Claims for Patent: 9,029,533

Summary 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: in which the variable groups are as defined herein, and to their preparation and use.
Inventor(s):	Dong Zou, Wei-Sheng Huang, R. Mathew Thomas, Jan Antoinette C. Romero, Jiwei Qi, Yihan Wang, Xiaotian Zhu, William C. Shakespeare, Rajeswari Sundaramoorthi, Chester A. Metcalf, III, David C. Dalgarno, Tomi K. Sawyer
Assignee:	Takeda Pharmaceuticals USA Inc
Application Number:	US13/801,116
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: 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 Ra groups; Ring B represents a 5- or 6-membered aryl or heteroaryl ring; L1 is selected from NR1C(O), C(O)NR1, NR1C(O)O, NR1C(O)NR1, and OC(O)NR1; each occurrence of Ra and Rb is independently selected from the group consisting of halo, —CN, —NO2, —R4, —OR2, —NR2R3, —C(O)YR2, —OC(O)YR2, —NR2C(O)YR2, —SC(O)YR2, —NR2C(═S)YR2, —OC(═S)YR2, —C(═S)YR2, —YC(═NR3)YR2, —YP(═O)(YR4)(YR4), —Si(R2)3, —NR2SO2R2, —S(O)rR2, —SO2NR2R3 and —NR2SO2NR2R3, wherein each Y is independently a bond, —O—, —S— or —NR3—; Re, at each occurrence, is independently selected from the group consisting of halo, ═O, —CN, —NO2, —R4, —OR2, —NR2R3, —C(O)YR2, —OC(O)YR2, —NR2C(O)YR2, —SC(O)YR2, —NR2C(═S)YR2, —OC(═S)YR2, —C(═S)YR2, —YC(═NR3)YR2, —YP(═O)(YR4)(YR4), —Si(R2)3, —NR2SO2R2, —S(O)rR2, —SO2NR2R3 and —NR2SO2NR2R3, wherein each Y is independently a bond, —O—, —S— or —NR3—; R1, R2 and R3 are independently selected from H, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heterocyclyl and heteroaryl; or R2 and R3, 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)r; each occurrence of R4 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, —R4, —OR2, —S(O)rR2, —SO2NR2R3, —NR2R3, —(CO)YR2, —O(CO)YR2, —NR2(CO)YR2, —S(CO)YR2, —NR2C(═S)YR2, —OC(═S)YR2, —C(═S)YR2, —YC(═NR3)Y′R2, —COCOR2, —COMCOR2, —YP(═O)(YR4)(YR4), —Si(R2)3, —NO2, —NR2SO2R2, —NR2SO2NR2R3, ═O, ═S, ═NH, ═NNR2R3, ═NNHC(O)R2, ═NNHCO2R2, and ═NNHSO2R2, 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, —R4, —OR2, —S(O)rR2, —SO2NR2R3, —NR2R3, —(CO)YR2, —O(CO)YR2, —NR2(CO)YR2, —S(CO)YR2, —NR2C(═S)YR2, —OC(═S)YR2, —C(═S)YR2, —YC(═NR3)Y′R2, —COCOR2, —COMCOR2, —YP(═O)(YR4)(YR4), —Si(R2)3, —NO2, —NR2SO2R2, and —NR2SO2NR2R3; 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)phenyl)-3-(imidazo[1,2-b]pyridazin-3-ylethynyl)-4-methylbenzamide; N-(3-(Imidazo[1,2-b]pyridazin-3-ylethynyl)-4-methylphenyl)-4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethy)benzamide; 3-(Imidazo [1,2-b]pyridazin-3-ylethynyl)-4-methyl-N-(4-((4-methylpiperazin-1-yl)methyl)-3-((trifluoromethyl)phenyl)benzamide; N-(3—Chloro-4-((4-methylpiperazin-1-yl)methyl)phenyl)-3-(imidazo[1,2-b]pyridazin-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)methyl)-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-ylmethyl)-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-methylpiperazin-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-methylpiperazin-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.