Purine compounds, compositions containing them and uses thereof

Abstract

The present invention relates to purine compounds, pharmaceutical compositions containing same, and their use in the treatment or prevention of diseases and disorders associated with the cannabinoid CB1 receptor. For example, the purine compounds, or tautomeric forms and / or salts thereof, are of the formula: 1 ~R 4 is as defined herein. JPEG2025535504000108.jpg36170

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority under applicable law to U.S. Provisional Application No. 63 / 381,036, filed October 26, 2022, the contents of which are incorporated herein by reference in their entirety and for all purposes. FIELD OF THE DISCLOSURE This disclosure relates generally to compounds, particularly purine compounds, pharmaceutical compositions containing them, and their uses and methods of use in the treatment and prevention of diseases and disorders. [Background technology]

[0002] Activation of the cannabinoid CB1 receptor is generally known to increase appetite, increase lipid synthesis and storage, inhibit the action of insulin and leptin, and promote inflammation and fibrosis. Therefore, research has focused on developing CB1 receptor inhibitors for the potential treatment of obesity and its associated metabolic disorder, known as metabolic syndrome. Rimonabant was shown to be effective in treating metabolic syndrome, but was withdrawn from the market due to its neuropsychiatric (i.e., CNS-related) side effects.

[0003] There remains a need for the development of alternative compounds that target the CB1 receptor for the treatment or prevention of disorders associated therewith. Summary of the Invention

[0004] According to one aspect, the present technology relates to compounds and their pharmaceutically acceptable salts, pharmaceutical compositions thereof, uses thereof, and methods of treatment comprising their administration. More specifically, the following embodiments are provided:

[0005] Embodiment 1. A compound of Formula I, [ka] During the ceremony, R 1is an optionally substituted C6 aryl group; R 2 is an optionally substituted C6 aryl group or a C5-C6 heteroaryl group; R 3 But R 7 O-, N(R 8 )2-, C4- 10 Heterocycloalkyl, and C 5-6 an optionally substituted group selected from heteroaryl; R 4 But R 5 O- and N(R 6 )2-, R 5 C1-C6 alkyl, C3-C7 cycloalkyl, C4-C 10 Heterocycloalkyl, C5-C6 heteroaryl, C3-C7 cycloalkyl, C1-C3 alkyl, C4-C 10 is a group selected from heterocycloalkyl C1-C3 alkyl, C5-C6 heteroaryl C1-C3 alkyl, R 6 is H or C1-C6 alkyl, C3-C7 cycloalkyl, C4-C 10 Heterocycloalkyl, C5-C6 heteroaryl, C3-C7 cycloalkyl, C1-C3 alkyl, C4-C 10 heterocycloalkyl C1-C3 alkyl, C5-C6 heteroaryl C1-C3 alkyl, wherein at least one R 6 is other than H or two R 6 The groups, together with their adjacent nitrogen atoms, form a C4-C 10 forming a heterocycloalkyl or C5-C6 heteroaryl group, In the formula, R 5 or R 6 at least one of the alkyl, cycloalkyl, heterocycloalkyl, or heteroaryl in is substituted with at least one hydroxyl or hydroxy-substituted C1-C4 alkyl group, and optionally further substituted with other substituents; R7 is optionally substituted C1-C6 alkyl; R 8 is independently in each occurrence hydrogen, C1-C6 alkyl, C3-C7 cycloalkyl, and C4-C 10 heterocycloalkyl; wherein each of the alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl groups is optionally substituted. or an isomer or tautomer thereof, or a pharmaceutically acceptable salt thereof.

[0006] Embodiment 2. The compound is of Formula II: [ka] During the ceremony, R 4 is as defined in embodiment 1; X 1 But C and X 2 ~X 6 are each independently N and CR 21 n is 1; and X is 2 ~X 6 At most three of are N, or X 1 is C or N, and X 2 ~X 5 However, each independently, CR 21 , O, S, N, or NR 11 n is zero and X is selected from 6 But absent, X 1 and X 5 is replaced by the bond between X 1 ~X 5 Up to three of them are C or CR 21 Other than that, X 7 and X 8 are each independently O, S, SO2, NR 36 , or C(R 35 )2 and X 7 and X 8One of the is O, S, or NR 36 If the other is C(R 35 )2, R 9 is independently in each occurrence optionally substituted C1-C6 alkyl, C3-C7 cycloalkyl, C4-C 10 Heterocycloalkyl, C5-C6 heteroaryl, C3-C7 cycloalkyl, C1-C3 alkyl, C4-C 10 heterocycloalkylC1-C3 alkyl, and C5-C6 heteroarylC1-C3 alkyl; R 10 is independently in each occurrence H, or optionally substituted C1-C6 alkyl, C3-C7 cycloalkyl, C4-C 10 Heterocycloalkyl, C5-C6 heteroaryl, C3-C7 cycloalkyl, C1-C3 alkyl, C4-C 10 heterocycloalkyl C1-C3 alkyl, and C5-C6 heteroaryl C1-C3 alkyl, or two R 10 The groups, together with their adjacent nitrogen atoms, form an optionally substituted C-C 10 forming a heterocycloalkyl or a C5-C6 heteroaryl; R 11 is independently in each occurrence H, or optionally substituted C1-C6 alkyl, C3-C7 cycloalkyl, C4-C 10 Heterocycloalkyl, C5-C6 heteroaryl, C3-C7 cycloalkyl, C1-C3 alkyl, C4-C 10 heterocycloalkyl C1-C3 alkyl, C5-C6 heteroaryl C1-C3 alkyl; R 12 is independently in each occurrence selected from F, Cl, CN, NH, N(H)C1-C3 alkyl, N(C1-C3 alkyl)2, and C1-C3 alkyl; p is 0, 1, 2, or 3, preferably 0 or 1; R 21 may independently in each occurrence be hydrogen, halogen, OH, OR 9, CN, NO2, C(O)R 9 , C(O)N(R 10 )2, C(R 11 )=NR 11 , SO2R 9 , SO2N(R 10 )2, N(R 11 )C(O)R 9 , N(R 11 )SO2R 9 , N(R 11 )C(O)N(R 10 )2, N(R 11 )SO2N(R 10 )2, N(R 10 )2, P(O)(R 10 )2, P(O)(OR 10 )2, B(OR 10 )2, and optionally substituted C 1-6 Alkyl group, C 2-6 Alkenyl group, C 2-6 Alkynyl group, C 6-10 Aryl group, C 5-10 Heteroaryl groups, C 3-10 Cycloalkyl groups, and C 4-10 heterocycloalkyl groups, R 31 ~R 35 may independently in each occurrence be hydrogen, halogen, OH, OR 9 , CN, NO2, C(O)OH, C(O)OR 9 , C(O)R 9 , C(O)N(R 10 )2, C(R 11 )=NR 11 , SO2R 9 , SO2N(R 10 )2, N(R 11 )C(O)R 9 , N(R 11 )SO2R 9 , N(R 11 )C(O)N(R 10 )2, N(R 11 )SO2N(R 10 )2, N(R 10 )2, P(O)(R 10 )2, P(O)(OR 10 )2, B(OR 10)2, and optionally substituted C 1-6 Alkyl group, C 2-6 Alkenyl group, C 2-6 Alkynyl group, C 6-10 Aryl group, C 5-10 Heteroaryl groups, C 3-10 Cycloalkyl groups, and C 4-10 heterocycloalkyl groups, R 36 But hydrogen, C(O)R 9 , C(O)OR 9 , C(O)N(R 10 )2, C(R 11 )=NR 11 , SO2R 9 , SO2N(R 10 )2, P(O)(R 10 )2, P(O)(OR 10 )2, B(OR 10 )2, and optionally substituted C 1-6 Alkyl group, C 2-6 Alkenyl group, C 2-6 Alkynyl group, C 6-10 Aryl group, C 5-10 Heteroaryl groups, C 3-10 Cycloalkyl groups, and C 4-10 heterocycloalkyl groups, or R 31 ~R 36 two of which, together with their adjacent atoms, form a ring, preferably a bridged or spiro heterocycle; m is 0, 1, 2, or 3; The compound of embodiment 1, wherein each of the alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl groups is optionally substituted. or an isomer or tautomer thereof, or a pharmaceutically acceptable salt thereof.

[0007] Embodiment 3. m is zero and X 7 and X 8 are each independently C(R 35 )2, preferably X 7is CH2.

[0008] Embodiment 4. X 8 However, C(R 35 )2 and two R 35 One of them is fluorine, C(O)R 9 , C(O)OR 9 , C(O)N(R 10 )2, N(R 11 )C(O)R 9 , or optionally substituted C 1-6 alkyl and two R 35 The other of these is hydrogen, fluorine, CN, OH, OR 9 , N(R 10 )2, or optionally substituted C 1-6 The compound of embodiment 3, wherein the aryl group is alkyl.

[0009] Embodiment 5. X 8 is C(R 35 )2 and two R 35 together with their adjacent carbon atoms to form spiro C 4-5 The compound of embodiment 3, wherein the compound forms a heterocycle.

[0010] Embodiment 6. m is 1 and X 7 and X 8 are each independently C(R 35 )2, preferably X 7 is CH2.

[0011] Embodiment 7. X 8 However, C(R 35 )2 and two R 35 One of them is fluorine, C(O)R 9 , C(O)OR 9 , C(O)N(R 10 )2, N(R 11 )C(O)R 9 , or optionally substituted C 1-6 alkyl and two R 35 The other of these is hydrogen, fluorine, CN, OH, OR 9, N(R 10 )2, or optionally substituted C 1-6 The compound of embodiment 6, wherein the aryl is alkyl.

[0012] Embodiment 8. X 8 is C(R 35 )2 and two R 35 together with their adjacent carbon atoms to form spiro C 4-5 The compound of embodiment 6, which forms a heterocycle.

[0013] Embodiment 9. m is 2 and X 7 and X 8 are each independently C(R 35 )2. The compound of embodiment 2, wherein

[0014] Embodiment 10. X 8 is CH2 and X 7 However, C(R 35 )2 and two R 35 One of them is fluorine, C(O)R 9 , C(O)OR 9 , C(O)N(R 10 )2, N(R 11 )C(O)R 9 , or optionally substituted C 1-6 alkyl and two R 35 The other of these is hydrogen, fluorine, CN, OH, OR 9 , N(R 10 )2, or optionally substituted C 1-6 The compound of embodiment 9, wherein the aryl is alkyl.

[0015] Embodiment 11. Two R 35 One of them is C(O)N(R 10 )2, or N(R 11 )C(O)R 9 and two R 35 The other of OR 9 or optionally substituted C 1-4 The compound of embodiment 10, wherein the aryl group is alkyl.

[0016] Embodiment 12. Two R 35 The other of the two is OR 9 and R 9 is C1 -6 Alkyl, preferably C 2-4 The compound of embodiment 11, wherein the aryl group is alkyl.

[0017] Embodiment 13. Two R 35 The other of the two is OR 9 and R 9 is selected from methyl, ethyl, n-propyl, isopropyl, i-butyl, and sec-butyl, preferably ethyl or isopropyl, most preferably isopropyl.

[0018] Embodiment 14. X 8 is CH2 and X 7 is C(R 35 )2 and two R 35 together with their adjacent carbon atoms to form spiro C 4-5 The compound of embodiment 9, which forms a heterocycle.

[0019] Embodiment 15. X 7 is CH2 and X 8 is C(R 35 )2 and two R 35 One of them is fluorine, C(O)R 9 , C(O)OR 9 , C(O)N(R 10 )2, N(R 11 )C(O)R 9 , or optionally substituted C 1-6 alkyl and two R 35 The other of these is hydrogen, fluorine, CN, OH, OR 9 , N(R 10 )2, or optionally substituted C 1-6 The compound of embodiment 9, wherein the aryl is alkyl.

[0020] Embodiment 16. Two R 35 One of them is C(O)N(R 10)2, or N(R 11 )C(O)R 9 and two R 35 The other of OR 9 or optionally substituted C 1-4 The compound of embodiment 15, wherein the aryl is alkyl.

[0021] Embodiment 17. Two R 35 The other of the two is OR 9 and R 9 is C1 -6 Alkyl, preferably C 2-4 The compound of embodiment 16, wherein the aryl is alkyl.

[0022] Embodiment 18. Two R 35 The other of the two is OR 9 and R 9 is selected from methyl, ethyl, n-propyl, isopropyl, i-butyl, and sec-butyl, preferably ethyl or isopropyl, most preferably isopropyl.

[0023] Embodiment 19. X 7 is CH2 and X 8 is C(R 35 )2 and two R 35 together with their adjacent carbon atoms to form spiro C 4-5 The compound of embodiment 9, which forms a heterocycle.

[0024] Embodiment 20. m is 2 or 3, and X 7 but O, S, SO2, or NR 36 and X 8 However, C(R 35 )2. The compound of embodiment 2, wherein

[0025] Embodiment 21 The compound of embodiment 20, wherein m is 2.

[0026] Embodiment 22 The compound of embodiment 20, wherein m is 3.

[0027] Embodiment 23. X 7 but O, SO2, or NR 36 23. The compound of any one of embodiments 20-22, wherein

[0028] Embodiment 24. X 7 But NR 36 and R 36 But hydrogen, C(O)R 9 , C(O)OR 9 , C(O)N(R 10 )2, and optionally substituted C 1-6 The compound of embodiment 23, wherein the aryl group is selected from alkyl.

[0029] Embodiment 25. Two R 35 One of the following is hydrogen, fluorine, or C(O)R 9 , C(O)OR 9 , C(O)N(R 10 )2, N(R 11 )C(O)R 9 , or optionally replaced by C 1-6 alkyl and two R 35 The other is hydrogen, fluorine, OH, OR 9 , N(R 10 )2, or optionally substituted C 1-6 alkyl or R 35 One of them is R 33 and taken together with their adjacent atoms form a bridged ring.

[0030] Embodiment 26. Both R 35 is hydrogen.

[0031] Embodiment 27. Two R 35 One of them is fluorine, C(O)R 9 , C(O)OR 9 , C(O)N(R 10 )2, N(R 11 )C(O)R 9 , or optionally replaced by C 1-6alkyl and two R 35 and the other of is hydrogen.

[0032] Embodiment 28. R 35 One of them is R 33 Together with C 1-3 The compound of embodiment 25, which forms an alkylene group.

[0033] Embodiment 29. R 33 is independently in each occurrence hydrogen, fluorine, and optionally substituted C 1-6 The compound of any one of embodiments 2-27, wherein the alkyl is selected from:

[0034] Embodiment 30. R 34 is independently in each occurrence hydrogen, fluorine, and optionally substituted C 1-6 The compound of any one of embodiments 2-29, wherein the alkyl is selected from:

[0035] Embodiment 31. R 31 and R 32 and R are each a hydrogen atom.

[0036] Embodiment 32. R 3 is selected from the group of C1 to C7, C10, C15, C16, C18 to C22, C24 to C28, C32 to C40, and C47 to C69, preferably C1, C16 or C18, more preferably C18.

[0037] Embodiment 33. The compound is of Formula III: [ka] During the ceremony, R 13 But R 7 O-, N(R 8 )2-, and C5-6 heteroaryl, R 4 , R 7 , and R 8 is as defined in embodiment 1; R 12 , X 1 ~X 6 The compound of embodiment 1, wherein n, and p are as defined in embodiment 2. or an isomer or tautomer thereof, or a pharmaceutically acceptable salt thereof.

[0038] Embodiment 34. R 13 But R 7 The compound of embodiment 33, wherein:

[0039] Embodiment 35. R 7 is optionally substituted C1-C4 alkyl.

[0040] Embodiment 36. R 13 is N(R 8 )2-.

[0041] Embodiment 37. One R 8 optionally substituted C4-C 10 heterocycloalkyl, and the other R 8 is hydrogen or optionally substituted C1-C6 alkyl.

[0042] Embodiment 38. One R 8 is an optionally substituted C-C heterocycloalkyl, and the other R 8 is hydrogen or optionally substituted C1-C4 alkyl.

[0043] Embodiment 39. One R 8 is optionally substituted C1-C6 alkyl, and the other R 8 is hydrogen or optionally substituted C1-C6 alkyl.

[0044] Embodiment 40. R 13 is selected from C8, C9, C11-C14, C17, C23, C29-C31, and C41-C46.

[0045] Embodiment 41. R 12 The compound according to any one of embodiments 2 to 40, wherein is Cl and p is 1, preferably forming a 4-chlorophenyl group.

[0046] Embodiment 42. p is zero and R 12 The compound of any one of embodiments 2-40, wherein is absent, forming an unsubstituted phenyl group.

[0047] Embodiment 43. n is 1 and X 1 is C and X 2 ~X 6 However, each independently CR 21 The compound of any one of embodiments 2-42, wherein

[0048] Embodiment 44. n is 1 and X 1 is C and X 2 ~X 6 One of them is N and the others are CR 21 The compound of any one of embodiments 2-42, wherein

[0049] Embodiment 45. n is zero and X 6 is absent and X 1 The compound of any one of embodiments 2-42, wherein is C.

[0050] Embodiment 46. X 2 ~X 5 One or two of the following are N or NR 11 and the rest are CR 21 and preferably R 11 is C1-C6 alkyl.

[0051] Embodiment 47. X 2 ~X 5 One of them is S and the other is CR 21 46. ​​The compound of embodiment 45, wherein

[0052] Embodiment 48. All CR 21 The compound of any one of embodiments 43-47, wherein is CH.

[0053] Embodiment 49. One CR 21 is other than CH, preferably R 21 However, halogens, CN, N(C 1-6 alkyl)2, and C 1-6 Compounds according to embodiment 43, wherein R is selected from alkyl, more preferably halogen or CN, most preferably halogen (eg, Cl).

[0054] Embodiment 50. One CR 21 is other than CH, preferably R 21 However, halogens, CN, N(C 1-6 alkyl)2, and C 1-6 Alkyl, more preferably halogen, CN, and C 1-6 Compounds according to embodiment 44, wherein R is selected from alkyl, most preferably CN.

[0055] Embodiment 51. One CR 21 is other than CH, preferably R 21 is halogen, CN, N(C1-6 alkyl)2, and C 1-6 Alkyl, more preferably CN and C 1-6 Alkyl, most preferably C 1-6 The compound of any one of embodiments 45-47, wherein the alkyl is selected from:

[0056] Embodiment 52. R 2 The compound according to any one of embodiments 1 to 51, wherein is selected from the group B1 to B23 as defined herein.

[0057] Embodiment 53. R 2is selected from the group B1 to B4, for example, R 2 The compound of embodiment 52, wherein is B1.

[0058] Embodiment 54. R 2 is selected from the groups B5 to B8, B12 to B19, and B21 to B23, for example, R 2 The compound of embodiment 52, wherein is B14.

[0059] Embodiment 55. R 2 is selected from groups B9-B11 and B20.

[0060] Embodiment 56. R 4 R 5 O-group, where R 5 The compound of any one of embodiments 1-55, wherein: is as defined in embodiment 1 and is substituted with at least one hydroxyl group or a C1-C4 alkyl group substituted with a hydroxyl.

[0061] Embodiment 57. R 5 C2-C6 alkyl, C4-C 10 Heterocycloalkyl, or C4-C 10 The compound of embodiment 56, which is a heterocycloalkyl C1-C3 alkyl group.

[0062] Embodiment 58. R 5 is selected from 2-hydroxyethyl, 3-hydroxy-1-propyl, 2-hydroxy-1-propyl, 1-hydroxy-2-propyl, 2-hydroxy-2-methyl-1-propyl, 3-hydroxy-2-methyl-1-propyl, 2-hydroxy-1-methyl-1-propyl, 3-hydroxy-1-methyl-1-propyl, and 2-hydroxy-1,1-dimethyl-1-ethyl.

[0063] Embodiment 59. R 5is a C4-C6 heterocycloalkyl or a C4-C6 heterocycloalkyl C1-C3 alkyl group substituted with a hydroxy group and optionally other substituents, preferably wherein the C4-C6 heterocycloalkyl is selected from pyrrolidinyl, imidazolidinyl, piperidinyl, and piperazinyl groups.

[0064] Embodiment 60. R 4 But N(R 6 )2-group, wherein R 6 is as defined in embodiment 1, and at least one R 6 is substituted with at least one hydroxyl group or a C1-C4 alkyl group substituted with hydroxy, and optionally substituted with one or more other substituents.

[0065] Embodiment 61. One R 6 C2-C6 alkyl, C3-C7 cycloalkyl, C4-C 10 Heterocycloalkyl, C3-C7 cycloalkyl, C1-C3 alkyl, or C4-C substituted with at least one hydroxyl or hydroxy-substituted C1-C4 alkyl group. 10 heterocycloalkyl C1-C3 alkyl group, and the other R 6 is hydrogen or C1-C6 alkyl, optionally substituted with one or more other substituents.

[0066] Embodiment 62. One R 6 is a C2-C6 alkyl or C3-C7 cycloalkyl C1-C3 alkyl group substituted with hydroxyl or a C1-C4 alkyl group substituted with hydroxy, and the other R 6 is hydrogen or C1-C6 alkyl.

[0067] Embodiment 63. Two R 6groups, together with their adjacent nitrogen atoms, are substituted with at least one hydroxyl or hydroxy-substituted C1-C4 alkyl group, optionally substituted with one or more other substituents; 10 The compound of embodiment 60, which forms a heterocycloalkyl or C5 heteroaryl group.

[0068] Embodiment 64. Two R 6 Compounds according to embodiment 63, wherein groups, taken together with their adjacent nitrogen atom, form a C4-C7 heterocycloalkyl substituted with at least one hydroxyl or hydroxy-substituted C1-C4 alkyl group, and optionally substituted with one or more other substituents.

[0069] Embodiment 65. A compound according to embodiment 64, wherein the C4-C7 heterocycloalkyl group is selected from pyrrolidinyl, imidazolidinyl, piperidinyl, and piperazinyl groups substituted with at least one hydroxyl or hydroxy-substituted C1-C4 alkyl group, and optionally substituted with one or more other substituents.

[0070] Embodiment 66. Two R 6 Compounds according to embodiment 63, wherein the groups, taken together with their adjacent nitrogen atoms, form a C5 heteroaryl group substituted with at least one hydroxyl or hydroxy-substituted C1-C4 alkyl group, and optionally substituted with one or more other substituents.

[0071] Embodiment 67. The compound of embodiment 66, wherein the C5 heteroaryl group is selected from imidazole and a pyrrole group substituted with at least one hydroxyl or hydroxy-substituted C1-C4 alkyl group, and optionally substituted with one or more other substituents.

[0072] Embodiment 68. R 4is selected from the groups D5 to D9, D12, D13, D19 to D21, D23, D25, D27, D28, D30 to D32, D36, D37, D43 to D49, D52, D53, D67, D71, D75, D76, and D78 to D81.

[0073] Embodiment 69. R 4 is selected from the groups D6 to D9, D43 to D47, D75 and D76.

[0074] Embodiment 70. R 4 is selected from groups D6 to D9 and D43 to D47, preferably D9.

[0075] Embodiment 71. R 4 is selected from the groups D12, D19, D21, D23, D30 to D32, D36, D37, D48, D49, and D78 to D81, preferably D19 or D21.

[0076] Embodiment 72. R 4 is selected from groups D5, D13, D20, D52, D53, D67 and D71, preferably D20.

[0077] Embodiment 73. A compound of Formula IV, [ka] In the formula, X 1 ~X 8 , R 12 , R 31 ~R 34 , m, n and p are as defined in any one of the above embodiments; R 14 But N(R 16 )2- or optionally substituted C5-C6 heteroaryl; R 16is H, or optionally substituted C1-C6 alkyl, C3-C7 cycloalkyl, C4-C 10 Heterocycloalkyl, C5-C6 heteroaryl, C3-C7 cycloalkyl, C1-C3 alkyl, C4-C 10 heterocycloalkyl C1-C3 alkyl, C5-C6 heteroaryl C1-C3 alkyl, or two R 16 The groups, together with their adjacent nitrogen atoms, form an optionally substituted C-C 10 Compounds forming heterocycloalkyl or C5-C6 heteroaryl, or an isomer or tautomer thereof, or a pharmaceutically acceptable salt thereof.

[0078] Embodiment 74. R 14 is N(R 16 )2-.

[0079] Embodiment 75. One R 16 optionally substituted C1-C6 alkyl, C3-C7 cycloalkyl, C4-C 10 Heterocycloalkyl, C3-C7 cycloalkyl, C1-C3 alkyl, or C4-C 10 heterocycloalkyl C1-C3 alkyl group, and the other R 16 is hydrogen or C1-C6 alkyl.

[0080] Embodiment 76. One R 16 is a C2-C6 alkyl group substituted with one or more substituents, and the other R 16 is hydrogen or C1-C6 alkyl.

[0081] Embodiment 77. A compound according to embodiment 76, wherein the substituents are selected from F, OH, CN, alkoxy, alkylcarbonylamino, akoxycarbonylamino, alkylsulfonamido, benzylamino, aminocarbonyl, dialkylphosphino, phosphonato, dialkylamino, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl.

[0082] Embodiment 78. Two R 16 The groups, together with their adjacent nitrogen atoms, are optionally substituted C-C 10 The compound of embodiment 74, which forms a heterocycloalkyl or C5 heteroaryl group.

[0083] Embodiment 79. Two R's 16 Compounds according to embodiment 78, wherein the groups, taken together with their adjacent nitrogen atom, form an optionally substituted C4-C7 heterocycloalkyl bonded through the nitrogen.

[0084] Embodiment 80. The compound of embodiment 79, wherein the C4-C7 heterocycloalkyl is selected from optionally substituted pyrrolidinyl, imidazolidinyl, piperidinyl, and piperazinyl groups.

[0085] Embodiment 81. Two R 16 Compounds according to embodiment 78, wherein groups taken together with their adjacent nitrogen atom form an optionally substituted C5 heteroaryl group bonded through the nitrogen atom.

[0086] Embodiment 82. The compound of embodiment 81, wherein the C5 heteroaryl group is selected from optionally substituted imidazole and pyrrole groups.

[0087] Embodiment 83. R 14 is an optionally substituted C5-C6 heteroaryl.

[0088] Embodiment 84. R 14 is selected from D3 to D5, D11 to D16, D19 to D28, D30 to D32, D36, D37, D39 to D41, D48 to D54, D56, D57, D63 to D67, D71, and D78 to D81.

[0089] Embodiment 85. A compound of Formula V, [ka] In the formula, X 1 ~X 6 , R 12 , R 13 , R 14 , n and p are as defined in any one of the above embodiments; or an isomer or tautomer thereof, or a pharmaceutically acceptable salt thereof.

[0090] Embodiment 86. A compound of Formula VI, [ka] In the formula, X 1 ~X 8 , R 12 , R 31 ~R 34 , m, n and p are as defined in any one of the above embodiments; R 15 C1-C6 alkyl, C3-C7 cycloalkyl, C4-C 10 Heterocycloalkyl, C5-C6 heteroaryl, C3-C7 cycloalkyl, C1-C3 alkyl, C4-C 10 a compound which is a group selected from heterocycloalkyl C1-C3 alkyl, C5-C6 heteroaryl C1-C3 alkyl; or an isomer or tautomer thereof, or a pharmaceutically acceptable salt thereof.

[0091] Embodiment 87. R 15 optionally substituted C1-C6 alkyl, C4-C 10Heterocycloalkyl, or C4-C 10 The compound of embodiment 86, which is a heterocycloalkyl C1-C3 alkyl group.

[0092] Embodiment 88. R 15 is a C1-C6 alkyl group substituted with one or more substituents selected from, for example, F, OH, CN, alkoxy, alkylcarbonylamino, akoxycarbonylamino, alkylsulfonamido, benzylamino, aminocarbonyl, dialkylphosphino, phosphonato, dialkylamino, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl.

[0093] Embodiment 89. R 15 is an optionally substituted C4-C6 heterocycloalkyl or C4-C6 heterocycloalkyl C1-C3 alkyl group, preferably wherein the C4-C6 heterocycloalkyl is selected from a pyrrolidinyl group, an imidazolidinyl group, a morpholinyl group, a piperidinyl group, and a piperazinyl group.

[0094] 90. OR 15 87. The compound of embodiment 86, wherein groups are selected from D6 to D10, D17, D29, D33 to D35, D43 to D47, D55, D68 to D70, and D72 to D77.

[0095] Embodiment 91. A compound of Formula VII, [ka] In the formula, X 1 ~X 6 , R 12 , R 13 , R 15 , n and p are as defined in any one of the above embodiments; or an isomer or tautomer thereof, or a pharmaceutically acceptable salt thereof.

[0096] Embodiment 92. A compound of Formula VIII, [ka] In the formula, X 1 ~X 8 , R 12 , R 31 ~R 34 , m, n and p are as defined in any one of the above embodiments; R 24 Cl, CN, C(O)OH, R 9 C(O)N(R 11 )-, R 9 C(O)NHC(NH)NH-, R 9 S(O)2-, N(R 10 )2C(O)-, and optionally substituted C1-C6 alkyl groups, wherein R 9 ~R 11 is as previously defined, or an isomer or tautomer thereof, or a pharmaceutically acceptable salt thereof.

[0097] Embodiment 93. A compound of Formula IX, [ka] In the formula, X 1 ~X 6 , R 12 , R 13 , R 24 , n and p are as defined in any one of the above embodiments; or an isomer or tautomer thereof, or a pharmaceutically acceptable salt thereof.

[0098] Embodiment 94. R 24 is selected from the groups D1, D2, D18, D38, D42 and D58 to D62.

[0099] Embodiment 95. A compound selected from compounds 1 to 158 and 160 to 240, as defined herein, or an isomer or tautomer thereof, or a pharmaceutically acceptable salt thereof.

[0100] Embodiment 96. The compound of embodiment 95, or an isomer or tautomer thereof, or a pharmaceutically acceptable salt thereof, wherein the compound is selected from compounds 1-12, 14-28, 30-69, 71-97, 99-102, 104-115, 117-131, 133-137, 139-148, 150-158, 160-175, and 177-240.

[0101] Embodiment 97. The compound of embodiment 95, or an isomer or tautomer thereof, or a pharmaceutically acceptable salt thereof, wherein the compound is selected from compounds 1-12, 14-28, 31-36, 38-50, 52-56, 60-62, 64-68, 72-96, 99, 101, 102, 108, 110, 113, 114, 117, 119-121, 123-128, 130, 131, 133, 135-137, 140-146, 148, 150-155, 157, 158, 160-174, 177-204, 206, 207, 209-216, 220-237, and 240.

[0102] Embodiment 98. The compound is selected from the group consisting of compounds 6-10, 12, 15-17, 19, 20, 23-26, 32, 33, 35, 36, 38, 41-44, 46-48, 54-56, 62, 65-67, 72-76, 78-83, 85, 86, 88-94, 96, 117, 123, 130, 131, 133, 136, 140-146, 148, 150, 152-154, 157, 158, 161-163, 165-167, 169-171, 173, 174, 177-186, 188, 189, 191, 192, 194-197, 199, 203, 206, 207, 211, 213-216, 222-226, 228, 230-232, 234, and 237, or an isomer or tautomer thereof, or a pharmaceutically acceptable salt thereof.

[0103] Embodiment 99. The compound of embodiment 1, or an isomer or tautomer thereof, or a pharmaceutically acceptable salt thereof, wherein the compound is selected from compounds 5-9, 12, 13, 19, 20, 23-26, 29, 35-38, 40, 41, 43, 46-52, 54-59, 63-67, 72-76, 78-88, 90, 93-101, 103-116, 118-124, 128-133, 135-143, 148, 153-155, 157, 158, 161-163, 165-204, 206-227, 231, 233-238, and 240.

[0104] Embodiment 100. The compound of embodiment 99, or an isomer or tautomer thereof, or a pharmaceutically acceptable salt thereof, wherein the compound is selected from compounds 5-9, 12, 19, 20, 23-26, 29, 35-38, 40, 41, 43, 46-52, 54-59, 63-67, 72-76, 78-88, 90, 93-97, 99-101, 104-115, 118-124, 128-131, 133, 135-137, 139-143, 148, 153-155, 157, 158, 161-163, 165-175, 177-204, 206-227, 231, 233-238, and 240.

[0105] Embodiment 101. The compound is selected from the group consisting of compounds 5-9, 12, 19, 20, 23-26, 35, 36, 38, 40, 41, 43, 46-50, 52, 54-56, 64-67, 72-76, 78-88, 90, 93, 94, 96, 99, 101, 108, 110, 113, 114, 119-121, 123, 124, 128, 130, 131, 133, 135-136, 137-138, 138-139, 140-141, 142-143, 144-145, 146-147, 148-149, 149-200, 149-201, 150-202, 151-203, 152-204, 153-205, 154-206, 155-207, 156-208, 157-209, 158-210, 159-211, 160-212, 161-213, 162-214, 163-215, 164-216, 165-217, 166-218, 167-219, 168-219, 169-220, 169-221, 170-222, 171-223, 172-224, 173-225, 174-226, 37, 140-143, 148, 153-155, 157, 158, 161-163, 165-174, 177-204, 206, 207, 209-216, 220-227, 231, 233-237, and 240, or an isomer or tautomer thereof, or a pharmaceutically acceptable salt thereof.

[0106] Embodiment 102. The compound is selected from the group consisting of compounds 6-9, 12, 19, 20, 23-26, 35, 36, 38, 41, 43, 46-48, 54-56, 65-67, 72-76, 78-83, 85, 86, 88, 90, 93, 94, 96, 123, 130, 131, 133, 136, 140-143, 148, 153, 154, 157, 158, 161-163, 165-166, 167-168, 168-169, 169-200, 170-171, 171-202, 172-203, 173-204, 174-205, 175-206, 176-207, 177-208, 178-209, 179-210, 179-211, 179-212, 180-213, 181-214, 182-215, 183-216, 184-217, 185-218, 186-219, 187-219, 188-219, 189-300, 189-301, 189-302, 189-303, 190-304, 191-305, 192-306, 193-307, 194-308, 195-309, 196- 67, 169-171, 173, 174, 177-186, 188, 189, 191, 192, 194-197, 199, 203, 206, 207, 211, 213-216, 222-226, 231, 234, and 237, or an isomer or tautomer thereof, or a pharmaceutically acceptable salt thereof.

[0107] Embodiment 103. A pharmaceutical composition comprising a compound defined in any one of embodiments 1 to 102, together with a pharmaceutically acceptable carrier, diluent, or excipient.

[0108] Embodiment 104. Use of a compound as defined in any one of embodiments 1 to 102 or a pharmaceutical composition as defined in embodiment 103 for the treatment of an appetite-related disorder or one of its complications, a glucose regulation-related disorder or one of its complications, a fibrosis-related disorder or one of its complications, a metabolism-related disorder or one of its complications, a skin and hair growth and healing disorder, a gastrointestinal tract-related disorder, an obesity-related disorder or one of its complications, or a combination thereof.

[0109] Embodiment 105. The use of embodiment 104, wherein one of the appetite-related disorders or complications thereof is selected from Prader-Willi syndrome (PWS), hypothalamic obesity, proopiomelanocortin (POMC) deficiency (including POMC obesity, heterozygous POMC deficiency obesity, and POMC epigenetic disorders), leptin receptor (LepR) deficiency, Bardet-Biedl (BB) syndrome, and Alström syndrome.

[0110] Embodiment 106. The use of embodiment 104, wherein the glucose regulation-related disorder or one of its complications is selected from type I diabetes, type II diabetes, insulin resistance, prediabetes, pancreatic disease (due to beta cell protection and / or increased insulin production), and associated nephropathy, neuropathy, and retinopathy.

[0111] Embodiment 107. The use of embodiment 104, wherein the fibrosis-related disorder or one of its complications is selected from progressive fibrosis associated with interstitial lung disease, idiopathic pulmonary fibrosis (IPF), Hermansky-Pudlak syndrome pulmonary fibrosis (HPS-PF), cirrhosis and other liver fibrosis disorders (such as non-alcoholic steatohepatitis (NASH), primary sclerosing cholangitis, primary biliary cholangitis), skin fibrotic disorders (such as scleroderma), fibrotic kidney disease, and chronic kidney disease.

[0112] Embodiment 108. The use of embodiment 104, wherein one of the metabolic disorders or complications thereof is selected from metabolic syndrome and hyperlipidemia (e.g., hypertriglyceridemia, hypertriglyceridemia in the setting of low HDL cholesterol, elevated LDL and / or total cholesterol and / or VLDL, and / or elevated apolipoprotein B, atherosclerotic cardiovascular disease, etc.).

[0113] Embodiment 109. The use of embodiment 104, wherein one of the obesity-related disorders or complications thereof is selected from sleep apnea, snoring, asthma, pulmonary hypoventilation syndrome, dementia, heart disease, high blood pressure, gallbladder disease, gastrointestinal disorders, menstrual irregularities, osteoarthritis, venous stasis ulcers, coronary artery disease, arteriosclerosis, pseudotumor cerebri, osteoarthritis, high cholesterol, and increased incidence of malignant tumors of the liver, ovary, cervix, uterus, breast, prostate, or gallbladder.

[0114] Embodiment 110. The use of embodiment 104, wherein the skin and hair disorder is selected from alopecia (androgenetic alopecia and alopecia associated with metabolic syndrome), excessive scarring (scars and keloids), and scleroderma.

[0115] Embodiment 111. The use of embodiment 104, wherein the gastrointestinal tract-related disorder is selected from constipation, irritable bowel syndrome, and inflammatory bowel syndrome, including ulcerative colitis and Crohn's disease.

[0116] Embodiment 112. A method for treating a disorder selected from appetite-related disorders or complications thereof, glucose regulation-related disorders or complications thereof, fibrosis-related disorders or complications thereof, metabolism-related disorders or complications thereof, skin and hair growth and healing-related disorders, gastrointestinal tract-related disorders, obesity-related disorders or complications thereof, or combinations thereof, comprising administering to a subject in need thereof a compound defined in any one of embodiments 1 to 102 or a pharmaceutical composition defined in embodiment 103.

[0117] Embodiment 113. The method of embodiment 112, wherein the appetite-related disorder or complication thereof is selected from Prader-Willi syndrome (PWS), hypothalamic obesity, proopiomelanocortin (POMC) deficiency (including POMC obesity, heterozygous POMC deficiency obesity, and POMC epigenetic disorders), leptin receptor (LepR) deficiency, Bardet-Biedl (BB) syndrome, and Alström syndrome.

[0118] Embodiment 114. The method of embodiment 112, wherein the disorder associated with glucose regulation or a complication thereof is selected from type I diabetes, type II diabetes, insulin resistance, prediabetes, pancreatic disease (through beta cell protection and / or increased insulin production), and associated nephropathy, neuropathy, and retinopathy.

[0119] Embodiment 115. The method of embodiment 112, wherein the fibrosis-related disorder or complication thereof is selected from progressive fibrosis associated with interstitial lung disease, idiopathic pulmonary fibrosis (IPF), Hermansky-Pudlak syndrome pulmonary fibrosis (HPS-PF), cirrhosis and other liver fibrosis disorders (such as nonalcoholic steatohepatitis (NASH), primary sclerosing cholangitis, primary biliary cholangitis), skin fibrotic disorders (such as scleroderma), fibrotic kidney disease, and chronic kidney disease.

[0120] Embodiment 116. The method of embodiment 112, wherein the metabolic disorder or complication thereof is selected from metabolic syndrome and hyperlipidemia (e.g., hypertriglyceridemia, hypertriglyceridemia in the setting of low HDL cholesterol, elevated LDL and / or total cholesterol and / or VLDL, and / or elevated apolipoprotein B, atherosclerotic cardiovascular disease, etc.).

[0121] Embodiment 117. The method of embodiment 112, wherein the obesity-related disorder or complication thereof is selected from sleep apnea, snoring, asthma, pulmonary hypoventilation syndrome, dementia, heart disease, high blood pressure, gallbladder disease, gastrointestinal disorders, menstrual irregularities, osteoarthritis, venous stasis ulcers, coronary artery disease, arteriosclerosis, pseudotumor cerebri, osteoarthritis, high cholesterol, and an increased incidence of malignant tumors of the liver, ovary, cervix, uterus, breast, prostate, or gallbladder.

[0122] Embodiment 118. The method of embodiment 112, wherein the skin and hair disorder is selected from alopecia (androgenetic alopecia and alopecia associated with metabolic syndrome), excessive scarring (scars and keloids), and scleroderma.

[0123] Embodiment 119. The method of embodiment 112, wherein the gastrointestinal tract-related disorder is selected from constipation, irritable bowel syndrome, and inflammatory bowel syndrome, including ulcerative colitis and Crohn's disease. Further objects and features of the present compounds, compositions, methods and uses will become more apparent upon reading the following non-limiting description of exemplary embodiments and examples section, which should not be construed as limiting the scope of the invention. DETAILED DESCRIPTION OF THE INVENTION

[0124] All technical terms and expressions used herein have the same definition as that generally understood by those skilled in the art to which this technology pertains.However, the definitions of some terms and expressions used are provided below.If the definitions of terms in the publications, patents and patent applications incorporated herein by reference are contrary to the definitions set forth herein, the definitions in this specification shall prevail.The section headings used herein are for organizational purposes only and should not be interpreted as limiting the subject matter disclosed.

[0125] The chemical structures described herein are drawn according to conventional standards. Also, when an atom, such as a drawn carbon atom, appears to have incomplete valences, it is assumed that the valences are satisfied by one or more hydrogen atoms, although not necessarily explicitly drawn. The hydrogen atoms should be assumed to be part of the compound.

[0126] The terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting. The singular forms "a," "an," and "the" include the plural unless the context clearly dictates otherwise. Thus, for example, reference to a composition containing a "compound" also contemplates a mixture of two or more compounds. It should also be noted that the term "or" is generally used in its sense, including "and / or," unless the context clearly dictates otherwise. Furthermore, when the terms "including," "includes," "having," "has," "with," or variations thereof are used in either the detailed description and / or claims, such terms are intended to be inclusive in a manner similar to the term "comprising."

[0127] The term "about" or "approximately" means within an acceptable error range for a particular value as determined by one of ordinary skill in the art, which depends in part on how the value is measured or determined, i.e., the limitations of the measurement system. For example, "about" can mean within one or more standard deviations, according to practice in the art. Alternatively, "about" can mean a range of up to 20%, preferably up to 10%, more preferably up to 5%, and even more preferably up to 1% of a given value. Alternatively, particularly with respect to biological systems or processes, the term can mean preferably within 5-fold, and more preferably within 2-fold, of a value. When a particular value is described in this application and claims, unless otherwise specified, the term "about" should be assumed to mean within an acceptable error range for the particular value.

[0128] As used herein, the terms "compound," "compounds described herein," "compounds of the present application," "purine," "purine compound," and equivalent expressions refer to compounds described in the present application, e.g., those encompassed by structural formulas I-IX, optionally with reference to any of the applicable embodiments, and also include exemplary compounds, e.g., compounds 1-240, their pharmaceutically acceptable salts and tautomeric forms, and, where applicable, solvates, esters, and prodrugs thereof. Where a zwitterionic form is possible, the compound may be depicted as its neutral form for practical purposes, but it is understood that the compound also includes its zwitterionic form. Embodiments herein may also exclude one or more of the compounds. Compounds may be identified by either their chemical structure or their chemical name. In the event of a conflict between the chemical structure and the chemical name, the chemical structure shall prevail.

[0129] Unless otherwise specified, structures depicted herein are also meant to include all isomeric (e.g., enantiomers, diastereomers, tautomers, and geometric (or conformational)) forms of the structure, where applicable, e.g., R and S configurations of each asymmetric center, unless otherwise specified. Accordingly, single stereochemical isomers as well as enantiomeric, diastereomeric, tautomeric, and geometric (or conformational) mixtures of the present compounds are within the scope of this specification. The present compounds also encompass all possible tautomers of the depicted compounds, if present, unless otherwise specified. This term also includes isotopically labeled compounds where one or more atoms have an atomic mass different from the atomic mass most abundantly found in nature. Examples of isotopes that may be incorporated into the present compounds include, but are not limited to, 2 H(D), 3 H(T), 11 C. 13 C. 14 C. 15 N, 18 O. 17The compounds may also exist in solvated forms, including unsolvated forms as well as hydrated forms. The compounds may also exist in multiple crystalline forms or in amorphous forms. Generally, all physical forms are equivalent for the uses contemplated herein and are intended to be within the scope of the present invention.

[0130] When a particular enantiomer is preferred, it may, in some embodiments, be provided substantially free of the corresponding enantiomer or may be enantiomerically enriched. "Enantiomerically enriched" means that the compound is composed of a significantly greater proportion of one enantiomer. In certain embodiments, the compound is composed of at least about 90% by weight of the preferred enantiomer. In other embodiments, the compound is composed of at least about 95%, 98%, or 99% by weight of the preferred enantiomer. Preferred enantiomers may be isolated from racemic mixtures by any method known to those skilled in the art, including high-pressure liquid chromatography (HPLC) or supercritical fluid chromatography (SFC) on chiral supports, or by the formation and crystallization of chiral salts, or may be prepared by asymmetric synthesis.

[0131] The expression "pharmaceutically acceptable salt" refers to a salt of the compound of the present invention that is suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic responses, and the like, within the scope of sound medical judgment, and is compatible with a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are known in the art. For example, S.M. Berge, et al., describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 66: 1-19 (1977). Salts can be prepared in situ during the final isolation and purification of the compound of the present invention, or can be prepared separately by reacting the free base function of the compound with a suitable organic or inorganic acid (acid addition salts), or by reacting the acidic function of the compound with a suitable organic or inorganic base (base addition salts).

[0132] The term "solvate" refers to a physical association of one of the present compounds with one or more solvent molecules, including water and non-aqueous solvent molecules. This physical association may involve hydrogen bonding. In certain instances, a solvate can be isolated, for example, when one or more solvent molecules are incorporated into the crystal lattice of a crystalline solid. The term "solvate" encompasses both solution-phase solvates and isolatable solvates. Exemplary solvates include, but are not limited to, hydrates, hemihydrates, ethanolates, hemiethanolates, n-propanolates, isopropanolates, 1-butanolates, 2-butanolates, and solvates of other physiologically acceptable solvents, such as Class 3 solvents listed in the International Conference on Harmonization (ICH), Guide for Industry, Q3C Impurities: Residual Solvents (1997). Thus, the compounds described herein also include each of their solvates and mixtures thereof.

[0133] As used herein, the expression "pharmaceutically acceptable ester" refers to an ester of a compound formed by the process herein, including those that readily decompose in vivo in the human body to leave the parent compound or its salt. Suitable ester groups include, for example, those derived from pharmaceutically acceptable aliphatic carboxylic acids, particularly alkanoic, alkenoic, cycloalkanoic, and alkanedioic acids, where each alkyl or alkenyl moiety advantageously has six or fewer carbon atoms. Examples of specific esters include, but are not limited to, formates, acetates, propionates, butyrates, acrylates, and ethylsuccinates of hydroxyl groups, and alkyl esters of acidic groups. Other ester groups include sulfonates or sulfates.

[0134] As used herein, the expression "pharmaceutically acceptable salt" refers to prodrugs of compounds formed by the processes herein that are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response, and the like, and that are commensurate with a reasonable benefit / risk ratio and are effective for their intended use. As used herein, the term "prodrug" means a compound that is convertible in vivo by metabolic means (e.g., hydrolysis) to yield any compound depicted by the formulas of the present description.

[0135] Unless otherwise specified, abbreviations may be used throughout this application and are intended to have the meanings commonly understood by the art. Examples of such abbreviations include Me (methyl), Et (ethyl), Pr (propyl), i-Pr (isopropyl), Bu (butyl), t-Bu (tert-butyl), i-Bu (iso-butyl), s-Bu (sec-butyl), c-Bu (cyclobutyl), Ph (phenyl), Bn (benzyl), Bz (benzoyl), CBz or Cbz or Z (carbobenzyloxy), Boc or BOC (tert-butoxycarbonyl), and Su or Suc (succinimide).

[0136] The number of carbon atoms in a hydrocarbon substituent is indicated by the prefix "C x -C y " or "C x - y " where x is the minimum number of carbon atoms in the substituent and y is the maximum number of carbon atoms in the substituent. However, the prefix "C x -C y " or "C x - y " is associated with a group that by definition incorporates one or more heteroatoms (e.g., heterocycloalkyl, heteroaryl, etc.), x and y define the minimum and maximum number of atoms, respectively (e.g., in one or more periods), including carbon atoms and heteroatoms.

[0137] The term "heteroatom" includes atoms other than carbon and hydrogen, such as, but not limited to, nitrogen, oxygen, or sulfur, including any oxidized form of nitrogen or sulfur, substituted forms of nitrogen, and any quaternized form of a basic nitrogen.

[0138] As used herein, the term "alkyl" refers to a saturated, straight- or branched-chain hydrocarbon radical typically containing 1 to 20 carbon atoms. For example, a "C alkyl" contains 1 to 8 carbon atoms. Examples of alkyl radicals include, but are not limited to, methyl, ethyl, propyl, isopropyl, n-butyl, tert-butyl, neopentyl, n-hexyl, heptyl, octyl radicals, and the like.

[0139] As used herein, the term "alkenyl" refers to a straight- or branched-chain hydrocarbon radical containing one or more double bonds and typically 2 to 20 carbon atoms. For example, a "C2-8 alkenyl" contains 2 to 8 carbon atoms. Alkenyl groups include, but are not limited to, ethenyl, propenyl, butenyl, 1-methyl-2-buten-1-yl, heptenyl, octenyl, and the like.

[0140] As used herein, the term "alkynyl" refers to a straight- or branched-chain hydrocarbon radical containing one or more triple bonds and typically 2 to 20 carbon atoms. For example, a "C2-8 alkynyl" contains 2 to 8 carbon atoms. Representative alkynyl groups include, but are not limited to, ethynyl, 1-propynyl, 1-butynyl, heptynyl, octynyl, and the like.

[0141] The terms "cycloalkyl," "alicyclic," "carbocyclic," and equivalent expressions refer to groups containing saturated or partially unsaturated (non-aromatic) carbocyclic rings in monocyclic or polycyclic ring systems, including spiro (sharing one atom), fused (sharing at least one bond), or bridged (sharing two or more bonds) carbocyclic ring systems, having 3 to 15 ring members. Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopenten-1-yl, cyclopenten-2-yl, cyclopenten-3-yl, cyclohexyl, cyclohexen-1-yl, cyclohexen-2-yl, cyclohexen-3-yl, cycloheptyl, bicyclo[4.3.0]nonanyl, norbornyl, and the like. The term cycloalkyl includes both unsubstituted and substituted cycloalkyl groups. The term "C3- n "Cycloalkyl" refers to cycloalkyl groups having from 3 to the indicated "n" number of carbon atoms in their ring structure. Unless the carbon number is otherwise specified, "lower cycloalkyl" groups as used herein have at least 3 and no more than 8 carbon atoms in their ring structure.

[0142] As used herein, the terms "heterocycloalkyl," "heterocyclyl," and the like are used interchangeably and refer to a chemically stable 3- to 7-membered monocyclic or 7- to 10-membered bicyclic heterocycloalkyl moiety, as defined above, that is either saturated or partially unsaturated and has, in addition to carbon atoms, one or more, preferably one to four, heteroatoms. As an example, in a saturated or partially unsaturated ring having one to three heteroatoms selected from oxygen, sulfur, or nitrogen, the nitrogen may be N (as in 3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl), or NR (as in N-substituted pyrrolidinyl). A heterocycloalkyl can be attached to its pendant group at any heteroatom or carbon atom that results in a chemically stable structure, and any of the ring atoms can be optionally substituted. Examples of heterocycloalkyl groups include, but are not limited to, 1,3-dioxolanyl, pyrrolidinyl, pyrrolidonyl, pyrazolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, piperidinyl, piperazinyl, oxazolidinyl, isoxazolidinyl, morpholinyl, thiazolidinyl, isothiazolidinyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothiopyranyl, tetrahydrodithienyl, tetrahydrothienyl, thiomorpholino, thioxanyl, azetidinyl, oxetanyl, thietanyl, homopiperidinyl, and the like. Examples of aryl include aryl, oxepanyl, thiepanyl, oxazepinyl, diazepinyl, thiazepinyl, 1,2,3,6-tetrahydropyridinyl, 2-pyrrolinyl, 3-pyrrolinyl, 2H-pyranyl, 4H-pyranyl, dioxanyl, dithianyl, dithiolanyl, dihydropyranyl, dihydrothienyl, dihydrofuranyl, 3-azabicyclo[3.1.0]hexanyl, 3-azabicyclo[4.1.0]heptanyl, quinolidinyl, quinuclidinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, and the like.Heterocycloalkyl groups also include groups in which the heterocycloalkyl ring is fused to one or more aryl, heteroaryl, or alicyclic rings, such as indolinyl, 3H-indolyl, chromanyl, chromenyl, phenanthridinyl, 2-azabicyclo[2.2.1]heptanyl, octahydroindolyl, or tetrahydroquinolinyl, when the radical or point of attachment is on the heterocycloalkyl ring. Heterocycloalkyl groups can be monocyclic or bicyclic. The term "heterocyclylalkyl" refers to an alkyl group substituted by a heterocycloalkyl, where the alkyl and heterocyclyl portions are independently optionally substituted. For example, the term "C3- n "Heterocycloalkyl" refers to a heterocycloalkyl group having from 3 to the indicated "n" number of atoms in the ring structure, including carbon atoms and heteroatoms.

[0143] As used herein, the term "partially unsaturated" refers to a ring moiety that contains at least one double or triple bond between ring atoms but is not aromatic. The term "partially unsaturated" is intended to encompass rings with one or more sites of unsaturation, but is not intended to include aryl or heteroaryl moieties as defined herein.

[0144] The term "aryl," used alone or as part of a larger moiety such as "aralkyl," "aralkoxy," "aryloxy," or "aryloxyalkyl," refers to an aromatic group having 4n+2 conjugated π (pi) electrons, where n is an integer from 1 to 3 in a monocyclic moiety or a bicyclic or tricyclic fused ring system having a total of 6 to 15 ring members, at least one ring in the system is aromatic, and each ring in the system contains 3 to 7 ring members. The term "aryl" may be used interchangeably with the expression "aryl ring." In certain embodiments herein, "aryl" refers to an aromatic ring or ring system, including, but not limited to, phenyl, biphenyl, naphthyl, azulenyl, anthracyl, and the like, which may bear one or more substituents. The term "aralkyl" or "arylalkyl" refers to an alkyl residue attached to an aryl ring. Examples of aralkyls include, but are not limited to, benzyl, phenethyl, and the like. Also included within the scope of the term "aryl," as used herein, are groups in which an aromatic ring is fused to one or more non-aromatic rings, such as indanyl, indenyl, phthalimidyl, naphthymidyl, fluorenyl, phenanthridinyl, or tetrahydronaphthyl, and the like. n "Aryl" refers to an aryl group having 6 to the indicated "n" number of atoms in the ring structure.

[0145] The term "heteroaryl," e.g., "heteroaralkyl" or "heteroaralkoxy," used alone or as part of a larger moiety, refers to an aromatic group having 4n+2 conjugated π (pi) electrons, where n is an integer from 1 to 3 (e.g., having 5 to 18 ring atoms, preferably 5, 6, or 9 ring atoms; having 6, 10, or 14 π electrons shared in the cyclic array), and having 1 to 5 heteroatoms in addition to the carbon atoms. The term "heteroatom" is as defined above. A heteroaryl can be a single ring or two or more fused rings. As used herein, the term "heteroaryl" also includes groups in which a heteroaromatic ring is fused to one or more aryl, cycloalkyl, or heterocycloalkyl rings. Non-limiting examples of heteroaryl groups include thienyl, furanyl (furyl), pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, indolyl, 3H-indolyl, isoindolyl, indolizinyl, benzothienyl (benzothiophenyl), benzofuranyl, dibenzofuranyl, indazolyl, benzimidazolyl, benzoxazolyl, benzothiazolyl, benzotriazolyl, pyrrolopyridinyl (e.g., pyrrolo[3,2-b]pyridinyl or pyrrolo[3,2-c]pyridinyl). ]pyridinyl), pyrazolopyridinyl (e.g., pyrazolo[1,5-a]pyridinyl), furopyridinyl, purinyl, imidazopyrazinyl (e.g., imidazo[4,5-b]pyrazinyl), quinolyl (quinolinyl), isoquinolyl (isoquinolinyl), quinolonyl, isoquinolonyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 4H-quinolizinyl, naphthyridinyl, as well as pteridinylcarbazolyl, acridinyl, phenanthridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, and pyrido[2,3-b]-l,4-oxazin-3(4H)-one. Heteroaryl groups can be monocyclic or bicyclic. Heteroaryl groups include optionally substituted rings.The term "heteroaralkyl" refers to an alkyl group substituted by a heteroaryl, wherein the alkyl and heteroaryl portions independently are optionally substituted. Examples include, but are not limited to, pyridinylmethyl, pyrimidinylethyl, and the like. For example, the term "C5- n "Heteroaryl" refers to a heteroaryl group having from 5 to the indicated "n" number of atoms in the ring structure, including carbon atoms and heteroatoms.

[0146] The terms "halogen" or "halo" refer to a halogen atom, ie, a fluorine, chlorine, bromine, or iodine atom, preferably fluorine or chlorine.

[0147] As described herein, the compounds herein may contain "optionally substituted" moieties. Generally, the term "substituted" means that one or more hydrogens of the specified moiety have been replaced with a suitable substituent. Unless otherwise indicated, an "optionally substituted" group may have a suitable substituent at any or each substitutable position of the group, and if more than one position in any given structure may be substituted with more than one substituent selected from a specified group, the substituents may be the same or different at each position. The combinations of substituents envisioned herein preferably result in the formation of chemically stable or chemically feasible compounds. As used herein, the term "chemically stable" refers to compounds that do not change substantially when subjected to conditions that allow for their production, detection, and, in certain embodiments, their recovery, purification, and use for one or more of the purposes disclosed herein.

[0148] Examples of substituents include, but are not limited to, halogen (F, CI, Br, I), OH, COH, alkoxy, oxo, thioxo, NO, CN, CF, CHF, NH, NH alkyl, NH alkenyl, NH alkynyl, NH cycloalkyl, NH aryl, NH heteroaryl, NH heterocycloalkyl, dialkylamino, diarylamino, diheteroarylamino, dicycloalkylamino, diheterocycloalkylamino, N-alkyl-N-arylamino, N-alkyl-N-heteroarylamino, N-alkyl-N -Cycloalkylamino, N-alkyl-N-heterocycloalkylamino, O-alkyl, O-alkenyl, O-alkynyl, O-cycloalkyl, O-aryl, O-heteroaryl, O-haloalkyl, O-heterocycloalkyl, C(O)alkyl, C(O)alkenyl, C(O)alkynyl, C(O)cycloalkyl, C(O)aryl, C(O)heteroaryl, C(O)heterocycloalkyl, CO2alkyl, CO2alkenyl, CO2alkynyl, CO2cycloalkyl, CO2aryl, CO2heteroaryl, CO2heterocyclo alkyl, OC(O)alkyl, OC(O)alkenyl, OC(O)alkynyl, OC(O)cycloalkyl, OC(O)aryl, OC(O)heteroaryl, OC(O)heterocycloalkyl, C(O)NH2, C(O)NHalkyl, C(O)NHalkenyl, C(O)NHalkynyl, C(O)NHcycloalkyl, C(O)NHaryl, C(O)NHheteroaryl, C(O)NHheterocycloalkyl, OCO2alkyl, OCO2alkenyl, OCO2alkynyl, OCO2cycloalkyl, OCO2aryl, OCO2heteroaryl OCO2 heterocycloalkyl, OC(O)NH2, OC(O)NH alkyl, OC(O)NH alkenyl, OC(O)NH alkynyl, OC(O)NH cycloalkyl, OC(O)NH aryl, OC(O)NH heteroaryl, OC(O)NH heterocycloalkyl, OP(O)(Oalkyl)2, OP(O)(OH)2, OP(O)(Oalkenyl)2, OP(O)(Oalkynyl)2, OP(O)(Ocycloalkyl)2, OP(O)(Oaryl)2, OP(O)(Oheteroaryl)2, OP(O)(Oheterocycloalkyl)2,P(O)(Oalkyl)2, P(O)(OH)2, P(O)(Oalkenyl)2, P(O)(Oalkynyl)2, P(O)(Ocycloalkyl)2, P(O)(Oaryl)2, P(O)(Oheteroaryl)2, P(O)(Oheterocycloalkyl)2, P(O)(alkyl)2, P(O)(alkenyl)2, P(O)(alkynyl)2, P(O)(cycloalkyl)2, P(O)(aryl)2, P(O)(heteroaryl)2, P(O)(heterocycloalkyl)2, NHC(O)alkyl, NHC(O)alkenyl, NHC(O)alkynyl, N HC(O)cycloalkyl, NHC(O)aryl, NHC(O)heteroaryl, NHC(O)heterocycloalkyl, NHCO2alkyl, NHCO2alkenyl, NHCO2alkynyl, NHCO2cycloalkyl, NHCO2aryl, NHCO2heteroaryl, NHCO2heterocycloalkyl, NHC(O)NH2, NHC(O)NHalkyl, NHC(O)NHalkenyl, NHC(O)NHalkenyl, NHC(O)NHcycloalkyl, NHC(O)NHaryl, NHC(O)NHheteroaryl, NHC(O)NHheterocyclo Alkyl, NHC(S)NH2, NHC(S)NH alkyl, NHC(S)NH alkenyl, NHC(S)NH alkynyl, NHC(S)NH cycloalkyl, NHC(S)NH aryl, NHC(S)NH heteroaryl, NHC(S)NH heterocycloalkyl, NHC(NH)NH2, NHC(NH)NH alkyl, NHC(NH)NH alkenyl, NHC(NH)NH alkenyl, NHC(NH)NH cycloalkyl, NHC(NH)NH aryl, NHC(NH)NH heteroaryl, NHC(NH)NH heterocycloalkyl, NHC(NH ) alkyl, NHC(NH) alkenyl, NHC(NH) alkenyl, NHC(NH) cycloalkyl, NHC(NH) aryl, NHC(NH) heteroaryl, NHC(NH) heterocycloalkyl, C(NH) NH alkyl, C(NH) NH alkenyl, C(NH) NH alkynyl, C(NH) NH cycloalkyl, C(NH) NH aryl, C(NH) NH heteroaryl, C(NH) NH heterocycloalkyl, S(O) alkyl, S(O) alkenyl, S(O) alkynyl, S(O) cycloalkyl, S(O) aryl, S(O) alkyl,S(O)2 alkenyl, S(O)2 alkynyl, S(O)2 cycloalkyl, S(O)2 aryl, S(O)heteroaryl, S(O)heterocycloalkyl, SO2NH2, SO2NH alkyl, SO2NH alkenyl, SO2NH alkynyl, SO2NH cycloalkyl, SO2NH aryl, SO2NH heteroaryl, SO2NH heterocycloalkyl, NHSO2 alkyl, NHSO2 alkenyl, NHSO2 alkynyl, NHSO2 cycloalkyl, NHSO2 aryl, NHSO2 heteroaryl, NHSO2 Examples of substituents include heterocycloalkyl, CH2NH2, CH2SO2CH3, alkyl, alkenyl, alkynyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl, cycloalkyl, carbocyclic, heterocycloalkyl, polyalkoxyalkyl, polyalkoxy, methoxymethoxy, methoxyethoxy, SH, S-alkyl, S-alkenyl, S-alkynyl, S-cycloalkyl, S-aryl, S-heteroaryl, S-heterocycloalkyl, and methylthiomethyl. Each of these substituents may also be further substituted, if possible.

[0149] Thus, this document to the purine compounds defined herein and in the following paragraphs. When referring to chemical moieties, the recitation of a list of chemical groups in any definition of a variable includes a definition of that variable as any single group or combination of the listed groups. Similarly, the recitation of an embodiment for a variable herein includes that embodiment as any single embodiment or in combination with any other embodiment or portion thereof. Thus, the following embodiments occur alone or, where applicable, in combination:

[0150] The compounds exhibit a purine core structure attached to the defined substituents. Exemplary compounds defined herein have the general formula: [ka] During the ceremony, R 1 and R 2 are each independently an optionally substituted C-10 Aryl and optionally substituted C5- 10 heteroaryl; R 3 is optionally replaced by R 7 O-, N(R 8 )2-, or a C5-6 heteroaryl group; R 4 are Cl, CN, C(O)OH, and R 9 C(O)N(R 11 )-, R 9 C(O)NHC(NH)NH-, R 9 S(O)2-, N(R 10 )2C(O)-, R 5 O-, N(R 6 ) optionally substituted groups selected from 2-, C1-C6 alkyl, C5-C6 heteroaryl; R 5 is C1-C6 alkyl, C3-C7 cycloalkyl, C4-C 10 Heterocycloalkyl, C5-C6 heteroaryl, C3-C7 cycloalkyl, C1-C3 alkyl, C4-C 10 is a group selected from heterocycloalkyl C1-C3 alkyl, C5-C6 heteroaryl C1-C3 alkyl, R 6 is H or C1-C6 alkyl, C3-C7 cycloalkyl, C4-C 10 Heterocycloalkyl, C5-C6 heteroaryl, C3-C7 cycloalkyl, C1-C3 alkyl, C4-C 10 heterocycloalkyl C1-C3 alkyl, C5-C6 heteroaryl C1-C3 alkyl, wherein at least one R 6 is other than H or two R 6 The groups, together with their adjacent nitrogen atoms, form a C4-C 10 forming a heterocycloalkyl or C5-C6 heteroaryl group, R 7 is an optionally substituted C1-C6 alkyl; R 8is independently in each occurrence hydrogen, C1-C6 alkyl, C3-C7 cycloalkyl, and C4-C 10 heterocycloalkyl; R 9 is independently in each occurrence optionally substituted C1-C6 alkyl, C3-C7 cycloalkyl, C4-C 10 Heterocycloalkyl, C5-C6 heteroaryl, C3-C7 cycloalkyl, C1-C3 alkyl, C4-C 10 heterocycloalkylC1-C3 alkyl, and C5-C6 heteroarylC1-C3 alkyl; R 10 is independently in each occurrence H, or optionally substituted C1-C6 alkyl, C3-C7 cycloalkyl, C4-C 10 Heterocycloalkyl, C5-C6 heteroaryl, C3-C7 cycloalkyl, C1-C3 alkyl, C4-C 10 heterocycloalkyl C1-C3 alkyl, and C5-C6 heteroaryl C1-C3 alkyl, or two R 10 The groups, together with their adjacent nitrogen atoms, form an optionally substituted C-C 10 forming a heterocycloalkyl or a C5-C6 heteroaryl; R 11 is independently in each occurrence H, or optionally substituted C1-C6 alkyl, C3-C7 cycloalkyl, C4-C 10 Heterocycloalkyl, C5-C6 heteroaryl, C3-C7 cycloalkyl, C1-C3 alkyl, C4-C 10 heterocycloalkyl C1-C3 alkyl, C5-C6 heteroaryl C1-C3 alkyl; wherein each of the alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl groups is optionally substituted; or an isomer or tautomer thereof, or a pharmaceutically acceptable salt thereof. R 1 Non-limiting examples include the groups A1 and A2: [ka] R 2 Non-limiting examples include groups B1 to B23: [ka] R 3 Non-limiting examples include C1-C69 groups: [ka] [ka] [ka] R 4 Non-limiting examples include groups D1 to D81: [ka] [ka]

[0151] The exemplary compounds defined herein are also further exemplified by compounds 1-240, or an isomer or tautomer thereof, or a pharmaceutically acceptable salt thereof, as defined in Table 1 below. [Table 1-1] [Table 1-2] [Table 1-3] [Table 1-4] [Table 1-5]

[0152] In a preferred embodiment, R 4 The group contains a hydroxyl-substituted functional group, and the present technology provides a compound represented by formula I [ka] During the ceremony, R 1 is an optionally substituted C6 aryl group; R 2 is an optionally substituted C6 aryl group or a C5-C6 heteroaryl group; R 3 But R 7 O-, N(R 8 )2-, C4- 10 an optionally substituted group selected from heterocycloalkyl, and C heteroaryl; R 4 But R 5 O- and N(R 6 )2-, R 5 C1-C6 alkyl, C3-C7 cycloalkyl, C4-C 10 Heterocycloalkyl, C5-C6 heteroaryl, C3-C7 cycloalkyl, C1-C3 alkyl, C4-C 10 is a group selected from heterocycloalkyl C1-C3 alkyl, C5-C6 heteroaryl C1-C3 alkyl, R 6 is H or C1-C6 alkyl, C3-C7 cycloalkyl, C4-C 10 Heterocycloalkyl, C5-C6 heteroaryl, C3-C7 cycloalkyl, C1-C3 alkyl, C4-C 10 heterocycloalkyl C1-C3 alkyl, C5-C6 heteroaryl C1-C3 alkyl, wherein at least one R 6 is other than H or two R 6 The groups, together with their adjacent nitrogen atoms, form a C4-C 10 forming a heterocycloalkyl or C5-C6 heteroaryl group, In the formula, R 5or R 6 at least one of the alkyl, cycloalkyl, heterocycloalkyl, or heteroaryl in is substituted with at least one hydroxyl or hydroxy-substituted C1-C4 alkyl group, and optionally further substituted with other substituents; R 7 is an optionally substituted C1-C6 alkyl; R 8 is independently in each occurrence hydrogen, C1-C6 alkyl, C3-C7 cycloalkyl, and C4-C 10 heterocycloalkyl; wherein each of the alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl groups is optionally substituted; or an isomer and / or tautomer thereof, or a pharmaceutically acceptable salt thereof.

[0153] In another embodiment, the compound has formula II [ka] During the ceremony, R 4 is as defined in formula I; X 1 is C and X 2 ~X 6 are each independently N and CR 21 wherein n is 1, and wherein X 2 ~X 6 At most three of are N, or X 1 is C or N, and X 2 ~X 5 However, each independently, CR 21 , O, S, N, or NR 11 where n is zero and X 6 is absent and X 1 and X 5 forms a bond between X 1 ~X 5 Up to three of them are C or CR 21 Other than that, X 7 and X 8 are each independently O, S, SO2, NR 36 , or C(R 35 )2 and X 7 and X 8 One of the following is O, S, or NR 36 If the other is C(R 35 )2, R 9 is independently in each occurrence optionally substituted C1-C6 alkyl, C3-C7 cycloalkyl, C4-C 10 Heterocycloalkyl, C5-C6 heteroaryl, C3-C7 cycloalkyl, C1-C3 alkyl, C4-C 10 heterocycloalkylC1-C3 alkyl, and C5-C6 heteroarylC1-C3 alkyl; R 10 is independently in each occurrence H, or optionally substituted C1-C6 alkyl, C3-C7 cycloalkyl, C4-C 10 Heterocycloalkyl, C5-C6 heteroaryl, C3-C7 cycloalkyl, C1-C3 alkyl, C4-C 10 heterocycloalkyl C1-C3 alkyl, and C5-C6 heteroaryl C1-C3 alkyl, or two R 10 The groups, together with their adjacent nitrogen atoms, form an optionally substituted C-C 10 forming a heterocycloalkyl or a C5-C6 heteroaryl; R 11 is independently in each occurrence H, or optionally substituted C1-C6 alkyl, C3-C7 cycloalkyl, C4-C 10 Heterocycloalkyl, C5-C6 heteroaryl, C3-C7 cycloalkyl, C1-C3 alkyl, C4-C 10 heterocycloalkyl C1-C3 alkyl, C5-C6 heteroaryl C1-C3 alkyl; R 12is independently in each occurrence selected from F, Cl, CN, NH, N(H)C1-C3 alkyl, N(C1-C3 alkyl)2, and C1-C3 alkyl; p is 0, 1, 2, or 3, preferably 0 or 1; R 21 may independently in each occurrence be hydrogen, halogen, OH, OR 9 , CN, NO2, C(O)R 9 , C(O)N(R 10 )2, C(R 11 )=NR 11 , SO2R 9 , SO2N(R 10 )2, N(R 11 )C(O)R 9 , N(R 11 )SO2R 9 , N(R 11 )C(O)N(R 10 )2, N(R 11 )SO2N(R 10 )2, N(R 10 )2, P(O)(R 10 )2, P(O)(OR 10 )2, B(OR 10 )2, and optionally substituted C 1-6 Alkyl group, C 2-6 Alkenyl group, C 2-6 Alkynyl group, C 6-10 Aryl group, C 5-10 Heteroaryl groups, C 3-10 Cycloalkyl groups, and C 4-10 heterocycloalkyl groups, R 31 ~R 35 may independently in each occurrence be hydrogen, halogen, OH, OR 9 , CN, NO2, C(O)OH, C(O)OR 9 , C(O)R 9 , C(O)N(R 10 )2, C(R 11 )=NR 11 , SO2R 9 , SO2N(R 10 )2, N(R 11 )C(O)R 9 , N(R 11 )SO2R9 , N(R 11 )C(O)N(R 10 )2, N(R 11 )SO2N(R 10 )2, N(R 10 )2, P(O)(R 10 )2, P(O)(OR 10 )2, B(OR 10 )2, and optionally substituted C 1-6 Alkyl group, C 2-6 Alkenyl group, C 2-6 Alkynyl group, C 6-10 Aryl group, C 5-10 Heteroaryl groups, C 3-10 Cycloalkyl groups, and C 4-10 heterocycloalkyl groups, R 36 But hydrogen, C(O)R 9 , C(O)OR 9 , C(O)N(R 10 )2, C(R 11 )=NR 11 , SO2R 9 , SO2N(R 10 )2, P(O)(R 10 )2, P(O)(OR 10 )2, B(OR 10 )2, and optionally substituted C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 6-10 Aryl, C 5-10 Heteroaryl, C 3-10 Cycloalkyl, and C 4-10 heterocycloalkyl groups, or R 31 ~R 36 two of which, together with their adjacent atoms, form a ring, preferably a bridged or spiro heterocycle; m is 0, 1, 2, or 3; wherein the alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl group is optionally further substituted; or an isomer or tautomer thereof, or a pharmaceutically acceptable salt thereof.

[0154] In some embodiments, m is zero and X 7 and X 8 are each independently C(R 35 )2, preferably X 7 is CH2. For example, X 8 is C(R 35 )2 and two R 35 One of them is fluorine, C(O)R 9 , C(O)OR 9 , C(O)N(R 10 )2, N(R 11 )C(O)R 9 , or optionally replaced by C 1-6 alkyl and two R 35 The other is hydrogen, fluorine, CN, OH, OR 9 , N(R 10 )2, or optionally substituted C 1-6 alkyl, or X 8 is C(R 35 )2 and two R 35 together with their adjacent carbon atoms to form spiro C 4-5 Forms a heterocyclic ring.

[0155] In other embodiments, m is 1 and X 7 and X 8 are each independently C(R35)2, and preferably X 7 is CH2. For example, X 8 is C(R 35 )2 and two R 35 One of them is fluorine, C(O)R 9 , C(O)OR 9 , C(O)N(R 10 )2, N(R 11 )C(O)R 9 , or optionally replaced by C 1-6 alkyl and two R 35 The other is hydrogen, fluorine, CN, OH, OR 9 , N(R10)2, or optionally substituted C1-6 alkyl, or X 8 is C(R 35 )2 and two R 35 together with their adjacent carbon atoms to form spiro C 4-5 Forms a heterocyclic ring.

[0156] According to a further embodiment, m is 2 and X 7 and X 8 are each independently C(R 35 )2. For example, X 8 is CH2 and X 7 is C(R 35 )2 and two R 35 One of them is fluorine, C(O)R 9 , C(O)OR 9 , C(O)N(R 10 )2, N(R 11 )C(O)R 9 , or optionally replaced by C 1-6 alkyl and two R 35 The other is hydrogen, fluorine, CN, OH, OR 9 , N(R 10 )2, or optionally substituted C 1-6 In some preferred embodiments, R 35 is C(O)N(R 10 )2, or N(R 11 )C(O)R 9 and two R 35 The other is OR 9 or optionally replaced by C 1-4 alkyl, e.g., R 35 is OR 9 and R 9 is C 1-6 Alkyl, preferably C 2-4 Alkyl, for example methyl, ethyl, n-propyl, isopropyl, i-butyl, or sec-butyl, preferably ethyl or isopropyl, most preferably isopropyl.

[0157] In other embodiments, m is 2 and X 7 and X 8are each independently C(R 35 )2, for example, X 8 is CH2 and X 7 is C(R 35 )2 and two R 35 together with their adjacent carbon atoms to form spiro C 4-5 Form a heterocyclic ring, or X 7 is CH2 and X 8 is C(R 35 )2 and two R 35 One of them is fluorine, C(O)R 9 , C(O)OR 9 , C(O)N(R 10 )2, N(R 11 )C(O)R 9 , or optionally replaced by C 1-6 alkyl and two R 35 The other is hydrogen, fluorine, CN, OH, OR 9 , N(R 10 )2, or optionally substituted C 1-6 alkyl. For example, two R 35 One of them is C(O)N(R 10 )2, or N(R 11 )C(O)R 9 and two R 35 The other of the two is OR 9 or optionally replaced by C 1-4 alkyl, preferably R 35 is OR 9 and R 9 is C 1-6 Alkyl, preferably C 2-4 Alkyl, for example, methyl, ethyl, n-propyl, isopropyl, i-butyl, or sec-butyl, preferably ethyl or isopropyl, most preferably isopropyl.

[0158] In other embodiments, m is 2 and X 7 and X 8 are each independently C(R 35 )2, for example, X 7 is CH2 and X 8 is C(R35 )2 and two R 35 together with their adjacent carbon atoms to form spiro C 4-5 Forms a heterocyclic ring.

[0159] In still other embodiments of compounds of Formula II, m is 2 or 3 and X 7 is O, S, SO2, or NR 36 and preferably O, SO, or NR 36 and X 8 is C(R 35 )2. For example, X 7 is NR 36 and R 36 is hydrogen, C(O)R 9 , C(O)OR 9 , C(O)N(R 10 )2, and optionally substituted C 1-6 In one embodiment, X is selected from alkyl. 8 The two R's in 35 One of them is hydrogen, fluorine, C(O)R 9 , C(O)OR 9 , C(O)N(R 10 )2, N(R 11 )C(O)R 9 , or optionally replaced by C 1-6 alkyl and two R 35 The other is hydrogen, fluorine, OH, OR 9 , N(R 10 )2, or optionally substituted C 1-6 alkyl or R 35 One of them is R 33 and together with their adjacent atoms form a bridged ring. For example, X 8 Both R 35 is hydrogen. Alternatively, two R 35 One of them is fluorine, C(O)R 9 , C(O)OR 9 , C(O)N(R 10 )2, N(R 11 )C(O)R 9 , or optionally replaced by C 1-6 alkyl and two R35 The other of R is hydrogen. 35 is R 33 Along with C 1-3 Forms an alkylene group.

[0160] In some embodiments of the compounds of Formula II, R 33 represents, independently in each occurrence, hydrogen, fluorine, and optionally substituted C 1-6 alkyl, and / or R 34 represents, independently in each occurrence, hydrogen, fluorine, and optionally substituted C 1-6 alkyl, and / or R 31 and R 32 are each hydrogen atoms.

[0161] Within the context of Formula II, R present in Formula I 3 Examples of groups include the C1 to C7 groups, C10 groups, C15 groups, C16 groups, C18 to C22 groups, C24 to C28 groups, C32 to C40 groups, and C47 to C69 groups defined above, preferably C1, C16 or C18 groups, more preferably C18 groups.

[0162] In a further embodiment, the compound has formula III [ka] During the ceremony, R 13 But R 7 O-, N(R 8 )2-, and C5-6 heteroaryl, R 4 , R 7 , and R 8 is as defined for formula I, R 12 , X 1 ~X 6 , n and p are as defined for formula II, or an isomer or tautomer thereof, or a pharmaceutically acceptable salt thereof.

[0163] In some embodiments, R 13 is R 7 O-. For example, R 7 may be an optionally substituted C1-C4 alkyl.

[0164] In other embodiments, R 13 is N(R 8 )2-, preferably one R 8 is an optionally substituted C4-C 10 heterocycloalkyl, and the other R 8 is hydrogen or optionally substituted C1-C6 alkyl, or one R 8 is an optionally substituted C-C heterocycloalkyl, and the other R 8 is hydrogen or optionally substituted C1-C4 alkyl, or R 8 is an optionally substituted C1-C6 alkyl, and the other R 8 is hydrogen or optionally substituted C1-C6 alkyl.

[0165] In Formula I or III, R 3 or R 13 Examples of groups include C8 groups, C9 groups, C11-C14 groups, C17-C23 groups, C29-C31 groups, and C41-C46 groups as defined above.

[0166] In some compounds of formula II and III, R 12 is Cl and p is 1, preferably forming a 4-chlorophenyl group. In other compounds, p is zero and R 12 is absent, thereby forming an unsubstituted phenyl group.

[0167] In some embodiments of compounds of Formula II and III, n is 1 and X 1 is C and X 2 ~X 6 are each independently CR 21 or n is 1 and X 1 is C and X 2 ~X6 One of them is N and the other is CR 21 Alternatively, n is zero and X 6 is absent, and X 1 is C, preferably X 2 ~X 5 One or two of these are N or NR 11 and the other is CR 21 and preferably R 11 is C1-C6 alkyl, or X 2 ~X 5 One of them is S and the other is CR 21 In these examples, all CR 21 The group can be CH. Alternatively, one CR 21 is other than CH, preferably R 21 are halogens, CN, N(C 1-6 alkyl)2, and C 1-6 alkyl, more preferably halogen or CN, most preferably halogen (e.g., Cl), or one CR 21 is other than CH, preferably R 21 are halogens, CN, N(C 1-6 alkyl)2, and C 1-6 Alkyl, more preferably halogen, CN, and C 1-6 alkyl, most preferably CN, or one CR 21 is other than CH, preferably R 21 are halogens, CN, N(C 1-6 alkyl)2, and C 1-6 Alkyl, more preferably CN and C 1-6 Alkyl, most preferably C 1-6 alkyl.

[0168] R of Formula I, II or III 2 Examples of R include groups B1 to B23 as defined herein. 2 may be selected from groups B1 to B4, for example, R 2 is B1. Or, R 2is selected from the groups B5 to B8, B12 to B19, and B21 to B23, for example, R 2 is B14. In yet another embodiment, R 2 may be selected from groups B9 to B11 and B20.

[0169] In some embodiments, the compound is a compound of Formula I, II, or III, wherein R 4 is R 5 O-group, where R 5 is as defined above and is substituted with at least one hydroxyl group or hydroxy-substituted C1-C4 alkyl group. For example, R 5 is a C2-C6 alkyl substituted with hydroxy groups and optionally other substituents, C4-C 10 Heterocycloalkyl, or C4-C 10 It may also be a heterocycloalkyl C1-C3 alkyl group. In some embodiments, R 5 is selected from 2-hydroxyethyl, 3-hydroxy-1-propyl, 2-hydroxy-1-propyl, 1-hydroxy-2-propyl, 2-hydroxy-2-methyl-1-propyl, 3-hydroxy-2-methyl-1-propyl, 2-hydroxy-1-methyl-1-propyl, 3-hydroxy-1-methyl-1-propyl, and 2-hydroxy-1,1-dimethyl-1-ethyl. 5 is a C4-C6 heterocycloalkyl or a C4-C6 heterocycloalkyl C1-C3 alkyl group substituted with a hydroxy group and optionally other substituents, preferably the C4-C6 heterocycloalkyl is selected from pyrrolidinyl, imidazolidinyl, piperidinyl, and piperazinyl groups.

[0170] In other embodiments, the compound is a compound of Formula I, II, or III, and R 4 is N(R 6 )2-group, wherein R 6 is as defined herein, and at least one R 6is substituted with at least one hydroxyl group or hydroxy-substituted C1-C4 alkyl group, and optionally substituted with one or more other substituents. In one embodiment of these examples, one R 6 is C2-C6 alkyl, C3-C7 cycloalkyl, C4-C 10 Heterocycloalkyl, C3-C7 cycloalkyl, C1-C3 alkyl, or C4-C substituted with at least one hydroxyl or hydroxy-substituted C1-C4 alkyl group. 10 Heterocycloalkyl C1-C3 alkyl group, other R 6 is hydrogen or C1-C6 alkyl, optionally substituted with one or more other substituents, preferably R 6 is a C2-C6 alkyl or C3-C7 cycloalkyl C1-C3 alkyl group substituted with hydroxyl or a C1-C4 alkyl group substituted with hydroxy, and other R 6 is hydrogen or C1-C6 alkyl. In another embodiment of these examples, two R 6 The groups, together with their adjacent nitrogen atoms, are substituted with at least one hydroxyl or hydroxy-substituted C1-C4 alkyl group, optionally substituted with one or more other substituents. 10 Form a heterocycloalkyl or C5 heteroaryl group. For example, two R 6 groups together with their adjacent nitrogen atoms form a C4-C7 heterocycloalkyl substituted with at least one hydroxyl or hydroxy-substituted C1-C4 alkyl group and optionally substituted with one or more other substituents, preferably the C4-C7 heterocycloalkyl group is selected from a pyrrolidinyl group, an imidazolidinyl group, a piperidinyl group, and a piperazinyl group substituted with at least one hydroxyl or hydroxy-substituted C1-C4 alkyl group and optionally substituted with one or more other substituents, or two R 6The groups together with their adjacent nitrogen atoms form a C5 heteroaryl group substituted with at least one hydroxyl or hydroxy-substituted C1-C4 alkyl group and optionally substituted with one or more other substituents, preferably the C5 heteroaryl group is selected from imidazole and a pyrrole group substituted with at least one hydroxyl or hydroxy-substituted C1-C4 alkyl group and optionally substituted with one or more other substituents.

[0171] R of Formula I, II or III 4 Examples of R include groups D5 to D9, D12, D13, D19 to D21, D23, D25, D27, D28, D30 to D32, D36, D37, D43 to D49, D52, D53, D67, D71, D75, D76, and D78 to D81 as defined herein. 4 may be selected from the groups D6 to D9, D43 to D47, D75 and D76, preferably D6 to D9 and D43 to D47, preferably D9, or the groups D12, D19, D21, D23, D30 to D32, D36, D37, D48, D49, and D78 to D81, preferably D19 or D21, preferably D5, D13, D20, D52, D53, D67 and D71, preferably D20.

[0172] Examples of compounds of Formula I, II, or III include, but are not limited to, compounds 5-9, 12, 13, 19, 20, 23-26, 29, 35-38, 40, 41, 43, 46-52, 54-59, 63-67, 72-76, 78-88, 90, 93-101, 103-116, 118-124, 128-133, 135-143, 148, 153-155, 157, 158, 161-163, 165-204, 206-227, 231, 233-238, and 240, or an isomer or tautomer thereof, or a pharmaceutically acceptable salt thereof. Preferably, the compound is selected from compounds 5-9, 12, 19, 20, 23-26, 29, 35-38, 40, 41, 43, 46-52, 54-59, 63-67, 72-76, 78-88, 90, 93-97, 99-101, 104-115, 118-124, 128-131, 133, 135-137, 139-143, 148, 153-155, 157, 158, 161-163, 165-175, 177-204, 206-227, 231, 233-238, and 240, or an isomer or tautomer thereof, or a pharmaceutically acceptable salt thereof. More preferably, the compound is any of compounds 5 to 9, 12, 19, 20, 23 to 26, 35, 36, 38, 40, 41, 43, 46 to 50, 52, 54 to 56, 64 to 67, 72 to 76, 78 to 88, 90, 93, 94, 96, 99, 101, 108, 110, 113, 114, 119 to 121, 123, 124, 128, 130, and 131. , 133, 135-137, 140-143, 148, 153-155, 157, 158, 161-163, 165-174, 177-204, 206, 207, 209-216, 220-227, 231, 233-237, and 240, or an isomer or tautomer thereof, or a pharmaceutically acceptable salt thereof.Most preferably, the compound is selected from the group consisting of compounds 6-9, 12, 19, 20, 23-26, 35, 36, 38, 41, 43, 46-48, 54-56, 65-67, 72-76, 78-83, 85, 86, 88, 90, 93, 94, 96, 123, 130, 131, 133, 136, 140-143, 148, 153, 154, 157, 158, 161 to 163, 165 to 167, 169 to 171, 173, 174, 177 to 186, 188, 189, 191, 192, 194-197, 199, 203, 206, 207, 211, 213 to 216, 222 to 226, 231, 234, and 237, or an isomer or tautomer thereof, or a pharmaceutically acceptable salt thereof.

[0173] In another embodiment, the compound is a compound of formula IV, [ka] In the formula, X 1 ~X 8 , R 12 , R 31 ~R 34 , m, n and p are as defined herein; R 14 is N(R 16 )2- or optionally substituted C5-C6 heteroaryl; R 16 is H, or optionally substituted C1-C6 alkyl, C3-C7 cycloalkyl, C4-C 10 Heterocycloalkyl, C5-C6 heteroaryl, C3-C7 cycloalkyl, C1-C3 alkyl, C4-C 10 heterocycloalkyl C1-C3 alkyl, C5-C6 heteroaryl C1-C3 alkyl, or two R 16 The groups, together with their adjacent nitrogen atoms, form an optionally substituted C-C 10 Compounds forming heterocycloalkyl or C5-C6 heteroaryl, or an isomer or tautomer thereof, or a pharmaceutically acceptable salt thereof.

[0174] In some embodiments, R 14 is N(R 16 )2-. In one embodiment, one R 16 is optionally substituted C1-C6 alkyl, C3-C7 cycloalkyl, C4-C 10 Heterocycloalkyl, C3-C7 cycloalkyl, C1-C3 alkyl, or C4-C 10 heterocycloalkyl C1-C3 alkyl group, and the other R 16 is hydrogen or C1-C6 alkyl. For example, one R 16 is a C2-C6 alkyl group substituted with one or more substituents, and other R 16 is hydrogen or C1-C6 alkyl, and the substituents are preferably selected from F, OH, CN, alkoxy, alkylcarbonylamino, akoxycarbonylamino, alkylsulfonamido, benzylamino, aminocarbonyl, dialkylphosphino, phosphonato, dialkylamino, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl. 16 The groups, together with their adjacent nitrogen atoms, form an optionally substituted C-C bonded through the nitrogen. 10 Form a heterocycloalkyl or C5 heteroaryl group. For example, two R 16 groups together with their adjacent nitrogen atom form an optionally substituted C4-C7 heterocycloalkyl group bonded through the nitrogen, preferably the C4-C7 heterocycloalkyl group is selected from optionally substituted pyrrolidinyl, imidazolidinyl, piperidinyl, and piperazinyl groups. Alternatively, two R 16 The groups together with their adjacent nitrogen atom form an optionally substituted C5 heteroaryl group bonded through the nitrogen atom, preferably the C5 heteroaryl group is selected from optionally substituted imidazole and pyrrole groups.

[0175] In other embodiments, R 14 is an optionally substituted C5-C6 heteroaryl.

[0176] R 14 Examples of groups include D3 to D5, D11 to D16, D19 to D28, D30 to D32, D36, D37, D39 to D41, D48 to D54, D56, D57, D63 to D67, D71, and D78 to D81.

[0177] In yet another embodiment, the compound is a compound of formula V: [ka] In the formula, X 1 ~X 6 , R 12 , R 13 , R 14 , n and p are as previously defined, or an isomer or tautomer thereof, or a pharmaceutically acceptable salt thereof.

[0178] In a further embodiment, the compound is a compound of formula VI: [ka] In the formula, X 1 ~X 8 , R 12 , R 31 ~R 34 , m, n, and p are as previously defined; R 15 is C1-C6 alkyl, C3-C7 cycloalkyl, C4-C 10 Heterocycloalkyl, C5-C6 heteroaryl, C3-C7 cycloalkyl, C1-C3 alkyl, C4-C 10 a compound, wherein the group is selected from heterocycloalkyl C1-C3 alkyl, C5-C6 heteroaryl C1-C3 alkyl, or an isomer or tautomer thereof, or a pharmaceutically acceptable salt thereof.

[0179] In some embodiments, R 15 is optionally substituted C1-C6 alkyl, C4-C 10Heterocycloalkyl, or C4-C 10 Heterocycloalkyl C1-C3 alkyl groups. For example, R 15 is a C1-C6 alkyl group substituted with one or more substituents, for example, selected from F, OH, CN, alkoxy, alkylcarbonylamino, akoxycarbonylamino, alkylsulfonamido, benzylamino, aminocarbonyl, dialkylphosphino, phosphonato, dialkylamino, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, or R 15 is an optionally substituted C4-C6 heterocycloalkyl or C4-C6 heterocycloalkyl C1-C3 alkyl group, preferably the C4-C6 heterocycloalkyl is selected from pyrrolidinyl, imidazolidinyl, morpholinyl, piperidinyl, and piperazinyl groups. OR 15 Examples of groups include D6 to D10, D17, D29, D33 to D35, D43 to D47, D55, D68 to D70, and D72 to D77.

[0180] In a further embodiment, the compound is a compound of formula VII: [ka] In the formula, X 1 ~X 6 , R 12 , R 13 , R 15 , n and p are as previously defined, or an isomer or tautomer thereof, or a pharmaceutically acceptable salt thereof.

[0181] In another embodiment, the compound is a compound of formula VIII: [ka] In the formula, X 1 ~X 8 , R 12 , R 31 ~R 34, m, n, and p are as previously defined; R 24 are Cl, CN, C(O)OH, R 9 C(O)N(R 11 )-, R 9 C(O)NHC(NH)NH-, R 9 S(O)2-, N(R 10 )2C(O)-, and optionally substituted C1-C6 alkyl groups, wherein R 9 ~R 11 is as previously defined, or an isomer or tautomer thereof, or a pharmaceutically acceptable salt thereof.

[0182] In a further embodiment, the compound is a compound of formula IX, [ka] In the formula, X 1 ~X 6 , R 12 , R 13 , R 24 , n and p are as previously defined, or an isomer or tautomer thereof, or a pharmaceutically acceptable salt thereof.

[0183] In some embodiments of compounds of Formula VIII and IX, R 24 is selected from the groups D1, D2, D18, D38, D42, and D58 to D62.

[0184] In one embodiment, the compound is selected from compounds 1-240, as defined herein, or an isomer or tautomer thereof, or a pharmaceutically acceptable salt thereof.

[0185] In another embodiment, the compound is selected from compounds 1-12, 14-28, 30-69, 71-97, 99-102, 104-115, 117-131, 133-137, 139-148, 150-158, 160-175, and 177-240, or an isomer or tautomer thereof, or a pharmaceutically acceptable salt thereof.

[0186] In further embodiments, the compound is selected from compounds 1-12, 14-28, 31-36, 38-50, 52-56, 60-62, 64-68, 72-96, 99, 101, 102, 108, 110, 113, 114, 117, 119-121, 123-128, 130, 131, 133, 135-137, 140-146, 148, 150-155, 157, 158, 160-174, 177-204, 206, 207, 209-216, 220-237, and 240, or an isomer or tautomer thereof, or a pharmaceutically acceptable salt thereof.

[0187] In yet another embodiment, the compound is selected from the group consisting of compounds 6-10, 12, 15-17, 19, 20, 23-26, 32, 33, 35, 36, 38, 41-44, 46-48, 54-56, 62, 65-67, 72-76, 78-83, 85, 86, 88-94, 96, 117, 123, 130, 131, 133, 136, 140-146, 148, 150, 152-154, 157, 158, 161-163, 165-167, 169-171, 173, 174, 177-186, 188, 189, 191, 192, 194-197, 199, 203, 206, 207, 211, 213-216, 222-226, 228, 230-232, 234, and 237, or an isomer or tautomer thereof, or a pharmaceutically acceptable salt thereof.

[0188] The compounds can be prepared by conventional chemical synthesis, such as those described in the Examples section below. As one skilled in the art will appreciate, additional methods for synthesizing compounds of the formulae herein will be apparent to those skilled in the art. In addition, the various synthetic steps can be performed in an alternative sequence or order to obtain the desired compounds.

[0189] The compounds defined herein can be formulated in pharmaceutical compositions for administration to a subject, where the compounds are typically mixed with at least one pharmaceutically acceptable carrier, diluent, or excipient.

[0190] The phrase "pharmaceutically acceptable carrier, diluent, or excipient" and equivalent phrases refers to a non-toxic carrier, diluent, or excipient that does not destroy the pharmacological activity of the compound with which it is formulated.

[0191] The compositions described herein may be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, bucally, or via an implanted reservoir. As used herein, the term "parenteral" includes subcutaneous, intravenous, intramuscular, intra-articular, intra-synovial, intrasternal, intrathecal, intrahepatic, and intralesional injection or infusion techniques. Other modes of administration also include intradermal or transdermal administration.

[0192] For example, solid dosage forms for oral administration include capsules, tablets, pills and granules.In a preferred alternative, the composition is a solid dosage form comprising the compound as described herein and at least one binder as defined in the preceding paragraph, and the binder preferably comprises microcrystalline cellulose.

[0193] Pharmaceutically acceptable carriers, diluents, or excipients that can be used in the oral compositions of the present disclosure include, but are not limited to, binders, sweeteners, disintegrants, diluents, flavorings, coating agents, preservatives, lubricants, and / or polymers. Examples of binders include cellulose-based substances such as microcrystalline cellulose and carboxymethylcellulose, as well as other binders such as acacia gum, gelatin, corn starch, tragacanth gum, sodium alginate, or polyethylene glycol (PEG). Examples of sweeteners include sucrose, lactose, glucose, aspartame, or saccharin. Disintegrants include corn starch, methylcellulose, polyvinylpyrrolidone, xanthan gum, bentonite, alginic acid, or agar. Examples of diluents include lactose, sorbitol, mannitol, dextrose, kaolin, cellulose, calcium carbonate, calcium silicate, or dicalcium phosphate. Flavoring agents include peppermint oil, oil of wintergreen, cherry, orange, or raspberry flavoring. Coating agents include polymers or copolymers of acrylic acid and / or methacrylic acid and / or their esters, waxes, fatty alcohols, zein, shellac, or gluten. Suitable preservatives include sodium benzoate, vitamin E, alpha-tocopherol, ascorbic acid, methylparaben, propylparaben, or sodium bisulfite. Suitable lubricants include magnesium stearate, stearic acid, sodium oleate, sodium chloride, or talc. Examples of excipients may further include a polymer selected from the group consisting of polyvinylpyrrolidone (PVP), polyvinylpyrrolidone-vinyl acetate copolymer (PVP-VA), hydroxypropylmethylcellulose (HPMC), hypromellose-acetate-succinate (HPMCAS), and mixtures thereof.

[0194] The present composition can also be used as a filler in soft and hard-filled capsules.The solid dosage forms of tablets, dragees, capsules, pills and granules can be prepared with coatings and shells, such as enteric coatings and other coatings well known in pharmaceutical formulation technology.They can optionally contain emulsifying agents, and can optionally be of a composition that releases active ingredient only or preferentially in a certain part of the intestinal tract in a delayed manner.Examples of embedding compositions that can be used include polymeric substances and waxes.The composition can also be in microencapsulated form with one or more of the above-mentioned excipients.

[0195] Liquid dosage forms for oral administration include, but are not limited to, pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs.In addition to active compounds, liquid dosage forms can contain inert diluents commonly used in the art, such as water or other solvents, solubilizers and emulsifiers, for example, ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (especially cottonseed oil, peanut oil, corn oil, germ oil, olive oil, castor oil and sesame oil), glycerol, tetrahydrofuryl alcohol, polyethylene glycol and fatty acid esters of sorbitan, and their mixtures.In addition to inert diluents, these oral compositions can also contain adjuvants such as wetting agents, emulsifiers and suspending agents, surfactants, sweeteners, flavorings and fragrances.

[0196] Injectable preparations, for example, sterile injectable aqueous or oily suspensions, can be formulated according to known techniques using suitable dispersants or wetting agents and suspending agents.Sterile injectable preparations can also be sterile injectable solutions, suspensions, or emulsions in non-toxic parenterally acceptable diluents or solvents, for example, as solutions in 1,3-butanediol.Acceptable vehicles and solvents that can be used include water, Ringer's solution (USP), and isotonic sodium chloride solution.In addition, sterile fixed oils are conventionally used as solvents or suspending media.For this purpose, any non-irritating fixed oil can be used, including synthetic monoglycerides or diglycerides.In addition, fatty acids such as oleic acid can be used to prepare injectables.

[0197] The injectable formulations can be sterilized, for example, by filtration through a bacterial-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable medium before use.

[0198] In order to prolong the effect of a compound provided, it is often desirable to delay the absorption of the compound from subcutaneous or intramuscular injection.This can be achieved by using a liquid suspension of crystalline or amorphous material with poor water solubility.The absorption rate of the compound then depends on its dissolution rate, which in turn depends on crystal size and crystalline form.Alternatively, the delayed absorption of parenterally administered compound forms can be achieved by dissolving or suspending the compound in an oil vehicle.Injectable depot forms can be made by forming microencapsule matrices of the compound in biodegradable polymers such as polylactide-polyglycolide.Depending on the ratio of compound to polymer and the properties of the specific polymer used, the compound release rate can be controlled.

[0199] Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides). Depot injectable formulations are also prepared by entrapping the compound in liposomes or microemulsions that are compatible with body tissues.

[0200] The dosage forms for topical or transdermal administration of the compounds herein include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants, or patches.The active ingredient is mixed under sterile conditions with a pharmaceutically acceptable carrier, and any necessary preservatives or buffers, if necessary.Ophthalmic formulations, ear drops, and eye drops are also contemplated within the scope of this specification.In addition, this specification contemplates the use of transdermal patches, which have the additional advantage of providing controlled delivery of the compound to the body.Such dosage forms can be made by dissolving or dispensing the compound in a suitable medium.Absorption enhancers can also be used to increase the flux of the compound across the skin.The rate can be controlled by providing a rate-controlling membrane or by dispersing the compound in a polymer matrix or gel.

[0201] The pharmaceutically acceptable compositions provided herein may also be administered by nasal aerosol or inhalation. Such compositions are prepared according to techniques known in the pharmaceutical formulation art and may be prepared as solutions in saline using benzyl alcohol or other suitable preservatives, absorption enhancers to enhance bioavailability, fluorocarbons, and / or other conventional solubilizing or dispersing agents.

[0202] The amount of compound that may be combined with the carrier materials to produce a composition in a single dosage form will vary depending upon the patient treated and the particular mode of administration.

[0203] As used herein, the term "effective amount" refers to an amount of a compound that elicits the biological or medical response of a tissue, system, animal, or human that is desired, for example, by a researcher or clinician. Furthermore, the term "therapeutically effective amount" refers to any amount that results in the treatment, cure, prevention, or amelioration of a disease, disorder, or its symptoms, or a reduction in the rate of progression of a disease or disorder, compared to a corresponding subject who does not receive such amount. This term also includes amounts within that range that are effective to enhance normal physiological function.

[0204] As used herein, the terms "treatment," "treat," and "treating" refer to reversing, alleviating, delaying the onset of, or inhibiting the progression of a disease or disorder described herein, or one or more symptoms thereof. In some embodiments, treatment may be administered after one or more symptoms have developed. In other embodiments, treatment may be administered in the absence of symptoms. For example, treatment may be administered to a susceptible individual prior to the onset of symptoms (e.g., in light of a history of symptoms and / or in light of genetic or other susceptibility factors). Treatment may also be continued after symptoms have disappeared, e.g., to prevent or delay their recurrence.

[0205] As used herein, the term "patient" or "subject" refers to an animal, such as a mammal. Thus, a subject may refer to, for example, a mouse, rat, dog, cat, horse, cow, pig, guinea pig, primate, including humans and the like, etc. Preferably, the subject is a human.

[0206] The present compound is useful for treating diseases and disorders in which the inhibition of cannabinoid receptor CB1 is indicated.Therefore, the present invention contemplates the use of the present compound for treating the diseases or disorders defined herein, the use of the present compound in the manufacture of medicines for treating the diseases or disorders defined herein, the compounds defined herein for use in treating the diseases or disorders, and the method for treating the diseases or disorders defined herein, comprising administering one of the present compounds to a subject in need thereof.Such diseases and disorders may be related to diabetes and metabolic disorders (e.g., metabolic syndrome).Preferably, the compound does not interact or does not primarily interact with CB1 receptors in brain tissue, while selectively targeting CB1 receptors in peripheral tissues (e.g., adipose tissue, liver, muscle, lung, kidney, macrophage, splenic beta cells, and gastrointestinal tract), thereby avoiding or reducing CNS-related side effects.

[0207] The effects of the compounds may include reduced food intake, reduced body weight, reversal of insulin and leptin resistance, reversal of hepatic steatosis (fatty liver), and improvement of dyslipidemia. Examples of diseases and disorders to be treated include obesity, diabetes mellitus (type I or type II), non-alcoholic and alcoholic fatty liver disease (risk factors for insulin resistance), comorbidities of obesity, comorbidities of diabetes, Prader-Willi syndrome (PWS), pro-opiomelanocortin (POMC) deficiency obesity, leptin receptor (LepR) deficiency obesity, POMC heterozygous deficiency obesity, POMC epigenetic disorders, Bardet-Biedl (BB) syndrome, Alström syndrome, dyslipidemia predisposing to atherosclerotic heart disease, diabetic nephropathy, fibrosis and fibrotic diseases of the skin, liver, lung, or kidney such as idiopathic pulmonary fibrosis (IPF), progressive fibrotic interstitial lung disease, Hermansky-Pudl syndrome pulmonary fibrosis (HPS-PF), liver cirrhosis, renal fibrosis, scleroderma, and gout. In addition, skin disorders include reducing scar formation (scar, keloid) and alopecia, especially male pattern baldness and those related to metabolic syndrome.For example, obesity comorbidities are selected from metabolic syndrome, dementia, heart disease, dementia, heart disease, hypertension, gallbladder disease, gastrointestinal disorder, menstrual irregularities, osteoarthritis, venous stasis ulcer, pulmonary hypoventilation syndrome, sleep apnea, snoring, asthma, obesity asthma, coronary artery disease, arteriosclerosis, pseudotumor cerebri, osteoarthritis, high cholesterol, and the increased incidence of liver, ovary, cervix, uterus, breast, prostate or gallbladder malignant tumor.In a preferred example, disease or disorder includes diabetes (type I or type II), obesity, and non-alcoholic fatty liver disease (for example, non-alcoholic fatty liver disease).Examples of diabetes (for example, type I) comorbidities include diabetic nephropathy, chronic kidney disease, diabetic retinopathy, and peripheral and autonomic neuropathy.

[0208] The diseases, disorders and conditions to be treated, including those mentioned above, can be divided into various categories, and some conditions may coexist in a given subject.Examples of categories include appetite-related disorders and their complications, glucose regulation-related disorders and their complications, fibrosis-related disorders and their complications, metabolism-related disorders and their complications, skin and hair growth and healing-related disorders, gastrointestinal tract-related disorders, and obesity-related disorders and their complications.

[0209] Examples of appetite-related disorders and their complications include, but are not limited to, Prader-Willi syndrome (PWS), hypothalamic obesity, proopiomelanocortin (POMC) deficiency (including POMC obesity, heterozygous POMC deficiency obesity, and POMC epigenetic disorders), leptin receptor (LepR) deficiency, Bardet-Biedl (BB) syndrome, and Alström syndrome.

[0210] Examples of disorders related to glucose regulation and their complications include, but are not limited to, type I diabetes, type II diabetes, insulin resistance, prediabetes, pancreatic disease (due to beta cell protection and / or increased insulin production), and associated nephropathy, neuropathy, and retinopathy.

[0211] Examples of fibrosis-related disorders or their complications include, but are not limited to, progressive fibrosis associated with interstitial lung disease, idiopathic pulmonary fibrosis (IPF), Hermansky-Pudlak syndrome pulmonary fibrosis (HPS-PF), cirrhosis and other liver fibrosis disorders (such as nonalcoholic steatohepatitis (NASH), primary sclerosing cholangitis, primary biliary cholangitis), fibrotic kidney disease, skin fibrosis disorders (such as scleroderma), and chronic kidney disease.

[0212] Examples of metabolic disorders or their complications include, but are not limited to, metabolic syndrome and hyperlipidemia (e.g., hypertriglyceridemia, hypertriglyceridemia in the setting of low HDL cholesterol, elevated LDL and / or total cholesterol and / or VLDL, and / or elevated apolipoprotein B, atherosclerotic cardiovascular disease, etc.).

[0213] Examples of obesity-related disorders or their complications include, but are not limited to, sleep apnea, snoring, asthma, pulmonary hypoventilation syndrome, dementia, heart disease, high blood pressure, gallbladder disease, gastrointestinal disorders, menstrual irregularities, osteoarthritis, venous stasis ulcers, coronary artery disease, arteriosclerosis, pseudotumor cerebri, osteoarthritis, high cholesterol, and an increased incidence of malignant tumors of the liver, ovary, cervix, uterus, breast, prostate, or gallbladder.

[0214] Examples of skin and hair disorders include alopecia (androgenetic alopecia and alopecia associated with metabolic syndrome), excessive scarring (scars and keloids), and scleroderma, among others.

[0215] Examples of disorders related to the gastrointestinal tract include constipation, irritable bowel syndrome, and inflammatory bowel syndrome, including ulcerative colitis and Crohn's disease.

[0216] Other disorders may also benefit from the compounds, including muscle wasting disorders including muscular dystrophies (such as Duchenne muscular dystrophy (DMD)), amyotrophic lateral sclerosis (ALS), multiple sclerosis (MS), spinal muscular atrophy, and others.

[0217] The solid compounds and compositions may also be used in methods for preventing or reversing the deposition of adipose tissue in a subject, which is expected to contribute to a reduction in the incidence or severity of obesity, which in turn will reduce the incidence or severity of associated comorbidities.

[0218] The present disclosure provides a method for treating a disorder (described herein) in a subject, the method comprising administering a compound or composition of the present disclosure to a subject identified as needing the treatment. Identifying patients who need treatment for the above-mentioned disorders is well within the ability and knowledge of those skilled in the art. Certain methods for identifying patients at risk of developing the above-mentioned disorders that can be treated by the subject method are understood in the medical arts, such as family history and the presence of risk factors associated with the development of the disease state in the subject patient. A clinician skilled in the art can easily identify such candidate patients, for example, by using clinical tests, physical examinations, medical / family history, and genetic testing.

[0219] A method for evaluating the effectiveness of treatment in a subject includes determining the pre-treatment symptoms of the disorder by methods known in the art, and then administering a therapeutically effective amount of a compound of the present invention to the subject. After an appropriate period (e.g., 1 week, 2 weeks, 1 month, 6 months) after administration of the compound, the symptoms of the disorder are reassessed. Modulation (e.g., reduction) of the symptoms and / or biomarkers of the disorder indicates the effectiveness of the treatment. The symptoms and / or biomarkers of the disorder may be determined periodically throughout the treatment. For example, the symptoms and / or biomarkers of the disorder may be checked every few days, weeks, or months to further evaluate the effectiveness of the treatment. A reduction in the symptoms and / or biomarkers of the disorder indicates that the treatment is effective.

[0220] The pharmaceutical compositions provided herein are preferably adapted for oral administration.These formulations can be administered with or without food.The compositions are formulated in unit dosage form for ease of administration and uniformity of dosage.As used herein, the expression "unit dosage form" refers to a physically separate pharmaceutical unit suitable for the patient to be treated.However, it will be understood that the total daily dosage of the solid dispersion and composition of the present disclosure will be determined by the attending physician within the scope of sound medical judgment.

[0221] The amount of composition that can be included in a single dosage form varies depending on the patient being treated (e.g., child vs. adult) and the particular compound included in the composition. Provided compositions can be formulated so that a total daily dose of, for example, 0.01 to 100 mg / kg body weight / day or 0.01 to 20 mg / kg body weight / day of the compound can be administered to a patient receiving these compositions. A single-dose composition may contain such amounts, or the total daily dose may be divided into multiple dosage forms to be taken, for example, once, twice, or three times daily. For example, a single dose may contain 5 to 500 mg of active ingredient, or 20 to 200 mg. A treatment regimen may involve administering to a patient a total amount of about 10 mg to about 1000 mg of the compound herein per day, either in a single dose or divided into multiple doses.

[0222] It will be understood that the total daily dose of compound will be determined by the attending physician within the scope of sound medical judgment.For example, the specific dose or treatment regimen for any specific patient will depend on various factors, including age, body weight, general health, sex, diet, administration time, excretion rate, drug combination, the judgment of treating physician and the severity of the symptoms associated with disease or disorder.

[0223] Depending on the disease or disorder to be treated, additional therapeutic agents may also be present in the composition of the present disclosure or may be separately co-administered.Non-limiting examples of additional therapeutic agents that can be used in combination with the present solid dispersions and formulations include antidiabetic drugs, cholesterol-lowering drugs, anti-inflammatory agents, antibacterial agents, matrix metalloproteinase inhibitors, lipoxygenase inhibitors, cytokine antagonists, immunosuppressants, anticancer drugs, antiviral agents, cytokines, growth factors, immunomodulators, prostaglandins, or anti-vascular hyperproliferation compounds.Treatment can also be supplemented with other treatments or interventions, such as surgery, radiation therapy (e.g., gamma radiation, neutron radiation therapy, electron beam radiation therapy, proton therapy, brachytherapy, and whole-body radioisotopes), biological response modifiers (e.g., interferon, interleukin, tumor necrosis factor (TNF)), and drugs used to attenuate the adverse effects of the present compound or co-administered components.

[0224] The recitation of an embodiment for a variable herein includes that embodiment in any single embodiment or in combination with any other embodiment or portion thereof. The recitation of an embodiment herein includes that embodiment in any single embodiment or in combination with any other embodiment or portion thereof. [Example]

[0225] The following non-limiting examples are illustrative embodiments and should not be construed as further limiting the scope of the invention.

[0226] Unless otherwise indicated, all numbers expressing quantities of ingredients, reaction conditions, concentrations, properties, stability, and the like used in the specification and claims should be understood to be modified in all instances by the term "about." At the very least, each numerical parameter should be construed in light of the number of reported significant digits and by applying ordinary rounding techniques. Accordingly, unless indicated to the contrary, the numerical parameters set forth in the specification and appended claims are approximations that may vary depending on the properties sought to be obtained. Notwithstanding that the numerical ranges and parameters setting forth the broad scope of the embodiments are approximations, the numerical values ​​set forth in the specific examples are reported as precisely as possible. However, any numerical value inherently contains certain errors resulting from variations in experiments, testing measurements, statistical analyses and the like.

[0227] Abbreviation -DIPEA: N,N-diisopropylethylamine -DMSO: Dimethyl sulfoxide - NMP: N-methyl-2-pyrrolidone -DCM: dichloromethane

[0228] [Example 1] Preparation of starting materials

[0229] (i) Preparation of 6-chloro-N-(4-chlorophenyl)-2-methylsulfanyl-5-nitro-pyrimidin-4-amine (B-2) To a solution of 4,6-dichloro-2-methylsulfanyl-5-nitro-pyrimidine (10 g, 41.7 mmol, 1 equiv.) and potassium carbonate (17.2 g, 125 mmol, 3 equiv.) in N,N-dimethylformamide (50 mL) was added 4-chloroaniline (5.6 g, 44.2 mmol, 1.06 equiv.) with stirring at 0° C. The mixture was stirred at 0° C. for 1 hour. The reaction mixture was stirred at 25° C. for 0.5 hours. The reaction mixture was added to water (200 mL) with stirring to give a yellow solid. The residue was purified by flash silica gel chromatography (ISCO®, 120 g SepaFlash® silica flash column, eluent of 0-50% ethyl acetate / petroleum ether gradient at 100 mL / min) to give 6-chloro-N-(4-chlorophenyl)-2-methylsulfanyl-5-nitro-pyrimidin-4-amine (Intermediate B-2, 10 g, 30.2 mmol, 72.4% yield) as a yellow solid. 1 H NMR(400MHz, CDCl3-d)δ=9.66(br s,1H),7.49(d,J=8.8Hz,2H),7.42-7.35(m,2H),2.49(s,3H).

[0230] (ii) Preparation of 1-hydroxy-N-methyl-cyclopropanecarboxamide To a solution of 1-hydroxycyclopropanecarboxylic acid (4.50 g, 44.1 mmol, 1.0 equiv.) in dichloromethane (50 mL) and N,N-dimethylformamide (10 mL), triethylamine (15.6 g, 154 mmol, 3.5 equiv.), methanamine, hydrochloride (5.95 g, 88.2 mmol, 2.0 equiv.), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (10.1 g, 52.9 mmol, 1.2 equiv.), and 1-hydroxybenzotriazole (7.15 g, 52.9 mmol, 1.2 equiv.) were added, and the resulting mixture was stirred at 25° C. for 15 hours. The reaction mixture was concentrated in vacuo, triturated with ethyl acetate (100 mL), filtered, and then concentrated in vacuo. The residue was purified by flash silica gel chromatography (ISCO®, 25 g SepaFlash® silica flash column, eluent of 0-20% dichloromethane / methanol ether gradient at 20 mL / min) to give 1-hydroxy-N-methyl-cyclopropanecarboxamide (2.4 g, 20.8 mmol, 47.2% yield) as a white solid. 1 H NMR(400MHz,DMSO-d6)δ= 7.84(br s,1H),6.14(s,1H),2.63(d,J=4.8Hz,3H),1.05-0.92(m,2H),0.85-0.61(m,2H).

[0231] (iii) Preparation of 1-(methylaminomethyl)cyclopropanol To a solution of 1-hydroxy-N-methyl-cyclopropanecarboxamide (500 mg, 4.34 mmol, 1.0 equiv.) in tetrahydrofuran (5 mL), lithium aluminum hydride (494 mg, 13.0 mmol, 3 equiv.) was added at 0° C., and the mixture was then stirred at 60° C. for 1 hour. Sodium sulfate decahydrate was added to the reaction mixture until no more bubbles remained, and the mixture was filtered and concentrated under reduced pressure to obtain the crude product. The compound 1-(methylaminomethyl)cyclopropanol (400 mg, 3.95 mmol, 91.0% yield) was obtained as a yellow oil.

[0232] (iv) Preparation of 2-[(5-iodoimidazol-1-yl)methoxy]ethyl-trimethyl-silane To a solution of 4-iodo-1H-imidazole (5.48 g, 28.2 mmol, 1.0 equiv) in N,N-dimethylformamide (50 mL) was added sodium hydride (1.36 g, 33.9 mmol, 60% purity, 1.2 equiv) and the resulting mixture was stirred at 25° C. for 0.5 h, then 2-(chloromethoxy)ethyl-trimethyl-silane (5.65 g, 33.9 mmol, 1.2 equiv) was added dropwise to the reaction mixture, which was then stirred at 25° C. for 1 h. The mixture was diluted with (200 mL), extracted with ethyl acetate (100 mL×3), washed with brine (200 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give a residue. The residue was purified by flash silica gel chromatography (ISCO®, 50 g SepaFlash® silica flash column, elution with a 0-60% ethyl acetate / petroleum ether gradient at 50 mL / min) to give 2-[(4-iodoimidazol-1-yl)methoxy]ethyl-trimethyl-silane (P1, 3.18 g, 9.81 mmol, 34.7% yield) as a colorless oil and 2-[(5-iodoimidazol-1-yl)methoxy]ethyl-trimethyl-silane (P2, 2.21 g, 6.82 mmol, 24.1% yield) as a colorless oil. P1: 1 P2: 1 H NMR(400MHz,DMSO-d6)δ=8.01(d,J=0.8Hz,1H),7.05(d,J=0.8Hz,1H),5.28(s,2H),3.50-3.46(m,2H),0.86-0.82(m,2H),0.03(s,9H).

[0233] (v) Preparation of trimethyl-[2-[(5-tributylstannylimidazol-1-yl)methoxy]ethyl]silane To a solution of 2-[(5-iodoimidazol-1-yl)methoxy]ethyl-trimethyl-silane (2.90 g, 8.94 mmol, 1.0 equiv) in tetrahydrofuran (10 mL) was added chloro(isopropyl)magnesium (2.0 M, 6.70 mL, 1.5 equiv) at −10° C. The mixture was stirred at −10° C. for 1 h, then tributyl(chloro)stannane (3.49 g, 10.7 mmol, 1.2 equiv) was added dropwise at −10° C. and the resulting mixture was stirred at 25° C. for 15 h. The mixture was quenched with saturated ammonium chloride (20 mL), diluted with ethyl acetate (100 mL), washed with water (50 mL), brine (50 mL), filtered, and concentrated in vacuo. The brown oil was purified by flash silica gel chromatography (ISCO®, 25 g SepaFlash® silica flash column, eluent: 0–80% ethyl acetate / petroleum ether gradient at 30 mL / min) to give trimethyl-[2-[(5-tributylstannylimidazol-1-yl)methoxy]ethyl]silane (2.1 g, 4.31 mmol, 48.1% yield) as a yellow solid. 1 H NMR(400MHz,CDCl3-d)δ=7.74(s,1H),7.09(d,J=0.6Hz,1H),5.23(s,2H),3.50-3.25(m, 2H),1.59-1.47(m,6H),1.34(s,6H),1.12(s,6H),0.90(t,J=7.3Hz,11H),-0.01(s,9H).

[0234] (vi) Preparation of ethyl 2-(1H-imidazol-4-yl)acetate To a solution of 2-(1H-imidazol-4-yl)ethanol (1.2 g, 10.70 mmol, 1 equiv.) and triethylamine (3.25 g, 32.11 mmol, 4.47 mL, 3 equiv.) in dichloromethane (15 mL), acetyl chloride (1.26 g, 16.0 mmol, 1.15 mL, 1.5 equiv.) was added dropwise at 0 °C, and the resulting mixture was stirred at 25 °C for 15 h. The mixture was diluted with water (150 mL) and extracted with dichloromethane (60 mL × 5). The combined organic layers were washed with saturated aqueous sodium bicarbonate (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by flash silica gel chromatography (ISCO®, 20 g SepaFlash® silica flash column, eluent: 0–10% methanol / dichloromethane at 20 mL / min). The cleaved fraction was concentrated under reduced pressure to obtain the compound ethyl 2-(1H-imidazol-4-yl)acetate (0.36 g, 2.34 mmol, yield 21.8%) as a pale yellow oil.

[0235] (vii) Preparation of 4-methylpiperidine-4-carboxamide To a solution of tert-butyl 4-carbamoyl-4-methyl-piperidine-1-carboxylate (5 g, 20.63 mmol, 1 equiv.) in dichloromethane (25 mL) was added hydrochloride in dioxane (4 M, 25 mL). The mixture was stirred at 25° C. for 1 hour. The mixture was concentrated in vacuo to give 4-methylpiperidine-4-carboxamide (3.6 g, 20.2 mmol, 97.6% yield, hydrochloride salt) as a white solid.

[0236] (viii) Preparation of (2R)-1-(methylamino)propan-2-ol To a solution of tert-butyl N-[(2R)-2-hydroxypropyl]carbamate (5 g, 28.53 mmol, 1 equiv.) in tetrahydrofuran (50 mL) was added lithium aluminum hydride (3.25 g, 85.60 mmol, 3 equiv.) at 0° C. The mixture was then stirred at 60° C. for 1 h. The reaction mixture was added to sodium sulfate decahydrate, filtered, and concentrated under reduced pressure to give (2R)-1-(methylamino)propan-2-ol (2 g, crude) as a colorless oil.

[0237] (ix) Preparation of (2S)-1-(methylamino)propan-2-ol To a solution of tert-butyl N-[(2S)-2-hydroxypropyl]carbamate (3 g, 17.1 mmol, 1 equiv.) in tetrahydrofuran (50 mL) was added lithium aluminum hydride (1.95 g, 51.36 mmol, 3 equiv.) at 0° C. The mixture was then stirred at 60° C. for 1 h. The reaction mixture was added to sodium sulfate decahydrate, filtered, and concentrated under reduced pressure to give (2S)-1-(methylamino)propan-2-ol (1 g, crude) as a colorless oil.

[0238] (x) Preparation of 1,4-dimethylimidazole-2-carbaldehyde and 1,5-dimethyl-1H-imidazole-2-carbaldehyde To a solution of 4-methyl-1H-imidazole-2-carbaldehyde (500 mg, 4.54 mmol, 1 equiv.) in N,N-dimethylformamide (5 mL) was added potassium carbonate (753 mg, 5.45 mmol, 1.2 equiv.) and potassium iodide (773 mg, 5.45 mmol, 1.2 equiv.). The mixture was stirred at 25 °C for 12 h. The mixture was diluted with water (80 mL) and extracted with ethyl acetate (60 mL × 3). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give 1,4-dimethylimidazole-2-carbaldehyde (200 mg, 1.61 mmol, 35.4% yield) and 1,5-dimethyl-1H-imidazole-2-carbaldehyde as yellow oils. 1H NMR(400MHz, CDCl3-d)δ=9.83-9.37(m,2H),7.02(s,1H),6.82(s,1H),3.91(s,3H),3.86(s,4H),2.23(s,7H).

[0239] (xi) Preparation of (2S)-2-(methylamino)propan-1-ol To a solution of tert-butyl N-[(1S)-2-hydroxy-1-methyl-ethyl]carbamate (5 g, 28.5 mmol, 1 equiv.) in tetrahydrofuran (50 mL) was added lithium aluminum hydride (3.25 g, 85.6 mmol, 3 equiv.) at 0° C., and the mixture was then stirred at 60° C. for 1 h. The reaction mixture was added to sodium sulfate decahydrate, filtered, and concentrated under reduced pressure to give (2S)-2-(methylamino)propan-1-ol (2 g, 22.4 mmol, 78.6% yield) as a colorless oil. 1 H NMR(400MHz,DMSO-d6)δ=3.25-3.20(m,2H),2.48-2.40(m,1H),2.25(s,3H),0.87(d,J=6.4Hz,3H).

[0240] (xii) Preparation of (2R)-2-(methylamino)propan-1-ol To a solution of tert-butyl N-[(1R)-2-hydroxy-1-methyl-ethyl]carbamate (5 g, 28.5 mmol, 1 equiv.) in tetrahydrofuran (50 mL) was added lithium aluminum hydride (3.25 g, 85.6 mmol, 3 equiv.) at 0° C., and the mixture was stirred at 60° C. for 1 h. The reaction mixture was added to sodium sulfate decahydrate, filtered, and concentrated under reduced pressure to give (2R)-2-(methylamino)propan-1-ol (1 g, 11.2 mmol) as a colorless oil. 1 H NMR(400MHz,DMSO-d6)δ=3.23-3.20(m,2H),2.48-2.40(m,1H),2.25(s,3H),0.87(d,J=6.4Hz,3H).

[0241] (xiii) Preparation of dimethyl((methylamino)methyl)phosphine oxide To a solution of 1,3,5-trimethyl-1,3,5-triazinane (5 g, 38.7 mmol, 5.44 mL, 1 equiv.) in toluene (50 mL) was added methylphosphonoylmethane (3 g, 38.7 mmol, 1 equiv.). The mixture was stirred at 120 °C for 15 h. The reaction mixture was concentrated in vacuo. The residue was purified by flash silica gel chromatography (ISCO®, 120 g SepaFlash® silica flash column, eluent 0–20% methanol / dichloromethane at 100 mL / min) to afford dimethyl((methylamino)methyl)phosphine oxide (2.5 g, 20.6 mmol, 53.3% yield) as a colorless oil. 1 H NMR(400MHz,CDCl3-d)δ=2.86-2.59(m,2H),2.51-2.22(m,3H),1.55-1.24(m,6H)

[0242] (xiv) Preparation of 5-formyl-6-methyl-pyridine-2-carbonitrile Step 1: A suspension of 5-bromo-6-methyl-pyridine-2-carbonitrile (2.43 g, 12.3 mmol, 1.0 equiv.), 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane (5.70 g, 37.0 mmol, 6.28 mL, 3.0 equiv.), palladium triphenylphosphane (713 mg, 0.62 mmol, 0.05 equiv.), and sodium carbonate (4.44 g, 41.9 mmol, 3.4 equiv.) in toluene (10 mL), water (1.5 mL), and ethanol (5 mL) was stirred at 90° C. for 1 hour under a nitrogen atmosphere. The reaction mixture was cooled to room temperature, filtered, and the resulting filter cake was washed with ethanol (5 mL × 3). The filtrate was concentrated under reduced pressure to provide a residue. The residue was purified by flash silica gel chromatography (ISCO®, 40 g SepaFlash® silica flash column, elution with a 0-50% ethyl acetate / petroleum ether gradient at 40 mL / min). The cleavage fractions were concentrated under reduced pressure to give the compound 6-methyl-5-vinyl-pyridine-2-carbonitrile (460 mg, 3.19 mmol, 25.87% yield) as a white solid.

[0243] Step 2: A mixture of 6-methyl-5-vinyl-pyridine-2-carbonitrile (360 mg, 2.50 mmol, 1.0 equiv.) and dipotassium dioxide(dioxo)osmium, dihydrate (680.82 mg, 1.85 mmol, 0.74 equiv.) and sodium periodate (2.67 g, 12.49 mmol, 5.0 equiv.) in acetone (6 mL) and water (1 mL) was stirred at 25° C. for 2 hours. The reaction mixture was then filtered, and the filter cake was washed with acetone (3 mL×3). The filtrate was diluted with water (50 mL) and extracted with ethyl acetate (20 mL×3). The combined organic layers were washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to provide a residue. The residue was purified by flash silica gel chromatography (ISCO®, 20 g SepaFlash® silica flash column, elution with a 0-50% ethyl acetate / petroleum ether gradient at 30 mL / min). The cleavage fractions were concentrated under reduced pressure to give the compound 5-formyl-6-methyl-pyridine-2-carbonitrile (142 mg, 0.97 mmol, 38.9% yield) as a pale yellow solid. 1 H NMR(400MHz, CDCl3)δ=10.40(s,1H),8.25(d,J=7.8Hz,1H),7.75(d,J=7.8Hz,1H),2.96(s,3H).

[0244] (xv) Preparation of 5-formyl-4-methyl-pyridine-2-carbonitrile Step 1:A suspension of 5-bromo-4-methyl-pyridine-2-carbonitrile (2.00 g, 10.2 mmol, 1.0 equiv.), 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane (4.70 g, 30.46 mmol, 5.16 mL, 3 equiv.), palladium triphenylphosphane (586.48 mg, 507.54 μmol, 0.05 equiv.), and sodium carbonate (3.66 g, 34.52 mmol, 3.4 equiv.) in toluene (15 mL), water (2 mL), and ethanol (7 mL) was stirred at 90° C. for 1 hour under a N atmosphere. The reaction mixture was cooled to room temperature, filtered, and the resulting filter cake was washed with ethanol (5 mL×3). The filtrate was concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®, 40 g SepaFlash® silica flash column, elution with a 0-10% ethyl acetate / petroleum ether gradient at 40 mL / min). The cleavage fraction was concentrated under reduced pressure to give 4-methyl-5-vinyl-pyridine-2-carbonitrile (0.55 g, 3.74 mmol, 36.9% yield) as a white solid.

[0245] Step 2:A mixture of 4-methyl-5-vinyl-pyridine-2-carbonitrile (550 mg, 3.81 mmol, 1 equiv.) and dipotassium(dioxo)osmium dioxide dihydrate (1.04 g, 2.82 mmol, 0.74 equiv.) and sodium periodate (2.45 g, 11.44 mmol, 3.0 equiv.) in acetone (6 mL) and water (1 mL) was stirred at 25 °C for 3 h. The reaction mixture was then filtered, and the filter cake was washed with acetone (3 mL × 3). The resulting filtrate was diluted with water (100 mL) and extracted with ethyl acetate (50 mL × 2). The combined organic layers were washed with brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure, and the resulting residue was purified by flash silica gel chromatography (ISCO®, 20 g SepaFlash® silica flash column, eluent: 0% to 50% ethyl acetate / petroleum ether gradient at 40 mL / min). The cleavage fractions were concentrated under reduced pressure to give 5-formyl-4-methyl-pyridine-2-carbonitrile (140 mg, 0.96 mmol, 25.1% yield) as a pale yellow solid. 1 H NMR(400MHz,DMSO-d6)δ=10.34(s,1H),9.03(s,1H),8.12(s,1H),2.69(s,3H).

[0246] (xvi) Preparation of 4-ethoxypiperidine-4-carboxamide A mixture of tert-butyl 4-carbamoyl-4-ethoxy-piperidine-1-carboxylate (650 mg, 2.39 mmol, 1.0 equiv) and hydrochloride in dioxane (2 M, 6 mL, 10.1 equiv) was stirred for 1 hour at 25° C. The reaction mixture was concentrated under reduced pressure to give 4-ethoxypiperidine-4-carboxamide (600 mg, crude) as a white solid. 1 H NMR(400MHz,MeOD-d4)δ=3.46-3.41(m,2H),3.24-3.17(m,2H),2.99(s,1H),2.86(s,1H),2.24-2.05(m,4H),1.28(t,J=7.2Hz,3H).

[0247] (xvii) Preparation of 3-methylazetidin-3-ol A solution of tert-butyl 3-hydroxy-3-methyl-azetidine-1-carboxylate (2 g, 10.68 mmol, 1 equiv) in hydrochloride / dioxane (4 M, 20 mL) was stirred for 1 h at 25° C. The reaction mixture was concentrated under reduced pressure to give the crude product 3-methylazetidin-3-ol (1 g, 8.09 mmol, 75.7% yield, hydrochloride salt) as a white solid. 1 H NMR(400MHz,CDCl3-d)δ=5.06(br s,2H),3.71(s,2H).

[0248] (xviii) Preparation of tert-butyl 3-methoxy-3-methyl-azetidine-1-carboxylate Step 1: To a solution of tert-butyl 3-hydroxy-3-methyl-azetidine-1-carboxylate (2 g, 10.68 mmol, 1 equiv.) in tetrahydrofuran (20 mL), sodium hydride (1 g, 32.05 mmol, 60% purity, 3 equiv.) was added with stirring, followed by the addition of methyl iodide (9 g, 64.09 mmol, 4 mL, 6 equiv.). The mixture was stirred at 25° C. for 1 hour. The mixture was diluted with water (50 mL) and extracted with ethyl acetate (60 mL×3). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by flash silica gel chromatography (ISCO®, 40 g SepaFlash® silica flash column, eluent: 0-30% ethyl acetate / petroleum ether gradient at 100 mL / min) to give a spot (Rf=0.6) of tert-butyl 3-methoxy-3-methyl-azetidine-1-carboxylate as a white oil (1.9 g, 9.44 mmol, 88.3% yield). 1 H NMR(400MHz, CDCl3-d)δ=3.89(d,J=8.9Hz,2H),3.65(d,J=9.0Hz,2H),3.22(s,3H),1.44(br s,3H),1.43(s,9H).

[0249] Step 2:A solution of tert-butyl 3-methoxy-3-methyl-azetidine-1-carboxylate (300 mg, 1.49 mmol, 1 equiv) in hydrochloride / dioxane (4 M, 3 mL) was stirred for 0.5 h at 25° C. The reaction mixture was concentrated under reduced pressure to give the crude product 3-methoxy-3-methyl-azetidine (195 mg, crude, hydrochloride salt) as a white solid, which was used in the next step without further purification.

[0250] (xix) Preparation of 4-carbamoyl-4-isopropoxypiperidin-1-ium trifluoroacetate Sodium hydride 60% (3.9 mg, 98 mmol) in a dispersion in mineral oil was added portionwise over 20 min to a flask containing 2-propanol (150 mL) at room temperature. The heterogeneous solution was stirred for 20 min at that temperature and then slowly transferred to a solution of 1-Boc-4-piperidone (5.00 g, 24.6 mmol) in bromoform (8.96 mL, 98.4 mmol) at 0 °C. Complete conversion was observed by LCMS after 10 min. Saturated NH4Cl (10 mL) was added, and the reaction mixture was concentrated to dryness. The residue was dissolved in EtOAc and washed 2 × with NH4Cl. The organic layer was dried over anhydrous Na2SO4 and concentrated. The resulting material was purified by normal-phase flash chromatography (loaded with DCM, 25 g) using 0–30% EtOAc in hexane to give the desired intermediate ester compound (1.53 g, 19%).

[0251] Lithium hydroxide (742 mg, 30.4 mmol) was added to a vial containing a solution of the ester intermediate compound (2.00 g, 6.07 mmol) in EtOH (20 mL). The heterogeneous solution was vigorously stirred at 80 °C, and complete conversion was observed over the weekend by LCMS. The reaction mixture was concentrated under reduced pressure and acidified to pH = 1 with 3 N HCl. The aqueous solution was extracted with EtOAc, and the organic layers were combined, dried over anhydrous Na2SO4, and concentrated to give the carboxylic acid (1.40 g, 80%) as a clear oil, which was used directly in the next step. DMF (10 mL) was added to a flask containing the acid (1.40 g, 4.87 mmol) and HATU (2.1 g, 5.36 mmol). The solution was cooled to 0 °C, and N,N-diisopropylethylamine (1.7 mL, 9.74 mmol) was added in one portion. The ice bath was removed, and the reaction mixture was stirred at room temperature for 45 minutes. The solution was cooled to 0 °C, and ammonia (10 mL, 20 mmol) (2 M in IPA) was added over 5 min. The ice bath was then removed, and the reaction mixture was stirred at room temperature overnight. EtOAc (100 mL) was added, and the solution was washed five times with saturated NH4Cl, dried over anhydrous Na2SO4, and concentrated. The residue was purified by normal-phase flash chromatography (loaded with DCM, 50 g) using 0-100% ACN in DCM to give the desired intermediate amide compound (350 mg, 25%).

[0252] Trifluoroacetic acid (4.21 mL, 54.5 mmol) was added to a solution of the compound (780 mg, 2.72 mmol) in DCM (5.45 mL). The reaction mixture was stirred at room temperature for 30 minutes, and complete conversion was observed by LCMS. The solvent was removed under reduced pressure, and the residue was lyophilized over the weekend. 880 mg (100%) of 4-carbamoyl-4-isopropoxypiperidin-1-ium trifluoroacetate was obtained.

[0253] (xx) Preparation of ethyl 4-ethoxypiperidine-4-carboxylate A solution of 1-boc-4-piperidinone (1.63 g, 8.04 mmol) in bromoform (10.5 mL, 116 mmol) was cooled to 0 °C. Potassium hydroxide (4.25 g, 64.3 mmol) was dissolved in absolute ethanol (25 mL) and added dropwise to the solution over 20 minutes. The mixture was then stirred at room temperature for 19 hours and then concentrated in vacuo. The residue was partitioned between ethyl acetate (100 mL × 2) and water (60 mL). The organic layer was dried over MgSO4 and concentrated under reduced pressure to give a yellow oily residue. The residue was purified using 0% to 15% ethyl acetate in hexane to give tert-butyl 4-carbamoyl-4-methylpiperidine-1-carboxylate (2.41 g, 99%) as an oil. To tert-butyl 4-carbamoyl-4-methylpiperidine-1-carboxylate (351 mg, 1.16 mmol) in DCM (8.5 mL) was added trifluoroacetic acid (2.2 mL, 28.4 mmol). The solution was stirred at room temperature for 1.5 hours and analyzed. The reaction mixture was evaporated, co-evaporated with diethyl ether, and lyophilized to a yellow oil containing ethyl 4-ethoxypiperidine-4-carboxylate (148 mg, 40% yield), which was used without further purification or analysis.

[0254] [Example 2] [Preparation of Intermediate A-2] [ka]

[0255] Preparation of A-2 intermediate: Method A: To a solution of 6-chloro-8-(2-chlorophenyl)-9-(4-chlorophenyl)-2-methylsulfanyl-purine (Intermediate A-1) (1 equivalent) and the nucleophile NHRaRb (1.5 equivalents) in N,N-dimethylformamide (5 mL) was added a base (3 equivalents). The mixture was stirred at 60 °C for 12 hours. The reaction mixture was added to water (50 mL) with stirring. The mixture was filtered to give a filter residue as a yellow solid. The residue was purified by flash silica gel chromatography (ISCO®, 20 g SepaFlash® silica flash column, eluent: 0–45% ethyl acetate / petroleum ether gradient at 100 mL / min) to give Intermediate A-2 (70–89% yield) as an off-white solid.

[0256] Response Scale: 500 mg of intermediate A-1.

[0257] Method B: A mixture of 6-chloro-8-(2-chlorophenyl)-9-(4-chlorophenyl)-2-methylsulfanyl-purine (Intermediate A-1) (1 equivalent), the nucleophile NHRaRb (5 equivalents), and a base (2 equivalents) in N,N-dimethylformamide (8 mL) was stirred at 60 °C for 1-2 hours. The reaction mixture was cooled to room temperature, diluted with water (100 mL), and then extracted with ethyl acetate (50 mL × 3). The combined organic layers were washed with brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give Intermediate A-2 as a brown oil or brown solid, which was used directly in the next step without further purification.

[0258] Response Scale: 500 mg of intermediate A-1.

[0259] Method C: To a solution of 6-chloro-8-(2-chlorophenyl)-9-(4-chlorophenyl)-2-methylsulfanyl-purine (Intermediate A-1) (1.0 equiv.) in N,N-dimethylformamide (3 mL) was added base (2.0 equiv.) and the nucleophile NHRaRb (5.0 equiv.). The mixture was stirred at 25 °C for 1 h. The reaction mixture was washed with water (10 mL) and extracted with 30 mL of ethyl acetate (10 mL × 3). The combined organic layers were washed with 20 mL of brine (10 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®, 20 g SepaFlash® silica flash column, eluent: 0–100% ethyl acetate / petroleum ether gradient at 30 mL / min), and the organic phase was concentrated under reduced pressure to give Intermediate A-2 (93–xx% yield) as a yellow solid.

[0260] Response Scale: 300 mg of intermediate A-1.

[0261] Method D: To a solution of 6-chloro-8-(2-chlorophenyl)-9-(4-chlorophenyl)-2-methylsulfanyl-purine (Intermediate A-1) (1.0 equiv.) in N,N-dimethylformamide (2 mL) was added base (3.0 equiv.) and the nucleophile NHRaRb (1.2 equiv.). The mixture was stirred at 60 °C for 2 h. The reaction mixture was washed with water (10 mL) and extracted with 30 mL of ethyl acetate (10 mL × 3). The combined organic layers were washed with 20 mL of brine (10 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®, 20 g SepaFlash® silica flash column, eluent: 0–100% ethyl acetate / petroleum ether gradient at 30 mL / min), and the organic phase was concentrated under reduced pressure to give Intermediate A-2 (xx–87% yield) as a yellow solid.

[0262] Response Scale: 200 mg of intermediate A-1.

[0263] Method E: Base (2 equivalents) was added to a vial containing a solution of 6-chloro-8-(2-chlorophenyl)-9-(4-chlorophenyl)-2-(methylthio)-9H-purine (Intermediate A-1) (1 equivalent) and the nucleophile NHRaRb (1 equivalent) in NMP (2.4 mL). The reaction mixture was stirred at room temperature until complete conversion was observed by LCMS (1 h). The reaction mixture was poured into ice water (100 mL). The solid was collected by filtration through a Buchner funnel and washed with cold water to give crude Intermediate A-2 (94% yield).

[0264] Response Scale: 400 mg of intermediate A-1.

[0265] Method F: The nucleophile NHRaRb (1.7 equiv.) was added to an 8 mL vial containing a solution of 6-chloro-8-(2-chlorophenyl)-9-(4-chlorophenyl)-2-(methylthio)-9H-purine (Intermediate A-1) (1 equiv.) and base (7 equiv.) in NMP (1.1 mL). The reaction mixture was stirred at room temperature for 2.5 h. Water was added, and the precipitate formed was filtered through a Buchner funnel. The aqueous filtrate was also extracted with DCM, and the DCM extract was evaporated and combined with the filtered material to give crude Intermediate A-2, which was used in the next step.

[0266] Response Scale: 100 mg of intermediate A-1. [Table 2-1] [Table 2-2] [Table 2-3] [Table 2-4] [Table 2-5]

[0267] [Example 3] [Preparation of Intermediate A-3] [ka]

[0268] Preparation of A-3 intermediate: Method A: To a solution of intermediate A-2 (1 equivalent) and potassium peroxymonosulfate (10 equivalents) in N-methylpyrrolidone (3 mL) was added water (0.3 mL). The mixture was stirred at 60 °C for 12 hours. The reaction mixture was added to water (30 mL) with stirring. The mixture was filtered to give intermediate A-3 (90-93% yield) as a yellow or brown solid.

[0269] Response Scale: 200 mg of intermediate A-2.

[0270] Method B: To a solution of intermediate A-2 (1 equivalent) in N-methyl-2-pyrrolidone (10 mL) was added a solution of potassium peroxymonosulfate (6 equivalents) in water (1 mL), and the resulting mixture was stirred at 60 °C for 27 h. The reaction mixture was added to water (100 mL) and filtered. The resulting filter cake was purified by flash silica gel chromatography (ISCO®, 20 g SepaFlash® silica flash column, eluent: 0-80% ethyl acetate / petroleum ether gradient at 40 mL / min). The cleavage fractions were concentrated under reduced pressure to afford intermediate A-3 (46% yield) as a white solid.

[0271] Response Scale: 500 mg of intermediate A-2.

[0272] Method C: To a solution of intermediate A-2 (1.0 equiv.) in N-methyl-2-pyrrolidone (5 mL) and water (0.5 mL), potassium peroxymonosulfate (1.17 g, 6.95 mmol, 10 equiv.) was added. The mixture was stirred at 60 °C for 1 h. The reaction mixture was added dropwise to water (40 mL), filtered, and the residue was concentrated under reduced pressure to give intermediate A-3 (73-94% yield) as a pale yellow solid.

[0273] Response Scale: 300 mg of intermediate A-2.

[0274] Method D: To a solution of intermediate A-2 (1.0 equiv.) in N-methyl-2-pyrrolidone (10 mL), a solution of potassium peroxymonosulfate (8.0 equiv.) in water (2 mL) was added, and the resulting mixture was stirred at 60° C. for 18 hours. The reaction mixture was diluted with water (100 mL) and extracted with ethyl acetate (50 mL×2). The combined organic layers were washed with brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give intermediate A-3 (crude) as a yellow solid.

[0275] Response Scale: 500 mg of intermediate A-2.

[0276] Method E: A mixture of intermediate A-2 (1.0 equivalent) and potassium peroxymonosulfate (8.0 equivalents) in N-methyl-2-pyrrolidone (6 mL) was stirred at 60° C. for 4 hours. The reaction mixture was diluted with water (100 mL) and extracted with ethyl acetate (30 mL×3). The combined organic layer was washed with brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give intermediate A-3 (crude) as a yellow solid, which was used directly in the next step without further purification.

[0277] Response Scale: 500 mg of intermediate A-2.

[0278] Method F: Crude intermediate A-2 (1 eq) was dissolved in NMP (5.5 mL), then water (0.55 mL) was added dropwise, ensuring that the solution remained clear. Potassium peroxymonosulfate (3 eq) was then added in another portion, and the reaction mixture was stirred at room temperature overnight. Water (50 mL) was slowly added, and the precipitate was collected by filtration through a Buchner funnel. The solid was washed with water and then lyophilized to give intermediate A-3 (90% yield).

[0279] Method G: Potassium peroxymonosulfate (3.5 equiv.), NMP (1.6 mL), and water (160 μL) were added to an 8 mL vial containing crude intermediate A-2 overnight at 60° C. Water was added, and the resulting precipitate was filtered through a Buchner funnel to give intermediate A-3 (97% yield), which was used in the next step without purification.

[0280] Response Scale: 100 mg of intermediate A-2. [Table 3-1] [Table 3-2] [Table 3-3] [Table 3-4] [Table 3-5]

[0281] [Example 4] [Preparation of Intermediate B-3] [ka]

[0282] (i) Preparation of intermediate B-3 (36) (NRaRb: 4-methyl-piperidine-4-carboxamide): To a solution of 6-chloro-N-(4-chlorophenyl)-2-methylsulfanyl-5-nitro-pyrimidin-4-amine (Intermediate B-2, Example 2i) (1 g, 3.02 mmol, 1 eq.) and 4-methylpiperidine-4-carboxamide (539 mg, 3.02 mmol, 1 eq., hydrochloride salt) in N,N-dimethylformamide (5 mL) was added potassium carbonate (417.32 mg, 3.02 mmol, 1 eq.). The mixture was stirred at 25° C. for 12 hours. The reaction mixture was then poured into water (100 mL) with stirring. The mixture was filtered to give a filter residue as a yellow solid. The yellow solid was purified by flash silica gel chromatography (ISCO®, 40 g SepaFlash® silica flash column, elution with a 0-30% ethyl acetate / petroleum ether gradient at 100 mL / min) to give 1-[6-(4-chloroanilino)-2-methylsulfanyl-5-nitro-pyrimidin-4-yl]-4-methyl-piperidine-4-carboxamide (Intermediate B-3 (36), 1 g, 2.21 mmol, 73.0% yield) as a yellow solid (R f =0.5). 1 H NMR(400MHz,DMSO-d6)δ=10.28(s,1H),7.63(d,J=8.8Hz,2H),7.41(d,J=8.9Hz,2H),7.29(s,1H),7.04-6.96(m,1H),3.62(br d,J=13.6Hz,2H),3.28-3.14(m,2H),2.40(s,3H),2.09(br d,J=14.2Hz,2H),1.61-1.29(m,2H).

[0283] (ii) Preparation of intermediate B-3 (112) (NRaRb:3-methyl-azetidin-3-ol): To a solution of 6-chloro-N-(4-chlorophenyl)-2-methylsulfanyl-5-nitro-pyrimidin-4-amine (Intermediate B-2, Example 2i) (250 mg, 0.75 mmol, 1.0 equiv.) and 3-methylazetidin-3-ol (140 mg, 1.13 mmol, 1.5 equiv., hydrochloride salt) in N,N-dimethylformamide (4 mL) was added cesium carbonate (738 mg, 2.26 mmol, 3.0 equiv.). The mixture was stirred at 25° C. for 1 hour. Water (20 mL) was added to the reaction mixture, and the mixture was filtered to give a yellow solid. The residue was purified by flash silica gel chromatography (ISCO®, 20 g SepaFlash® silica flash column, eluent of 0-40% ethyl acetate / petroleum ether gradient at 80 mL / min) to give spot (Rf=0.4) 1-[6-(4-chloroanilino)-2-methylsulfanyl-5-nitro-pyrimidin-4-yl]-3-methyl-azetidin-3-ol (Intermediate B-3 (112), 170 mg, 0.44 mmol, 58% yield, 98.6% purity) as a yellow solid. 1 H NMR(400MHz,DMSO-d6)δ=10.32(s,1H),7.62(br d,J=8.7Hz,2H),7.42(br d,J=8.7Hz,2H),5.75(s,1H),4.09-3.88(m,4H),3.30(br s,3H),1.38(s,3H).

[0284] (iii) Preparation of Intermediate B-3(c) (NRaRb: 3-methyl-azetidine-3-carbonitrile): To a solution of 6-chloro-N-(4-chlorophenyl)-2-methylsulfanyl-5-nitro-pyrimidin-4-amine (Intermediate B-2, Example 2i) (1 g, 3.02 mmol, 1.0 equiv.) and 3-methyl-3-azetidinecarbonitrile hydrochloride (480 mg, 3.62 mmol, 1.2 equiv.) in N,N-dimethylformamide (10 mL) was added cesium carbonate (2.95 g, 9.06 mmol, 3.0 equiv.). The mixture was stirred at 25° C. for 1 hour. The reaction mixture was added dropwise to 150 mL of water, filtered, and the filter residue was concentrated under reduced pressure to give 1-[6-(4-chloroanilino)-2-methylsulfanyl-5-nitro-pyrimidin-4-yl]-3-methyl-azetidine-3-carbonitrile (Intermediate B-3 (113), 1.17 g, 2.99 mmol, 99.1% yield) as a yellow solid. 1 H NMR(400MHz,DMSO-d6)δ=10.39(s,1H),7.66-7.57(m,2H),7.46-7.39(m,2H ),4.47(d,J=10.4Hz,2H),4.11(d,J=10.4Hz,2H),2.39(s,3H),1.64(s,3H).

[0285] (iv) Preparation of intermediate B-3 (114) (NRaRb: 3-methoxy-3-methyl-azetidin-1-yl): A mixture of 6-chloro-N-(4-chlorophenyl)-2-methylsulfanyl-5-nitro-pyrimidin-4-amine (Intermediate B-2, 600 mg, 1.81 mmol, 1.0 equiv), 3-methoxy-3-methyl-azetidine (274 mg, 1.99 mmol, 1.1 equiv), and potassium carbonate (751 mg, 5.44 mmol, 3 equiv) in N,N-dimethylformamide (6 mL) was stirred at 25° C. for 1 hour. The reaction mixture was washed with water (20 mL) and extracted with 60 mL of ethyl acetate (20 mL×3). The combined organic layers were washed with 40 mL of brine (20 mL×2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®, 40 g SepaFlash® silica flash column, elution with a 0-100% ethyl acetate / petroleum ether gradient at 60 mL / min), and the organic phase was concentrated under reduced pressure to give N-(4-chlorophenyl)-6-(3-methoxy-3-methyl-azetidin-1-yl)-2-methylsulfanyl-5-nitro-pyrimidin-4-amine (Intermediate B-3 (114), 250 mg, 625 μmol, 34.5% yield) as a yellow solid.

[0286] (v) Preparation of intermediate B-3 (118) (NRaRb: 4-methyl-piperidine-4-carboxylate): To a solution of 6-chloro-N-(4-chlorophenyl)-2-methylsulfanyl-5-nitro-pyrimidin-4-amine (Intermediate B-2, 500 mg, 1.51 mmol, 1.0 equiv.) and ethyl 4-methylpiperidine-4-carboxylate (345 mg, 1.66 mmol, 1.1 equiv.) in N,N-dimethylformamide (5 mL) was added cesium carbonate (1.48 g, 4.53 mmol, 3.0 equiv.), and the mixture was stirred at 25° C. for 1 hour. The reaction mixture was added to water (50 mL) with stirring, the mixture was filtered, and the residue was washed with ethyl alcohol (20 mL) and concentrated under reduced pressure to give ethyl 1-[6-(4-chloroanilino)-2-methylsulfanyl-5-nitro-pyrimidin-4-yl]-4-methyl-piperidine-4-carboxylate (Intermediate B-3 (118), 600 mg, 1.20 mmol, 79.3% yield) as a yellow solid. 1 H NMR(400MHz,DMSO-d6)δ=10.28(s,1H),7.63(d,J=8.8Hz,2H),7.42(d,J=8.8Hz,2H),4.21-4.07(m,2H),3.67 (d,J=14.0Hz,2H),3.30-3.18(m,2H),2.40(s,3H),2.12-2.02(m,2H),1.59-1.49(m,2H),1.25-1.16(m,6H).

[0287] (vi) Preparation of intermediate B-3 (120) (NRaRb: 4-ethoxy-piperidine-4-carboxamide): A mixture of 6-chloro-N-(4-chlorophenyl)-2-methylsulfanyl-5-nitro-pyrimidin-4-amine (Intermediate B-2, 550 mg, 1.66 mmol, 1.0 equiv), 4-ethoxypiperidine-4-carboxamide (416 mg, 1.99 mmol, 1.2 equiv), and cesium carbonate (1.62 g, 4.98 mmol, 3.0 equiv) in N,N-dimethylformamide (5.5 mL) was stirred for 1 hour at 25° C. The reaction mixture was washed with water (20 mL) and extracted with 60 mL of ethyl acetate (20 mL × 3). The combined organic layers were washed with 40 mL of brine (20 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give 1-[6-(4-chloroanilino)-2-methylsulfanyl-5-nitro-pyrimidin-4-yl]-4-ethoxy-piperidine-4-carboxamide (Intermediate B-3 (120), 590 mg, 1.12 mmol, 67.6% yield) as a yellow solid. 1 H NMR(400MHz,DMSO-d6)δ=10.29(s,1H),7.68-7.58(m,2H),7.42(d,J=8.8Hz,2H),7.35-7.19(m,2H),3.77-3.62(m, 2H),3.45-3.41(m,2H),3.35(d,J=7.2Hz,2H),2.41(s,3H),1.98-1.90(m,2H),1.19(s,2H),1.05(t,J=7.2Hz,3H).

[0288] (vii) Preparation of intermediate B-3 (135) (NRaRb: 4-isopropoxy-piperidine-4-carboxamide): A mixture of 6-chloro-N-(4-chlorophenyl)-2-methylsulfanyl-5-nitro-pyrimidin-4-amine (Intermediate B-2, 1.00 g, 3.02 mmol, 1.0 equiv), 4-isopropoxypiperidine-4-carboxamide (740 mg, 3.32 mmol, 1.1 equiv hydrochloride salt), and cesium carbonate (2.95 g, 9.06 mmol, 3.0 equiv) in N,N-dimethylformamide (12 mL) was stirred for 4 hours at 25° C. The reaction mixture was diluted with water (200 mL) and extracted with dichloromethane (50 mL × 3). The combined organic layers were washed with brine (200 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by flash silica gel chromatography (ISCO®, 40 g SepaFlash® silica flash column, eluent of 0-50% ethyl acetate / petroleum ether gradient at 50 mL / min) to give 1-[6-(4-chloroanilino)-2-methylsulfanyl-5-nitro-pyrimidin-4-yl]-4-isopropoxy-piperidine-4-carboxamide (Intermediate B-3 (135), 1.08 g, 2.20 mmol, 73% yield) as a yellow solid. 1 H NMR(400MHz,DMSO-d6)δ=10.30(s,1H),7.67-7.60(m,2H),7.46-7.39(m,2H),7.36-7.22(m,2H),3.78-3 .69(m,1H),3.67-3.57(m,2H),3.45-3.35(m,2H),2.41(s,3H),1.99-1.85(m,4H),1.14(d,J=6.0Hz,6H).

[0289] [Example 5] [Preparation of Intermediate B-5] [ka]

[0290] (i) Preparation of intermediate B-5 (36) (NRaRb: 4-methyl-piperidine-4-carboxamide / Nu: (2S)-2-(hydroxymethyl)pyrrolidin-1-yl): Step 1:To a solution of 1-[6-(4-chloroanilino)-2-methylsulfanyl-5-nitro-pyrimidin-4-yl]-4-methyl-piperidine-4-carboxamide (Intermediate B-3 (36), Example 3i) (950 mg, 2.17 mmol, 1 equiv.) in N-methylpyrrolidone (10 mL), potassium oxidoxyhydrogen sulfate (3.66 g, 21.74 mmol, 10 equiv.) and water (1 mL) were added. The mixture was stirred at 60° C. for 1 hour. The reaction mixture was added to water (100 mL) with stirring. The mixture was filtered to give a filter residue of 1-[6-(4-chloroanilino)-2-methylsulfonyl-5-nitro-pyrimidin-4-yl]-4-methyl-piperidine-4-carboxamide (Intermediate B-4 (36), 680 mg, 938 μmol, 43.1% yield) as a yellow solid. 1 H NMR(400MHz,DMSO-d6)δ=10.36(s,1H),7.66-7.56(m,2H),7.45(d,J=8.9Hz,2H),7.32(s,1H),7.04(s,1H),3.79-3.60( m,2H),3.29-3.28(m,2H),3.24-3.18(m,3H),2.19-1.99(m,2H),1.48(ddd,J=3.4,10.4,13.7Hz,2H),1.20-1.10(m,3H).

[0291] Step 2: A solution of 1-[6-(4-chloroanilino)-2-methylsulfonyl-5-nitro-pyrimidin-4-yl]-4-methyl-piperidine-4-carboxamide (Intermediate B-4(36)) (680 mg, 1.45 mmol, 1 equiv) in [(2S)-pyrrolidin-2-yl]methanol (2.20 g, 21.7 mmol, 2.12 mL, 15 equiv) was stirred at 60° C. for 12 hours. The reaction mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC (basic conditions) to give compound 1-[6-(4-chloroanilino)-2-[(2S)-2-(hydroxymethyl)pyrrolidin-1-yl]-5-nitro-pyrimidin-4-yl]-4-methyl-piperidine-4-carboxamide (Intermediate B-5 (36), 500 mg, 1.02 mmol, 70.3% yield) as a yellow solid. 1H NMR(400MHz,CDCl3-d)δ=10.92-10.56(m,1H),7.64(d,J=8.8Hz,1H),7.47(br d,J=8.8Hz,1H),7.39-7.29(m,2H),5.68(br d,J=5.1Hz,1H),5.41(br s,1H),4.56-4.14(m,1H),3.79-3.35(m,8H),2.25-1.67(m,8H),1.40-1.23(m,3H).

[0292] (ii) Preparation of intermediate B-5 (48) (NRaRb: 4-methyl-piperidine-4-carboxamide / Nu: 2-hydroxyethyl(methyl)amino): Step 1: Synthesis of 1-[6-(4-chloroanilino)-2-methylsulfonyl-5-nitro-pyrimidin-4-yl]-4-methyl-piperidine-4-carboxamide from 1-[6-(4-chloroanilino)-2-methylsulfanyl-5-nitro-pyrimidin-4-yl]-4-methyl-piperidine-4-carboxamide (Intermediate B-3 (36), Example 3i) as described in Step 1 of Example 4i.

[0293] Process 2A mixture of 1-[6-(4-chloroanilino)-2-methylsulfonyl-5-nitropyrimidin-4-yl]-4-methyl-piperidine-4-carboxamide (1 g, 2.13 mmol, 1 equiv.) in 2-(methylamino)ethanol (2 g, 32.0 mmol, 2.57 mL, 15 equiv.) was stirred at 60° C. for 1 hour. The reaction mixture was concentrated under reduced pressure. The residue was purified by column chromatography (silicon dioxide, dichloromethane / methanol = 1 / 0 to 0 / 1) and concentrated under vacuum to give 1-[6-(4-chloroanilino)-2-[2-hydroxyethyl(methyl)amino]-5-nitro-pyrimidin-4-yl]-4-methyl-piperidine-4-carboxamide (580 mg, 1.25 mmol, 58.6% yield) as a yellow solid. The yellow solid was dissolved in methanol (1 mL) and dimethyl sulfoxide (2 mL) to obtain a pure product. The residue was purified by preparative HPLC (Waters Xbridge 150 × 25 mm × 5 μm column, mobile phase: [water (ammonia hydroxide v / v)-ACN], B%: 28% to 58%, 9 min) to obtain 1-[6-(4-chloroanilino)-2-[2-hydroxyethyl(methyl)amino]-5-nitro-pyrimidin-4-yl]-4-methyl-piperidine-4-carboxamide (Intermediate B-5 (48), 105 mg, 182.07 μmol, 28.1% yield) as a yellow solid. 1 H NMR(400MHz,CDCl3-d)δ=11.00-10.52(m,1H),7.61(br d,J=8.6Hz,1H),7.49(br d,J=8.3Hz,1H),7.33(br d,J=8.6Hz,2H),5.80-5.10(m,2H),3.97-3.56(m,6H),3.51-3.35(m,2H),3.22(br s,3H),2.23-2.07(m,2H),1.71-1.61(m,2H).

[0294] (iii) Preparation of intermediate B-5 (103) (NRaRb: 4-methyl-piperidine-4-carboxamide / Nu: 2-hydroxy-2-methyl-propoxy): Step 1:Synthesis of 1-[6-(4-chloroanilino)-2-methylsulfonyl-5-nitro-pyrimidin-4-yl]-4-methyl-piperidine-4-carboxamide from 1-[6-(4-chloroanilino)-2-methylsulfanyl-5-nitro-pyrimidin-4-yl]-4-methyl-piperidine-4-carboxamide (Intermediate B-3 (36), Example 3i) as described in Step 1 of Example 4i.

[0295] Process 2 To a solution of 2-methylpropane-1,2-diol (288 mg, 3.20 mmol, 5.0 equiv.) in tetrahydrofuran (3 mL) was added sodium hydride (77 mg, 1.92 mmol, 60% purity, 3.0 equiv.). The mixture was then stirred under nitrogen at 25° C. for 10 minutes. 1-[6-(4-chloroanilino)-2-methylsulfonyl-5-nitro-pyrimidin-4-yl]-4-methyl-piperidine-4-carboxamide (300 mg, 640 μmol, 1.0 equiv.) was then added to the mixture. The mixture was stirred under nitrogen at 25° C. for 50 minutes. The mixture was diluted with water (10 mL) and extracted with ethyl acetate (10 mL×3). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give a residue. The crude product was washed with dichloromethane (5 mL) and the mixture was filtered to give a filter residue of 1-[6-(4-chloroanilino)-2-(2-hydroxy-2-methyl-propoxy)-5-nitro-pyrimidin-4-yl]-4-methyl-piperidine-4-carboxamide (Intermediate B-5 (103), 130 mg, 0.26 mmol, 40.7% yield) as a yellow solid.

[0296] (iv) Preparation of intermediate B-5 (110) (NRaRb: 4-methyl-piperidine-4-carboxamide / Nu: (2-hydroxy-2-methyl-propyl)-methyl-amino): Step 1:Synthesis of 1-[6-(4-chloroanilino)-2-methylsulfonyl-5-nitro-pyrimidin-4-yl]-4-methyl-piperidine-4-carboxamide from 1-[6-(4-chloroanilino)-2-methylsulfanyl-5-nitro-pyrimidin-4-yl]-4-methyl-piperidine-4-carboxamide (Intermediate B-3 (36), Example 3i) as described in Step 1 of Example 4i.

[0297] Step 2: A solution of 1-[6-(4-chloroanilino)-2-methylsulfonyl-5-nitro-pyrimidin-4-yl]-4-methyl-piperidine-4-carboxamide (200 mg, 0.43 mmol, 1.0 equiv.) in 2-methyl-1-(methylamino)propan-2-ol (660 mg, 6.40 mmol, 15 equiv.) was stirred at 120° C. for 1 hour. Methanol (1 mL) was added to the reaction mixture until pure. The residue was purified by preparative HPLC (column: Phenomenex luna C18 150 × 25 mm × 10 μm, mobile phase: [water (formic acid)-acetonitrile], B%: 44% to 74%, 10 min) to give 1-[6-(4-chloroanilino)-2-[(2-hydroxy-2-methyl-propyl)-methyl-amino]-5-nitro-pyrimidin-4-yl]-4-methyl-piperidine-4-carboxamide (intermediate B-5 (110), 100 mg, 0.20 mmol, 47.0% yield) as a yellow solid. 1 H NMR(400MHz,DMSO-d6)δ=7.77(d,J=8.8Hz,1H),7.66(d,J=8.8Hz,1H),7.40(t,J=8.8Hz,2H),7.26(d,J=2.0Hz,1H),6.98(br s,1H),4.63-4.35(m,1H),4.19-3.98(m,3H),3.67-3.49(m,4H),2.13-1.94(m,2H),1.52-1.29(m,2H),1.19-1.05(m,6H),0.99(s,3H).

[0298] (v) Preparation of Intermediate B-5 (111) (NRaRb: 4-methyl-piperidine-4-carboxamide / Nu: (2-hydroxy-2-methyl-propyl)amino): Step 1: Synthesis of 1-[6-(4-chloroanilino)-2-methylsulfonyl-5-nitro-pyrimidin-4-yl]-4-methyl-piperidine-4-carboxamide from 1-[6-(4-chloroanilino)-2-methylsulfanyl-5-nitro-pyrimidin-4-yl]-4-methyl-piperidine-4-carboxamide (Intermediate B-3 (36), Example 3i) as described in Step 1 of Example 4i.

[0299] Step 2: A mixture of 1-[6-(4-chloroanilino)-2-methylsulfonyl-5-nitropyrimidin-4-yl]-4-methyl-piperidine-4-carboxamide (compound 1, 400 mg, 0.85 mmol, 1.0 equiv.) and 1-amino-2-methyl-propan-2-ol (compound 2, 2.28 g, 25.6 mmol, 30 equiv.) was stirred at 60° C. for 3 hours. The reaction mixture was cooled to room temperature, diluted with water (30 mL), and extracted with ethyl acetate (10 mL × 3). The combined organic layers were washed with brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure, and the resulting residue was purified by flash silica gel chromatography (ISCO®, 20 g SepaFlash® silica flash column, eluting with a 0% to 100% ethyl acetate / petroleum ether gradient at 20 mL / min). The cleaved fractions were concentrated under reduced pressure to give compound 1-[6-(4-chloroanilino)-2-[(2-hydroxy-2-methyl-propyl)amino]-5-nitro-pyrimidin-4-yl]-4-methyl-piperidine-4-carboxamide (Intermediate B-5 (111), 230 mg, 0.48 mmol, 56.4% yield) as a yellow solid.

[0300] (vi) Preparation of intermediate B-5 (112) (NRaRb: 3-methyl-azetidin-3-ol / Nu: 2-hydroxy-2-methyl-propoxy): Step 1:To a solution of 1-[6-(4-chloroanilino)-2-methylsulfanyl-5-nitro-pyrimidin-4-yl]-3-methyl-azetidin-3-ol (Intermediate B-3 (112), Example 3ii) (170 mg, 0.45 mmol, 1.0 equiv.) in N-methylpyrrolidone (5 mL) and water (0.5 mL), potassium hydrogen oxidoxysulfate (749 mg, 4.45 mmol, 10 equiv.) was added. The mixture was stirred at 60° C. for 12 hours. The reaction mixture was added to water (50 mL) with stirring, and the mixture was filtered to give 1-[6-(4-chloroanilino)-2-methylsulfonyl-5-nitro-pyrimidin-4-yl]-3-methyl-azetidin-3-ol (150 mg, 344.41 μmol, 77.3% yield, 95.0% purity) as a yellow solid. 1 H NMR(400MHz,DMSO-d6)δ=10.35(s,1H),7.62-7.57(m,2H),7.47-7.43(m,2H),5.88-5.82(m,1H),5.78-5.71(m,2H),4.04(br s,2H),3.20(s,3H),1.40(s,3H).

[0301] Process 2To a solution of 2-methylpropane-1,2-diol (109 mg, 1.21 mmol, 5 equiv.) in tetrahydrofuran (3 mL) was added sodium hydride (39 mg, 0.97 mmol, 60% purity, 4.0 equiv.). The mixture was stirred at 25° C. for 10 minutes. Then, 1-[6-(4-chloroanilino)-2-methylsulfonyl-5-nitro-pyrimidin-4-yl]-3-methyl-azetidin-3-ol (100 mg, 0.24 mmol, 1.0 equiv.) was added. The mixture was stirred at 25° C. for 50 minutes. The mixture was diluted with water (20 mL) and extracted with ethyl acetate (20 mL×3). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give a residue. The residue was purified by preparative HPLC (column: Phenomenex luna C18 150 × 25 mm × 10 μm, mobile phase: [water (formic acid)-ACN], B%: 36% to 66%, 10 min) to obtain compound 1-[6-(4-chloroanilino)-2-(2-hydroxy-2-methyl-propoxy)-5-nitro-pyrimidin-4-yl]-3-methyl-azetidin-3-ol (intermediate B-5 (112), 100 mg, 0.23 mmol, yield 96.8%) as a yellow solid. 1 H NMR(400MHz,DMSO-d6)δ=10.41(s,1H),7.72-7.59(m,2H),7.42(d,J=8.8Hz,2H),5.74(s,1H),4.64(s,1H),3.99(s,4H),1.38(s,3H),1.13(s,6H).

[0302] (vii) Preparation of intermediate B-5 (113) (NRaRb: 3-methyl-azetidine-3-carbonitrile / Nu: 2-hydroxy-2-methyl-propoxy): Step 1:To a solution of 1-[6-(4-chloroanilino)-2-methylsulfanyl-5-nitro-pyrimidin-4-yl]-3-methyl-azetidine-3-carbonitrile (Intermediate B-3 (113), Example 3iii) (1.1 g, 2.81 mmol, 1.0 equivalent) in N-methyl-2-pyrrolidone (20 mL) and water (2 mL), potassium peroxymonosulfate (4.73 g, 28.14 mmol, 10 equivalents) was added. The mixture was stirred at 60 ° C. for 1 hour. The reaction mixture was added dropwise to 80 mL of water, filtered, and the filter residue was concentrated under reduced pressure to give 1-[6-(4-chloroanilino)-2-methylsulfonyl-5-nitro-pyrimidin-4-yl]-3-methyl-azetidine-3-carbonitrile (1.1 g, 2.45 mmol, 87.0% yield) as a yellow solid. 1 H NMR(400MHz,DMSO-d6)δ=10.42(s,1H),7.63-7.56(m,2H),7.49-7.43(m,2H),4 .53(d,J=10.4Hz,2H),4.16(d,J=10.4Hz,2H),3.24-3.19(m,3H),1.66(s,3H).

[0303] Process 2To a solution of 1-[6-(4-chloroanilino)-2-methylsulfonyl-5-nitro-pyrimidin-4-yl]-3-methyl-azetidine-3-carbonitrile (1 g, 2.36 mmol, 1.0 equiv.) in N-methyl-2-pyrrolidone (10 mL) was added 2-methylpropane-1,2-diol (1.07 g, 11.82 mmol, 5.0 equiv.) and potassium tert-butoxide (796 mg, 7.09 mmol, 3.0 equiv.). The mixture was stirred at 80° C. for 1 hour. The reaction mixture was washed with saturated ammonium chloride solution (30 mL) and extracted with 90 mL of ethyl acetate (30 mL×3). The combined organic layers were washed with 60 mL of brine (30 mL×2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®, 40 g SepaFlash® silica flash column, elution with 0-100% ethyl acetate / petroleum ether to 0-100% methanol / petroleum ether gradient at 30 mL / min), and the organic phase was concentrated under reduced pressure to give 1-[6-(4-chloroanilino)-2-(2-hydroxy-2-methyl-propoxy)-5-nitro-pyrimidin-4-yl]-3-methyl-azetidine-3-carbonitrile (Intermediate B-5 (113), 230 mg, 0.50 mmol, 21% yield) as a yellow solid.

[0304] (viii) Preparation of intermediate B-5 (114) (NRaRb: 3-methoxy-3-methyl-azetidin-1-yl / Nu: oxy-2-methyl-propan-2-ol): Step 1:To a solution of N-(4-chlorophenyl)-6-(3-methoxy-3-methyl-azetidin-1-yl)-2-methylsulfanyl-5-nitro-pyrimidin-4-amine (Intermediate B-3 (114), Example 3iv) (230 mg, 0.58 mmol, 1.0 equiv.) in N-methyl-2-pyrrolidone (3 mL) and water (0.3 mL), potassium peroxymonosulfate (977 mg, 5.81 mmol, 10 equiv.) was added. The mixture was stirred at 60 ° C. for 1 hour. The reaction mixture was added dropwise to 20 mL of water, filtered, and the residue was concentrated under reduced pressure to give N-(4-chlorophenyl)-6-(3-methoxy-3-methyl-azetidin-1-yl)-2-methylsulfonyl-5-nitro-pyrimidin-4-amine (210 mg, 0.49 mmol, 84.4% yield) as a white solid.

[0305] Process 2 To a mixture of N-(4-chlorophenyl)-6-(3-methoxy-3-methyl-azetidin-1-yl)-2-methylsulfonyl-5-nitro-pyrimidin-4-amine (200 mg, 0.47 mmol, 1.0 equiv.) in N-methyl-2-pyrrolidone (3 mL), 2-methylpropane-1,2-diol (211 mg, 2.34 mmol, 5.0 equiv.) and potassium tert-butoxide (157 mg, 1.40 mmol, 3.0 equiv.) were added. The mixture was stirred at 80° C. for 1 hour. The reaction mixture was washed with saturated ammonium chloride solution (10 mL) and extracted with 30 mL of ethyl acetate (10 mL×3). The combined organic layers were washed with 20 mL of brine (10 mL×2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®, 12 g SepaFlash® silica flash column, elution with a 0-100% ethyl acetate / petroleum ether gradient at 20 mL / min), and the organic phase was concentrated under reduced pressure to give 1-[4-(4-chloroanilino)-6-(3-methoxy-3-methyl-azetidin-1-yl)-5-nitro-pyrimidin-2-yl]oxy-2-methyl-propan-2-ol (Intermediate B-5 (113), 50 mg, 0.11 mmol, 24.0% yield) as a yellow solid.

[0306] (ix) Preparation of intermediate B-5 (118) (NRaRb: 4-methyl-piperidine-4-carboxylic acid / Nu: 2-hydroxy-2-methyl-propoxy): Step 1: To a solution of ethyl 1-[6-(4-chloroanilino)-2-methylsulfanyl-5-nitro-pyrimidin-4-yl]-4-methyl-piperidine-4-carboxylate (Intermediate B-3 (118), Example 3v) (600 mg, 1.29 mmol, 1.0 equiv.) in N-methyl-2-pyrrolidone (10 mL) and water (1 mL), potassium peroxymonosulfate (2.17 g, 12.88 mmol, 10 equiv.) was added. The mixture was stirred at 60 ° C. for 1 hour. The reaction mixture was added dropwise to 50 mL of water, filtered, and the filter residue was concentrated under reduced pressure to give ethyl 1-[6-(4-chloroanilino)-2-methylsulfonyl-5-nitro-pyrimidin-4-yl]-4-methyl-piperidine-4-carboxylate (590 mg, 1.14 mmol, 88.2% yield) as a yellow solid. 1 H NMR(400MHz,DMSO-d6)δ=10.37(s,1H),7.64-7.58(m,2H),7.45(d,J=8.8Hz,2H),4.26-4.07(m,2H),3.71(d,J= 14.0Hz,2H),3.30(d,J=2.8Hz,2H),3.22(s,3H),2.10(d,J=14.0Hz,2H),1.64-1.53(m,2H),1.25-1.19(m,6H).

[0307] Process 2To a solution of ethyl 1-[6-(4-chloroanilino)-2-methylsulfonyl-5-nitro-pyrimidin-4-yl]-4-methyl-piperidine-4-carboxylate (490 mg, 0.98 mmol, 1.0 equiv.) in N-methyl-2-pyrrolidone (5 mL), 2-methylpropane-1,2-diol (443 mg, 4.92 mmol, 5 equiv.) and potassium tert-butoxide (331 mg, 2.95 mmol, 3.0 equiv.) were added. The mixture was stirred at 80° C. for 1 hour. The reaction mixture was added to an aqueous citric acid solution (20 mL) (pH=3) and extracted with 60 mL of ethyl acetate (20 mL×3). The combined organic layer was washed with 20 mL of brine (10 mL×2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®, 20 g SepaFlash® silica flash column, eluent of 0-100% petroleum ether gradient / ethyl acetate at 30 mL / min), and the organic phase was concentrated under reduced pressure to give 1-[6-(4-chloroanilino)-2-(2-hydroxy-2-methyl-propoxy)-5-nitro-pyrimidin-4-yl]-4-methyl-piperidine-4-carboxylic acid (Intermediate B-5 (118), 191 mg, 0.40 mmol, 40.4% yield) as a yellow solid. 1 H NMR(400MHz,DMSO-d6)δ=10.36(s,1H),7.70-7.63(m,2H),7.46-7.39(m,2H),4.00(s,2H),3.71- 3.59(m,2H),3.26-3.17(m,2H),2.10-2.00(m,2H),1.56-1.44(m,2H),1.19(s,3H),1.14(s,6H).

[0308] (x) Preparation of intermediate B-5 (120) (NRaRb: 4-ethoxy-piperidine-4-carboxamide / Nu: 2-hydroxy-2-methyl-propoxy): Step 1:To a solution of 1-[6-(4-chloroanilino)-2-methylsulfanyl-5-nitro-pyrimidin-4-yl]-4-ethoxy-piperidine-4-carboxamide (Intermediate B-3 (120), Example 3vi) (590 mg, 1.26 mmol, 1.0 equiv.) in N-methyl-2-pyrrolidone (6 mL) and water (0.6 mL), potassium peroxymonosulfate (2.12 g, 12.64 mmol, 10 equiv.) was added. The mixture was stirred at 60° C. for 1 hour. The reaction mixture was added dropwise to 80 mL of water, filtered, and the filter residue was concentrated under reduced pressure to give 1-[6-(4-chloroanilino)-2-methylsulfonyl-5-nitro-pyrimidin-4-yl]-4-ethoxy-piperidine-4-carboxamide (300 mg, 0.52 mmol, 40.9% yield) as a pale yellow solid. 1 H NMR(400MHz,DMSO-d6)δ=10.37(s,1H),7.66-7.57(m,2H),7.45(d,J=8.8Hz,2H),7.38-7.23(m,2H),3.79-3.65 (m,2H),3.36(d,J=6.4Hz,4H),3.22(s,3H),2.02-1.89(m,4H),1.23-1.17(m,3H).LCMS:(ES+)m / z=499.1(M+H).

[0309] Process 2To a solution of 1-[6-(4-chloroanilino)-2-methylsulfonyl-5-nitro-pyrimidin-4-yl]-4-ethoxy-piperidine-4-carboxamide (250 mg, 0.50 mmol, 1.0 equiv.) in N-methyl-2-pyrrolidone (5 mL) was added 2-methylpropane-1,2-diol (226 mg, 2.51 mmol, 5 equiv.) and potassium tert-butoxide (169 mg, 1.50 mmol, 3 equiv.). The mixture was stirred at 80° C. for 1 hour. The reaction mixture was washed with water (20 mL) and extracted with 60 mL of ethyl acetate (20 mL×3). The combined organic layer was washed with 60 mL of brine (30 mL×2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®, 20 g SepaFlash® silica flash column, eluent of 0–100% ethyl acetate / methanol at 30 mL / min), and the organic phase was concentrated under reduced pressure to give 1-[6-(4-chloroanilino)-2-(2-hydroxy-2-methyl-propoxy)-5-nitro-pyrimidin-4-yl]-4-ethoxy-piperidine-4-carboxamide (Intermediate B-5 (120), 200 mg, 0.33 mmol, 66.3% yield) as a yellow solid.

[0310] (xi) Preparation of intermediate B-5 (131) (NRaRb: 4-methyl-piperidine-4-carboxamide / Nu: (3R)-3-hydroxypyrrolidin-1-yl): Step 1: Synthesis of 1-[6-(4-chloroanilino)-2-methylsulfonyl-5-nitro-pyrimidin-4-yl]-4-methyl-piperidine-4-carboxamide from 1-[6-(4-chloroanilino)-2-methylsulfanyl-5-nitro-pyrimidin-4-yl]-4-methyl-piperidine-4-carboxamide (Intermediate B-3 (36), Example 3i) as described in Step 1 of Example 4i.

[0311] Step 2:A mixture of 1-[6-(4-chloroanilino)-2-methylsulfonyl-5-nitro-pyrimidin-4-yl]-4-methyl-piperidine-4-carboxamide (1.00 g, 2.13 mmol, 1.0 equiv) and (3R)-pyrrolidin-3-ol (1.05 g, 12.05 mmol, 1 mL, 5.7 equiv) was stirred at 100° C. for 1 hour. The reaction mixture was cooled to room temperature and concentrated under reduced pressure to give a residue. The residue was purified by trituration with methanol (8 mL) at 25° C. The filter cake was then collected and concentrated under reduced pressure to give compound 1-[6-(4-chloroanilino)-2-[(3R)-3-hydroxypyrrolidin-1-yl]-5-nitro-pyrimidin-4-yl]-4-methyl-piperidine-4-carboxamide (Intermediate B-5 (131), 850 mg, 1.79 mmol, 83.7% yield) as a yellow solid. 1 H NMR(400MHz,DMSO-d6)δ=10.63(d,J=5.6Hz,1H),7.86-7.76(m,2H),7.41(d,J=8.9Hz,2H),7.30-6.94(m,2H),4.99(br s,1H),4.35(br s,1H),3.67-3.45(m,6H),3.26-3.14(m,2H),2.10-1.83(m,4H),1.48-1.36(m,2H),1.14(s,3H).

[0312] (xii) Preparation of intermediate B-5 (132) (NRaRb: 4-ethoxy-piperidine-4-carboxamide / Nu: (2-hydroxy-2-methyl-propyl)amino): Step 1: Synthesis of 1-[6-(4-chloroanilino)-2-methylsulfonyl-5-nitro-pyrimidin-4-yl]-4-ethoxy-piperidine-4-carboxamide from 1-[6-(4-chloroanilino)-2-methylsulfanyl-5-nitro-pyrimidin-4-yl]-4-ethoxy-piperidine-4-carboxamide (Intermediate B-3 (120), Example 3vi) as described in Step 1 of Example 4x.

[0313] Step 2:A solution of 1-[6-(4-chloroanilino)-2-methylsulfonyl-5-nitro-pyrimidin-4-yl]-4-ethoxy-piperidine-4-carboxamide (180 mg, 0.36 mmol, 1.0 equivalent) in 1-amino-2-methyl-propan-2-ol (322 mg, 3.61 mmol, 10 equivalents) was stirred for 1 hour at 120° C. Water (5 mL) was added to the reaction mixture, filtered, and the filtration residue was concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®, 12 g SepaFlash® silica flash column, eluent of 0–100% dichloromethane / methanol at 20 mL / min), and the organic phase was concentrated under reduced pressure to give 1-[6-(4-chloroanilino)-2-(2-hydroxy-2-methyl-propyl)amino]-5-nitro-pyrimidin-4-yl]-4-ethoxy-piperidine-4-carboxamide (Intermediate B-5 (132), 110 mg, 0.21 mmol, 58.7% yield) as a yellow solid.

[0314] (xiii) Preparation of intermediate B-5 (133) (NRaRb: 4-ethoxy-piperidine-4-carboxamide / Nu: (2S)-2-(hydroxymethyl)pyrrolidin-1-yl): Step 1: Synthesis of 1-[6-(4-chloroanilino)-2-methylsulfonyl-5-nitro-pyrimidin-4-yl]-4-ethoxy-piperidine-4-carboxamide from 1-[6-(4-chloroanilino)-2-methylsulfanyl-5-nitro-pyrimidin-4-yl]-4-ethoxy-piperidine-4-carboxamide (Intermediate B-3 (120)) as described in step 1 of Example 4x.

[0315] Step 2:A solution of 1-[6-(4-chloroanilino)-2-methylsulfonyl-5-nitro-pyrimidin-4-yl]-4-ethoxy-piperidine-4-carboxamide (180 mg, 0.36 mmol, 1 equiv) in [(2S)-pyrrolidin-2-yl]methanol (365 mg, 3.61 mmol, 0.35 mL, 10 equiv) was stirred at 120° C. for 1 h. The residue was purified by flash silica gel chromatography (ISCO®, 12 g SepaFlash® silica flash column, eluent of 0–100% dichloromethane / methanol at 20 mL / min), and the organic phase was concentrated under reduced pressure to give 1-[6-(4-chloroanilino)-2-[(2S)-2-(hydroxymethyl)pyrrolidin-1-yl]5-nitro-pyrimidin-4-yl]-4-ethoxy-piperidine-4-carboxamide (Intermediate B-5 (133), 180 mg, 0.34 mmol, 94.5% yield) as a yellow solid.

[0316] (xiv) Preparation of intermediate B-5 (135) (NRaRb: 4-isopropoxy-piperidine-4-carboxamide / Nu: 2-hydroxy-2-methyl-propoxy): Step 1:A mixture of 1-[6-(4-chloroanilino)-2-methylsulfanyl-5-nitro-pyrimidin-4-yl]-4-isopropoxy-piperidine-4-carboxamide (Intermediate B-3 (135)) (1.00 g, 2.08 mmol, 1 equiv.) and potassium oxidoxyhydrogen sulfate (3.50 g, 20.79 mmol, 10 equiv.) in N-methylpyrrolidone (16 mL) and water (4 mL) was stirred at 60° C. for 3 hours. The reaction mixture was cooled to room temperature, diluted with water (200 mL), and extracted with ethyl acetate (50 mL×3). The combined organic layer was washed with brine (200 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®, 40 g SepaFlash® silica flash column, eluting with a 50-100% ethyl acetate / petroleum ether gradient at 40 mL / min). The cleavage fractions were concentrated under reduced pressure to give 1-[6-(4-chloroanilino)-2-methylsulfonyl-5-nitro-pyrimidin-4-yl]-4-isopropoxy-piperidine-4-carboxamide (700 mg, 1.36 mmol, 66% yield) as a yellow solid. 1 H NMR(400MHz,DMSO-d6)δ=10.38(s,1H),7.66-7.59(m,2H),7.49-7.42(m,2H),7.39-7.24(m,2 H),3.79-3.62(m,3H),3.51-3.40(m,2H),3.23(s,3H),1.99-1.88(m,4H),1.16-1.15(m,6H).

[0317] Step 2: A mixture of 1-[6-(4-chloroanilino)-2-methylsulfonyl-5-nitro-pyrimidin-4-yl]-4-isopropoxy-piperidine-4-carboxamide (350 mg, 0.69 mmol, 1.0 equiv) and nucleophile (10.3 mmol, 1 mL, 15.1 equiv) was heated at 120° C. for 1 h. The mixture was triturated with ethyl acetate (10 mL) and filtered to give intermediate B-5 (135) (200 mg, 374.5 μmol, 55% yield) as a yellow solid. 1H NMR(400MHz,DMSO-d6)δ=10.71-10.59(m,1H),7.85-7.74(m,2H),7.45-7.36(m,2H),7.34-7.29(m,1H),7.27-7.12(m,1H),4.82-4 .70(m,1H),4.23-4.03(m,1H),3.86-3.66(m,1H),3.66-3.48(m,5H),3.47-3.35(m,2H),2.09-1.80(m,8H),1.14(d,J=6.0Hz,6H).

[0318] (xv) Preparation of intermediate B-5 (136) (NRaRb: 4-isopropoxy-piperidine-4-carboxamide / Nu: (2S)-2-(hydroxymethyl)pyrrolidin-1-yl): Step 1: Synthesis of 1-[6-(4-chloroanilino)-2-methylsulfonyl-5-nitro-pyrimidin-4-yl]-4-isopropoxy-piperidine-4-carboxamide from 1-[6-(4-chloroanilino)-2-methylsulfanyl-5-nitro-pyrimidin-4-yl]-4-isopropoxy-piperidine-4-carboxamide (Intermediate B-3 (135)) as described in step 1 of Example 4xiv.

[0319] Step 2: A mixture of 1-[6-(4-chloroanilino)-2-methylsulfonyl-5-nitro-pyrimidin-4-yl]-4-isopropoxy-piperidine-4-carboxamide (350 mg, 0.68 mmol, 1 equiv.) and [(2S)-pyrrolidin-2-yl]methanol (10.3 mmol, 1 mL, 15 equiv.) was heated at 120° C. for 1 hour. The mixture was triturated with ethyl acetate (10 mL) and filtered to give 1-[6-(4-chloroanilino)-2-[(2S)-2-(hydroxymethyl)pyrrolidin-1-yl]-5-nitro-pyrimidin-4-yl]-4-isopropoxy-piperidine-4-carboxamide (Intermediate B-5 (136), 200 mg, 0.37 mmol, 54.8% yield) as a yellow solid. 1H NMR(400MHz,DMSO-d6)δ=10.71-10.59(m,1H),7.85-7.74(m,2H),7.45-7.36(m,2H),7.34-7.29(m,1H),7.27-7.12(m,1H),4.82-4 .70(m,1H),4.23-4.03(m,1H),3.86-3.66(m,1H),3.66-3.48(m,5H),3.47-3.35(m,2H),2.09-1.80(m,8H),1.14(d,J=6.0Hz,6H).

[0320] [Example 6] Preparation of intermediates from general synthetic procedure C [ka]

[0321] (i) Preparation of intermediate C-1: To a solution of 6-chloro-8-(2-chlorophenyl)-9-(4-chlorophenyl)-2-methylsulfanyl-purine (850 mg, 2.02 mmol, 1.0 equiv) and N,N-diisopropylethylamine (783 mg, 6.06 mmol, 3.0 equiv) in N,N-dimethylformamide (5 mL) was added 4-methylpiperidine-4-carboxamide (433 mg, 2.42 mmol, 1.2 equiv, HCl salt) and the resulting mixture was stirred at 60° C. for 1 hour. The reaction mixture was added to water (50 mL) and filtered to give a residue. The residue was triturated with acetonitrile (20 mL) to give 1-[8-(2-chlorophenyl)-9-(4-chlorophenyl)-2-methylsulfanyl-purin-6-yl]-4-methyl-piperidine-4-carboxamide (Intermediate C-1, 850 mg, 1.61 mmol, 79.7% yield) as an off-white solid.

[0322] (ii) Preparation of intermediate C-2: See Example 9, synthesis of compound 68.

[0323] (iii) Preparation of Intermediate C-8: Step 1:A mixture of 1-[8-(2-chlorophenyl)-9-(4-chlorophenyl)-2-methylsulfonyl-purin-6-yl]-4-methyl-piperidine-4-carboxamide (Compound 68, Intermediate C-2) (300 mg, 535 μmol, 1 equiv.) and (2,4-dimethoxyphenyl)methanamine (555 mg, 3.32 mmol, 6.20 equiv.) was stirred at 140° C. for 1 hour. After cooling to room temperature, the reaction mixture was purified by flash silica gel chromatography (ISCO®, 25 SepaFlash® silica flash column, elution with a 10-100% ethyl acetate / petroleum ether gradient at 50 mL / min) to afford 1-[8-(2-chlorophenyl)-9-(4-chlorophenyl)-2-[(2,4-dimethoxyphenyl)methylamino]purin-6-yl]-4-methyl-piperidine-4-carboxamide (290 mg, 448 μmol, 83.8% yield) as a yellow solid. 1 H NMR(400MHz,DMSO-d6)δ=7.64-7.59(m,1H),7.50-7.37(m,5H),7.30-7.18(m, 3H),7.13-7.06(m,1H),6.96-6.90(m,1H),6.77-6.68(m,1H),6.53-6.48(m,1H) ),6.44-6.37(m,1H),5.01-4.39(m,2H),4.36-4.24(m,2H),3.77(s,3H),3.71 (s,3H),3.68-3.41(m,2H),2.08-2.00(m,2H),1.43-1.26(m,2H),1.12(s,3H).

[0324] Step 2:A mixture of 1-[8-(2-chlorophenyl)-9-(4-chlorophenyl)-2-[(2,4-dimethoxyphenyl)methylamino]purin-6-yl]-4-methyl-piperidine-4-carboxamide (290 mg, 448.52 μmol, 1 equiv) in trifluoroacetic acid (3 mL, 90 equiv) was stirred at 65° C. for 1 hour. The mixture was concentrated in vacuo to give a residue. The residue was purified by flash silica gel chromatography (ISCO®, 25 g SepaFlash® silica flash column, elution with a 0-50% MeOH / DCM ether gradient at 30 mL / min) to afford 1-[2-amino-8-(2-chlorophenyl)-9-(4-chlorophenyl)purin-6-yl]-4-methyl-piperidine-4-carboxamide (Intermediate C-8, 180 mg, 362.62 μmol, 80.8% yield) as a yellow solid. 1 H NMR(400MHz,DMSO-d6)δ=7.63(d,J=7.1Hz,1H),7.57-7.25(m,7H),6.98(br s,1H),3.86(br s,4H),2.20-2.05(m,2H),1.55-1.38(m,2H),1.17(s,3H).

[0325] [Example 7] Preparation of intermediates from general synthetic procedure D [ka]

[0326] (i) Preparation of intermediate D-1: To a solution of 6-chloro-8-(2-chlorophenyl)-9-(4-chlorophenyl)-2-methylsulfanyl-purine (Intermediate A-1) (1.00 g, 2.37 mmol, 1.0 equiv.) and N,N-diisopropylethylamine (368 mg, 2.85 mmol, 1.2 equiv.) in tetrahydrofuran (10 mL), 4-(trifluoromethyl)piperidine (436 mg, 2.85 mmol, 1.2 equiv.) was added, and the resulting mixture was stirred at 60 °C for 15 hours. The reaction mixture was concentrated under reduced pressure. The residue was triturated with ethanol (15 mL) and filtered to give 8-(2-chlorophenyl)-9-(4-chlorophenyl)-2-methylsulfanyl-6-[4-(trifluoromethyl)-1-piperidyl]purine (Intermediate D-1, 1.20 g, 2.23 mmol, 93.9% yield) as a red solid. 1 H NMR(400MHz,DMSO-d6)δ=7.69(s,1H),7.50(,J=8.4Hz,5H),7.32(d,J=8.4Hz,2H),6 .06-4.89(m,2H),3.25-3.02(m,2H),2.86-2.66(m,1H),2.46-2.41(m,3H),1.97(br s,2H),1.61-1.39(m,2H).

[0327] (ii) Preparation of intermediate D-2: To a solution of 8-(2-chlorophenyl)-9-(4-chlorophenyl)-2-methylsulfanyl-6-[4-(trifluoromethyl)-1-piperidyl]purine (Intermediate D-1) (1.15 g, 2.14 mmol, 1.0 equiv.) in N-methylpyrrolidone (15 mL) was added a solution of potassium hydrogen oxidoxysulfate (1.08 g, 6.42 mmol, 3.0 equiv.) in water (1.5 mL), and the mixture was stirred for 15 hours at 25° C. The reaction mixture was added to water (50 mL), filtered, and concentrated in vacuo to give 8-(2-chlorophenyl)-9-(4-chlorophenyl)-2-methylsulfinyl-6-[4-(trifluoromethyl)-1-piperidyl]purine (Intermediate D-2, 1.10 g, 1.98 mmol, 92.7% yield) as a red solid. 1H NMR(400MHz,DMSO-d6)δ=7.94-7.71(m,1H),7.63-7.24(m,6H),3.36-3.22(m,4H),2.82(s,3H),2.24-1.85(m,3H),1.69-1.41(m,2H).

[0328] (iii) Preparation of intermediate D-3: From D-2: To a solution of 8-(2-chlorophenyl)-9-(4-chlorophenyl)-2-methylsulfinyl-6-[4-(trifluoromethyl)-1-piperidyl]purine (Intermediate D-2) (400 mg, 0.72 mmol, 1.0 equiv.) in N-methylpyrrolidone (3.5 mL) and water (0.35 mL), oxone (121 mg, 0.72 mmol, 1.0 equiv.) was added, and the reaction mixture was stirred at 60° C. for 1 hour. The reaction mixture was added to water (15 mL) and filtered to obtain a solid. The solid was triturated with ethanol (15 mL) and filtered to obtain a solid. 8-(2-chlorophenyl)-9-(4-chlorophenyl)-2-methylsulfonyl-6-[4-(trifluoromethyl)-1-piperidyl]purine (Intermediate D-3, 300 mg, 0.53 mmol, 72.9% yield) was obtained as an off-white color. 1 H NMR(400MHz,DMSO-d6)δ=7.74(br d,J=7.0Hz,1H),7.61-7.47(m,4H),7.47-7.46(m,1H),7.45-7.34(m,2H),3.34-2.99(m,7H),2.95-2.73(m,1H),2.05(br d,J=11.4Hz,2H),1.67-1.45(m,2H).

[0329] [Example 8] [Preparation of other intermediates]

[0330] (i) Preparation of intermediate J: [ka]

[0331] Preparation of Intermediate J-1: Method A: A mixture of propan-2-ol (171 mg, 2.85 mmol, 1.2 equiv) and sodium hydride (332 mg, 8.30 mmol, 60% purity, 3.5 equiv) in N,N-dimethylformamide (10 mL) was stirred at 25° C. for 30 minutes, and then 6-chloro-8-(2-chlorophenyl)-9-(4-chlorophenyl)-2-methylsulfanyl-purine (Intermediate A-1) (1 g, 2.37 mmol, 1 equiv) was added to the mixture, and the mixture was stirred at 25° C. for 1.5 hours. The reaction mixture was added to water (60 mL), filtered, and the resulting filter cake was washed with water (3 mL × 3) to give crude Intermediate J-1 (86) (0.8 g) as a yellow solid.

[0332] Method B: A mixture of ethanol (109.24 mg, 2.37 mmol, 2.0 equiv) and sodium hydride (142.27 mg, 3.56 mmol, 60% purity, 3 equiv) in N,N-dimethylformamide (8 mL) was stirred at 25 °C for 30 minutes. Then, 6-chloro-8-(2-chlorophenyl)-9-(4-chlorophenyl)-2-methylsulfanyl-purine (Intermediate A-1) (500 mg, 1.19 mmol, 1.0 equiv) was added to the mixture, and the mixture was stirred at 25 °C for 1.5 hours. The mixture was diluted with water (100 mL) and extracted with ethyl acetate (30 mL × 3). The combined organic layers were washed with brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give crude Intermediate J-1 (99) (0.59 g) as a brown solid, which was used directly in the next step without further purification. [Table 4]

[0333] Preparation of Intermediate J-2: Method A: To a solution of 8-(2-chlorophenyl)-9-(4-chlorophenyl)-6-isopropoxy-2-methylsulfanyl-purine (Intermediate J-1 (86)) (0.8 g, 1.80 mmol, 1 equiv.) in N-methyl-2-pyrrolidone (12 mL) was added a solution of potassium hydrogen oxidoxysulfate (2.82 g, 16.7 mmol, 9.3 equiv.) in water (3 mL), and the resulting mixture was stirred at 60 °C for 40 h. The reaction mixture was added to water (120 mL) and filtered. The resulting filter cake was purified by flash silica gel chromatography (ISCO®, 40 g SepaFlash® silica flash column, eluent: 0-80% ethyl acetate / petroleum ether gradient at 50 mL / min). The cleaved fractions were concentrated under reduced pressure to give intermediate J-2 (86) (0.56 g, 1.16 mmol, 65.1% yield) as a white solid.

[0334] Method B: A solution of 8-(2-chlorophenyl)-9-(4-chlorophenyl)-6-ethoxy-2-methylsulfanyl-purine (0.59 g, 1.37 mmol, 1.0 equiv) in N-methyl-2-pyrrolidone (10 mL) was added to a solution of potassium oxidoxyhydrogen sulfate (1.84 g, 10.94 mmol, 8.0 equiv) in water (2 mL), and the resulting mixture was stirred at 60° C. for 18 hours. The reaction mixture was diluted with water (20 mL), filtered, and the resulting filter cake was purified by trituration with acetonitrile (2 mL) at 25° C. to afford intermediate J-2 (99) (378.5 mg, crude) as an off-white solid. [Table 5]

[0335] (ii) Preparation of intermediate L-1: To a solution of 4,6-dichloro-2-methylsulfanyl-5-nitro-pyrimidine e (Intermediate B-1) (5 g, 20.8 mmol, 1 equiv.) in N,N-dimethylformamide (20 mL) was added potassium carbonate (8.64 g, 62.5 mmol, 3 equiv.) and aniline (2.06 g, 22.1 mmol, 2.02 mL, 1.06 equiv.) at 0° C., and the mixture was stirred at 0° C. for 1 hour. The mixture was then stirred at 25° C. for 0.5 hours. The reaction mixture was washed with water (50 mL) and extracted with 300 mL of ethyl acetate (100 mL×2). The combined organic layer was washed with 100 mL of brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®, 80 g SepaFlash® silica flash column, elution with a 0-100% ethyl acetate / petroleum ether gradient at 60 mL / min), and the organic phase was concentrated under reduced pressure to give 6-chloro-2-methylsulfanyl-5-nitro-N-phenyl-pyrimidin-4-amine (intermediate L-1, 7 g, 17.9 mmol, 86.0% yield, 76% purity) as a yellow solid. 1 H NMR(400MHz,DMSO-d6)δ=7.52(d,J=7.6Hz,2H),7.47-7.30(m,3H),7.25-7.19(m,1H),2.40(s,3H).

[0336] (iii) Preparation of Intermediates K-2 and K-3: Preparation of intermediate K-2 To a solution of 4,6-dichloro-2-methyl-5-nitro-pyrimidine (Intermediate K-1) (5 g, 24.04 mmol, 1.0 equivalent) in N,N-dimethylformamide (20 mL) were added potassium carbonate (9.97 g, 72.11 mmol, 3.0 equivalent) and 4-chloroaniline (3.07 g, 24.04 mmol, 1.0 equivalent) at 0° C., and the mixture was stirred at 0° C. for 1 hour. The mixture was then stirred at 25° C. for 0.5 hours. 150 mL of water was added dropwise to the reaction mixture, filtered, and the filter residue was concentrated under reduced pressure to obtain a residue. The residue was added to 50 mL of ethyl alcohol, filtered, and the filter residue was concentrated under reduced pressure to obtain a residue. The residue was added to 50 mL of ethyl acetate, filtered, and the filtrate was concentrated under reduced pressure to give 6-chloro-N-(4-chlorophenyl)-2-methyl-5-nitro-pyrimidin-4-amine (Intermediate K-2, 5 g, 16.16 mmol, 67.2% yield) as a yellow solid. 1 H NMR(400MHz,DMSO-d6)δ=10.00(s,1H),7.63-7.55(m,2H),7.47-7.40(m,2H),2.46-2.38(m,3H).

[0337] Preparation of intermediates K-3 (127) and K-3 (134) K-3 (127): To a solution of 6-chloro-N-(4-chlorophenyl)-2-methyl-5-nitro-pyrimidin-4-amine (Intermediate K-2) (200 mg, 0.67 mmol, 1 equiv.) in N,N-dimethylformamide (2 mL) was added N,N-diisopropylethylamine (259 mg, 2.01 mmol, 0.35 mL, 3 equiv.) and 4-methylpiperidine-4-carboxamide (143 mg, 0.80 mmol, 1.2 equiv.). The mixture was stirred at 60° C. for 1 hour. The reaction mixture was added dropwise to 20 mL of water, filtered, and the filter residue was concentrated under reduced pressure to give 1-[6-(4-chloroanilino)-2-methyl-5-nitro-pyrimidin-4-yl]-4-methyl-piperidine-4-carboxamide (Intermediate K-3 (127), 260 mg, 0.61 mmol, 90.8% yield) as a pale yellow solid. 1H NMR(400MHz,DMSO-d6)δ=10.11(s,1H),7.75-7.66(m,2H),7.43-7.37(m,2H),7.29(s,1H),7.00(s,1H),3 .63(d,J=14.0Hz,2H),3.26-3.18(m,2H),2.28(s,3H),2.11-2.05(m,2H),1.46-1.37(m,2H),1.14(s,3H).

[0338] K-3 (134): To a solution of 6-chloro-N-(4-chlorophenyl)-2-methyl-5-nitro-pyrimidin-4-amine (Intermediate K-2) (200 mg, 0.67 mmol, 1 equiv.) in N,N-dimethylformamide (2 mL) was added N,N-diisopropylethylamine (259 mg, 2.01 mmol, 0.35 mL, 3 equiv.) and 4-ethoxypiperidine-4-carboxamide (167 mg, 0.80 mmol, 1.2 equiv.). The mixture was stirred at 60° C. for 1 hour. The reaction mixture was added dropwise to 20 mL of water, filtered, and the filter residue was concentrated under reduced pressure to give 1-[6-(4-chloroanilino)-2-methyl-5-nitro-pyrimidin-4-yl]-4-ethoxy-piperidine-4-carboxamide (Intermediate K-3 (134), 280 mg, 0.62 mmol, 92.1% yield) as a pale yellow solid. 1 H NMR(400MHz,DMSO-d6)δ=10.12(s,1H),7.74-7.66(m,2H),7.44-7.37(m,2H),7.30(s,1H),7.24(s,1 H),3.77-3.64(m,2H),3.38-3.32(m,2H),3.30-3.24(m,2H),2.29(s,3H),1.88(s,4H),1.19(s,3H).

[0339] [Example 9] [Preparation of Compounds 1-240] (i) General synthesis method A: [ka]

[0340] Preparation of Compound A-4: Method A: Crude intermediate A-3 was dissolved in nucleophile Nu-H (1 mL), and the reaction mixture was stirred at 100 °C overnight. EtOAc (15 mL) was added, and the solution was washed five times with saturated NH4Cl, dried over anhydrous Na2SO4, and concentrated. The crude residue was purified (injected in DMSO) on a Buchi semi-preparative (C18 column) using 20-60% ACN in AmF. The fractions were lyophilized to give compound A-4 (57% yield).

[0341] Response Scale: 50 mg of intermediate A-3

[0342] Method B: Sodium hydride 60% in a dispersion in mineral oil (2 equiv.) was added to a vial containing ethylene glycol (600 μL) in NMP (200 μL). The solution was stirred for 10 min at 40 °C, and then a solution of intermediate A-3 (1 equiv.) in NMP (200 μL) was added in one portion. The reaction mixture was stirred at 80 °C overnight, and complete conversion was observed by LCMS. One drop of water was added, and the reaction mixture was purified on a Buchi semi-preparative (C18 column) using 20–60% ACN in AmF (direct injection of the reaction mixture). The desired fraction was lyophilized to compound A-4 (57% yield) as an off-white powder.

[0343] Response Scale: 40 mg of intermediate A-3

[0344] Method C: To intermediate A-3 in an 8 mL vial, potassium carbonate (2 equiv.), nucleophile Nu-H (11 equiv.), and DMF (1.2 mL) were added, and the mixture was stirred at 110 °C for 19 h. The reaction mixture was purified by reverse-phase flash chromatography using 10% to 100% MeCN in 10 mM AmF (product elution at 72% MeCN) to give compound A-4 (73% yield).

[0345] Response Scale: 120 mg of intermediate A-3

[0346] Method D: A solution of intermediate A-3 (74) (1 equivalent) in nucleophile (Nu-H) (15 equivalents) was stirred at 140 °C for 12 hours. The reaction mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC (column: Unisil 3-100 C18 Ultra 150 × 50 mm × 3 μm, mobile phase: [water (formic acid)-ACN]) to give compound A-4 as a white solid.

[0347] Response Scale: 100 mg of intermediate A-3

[0348] Method E: A mixture of intermediate A-3 (1 equiv.), nucleophile (Nu-H) (110 mg, 1.22 mmol, 5 equiv.), and potassium carbonate (67 mg, 0.48 mmol, 3 equiv.) in N,N-dimethylformamide (1 mL) was stirred at 100 °C for 2–14 h. The reaction mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC (column: C18 150 × 25 mm × 10 μm, mobile phase: [water-ACN]), and the organic phase was concentrated under reduced pressure to remove acetonitrile. The liquid was lyophilized to give compound A-4 as a white solid.

[0349] Response Scale: 120 mg of intermediate A-3 [Table 6-1] [Table 6-2] [Table 6-3] [Table 6-4] [Table 6-5] [Table 6-6] [Table 6-7] [Table 6-8] [Table 6-9] [Table 6-10] [Table 6-11]

[0350] (iv) General synthesis method B: [ka]

[0351] The preparation of B compound can be found in the detailed protocol below. (v) General synthesis method C: [ka]

[0352] The preparation of C compound can be found in the detailed protocol below. (vi) General synthesis method D: [ka]

[0353] The preparation of the D compounds can be found in the detailed protocols below. (vii) General synthesis method E: [ka]

[0354] Preparation of E-3 compound: Method for Compound 144: In step 1, a suspension of 8-(2-chlorophenyl)-9-(4-chlorophenyl)-1H-purine-2,6(3H,9H)-dione (400 mg, 1.07 mmol) in phosphorus oxychloride (4.4 mL, 47 mmol) was heated to 100 °C. The solution was stirred at that temperature for 1 week. 20% SM still remained after 1 week, at which point the reaction was stopped. The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in DCM and then saturated and transferred to a separatory funnel containing saturated NaHCO3. The solution was neutralized, dried over anhydrous Na2SO4, and then concentrated. The residue was purified by normal-phase flash chromatography (DCM, 25 g loaded) using 50–100% DCM in hexanes to give 2,6-dichloro-8-(2-chlorophenyl)-9-(4-chlorophenyl)-9H-purine (220 mg, 50%).

[0355] In step 2, N,N-diisopropylethylamine (188 μL, 1.07 mmol) was added to a vial containing a solution of 2,6-dichloro-8-(2-chlorophenyl)-9-(4-chlorophenyl)-9H-purine (220 mg, 536 μmol) and 4-(ethylamino)piperidine-4-carboxamide (97 mg, 563 μmol) in NMP (1.3 mL). The reaction mixture was stirred at room temperature until complete conversion was observed by LCMS (3 h). Water (15 mL) was slowly added to the reaction mixture, and the suspension was removed by filtration through a Buchner funnel. 15 mg of the crude product was purified on a semi-preparative system (injection of the reaction mixture) using a gradient of 40–70% ACN in 10 mM AmB (pH 4) to give, after lyophilization of the pure fractions, 1-(2-chloro-8-(2-chlorophenyl)-9-(4-chlorophenyl)-9H-purin-6-yl)-4-(ethylamino)piperidine-4-carboxamide (compound 144, 10.5 mg). 1H NMR(400MHz,DMSO-d6)δ 7.70(dd,1H),7.55-7.49(m,4H),7.49-7.42(m,1H),7.37-7.31(m,3H),7.05(s,1H),5.07(br s,1H),4.28(br s,1H),4.10(br s,1H),3.63(br s,1H),2.39(q,2H),1.88(br s,2H),1.69(br d,2H),1.04(t,3H).LCMS:(ES + ) m / z = 544.2 (M+H).

[0356] (viii) General synthesis method F: [ka]

[0357] Preparation of F compound: Method A: To a solution of 1-[8-(2-chlorophenyl)-9-(4-chlorophenyl)-2-methylsulfonyl-purin-6-yl]-4-methyl-piperidine-4-carboxamide (Intermediate A-3) (500 mg, 0.89 mmol, 1 equiv.) in dimethyl sulfoxide (5 mL) was added potassium cyanide (87 mg, 1.34 mmol, 1.5 equiv.), and the resulting mixture was stirred at 100° C. for 15 hours. The mixture was diluted with ethyl acetate (50 mL), washed with brine (3×15 mL), dried over sodium sulfate, filtered, and concentrated in vacuo to afford Intermediate F-1 1-[8-(2-chlorophenyl)-9-(4-chlorophenyl)-2-cyano-purin-6-yl]-4-methyl-piperidine-4-carboxamide (Compound 146, 450 mg, crude) as a yellow solid.

[0358] Method B: A vial was charged with lithium hydroxide (0.4 mg, 18 μmol). Water (250 μL) was added, followed by hydrogen peroxide (2.5 μL, 23.9 μmol) (30 wt % in water) in one portion. A solution of 1-(8-(2-chlorophenyl)-9-(4-chlorophenyl)-2-cyano-9H-purin-6-yl)-4-(ethylamino)piperidine-4-carboxamide (compound 146, intermediate F-1) (8.0 mg, 14.9 μmol) in THF (250 μL) was then added, and the reaction mixture was stirred at room temperature for 3 h, at which point complete conversion was observed by LCMS. EtOAc (15 mL) was added, and the solution was washed five times with saturated NH4Cl, dried over anhydrous Na2SO4, and concentrated. The residue was purified by reverse-phase flash chromatography (DMSO, loaded with 12 g of C18) using 10–60% ACN in 10 mM AmF (pH 4) to give intermediate F-2,6-(4-carbamoyl-4-(ethylamino)piperidin-1-yl)-8-(2-chlorophenyl)-9-(4-chlorophenyl)-9H-purine-2-carboxamide (compound 147, 3.5 mg, 42% yield) after lyophilization.

[0359] Method C: To a solution of sodium hydroxide (178 mg, 4.44 mmol, 5.0 equiv.) in water (3 mL) and ethanol (3 mL), 1-[8-(2-chlorophenyl)-9-(4-chlorophenyl)-2-cyano-purin-6-yl]-4-methyl-piperidine-4-carboxamide (compound 146, intermediate F-1) (450 mg, 0.89 mmol, 1.0 equiv.) was added, and the mixture was stirred at 60° C. for 3 hours. The mixture was diluted with water (10 mL), washed with ethyl acetate (2×10 mL), and the pH of the aqueous phase was acidified to pH=3 with hydrochloric acid (1 N), then extracted with ethyl acetate (2×20 mL). The organic layer was washed with brine (5 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by preparative HPLC (Phenomenex Luna C18 150 × 40 mm × 15 μm column, mobile phase: [water (FA)-ACN], B%: 42% to 72%, 10 min) to give the crude product. The residue was purified by preparative HPLC (Phenomenex Luna C18 150 × 25 mm × 10 μm column, mobile phase: [water (FA)-ACN], B%: 40% to 70%, 10 min) to give intermediate F-3,6-(4-carbamoyl-4-methyl-1-piperidyl)-8-(2-chlorophenyl)-9-(4-chlorophenyl)purine-2-carboxylic acid (Compound 77, 8.06 mg, 15.3 μmol, 2.8% yield) as an off-white solid.

[0360] Method D: To a solution of 6-(4-carbamoyl-4-methyl-1-piperidyl)-8-(2-chlorophenyl)-9-(4-chlorophenyl)purine-2-carboxylic acid (Compound 77, Intermediate F-3) (45 mg, 85.6 μmol, 1 equiv.) in N,N-dimethylformamide (0.5 mL), N,N-diisopropylethylamine (44 mg, 0.34 mmol, 0.06 mL, 4 equiv.), 1-hydroxybenzotriazole (14 mg, 0.10 mmol, 1.2 equiv.), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (20 mg, 0.10 mmol, 1.2 equiv.) were added, and the mixture was stirred at 25° C. for 0.5 h. Then, hydrochloride (14 mg, 0.17 mmol, 2 equiv.) was added to the mixture, and the mixture was stirred at 25° C. for 2 h. The residue was dissolved in acetonitrile (2 mL) and purified by preparative HPLC (Waters Xbridge 150 × 25 mm × 5 μm column, mobile phase: [water (ammonium bicarbonate)-acetonitrile], B%: 40% to 70%, 8 min) and preparative HPLC (Phenomenex Luna C18 150 × 25 mm × 10 μm column, mobile phase: [water (methanoic acid)-acetonitrile], B%: 40% to 70%, 10 min). The organic phase was concentrated under reduced pressure to remove acetonitrile, and the liquid was lyophilized to give intermediate F-4, 6-(4-carbamoyl-4-methyl-1-piperidyl)-8-(2-chlorophenyl)-9-(4-chlorophenyl)-N,N-dimethyl-purine-2-carboxamide (compound 2, 16.52 mg, 30 μmol, 35% yield) as a yellow solid. [Table 7]

[0361] (ix) General synthesis method G: [ka]

[0362] Preparation of G-4 compound: Procedure: Step 1. Intermediate G-1 (515 μmol) was dissolved in NMP (3.1 mL), then water (300 μL) was added dropwise, ensuring that the solution remained clear. Another portion of Oxone (950 mg, 1.55 mmol) was then added, and the reaction mixture was stirred at room temperature overnight. Water (30 mL) was slowly added, and the precipitate was collected by filtration through a Buchner funnel. The solid was washed with water and then lyophilized to give Intermediate G-2 (92% yield).

[0363] In step 2, cesium carbonate (494 μmol) was added to a solution of intermediate G-2 (165 μmol) in nucleophile (6.6 mmol). The solution was heated to 100 °C overnight. LCMS indicated that the major product was the desired product. EtOAc (15 mL) was added, and the solution was washed five times with saturated NH4Cl, dried over anhydrous Na2SO4, and concentrated. The residue was purified by reverse-phase flash chromatography (DMSO, loaded with 12 g of C18) using 10–60% ACN in 10 mM Ammonium Fluoride (AmF, pH 4). The fractions were concentrated under reduced pressure. The residue was dissolved in DCM, dried over anhydrous Na2SO4, filtered, and concentrated to give intermediate G-3 (78% yield).

[0364] In step 3, triethylamine (361 μmol) was added to a solution of intermediate G-3 (120 μmol) and phenol carbamate (181 μmol) in DCM (1.2 mL) at room temperature. Complete conversion was observed by LCMS after 90 min. The reaction mixture was concentrated to dryness, and the residue was purified by reverse-phase flash chromatography (DMSO, loaded with 12 g of C18) using 10–70% ACN in 10 mM AmF (pH 4) to give compound G-4 (11% yield) after lyophilization.

[0365] Response Scale: 265 mg of intermediate G-1. [Table 8]

[0366] (x) General synthesis method H: [ka]

[0367] Preparation of H-2 compound: Method A: Step 1. 1,1'-Bis(diphenylphosphino)ferrocenedichloropalladium(II) (0.2 equiv.) was added to a mixture of 6-chloro-8-(2-chlorophenyl)-9-(4-chlorophenyl)-2-(methylthio)-9H-purine (Intermediate A-1) (1 equiv.), 2-(trifluoromethyl)pyridine-5-boronic acid (1.6 equiv.), and sodium carbonate (4 equiv.) in dioxane (10 mL) and water (1.6 mL). The reaction mixture was stirred at 70°C for 4 hours. The reaction mixture was filtered over Celite (with EtOAc and traces of MeCN rinse). The filtrate was partially concentrated in vacuo, then diluted with water (15 mL) and extracted with ethyl acetate (70 mL x 2). The organic phase was dried over magnesium sulfate and evaporated to give crude 8-(2-chlorophenyl)-9-(4-chlorophenyl)-2-(methylthio)-6-(6-(trifluoromethyl)pyridin-3-yl)-9H-purine (intermediate H-1, quantitative conversion).

[0368] In step 2, crude intermediate H-1 (1 eq) was dissolved in NMP (8 mL), followed by the dropwise addition of water (600 μL), ensuring that the solution remained clear. Oxone (3 eq) was then added in one portion, and the reaction mixture was stirred at room temperature for 16 hours; LCMS showed low conversion. Additional Oxone (3 eq) was added, and the reaction was continued for another 24 hours, for a total of 40 hours. Upon completion of the reaction, water (50 mL) was added, and the mixture was extracted with DCM (80 mL × 2), dried over MgSO4, and concentrated. Water (600 μL) was added to the residue (in NMP), Oxone (3.2 eq) was added, and the reaction was heated at 60 °C for 20 hours. Water (50 mL) was added, and the mixture was extracted with DCM (90 mL × 2), dried over MgSO4, and evaporated to a yellow oil. Water (6 mL) was added to this oil (no precipitation). MeCN (3 mL) was then added and the resulting mixture was lyophilized and then subjected to flash chromatography using 0% to 40% ethyl acetate in hexane to give the intermediate 8-(2-chlorophenyl)-9-(4-chlorophenyl)-2-(methylsulfonyl)-6-(6-(trifluoromethyl)pyridin-3-yl)-9H-purine (81% yield).

[0369] In step 3, a solution of 8-(2-chlorophenyl)-9-(4-chlorophenyl)-2-(methylsulfonyl)-6-(6-(trifluoromethyl)pyridin-3-yl)-9H-purine (1 equivalent) in nucleophile Nu-H (30 equivalents) was stirred at 100 °C for 21 hours. The compound was precipitated by standing at room temperature. The compound was loaded onto a C-18 column for purification using DMF, a trace of water, and a trace of MeCN. Purification using 15% to 80% MeCN in AmF buffer resulted in an impure product. All fractions containing the product were evaporated to give a yellow solid. The solid was removed using MeCN (3 mL) and water (15 mL), which was then filtered, rinsed with water, and dried to give H-2 compound.

[0370] Response Scale: 200mg of intermediate A-1

[0371] Method B: In step 1, to a solution of 6-chloro-8-(2-chlorophenyl)-9-(4-chlorophenyl)-2-methylsulfanyl-purine (Intermediate A-1) (1 equivalent) in dioxane (10 mL) and water (2 mL) was added [6-(trifluoromethyl)-3-pyridyl]boronic acid (2.0 equivalents), potassium phosphate (2.0 equivalents), and tetrakis(triphenylphosphine)palladium (0.06 equivalents). The mixture was stirred at 80° C. under a nitrogen atmosphere for 2 hours. The reaction mixture was washed with water (50 mL) and extracted with 150 mL of ethyl acetate (50 mL×3). The combined organic layer was washed with 200 mL of brine (100 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was stirred with ethanol (100 mL), filtered, and the filtration residue was concentrated under reduced pressure to give compound 8-(2-chlorophenyl)-9-(4-chlorophenyl)-2-methylsulfanyl-6-[6-(trifluoromethyl)-3-pyridyl]purine (Intermediate H-1, yield 87.1%) as a white solid. 1 H NMR(400MHz,CDCl3)δ=10.16(s,1H),9.40-9.37(m,1H),7.86(d,J=8.0Hz, 1H),7.63-7.58(m,1H),7.51-7.37(m,5H),7.27-7.24(m,2H),2.68(s,3H).

[0372] In step 2, to a solution of 8-(2-chlorophenyl)-9-(4-chlorophenyl)-2-methylsulfanyl-6-[6-(trifluoromethyl)-3-pyridyl]purine (Intermediate H-1) (1 equivalent) in NMP (10 mL) and water (1 mL) was added potassium hydrogen oxidoxysulfate (3.16 g, 18.78 mmol, 10 equivalents). The mixture was stirred at 60 °C for 1 hour. The reaction mixture was added dropwise to 50 mL of water, filtered, and the filter residue was concentrated under reduced pressure to obtain the compound 8-(2-chlorophenyl)-9-(4-chlorophenyl)-2-methylsulfonyl-6-[6-(trifluoromethyl)-3-pyridyl]purine (crude) as a pale yellow solid, which was used in the next step without further purification. 1H NMR(400MHz,CDCl3)δ=10.26(d,J=1.6Hz,1H),9.43(dd,J=1.7,8.3Hz,1H),7.91(d,J=8.3Hz, 1H),7.64-7.59(m,1H),7.56-7.50(m,1H),7.50-7.40(m,4H),7.31-7.27(m,2H),3.48(s,3H).

[0373] In step 3, a mixture of 8-(2-chlorophenyl)-9-(4-chlorophenyl)-2-methylsulfonyl-6-[6-(trifluoromethyl)-3-pyridyl]purine (1 equivalent), nucleophile Nu-H (5 equivalents), and potassium carbonate (2 equivalents) in N,N-dimethylformamide (1 mL) was stirred at 100 °C for 2 hours. The reaction mixture was diluted with N,N-dimethylformamide (1 mL) and filtered to obtain a filtrate. The filtrate was purified by reverse-phase HPLC (column: Waters Xbridge 150 × 25 mm × 5 μm, mobile phase: [water (ammonium bicarbonate)-ACN], B%: 63% to 93%, 8 min). The cleavage fraction was concentrated under reduced pressure to remove acetonitrile. The residue was lyophilized to obtain compound H-2 as a white solid.

[0374] Response Scale: 1g of Intermediate A-1

[0375] Method C: Steps 1 and 2 can be achieved according to Method A or Method B. In Step 3, a mixture of 8-(2-chlorophenyl)-9-(4-chlorophenyl)-2-methylsulfonyl-6-[6-(trifluoromethyl)-3-pyridyl]purine (1 equivalent) and nucleophile Nu-H (30 equivalents) was stirred at 120 °C for 2 hours. The reaction mixture was cooled to room temperature and purified by reverse-phase HPLC (Phenomenex Luna C18 150 × 25 mm × 10 μm column, mobile phase: [water (formic acid)-ACN], B%: 67% to 97%, 10 min). The cleaved fraction was concentrated under reduced pressure to remove acetonitrile. The residue was lyophilized to give compound H-2 as a yellow solid.

[0376] Response Scale:70 mg of 8-(2-chlorophenyl)-9-(4-chlorophenyl)-2-methylsulfonyl-6-[6-(trifluoromethyl)-3-pyridyl]purine

[0377] Preparation of H-4 compound: Method D: In step 1, sodium hydride 60% in dispersion in mineral oil (1.5 equiv.) was added in one portion to a solution of intermediate H-3 (1 equiv.) in NMP (1.6 mL) at room temperature. The reaction mixture was stirred for 5 minutes, and then iodomethane (2 equiv.) was added. Complete conversion was observed by LCMS after 5 minutes. The reaction mixture was transferred to a separatory funnel containing saturated NH4Cl. The aqueous solution was extracted with EtOAc, and the organic layers were combined, dried over anhydrous Na2SO4, and concentrated to give the crude intermediate (quantitative conversion).

[0378] In step 2, the solid was dissolved in NMP (3.0 mL). Water (300 μL) was added, followed by Oxone (3 equivalents). The reaction mixture was stirred at room temperature for 2 hours. Water (35 mL) was then added, and the precipitate was collected using a Buchner funnel.

[0379] In step 3, the resulting sulfone was dissolved in 2-(methylamino)ethanol (Nu-H) (25 equiv.) and heated to 100 °C overnight. The reaction mixture was loaded onto a reverse-phase column (C18 12 g) and purified using 40–70% ACN in 10 mM AmF (pH 4) to give compound H-4 (33% yield).

[0380] Response Scale: 150 mg of intermediate H-3

[0381] Preparation of H-5 compound:

[0382] Method E: To a solution of intermediate A-2 (1 equivalent) in tetrahydrofuran (6 mL), tert-butyl 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole-1-carboxylate (2 equivalents), palladium, triphenylphosphane (0.1 equivalents), and copper 2-hydroxy-3-methylbenzoate (3 equivalents) were added, and the mixture was stirred at 60° C. for 12 hours. The mixture was diluted with water (10 mL) and extracted with ethyl acetate (10 mL×3). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by column chromatography (silicon dioxide) and concentrated in vacuo. The residue was purified by preparative HPLC (column: C18, mobile phase: [water(formic acid)-ACN]) and dried by lyophilization. The crude compound was then purified by normal-phase HPLC (column: Welch Ultimate XB-CN 250 × 50 × 10 μm; mobile phase: [hexane-ethanol (0.1% ammonia hydroxide)]) and concentrated under vacuum to give compound H-5 as an off-white solid.

[0383] Response Scale: 300 mg of intermediate A-2

[0384] Method F: In step 1, to a solution of intermediate A-2 (1.0 equiv.) in tetrahydrofuran (5 mL), trimethyl-[2-[(5-tributylstannylimidazol-1-yl)methoxy]ethyl]silane (2 equiv.), palladium-triphenylphosphane (0.1 equiv.), and copper-2-hydroxy-3-methyl-benzoate (3.0 equiv.) were added, and the mixture was stirred at 60 °C for 2 h. The reaction mixture was filtered and concentrated in vacuo. The dark brown oil was purified by preparative HPLC (column: Phenomenex Luna C18 150 × 25 mm × 10 μm, mobile phase: [water (FA)-ACN], B%: 42% to 72%, 10 min) to give the intermediate (100 mg, 0.15 μmol, 15.5% yield) as a yellow oil.

[0385] In step 2, to a solution of the intermediate compound (50 mg, 73.8 μmol, 1.0 equiv.) in dichloromethane (6 mL) and ethanol (0.2 mL), trifluoroacetic acid (2 mL) was added, and the mixture was stirred at 25° C. for 3 hours. The mixture was concentrated in vacuo, and then tetrahydrofuran (10 mL) and sodium hydroxide (30 mg) were added. The resulting mixture was stirred at 80° C. for 1 hour, and then concentrated in vacuo. The residue was triturated with N,N-dimethylformamide (5 mL), filtered, and the filtrate was concentrated in vacuo. The residue was purified by preparative HPLC (column: Phenomenex Luna C18 150 × 25 mm × 10 μm, mobile phase: [water (formic acid)-ACN]; B%: 16% to 46%, 10 min) to give compound H-5 as an off-white solid.

[0386] Response Scale: 500mg of intermediate A-2 [Table 9-1] [Table 9-2]

[0387] (xi) General synthesis method I: [ka]

[0388] Preparation of Compound I-2: Method A: In step 1, the amine derivative (1.2 equivalents) was added to a vial containing a solution of intermediate A-1 (1 equivalent) and N,N-diisopropylethylamine (2.2 equivalents) in NMP (4.0 mL). The reaction mixture was stirred at room temperature overnight until complete conversion was observed by LCMS. Water (50 mL) was slowly added to the reaction mixture, and the precipitate was collected by filtration through a Buchner funnel. The solid was washed with water and dried under vacuum. The crude intermediate (89% yield) was obtained as a solid and used in the next reaction without purification.

[0389] The solid was dissolved in DCM (10.0 mL), acetone (1 mL), and tetrabutylammonium bromide (0.05 equiv.), followed by the addition of a solution of oxone (2.6 mmol) in water (5.0 mL). The biphasic solution was vigorously stirred at 40 °C overnight, and 70% conversion to the desired sulfone was observed by LCMS. DCM was added, and the organic solution was washed three times with brine, then dried over anhydrous Na2SO4 and concentrated under reduced pressure to give the crude intermediate material (59% yield).

[0390] The crude intermediate material was then dissolved in nucleophile (Nu-H) (2.6 equiv.) and NMP (200 μL). The reaction mixture remained cloudy after heating at 100 °C but became clear as the product formed. Complete conversion was observed by LCMS overnight. EtOAc (30 mL) was added, and the solution was washed five times with saturated NH4Cl, dried over anhydrous Na2SO4, and concentrated. The residue was purified by normal-phase flash chromatography (loaded with DCM, 25 g) using 0–30% EtOAc in DCM to give intermediate I-1 (20% yield).

[0391] In step 2, trifluoroacetic acid (14 equivalents) was added to a solution of intermediate I-1 (1 equivalent) in DCM (700 μL) at room temperature. The solution was stirred for 1 hour, and complete conversion was observed by LCMS. The reaction mixture was concentrated to dryness, diluted with DCM, and washed three times with saturated NaHCO. The organic layer was dried over anhydrous NaSO, filtered, and concentrated under reduced pressure to give crude compound I-2 (quantitative conversion).

[0392] Response Scale: 1g of Intermediate A-1

[0393] Preparation of Compound I-3: Method B: Sodium triacetoxyborohydride (3 equiv.) was added portionwise to a solution of intermediate I-2 (1 equiv.) and formaldehyde (5 equiv.) (37% in water) in MeOH (2.9 mL) and AcOH (600 μL) at room temperature. Complete conversion was observed after 2.5 h. The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in DCM. The organic layer was washed with saturated NaHCO3 (3×) and 1 M NaOH (2×). The residue obtained after concentration was purified by reverse-phase flash chromatography (DMSO, C18 12 g, 4 CV loaded) using 10–100% ACN in 10 mM AmF (pH 4) to give compound I-3 (58% yield) as a solid.

[0394] Response Scale: 125 mg of intermediate I-2 [Table 10]

[0395] (xii) General synthesis method J: [ka]

[0396] Preparation of compound J-3: Method A: A mixture of intermediate J-2 (1 equivalent), nucleophile (Nu-H) (5 equivalents), and potassium carbonate (2 equivalents) in N,N-dimethylformamide (1 mL) was stirred at 100 °C for 14 hours. The reaction mixture was cooled to room temperature and diluted with N,N-dimethylformamide (1 mL). The resulting mixture was filtered to obtain a filtrate. The filtrate was purified by reverse-phase HPLC (Column: Waters Xbridge 150 × 25 mm × 5 μm, Mobile phase: [water (ammonium bicarbonate)-ACN]; B%: 50%-80%) to obtain compound J-3 as a white solid.

[0397] Response Scale: 80 mg of intermediate J-2

[0398] Method B: A mixture of intermediate J-2 (1 equivalent), nucleophile (Nu-H) (5 equivalents), and potassium carbonate (2 equivalents) in N,N-dimethylformamide (4 mL) was stirred at 100 °C for 6 hours. The reaction mixture was cooled to room temperature and filtered to obtain a filtrate. The filtrate was purified by preparative HPLC (column: Waters Xbridge 150 × 25 mm × 5 μm, mobile phase: [water (ammonium bicarbonate)-ACN]; B%: 51%-81%) to obtain the desired compound as a white solid, which was further separated by SFC (column: DAICEL CHIRALPAK IC (250 mm × 30 mm × 10 μm), mobile phase: [0.1% ammonia hydroxide in methanol] to obtain compound J-3 as a white solid.

[0399] Response Scale: 300mg of intermediate J-2

[0400] Method C: A mixture of 8-(2-chlorophenyl)-9-(4-chlorophenyl)-6-ethoxy-2-methylsulfonyl-purine (1 equivalent), nucleophile (Nu-H) (5 equivalents), and potassium carbonate (2 equivalents) in N,N-dimethylformamide (1.5 mL) was stirred at 100 °C for 6 hours. The reaction mixture was cooled to room temperature and diluted with N,N-dimethylformamide (2 mL). The resulting mixture was filtered to obtain a filtrate. The filtrate was purified by reverse-phase HPLC (column: Unisil 3-100 C18 Ultra 150 × 50 mm × 3 μm, mobile phase: [water (formic acid)-ACN], B%: 45% to 75%, 7 min). The cleavage fraction was concentrated under reduced pressure to remove acetonitrile. The residue was lyophilized to obtain compound J-3 as a white solid.

[0401] Response Scale: 120 mg of intermediate J-2

[0402] Method D: Intermediate J-2 (1 equiv.) was dissolved in nucleophile (Nu-H) (1 mL), and the reaction mixture was stirred at 100 °C overnight. EtOAc (15 mL) was added, and the solution was washed five times with saturated NH4Cl, dried over anhydrous Na2SO4, and concentrated. The crude residue was purified (injected in DMSO) on a Buchi semi-preparative (C18 column) using 20-60% ACN in AmF. The fractions were lyophilized to afford compound J-3.

[0403] Response Scale: 50 mg of intermediate J-2

[0404] Method E: To intermediate J-2 (1 equiv.) in an 8 mL vial was added potassium carbonate (2.2 equiv.), nucleophile (Nu-H) (11 equiv.), and DMF (1.2 mL), and the mixture was stirred at 110° C. for 19 h. The reaction mixture was purified by reverse-phase flash chromatography using 10% to 100% MeCN in 10 mM AmF (product elution at 72% MeCN) to give compound J-3.

[0405] Response Scale: 120 mg of intermediate J-2 [Table 11]

[0406] (xiii) General synthesis method K: [ka]

[0407] Preparation of K-4 compound:

[0408] To a mixture of intermediate K-3 (1 equivalent) and the aldehyde derivative (5 equivalents) in ethyl alcohol (2.5 mL), iron (10 equivalents) and acetic acid (1 mL) were added, and the mixture was stirred at 80 °C for 1 hour. The reaction mixture was filtered and concentrated under reduced pressure to obtain a residue. The residue was dissolved in acetonitrile (2 mL) and analyzed by preparative HPLC (column: Phenomenex Luna C18 150 × 25 mm × 10 μm, mobile phase: [water (formic acid)-ACN], B%: 40% to 70%, 10 min). The organic phase was concentrated under reduced pressure to remove acetonitrile, and the liquid was lyophilized to obtain compound K-4 as a yellow solid.

[0409] Response Scale: 220 mg of intermediate K-3. [Table 12] (xiv) General synthesis method L: [ka]

[0410] Preparation of L-5 Compound: Method for Compound 95: In step 1, to a solution of 6-chloro-2-methylsulfanyl-5-nitro-N-phenyl-pyrimidin-4-amine (Intermediate L-1) (700 mg, 1.79 mmol, 76% purity, 1 equiv) in N,N-dimethylformamide (5 mL) was added 4-methylpiperidine-4-carboxamide (384 mg, 2.15 mmol, 1.2 equiv) and potassium carbonate (743 mg, 5.38 mmol, 3 equiv) and the mixture was stirred at 25° C. for 1 h. The reaction mixture was added dropwise to 40 mL of water, filtered, and the filter residue was washed with 50 mL of (petroleum ether: ethyl acetate = 10:1) and concentrated under reduced pressure to give 1-(6-anilino-2-methylsulfanyl-5-nitro-pyrimidin-4-yl)-4-methyl-piperidine-4-carboxamide (Intermediate L-2, 600 mg, 1.49 mmol) as a yellow solid. 1H NMR(400MHz,DMSO-d6)δ=10.29(s,1H),7.61(d,J=7.6Hz,2H),7.37(t,J=8.0Hz,2H),7.29(s,1H),7.22-7.13(m,1H),7.0 1(s,1H),3.63(d,J=13.2Hz,2H),3.28-3.21(m,2H),2.41(s,3H),2.09(d,J=14.0Hz,2H),1.51-1.38(m,2H),1.15(s,3H).

[0411] In step 2, to a solution of 1-(6-anilino-2-methylsulfanyl-5-nitro-pyrimidin-4-yl)-4-methyl-piperidine-4-carboxamide (Intermediate L-2) (400 mg, 0.99 mmol, 1 equiv.) in N-methyl-2-pyrrolidone (8 mL) and water (0.8 mL) was added potassium peroxymonosulfate (1.67 g, 9.94 mmol, 10 equiv.). The mixture was stirred at 60° C. for 1 hour. The reaction mixture was washed with water (30 mL) and extracted with 90 mL of ethyl acetate (30 mL×3). The combined organic layer was washed with 100 mL of brine (50 mL×2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®, 40 g SepaFlash® silica flash column, elution with a 0-100% ethyl acetate / petroleum ether gradient at 30 mL / min), and the organic phase was concentrated under reduced pressure to give 1-(6-anilino-2-methylsulfonyl-5-nitro-pyrimidin-4-yl)-4-methyl-piperidine-4-carboxamide (intermediate L-3, 400 mg, 0.91 mmol) as a yellow solid. 1 H NMR(400MHz,CDCl3-d)δ=10.25(s,1H),7.54(d,J=7.8Hz,2H),7.40(t,J=7.9Hz,2H),7.26-7.21(m,1H),5.92-5.38 (m,2H),3.54(t,J=10.6Hz,2H),3.17(s,3H),2.25-2.14(m,2H),2.03-2.01(m,2H),1.70-1.62(m,2H),1.33(s,3H).

[0412] In step 3, a mixture of 2-methylpropane-1,2-diol (236 mg, 2.62 mmol, 3 equiv.) in tetrahydrofuran (5 mL) was added to sodium hydride (105 mg, 2.62 mmol, 60% purity, 3.0 equiv.) and stirred at 25° C. for 10 minutes. Then, 1-(6-anilino-2-methylsulfonyl-5-nitro-pyrimidin-4-yl)-4-methyl-piperidine-4-carboxamide (Intermediate L-3) (380 mg, 0.87 mmol, 1 equiv.) was added to the mixture and stirred at 25° C. for 50 minutes. The reaction mixture was added dropwise to water (20 mL) and extracted with 30 mL of ethyl acetate (10 mL×3). The combined organic layers were washed with 20 mL of brine (10 mL×2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®, 20 g SepaFlash® silica flash column, elution with a 0-100% ethyl acetate / petroleum ether gradient at 30 mL / min). The organic phase was concentrated under reduced pressure to give the crude product. The residue was dissolved in acetonitrile (2 mL) and purified by preparative HPLC (column: Phenomenex Luna C18 150 × 25 mm × 10 μm, mobile phase: [water (formic acid)-ACN], B%: 32%-62%, 10 min). The organic phase was concentrated under reduced pressure to remove acetonitrile. The liquid was lyophilized to give 1-[6-anilino-2-(2-hydroxy-2-methyl-propoxy)-5-nitro-pyrimidin-4-yl]-4-methyl-piperidine-4-carboxamide (intermediate L-4, 300 mg, 675 μmol, 77.1% yield) as a yellow solid. 1 H NMR(400MHz,CDCl3-d)δ=10.48(s,1H),7.59(d,J=7.6Hz,2H),7.40(t,J=8.0Hz,2H),7.24-7.19(m,1H),5.73-5.28(m,2H),4.17(s, 2H),3.69(d,J=13.2Hz,2H),3.54-3.40(m,2H),2.65-2.37(m,1H),2.22-2.09(m,2H),1.70-1.63(m,2H),1.33(s,3H),1.29(s,6H).

[0413] Step 4: To a mixture of 1-[6-anilino-2-(2-hydroxy-2-methyl-propoxy)-5-nitro-pyrimidin-4-yl]-4-methyl-piperidine-4-carboxamide (Intermediate L-4) (80 mg, 180 mmol, 1 equiv.) and 2-chlorobenzaldehyde (253 mg, 1.80 mmol, 0.20 mL, 10 equiv.) in ethyl alcohol (1 mL), iron (101 mg, 1.80 mmol, 10 equiv.) and acetic acid (0.4 mL) were added, and the mixture was stirred at 80 °C for 1 hour. The reaction mixture was washed with water (10 mL) and extracted with 30 mL of ethyl acetate (10 mL × 3). The combined organic layer was washed with 20 mL of brine (10 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The residue was dissolved in acetonitrile (2 mL) and purified by preparative HPLC (column: Waters Xbridge 150 × 25 mm, 5 μm, mobile phase: [water (ammonium bicarbonate)-ACN], B%: 39% to 69%, 8 min), the organic phase was concentrated under reduced pressure to remove acetonitrile, and the liquid was freeze-dried to obtain the crude product. The residue was dissolved in acetonitrile (2 mL) and purified by preparative HPLC (column: Phenomenex luna C18 150 × 25 mm × 10 μm, mobile phase: [water (formic acid)-ACN], B%: 45% to 65%, 10 min), the organic phase was concentrated under reduced pressure to remove acetonitrile, and the liquid was lyophilized to give 1-[8-(2-chlorophenyl)-2-(2-hydroxy-2-methyl-propoxy)-9-phenyl-purin-6-yl]-4-methyl-piperidine-4-carboxamide (compound 95, 48.12 mg, 89.9 μmol, 50% yield) as an off-white solid. 1 H NMR(400MHz,DMSO-d6)δ=7.68-7.61(m,1H),7.51-7.32(m,6H),7.31-7.17(m,3H),6.97(s,1H),5.30-4.67(m,1H),4.61(s,1 H),4.57-4.10(m,1H),3.96(s,2H),3.91-3.36(m,2H),2.14-2.06(m,2H),1.43(t,J=10.0Hz,2H),1.16(s,3H),1.14(s,6H). LCMS:(ES+)m / z=535.4(M+H).

[0414] (xv) General synthesis method M: [ka]

[0415] Preparation of M-2 compound: Method A: In step 1, 4-methyl-piperidine-4-carboxamide (1.7 equiv.) was added to an 8 mL vial containing a solution of 6-chloro-8-(2-chlorophenyl)-9-(4-chlorophenyl)-2-(methylthio)-9H-purine (Intermediate A-1) (1 equiv.) and N,N-diisopropylethylamine (7 equiv.) in NMP (1.1 mL). The reaction mixture was stirred at room temperature for 2.5 hours. Water was added, and the precipitate formed was filtered through a Buchner funnel. The aqueous filtrate was also extracted with DCM, and the DCM extract was evaporated and combined with the filtered material to give the crude intermediate, which was used in the next step.

[0416] In step 2, oxone (3.5 equiv.), NMP (1.6 mL), and water (160 uL) were added to an 8 mL vial containing the crude intermediate overnight at 60° C. Water was added, and the resulting precipitate was filtered through a Buchner funnel to afford the intermediate (97% yield), which was used in the next step without purification.

[0417] In step 3, to the intermediate in an 8 mL vial was added potassium carbonate (2 equivalents), 1-Boc-2-pyrrolidinemethanol derivative (11 equivalents), and DMF (1.2 mL), and the mixture was stirred at 110° C. for 19 hours. The reaction mixture was purified by reverse-phase flash chromatography using 10% to 100% MeCN in 10 mM AmF (product elution at 72% MeCN) to give intermediate M-1 (73% yield).

[0418] Response Scale: 100 mg of intermediate A-1.

[0419] Method B: In step 1, to intermediate M-1 (1 equivalent) was added DCM (1.1 mL) and trifluoroacetic acid (360 μL). The solution was stirred at room temperature for 1 hour. Then, additional trifluoroacetic acid (800 μL) was added, and the reaction was continued for another 2.5 hours. The mixture was quenched with saturated NaHCO (20 mL) and extracted with DCM (2×). The organic layer was dried (MgSO) and evaporated in vacuo to give the intermediate deprotected pyrrolidine (quantitative yield).

[0420] In step 2, a solution of the intermediate deprotected pyrrolidine (1 equiv.) and formaldehyde (6 equiv.) (37% in water) in MeOH (3.7 mL) and AcOH (739 μL) was stirred at room temperature for 3 min before cooling on ice. Sodium triacetoxyborohydride (3 equiv.) was added in small portions, and the mixture was stirred at room temperature for 30 min. The reaction mixture was diluted with saturated NaHCO (25 mL) and extracted with DCM (50 mL). The organic layer was separated, and the aqueous layer was extracted again with DCM (50 mL). The extraction funnel was shaken vigorously because a white emulsion tended to settle to the bottom. The combined DCM layers were dried over MgSO and evaporated in vacuo. The residue was then purified on a 12 g C-18 column using 0% to 80% MeCN in 10 mM aqueous ammonium formate (product elution at 32% MeCN) to give compound M-2 (47% yield).

[0421] Response Scale: 100mg of intermediate M-1 [Table 13]

[0422] (xvi) General synthesis method N: [ka]

[0423] Preparation of N-4 compound:

[0424] Method A: In step 1, to a solution of 6-chloro-8-(2-chlorophenyl)-9-(4-chlorophenyl)-2-methylsulfanyl-purine (Intermediate A-1) (1 equivalent) in N,N-dimethylformamide (5 mL) was added N,N-diisopropylethylamine (3 equivalents) and a secondary amine derivative (1.2 equivalents). The mixture was stirred at 60 °C for 16 hours. The reaction mixture was washed with water (20 mL) and extracted with 60 mL of ethyl acetate (20 mL × 3). The combined organic layers were washed with 40 mL of brine (20 mL × 2), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®, 20 g SepaFlash® silica flash column, eluent: 0–100% ethyl acetate / petroleum ether gradient at 30 mL / min), and the organic phase was concentrated under reduced pressure to give Intermediate N-1 (92% yield) as a pale yellow solid.

[0425] In step 2, to a mixture of intermediate N-1 (1 equivalent) in N-methyl-2-pyrrolidone (5 mL) and water (0.5 mL) was added potassium peroxymonosulfate (10 equivalents). The mixture was stirred at 60° C. for 1 hour. The reaction mixture was added dropwise to 40 mL of water, filtered, and the filter residue was concentrated under reduced pressure to give intermediate N-2 (crude) as a yellow solid.

[0426] In step 3, a mixture of intermediate N-2 (1 equivalent), nucleophile (Nu-H) (5 equivalents), and N,N-diisopropylethylamine (8.8 equivalents) in N-methyl-2-pyrrolidone (5 mL) was stirred at 140 °C for 2 hours. The reaction mixture was washed with water (10 mL) and extracted with 30 mL of ethyl acetate (10 mL × 3). The combined organic layers were washed with 20 mL of brine (10 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®, 40 g SepaFlash® silica flash column, eluent: 0–100% ethyl acetate / petroleum ether gradient at 60 mL / min), and the organic phase was concentrated under reduced pressure to give intermediate N-3 (92% yield) as a white solid.

[0427] In step 4, to a mixture of intermediate N-3 (1 equivalent) in ethyl alcohol (1 mL) and water (0.1 mL) was added hydrido(dimethylphosphinic acid-kp)[hydrogen bis(dimethylphosphinite-kp)]platinum(II) (1 equivalent). The mixture was stirred at 60° C. for 2 hours. The reaction mixture was filtered and concentrated under reduced pressure to obtain a residue. The residue was purified by preparative HPLC (column: Waters Xbridge 150×25 mm×5 μm, mobile phase: [water (ammonium hydroxide or ammonium bicarbonate)-ACN]) to obtain compound N-4 as a white solid.

[0428] Response Scale: 500mg of intermediate A-1

[0429] Method B: In step 1, to a solution of 6-chloro-8-(2-chlorophenyl)-9-(4-chlorophenyl)-2-methylsulfanyl-purine (Intermediate A-1) (1.0 equivalent) in N,N-dimethylformamide (5 mL) was added N,N-diisopropylethylamine (3.0 equivalents) and a secondary amine derivative (1.2 equivalents). The mixture was stirred at 60° C. for 2 hours. The reaction mixture was added dropwise to 30 mL of water, filtered, and the residue was concentrated under reduced pressure to give Intermediate N-1 (94% yield) as a pale yellow solid.

[0430] In step 2, to a mixture of intermediate N-1 (1 equivalent) in N-methyl-2-pyrrolidone (5 mL) and water (0.5 mL) was added potassium peroxymonosulfate (10 equivalents). The mixture was stirred at 60° C. for 1 hour. The reaction mixture was added dropwise to 40 mL of water, filtered, and the filter residue was concentrated under reduced pressure to give intermediate N-2 (crude) as a yellow solid.

[0431] In step 3, a solution of intermediate N-2 (1.0 equiv.) in nucleophile (Nu-H) (10 equiv.) was stirred at 140° C. for 12 h. The residue was dissolved in acetonitrile (2 mL) and purified by preparative HPLC (column: Phenomenex Luna C18 150 × 25 mm × 10 μm, mobile phase: [water (formic acid)-ACN], B%: 60% to 90%, 10 min). The organic phase was concentrated under reduced pressure to remove acetonitrile, and the liquid was lyophilized to give intermediate N-3 (54% yield) as a white solid.

[0432] In step 4, to a solution of intermediate N-3 (1.0 equivalent) in ethyl alcohol (1 mL) and water (0.1 mL) was added hydrido(dimethylphosphinic acid-kp)[hydrogen bis(dimethylphosphinite-kp)]platinum(II) (1.0 equivalent). The mixture was stirred at 60 °C for 1 hour. The reaction mixture was filtered and concentrated under reduced pressure to obtain a residue. The residue was dissolved in acetonitrile (2 mL) and purified by preparative HPLC (column: Phenomenex Luna C18 150 × 25 mm × 10 μm, mobile phase: [water (formic acid)-ACN], B%: 39% to 69%, 10 min). The organic phase was concentrated under reduced pressure to remove acetonitrile, and the liquid was lyophilized to obtain compound N-4 as a white solid.

[0433] Response Scale: 500mg of intermediate A-1 [Table 14]

[0434] (xvii) General synthesis method O: [ka]

[0435] Preparation of O-5 compound: Method A: In step 1, to a solution of 6-chloro-N-(4-chlorophenyl)-2-methylsulfanyl-5-nitro-pyrimidin-4-amine (Intermediate B-2) (1 g, 3.02 mmol, 1 equiv.) in N,N-dimethylformamide (10 mL) was added N,N-diisopropylethylamine (1.17 g, 9.06 mmol, 1.58 mL, 3 equiv.) and azetidine-3-carbonitrile hydrochloride (430 mg, 3.62 mmol, 1.2 equiv.). The mixture was stirred at 60° C. for 1 hour. The reaction mixture was added dropwise to 50 mL of water, filtered, and the residue was concentrated under reduced pressure to give 1-[6-(4-chloroanilino)-2-methylsulfanyl-5-nitro-pyrimidin-4-yl]azetidine-3-carbonitrile (Intermediate O-1, crude) as a pale yellow solid. 1 H NMR(400MHz,DMSO-d6)δ=10.38(s,1H),7.67-7.53(m,2H),7.48-7.35(m,2H ),4.53-4.35(m,2H),4.33(d,J=6.0Hz,2H),3.90-3.79(m,1H),2.39(s,3H).

[0436] In step 2, to a solution of 1-[6-(4-chloroanilino)-2-methylsulfanyl-5-nitro-pyrimidin-4-yl]azetidine-3-carbonitrile (Intermediate O-1) (1.2 g, 3.18 mmol, 1 equivalent) in N-methyl-2-pyrrolidone (12 mL) and water (1.2 mL) was added potassium peroxymonosulfate (5.36 g, 31.85 mmol, 10 equivalents). The mixture was stirred at 60 °C for 1 hour. The reaction mixture was added dropwise to 50 mL of water, filtered, and the filter residue was concentrated under reduced pressure to give 1-[6-(4-chloroanilino)-2-methylsulfonyl-5-nitro-pyrimidin-4-yl]azetidine-3-carbonitrile (Intermediate O-2, 74% yield) as a pale yellow solid. 1 H NMR(400MHz,DMSO-d6)δ=10.43(s,1H),7.62-7.56(m,2H),7.48-7.43(m,2 H),4.54-4.42(m,2H),4.41-4.33(m,2H),3.95-3.85(m,1H),3.21(s,3H). LCMS:(ES +) m / z = 409.0 (M+H).

[0437] In step 3, a solution of 1-[6-(4-chloroanilino)-2-methylsulfonyl-5-nitro-pyrimidin-4-yl]azetidine-3-carbonitrile (Intermediate O-2) (1 equivalent) in nucleophile (Nu-H) (5 equivalents) was stirred at 140° C. for 1 hour. , **The reaction mixture was filtered and concentrated under reduced pressure to give a residue which was purified by flash silica gel chromatography and the organic phase was concentrated under reduced pressure to give intermediate O-3 (59% yield) as a yellow solid.

[0438] Response Scale: 400mg of intermediate O-2

[0439] *For compound 137: tBuOK (3 eq) in NMP (4 mL) at 80° C. for 1 hour. Extraction with EtOAc.

[0440] **For compound 140: 60°C, 1 hour.

[0441] In step 4, to a solution of intermediate O-3 (1 equivalent) in ethyl alcohol (2.5 mL) and water (0.25 mL) was added hydrido(dimethylphosphinic acid-kp)[hydrogen bis(dimethylphosphinite-kp)]platinum(II) (1 equivalent). The mixture was stirred at 60 °C for 1 hour. The reaction mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®, 12 g SepaFlash® silica flash column, eluent: 0-100% ethyl acetate / petroleum ether gradient at 20 mL / min), and the organic phase was concentrated under reduced pressure to give intermediate O-4 (86% yield) as a yellow solid.

[0442] Response Scale: 250mg of intermediate O-3

[0443] In step 5, a mixture of intermediate O-4 (1 equivalent) and aldehyde derivative (5 equivalents) in ethyl alcohol (1.5 mL) was added with iron (10 equivalents) and acetic acid (0.6 mL), and the mixture was stirred at 80° C. for 1 hour. The reaction mixture was filtered and concentrated under reduced pressure to obtain a residue. The residue was purified by preparative HPLC (column: Phenomenex Luna C18 150×25 mm×10 μm, mobile phase: [water (formic acid)-ACN]), and the organic phase was concentrated under reduced pressure to remove acetonitrile. The liquid was lyophilized to obtain compound O-5 as a yellow solid.

[0444] Response Scale: 170 mg of intermediate O-4

[0445] Method B: In step 1, a mixture of 6-chloro-N-(4-chlorophenyl)-2-methylsulfanyl-5-nitro-pyrimidin-4-amine (Intermediate B-2) (1 equivalent), a secondary amine derivative (1.1 equivalents), and cesium carbonate (3 equivalents) in N,N-dimethylformamide (30 mL) was stirred for 2 hours at 25° C. The reaction mixture was added dropwise to 200 mL of water, filtered, and the filter cake was concentrated under reduced pressure to give Intermediate O-1 (crude) as a yellow solid, which was used directly in the next step without further purification.

[0446] Response Scale: 2.3 g of intermediate B-2

[0447] In step 2, a mixture of intermediate O-1 (1 equivalent) and potassium hydrogen oxidoxide (10 equivalents) in N-methyl-2-pyrrolidone (30 mL) and water (5 mL) was stirred at 60° C. for 2 hours. The reaction mixture was added dropwise to water (150 mL), filtered, the filter cake was concentrated under reduced pressure, and the resulting residue was purified by flash silica gel chromatography (ISCO®, 80 g SepaFlash® silica flash column, eluent: approximately 30% to approximately 80% ethyl acetate / petroleum ether gradient at 50 mL / min). The cleavage fractions were concentrated under reduced pressure to give intermediate O-2 (crude) as a yellow solid.

[0448] Response Scale: 2.6g of intermediate O-1

[0449] In step 3, sodium hydride (60% purity, 5.0 equiv.) was added to a solution of the nucleophile (Nu-H) (5 equiv.) in tetrahydrofuran (5 mL), and the resulting mixture was stirred at 25 °C for 0.5 h. Intermediate O-2 (1 equiv.) was then added to the mixture, and the mixture was stirred at 25 °C for 1.5 h. The reaction mixture was diluted with water (50 mL) and extracted with ethyl acetate (20 mL × 3). The combined organic layers were washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by flash silica gel chromatography (ISCO®, 20 g SepaFlash® silica flash column, eluent: 0% to 50% ethyl acetate / petroleum ether gradient at 30 mL / min). The cleaved fraction was concentrated under reduced pressure to give intermediate O-3 (89% yield) as a yellow solid.

[0450] Response Scale: 0.5g of intermediate O-2

[0451] In step 4, a mixture of intermediate O-3 (1 equivalent) and hydrido(dimethylphosphinic acid-kp)[hydrogen bis(dimethylphosphinite-kp)]platinum(II) (1 equivalent) in ethanol (5 mL) and water (0.5 mL) was stirred at 80 °C for 1 h. The reaction mixture was cooled to room temperature, filtered, and the resulting filtrate was concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®, 20 g SepaFlash® silica flash column, eluent: 50–100% ethyl acetate / petroleum ether gradient at 40 mL / min). The cleavage fraction was concentrated under reduced pressure to give intermediate O-4 (70% yield) as a yellow solid. Response Scale: 300mg of intermediate O-3

[0452] In step 5, a mixture of intermediate O-4 (1 equivalent), aldehyde derivative (5 equivalents), and iron (10 equivalents) in ethanol (3 mL) and acetic acid (1.2 mL) was stirred at 80 °C for 2 hours. The reaction mixture was cooled to room temperature and filtered. The resulting filtrate was concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®, 20 g SepaFlash® silica flash column, elution with a 50-100% ethyl acetate / petroleum ether gradient at 35 mL / min). The cleavage fraction was concentrated under reduced pressure, and the resulting crude product was purified by reverse-phase HPLC (column: Phenomenex Synergi C18 150 × 25 mm × 10 μm, mobile phase: [water (formic acid)-ACN], B%: 33%-63%). The cleavage fraction was concentrated under reduced pressure to remove acetonitrile. The residue was lyophilized to give compound O-5 as a yellow solid. Response Scale: 200mg of intermediate O-4

[0453] Preparation of O-8 compound:

[0454] Method C: In step 1, a mixture of 6-chloro-N-(4-chlorophenyl)-2-methylsulfanyl-5-nitro-pyrimidin-4-amine (912 mg, 2.75 mmol, 1.0 equivalent), 3-ethoxyazetidine-3-carboxylic acid hydrochloride (500 mg, 2.75 mmol, 1.0 equivalent) and cesium carbonate (2.69 g, 8.26 mmol, 3.0 equivalent) in N,N-dimethylformamide (10 mL) was stirred for 1 hour at 25° C. The reaction mixture was added dropwise to 80 mL of 1N hydrochloric acid (pH=3), filtered, and the filter cake was concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®, 20 g SepaFlash® silica flash column, elution with a 0-100% ethyl acetate / petroleum ether gradient at 30 mL / min), and the organic phase was concentrated under reduced pressure to give 1-[6-(4-chloroanilino)-2-methylsulfanyl-5-nitro-pyrimidin-4-yl]-3-ethoxy-azetidine-3-carboxylic acid (1 g, 2.27 mmol, 82.5% yield) as a yellow solid. 1H NMR(400MHz,DMSO-d6)δ=10.39(s,1H),7.62(d,J=8.8Hz,2H),7.43(d,J=8.8Hz,2H),4.67- 4.25(m,2H),4.18(d,J=10.8Hz,2H),3.51(q,J=6.8Hz,2H),2.39(s,3H),1.19-1.13(m,3H).

[0455] Step 2: A mixture of 1-[6-(4-chloroanilino)-2-methylsulfanyl-5-nitro-pyrimidin-4-yl]-3-ethoxy-azetidine-3-carboxylic acid (400 mg, 0.91 mmol, 1.0 equiv), ammonium chloride (107 mg, 2.00 mmol, 2.2 equiv), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (261 mg, 1.36 mmol, 1.5 equiv), 1-hydroxybenzotriazole (184 mg, 1.36 mmol, 1.5 equiv), and N,N-diisopropylethylamine (259 mg, 2.00 mmol, 0.35 mL, 2.2 equiv) in N,N-dimethylformamide (4 mL) was stirred at 25° C. for 2 hours. The mixture was concentrated in vacuo to remove N,N-dimethylformamide, then dissolved in 150 mL of dichloromethane, washed with 150 mL of 10% citric acid, washed with 80 mL of saturated sodium bicarbonate, saturated with brine (80 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give 1-[6-(4-chloroanilino)-2-methylsulfanyl-5-nitro-pyrimidin-4-yl]-3-ethoxy-azetidine-3-carboxamide (390 mg, 0.89 mmol, 97.7% yield) as a yellow solid. 1 H NMR(400MHz,DMSO-d6)δ=10.38(s,1H),7.65-7.60(m,2H),7.59-7.47(m,2H),7.46-7 .40(m,2H),4.52-4.08(m,4H),3.52-3.41(m,2H),2.39(s,3H),1.20(t,J=6.8Hz,3H).

[0456] In step 3, to a solution of 1-[6-(4-chloroanilino)-2-methylsulfanyl-5-nitro-pyrimidin-4-yl]-3-ethoxy-azetidine-3-carboxamide (390 mg, 0.89 mmol, 1 equiv.) in N-methyl-2-pyrrolidone (4 mL) and water (0.4 mL) was added potassium peroxymonosulfate (1.49 g, 8.89 mmol, 10 equiv.). The mixture was stirred at 60° C. for 1 hour. The reaction mixture was added dropwise to 100 mL of water, filtered, and the filter residue was washed with 100 mL of acetonitrile and concentrated under reduced pressure to give 1-[6-(4-chloroanilino)-2-methylsulfonyl-5-nitro-pyrimidin-4-yl]-3-ethoxy-azetidine-3-carboxamide (380 mg, 0.81 mmol, 90.8% yield) as a yellow solid. 1 H NMR(400MHz,DMSO-d6)δ=10.43(s,1H),7.59(d,J=8.8Hz,4H),7.45(d,J=8.8 Hz,2H),4.23(s,4H),3.49-3.44(m,2H),3.22(s,3H),1.21(t,J=6.8Hz,3H). LCMS:(ES + ) m / z = 471.2 (M+H).

[0457] To a solution of 1-[6-(4-chloroanilino)-2-methylsulfonyl-5-nitro-pyrimidin-4-yl]-3-ethoxy-azetidine-3-carboxamide (320 mg, 0.68 mmol, 1.0 equiv.) in N-methyl-2-pyrrolidone (3 mL), potassium tert-butoxide (229 mg, 2.04 mmol, 3.0 equiv.) and 2-methylpropane-1,2-diol (306 mg, 3.40 mmol, 5.0 equiv.) were added. The mixture was stirred at 80° C. for 1 hour. The reaction mixture was washed with water (10 mL) and extracted with 30 mL of ethyl acetate (10 mL×3). The combined organic layers were washed with 20 mL of brine (10 mL×2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The resulting residue was purified by flash silica gel chromatography (ISCO®, 20 g SepaFlash® silica flash column, elution with a 0% to approximately 100% ethyl acetate / petroleum ether gradient at 30 mL / min), and the organic phase was concentrated under reduced pressure to give 1-[6-(4-chloroanilino)-2-(2-hydroxy-2-methyl-propoxy)-5-nitro-pyrimidin-4-yl]-3-ethoxy-azetidine-3-carboxamide (200 mg, 0.37 mmol, 54% yield) as a yellow solid.

[0458] To a mixture of 1-[6-(4-chloroanilino)-2-(2-hydroxy-2-methyl-propoxy)-5-nitro-pyrimidin-4-yl]-3-ethoxy-azetidine-3-carboxamide (170 mg, 0.35 mmol, 1.0 equiv) and 5-formylpyridine-2-carbonitrile (234 mg, 1.77 mmol, 5 equiv) in ethyl alcohol (1.7 mL) was added iron (197 mg, 3.54 mmol, 10 equiv) and acetic acid (0.34 mL), and the mixture was stirred at 80° C. for 1 hour. The reaction mixture was filtered and concentrated under reduced pressure to provide a residue. The residue was dissolved in N,N-dimethylformamide (2 mL) and purified by preparative HPLC (column: Phenomenex Luna C18 150 × 25 mm × 10 μm, mobile phase: [water (formic acid)-ACN], B%: 44%–74%, 10 min). The organic phase was concentrated under reduced pressure to remove acetonitrile, and the liquid was lyophilized to obtain compound J-3, 1-[9-(4-chlorophenyl)-8-(6-cyano-3-pyridyl)-2-(2-hydroxy-2-methyl-propoxy)purin-6-yl]-3-ethoxy-azetidine-3-carboxamide (compound 139, 48.34 mg, 81.57 μmol, 23% yield), as a yellow solid. [Table 15]

[0459] (xviii) General synthesis method P: [ka]

[0460] Preparation of P-3 and P-5 compounds: Method A (for P-3 compound): In step 1, 6-chloro-8-(2-chlorophenyl)-9-(4-chlorophenyl)-2-(methylthio)-9H-purine (intermediate A-1) (1 equivalent) and N,N-diisopropylethylamine (30 equivalents) were added to a secondary amine derivative (3 equivalents). NMP (2.5 mL) was then added, and the reaction mixture was stirred at room temperature overnight. Upon addition of water, a precipitate and an emulsion formed, which was filtered. The filtrate was extracted with ethyl acetate. The filtered precipitate was dissolved in the ethyl acetate extract, which was mixed, dried over magnesium sulfate, and evaporated to form intermediate P-1 (quantitative conversion) as an oil. The residue was used in the next step without purification.

[0461] Step 2: To intermediate P-1 (1 equivalent) in THF (2.2 mL) was added 4 M sodium hydroxide (27 equivalents). The mixture was stirred at 60° C. for 2.5 hours. After the reaction flask was cooled to room temperature, the mixture was concentrated. The mixture was acidified to pH 4 using 6 M HCl. The precipitate that formed was filtered through a Buchner funnel to give the crude intermediate carboxylic acid, which was used without further purification.

[0462] A mixture of the intermediate carboxylic acid (1 equiv.), HATU (2.2 equiv.), and N,N-diisopropylethylamine (12 equiv.) in EtOAc (5.5 mL) was stirred at room temperature for 15 minutes, after which 0.5 M ammonia in dioxane (2 equiv.) was added. The mixture was stirred at room temperature for 1.5 hours. The crude mixture was diluted with water (130 mL) and extracted with ethyl acetate (350 mL × 2). The combined organic layers were dried over magnesium sulfate and evaporated in vacuo to give intermediate P-2 (quantitative conversion) as a viscous oil, which was used without further drying or purification.

[0463] In step 3, intermediate P-2 (1 equivalent) was dissolved in NMP (3.5 mL), and then water (300 μL) was added dropwise, ensuring that the solution remained clear. Another portion of oxone (3.2 equivalents) was then added, and the reaction mixture was stirred at room temperature overnight. Cold water was added, and the resulting precipitate was filtered through a Buchner funnel. The solid was filtered and purified on a C-18 column (loaded with minimal DMF and water) using 20%-100% acetonitrile / aqueous AmF (product elution, 53% acetonitrile) to give the crude sulfone intermediate (43% yield).

[0464] A solution of the sulfone intermediate (1 equiv.) in the nucleophile (Nu-H) (100 equiv.) was stirred overnight at 100 °C. Upon cooling, the solution was directly injected onto a C-18 column and purified using 3% to 100% acetonitrile in 10 mM aqueous ammonium formate as the eluent (product elution at 90% acetonitrile) to give compound P-3 (27% yield). Response Scale: 185 mg of intermediate A-1

[0465] Method B (for compound P-5): To a solution of intermediate P-4 (1 equivalent) in THF (1.56 mL) was added 4 M sodium hydroxide (70 equivalents). The mixture was stirred at 80 °C for 2 hours. The mixture was concentrated in vacuo, acidified using minimal aqueous HCl, and lyophilized. The product was purified on a 12 g C-18 column using 15% to 100% MeCN in aqueous AmF buffer to give compound P-5 (73% yield) after lyophilization. Response Scale: 140 mg of intermediate P-4 [Table 16]

[0466] (xix) General synthesis method Q: [ka]

[0467] Preparation of Q-3 Compound: Method for compound 239: In step 1, dibenzyl N,N-diisopropylphosphoramidite technical grade, 90% (84.1 μL, 238 μmol) followed by tetrazole solution (880 μL, 396 μmol) (0.45 M in MeCN) were added to a solution of intermediate Q-1 (44.0 mg, 79.2 μmol) in DCM (792 μL) at room temperature. The reaction mixture was stirred at that temperature for 5 minutes.

[0468] In step 2, 3-chloroperbenzoic acid (28.4 mg, 127 μmol) was added in one portion to the reaction mixture, and the solution was stirred at room temperature for an additional 5 minutes, at which point complete conversion was observed by LCMS. Water (30 mL) and EtOAc (30 mL) were added, and the organic layer was separated and washed successively with saturated aqueous sodium bicarbonate (50 mL), 10% aqueous sodium bisulfite (50 mL), saturated aqueous sodium bicarbonate (50 mL), and brine (50 mL). The organic layer was then dried (magnesium sulfate), filtered, and concentrated. The crude material (Intermediate Q-2) was used in the next step without purification.

[0469] In step 3, the residue was dissolved in DCM (500 μL) and hydrochloric acid (4 M in dioxane) (198 μL, 792 μmol) was added. The reaction mixture was stirred at room temperature overnight. Volatiles were removed under reduced pressure, and the residue was purified by reverse-phase flash chromatography (DMSO, loaded with 12 g of C18) using 10–60% ACN in 10 mM Ammonium Chloride (AmB, pH 10) to give 1-((6-(3-acetamido-3-methylazetidin-1-yl)-8-(2-chlorophenyl)-9-(4-chlorophenyl)-9H-purin-2-yl)oxy)-2-methylpropan-2-yl dihydrogen phosphate (compound 239, 27.6 mg, 55% yield). 1 H NMR(400MHz,DMSO-d6):δ=8.45(s,1H),7.67(dd,1H),7.55-7.39(m,5H),7.33-7.26(m,2H),4.60(br d,1H),4.42-4.24(br m,2H),4.15(br d,2H),4.07(br s,1H),1.83(s,3H),1.54(s,3H),1.36(s,6H).LCMS:(ES +) m / z = 635.2 (M+H) + .

[0470] (xx) Compound 1: To a solution of N-[8-(2-chlorophenyl)-9-(4-chlorophenyl)-6-(4-cyano-4-methyl-1-piperidyl)purin-2-yl]-2-methyl-propanamide (compound 89) (22 mg, 40.1 μmol, 1.0 equiv.) in ethanol (0.9 mL) and water (0.1 mL) was added dimethylphosphinite; platinum dimethylphosphinate (17 mg, 40.1 mol, 1.0 equiv.), and the mixture was stirred at 80° C. for 15 hours. The reaction was concentrated in vacuo. The residue was purified by preparative HPLC (column: Unisil 3-100 C18 Ultra 150 × 50 mm × 3 μm, mobile phase: [water (formic acid)-acetonitrile], B%: 42% to 72%, 7 min) to give 1-[8-(2-chlorophenyl)-9-(4-chlorophenyl)-2-(2-methylpropanoylamino)purin-6-yl]-4-methyl-piperidine-4-carboxamide (compound 1, 16.84 mg, 11.5 μmol, yield 28.6%) as an off-white solid. 1 H NMR(400MHz,MeOD-d4)δ=7.60(br d,J=7.6Hz,1H),7.53-7.19(m,7H),4.84-4.61(m,2H),4.09-3.59(m,2H),3.01-2.8 0(m,1H),2.32-2.11(m,2H),1.75-1.47(m,2H),1.28(s,3H),1.17(d,J=6.8Hz,6H). LCMS:(ES + ) m / z = 566.3 (M+H).

[0471] (xxi) Compound 3: To a solution of 4-methyl-1H-pyrazole (37 mg, 447 μmol, 5 equivalents) in N,N-dimethylformamide (0.5 mL) was added sodium hydride (5 mg, 107 μmol, 60% purity, 1.2 equivalents) at 0° C., and the resulting mixture was stirred at 25° C. for 0.5 hours. Then, 1-[8-(2-chlorophenyl)-9-(4-chlorophenyl)-2-methylsulfonyl-purin-6-yl]-4-methyl-piperidine-4-carboxamide (Compound 68) (50 mg, 89.4 μmol, 1 equivalent) was added to the mixture, and the resulting mixture was stirred at 25° C. for 2 hours. The mixture was diluted with saturated ammonium chloride solution (2 mL) and extracted with ethyl acetate (2 mL × 3). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by preparative HPLC (column: Waters Xbridge 150 × 25 mm × 5 μm, mobile phase: [water (ammonium bicarbonate)-ACN], B%: 53% to 83%, 10 min) and dried by lyophilization to give 1-[8-(2-chlorophenyl)-9-(4-chlorophenyl)-2-(4-methylpyrazol-1-yl)purin-6-yl]-4-methyl-piperidine-4-carboxamide (compound 3, 16.05 mg, 28.6 μmol, 32% yield) as a white solid. 1 H NMR(400MHz,DMSO-d6)δ=8.33(s,1H),7.75-7.67(m,1H),7.57-7.42(m,6H),7.40-7.33(m,2H),7.29(s,1H),6.97( s,1H),5.25-4.31(m,2H),4.12-3.46(m,2H),2.14(d,J=14.0Hz,2H),2.08(s,3H),1.50-1.45(m,2H),1.18(s,3H). LCMS:(ES + ) m / z = 561.1 (M+H).

[0472] (xxii) Compound 4: To a solution of 3-methyl-1H-pyrazole (73 mg, 894 μmol, 5 equivalents) in N,N-dimethylformamide (1 mL) was added sodium hydride (9 mg, 214 μmol, 60% purity, 1.2 equivalents) at 0° C., and the resulting mixture was stirred at 25° C. for 0.5 hours. Then, 1-[8-(2-chlorophenyl)-9-(4-chlorophenyl)-2-methylsulfonyl-purin-6-yl]-4-methyl-piperidine-4-carboxamide (Compound 68) (0.1 g, 178.74 μmol, 1 equivalent) was added to the mixture, and the resulting mixture was stirred at 25° C. for 2 hours. The mixture was diluted with saturated ammonium chloride solution (2 mL) and extracted with ethyl acetate (2 mL × 3). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by preparative HPLC (column: Waters Xbridge 150 × 25 mm × 5 μm, mobile phase: [water (ammonium bicarbonate)-ACN], B%: 53% to 83%, 10 min) and dried by lyophilization to give the product 1-[8-(2-chlorophenyl)-9-(4-chlorophenyl)-2-(3-methylpyrazol-1-yl)purin-6-yl]-4-methyl-piperidine-4-carboxamide (compound 4, 50.64 mg, 90.2 μmol, 50.4% yield) as a white solid. 1 H NMR(400MHz,DMSO-d6)δ=8.46(d,J=2.4Hz,1H),7.74-7.68(m,1H),7.57-7.42(m,5H),7.41-7.34(m,2H),7.29(s,1H),6.97(s,1H) ,6.29(d,J=2.4Hz,1H),5.39-4.24(m,2H),4.14-3.43(m,2H),2.24(s,3H),2.14(d,J=13.6Hz,2H),1.50-1.48(m,2H),1.18(s,3H). LCMS:(ES + ) m / z = 561.1 (M+H).

[0473] (xxiii) Compound 5: To a solution of 1-[8-(2-chlorophenyl)-9-(4-chlorophenyl)-2-methylsulfonyl-purin-6-yl]-4-methyl-piperidine-4-carboxamide (compound 68) (50 mg, 0.09 mmol, 1 equiv.) in N-methyl-2-pyrrolidone (0.5 mL), tert-butyl (3S)-3-(hydroxymethyl)piperazine-1-carboxylate (193 mg, 0.89 mmol, 10 equiv.) was added, and the mixture was stirred at 200° C. under microwave irradiation for 2 hours. The reaction mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC (column: Waters Xbridge 150 × 25 mm × 5 μm, mobile phase: [water (ammonium bicarbonate)-acetonitrile], B%: 40% to 70%, 8 min) to give 1-[8-(2-chlorophenyl)-9-(4-chlorophenyl)-2-[(2S)-2-(hydroxymethyl)piperazin-1-yl]purin-6-yl]-4-methyl-piperidine-4-carboxamide (compound 5, 23.8 mg, 39.96 μmol, 44.7% yield) as a yellow solid. 1 H NMR(400MHz,DMSO-d6)δ=7.66-7.63(m,1H),7.51-7.40(m,5H),7.31-7.21(m,3H),6.93(s,1H),4.99-4.14(m,5H),3.93-3.48(m,2H),2 .90(d,J=11.6Hz,1H),2.79-2.70(m,1H),2.62-2.53(m,3H),2.44(d,J=12.4Hz,1H),2.12-2.01(m,2H),1.46-1.34(m,2H),1.15(s,3H). LCMS:(ES + ) m / z = 595.2 (M+H).

[0474] (xxiv) Compound 6: To a solution of 1-[8-(2-chlorophenyl)-9-(4-chlorophenyl)-2-methylsulfonyl-purin-6-yl]-4-methyl-piperidine-4-carboxamide (Compound 68) (80 mg, 143 μmol, 1 equiv.) and propane-1,3-diol (54 mg, 714.97 μmol, 5 equiv.) in N,N-dimethylformamide (1 mL), potassium carbonate (40 mg, 286 μmol, 2 equiv.) was added, and the resulting mixture was stirred at 100° C. for 12 hours. The mixture was diluted with water (2 mL) and extracted with ethyl acetate (2 mL × 3). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by preparative HPLC (column: Waters Xbridge 150 × 25 mm × 5 μm, mobile phase: [water (ammonium bicarbonate)-ACN], B%: 42% to 72%, 9 min) and dried by lyophilization to give the product 1-[8-(2-chlorophenyl)-9-(4-chlorophenyl)-2-(3-hydroxypropoxy)purin-6-yl]-4-methyl-piperidine-4-carboxamide (compound 6, 45.86 mg, 82.06 μmol, 57.3% yield) as a yellow solid. 1 H NMR(400MHz,MeOD-d4)δ=7.61-7.55(m,1H),7.48-7.35(m,5H),7.29-7.23(m,2H),4.75(br s,2H),4.41-4.38(m,2H),3.72-3.69(m,4H),2.20(d,J=14.2Hz,2H),1.98-1.95(m,2H),1.61-1.55(m,2H),1.28(s,3H).LCMS:(ES + ) m / z = 555.2 (M+H).

[0475] (xxv) Compound 7: To a solution of 1-[8-(2-chlorophenyl)-9-(4-chlorophenyl)-2-methylsulfonyl-purin-6-yl]-4-methyl-piperidine-4-carboxamide (Compound 68) (150 mg, 268 μmol, 1 equiv.) and propane-1,2-diol (102 mg, 1.34 mmol, 5 equiv.) in N,N-dimethylformamide (2 mL), potassium carbonate (74 mg, 536 μmol, 2 equiv.) was added, and the resulting mixture was stirred at 100° C. for 1 hour. The mixture was diluted with water (2 mL) and extracted with ethyl acetate (2 mL×3). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by preparative HPLC (column: Waters Xbridge 150 × 25 mm × 5 μm; mobile phase: [water (ammonium bicarbonate)-ACN]; B%: 43% to 73%, 10 min) and dried by lyophilization to give a mixture (120 mg).

[0476] The mixture was separated by chiral SFC (column: DAICEL CHIRALPAK AD (250 mm × 30 mm, 10 μm), mobile phase: [0.1% ammonium hydroxide IPA], B%: 35% to 35%, 5 min) to obtain two peaks.

[0477] One peak was purified by preparative HPLC (column: Waters Xbridge 150 × 25 mm × 5 μm, mobile phase: [water (NH4HCO3)-ACN], B%: 43%-73%, 10 min) and dried by lyophilization to give 1-[8-(2-chlorophenyl)-9-(4-chlorophenyl)-2-(2-hydroxy-1-methyl-ethoxy)purin-6-yl]-4-methyl-piperidine-4-carboxamide (compound 8, 19.08 mg, 33.0 μmol, 15.3% yield) as a white solid. 1H NMR(400MHz,MeOD-d4)δ=7.61-7.56(m,1H),7.49-7.35(m,5H),7.29-7.23(m,2H),5.21-5.09(m,1H),4.85-4 .66(m,2H),3.98-3.55(m,4H),2.20(d,J=14.0Hz,2H),1.66-1.51(m,2H),1.32(d,J=6.4Hz,3H),1.28(s,3H). LCMS:(ES + ) m / z = 555.3 (M+H).

[0478] (xxvi) Compound 8: Following the procedure from Compound 7, the other peak was purified by preparative HPLC (Column: Waters Xbridge 150 × 25 mm × 5 μm, Mobile phase: [water (ammonium bicarbonate)-ACN], B%: 43% to 73%, 10 min) and dried by lyophilization to give 1-[8-(2-chlorophenyl)-9-(4-chlorophenyl)-2-(2-hydroxypropoxy)purin-6-yl]-4-methyl-piperidine-4-carboxamide (Compound, 93.20 mg, 167.79 μmol, Yield 77.6%) as a white solid. 1 H NMR(400MHz,MeOD-d4)δ=7.61-7.56(m,1H),7.49-7.34(m,5H),7.30-7.23(m,2H),4.84-4.67(m,2H),4.24-4.15(m,2H) ),4.13-4.04(m,1H),3.95-3.65(m,2H),2.20(d,J=14.0Hz,2H),1.62-1.56(m,2H),1.28(s,3H),1.23(d,J=6.4Hz,3H). LCMS:(ES+)m / z=555.2(M+H).

[0479] (xxvii) Compound 9: To a solution of 1-[8-(2-chlorophenyl)-9-(4-chlorophenyl)-2-methylsulfonyl-purin-6-yl]-4-methyl-piperidine-4-carboxamide (Compound 68) (80 mg, 0.14 mmol, 1.0 equiv.) and 2-methylpropane-1,2-diol (64 mg, 0.71 mmol, 5.0 equiv.) in N,N-dimethylformamide (2 mL), potassium carbonate (40 mg, 0.29 mmol, 2.0 equiv.) was added, and the resulting mixture was stirred at 100° C. for 12 hours. The mixture was diluted with water (2 mL) and extracted with ethyl acetate (2 mL × 3). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by preparative HPLC (column: Waters Xbridge C18 150 × 50 mm × 10 μm, mobile phase: [water (ammonium bicarbonate)-acetonitrile], B%: 47% to 77%, 10 min), and then lyophilized to give the product 1-[8-(2-chlorophenyl)-9-(4-chlorophenyl)-2-[2-hydroxy-2-methyl-propoxy)purin-6-yl]-4-methyl-piperidine-4-carboxamide (compound 9, 37.57 mg, 65.09 μmol, 45.5% yield) as a white solid. 1 H NMR(400MHz,MeOD-d4)δ=7.5-7.57(m,1H),7.50-7.36(m,5H),7.32-7.25(m,2H),4.90(br s,2H),4.16(s,2H),4.00-3.71(m,2H),2.22(d,J=14.4Hz,2H),1.70-1.52(m,2H),1.32-1.26(m,9H).LCMS:(ES + ) m / z = 569.2 (M+H).

[0480] (xxviii) Compound 10: To a solution of 1-[8-(2-chlorophenyl)-9-(4-chlorophenyl)-2-methylsulfonyl-purin-6-yl]-4-methyl-piperidine-4-carboxamide (Compound 68) (80 mg, 143 μmol, 1 equiv.) and 2-methoxyethanol (54 mg, 715 μmol, 5 equiv.) in N,N-dimethylformamide (1 mL), potassium carbonate (40 mg, 286 μmol, 2 equiv.) was added, and the resulting mixture was stirred at 100° C. for 12 hours. The mixture was diluted with water (2 mL) and extracted with ethyl acetate (2 mL×3). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by preparative HPLC (column: Waters Xbridge 150 × 25 mm × 5 μm, mobile phase: [water (NH4HCO3)-ACN], B%: 47%-77%, 9 min) and dried by lyophilization to give 1-[8-(2-chlorophenyl)-9-(4-chlorophenyl)-2-(2-methoxyethoxy)purin-6-yl]-4-methyl-piperidine-4-carboxamide (compound 10, 46.71 mg, 83.36 μmol, 58.3% yield) as a white solid. 1 H NMR(400MHz,MeOD-d4)δ=7.61-7.55(m,1H),7.49-7.35(m,5H),7.30-7.22(m,2H),4.82-4.80(m,1H), 4.44-4.41(m,2H),3.98-3.65(m,4H),3.38(s,3H),2.25-2.15(m,2H),1.61-1.54(m,2H),1.28(s,3H). LCMS:(ES + ) m / z = 555.2 (M+H).

[0481] (xxix) Compound 11: A mixture of 1-[8-(2-chlorophenyl)-9-(4-chlorophenyl)-2-methylsulfonyl-purin-6-yl]-4-methyl-piperidine-4-carboxamide (compound 68) (0.2 g, 357 μmol, 1 equiv.), 2-methylsulfonylethanamine (220.16 mg, 1.79 mmol, 5 equiv.), and potassium carbonate (247 mg, 1.79 mmol, 5 equiv.) in N-methylpyrrolidone (2 mL) was stirred at 140 °C for 15 h. The reaction mixture was cooled to room temperature and filtered. The filtrate was purified by reverse-phase HPLC (Phenomenex Luna C18 150 × 25 mm × 10 μm column, mobile phase: [water (formic acid)-ACN], B%: 36%-66%, 10 min). The cleaved fraction was concentrated under reduced pressure to remove acetonitrile. The residue was lyophilized to give 1-[8-(2-chlorophenyl)-9-(4-chlorophenyl)-2-(2-methylphosphonylethylamino)purin-6-yl]-4-methyl-piperidine-4-carboxamide (compound 11, 21.43 mg, 35.57 μmol, 9.9% yield) as a white solid. 1 H NMR(400MHz,CDCl3-d)δ=7.49(d,J=7.2Hz,1H),7.38-7.29(m,5H),7.17(d,J=8.8Hz,2H),5.73-5.57(m,2H),5.44-5.32(m,1H),4. 62(s,1H),4.02(s,2H),3.90-3.85(m,2H),3.38(t,J=6.4Hz,2H),2.89(s,3H),2.21-2.10(m,2H),1.70-1.59(m,2H),1.33(s,3H). LCMS:(ES+)m / z=602.1(M+H).

[0482] (xxx) Compound 12: Step 1:A mixture of 1-[8-(2-chlorophenyl)-9-(4-chlorophenyl)-2-methylsulfonyl-purin-6-yl]-4-methyl-piperidine-4-carboxamide (Compound 68) (300 mg, 0.54 mmol, 1 equiv) and 2-aminoethanol (327 mg, 5.36 mmol, 0.32 mL, 10 equiv) was stirred at 140° C. for 12 hours. The reaction mixture was filtered and concentrated under reduced pressure to give a residue. The resulting residue was purified by flash silica gel chromatography (ISCO®, 20 g SepaFlash® silica flash column, elution with a 0% to 100% ethyl acetate / petroleum ether gradient at 20 mL / min), and the organic phase was concentrated under reduced pressure to give 1-[8-(2-chlorophenyl)-9-(4-chlorophenyl)-2-(2-hydroxyethylamino)purin-6-yl]-4-methyl-piperidine-4-carboxamide (300 mg) as a yellow solid.

[0483] Step 2: A mixture of 1-[8-(2-chlorophenyl)-9-(4-chlorophenyl)-2-(2-hydroxyethylamino)purin-6-yl]-4-methyl-piperidine-4-carboxamide (100 mg, 0.18 mmol, 1 equiv), bromomethylbenzene (63 mg, 0.37 mmol, 2 equiv), potassium carbonate (51 mg, 0.37 mmol, 2 equiv) in acetonitrile (1 mL) was stirred at 80° C. for 16 hours. The reaction mixture was filtered and concentrated under reduced pressure to provide a residue. The residue was dissolved in acetonitrile (2 mL) and purified by preparative HPLC (column: Waters Xbridge 150 × 25 mm × 5 μm, mobile phase: [water (ammonium bicarbonate)-acetonitrile], B%: 61%-81%, 8 min) and preparative HPLC (column: Phenomenex luna C18 150 × 25 mm × 10 μm, mobile phase: [water (methanoic acid)-acetonitrile], B%: 53%-83%, 10 min) to give 1-[2-[benzyl(2-hydroxyethyl)amino]-8-(2-chlorophenyl)-9-(4-chlorophenyl)purin-6-yl]-4-methyl-piperidine-4-carboxamide (compound 12, 6.58 mg, 10.4 μmol, 5.6% yield) as an off-white solid.1 H NMR(400MHz,MeOD-d4)δ=7.61-7.55(m,1H),7.47-7.35(m,3H),7.35-7.08(m,9H),4.88-4.87(m,1H),4.83- 4.81(m,1H),4.70-4.57(m,2H),3.73-3.71(m,6H),2.17-2.04(m,2H),1.49(t,J=10.0Hz,2H),1.24(s,3H). LCMS:(ES + ) m / z = 630.2 (M+H).

[0484] (xxxi) Compound 13: A mixture of 1-[8-(2-chlorophenyl)-9-(4-chlorophenyl)-2-methylsulfonyl-purin-6-yl]-4-methyl-piperidine-4-carboxamide (Compound 68) (100 mg, 179 μmol, 1 equivalent) and [(2R)-pyrrolidin-2-yl]methanol (181 mg, 1.79 mmol, 0.17 mL, 10 equivalents) was stirred at 140° C. for 12 hours. The reaction mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC (column: Waters Xbridge 150 × 25 mm × 5 μm, mobile phase: [water (ammonium bicarbonate)-ACN], B%: 53% to 83%, 10 min) to give 1-[8-(2-chlorophenyl)-9-(4-chlorophenyl)-2-[(2R)-2-(hydroxymethyl)pyrrolidin-1-yl)purin-6-yl]-4-methyl-piperidine-4-carboxamide (compound 13, 50.93 mg, 87.7 μmol, 49.0% yield) as a white solid. 1 H NMR(400MHz,MeOD-d4)δ=7.61-7.54(m,1H),7.47-7.32(m,5H),7.28-7.22(m,2H),4.78-4.59(m,2H),4.14(d,J=4.0Hz,1H),3.8 9-3.61(m,4H),3.58-3.54(m,2H),2.17(d,J=14.4Hz,2H),2.09-1.94(m,2H),1.92-1.79(m,2H),1.60-1.53(m,2H),1.27(s,3H). LCMS:(ES + ) m / z = 580.3 (M+H).

[0485] (xxxii) Compound 14: A mixture of 1-[8-(2-chlorophenyl)-9-(4-chlorophenyl)-2-methylsulfonyl-purin-6-yl]-4-methyl-piperidine-4-carboxamide (Compound 68) (0.05 g, 89.4 μmol, 1 equivalent), 1,2,3,3a,4,5,6,6a-octahydrocyclopenta[c]pyrrole, hydrochloride (66 mg, 447 μmol, 5 equivalents), and potassium carbonate (99 mg, 715 μmol, 8 equivalents) in N-methylpyrrolidone (0.5 mL) was stirred at 100° C. for 12 hours. The reaction mixture was cooled to room temperature and diluted with N-methylpyrrolidone (1 mL). The resulting mixture was filtered to obtain a filtrate. The filtrate was purified by preparative HPLC (Waters Xbridge 150 × 25 mm × 5 μm column, mobile phase: [water (ammonium bicarbonate)-ACN], B%: 66% to 96%, 9 min). The cleavage fraction was concentrated under reduced pressure to remove acetonitrile. The residue was lyophilized to give 1-[2-[(3aS,6aR)-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrol-2-yl]-8-(2-chlorophenyl)-9-(4-chlorophenyl)purin-6-yl]-4-methyl-piperidine-4-carboxamide (compound 14, 21 mg, 35.56 μmol, 39.7% yield) as a white solid. 1 H NMR(400MHz, CDCl3-d)δ=7.51(d,J=6.8Hz,1H),7.39-7.29(m,5H),7.27- 7.21(m,2H),5.74-5.35(m,2H),4.72-4.48(m,2H),4.14-3.96(m,2H),3.8 9-3.72(m,2H),3.36(d,J=10.0Hz,2H),2.78-2.68(m,2H),2.20-2.10(m,2 H),1.87-1.79(m,2H),1.71-1.60(m,4H),1.56-1.52(m,2H),1.33(s,3H). LCMS: (ES+) m / z = 590.2 (M+H).

[0486] (xxxiii) Compound 15: A mixture of 1-[8-(2-chlorophenyl)-9-(4-chlorophenyl)-2-methylsulfonyl-purin-6-yl]-4-methyl-piperidine-4-carboxamide (Compound 68) (100 mg, 0.18 mmol, 1 equiv.), 3-azabicyclo[3.1.0]hexane hydrochloride (107 mg, 0.89 mmol, 5 equiv.), and cesium carbonate (291 mg, 0.89 mmol, 5 equiv.) in N-methyl-2-pyrrolidone (1 mL) was stirred at 100° C. for 2 hours. The reaction mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC (column: Waters Xbridge 150 × 25 mm × 5 μm; mobile phase: [water (trifluoroacetic acid)-acetonitrile], B%: 68% to 98%, 8 min) to give 1-[2-[(1R,5S)-3-azabicyclo[3.1.0]hexan-3-yl]-8-(2-chlorophenyl)-9-(4-chlorophenyl)purin-6-yl]-4-methyl-piperidine-4-carboxamide (compound 15, 19.99 mg, 35.54 μmol, 19.9% ​​yield) as a white solid. 1 H NMR(400MHz,MeOD-d4)δ=7.58-7.56(m,1H),7.48-7.30(m,5H),7.30-7.22(m,2H),4.73-4.62(m,2H),3.89-3.66(m,4 H),3.41(d,J=11.2Hz,2H),2.19-2.09(m,2H),1.64-1.52(m,4H),1.27(s,3H),0.72-0.67(m,1H),0.17-0.14(m,1H). LCMS:(ES + ) m / z = 562.1 (M+H).

[0487] (xxxiv) Compound 16: Step 1:1-[8-(2-chlorophenyl)-9-(4-chlorophenyl)-2-methylsulfinyl-purin-6-yl]-4-methyl-piperidine-4-carboxamide (Intermediate C-11) (0.3 g, 552 μmol, 1 equiv.) and thiomorpholine (569 mg, 5.52 mmol, 0.5 mL, 10 equiv.) were placed in a microwave tube in N-methylpyrrolidone (3 mL). The sealed tube was heated at 160° C. in a microwave oven for 1 hour. The mixture was diluted with water (2 mL) and extracted with ethyl acetate (2 mL×3). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by preparative HPLC (column: Waters Xbridge 150 × 25 mm × 5 μm, mobile phase: [water (ammonium bicarbonate)-ACN], B%: 60% to 90%, 8 min) and concentrated in vacuo to give 1-[8-(2-chlorophenyl)-9-(4-chlorophenyl)-2-thiomorpholino-purin-6-yl]-4-methyl-piperidine-4-carboxamide (100 mg, 172 μmol, 31.1% yield) as a yellow solid.

[0488] Process 2 To a solution of 1-[8-(2-chlorophenyl)-9-(4-chlorophenyl)-2-thiomorpholino-purin-6-yl]-4-methyl-piperidine-4-carboxamide (90 mg, 154 μmol, 1 equiv.) in N-methylpyrrolidone (1 mL) was added potassium hydrogen oxysulfate (156 mg, 926.97 μmol, 6 equiv.) and water (0.2 mL). The mixture was stirred at 60° C. for 12 hours. The yellow solid was purified by preparative HPLC (column: Waters Xbridge 150×25 mm×5 um, mobile phase: [water (ammonium bicarbonate)-ACN], B%: 48%-78%, 8 min) to give compound 1-[8-(2-chlorophenyl)-9-(4-chlorophenyl)-2-(1,1-dioxo-1,4-thiazinan-4-yl)purin-6-yl]-4-methyl-piperidine-4-carboxamide (compound 16, 47.74 mg, 77.68 μmol, 50.2% yield) as a white solid. 1H NMR(400MHz,CDCl3-d)δ=7.49(d,J=6.8Hz,1H),7.40-7.28(m,5H),7.14(d,J=8.6Hz,2H),5.81-5.12(m,2H),4.8 6-4.18(m,6H),4.12-3.73(m,2H),3.19-2.87(m,4H),2.26-2.05(m,2H),1.69-1.59(m,2H),1.33(s,3H)LCMS:(ES + ) m / z = 614.2 (M+H).

[0489] (xxxv) Compound 17: To a solution of 1-[8-(2-chlorophenyl)-9-(4-chlorophenyl)-2-methylsulfonyl-purin-6-yl]-4-methyl-piperidine-4-carboxamide (Compound 68) (80 mg, 143 μmol, 1 equiv.) and tetrahydropyran-3-ol (73 mg, 715 μmol, 5 equiv.) in N,N-dimethylformamide (1 mL), potassium carbonate (40 mg, 286 μmol, 2 equiv.) was added, and the resulting mixture was stirred at 100° C. for 12 hours. The mixture was diluted with water (2 mL) and extracted with ethyl acetate (2 mL×3). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by preparative HPLC (column: Waters Xbridge 150 × 25 mm × 5 μm, mobile phase: [water (ammonium bicarbonate)-ACN], B%: 53% to 83%, 9 min) and dried by lyophilization to give the product 1-[8-(2-chlorophenyl)-9-(4-chlorophenyl)-2-tetrahydropyran-3-yloxy-purin-6-yl]-4-methyl-piperidine-4-carboxamide (compound 17, 44.19 mg, 75.99 μmol, 53.1% yield) as an off-white solid. 1H NMR(400MHz,MeOD-d4)δ=7.61-7.55(m,1H),7.50-7.35(m,5H),7.28-7.21(m,2H),4.99-4.93(m,4H),3.96-3.92(m,1H),3.84-3.75(m,1) H),3.71-3.69(m,1H),3.66-3.56(m,2H),2.20(d,J=14.4Hz,2H),2.10-2.09(m,1H),1.98-1.78(m,2H),1.67-1.53(m,3H),1.28(s,3H). LCMS:(ES + ) m / z = 581.1 (M+H).

[0490] (xxxvi) Compound 18: A mixture of 1-[8-(2-chlorophenyl)-9-(4-chlorophenyl)-2-methylsulfonyl-purin-6-yl]-4-methyl-piperidine-4-carboxamide (Compound 68) (100 mg, 179 μmol, 1 equiv.), N-carbamidoylacetamide (90 mg, 894 μmol, 5 equiv.), and potassium carbonate (123 mg, 894 μmol, 5 equiv.) in dimethyl sulfoxide (1 mL) was stirred at 100° C. for 12 hours. The reaction mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC (column: Waters Xbridge 150 × 25 mm × 5 μm, mobile phase: [water (ammonium bicarbonate)-ACN], B%: 43%-73%, 10 min) to give 1-[2-[(N-acetylcarbamimidoyl)amino]-8-(2-chlorophenyl)-9-(4-chlorophenyl)purin-6-yl]-4-methyl-piperidine-4-carboxamide (compound 18, 22.95 mg, 39.5 μmol, 22.1% yield, 100% purity) as a white solid. 1 H NMR(400MHz,MeOD-d4)δ=7.64-7.57(m,1H),7.49-7.40(m,5H),7.33-7.26(m,2H),4.81-4.7 8(m,2H),3.90-3.69(m,2H),2.25-2.18(m,2H),2.06(s,3H),1.64-1.55(m,2H),1.29(s,3H). LCMS:(ES + ) m / z = 580.3 (M+H).

[0491] (xxxvii) Compound 19: A mixture of 1-[8-(2-chlorophenyl)-9-(4-chlorophenyl)-2-methylsulfonyl-purin-6-yl]-4-methyl-piperidine-4-carboxamide (compound 68) (130 mg, 232 μmol, 1 equiv.) and 2-(methylamino)ethanol (935 mg, 12.45 mmol, 1 mL, 54 equiv.) was stirred at 100°C for 18 hours. The reaction mixture was cooled to room temperature and diluted with N,N-dimethylformamide (2 mL). The resulting mixture was purified by reverse-phase HPLC (Waters Xbridge 150 × 25 mm × 5 μm column, mobile phase: [water (ammonium bicarbonate)-ACN], B%: 46% to 76%, 8 min). The cleaved fraction was concentrated under reduced pressure to remove acetonitrile. The residue was lyophilized to give 1-[8-(2-chlorophenyl)-9-(4-chlorophenyl)-2-[2-hydroxyethyl(methyl)amino]purin-6-yl]-4-methyl-piperidine-4-carboxamide (compound 19, 48.31 mg, 87.13 μmol, 37.5% yield) as an off-white solid. 1 H NMR(400MHz,DMSO-d6)δ=7.64(d,J=7.2Hz,1H),7.54-7.39(m,5H),7.27(d,J=8.8Hz,3H),6.94(s,1H), 4.98-4.26(m,3H),3.70-3.52(m,6H),3.07(s,3H),2.12-2.02(m,2H),1.48-1.34(m,2H),1.16(s,3H). LCMS:(ES+)m / z=554.2.

[0492] (xxxviii) Compound 20: A mixture of 1-[8-(2-chlorophenyl)-9-(4-chlorophenyl)-2-methylsulfinyl-purin-6-yl]-4-methyl-piperidine-4-carboxamide (Compound 68) (100 mg, 184 μmol, 1 equivalent) and [(2S)-pyrrolidin-2-yl]methanol (186 mg, 1.84 mmol, 0.18 mL, 10 equivalents) was stirred at 140° C. for 12 hours. The reaction mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC (column: Waters Xbridge 150 × 25 mm × 5 μm, mobile phase: [water (ammonium bicarbonate)-ACN], B%: 52% to 82%, 10 min) to give 1-[8-(2-chlorophenyl)-9-(4-chlorophenyl)-2-[(2S)-2-(hydroxymethyl)pyrrolidin-1-yl)purin-6-yl]-4-methyl-piperidine-4-carboxamide (compound 20, 53.2 mg, 91.09 μmol, 49.5% yield) as an off-white solid. 1 H NMR(400MHz,MeOD-d4)δ=7.59-7.52(m,1H),7.47-7.33(m,5H),7.24(d,J=8.4Hz,2H),4.75-4.62(m,2H),4.14(s,1H),3.81-3 .63(m,4H),3.58-3.54(m,2H),2.16(d,J=14.4Hz,2H),2.08-1.93(m,2H),1.90-1.80(m,2H),1.63-1.49(m,2H),1.27(s,3H). LCMS:(ES + ) m / z = 580.3 (M+H).

[0493] (xxxix) Compound 21: To a solution of 4-methyl-1H-pyrazole (72 mg, 877 μmol, 5 equivalents) in N,N-dimethylformamide (1 mL) was added sodium hydride (8 mg, 210 μmol, 60% purity, 1.2 equivalents) at 0° C., and the resulting mixture was stirred at 25° C. for 0.5 hours. 8-(2-chlorophenyl)-9-(4-chlorophenyl)-2-methylsulfonyl-6-[4-(trifluoromethyl)-1-piperidyl]purine (Intermediate D-3) (0.1 g, 175 μmol, 1 equivalent) was then added to the mixture. The resulting mixture was stirred at 25° C. for 2 hours. The mixture was diluted with saturated ammonium chloride solution (2 mL) and extracted with ethyl acetate (2 mL × 3). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by preparative HPLC (column: Waters Xbridge 150 × 25 mm × 5 μm, mobile phase: [water (ammonium bicarbonate)-ACN], B%: 70% to 100%, 8 min) and dried by lyophilization to give the product 8-(2-chlorophenyl)-9-(4-chlorophenyl)-2-(4-methylpyrazol-1-yl)-6-[4-(trifluoromethyl)-1-piperidyl]purine (compound 21, 78.63 mg, 137 μmol, 78.3% yield) as an off-white solid. 1 H NMR(400MHz,CDCl3-d)δ=8.27(s,1H),7.60(s,1H),7.53-7.52(m,1H),7.44-7.32(m,5H),7.26-7.21(m,2H),6. 10-5.38(m,2H),3.17-3.12(m,2H),2.44-2.41(m,1H),2.15(s,3H),2.08(d,J=11.6Hz,2H),1.80-1.73(m,2H). 19 F NMR (377MHz, CDCl3-d) δ=-73.85(s, 1F). LCMS:(ES + ) m / z = 572.2 (M+H).

[0494] (xl) Compound 22: To a solution of 3-methyl-1H-pyrazole (72 mg, 876.56 μmol, 5 equivalents) in N,N-dimethylformamide (1 mL) was added sodium hydride (8 mg, 210.37 μmol, 60% purity, 1.2 equivalents) at 0° C., and the resulting mixture was stirred at 25° C. for 0.5 hours. 8-(2-chlorophenyl)-9-(4-chlorophenyl)-2-methylsulfonyl-6-[4-(trifluoromethyl)-1-piperidyl]purine (Intermediate D-3) (0.1 g, 175 μmol, 1 equivalent) was then added to the mixture. The resulting mixture was stirred at 25° C. for 2 hours. The mixture was diluted with saturated ammonium chloride solution (2 mL) and extracted with ethyl acetate (2 mL × 3). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by preparative HPLC (column: Waters Xbridge 150 × 25 mm × 5 μm, mobile phase: [water (ammonium bicarbonate)-ACN], B%: 67% to 97%, 10 min) and dried by lyophilization to give the product 8-(2-chlorophenyl)-9-(4-chlorophenyl)-2-(3-methylpyrazol-1-yl)-6-[4-(trifluoromethyl)-1-piperidyl]purine (compound 22, 23.98 mg, 41.89 μmol, 23.9% yield) as an off-white solid. 1 H NMR(400MHz,DMSO-d6)δ=8.48(d,J=2.4Hz,1H),7.73-7.71(m,1H),7.57-7.43(m,5H),7.42-7.36(m,2H),6.30(d,J=2.8H) z,1H),6.15-4.98(m,2H),3.30-3.05(m,2H),2.87-2.70(m,1H),2.24(s,3H),2.03(d,J=11.2Hz,2H),1.58-1.50(m,2H). 19 F NMR (377MHz, DMSO-d6) δ=-72.46(s, 1F). LCMS:(ES + ) m / z = 572.1 (M+H).

[0495] (xli) Compound 23: To a solution of 8-(2-chlorophenyl)-9-(4-chlorophenyl)-2-methylsulfinyl-6-[4-(trifluoromethyl)-1-piperidyl]purine (Intermediate D-3) (100 mg, 0.18 mol, 1 equiv.) and propane-1,3-diol (68 mg, 0.90 mmol, 5 equiv.) in N,N-dimethylformamide (1 mL), potassium carbonate (50 mg, 0.36 mmol, 2 equiv.) was added, and the resulting mixture was stirred at 100 °C for 12 h. The mixture was diluted with water (2 mL) and extracted with ethyl acetate (4 mL × 3). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by preparative HPLC (Column: Waters Xbridge 150 × 25 mm × 5 μm, Mobile phase: [water (ammonium bicarbonate)-ACN], B%: 59%-89%, 9 min) and dried by lyophilization. The residue was purified by preparative HPLC (column: Waters Xbridge 150 × 25 mm × 5 μm, mobile phase: [water (ammonia hydroxide v / v)-ACN], B%: 54% to 84%, 9 min) and dried by lyophilization to give 3-[8-(2-chlorophenyl)-9-(4-chlorophenyl)-6-[4-(trifluoromethyl)-1-piperidyl]purin-2-yl]oxypropan-1-ol (compound 23, 57.46 mg, 101.45 μmol, 56.2% yield) as a white solid. 1 H NMR(400MHz,MeOH-d4)δ=7.59(d,J=7.6Hz,1H),7.46-7.36(m,5H),7.27(d,J=8.8Hz,2H),5.71-5.45(m,2H),4. 42-4.39(m,2H),3.73-3.69(m,2H),3.22-3.08(m,2H),2.73-2.51(m,1H),2.08-1.93(m,4H),1.68-1.54(m,2H). 19 F NMR (377MHz, MeOH-d4) δ=-75.50(s, 1F). LCMS:(ES + ) m / z = 566.2 (M+H).

[0496] (xlii) Compound 24: To a solution of 8-(2-chlorophenyl)-9-(4-chlorophenyl)-2-methylsulfonyl-6-[4-(trifluoromethyl)-1-piperidyl]purine (Intermediate D-3) (150 mg, 263 μmol, 1 equiv.) and propane-1,2-diol (100 mg, 1.31 mmol, 5 equiv.) in N,N-dimethylformamide (2 mL), potassium carbonate (73 mg, 526 μmol, 2 equiv.) was added, and the resulting mixture was stirred at 100° C. for 12 hours. The mixture was diluted with water (2 mL) and extracted with ethyl acetate (2 mL × 3). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by preparative HPLC (Waters Xbridge 150 × 25 mm × 5 μm column, mobile phase: [water (ammonium bicarbonate)-ACN], B%: 66% to 96%, 9 min), and lyophilized to dryness to obtain a mixture (60 mg). The mixture was separated by chiral SFC (Daicel ChiralPak IG (250 × 30 mm, 10 μm column, mobile phase: [0.1% ammonium hydroxide ethanol], B%: 30% to 30%, 3.4 min), to obtain two peaks.

[0497] One peak was purified by preparative HPLC (column: Waters Xbridge 150 × 25 mm × 5 μm, mobile phase: [water (ammonium bicarbonate)-ACN]; B%: 62% to 92%, 10 min) and dried by lyophilization to give 2-[8-(2-chlorophenyl)-9-(4-chlorophenyl)-6-[4-(trifluoromethyl)-1-piperidyl]purin-2-yl]oxypropan-1-ol (compound 24, 11.07 mg, 19.54 μmol, 18.45% yield) as an off-white solid. 1 H NMR(400MHz,MeOD-d4)δ=7.63-7.57(m,1H),7.49-7.35(m,5H),7.30-7.23(m,2H),5.76-5.39(m,2H),5.24-5.11(m,1H),3 .76-3.58(m,2H),3.18-3.11(m,2H),2.61-2.59(m,1H),2.02(d,J=11.2Hz,2H),1.71-1.55(m,2H),1.32(d,J=6.4Hz,3H). 19F NMR (376MHz, MeOD-d4) δ = -75.51 (br s, 1F). LCMS:(ES+)m / z=566.3(M+H).

[0498] (xliiii) Compound 25: Following the procedure from compound 24, the other peak was purified by preparative HPLC (column: Waters Xbridge 150 × 25 mm × 5 μm, mobile phase: [water (ammonium bicarbonate)-ACN]; B%: 62%-92%, 10 min) and dried again by lyophilization to give 1-[8-(2-chlorophenyl)-9-(4-chlorophenyl)-6-[4-(trifluoromethyl)-1-piperidyl]purin-2-yl]oxypropan-2-ol (compound 25, 28.11 mg, 49.6 μmol, 46.8% yield) as a white solid. 1 H NMR(400MHz,MeOD-d4)δ=7.62-7.56(m,1H),7.49-7.36(m,5H),7.31-7.24(m,2H),5.75-5.41(m,2H),4.25-4.15(m,2H) ,4.14-4.02(m,1H),3.18-3.12(m,2H),2.61-2.59(m,1H),2.09-1.96(m,2H),1.67-1.60(m,2H),1.23(d,J=6.4Hz,3H). 19 F NMR (377MHz, MeOD-d4) δ=-75.51(s, 1F). LCMS:(ES + ) m / z = 566.2 (M+H).

[0499] (xliv) Compound 26: To a solution of 8-(2-chlorophenyl)-9-(4-chlorophenyl)-2-methylsulfonyl-6-[4-(trifluoromethyl)-1-piperidyl]purine (Intermediate D-3) (100 mg, 175 μmol, 1 equiv.) and 2-methylpropane-1,2-diol (79 mg, 877 μmol, 5 equiv.) in N,N-dimethylformamide (2 mL), potassium carbonate (48 mg, 351 μmol, 2 equiv.) was added, and the resulting mixture was stirred at 100° C. for 12 hours. The mixture was diluted with water (2 mL) and extracted with ethyl acetate (2 mL × 3). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by preparative HPLC (column: Waters Xbridge 150 × 25 mm × 5 μm, mobile phase: [water (ammonium bicarbonate)-ACN], B%: 62% to 92%, 9 min) and dried by lyophilization to give the product 1-[8-(2-chlorophenyl)-9-(4-chlorophenyl)-6-[4-(trifluoromethyl)-1-piperidyl]purin-2-yl]oxy-2-methyl-propan-2-ol (compound 26, 50.93 mg, 87.7 μmol, 50.0% yield) as a white solid. 1 H NMR(400MHz,MeOD-d4)δ=7.57(d,J=8.8Hz,2H),7.50-7.49(m,2H),7.33-7.28(m,2H),7.24(d,J=7.2Hz,1 H),7.21-7.14(m,5H),4.59(s,2H),4.44-4.30(m,2H),2.42-2.25(m,1H),2.14(s,3H),2.09-2.05(m,1H). 19 F NMR (377MHz, MeOD-d4) δ = -110.05 (br s, 1F). LCMS:(ES + ) m / z = 573.2 (M+H).

[0500] (xlv) Compound 27: To a solution of 8-(2-chlorophenyl)-9-(4-chlorophenyl)-2-methylsulfonyl-6-[4-(trifluoromethyl)-1-piperidyl]purine (Intermediate D-3) (50 mg, 0.88 mmol, 1.0 equiv.) and 2-methoxyethanol (20 mg, 0.26 mmol, 3.0 equiv.) in tetrahydrofuran (1 mL), sodium hydride (4 mg, 0.10 mmol, 60% purity, 1.2 equiv.) was added, and the resulting mixture was stirred at 80 °C for 1 hour. The mixture was diluted with saturated ammonium chloride solution (2 mL) and extracted with ethyl acetate (2 mL × 3). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give the crude product (60 mg). To a solution of 8-(2-chlorophenyl)-9-(4-chlorophenyl)-2-methylsulfonyl-6-[4-(trifluoromethyl)-1-piperidyl]purine (20 mg, 0.04 mmol, 1.0 equiv.) and 2-methoxyethanol (13 mg, 0.18 mmol, 5.0 equiv.) in N,N-dimethylformamide (0.5 mL), potassium carbonate (10 mg, 0.07 mmol, 2.0 equiv.) was added, and the resulting mixture was stirred at 100° C. for 12 hours. The mixture was diluted with water (1 mL) and extracted with ethyl acetate (1 mL × 3). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give the crude product (20 mg).

[0501] To a solution of potassium tert-butoxide (8 mg, 0.07 mmol, 2.0 equiv.) in tetrahydrofuran (0.5 mL) was added 2-methoxyethanol (13 mg, 0.18 mmol, 5.0 equiv.) and 8-(2-chlorophenyl)-9-(4-chlorophenyl)-2-methylsulfonyl-6-[4-(trifluoromethyl)-1-piperidyl]purine (20 mg, 0.04 mmol, 1.0 equiv.) at 0° C., and the resulting mixture was stirred at 60° C. for 12 hours. The mixture was diluted with water (1 mL) and extracted with ethyl acetate (1 mL × 3). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give the crude product (20 mg).

[0502] The three batches were combined and purified by preparative HPLC (column: Waters Xbridge 150 × 25 mm × 5 μm, mobile phase: [water (ammonium bicarbonate)-ACN]; B%: 67%-97%, 10 min) and lyophilized to dryness to give the product 8-(2-chlorophenyl)-9-(4-chlorophenyl)-2-(2-methoxyethoxy)-6-[4-(trifluoromethyl)-1-piperidyl]purine (compound 27, 56.92 mg, 99.57 μmol, yield 63.1%, purity 99.0%) as an off-white solid. 1 H NMR(400MHz,MeOD-d4)δ=7.59(d,J=7.6Hz,1H),7.50-7.34(m,5H),7.27(d,J=8.8Hz,2H),5.57(s,2H),4.49-4.40(m, 2H),3.76-3.68(m,2H),3.38(s,3H),3.17-3.11(m,2H),2.67-2.55(m,1H),2.02(d,J=13.2Hz,2H),1.70-1.57(m,2H). 19 F NMR (376MHz, MeOD-d4) δ=75.514(m, 1F). LCMS:(ES + ) m / z = 566.1 (M+H).

[0503] (xlvi) Compound 28: A mixture of 8-(2-chlorophenyl)-9-(4-chlorophenyl)-2-methylsulfonyl-6-[4-(trifluoromethyl)-1-piperidyl]purine (Intermediate D-3) (0.2 g, 0.35 μmol, 1 equiv.), 2-methylsulfonylethanamine (216 mg, 1.75 mmol, 5 equiv.), and potassium carbonate (242.29 mg, 1.75 mmol, 5 equiv.) in N-methyl-2-pyrrolidone (2 mL) was stirred at 140 °C for 12 h. The reaction mixture was cooled to room temperature and filtered. The resulting filtrate was purified by reverse-phase HPLC (column: Phenomenex Synergi C18 150 × 25 mm × 10 μm, mobile phase: [water (formic acid)-ACN], B%: 57% to 87%, 10 min). The cleaved fraction was concentrated under reduced pressure to remove acetonitrile. The residue was lyophilized to give 8-(2-chlorophenyl)-9-(4-chlorophenyl)-N-(2-methylsulfonylethyl)-6-[4-(trifluoromethyl)-1-piperidyl]purin-2-amine (compound 28, 13.62 mg, 22.2 μmol, 6.3% yield) as a white solid. 1 H NMR(400MHz,CDCl3-d)δ=7.53-7.47(m,1H),7.40-7.30(m,5H),7.21-7.15(m,2H),5.76-5.53(m,2H),5.27-5.13(m,1H),3.93-3.8 5(m,2H),3.38(t,J=6.4Hz,2H),3.04(t,J=12.8Hz,2H),2.88(s,3H),2.43-2.38(m,1H),2.03(d,J=12.8Hz,2H),1.76-1.69(m,2H). LCMS:(ES+)m / z=613.0(M+H).

[0504] (xlvii) Compound 29: A mixture of 8-(2-chlorophenyl)-9-(4-chlorophenyl)-2-methylsulfonyl-6-[4-(trifluoromethyl)-1-piperidyl]purine (Intermediate D-3) (50 mg, 87.7 μmol, 1 equivalent) and [(2R)-pyrrolidin-2-yl]methanol (89 mg, 0.88 mmol, 0.09 mL, 10 equivalents) was stirred at 140° C. for 5 hours. The reaction mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC (column: Waters Xbridge 150 × 25 mm × 5 μm, mobile phase: [water (ammonium bicarbonate)-ACN], B%: 80% to 100%, 10 min) to give [(2R)-1-[8-(2-chlorophenyl)-9-(4-chlorophenyl)-6-[4-(trifluoromethyl)-1-piperidyl]purin-2-yl]pyrrolidin-2-yl]methanol (compound 29, 29.97 mg, 50.7 μmol, yield 57.8%) as a white solid. 1 H NMR(400MHz,MeOD-d4)δ=7.61-7.55(m,1H),7.50-7.32(m,5H),7.29-7.21(m,2H),5.52(d,J=12.8Hz,2H),4.1 4(s,1H),3.77-3.49(m,4H),3.08(t,J=12.8Hz,2H),2.65-2.49(m,1H),2.12-1.80(m,6H),1.66-1.55(m,2H). LCMS:(ES + ) m / z = 591.2 (M+H).

[0505] (xlviii) Compound 30: A mixture of 8-(2-chlorophenyl)-9-(4-chlorophenyl)-2-methylsulfinyl-6-[4-(trifluoromethyl)-1-piperidyl]purine (Intermediate D-2) (50 mg, 90.2 μmol, 1 equiv.), 1,2,3,3a,4,5,6,6a-octahydrocyclopenta[c]pyrrole hydrochloride (27 mg, 180 μmol, 2 equiv.), and potassium carbonate (37.39 mg, 271 μmol, 3 equiv.) in dimethyl sulfoxide (0.5 mL) was stirred at 100° C. for 20 h. The reaction mixture was cooled to room temperature and diluted with water (20 mL). The mixture was extracted with ethyl acetate (10 mL × 3), and the combined organic layers were concentrated under reduced pressure. The resulting residue was purified by flash silica gel chromatography (ISCO®, 12 g SepaFlash® silica flash column, eluting with a 0% to 50% ethyl acetate / petroleum ether gradient at 20 mL / min). The cleavage fraction was concentrated under reduced pressure and lyophilized to give compound 2-[(3aS,6aR)-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrol-2-yl]-8-(2-chlorophenyl)-9-(4-chlorophenyl)-6-[4-(trifluoromethyl)-1-piperidyl]purine (compound 30, 0.02 g, 32.59 μmol, 36.1% yield) as a white solid. 1 H NMR(400MHz,DMSO-d6)δ=7.78-7.60(m,1H),7.58-7.38(m,5H),7.28(d,J=8.8Hz,2H),5.70-5.15(m,2H),3.70 -3.61(m,2H),3.26-2.97(m,4H),2.79-2.62(m,3H),2.03-1.88(m,2H),1.83-1.62(m,3H),1.59-1.34(m,5H). LCMS:(ES+)m / z=602.9(M+H).

[0506] (xlix) Compound 31: A mixture of 8-(2-chlorophenyl)-9-(4-chlorophenyl)-2-methylsulfonyl-6-[4-(trifluoromethyl)-1-piperidyl]purine (Intermediate D-2) (0.1 g, 175 μmol, 1 equiv.), 3-azabicyclo[3.1.0]hexane hydrochloride (210 mg, 1.75 mmol, 10 equiv.), and cesium carbonate (856.80 mg, 2.63 mmol, 15 equiv.) in N-methyl-2-pyrrolidone (0.5 mL) was stirred at 100° C. for 12 hours. The reaction mixture was cooled to room temperature and diluted with N-methyl-2-pyrrolidone (1 mL). The resulting mixture was filtered to obtain a filtrate. The filtrate was purified by reverse-phase HPLC (Waters Xbridge 150 × 25 mm × 5 μm column, mobile phase: [water (ammonium bicarbonate)-ACN], B%: 80% to 100%, 9 min). The cleavage fraction was concentrated under reduced pressure to remove acetonitrile. The residue was lyophilized to give 2-[(1R,5S)-3-azabicyclo[3.1.0]hexan-3-yl]-8-(2-chlorophenyl)-9-(4-chlorophenyl)-6-[4-(trifluoromethyl)-1-piperidyl]purine (Compound 31, 20 mg, 34.9 μmol, 19.8% yield) as a white solid. 1 H NMR(400MHz,CDCl3-d)δ=7.31-7.26(m,1H),7.14-7.04(m,5H),7.01-6.96(m,2H),5.52-5.27(m,2H),3.64(d,J=10.8Hz,2H),3.22(d,J=10.4Hz) ,2H),2.76(t,J=12.8Hz,2H),2.19-2.05(m,1H),1.79-1.70(m,2H),1.5 8-1.38(m,2H),1.31-1.26(m,2H),0.52-0.38(m,1H),0.09-0.03(m,1H). LCMS: (ES+)m / z=573.1(M+H), Rt=1.215 min.

[0507] (l) Compound 32: Step 1:8-(2-Chlorophenyl)-9-(4-chlorophenyl)-2-methylsulfinyl-6-[4-(trifluoromethyl)-1-piperidyl]purine (Intermediate D-2) (300 mg, 541 μmol, 1 equiv.) and thiomorpholine (558 mg, 5.41 mmol, 10 equiv.) were placed in a microwave tube in N-methylpyrrolidone (3 mL). The sealed tube was heated at 160 °C for 1 hour in a microwave oven. The mixture was diluted with water (2 mL) and extracted with ethyl acetate (2 mL × 3). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by preparative HPLC (Column: Waters Xbridge C18 150 × 50 mm × 10 μm, Mobile phase: [water (ammonium bicarbonate)-ACN]; B%: 64%-94%, 10 min) and dried by lyophilization. The residue was purified by column chromatography (silicon dioxide, petroleum ether / ethyl acetate=1 / 0 to 10 / 1) and concentrated under vacuum to give the product 4-[8-(2-chlorophenyl)-9-(4-chlorophenyl)-6-[4-(trifluoromethyl)-1-piperidyl]purin-2-yl]thiomorpholine (60 mg, 101 μmol, 18.6% yield) as a white solid.

[0508] Process 2 To a solution of 4-[8-(2-chlorophenyl)-9-(4-chlorophenyl)-6-[4-(trifluoromethyl)-1-piperidyl]purin-2-yl]thiomorpholine (50 mg, 84.2 μmol, 1 equiv.) in N-methylpyrrolidone (0.5 mL) was added a solution of potassium hydrogen oxidoxysulfate (85 mg, 505 μmol, 6 equiv.) in water (0.1 mL) and the mixture was stirred at 60° C. for 12 h. The residue was purified by preparative HPLC (column: Phenomenex Synergi C18 150 × 25 mm × 10 μm, mobile phase: [water (formic acid)-ACN], B%: 69% to 99%, 10 min) and dried by lyophilization to give the product 4-[8-(2-chlorophenyl)-9-(4-chlorophenyl)-6-[4-(trifluoromethyl)-1-piperidyl]purin-2-yl]-1,4-thiazinane 1,1-dioxide (compound 32, 16.17 mg, 25.8 μmol, yield 30.6%) as a white solid.1 H NMR(400MHz,CDCl3-d)δ=7.50-7.48(m,1H),7.38-7.29(m,5H),7.18-7.13(m,2H),5.84-5.39(m,2 H),4.30(s,4H),3.13-2.93(m,6H),2.52-2.29(m,1H),2.02(d,J=11.6Hz,2H),1.72-1.63(m,2H). 19 F NMR(376MHz, CDCl3-d)δ=-73.89(s, 1F)LCMS:(ES + ) m / z = 626.9 (M+H).

[0509] (li) Compound 33: To a solution of 8-(2-chlorophenyl)-9-(4-chlorophenyl)-2-methylsulfonyl-6-[4-(trifluoromethyl)-1-piperidyl]purine (Intermediate D-3) (80 mg, 140 μmol, 1 equiv.) and tetrahydropyran-3-ol (72 mg, 701 μmol, 5 equiv.) in N,N-dimethylformamide (1 mL), potassium carbonate (39 mg, 280 μmol, 2 equiv.) was added, and the resulting mixture was stirred at 100° C. for 12 hours. The mixture was diluted with water (2 mL) and extracted with ethyl acetate (2 mL × 3). The organic layer was dried over anhydrous NaSO, filtered, and concentrated in vacuo. The residue was purified by preparative HPLC (column: Waters Xbridge 150 × 25 mm × 5 μm, mobile phase: [water (ammonium bicarbonate)-ACN], B%: 70% to 100%, 10 min) and dried by lyophilization to give the product 8-(2-chlorophenyl)-9-(4-chlorophenyl)-2-tetrahydropyran-3-yloxy-6-[4-(trifluoromethyl)-1-piperidyl]purine (compound 33, 50.81 mg, 85.8 μmol, yield 61.1%) as a white solid. 1H NMR(400MHz,MeOD-d4)δ=7.62-7.56(m,1H),7.51-7.35(m,5H),7.26(d,J=8.8Hz,2H),5.69-5.44(m,2H),4.97-4.94(m,1H),3.95 -3.92(m,1H),3.75-3.56(m,3H),3.21-3.09(m,2H),2.61-2.60(m,1H),2.14-1.98(m,3H),1.96-1.79(m,2H),1.70-1.54(m,3H). 19 F NMR (376MHz, MeOD-d4) δ=-75.51(s, 1F). LCMS: (ES+)m / z=592.2(M+H), Rt=1.160 min (Method 4).

[0510] (lii) Compound 34: A mixture of 8-(2-chlorophenyl)-9-(4-chlorophenyl)-2-methylsulfinyl-6-[4-(trifluoromethyl)-1-piperidyl]purine (Intermediate D-2) (100 mg, 180 μmol, 1 equiv.), N-carbamidoylacetamide (36 mg, 360 μmol, 2 equiv.), and potassium carbonate (75 mg, 541 μmol, 3 equiv.) in dimethyl sulfoxide (1 mL) was stirred at 100° C. for 12 hours. The reaction mixture was filtered and concentrated under reduced pressure to provide a residue. The residue was dissolved in acetonitrile (2 mL) and purified by preparative HPLC (column: Waters Xbridge 150 × 25 mm × 5 μm, mobile phase: [water (ammonium bicarbonate)-ACN], B%: 61%-91%, 10 min). The organic phase was concentrated under reduced pressure to remove acetonitrile, and the liquid was lyophilized to give N-[N-[8-(2-chlorophenyl)-9-(4-chlorophenyl)-6-[4-(trifluoromethyl)-1-piperidyl]purin-2-yl]carbamidoyl]acetamide (compound 34, 16.09 mg, 27.2 μmol, 15.0% yield) as an off-white solid. 1H NMR(400MHz,MeOD-d4)δ=7.67-7.60(m,1H),7.53-7.41(m,5H),7.37-7.29(m,2H),5.03-4.92(m,2 H),3.28-3.04(m,2H),2.78-2.54(m,1H),2.18(s,3H),2.08(d,J=11.6Hz,2H),1.71-1.59(m,2H). LCMS:(ES + ) m / z = 591.3 (M+H).

[0511] (liiii) Compound 35: A mixture of 8-(2-chlorophenyl)-9-(4-chlorophenyl)-2-methylsulfinyl-6-[4-(trifluoromethyl)-1-piperidyl]purine (Intermediate D-2) (200 mg, 361 μmol, 1 equiv.), [(2S)-pyrrolidin-2-yl]methanol (73 mg, 721 μmol, 0.07 mL, 2 equiv.) and potassium carbonate (150 mg, 1.08 mmol, 3 equiv.) in dimethyl sulfoxide (2 mL) was stirred at 60° C. for 12 hours. The reaction mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC (column: Waters Xbridge 150 × 25 mm × 5 μm, mobile phase: [water (ammonium bicarbonate)-ACN], B%: 67% to 97%, 9 min) to give [(2S)-1-[8-(2-chlorophenyl)-9-(4-chlorophenyl)-6-[4-(trifluoromethyl)-1-piperidyl]purin-2-yl]pyrrolidin-2-yl]methanol (compound 35, 6.44 mg, 10.9 μmol, yield 3.02%) as a white solid. 1 H NMR(400MHz,MeOD-d4)δ=7.61-7.55(m,1H),7.48-7.33(m,5H),7.30-7.22(m,2H),5.52(d,J=12.0Hz,2H),4.2 5-4.05(m,1H),3.77-3.47(m,4H),3.15-3.00(m,2H),2.65-2.48(m,1H),2.09-1.85(m,6H),1.66-1.56(m,2H). LCMS:(ES + ) m / z = 591.3 (M+H).

[0512] (liv) Compound 36: To a solution of 1-[6-(4-chloroanilino)-2-[(2S)-2-(hydroxymethyl)pyrrolidin-1-yl]-5-nitro-pyrimidin-4-yl]-4-methyl-piperidine-4-carboxamide (Intermediate B-5 (36), Example 4i) (80 mg, 163 μmol, 1 equiv.) and 4-formylbenzonitrile (107 mg, 816.40 μmol, 5 equiv.) in ethanol (1 mL) and acetic acid (0.4 mL), iron (91 mg, 1.63 mmol, 10 equiv.) was added. The mixture was stirred at 80° C. for 12 hours. The reaction mixture was filtered and concentrated in vacuo. The residue was purified by preparative HPLC (Unisil 3-100 C18 Ultra 150 × 50 mm × 3 μm column, mobile phase: [water (formic acid)-ACN]; B%: 41% to 71%, 7 min) to give a yellow solid. The yellow solid was then purified by preparative HPLC (Waters Xbridge 150 × 25 mm × 5 μm column, mobile phase: [water (ammonium bicarbonate)-ACN]; B%: 51% to 81%, 8 min) to give 1-[9-(4-chlorophenyl)-8-(4-cyanophenyl)-2-[(2S)-2-(hydroxymethyl)pyrrolidin-1-yl]purin-6-yl]-4-methyl-piperidine-4-carboxamide (Compound 36, 10.04 mg, 17.3 μmol, 10.6% yield) as a yellow solid. 1 H NMR(400MHz,DMSO-d6)δ=7.82(d,J=8.4Hz,2H),7.56(m,4H),7.40(d,J=8.7Hz,2H),7.25(s,1H),7.01-6.86(m,1H),5.28-4.40( m,2H),4.08-3.92(m,1H),3.73-3.52(m,2H),3.36-3.28(m,4H),2.21-2.02(m,2H),1.99-1.62(m,4H),1.40(m,2H),1.15(s,3H). LCMS:(ES+)m / z=571.4(M+H).

[0513] (lv) Compound 37: To a solution of 1-[6-(4-chloroanilino)-2-[(2S)-2-(hydroxymethyl)pyrrolidin-1-yl]-5-nitro-pyrimidin-4-yl]-4-methyl-piperidine-4-carboxamide (Intermediate B-5 (36), Example 4i) (80 mg, 163 μmol, 1 equiv.) and 3-formylbenzonitrile (107 mg, 816 μmol, 5 equiv.) in ethanol (1 mL) and acetic acid (0.4 mL) was added iron (91 mg, 1.63 mmol, 10 equiv.). The mixture was stirred at 80° C. for 2 h. The reaction mixture was filtered and concentrated in vacuo. The resulting residue was purified by flash silica gel chromatography (ISCO®, 1 g SepaFlash® silica flash column, eluting with 0-10% methanol / dichloromethane at 80 mL / min) to give a yellow solid (R f =0.3). The white solid was purified by preparative HPLC (column: Waters Xbridge 150 × 25 mm × 5 μm, mobile phase: [water (ammonia hydroxide)-ACN]; B%: 50% to 80%, 8 min) to give a yellow solid. The yellow solid was then purified by preparative HPLC (column: Phenomenex luna C18 150 × 25 mm × 10 μm, mobile phase: [water (formic acid)-ACN]; B%: 42% to 72%, 10 min) to give compound 1-[9-(4-chlorophenyl)-8-(3-cyanophenyl)-2-[(2S)-2-(hydroxymethyl)pyrrolidin-1-yl]purin-6-yl]-4-methyl-piperidine-4-carboxamide (compound 37, 28.10 mg, 48.6 μmol, 29.7% yield) as a yellow solid. 1 H NMR(400MHz,CDCl3-d)δ=7.95(s,1H),7.68-7.41(m,4H),7.38-7.31(m,1H),7.23(d,J=8.6Hz,2H),6.43-5.84(m,1H),5.77-5.31(m, 2H),5.08-4.33(m,2H),4.23-3.94(m,2H),3.84-3.45(m,4H),2.25-2.02(m,3H),1.97-1.78(m,2H),1.70-1.56(m,4H),1.34(s,3H). LCMS:(ES+)m / z=571.3(M+H).

[0514] (lvi) Compound 38: A mixture of 8-(2-chlorophenyl)-9-(4-chlorophenyl)-2-methylsulfonyl-6-[4-(trifluoromethyl)-1-piperidyl]purine (Intermediate D-3) (50 mg, 87.7 μmol, 1 equiv.) and 2-methyl-1-(methylamino)propan-2-ol (90 mg, 0.88 mmol, 10 equiv.) was stirred at 140° C. for 12 hours. The reaction mixture was diluted with 1 mL of N,N-dimethylformamide, and the residue was purified by preparative HPLC (column: Waters Xbridge 150 × 25 mm × 5 μm, mobile phase: [water (ammonia hydroxide)-ACN], B%: 66%-96%, 11 min) to give 1-[[8-(2-chlorophenyl)-9-(4-chlorophenyl)-6-[4-(trifluoromethyl)-1-piperidyl]purin-2-yl]-methyl-amino]-2-methyl-propan-2-ol (compound 38, 25.10 mg, 41.9 μmol, 47.8% yield) as a white solid. 1 H NMR(400MHz,MeOD-d4)δ=7.60-7.57(m,1H),7.51-7.31(m,5H),7.25(d,J=8.8Hz,2H),5.59-5.41(m,2H),3.60(s ,2H),3.21(s,3H),3.15-3.02(m,2H),2.61-2.52(m,1H),2.00(d,J=11.6Hz,2H),1.67-1.56(m,2H),1.18(s,6H). LCMS:(ES + ) m / z = 593.2 (M+H).

[0515] (lvii) Compound 40: A mixture of 1-[8-(2-chlorophenyl)-9-(4-chlorophenyl)-2-methylsulfonyl-purin-6-yl]-4-methyl-piperidine-4-carboxamide (Compound 68) (100 mg, 179 μmol, 1 equivalent) and 2-methyl-1-(methylamino)propan-2-ol (184 mg, 1.79 mmol, 10 equivalents) was stirred at 140° C. for 12 hours. The reaction mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC (column: Waters Xbridge 150 × 25 mm × 5 μm, mobile phase: [water (ammonium bicarbonate)-ACN], B%: 55% to 85%, 10 min) to give 1-[8-(2-chlorophenyl)-9-(4-chlorophenyl)-2-[(2-(hydroxy-2-methyl-propyl)-methyl-amino]purin-6-yl]-4-methyl-piperidine-4-carboxamide (compound 40, 60.69 mg, 103 μmol, 57.5% yield) as an off-white solid. 1 H NMR(400MHz,MeOD-d4)δ=7.60-7.54(m,1H),7.47-7.32(m,5H),7.23(d,J=8.8Hz,2H),4.71-4.70(m,2H),3.77(t ,J=10.4Hz,2H),3.59(s,2H),3.20(s,3H),2.17(d,J=14.4Hz,2H),1.60-1.53(m,2H),1.27(s,3H),1.18(s,6H). LCMS:(ES+)m / z=582.5(M+H).

[0516] (lviii) Compound 41: A mixture of 1-[8-(2-chlorophenyl)-9-(4-chlorophenyl)-2-methylsulfonyl-purin-6-yl]-4-methyl-piperidine-4-carboxamide (Compound 68) (100 mg, 179 μmol, 1.0 equiv.) and 1-(methylaminomethyl)cyclopropanol (181 mg, 1.79 mmol, 10 equiv.) in N-methylpyrrolidone (0.3 mL) was stirred at 140° C. for 12 hours. The reaction mixture was filtered and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (ISCO®, 25 g SepaFlash® silica flash column, elution with a 0–50% methanol / dichloroethane ether gradient at 30 mL / min) and preparative HPLC (column: Phenomenex luna C18 150 × 25 mm × 10 μm, mobile phase: [water (FA)-ACN], B%: 51%–81%, 10 min) to give 1-[8-(2-chlorophenyl)-9-(4-chlorophenyl)-2-[(1-hydroxycyclopropyl)methyl-methyl-amino]purin-6-yl]-4-methyl-piperidine-4-carboxamide (compound 41, 7 mg, 11.9 μmol, 3.4% yield). 1 H NMR(400MHz,MeOD-d4)δ=7.69-7.15(m,8H),4.77-4.63(m,2H),4.25(s,2H),3.86-3.58(m,2H),3.24 -3.17(m,3H),2.50-2.33(m,2H),2.28-2.01(m,2H),1.71-1.46(m,2H),1.28(s,3H),0.98(t,J=7.2Hz,2H). LCMS:(ES + ) m / z = 580.3 (M+H).

[0517] (lix) Compound 42: A mixture of 1-[8-(2-chlorophenyl)-9-(4-chlorophenyl)-2-methylsulfonyl-purin-6-yl]-4-methyl-piperidine-4-carboxamide (compound 68) (0.4 g, 0.71 mmol, 1 equiv.) and 2-methoxy-N-methyl-ethanamine (1.25 g, 14.0 mmol, 1.5 mL, 20 equiv.) was stirred at 100 °C for 48 h. The reaction mixture was cooled to room temperature and diluted with N,N-dimethylformamide (3 mL). The resulting mixture was purified by reverse-phase HPLC (Waters Xbridge 150 × 25 mm × 5 μm column, mobile phase: [water (ammonium bicarbonate)-ACN], B%: 58% to 88%, 8 min). The cleaved fraction was concentrated under reduced pressure to remove acetonitrile. The residue was lyophilized to give 1-[8-(2-chlorophenyl)-9-(4-chlorophenyl)-2-[2-methoxyethyl(methyl)amino]purin-6-yl]-4-methyl-piperidine-4-carboxamide (compound 42, 103 mg, 181 μmol, 25.3% yield) as a white solid. 1 H NMR(400MHz,CDCl3-d)δ=7.53-7.49(m,1H),7.39-7.29(m,5H),7.24-7.19(m,2H),5.82-5.31(m,2H),4.75-4.43(m,2H),4.12-3 .90(m,2H),3.83-3.76(m,2H),3.65-3.59(m,2H),3.36(s,3H),3.21(s,3H),2.21-2.12(m,2H),1.70-1.65(m,2H),1.33(s,3H). LCMS:(ES+)m / z=569.9(M+H).

[0518] (lx) Compound 43: A mixture of 1H-imidazol-2-ylmethanol (140 mg, 1.43 mmol, 8 equiv.) and sodium hydride (36 mg, 0.89 mmol, 60% purity, 5 equiv.) in N,N-dimethylformamide (1.5 mL) was stirred at 25° C. for 30 minutes, and then 1-[8-(2-chlorophenyl)-9-(4-chlorophenyl)-2-methylsulfonyl-purin-6-yl]-4-methyl-piperidine-4-carboxamide (Compound 68) (100 mg, 179 μmol, 1 equiv.) was added to the mixture, and the mixture was stirred at 60° C. for 1.5 hours. The reaction mixture was cooled to room temperature and diluted with N,N-dimethylformam...

Claims

1. A compound of formula I, 【Chemical 1】 During the ceremony, R １ is optionally substituted C ６ is an aryl group, R ２ is optionally substituted C ６ Aryl group or C ５ -C ６ is a heteroaryl group, R ３ But, R ７ O-, N(R ８ ) ２ -, C ４ - １０ heterocycloalkyl, and C ５－６ an optionally substituted group selected from heteroaryl; R ４ But, R ５ O- and N(R ６ ) ２ - is an optionally substituted group selected from R ５ But C １ -C ６ Alkyl, C ３ -C ７ Cycloalkyl, C ４ -C １０ Heterocycloalkyl, C ５ -C ６ Heteroaryl, C ３ -C ７ Cycloalkyl C １ -C ３ Alkyl, C ４ -C １０ Heterocycloalkyl C １ -C ３ Alkyl, C ５ -C ６ Heteroaryl C １ -C ３ alkyl, R ６ is H or C １ -C ６ Alkyl, C ３ -C ７ Cycloalkyl, C ４ -C １０ Heterocycloalkyl, C ５ -C ６ Heteroaryl, C ３ -C ７ Cycloalkyl C １ -C ３ Alkyl, C ４ -C １０ Heterocycloalkyl C １ -C ３ Alkyl, C ５ -C ６ Heteroaryl C １ -C ３ alkyl, and at least one R ６ is other than H, or two R ６ The groups, together with their adjacent nitrogen atoms, are C ４ -C １０ Heterocycloalkyl or C ５ -C ６ forming a heteroaryl group, In the formula, R ５ or R ６ wherein at least one of the alkyl, cycloalkyl, heterocycloalkyl, or heteroaryl is substituted with at least one hydroxyl or hydroxy. １ -C ４ substituted with an alkyl group, and optionally further substituted with other substituents; R ７ is optionally substituted C １ -C ６ is alkyl, R ８ may independently in each occurrence be hydrogen, C １ -C ６ Alkyl, C ３ -C ７ cycloalkyl, and C ４ -C １０ heterocycloalkyl; wherein said alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl group is optionally further substituted; or an isomer or tautomer thereof, or a pharmaceutically acceptable salt thereof.

2. The compound is a compound of formula II, 【Chemistry 2】 During the ceremony, R ４ is as defined in claim 1, X １ is C and X ２ ~X ６ each independently represents N and CR ２１ n is 1; and X ２ ~X ６ At most three of are N, or X １ is C or N, and X ２ ~X ５ However, each independently, CR ２１ , O, S, N, or NR １１ n is zero; and X ６ But absent, X １ and X ５ and X is replaced by a bond between １ ~X ５ Up to three of these are C or CR ２１ Other than that, X ７ and X ８ are each independently O, S, SO ２ , N.R. ３６ , or C(R ３５ ) ２ is selected from X ７ and X ８ One of the groups is O, S, or NR. ３６ If the other is C(R ３５ ) ２ and R ９ is, independently in each occurrence, optionally substituted C １ -C ６ Alkyl, C ３ -C ７ Cycloalkyl, C ４ -C １０ Heterocycloalkyl, C ５ -C ６ Heteroaryl, C ３ -C ７ Cycloalkyl C １ -C ３ Alkyl, C ４ -C １０ Heterocycloalkyl C １ -C ３ Alkyl, and C ５ -C ６ Heteroaryl C １ -C ３ alkyl, R １０ is independently in each occurrence H, or optionally substituted C １ -C ６ Alkyl, C ３ -C ７ Cycloalkyl, C ４ -C １０ Heterocycloalkyl, C ５ -C ６ Heteroaryl, C ３ -C ７ Cycloalkyl C １ -C ３ Alkyl, C ４ -C １０ Heterocycloalkyl C １ -C ３ Alkyl, and C ５ -C ６ Heteroaryl C １ -C ３ alkyl, or two R １０ groups, together with their adjacent nitrogen atoms, are optionally substituted C ４ -C １０ Heterocycloalkyl or C ５ -C ６ forming a heteroaryl, R １１ is independently in each occurrence H, or optionally substituted C １ -C ６ Alkyl, C ３ -C ７ Cycloalkyl, C ４ -C １０ Heterocycloalkyl, C ５ -C ６ Heteroaryl, C ３ -C ７ Cycloalkyl C １ -C ３ Alkyl, C ４ -C １０ Heterocycloalkyl C １ -C ３ Alkyl, C ５ -C ６ Heteroaryl C １ -C ３ alkyl, R １２ may independently in each occurrence be F, Cl, CN, NH ２ , N(H)C １ -C ３ Alkyl, N(C １ -C ３ alkyl) ２ , and C １ -C ３ alkyl, where p is 0, 1, 2, or 3, preferably 0 or 1; R ２１ is independently in each occurrence hydrogen, halogen, OH, OR ９ , C.N., N.O. ２ , C(O)R ９ , C(O)N(R １０ ) ２ , C(R １１ ) = NR １１ , S.O. ２ R ９ , S.O. ２ N (R １０ ) ２ , N(R １１ ) C(O)R ９ , N(R １１ ) SO ２ R ９ , N(R １１ )C(O)N(R １０ ) ２ , N(R １１ ) SO ２ N (R １０ ) ２ , N(R １０ ) ２ , P(O)(R １０ ) ２ , P(O)(OR １０ ) ２ , B(OR １０ ) ２ and optionally substituted C １－６ Alkyl group, C ２－６ Alkenyl group, C ２－６ Alkynyl group, C ６－１０ Aryl group, C ５－１０ Heteroaryl group, C ３－１０ Cycloalkyl groups, and C ４－１０ heterocycloalkyl groups, R ３１ ~R ３５ is independently in each occurrence hydrogen, halogen, OH, OR ９ , C.N., N.O. ２ , C(O)OH, C(O)OR ９ , C(O)R ９ , C(O)N(R １０ ) ２ , C(R １１ ) = NR １１ , S.O. ２ R ９ , S.O. ２ N (R １０ ) ２ , N(R １１ ) C(O)R ９ , N(R １１ ) SO ２ R ９ , N(R １１ )C(O)N(R １０ ) ２ , N(R １１ ) SO ２ N (R １０ ) ２ , N(R １０ ) ２ , P(O)(R １０ ) ２ , P(O)(OR １０ ) ２ , B(OR １０ ) ２ and optionally substituted C １－６ Alkyl group, C ２－６ Alkenyl group, C ２－６ Alkynyl group, C ６－１０ Aryl group, C ５－１０ Heteroaryl group, C ３－１０ Cycloalkyl groups, and C ４－１０ heterocycloalkyl groups, R ３６ is hydrogen, C(O)R ９ , C(O)OR ９ , C(O)N(R １０ ) ２ , C(R １１ ) = NR １１ , S.O. ２ R ９ , S.O. ２ N (R １０ ) ２ , P(O)(R １０ ) ２ , P(O)(OR １０ ) ２ , B(OR １０ ) ２ and optionally substituted C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C ６－１０ Aryl, C ５－１０ Heteroaryl, C ３－１０ cycloalkyl, and C ４－１０ heterocycloalkyl groups, or R ３１ ~R ３６ two of these together with their adjacent atoms form a ring, preferably a bridged or spiro heterocycle, m is 0, 1, 2, or 3; 2. The compound of claim 1, wherein each of the alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl groups is optionally further substituted. or an isomer or tautomer thereof, or a pharmaceutically acceptable salt thereof.

3. m is zero and X ７ and X ８ are each independently C(R ３５ ) ２ and preferably X ７ is CH ２ 3. The compound of claim 2, wherein:

4. X ８ But C(R ３５ ) ２ and the two R ３５ One of the groups is fluorine, C(O)R ９ , C(O)OR ９ , C(O)N(R １０ ) ２ , N(R １１ ) C(O)R ９ or optionally substituted C １－６ alkyl, and the two R ３５ The other of these is hydrogen, fluorine, CN, OH, OR ９ , N(R １０ ) ２ or optionally substituted C １－６ The compound of claim 3, wherein the aryl group is alkyl.

5. X ８ is C(R ３５ ) ２ and the two R ３５ together with their adjacent carbon atoms to form spiro C ４－５ The compound of claim 3 which forms a heterocycle.

6. m is 1, and X ７ and X ８ are each independently C(R ３５ ) ２ and preferably X ７ is CH ２ 3. The compound of claim 2, wherein:

7. X ８ But C(R ３５ ) ２ and the two R ３５ One of the groups is fluorine, C(O)R ９ , C(O)OR ９ , C(O)N(R １０ ) ２ , N(R １１ ) C(O)R ９ or optionally substituted C １－６ alkyl, and the two R ３５ The other of these is hydrogen, fluorine, CN, OH, OR ９ , N(R １０ ) ２ or optionally substituted C １－６ The compound of claim 6, wherein the compound is alkyl.

8. X ８ is C(R ３５ ) ２ and the two R ３５ together with their adjacent carbon atoms to form spiro C ４－５ The compound of claim 6 which forms a heterocycle.

9. m is 2, and X ７ and X ８ are each independently C(R ３５ ) ２ 3. The compound of claim 2, wherein:

10. X ８ is CH ２ and X ７ is C(R ３５ ) ２ and the two R ３５ One of the groups is fluorine, C(O)R ９ , C(O)OR ９ , C(O)N(R １０ ) ２ , N(R １１ ) C(O)R ９ or optionally substituted C １－６ alkyl, and the two R ３５ The other is hydrogen, fluorine, CN, OH, OR ９ , N(R １０ ) ２ or optionally substituted C １－６ The compound of claim 9, wherein the compound is alkyl.

11. The two R ３５ One of them is C(O)N(R10) ２ , or N(R １１ ) C(O)R ９ and the two R ３５ The other of the two is OR ９ or optionally substituted C １－４ The compound of claim 10, wherein the compound is alkyl.

12. The two R ３５ The other of the two is OR ９ and R ９ is C １－６ Alkyl, preferably C ２－４ The compound of claim 11 , wherein the compound is alkyl.

13. The two R ３５ The other of the two is OR ９ and R ９ The compound of claim 11, wherein is selected from methyl, ethyl, n-propyl, isopropyl, i-butyl, and sec-butyl, preferably ethyl or isopropyl, most preferably isopropyl.

14. X ８ is CH ２ and X ７ is C(R ３５ ) ２ and the two R ３５ together with their adjacent carbon atoms to form spiro C ４－５ The compound of claim 9 which forms a heterocycle.

15. X ７ is CH ２ and X ８ is C(R ３５ ) ２ and the two R ３５ One of the groups is fluorine, C(O)R ９ , C(O)OR ９ , C(O)N(R １０ ) ２ , N(R １１ ) C(O)R ９ or optionally substituted C １－６ alkyl, and the two R ３５ The other is hydrogen, fluorine, CN, OH, OR ９ , N(R １０ ) ２ or optionally substituted C １－６ The compound of claim 9, wherein the compound is alkyl.

16. The two R ３５ One of them is C(O)N(R １０ ) ２ , or N(R １１ ) C(O)R ９ and the two R ３５ The other of the two is OR ９ or optionally substituted C １－４ 16. The compound of claim 15, wherein the compound is alkyl.

17. The two R ３５ The other of the two is OR ９ and R ９ is C １－６ Alkyl, preferably C ２－４ 17. The compound of claim 16, wherein the compound is alkyl.

18. The two R ３５ The other of the two is OR ９ and R ９ 17. The compound of claim 16, wherein is selected from methyl, ethyl, n-propyl, isopropyl, i-butyl, and sec-butyl, preferably ethyl or isopropyl, most preferably isopropyl.

19. X ７ is CH ２ and X ８ is C(R ３５ ) ２ and the two R ３５ together with their adjacent carbon atoms to form spiro C ４－５ The compound of claim 9 which forms a heterocycle.

20. m is 2 or 3, and X ７ O, S, SO ２ , or NR ３６ and X ８ is C(R ３５ ) ２ 3. The compound of claim 2, wherein:

21. 21. The compound of claim 20, wherein m is 2.

22. 21. The compound of claim 20, wherein m is 3.

23. X ７ But, O, SO ２ , or NR ３６ The compound according to any one of claims 20 to 22, wherein

24. X ７ But NR ３６ and R ３６ is hydrogen, C(O)R ９ , C(O)OR ９ , C(O)N(R １０ ) ２ and optionally substituted C １－６ 24. The compound of claim 23, wherein the alkyl is selected from:

25. The two R ３５ One of the following is hydrogen, fluorine, or C(O)R ９ , C(O)OR ９ , C(O)N(R １０ ) ２ , N(R １１ ) C(O)R ９ or optionally substituted C １－６ alkyl, and the two R ３５ The other of these is hydrogen, fluorine, OH, OR ９ , N(R １０ ) ２ or optionally substituted C １－６ alkyl, or ３５ One of them is R ３３ and together with their adjacent atoms form a bridged ring.

26. Both R ３５ 26. The compound of claim 25, wherein is hydrogen.

27. The two R ３５ One of the groups is fluorine, C(O)R ９ , C(O)OR ９ , C(O)N(R １０ ) ２ , N(R １１ ) C(O)R ９ or optionally substituted C １－６ alkyl, and the two R ３５ 26. The compound of claim 25, wherein the other of is hydrogen.

28. The R ３５ One of them is R ３３ Along with C １－３ 26. The compound of claim 25, which forms an alkylene group.

29. R ３３ is independently in each occurrence hydrogen, fluorine, and optionally substituted C １－６ The compound of any one of claims 2 to 27, wherein the aryl group is selected from alkyl.

30. R ３４ is independently in each occurrence hydrogen, fluorine, and optionally substituted C １－６ 30. The compound of any one of claims 2 to 29, wherein the aryl group is selected from alkyl.

31. R ３１ and R ３２ The compound according to any one of claims 2 to 30, wherein each is a hydrogen atom.

32. R ３ is selected from the group C1 to C7, C10, C15, C16, C18 to C22, C24 to C28, C32 to C40, and C47 to C69, preferably C1, C16 or C18, more preferably C18.

33. The compound is a compound of formula III, 【Chemistry 3】 During the ceremony, R １３ But, R ７ O-, N(R ８ ) ２ -, and C ５ - ６ an optionally substituted group selected from heteroaryl; R ４ , R ７ , and R ８ is as defined in claim 1, R １２ , X １ ~X ６ 10. The compound of claim 1, wherein n and p are as defined in claim 2. or an isomer or tautomer thereof, or a pharmaceutically acceptable salt thereof.

34. R １３ But, R ７ The compound of claim 33, wherein the group is O-.

35. R ７ is optionally substituted C １ -C ４ 35. The compound of claim 34, which is alkyl.

36. R １３ But N(R ８ ) ２ The compound of claim 33, wherein

37. One R ８ is optionally substituted C ４ -C １０ heterocycloalkyl, and the other R ８ is hydrogen or optionally substituted C １ -C ６ 37. The compound of claim 36, which is alkyl.

38. One R ８ is optionally substituted C ４ -C ７ heterocycloalkyl, and the other R ８ is hydrogen or optionally substituted C １ -C ４ 37. The compound of claim 36, which is alkyl.

39. One R ８ is optionally substituted C １ -C ６ alkyl, and the other R ８ is hydrogen or optionally substituted C １ -C ６ 37. The compound of claim 36, which is alkyl.

40. R １３ is selected from the groups C8, C9, C11-C14, C17, C23, C29-C31, and C41-C46.

41. R １２ A compound according to any one of claims 2 to 40, wherein is Cl and p is 1, preferably forming a 4-chlorophenyl group.

42. p is zero and R １２ The compound of any one of claims 2 to 40, wherein is absent, forming an unsubstituted phenyl group.

43. n is 1 and X １ is C and X ２ ~X ６ Each independently CR ２１ The compound according to any one of claims 2 to 42,

44. n is 1 and X １ is C and X ２ ~X ６ One of them is N and the others are CR ２１ The compound according to any one of claims 2 to 42,

45. n is zero and X ６ is absent, and X １ The compound of any one of claims 2 to 42, wherein is C.

46. X ２ ~X ５ One or two of the following are N or NR １１ and the other is CR ２１ and preferably, R １１ is C １ -C ６ 46. ​​The compound of claim 45, which is alkyl.

47. X ２ ~X ５ One of them is S and the other is CR ２１ 46. ​​The compound of claim 45, wherein:

48. All CRs ２１ The compound of any one of claims 43 to 47, wherein is CH.

49. One CR ２１ is other than CH, preferably R ２１ But halogens, CN, N(C １－６ alkyl) ２ , and C １－６ 44. A compound according to claim 43, wherein said alkyl is selected from alkyl, more preferably halogen or CN, most preferably halogen (e.g. Cl).

50. One CR ２１ is other than CH, preferably R ２１ But halogens, CN, N(C １－６ alkyl) ２ , and C １－６ Alkyl, more preferably halogen, CN, and C １－６ 45. The compound of claim 44, wherein the alkyl is selected from alkyl, most preferably CN.

51. One CR ２１ is other than CH, preferably R ２１ But halogens, CN, N(C １ - ６ alkyl) ２ , and C １－６ Alkyl, more preferably CN and C １－６ Alkyl, most preferably C １－６ 48. The compound of any one of claims 45 to 47, wherein the compound is selected from alkyl.

52. R ２ A compound according to any one of claims 1 to 51, wherein is selected from groups B1 to B23 as defined herein.

53. R ２ is selected from groups B1 to B4, for example, R ２ 53. The compound of claim 52, wherein is B1.

54. R ２ is selected from groups B5 to B8, B12 to B19, and B21 to B23, for example, R ２ 53. The compound of claim 52, wherein is B14.

55. R ２ is selected from the groups B9-B11 and B20.

56. R ４ is R ５ O- group, and R ５ is as defined in claim 1, and is C substituted with at least one hydroxyl group or hydroxy １ -C ４ 56. The compound of any one of claims 1 to 55, substituted with an alkyl group.

57. R ５ is substituted with a hydroxy group and optionally other substituents; ２ -C ６ Alkyl, C ４ -C １０ heterocycloalkyl, or C ４ -C １０ Heterocycloalkyl C １ -C ３ 57. The compound of claim 56, which is an alkyl group.

58. R ５ is selected from 2-hydroxyethyl, 3-hydroxy-1-propyl, 2-hydroxy-1-propyl, 1-hydroxy-2-propyl, 2-hydroxy-2-methyl-1-propyl, 3-hydroxy-2-methyl-1-propyl, 2-hydroxy-1-methyl-1-propyl, 3-hydroxy-1-methyl-1-propyl, and 2-hydroxy-1,1-dimethyl-1-ethyl.

59. R ５ But C ４ -C ６ Heterocycloalkyl or C substituted with hydroxy groups and optionally other substituents ４ -C ６ Heterocycloalkyl C １ -C ３ is an alkyl group, preferably C ４ -C ６ 58. The compound of claim 57, wherein the heterocycloalkyl is selected from pyrrolidinyl, imidazolidinyl, piperidinyl, and piperazinyl groups.

60. R ４ But N(R ６ ) ２ - group, and R ６ is as defined in claim 1, and at least one R ６ has at least one hydroxyl group or hydroxy-substituted C １ -C ４ 56. The compound of any one of claims 1 to 55, which is substituted with an alkyl group and optionally substituted with one or more other substituents.

61. One R ６ is substituted with at least one hydroxyl or hydroxyl １ -C ４ C substituted with alkyl group ２ -C ６ Alkyl, C ３ -C ７ Cycloalkyl, C ４ -C １０ Heterocycloalkyl, C ３ -C ７ Cycloalkyl C １ -C ３ Alkyl, or C ４ -C １０ Heterocycloalkyl C １ -C ３ is an alkyl group, and the other R ６ is hydrogen or C １ -C ６ 61. The compound of claim 60, which is alkyl and optionally substituted with one or more other substituents.

62. One R ６ is hydroxyl or hydroxy-substituted C １ -C ４ C substituted with alkyl group ２ -C ６ Alkyl or C ３ -C ７ Cycloalkyl C １ -C ３ is an alkyl group, and the other R ６ is hydrogen or C １ -C ６ 62. The compound of claim 61, which is alkyl.

63. The two R ６ groups, together with their adjacent nitrogen atoms, substituted with at least one hydroxyl or hydroxy １ -C ４ C substituted with an alkyl group and optionally substituted with one or more other substituents ４ -C １０ Heterocycloalkyl or C ５ 61. The compound of claim 60, which forms a heteroaryl group.

64. The two R ６ groups, together with their adjacent nitrogen atoms, substituted with at least one hydroxyl or hydroxy １ -C ４ C substituted with an alkyl group and optionally substituted with one or more other substituents ４ -C ７ 64. The compound of claim 63, which forms a heterocycloalkyl.

65. Said C ４ -C ７ The heterocycloalkyl group is a C substituted with at least one hydroxyl or hydroxyl. １ -C ４ 65. The compound of claim 64, which is selected from pyrrolidinyl, imidazolidinyl, piperidinyl, and piperazinyl groups substituted with an alkyl group, optionally substituted with one or more other substituents.

66. The two R ６ groups, together with their adjacent nitrogen atoms, substituted with at least one hydroxyl or hydroxy １ -C ４ C substituted with an alkyl group and optionally substituted with one or more other substituents ５ 64. The compound of claim 63, which forms a heteroaryl group.

67. Said C ５ The heteroaryl group is selected from the group consisting of imidazole and at least one hydroxyl or hydroxy-substituted C １ -C ４ 67. The compound of claim 66, wherein the pyrrole group is selected from a pyrrole group substituted with an alkyl group and optionally substituted with one or more other substituents.

68. R ４ is selected from the group D5 to D9, D12, D13, D19 to D21, D23, D25, D27, D28, D30 to D32, D36, D37, D43 to D49, D52, D53, D67, D71, D75, D76, and D78 to D81.

69. R ４ is selected from the groups D6 to D9, D43 to D47, D75 and D76.

70. R ４ is selected from the groups D6 to D9 and D43 to D47, preferably D9.

71. R ４ is selected from the groups D12, D19, D21, D23, D30 to D32, D36, D37, D48, D49, and D78 to D81, preferably D19 or D21.

72. R ４ 69. The compound according to claim 68, wherein is selected from the groups D5, D13, D20, D52, D53, D67 and D71, preferably D20.

73. A compound of formula IV, 【Chemistry 4】 In the formula, X １ ~X ８ , R １２ , R ３１ ~R ３４ , m, n and p are as defined in any one of the preceding claims; R １４ But N(R １６ ) ２ - or optionally substituted C ５ -C ６ is heteroaryl, R １６ is selected from H or optionally substituted C １ -C ６ Alkyl, C ３ -C ７ Cycloalkyl, C ４ -C １０ Heterocycloalkyl, C ５ -C ６ Heteroaryl, C ３ -C ７ Cycloalkyl C １ -C ３ Alkyl, C ４ -C １０ Heterocycloalkyl C １ -C ３ Alkyl, C ５ -C ６ Heteroaryl C １ -C ３ alkyl, or two R １６ The groups, together with their adjacent nitrogen atoms, form an optionally substituted C ４ -C １０ Heterocycloalkyl or C ５ -C ６ heteroaryl-forming compounds, or an isomer or tautomer thereof, or a pharmaceutically acceptable salt thereof.

74. R １４ But N(R １６ ) ２ The compound of claim 73, wherein

75. One R １６ is optionally substituted C １ -C ６ Alkyl, C ３ -C ７ Cycloalkyl, C ４ -C １０ Heterocycloalkyl, C ３ -C ７ Cycloalkyl C １ -C ３ Alkyl, or C ４ -C １０ Heterocycloalkyl C １ -C ３ is an alkyl group, and the other R １６ is hydrogen or C １ -C ６ 75. The compound of claim 74, which is alkyl.

76. On the other hand, R １６ is substituted with one or more substituents ２ -C ６ is an alkyl group, and the other R １６ is hydrogen or C １ -C ６ 76. The compound of claim 75, which is alkyl.

77. 77. The compound of claim 76, wherein the substituents are selected from F, OH, CN, alkoxy, alkylcarbonylamino, akoxycarbonylamino, alkylsulfonamido, benzylamino, aminocarbonyl, dialkylphosphino, phosphonato, dialkylamino, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl.

78. The two R １６ The groups, together with their adjacent nitrogen atoms, form an optionally substituted C bonded through said nitrogen. ４ -C １０ Heterocycloalkyl or C ５ 75. The compound of claim 74, which forms a heteroaryl group.

79. The two R １６ The groups, together with their adjacent nitrogen atoms, form an optionally substituted C bonded through said nitrogen. ４ -C ７ 79. The compound of claim 78, which forms a heterocycloalkyl.

80. Said C ４ -C ７ 80. The compound of claim 79, wherein the heterocycloalkyl is selected from optionally substituted pyrrolidinyl, imidazolidinyl, piperidinyl, and piperazinyl groups.

81. The two R １６ The groups, together with their adjacent nitrogen atoms, form an optionally substituted C bonded through said nitrogen atom. ５ 79. The compound of claim 78, which forms a heteroaryl group.

82. Said C ５ 82. The compound of claim 81, wherein the heteroaryl group is selected from optionally substituted imidazole and pyrrole groups.

83. R １４ is optionally substituted C ５ -C ６ 74. The compound of claim 73 which is heteroaryl.

84. R １４ is selected from D3 to D5, D11 to D16, D19 to D28, D30 to D32, D36, D37, D39 to D41, D48 to D54, D56, D57, D63 to D67, D71, and D78 to D81.

85. A compound of formula V, 【Chemistry 5】 In the formula, X １ ~X ６ , R １２ , R １３ , R １４ , n and p are as defined in any one of the preceding claims, or an isomer or tautomer thereof, or a pharmaceutically acceptable salt thereof.

86. A compound of formula VI, 【Chemistry 6】 In the formula, X １ ~X ８ , R １２ , R ３１ ~R ３４ , m, n and p are as defined in any one of the preceding claims; R １５ But C １ -C ６ Alkyl, C ３ -C ７ Cycloalkyl, C ４ -C １０ Heterocycloalkyl, C ５ -C ６ Heteroaryl, C ３ -C ７ Cycloalkyl C １ -C ３ Alkyl, C ４ -C １０ Heterocycloalkyl C １ -C ３ Alkyl, C ５ -C ６ Heteroaryl C １ -C ３ a compound in which the group is selected from alkyl, or an isomer or tautomer thereof, or a pharmaceutically acceptable salt thereof.

87. R １５ is optionally substituted C １ -C ６ Alkyl, C ４ -C １０ heterocycloalkyl, or C ４ -C １０ Heterocycloalkyl C １ -C ３ 87. The compound of claim 86, which is an alkyl group.

88. R １５ is substituted with one or more substituents selected from, for example, F, OH, CN, alkoxy, alkylcarbonylamino, akoxycarbonylamino, alkylsulfonamido, benzylamino, aminocarbonyl, dialkylphosphino, phosphonato, dialkylamino, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl; １ -C ６ 88. The compound of claim 87, which is an alkyl group.

89. R １５ is optionally substituted C ４ -C ６ Heterocycloalkyl or C ４ -C ６ Heterocycloalkyl C １ -C ３ alkyl group, preferably the C ４ -C ６ 88. The compound of claim 87, wherein the heterocycloalkyl is selected from pyrrolidinyl, imidazolidinyl, morpholinyl, piperidinyl, and piperazinyl groups.

90. OR １５ 87. The compound of claim 86, wherein the groups are selected from D6 to D10, D17, D29, D33 to D35, D43 to D47, D55, D68 to D70, and D72 to D77.

91. A compound of formula VII, 【Chemistry 7】 In the formula, X １ ~X ６ , R １２ , R １３ , R １５ , n and p are as defined in any one of the preceding claims, or an isomer or tautomer thereof, or a pharmaceutically acceptable salt thereof.

92. A compound of formula VIII, 【Chemistry 8】 In the formula, X １ ~X ８ , R １２ , R ３１ ~R ３４ , m, n and p are as defined in any one of the preceding claims; R ２４ is Cl, CN, C(O)OH, R ９ C(O)N(R １１ ) -, R ９ C(O)NHC(NH)NH-,R ９ S (O) ２ -, N(R １０ ) ２ C(O)—, and optionally substituted C １ -C ６ alkyl groups, R ９ ~R １１ is as previously defined, or an isomer or tautomer thereof, or a pharmaceutically acceptable salt thereof.

93. A compound of formula IX, 【Chemistry 9】 In the formula, X １ ~X ６ , R １２ , R １３ , R ２４ , n and p are as defined in any one of the preceding claims, or an isomer or tautomer thereof, or a pharmaceutically acceptable salt thereof.

94. R ２４ is selected from the groups D1, D2, D18, D38, D42 and D58 to D62.

95. A compound selected from compounds 1-158 and 160-240 as defined herein, or an isomer or tautomer thereof, or a pharmaceutically acceptable salt thereof.

96. 96. The compound of claim 95, or an isomer or tautomer thereof, or a pharmaceutically acceptable salt thereof, wherein the compound is selected from compounds 1-12, 14-28, 30-69, 71-97, 99-102, 104-115, 117-131, 133-137, 139-148, 150-158, 160-175, and 177-240.

97. 96. The compound of claim 95, or an isomer or tautomer thereof, or a pharmaceutically acceptable salt thereof, wherein the compound is selected from compounds 1-12, 14-28, 31-36, 38-50, 52-56, 60-62, 64-68, 72-96, 99, 101, 102, 108, 110, 113, 114, 117, 119-121, 123-128, 130, 131, 133, 135-137, 140-146, 148, 150-155, 157, 158, 160-174, 177-204, 206, 207, 209-216, 220-237, and 240.

98. The compound is selected from the group consisting of compounds 6 to 10, 12, 15 to 17, 19, 20, 23 to 26, 32, 33, 35, 36, 38, 41 to 44, 46 to 48, 54 to 56, 62, 65 to 67, 72 to 76, 78 to 83, 85, 86, 88 to 94, 96, 117, 123, 130, 131, 133, 136, 140 to 146, 148, 150, 152 to 154, 157, 158, and 161 to 163.

96. The compound of claim 95, wherein the compound is selected from the group consisting of: 165-167, 169-171, 173, 174, 177-186, 188, 189, 191, 192, 194-197, 199, 203, 206, 207, 211, 213-216, 222-226, 228, 230-232, 234, and 237, or an isomer or tautomer thereof, or a pharmaceutically acceptable salt thereof.

99. 2. The compound of claim 1, or an isomer or tautomer thereof, or a pharmaceutically acceptable salt thereof, wherein the compound is selected from compounds 5-9, 12, 13, 19, 20, 23-26, 29, 35-38, 40, 41, 43, 46-52, 54-59, 63-67, 72-76, 78-88, 90, 93-101, 103-116, 118-124, 128-133, 135-143, 148, 153-155, 157, 158, 161-163, 165-204, 206-227, 231, 233-238, and 240.

100. 100. The compound of claim 99, or an isomer or tautomer thereof, or a pharmaceutically acceptable salt thereof, wherein the compound is selected from compounds 5-9, 12, 19, 20, 23-26, 29, 35-38, 40, 41, 43, 46-52, 54-59, 63-67, 72-76, 78-88, 90, 93-97, 99-101, 104-115, 118-124, 128-131, 133, 135-137, 139-143, 148, 153-155, 157, 158, 161-163, 165-175, 177-204, 206-227, 231, 233-238, and 240.

101. The compound is selected from the group consisting of compounds 5 to 9, 12, 19, 20, 23 to 26, 35, 36, 38, 40, 41, 43, 46 to 50, 52, 54 to 56, 64 to 67, 72 to 76, 78 to 88, 90, 93, 94, 96, 99, 101, 108, 110, 113, 114, 119 to 121, 123, 124, 128, 130, 131, 133, 135 to 100. The compound of claim 99, selected from: 137, 140-143, 148, 153-155, 157, 158, 161-163, 165-174, 177-204, 206, 207, 209-216, 220-227, 231, 233-237, and 240, or an isomer or tautomer thereof, or a pharmaceutically acceptable salt thereof.

102. The compound is selected from the group consisting of compounds 6 to 9, 12, 19, 20, 23 to 26, 35, 36, 38, 41, 43, 46 to 48, 54 to 56, 65 to 67, 72 to 76, 78 to 83, 85, 86, 88, 90, 93, 94, 96, 123, 130, 131, 133, 136, 140 to 143, 148, 153, 154, 157, 158, 161 to 163, 165 to 166, 100. The compound of claim 99, selected from: 167, 169-171, 173, 174, 177-186, 188, 189, 191, 192, 194-197, 199, 203, 206, 207, 211, 213-216, 222-226, 231, 234, and 237, or an isomer or tautomer thereof, or a pharmaceutically acceptable salt thereof.

103. A pharmaceutical composition comprising a compound according to any one of claims 1 to 102 together with a pharmaceutically acceptable carrier, diluent or excipient.

104. 104. Use of a compound according to any one of claims 1 to 102 or a pharmaceutical composition according to claim 103 for the treatment of an appetite-related disorder or one of its complications, a glucose regulation-related disorder or one of its complications, a fibrosis-related disorder or one of its complications, a metabolism-related disorder or one of its complications, a skin and hair growth and healing-related disorder, a gastrointestinal tract-related disorder, an obesity-related disorder or one of its complications, or a combination thereof.

105. The use of claim 104, wherein the appetite-related disorder or one of its complications is selected from Prader-Willi syndrome (PWS), hypothalamic obesity, proopiomelanocortin (POMC) deficiency (including POMC obesity, heterozygous POMC deficiency obesity, and POMC epigenetic disorders), leptin receptor (LepR) deficiency, Bardet-Biedl (BB) syndrome, and Alström syndrome.

106. 105. The use of claim 104, wherein the disorder associated with glucose regulation or one of its complications is selected from type I diabetes, type II diabetes, insulin resistance, prediabetes, pancreatic disease (due to beta cell protection and / or increased insulin production), and associated nephropathy, neuropathy, and retinopathy.

107. 105. The use of claim 104, wherein the fibrosis-related disorder or one of its complications is selected from progressive fibrosis associated with interstitial lung disease, idiopathic pulmonary fibrosis (IPF), Hermansky-Pudlak syndrome pulmonary fibrosis (HPS-PF), cirrhosis and other liver fibrotic disorders (such as non-alcoholic steatohepatitis (NASH), primary sclerosing cholangitis, primary biliary cholangitis), skin fibrotic disorders (such as scleroderma), fibrotic kidney disease, and chronic kidney disease.

108. The use of claim 104, wherein one of the metabolic disorders or complications thereof is selected from metabolic syndrome and hyperlipidemia (e.g., hypertriglyceridemia, hypertriglyceridemia in the setting of low HDL cholesterol, elevated LDL and / or total cholesterol and / or VLDL, and / or elevated apolipoprotein B, atherosclerotic cardiovascular disease, etc.).

109. 105. The use of claim 104, wherein one of the obesity-related disorders or complications thereof is selected from sleep apnea, snoring, asthma, pulmonary hypoventilation syndrome, dementia, heart disease, high blood pressure, gallbladder disease, gastrointestinal disorders, menstrual irregularities, osteoarthritis, venous stasis ulcers, coronary artery disease, arteriosclerosis, pseudotumor cerebri, osteoarthritis, high cholesterol, and increased incidence of malignant tumors of the liver, ovary, cervix, uterus, breast, prostate, or gallbladder.

110. 105. The use of claim 104, wherein the skin and hair disorder is selected from alopecia (androgenetic alopecia and alopecia associated with metabolic syndrome), excessive scarring (scars and keloids), and scleroderma.

111. 105. The use of claim 104, wherein the gastrointestinal tract-related disorder is selected from constipation, irritable bowel syndrome, and inflammatory bowel syndrome, including ulcerative colitis and Crohn's disease.

112. 104. A method for the treatment of a disorder selected from appetite-related disorders or complications thereof, glucose regulation-related disorders or complications thereof, fibrosis-related disorders or complications thereof, metabolism-related disorders or complications thereof, skin and hair growth and healing-related disorders, gastrointestinal tract-related disorders, obesity-related disorders or complications thereof, or combinations thereof, comprising administering to a subject in need thereof a compound of any one of claims 1 to 102 or a pharmaceutical composition of claim 103.

113. 113. The method of claim 112, wherein the appetite-related disorder or a complication thereof is selected from Prader-Willi syndrome (PWS), hypothalamic obesity, proopiomelanocortin (POMC) deficiency (including POMC obesity, heterozygous POMC deficiency obesity, and POMC epigenetic disorders), leptin receptor (LepR) deficiency, Bardet-Biedl (BB) syndrome, and Alström syndrome.

114. 113. The method of claim 112, wherein the disorder associated with glucose regulation or a complication thereof is selected from type I diabetes, type II diabetes, insulin resistance, prediabetes, pancreatic disease (due to beta cell protection and / or increased insulin production), and associated nephropathy, neuropathy, and retinopathy.

115. 113. The method of claim 112, wherein the fibrosis-related disorder or complication thereof is selected from progressive fibrosis associated with interstitial lung disease, idiopathic pulmonary fibrosis (IPF), Hermansky-Pudlak syndrome pulmonary fibrosis (HPS-PF), cirrhosis and other liver fibrotic disorders (such as non-alcoholic steatohepatitis (NASH), primary sclerosing cholangitis, primary biliary cholangitis), skin fibrotic disorders (such as scleroderma), fibrotic kidney disease, and chronic kidney disease.

116. 113. The method of claim 112, wherein the metabolic disorder or complication thereof is selected from metabolic syndrome and hyperlipidemia (e.g., hypertriglyceridemia, hypertriglyceridemia in the setting of low HDL cholesterol, elevated LDL and / or total cholesterol and / or VLDL, and / or elevated apolipoprotein B, atherosclerotic cardiovascular disease, etc.).

117. 113. The method of claim 112, wherein the obesity-related disorder or complication thereof is selected from sleep apnea, snoring, asthma, pulmonary hypoventilation syndrome, dementia, heart disease, hypertension, gallbladder disease, gastrointestinal disorders, menstrual irregularities, osteoarthritis, venous stasis ulcers, coronary artery disease, arteriosclerosis, pseudotumor cerebri, osteoarthritis, high cholesterol, and an increased incidence of malignant tumors of the liver, ovary, cervix, uterus, breast, prostate, or gallbladder.

118. 113. The method of claim 112, wherein the skin and hair disorder is selected from alopecia (androgenetic alopecia and alopecia associated with metabolic syndrome), excessive scarring (scars and keloids), and scleroderma.

119. 113. The method of claim 112, wherein the gastrointestinal tract-related disorder is selected from constipation, irritable bowel syndrome, and inflammatory bowel syndrome, including ulcerative colitis and Crohn's disease.

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