Claims for Patent: 8,114,874

Summary for Patent: 8,114,874

Title:	Substituted acetylenic imidazo[1,2-B]pyridazine compounds 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. In particular, the compounds include embodiments in which Ring T is an imidazo[1,2-b]pyridazine ring system, Rings A and B are each aryl and L1 is —C(O)NR1— or —NR1C(O)—. Uses for the compounds and for compositions containing them include treatment of cancer and other diseases mediated by protein kinases.
Inventor(s):	Dong Zou, Wei-Sheng Huang, R. Mathew Thomas, Jan Antionette 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:	US11/644,849
Patent Litigation and PTAB cases:	See patent lawsuits and PTAB cases for patent 8,114,874
Patent Claims:	1. A compound of formula: wherein: L1 is NR1C(O) or C(O)NR1; Ring D represents a 5- or 6-membered heterocyclic or heteroaryl ring comprising carbon atoms and 1-3 heteroatoms independently selected from O, N and S(O)r; Ring C is a 5- or 6-membered heterocyclic or heteroaryl ring, comprising carbon atoms and 1-3 heteroatoms independently selected from O, N and S(O)r; L2 is —(CH2)z—; each occurrence of Ra is independently selected from the group consisting of halo, alkyl and cycloalkyl; each occurrence of Rb is independently selected from the group consisting of halo, alkyl and cycloalkyl; each occurrence of Rc is independently selected from the group consisting of halo, alkyl and cycloalkyl; each occurrence of Rd is independently selected from the group consisting of halo, alkyl and cycloalkyl and —NR2R3; each occurrence of Re is independently selected from the group consisting of halo, alkyl, cycloalkyl, —NR2R3, alkoxy, amino, —NH-alkyl, —C(O)NH-alkyl, —NHC(O)-alkyl, —NHC(O)NH-alkyl, —NHC(NH)-alkyl, —NHC(NH)NH2, —NH(CH2)x-heteroaryl, —NH(CH2)x-heterocyclyl, —NH(CH2)x-aryl, and —(CH2)xC(O)NH2, wherein x is 0, 1, 2 or 3; each of R1, R2 and R3 is independently selected from H, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heterocyclyl, and heteroaryl, or R2 and R3, taken together with the nitrogen atom to which at least one of R2 and R3 is attached, form a 5- or 6-membered heterocyclyl or heteroaryl ring; each of the alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, and heterocyclyl moieties is unsubstituted or substituted with one or more groups selected from amino, alkylamino, dialkylamino, aminocarbonyl, halogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, carbocyclyl, heterocyclyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylaminocarbonyloxy, dialkylaminocarbonyloxy, nitro, cyano, carboxy, alkoxycarbonyl, alkylcarbonyl, hydroxy, alkoxy, acyloxy, haloalkoxy, ═O, ═S, ═NH, ═NNR2R3, ═NNHC(O)R2, ═NNHCO2R2, and ═NNHSO2R2, and each of the aryl and heteroaryl moieties is unsubstituted or substituted with one or more groups selected from amino, alkylamino, dialkylamino, aminocarbonyl, halogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, carbocyclyl, heterocyclyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylaminocarbonyloxy, dialkylaminocarbonyloxy, nitro, cyano, carboxy, alkoxycarbonyl, alkylcarbonyl, hydroxy, alkoxy, acyloxy, and haloalkoxy; m is 0, 1, 2, 3, or 4; p is 0, 1, 2, 3, or 4; r is 0, 1, or 2; s is 0, 1, 2, or 3; v is 0, 1, 2, 3, 4, or 5; w is 0, 1, 2, 3, 4, or 5; and z is 1, 2, 3 or 4; or a pharmaceutically acceptable salt thereof. 2. The compound of claim 1 of the formula: wherein: L1 is NR1C(O) or C(O)NR1; Ring C is a 5-or 6-membered heterocyclyl or heteroaryl ring, comprising carbon atoms and 1-3 heteroatoms independently selected from O, N, and S(O)r; each occurrence of Ra is independently selected from the group consisting of halo, alkyl, and cycloalkyl; each occurrence of Rb is independently selected from the group consisting of halo, alkyl, and cycloalkyl; each occurrence of Rc is independently selected from the group consisting of halo, alkyl, and cycloalkyl; each occurrence of Re is independently selected from the group consisting of halo, alkyl, cycloalkyl, —NR2R3, alkoxy, amino, —NH-alkyl, —C(O)NH-alkyl, —NHC(O)-alkyl, —NHC(O)NH-alkyl, —NHC(NH)-alkyl, —NHC(NH)NH2, —NH(CH2)x-heteroaryl, —NH(CH2)x-heterocyclyl, —NH(CH2)x-aryl, and —(CH2)xC(O)NH2, wherein x is 0, 1, 2 or 3; each of R1, R2 and R3 is independently selected from H, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heterocyclyl, and heteroaryl, or R2 and R3, taken together with the nitrogen atom to which at least one of R2 and R3 is attached, form a 5- or 6-membered heterocyclyl or heteroaryl ring; each of the alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, and heterocyclyl moieties is unsubstituted or substituted with one or more groups selected from amino, alkylamino, dialkylamino, aminocarbonyl, halogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, carbocyclyl, heterocyclyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylaminocarbonyloxy, dialkylaminocarbonyloxy, nitro, cyano carboxy, alkoxycarbonyl, alkylcarbonyl, hydroxy, alkoxy, acyloxy, haloalkoxy, ═O, ═S, ═NH, ═NNR2R3, ═NNHC(O)R2, ═NNHCO2R2, and ═NNHSO2R2, and each of the aryl and heteroaryl moieties is unsubstituted or substituted with one or more groups selected from amino, alkylamino, dialkylamino, aminocarbonyl, halogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, carbocyclyl, heterocyclyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylaminocarbonyloxy, dialkylaminocarbonyloxy, nitro, cyano, carboxy, alkoxycarbonyl, alkylcarbonyl, hydroxy, alkoxy, acyloxy, and haloalkoxy; m is 0, 1, 2, 3, or 4; p is 0, 1, 2, 3, or 4; r is 0, 1, or 2; s is 0, 1, 2, or 3; and v is 0, 1, 2, 3, 4, or 5; or a pharmaceutically acceptable salt thereof. 3. The compound of claim 2 in which Ring C is imidazolyl. 4. The compound of claim 2 of Formula IIc: 5. The compound of claim 4 wherein s is 0; m, p and v are 1; Ra and Rc are methyl; and Rb is CF3. 6. The compound of claim 1 of the formula: wherein: L1 is NR1C(O) or C(O)NR1; Ring D is a 5- or 6-membered heterocyclyl or heteroaryl ring comprising carbon atoms and 1-3 heteroatoms independently selected from O, N, and S(O)r; L2 is —(CH2)z—; each occurrence of Ra is independently selected from the group consisting of halo, alkyl, and cycloalkyl; each occurrence of Rb is independently selected from the group consisting of halo, alkyl, and cycloalkyl; each occurrence of Rd is independently selected from the group consisting of halo, alkyl, cycloalkyl, and —NR2R3; each occurrence of Re is independently selected from the group consisting of halo, alkyl, cycloalkyl, —NR2R3, alkoxy, amino, —NH-alkyl, —C(O)NH-alkyl, —NHC(O)-alkyl, —NHC(O)NH-alkyl, —NHC(NH)-alkyl, —NHC(NH)NH2, —NH(CH2)x-heteroaryl, —NH(CH2)x-heterocyclyl, —NH(CH2)x-aryl, and —(CH2)xC(O)NH2, wherein x is 0, 1, 2 or 3; each of R1, R2 and R3 is independently selected from H, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heterocyclyl, and heteroaryl, or R2 and R3, taken together with the nitrogen atom to which at least one of R2 and R3 is attached, form a 5- or 6-membered heterocyclyl or heteroaryl ring; each of the alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, and heterocyclyl moieties is unsubstituted or substituted with one or more groups selected from amino, alkylamino, dialkylamino, aminocarbonyl, halogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, carbocyclyl, heterocyclyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylaminocarbonyloxy, dialkylaminocarbonyloxy, nitro, cyano, carboxy, alkoxycarbonyl, alkylcarbonyl, hydroxy, alkoxy, acyloxy, haloalkoxy, ═O, ═S, ═NH, ═NNR2R3, ═NNHC(O)R2, ═NNHCO2R2, and ═NNHSO2R2, and each of the aryl and heteroaryl moieties is unsubstituted or substituted with one or more groups selected from amino, alkylamino, dialkylamino, aminocarbonyl, halogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, carbocyclyl, heterocyclyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylaminocarbonyloxy, dialkylaminocarbonyloxy, nitro, cyano, carboxy, alkoxycarbonyl, alkylcarbonyl, hydroxy, alkoxy, acyloxy, and haloalkoxy; m is 0, 1, 2, 3, or 4; p is 0, 1, 2, 3, or 4; r is 0, 1, or 2; s is 0, 1, 2, or 3; w is 0, 1, 2, 3, 4, or 5; and z is 1, 2, 3 or 4; or a pharmaceutically acceptable salt thereof. 7. The compound of claim 6 wherein Ring D is piperazinyl. 8. The compound of claim 7 of Formula IIIc: wherein Rd is a C1-C6 alkyl, unsubstituted or substituted with one or more groups selected from amino, alkylamino, dialkylamino, aminocarbonyl, halogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, carbocyclyl, heterocyclyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylaminocarbonyloxy, dialkylaminocarbonyloxy, nitro, cyano, carboxy, alkoxycarbonyl, alkylcarbonyl, hydroxy, alkoxy, acyloxy, haloalkoxy, ═O, ═S, ═NH, ═NNR2R3, ═NNHC(O)R2, ═NNHCO2R2, and ═NNHSO2R2. 9. The compound of claim 8 wherein s is 0, m is 1, p is 1, Ra is methyl, Rb is CF3, and Rd is methyl or —CH2CH2OH. 10. A compound of formula: wherein: L1 is NR1C(O) or C(O)NR1; each occurrence of Ra is independently selected from the group consisting of halo, alkyl, and cycloalkyl; each occurrence of Rb is independently selected from the group consisting of halo, alkyl, and cycloalkyl; each occurrence of Re is independently selected from the group consisting of halo, alkyl, cycloalkyl, —NR2R3, alkoxy, amino, —NH-alkyl, —C(O)NH-alkyl, —NHC(O)-alkyl, —NHC(O)NH-alkyl, —NHC(NH)-alkyl, —NHC(NH)NH2, —NH(CH2)x-heteroaryl, —NH(CH2)x-heterocyclyl, —NH(CH2)x-aryl, and —(CH2)xC(O)NH2, wherein x is 0, 1, 2 or 3; each of R1, R2 and R3 is independently selected from H, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heterocyclyl, and heteroaryl, or R2 and R3, taken together with the nitrogen atom to which at least one of R2 and R3 is attached, form a 5- or 6-membered heterocyclyl or heteroaryl ring; each of the alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, and heterocyclyl moieties is unsubstituted or substituted with one or more groups selected from amino, alkylamino, dialkylamino, aminocarbonyl, halogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, carbocyclyl, heterocyclyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylaminocarbonyloxy, dialkylaminocarbonyloxy, nitro, cyano, carboxy, alkoxycarbonyl, alkylcarbonyl, hydroxy, alkoxy, acyloxy, haloalkoxy, ═O, ═S, ═NH, ═NNR2R3, ═NNHC(O)R2, ═NNHCO2R2, and ═NNHSO2R2, and each of the aryl and heteroaryl moieties is unsubstituted or substituted with one or more groups selected from amino, alkylamino, dialkylamino, aminocarbonyl, halogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, carbocyclyl, heterocyclyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylaminocarbonyloxy, dialkylaminocarbonyloxy, nitro, cyano, carboxy, alkoxycarbonyl, alkylcarbonyl, hydroxy, alkoxy, acyloxy, and haloalkoxy; m is 0, 1, 2, 3, or 4; p is 0, 1, 2, 3, 4, or 5; and s is 0, 1, 2, or 3; or a pharmaceutically acceptable salt thereof. 11. A composition comprising a compound of claim 10, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable vehicle. 12. The compound, (R)—N—(4((3-(Dimethylamino)pyrrolidin-1-yl)methyl)-3-(trifluoromethyl)phenyl)-3-(imidazo[1,2-b]pyridazin-3-ylethynyl)-4-methylbenzamide. 13. The compound, 3-(Imidazo[1,2-b]pyridazin-3-ylethynyl)-4-methyl-N-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)benzamide. 14. The compound, N-(3-Chloro-4-((4-methylpiperazin-1-yl)methyl)phenyl)-3-(imidazo[1,2-b]pyridazin-3-ylethynyl)-4-methylbenzamide, or a pharmaceutically acceptable salt thereof. 15. The compound, N-(3-(Imidazo[1,2-b]pyridazin-3-ylethynyl)-4-methylphenyl)-4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)benzamide. 16. The compound, N-(3-Cyclopropyl-4-((4-methylpiperazin-1-yl)methyl)phenyl)-3-(imidazo[1,2-b]pyridazin-3-ylethynyl)-4-methylbenzamide. 17. The compound, 3-(Imidazo[1,2-b]pyridazin-3-ylethynyl)-N-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)benzamide. 18. The compound, N-(4-((4-(2-Hydroxyethyl)piperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)-3-(imidazo[1,2-b]pyridazin-3-ylethynyl)-4-methylbenzamide. 19. The compound, 3-(Imidazo[1,2-b]pyridazin-3-ylethynyl)-4-methyl-N-(4-(piperazin-1-ylmethyl)-3-(trifluoromethyl)phenyl)benzamide. 20. The compound, (R)-N-(4-((3-(Dimethylamino)pyrrolidin-1-yl)methyl)-3 -(trifluoromethyl)phenyl)-3-(imidazo[1 ,2-b]pyridazin-3-ylethynyl)-4-methylbenzamide, or a pharmaceutically acceptable salt thereof. 21. The compound, N-(3-(Imidazo[1,2-b]pyridazin-3-ylethynyl)-4-methylphenyl)-4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)benzamide, or a pharmaceutically acceptable salt thereof 22. The compound, 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. 23. The compound, N-(3-Chloro-4-((4-methylpiperazin-1-yl)methyl)phenyl) -3-(imidazo[1,2-b]pyridazin-3-ylethynyl)-4-methylbenzamide. 24. The compound, N-(3-Cyclopropyl-4-((4-methylpiperazin-1-yl)methyl)phenyl)-3-(imidazo[1,2-b]pyridazin-3-ylethynyl)-4-methylbenzamide, or a pharmaceutically acceptable salt thereof. 25. The compound, 3-(Imidazo[1,2-b]pyridazin-3-ylethynyl)-N-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)benzamide, or a pharmaceutically acceptable salt thereof. 26. The compound, N-(4-((4-(2-Hydroxyethyl)piperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)-3-(imidazo[1,2-b]pyridazin-3-ylethynyl)-4-methylbenzamide, or a pharmaceutically acceptable salt thereof. 27. The compound, 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. 28. A hydrochloride salt of the compound, (R)-N-(4-((3-(Dimethylamino)pyrrolidin-1-yl)methyl)-3-(trifluoromethyl)phenyl)-3-(imidazo[1,2-b]pyridazin-3-ylethynyl)-4-methylbenzamide. 29. A hydrochloride salt of the compound, 3-(Imidazo[1,2-b]pyridazin-3-ylethynyl)-4-methyl-N-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)benzamide. 30. A hydrochloride salt of the compound, N-(3-Chloro-4-((4-methylpiperazin-1-yl)methyl)phenyl)-3-(imidazo[1,2-b]pyridazin-3-ylethynyl)-4-methylbenzamide. 31. A composition comprising a compound of formula: wherein L1 is NR1C(O) or C(O)NR1; Ring D is a 5- or 6-membered heterocyclyl or heteroaryl ring comprising carbon atoms and 1-3 heteroatoms independently selected from O, N, and S(O)r; Ring C is a 5-or 6-membered heterocyclyl or heteroaryl ring, comprising carbon atoms and 1-3 heteroatoms independently selected from O, N, and S(O)r; L2 is —(CH2)z—; each occurrence of Ra is independently selected from the group consisting of halo, alkyl, and cycloalkyl; each occurrence of Rb is independently selected from the group consisting of halo, alkyl, and cycloalkyl; each occurrence of Rc is independently selected from the group consisting of halo, alkyl, and cycloalkyl; each occurrence of Rd is independently selected from the group consisting of halo, alkyl, cycloalkyl, and —NR2R3; each occurrence of Re is independently selected from the group consisting of halo, alkyl, cycloalkyl, —NR2R3, alkoxy, amino, —NH-alkyl, —C(O)NH-alkyl, —NHC(O)-alkyl, —NHC(O)NH-alkyl, —NHC(NH)-alkyl, —NHC(NH)NH2, —NH(CH2)x-heteroaryl, —NH(CH2)x-heterocyclyl, —NH(CH2)x-aryl, and —(CH2)xC(O)NH2, wherein x is 0, 1, 2 or 3; each of R1, R2 and R3 is independently selected from H, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heterocyclyl, and heteroaryl, or R2 and R3, taken together with the nitrogen atom to which at least one of R2 and R3 is attached, form a 5- or 6- membered heterocyclyl or heteroaryl ring; each of the alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, and heterocyclyl moieties is unsubstituted or substituted with one or more groups selected from amino, alkylamino, dialkylamino, aminocarbonyl, halogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, carbocyclyl, heterocyclyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylaminocarbonyloxy, dialkylaminocarbonyloxy, nitro, cyano, carboxy, alkoxycarbonyl, alkylcarbonyl, hydroxy, alkoxy, acyloxy, haloalkoxy, ═O, ═S, ═NH, ═NNR2R3, ═NNHC(O)R2, ═NNHCO2R2, and ═NNHSO2R2, and each of the aryl and heteroaryl moieties is unsubstituted or substituted with one or more groups selected from amino, alkylamino, dialkylamino, aminocarbonyl, halogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, carbocyclyl, heterocyclyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylaminocarbonyloxy, dialkylaminocarbonyloxy, nitro, cyano, carboxy, alkoxycarbonyl, alkylcarbonyl, hydroxy, alkoxy, acyloxy, and haloalkoxy; m is 0, 1, 2, 3, or 4; p is 0, 1, 2, 3, or 4; r is 0, 1, or 2; s is 0, 1, 2, or 3; v is 0, 1, 2, 3, 4, or 5; w is 0, 1, 2, 3, 4, or 5; and z is 1, 2, 3 or 4; or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable vehicle. 32. The composition of claim 31, wherein said compound is of the formula: wherein: Ring D is a 5- or 6-membered heterocyclyl or heteroaryl ring comprising carbon atoms and 1-3 heteroatoms independently selected from O, N, and S(O)r; L1 is NR1C(O) or C(O)NR1; L2 is —(CH2)z—; each occurrence of Ra is independently selected from the group consisting of halo, alkyl, and cycloalkyl; each occurrence of Rb is independently selected from the group consisting of halo, alkyl, and cycloalkyl; each occurrence of Rd is independently selected from the group consisting of halo, alkyl, cycloalkyl, and —NR2R3; each occurrence of Re is independently selected from the group consisting of halo, alkyl, cycloalkyl, —NR2R3, alkoxy, amino, —NH-alkyl, —C(O)NH-alkyl, —NHC(O)-alkyl, —NHC(O)NH-alkyl, —NHC(NH)-alkyl, —NHC(NH)NH2, —NH(CH2)x-heteroaryl, —NH(CH2)x-heterocyclyl, —NH(CH2)x-aryl, and —(CH2)xC(O)NH2, wherein x is 0, 1, 2 or 3; each of R1, R2 and R3 is independently selected from H, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heterocyclyl, and heteroaryl, or R2 and R3, taken together with the nitrogen atom to which at least one of R2 and R3 is attached, form a 5- or 6-membered heterocyclyl or heteroaryl ring; each of the alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, and heterocyclyl moieties is unsubstituted or substituted with one or more groups selected from amino, alkylamino, dialkylamino, aminocarbonyl, halogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, carbocyclyl, heterocyclyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylaminocarbonyloxy, dialkylaminocarbonyloxy, nitro, cyano, carboxy, alkoxycarbonyl, alkylcarbonyl, hydroxy, alkoxy, acyloxy, haloalkoxy, ═O, ═S, ═NH, ═NNR2R3, ═NNHC(O)R2, ═NNHCO2R2, and ═NNHSO2R2, and each of the aryl and heteroaryl moieties is unsubstituted or substituted with one or more groups selected from amino, alkylamino, dialkylamino, aminocarbonyl, halogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, carbocyclyl, heterocyclyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylaminocarbonyloxy, dialkylaminocarbonyloxy, nitro, cyano, carboxy, alkoxycarbonyl, alkylcarbonyl, hydroxy, alkoxy, acyloxy, and haloalkoxy; m is 0, 1, 2, 3, or 4; p is 0, 1, 2, 3, or 4; r is 0, 1, or 2; s is 0, 1, 2, or 3; w is 0, 1, 2, 3, 4, or 5; and z is 1, 2, 3 or 4; or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable vehicle. 33. The composition of claim 32, wherein said compound comprises a moiety: which is selected from the following: or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable vehicle. 34. The composition of claim 32, wherein said compound comprises a moiety: which is selected from the following: or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable vehicle. 35. The composition of claim 32, in which Ring D is a piperazinyl; Rd is C1-C6 alkyl; and w is 1. 36. The composition of claim 31, wherein said compound is of the formula: wherein: L1 is NR1C(O) or C(O)NR1; Ring C is a 5-or 6-membered heterocyclyl or heteroaryl ring, comprising carbon atoms and 1-3 heteroatoms independently selected from O, N, and S(O)r; each occurrence of Ra is independently selected from the group consisting of halo, alkyl, and cycloalkyl; each occurrence of Rb is independently selected from the group consisting of halo, alkyl, and cycloalkyl; each occurrence of Rc is independently selected from the group consisting of halo, alkyl, and cycloalkyl; each occurrence of Re is independently selected from the group consisting of halo, alkyl, cycloalkyl, —NR2R3, alkoxy, amino, —NH-alkyl, —C(O)NH-alkyl, —NHC(O)-alkyl, —NHC(O)NH-alkyl, —NHC(NH)-alkyl, —NHC(NH)NH2, —NH(CH2)x-heteroaryl, —NH(CH2)x-heterocyclyl, —NH(CH2)x-aryl, and —(CH2)xC(O)NH2, wherein x is 0, 1, 2 or 3; each of R1, R2 and R3 is independently selected from H, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heterocyclyl, and heteroaryl, or R2 and R3, taken together with the nitrogen atom to which at least one of R2 and R3 is attached, form a 5- or 6-membered heterocyclyl or heteroaryl ring; each of the alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, and heterocyclyl moieties is unsubstituted or substituted with one or more groups selected from amino, alkylamino, dialkylamino, aminocarbonyl, halogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, carbocyclyl, heterocyclyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylaminocarbonyloxy, dialkylaminocarbonyloxy, nitro, cyano, carboxy, alkoxycarbonyl, alkylcarbonyl, hydroxy, alkoxy, acyloxy, haloalkoxy, ═O, ═S, ═NH, ═NNR2R3, ═NNHC(O)R2, ═NNHCO2R2, and ═NNHSO2R2, and each of the aryl and heteroaryl moieties is unsubstituted or substituted with one or more groups selected from amino, alkylamino, dialkylamino, aminocarbonyl, halogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, carbocyclyl, heterocyclyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylaminocarbonyloxy, dialkylaminocarbonyloxy, nitro, cyano, carboxy, alkoxycarbonyl, alkylcarbonyl, hydroxy, alkoxy, acyloxy, and haloalkoxy; m is 0, 1, 2, 3, or 4; p is 0, 1, 2, 3, or 4; r is 0, 1, or 2; s is 0, 1, 2, or 3; and v is 0, 1, 2, 3, 4, or 5; or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable vehicle. 37. The composition of claim 31, wherein Ring C is imidazolyl. 38. The composition of claim 31, wherein said compound comprises a moiety: which has one of the following structures: 39. A composition comprising a compound of Formula IIc: wherein: each occurrence of Ra is independently selected from the group consisting of halo, alkyl, and cycloalkyl; each occurrence of Rb is independently selected from the group consisting of halo, alkyl, and cycloalkyl; each occurrence of Rc is independently selected from the group consisting of halo, alkyl, and cycloalkyl; each occurrence of Re is independently selected from the group consisting of halo, alkyl, cycloalkyl, —NR2R3, alkoxy, amino, —NH-alkyl, —C(O)NH-alkyl, —NHC(O)-alkyl, —NHC(O)NH-alkyl, —NHC(NH)-alkyl, —NHC(NH)NH2, —NH(CH2)x-heteroaryl, —NH(CH2)x-heterocyclyl, —NH(CH2)x-aryl, and —(CH2)xC(O)NH2, wherein x is 0, 1, 2 or 3; each of R2 and R3 is independently selected from H, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heterocyclyl, and heteroaryl, or R2 and R3, taken together with the nitrogen atom to which at least one of R2 and R3 is attached, form a 5- or 6-membered heterocyclyl or heteroaryl ring; each of the alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, and heterocyclyl moieties is unsubstituted or substituted with one or more groups selected from amino, alkylamino, dialkylamino, aminocarbonyl, halogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, carbocyclyl, heterocyclyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylaminocarbonyloxy, dialkylaminocarbonyloxy, nitro, cyano, carboxy, alkoxycarbonyl, alkylcarbonyl, hydroxy, alkoxy, acyloxy, haloalkoxy, ═O, ═S, ═NH, ═NNR2R3, ═NNHC(O)R2, ═NNHCO2R2, and ═NNHSO2R2, and each of the aryl and heteroaryl moieties is unsubstituted or substituted with one or more groups selected from amino, alkylamino, dialkylamino, aminocarbonyl, halogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, carbocyclyl, heterocyclyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylaminocarbonyloxy, dialkylaminocarbonyloxy, nitro, cyano, carboxy, alkoxycarbonyl, alkylcarbonyl, hydroxy, alkoxy, acyloxy, and haloalkoxy; m is 0, 1, 2, 3, or 4; p is 0, 1, 2, 3, or 4; s is 0, 1, 2, or 3; and v is 0, 1, 2, 3, 4, or 5; or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable vehicle. 40. The composition of claim 39, wherein s is 0; m, p and v are 1; Ra and Rc are methyl; and Rb is CF3. 41. A composition comprising a compound of Formula IIIc: wherein: each occurrence of Ra is independently selected from the group consisting of halo, alkyl, and cycloalkyl; each occurrence of Rb is independently selected from the group consisting of halo, alkyl, and cycloalkyl; Rd is a C1-C6 alkyl group, unsubstituted or substituted with one or more groups selected from amino, alkylamino, dialkylamino, aminocarbonyl, halogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, carbocyclyl, heterocyclyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylaminocarbonyloxy, dialkylaminocarbonyloxy, nitro, cyano, carboxy, alkoxycarbonyl, alkylcarbonyl, hydroxy, alkoxy, acyloxy, haloalkoxy, ═O, ═S, ═NH, ═NNR2R3, ═NNHC(O)R2, ═NNHCO2R2, and ═NNHSO2R2; each occurrence of Re is independently selected from the group consisting of halo, alkyl, cycloalkyl, —NR2R3, alkoxy, amino, —NH-alkyl, —C(O)NH-alkyl, —NHC(O)-alkyl, —NHC(O)NH-alkyl, —NHC(NH)-alkyl, —NHC(NH)NH2, —NH(CH2)x-heteroaryl, —NH(CH2)x-heterocyclyl, —NH(CH2)x-aryl, and —(CH2)xC(O)NH2, wherein x is 0, 1, 2 or 3; each of R2 and R3 is independently selected from H, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heterocyclyl, and heteroaryl, or R2 and R3, taken together with the nitrogen atom to which at least one of R2 and R3 is attached, form a 5- or 6-membered heterocyclyl or heteroaryl ring; each of the alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, and heterocyclyl moieties is unsubstituted or substituted with one or more groups selected from amino, alkylamino, dialkylamino, aminocarbonyl, halogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, carbocyclyl, heterocyclyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylaminocarbonyloxy, dialkylaminocarbonyloxy, nitro, cyano, carboxy, alkoxycarbonyl, alkylcarbonyl, hydroxy, alkoxy, acyloxy, haloalkoxy, ═O, ═S, ═NH, ═NNR2R3, ═NNHC(O)R2, ═NNHCO2R2, and ═NNHSO2R2, and each of the aryl and heteroaryl moieties is unsubstituted or substituted with one or more groups selected from amino, alkylamino, dialkylamino, aminocarbonyl, halogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, carbocyclyl, heterocyclyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylaminocarbonyloxy, dialkylaminocarbonyloxy, nitro, cyano, carboxy, alkoxycarbonyl, alkylcarbonyl, hydroxy, alkoxy, acyloxy, and haloalkoxy; m is 0, 1, 2, 3, or 4; p is 0, 1, 2, 3, or 4; and s is 0, 1, 2, or 3; or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable vehicle. 42. The composition of claim 41 in which s is 0; m and p are 1; and Ra is CH3, Rb is CF3 and, Rd is CH3 or —CH2CH2OH. 43. The composition of either of claim 39 or 41 in which s is 0. 44. The composition of either of claim 39 or 41, in which s is 1, 2, or 3 and at least one Re is halo, C1-C6 alkyl, amino, —NH-alkyl, —C(O)NH-alkyl, —NHC(O)-alkyl, —NHC(O)NH-alkyl, —NHC(NH)-alkyl, —NHC(NH)NH2, —NH(CH2)x-heteroaryl, —NH(CH2)x-heterocyclyl, —NH(CH2)x-aryl or —(CH2)xC(O)NH2, in which x is 0, 1, 2 or 3. 45. A composition comprising a hydrochloride salt of the compound of claim 12, and a pharmaceutically acceptable carrier. 46. A composition comprising a hydrochloride salt of the compound of claim 13, and a pharmaceutically acceptable carrier. 47. A composition comprising a hydrochloride salt of the compound of claim 14, and a pharmaceutically acceptable carrier. 48. A composition comprising the compound, (R)-N-(4-((3-(Dimethylamino)pyrrolidin-1-yl)methyl)-3-(trifluoromethyl)phenyl)-3-(imidazo[1,2-b]pyridazin-3-ylethynyl)-4-methylbenzamide, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. 49. A composition comprising the compound, N-(3-(Imidazo[1,2-b]pyridazin -3-ylethynyl)-4-methylphenyl)-4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)benzamide, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. 50. A composition comprising the compound, 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, and a pharmaceutically acceptable carrier. 51. A composition comprising the compound, N-(3-Chloro-4-((4-methylpiperazin-1-yl)methyl)phenyl)-3-(imidazo [1,2-b]pyridazin-3-ylethynyl)-4-methylbenzamide, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. 52. A composition comprising the compound, N-(3-Cyclopropyl-4-((4-methylpiperazin-1-yl)methyl)phenyl)-3-(imidazo[1,2-b]pyridazin-3-ylethynyl)-4-methylbenzamide, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. 53. A composition comprising the compound, 3-(Imidazo[1,2-b]pyridazin-3-ylethynyl)-N-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)benzamide, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. 54. A composition comprising the compound, N-(4-((4-(2-Hydroxyethyl)piperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)-3-(imidazo[1,2-b]pyridazin-3-ylethynyl)-4-methylbenzamide, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. 55. A composition comprising the compound, 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, and a pharmaceutically acceptable carrier.