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Claims for Patent: 9,029,533

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Claims for Patent: 9,029,533

Title:Substituted acetylenic imidazo[1,2-A]pyridazines as kinase inhibitors
Abstract: This invention relates to compounds of the general formula: ##STR00001## in which the variable groups are as defined herein, and to their preparation and use.
Inventor(s): Zou; Dong (Concord, MA), Huang; Wei-Sheng (Acton, MA), Thomas; R. Mathew (Sharon, MA), Romero; Jan Antoinette C. (Somerville, MA), Qi; Jiwei (West Roxbury, MA), Wang; Yihan (Newton, MA), Zhu; Xiaotian (Newton, MA), Shakespeare; William C. (Southborough, MA), Sundaramoorthi; Rajeswari (Watertown, MA), Metcalf, III; Chester A. (Needham, MA), Dalgarno; David C. (Brookline, MA), Sawyer; Tomi K. (Southborough, MA)
Assignee: ARIAD Pharmaceuticals, Inc. (Cambridge, MA)
Application Number:13/801,116
Patent Claims: 1. A method for treating a leukemia in a subject in need thereof comprising administering to the subject a therapeutically effective amount of a compound of Formula I: ##STR00167## or a tautomer, or an individual stereoisomer or a mixture of stereoisomers thereof wherein: Ring A represents a 5- or 6-membered aryl or heteroaryl ring and is optionally substituted with 1-4 R.sup.a groups; Ring B represents a 5- or 6-membered aryl or heteroaryl ring; L.sup.1 is selected from NR.sup.1C(O), C(O)NR.sup.1, NR.sup.1C(O)O, NR.sup.1C(O)NR.sup.1, and OC(O)NR.sup.1; each occurrence of R.sup.a and R.sup.b is independently selected from the group consisting of halo, --CN, --NO.sub.2, --R.sup.4, --OR.sup.2, --NR.sup.2R.sup.3, --C(O)YR.sup.2, --OC(O)YR.sup.2, --NR.sup.2C(O)YR.sup.2, --SC(O)YR.sup.2, --NR.sup.2C(.dbd.S)YR.sup.2, --OC(.dbd.S)YR.sup.2, --C(.dbd.S)YR.sup.2, --YC(.dbd.NR.sup.3)YR.sup.2, --YP(.dbd.O)(YR.sup.4)(YR.sup.4), --Si(R.sup.2).sub.3, --NR.sup.2SO.sub.2R.sup.2, --S(O).sub.rR.sup.2, --SO.sub.2NR.sup.2R.sup.3 and --NR.sup.2SO.sub.2NR.sup.2R.sup.3, wherein each Y is independently a bond, --O--, --S-- or --NR.sup.3--; R.sup.e, at each occurrence, is independently selected from the group consisting of halo, .dbd.O, --CN, --NO.sub.2, --R.sup.4, --OR.sup.2, --NR.sup.2R.sup.3, --C(O)YR.sup.2, --OC(O)YR.sup.2, --NR.sup.2C(O)YR.sup.2, --SC(O)YR.sup.2, --NR.sup.2C(.dbd.S)YR.sup.2, --OC(.dbd.S)YR.sup.2, --C(.dbd.S)YR.sup.2, --YC(.dbd.NR.sup.3)YR.sup.2, --YP(.dbd.O)(YR.sup.4)(YR.sup.4), --Si(R.sup.2).sub.3, --NR.sup.2SO.sub.2R.sup.2, --S(O).sub.rR.sup.2, --SO.sub.2NR.sup.2R.sup.3 and --NR.sup.2SO.sub.2NR.sup.2R.sup.3, wherein each Y is independently a bond, --O--, --S-- or --NR.sup.3--; R.sup.1, R.sup.2 and R.sup.3 are independently selected from H, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heterocyclyl and heteroaryl; or R.sup.2 and R.sup.3, taken together with the atom to which they are attached, form a 5- or 6-membered saturated, partially saturated or unsaturated ring, which contains 0-2 heteroatoms selected from N, O and S(O).sub.r; each occurrence of R.sup.4 is independently selected from alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heterocyclyl and heteroaryl; each of the alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heterocyclyl and heteroaryl moieties is optionally substituted with one or more groups selected from the group consisting of halo, --CN, --R.sup.4, --OR.sup.2, --S(O).sub.rR.sup.2, --SO.sub.2NR.sup.2R.sup.3, --NR.sup.2R.sup.3, --(CO)YR.sup.2, --O(CO)YR.sup.2, --NR.sup.2(CO)YR.sup.2, --S(CO)YR.sup.2, --NR.sup.2C(.dbd.S)YR.sup.2, --OC(.dbd.S)YR.sup.2, --C(.dbd.S)YR.sup.2, --YC(.dbd.NR.sup.3)Y'R.sup.2, --COCOR.sup.2, --COMCOR.sup.2, --YP(.dbd.O)(YR.sup.4)(YR.sup.4), --Si(R.sup.2).sub.3, --NO.sub.2, --NR.sup.2SO.sub.2R.sup.2, --NR.sup.2SO.sub.2NR.sup.2R.sup.3, .dbd.O, .dbd.S, .dbd.NH, .dbd.NNR.sup.2R.sup.3, .dbd.NNHC(O)R.sup.2, .dbd.NNHCO.sub.2R.sup.2, and .dbd.NNHSO.sub.2R.sup.2, wherein M is a 1-6 carbon alkyl group; each of the aryl and heteroaryl moieties is optionally substituted on an unsaturated carbon atom with one or more groups selected from the group consisting of halo, --CN, --R.sup.4, --OR.sup.2, --S(O).sub.rR.sup.2, --SO.sub.2NR.sup.2R.sup.3, --NR.sup.2R.sup.3, --(CO)YR.sup.2, --O(CO)YR.sup.2, --NR.sup.2(CO)YR.sup.2, --S(CO)YR.sup.2, --NR.sup.2C(.dbd.S)YR.sup.2, --OC(.dbd.S)YR.sup.2, --C(.dbd.S)YR.sup.2, --YC(.dbd.NR.sup.3)Y'R.sup.2, --COCOR.sup.2, --COMCOR.sup.2, --YP(.dbd.O)(YR.sup.4)(YR.sup.4), --Si(R.sup.2).sub.3, --NO.sub.2, --NR.sup.2SO.sub.2R.sup.2, and --NR.sup.2SO.sub.2NR.sup.2R.sup.3; m is 0,1, 2, 3 or 4; p is 0, 1, 2, 3, 4 or 5; r is 0, 1 or 2; and s is 0, 1, 2, or 3; or a pharmaceutically acceptable salt thereof.

2. A method according to claim 1, wherein the leukemia is chronic myeloid leukemia.

3. A method according to claim 1, wherein the leukemia is acute lymphoblastic leukemia.

4. A method according to claim 1, wherein the leukemia results from a mutation in the Bcr-Abl kinase domain.

5. A method according to claim 1, wherein the compound of Formula I is selected from the group consisting of: (R)-N-(4((3-(Dimethylamino)pyrrolidin-1-yl)methyl)-3-(trifluoromethy)phen- yl)-3-(imidazo[1,2-b]pyridazin-3-ylethynyl)-4-methylbenzamide; N-(3-(Imidazo[1,2-b]pyridazin-3-ylethynyl)-4-methylphenyl)-4-((4-methylpi- perazin-1-yl)methyl)-3-(trifluoromethy)benzamide; 3-(Imidazo [1,2-b]pyridazin-3-ylethynyl)-4-methyl-N-(4-((4-methylpiperazin-1-yl)meth- yl)-3-((trifluoromethyl)phenyl)benzamide; N-(3--Chloro-4-((4-methylpiperazin-1-yl)methyl)phenyl)-3-(imidazo[1,2-b]p- yridazin-3-ylethynyl)-4-methylbenzamide; N-(3--Cyclopropyl-4-((4-methylpiperazin-1-)methyl)phenyl)-3-(imidazo[1,2-- b]pyridazin-3-ylethynyl)-4-methylbenzamide; 3-(Imidazo[1,2-b]pyridazin-3-ylethynyl)-N-(4-((4-methylpiperazin-1-yl)met- hyl)-3-(trifluoromethyl)phenyl)benzamide; N-(4-((4-(2-Hydroxyethyl)piperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl- )-3-(imidazo[1,2-b]pyridazin-3-ylethynyl)-4-methylbenzamide; and 3-(Imidazo[1,2-b]pyridazin-3-ylethynyl)-4-methyl-N-(4-(piperazin-1-ylmeth- yl)-3-(trifluoromethyl)phenyl)benzamide, or a pharmaceutically acceptable salt thereof.

6. A method for treating a leukemia in a subject in need thereof comprising administering to the subject a therapeutically effective amount of 3-(Imidazo[1,2-b]pyridazin-3-ylethynyl)-4-methyl-N-(4-((4-methy- lpiperazin-1-yl)methyl)-3-((trifluoromethyl)phenyl)benzamide, or a pharmaceutically acceptable salt thereof.

7. A method according to claim 6, wherein the leukemia is chronic myeloid leukemia.

8. A method according to claim 6, wherein the leukemia is acute lymphoblastic leukemia.

9. A method according to claim 6, wherein the leukemia results from a mutation in the Bcr-Abl kinase domain.

10. A method for treating a leukemia in a subject in need thereof comprising administering to the subject a therapeutically effective amount of 3-(Imidazo[1,2-b]pyridazin-3-ylethynyl)-4-methyl-N-(4-((4-methy- lpiperazin-1-yl)methyl)-3-((trifluoromethyl)phenyl)benzamide.

11. A method for treating a leukemia in a subject in need thereof comprising administering to the subject a therapeutically effective amount of a hydrochloride salt of 3-(Imidazo[1,2-b]pyridazin-3-ylethynyl)-4-methyl-N-(4-((4-methylpiperazin- -1-yl)methyl)-3-((trifluoromethyl)phenyl)benzamide.

12. A method for treating chronic myeloid leukemia in a subject in need thereof comprising administering to the subject a therapeutically effective amount of 3-(Imidazo[1,2-b]pyridazin-3-ylethynyl)-4-methyl-N-(4-((4-methylpiperazin- -1-yl)methyl)-3-((trifluoromethyl)phenyl)benzamide.

13. A method for treating chronic myeloid leukemia in a subject in need thereof comprising administering to the subject a therapeutically effective amount of 3-(Imidazo[1,2-b]pyridazin-3-ylethynyl)-4-methyl-N-(4-((4-methylpiperazin- -1-yl)methyl)-3-((trifluoromethyl)phenyl)benzamide, or a pharmaceutically acceptable salt thereof.

14. A method for treating chronic myeloid leukemia in a subject in need thereof comprising administering to the subject a therapeutically effective amount of a hydrochloride salt of 3-(Imidazo[1,2-b]pyridazin-3-ylethynyl)-4-methyl-N-(4-((4-methylpiperazin- -1-yl)methyl)-3-((trifluoromethyl)phenyl)benzamide.

15. A method for treating Philadelphia chromosome positive acute lymphoblastic leukemia in a subject in need thereof comprising administering to the subject a therapeutically effective amount of 3-(Imidazo[1,2-b]pyridazin-3-ylethynyl)-4-methyl-N-(4-((4-methylpiperazin- -1-yl)methyl)-3-((trifluoromethyl)phenyl)benzamide.

16. A method for treating Philadelphia chromosome positive acute lymphoblastic leukemia in a subject in need thereof comprising administering to the subject a therapeutically effective amount of 3-(Imidazo[1,2-b]pyridazin-3-ylethynyl)-4-methyl-N-(4-((4-methylpiperazin- -1-yl)methyl)-3-((trifluoromethyl)phenyl)benzamide, or a pharmaceutically acceptable salt thereof.

17. A method for treating Philadelphia chromosome positive acute lymphoblastic leukemia in a subject in need thereof comprising administering to the subject a therapeutically effective amount of a hydrochloride salt of 3-(Imidazo[1,2-b]pyridazin-3-ylethynyl)-4-methyl-N-(4-((4-methylpiperazin- -1-yl)methyl)-3-((trifluoromethyl)phenyl)benzamide.
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