted or substituted; R.sup.g2 is H, halo, CN, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, heteroalkyl, or, R.sup.g2 and R.sup.g 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; R.sup.g1 is H, F, or a 5 or 6 member heterocyclic ring comprising 1 or 2 N atoms, the heterocyclic ring being unsubstituted or substituted; R.sup.b2 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; R.sup.b4 is H, halo, CN, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, heteroalkyl, C.sub.1-6 alkoxy, C.sub.3-6 alkenyloxy, or C.sub.3-6 cycloalkyloxy, --OC(O)N(R.sup.5A)(R.sup.5B), --NR.sup.5CC(O)OR.sup.5D; a 5 or 6 member heterocyclic ring comprising 1, 2 or 3 N or O atoms, the heterocyclic ring being unsubstituted or substituted, or, R.sup.b4 and R.sup.a1 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 R.sup.5A, R.sup.5B, R.sup.5C, and R.sup.5D is, independently, selected from H, alkyl, alkenyl, alkynyl, and heteroalkyl, or R.sup.5A and R.sup.5B, together with the atoms to which they are attached, combine to form a 5- or 6-membered heterocyclic ring which is unsubstituted or substituted; R.sup.a1 combines with R.sup.b4 to form a 6 member heterocyclic ring, or is H, halo, --CN, --NO.sub.2, --R.sup.1, --OR.sup.2, --O--NR.sup.1R.sup.2, --NR.sup.1R.sup.2, --NR.sup.1--NR.sup.1R.sup.2, --NR.sup.1--OR.sup.2, --C(O)YR.sup.2, --OC(O)YR.sup.2, --NR.sup.1C(O)YR.sup.2, --SC(O)YR.sup.2, --NR.sup.1C(.dbd.S)YR.sup.2, --OC(.dbd.S)YR.sup.2, --C(.dbd.S)YR.sup.2, --YC(.dbd.NR.sup.1)YR.sup.2, --YC(.dbd.N--OR.sup.1)YR.sup.2, --YC(.dbd.N--NR.sup.1R.sup.2)YR.sup.2, --YP(.dbd.O)(YR.sup.1)(YR.sup.2), --NR.sup.1SO.sub.2R.sup.2, --S(O).sub.rR.sup.2, --SO.sub.2NR.sup.1R.sup.2, --NR.sup.1SO.sub.2NR.sup.1R.sup.2, or ##STR00036## each Y is, independently, a bond, --O--, --S-- or --NR.sup.1--; each occurrence of R.sup.1 and R.sup.2 is, independently, selected from H, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroalkyl, heterocyclic and heteroaryl; each of X.sub.1 and X.sub.2 is, independently, selected from CH and N; and R.sup.4 is selected from alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroalkyl, heterocyclic and heteroaryl, or a pharmaceutically acceptable salt thereof, in an amount sufficient to treat said cancer, and wherein the term CH5424802 refers to the compound, ##STR00037## and the term ASP3026 refers to the compound, ##STR00038## 9. A method of treating an ALK-driven cancer refractory to an inhibitor of wild-type ALK in a subject, said method comprising administering to said subject a compound of formula I: ##STR00039## wherein R.sup.d is H, C.sub.1-4 alkyl, or halo; and R.sup.e is H; or R.sup.d and R.sup.e, 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 R.sup.h; R.sup.h is H, C.sub.1-4 alkyl, or halo; R.sup.a2 is H, C.sub.1-6 alkoxy, C.sub.3-6 alkenyloxy, or C.sub.3-6 cycloalkyloxy; R.sup.g is --P(O)(R.sup.3A)(R.sup.3B); each of R.sup.3A and R.sup.3B is, independently, selected from H, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, and heteroalkyl, or R.sup.3A and R.sup.3B, together with the atoms to which they are attached, combine to form a 5- or 6-membered heterocyclic ring which is unsubstituted or substituted; R.sup.g2 is H, halo, CN, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, heteroalkyl, or, R.sup.g2 and R.sup.g 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; R.sup.g1 is H, F, or a 5 or 6 member heterocyclic ring comprising 1 or 2 N atoms, the heterocyclic ring being unsubstituted or substituted; R.sup.b2 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; R.sup.b4 is H, halo, CN, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, heteroalkyl, C.sub.1-6 alkoxy, C.sub.3-6 alkenyloxy, or C.sub.3-6 cycloalkyloxy, --OC(O)N(R.sup.5A)(R.sup.5B), --NR.sup.5CC(O)OR.sup.5D; a 5 or 6 member heterocyclic ring comprising 1, 2 or 3 N or O atoms, the heterocyclic ring being unsubstituted or substituted, or, R.sup.b4 and R.sup.a1 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 R.sup.5A, R.sup.5B, R.sup.5C, and R.sup.5D is, independently, selected from H, alkyl, alkenyl, alkynyl, and heteroalkyl, or R.sup.5A and R.sup.5B, together with the atoms to which they are attached, combine to form a 5- or 6-membered heterocyclic ring which is unsubstituted or substituted; R.sup.a1 combines with R.sup.b4 to form a 6 member heterocyclic ring, or is H, halo, --CN, --NO.sub.2, --R.sup.1, --OR.sup.2, --O--NR.sup.1R.sup.2, --NR.sup.1R.sup.2, --NR.sup.1--NR.sup.1R.sup.2, --NR.sup.1--OR.sup.2, --C(O)YR.sup.2, --OC(O)YR.sup.2, --NR.sup.1C(O)YR.sup.2, --SC(O)YR.sup.2, --NR.sup.1C(.dbd.S)YR.sup.2, --OC(.dbd.S)YR.sup.2, --C(.dbd.S)YR.sup.2, --YC(.dbd.NR.sup.1)YR.sup.2, --YC(.dbd.N--OR.sup.1)YR.sup.2, --YC(.dbd.N--NR.sup.1R.sup.2)YR.sup.2, --YP(.dbd.O)(YR.sup.1)(YR.sup.2), --NR.sup.1SO.sub.2R.sup.2, --S(O).sub.rR.sup.2, --SO.sub.2NR.sup.1R.sup.2, --NR.sup.1SO.sub.2NR.sup.1R.sup.2, or ##STR00040## each Y is, independently, a bond, --O--, --S-- or --NR.sup.1--; each occurrence of R.sup.1 and R.sup.2 is, independently, selected from H, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroalkyl, heterocyclic and heteroaryl; each of X.sub.1 and X.sub.2 is, independently, selected from CH and N; and R.sup.A is selected from alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroalkyl, heterocyclic and heteroaryl, or a pharmaceutically acceptable salt thereof, in an amount sufficient to treat said cancer. 10. 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), and (b) administering to said subject a therapeutically effective amount of compound 1, having the following structure, ##STR00041## or a pharmaceutically acceptable salt thereof. 11. The method of claim 10, wherein said ALK is full-length ALK. 12. The method of claim 10, wherein said ALK is an ALK-fusion product. 13. The method of claim 10, wherein said mutation is selected from mutations corresponding to the amino acid positions in SEQ ID NO: 2 for: (i) a substitution for threonine at amino acid position 1151; (ii) a substitution for leucine at amino acid position 1152; (iii) a substitution for cysteine at amino acid position 1156; (iv) a substitution for isoleucine at amino acid position 1171; (v) a substitution for phenylalanine at amino acid position 1174; (vi) a substitution for valine at amino acid position 1180; (vii) a substitution for arginine at amino acid position 1181; (viii) a substitution for leucine at amino acid position 1196; (ix) a substitution for leucine at amino acid position 1198; (x) a substitution for glycine at amino acid position 1202; (xi) a substitution for aspartic acid at amino acid position 1203; (xii) a substitution for serine at amino acid position 1206; (xiii) a substitution for glutamic acid at amino acid position 1210; (xiv) a substitution for glutamic acid at amino acid position 1241; (xv) a substitution for phenylalanine at amino acid position 1245; (xvi) a substitution for isoleucine at amino acid position 1268; (xvii) a substitution for glycine at amino acid position 1269; and (xviii) insertion of an amino acid following amino acid position 1151. 14. The method of claim 13, wherein said mutation is selected from mutations corresponding to the amino acid positions in SEQ ID NO: 2 for: (i) a substitution for leucine to arginine at amino acid position 1152; (ii) a substitution for cysteine to tyrosine at amino acid position 1156; (iii) a substitution for isoleucine to serine at amino acid position 1171; (iv) a substitution for isoleucine to asparagine at amino acid position 1171; (v) a substitution for isoleucine to threonine at amino acid position 1171; (vi) a substitution for phenylalanine to leucine at amino acid position 1174; (vii) a substitution for phenylalanine to cysteine at amino acid position 1174; (viii) a substitution for valine to leucine at amino acid position 1180; (ix) a substitution for leucine to methionine at amino acid position 1196; (x) a substitution for glycine to arginine at amino acid position 1202; (xi) a substitution for aspartic acid to asparagine at amino acid position 1203; (xii) a substitution for serine to tyrosine at amino acid position 1206; (xiii) a substitution for serine with arginine at amino acid position 1206; (xiv) a substitution for glutamic acid to lysine at amino acid position 1210; (xv) a substitution for phenylalanine to cysteine at amino acid position 1245; (xvi) a substitution for glycine to alanine at amino acid position 1269; (xvii) a substitution for glycine to serine at amino acid position 1269; and (xviii) insertion of threonine following position 1151. 15. 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 leucine to arginine at amino acid position 1152; (ii) a substitution for cysteine to tyrosine at amino acid position 1156; (iii) a substitution for isoleucine to serine at amino acid position 1171; (iv) a substitution for isoleucine to asparagine at amino acid position 1171; (v) a substitution for isoleucine to threonine at amino acid position 1171; (vi) a substitution for phenylalanine to leucine at amino acid position 1174; (vii) a substitution for phenylalanine to cysteine at amino acid position 1174; (viii) a substitution for valine to leucine at amino acid position 1180; (ix) a substitution for leucine to methionine at amino acid position 1196; (x) a substitution for aspartic acid to asparagine at amino acid position 1203; (xi) a substitution for serine with arginine at amino acid position 1206; (xii) a substitution for glutamic acid to lysine at amino acid position 1210; (xiii) a substitution for phenylalanine to cysteine at amino acid position 1245; (xiv) a substitution for glycine to alanine at amino acid position 1269; and (xv) a substitution for glycine to serine at amino acid position 1269; and b) administering to said subject a therapeutically effective amount of compound of formula (I), or a pharmaceutically acceptable salt thereof: ##STR00042## wherein R.sup.d is H, C.sub.1-4 alkyl, or halo; and R.sup.e is H; or R.sup.d and R.sup.e, 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 R.sup.h; R.sup.h is H, C.sub.1-4 alkyl, or halo; R.sup.a2 is H, C.sub.1-6 alkoxy, C.sub.3-6 alkenyloxy, or C.sub.3-6 cycloalkyloxy; R.sup.g is --P(O)(R.sup.3A)(R.sup.3B); each of R.sup.3A and R.sup.3B is, independently, selected from H, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, and heteroalkyl, or R.sup.3A and R.sup.3B, together with the atoms to which they are attached, combine to form a 5- or 6-membered heterocyclic ring which is unsubstituted or substituted; R.sup.g2 is H, halo, CN, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, heteroalkyl, or, R.sup.g2 and R.sup.g 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; R.sup.g1 is H, F, or a 5 or 6 member heterocyclic ring comprising 1 or 2 N atoms, the heterocyclic ring being unsubstituted or substituted; R.sup.b2 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; R.sup.b4 is H, halo, CN, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, heteroalkyl, C.sub.1-6 alkoxy, C.sub.3-6 alkenyloxy, or C.sub.3-6 cycloalkyloxy, --OC(O)N(R.sup.5A)(R.sup.5B), --NR.sup.5CC(O)OR.sup.5D; a 5 or 6 member heterocyclic ring comprising 1, 2 or 3 N or O atoms, the heterocyclic ring being unsubstituted or substituted, or, R.sup.b4 and R.sup.a1 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 R.sup.5A, R.sup.5B, R.sup.5C, and R.sup.5D is, independently, selected from H, alkyl, alkenyl, alkynyl, and heteroalkyl, or R.sup.5A and R.sup.5B, together with the atoms to which they are attached, combine to form a 5- or 6-membered heterocyclic ring which is unsubstituted or substituted; R.sup.a1 combines with R.sup.b4 to form a 6 member heterocyclic ring, or is H, halo, --CN, --NO.sub.2, --R.sup.1, --OR.sup.2, --O--NR.sup.1R.sup.2, --NR.sup.1R.sup.2, --NR.sup.1--NR.sup.1R.sup.2, --NR.sup.1--OR.sup.2, --C(O)YR.sup.2, --OC(O)YR.sup.2, --NR.sup.1C(O)YR.sup.2, --SC(O)YR.sup.2, --NR.sup.1C(.dbd.S)YR.sup.2, --OC(.dbd.S)YR.sup.2, --C(.dbd.S)YR.sup.2, --YC(.dbd.NR.sup.1)YR.sup.2, --YC(.dbd.N--OR.sup.1)YR.sup.2, --YC(.dbd.N--NR.sup.1R.sup.2)YR.sup.2, --YP(.dbd.O)(YR.sup.1)(YR.sup.2), --NR.sup.1SO.sub.2R.sup.2, --S(O).sub.rR.sup.2, --SO.sub.2NR.sup.1R.sup.2, --NR.sup.1SO.sub.2NR.sup.1R.sup.2, or ##STR00043## each Y is, independently, a bond, --O--, --S-- or --NR.sup.1--; each occurrence of R.sup.1 and R.sup.2 is, independently, selected from H, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroalkyl, heterocyclic and heteroaryl; each of X.sub.1 and X.sub.2 is, independently, selected from CH and N; and R.sup.4 is selected from alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroalkyl, heterocyclic and heteroaryl. 16. The method of claim 15, wherein said ALK is full-length ALK. 17. The method of claim 15, wherein said ALK is an ALK-fusion product.