OMEARA JEFF (CA)
AHMAR SIAWASH (CA)
SIMPSON GRAHAM (GB)
HUNT PETER (GB)
ROSA DAVID (GB)
PARK JI SUNG (GB)
DUNAD THERAPEUTICS LTD (GB)
WO2019141694A1 | 2019-07-25 | |||
WO2010151710A2 | 2010-12-29 | |||
WO2018071794A1 | 2018-04-19 | |||
WO2012101239A1 | 2012-08-02 |
US5846514A | 1998-12-08 | |||
US6334997B1 | 2002-01-01 | |||
US6334997B1 | 2002-01-01 |
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CLAIMS What is claimed is: 1. A compound of Formula (I), or a salt, solvate, tautomer, or regioisomer thereof: Formula (I) wherein, GR is alkyl, haloalkyl, heteroalkyl, -N(R5)2, or G; G is or comprises a protein-binding ligand, is or comprises (e.g., unsaturated) carbocycle, is or comprises (e.g., unsaturated) heterocycle, or is –L2–G1, wherein L2 is a linker (e.g., - O- or -NR5-), and G1 is hydrogen or an organic residue (e.g., is or comprises a protein- binding ligand, is or comprises (e.g., unsaturated) carbocycle, or is or comprises (e.g., unsaturated) heterocycle); X1 is absent, O or NR; each Y1, Y2, and Y3 is independently hydrogen, halo, alkyl, haloalkyl (e.g., with at least two Y being halo or haloalkyl, such as fluoroalkyl, e.g., at least one Y (e.g., Y2) being halo) (e.g., Y1, Y2, Y3 all being F), or G; R is hydrogen or R7; R1 is R7; R2 is hydrogen, halogen, or R7; each R3 is independently hydrogen, -L1R4, -C(=O)L1R4, -C(=O)OL1R4, or -C(=O)NR4L1R4, wherein each L1 is independently alkyl, heteroalkyl, aryl, or heteroaryl; and each R4 is independently hydrogen, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; each R5 is independently hydrogen, -CN, -C(=O)R6, -C(=O)OR6, -C(=O)NR3R6, alkyl, heteroalkyl, aryl, or heteroaryl; each R6 is independently hydrogen, alkyl, or heteroalkyl; each R7 is independently x is 0, 1, or 2; provided that when X1 is O, GR is G, G is L2G1 and L2 is amino or -NR5, then Y1, Y2, and Y3 are not all F. 2. The compound of claim 1, wherein the compound comprises only one G. 3. The compound according to claim 1 or 2, or a salt, solvate, tautomer, or regioisomer thereof, wherein when -S(=O)(=X1)GR is -S(=O)(=X1)G, X1 is O, then G is not: (R)-3-(4-phenoxyphenyl)-1-(1λ2-piperidin-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine; 1-(2-(λ2-azaneyl)ethyl)-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine; (R)-3-(4-phenoxyphenyl)-1-(1λ2-pyrrolidin-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine; 4-(λ2-azaneyl)-7H-pyrrolo[2,3-d]pyrimidine; N4-(3-(λ2-azaneyl)phenyl)-5-fluoro-N2-(4-(2-methoxyethoxy)phenyl)pyrimidine-2,4-diamine; 4-(λ2-azaneyl)-5-fluoro-N-(4-(2-methoxyethoxy)phenyl)pyrimidin-2-amine; or 3-(4-phenoxyphenyl)-1λ2-pyrazolo[5,4-d]pyrimidin-4-amine. 4. The compound according to claim 1 or 2, or a salt, solvate, tautomer, or regioisomer thereof, wherein when -S(=O)(=X1)GR is -S(=O)(=X1)N(R5)G, X1 is O, then one or more of G and R5 is not or does not comprise: substituted or unsubstituted phenyl; substituted or unsubstituted benzyl; 1-naphthyl; pyridin-3- yl; pyridin-4-yl; 2-fluoropyridin-4-yl; or 2,6-difluoropyridin-3-yl. 5. The compound of any one of claims 1-4, or a salt, solvate, tautomer, or regioisomer thereof, wherein G is –L2–G1, wherein L2 is a linker, and G1 is an organic residue (e.g., is or comprises a protein-binding ligand, is or comprises (e.g., unsaturated) carbocycle, or is or comprises (e.g., unsaturated) heterocycle). 6. The compound of claim 5, or a salt, solvate, tautomer, or regioisomer thereof, wherein L2 is a substituted or unsubstituted unsaturated alkylene (e.g., alkenylene or alkynylene), substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene, and G1 is an organic residue (e.g., is or comprises a protein-binding ligand). 7. The compound of claim 5, or a salt, solvate, tautomer, or regioisomer thereof, wherein L2 is a bond, -O-, –NR8-, –N(R8)2+-, -S-, -S(=O)-, -S(=O)2-, -CH=CH-, =CH-, -C≡C-, -C(=O)-, - C(=O)O-, -OC(=O)-, -OC(=O)O-, -C(=O)NR8-, -NR8C(=O)-, -OC(=O)NR8-, -NR8C(=O)O-, - NR8C(=O)NR8-, -NR8S(=O)2-, -NR8S(=O)(=NR8)-, -S(=O)2NR8-, -S(=O)(=NR8)NR8-, - C(=O)NR8S(=O)2-, -S(=O)2NR8C(=O)-, substituted or unsubstituted C1-C4 alkylene, substituted or unsubstituted C1-C8 heteroalkylene, -(C1-C4 alkylene)-O-, -O-(C1-C4 alkylene)-, -(C1-C4 alkylene)-NR8-, -NR8-(C1-C4 alkylene)-, -(C1-C4 alkylene)-N(R8)2+-, or -N(R8)2+-(C1-C4 alkylene)-; each R8 is independently hydrogen, substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 haloalkyl, substituted or unsubstituted C1-C4 heteroalkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C5 alkynyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C2-C7 heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; and G1 is an organic residue (e.g., is or comprises a protein-binding ligand). 8. The compound of any one of claims 1-4, or a salt, solvate, tautomer, or regioisomer thereof, wherein G is substituted or unsubstituted unsaturated carbocycle or substituted or unsubstituted unsaturated heterocycle, wherein G and R5 on a single N, if present, are optionally taken together to form a substituted or unsubstituted N-containing heterocycloalkyl. 9. The compound of any one of claims 1-8, or a salt, solvate, tautomer, or regioisomer thereof, wherein G comprises one or more cyclic ring systems selected from substituted or unsubstituted unsaturated carbocycles and substituted or unsubstituted unsaturated heterocycles. 10. The compound of any one of claims 1-9, or a salt, solvate, tautomer, or regioisomer thereof, wherein G comprises two or more cyclic ring systems selected from substituted or unsubstituted unsaturated carbocycles and substituted or unsubstituted unsaturated heterocycles. 11. The compound of any one of claims 5-7, or a salt, solvate, tautomer, or regioisomer thereof, wherein G1 comprises one or more cyclic ring systems selected from substituted or unsubstituted carbocycles and substituted or unsubstituted heterocycles. 12. The compound of any one of claims 5-7 or 11, or a salt, solvate, tautomer, or regioisomer thereof, wherein G1 comprises two or more cyclic ring systems selected from substituted or unsubstituted carbocycles and substituted or unsubstituted heterocycles. 13. The compound of claim 10 or 12, or a salt, solvate, tautomer, or regioisomer thereof, wherein the two or more cyclic ring systems are connected via a bond. 14. The compound of claim 10 or 12, or a salt, solvate, tautomer, or regioisomer thereof, wherein the two or more cyclic ring systems are connected via one or more linker and/or bond. 15. The compound of claim 14, or a salt, solvate, tautomer, or regioisomer thereof, wherein the linker is -O-, –NR8-, –N(R8)2+-, -S-, -S(=O)-, -S(=O)2-, -CH=CH-, =CH-, -C≡C-, -C(=O)-, - C(=O)O-, -OC(=O)-, -OC(=O)O-, -C(=O)NR8-, -NR8C(=O)-, -OC(=O)NR8-, -NR8C(=O)O-, - NR8C(=O)NR8-, -NR8S(=O)2-, -S(=O)2NR8-, -C(=O)NR8S(=O)2-, -S(=O)2NR8C(=O)-, substituted or unsubstituted C1-C4 alkylene, substituted or unsubstituted C1-C8 heteroalkylene, - (C1-C4 alkylene)-O-, -O-(C1-C4 alkylene)-, -(C1-C4 alkylene)-NR8-, -NR8-(C1-C4 alkylene)-, - (C1-C4 alkylene)-N(R8)2+-, or -N(R8)2+-(C1-C4 alkylene)-; and each R8 is independently hydrogen, substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 haloalkyl, substituted or unsubstituted C1-C4 heteroalkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C5 alkynyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C2-C7 heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. 16. The compound of any one of claims 9-15, or a salt, solvate, tautomer, or regioisomer thereof, wherein the cyclic ring system comprises substituted or unsubstituted monocyclic aryl or substituted or unsubstituted monocyclic heteroaryl. 17. The compound of any one of claims 9-15, or a salt, solvate, tautomer, or regioisomer thereof, wherein the cyclic ring system comprises substituted or unsubstituted bicyclic aryl or substituted or unsubstituted bicyclic heteroaryl. 18. The compound of any one of claims 1-4, or a salt, solvate, tautomer, or regioisomer thereof, wherein G or G1 is or comprises a protein-binding ligand selected from a BTK, EGFR (e.g., EGFR T790M), JAK3, RIPK2, or tubulin binding ligand. 19. The compound of any one of claims 1-4, or a salt, solvate, tautomer, or regioisomer thereof, wherein G or G1 is or comprises a protein-binding ligand selected from: , , , , , , , , , , and . 20. The compound of any one of claims 1-4, or a salt, solvate, tautomer, or regioisomer thereof, wherein G or G1 is or comprises a protein-binding ligand selected from: , , , , , and . 21. The compound of any one of claims 1-4, or a salt, solvate, tautomer, or regioisomer thereof, wherein G or G1 is or comprises a protein-binding ligand that is: . 22. The compound of any one of claims 1-4, or a salt, solvate, tautomer, or regioisomer thereof, wherein G or G1 is or comprises a protein-binding ligand that is: . 23. The compound of any one of claims 1-4, or a salt, solvate, tautomer, or regioisomer thereof, wherein G or G1 is or comprises a protein-binding ligand that is: N N HN or . 24. The compound of any one of claims 1-18, or a salt, solvate, tautomer, or regioisomer thereof, wherein each R5 is independently hydrogen, -CN, -CH3, -CH2CH3, -CH2NH2, - CH2NHCH3, -CH2N(CH3)2, -CH2F, -CHF2, -CF3, cyclopropyl, cyclobutyl, or cyclopentyl. 25. The compound of any one of claims 1-18, or a salt, solvate, tautomer, or regioisomer thereof, wherein each R5 is independently hydrogen, -CN, -CH3, -CF3, or cyclopropyl. 26. The compound of any one of claims 1-18, or a salt, solvate, tautomer, or regioisomer thereof, wherein each R5 is hydrogen. 27. The compound of any one of claims 1-26, or a salt, solvate, tautomer, or regioisomer thereof, wherein each R8 is independently hydrogen, substituted or unsubstituted C1-C4 alkyl, or substituted or unsubstituted C1-C4 heteroalkyl. 28. The compound of any one of claims 1-26, or a salt, solvate, tautomer, or regioisomer thereof, wherein each R8 is independently hydrogen, -OCH2F, -OCHF2, -OCF3, -OCH2CH2F, - OCH2CHF2, -OCH2CF3, -NHCF3, or -NHCH2CF3. 29. The compound of any one of claims 1-26, or a salt, solvate, tautomer, or regioisomer thereof, wherein each R8 is independently hydrogen, -OCH3, -OCH2CH3, -OCH2F, -OCHF2, - OCF3, -OCH2CH2F, -OCH2CHF2, -OCH2CF3, cyclopropyloxy, or cyclobutyloxy. 30. The compound of any one of claims 1-26, or a salt, solvate, tautomer, or regioisomer thereof, wherein each R8 is independently hydrogen, -CH3, or -OCH3. 31. The compound of any one of claims 1-30, or a salt, solvate, tautomer, or regioisomer thereof, wherein X1 is O, NH, or N(substituted or unsubstituted alkyl). 32. The compound of any one of claims 1-30, or a salt, solvate, tautomer, or regioisomer thereof, wherein X1 is O, NH, or N(alkyl). 33. The compound of any one of claims 1-30, or a salt, solvate, tautomer, or regioisomer thereof, wherein X1 is O, NH, or N(CH3). 34. The compound of any one of claims 1-30, or a salt, solvate, tautomer, or regioisomer thereof, wherein X1 is O. 35. The compound of any one of claims 1-30, or a salt, solvate, tautomer, or regioisomer thereof, wherein X1 is NH or N(CH3). 36. The compound of any one of claims 1-35, or a salt, solvate, tautomer, or regioisomer thereof, wherein each Y1, Y2, and Y3 is independently halo or alkyl. 37. The compound of claim 36, or a salt, solvate, tautomer, or regioisomer thereof, wherein Y2 is fluoro. 38. The compound of any one of the preceding claims, wherein R2 is fluoro. 39. The compound of any one of the preceding claims, wherein Y1 and Y3 are fluoro. 40. The compound of any one of the preceding claims, wherein R2, Y1, and Y3 are fluoro. 41. The compound of any one of the preceding claims, wherein R2, Y1, and Y3 are fluoro and GR is G. 42. The compound of any one of the preceding claims, wherein R2, Y1, and Y3 are fluoro, R1 is R7 (e.g., sulfone (e.g., -SO2CH3), sulfoxide (e.g., -S(=O)CH3), sulfonamide (e.g., -SO2NH2 or - SO2N(CH3)2), -OR3 (e.g., R3 being hydrogen, substituted or unsubstituted alkyl (e.g., haloalkyl), or substituted or unsubstituted aryl (e.g., phenyl)), or substituted or unsubstituted alkyl (e.g., haloalkyl)), and GR is G. 43. The compound of any one of the preceding claims, wherein R2, Y1, Y2, and Y3 are fluoro and R1 is G. 44. The compound of any one of the preceding claims, wherein X is absent or O; R2, Y1, Y2, and Y3 are fluoro; GR is -NH2, -N(CH3)2, or substituted or unsubstituted alkyl; and R1 is G. 45. The compound of any one of claims 1-34 or 36-40, wherein is selected from , , , , , , , , , , , , , , , , , , , and . 46. The compound of any one of claims 1-34 or 36-40, wherein is selected from , , , , , , , and . 47. The compound of any one of claims 1-34 or 36-40, wherein is selected from , , , and . 48. A compound or a salt, solvate, tautomer, or regioisomer thereof, wherein the compound is a compound from Table 1, Table 2, or Table 3. 49. A compound having a structure represented by Formula (I-A): D1-L-D2 Formula (I-A) wherein: D1 is a radical of a protein-binding ligand; D2 is a warhead radical (e.g., an aromatic (e.g., substituted phenyl) warhead radical); and L is a linker, or a pharmaceutically acceptable salt or solvate thereof. 50. The compound of claim 49, wherein D2 covalently modifies a target protein (e.g., tubulin (e.g., β-tubulin), Janus kinase 3 (JAK3), epidermal growth factor receptor (EGFR), Bruton's tyrosine kinase (BTK), Fibroblast Growth Factor Receptor 4 (FGFR4), receptor-interacting serine/threonine-protein kinase 2 (RIPK2), or cytoplasmic tyrosine-protein kinase (BMX)). 51. The compound according to claim 49 or 50, wherein D2 binds to, disrupts, and/or modifies a target protein (e.g., tubulin, JAK3, EGFR, BTK, FGFR4, RIPK2, or BMX). 52. The compound of any one of claims 49-51, wherein D2 comprises one or more warhead group, each warhead group being independently selected from the group consisting of substituted or unsubstituted sulfonamide (e.g., unsubstituted sulfonamide or sulfonamide substituted with alkyl (e.g., methyl)), sulfone, sulfoxide, substituted or unsubstituted amino (e.g., a secondary amine (e.g., -NH- or -NCH3-) or a tertiary amine (e.g., >N-)), or substituted aryl (e.g., aryl substituted with one or more substituent, each substituent being independently selected from sulfone, sulfoxide, sulfonamide, halogen (e.g., fluoro), hydroxy, substituted or unsubstituted alkoxy (e.g., unsubstituted alkoxy (e.g., methoxy), alkoxy substituted with halogen (e.g., fluoro) (e.g., -OCH2F, -OCHF2, or -OCF3), or alkoxy substituted with substituted or unsubsituted aryl (e.g., phenyl)), substituted or unsubstituted alkyl (e.g., alkyl substituted with halogen (e.g., fluoro) (e.g., -CH2F, -CHF2, or -CF3)))). 53. The compound of any one of claims 49-52, wherein D2 comprises an aryl substituted with one or more substituent, each substituent being independently selected from halogen (e.g., fluoro), hydroxy, substituted or unsubstituted alkoxy (e.g., unsubstituted alkoxy (e.g., methoxy), alkoxy substituted with halogen (e.g., fluoro) (e.g., -OCH2F, -OCHF2, or -OCF3), or alkoxy substituted with substituted or unsubsituted aryl (e.g., phenyl)), substituted or unsubstituted alkyl (e.g., alkyl substituted with halogen (e.g., fluoro) (e.g., -CH2F, -CHF2, or -CF3))). 54. The compound of any one of claims 49-53, wherein D2 comprises a sulfone, a sulfoxide, or a sulfonamide. 55. The compound of any one of claims 49-54, wherein D2 comprises a sulfone and an aryl substituted with one or more substituent, each substituent being independently selected from halogen (e.g., fluoro), hydroxy, substituted or unsubstituted alkoxy (e.g., unsubstituted alkoxy (e.g., methoxy), alkoxy substituted with halogen (e.g., fluoro) (e.g., -OCH2F, -OCHF2, or -OCF3), or alkoxy substituted with substituted or unsubsituted aryl (e.g., phenyl)), substituted or unsubstituted alkyl (e.g., alkyl substituted with halogen (e.g., fluoro) (e.g., -CH2F, -CHF2, or - CF3))). 56. The compound of any one of claims 49-55, wherein D2 comprises a sulfoxide and an aryl substituted with one or more substituent, each substituent being independently selected from halogen (e.g., fluoro), hydroxy, substituted or unsubstituted alkoxy (e.g., unsubstituted alkoxy (e.g., methoxy), alkoxy substituted with halogen (e.g., fluoro) (e.g., -OCH2F, -OCHF2, or -OCF3), or alkoxy substituted with substituted or unsubsituted aryl (e.g., phenyl)), substituted or unsubstituted alkyl (e.g., alkyl substituted with halogen (e.g., fluoro) (e.g., -CH2F, -CHF2, or - CF3))). 57. The compound of any one of claims 49-56, wherein D2 comprises a sulfonamide and an aryl substituted with one or more substituent, each substituent being independently selected from halogen (e.g., fluoro), hydroxy, substituted or unsubstituted alkoxy (e.g., unsubstituted alkoxy (e.g., methoxy), alkoxy substituted with halogen (e.g., fluoro) (e.g., -OCH2F, -OCHF2, or -OCF3), or alkoxy substituted with substituted or unsubsituted aryl (e.g., phenyl)), substituted or unsubstituted alkyl (e.g., alkyl substituted with halogen (e.g., fluoro) (e.g., -CH2F, -CHF2, or - CF3))). 58. The compound of any one of claims 49-57, wherein D2 is or comprises an aryl substituted with halogen (e.g., fluoro). 59. The compound of any one of claims 49-58, wherein D2 is or comprises an aryl substituted with halogen (e.g., fluoro) and alkyl substituted with halogen (e.g., fluoro) (e.g., -CH2F, -CHF2, or -CF3). 60. The compound of any one of claims 49-59, wherein D2 is or comprises an aryl substituted with halogen (e.g., fluoro) and hydroxy. 61. The compound of any one of claims 49-60, wherein D2 is or comprises an aryl substituted with halogen (e.g., fluoro) and unsubstituted alkoxy (e.g., methoxy). 62. The compound of any one of claims 49-61, wherein D2 is or comprises an aryl substituted with halogen (e.g., fluoro) and alkoxy substituted with substituted or unsubsituted an aryl (e.g., phenyl). 63. The compound of any one of claims 49-62, wherein D2 is or comprises an aryl substituted with halogen (e.g., fluoro) and alkoxy substituted with halogen (e.g., fluoro) (e.g., -OCH2F, - OCHF2, or -OCF3). 64. The compound of any one of claims 49-63, wherein D2 is or comprises an aryl substituted with halogen (e.g., fluoro) and sulfone. 65. The compound of any one of claims 49-64, wherein D2 is or comprises an aryl substituted with halogen (e.g., fluoro) and sulfoxide. 66. The compound of any one of claims 49-65, wherein D2 is or comprises an aryl substituted with halogen (e.g., fluoro) and unsubstituted sulfonamide. 67. The compound of any one of claims 49-66, wherein D2 is or comprises an aryl substituted with halogen (e.g., fluoro) and substituted sulfonamide (e.g., sulfonamide substituted with alkyl (e.g., methyl)). 68. The compound of any one of claims 49-63, wherein D2 comprises a sulfone. 69. The compound of any one of claims 49-63, wherein D2 comprises a sulfonamide. 70. The compound of any one of claims 49-63, wherein D2 comprises a sulfoxide. 71. The compound of any one of claims 49-70, wherein the linker is a non-releasable linker (e.g., the linker does not decompose (e.g., hydrolyze) or release the warhead radical (or a free form thereof), the radical of the protein-binding ligand (or a free form thereof), or any other portion of the compound (e.g., a radical of any Formula provided herein) (or a free form thereof)). 72. The compound of any one of claims 49-71, wherein the linker comprises one or more linker group, each linker group being independently selected from the group consisting of -O-, (substituted or unsubstituted) amino, substituted or unsubstituted (e.g., acyclic (e.g., straight or branched) or cyclic) alkyl(ene), substituted or unsubstituted (e.g., acyclic (e.g., straight or branched) or cyclic) heteroalkyl(ene), and substituted or unsubstituted alkoxy. 73. The compound of any one of claims 49-72, wherein the linker comprises one or more linker group, each linker group being independently selected from the group consisting of (substituted or unsubstituted) amino and substituted or unsubstituted (e.g., acyclic (e.g., straight or branched) or cyclic) heteroalkyl(ene). 74. The compound of any one of claims 49-73, wherein the linker is -O-, (substituted or unsubstituted) amino or substituted or unsubstituted (e.g., acyclic (e.g., straight or branched) or cyclic) heteroalkyl(ene). 75. The compound of any one of claims 49-74, wherein L is a bond, substituted or unsubstituted alkylene (e.g., C(=O), methylene, ethylene, or alkyl substituted with oxo and/or heterocyclyl (e.g., azetidinyl, pyrrolidinyl, or pipiridinyl)), substituted or unsubstituted heteroalkylene (e.g., -N=CH-, -CH2NH-, -CH2NCH3-, -CH2CH2NH-, -NHCH2CH2NH-, - CH2CH2NCH3-, -CH2CH2NHCH2-, -NHCH2CH2NHCH2-, -NHCH2CH2CH2NH-, - CH2CH2CH2NH-, or heteroalkyl substituted with oxo (e.g., -C(=O)NH-, -CH2CH2N(CH3)C(=O)- , -CH2CH2NHC(=O)-, -NHCH2CH2N(CH3)C(=O)-, -NHCH2CH2NHC(=O)-, - CH2CH2CH2N(CH3)C(=O)-, or -CH2CH2CH2NHC(=O)-)), substituted or unsubstituted alkoxy (e.g., methoxy), substituted or unsubstituted pipiridinyl, substituted or unsubstituted pyrrolidinyl, substituted or unsubstituted azetidinyl, or substituted or unsubstituted amino (e.g., -NH-, amino substituted with substituted or unsubstituted aryl (e.g., -NH-phenyl-, aryl substituted with amino (e.g., -NH-phenyl-NH-) or aryl substituted with alkoxy (e.g., -NH-phenyl-OCH2-))). 76. The compound of any one of claims 49-75, wherein L is a bond. 77. The compound of any one of claims 49-76, wherein D1 has a structure represented in Table 2 or Table 3 (e.g., and L is a bond). 78. A compound selected from Table 4, Table 5, Table 6, Table 7, or Table 8. 79. A pharmaceutically acceptable composition comprising a compound of any one of the preceding claims, or a salt, solvate, tautomer, or regioisomer thereof, and one or more of pharmaceutically acceptable excipients. 80. A protein modified with a compound of any one of the preceding claims, or a salt, solvate, tautomer, or regioisomer thereof, wherein the compound forms a covalent bond with a sulfur atom of a cysteine residue of the protein. 81. A method of modifying (e.g., attaching to and/or degrading) a polypeptide with a compound, comprising contacting the polypeptide with a compound of any one of the preceding claims, or a salt, solvate, tautomer, or regioisomer thereof, to form a covalent bond with a sulfur atom of a cysteine residue of the polypeptide. 82. A method of binding a compound to a polypeptide, comprising contacting the polypeptide with a compound of any one of the preceding claims, or a salt, solvate, tautomer, or regioisomer thereof. 83. A method of disrupting a polypeptide (e.g. the function thereof), comprising contacting the polypeptide with a compound of any one of the preceding claims, or a salt, solvate, tautomer, or regioisomer thereof. |
[00275] In some embodiments, D2 is selected from , , , and . [00276] In some embodiments, D2 or is selected from , , , , , , , , , , , , , , , , , , , and . [00277] In some embodiments, is selected from , , , , , , , and . [00278] In some embodiments, is selected from , , , and . [00279] In some embodiments, the benzenesulfonamide derivative compound described herein has a structure provided in Table 1. In Table 1 and in other tables herein, when stating R 1 =R 2 , it is to be understood that R 1 and R 2 are the same as R 1 in the previous recitation. For example, in compound 7aaa, R 1 =R 2 , means that R 1 and R 2 are both H because R 1 is H in the previously recited compound 7aa. Thus, in compound 7aaa, R 1 /R 2 /Y is H/H/F. Table 1
[00280] In some embodiments, disclosed herein is a pharmaceutically acceptable salt, solvate, tautomer, regioisomer, or stereoisomer of a compound of Table 1. [00281] In some embodiments, the benzenesulfonamide derivative compound described herein has a structure provided in Table 2. For the benzenesulfonamide derivative compound in Table 2, R 1 , R 2 , Y 1 , Y 2 , and Y 3 are as described in Table 1. Table 2 [00282] In some embodiments, disclosed herein is a pharmaceutically acceptable salt, solvate, tautomer, regioisomer, or stereoisomer of a compound of Table 2. [00283] In some embodiments, the benzenesulfonamide derivative compound described herein has a structure provided in Table 3. For the benzenesulfonamide derivative compound in Table 3, R 1 , R 2 , Y 1 , Y 2 , and Y 3 are as described in Table 1. Table 3 [0 0284] In some embodiments, disclosed herein is a pharmaceutically acceptable salt, solvate, tautomer, regioisomer, or stereoisomer of a compound of Table 3. [00285] In some embodiments, the compound described herein has a structure provided in Table 4. Table 4 [00286] In some embodiments, the compound described herein has a structure provided in Table 5. Table 5 [00287] In some embodiments, the compound described herein has a structure provided in Table 6. Table 6 [00288] In some embodiments, the compound described herein has a structure provided in Table 7. Tbl 7 [00289] In some embodiments, the compound described herein has a structure provided in Table 8. Table 8 Preparation of Compounds [00290] The compounds used in the reactions described herein are made according to organic synthesis techniques known to those skilled in this art, starting from commercially available chemicals and/or from compounds described in the chemical literature. "Commercially available chemicals" are obtained from standard commercial sources including Acros Organics (Pittsburgh, PA), Aldrich Chemical (Milwaukee, WI, including Sigma Chemical and Fluka), Apin Chemicals Ltd. (Milton Park, UK), Avocado Research (Lancashire, U.K.), BDH Inc. (Toronto, Canada), Bionet (Cornwall, U.K.), Chemservice Inc. (West Chester, PA), Crescent Chemical Co. (Hauppauge, NY), Eastman Organic Chemicals, Eastman Kodak Company (Rochester, NY), Fisher Scientific Co. (Pittsburgh, PA), Fisons Chemicals (Leicestershire, UK), Frontier Scientific (Logan, UT), ICN Biomedicals, Inc. (Costa Mesa, CA), Key Organics (Cornwall, U.K.), Lancaster Synthesis (Windham, NH), Maybridge Chemical Co. Ltd. (Cornwall, U.K.), Parish Chemical Co. (Orem, UT), Pfaltz & Bauer, Inc. (Waterbury, CN), Polyorganix (Houston, TX), Pierce Chemical Co. (Rockford, IL), Riedel de Haen AG (Hanover, Germany), Spectrum Quality Product, Inc. (New Brunswick, NJ), TCI America (Portland, OR), Trans World Chemicals, Inc. (Rockville, MD), and Wako Chemicals USA, Inc. (Richmond, VA). [00291] Suitable reference books and treatise that detail the synthesis of reactants useful in the preparation of compounds described herein, or provide references to articles that describe the preparation, include for example, "Synthetic Organic Chemistry", John Wiley & Sons, Inc., New York; S. R. Sandler et al., "Organic Functional Group Preparations," 2nd Ed., Academic Press, New York, 1983; H. O. House, "Modern Synthetic Reactions", 2nd Ed., W. A. Benjamin, Inc. Menlo Park, Calif.1972; T. L. Gilchrist, "Heterocyclic Chemistry", 2nd Ed., John Wiley & Sons, New York, 1992; J. March, "Advanced Organic Chemistry: Reactions, Mechanisms and Structure", 4th Ed., Wiley-Interscience, New York, 1992. Additional suitable reference books and treatise that detail the synthesis of reactants useful in the preparation of compounds described herein, or provide references to articles that describe the preparation, include for example, Fuhrhop, J. and Penzlin G. "Organic Synthesis: Concepts, Methods, Starting Materials", Second, Revised and Enlarged Edition (1994) John Wiley & Sons ISBN: 3-527-29074-5; Hoffman, R.V. "Organic Chemistry, An Intermediate Text" (1996) Oxford University Press, ISBN 0-19-509618- 5; Larock, R. C. "Comprehensive Organic Transformations: A Guide to Functional Group Preparations" 2nd Edition (1999) Wiley-VCH, ISBN: 0-471-19031-4; March, J. "Advanced Organic Chemistry: Reactions, Mechanisms, and Structure" 4th Edition (1992) John Wiley & Sons, ISBN: 0-471-60180-2; Otera, J. (editor) "Modern Carbonyl Chemistry" (2000) Wiley-VCH, ISBN: 3-527-29871-1; Patai, S. "Patai's 1992 Guide to the Chemistry of Functional Groups" (1992) Interscience ISBN: 0-471-93022-9; Solomons, T. W. G. "Organic Chemistry" 7th Edition (2000) John Wiley & Sons, ISBN: 0-471-19095-0; Stowell, J.C., "Intermediate Organic Chemistry" 2nd Edition (1993) Wiley-Interscience, ISBN: 0-471-57456-2; "Industrial Organic Chemicals: Starting Materials and Intermediates: An Ullmann's Encyclopedia" (1999) John Wiley & Sons, ISBN: 3-527-29645-X, in 8 volumes; "Organic Reactions" (1942-2000) John Wiley & Sons, in over 55 volumes; and "Chemistry of Functional Groups" John Wiley & Sons, in 73 volumes. [00292] Specific and analogous reactants are optionally identified through the indices of known chemicals prepared by the Chemical Abstract Service of the American Chemical Society, which are available in most public and university libraries, as well as through on-line databases (contact the American Chemical Society, Washington, D.C. for more details). Chemicals that are known but not commercially available in catalogs are optionally prepared by custom chemical synthesis houses, where many of the standard chemical supply houses (e.g., those listed above) provide custom synthesis services. A reference useful for the preparation and selection of pharmaceutical salts of the benzenesulfonamide derivative compounds described herein is P. H. Stahl & C. G. Wermuth "Handbook of Pharmaceutical Salts", Verlag Helvetica Chimica Acta, Zurich, 2002. Pharmaceutical Compositions [00293] In certain embodiments, the benzenesulfonamide derivative compound described herein is administered as a pure chemical. In other embodiments, the benzenesulfonamide derivative compound described herein is combined with a pharmaceutically suitable or acceptable carrier (also referred to herein as a pharmaceutically suitable (or acceptable) excipient, physiologically suitable (or acceptable) excipient, or physiologically suitable (or acceptable) carrier) selected on the basis of a chosen route of administration and standard pharmaceutical practice as described, for example, in Remington: The Science and Practice of Pharmacy (Gennaro, 21 st Ed. Mack Pub. Co., Easton, PA (2005)). [00294] Provided herein is a pharmaceutical composition comprising at least one benzenesulfonamide derivative compound as described herein, or a stereoisomer, pharmaceutically acceptable salt, hydrate, or solvate thereof, together with one or more pharmaceutically acceptable carriers. The carrier(s) (or excipient(s)) is acceptable or suitable if the carrier is compatible with the other ingredients of the composition and not deleterious to the recipient (i.e., the subject or the patient) of the composition. [00295] One embodiment provides a pharmaceutical composition comprising a pharmaceutically acceptable excipient and a compound of Formula (I), or a compound disclosed in Table 1, Table 2, or Table 3, or a pharmaceutically acceptable salt, solvate, tautomer, or regioisomer thereof. [00296] One embodiment provides a method of preparing a pharmaceutical composition comprising mixing a compound of Formula (I), or a compound disclosed in Table 1, Table 2, or Table 3, or a pharmaceutically acceptable salt, solvate, tautomer, or regioisomer thereof, and a pharmaceutically acceptable carrier. [00297] In certain embodiments, the benzenesulfonamide derivative compound as described by Formula (I), or a compound disclosed in Table 1, Table 2, or Table 3, is substantially pure, in that it contains less than about 5%, or less than about 1%, or less than about 0.1%, of other organic small molecules, such as unreacted intermediates or synthesis by-products that are created, for example, in one or more of the steps of a synthesis method. [00298] Suitable oral dosage forms include, for example, tablets, pills, sachets, or capsules of hard or soft gelatin, methylcellulose or of another suitable material easily dissolved in the digestive tract. In some embodiments, suitable nontoxic solid carriers are used which include, for example, pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, sodium saccharin, talcum, cellulose, glucose, sucrose, magnesium carbonate, and the like. (See, e.g., Remington: The Science and Practice of Pharmacy (Gennaro, 21 st Ed. Mack Pub. Co., Easton, PA (2005)). [00299] In some embodiments, the compound as described by Formula (I), or a compound disclosed in Table 1, Table 2, or Table 3, or pharmaceutically acceptable salt, solvate, tautomer, or regioisomer thereof, is formulated for administration by injection. In some instances, the injection formulation is an aqueous formulation. In some instances, the injection formulation is a non-aqueous formulation. In some instances, the injection formulation is an oil-based formulation, such as sesame oil, or the like. [00300] The dose of the composition comprising at least one compound as described herein differs depending upon the subject or patient's (e.g., human) condition. In some embodiments, such factors include general health status, age, and other factors. [00301] Pharmaceutical compositions are administered in a manner appropriate to the disease to be treated (or prevented). An appropriate dose and a suitable duration and frequency of administration will be determined by such factors as the condition of the patient, the type and severity of the patient's disease, the particular form of the active ingredient, and the method of administration. In general, an appropriate dose and treatment regimen provides the composition(s) in an amount sufficient to provide therapeutic and/or prophylactic benefit (e.g., an improved clinical outcome, such as more frequent complete or partial remissions, or longer disease-free and/or overall survival, or a lessening of symptom severity. Optimal doses are generally determined using experimental models and/or clinical trials. The optimal dose depends upon the body mass, weight, or blood volume of the patient. [00302] Oral doses typically range from about 1.0 mg to about 1000 mg, one to four times, or more, per day. Methods of Treatment [00303] One embodiment provides a compound of Formula (I), or a compound disclosed in Table 1, Table 2, or Table 3, or a pharmaceutically acceptable salt, solvate, tautomer, or regioisomer thereof, for use in a method of treatment of the human or animal body. [00304] One embodiment provides a compound of Formula (I), or a compound disclosed in Table 1, Table 2, or Table 3, or a pharmaceutically acceptable salt, solvate, tautomer, or regioisomer thereof, for use in a method of treatment of cancer or neoplastic disease. [00305] One embodiment provides a use of a compound of Formula (I), or a compound disclosed in Table 1, Table 2, or Table 3, or a pharmaceutically acceptable salt, solvate, tautomer, or regioisomer thereof, in the manufacture of a medicament for the treatment of cancer or neoplastic disease. [00306] In some embodiments, described herein is a method of treating cancer in a patient in need thereof comprising administering to the patient a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, tautomer, or regioisomer thereof. [00307] In some embodiments, described herein is a method of treating cancer in a patient in need thereof comprising administering to the patient a compound disclosed in Table 1, Table 2, or Table 3, or a pharmaceutically acceptable salt, solvate, tautomer, or regioisomer thereof. [00308] In some embodiments, also described herein is a method of treating cancer in a patient in need thereof comprising administering to the patient a pharmaceutical composition comprising a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, tautomer, or regioisomer thereof, and a pharmaceutically acceptable excipient. [00309] In some embodiments, also described herein is a method of treating cancer in a patient in need thereof comprising administering to the patient a pharmaceutical composition comprising a compound disclosed in Table 1, Table 2, or Table 3, or a pharmaceutically acceptable salt, solvate, tautomer, or regioisomer thereof, and a pharmaceutically acceptable excipient. In some embodiments, the cancer is selected from chronic and acute myeloid leukemia. In some embodiments, the cancer is selected from chronic lymphocytic leukemia and small lymphocytic lymphoma. [00310] Provided herein is the method wherein the pharmaceutical composition is administered orally. Provided herein is the method wherein the pharmaceutical composition is administered by injection. [00311] One embodiment provides a protein, or an active fragment thereof, modified with a benzenesulfonamide derivative compound as described herein, or a pharmaceutically acceptable salt, solvate, tautomer, or regioisomer thereof, wherein the compound forms a covalent bond with a sulfur atom of a cysteine residue of the protein. In some embodiments, the protein is tubulin. In some embodiments, the protein is BTK. In some embodiments, the protein is EGFR. In some embodiments, the protein is JAK3. [00312] One embodiment provides a method of modifying (e.g., attaching to and/or degrading) a polypeptide with a benzenesulfonamide derivative compound as described herein, or a pharmaceutically acceptable salt, solvate, tautomer, or regioisomer thereof, comprising contacting the polypeptide with the compound to form a covalent bond with a sulfur atom of a cysteine residue of the polypeptide. [00313] One embodiment provides a method of binding a compound to a polypeptide, comprising contacting the polypeptide with a benzenesulfonamide derivative compound as described herein, or a pharmaceutically acceptable salt, solvate, tautomer, or regioisomer thereof. In some embodiments, the polypeptide is tubulin. In some embodiments, the polypeptide is BTK. In some embodiments, the polypeptide is EGFR. In some embodiments, the polypeptide is JAK3. [00314] One embodiment provides a method of disrupting a protein, or an active fragment thereof (e.g. a function thereof), comprising contacting the protein or an active fragment thereof (e.g., polypeptide thereof) with a compound of any one of the preceding claims, or a salt, solvate, tautomer, or regioisomer thereof. [00315] Other embodiments and uses will be apparent to one skilled in the art in light of the present disclosures. The following examples are provided merely as illustrative of various embodiments and shall not be construed to limit the present disclosure in any way. EXAMPLES I. Chemical Synthesis [00316] In some embodiments, the benzenesulfonamide derivative compounds disclosed herein are synthesized according to the following examples. As used below, and throughout the specification, the following abbreviations, unless otherwise indicated, shall be understood to have the following meanings: o C degrees Celsius δ chemical shift in parts per million downfield from tetramethylsilane ACN acetonitrile bs or brs broad singlet DCM dichloromethane (CH2Cl2) dd doublet of doublets DMF dimethylformamide DMSO dimethylsulfoxide EA or EtOAc ethyl acetate ESI electrospray ionization Et ethyl FA formic acid g gram(s) h/hr/hrs hour(s) HPLC high performance liquid chromatography Hz hertz J coupling constant (in NMR spectrometry) LCMS liquid chromatography mass spectrometry μ micro m multiplet (spectral); meter(s); milli M molar M + parent molecular ion Me methyl MHz megahertz min minute(s) mol mole(s); molecular (as in mol wt) mL milliliter MS mass spectrometry nm nanometer(s) NMR nuclear magnetic resonance pH potential of hydrogen; a measure of the acidity or basicity of an aqueous solution PE petroleum ether PMB para-methoxybenzyl RT room temperature s singlet (spectral) t triplet (spectral) T temperature TFA trifluoroacetic acid THF tetrahydrofuran [00317] Exemplary compounds of the application are synthesized using the methods described herein, or other methods, which are known in the art. Unless otherwise noted, reagents and solvents are obtained from commercial suppliers. [00318] Anhydrous solvents, methanol, acetonitrile, dichloromethane, tetrahydrofuran and dimethylformamide, are purchased from Sigma Aldrich and used directly from Sure-Seal bottles. Reactions are performed under an atmosphere of dry nitrogen in oven-dried glassware and are monitored for completeness by thin-layer chromatography (TLC) using silica gel (visualized by UV light, or developed by treatment with KMnO4 stain and ninhydrin stain) or by LC/MS. NMR spectra are recorded in Bruker Avance III spectrometer at 23°C, unless otherwise stated, operating at 400 MHz for 1 H NMR and 376 MHz 19 F NMR spectroscopy either in CDCl 3 , CD 3 OD, CD 3 CN or DMSO-d6. Chemical shifts (d) are reported in parts per million (ppm) after calibration to residual isotopic solvent. Coupling constants (J) are reported in Hz. Mass spectrometry was performed with an Agilent G6110A single quad mass spectrometer with an ESI source associated with an Agilent 1100 HPLC system. Before biological testing, inhibitor purity was evaluated by reversed-phase HPLC (rpHPLC). The following conditions were employed for analysis by rpHPLC: [00319] Method I: Mobile phase is a linear gradient consisting of a changing solvent composition of 10 % to 90% ACN in H2O with 0.1 % TFA (v/v) over 7 minutes, followed by 5 minutes of 100% ACN. Method was run on a Waters Atlantis 5 μm C18, 150 mm x 4.6 mm column; maintained at a temperature of 30°C; flow rate of 1.0 mL/min. [00320] Method II: Mobile phase is a linear gradient consisting of a changing solvent composition of 10 % to 90% ACN in H 2 O with 0.1 % Ammonia (v/v) over 7 minutes, followed by 5 minutes of 100% ACN. Method was run on a Waters Atlantis 5 μm C18, 150 mm x 4.6 mm column; maintained at a temperature of 30°C; flow rate of 1.0 mL/min. [00321] Method III: Mobile phase is a linear gradient consisting of a changing solvent composition of 15 % to 100% ACN in H 2 O with 0.1 % TFA (v/v) over 15 minutes. Method was run on a Phenomenex Luna 5μm C18 150 mm x 4.6 mm column; column maintained at a temperature of 25°C; flow rate of 1.0 mL/min. [00322] For reporting HPLC data, percentage purity is given after the retention time for each condition. All biologically evaluated compounds are >95 % chemical purity as measured by HPLC. [00323] In some embodiments, compounds of the present disclosure are synthesized using similar protocols based on the general procedures A-J, and Examples 1-10 below. General procedure A’ [00324] A substituted fluoro-arene (1 eq) was added to a cold solution of chlorosulfonic acid cooled to 0°C. The reaction vessel was outfitted with a water jacketed reflux condenser and subsequently heated to 120°C using a sand bath for 1-16 hrs. Once starting material was consumed, the reaction was cooled to room temperature then poured slowly over crushed ice. The resulting mixture was partitioned between DCM and 1M HCl and the organic phase separated. The remaining aqueous phase was extracted twice more with DCM. The combined organic phases were washed with brine, dried over sodium sulfate, and concentrated in vacuo to afford the desired arylsulfonylchloride. General procedure B’ [00325] A substituted fluoro-arene (1 eq) was dissolved in anhydrous THF under a positive pressure of argon. The resulting solution was cooled to -78 °C. Once at temperature, n- butyllithium (2.5 M in hexane, 1.2 eq) was added dropwise to limit excess evolution of heat. After 30 minutes, a solution of sulfuryl chloride (1.1 eq) in hexanes (0.1 M) was added quickly via syringe. After 1 hour, water was added to quench the reaction and the resulting mixture partitioned between ethyl acetate and cold water. The organic phase was separated, washed with cold water twice, dried over sodium sulfate and concentrated in vacuo to afford the anticipated sulfonylchloride. General Procedure C’ [00326] Under an inert atmosphere of argon, an appropriate aryl sulfonamide was added to a suspension of pyrylium tetrafluoroborate (2 eq) and magnesium chloride (2.5 eq) in acetonitrile (0.1 M) stirring at room temperature. The reaction was heated to 75 °C for 6 hours then cooled to room temperature. Once cooled, the mixture was filtered through a short plug of silica and the filtrate concentrated under reduced pressure. The concentrate was separated using flash column chromatography techniques to afford the desired sulfonylchloride. General Procedure D’ [00327] To a solution of thioether (1 eq) in DCM (0.1M – 0.3M) at room temperature was added 3-Chloroperoxybenzoic acid (4 eq, 77% purity). Reaction progress was monitored by TLC. Once the starting material was consumed, the reaction was quenched with a 1M aqueous solution of sodium hydroxide. The organic phase was sepateated and the remaining aqueous extracted twice with dichloromethane. The combined organic phases were washed with brine, dried over anhydrous sodium sulfate and concentrated under vacuum. The crude material was separated using flash column chromatography techniques to afford the desired methylsulfone. Synthesis of sulfonamides: General Procedure E’ [00328] An appropriate sulfonylchloride (0.9-1.2 eq) was incubated with its corresponding pyrazololopyrimidine (1 eq) in anhydrous DCM (0.1 M-0.25 M) under an atmosphere of argon. The resulting mixture was cooled to 0°C and stirred for 15 minutes. Neat triethylamine (3-5 eq) was slowly added to the mixture and it was stirred at 0°C for a further 3-16 hrs. The reaction quenched with 0.1M HCl (aq) and vigorously stirred for 10-15 min, after which the organic layer was separated. The aqueous layer was extracted with DCM one further time. The combined organic layers were dried over sodium sulfate, filtered, and evaporated. The crude material was purified by either normal-phase flash column chromatography on silica gel or reverse-phase chromatography. Synthesis of direct-linked Sulfones: General Procedure F’ [00329] Methods to oxidize analogous thioethers to the corresponding sulfone are known in the art (WO2019/141694). The G linked sulfone can be prepared from the corresponding thioether in the presence of 3-Chloroperoxybenzoic acid (mCPBA, 4 eq.) in DCM under inert conditions (argon or nitrogen). The reaction can be worked up with water, brine and DCM, and the desired sulfone isolated using normal-phase flash column chromatography on silica gel or reverse-phase chromatography. Synthesis of direct-linked Sulfoximines: General Procedure G’ [00330] Methods to oxidize analogous thioethers to the corresponding sulfoximine are known in the art (Chem. Comm., 2017, 12, p. 2064 - 2067). The G linked sulfoximine can be prepared from the corresponding thioether in the presence of ammonium carbamate (1.5 eq.), iodobenzenediacetate (PIDA, 2.1 eq.) in methanol at room temperature. The reaction can be worked up with water, brine and DCM, and the desired sulfoximine isolated using normal-phase flash column chromatography on silica gel or reverse-phase chromatography. Synthesis of Sulfonimidamides: General Procedure H’ [00331] The starting material, compound (I), can be prepared according to previously reported procedures (Angew. Chem. Int. Ed.2017, 56, 14937). An oven-dried flask charged with (I) (1.0 equiv.) and THF (0.1 M) is cooled to 0 °C. Then the corresponding organometallic reagent (1.0 equiv.) can be added dropwise and stirred at 0 °C for 5 min. Next, in a dark fume hood, tert-butyl hypochlorite (1.05 equiv.) is added and the reaction mixture is allowed to stir for 15 min, followed by the addition of triethylamine (1.0 equiv.) and the corresponding ligand (G or GNR) (1.0-1.2 equiv.). The reaction mixture is left stirring at room temperature for 16 h. Finally, methanesulfonic acid (5.0 equiv.) is added, and the reaction stirred vigorously for 15 min at room temperature. The reaction is quenched by diluting it with DCM and the addition of a saturated aqueous solution of sodium bicarbonate. The two layers are partitioned and the aqueous layer is extracted with DCM (×3). Combined organic layers are dried over magnesium sulfate (MgSO4), filtered and concentrated in vacuo. Crude samples can be purified by either normal-phase flash column chromatography on silica gel or reverse-phase chromatography. Synthesis of para-direct-linked Sulfones: General Procedure I’ [00332] Procedures detailing the addition of a nucleophile to the 4-position of the pentafluorobenzene methyl sulfone are known (J. Chem. Soc., Perkin Trans. 2000, 4265–4278). In one embodiment, G-NHR can be deprotonated in THF using sodium hexamethyldisilazane to prepare the corresponding sodium amide. The sodium amide can then be added to a cold solution (0 °C) of 1,2,3,4,5-pentafluoro-6-(methylsulfonyl)benzene in THF to prepare the anticipated para- substituted tetrafluorobenzene sulfone. The reaction can be worked up with water, brine and EtOAc, and the desired product isolated using normal-phase flash column chromatography on silica gel or reverse-phase chromatography. Synthesis of ortho-direct-linked Sulfones: General Procedure J’ [00333] Procedures detailing the addition of a nucleophile to the 2-position of the pentafluorobenzene methyl sulfone/sulfoxide are known (Zhurnal Organicheskoi Khimii, 1980, 5, 1029-1034). In one embodiment, G-NHR can be deprotonated in THF using a strong base, such as methyl lithium, to prepare the corresponding lithium amide. The lithium amide can then be added to a cold solution (0 °C) of 1,2,3,4,5-pentafluoro-6-(methylsulfonyl)benzene in toluene to prepare the anticipated ortho-substituted tetrafluorobenzene sulfone. The reaction can be worked up with water, brine and EtOAc, and the desired product isolated using normal-phase flash column chromatography on silica gel or reverse-phase chromatography. Example 1: N-((3S,6S)-1-((2-(difluoromethoxy)-3,4,5,6-tetrafluorophenyl )sulfonyl)-6- methylpiperidin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine (Compound 7ae, Table 1) [00334] Compound 7ae, as an example for analogous routes to similar compounds, is synthesized by SNAr displacement of commercially available chloride followed by Boc- deprotection and sulfonamide formation (detailed in General Procedure E’) with the previously described sulfonyl chlorides to give final product 7ae. Example 2: (R)-N-(7-chloro-1-(1-methylazepan-3-yl)-1H-benzo[d]imidazol- 2-yl)-2- (difluoromethyl)-3,4,5,6-tetrafluorobenzenesulfonamide and (R)-7-chloro-1-(1-((2- (difluoromethoxy)-3,4,5,6-tetrafluorophenyl)sulfonyl)azepan- 3-yl)-1H-benzo[d]imidazol-2- amine (Compound 26a and 28a, Table 2) Scheme 1 Scheme 2 [00335] Compound 26a2 (Scheme 1) or 28a2 (Scheme 2), for example, can be prepared as described in Journal of Medicinal Chemistry 201659 (14), 6671-6689 by treatment of 1-chloro- 2-fluoro-3-nitrobenzene with 26a1 or 28a1 or appropriately protected diamines, followed by nitro reduction and cyclization with cyanogen bromide to afford 2-aminobenzimidazole intermediates 26a2 and 28a2. Reaction of 28a2 with previously prepared sulfonyl chlorides (General Procedure E) will prepare final compound 28a. Similarly, a protection of amine 26a2 as the 1-chloro- ethylcarbamate, followed by Boc-deprotection, coupling with the appropriate sulfonyl chloride, using General Procedure G’, and final deprotection of the carbamate furnishes compound 26a. Example 3: (S)-3-(4-phenoxyphenyl)-1-(1-((2,3,4,5-tetrafluoro-6- (fluoromethyl)phenyl)sulfonyl)piperidin-3-yl)-1H-pyrazolo[3, 4-d]pyrimidin-4-amine (Compound 45a) Scheme 3 [00336] Compound 45a and related examples can be prepared according to the route in Scheme 3 starting from commercially available 1H-Pyrazolo[3,4-d]pyrimidin-4-amine. Iodination using NIS, followed by Mitsunobu functionalization with cyclic and acyclic alcohols provides the appropriate intermediate, example A-2. Suzuki coupling followed by Boc-deprotection and sulfonamide formation accorind to General Procedure G’ affords the product example 45a. Example 4: N-(3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidi n-1-yl)phenyl)- 2,3,4,5-tetrafluoro-6-(trifluoromethoxy)benzenesulfonamide (Compound 47a) Scheme 4 [00337] Compound 47a and related examples can be prepared via Scheme 4 starting from commercially available 3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine. Copper mediated cross-coupling with (3-nitrophenyl)boronic acid, followed by reduction of the installed nitro-group affords intermediate B-1 which can be further derivatized. Sulfonamide formation using General Procedure G affords the final products 47a. Example 5: 5-fluoro-N 4 -(4-(2-methoxyethoxy)phenyl)-N 2 -(3-((2,3,4,5-tetrafluoro-6- (methylsulfonyl)phenyl)amino)phenyl)pyrimidine-2,4-diamine (Compound 75a) Scheme 5 [00338] Compound 75a and related examples can be synthesized from commercially available 2,4-dichloro-5-fluoropyrimidine using Scheme 5 and analogous routes known to those in the art. SNAr substitution using the appropriate amine or aniline affords intermediate 75a1. A second SNAr substitution at higher temperature, followed by nitro reduction using iron and ammonium chloride affords the intermdediate 75a3. Direct-linked sulfone product 75a can be formed through direct substitution of a methyl sulfone, according to General Procedure I’, using LDA as base. Example 6: N-(2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxy-5-((4 -(1-methyl-1H- indol-3-yl)pyrimidin-2-yl)amino)phenyl)-2,3,4,5-tetrafluoro- 6-methoxybenzenesulfonamide (Compounds 85ac, Table 1) Scheme 6 [00339] Compound 85ac can be prepared from commercially available 4-fluoro-2- methoxyaniline using similar conditions to those in Journal of Heterocyclic Chemistry, 54(5), 2898-2901. 85a1 was nitrated using H 2 SO 4 /KNO 3 conditions, followed by guanidinylation with cyanamide and substitution by N,N,N-trimethylethane-1,2-diamine to give the key intermediate 85a4, which is used directly in the next step. The other intermediate 85a6 was prepared by methylation of 1-(1H-indol-3-yl)ethan-1-one and condensation with N,N-dimethylformamide dimethyl acetal. Heating compounds 85a6 and 85a4 in 1-butanol at 100°C followed by catalytic hydrogenation using H2/Raney Ni afford 85a8, which can be reacted with previously prepared sulfonylchlorides to afford 85ac, according to General Procedure G’. [00340] Example 7: N-(4-((3-chloro-4-(pyridin-2-ylmethoxy)phenyl)amino)-3-cyano -7- ethoxyquinolin-6-yl)-2-(difluoromethyl)-3,4,5,6-tetrafluorob enzenesulfonimidamide (Compound 21c) Scheme 7 [00341] Compound 21c-7 can be prepared from commercially available methyl 3-amino-4- hydroxybenzoate as described in Org. Process Res. Dev.2012, 16, 12, 1970–1973. Compound 21c-8 can be prepared from Compound 21c-7 as described in WO2010/151710, 2010, whereby a mixture of Compound 21c-7, commercially available 3-chloro-4-(pyridin-2-ylmethoxy)aniline and methanesulfonic acid in ethanol is refluxed for 6 hours, which is sequentially added with HCl and lastly, the isolated product is treated with aqueous K 2 CO 3 in MeOH to yield the desired Compound 21c-8. The Compound 21c can be prepared from sulfonylation of Compound 21c- 8 with 2-(difluoromethyl)-3,4,5,6-tetrafluorobenzenesulfonimidoyl chloride (prepared as described in General Procedure H’) by using General Procedure H’. [00342] Example 8: 2,3,4,5-tetrafluoro-N-(7-fluoro-4-(o-tolylamino)imidazo[1,5- a]quinoxalin-8-yl)-N,6-dimethylbenzenesulfonamide (Compound 49b) Scheme 8 [00343] Compound 49b-1 can be prepared from commercially available 4,5-difluoro-2- nitroaniline as described in Bioorg. Med. Chem. Lett.21 (2011) 6258–6263. The Compound 49b can be prepared from sulfonylation of Compound 49b-1 with 2,3,4,5-tetrafluoro-6- methylbenzenesulfonyl chloride (prepared as described in General Procedure B’) by using General Procedure E’. Example 9: 2,3,4,5-tetrafluoro-6-methoxy-N-(6-((3-phenoxybenzyl)amino)p yridin-2- yl)benzenesulfonamide (Compound 69a) Scheme 9 [00344] Compound 69a-1 can be prepared from commercially available 2-chloro-6- nitropyridine and (3-phenoxyphenyl)methanamine, which are added with sodium bicarbonate in DMSO and stirred at 80 o C for 4 hours to yield Compound 69a-1 according to the procedure adapted from WO2018/71794, 2018. Compound 69a-2 can be prepared from Compound 69a-1 by reductive hydrogenation with palladium on charcoal in methanol in hydrogen atmosphere using a procedure analogous to the one known in the art. Lastly, Compound 69a can be prepared from sulfonylation of Compound 69a-2 with 2,3,4,5-tetrafluoro-6-methoxybenzenesulfonyl chloride (prepared as described in General Procedure B’) by using General Procedure E’. Example 10: N-(3-phenoxybenzyl)-6-((2,3,4,5-tetrafluoro-6-methylphenyl)s ulfonyl)pyridin-2- amine (Compound 69a) Scheme 10 [00345] Compound 69a-1 can be prepared from reductive amination of commercially available 3-phenoxybenzaldehyde with 6-chloropyridin-2-amine using sodium triacetoxyborohydride in DCE according to the procedure adapted from J. Med. Chem.2010, 53, 24, 8556–8568. Compound 69a-2 can be prepared from Compound 69a-1 by nucleophilic aromatic substitution with 2,3,4,5-tetrafluoro-6-methylbenzenethiol in the presence of K 2 CO 3 in acetonitrile using a procedure analogous to WO2012/101239, 2012. Lastly, Compound 69a can be prepared from oxidation of Compound 69a-2 by mCPBA using a General Procedure F’. Scheme 11: Synthesis of 2,3,4,5-tetrafluoro-6-(trifluoromethyl)benzenesulfonyl chloride Synthesis of A1 [00346] A dry 25 mL rbf was equipped with a stir bar, sealed with a rubber septum, and flushed with nitrogen for 5 min. After flushing, a solution of phenylmethanethiol (300 mg, 2.42 mmol, 283.55 μL) in THF (5.64 mL) was introduced into the flask. While stirring @ r.t., neat 1- chloropyrrolidine-2,5-dione (354.79 mg, 2.66 mmol, 215.02 μL) was added in one portion to prepare a pale yellow mixture. After 1 hour, the reaction became a dark yellow solution. The solution was used in the next reaction without any further manipulation/purification. Synthesis of A2 [00347] An oven-dried 25 mL rbf was equipped with a stir bar, capped with a rubber septum, and flushed with dry argon for 10 min. @ r.t. To the flask was added 1,2,3,4-tetrafluoro-5- (trifluoromethyl)benzene (479.76 mg, 2.2 mmol) and THF (10 mL) to prepare a colourless solution. The reaction was cooled to -78 °C before nBuLi (2.5 M in hexanes, 968.00 μL) was added to prepare the corresponding aryl-lithium species. After 20 min, the aryl lithium species (a faint purple colour) was added to a cold (0°C) solution of benzylsulfinyl chloride (383.93 mg, 2.42 mmol) in THF (6 mL) via cannula. Extra caution was taken to ensure that the organolithium was added directly to the benzylsulfenyl chloride solution. After addition was complete, the rxn was warmed slowly to r.t. over 1 hours. After 2 hours, the reaction was quenched with a 1M HCl and the organic layer separated. The aqueous phase was extracted 2x with EtOAc and the combined organic extracts washed with brine, dried over anhydrous sodium sulfate, and concentrated under vacuum to afford the product (650 mg, 1.9 mmol, 87% yield) as a pale yellow oil. The crude material was used in the next reaction without any further purification. Synthesis of A3: 2,3,4,5-tetrafluoro-6-(trifluoromethyl)benzenesulfonyl chloride [00348] Neat 1,3-dichloro-5,5-dimethyl-imidazolidine-2,4-dione (752.74 mg, 3.82 mmol, 501.82 μL) was added to an ice cold solution of 1-benzylsulfanyl-2,3,4,5-tetrafluoro-6- (trifluoromethyl)benzene (650 mg, 1.91 mmol) in CH3CN/AcOH/H2O (2 mL/0.075 mL/0.05 mL). The resulting pale yellow mixture was stirred @ 0 °C for 4 hours, then warmed to r.t. overnight. Afte the overnight period, the rxn was partitioned between DCM and a saturated aqueous solution of NaHCO3. The organic layer was removed and the remaining aqueous phase extracted 2x with DCM. The organic extracts were combined, washed with brine, dried over anhydrous sodium sulfate, and concentrated in vaccuo to afford 2,3,4,5-tetrafluoro-6- (trifluoromethyl)benzenesulfonyl chloride as a beige semi-solid. The crude material was used without any further purification 19 F NMR (376 MHz, CDCl3) δ -50.67 (d, J = 37.7 Hz), -122.70 (ddd, J = 23.5, 14.6, 8.8 Hz), -129.90 (ddt, J = 37.7, 20.4, 9.6 Hz), -138.15 (td, J = 20.6, 13.9 Hz), -142.22 (ddd, J = 22.9, 19.8, 10.7 Hz). Scheme 12: Synthesis of (2-bromo-3,4,5,6-tetrafluorophenyl)(methyl)sulfane Synthesis of B1 [00349] A solution of (4-methoxyphenyl)methanethiol (16 g, 51.94 mmol), 1,2-dibromo- 3,4,5,6-tetrafluorobenzene (8 g, 51.94 mmol), and DIPEA (13.40mL, 103.00mmol), in toluene (150 mL) was purged with N2 for 15 minutes. Once purged, Pd2dba3 (1.28 g, 1.40 mmol) and Xanthphos (1.23 g, 2.00 mmol) were added at room temperature. The resulting mixture was heated to 100°C overnight. After 16 hours, the mixture was diluted with water (100 mL) and extracted with EtOAc (2 x 200 mL). The combined organic phases were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude material was purified by flash column chromatography (0.2% EtOAc in hexane) to afford title compound as white solid (8.0 g, 20.99 mmol, 40% yield). 1 H NMR (400 MHz, DMSO-d6) δ 7.12 (d, J=8.8Hz, 2H), 6.83 (d, J=8.8Hz, 2H), 4.11 (s, 2H), 3.71 (s, 3H). Synthesis of B2 [00350] (2-bromo-3,4,5,6-tetrafluorophenyl)(4-methoxybenzyl)sulfane (8.7g, 22.83mmol) was added to ice-cold (0 o C) TFA (87 mL). The reaction was gradually warmed to room temperature, then heated to 70°C. After 3 hours, reaction mixture was concentrated under reduced pressure and co-distilled with DCM (5 x 100mL) to afford title compound as brown sticky oil (8 g, 30.79mmol). The obtained material was used in next step without purification. Synthesis of B3: (2-bromo-3,4,5,6-tetrafluorophenyl)(methyl)sulfane [00351] To a stirred solution of 2-bromo-3,4,5,6-tetrafluorobenzenethiol (8.0 g, 30.78 mmol) in THF (1.5 mL) @ 0 o C was added DIPEA (16 mL, 92.37mmol), followed by addition of MeI (2.8 mL, 46.17 mmol). The reaction was permitted to warm to room temperature. After 1.5 hours, mixture was concentrated via fractional distillation to remove THF. The crude material was purified by flash column chromatography (100% hexanes) to afford title compound as colourless liquid (4.5g, 16.36 mmol, 53% yield). 1 H NMR (400 MHz, CDCl3) δ 2.51 (s, 3H). 19 F NMR (376 MHz, CDCl 3 ) δ -125.99 - -126.08 (m, 1F), -127.66 - -127.75 (m, 1F), -152.66 - -152.78 (m, 1F), -154.53 - -154.65 (m, 1F). Scheme 13: Synthesis of (2-(bromomethyl)-3,4,5,6-tetrafluorophenyl)(methyl)sulfane Synthesis of C1 [00352] To a stirred solution of 2,3,4,5-tetrafluoro-6-(methylthio)benzoic acid (1.0 g, 4.16 mmol) in THF (8mL) at 0°C was added BH3-THF (8.3 ml, 8.32 mmol). The reaction was heated to 70 0 C for 1h. Once complete, the reaction was cooled to 0 0 C. Once cold, the reaction was quenched via dropwise addition of methanol. The mixture was concentrated under reduced pressure and the obtained residue diluted with water (35mL) then extracted with EtOAc (2 x 30 mL).^ The combined organic phases were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to afford title compound as a yellow liquid (0.33 g, 1.45 mmol, 35% yield). The obtained material was used without purification. 1 H NMR (400 MHz, DMSO-d6) δ 5.39 (t, J = 5.2, 1H), 4.71-4.69 (m, 2H), 2.42 (s, 3H). 19 F NMR (376 MHz, DMSO-d 6 ) δ -131.05 - -131.14 (m, 1F), -142.17 - -142.25 (m, 1F), -156.17 - -156.39 (m, 2F). Synthesis of C2: (2-(bromomethyl)-3,4,5,6-tetrafluorophenyl)(methyl)sulfane [00353] To a stirred solution of (2,3,4,5-tetrafluoro-6-(methylthio)phenyl)methanol (0.3 g, 1.32 mmol) in DCM (3 mL) at 0 0 C was added PBr3 (0.43 g, 1.59 mmol). The reaction was warmed to room temperature. After 1 hr, the reaction was diluted with water (10 mL) and extracted with EtOAc (3 x 10 mL). The combined organic phases were dried over anhydrous Na 2 SO 4 , filtered, and concentrated under reduced pressure to afford title compound as a yellow liquid (0.25 g, 0.86 mmol, 65% yield). The obtained material was used without purification. 1 H NMR (400 MHz, DMSO-d6) δ 4.78 (d, J = 2.4, 2H), 2.51 (s, 3H). 19 F NMR (376 MHz, DMSO-d6) δ -129.51 - - 129.62 (m, 1F), -139.04 - -139.13 (m, 1F), -153.35 - -153.48 (m, 1F), -153.95 - -153.07 (m, 1F). Synthesis of 2-(N,N-bis(4-methoxybenzyl)sulfamoyl)-3,4,5,6-tetrafluoroben zoic acid Synthesis of D1 [00354] To a cold solution of chlorosulfonic acid (100mL, 1499mmol) was added 1,2,3,4- tetrafluorobenzene (45.0g, 299.8mmol) in a drop wise manner at 0 o C. The resulting solution was heated to reflux (150°C) for 3 hrs. After completion of reaction, the reaction mixture was quenched slowly over ice, diluted with 1M HCl (100 mL), then water (500 mL), and extracted with EtOAc (50 mL X 3). The combined organic phase was dried over anhydrous Na 2 SO 4 , filtered, and concentrated under reduced pressure to afford the title compound as light brown oil (70.0 g, 281.5mmol, 94% yield). Synthesis of D2: 2,3,4,5-tetrafluoro-N,N-bis(4-methoxybenzyl)benzenesulfonami de [00355] To a stirred solution of 2,3,4,5-tetrafluorobenzenesulfonyl chloride (49.0 g, 197.11 mmol) in DCM (500 mL) was added TEA (41 mL, 295.60 mmol), followed by addition of Bis(4- methoxybenzyl)amine (50.72 g, 197.11 mmol) while at 0°C temperature. The reaction was warmed to room temperature. After 1 hr, the reaction was diluted with water (400 mL) and extracted with EtOAc (100mL x 2). The combined organic phases were dried over anhydrous Na 2 SO 4 , filtered, and concentrated under reduced pressure. The obtained crude was purified by column chromatography (10% EtOAc in hexanes) to afford the title compound as an off white solid (37.0 g, 78.81mmol, 40% yield). 1 H NMR (400 MHz, DMSO-d6) δ 7.63 – 7.58 (m, 1H), 7.06 (d, J = 8.4 Hz, 4H), 6.82 (d, J = 8.8 Hz, 4H), 4.35(s, 4H), 3.71 (s, 6H). Synthesis of D3: 2-(N,N-bis(4-methoxybenzyl)sulfamoyl)-3,4,5,6-tetrafluoroben zoic acid [00356] A stirred solution of 2,3,4,5-tetrafluoro-N,N-bis(4- methoxybenzyl)benzenesulfonamide (20.0 g, 42.60 mmol) in THF (200 mL) was cooled to -78 0 C temperature under N 2 atmosphere. To this solution, n-BuLi (25.6mL, 63.90mmol, 2.5M in hexane) was added drop wise, followed by addition of TMEDA (9.6 mL, 63.90mmol). The resulting reaction mixture was stirred at -78 0 C temperature. After 1hr, powdered dry-ice was added to the reaction mixture and stirring maintained for a further 2 hrs at -78°C. The reaction was gradually warmed to room temperature. Once warm, the reaction was quenched with 1M HCl (100 mL), then water (100 mL) and extracted with EtOAc (50 mL X 3). The combined organic phase was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude material was purified by column chromatography (3% MeOH in DCM) to afford the title compound as white solid (5.0 g, 9.73 mmol, 23% yield). 1 H NMR (400 MHz, DMSO- d6) δ 14.75 (brs, 1H), 7.02 (d, J = 8.4 Hz, 1H), 6.83 (d, J = 8.4 Hz, 4H), 4.35(s, 4H), 3.71 (s, 6H). Scheme 14: Preparation of 2-(difluoromethoxy)-3,4,5,6-tetrafluorobenzenesulfonyl chloride Synthesis of E1: 2-(difluoromethoxy)-3,4,5,6-tetrafluoro-N,N-bis(4-methoxyben zyl) benzenesulfonamide [00357] To a stirred solution of 2,3,4,5-tetrafluoro-6-hydroxy-N,N-bis(4- methoxybenzyl)benzenesulfonamide (7.0 g, 14.43mmol) in Acetone (70 mL) was added Cs2CO3 (13.68 g, 43.29 mmol) and ethyl 2-bromo-2,2-difluoroacetate (8.78 g, 43.29 mmol). The resulting mixture was heated to 85°C. After 4 hrs, the reaction was cooled to room temperature and concentrated under reduced pressure. The crude material was purified by flash column chromatography (15% EtOAc in hexanes) to afford the title compound as a yellow solid (6.0 g, 11.20 mmol, 77% yield). 1 H NMR (400 MHz, CDCl3) δ 7.07 (d, J= 8.4 Hz, 4H), 6.81 (d, J = 8.4 Hz, 4H), 6.69 (t, J = 72 Hz, 1H), 4.44 (s, 4H), 3.8 (s, 6H). Synthesis of E2: 2-(difluoromethoxy)-3,4,5,6-tetrafluorobenzenesulfonamide [00358] To a stirred solution of 2-(difluoromethoxy)-3,4,5,6-tetrafluoro-N,N-bis(4- methoxybenzyl) benzenesulfonamide (6.5 g, 12.13 mmol) in DCM (65 mL) was added anisole (5.25 g, 48.55 mmol) and the flask purged with N 2 for 10 min. Once flushed, TFA (60.5 mL) was introduced and the reaction heated to 75°C. After 16 hrs, the reaction was cooled to room temperature and concentrated under reduced pressure. The crude material was purified by flash column chromatography (20% EtOAc in hexanes) to afford the title compound as yellow solid (2.7 g, 9.14 mmol, 75% yield). 1 H NMR (400 MHz, DMSO-d6) δ 8.30 (s, 2H), 7.07 (t, J =72 Hz, 1H), 19 F NMR (400 MHz, DMSO-d6) δ -81.82 - -82.03 (m, 2F), -136.75 - - 136.85 (m, 1F), -149.04 - -149.18 (m, 1F), -150.03 - -150.17 (m, 1F), -152.17 - -152.25 (m, 1F). Synthesis of E3: 2-(difluoromethoxy)-3,4,5,6-tetrafluorobenzenesulfonyl chloride [00359] A suspension of 2-(difluoromethoxy)-3,4,5,6-tetrafluoro-benzenesulfonamide (700 mg, 2.37 mmol), pyrylium tetrafluoroborate (995.46 mg, 5.93 mmol) and magensium chloride (677.41 mg, 7.11 mmol) in Acetonitrile (23.7 mL) was stirred for 10 minutes under a nitrogen atmosphere. To ensure that the reactants were solubilized, the mixture was sonicated for 5 minutes before being heated to 75°C. After 16 hours, the reaction mixture was cooled to room temperature and filtered through a small plug of silica using EtOAc as the eluent. The filtrate was concentrated down under vacuum and the crude material isolated by flash column chromatography (0-20% EtOAc in Hexanes). The desired compound was isolated as an oily solid (384 mg, 1.2 mmol, 51% yield) 1 H NMR (400 MHz, CDCl 3 ) δ 6.70 (t, J =72 Hz, 1H). 19 F NMR (400 MHz, CDCl 3 ) δ - 82.39 - -82.62 (m, 2F), -131.17 - -131.28 (m, 1F), -140.23 - -140.36 (m, 1F), -145.88 - -145.97 (m, 1F), -152.67 - -152.80 (m, 1F). Scheme 15: Preparation of 2-(N,N-dimethylsulfamoyl)-3,4,5,6-tetrafluorobenzoic acid Synthesis of F1: 2,3,4,5-tetrafluoro-N,N-dimethylbenzenesulfonamide [00360] To a stirred solution of 2,3,4,5-tetrafluorobenzenesulfonyl chloride (15 g, 60.31 mmol) in DCM (150 mL) at 0°C was added N,N-dimethylamine (2M in THF, 39mL, 78.44mmol). The reaction was warmed to room temperature. After 2 hrs, the reaction was concentrated under reduced pressure. The crude material was purified by column chromatography (20% EtOAc in hexanes) to afford the title compound as white solid (9.0 g, 34.99 mmol, 67% yield). 1 H NMR (400 MHz, DMSO-d 6 ) δ 7.76- 7.83 (m,1H), 2.78 (s, 6H). Synthesis of F2: 2-(N,N-dimethylsulfamoyl)-3,4,5,6-tetrafluorobenzoic acid [00361] A solution of 2,3,4,5-tetrafluoro-N,N-dimethylbenzenesulfonamide (9.0 g, 35 mmol) in THF (90mL) was cooled to -78°C while under a positive pressure of N 2 . To this solution, n-BuLi (2.5M in hexane, 21mL, 52.52 mmol) was added drop wise, followed by addition of TMEDA (6.10 mL, 52.52 mmol). After 1h, powdered dry ice was added to the reaction mixture and stirring was maintained for a further hour. The reaction was gradually warmed to room temperature. Once warm, the reaction was quenched with 1M HCl (50mL), then water (100mL), and extracted with EtOAc (50 mL x 4). The combined organic phase was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude material was purified by column chromatography (2% MeOH in DCM) to afford the title compound as white solid (5.0 g, 16.59 mmol, 47% yield).1H NMR (400 MHz, DMSO- d6) δ 14.50 (brs, 1H), 2.84 (s, 6H). Preparation of (3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin- 1-yl)azetidin-1- yl)(2,3,4,5-tetrafluoro-6-(methylsulfonyl)phenyl)methanone Compound I-27 and (3-(4-amino-3- (4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)azetidin- 1-yl)(2,3,4,5-tetrafluoro-6- (methylsulfinyl)phenyl)methanone Compound I-37 (3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin- 1-yl)azetidin-1-yl)(2,3,4,5- tetrafluoro-6-(methylthio)phenyl)methanone [00362] To a stirred, ice-cold (0°C) solution of 2,3,4,5-tetrafluoro-6- (methylsulfonyl)benzoic acid (0.4 g, 1.66 mmol) in DCM (5mL) was added oxalyl chloride (0.42g, 3.33mmol) and DMF (0.1mL). The reaction mixture was stirred warmed to and maintained at room temperature for 1 hr. After I hr had elapsed, the reaction mixture was concentrated under reduced pressure and stored under a nitrogen atmosphere. The obtained residue was dissolved in THF (5mL) and added dropwise to a stirring solution of 1-(azetidin-3-yl)-3-(4-phenoxyphenyl)- 1H-pyrazolo[3,4-d]pyrimidin-4-amine (0.89 g, 2.42 mmol) in THF (5mL) and TEA (1.1mL, 8.33mmol) cooled to 0 ° C. The reaction was permitted to warm to room temperature over a 2 hrs. Once the reaction was complete, the mixture was diluted with water (50 mL) and extracted with EtOAc (2 x 20 mL).^ The combined organic phases were dried over anhydrous Na 2 SO 4 , filtered, and concentrated under reduced pressure. The resulting crude was purified by flash column chromatography (50-100% EtOAc in hexane) to afford the title compound as an off-white solid (0.42 g, 0.72 mmol, 43% yield). 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.26 (s, 1H), 7.70 (d, J = 8.4 Hz, 2H), 7.45 (t, J = 8.0 Hz, 2H), 7.22-7.13 (m, 5H), 5.84 - 5.79 (m, 1H), 4.68 - 4.63 (m, 1H), 4.57 - 4.53 (m, 1H), 4.43 (d, J = 6.4 Hz, 2H), 2.45 (s, 3H). 19 F NMR (376 MHz, DMSO-d6) δ - 130.57 - -130.67 (m, 1F), -141.42 - -141.51 (m, 1F), -153.26 - -153.61 (m, 2F). ESI-MS: measured m/z 581.29 [M+1] + . HPLC (Method I): RT = 7.21, 99.6% (3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin- 1-yl)azetidin-1-yl)(2,3,4,5- tetrafluoro-6-(methylsulfonyl)phenyl)methanone Compound I-27 [00363] To the stirred solution of (3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4- d]pyrimidin-1-yl)azetidin-1-yl)(2,3,4,5-tetrafluoro-6-(methy lthio)phenyl)methanone (0.13 g, 0.22 mmol) in DCM (2mL) was added oxone (0.68g, 2.2mmol). The resulting mixture was stirred at room temperature for 48 hrs. After 48 hrs, the reaction mixture was diluted with saturated aqueous solution of NaHCO3 (30 mL) and extracted with DCM (3 x 30mL). The combined organic phases were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The obtained crude was purified by flash column chromatography (0 - 15% MeOH in DCM) to afford the title compound as an off-white solid (0.03 g, 0.049 mmol, 22% yield). 1 H NMR (400 MHz, DMSO-d6) δ 8.27 (s, 1H, rotameric peak), 7.72 (d, J = 8.8 Hz, 2H), 7.45 (t, J = 8.4 Hz, 2H), 7.22-7.13 (m, 5H), 5.75-5.74 (m, 1H), 4.63-4.40 (m, 4H), 3.50 (s, 2H, combined rotameric peak), 3.42 (s, 1H, combined rotameric peak). 19 F NMR (376 MHz, DMSO-d6) δ -132.10 - -132.36 (m, 1F), -139.68 - -139.96 (m, 1F), -143.95 - -144.29 (m, 1F), - 150.94 - -151.10 (m, 1F). ESI-MS: measured m/z 613.24 [M+1] + . HPLC (Method I) RT = 6.53 min., 95.7%. (3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin- 1-yl)azetidin-1-yl)(2,3,4,5- tetrafluoro-6-(methylsulfinyl)phenyl)methanone Compound I-37 [00364] (3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin- 1-yl)azetidin-1- yl)(2,3,4,5-tetrafluoro-6-(methylsulfinyl)phenyl)methanone was separated from the reaction described for the synthesis of (3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin- 1- yl)azetidin-1-yl)(2,3,4,5-tetrafluoro-6-(methylsulfonyl)phen yl)methanone. The title compound was isolated as a yellow solid (0.015 g, 0.025 mmol, 10% yield). 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.27 (s, 1H), 7.72 (t, J = 8.8 Hz, 2H), 7.47-7.43 (m, 2H), 7.22-7.13 (m, 5H), 5.81-5.69 (m, 1H), 4.63-4.57 (m, 1H), 4.55-4.45 (m, 3H), 3.12 (s, 2H, combined rotameric peaks) 3.07 (s, 1H, combined rotameric peak). 19 F NMR (376 MHz, DMSO-d 6 ) δ -132.10 - -132.36 (m, 1F), - 139.69 - -139.96 (m, 1F), -143.99 - -144.32 (m, 1F), -150.96 - -151.11 (m, 1F). ESI-MS: measured m/z 597.24[M+1] + . HPLC RT = 6.48 min., 95.3%. General Procedure A: N-(2-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidi n-1-yl)ethyl)-2-(N,N- dimethylsulfamoyl)-3,4,5,6-tetrafluoro-N-methylbenzamide Compound I-30 [00365] N-(2-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidi n-1-yl)ethyl)-2-(N,N- dimethylsulfamoyl)-3,4,5,6-tetrafluoro-N-methylbenzamide was prepared from 2-(N,N- dimethylsulfamoyl)-3,4,5,6-tetrafluorobenzoic acid (0.4 g, 1.32 mmol) and 1-(2- (methylamino)ethyl)-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]py rimidin-4-amine (0.62g, 1.72mmol) according to the protocol described in general procedure A and isolated as a white solid (0.4 g, 0.62 mmol, 51% yield). 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.29 - 8.17 (s, 0.5H, 0.34H, rotameric peaks integrated separately), 7.71 (d, J= 8.4 Hz, 1H), 7.65 (d, J= 8.4 Hz, 1H), 7.45 (t, J = 7.6 Hz, 2H), 7.23-7.13 (m, 5H), 6.67(s, 1H), 6.62 (s, 1H), 4.68 - 4.57 (m, 2H), 4.15 - 4.44 (m, 1H), 3.81 - 3.87 (m, 1H), 2.88 - 2.85 (m, 9H). 19 F NMR (376 MHz, DMSO- d6) δ -130.79 - -130.94 (m, 1F), -139.78 - -130.86 (m, 0.33 F), -140.79 - -140.88 (m, 0.67 F), - 145.98 - -146.06 (m, 0.33 F), -146.18 - -146.32 (m, 0.67 F), -152.05 - -152.33 (m, 1F). ESI-MS: measured m/z 644.2 [M+1] + , HPLC (Method I): RT = 6.59 min., 98.2%. N-(2-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidi n-1-yl)ethyl)-2,3,4,5- tetrafluoro-N-methyl-6-sulfamoylbenzamide Compound I-33
N-(2-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrim idin-1-yl)ethyl)-2-(N,N-bis(4- methoxybenzyl)sulfamoyl)-3,4,5,6-tetrafluoro-N-methylbenzami de [00366] N-(2-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidi n-1-yl)ethyl)-2- (N,N-bis(4-methoxybenzyl)sulfamoyl)-3,4,5,6-tetrafluoro-N-me thylbenzamide was prepared from 2-(N,N-bis(4-methoxybenzyl)sulfamoyl)-3,4,5,6-tetrafluoroben zoic acid (0.25 g, 0.48 mmol) and 1-(2-(methylamino)ethyl)-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4 -d]pyrimidin-4- amine (0.263 g, 0.73 mmol) according to the protocol described in general procedure A and isolated as a yellow solid (0.21 g, 0.24 mmol, 50% yield). ESI-MS: measured m/z 856.3 [M+1] + . N-(2-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidi n-1-yl)ethyl)-2,3,4,5- tetrafluoro-N-methyl-6-sulfamoylbenzamide Compound I-33 [00367] To a stirred solution of N-(2-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4- d]pyrimidin-1-yl)ethyl)-2-(N,N-bis(4-methoxybenzyl)sulfamoyl )-3,4,5,6-tetrafluoro-N- methylbenzamide (0.21 g, 0.24 mmol) in DCM (2 mL) was added TFA (2 mL). The reaction was stirred at room temperature for 16 hrs. Once complete, the reaction mixture was diluted with saturated aqueous NaHCO3 (30 mL) and extracted with EtOAc (3 x 30mL). The combined organic phases were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude material was purified by flash column chromatography (56% EtOAc in hexanes) to afford the title compound as an off-white solid (0.085 g, 0.13 mmol, 56% yield). 1 H NMR (400 MHz, DMSO-d6) δ 8.27-8.20 (d, 2H), 8.12 (s, 1H), 7.68 - 7.60 (m, 2H), 7.44 (t, J = 7.6 Hz, 2H) 7.21- 7.12(m, 5H), 4.61 – 4.31 (m, 2H) 4.10 – 3.60 (m, 2H), 2.81 – 2.67 (s, 3H, rotameric peaks integrated together). 19 F NMR (376 MHz, DMSO-d 6 ) δ -134.64 - -134.78 (m, 1F), -140.72 - -141.61(m, 1F), -147.71 - -147.96 (m, 1F), -153.22 - -153.49 (m, 1F). ESI-MS: m/z 616.4 [M+1] + , HPLC (Method I): RT = 6.10 min., 96%. Preparation of N-(2-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidi n-1-yl)ethyl)- 2,3,4,5-tetrafluoro-N-methyl-6-(methylsulfonyl)benzamideComp ound I-28
General Procedure D: N-(2-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidi n-1-yl)ethyl)-2,3,4,5- tetrafluoro-N-methyl-6-(methylthio)benzamide [00368] To a stirred solution of 2,3,4,5-tetrafluoro-6-(methylthio)benzoic acid (0.3 g, 1.25 mmol) and 1-(2-(methylamino)ethyl)-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4 -d]pyrimidin-4- amine (0.54 g, 1.5 mmol) in DMF (3mL) was added PyBop (0.975g, 1.87mmol) and reaction mixture was stirred for 5 min at room temperature. DIPEA (0.48g, 3.75mmol) was introduced via syringe and the reaction was permitted to stir for a further 12 hrs. After reaction completion, the mixture was diluted with water (50 mL) and extracted with EtOAc (3 x 30 mL). The combined organic phases were dried over anhydrous Na 2 SO 4 , filtered, and concentrated under reduced pressure. The resulting crude was purified by flash column chromatography (5% MeOH in DCM) to afford the title compound as an off-white solid (0.450 g, 0.430 mmol, 62% yield). ESI-MS: measured m/z 582.20 [M+1] + . General Procedure C: N-(2-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidi n-1-yl)ethyl)-2,3,4,5- tetrafluoro-N-methyl-6-(methylsulfonyl)benzamide Compound I-28 [00369] To an ice cold (0°C) solution of N-(2-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4- d]pyrimidin-1-yl)ethyl)-2,3,4,5-tetrafluoro-N-methyl-6-(meth ylthio)benzamide (0.25 g, 0.42 mmol) in DCM (2.5 mL) was added oxone (0.326 g, 2.14 mmol). The reaction was warmed to room temperature and stirred for 16 hrs. Once the reaction was deemed completed, the mixture was diluted with saturated aqueous Na 2 CO 3 (50 mL) and extracted with EtOAc (2 x 30mL).^ The combined organic phases were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The resulting crude was purified by flash column chromatography using reverse phase silica (55% acetonitrile in water) to afford title compound as a brown solid (0.057 g, 0.092 mmol, 22 % yield). 1 H NMR (400 MHz, DMSO-d6) δ 8.27 (s, 1H), 7.67 (d, J = 8.4 Hz, 2H), 7.44 (t, J = 7.6 Hz, 2H), 7.21-7.12 (m, 5H), 4.60 (t, J = 6.4 Hz, 2H), 4.22-4.15 (m, 1H), 3.77- 3.72 (m, 1H), 3.39 (s, 3H), 2.88 (s, 3H). 19 F NMR (376 MHz, DMSO-d6) δ -132.57 - -132.69 (m, 1F), 140.79 - -140.87 (m, 1F), -144.61 - -144.76 (m, 1F), -152.26 - -152.39 (m, 1F). ESI-MS: measured m/z 615.4 [M+1] + . HPLC (Method I): RT = 7.50 min. and 7.61, 10.3% and 82.2%, respectively (anticipated mixture of rotamers). 2-(3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidi n-1-yl)azetidine-1-carbonyl)- 3,4,5,6-tetrafluoro-N,N-dimethylbenzenesulfonamide Compound I-29 [00370] 2-(3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidi n-1-yl)azetidine-1- carbonyl)-3,4,5,6-tetrafluoro-N,N-dimethylbenzenesulfonamide was prepared from 2-(N,N- dimethylsulfamoyl)-3,4,5,6-tetrafluorobenzoic acid (0.3g, 1.00mmol) and 1-(azetidin-3-yl)-3-(4- phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (0.42g, 1.2mmol) according to the protocol described in general procedure A and isolated as an off-white solid (0.083 g, 0.12 mmol, 13 % yield). 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.27 (s, 1H), 7.73-7.69 (m, 2H) 7.45 (t, J = 8.4 Hz, 2H), 7.22 - 7.13 (m, 5H), 5.75 - 5.73 (m, 1H), 4.60 - 4.52 (m, 2H), 4.44 - 4.34 (m, 2H), 2.88 – 2.84 (m, 6H). 19 F NMR (376 MHz, DMSO-d 6 ) δ -130.29 - -130.74 (m, 1F), - 139.67 - -139.82 (m, 1F), -145.53 - -145.93 (m, 1F), -150.89 - -151.08 (m, 1F). ESI+MS: measured m/z 642.24 [M+1] + . HPLC (Method I): RT = 4.28 min., 97.5%. Preparation of 2-(3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidi n-1- yl)azetidine-1-carbonyl)-3,4,5,6-tetrafluorobenzenesulfonami de Compound I-32
2-(3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrim idin-1-yl)azetidine-1- carbonyl)-3,4,5,6-tetrafluoro-N,N-bis(4-methoxybenzyl)benzen esulfonamide [00371] 2-(3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidi n-1-yl)azetidine-1- carbonyl)-3,4,5,6-tetrafluoro-N,N-bis(4-methoxybenzyl)benzen esulfonamide was prepared from 2-(N,N-bis(4-methoxybenzyl)sulfamoyl)-3,4,5,6-tetrafluoroben zoic acid (0.25 g, 0.48 mmol) and 1-(azetidin-3-yl)-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyri midin-4-amine (0.20 g, 0.58 mmol) according to the protocol described in general procedure A and isolated as an off-white solid (0.21 g, 0.25 mmol, 72% yield). ESI-MS: measured m/z 854.2 [M+1] + . General Procedure B: 2-(3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidi n-1-yl)azetidine-1-carbonyl)- 3,4,5,6-tetrafluorobenzenesulfonamide Compound I-32 [00372] To a stirred solution of 2-(3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4- d]pyrimidin-1-yl)azetidine-1-carbonyl)-3,4,5,6-tetrafluoro-N ,N-bis(4- methoxybenzyl)benzenesulfonamide (0.2 g, 0.23 mmol) in DCM (2 mL) was added TFA (4 mL) at room temperature. The resulting solution mixture was stirred at 50 O C (oil bath) for 16 hrs. once the reaction was deemed completed, the solution was diluted with a saturated aqueous solution of NaHCO3 (20 mL) and extracted with EtOAc (2 x 20 mL). The combined organic phases were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The obtained crude was purified by reverse phase column chromatography (70-80% ACN in water) to afford the title compound as a white solid (0.05 g, 0.08 mmol, 35% yield). 1 H NMR (376 MHz, DMSO-d6) δ 8.27 (s, 1H), 7.75 - 7.71 (m, 2H), 7.45 (t, J = 7.6 Hz, 2H), 7.20 - 7.13 (m, 5H), 5.75 - 5.72 (m, 1H), 4.61 - 4.51 (m, 2H), 4.43 - 4.41 (m, 2H). 19 F NMR (376 MHz, DMSO-d 6 ) δ - 134.39 - -134.49 (m, 1F), -140.40 - -140.72 (m, 1F), -147.55 - -147.65 (m, 1F), -152.10 - - 152.20 (m, 1F). ESI-MS: m/z 614.2 [M+1] + . HPLC (Method I) RT = 6.32 min., 96.6%. (R)-2-(3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyri midin-1-yl)piperidine-1- carbonyl)-3,4,5,6-tetrafluoro-N,N-dimethylbenzenesulfonamide Compound I-31
[00373] (R)-2-(3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyri midin-1- yl)piperidine-1-carbonyl)-3,4,5,6-tetrafluoro-N,N-dimethylbe nzenesulfonamide was prepared from 2-(N,N-dimethylsulfamoyl)-3,4,5,6-tetrafluorobenzoic acid (0.3 g, 1.0 mmol) and (R)-3-(4- phenoxyphenyl)-1-(piperidin-3-yl)-1H-pyrazolo[3,4-d]pyrimidi n-4-amine (0.46 g, 1.2 mmol) according to the protocol described in general procedure A and isolated as an off-white solid (0.009 g, 0.013 mmol, 1% yield). 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.82-8.13 (m, 1H), 7.71-7.68 (m, 1H), 7.63-7.59 (m, 1H), 7.47-7.41 (m, 2H), 7.21-7.11 (m, 5H), 4.90-4.50 (m, 2H), 4.65-4.60 (m, 0.5H), 3.90-4.00 (m, 0.5H), 4.00-3.80 (m, 0.5H), 4.80-3.70 (m, 0.5H), 3.50- 3.40 (m, 1H), 2.90-2.70 (m, 6H), 2.30-2.30-2.20 (m, 1H), 2.20-2.10 (m, 1H), 2.0-1.90 (m, 1H), 1.80-1.60 (m, 1H). 19 F NMR (376 MHz, DMSO-d6) -130.66 - -131.74 (m, 1F), -140.60 - - 140.83 (m, 1F), 146.04 - -146.24 (m, 1F), -152.36 - -152.51 (m, 1F). ESI-MS: measured m/z 670.7 [M+1] + . HPLC (Method I): RT = 6.94 min. and 7.00 min., 68.4% and 17.0%, respectively (anticipated mixture of rotamers). Preparation of (R)-2-(3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyri midin-1- yl)piperidine-1-carbonyl)-3,4,5,6-tetrafluorobenzenesulfonam ide Compound I-35 (R)-2-(3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyri midin-1-yl) piperidine-1- carbonyl)-3,4,5,6-tetrafluoro-N,N-bis(4-methoxybenzyl)benzen esulfonamide [00374] (R)-2-(3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyri midin-1-yl) piperidine-1-carbonyl)-3,4,5,6-tetrafluoro-N,N-bis(4-methoxy benzyl)benzenesulfonamide was prepared from 2-(N,N-bis(4-methoxybenzyl)sulfamoyl)-3,4,5,6-tetrafluoroben zoic acid (0.3 g, 0.58 mmol) and (R)-3-(4-phenoxyphenyl)-1-(piperidin-3-yl)-1H-pyrazolo[3,4-d ]pyrimidin-4- amine (0.22 g, 0.70 mmol) according to the protocol described in general procedure A and isolated as an an off-white solid (0.45 g, 0.51 mmol, 80% yield). 19 F NMR (376 MHz, DMSO-d 6 ) δ - 132.06 - -132.77 (m, 1F), -139.73 - -140.19 (m, 1F), -145.37 - -145.93 (m, 1F), -152.71 - - 153.00 (m, 1F). ESI-MS: measured m/z 882.6 [M+1] + . (R)-2-(3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyri midin-1-yl)piperidine-1- carbonyl)-3,4,5,6-tetrafluorobenzenesulfonamide Compound I-35 [00375] (R)-2-(3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyri midin-1- yl)piperidine-1-carbonyl)-3,4,5,6-tetrafluorobenzenesulfonam ide was prepared from (R)-2-(3-(4- amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)p iperidine-1-carbonyl)-3,4,5,6- tetrafluoro-N,N-bis(4-methoxybenzyl) benzene sulfonamide (0.35 g, 0.39 mmol) according to the protocol described in general procedure B and isolated as a white solid (0.1 g, 0.15 mmol, 46% yield). 1 H NMR (400 MHz, DMSO-d6) δ 8.27 – 8.07 (m, 3H), 7.71 - 7.68 (m, 1H), 7.62 - 7.60 (m, 1H), 7.46-7.41 (m, 2H), 7.21 – 7.11 (m, 5H), 4.97 – 61 (m, 2H), 3.67 – 3.56 (m, 1H) 3.50 – 3.41 (m, 1H), 3.22 – 3.09 (m, 1H), 2.35 – 2.22 (m, 1H), 2.19 – 2.09 (m, 1H), 2.01 – 1.99 (m, 1H), 1.73 – 1.65 (m, 1H). 19 F NMR (376 MHz, DMSO-d6) δ -134.59 – -135.02 (m, 1F), -141.38 – -141.75(m, 1F), -148.29 – -149.00 (m, 1F), -153.56 – -153.78 (m, 1F). ESI-MS: m/z 642.4 [M+1] + , HPLC (Method I): RT = 6.38 min., 6.60 min. and 6.89 min., 28%, 32% and 38.9%, respectively (anticipated mixture of rotamers). Preparation of ((R)-3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimi din-1- yl)piperidin-1-yl)(2,3,4,5-tetrafluoro-6-(methylsulfinyl)phe nyl)methanone Compound I-36 (R)-(3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimi din-1-yl)piperidin-1- yl)(2,3,4,5-tetrafluoro-6-(methylthio)phenyl)methanone [00376] (R)-(3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimi din-1-yl)piperidin-1- yl)(2,3,4,5-tetrafluoro-6-(methylthio)phenyl)methanone was prepared from 2,3,4,5-tetrafluoro-6- (methylthio)benzoic acid (0.2 g, 0.83 mmol) and (R)-3-(4-phenoxyphenyl)-1-(piperidin-3-yl)- 1H-pyrazolo[3,4-d]pyrimidin-4-amine (0.32g , 0.83 mmol) according to the protocol described in general procedure A and isolated as a colorless oil (0.4 g, 0.65 mmol, 70% yield). 1 H NMR (400 MHz, DMSO-d6) δ 8.27 (s, 1H), 7.67 (d, J = 8.8Hz, 1H), 7.60 – 7.57 (m, 1H), 7.45 – 7.40 (m, 2H), 7.20 – 7.08 (m, 5H), 4.80 – 4.73 (m, 1H), 4.65 – 4.58 (m, 1H), 4.45 – 4.38 (m, 1H), 4.22 – 4.15 (m, 1H), 3.48 – 3.40 (m, 2H), 3.35 – 3.18 (m, 3 H), 2.35 – 2.22 (m, 3H). 19 F NMR (376 MHz, DMSO-d6) δ -130.69 – -131.58 (m, 1F), -141.41 – -142.50 (m, 1F), -153.86 – -154.01 (m, 1F), -154.36 – -154.47 (m, 1F). ESI-MS: measured m/z 609.2 [M+1] + . ((R)-3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimi din-1-yl)piperidin-1- yl)(2,3,4,5-tetrafluoro-6-(methylsulfinyl)phenyl)methanone Compound I-36 [00377] To a stirred, ice-cold (0°C) solution of (R)-(3-(4-amino-3-(4-phenoxyphenyl)-1H- pyrazolo[3,4-d]pyrimidin-1-yl)piperidin-1-yl)(2,3,4,5-tetraf luoro-6- (methylthio)phenyl)methanone (0.4 g, 0.65 mmol) in DCM (5mL) was added m-CPBA (0.56 g, 3.28 mmol). The reaction was gradually warmed to room temperature and for 16 hrs. Once deemed complete, the reaction mixture was diluted with a saturated aqueous solution of NaHCO 3 (20 mL) and extracted with EtOAc (2 x 20mL). The combined organic phases were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude material was purified by reverse phase column chromatography (60-70% ACN in water) to afford the title compound as an off-white solid (0.05 g, 0.08 mmol, 12% yield). 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.29 - 8.17 (m, 1H), 7.71 – 7.59 (m, 2H), 7.46-7.41 (m, 2H), 7.21- 7.11 (m, 5H), 4.99 – 4.85 (m, 1H), 4.74 – 4.65 (m, 1H), 4.55 – 4.44 (m, 1H), 3.80 – 3.65 (m, 1H), 3.52 – 3.45 (m, 1H), 3.14 – 3.02 (m, 3H), 2.30 - 2.10 (m, 2H), 2.20 – 1.80 (m, 2H). ESI-MS: m/z 625.25 [M+1] + , HPLC (Method II): RT = 9.12 min. and 9.50 min, 90.2%, 9%, respectively (anticipated mixture of rotamers). Preparation of N-(3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidi n-1- yl)propyl)-2,3,4,5-tetrafluoro-6-sulfamoylbenzamide Compound I-34 N-(3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidi n-1-yl)propyl)-2-(N,N- bis(4-methoxybenzyl)sulfamoyl)-3,4,5,6-tetrafluorobenzamide [00378] N-(3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidi n-1-yl)propyl)-2- (N,N-bis(4-methoxybenzyl)sulfamoyl)-3,4,5,6-tetrafluorobenza mide was prepared from 2-(N,N- bis(4-methoxybenzyl)sulfamoyl)-3,4,5,6-tetrafluorobenzoic acid (0.4 g, 0.77 mmol) and 1-(3- aminopropyl)-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin -4-amine (0.3 g, 0.78 mmol) according to the protocol described in general procedure A and isolated as a white solid (0.33 g, 0.39 mmol, 50% yield). ESI-MS: measured m/z 856.19 [M+1] + . N-(3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidi n-1-yl)propyl)-2,3,4,5- tetrafluoro-6-sulfamoylbenzamide Compound I-34 [00379] N-(3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidi n-1-yl)propyl)- 2,3,4,5-tetrafluoro-6-sulfamoylbenzamide was prepared from N-(3-(4-amino-3-(4- phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)propyl)-2-(N ,N-bis(4- methoxybenzyl)sulfamoyl)-3,4,5,6-tetrafluorobenzamide (0.31 g, 0.36 mmol) according to the protocol described in general procedure B and isolated as an off-white solid (0.080 g, 0.13 mmol, 36% yield). 1 H NMR (400 MHz, DMSO-d6) δ 8.69 (s, 1H), 8.260 (s, 1H), 7.95 (br s, 2H), 7.68 (d, J = 8.8 Hz, 2H), 7.443 (t, J = 8.4 Hz, 2H), 7.21-7.12 (m, 5H), 4.42 (t, J = 7.2 Hz, 2H), 3.28-3.26 (m, 2H), 2.09 (t, J = 6.8 Hz, 2H). 19 F NMR (376 MHz, DMSO-d 6 ) δ -134.70 - -134.81 (m, 1F), 141.12 - -141.21 (m, 1F), -149.20 – 149.30 (m, 1F). -153.35 - -153.46 (m, 1F). ESI-MS: measured m/z 616.20 [M+1] + . HPLC (Method I): RT = 6.06 min., 98.6%. Preparation of N-(3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidi n-1- yl)propyl)-2,3,4,5-tetrafluoro-6-(methylsulfonyl)benzamide Compound I-39 N-(3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidi n-1-yl)propyl)-2,3,4,5- tetrafluoro-6-(methylthio)benzamide [00380] To a stirred solution of 2,3,4,5-tetrafluoro-6-(methylthio)benzoic acid (0.3 g, 1.24 mmol) in THF (2 mL) was added DIPEA (0.32 g, 2.49 mmol) and PyBOP (0.97 g, 1.87 mmol), and the resulting solution cooled to 0°C. After 5 min., a solution of 1-(3-aminopropyl)- 3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (0.59 g, 1.49 mmol) was introduced, and the reaction warmed to room temperature. After 16 hrs, the reaction was diluted with water (100mL) and extracted with EtOAc (2x100mL). The combined organic phases were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude material was purified by flash column chromatography (60% EtOAc in hexane) to afford the title compound (0.5 g, 0.85 mmol, 69% yield). 19 F NMR (376 MHz, DMSO- d6) δ -131.26 - - 131.35 (m, 1F), -142.21 - -142.30 (m, 1F), -154.42 - -154.65 (m, 2F). ESI-MS: measured m/z 583.2 [M+1] + . N-(3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidi n-1-yl)propyl)-2,3,4,5- tetrafluoro-6-(methylsulfonyl)benzamide Compound I-39 [00381] N-(3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidi n-1-yl)propyl)- 2,3,4,5-tetrafluoro-6-(methylsulfonyl)benzamide was prepared from N-(3-(4-amino-3-(4- phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)propyl)-2,3, 4,5-tetrafluoro-6- (methylthio)benzamide (0.5 g, 0.85 mmol) according to the protocol described in general procedure C and isolated as an off-white solid (0.26 g, 0.42 mmol, 49% yield). 1 H NMR (400 MHz, DMSO- d6) δ 8.92 (t, J = 5.6 Hz, 1H), 8.26 (s, 1H), 7.68 (d, J = 8.8 Hz, 2H), 7.44 (t, J = 7.6 Hz, 2H), 7.21 - 7.12 (m, 5H) , 4.42 (t, J=6.8 Hz, 2H), 3.41 (s, 3H), 3.30-3.29 (m, 2H), 2.10 (t, J = 7.2 Hz, 2H). 19 F NMR (376 MHz, DMSO- d 6 ) δ -132.73 - -132.85 (m, 1F), -140.20 - -140.31 (m, 1F), -145.47 - -145.62(m, 1F), -151.82 - -151.94 (m, 1F). ESI-MS: measured m/z 615.3 [M+1] + . HPLC (Method I): RT = 6.25 min, 99.4%. N-(3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidi n-1-yl)propyl)-2-(N,N- dimethylsulfamoyl)-3,4,5,6-tetrafluorobenzamide Compound I-41 [00382] N-(3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidi n-1-yl)propyl)-2- (N,N-dimethylsulfamoyl)-3,4,5,6-tetrafluorobenzamide was prepared from 2-(N,N- dimethylsulfamoyl)-3,4,5,6-tetrafluorobenzoic acid (0.3 g, 0.99 mmol) and 1-(3-aminopropyl)-3- (4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (0.43 g, 1.2 mmol) according to the protocol described in general procedure A and isolated as an off-white solid (0.11 g, 0.17 mmol, 17% yield). 1 H NMR (400 MHz, DMSO- d6) δ 8.78 (t, J = 5.6 Hz, 1H), 8.23 (s, 1H), 7.68 (d, J = 8.8 Hz, 2H), 7.44 (t, J = 8.0 Hz, 2H), 7.21 - 7.12 (m, 5H), 4.42 - 4.40 (m, 2H) , 3.33 - 3.28 (m, 2H), 2.82 (d, J = 1.6 Hz, 6H), 2.08 (m, 2H), 19 F NMR (376 MHz, DMSO- d6) δ -131.09 - - 131.21 (m, 1F), -140.46 - -140.55 (m, 1F), -147.32 - -147.46(m, 1F), -152.17 - -152.28 (m, 1F). ESI-MS: measured m/z 644.3 [M+1] + . HPLC (Method I) RT = 6.47 min., 99.4%. N-(2-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidi n-1-yl)ethyl)-2-(N,N- dimethylsulfamoyl)-3,4,5,6-tetrafluorobenzamide Compound I-40 [00383] N-(2-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidi n-1-yl)ethyl)-2-(N,N- dimethylsulfamoyl)-3,4,5,6-tetrafluorobenzamide was prepared from 2-(N,N-dimethylsulfamoyl)- 3,4,5,6-tetrafluorobenzoic acid (0.4 g, 1.32 mmol) and 1-(2-aminoethyl)-3-(4-phenoxyphenyl)- 1H-pyrazolo[3,4-d] pyrimidin-4-amine (0.59 g, 1.72 mmol) according to the protocol described in general procedure A and isolated as an off-white solid (0.35 g, 0.55 mmol, 51% yield). 1 H NMR (400 MHz, DMSO-d6) δ 8.89 (t, J = 5.6 Hz, 1H), 8.26 (s, 1H), 7.68 (d, J = 8.4 Hz, 2H), 7.44 (t, J = 8.4 Hz, 2H), 7.12 - 7.21 (m, 5H), 4.54 - 4.42 (m, 2H), 3.76 (brs, 2H), 2.83 – 2.80 (m, 6H). 19 F NMR (376 MHz, DMSO-d 6 ) δ -131.07 - -131.19 (m, 1F), -140.16 - -140.25 (m, 1F), -147.31 - - 147.45 (m, 1F), -151.94 - -152.05 (m, 1F). ESI-MS: measured m/z 630.3 [M+1] + . HPLC (Method I) RT = 6.38 min., 98.4%. Preparation of N-(2-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidi n-1-yl)ethyl)- 2,3,4,5-tetrafluoro-6-(methylsulfonyl)benzamide Compound I-38
N-(2-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrim idin-1-yl)ethyl)-2,3,4,5- tetrafluoro-6-(methylthio)benzamide [00384] N-(2-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidi n-1-yl)ethyl)- 2,3,4,5-tetrafluoro-6-(methylthio)benzamide was prepared from 2,3,4,5-tetrafluoro-6- (methylthio)benzoic acid (0.3 g, 1.24 mmol) and 1-(2-aminoethyl)-3-(4-phenoxyphenyl)-1H- pyrazolo[3,4-d]pyrimidin-4-aminein (0.47 g, 1.37 mmol) according to the protocol described in general procedure D and isolated as an off-white solid (0.5 g, 0.88 mmol, 43% yield). 1 H NMR (400 MHz, DMSO-d6) δ 8.87 (t, J = 5.6 Hz, 1H), 8.25 (s, 1H), 7.68 (d, J = 8.8 Hz, 2H), 7.44 (t, J = 7.6 Hz, 2H), 7.21-7.12 (m, 5H), 4.52 (t, J = 6.0 Hz, 2H) 3.86-3.81 (m, 2H), 2.28 (s, 3H). 19 F NMR (376 MHz, DMSO-d6) δ -131.33 - -131.43 (m, 1F), -141.87 - -141.96 (m, 1F), -154.36 - - 154.79 (m, 2F). ESI-MS: m/z 569.2 [M+1] + HPLC (Method I) RT = 6.53min., 95.6%. N-(2-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidi n-1-yl)ethyl)-2,3,4,5- tetrafluoro-6-(methylsulfonyl)benzamide Compound I-38 [00385] N-(2-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidi n-1-yl)ethyl)-2,3,4,5- tetrafluoro-6-(methylsulfonyl)benzamide was prepared from N-(2-(4-amino-3-(4- phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-2,3,4 ,5-tetrafluoro-6- (methylthio)benzamide (0.40 g, 0.70 mmol) according to the protocol described in general procedure C and isolated as a yellow solid (0.07 g, 0.116 mmol, 17% yield). 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.00 (s, 1H), 8.26 (d, J = 2.4 Hz, 1H), 7.67 (d, J = 8.8 Hz, 2H), 7.43 (t, J = 7.6 Hz, 2H), 7.20-7.12 (m, 5H), 4.49 (br s, 2H), 3.76 (br s, 2H), 3.39 (s, 3H). 19 F NMR (376 MHz, DMSO-d6) δ -132.68 - -132.80 (m, 1F), -140.02 - -140.11 (m, 1F), -145.48 - -145.62 (m, 1F), - 151.62 - -151.73 (m, 1F). ESI-MS: measured m/z 601.2 [M+1] + . HPLC (Method I) RT = 6.11 min., 98.3%. Preparation of 1-(2-(methyl(2,3,4,5-tetrafluoro-6-(methylsulfonyl)phenyl)am ino)ethyl)-3-(4- phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine Compound I-43 1-(2-(methyl(2,3,4,5-tetrafluoro-6-(methylthio)phenyl)amino) ethyl)-3-(4-phenoxyphenyl)- 1H-pyrazolo[3,4-d]pyrimidin-4-amine [00386] To a stirred solution of 1-(2-(methylamino)ethyl)-3-(4-phenoxyphenyl)-1H- pyrazolo[3,4-d]pyrimidin-4-amine (0.2 g, 0.55 mmol) in THF (5 mL) was added cesium carbonate (0.54 g, 1.66 mmol) at room temperature. This resulting reaction mixture was purged with N2 for 10 minutes, followed by addition of (2-bromo-3,4,5,6- tetrafluorophenyl)(methyl)sulfane (0.15 g, 0.55 mmol), CuI (0.021 g, 0.11 mmol) and trans-N,N'- Dimethylcyclohexane-1,2-diamine (0.031 g, 0.22 mmol). The reaction was heated to 80°C. After 16 hrs, the reaction was cooled to ambient temperature and diluted with water (20 mL). The resulting suspension was extracted with EtOAc (2 x 20 mL) and the combined organic phases were dried over anhydrous Na 2 SO 4 , filtered, and concentrated under reduced pressure. The crude material was purified by reverse phase column chromatography (70-80% ACN in Water) to afford the title compound as resin (0.16 g, 0.25 mmol, 29% yield). 1 H NMR (400 MHz, DMSO- d 6 ) δ 8.25-8.20 (brs, 2H), 7.99 (brs, 1H), 7.44 - 7.40 (m, 2H), 7.19 - 7.14 (m, 1H), 7.08- 6.98(m, 3H), 4.42 (t, J= 6.0 Hz, 2H), 3.04 (m, 2H), 2.34 (s, 3H), 2.31 (s, 3H). ESI-MS: measured m/z 555.2 [M+1] + . 1-(2-(methyl(2,3,4,5-tetrafluoro-6-(methylsulfonyl)phenyl)am ino)ethyl)-3-(4-phenoxyphenyl)- 1H-pyrazolo[3,4-d]pyrimidin-4-amine Compound I-43 [00387] To a stirred solution of 1-(2-(methyl(2,3,4,5-tetrafluoro-6- (methylthio)phenyl)amino)ethyl)-3-(4-phenoxyphenyl)-1H-pyraz olo[3,4-d]pyrimidin-4- amine (0.04 g, 0.072 mmol) in THF:MeOH:Water (8:1:1, 1.6mL) at 0°C was added oxone (0.12 g, 0.39 mmol). The reaction mixture was permitted to warm to room temperature. After 16 hrs, a saturated aqueous solution of NaHCO3 (20 mL) was added and the mixture extracted with DCM (2 x 20 mL). The combined organic phases were dried over anhydrous Na 2 SO 4 , filtered, and concentrated under reduced pressure. The crude material was purified by reverse phase column chromatography (30% Water in MeCN) to isolate an enriched crude which was further purified using Prep-HPLC to afford title compound as a white solid (0.006 g, 0.011 mmol, 5% yield). 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.42 (d, J = 8.4 Hz, 1H), 7.83 (d, J = 7.6 Hz, 2H), 7.40 (t, J = 7.2 Hz, 2H), 7.14 (t, J = 7.2 Hz, 1H), 7.02 (d, J = 7.6 Hz, 2H), 6.96 (d, J = 8.8Hz, 2H), 4.36 (t, J = 6.0 Hz, 2H), 3.24 (s, 3H), 3.04 (t, J = 6.0Hz, 2H), 2.45 (s, 3H). 19 F NMR (376 MHz, DMSO-d6) δ -142.55 - -142.64 (m, 1F), -144.60 - -144.69 (m, 1F), -152.87 - -152.95 (m, 1F), -170.75 - - 170.85 (m, 1F). ESI-MS: measured m/z 587.4 [M+1] + . HPLC (Method I): RT = 6.35 min., 95.1%. Preparation of 3-(4-phenoxyphenyl)-1-(2-((2,3,4,5-tetrafluoro-6- (methylsulfonyl)benzyl)amino) ethyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine Compound I-44
3-(4-phenoxyphenyl)-1-(2-((2,3,4,5-tetrafluoro-6-(methylt hio)benzyl)amino) ethyl)-1H- pyrazolo[3,4-d]pyrimidin-4-amine [00388] To a stirred solution of 2,3,4,5-tetrafluoro-6-(methylthio) benzaldehyde (1.0 g, 4.46 mmol) in 2,2,2 Trifluroethanol (10 mL) was added 1-(2-aminoethyl)-3-(4-phenoxyphenyl)-1H- pyrazolo [3,4-d] pyrimidin-4-amine (1.54 g, 4.46 mmol). The reaction mixture was stirred at room temperature for 1h and cooled 0°C. Once at temperature, neat sodium cyanoborohydride (2.79 g, 13.38 mmol) was added, and the reaction was permitted to warm to room temperature. After 16 hours, the mixture was concentrated under reduced pressure and the crude material purified by flash column chromatography (60% EtOAc in hexane) to afford the title compound as a white solid (0.27 g, 0.48mmol, 99% yield). ESI-MS: measured m/z 555.25, [M+1] + . 3-(4-phenoxyphenyl)-1-(2-((2,3,4,5-tetrafluoro-6-(methylsulf onyl)benzyl)amino) ethyl)-1H- pyrazolo[3,4-d]pyrimidin-4-amine Compound I-44 [00389] To a stirred solution of 3-(4-phenoxyphenyl)-1-(2-((2,3,4,5-tetrafluoro-6- (methylthio)benzyl)amino) ethyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (0.05 g, 0.09 mmol) in THF (10 mL) was added oxone (0.138 g, 0.45 mmol). The resulting reaction was stirred at room temperature for 32 hrs. Once the reaction was deemed completed, it was diluted with a saturated aqueous solution of NaHCO3 (100 mL) and extracted with ethyl acetate (2 x 50 mL). The combined organic phases were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude material was purified by reverse phase chromatography (27% acetonitrile in water) to afford the title compound as a white solid (0.015 g, 0.025 mmol, 6% yield). 1 H NMR (400 MHz, DMSO-d6) δ 8.21 (s, 1H), 7.64 (d, J = 8.8 Hz, 2H), 7.44 (t, J = 8.4 Hz, 2H), 7.21-7.12 (m, 6H), 4.39 (t, J = 6 Hz, 2H), 4.14 (br s, 2H), 3.20 (s, 3H), 3.05-3.10 (m, 2H). 19 F NMR (376 MHz, DMSO-d6) δ -132.00 - - 132.07 (m, 1F), -138.35 - -138.43 (m, 1F), -146.17 - -146.25 (m, 1F), -153.65 - -153.77 (m, 1F). ESI-MS: measured m/z 587.25 [M+1] + . HPLC (Method I): RT = 5.59 min., 96.3%. Preparation of N-(2-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidi n-1-yl)ethyl)- 2,3,4,5-tetrafluoro-6-sulfamoylbenzamide Compound I-42 N-(2-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidi n-1-yl)ethyl)-2-(N,N-bis(4- methoxybenzyl)sulfamoyl)-3,4,5,6-tetrafluorobenzamide [00390] N-(2-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidi n-1-yl)ethyl)-2- (N,N-bis(4-methoxybenzyl)sulfamoyl)-3,4,5,6-tetrafluorobenza mide was prepared from 2-(N,N- bis(4-methoxybenzyl)sulfamoyl)-3,4,5,6-tetrafluorobenzoic acid (0.4 g, 0.77 mmol) and 1-(2- aminoethyl)-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin- 4-amine (0.35 g, 1.01 mmol) according to the protocol described in general procedure A and isolated as an off-white solid (0.35 g, 0.41 mmol, 53% yield). ESI-MS: measured m/z 843.0 [M+1] + . N-(2-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidi n-1-yl)ethyl)-2,3,4,5- tetrafluoro-6-sulfamoylbenzamide Compound I-42 [00391] N-(2-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidi n-1-yl)ethyl)-2,3,4,5- tetrafluoro-6-sulfamoylbenzamide was prepared from N-(2-(4-amino-3-(4-phenoxyphenyl)-1H- pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-2-(N,N-bis(4-methoxyben zyl)sulfamoyl)-3,4,5,6- tetrafluorobenzamide (0.35 g, 0.41 mmol) according to the protocol described in general procedure B and isolated as a white solid (0.04 g, 0.06 mmol, 35% yield). 1 H NMR (400 MHz, DMSO-d6) δ 8.27 (s, 1H), 8.26 (s, 1H), 8.08 (brs, 2H) 7.68 (d, J = 8.8 Hz, 2H), 7.44 (t, J = 8.0 Hz, 3H), 7.21-7.12 (m, 5H), 5.73 (m, 1H), 4.48 (m, 2H), 3.73- 3.72 (m, 2H). 19 F NMR (376 MHz, DMSO-d 6 ) δ -134.62 - -134.68 (m, 1F), -140.90 - -140.99 (m, 1F), -149.08 - -149.17 (m, 1F), - 153.02 - -153.14 (m, 1F). ESI-MS: m/z 602.3 [M+1] + . HPLC (Method I): RT = 5.94 min., 98.2%. General Procedure E: (R)-3-(4-phenoxyphenyl)-1-(1-((2,3,4,5-tetrafluoro-6-(fluoro methoxy)phenyl)sulfonyl) pyrrolidin-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine Compound I-24
[00392] 2,3,4,5-tetrafluoro-6-(fluoromethoxy)benzenesulfonyl chloride (382 mg, 1.29 mmol) was added dropwise to a solution of 3-(4-phenoxyphenyl)-1-[(3R)-pyrrolidin-3- yl]pyrazolo[3,4-d]pyrimidin-4-amine (400 mg, 1.07 mmol) in anhydrous dichloromethane (10 mL) at 0°C under argon and stirred for 15 minutes. Triethylamine (217 mg, 2.15 mmol, 299 uL) was slowly added to the mixture and the reaction permitted to warm to room temperature. After 2 hrs, the reaction was diluted with 0.1M HCl and the organic layer was separated. The aqueous layer was extracted with DCM once more. The combined organic layers were dried over sodium sulfate and evaporated to dryness, providing crude product as a beige foam. The crude material was purified by flash column chromatography (30-50% ethyl acetate/DCM) to afford the title compound as a white foam (54 mg, 0.085 mmol, 8% yield). 1 H NMR (400 MHz, CDCl 3 ) δ 8.34 (s, 1H), 7.53 – 7.33 (m, 4H), 7.21 (s, 1H), 7.17 – 7.05 (m, 4H), 5.74 – 5.46 (m, 5H), 4.01 (d, J = 5.2 Hz, 2H), 3.89 (t, J = 8.4 Hz, 1H), 3.75 (ddd, J = 9.4, 7.9, 4.2 Hz, 1H), 2.62 – 2.44 (m, 2H). 19 F NMR (376 MHz, CDCl 3 ) δ -132.92 (dt, J = 24.2, 8.1 Hz), -145.98 (td, J = 21.7, 6.9 Hz), - 148.65 (td, J = 22.0, 9.1 Hz), -149.19 – -150.02 (m), -156.36 (dd, J = 24.6, 21.2 Hz). ESI-MS: m/z 633.2 [M+1] + . HPLC (Method III): RT = 5.70 min., 95.2%. N-(2-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidi n-1-yl)ethyl)-2,3,4,5- tetrafluoro-6-(fluoromethoxy)benzenesulfonamide Compound I-25
[00393] N-(2-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidi n-1-yl)ethyl)-2,3,4,5- tetrafluoro-6-(fluoromethoxy)benzenesulfonamide was prepared from 2,3,4,5-tetrafluoro-6- (fluoromethoxy)benzenesulfonyl chloride (216.92 mg, 731.36 μmol) and 1-(2-aminoethyl)-3-(4- phenoxyphenyl)pyrazolo[3,4-d]pyrimidin-4-amine hydrochloride (0.28 g, 731.36 μmol) according to the protocol described in general procedure E and isolated as a white solid (0.062 g, 102 μmol, 14% yield). 1 H NMR (400 MHz, CDCl3) δ 8.35 (s, 1H), 7.72 – 7.57 (m, 2H), 7.54 – 7.36 (m, 2H), 7.29 – 7.11 (m, 5H), 7.08 (s, 1H), 5.79 (bs, 2H), 5.61 (d, J = 53.4 Hz, 2H), 4.70 – 4.56 (m, 2H), 3.81 (s, 2H). 19 F NMR (376 MHz, CDCl3) δ -135.21 – -136.26 (m), -146.54 – - 146.90 (m), -149.04 – -149.65 (m), -156.26 (dd, J = 23.8, 20.8 Hz). ESI-MS: m/z 607.2 [M+1] + . HPLC (Method III): RT = 4.62 min., 98%. 3-(4-phenoxyphenyl)-1-((2,3,4,5-tetrafluoro-6-methoxyphenyl) sulfonyl)-1H-pyrazolo[3,4- d]pyrimidin-4-amine Compound I-23 [00394] 3-(4-phenoxyphenyl)-1-((2,3,4,5-tetrafluoro-6-methoxyphenyl) sulfonyl)-1H- pyrazolo[3,4-d]pyrimidin-4-amine was prepared from 2,3,4,5-tetrafluoro-6- methoxybenzenesulfonyl chloride (130 mg, 0.47 mmol) and 3-(4-phenoxyphenyl)-1H- pyrazolo[3,4-d]pyrimidin-4-amine (0.156 g, 0.51 mmol) according to the protocol described in general procedure E and isolated as a white solid (0.004 g, 8 μmol, 2% yield). 1 H NMR (400 MHz, CDCl 3 ) δ 8.55 (s, 1H), 7.70 (d, J = 7.8 Hz, 2H), 7.41 (t, J = 8.1 Hz, 2H), 7.23 (t, J = 8.1 Hz, 1H), 7.12 (d, J = 7.8 Hz, 2H), 7.05 (d, J = 8.1 Hz, 2H), 5.80 (bs, 2H), 4.05 (s, 1H). 19 F NMR (376 MHz, CDCl 3 ) δ -134.04 – -134.15 (m, 1F), -143.52 – -143.65 (m, 1F), -152.75 – -152.83 (m, 1F), - 159.47 – -159.59 (m, 1F). ESI-MS: m/z 546.17 [M+1] + . HPLC (Method III): RT = 5.61 min., 95%. N-(2-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidi n-1-yl)ethyl)-2- (difluoromethyl)-3,4,5,6-tetrafluorobenzenesulfonamide Compound I-22 [00395] N-(2-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidi n-1-yl)ethyl)-2- (difluoromethyl)-3,4,5,6-tetrafluorobenzenesulfonamide was prepared from 2-(difluoromethyl)- 3,4,5,6-tetrafluorobenzenesulfonyl chloride (60 mg, 167 μmol) and 1-(2-aminoethyl)-3-(4- phenoxyphenyl)pyrazolo[3,4-d]pyrimidin-4-amine hydrochloride (0.71 g, 186 μmol) according to the protocol described in general procedure E and isolated as a white solid (0.041 g, 67 μmol, 36% yield). 1 H NMR (400 MHz, CDCl 3 ) δ 8.27 (d, J = 1.5 Hz, 1H), 7.81 (t, J = 52.2 Hz, 1H), 7.64 – 7.53 (m, 2H), 7.47 – 7.38 (m, 2H), 7.24 – 7.07 (m, 4H), 5.90 (s, 2H), 4.61 (td, J = 4.9, 1.9 Hz, 2H), 3.81 (t, J = 5.2 Hz, 2H). 19 F NMR (376 MHz, CDCl3) δ -112.75 (dd, J = 52.3, 27.8 Hz, 2F), -133.47 (dt, J = 21.2, 9.9 Hz, 1F), -133.94 (tdt, J = 28.7, 19.1, 9.2 Hz, 1F), -145.51 (td, J = 20.5, 9.3 Hz, 1F), -147.45 (td, J = 21.7, 7.8 Hz, 1F). LC-MS (ESI-) m/z calc’d for [C 26 H 18 F 6 N 6 O 3 S]- : 607.1. found: 607.1. HPLC purity : 96% (R)-1-(1-((2-(difluoromethoxy)-3,4,5,6-tetrafluorophenyl)sul fonyl)pyrrolidin-3-yl)-3-(4- phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine Compound I-26
[00396] (R)-1-(1-((2-(difluoromethoxy)-3,4,5,6-tetrafluorophenyl)sul fonyl)pyrrolidin-3-yl)-3- (4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine was prepared from 2- (difluoromethoxy)-3,4,5,6-tetrafluorobenzenesulfonyl chloride (25 mg, 79 μmol) and 3-(4- phenoxyphenyl)-1-[(3R)-pyrrolidin-3-yl]pyrazolo[3,4-d]pyrimi din-4-amine (27 mg, 72 mmol) according to the protocol described in general procedure E and isolated as a white solid (0.028 g, 43 μmol, 60% yield). 1 H NMR (400 MHz, CDCl3) δ 8.35 (s, 1H), 7.55 – 7.39 (m, 4H), 7.31 – 7.23 (m, 1H), 7.23 – 7.11 (m, 4H), 6.64 (td, J = 74.7, 1.0 Hz, 1H), 5.75 – 5.53 (m, 3H), 4.05 (d, J = 5.0 Hz, 2H), 3.94 (q, J = 8.5 Hz, 1H), 3.80 (ddd, J = 9.4, 7.4, 4.5 Hz, 1H), 2.62 – 2.46 (m, 2H). 19 F NMR (376 MHz, CDCl3) δ -83.13 (dd, J = 74.8, 13.7 Hz), -132.27 (dt, J = 24.4, 8.0 Hz), -145.47 (td, J = 21.4, 7.0 Hz), -146.97 (td, J = 23.3, 22.8, 13.5 Hz), -154.19 (ddd, J = 23.7, 21.0, 2.2 Hz). LC-MS (ESI-) m/z calc’d for [C 28 H 20 F 6 N 6 O 4 S]+ : 651.1. Found: 651.2. LC-MS purity : 97.2% 2-(difluoromethyl)-3,4,5,6-tetrafluoro-N-(3-((5-fluoro-2-((4 -(2-methoxyethoxy) phenyl)amino)pyrimidin-4-yl)amino)phenyl)benzenesulfonamide Compound I-51 [00397] 2-(difluoromethyl)-3,4,5,6-tetrafluoro-N-(3-((5-fluoro-2-((4 -(2-methoxyethoxy) phenyl)amino)pyrimidin-4-yl)amino)phenyl)benzenesulfonamide was prepared from 2- (difluoromethyl)-3,4,5,6-tetrafluoro-benzenesulfonyl chloride (50 mg, 0.167 mmol) and N 4 -(3- aminophenyl)-5-fluoro-N 2 -[4-(2-methoxyethoxy)phenyl]pyrimidine-2,4-diamine (123 mg, 0.334 mmol) according to the protocol described in general procedure E and isolated as a white solid (0.005 g, 8.71 μmol, 5.2% yield). 1 H NMR (400 MHz, CDCl 3 ) δ 7.98 – 7.63 (m, 3H), 7.44 (s, 1H), 7.38 (d, J = 8.6 Hz, 2H), 7.28 – 7.20 (m, 2H), 7.00 – 6.85 (m, 4H), 4.20 – 4.08 (m, 2H), 3.83 – 3.75 (m, 2H), 3.49 (s, 3H). 19 F NMR (376 MHz, CDCl3) δ -112.90 (dd, J = 52.2, 27.4 Hz, 2F), - 132.29 – -132.51 (m, 1F), -132.90 – -133.26 (m, 1F), -143.48 (td, J = 20.6, 10.2 Hz, 1F), -146.89 (td, J = 22.4, 8.1 Hz, 1F), -166.90 (m, 1F). Analytical HPLC purity : 96.0% 2-(difluoromethyl)-3,4,5,6-tetrafluoro-N-(3-((5-fluoro-2-((4 -(2-methoxyethoxy) phenyl)amino)pyrimidin-4-yl)amino)propyl)benzenesulfonamide Compound I-52 [00398] A mixture of N 4 -(3-aminopropyl)-5-fluoro-N 2 -[4-(2- methoxyethoxy)phenyl]pyrimidine-2,4-diamine (60 mg, 178.90 μmol) and DIPEA (46.24 mg, 357.81 μmol, 62.32 uL) in DCM (1.8 mL) was stirred at 0°C while a solution of 2- (difluoromethyl)-3,4,5,6-tetrafluoro-benzenesulfonyl chloride (48.08 mg, 161.01 μmol, 23.84 uL) in DCM (1.8 mL)was added dropwise. The resulting mixture was warmed to room temperature over 4 hours. The reaction was quenched with water and extracted with EtOAc (10^mL^×^3), washed with brine, and dried over Na 2 SO 4 . The solvent was removed under reduced pressure, and the residue was separated on a pad of silica eluting with a gradient of EtOAc in Hexanes (30 - 40%) to obtain the title compound as a beige solid (0.010 g, 16.4 μmol, 9% yield). 1 H NMR (400 MHz, CDCl 3 ) δ 7.99 – 7.59 (m, 2H), 7.47 – 7.41 (m, 2H), 7.24 (s, 1H), 6.94 – 6.86 (m, 2H), 4.21 – 4.05 (m, 3H), 3.80 – 3.73 (m, 2H), 3.66 (q, J = 6.3 Hz, 2H), 3.47 (s, 3H), 3.20 (t, J = 6.0 Hz, 2H). 19 F NMR (376 MHz, CDCl3) δ -112.76 (dd, J = 52.4, 27.5 Hz, 2F), -133.73 (tdt, J = 28.7, 20.2, 9.6 Hz, 1F), -134.45 (dt, J = 21.2, 10.2 Hz, 1F), -145.33 (td, J = 20.4, 9.2 Hz, 1F), -147.24 (td, J = 21.8, 20.6, 7.8 Hz, 1F), -169.11 (1F). Analytical HPLC purity : 97.3% 2,3,4,5-tetrafluoro-N-(3-((5-fluoro-2-((4-(2-methoxyethoxy)p henyl)amino)pyrimidin-4- yl)amino)phenyl)-6-(trifluoromethyl)benzenesulfonamide Compound I-53 [00399] A mixture of N 4 -(3-aminophenyl)-5-fluoro-N 2 -[4-(2- methoxyethoxy)phenyl]pyrimidine-2,4-diamine (175.02 mg, 473.81 μmol), DCM (0.1 M) (3.16 mL) and sodium carbonate (33.48 mg, 315.87 μmol, 13.23 uL) ) was stirred at 0°C while a solution of 2,3,4,5-tetrafluoro-6-(trifluoromethyl)benzenesulfonyl chloride (0.1 g, 315.87 μmol, 21.05 uL) in DCM (0.1 M) (3.16 mL) was added dropwise and the resulting mixture allowed to warm to room temperature. After 3 hrs, the reaction was quenched with water and extracted with DCM (×^3), washed with brine, and dried over Na2SO4. The solvent was removed under reduced pressure, and the residue was separated Biotage Isolera equipped with a reverse phase cartridge (90% to 50% MiliQ water in HPLC-grade acetonitrile) to afford the desired product as light yellow solid (0.014 g, 21.5 μmol, 7% yield). 1 H NMR (400 MHz, CDCl 3 ) δ 7.78 (s, 3H), 7.33 (d, J = 8.4 Hz, 2H), 7.24 (d, J = 7.9 Hz, 0H), 7.05 (s, 1H), 6.91 (d, J = 8.3 Hz, 2H), 4.16 (s, 2H), 3.79 (d, J = 4.8 Hz, 2H), 3.48 (s, 3H). 19 F NMR (376 MHz, CDCl 3 ) δ -51.47 (3F), -129.21 (1F), -130.42 (1F), -143.10 (1F), -144.14 (1F). LC-MS (ESI+) m/z calc’d for [C 26 H 19 F 8 N 5 O 4 S]+ : 648.1. Found: 648.1. Analytical HPLC purity : 97.2% 2-(difluoromethoxy)-3,4,5,6-tetrafluoro-N-(3-((5-fluoro-2-(( 4-(2-methoxyethoxy) phenyl)amino)pyrimidin-4-yl)amino)phenyl)benzenesulfonamide Compound I-54
[00400] A mixture of N 4 -(3-aminophenyl)-5-fluoro-N 2 -[4-(2- methoxyethoxy)phenyl]pyrimidine-2,4-diamine (27.96 mg, 75.68 μmol), ACN (0.8 mL) and sodium carbonate (8.02 mg, 75.68 μmol) was stirred at 0°C while a solution of 2- (difluoromethoxy)-3,4,5,6-tetrafluoro-benzenesulfonyl chloride (0.025 g, 79.47 μmol, 21.05 uL) in CAN (0.8 mL) was added dropwise and the resulting mixture allowed to warm to room temperature. After 3 hrs, the reaction was quenched with water and extracted with DCM (×^3), washed with brine, and dried over Na 2 SO 4 . The solvent was removed under reduced pressure, and the residue was separated on a Biotage Isolera equipped with a normal phase cartridge (30-40% EtOAc in hexanes) to afford the desired product as an oil (0.015 g, 23.2 μmol, 30% yield). 1 H NMR (400 MHz, CDCl3) δ 7.98 (d, J = 3.1 Hz, 1H), 7.87 (s, 1H), 7.45 – 7.38 (m, 2H), 7.28 – 7.22 (m, 2H), 6.97 – 6.84 (m, 5H), 6.79 (d, J = 3.1 Hz, 1H), 6.58 (d, J = 73.5 Hz, 1H), 4.20 – 4.13 (m, 2H), 3.82 – 3.76 (m, 2H), 3.49 (s, 3H). 19 F NMR (376 MHz, CDCl3) δ -81.85 (dd, J = 73.5, 12.8 Hz, 2F), -134.21 (dt, J = 24.0, 8.5 Hz, 1F), -144.20 (td, J = 21.0, 7.8 Hz, 1F), -146.83 – -147.02 (m, 1F), -153.21 (d, J = 2.5 Hz, 1F), -167.76 (t, J = 3.2 Hz, 1F). LC-MS (ESI-) m/z calc’d for [C 26 H 20 F 7 N 5 O 5 S]- : 646.1. Found: 646.1. 2-(difluoromethoxy)-3,4,5,6-tetrafluoro-N-(3-((5-fluoro-2-(( 4-(2-methoxyethoxy) phenyl)amino)pyrimidin-4-yl)amino)propyl)benzenesulfonamide Compound I-55
[00401] A mixture of N 4 -(3-aminopropyl)-5-fluoro-N 2 -[4-(2- methoxyethoxy)phenyl]pyrimidine-2,4-diamine (31.98 mg, 95.36 μmol), ACN (1 mL) and TEA (29 mg, 286 μmol) was stirred at 0°C while a solution of 2-(difluoromethoxy)-3,4,5,6-tetrafluoro- benzenesulfonyl chloride (0.025 g, 79.47 μmol, 21.05 uL) in ACN (1 mL) was added dropwise and the resulting mixture allowed to warm to room temperature. After 4 hrs, the reaction was quenched with water and extracted with DCM (×^3), washed with brine, and dried over Na2SO4. The solvent was removed under reduced pressure, and the residue was separated on a Biotage Isolera equipped with a normal phase cartridge (30-40% EtOAc in hexanes) to afford the desired product (0.02 g, 32.6 μmol, 34% yield). 1 H NMR (400 MHz, CDCl3) δ 7.80 (d, J = 3.0 Hz, 1H), 7.49 – 7.41 (m, 2H), 7.19 (s, 1H), 6.98 – 6.87 (m, 3H), 6.82 – 6.47 (m, 1H), 5.22 – 5.14 (m, 1H), 4.15 – 4.08 (m, 3H), 3.80 – 3.75 (m, 2H), 3.64 (t, J = 6.3 Hz, 2H), 3.47 (s, 3H), 3.23 (t, J = 6.1 Hz, 2H), 1.84 (p, J = 6.1 Hz, 2H). 19 F NMR (376 MHz, CDCl3) δ -82.37 (dd, J = 73.8, 12.7 Hz, 2F), -135.31 (ddd, J = 23.8, 9.2, 7.1 Hz, 1F), -146.15 (d, J = 7.0 Hz, 1F), -147.07 – -147.25 (m, 1F), -153.84 (t, J = 2.8 Hz, 1F), -169.74 (t, J = 2.8 Hz, 1F). LC-MS (ESI+) m/z calc’d for [C 23 H 22 F 7 N 5 O 5 S]+ : 614.1. Found: 614.2. 2,3,4,5-tetrafluoro-N-(3-((5-fluoro-2-((4-(2-methoxyethoxy)p henyl)amino)pyrimidin-4- yl)amino)propyl)-6-(fluoromethyl)benzenesulfonamide Compound I-56
[00402] A mixture of N 4 -(3-aminopropyl)-5-fluoro-N 2 -[4-(2- methoxyethoxy)phenyl]pyrimidine-2,4-diamine (60 mg, 179 μmol), DCM (1 mL) and DIPEA (46 mg, 358 μmol, 62 uL) was stirred at 0°C while a solution of (fluoromethyl)benzenesulfonyl chloride (45.18 mg, 161.01 μmol, 23.85 uL) in DCM (1 mL) was added dropwise and the resulting mixture allowed to warm to room temperature. After 2 hrs, the reaction was quenched with water and extracted with DCM (×^3), washed with brine, and dried over Na 2 SO 4 . The solvent was removed under reduced pressure, and the residue was separated on a Prep-HPLC equipped with a reverse phase column (90-0% water in ACN) to afford the desired product (0.016 g, 27.6 μmol, 15% yield). 1 H NMR (400 MHz, CDCl 3 ) δ 7.77 (d, J = 3.2 Hz, 1H), 7.49 – 7.43 (m, 2H), 7.38 (s, 1H), 7.09 (s, 1H), 6.97 – 6.85 (m, 2H), 5.90 (dd, J = 46.2, 3.0 Hz, 2H), 5.36 (s, 1H), 4.16 – 4.09 (m, 2H), 3.76 (dd, J = 5.5, 3.9 Hz, 2H), 3.64 (q, J = 6.3 Hz, 2H), 3.47 (s, 3H), 3.22 (s, 2H), 2.67 (s, 1H), 1.84 (p, J = 6.2 Hz, 2H). 19 F NMR (376 MHz, CDCl 3 ) δ -132.30 – -132.51 (m, 1F), -137.37 (dddt, J = 20.9, 11.6, 5.9, 3.3 Hz, 1F), -146.46 (td, J = 20.8, 9.0 Hz, 1F), -149.07 (ddt, J = 22.8, 20.0, 6.2 Hz, 1F), -169.18 (1F), -205.51 – -205.63 (m, 1F). 2,3,4,5-tetrafluoro-N-(3-((5-fluoro-2-((4-(2-methoxyethoxy)p henyl)amino)pyrimidin-4- yl)amino)phenyl)-6-(fluoromethoxy)benzenesulfonamide Compound I-57 [00403] A mixture of N 4 -(3-aminophenyl)-5-fluoro-N 2 -[4-(2- methoxyethoxy)phenyl]pyrimidine-2,4-diamine (56 mg, 150 μmol), ACN (1.5 mL) and sodium carbonate (16 mg, 150 μmol) was stirred at 0°C while a solution of 2,3,4,5-tetrafluoro-6- (fluoromethoxy)benzenesulfonyl chloride (46.84 mg, 157.94 μmol, 21.05 uL) in ACN (1.5 mL) was added dropwise and the resulting mixture allowed to warm to room temperature. After 16 hrs, the reaction was quenched with water and extracted with DCM (×^3), washed with brine, and dried over Na2SO4. The solvent was removed under reduced pressure, and the residue was separated on a Prep-HPLC equipped with a reverse phase column (90-0% water in ACN) to afford the desired product (0.018 g, 28.6 μmol, 19% yield). 1 H NMR (400 MHz, CDCl 3 ) δ 7.94 (s, 1H), 7.82 (s, 1H), 7.71 (s, 1H), 7.43 (d, J = 8.9 Hz, 2H), 7.27 – 7.21 (m, 2H), 6.94 (dd, J = 7.4, 4.9 Hz, 4H), 6.87 (s, 1H), 5.75 (s, 1H), 5.62 (s, 1H), 4.17 (dd, J = 5.7, 3.8 Hz, 2H), 3.83 – 3.76 (m, 2H), 3.49 (s, 3H). 19 F NMR (376 MHz, CDCl 3 ) δ -134.90 (dt, J = 24.2, 8.6 Hz), -144.74 (td, J = 21.1, 7.7 Hz), -148.76 (td, J = 52.4, 19.7 Hz), -149.39 (td, J = 20.3, 9.3 Hz), -155.65 – -155.85 (m), - 167.39. 2,3,4,5-tetrafluoro-N-(3-((5-fluoro-2-((4-(2-methoxyethoxy)p henyl)amino)pyrimidin-4- yl)amino)phenyl)-6-(fluoromethyl)benzenesulfonamide Compound I-58
[00404] A mixture of N 4 -(3-aminophenyl)-5-fluoro-N 2 -[4-(2- methoxyethoxy)phenyl]pyrimidine-2,4-diamine (60 mg, 164 μmol), THF (1.5 mL) and sodium carbonate (22 mg, 211 μmol) was stirred at 0°C while a solution of 2,3,4,5-tetrafluoro-6- (fluoromethyl)benzenesulfonyl chloride (59 mg, 211 μmol) in THF (1.5 mL) was added dropwise and the resulting mixture allowed to warm to room temperature. After 3 hrs, the reaction was quenched with water and extracted with DCM (×^3), washed with brine, and dried over Na 2 SO 4 . The solvent was removed under reduced pressure, and the residue was separated on a Prep-HPLC equipped with a reverse phase column (50-0% water in ACN + 0.1% FA) to afford the desired product (0.005 g, 9 μmol, 5% yield). 1 H NMR (400 MHz, CDCl 3 ) δ 7.98 (d, J = 3.2 Hz, 1H), 7.83 (s, 1H), 7.42 (d, J = 8.8 Hz, 2H), 7.23 (t, J = 8.2 Hz, 1H), 6.96 (d, J = 8.9 Hz, 1H), 6.94 – 6.73 (m, 4H), 5.91 (d, J = 46.1 Hz, 2H), 4.17 (t, J = 4.8 Hz, 2H), 3.83 – 3.76 (m, 1H), 3.48 (d, J = 5.1 Hz, 3H). 19 F NMR (376 MHz, CDCl 3 ) δ -131.18 (1F), -136.56 (1F) -144.56 (1F), -148.46 (1F), -167.89 (1F), -206.62 (1F). 2-(N,N-dimethylsulfamoyl)-3,4,5,6-tetrafluoro-N-(3-((5-fluor o-2-((4-(2-methoxy ethoxy)phenyl)amino)pyrimidin-4-yl)amino)phenyl)benzamide Compound I-59
[00405] 2-(N,N-dimethylsulfamoyl)-3,4,5,6-tetrafluoro-N-(3-((5-fluor o-2-((4-(2-methoxy ethoxy)phenyl)amino)pyrimidin-4-yl)amino)phenyl)benzamide was prepared from 2-(N,N- dimethylsulfamoyl)-3,4,5,6-tetrafluorobenzoic acid (0.1 g, 0.33 mmol) and N4-(3-aminophenyl)- 5-fluoro-N2-(4-(2-methoxyethoxy)phenyl)pyrimidine-2,4-diamin e (0.18 g, 0.49 mmol) according to the protocol described in general procedure A and isolated as an off-white solid (0.06 g, 0.092 mmol, 28% yield). 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.75 (s, 1H), 9.43 (s, 1H), 8.94 (s, 1H), 8.06 (d, J = 4 Hz, 1H), 7.80 (s, 1H), 7.77 (d, J = 8.0 Hz, 1H), 7.53 (d, J = 9.2 Hz, 2H), 7.35-7.27 (m, 2H), 6.80 (d, J = 8.8 Hz, 2H), 4.04 - 4.01 (m, 2H), 3.65 -3.63 (m, 2H), 3.31 (s, 3H), 2.86 (s, 6H). 19 F NMR (376 MHz, DMSO-d 6 ) δ -130.83 - -130.95 (m, 1F), -140.38 - -140.47 (m, 1F), - 146.96 - -147.11 (m, 1F), -151.49 - -151.60 (m, 1F), -164.76 (1F). ESI-MS: measured m/z 653.2 [M+1] + . HPLC (Method I) RT = 5.96 min., 98.6%. 2-(difluoromethoxy)-3,4,5,6-tetrafluoro-N-((2-((4-(4-methylp iperazin-1- yl)phenyl)amino)pyrimidin-5-yl)methyl)benzenesulfonamide Compound I-60
[00406] To a stirred solution of 2-(difluoromethoxy)-3,4,5,6-tetrafluorobenzenesulfonyl chloride (0.3 g, 0.95 mmol) in THF (1.5mL) under an N 2 atmosphere was added 4-(amino methyl)-N-(4-(4-methylpiperazin-1-yl) phenyl) pyrimidin-2-amine (0.28 g, 0.95 mmol) in THF (1.5 mL) and TEA (1.9 mmol, 0.265 mL). After 30 min., the reaction mixture was diluted with water (100mL) and extracted with EtOAc (2 x 50 mL). The combined organic phases were dried over anhydrous Na 2 SO 4 , and concentrated under reduced pressure. The crude material was purified by Prep HPLC to afford title compound as a brown solid (0.009 g, 0.015 mmol, 2% yield). 1 H NMR (400 MHz, DMSO-d6) δ 9.27 (s,1H), 8.34 (d, J=4.8Hz, 1H), 8.24 (s,1H), 7.52 (d, J=9.2Hz, 2H), 7.25-6.89 (t, J = 73.6Hz, 1H), 6.84 (d, J = 9.2 Hz, 2H), 6.71(d, J = 5.2 Hz, 1H), 4.18 (s, 2H), 3.05 (t, J = 4.4Hz, 4H), 2.46 (t, J = 5.2Hz, 4H), 2.22 (s, 3H). 19 F NMR (376 MHz, DMSO -d6) δ–81.01 - -83.15 (m, 2F), - 135.63 - -135.72 (m, 1F), -149.68 - -150.20 (m, 1F), -156.20 - -156.33 (m, 1F). ESI-MS: measured m/z 577.2, [M+1]. HPLC (Method I): RT = 5.52 min., 92.5% Preparation of 2,3,4,5-tetrafluoro-N-(3-((5-fluoro-2-((4-(2- methoxyethoxy)phenyl)amino)pyrimidin-4-yl)amino)phenyl)-6-(m ethylsulfonyl)benzamide Compound I-61 and 2,3,4,5-tetrafluoro-N-(3-((5-fluoro-2-((4-(2- methoxyethoxy)phenyl)amino)pyrimidin-4-yl)amino)phenyl)-6-(m ethylsulfinyl)benzamide Compound I-62 2,3,4,5-tetrafluoro-N-(3-((5-fluoro-2-((4-(2-methoxyethoxy)p henyl)amino)pyrimidin-4- yl)amino)phenyl)-6-(methylthio)benzamide [00407] 2,3,4,5-tetrafluoro-N-(3-((5-fluoro-2-((4-(2-methoxyethoxy)p henyl)amino)pyrimidin- 4-yl)amino)phenyl)-6-(methylthio)benzamide was prepared from 2,3,4,5-tetrafluoro-6- (methylthio)benzoic acid (0.30 g, 1.10 mmol) and N 4 -(3-aminophenyl)-5-fluoro-N 2 -(4-(2- methoxyethoxy)phenyl)pyrimidine-2,4-diamine (0.48 g, 1.32 mmol) according to the protocol described in general procedure A and isolated as a white solid (0.42 g, 0.71 mmol, 61% yield). 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.87 (s, 1H), 9.44 (s, 1H), 8.97 (s, 1H), 8.07 (d, J = 3.6 Hz, 1H), 7.88 (s, 1H), 7.75 (d, J = 6.4 Hz, 1H), 7.53 (d, J = 9.2 Hz, 2H), 7.35-7.34 (m, 2H), 6.80 (d, J = 9.2 Hz, 2H), 4.03-4.01 (m, 2H), 3.64-3.62 (m, 2H), 3.30 (s, 3H), 2.46 (s, 3H). 19 F NMR (376 MHz, DMSO-d6) δ -131.04 - -131.14 (m, 1F), -141.87 - -141.96 (m, 1F), -153.76 - -154.34 (m, 2F), - 164.84 (1F). ESI-MS: measured m/z 592.2 [M+1] + . HPLC (Method I): RT = 6.14 min., 95.1%. 2,3,4,5-tetrafluoro-N-(3-((5-fluoro-2-((4-(2-methoxyethoxy)p henyl)amino)pyrimidin-4- yl)amino)phenyl)-6-(methylsulfonyl)benzamide Compound I-61 [00408] To a stirred solution of 2,3,4,5-tetrafluoro-N-(3-((5-fluoro-2-((4-(2- methoxyethoxy)phenyl)amino)pyrimidin-4-yl)amino)phenyl)-6-(m ethylthio)benzamide (0.19 g, 0.32 mmol) in DCM (5 mL) at 0 o C was added oxone (1.01g, 3.28mmol). The reaction was gradually warmed to room temperature. After 48 hrs, the reaction was diluted with a saturated aqueous solution of NaHCO 3 (50 mL) and extracted with EtOAc (3 x 40 mL). The combined organic phases were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude material was purified by prep TLC product (60% EtOAc in hexane) to afford the title compound as an off- white solid (0.035 g, 0.056 mmol, 11% yield). 1 H NMR (400 MHz, DMSO-d6) δ 10.89 (s, 1H), 9.43 (s, 1H), 8.96 (s, 1H), 8.07 (d, J = 3.6 Hz, 1H), 7.81 (s, 1H), 7.76 (d, J = 3.2 Hz, 1H), 7.54 (d, J = 8.8 Hz, 2H), 7.34 - 7.33 (m, 2H), 6.80 (d, J = 9.2 Hz, 2H), 4.03 - 4.01 (m, 2H), 3.64 - 3.62 (m, 2H), 3.46 (s, 3H), 3.31 (s, 3H). 19 F NMR (376 MHz, DMSO-d 6 ) δ - 132.44 - -132.53 (m, 1F), -140.09 - -140.18 (m, 1F), -145.19 - -145.28 (m, 1F), -151.15 - -151.27 (m, 1F), -164.77 (s, 1F). ESI-MS: measured m/z 624.2 [M+1] + . HPLC (Method I): RT = 5.74 min., 100%. 2,3,4,5-tetrafluoro-N-(3-((5-fluoro-2-((4-(2-methoxyethoxy)p henyl)amino)pyrimidin-4- yl)amino)phenyl)-6-(methylsulfinyl)benzamide Compound I-62 [00409] The title compound was isolated as a separate entity during the purification of 2,3,4,5- tetrafluoro-N-(3-((5-fluoro-2-((4-(2-methoxyethoxy)phenyl)am ino)pyrimidin-4- yl)amino)phenyl)-6-(methylsulfonyl)benzamide. 2,3,4,5-tetrafluoro-N-(3-((5-fluoro-2-((4-(2- methoxyethoxy)phenyl)amino)pyrimidin-4-yl)amino)phenyl)-6-(m ethylsulfinyl)benzamide was isolated as a pink solid (0.045 g, 0.074 mmol, 15% yield). 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.98 (s, 1H), 9.49 (s, 1H), 8.97 (s, 1H), 8.07 (d, J = 5.2 Hz, 1H), 7.89 (s, 1H), 7.75 (t, J = 5.2 Hz, 1H), 7.54 (d, J = 8.8 Hz, 2H), 7.34 (d, J = 4.4 Hz, 2H), 6.80 (d, J = 14 Hz, 2H), 4.03-4.01 (t, J = 4.4 Hz, 2H), 3.64-3.62 (m, 2H), 3.30 (s, 3H), 3.13 (s, 3H). 19 F NMR (376 MHz, DMSO-d 6 ) δ - 139.19 - -139.30 (m, 1F), -140.28 - -140.37 (m, 1F), -149.81 - -149.94 (m, 1F). -151.58 - -151.70 (m, 1F), 164.80 (s, 1F). ESI-MS: measured m/z 608.3 [M+1] + . HPLC (Method I): RT = 5.61 min., 100%. Preparation of 5-fluoro-N 2 -(4-(2-methoxyethoxy)phenyl)-N 4 -(3-((2,3,4,5-tetrafluoro-6- (methyl sulfinyl)phenyl)amino)phenyl)pyrimidine-2,4-diamine Compound I-63 and 5-fluoro- N 2 -(4-(2-methoxyethoxy)phenyl)-N 4 -(3-((2,3,4,5-tetrafluoro-6- (methylsulfonyl)phenyl)amino)phenyl)pyrimidine-2,4-diamine Compound I-64 5-fluoro-N 2 -(4-(2-methoxyethoxy)phenyl)-N 4 -(3-((2,3,4,5-tetrafluoro-6- (methylthio)phenyl)amino)phenyl)pyrimidine-2,4-diamine [00410] A reaction vessel containing N 4 -(3-aminophenyl)-5-fluoro-N 2 -(4-(2- methoxyethoxy)phenyl) pyrimidine-2,4-diamine (0.33 g, 0.90 mmol), 2-bromo-3,4,5,6- tetrafluorophenyl)(methyl) sulfane (0.25 g, 0.90 mmol), Cs2CO3 (0.59 g, 1.81 mmol) and 1,4- dioxane (2.5 mL) was purged with N 2 for 15 minutes. While under a positive pressure of inert atmosphere, Pd 2 dba 3 (0.08 g, 0.09 mmol) and Xanthphos (0.05 g, 0.09 mmol) were added. The resulting mixture was heated to 100°C and stirred overnight. After 16 hrs, the mixture was diluted with water (30 mL) and extracted with EtOAc (2 x 30 mL). The combined organic phases were dried over anhydrous Na 2 SO 4 , filtered, and concentrated under reduced pressure. The crude material was purified by flash column chromatography (38% EtOAc in hexane) to afford the title compound as white solid (0.28 g, 0.49 mmol, 55% yield). 1 H NMR (400 MHz, DMSO-d6) δ 9.10 (s, 1H), 8.93 (s, 1H), 8.05 (d, J=3.6Hz, 1H), 7.85 (s, 1H), 7.54 (d, J=8.8Hz, 2H), 7.47 (d, d, J=8.4Hz, 1H), 7.13 (t, J=8.0Hz, 1H), 7.00 (s, 1H), 6.82 (d, J=9.2Hz, 2H), 6.50 (d, J=7.6Hz, 1H), 4.01-3.99(m, 2H), 3.63-3.61 (m, 2H), 3.30 (s, 3H), 2.34 (s, 3H). 19 F NMR (376 MHz, DMSO-d6) δ -132.12 - -132.21 (m, 1F), -144.02 - -144.11 (m, 1F), -156.25 - -156.37 (m, 1F), -162.88 - - 163.01 (m, 1F), -164.93 (s, 1F). ESI-MS: measured m/z 564.2 [M+1] + . 5-fluoro-N 2 -(4-(2-methoxyethoxy)phenyl)-N 4 -(3-((2,3,4,5-tetrafluoro-6-(methyl sulfinyl)phenyl)amino)phenyl)pyrimidine-2,4-diamine Compound I-63 [00411] 5-fluoro-N 2 -(4-(2-methoxyethoxy)phenyl)-N 4 -(3-((2,3,4,5-tetrafluoro-6-(methyl sulfinyl)phenyl)amino)phenyl)pyrimidine-2,4-diamine was prepared from 5-fluoro-N 2 -(4-(3- methoxypropyl)phenyl)-N 4 -(3-((2,3,4,5-tetrafluoro-6- (methylthio)phenyl)amino)phenyl)pyrimidine-2,4-diamine (0.10 g, 0.17 mmol) according to the protocol described in general procedure C and isolated as a pink solid (0.025 g, 0.043 mmol, 24% yield). 1 H NMR (400 MHz, DMSO-d6) δ 9.15 (s, 1H), 8.96 (s, 1H), 8.27 (s, 1H), 8.06 (d, J= 3.6 Hz, 1H), 7.55 - 7.52 (m, 3H), 7.18 (t, J = 8.4 Hz, 1H), 7.08 (s, 1H), 6.82 (d, J=8.8Hz, 2H), 6.54 (d, J=8.4Hz, 1H), 4.00 (t, J = 4.8 Hz, 2H), 3.62(t, J = 4.8 Hz, 2H), 3.30 (s, 3H), 3.05 (s, 3H). 19 F NMR (376 MHz, DMSO-d 6 ) δ -141.46 - -141.52 (m, 1F), -143.15 - -143.24 (m, 1F), -150.76 - - 150.87 (m, 1F), -161.78 - -161.90 (m, 1F), -164.93 (s, 1F). ESI-MS: measured m/z 580.19 [M+1] + . HPLC (Method I): RT = 5.94 min., 97.3%. 5-fluoro-N 2 -(4-(2-methoxyethoxy)phenyl)-N 4 -(3-((2,3,4,5-tetrafluoro-6- (methylsulfonyl)phenyl)amino)phenyl)pyrimidine-2,4-diamine Compound I-64 [00412] To a stirred solution of 5-fluoro-N 2 -(4-(3-methoxypropyl)phenyl)-N 4 -(3-((2,3,4,5- tetrafluoro-6-(methylthio)phenyl)amino)phenyl)pyrimidine-2,4 -diamine (0.09 g, 0.15 mmol) in THF:MeOH: water (8:1:1 v/v) (1.0mL) at 0°C was added Oxone (0.24 g, 0.79 mmol). The resulting mixture was warmed to room temperature. After 16 hrs, another portion of Oxone (0.24 g, 0.79 mmol) was added and the reaction permitted to stir overnight. Once deemed complete, the reaction was diluted with saturated aqueous NaHCO 3 and extracted with EtOAc (2 x 30 mL). The combined organic phases were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude material was purified by flash column chromatography (39% EtOAc in hexanes) to afford the title compound as light pink solid (0.025 g, 0.042 mmol, 26% yield). 1 H NMR (400 MHz, DMSO-d6) δ 9.16(s, 1H), 8.96 (s, 1H), 8.06 (d, J = 3.6 Hz, 1H), 7.94 (s, 1H), 7.58 - 7.52 (m, 3H), 7.20 - 7.16 (m, 2H), 6.82 (d, J = 8.8 Hz, 2H), 6.62 (d, J = 8.0 Hz, 1H), 4.01 - 3.99 (m, 2H), 3.63 - 3.61 (m, 2H), 3.44 (s, 3H), 3.28 (s, 3H). 19 F NMR (376 MHz, DMSO-d 6 ) δ - 135.06 - -135.17 (m, 1F), -140.44 - -140.52 (m, 1F), -147.53 - -147.67 (m, 1F), -162.65 - -162.78 (m, 1F), -164.96 (s, 1F). ESI-MS: measured m/z 596.26 [M+1] + . HPLC (Method I): RT = 6.21 min., 96.6%. Preparation of 5-fluoro-N 2 -(4-(2-methoxyethoxy)phenyl)-N 4 -(3-((2,3,4,5-tetrafluoro-6- (methylsulfonyl)benzyl)oxy)phenyl)pyrimidine-2,4-diamine Compound I-65 5-fluoro-N 2 -(4-(2-methoxyethoxy)phenyl)-N 4 -(3-((2,3,4,5-tetrafluoro-6- (methylthio)benzyl)oxy)phenyl)pyrimidine-2,4-diamine [00413] To a stirred solution of 3-((5-fluoro-2-((4-(2-methoxyethoxy)phenyl)amino)pyrimidin- 4-yl)amino)phenol (0.32 g, 0.86 mmol) in DMF (3mL) at 0°C was added NaH (0.080 g, 3.29 mmol). The resulting mixture was heated to 70°C for 1 hour, after which neat (2-(bromomethyl)- 3,4,5,6-tetrafluorophenyl)(methyl)sulfane (0.25 g, 0.86 mmol) was added in one portion. The reaction was permitted to continue for a further hour after the addition. Once deemed completed, the reaction mixture was cooled to ambient temperature and diluted with ice cold water (25 mL). The resulting suspension was extracted with EtOAc (2 x 15mL) and^the combined organic phases were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude material was purified by flash column chromatography (43% EtOAc in hexanes) to afford the title compound as a yellow resin (0.11 g, 0.19 mmol, 35% yield). 1 H NMR (400 MHz, DMSO-d6) δ 9.28 (s, 1H), 9.02 (s, 1H), 8.08 (d, J = 4.0 Hz, 1H), 7.52 - 7.48 (m, 4H), 7.26 (t, 1H), 6.79 - 6.75 (m, 3H), 5.19 (s, 2H), 3.98- 3.96 (m, 2H), 3.62- 3.60 (m, 2H), 3.30 (s, 3H), 2.41 (s, 3H). 19 F NMR (376 MHz, DMSO-d 6 ) δ -130.43 - -130.53 (m, 1F), -140.77 - -140.87 (m, 1F), - 153.89 - -154.02 (m, 1F), -155.31 - -155.44 (m, 1F), -164.91 (s, 1F). ESI-MS: measured m/z 579.2 [M+1] + . 5-fluoro-N 2 -(4-(2-methoxyethoxy)phenyl)-N 4 -(3-((2,3,4,5-tetrafluoro-6- (methylsulfonyl)benzyl)oxy)phenyl)pyrimidine-2,4-diamine Compound I-65 [00414] To a stirred solution of 5-fluoro-N 2 -(4-(2-methoxyethoxy) phenyl)-N 4 -(4-((2,3,4,5- tetrafluoro-6-(methylthio)benzyl)oxy)phenyl)pyrimidine-2,4-d iamine (0.1 g, 0.17 mmol) in MeOH (1 mL) was added oxone (0.26 g, 0.86 mmol). After 16 hrs, a second portion of oxone (0.26 g, 0.86 mmol) was added and the reaction stirred overnight. After a further 16 hrs, the mixture was diluted with saturated aqueous NaHCO 3 and extracted with EtOAc (2 x 20 mL).^ The combined organic phases were dried over anhydrous Na 2 SO 4 , filtered, and concentrated under reduced pressure. The resulting crude material was purified by flash column chromatography (45% EtOAc in hexanes) to afford the title compound as a light pink solid (0.027 g, 0.044 mmol, 25% yield). 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.29 (s, 1H), 9.01 (s, 1H), 8.08 (d, J = 3.6 Hz, 1H), 7.56 - 7.50 (m, 3H), 7.42 (s, 1H), 7.27 (t, J = 8.4, 1H), 6.80- 6.73 (m, 3H), 5.39 (s, 2H), 3.99 (m, 2H), 3.62 (t, J = 4.4 Hz, 2H), 3.44 (s, 3H), 3.30 (s, 3H). 19 F NMR (376 MHz, DMSO-d 6 ) δ -131.21 - -131.33 (m, 1F), -138.98 - -139.05 (m, 1F), -146.24 - -146.38 (m, 1F), -151.26 - -151.37 (m, 1F), -164.91 (s, 1F). ESI-MS: measured m/z 611.2 [M+1] + . HPLC (Method I): RT = 6.17 min., 95.1%. N-(2-((7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)ethyl)-2-(N,N-d imethylsulfamoyl)-3,4,5,6- tetrafluorobenzamide Compound I-47 [00415] N-(2-((7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)ethyl)-2-(N,N-d imethylsulfamoyl)- 3,4,5,6-tetrafluorobenzamide was prepared from 2-(N,N-dimethylsulfamoyl)-3,4,5,6- tetrafluorobenzoic acid (0.30 g, 0.99 mmol) and N 1 -(7H-pyrrolo[2,3-d]pyrimidin-4-yl)ethane-1,2- diamine (0.26 g, 1.49 mmol)according to the protocol described in general procedure A and isolated as an off-white solid (0.25 g, 0.54 mmol, 55% yield). 1 H NMR (400 MHz, DMSO-d 6 ) δ 11.53 (s, 1H), 8.89 (t, J = 5.2 Hz, 1H), 8.11 (s, 1H), 7.35 (s, 1H), 7.09 - 7.085 (m, 1H), 6.49 (s, 1H), 3.62 (br s, 2H), 3.48 (br s, 2H), 2.84 (s, 6H). 19 F NMR (376 MHz, DMSO-d6) δ -130.96 - - 130.08 (m, 1F), -140.33 - -140.43 (m, 1F), -147.19 - -147.33 (m, 1F), -151.99 - -152.10 (m, 1F). ESI-MS: measured m/z 461.3 [M+1] + . HPLC (Method I): RT = 4.81 min., 99%. Preparation of N-(2-((7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)ethyl)-2,3,4,5- tetrafluoro-6- (methylsulfonyl)benzamide Compound I-45 Synthesis of N-(2-((7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)ethyl)-2,4,5-tr ifluoro-3-methyl- 6-(methylthio)benzamide [00416] Synthesis of N-(2-((7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)ethyl)-2,4,5-tr ifluoro-3- methyl-6-(methylthio)benzamide was prepared from 2,3,4,5-tetrafluoro-6-(methylthio)benzoic acid (0.40 g, 1.66 mmol) and N 1 -(7H-pyrrolo[2,3-d]pyrimidin-4-yl)ethane-1,2-diamine (0.44 g, 2.40 mmol)according to the protocol described in general procedure A and isolated as a brown solid (0.30 g, 0.75 mmol, 46% yield). 1 H NMR (400 MHz, DMSO-d 6 ) δ 11.51 (s, 1H), 8.90 - 8.89 (m, 1H), 8.11 (s, 1H), 7.45 (s, 1H), 7.08 (m, 1H), 6.50 (s, 1H), 3.67 - 3.62 (m, 2H), 3.54 - 3.51 (m, 2H), 2.39 (s, 3H). 19 F NMR (376 MHz, DMSO-d6) δ -131.25 - -131.35 (m, 1F), -142.02 - -142.12 (m, 1F), -154.40 - -154.69 (m, 2F). ESI-MS: measured m/z 400.29 [M+1] + . tert-butyl 4-((2-(2,3,4,5-tetrafluoro-6-(methylthio)benzamido)ethyl)ami no)-7H-pyrrolo[2,3- d]pyrimidine-7-carboxylate [00417] To the stirred solution of N-(2-((7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)ethyl)-2,4,5- trifluoro-3-methyl-6-(methylthio)benzamide (0.12 g, 0.30 mmol) in DCM (2 mL) at 0°C was added TEA (0.090 g, 0.9 mmol). The mixture was stirred for 10min prior to addition of (Boc)2O (0.065 g, 0.30 mmol). The reaction mixture was warmed to room temperature and stirred overnight. After 16 hrs, the mixture was diluted with water (30 mL) and extracted with EtOAc (2 x 10mL). The combined organic phases were dried over anhydrous Na 2 SO 4 , filtered, and concentrated under reduced pressure. The crude material was purified by normal phase chromatography (0-70% EtOAc in hexane) to afford title compound as a brown sticky solid (0.12 g, 0.24 mmol, 80% yield). 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.89 (t, J = 6.0 Hz, 1H), 8.28 (s, 1H), 7.79 (t, 1H), 7.73 (d, J = 4.0 Hz, 1H), 6.53 (d, J = 4.0 Hz, 1H), 3.66 - 3.62 (m, 2H), 3.55 - 3.50 (m, 2H), 2.39 (s, 3H), 1.59 (s, 9H). ESI-MS: measured m/z 500.27 [M+1] + . tert-butyl 4-((2-(2,3,4,5-tetrafluoro-6-(methylsulfonyl)benzamido)ethyl )amino)-7H- pyrrolo[2,3-d]pyrimidine-7-carboxylate [00418] tert-butyl 4-((2-(2,3,4,5-tetrafluoro-6-(methylsulfonyl)benzamido)ethyl )amino)-7H- pyrrolo[2,3-d]pyrimidine-7-carboxylate was prepared from tert-butyl 4-((2-(2,3,4,5-tetrafluoro-6- (methylthio) benzamido)ethyl)amino)-7H-pyrrolo[2,3-d]pyrimidine-7-carboxy late (0.20 g, 0.40 mmol) according to the protocol described in general procedure C and isolated as a brown resin (0.13 g, 0.32 mmol, 61% yield). 1 H NMR (400 MHz, DMSO-d6) δ 9.02 (t, J = 5.2 Hz, 1H), 8.29 (s, 1H), 7.69 (t, J = 6.0 Hz, 1H), 7.47 (d, J = 4.0 Hz, 1H), 6.74 (d, J = 4.0 Hz, 1H), 3.64 - 3.63 (m, 2H), 3.49 - 3.46 (m, 2H), 3.43 (s, 3H), 1.59 (s, 9H). 19 F NMR (376 MHz, DMSO-d6) δ -132.64 - -132.73 (m, 1F), -140.08 - -140.17 (m, 1F), -145.39 - -145.51 (m, 1F), -151.65 - -151.77 (m, 1F). ESI-MS: measured m/z 532.28 [M+1] + . N-(2-((7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)ethyl)-2,3,4,5- tetrafluoro-6- (methylsulfonyl)benzamide Compound I-45 [00419] A solution of tert-butyl 4-((2-(2,3,4,5-tetrafluoro-6- (methylsulfonyl)benzamido)ethyl)amino)-7H-pyrrolo[2,3-d]pyri midine-7-carboxylate (0.12 g, 0.22 mmol) in 4N HCl in Dioxane (2mL) was stirred at room temperature. After 16 hrs, the reaction mixture was diluted with a saturated solution of NaHCO3 (30 mL) and extracted with DCM (2 x 20 mL). The combined organic phases were dried over anhydrous Na 2 SO 4 , filtered, and concentrated under reduced pressure. The crude material was purified by reverse phase chromatography (0 - 40% ACN in water) to afford the title compound as a sticky brown solid (0.010 g, 0.023 mmol, 10% yield). 1 H NMR (400 MHz, DMSO-d6) δ 11.52 (s, 1H), 9.03 (t, J = 5.6 Hz, 1H), 8.11 (s, 1H), 7.35 (s, 1H), 7.08 (t, J = 3.2 Hz, 1H), 6.50 - 6.49 (m, 1H), 3.65 - 3.61 (m, 2H), 3.47 - 3.44 (m, 2H), 3.42 (s, 3H). 19 F NMR (376 MHz, DMSO-d6) δ -132.62 - -132.72 (m, 1F), -140.07 - -140.17 (m, 1F), -145.43 - -145.51 (m, 1F), -151.69 - -151.81 (m, 1F). ESI- MS: measured m/z 432.25 [M+1] + , HPLC (Method I): RT = 4.28 min., 90.7%. Preparation of 2,3,4,5-tetrafluoro-6-(methylsulfinyl)-N-(7H-pyrrolo[2,3-d]p yrimidin-4- yl)benzamide Compound I-46 tert-butyl 4-(2,3,4,5-tetrafluoro-6-(methylthio)benzamido)-7H-pyrrolo[2 ,3-d]pyrimidine-7- carboxylate [00420] To a stirred solution of 2,3,4,5-tetrafluoro-6-(methylthio)benzoic acid (0.4 g, 1.70 mmol) in DCM (4 mL) were added oxalyl chloride (0.433 g, 3.41 mmol) and DMF (2 drop) at 0 o C. The mixture was stirred at room temperature for 1 hr. After completion of reaction, the reaction mixture was concentrated under reduced pressure and stored under a nitrogen atmosphere. The obtained residue was dissolved in DCM (3 mL) and added dropwise to a pre- stirred solution of tert-butyl 4-amino-7H-pyrrolo[2,3-d]pyrimidine-7-carboxylate (0.61 g, 2.56 mmol) in DMF (5mL) and NaH (60% in mineral oil) (0.13 g, 3.41 mmol) at 0 o C. The resulting mixture was stirred for at 0 o C. After 30 min., the mixture was diluted with ice-cold water (50 mL) and extracted with EtOAc (3 x 50 mL). The combined organic phases were dried over anhydrous Na 2 SO 4 , filtered, and concentrated under reduced pressure. The crude material was purified by flash column chromatography (30% EtOAc in hexanes) to afford the title compound as a yellow solid (0.29 g, 0.63 mmol, 37% yield). 1 H NMR (400 MHz, DMSO-d6) δ 10.55 (s, 1H), 8.39 (s, 1H), 8.046 (s, 1H), 7.17 (d, J = 4 Hz, 1H), 2.27 (s, 3H), 1.51 (s, 9H). ESI-MS: measured m/z 401.2 [M-tBu]-. tert-butyl 4-(2,3,4,5-tetrafluoro-6-(methylsulfinyl)benzamido)-7H-pyrro lo[2,3- d]pyrimidine-7-carboxylate [00421] To a stirred solution of tert-butyl 4-(2,3,4,5-tetrafluoro-6-(methylthio)benzamido)-7H- pyrrolo[2,3-d]pyrimidine-7-carboxylate (0.25 g, 0.54 mmol) in DCM (3 mL) was added oxone (0.84 g, 2.74 mmol) at 0 o C. The resulting reaction mixture was stirred at room temperature for 30 h. After completion of reaction, the mixture was diluted with a saturated aqueous solution of NaHCO3 (50 mL) and extracted with EtOAc (3 x 40 mL). The combined organic phases were dried over anhydrous Na 2 SO 4 , filtered, and concentrated under reduced pressure. The crude material was purified by flash column chromatography (40% EtOAc in hexane) to afford title compound as a yellow solid (0.13 g, 0.27 mmol, 50% yield). 1 H NMR (400 MHz, DMSO-d6) δ 10.50 (s, 1H), 8.37 (s, 1H), 8.00 (s, 1H), 7.10 (d, J = 4 Hz, 1H), 2.61 (s, 3H), 1.51 (s, 9H). ESI- MS: measured m/z 473.2 [M+1] + . 2,3,4,5-tetrafluoro-6-(methylsulfinyl)-N-(7H-pyrrolo[2,3-d]p yrimidin-4-yl)benzamide Compound I-46 [00422] To a stirred solution of tert-butyl 4-(2,3,4,5-tetrafluoro-6-(methylsulfinyl)benzamido)- 7H-pyrrolo[2,3-d]pyrimidine-7-carboxylate (0.11 g, 0.23 mmol) in DCM (2 mL) was added 4N HCl in Dioxane (0.5 mL) at 0 o C. The resulting solution was stirred at room temperature. After 4 hrs, the reaction was diluted with a saturated aqueous solution of NaHCO 3 (30 mL) and extracted with EtOAc (3 x 30mL). The combined organic phases were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude material was purified by reverse phase chromatography (33% ACN in water) to afford title compound as a yellow solid (0.040 g, 0.107 mmol, 46% yield). 1 H NMR (400 MHz, DMSO-d6) δ 7.92 (s, 1H), 7.75 (s, 1H), 7.42 (s, 2H), 6.95 (d, J = 4 Hz, 1H), 3.05 (s, 3H). 19 F NMR (376 MHz, DMSO-d6) δ -137.80 - -137.92 (m, 1F), -142.08 - -142.20 (m, 1F), -151.05 - -151.12 (1F), -151.90 - -151.99 (m, 1F). ESI-MS: measured m/z 373.20 [M+1] + . HPLC (Method I) RT = 4.93 min., 97.3%. Preparation of N-(2-((7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)ethyl)-2-(N,N-b is(4- methoxybenzyl) sulfamoyl)-3,4,5,6-tetrafluorobenzamide Compound I-48 N-(2-((7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)ethyl)-2-(N,N-b is(4- methoxybenzyl)sulfamoyl)-3,4,5,6-tetrafluorobenzamide [00423] N-(2-((7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)ethyl)-2-(N,N-b is(4- methoxybenzyl)sulfamoyl)-3,4,5,6-tetrafluorobenzamide was prepared from 2-(N,N-bis(4- methoxybenzyl)sulfamoyl)-3,4,5,6-tetrafluorobenzoic acid (0.6 g, 1.17 mmol) and N 1 -(7H- pyrrolo[2,3-d]pyrimidin-4-yl)ethane-1,2-diamine (0.31 g, 1.75 mmol) according to the protocol described in general procedure A and isolated as a yellow solid (0.55 g, 0.82 mmol, 70% yield). ESI-MS: measured m/z 673.2 [M+1] + . N-(2-((7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)ethyl)-2-(N,N-b is(4-methoxybenzyl) sulfamoyl)- 3,4,5,6-tetrafluorobenzamide Compound I-48 [00424] To stirred solution of N-(2-((7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)ethyl)-2-(N,N- bis(4-methoxybenzyl)sulfamoyl)-3,4,5,6-tetrafluorobenzamide (0.15 g, 0.22 mmol) in DCM (1.5mL) was added TFA (1.5mL). After 16 hrs, the reaction was diluted with saturated aqueous NaHCO3 (30 mL) and extracted with EtOAc (3 x 30 mL). The combined organic phases were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude material was purified by flash column chromatography (96% EtOAc in hexanes) to afford the title compound as an off-white solid (0.016 g, 0.037 mmol, 16% yield). 1 H NMR (400 MHz, DMSO- d6) δ 11.51 (s, 1H), 8.80 (s, 1H), 8.11 (s, 2H), 7.30 (s, 1H), 7.08 (s, 1H), 6.50 (s, 1H), 3.64 (d, J = 6.4 Hz, 2H), 3.45 (t, J = 6.4, 2H). 19 F NMR (376 MHz, DMSO-d6) δ -134.69 - -134.60 (m, 1F), - 141.97 - -141.06 (m, 1F), -148.96 - -149.02 (m, 1F), -153.11 - -153.23 (m, 1F). ESI-MS: m/z 433.3 [M+1] + ,HPLC (Method I): RT = 4.05 min., 95.5%. Preparation of (4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)(2,3,4,5-tetrafluor o-6- (methylsulfonyl) phenyl)methanone Compound I-49 (4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)(2,3,4,5-tetrafluor o-6-(methylthio) phenyl)methanone [00425] (4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)(2,3,4,5-tetrafluor o-6-(methylthio) phenyl)methanone was prepared from 2,3,4,5-tetrafluoro-6-(methylthio)benzoic acid (0.4 g, 1.66 mmol) and 7H-pyrrolo[2,3-d]pyrimidin-4-amine (0.335 g, 2.49 mmol) according to the protocol described in general procedure D and isolated as a green oil (0.30 g, 0.84 mmol, 50% yield). 1 H NMR (400 MHz, DMSO-d 6 ) δ 7.21 (s, 1H), 7.08 (s, 1H), 6.76 (s, 2H), 6.29 (s, 1H), 2.61 (s, 3H). ESI-MS: measured m/z 357.42 [M+1] + . (4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)(2,3,4,5-tetrafluor o-6-(methylsulfonyl) phenyl)methanone Compound I-49 [00426] (4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)(2,3,4,5-tetrafluor o-6-(methylsulfonyl) phenyl)methanone was prepared from (4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)(2,3,4,5- tetrafluoro-6-(methylthio)phenyl)methanone (0.30 g, 0.84 mmol) according to the protocol described in general procedure C and isolated as a yellow solid (0.15 g, 0.38 mmol, 46% yield). 1 H NMR (400 MHz, DMSO-d6) δ 7.92 (s, 1H), 7.79 (d, J = 4 Hz, 1H), 7.50 (s, 2H), 7.00 (d, J= 4 Hz, 1H), 3.29 (s, 3H). 19 F NMR (376 MHz, DMSO-d 6 ) δ -133.08 - -133.16 (m, 1F), -141.65 - - 141.73 (m, 1F), -145.02 - -145.17 (m, 1F). -149.67 - -149.79 (m, 1F). ESI-MS: measured m/z 389.28 [M+1] + . HPLC (Method I): RT = 5.19 min., 100%. Preparation of N 1 -(7H-pyrrolo[2,3-d] pyrimidin-4-yl)-N2-(2,3,4,5-tetrafluoro-6-(methyl sulfonyl) benzyl) ethane-1,2-diamine Compound I-50 N 1 -(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-N2-(2,3,4,5-tetrafl uoro-6-(methylthio)benzyl)ethane- 1,2-diamine [00427] To a stirred solution of 2,3,4,5-tetrafluoro-6-(methylthio) benzaldehyde (1.0 g, 4.46 mmol) in 2,2,2-Trifluroethanol (10 mL) was added N 1 -(7H-pyrrolo[2,3-d] pyrimidin-4-yl) ethane-1,2-diamine (0.791 g, 4.46 mmol). The reaction mixture was allowed to stir at room temperature for 1 hr, followed by addition of sodium triacetoxyborohydride (2.79 g, 13.39 mmol) at 0°C. The resulting mixture was warmed to room temperature and stirred overnight. After 16 hrs, the reaction was concentrated under reduced pressure. The crude residue was purified by flash column chromatography (10% methanol in DCM) to afford title compound as a white solid (0.32 g, 0.83 mmol, Quantitative). 1 H NMR (400 MHz, DMSO-d6) δ 11.46 (s, 1H), 8.053 (s, 1H), 7.28 (t, J = 5.2 Hz, 1H), 7.04 (t, J = 3.2 Hz, 1H), 6.49 - 6.48 (m, 1H), 3.96 (d, J = 2.4 Hz, 2H), 3.53-3.52 (m, 2H), 2.74 (t, J = 6.4 Hz, 2H), 2.37 (s, 3H). 19 F NMR (376 MHz, DMSO-d6) δ -131.14 - -131.24 (m, 1F), -141.88 - -141.91 (m, 1F), -156.31 - -156.44 (m, 1F), -157.08 - -157.20 (m, 1F). ESI-MS: measured m/z 386.33 [M+1] + . tert-butyl 4-((2-((tert-butoxycarbonyl)(2,3,4,5-tetrafluoro-6- (methylthio)benzyl)amino)ethyl)amino)-7H-pyrrolo[2,3-d]pyrim idine-7-carboxylate [00428] To a stirred solution of N 1 -(7H-pyrrolo[2,3-d] pyrimidin-4-yl)-N2-(2,3,4,5-tetrafluoro- 6-(methylthio) benzyl) ethane-1,2-diamine (0.32 g, 0.83 mmol) in THF (5 mL) was added TEA, (0.633 g, 2.90 mmol), DMAP (0.01 g, 0.083 mmol) and Boc anhydride (0.633 g, 2.90 mmol). After 16 hrs, reaction mixture was diluted with water (100 mL) and extracted with ethyl acetate (2 x 50 mL). The combined organic phases were dried over anhydrous Na 2 SO 4 , filtered, and concentrated under reduced pressure. The crude material was purified by flash column chromatography (25% ethyl acetate in hexanes) to afford the title compound as a white solid (0.15 g, 0.25 mmol, 31% yield). 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.19 (s, 1H), 7.43 (s, 1H), 6.69 (s, 1H), 4.74 (s, 2H), 3.54 - 5.53 (m, 2H), 2.33 (s, 3H), 1.57 (s, 9H), 1.24 (s, 9H). ESI-MS: measured m/z 586.29 [M+1] + . tert-butyl 4-((2-((tert-butoxy carbonyl) (2,3,4,5-tetrafluoro-6-(methyl sulfonyl) benzyl) amino) ethyl) amino)-7H-pyrrolo[2,3-d] pyrimidine-7-carboxylate [00429] tert-butyl 4-((2-((tert-butoxy carbonyl) (2,3,4,5-tetrafluoro-6-(methyl sulfonyl) benzyl) amino) ethyl) amino)-7H-pyrrolo[2,3-d] pyrimidine-7-carboxylate was prepared from tert-butyl 4-((2-((tert-butoxy carbonyl) (2,3,4,5-tetrafluoro-6-(methyl lthio) benzyl) amino) ethyl) amino)- 7H-pyrrolo[2,3-d] pyrimidine-7-carboxylate (0.15 g, 0.25 mmol)according to the protocol described in general procedure C and isolated as a yellow resin (0.07 g, 0.113 mmol, 44% yield). ESI-MS: measured m/z 618.03 [M+1] + . N 1 -(7H-pyrrolo[2,3-d] pyrimidin-4-yl)-N2-(2,3,4,5-tetrafluoro-6-(methyl sulfonyl) benzyl) ethane-1,2-diamine Compound I-50 [00430] To a stirred solution of tert-butyl 4-(2-((tert-butoxy carbonyl) (2,3,4,5-tetrafluoro-6- (methyl sulfonyl) benzyl) amino) ethyl) amino)-7H-pyrrolo[2,3-d] pyrimidine-7-carboxylate (0.07 g, 1.97 mmol) in 1,4 dioxane (0.7 mL) at 0°C was added HCl in dioxane (4M, 0.7 mL) . The reaction was warmed to room temperature. After 5 hrs, the reaction mixture concentrated under reduced pressure. The resulting crude was triturated using n-Pantene to afford title compound as brown solid (0.021 g, 1.97 mmol, 21% yield). 1 H NMR (400 MHz, DMSO-d6) δ 12.52 (br s, 1H), 9.61 (br s, 2H), 8.35 (s, 1H), 7.39 (s, 1H), 6.96 (s, 1H), 4.66 (s, 2H), 3.95 (br s, 2H), 3.62 (s, 3H), 3.43-3.42 (m, 2H). 19 F NMR (376 MHz, DMSO-d 6 ) δ -130.79 - -130.88 (m, 1F), -133.87 - -133.98 (m, 1F), -145.73 - -145.85 (m, 1F), -149.43 - -149.55 (m, 1F). ESI-MS: measured m/z 418.2 [M+1] + . HPLC (Method I): RT = 3.07 min, 96.7% General Procedure F: 2,3,4,5-tetrafluoro-N-(3-fluoro-4-methoxyphenyl)-6-(trifluor omethyl) benzenesulfonamide Compound I-6 [00431] In a 20 mL scintillation vial, 2,3,4,5-tetrafluoro-6- (trifluoromethyl)benzenesulfonamide (0.1 g, 336.53 μmol) was dissolved in DCM (0.1 M) (3.36 mL) under air at r.t. The resulting solution was then added with (3-fluoro-4-methoxy- phenyl)boronic acid (114.38 mg, 673.06 μmol)and oven-dried molecular seives, followed by sequential addition of copper acetate (61.12 mg, 336.53 μmol) and N,N-diethylethanamine (68.11 mg, 673.06 μmol, 93.81 μL). The solution turned from milky heterogeneous blue solution to clear homogeneous blue solution upon addition of TEA. The resulting solution was left to stir until completion. After 3 hours, TLC indicated full consumption of the SM. The mixture was filtered through a pad of Celite and the collected filtrate was concentrated by rotary evaporation under reduced pressure. The mixture was dry-loaded onto a pad of silica equilibrated with 10% EtOAc in Hexanes on Biotage Isolera 25g catridge. The mixture was separated by eluting in gradient from 10% EtOAc to 25% EtOAc in Hexanes to afford the desired product as a beige powder (0.064 g, 0.152 mmol, 45% yield). 1 H NMR (400 MHz, CDCl3) δ 7.03 (dd, J = 11.6, 2.4 Hz, 1H), 7.00 – 6.85 (m, 3H), 3.89 (s, 3H). 19 F NMR (376 MHz, CDCl 3 ) δ -51.59 (d, J = 36.4 Hz, 3F), -129.02 (dt, J = 23.9, 10.3 Hz, 1F), -130.39 (qdt, J = 36.4, 20.2, 9.8 Hz, 1F), -131.24 (dd, J = 11.6, 8.0 Hz, 1F), -142.98 (td, J = 20.6, 11.1 Hz, 1F), -144.44 (ddd, J = 23.9, 20.1, 10.2 Hz, 1F). ESI+MS: m/z 421.1 [M+1] +, . HPLC (Method III): RT = 8.20 min, 96.5% 2,3,4,5-tetrafluoro-N-(3-fluoro-4-methoxyphenyl)-N-methyl-6- (trifluoromethyl) benzenesulfonamide Compound I-7 [00432] 2,3,4,5-tetrafluoro-N-(3-fluoro-4-methoxyphenyl)-N-methyl-6- (trifluoromethyl) benzenesulfonamide was prepared from 2,3,4,5-tetrafluoro-N-methyl-6- (trifluoromethyl)benzenesulfonamide (0.051 g, 0.164 mmol) and (3-fluoro-4- methoxyphenyl)boronic acid (0.056 g, 0.328 mmol) according to the protocol described in general procedure F and isolated as a beige resin (0.016 g, 0.036 mmol, 22% yield). 1 H NMR (400 MHz, CDCl3) δ 7.09 – 7.01 (m, 2H), 6.93 (t, J = 9.1 Hz, 1H), 3.91 (s, 3H), 3.47 (d, J = 2.6 Hz, 3H). 19 F NMR (376 MHz, CDCl3) δ -51.59 (d, J = 37.8 Hz, 3F), -127.98 (dt, J = 22.3, 10.1 Hz, 1F), -130.44 – -130.90 (m, 1F), -131.58 – -131.69 (m, 1F), -144.01 (td, J = 20.6, 10.6 Hz, 1F), -145.08 (ddd, J = 24.1, 20.1, 9.8 Hz, 1F). ESI+MS: m/z 434.1 [M-1]- . HPLC (Method III): RT = 8.66 min, 97.2% Preparation of 2,3,4,5-tetrafluoro-N-(3-fluoro-4-methoxyphenyl)-6- (methylsulfonyl)benzamide Compound I-8 and 2,3,4,5-tetrafluoro-N-(3-fluoro-4- methoxyphenyl)-6-(methylsulfinyl)benzamide Compound I-10 2,3,4,5-tetrafluoro-N-(3-fluoro-4-methoxyphenyl)-6-(methylth io)benzamide [00433] 2,3,4,5-tetrafluoro-N-(3-fluoro-4-methoxyphenyl)-6-(methylth io)benzamide was prepared from 2,3,4,5-tetrafluoro-6-(methylthio)benzoic acid (0.20 g, 0.83 mmol) and 3-fluoro- 4-methoxyaniline (0.11 g, 0.83 mmol) according to the protocol described in general procedure A and isolated as a yellow solid (0.24 g, 0.66 mmol, 80% yield). 1 H NMR (400 MHz, DMSO-d6) δ 10.82 (s, 1H), 7.62 (dd, J 1 = 2.4 Hz, J 2 = 13.2 Hz, 1H), 7.36-7.32 (m, 1H), 7.19 (t, J = 9.2 Hz, 1H), 3.83 (s, 3H), 2.50 (s, 3H). ESI-MS: measured m/z 364.3 [M+1] + . 2,3,4,5-tetrafluoro-N-(3-fluoro-4-methoxyphenyl)-6-(methylsu lfonyl)benzamide Compound I-8 [00434] 2,3,4,5-tetrafluoro-N-(3-fluoro-4-methoxyphenyl)-6-(methylsu lfonyl)benzamide was prepared from 2,3,4,5-tetrafluoro-N-(3-fluoro-4-methoxyphenyl)-6-(methylth io)benzamide (0.026 g, 0.07 mmol) according to the protocol described in general procedure C and isolated as a white solid (0.040 g, 0.101 mmol, 28% yield). 1 H NMR (400 MHz, DMSO-d 6 ) δ 11.09 (s, 1H), 7.56 (dd, J 1 = 1.6 Hz, J 2 = 13.2 Hz, 1H), 7.30-7.28 (m, 1H), 7.18 (t, J = 9.6 Hz, 1H), 3.83 (s, 3H), 3.47 (s, 3H). 19 F NMR (376 MHz, DMSO-d6) δ -132.51 - -132.63 (m, 1F), -133.76 (s, 1F), -140.26 - -140.35 (m, 1F), -145.15 - -145.29 (m, 1F), -151.08 - -151.20 (m, 1F). ESI-MS: measured m/z 394.30 [M-1]-, HPLC (Method I) RT = 6.37 min., 97.9%. 2,3,4,5-tetrafluoro-N-(3-fluoro-4-methoxyphenyl)-6-(methylsu lfinyl)benzamide Compound I-10 [00435] 2,3,4,5-tetrafluoro-N-(3-fluoro-4-methoxyphenyl)-6-(methylsu lfinyl)benzamide was isolated as a white solid (0.085 g, 0.224 mmol, 59% yield). 1 H NMR (400 MHz, DMSO-d 6 ) δ 11.09 (s, 1H), 7.60 (dd, J1 = 2.4 Hz, J2 = 13.2 Hz, 1H), 7.33-7.30 (m, 1H), 7.19 (t, J = 9.2 Hz, 1H), 3.83 (s, 3H), 3.143 (s, 3H). 19 F NMR (376 MHz, DMSO-d6) δ -133.57 (s, 1F), -139.03 - - 139.14 (m, 1F), -140.46 - -140.55 (m, 1F), -149.79 - -149.93 (m, 1F), -151.50 - -151.61 (m, 1F). ESI-MS: measured m/z 378.30 [M-1]-. HPLC RT = 6.21 min., 97.7%. 2-(N,N-dimethylsulfamoyl)-3,4,5,6-tetrafluoro-N-(3-fluoro-4- methoxyphenyl) benzamide Compound I-9 [00436] 2-(N,N-dimethylsulfamoyl)-3,4,5,6-tetrafluoro-N-(3-fluoro-4- methoxyphenyl) benzamide was prepared from 2-(N,N-dimethylsulfamoyl)-3,4,5,6-tetrafluorobenzoic acid (0.30 g, 1.0 mmol) and 3-fluoro-4-methoxyaniline (0.210 g, 1.5 mmol)according to the protocol described in general procedure A and isolated as a a yellow solid (0.07 g, 0.17 mmol, 18% yield). 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.79 (s, 1H), 7.54 (dd, J 1 =2.4 Hz, J 2 =13.2 Hz, 1H), 7.27-7.24 (m, 1H), 7.18 (t, J = 9.2 Hz, 1H), 2.85 (s, 6H). 19 F NMR (376 MHz, DMSO-d6) δ -130.66 - -130.78 (m, 1F), 133.65 - -133.72 (m, 1F), -140.47 - -140.58 (m, 1F), -146.81 - -146.96 (m, 1F), -151.13 - -151.26 (m, 1F). ESI-MS: measured m/z 425.3 [M+1] + . HPLC (Method I): RT = 6.78 min., 100%. Preparation of (E)-N-(3-fluoro-4-methoxyphenyl)-1-(2,3,4,5-tetrafluoro-6-(m ethylsulfonyl) phenyl) methanimine Compound I-11
2,3,4,5-tetrafluoro-N-methoxy-N-methyl-6-(methylthio) benzamide [00437] 2,3,4,5-tetrafluoro-N-methoxy-N-methyl-6-(methylthio) benzamide was prepared from 2,3,4,5-tetrafluoro-6-(methylthio) benzoic acid (1.0 g, 4.16 mmol) and N, O-dimethyl hydroxylamine hydrogen chloride (0.81 g, 8.33mmol) according to the protocol described in general procedure A and isolated as a yellow gum (0.9 g, 3.17 mmol, 76% yield). ESI-MS: measured m/z 284.2 [M+1] + . 2,3,4,5-tetrafluoro-6-(methylthio)benzaldehyde [00438] To a stirred solution of 2,3,4,5-tetrafluoro-N-methoxy-N-methyl-6-(methylthio) benzamide (0.8 g, 2.82 mmol) in anhydrous THF (8.0mL) at -78°C was added DIBAL-H (1M in toluene, 11.3 mL, 11.3 mmol) under a N2 atmosphere. The mixture was permitted to warm to 0°C. After 2 hrs, reaction was diluted with aqueous 1N HCl (100 mL) and extracted with EtOAc (2 x 50 mL). The combined organic phases were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to afford title compound as a yellow oil (0.46 g, 2.05 mmol). The obtained material was used without purification. 1 H NMR (400 MHz, CDCl 3 ) δ 10.49 (s, 1H), 2.55 (s, 3H), 19 F NMR (376 MHz, CDCl 3 ) δ -130.96 - -131.03 (m, 1F), -142.71 - -142.81 (m, 1F), -145.34 - -145.47 (m, 1F), -154.03 - -154.12 (m, 1F). 3-fluoro-4-methoxy-N-(2,3,4,5-tetrafluoro-6-(methylthio) benzyl) aniline [00439] To a stirred solution of 2,3,4,5-tetrafluoro-6-(methylthio) benzaldehyde (0.2 g, 0.89 mmol) in 2,2,2 Trifluroethanol (2 mL) was added 3-fluoro-4-methoxyaniline (0.12 g, 0.89 mmol). After 16 hrs, NaCNBH3 (0.16 g, 2.67 mmol) was added and stirring continued for a further 16 hrs. The reaction was concentrated under reduced pressure and the crude material purified by flash column chromatography (11% EtOAc in hexanes) to afford the title compound as a yellow oil (0.18 g, 0.51 mmol, 58% yield). 1 H NMR (400 MHz, DMSO-d6) δ 6.94 (t, J = 9.6 Hz, 1H), 6.58- 6.54 (dd, J1 = 2.8 Hz, J2 = 14.0 Hz, 1H), 6.44- 6.41 (dd, J1 = 1.6 Hz, J2 = 8.8 Hz, 1H), 5.74 (t, J=5.6, 1H), 4.38- 4.36 (m, 2H), 3.70 (s, 3H), 2.43 (s, 3H). 19 F NMR (376 MHz, DMSO-d 6 ) δ - 130.85 - -130.94 (m, 1F), -134.02 (s, 1F), -141.04 - -141.13 (m, 1F), -156.12 - -156.42(m, 2F). ESI-MS: measured m/z 350.3, [M+1] + . (E)-N-(3-fluoro-4-methoxyphenyl)-1-(2,3,4,5-tetrafluoro-6-(m ethylsulfonyl) phenyl) methanimine Compound I-11 [00440] To a stirred solution of 3-fluoro-4-methoxy-N-(2,3,4,5-tetrafluoro-6-(methylthio) benzyl) aniline (0.05 g, 0.14 mmol) in DCM (3 mL) was added m-CPBA (0.12 g, 0.71 mmol). After 2 hrs, the reaction mixture was diluted with a saturated aqueous solution of NaHCO 3 (50 mL) and extracted with DCM (2 x 25 mL). The combined organic phases were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude material was purified by flash column chromatography (20% EtOAc in hexanes) to afford the title compound as a yellow solid (0.018 g, 0.051 mmol, 33% yield). 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.79 (s, 1H), 7.92- 7.88 (dd, J1= 2.8 Hz, J2= 12.0 Hz, 1H), 7.82 - 7.79 (m, 1H), 7.36 (t, J = 8.8 Hz, 1H), 3.94 (s, 3H), 3.20 (s, 3H). 19 F NMR (376 MHz, DMSO-d6) δ - 132.74(s, 1F), -134.83 - -134.90(m, 1F), -139.40 - -139.51(m, 1F), -150.07 - -150.62 (m, 2F). ESI-MS: measured m/z 380.3, [M+1] + . HPLC RT = 6.04 min., 95.8%. Scheme --: Preparation of 2,3,4,5-tetrafluoro-N-(3-fluoro-4-methoxyphenyl)-6- (methylsulfonyl)aniline Compound I-12 and 2,3,4,5-tetrafluoro-N-(3-fluoro-4- methoxyphenyl)-6-(methylsulfinyl)aniline Compound I-13 2,3,4,5-tetrafluoro-N-(3-fluoro-4-methoxyphenyl)-6-(methylth io)aniline [00441] A solution of 3-fluoro-4-methoxyaniline (0.25 g, 0.90 mmol), (2-bromo-3,4,5,6- tetrafluorophenyl)(methyl)sulfane (0.13 g, 0.90 mmol), and Cs 2 CO 3 (0.59 g, 1.81mmol), in 1,4- dioxane (2.5 mL) was purged with N2 for 15 minutes. To this reaction mixture was added Pd2dba3 (0.08 g, 0.09 mmol) and Xanthphos (0.05 g, 0.09 mmol). The resulting mixture was heated to 100°C as left to stir overnight. After 16 hrs, the mixture was cooled to room temperature and diluted with water (50 mL), then extracted with EtOAc (2 x 30 mL). The combined organic phases were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude material was purified by flash column chromatography (16% EtOAc in hexanes) to afford the title compound as a light yellow solid (0.19 g, 0.56 mmol, 62% yield). 1 H NMR (400 MHz, DMSO- d6) δ7.84 (s, 1H), 6.99 (t, J=9.6 Hz, 1H), 6.71 - 6.68 (dd, J1=1.6 Hz, J2=13.6Hz, 1H), 6.56 - 6.53 (dd, J1=1.2Hz, J2=8.8 Hz, 1H), 3.76 (s, 3H), 2.32 (s, 3H). 19 F NMR (376 MHz, DMSO-d6) δ - 132.08 - -132.17 (m, 1F), -134.29 (s, 1F), -145.26 - -145.35 (m, 1F), -156.13 - -156.25 (m, 1F), - 163.86 - -163.99 (m, 1F). ESI-MS: measured m/z 336.2 [M+1] + . 2,3,4,5-tetrafluoro-N-(3-fluoro-4-methoxyphenyl)-6-(methylsu lfonyl)aniline Compound I-12 [00442] To a stirred solution of 2,3,4,5-tetrafluoro-N-(3-fluoro-4-methoxyphenyl)-6- (methylthio)aniline (0.10 g, 0.29 mmol) in THF:Water (0.8 mL:0.2 mL) at 0 o C was added Oxone (0.45 g, 1.49 mmol). The resulting mixture was warmed to room temperature and stirred overnight. After 16 hrs, a second portion of Oxone (0.45 g, 1.49 mmol) was added and the reaction stirred for 16 hrs. Once complete, the reaction was diluted with a saturated aqueous solution of NaHCO3 and extracted with EtOAc (2 x 30 mL). The combined organic phases were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude material was purified by flash column chromatography (20% EtOAc in hexanes) to afford the title compound as white solid (0.02 g, 0.054 mmol, 18% yield). 1 H NMR (400 MHz, DMSO-d6) δ 7.95 (s, 1H), 7.04 (t, J = 8.0 Hz, 1H), 6.90 (d, J = 12.4 Hz, 1H), 6.73 (d, J = 6.8 Hz, 1H), 3.78 (s, 3H), 3.42 (s, 3H). 19 F NMR (376 MHz, DMSO-d 6 ) δ -134.09 (s, 1F), -135.41 - -135.52 (m, 1F), -142.01 - - 142.09 (m, 1F), -147.24 - -147.38 (m, 1F), -163.41 - -163.53 (m, 1F). ESI-MS: measured m/z 366.4 [M-1]-. HPLC RT = 7.10 min., 97.5%. 2,3,4,5-tetrafluoro-N-(3-fluoro-4-methoxyphenyl)-6-(methylsu lfinyl)aniline Compound I-13 [00443] 2,3,4,5-tetrafluoro-N-(3-fluoro-4-methoxyphenyl)-6-(methylsu lfinyl)aniline was prepared from 2,3,4,5-tetrafluoro-N-(3-fluoro-4-methoxyphenyl)-6-(methylth io)aniline (0.08 g, 0.23mmol) according to the protocol described in general procedure C and isolated an a light pink solid (0.05 g, 0.14 mmol, 59% yield). 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.23 (s, 1H), 7.05 (t, J = 9.2Hz, 1H), 6.80 (d, J = 13.2 Hz, 1H), 6.63 (d, J = 8.4 Hz, 1H), 3.78 (s, 3H), 3.04 (s, 3H). 19 F NMR (376 MHz, DMSO-d6) δ -133.79 (s, 1F), -141.42 - -141.53 (m, 1F), -144.13 - -144.21 (m, 1F), -150.88 - -151.00 (m, 1F), -163.14 - -163.26 (m, 1F). ESI-MS: measured m/z 352.3 [M+1] + . HPLC RT = 8.29 min., 99%. Preparation of 1-(benzyloxy)-2,3,4,5-tetrafluoro-6-((3-fluoro-4- methoxybenzyl)sulfonyl)benzene Compound I-16, 2,3,4,5-tetrafluoro-6-((3-fluoro-4- methoxybenzyl)sulfonyl)phenol Compound I-14, 1-(difluoromethoxy)-2,3,4,5-tetrafluoro-6- ((3-fluoro-4-methoxybenzyl)sulfonyl) benzene Compound I-15 and 1,2,3,4-tetrafluoro-5-((3- fluoro-4-methoxybenzyl)sulfonyl)-6-methoxybenzene Compound I-19 (3-fluoro-4-methoxybenzyl)(perfluorophenyl)sulfane [00444] To a stirred solution of 2,3,4,5,6-pentafluorobenzenethiol (5 g, 25.0 mmol) in DCM (50 mL) at 0°C was added TEA (4.37 mL, 32.0 mmol) and 4-(bromomethyl)-2-fluoro-1- methoxybenzene (5.5 g, 25.0 mmol) . The reaction was warmed to room temperature and stirred for 1 hr. Once complete, the reaction mixture was diluted with water (200 mL) and extracted with DCM (2 x 50 mL). The combined organic phases were dried over anhydrous Na 2 SO 4 , filtered, and concentrated under reduced pressure to afford title compound as a brown solid (8.0 g, 23.66 mmol, 95% yield). 1 H NMR (400 MHz, DMSO-d6) δ 7.13 (dd, J = 2.0, 12.4 Hz, 1H), 7.04 (t, J = 8.4 Hz, 1H), 6.94 (d, J = 8.0 Hz, 1H), 4.07 (s, 2H), 3.80 (s, 3H). 19 F NMR (376 MHz, DMSO-d 6 ) δ -132.59 - -132.67 (m, 2F), -135.34 (s, 1F), -152.50 – 150.62 (m, 1F), -161.49 - - 161.60 (m, 1F). 1,2,3,4,5-pentafluoro-6-((3-fluoro-4-methoxybenzyl)sulfonyl) benzene [00445] To a stirred, ice-cold (0°C) solution of (3-fluoro-4- methoxybenzyl)(perfluorophenyl)sulfane (3.0 g, 8.8 mmol) in DCM (30 mL) was added m-CPBA (7.69g, 4.4mmol). The reaction was warmed to room temperature overnight. After 16 hrs, the mixture was diluted with a saturated aqueous solution of NaHCO 3 (250 mL) and extracted with DCM (2 x 50 mL). The combined organic phases were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to afford title compound as an off-white solid. (3.5 g, 9.45 mmol, Quantitative). 1 H NMR (400 MHz, DMSO-d6) δ 7.22 (dd, J1 = 2.4 Hz, J2 = 12 Hz, 1H), 7.15 (t, J = 8.8 Hz, 1H), 7.08 (d, J = 8.4 Hz, 1H), 4.87 (s, 2H), 3.84 (s, 3H). 1-(benzyloxy)-2,3,4,5-tetrafluoro-6-((3-fluoro-4-methoxybenz yl)sulfonyl)benzene Compound I- 16 [00446] A 1.6M MeLi solution in diethyl ether (3.37 mL, 5.4 mmol) was added dropwise to an ice-cold (0°C) solution of benzyl alcohol (0.35 g, 3.24 mmol) in Toluene:THF (9:1, 30 mL). The resulting reaction mixture was stirred at room temperature for 1 hr, after which it was slowly added to a stirred solution of 1,2,3,4,5-pentafluoro-6-((3-fluoro-4- methoxybenzyl)sulfonyl)benzene (1.0 g, 2.70 mmol) in Toluene:THF (9:1, 30 mL) maintained at 0°C. The reaction was heated to 100°C overnight. After 16 hrs, the reaction was cooled to room temperature and quenched with 1N HCl solution (50 mL). The resulting biphasic mixture was extracted with EtOAc (2 x 50 mL) and the combined organic phases were dried over anhydrous Na 2 SO 4 , filtered, and concentrated under reduced pressure. The crude material was purified by flash column chromatography (0-10% EtOAc in hexanes), followed by trituration using MeOH, to afford the title compound as an off-white solid (0.45 g, 0.98 mmol, 36% yield). 1 H NMR (400 MHz, DMSO-d 6 ) δ 7.56-7.54 (m, 2H), 7.49-7.43 (m, 3H), 7.11 (t, J = 8.8 Hz, 1H), 7.03 (dd, J = 12 Hz, 1H), 6.93 (d, J = 8.8 Hz, 1H), 5.18 (s, 2H), 4.72 (s, 2H), 3.81 (s, 3H) 19 F NMR (376 MHz, DMSO-d6) δ -135.31 - -135.33 (m, 1F), -138.02 - -138.11 (m, 1F), - 146.10 - -146.24 (m, 1F), -151.31 - -151.39 (m, 1F) -160.49 - -160.62 (m, 1F). HPLC (Method I): RT = 7.81 min., 95.4% . 2,3,4,5-tetrafluoro-6-((3-fluoro-4-methoxybenzyl)sulfonyl)ph enol Compound I-14 [00447] Under an inert atmosphere of nitrogen, 10% wet Pd/C (0.75 g) was added to a solution of 1-(benzyloxy)-2,3,4,5-tetrafluoro-6-((3-fluoro-4-methoxybenz yl)sulfonyl)benzene (0.75 g, 1.63 mmol) in MeOH:THF (1:1, 20 mL). The reaction vessel was flushed with H2 and the reaction stirre for 2 hrs while under a positive pressure of hydrogen. Once complete, the reaction mixture was filtered through a plug of celite and the filtrate concentrated under reduced pressure. The crude material was purified by reverse phase chromatography (0 - 30% acetonitrile in water) to afford the title compound as a pink solid (0.2 g, 0.28 mmol, 33% yield). 1 H NMR (400 MHz, DMSO-d 6 ) δ 7.14 - 7.10 (m, 2H), 7.01 - 6.99 (m, 1H), 4.78 (s, 2H), 3.82 (s, 3H). 19 F NMR (376 MHz, CDCl3) δ -132.85 (s, 1F), -136.93 - -137.03 (m, 1F), -143.35 - -143.48 (m, 1F), -157.71 - - 157.79 (m, 1F), -166.24 - -166.37 (m, 1F). ESI-MS: measured m/z 367.23 [M-1]-. HPLC (Method I): RT = 6.70 min., 93%. 1-(difluoromethoxy)-2,3,4,5-tetrafluoro-6-((3-fluoro-4-metho xybenzyl)sulfonyl) benzene Compound I-15 [00448] To a stirred solution of 2,3,4,5-tetrafluoro-6-((3-fluoro-4- methoxybenzyl)sulfonyl)phenol (0.06 g, 0.16 mmol) in acetonitrile (1 mL) was added ethyl- bromodifluoroacetate (0.099 g, 0.48 mmol) and Cs 2 CO 3 (0.15 g, 0.48 mmol) at room temperature. The reaction was heated to 80°C for 1 hr, after which it was cooled down and diluted with water (20 mL). The resulting biphasic mixture was extracted with EtOAc (2 x 10 mL) and the combined organic phases were dried over anhydrous Na 2 SO 4 , filtered, and concentrated under reduced pressure. The crude material was purified by flash column chromatography (0-7% EtOAc in hexanes) to afford title compound as an off-white solid (0.035 g, 0.10 mmol, 36% yield). 1 H NMR (400 MHz, DMSO-d 6 ) δ 7.20-7.13 (m, 2H), 7.06-6.84 (m, 2H), 4.80 (s, 2H), 3.84 (s, 3H). 19 F NMR (376 MHz, DMSO-d6) δ -81.89 - -81.92 (m, 2F), -134.55 - -134.66 (m, 1F), -135.31 (s, 1F), -144.60 - -144.74 (m, 1F), -148.99 - -149.07 (m, 1F), -155.16 - -155.29 (m, 1F). ESI-MS: measured m/z 415.1 [M-3]-. HPLC (Method I): RT = 7.15 min, 98.3%. 1,2,3,4-tetrafluoro-5-((3-fluoro-4-methoxybenzyl)sulfonyl)-6 -methoxybenzene Compound I-19 [00449] To a stirred solution of 2,3,4,5-tetrafluoro-6-((3-fluoro-4- methoxybenzyl)sulfonyl)phenol (0.08 g, 0.21 mmol) in DMF (1mL) was added MeI (0.06 g, 0.43 mmol) and K 2 CO 3 (0.059 g, 0.43 mmol). After 16 hrs, reaction mixture was diluted with cold water (20 mL) and extracted with EtOAc (2 x 10 mL). The combined organic phases were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The obtained crude was purified by flash column chromatography (0-30% EtOAc in hexane) to afford the title compound as an off-white solid (0.038 g, 0.10 mmol, 36% yield). 1 H NMR (400 MHz, DMSO-d6) δ 7.17 (dd, J1 = 2.4 Hz, J2 = 12 Hz, 1H), 7.15-7.11 (d, J = 8.8 Hz, 1H), 7.23 (dd, J 1 = 0.8 Hz, J 2 = 8.4 Hz, 1H), 4.77 (s, 2H), 4.01 (s, 3H), 3.83 (s, 3H). 19 F NMR (376 MHz, DMSO-d 6 ) δ -135.36 (s, 1F), -138.74 - -138.85 (m, 1F), -146.15 - -146.29 (m, 1F), -152.88 - -152.96 (m, 1F), -161.08 - -161.21 (m, 1F). ESI-MS: measured m/z 381.54 [M-1]- . HPLC (Method I): RT = 7.05 min., 99.3%. Preparation of 1,2,3,4-tetrafluoro-5-((3-fluoro-4-methoxyphenoxy)methyl)-6- (methylsulfonyl) benzene Compound I-17 methyl(2,3,4,5-tetrafluoro-6-((3-fluoro-4-methoxyphenoxy)met hyl)phenyl) sulfane [00450] To a stirred solution of (2-(bromomethyl)-3,4,5,6- tetrafluorophenyl)(methyl)sulfane (0.16 g, 1.12 mmol) in acetonitrile (5 mL) was added 3-fluoro- 4-methoxyphenol (0.39 g, 1.35 mmol) and K 2 CO 3 (0.46 g, 3.38 mmol). The resulting mixture was heated to 80°C for 6 hrs. Once complete, the reaction was cooled to room temperature and diluted with water (20 mL). The resulting biphasic mixture was extracted with EtOAc (2 x 20 mL) and^the combined organic phases dried over anhydrous Na 2 SO 4 , filtered, and concentrated under reduced pressure. The crude material was purified by flash column chromatography (0- 15% EtOAc in hexanes) to afford title compound as an off-white solid (0.19 g, 0.54 mmol, 40% yield). 1 H NMR (400 MHz, DMSO-d 6 ) δ 7.11 (t, J = 9.2 Hz, 1H), 7.05 - 7.01 (m, 1H), 6.85- 6.82 (m, 1H), 5.20 (d, J = 2.8 Hz, 2H), 3.79 (s, 3H), 2.42 (s, 3H). 19 F NMR (376 MHz, DMSO- d6) δ -130.37 - -130.46 (m, 1F), -132.44 (s, 1F), -140.86 - -140.96 (m, 1F), -153.66 - -153.78 (m, 1F), -155.23 - -155.35 (m, 1F). 1,2,3,4-tetrafluoro-5-((3-fluoro-4-methoxyphenoxy)methyl)-6- (methylsulfonyl) benzene Compound I-17 [00451] To a stirred, ice-cold (0°C) solution of methyl(2,3,4,5-tetrafluoro-6-((3-fluoro-4- methoxyphenoxy)methyl)phenyl)sulfane (0.18 g, 0.51 mmol) in DCM (2mL) was added m- CPBA (0.088 g, 0.51 mmol). The reaction mixture was stirred at room temperature for 1 hr, followed by addition of another portion of m-CPBA (0.088 g, 0.51 mmol) at 0°C. The reaction mixture was stirred at room temperature overnight. After 16 hrs, the reaction was diluted with a saturated aqueous solution of NaHCO3 (20 mL) and extracted with EtOAc (3 x 20 mL). The combined organic phases were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude material was purified by flash column chromatography (0- 30% EtOAc in hexanes) to afford the title compound as a brown sticky solid (0.020 g, 0.052 mmol, 10% yield). 1 H NMR (400 MHz, DMSO-d6) δ 7.12 (t, J = 9.6 Hz, 1H), 7.00 (dd, J1= 3.2 Hz, J2 = 13.2 Hz, 1H), 6.83 - 6.80 (m, 1H), 5.38 (d, J = 2.8 Hz, 2H), 3.79 (s, 3H), 3.45 (s, 3H). 19 F NMR (376 MHz, DMSO-d 6 ) δ -131.14 - -131.26 (m, 1F), -132.53 (s, 1F), -139.13 - -139.23 (m, 1F), -146.20 - -146.32 (m, 1F), -151.06 - -151.19 (m, 1F). 3-fluoro-4-methoxy-N-(2,3,4,5-tetrafluoro-6-(methyl sulfinyl) benzyl) aniline Compound I-18 [00452] To a stirred solution of (E)-N-(3-fluoro-4-methoxyphenyl)-1-(2,3,4,5-tetrafluoro-6- (methylsulfonyl) phenyl) methanimine (0.13 g, 0.342 mmol) in TFA (6.5 mL) was added Et 3 SiH (0.039 g, 0.342 mmol). The resulting solution heated to 60°C for 1 hr, after which it was cooled to room temperature and concentrated under reduced vacuum. The crude material was purified by flash column chromatography (37% EtOAc in hexanes) and triturated using 10 % diethyl ether in n-pentane to afford the title compound as a brown solid (0.025 g, 0.068 mmol, 20% yield). 1 H NMR (400 MHz, DMSO-d6) δ 6.96 (t, J = 9.2 Hz, 1H), 6.53 (dd, J1 = 2.4 Hz, J2 = 13.6 Hz, 1H), 6.39-6.36 (m, 1H), 5.93 (t, J = 4.8 Hz, 1H), 4.42-4.31 (m, 2H), 3.71 (s, 3H), 3.01 (s, 3H). 19 F NMR (376 MHz, DMSO-d 6 ) δ -133.82 (s, 1F), -140.31 - - 140.15 (m, 1F), -141.83 - -141.92 (m, 1F), -151.16 - -151.23 (m, 1F), -154.37 - -154.43 (m, 1F). ESI-MS: measured m/z 366.3 [M+1] + . HPLC (HP07_TFRA1): RT = 6.49 min., 96.5% Preparation of 3-fluoro-4-methoxy-N-methyl-N-(2,3,4,5-tetrafluoro-6- (methylsulfinyl)benzyl)aniline Compound I-20 3-fluoro-4-methoxy-N-methyl-N-(2,3,4,5-tetrafluoro-6(methylt hio)benzyl)aniline To a stirred solution of 3-fluoro-4-methoxy-N-methylaniline (0.75 g, 4.83 mmol) in 2,2,2- trifloroethanol (15 mL) was added 2,3,4,5-tetrafluoro-6-(methylthio)benzaldehyde (2.15 g, 9.6 mmol). The resulting mixture was stirred at room temperature for 1 hr, followed by addition of sodium triacetoxyborohydride (3.06 g, 14.51 mmol).. After 6 hrs, the reaction was diluted with water (50 mL) and extracted with EtOAc (2 x 45 mL).^ The combined organic phases were dried over anhydrous Na 2 SO 4 , filtered, and concentrated under reduced pressure. The crude material was purified by flash column chromatography (5% EtOAc in Hexanes) to afford the title compound as a yellow oil (0.35 g, 0.96 mmol, 20% yield). 1 H NMR (400 MHz, DMSO- d6) δ 7.02 (t, J = 9.2 Hz, 1H), 6.89 - 6.85 (dd, J 1 = 2.8Hz, J 2 =14.8Hz, 1H), 6.69-6.66 (m, 1H), 4.55 (s, 2H), 3.75 (s, 3H), 2.64 (s, 3H), 2.42 (s, 3H). 19 F NMR (376 MHz, DMSO-d 6 ) -130.56 - - 130.65 (m, 1F), -133.68 (s, 1F), 140.26 - -140.35 (m, 1F), -155.91 - -156.09 (m, 2F). 3-fluoro-4-methoxy-N-methyl-N-(2,3,4,5-tetrafluoro-6- (methylsulfinyl)benzyl)aniline Compound I-20 [00453] To a stirred solution of 3-fluoro-4-methoxy-N-methyl-N-(2,3,4,5-tetrafluoro- 6(methylthio)benzyl)aniline (0.1 g, 0.27 mmol) in THF:water:Methanol (8:1:1, 1mL) was added oxone (0.42 g, 1.3 mmol). After 1 hr, the reaction was diluted with aqueous Na 2 CO 3 (30 mL) and extracted with EtOAc (2 x 20 mL).^ The combined organic phases were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude material was purified by column chromatography (24% EtOAc in hexanes) and the enriched product purified by Prep TLC (50% EtOAc in Hexane). The title compound was isolated as an off- white solid (0.008 g, 0.02 mmol, 8% yield). 1 H NMR (400 MHz, DMSO-d6) δ 7.05 (t, J = 9.2 Hz, 1H), 6.93 (d, J =14.8 Hz, 1H), 6.71 (d, J= 7.2 Hz, 1H), 4.56 (d, J = 13.6 Hz, 1H), 4.31 (d, J=14.0 Hz,1H), 3.76(s, 3H), 2.91 (s, 3H), 2.59 (s, 3H). 19 F NMR (376 MHz, DMSO-d6) -133.49(s, 1F), - 140.30 - -140.36 (m, 1F), -141.76 - -144.85 (1F), -151.15 - -152.27(m, 1F), -151.24 - -152.35 (m, 1F). ESI-MS: measured m/z 380.4 [M+1] + . HPLC (Method I): RT = 6.77 min., 95.8%. (S)-N-(4-((3-chloro-4-fluorophenyl)amino)-7-((tetrahydrofura n-3-yl)oxy)quinazolin-6-yl)- 2,3,4,5-tetrafluoro-6-(trifluoromethyl)benzenesulfonamide (I--) Compound I-1 [00454] To a stirred solution of N 4 -(3-chloro-4-fluoro-phenyl)-7-[(3S)-tetrahydrofuran-3- yl]oxy-quinazoline-4,6-diamine (200 mg, 533.62 μmol) and silver carbonate (294.29 mg, 1.07 mmol) in THF (5 mL) at room temperature was added a solution of 2,3,4,5-tetrafluoro-6- (trifluoromethyl)benzenesulfonyl chloride (168.93 mg, 533.62 μmol) in THF (1 mL). Reaction progress was monitored by TLC. After 16 hrs, the reaction was partitioned between EtOAc and a saturated aqueous solution of ammonium chloride. The organic phase was removed and the remaining aqueous extracted 4x with EtOAc. The combined organic phases were washed with brine, dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was purified on a biotage isolera equipped with a 60 g C18 column running a solvent gradient of 30% to 100% ACN (0.1% FA) in water (0.1% FA). The product containing fractions were consolidated and concentrated. The product was lyophilized from ACN and water to afford N-[4- (3-chloro-4-fluoro-anilino)-7-[(3S)-tetrahydrofuran-3-yl]oxy -quinazolin-6-yl]-2,3,4,5- tetrafluoro-6-(trifluoromethyl)benzenesulfonamide (10 mg, 14.51 μmol, 2.72% yield) as a tan powder. 1 H NMR (400 MHz, CDCl 3 ) δ 8.70 (s, 1H), 8.13 (s, 1H), 8.01 (dd, J = 6.5, 2.7 Hz, 1H), 7.51 (dt, J = 8.9, 3.4 Hz, 1H), 7.24 – 7.19 (m, 3H), 5.13 (s, 1H), 4.04 (q, J = 7.7 Hz, 1H), 3.98 (d, J = 2.9 Hz, 2H), 3.96 – 3.86 (m, 1H), 2.42 (dt, J = 14.5, 7.1 Hz, 1H), 2.22 – 2.11 (m, 1H). 19 F NMR (376 MHz, CDCl 3 ) δ -50.94 (m, 3F), -119.55 (s, 1F), -127.01 – -127.13 (m, 1F), -130.15 – -130.48 (m, 1F), -141.83 – -141.89 (m, 1F), -143.65 – -143.80 (m, 1F). ESI-MS: measured m/z 653.1 [M-H]-, Purity by HPLC (procedure Method III): RT = 3.27 min (95.7%). Preparation of (S)-N-(4-((3-chloro-4-fluorophenyl)amino)-7-((tetrahydrofura n-3- yl)oxy)quinazolin-6-yl)-2,3,4,5-tetrafluoro-6-(methylthio)be nzamide (I--) (S)-N-(4-((3- chloro-4-fluorophenyl)amino)-7-((tetrahydrofuran-3-yl)oxy)qu inazolin-6-yl)-2,3,4,5- tetrafluoro-6-(methylsulfonyl)benzamide (I--) Compound I-5, and N-(4-((3-chloro-4- fluorophenyl)amino)-7-(((S)-tetrahydrofuran-3-yl)oxy)quinazo lin-6-yl)-2,3,4,5-tetrafluoro-6- (methylsulfinyl)benzamide (I--) Compound I-32 (S)-N-(4-((3-chloro-4-fluorophenyl)amino)-7-((tetrahydrofura n-3-yl)oxy)quinazolin-6-yl)- 2,3,4,5-tetrafluoro-6-(methylthio)benzamide (I--) [00455] To a stirred solution of 2,3,4,5-tetrafluoro-6-(methylthio)benzoic acid (0.52g, 2.16mmol) in DCM (5mL) were added oxalyl chloride (0.55 g, 2.91 mmol) and DMF (1-2 drop) at 0 0 ° C. The resulting reaction mixture was stirred at room temperature for 30min. After completion of reaction, the reaction mixture was concentrated under reduced pressure under an atmosphere of N 2 . The obtained residue was dissolved in THF (3 mL) and added dropwise to a stirring solution of (S)-N4-(3-chloro-4-fluorophenyl)-7-((tetrahydrofuran-3-yl) oxy) quinazoline- 4,6-diamine (0.40 g, 1.08 mmol) in THF (2mL) and TEA (1.09 g, 10.83 mmol) at 0 ° C. The resulting reaction mixture was stirred for 1h at room temperature. After completion of reaction, the mixture was diluted with water (30 mL) extracted with EtOAc (3 x 30 mL).^ The combined organic phases were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The resulting crude was purified by reverse phase column chromatography, eluted with 60-70% ACN in water to afford title compound as a brown solid (0.33 g, 0.55mmol, 51% yield). 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.30 (s, 1H), 10.02 (s, 1H), 8.89 (s, 1H), 8.56 (s, 1H), 8.10 (d, J = 6.4 Hz, 1H), 7.80-7.78 (m, 1H), 7.44 (t, J = 9.2 Hz, 1H), 7.30 (s, 1H), 5.33 (brs, 1H), 4.03- 3.75 (m, 4H), 2.50 (s, 3H). 2.36 - 2.30 (m, 1H), 2.15 - 2.08 (m, 1H). 19 F NMR (376 MHz, DMSO-d6) δ -122.90 (s, 1F), -131.24 - -131.33 (m, 1F), -141.52 - -141.61 (M, 1F), -153.98 - -154.10 (m, 1F), -154.60 - -154.72 (m, 1F). ESI-MS: measured m/z 597.2, [M+H] + , Purity by HPLC RT = 6.425 min (96.38%). (S)-N-(4-((3-chloro-4-fluorophenyl)amino)-7-((tetrahydrofura n-3-yl)oxy)quinazolin-6-yl)- 2,3,4,5-tetrafluoro-6-(methylsulfonyl)benzamide (I--) Compound I-5 To the stirred solution of (S)-N-(4-((3-chloro-4-fluorophenyl)amino)-7-((tetrahydrofura n-3- yl)oxy)quinazolin-6-yl)-2,3,4,5-tetrafluoro-6-(methylthio)be nzamide (0.04 g, 0.067 mmol) in THF:MeOH:Water (8:1:1, 4 mL) was added Oxone (0.10 g, 0.34 mmol) at 0 ° C. The resulting reaction mixture was stirred at room temperature for 16 hr. Four separate reactions were performed at this scale and later merged to facilitate the workup procedure. Upon completion of reaction, the reaction mixtures were combined and diluted with a saturated solution of NaHCO3 (20 mL) and extracted with EtOAc (2 x 20 mL). The combined organic phases were dried over anhydrous Na 2 SO 4 , filtered, and concentrated under reduced pressure. The obtained crude was purified by reverse phase column chromatography, eluting with 60-70% ACN in water to afford title compound as a white solid (0.035g, 0.05mmol, 13% yield). 1 H NMR (400 MHz, DMSO-d6) δ 10.31 (s, 1H), 10.01 (s, 1H), 8.93 (s, 1H), 8.54 (s, 1H), 8.07- 8.05 (dd, J 1 = 2.8 Hz, J 2 = 6.8 Hz, 1H), 7.78-7.74 (m, 1H), 7.44 (t, J = 9.2 Hz, 1H), 7.30 (s, 1H), 5.33 (brs, 1H), 3.99 (d, J = 4.0 Hz, 2H), 3.92-3.86 (m, 1H), 3.79-3.73 (m, 1H), 3.46 (s, 3H), 2.35-2.30 (m, 1H), 2.14- 2.09 (m, 1H). 19 F NMR (376 MHz, DMSO-d6) δ -122.95 (s, 1F), -132.93 - -133.05 (m, 1F), -139.90 - - 139.99 (m, 1F), -145.76 - -145.90 (m, 1F), -151.58 - -151.69 (m, 1F). ESI-MS: measured m/z 629.2, [M+H] + , Purity by HPLC RT = 6.053 min (97.29%). N-(4-((3-chloro-4-fluorophenyl)amino)-7-(((S)-tetrahydrofura n-3-yl)oxy)quinazolin-6-yl)- 2,3,4,5-tetrafluoro-6-(methylsulfinyl)benzamide (I--) Compound I-32 [00456] To the stirred solution of (S)-N-(4-((3-chloro-4-fluorophenyl)amino)-7- ((tetrahydrofuran-3-yl)oxy)quinazolin-6-yl)-2,3,4,5-tetraflu oro-6-(methylthio)benzamide (0.21 g, 0.35 mmol) in DCM (5 mL) at 0 ° C was added Oxone (0.16 g, 0.53 mmol). The resulting reaction mixture was warmed to room temperature and permitted to stir for 32 hr. Once complete, the reaction mixture was diluted with a saturated aqueous solution of NaHCO 3 (20 mL) and extracted with EtOAc (2 x 20 mL). The combined organic phases were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The obtained crude was purified by reverse phase column chromatography, eluting with 50-60% ACN in Water to afford title compound as a white solid (0.06g, 0.09mmol, 30% yield). 1 H NMR (400 MHz, DMSO-d6) δ 10.52 (d, J = 5.2 Hz, 1H), 9.98 (s, 1H), 8.81 (d, J = 4.4 Hz ,1H), 8.56 (s, 1H), 8.11- 8.09 (dd, J 1 = 2.4 Hz, J 2 = 6.8 Hz, 1H), 7.80-7.76 (m, 1H), 7.45 (t, J = 9.2 Hz, 1H), 7.31 (s, 1H), 5.34 (brs, 1H), 4.01- 3.88 (m, 3H), 3.81-3.77 (m, 1H), 3.14 (d, J = 1.6 Hz, 3H), 2.35- 2.31 (m, 1H), 2.12-2.08 (m, 1H). 19 F NMR (376 MHz, DMSO-d6) δ -122.83 (s, 1F), -139.93 - -140.09 (m, 2F), -149.96 - - 150.02 (m, 1F), -151.43 - -151.54 (m, 1F). ESI-MS: measured m/z 613.2, 615.2 [M+H] + , Purity by HPLCRT = 5.853 min (95.04%) Preparation of (S)-N 4 -(3-chloro-4-fluorophenyl)-N 6 -(2,3,4,5-tetrafluoro-6-(methylthio) phenyl) -7-((tetrahydrofuran-3-yl)oxy)quinazoline-4,6-diamine, (S)-N 4 -(3-chloro-4- fluorophenyl)-N 6 -(2,3,4,5-tetrafluoro-6-(methylsulfonyl)phenyl)-7-((te trahydrofuran-3- yl)oxy)quinazoline-4,6-diamine (I--) —Compound I-2, and N 4 -(3-chloro-4-fluorophenyl)-N 6 - (2,3,4,5-tetrafluoro-6-(methylsulfinyl)phenyl)-7-(((S)-tetra hydrofuran-3-yl)oxy)quinazoline- 4,6-diamine (I--) Compound I-4 (S)-N 4 -(3-chloro-4-fluorophenyl)-N 6 -(2,3,4,5-tetrafluoro-6-(methylthio) phenyl) -7- ((tetrahydrofuran-3-yl)oxy)quinazoline-4,6-diamine [00457] A stirred solution of (S)-N4-(3-chloro-4-fluorophenyl)-7-((tetrahydrofuran-3- yl)oxy)quinazoline-4,6-diamine (0.4 g, 1.09 mmol), (2-bromo-3,4,5,6-tetrafluorophenyl) (methyl)sulfane (0.3 g, 1.09 mmol), and Cs2CO3 (0.71 g, 2.18 mmol), in THF (3 mL) was purged with N2 for 15 minutes. To this reaction mixture were added Pd2dba3 (0.099 g, 0.11 mmol) and xanthphos (0.063 g, 0.11 mmol) at rt. The resulting reaction mixture was heated to 100 °C for 16h using conventional heating methods (oil bath). After completion of reaction, the mixture was diluted with water (50 mL) and extracted with EtOAc (2 x 30 mL). The combined organic phases were dried over anhydrous Na 2 SO 4 , filtered, and concentrated under reduced pressure. The resulting crude was purified by flash column chromatography employing a mobile phase comprised of 78% EtOAc in hexane. The title compound was isolated as white solid (0.3 g, 0.52 mmol, 48% yield). 1H NMR (400 MHz, DMSO-d6) δ 9.29 (s, 1H), 8.43 (s, 1H), 8.05-8.03 (dd, J1=2.8Hz, J2=6.8Hz,1H), 7.67-7.63 (m, 1H), 7.59 (s, 1H), 7.41 (t, J=9.2Hz, 1H), 7.28 (d, J=1.6Hz,1H), 7.22 (s, 1H), 5.36 (s, 1H), 4.03-3.99 (m, 4H), 2.36 (s, 3H), 2.34-2.26 (m, 1H), 2.16- 2.09 (m, 1H). 19F NMR (376 MHz, DMSO-d6) δ -122.95 (s, 1F), -132.29 - -132.39 (m, 1F), - 144.26 - -144.35 (m, 1F), -156.06 - -156.18 (m, 1F), -161.87 - -162.0 (m, 1F), ESI-MS: measured m/z 569.1 [M+H] + . (S)-N 4 -(3-chloro-4-fluorophenyl)-N 6 -(2,3,4,5-tetrafluoro-6-(methylsulfonyl)phenyl)-7- ((tetrahydrofuran-3-yl)oxy)quinazoline-4,6-diamine (I--) Compound I-2 [00458] To stirred solution of (S)-N 4 -(3-chloro-4-fluorophenyl)-N 6 -(2,3,4,5-tetrafluoro-6- (methylthio)phenyl)-7-((tetrahydrofuran-3-yl)oxy)quinazoline -4,6-diamine (0.15 g, 0.26 mmol) in DCM (1.5 mL) at 0 ° C was added Oxone (0.40 g, 1.32 mmol). The resulting mixture was stirred at room temperature for 16h. Another portion of Oxone (0.40 g, 1.32 mmol) was added and stirring continued for a further 16h. After completion of reaction, the mixture was diluted with saturated aqueous NaHCO 3 and extracted with EtOAc (2 x 30 mL). The combined organic phases were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The resulting crude was purified by flash column chromatography, employing a mobile phase comprised of 81% EtOAc in hexane to afford the title compound as a white solid (0.025 g, 0.041 mmol, 16% yield). 1H NMR (400 MHz, DMSO-d6) δ 9.41 (s, 1H), 8.49 (s, 1H), 8.18 (s, 1H), 8.08-8.06 (dd, J1=2.8 Hz, J2=7.2 Hz,1H), 7.70-7.66 (m, 1H), 7.59 (d, J=4.4 Hz,1H), 7.43 (t, J=9.2 Hz, 1H), 7.28 (s, 1H), 5.38 (s, 1H), 4.02-3.98 (m, 1H), 3.90-3.78 (m, 3H), 3.53 (s, 3H), 2.36-2.31 (m, 1H), 2.09-2.06 (m, 1H).19F NMR (376 MHz, DMSO-d6) δ -122.69 (s, 1F), -135.09 - -135.18 (m, 1F), -139.83 - -139.91 (m, 1F), -146.75 - -146.89 (m, 1F), -163.08 - -163.21 (m, 1F). ESI- MS: measured m/z 601.1 [M+H] + . HPLC RT = 6.02 min., (95.38%). N 4 -(3-chloro-4-fluorophenyl)-N 6 -(2,3,4,5-tetrafluoro-6-(methylsulfinyl)phenyl)-7-(((S )- tetrahydrofuran-3-yl)oxy)quinazoline-4,6-diamine (I--) Compound I-4 [00459] To a stirred solution of (S)-N 4 -(3-chloro-4-fluorophenyl)-N 6 -(2,3,4,5-tetrafluoro-6- (methylthio)phenyl)-7-((tetrahydrofuran-3-yl)oxy)quinazoline -4,6-diamine (0.10 g, 0.17 mmol )in DCM (1.0 mL) at 0 °C was added Oxone (0.27 g, 0.88 mmol). The resulting mixture was warmed to room temperature and stirred for 16h. After completion of reaction, the mixture was diluted with saturated aqueous NaHCO 3 and extracted with EtOAc (2 x 30 mL). The combined organic phases were dried over anhydrous Na 2 SO 4 , filtered, and concentrated under reduced pressure. The obtained crude was purified by flash column chromatography and eluted with 91% EtOAc in hexane to afford the title compound as a white solid (0.025 g, 0.064 mmol, 24% yield). 1H NMR (400 MHz, DMSO-d6) δ 9.41 (s, 1H), 8.69 (d, J = 4 Hz, 1H), 8.47 (s, 1H), 8.07-8.05 (dd, J 1 = 1.6Hz, J 2 = 6.8 Hz, 1H), 7.70-7.66 (m, 1H), 7.59 (t, J = 4.0 Hz, 1H), 7.43 (t, J = 8.8 Hz, 1H), 7.26 (d, J = 2.8 Hz, 1H), 5.36 (s, 1H), 4.02-3.98 (m, 1H), 3.91-3.78 (m, 3H), 3.09 (s, 3H), 2.34-2.31 (m, 1H), 2.09-2.05 (m, 1H).19F NMR (376 MHz, DMSO-d6) δ -122.77 (s, 1F), -140.30 - -140.36 (m, 2F), -150.27 - -150.46 (m, 1F), -163.49 - -163.68 (m, 1F), ESI-MS: measured m/z 585.1 [M+H] + . HPLC RT = 5.900 min (95.29%). II. Biological Evaluation Examples B1: In Vitro Cell Viability Studies [00460] Anti-cancer efficacy of exemplary compounds of this application is assessed in vitro in different cancer cell lines. Cell viability is examined following treatment at various concentration of inhibitor (0.097656-50µM) using a cell Titer-Blue cell viability assay. 1X104^cells (NHF cells)/well are plated in 96-well assay plates in culture medium.^All cells are grown in^DMEM,^IMDM and RPMI-1640 supplemented with 10% FBS. After 24hrs, test compounds and vehicle controls are added to appropriate wells so the final volume is 100µl in each well. The cells are cultured^for^the desired test exposure period (72hrs) at^37°C and 5%CO2. The^assay plates are removed from 37°C incubator and 20µl/well of CellTiter-Blue® Reagent is added. The plates are incubated using standard cell culture conditions for 1–4 hours and ^the plates are shaken for 10 seconds and record fluorescence at 560/590nm.^ Examples B2 Reactivity Profiling With Glutathione [00461] The experiment is started by placing 1 µL of 1 mM stocking solution of the test compound in DMSO in 199 µL of PBS buffer at pH 7.4 with 5 mM GSH to reach a final concentration of 5 µM. The final DMSO concentration is 0.5%. The solution is then incubated at 25 oC at 600 rpm, and is quenched with 600 µL solution of acetonitrile at 0, 30, 60 and 120 minutes. The quenched solution is vortexed for 10 minutes and centrifuged for 40 minutes at 3,220 g. An aliquot of 100 µL of the supernatant is diluted by 100 µL ultra-pure water, and the mixture is used for LC/MS/MS analysis. The data is processed and analyzed using Microsoft Excel. Examples B3 Parallel artificial membrane permeability assay (PAMPA) [00462] The stock solutions of positive controls are prepared in DMSO at the concentration of 10 mM. Testosterone and methotrexate are used as control compounds in this assay. Prepare a stock solution of compounds in DMSO at the concentration of 10 mM, and further dilute with PBS (pH 7.4). The final concentration of the test compound is 10 μM. [00463] Assay Procedures. 1) Prepare a 1.8 % solution (w/v) of lecithin in dodecane, and sonicate the mixture to ensure a complete dissolution. 2)Carefully pipette 5 μL of the lecithin/dodecane mixture into each acceptor plate well (top compartment), avoiding pipette tip contact with the membrane.3) Immediately after the application of the artificial membrane (within 10 minutes), add 300 μL of PBS (pH 7.4) solution to each well of the acceptor plate. Add 300 μL of drug-containing solutions to each well of the donor plate (bottom compartment) in triplicate. 4) Slowly and carefully place the acceptor plate into the donor plate, making sure the underside of the membrane is in contact with the drug-containing solutions in all wells.5) Replace the plate lid and incubate at 25℃, 60 rpm for 16 hours. 6) After incubation, aliquots of 50 μL from each well of acceptor and donor plate are transferred into a 96-well plate. Add 200 μL of methanol (containing IS: 100 nM Alprazolam, 200 nM Labetalol and 2 µM Ketoprofen) into each well. 7) Cover with plate lid. Vortex at 750 rpm for 100 seconds. Samples are centrifuged at 3,220 g for 20 minutes. Determine the compound concentrations by LC/MS/MS. Examples B4 Kinase Assay [00464] A 96-well half-area clear flat-bottom microplate (Corning ® # 3697) is pre-heated in a plate reader (Cytation 3, BioTek) at 37 °C for 15 minutes prior to the start of each assay. Kinase buffer (80 mM PIPES pH 6.9, 2 mM MgCl2, 0.5 mM EGTA, 15% glycerol, 1 mM GTP) is prepared from stock solutions and placed on ice. Inhibitors of this application are prepared to 10 μM concentrations in buffer (80 mM PIPES pH 6.9, 2 mM MgCl 2 , 0.5 mM EGTA, 5% DMSO) from DMSO stock solutions. After the assay plate is pre-warmed, 10 μL of inhibitor or buffer control is added to selected wells. Every assay contained a kinase only negative control for normalization of data, and a known compound positive control. The assay plate is incubated at 37 °C for 3 minutes. During this time, a frozen aliquot of the kinase (10 mg/mL) in buffer (80 mM PIPES pH 6.9, 2 mM MgCl2, 0.5 mM EGTA) is defrosted by placing in a room temperature water bath. Once thawed, 200 μL of the kinase is mixed with 420 μL of the ice-cold kinase buffer (3 mg/mL kinase in 80 mM PIPES, pH 6.9, 2 mM MgCl 2 , 0.5 mM EGTA, 1 mM GTP, 10.2% glycerol). To a 96-well plate on ice, aliquots of 100 μL kinase is added to each well. From this plate, 90 μL of the kinase is immediately pipetted into all sample wells of the warmed assay plate using a multi-channel pipette. The assay plate is immediately put in the reader at 37 °C and shook for 5 s with orbital shaking at medium speed. The reader records the absorbance at 340 nm every 15 s for 30 min. [00465] The resulting absorbance curves are normalized by subtracting each data point by the absorbance at time 0. The slope of the initial linear portion (“V max ”) is determined in mOD/min, and normalized to the Vmax value of the kinase only control, using the following equation, resulting in comparable % inhibition values: Intact mass analysis [00466] The covalent modification of the proteins with the compounds were evaluated using intact mass analysis by liquid chromatography-mass spectrometry instrument (LC-MS/MS). [00467] The reaction solution (20 µL) was prepared in 96-well plate and contained the protein (2 µM), the compound (100 µM), HEPES buffer (20 mM, pH 8), 2% DMSO, 2% glycerol, and 150 mM NaCl. The reaction was allowed to proceed for 24 h at 25 ºC. The reaction solution (1 µL) was injected into the LC/MS/MS without any further sample preparation. [00468] The LC-MS/MS instrument comprises of a Waters G2-XS quadrupole-time of flight (QTof) mass spectrometer and a Waters Acuity I-class Ultra-High Performance Liquid Chromatography (UPLC) system. The I-class UPLC system includes a binary solvent manager (BSM), and a Acquity sample manager (SM). The mobile phase consisted of: A) 0.1% (v/v) formic acid in MilliQ water; B) 0.1% (v/v) formic acid acetonitrile. Gradients were run over 5 min and proceeded as follows: A:B, 85:15, 0.0 – 0.7 min, 85:15 ^ 15:85, 0.7 – 1.5 min, 10:90, 1.5 – 4 min, 10:90 ^ 85:15, 4 – 4.5 min, 85:15, 4.5 – 5 min. The analytical column was a Waters BEH C4 column 1.7 µm (50 × 1 mm) column with pore sizes of 300 Å. The TOF MS data was collected in positive ion mode (m/z of 400-2000 Da) using MassLynx software (Waters). [00469] The spectral deconvolution was performed using UNIFI software (Waters). The added mass of the protein upon covalent modification to cysteine residues were specified. Multiple modification of up to 8 cysteine was allowed. All the adducts with signal intensities of <2% of the base peak were ignored. The % modification was calculated as the adduct signal intensity over the total intensities of the protein peaks and the adducts. Peptide mapping [00470] The site(s) of compounds covalent modification on proteins were identified using a peptide mapping analysis by liquid chromatography-mass spectrometry instrument (LC-MS/MS). [00471] The reaction solution (100 µL) was prepared in a 1.5-mL Eppendorf tube and contained protein (2-10 µM), the compound (10-100 µM), HEPES buffer (20 mM, pH 8), 2% DMSO, 2% glycerol, and 150 mM NaCl. The reaction was allowed to proceed for 5 - 24 h at 25 ºC or 37 ºC. Thereafter, the reaction was quenched by the addition of 500 µL of cold acetone and incubated at -20 ºC for 2 h. Then, the tube was centrifuged for 10 min at 10,000 ×g, and the supernatant was discarded. The pellet was washed by adding 200 µL of cold acetone and centrifugation at 10,000 ×g for 10 min. The pellet was re-dissolved in 50 µL of ammonium bicarbonate solution (ABC, 100 mM, pH 7.9) containing 8 M urea. The tube was centrifuged for 10 min at 10,000 ×g, and the supernatant was transferred to a new tube. The protein was first reduced by adding 1.25 µL of 200 mM DTT and incubation at 37 ºC for 30 min, then alkylated by adding 1.5 µL of 400 mM iodoacetamide incubation at room temperature for another 20 min. Then the solution was diluted 8 times in ammonium bicarbonate. Sequencing-grade trypsin (Promega) was added at an enzyme- to-protein ratio of 1:50, and the tube was incubated overnight at 37 ºC. After digestion, the solution was acidified by trifluoracetic acid at 0.1%, and tubes were centrifuged at 10,000 ×g for 10 min. The supernatant was transferred to an autosampler vial, and 2 µL was injected into the LC-MS/MS for peptide mapping analysis. [00472] The LC-MS/MS instrument comprises of a Waters G2-XS quadrupole-time of flight (QTof) mass spectrometer and a Waters Acuity M-class Ultra-High Performance Liquid Chromatography (UPLC) system. The M-class UPLC system includes a micro binary solvent manager (µBSM), a micro sample manager (µSM), and an IonKey (iKey) separation system. The mobile phase consisted of: A) 0.1% (v/v) formic acid in MilliQ water; B) 0.1% (v/v) formic acid acetonitrile. Gradients were run over 20 min and proceeded as follows: A:B, 97:3, 0.0 – 1 min, 97:3 ^ 60:40, 1 – 12 min, 60:40 ^ 15:85, 12-12.5 min, 15:85, 12.5 – 17 min, 15:85 ^ 97:3, 17.5 – 20 min. The analytical column was a Waters BEH C18 iKey 1.7 µm (50 × 0.15 mm) column with pore sizes of 150 Å. The TOF MSE data was collected in positive ion mode (m/z of 350- 2000 Da) using MassLynx software (Waters). [00473] The peptide mapping analysis was performed using UNIFI software (Waters). Carbamidomethyl (+57 Da) and the compound mass addition upon covalent modification were specified as variable modification to cysteine residues. HTRF Assay for Tyrosine Kinases (BTK, BMX, EGFR, FGFR4, JAK3) BTK [00474] Kinase activity was monitored using a HTRF® KinEASE-TK kit from Cisbio (62TK0PEC). For BTK, the 1X kinase buffer was supplemented with 10 mM MnCl2, 5 mM MgCl2, 1 uM ATP ^S, 1mM TCEP and 100 fold diluted Supplementary Enzyme Buffer. BTK was purchased from Promega. 0.111 ng/µL BTK (1.42 nM) was preincubated in the absence or presence of inhibitor at room temperature for 3 hours. Reaction with substrate was then initiated by adding biotinylated substrate and ATP and the reaction was allowed to proceed for 45 min. Final concentration of substrate in the reaction mixture was 1 uM and ATP was 28 uM (reported Km value). The reaction was terminated by adding 62.5 nM SA-XL665 and 100-fold diluted europium labelled antibody (Eu-Ab), diluted in 1X detection buffer that contained EDTA. After 60 min of incubation, the fluorescence emission was measured at 620 nm and 665 nm. The ratio of Em 665 nm to Em 620 nm was proportional to the amount of substrate phosphorylated by the kinase. BMX [00475] Kinase activity was monitored using a HTRF® KinEASE-TK kit from Cisbio (62TK0PEC). The buffer used was 1X kinase buffer supplemented with 2 mM MnCl2, 5 mM MgCl2, 1mM TCEP and 100X diluted Supplementary Enzyme Buffer. BMX was purchased from Promega. 0.333 ng/ul BMX (3.03 nM) was preincubated in the absence or presence of inhibitor at room temperature for 3 hours. The reaction with substrate was then initiated by adding biotinylated substrate and ATP. The concentration of substrate in the reaction mixture was 0.5 uM and ATP was 26 uM (reported Km value). Reaction was terminated by adding 31.25 nM SA- XL665 and 100 fold diluted europium labelled antibody (Eu-Ab), diluted in 1X detection buffer that contained EDTA. After 60 min of incubation, the fluorescence emission was measured at 620 nm and 665 nm. The ratio of Em 665 nm to Em 620 nm was proportional to the amount of substrate phosphorylated by the kinase. EGFR [00476] Kinase activity was monitored using a HTRF® KinEASE-TK kit from Cisbio (62TK0PEC). The buffer used was 1X kinase buffer supplemented with 2 mM MnCl2, 5 mM MgCl2, 1mM TCEP and 100X diluted Supplementary Enzyme Buffer. EGFR was purchased from Promega.0.041 ng/ul EGFR (0.46 nM) was preincubated in the absence or presence of inhibitor at room temperature for 3 hours. Reaction with substrate was then initiated by adding biotinylated substrate and ATP. The concentration of substrate in the reaction mixture was 0.5 uM and ATP was 1.57 uM (reported Km value). The reaction was terminated by adding 31.25 nM SA-XL665 and 100 fold diluted europium labelled antibody (Eu-Ab), diluted in 1X detection buffer that contained EDTA. After 60 min of incubation, the fluorescence emission was measured at 620 nm and 665 nm. The ratio of Em 665 nm to Em 620 nm was proportional to the amount of substrate phosphorylated by the kinase. FGFR4 [00477] Kinase activity was monitored using a HTRF® KinEASE-TK kit from Cisbio (62TK0PEC). The buffer used was 1X kinase buffer supplemented with 2 mM MnCl2, 5 mM MgCl2, 1mM TCEP and 100X diluted Supplementary Enzyme Buffer. FGFR-4 was purchased from Promega. 0.333 ng/ul FGFR4 (5.12 nM) was preincubated in the absence or presence of inhibitor at room temperature for 3 hours. Reaction with substrate was then initiated by adding biotinylated substrate and ATP. The concentration of substrate in the reaction mixture was 0.5 uM and ATP was 113 uM (reported Km value). The reaction was terminated by adding 31.25 nM SA- XL665 and 100 fold diluted europium labelled antibody (Eu-Ab), diluted in 1X detection buffer that contained EDTA. After 60 min of incubation, the fluorescence emission was measured at 620 nm and 665 nm. The ratio of Em 665 nm to Em 620 nm was proportional to the amount of substrate phosphorylated by the kinase. JAK3 [00478] Kinase activity was monitored using a HTRF® KinEASE-TK kit from Cisbio (62TK0PEC). The buffer used was 1X kinase buffer supplemented with 2 mM MnCl2, 5 mM MgCl2, 1mM TCEP and 100X diluted Supplementary Enzyme Buffer. JAK-3 was purchased from Promega.0.0133 ng/ul JAK3 (0.21 nM) was preincubated in the absence or presence of inhibitor at room temperature for 3 hours. Reaction with substrate was then initiated by adding biotinylated substrate and ATP. The concentration of substrate in the reaction mixture was 0.5 uM and ATP was 1.434 uM (reported Km value). The reaction was terminated by adding 31.25 nM SA-XL665 and 100 fold diluted europium labelled antibody (Eu-Ab), diluted in 1X detection buffer that contained EDTA. After 60 min of incubation, the fluorescence emission was measured at 620 nm and 665 nm. The ratio of Em 665 nm to Em 620 nm was proportional to the amount of substrate phosphorylated by the kinase. Inhibitor treatment [00479] For initial screening, enzymes were pre incubated with compounds at 2 different concentrations (1 and 10 uM final) and 0.5% DMSO. The top 13 compounds together with known inhibitor Ibrutinib were further selected for dose response analysis where compounds were tested from final concentrations ranging from 24 pM to 25 uM. Time-dependent inhibition BTK [00480] For the time-dependent inhibition experiments, the activity of BTK kinases was monitored using a HTRF® KinEASE-TK kit from Cisbio (62TK0PEC) as described above. Six compounds showing higher potency during dose response analysis were further evaluated for their change in inhibitory potency over time. Ibrutinib was used as a positive control. The selected compounds were pre incubated with the kinase at 11 different concentrations, ranging from 24 pM to 25 uM final compound concentrations. The pre incubation times were 0, 1, 3, 5, 10, 15, 30 and 45 min. After the preincubation, reaction was initiated by adding biotinylated substrate and ATP and the reaction was allowed to proceed for 45 min. The concentration of substrate in the reaction mixture was 1 uM and ATP was 28 uM (reported Km value). The reaction was terminated by adding 62.5 nM SA-XL665 and 100fold diluted europium labelled antibody (Eu-Ab), diluted in 1X detection buffer that contained EDTA. After 60 min of incubation, the fluorescence emission was measured at 620 nm and 665 nm. The ratio of Em 665 nm to Em 620 nm was proportional to the amount of substrate phosphorylated by the kinase. Product formation vs pre- incubation time data were fitted to a one phase exponential decay equation using GraphPad Prism. The same product formation vs inhibitor concentration data were also fitted to a log(antagonist) vs. response -- Variable slope equation in GraphPad Prism to provide IC50 values at different pre incubation times. EGFR [00481] For the time-dependent inhibition experiments, the activity of EGFR kinase was monitored using a HTRF® KinEASE-TK kit from Cisbio (62TK0PEC) as described above. Six compounds showing higher potency during dose response analysis against EGFR, were further evaluated for their change in inhibitory potency over time. Ibrutinib was used as a positive control. The selected compounds were pre incubated with the kinase at 11 different concentrations, ranging from 24 pM to 25 uM final compound concentrations. The pre incubation times were 0, 2, 5, 10, 15, 30, 45 and 60 min. After the preincubation, the reaction was initiated by adding biotinylated substrate and ATP and the reaction was allowed to proceed for 45 min. The concentration of substrate in the reaction mixture was 0.5 uM and ATP was 1.57 uM (reported Km value). The reaction was terminated by adding 31.25 nM SA-XL665 and 100 fold diluted europium labelled antibody (Eu-Ab), diluted in 1X detection buffer that contained EDTA. After 60 min of incubation, the fluorescence emission was measured at 620 nm and 665 nm. The ratio of Em 665 nm to Em 620 nm was proportional to the amount of substrate phosphorylated by the kinase. Product formation vs pre-incubation time data were fitted to a one phase exponential decay equation using GraphPad Prism. The same product formation vs inhibitor concentration data were also fitted to a log(antagonist) vs. response -- Variable slope equation in GraphPad Prism to provide IC 50 values at different pre incubation times. Cell viability assays (Ramos RA1, A549, K562, MIA PaCa-2) Ramos RA1 [00482] Ramos RA 1 cells (ATCC) were cultured in RPMI-1640 media (Wisent) supplemented with 10% heat-inactivated FBS and 1% penicillin/streptomycin. Cells were seeded in 96-well plates at 57,000 cells/well and incubated at 37 o C, 5% CO2 for 16 hours. Serially-diluted compounds or DMSO alone were added to cells and incubated at 37 o C, 5% CO 2 for 24 hours. Cell viability was measured using the CellTiter-Glo® Luminescent Cell Viability Assay (Promega) according to the manufacturer’s protocol. The luminescence signal of each treated well was normalized to the DMSO control well and the medium-only background was subtracted. Cell viability curves and IC 50 values were visualized using Prism (GraphPad). A549 [00483] A549 cells (ATCC) were cultured in Dulbecco’s Modified Eagle’s Medium (Wisent) supplemented with 10% FBS and 1% penicillin/streptomycin. Cells were seeded in 96-well plates at 17,500 cells/well and incubated at 37 o C, 5% CO2 for 16 hours. Serially-diluted compounds or DMSO alone were added to cells and incubated at 37 o C, 5% CO2 for 24 hours. Cell viability was measured using the CellTiter-Glo® Luminescent Cell Viability Assay (Promega) according to the manufacturer’s protocol. The luminescence signal of each treated well was normalized to the DMSO control well and the medium-only background was subtracted. Cell viability curves and IC50 values were visualized using Prism (GraphPad). K562 [00484] K562 cells (ATCC) were cultured in Iscove's Modified Dulbecco's Medium (IMDM) (Wisent) supplemented with 10% FBS and 1% penicillin/streptomycin. Cells were seeded in 96- well plates at 57,000 cells/well and incubated at 37 o C, 5% CO2 for 16 hours. Serially-diluted compounds or DMSO alone were added to cells and incubated at 37 o C, 5% CO 2 for 24 hours. Cell viability was measured using the CellTiter-Glo® Luminescent Cell Viability Assay (Promega) according to the manufacturer’s protocol. The luminescence signal of each treated well was normalized to the DMSO control well and the medium-only background was subtracted. Cell viability curves and IC50 values were visualized using Prism (GraphPad). Cell lysis and immunoassays Ramos RA1 cell lysis and immunoassay to detect BTK and phospho-BTK [00485] Ramos RA 1 cells (ATCC) were cultured in RPMI-1640 media (Wisent) supplemented with 10% heat-inactivated FBS and 1% penicillin/streptomycin. Cells were seeded in 6-well plates at 1.71 × 10 6 cells/well and incubated at 37 o C, 5% CO2 for 16 hours. Cells were treated with compound at the indicated concentrations or DMSO alone and incubated at 37 o C, 5% CO2 for 24 hours. Cell suspensions were centrifugated at 1,400-1,600 RPM for 5 minutes at room temperature and supernatants were discarded. Cell pellets were resuspended with 1X RIPA buffer (Millipore) and incubated on ice for 15 minutes. Protein lysates were extracted by centrifugating at 20,000 RPM for 20 minutes at 4 o C. Proteins were separated and total BTK protein levels were quantified by Simple Western Immunoassay (ProteinSimple) using the 12-230 kDa Jess Separation Module according to the manufacturer’s protocol, using a protein concentration of 0.25 ^g/ ^l and antibodies targeting BTK (clone# D3H5, Cell Signalling) and ^-Actin (clone# AC-15, Santa Cruz) diluted to 1:400 and 1:10, respectively, where the latter was used as a loading control. An equal ratio of rabbit and mouse HRP-conjugated secondary antibodies was used for detection. BTK protein levels were quantified relative to ^-Actin loading levels and subsequently normalized to the DMSO control. Phosphorylated BTK levels were quantified using the Protein Normalization Assay Module for Jess (ProteinSimple) according to the manufacturer’s protocol, using a protein concentration of 1.5 ^g/ ^l and an antibody targeting pBTK (Y223) (Cell Signalling) diluted to 1:50. Phosphorylated BTK levels were quantified relative to the Protein Normalization Reagent and subsequently normalized to the DMSO control. A549 cell lysis and immunoassay to detect total EGFR and phospho-EGFR [00486] A549 cells (ATCC) were cultured in Dulbecco’s Modified Eagle’s Medium (DMEM) (Wisent) supplemented with 10% FBS and 1% penicillin/streptomycin. Cells were seeded in 6- well plates at 530,000 cells/well and incubated at 37 o C, 5% CO2 for 16 hours. Cells were starved in DMEM containing 1% FBS for 4 hours before they were treated with the indicated concentrations of compound or DMSO alone and incubated at 37 o C, 5% CO2 for 24 hours. Prior to cell harvest and lysis, 50 ng/ml human epidermal growth factor (hEGF) (Sigma) was added to the cells and incubated at 37 o C, 5% CO2 for 10 minutes. Conditioned media was discarded, and adherent cells were washed with PBS before they were scraped on ice. Cell suspensions were centrifugated at 2,000 RPM for 5 minutes at 4 o C and supernatants were discarded. Cell pellets were resuspended with 1X RIPA buffer (Millipore) and incubated on ice for 15 minutes. Protein lysates were extracted by centrifugating at 20,000 RPM for 20 minutes at 4 o C. Proteins were separated and total EGFR protein levels were quantified by Simple Western Immunoassay (ProteinSimple) using the Protein Normalization Assay Module for Jess according to the manufacturer’s protocol, using a protein concentration of 0.125 ^g/ ^l and an antibody targeting EGFR (clone# EP38Y, Abcam) diluted to 1:400. Phosphorylated EGFR protein levels were quantified with the same assay using a protein concentration of 1 ^g/ ^l and an antibody targeting pEGFR (Y1068) (Cell Signalling) diluted to 1:25. EGFR and phosphorylated EGFR levels were normalized to the Jess Protein Normalization Reagent loading control and subsequently to the DMSO control. K562 cell lysis and immunoassay to detect ^-Tubulin [00487] K562 cells (ATCC) were cultured in Iscove's Modified Dulbecco's Medium (IMDM) (Wisent) supplemented with 10% FBS and 1% penicillin/streptomycin. Cells were seeded in 6- well plates at 1.71x10 6 cells/well and incubated at 37 o C, 5% CO2 for 16 hours. Cells were treated with compounds at the indicated concentrations or DMSO alone and incubated at 37 o C, 5% CO2 for 24 hours. Cell suspensions were centrifugated at 1,400 RPM for 5 minutes at room temperature and supernatants were discarded. Cell pellets were resuspended with 1X RIPA buffer (Millipore) and incubated on ice for 15 minutes. Protein lysates were extracted by centrifugating at 20,000 RPM for 20 minutes at 4 o C. Proteins were separated and total ^-Tubulin levels were quantified by Simple Western Immunoassay (ProteinSimple) using the Protein Normalization Assay Module for Jess (ProteinSimple) according to the manufacturer’s protocol, using a protein concentration of 0.05 ^g/ ^l and an antibody targeting ^-Tubulin (Abcam) diluted to 1:800. ^-Tubulin levels were quantified relative to the Protein Normalization Reagent and subsequently normalized to the DMSO control. Time-dependent inhibition BTK [00488] For the time-dependent inhibition experiments, the activity of BTK kinases was monitored using a HTRF® KinEASE-TK kit from Cisbio (62TK0PEC) as described above. Six compounds showing higher potency during dose response analysis were further evaluated for their change in inhibitory potency over time. Ibrutinib was used as a positive control. The selected compounds were pre incubated with the kinase at 11 different concentrations, ranging from 24 pM to 25 uM final compound concentrations. The pre incubation times were 0, 1, 3, 5, 10, 15, 30 and 45 min. After the preincubation, reaction was initiated by adding biotinylated substrate and ATP and the reaction was allowed to proceed for 45 min. The concentration of substrate in the reaction mixture was 1 uM and ATP was 28 uM (reported Km value). The reaction was terminated by adding 62.5 nM SA-XL665 and 100fold diluted europium labelled antibody (Eu-Ab), diluted in 1X detection buffer that contained EDTA. After 60 min of incubation, the fluorescence emission was measured at 620 nm and 665 nm. The ratio of Em 665 nm to Em 620 nm was proportional to the amount of substrate phosphorylated by the kinase. Product formation vs pre- incubation time data were fitted to a one phase exponential decay equation using GraphPad Prism. The same product formation vs inhibitor concentration data were also fitted to a log(antagonist) vs. response -- Variable slope equation in GraphPad Prism to provide IC 50 values at different pre incubation times. EGFR [00489] For the time-dependent inhibition experiments, the activity of EGFR kinase was monitored using a HTRF® KinEASE-TK kit from Cisbio (62TK0PEC) as described above. Six compounds showing higher potency during dose response analysis against EGFR, were further evaluated for their change in inhibitory potency over time. Ibrutinib was used as a positive control. The selected compounds were pre incubated with the kinase at 11 different concentrations, ranging from 24 pM to 25 uM final compound concentrations. The pre incubation times were 0, 2, 5, 10, 15, 30, 45 and 60 min. After the preincubation, the reaction was initiated by adding biotinylated substrate and ATP and the reaction was allowed to proceed for 45 min. The concentration of substrate in the reaction mixture was 0.5 uM and ATP was 1.57 uM (reported Km value). The reaction was terminated by adding 31.25 nM SA-XL665 and 100 fold diluted europium labelled antibody (Eu-Ab), diluted in 1X detection buffer that contained EDTA. After 60 min of incubation, the fluorescence emission was measured at 620 nm and 665 nm. The ratio of Em 665 nm to Em 620 nm was proportional to the amount of substrate phosphorylated by the kinase. Product formation vs pre-incubation time data were fitted to a one phase exponential decay equation using GraphPad Prism. The same product formation vs inhibitor concentration data were also fitted to a log(antagonist) vs. response -- Variable slope equation in GraphPad Prism to provide IC50 values at different pre incubation times. Jump dilution experiment BTK [00490] Six compounds, along with ibrutinib as a control compound (used at 10 times their IC 50 concentrations) were pre incubated with BTK (at 142 nM or 100-fold the normal assay concentration) for 1.5 h at room temperature. Sample containing only DMSO vehicle was used as a positive (full activity) control while sample with no enzyme was used as a negative (zero activity) control. After the preincubation, the mixture was diluted 100-fold into a reaction mixture containing 1^uM biotinylated substrate and 28^uM^ ATP and the reaction was allowed to proceed for various time points (2, 5, 10, 15, 20, 30, 45 and 60 min), at which the reaction was terminated by adding 1 ul of 0.5 M EDTA. 62.5 nM SA-XL665 and^100-fold^diluted^europium^labelled antibody (Eu-Ab), diluted in 1X detection buffer, was added as detection mixture. After 60 min of incubation, the fluorescence emission was measured at 620 nm and 665 nm. The ratio of Em 665 nm to Em 620 nm was proportional to the amount of substrate phosphorylated by the kinase. EGFR [00491] Six compounds (used at 10 times their IC50 concentrations) were pre incubated with EGFR (at 46 nM or 100-fold the normal assay concentration) for 1.5 h at room temperature. Sample containing only DMSO vehicle was used as a positive (full activity) control while sample with no enzyme was used as a negative (zero activity) control. After the preincubation, the mixture was diluted 100-fold into a reaction mixture containing 0.5 uM biotinylated substrate and 1.57 uM^ ATP and the reaction was allowed to proceed for various time points (2, 5, 10, 15, 30, 40, 45 and 60 min), at which the reaction was terminated by adding 1 ul of 0.5 M EDTA. 31.25 nM SA- XL665 and 100-fold diluted europiumlabelled antibody (Eu-Ab), diluted in 1X detection buffer, was added as detection mixture. After 60 min of incubation, the fluorescence emission was measured at 620 nm and 665 nm. The ratio of Em 665 nm to Em 620 nm was proportional to the amount of substrate phosphorylated by the kinase. [00492] In some instances, Table 9 – Table 24 demonstrate the (e.g., binding) activity of a compound provided herein. [00493] In some instances, Table 9 demonstrates the extent to which a compound binds to EGFR. In some instances, in vitro binding to EGFR shows the extent to which a compound binds to EGFR. In some instances, Table 9 shows the exent to which a compound binds to EGFR and inhibits phosphorylation of a peptide substrate. In some instances, a compound demonstrates strong binding to EGFR when the remaining EGFR activity is low. In some instances, in vitro EGFR inhibition is shown in Table 9. Table 9 A: >90 %; B: 50-90%; C: <50% [00494] In some instances, Table 10 demonstrates the extent to which a compound binds to EGFR. In some instances, in vitro EFGR inhibition shows the extent to which a compound binds to EGFR. In some instances, Table 10 shows the exent to which a compound binds to EGFR and inhibits phosphorylation of a peptide substrate across a dose response. In some instances, in vitro EGFR inhibition is shown in Table 10. Table 10 [00495] In some instances, Table 11 demonstrates the in cellulo EFGR inhibition of a compound provided herein. In some instances, the in cellulo EGFR inhibition demonstrates the extent to which a compound binds to EGFR in cells (e.g., and inhibits autophosphrylation of EGFR). In some instances, Table 11 shows in cellulo pEGFR inhibition in A549 cells. Table 11 n.d.: n ot determined X: EGFR bound and autophosphoration of EGFR inhibited in cells [00496] In some instances, Table 12 demonstrates the in cellulo EFGR degradation using a compound provided herein. In some instances, the in cellulo EGFR degradation demonstrates the extent to which a compound binds to EGFR in cells (e.g., and causes destabilization and degradation of EGFR). In some instances, Table 12 shows in cellulo EGFR degradation in A549 cells. Table 12 n.d.: not determined Y: EGFR bound in cells and EGFR degradation occurred [00497] In some instances, Table 13 demonstrates the extent to which a compound binds to BTK. In some instances, in vitro binding to BTK shows the extent to which a compound binds to BTK. In some instances, Table 13 shows the exent to which a compound binds to BTK and inhibits phosphorylation of a peptide substrate. In some instances, a compound demonstrates strong binding to BTK when the remaining BTK activity is low. In some instances, in vitro BTK inhibition is shown in Table 13. Table 13 A: >90%; B : 50-90%; C: <50% [00498] In some instances, Table 14 demonstrates the extent to which a compound binds to BTK. In some instances, in vitro BTK inhibition shows the extent to which a compound binds to BTK. In some instances, Table 14 shows the exent to which a compound binds to BTK and inhibits phosphorylation of a peptide substrate across a dose response. In some instances, in vitro BTK inhibition is shown in Table 14. Table 14 a: <1000 nM; b: >1000 nM [00499] In some instances, Table 15 demonstrates the in cellulo BTK inhibition of a compound provided herein. In some instances, the in cellulo BTK inhibition demonstrates the extent to which a compound binds to BTK in cells (e.g., and inhibits autophosphrylation of BTK). In some instances, Table 15 shows in cellulo phosphoEGFR inhibition in RAMOS cells. Table 15 n.d.: not determined X: BTK bound and autophosphoration of BTK inhibited in cells [00500] In some instances, Table 16 demonstrates the in cellulo BTK degradation using a compound provided herein. In some instances, the in cellulo BTK degradation demonstrates the extent to which a compound binds to BTK in cells (e.g., and causes destabilization and degradation of BTK). In some instances, Table 16 shows in cellulo BTK degradation in RAMOS cells. Table 16 n.d.: not determined Y: EGFR bound in cells and EGFR degradation occurred [00501] In some instances, Table 17 demonstrates the extent to which a compound binds to BMX. In some instances, in vitro binding to BMX shows the extent to which a compound binds to BMX. In some instances, Table 17 shows the exent to which a compound binds to BMX and inhibits phosphorylation of a peptide substrate. In some instances, a compound demonstrates strong binding to BMX when the remaining BMX activity is low. In some instances, in vitro BMX inhibition is shown in Table 17. Table 17 A: >90%; B: 50-90 %; C: <50% [00502] In some instances, Table 18 demonstrates the extent to which a compound binds to BMX. In some instances, in vitro BMX inhibition shows the extent to which a compound binds to BMX. In some instances, Table 18 shows the exent to which a compound binds to BMX and inhibits phosphorylation of a peptide substrate across a dose response. In some instances, in vitro BMX inhibition is shown in Table 18. Table 18 a: <1000 nM; b: >1000 nM [00503] In some instances, Table 19 demonstrates the extent to which a compound binds to JAK3. In some instances, in vitro binding to JAK3 shows the extent to which a compound binds to JAK3. In some instances, Table 19 shows the exent to which a compound binds to JAK3 and inhibits phosphorylation of a peptide substrate. In some instances, a compound demonstrates strong binding to JAK3 when the remaining JAK3 activity is low. In some instances, in vitro JAK3 inhibition is shown in Table 19. Table 19 A: >90%; B: 50-90%; C: <50% [00504] In some instances, Table 20 demonstrates the extent to which a compound binds to JAK3. In some instances, in vitro JAK3 inhibition shows the extent to which a compound binds to JAK3. In some instances, Table 20 shows the exent to which a compound binds to JAK3 and inhibits phosphorylation of a peptide substrate across a dose response. In some instances, in vitro JAK3 inhibition is shown in Table 20. Table 20 a: <1000 nM; b: >1000 nM [00505] In some instances, Table 21 demonstrates the extent to which a compound binds to FGFR4. In some instances, in vitro binding to FGFR4 shows the extent to which a compound binds to FGFR4. In some instances, Table 21 shows the exent to which a compound binds to FGFR4 and inhibits phosphorylation of a peptide substrate. In some instances, a compound demonstrates strong binding to FGFR4 when the remaining FGFR4 activity is low. In some instances, in vitro FGFR4 inhibition is shown in Table 21. Table 21 A: >90%; B: 50-90%; C: <50% [00506] In some instances, Table 22 demonstrates the extent to which a compound binds to FGFR4. In some instances, in vitro FGFR4 inhibition shows the extent to which a compound binds to FGFR4. In some instances, Table 22 shows the exent to which a compound binds to FGFR4 and inhibits phosphorylation of a peptide substrate across a dose response. In some instances, in vitro FGFR4 inhibition is shown in Table 22. Table 22 a: <1000 nM; b: >1000 nM [00507] In some instances, Table 23 demonstrates the extent to which a compound binds to RIPK2. In some instances, in vitro binding to RIPK2 shows the extent to which a compound binds to RIPK2. In some instances, Table 23 shows the exent to which a compound binds to RIPK2 and inhibits phosphorylation of a peptide substrate. In some instances, a compound demonstrates strong binding to RIPK2 when the remaining RIPK2 activity is high. In some instances, in vitro RIPK2 inhibition is shown in Table 23. Table 23 C: >90%; B: 5 0-90%; A: <50% [00508] In some instances, Table 24 demonstrates the in cellulo tubulin degradation using a compound provided herein. In some instances, the in cellulo tubulin degradation demonstrates the extent to which a compound binds to tubulin (e.g., β-tubulin) in cells (e.g., and causes destabilization and degradation of tubulin). In some instances, Table 24 shows in cellulo tubulin degradation in K562 cells. Table 24 n.d.: not determined Y: β-tubulin bound in cells and tubulin degradation occurred III. Preparation of Pharmaceutical Dosage Forms Example P1: Solution for injection [00509] The active ingredient is a compound of Table 1, Table 2, or Table 3, or a pharmaceutically acceptable salt thereof. A solution for intraperitoneal administration is prepared by mixing 1-1000 mg of active ingredient with 10-50 mL of a solvent mix made up by 25% dimethylacetamide, 50% propylene glycol and 25% Tween 80. Filter through millipore sterilizing filter and then distribute in 1 mL amber glass ampoules, performing all the operations under sterile conditions and under nitrogen atmosphere.1 mL of such solution is mixed with 100 or 200 mL of sterile 5% glucose solution before using intraperitoneally. [00510] The examples and embodiments described herein are for illustrative purposes only and various modifications or changes suggested to persons skilled in the art are to be included within the spirit and purview of this application and scope of the appended claims.
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